Analgesics and Antipyretics 1

Analgesics and Antipyretics

Elmar Friderichs, Grünenthal GmbH, Center of Research, Aachen, Germany
Thomas Christoph, Grünenthal GmbH, Center of Research, Aachen, Germany
Helmut Buschmann, Laboratorios Dr. Esteve S.A., Barcelona, España

1. Introduction . . . . . . . . . . . . . 1 3. Centrally Acting Analgesics . . 42

2. Nonsteroidal Anti-inflammatory 3.1. Opioids . . . . . . . . . . . . . . . . 42
Drugs (NSAIDs, COX 3.1.1. Opioids in Clinical Use . . . . . . 49
Inhibitors) . . . . . . . . . . . . . . 3 3.1.1.1. Morphine and Morphinane
2.1. Salicylates . . . . . . . . . . . . . . 7 Derivatives . . . . . . . . . . . . . . 49
2.2. para-Aminophenol Derivatives 8 3.1.1.2. Piperidine Derivatives . . . . . . . 56
2.3. Anthranilates . . . . . . . . . . . . 10 3.1.1.2.1. Meperidine and Congeners . . . . 56
2.4. Arylacetic Acids . . . . . . . . . . 12 3.1.1.3. Fentanyl and Congeners . . . . . . 58
2.5. Arylpropionic Acids . . . . . . . 19 3.1.1.4. Methadone and Congeners . . . . 60
2.6. Pyrazolinone Derivatives . . . . 27 3.1.2. Other Structures . . . . . . . . . . . 64
2.7. Acidic Enolic Compounds . . . . 28 3.1.2.1. Mixed Opioid Agonist – Antago-
2.7.1. Pyrazolidine-3,5-diones . . . . . . 28 nists and Partial Agonists . . . . . 66
2.7.2. Arylsulfonamides (Oxicames) . . 30 3.1.2.2. Opioid Antagonists . . . . . . . . 72
2.8. Other Structures . . . . . . . . . . 32 3.2. Antineuropathic Analgesics and
2.9. COX-2 Inhibitors . . . . . . . . . 33 Other Non-opioid Compounds . 74
2.9.1. Nonselective COX-2 Inhibitors . 33 3.2.1. Neuropathic Pain Treatment . . . 74
2.9.2. Selective COX-2 Inhibitors 3.2.2. Individual Compounds . . . . . . . 76
(Coxibs) . . . . . . . . . . . . . . . . 35 4. References . . . . . . . . . . . . . . 85

1. Introduction supposed additional mechanisms are widely un-

Compounds that are used for the treatment
of pain, inflammation, and fever are classified
into two main groups according to their mode
of action: nonsteroidal anti-inflammatory drugs
(NSAIDs) and so-called centrally acting anal-
gesics.
Nonsteroidal anti-inflammatory drugs are
compounds with a predominantly peripheral
mechanism of action. Besides inhibition of pain
they exert a more or less pronounced anti-
inflammatory and fever-reducing effect. In the
body key peripheral mediators of pain, in-
flammation, and fever are prostaglandins (→
Prostaglandins). NSAIDs and related “periph-
eral” or “weak analgesics” act via inhibition of
cyclooxygenase. Cyclooxygenase is the key en-
zyme of prostaglandin synthesis and its inhibi-
tion may be the most important, but not the ex-
clusive mechanism of action of NSAIDs. The
known.
The group of centrally acting analgesics is
dominated by the opioid compounds. They act
mainly within the central nervous system, but
more recent investigations indicate that an ad-
ditional peripheral action component may ex-
ist. The endogenous opioid system is the most
important pain control system within the body
and opioids are powerful tools for the treatment
of severe pain situations. Central neurotransmit-
ters like noradrenaline and serotonin are like-
wise involved in pain inhibition. Directly acting
compounds like, e.g., the α2 -adrenergic agonist
clonidine as well as indirectly acting inhibitors
of noradrenaline and serotonin reuptake (mainly
used as antidepressants) have a definite value as
primary analgesics or as co-analgesics in com-
bination with opioids.
Acute pain is an alarm signal to alert the or-
ganism to noxious tissue damage, irritation, or
injury. Ongoing, persistent or chronic pain may

c 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

10.1002/14356007.a02 269.pub2
2 Analgesics and Antipyretics
lose this function and may become a mere bur-
den to the patient. Pain does not only indicate
physical suffering, but involves a strong men-
tal and emotional component. According to the
definition of the International Association for the
Study of Pain “it is an unpleasant sensory and
emotional experience associated with actual or
potential tissue damage, or described in terms of
such damage”.
The nervous system contains an afferent fiber
system that is specialized for registration, trans-
mission, and processing of nociceptive infor-
mation. In the periphery small unmyelinated
nerve endings, called nociceptors, are activated
by mechanical, thermal, or chemical stimuli.
One type, the mechano-heat nociceptor is spe-
cialized for thermal and mechanical stimulation,
whereas the so-called polymodal receptor is less
specific and responds to all kinds of mechan-
ical, thermal, or chemical irritation. Mechano-
heat nociceptors have a high stimulation thresh-
old and respond only to strong stimuli. They
are linked to small myelinated and rapidly con-
ducting Aδ fibers which produce a sharp and
well located pain sensation. The sharp pain stim-
ulus activates withdrawal reflexes and has to
protect the body against further damage. The
polymodal receptors respond to weaker stim-
uli including endogenous compounds like his-
tamine, bradykinin, and prostaglandins. These
receptors are mediators of pain and inflamma-
tion and are released by tissue damage. The im-
pulses of polymodal nociceptors are transmitted
more slowly via thicker, unmyelinated C-fibers
and provoke a dull, aching, and less precisely
localized pain sensation. The nerve fibers origi-
nating from nociceptors are named primary af-
ferent fibers. They have their cell body in the
dorsal root ganglia and project to the dorsal root
of the spinal cord where they form synapses with
fibers of the ascending spino-thalamic pathway.
Most of the spino-thalamic pain fibers pass the
thalamus and project to the limbic system and
the cortex. The limbic system is responsible for
the emotional component of pain whereas in the
cortex realization and localization of the origin
of pain takes place. The spino-thalamic fibers
form connections with the formatio reticularis
of the brain stem, inducing the various vegeta-
tive reactions associated with the pain percep-
tion such as sweating, palpitation, nausea, and
blood pressure increase.
Inhibitory control of the pain process can take
place in the periphery at the level of the nocicep-
tors or the primary afferents. These are the re-
gions where local anesthetics and NSAIDs act.
Central pain inhibition can take place at the level
of the spinal cord, the thalamus, cortex, and the
limbic system. The pain transmission at the level
of the spinal cord is under inhibitory control of
descending fibers, which originate in different
parts of brain stem, mid brain, and cortex. They
contain opioid synapses as well as noradrener-
gic and serotoninergic synapses and represent
the descending spinal pain inhibitory system.
Inhibitory opioid synapses are not only found
in the spinal cord but are strategically located
along the whole pain pathway. Opioid receptors
are found in the cortex, limbic system, and for-
matio reticularis and this explains why opioids
not only inhibit pain perception but also reduce
the emotional component of pain suffering and
mitigate the vegetative pain symptoms.
According to the clinical situation, pain can
be classified as acute and chronic pain. Acute
pain is induced by trauma, tissue damage, or
disease and has a well defined localization and
time course. Acute pain normally responds well
to NSAIDs and opioid analgesics. Chronic pain
is more complex in nature and often contains an
inflammatory component. The association with
trauma and lesion can be lost and then pain
no longer fulfills its alarming function. Chronic
pain is often a heavy burden to the patient and
induces physical, psychological, and social dete-
rioration. Chronic pain treatment is an important
medical challenge.
Physiologically, pain can be differentiated
into nociceptive and neuropathic pain. Nocicep-
tive pain results from activation of nociceptors
by acute or chronic stimulation and is not associ-
ated with damage of nerves. Neuropathic or neu-
rogenic pain in contrast is the result of damage
or dysfunction of the peripheral nerves or of the
central parts of the pain processing system. Ex-
amples of neuropathic pain of peripheral origin
are deafferentiation pain (stump pain), diabetic
neuropathy, post herpetic neuralgia, trigeminal
neuralgia, and sympathetically maintained pain
like the complex regional pain syndrome. Cen-
tral neuropathic pain may result from lesions of
the spinal cord or brain lesions following stroke.
In chronic cancer pain, nociceptive pain is of-
ten associated with a neuropathic component in-

duced by neoplastic nerve infiltration or com-
pression of the nerve by tumor growth.
Cancer pain is one of the most important
forms of chronic severe pain and guidelines for
the treatment of cancer pain were published by
the WHO in 1986 (Fig. 1).
Figure 1. WHO-Guidelines for Cancer pain treatment
(“WHO-Ladder”)
Meanwhile these guidelines have become the
standard not only for treatment of chronic malig-
nant pain but also for benign chronic and acute
pain. The WHO proposal is often described as
“treatment by mouth, by the clock, and by the
ladder”. That means that for repeated applica-
tion of analgesics the oral route should be used.
The application interval should be regular and
selection of compounds should follow the in-
crease of potency and efficacy as indicated in the
three-step analgesic ladder. The first step starts
with the single use of a non-opioid analgesic. If
pain control is insufficient, a weak opioid may be
added. If this is not effective enough, the weak
opioid should be replaced by a strong opioid
and the non-opioid may be omitted. Each stage
of the treatment may be supplemented by the
use of co-analgesics and other pharmacological
and non-pharmacological treatments to improve
pain control and to reduce side effects.
2. Nonsteroidal Anti-inflammatory
Drugs (NSAIDs, COX Inhibitors)
In 1899 acetylsalicylic acid, the first non-
steroidal anti-inflammatory drug was regis-
tered under the name aspirin. Acetylsalicylic
acid is still the best-known nonsteroidal anti-
Analgesics and Antipyretics 3
inflammatory drug and is used in almost every
household for the treatment of mild to moder-
ate pain states and fever. In 1971, it was shown
that the analgesic action of nonsteroidal anti-
inflammatory drugs is due to the inhibition of
the enzymatic production of prostaglandins. Cy-
clooxygenase (COX) is the key enzyme in the
conversion of arachidonic acid derived from
lipids of the cell membrane to prostaglandins
and other eicosanoids (Fig. 2).
Figure 2. Simple scheme of the biosynthesis of
prostaglandins (PG), thromboxanes (TX), and leukotrienes
from arachidonic acid consequent to cell injury (modified
after [6])
The eicosanoids are important mediators in
pain and inflammation leading to hyperalgesia
by sensitization of nerve fibers and fever. Fur-
thermore they fulfill important roles in the pro-
tection of the gastric mucosa, in platelet aggre-
gation, and maintenance of normal kidney func-
tion [11]. The diversity of physiological func-
tions of the eicosanoids is reflected by a variety
of different receptors. Five main receptor types
have been described, designated DP, FP, IP, TP,
and EP, which show the greatest apparent affinity
for PGD, PGF, PGI2 , TXA2 , and PGE, respec-
tively [12]. PGE2 , the eicosanoid which plays a
key role in pain perception, exerts this and other
functions via the four subtypes of the EP recep-
tors, EP1 – 4.
COX exists in two different isoforms, COX-1
and COX-2, characterized by different expres-
sion patterns. Both forms are encoded by two
genes which have been cloned and sequenced
4 Analgesics and Antipyretics
[13–16]. The cloning of the two isoforms led
to further characterization of the enzymes by
means of a whole range of molecular biology
tools from knock-out mice [17–19] to protein
structures [20, 21].
COX-1 is constitutively expressed in many
cells of the body and responsible mainly for the
production of eicosanoids serving normal physi-
ological functions. One important physiological
role is the protection of the gastric mucosa. Pain
relief by inhibition of COX-1 is therefore often
accompanied with gastrointestinal side effects.
COX-2 expression is induced during inflam-
mation and is thought to be responsible for the
production of eicosanoids in inflammatory con-
ditions related to fever and pain. Furthermore,
COX-2 is expressed in the central nervous sys-
tem and might play a direct role in central pain
processing.
Many nonsteroidal anti-inflammatory drugs
of different chemical structures have been in-
troduced for the treatment of inflammatory and
painful conditions. Many years of clinical expe-
rience with these drugs have shown that there
is no induction of tolerance and dependence
and no respiratory depression as seen with opi-
oids. The major side effects of these compounds
with COX-1 specificity or balanced COX-1 and
COX-2 inhibition are damage of the gastric mu-
cosa, prolongation of bleeding time, and renal
failure. The discovery of the inducible isoform
led to the identification of drugs that show a
stronger inhibition of COX-2 compared to COX-
1 (Table 1).
The characteristic differences in expression
of the two COX isoforms suggest a potential for
new drugs addressing inflammatory and painful
conditions specifically via inhibition of COX-2.
The analgesic and anti-inflammatory potential
of selective COX-2 inhibitors should come with-
out the well known gastrointestinal side effects
of classical NSAIDs targeting COX-1 alone or
in combination with COX-2.
The first generation of COX-2 inhibitors like
meloxicam still shows inhibition of COX-1 in
physiological concentrations and hence, still
generates gastrointestinal side effects of COX-
1 inhibition although to a lower degree. The
second generation of COX-2 inhibitors reached
the market in 1999 with celecoxib and rofe-
coxib and shows a more than 100-fold selec-
tivity for COX-2 compared to COX-1 (see also
→ Prostaglandins, Chap. 3). As expected, the
gastrointestinal side effects of these drugs were
shown to be clearly lower than those of clas-
sical nonsteroidal anti-inflammatory drugs like
naproxen.
The ongoing research on the COX isoforms
revealed that the strict differentiation of COX-
1 as the constitutive enzyme and source of
physiological (good) prostaglandins and COX-
2 as the inflammation- and pain-mediated in-
duced form of the enzyme, producing the “bad”
prostaglandins is no longer valid. It was shown
that COX-1 expression is also subject to regula-
tory processes and can be increased in inflam-
matory conditions [25]. COX-2 expression on
the other hand is increased in the gastric mucosa
by inflammatory stimuli and Helicobacter pylori
infection [26, 27]. Finally, analysis of COX-1
and COX-2 knock-out mice indicated that both
isoforms can contribute to an inflammatory re-
sponse and have significant roles in the mainte-
nance of physiological homeostasis and carcino-
genesis [28]. These data suggest a more com-
plex situation than the initial idea on the roles of
COX-1 in normal and of COX-2 in inflammatory
conditions, respectively.
Nevertheless, the COX-2 inhibitors showed
a clearly improved gastrointestinal side effect
profile and up to the year 2000 the newly de-
veloped coxibs seemed to displace the classical
COX-1 selective NSAIDs from the market. The
situation totally changed when the results of on-
going clinical studies and case reports revealed
that COX-2 inhibitors seem to increase the risk
of adverse thromboembolic events. The case re-
ports came from patients with connective tissue
diseases who developed arterial thrombosis after
starting celecoxib treatment [29]. An increased
number of cardiovascular events as compared to
naproxen were seen in a large-scale randomized
controlled trial [30], which investigated the ef-
ficacy and tolerability of rofecoxib (the VIGOR
trial).
The concern about the risk associated with
the COX-2 inhibitors increased rapidly and in
September 2004 rofecoxib was withdrawn from
the market because a trial, designed to test the
hypothesis that COX-2 inhibitors would pre-
vent recurrent colonic polyps, indicated an in-
creased cardiovascular toxicity [31]. A similar
trial with celecoxib, performed at the National
Cancer Institute was stopped when an indepen-

Table 1. COX-2 specific inhibitors
Group Compound
First generation
etodolac
meloxicam
nimesulide
Second generation
celecoxib
rofecoxib
dent panel of cardiovascular experts reviewed
the data and also found a greater incidence of car-
diovascular events among patients treated with
celecoxib [32]. Negative data on cardiovascu-
lar tolerability were also seen with valdecoxib
and its intravenous prodrug, parecoxib, given
for pain treatment to patients recovering from
coronary-artery bypass surgery [33]. In the be-
ginning, the mechanism of the cardiovascular
toxicity of the COX-2 inhibitors was unclear, but
it emerged that it was a group effect of the coxibs
and the most likely mechanism is a reduced pro-
duction of the antithrombotic eicosanoid prosta-
cyclin without changing the production of the
prothrombotic compound thromboxane [34].
Besides the cardiovascular intolerability, the
COX-2 inhibitor valdecoxib showed an in-
creased risk of serious and potentially fatal skin
reactions which was the reason for the suspen-
sion of marketing autorization. The remaining
COX-2 inhibitors, etoricoxib and lumiracoxib,
although having in principle a similar cardiovas-
cular and skin tolerability risk, seem to be better
tolerated and are still on the market, but doctors
are advised to use COX-2 inhibitors only after
careful consideration, and to treat their patients
with the shortest course and the lowest possible
dose of these compounds.
The unexpected tolerability problems with
the COX-2 inhibitors have strongly reduced the
enthusiasm originally evoked by these com-
pounds and have re-established the therapeutic
reputation of the COX-1 inhibitors and of com-
pounds with a balanced COX-1 and COX-2 in-
hibition, although the gastrointestinal side ef-
fects remain a serious problem. Therefore there
is increased need for new anti-inflammatory
principles with better gastrointestinal tolerabil-
ity and research activities have been focussed
on new compounds combining COX-inhibition
with other analgesic and anti-inflammatory prin-
Analgesics and Antipyretics 5
COX-2 selectivity Reference
(< 100-fold)
10 [22]
10 [22, 23]
5 – 100 [22, 23]
(100 – 1000-fold)
375 [24]
800 [561]
ciples such as inhibition of 5-lipoxygenase (5-
LO) or release of nitric oxide (NO).
Dual COX and 5-LO Inhibitors. This
new class of compounds is reported to have
COX-2 and 5-lipoxygenase inhibiting proper-
ties [35]. The compounds were effective in sev-
eral animal models of arthritis and were devoid
of ulcerogenic properties. One of these com-
pounds, S-2474, ((E)-5-(3,5-di-tert-butyl-4-hy-
droxybenzylidene)-2-ethyl-1,2-isothiazolidine-
1,1-dioxide), which has a γ-sultam skeleton, ad-
ditionally inhibits the production of interleukin-
2 (IL-2) in in vitro assays. S-2474 was selected
as development candidate and is now under
clinical investigation [36].
ML-3000 ((2,2-dimethyl-6-(4-chlorophe-
nyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-
yl)-acetic acid) is a nonoxidant dual cy-
clooxygenase and 5-lipoxygenase inhibitor and
has been compared with indometacin in a num-
ber of experimental models of inflammation
and pain [37]. Corresponding to animal data
the compound showed a wide range of ac-
tivities in Phase II clinical studies, including
anti-inflammatory, analgesic, antiplatelet and
antiasthmatic properties [38, 39].
NO Releasing COX Inhibitors. Nitric
oxide (NO) releasing non-steroidal anti-
inflammatory drugs are a new and promising
goup of analgesic and anti-inflammatory com-
pounds. NO release is found as a mechanistically
not yet resolved property of a few new COX-
1 inhibitors such as amtolmetin [40] or it can
be induced by adding a NO releasing moiety
(e.g., nitroxybutyl) to existing COX-inhibitors
[41]. The most advanced compounds are NO-
naproxen and NO-flurbiprofen (NCX-2216).
Preclinical and clinical studies confirm that
both NO-release and COX-1 or COX-2 inhibi-
6 Analgesics and Antipyretics
tion take place in vivo, causing less adverse ef-
fects on the gastrointestinal tract than conven-
tional NSAIDs and coxibs. In addition, the com-
pounds reduce systemic blood pressure. Possi-
ble indications for NO-flurbiprofen are, besides
pain inhibition and anti-inflammation, urinary
incontinence, Alzheimer’s disease, osteoporosis
and Paget’s disease [42]. A topical formulation
is under development for the treatment of der-
matological disorders such as contact urticaria.
A further group of NO-donating drugs (e.g.,
NCX-4016) has been obtained by coupling
NO to aspirin. These compounds retain the
analgesic, anti-inflammatory and antithrombotic
properties of aspirin but show an increased
gastrointestinal tolerability [43]. Animal stud-
ies have shown that NO-aspirins and the NO-
donating NSAIDs maintain gastric mucosal
blood flow and reduce leucocyte-endothelial cell
adherence.
Up to 2006, no NO-COX inhibitor compound
has yet reached the market.
Aspirin as an Antithrombotic Drug. As-
pirin, the archetype of the COX inhibitors, is still
one of the most interesting compounds of this
group and has reached additional importance in
the last decades due to its inhibition of platelet
aggregation. It is used in low dose [44] in the
treatment of acute and the prevention of chronic
myocardial infarction and stroke (→ Cardiovas-
cular Drugs).
Classification of COX Inhibitors. COX in-
hibitors, as it is done here, can be classified ac-
cording to their chemical structure.
Classification According to Inhibition Speci-
ficity. A more functional classification is related
to the specificity for inhibition of the COX-1
or COX-2 isoforms of the enzyme. The inhi-
bition of the COX isoenzyme is strongly de-
pendent on the test system used. Inhibition of
COX can be quantified in recombinant or natu-
ral enzyme preparations, cellular systems, iso-
lated human cell populations, such as platelets
(COX-1) and white blood cells (COX-2), or in
ex vivo stimulated whole blood samples. The
more physiological the situation is, the smaller
is the selectivity of most of the COX-2 selec-
tive inhibitors. The standard test for comparison
is considered to be a whole blood assay which
mimics in vivo conditions like plasma binding
[45]. It is commonly accepted that reasonable
variations in COX inhibition is found in differ-
ent laboratories. Therefore, whenever possible,
data of several compounds, generated within the
same test situation, should be compared to each
other.
Using this classification based on isoenzyme
selectivity, there is besides low-dose aspirin no
COX-1 selective inhibitor on the market. In-
stead, most of the classical NSAIDs belong to
the group of nonselective COX inhibitors.
• Selective COX-1 inhibitors (low-dose as-
pirin)
• Nonselective COX inhibitors (e.g., high-dose
aspirin, indometacin, and other NSAIDs)
• Preferential COX-2 inhibitors (e.g., meloxi-
cam)
• Highly selective COX-2 inhibitors (e.g., cele-
coxib and other second- and third-generation
COX-2 inhibitors, now called coxibs)
Classification According to Drug – Protein
Interactions. Another classification is based on
the mode of interaction between the inhibitor
drug and the enzyme [46].
• Irreversible inhibitors of COX-1 (aspirin)
and COX-2 (APHS). Aspirin and APHS [47]
acetylate the amino acid serine in the cat-
alytic center of the enzyme to a stable ester
derivative so that the endogenic arachidonic
acid is prevented from interaction with the
enzyme.
• Reversible, competitive inhibitors of COX-
1 and COX-2. Inhibitors such as ibuprofen,
piroxicam, or mefenamic acid block the en-
zyme by competing with arachidonic acid for
binding at the catalytic center.
• Slow, time-dependent, reversible inhibitors
of COX-1 and COX-2. Compounds such as
indometacin and flurbiprofen act by ionic in-
teraction between the acidic carboxyl group
of the inhibitor and the basic arginine residue
of the enzyme. This seems to influence the
helix D of the protein followed by a signifi-
cant loss of flexibility of the enzyme protein.
• Slow, time-dependent, irreversible inhibitors
of COX-2. The coxibs such as celecoxib, rofe-
coxib and lumiracoxib induce a strong, time-
dependent inhibition of COX-2, but show
only a minor competitive inhibition of COX-
 Analgesics and Antipyretics 7

1, which is of no relevance compared to the therapy (75–100 mg/d). It is also available in

COX-2 inhibition. rectal and topical formulations and as soluble
lysine derivative for intravenous or intramuscu-
COX Inhibitors in Clinical Use lar application. Acetylsalicylic acid is often used
in multi-drug preparations. The main side ef-
fects are gastrointestinal disorders. The use in
2.1. Salicylates children is limited due to the risk of Reye’s syn-
drome [53]. The lithium, magnesium, calcium,
Acetylsalicylic acid [50-78-2], aspirin, 2- and aluminum salts of acetylsalicylic acid are
acetoxybenzoic acid, C9 H8 O4 , M r 180.04, mp used in some special preparations.
135 ◦ C (for properties and synthesis, see → Trade names: Aspirine (France), Aspirin,
Salicylic Acid). Aspisol (Germany), Aspro (UK), Alka Seltzer
Synthesis [48, 49]: (USA).

Diflunisal [22494-42-4], 2 4 -di-

fluoro-4-hydroxybiphenyl-3-carboxylic acid,
C13 H8 F2 O3 , M r 250.20, mp 210–211 ◦ C (also
reported as 212–213 ◦ C).
Synthesis [48, 54–58, 505]: The diazotation
of 2,4-difluoroaniline with isoamyl nitrite and
Clinical use: Acetylsalicylic acid is the pro- condensation with anisole gives 4-(2,4-difluoro-
totype of a nonsteroidal anti-inflammatory drug phenyl)anisole, which is hydrolyzed with HI in
and is used in a large number of inflammatory refluxing acetic acid yielding 4-(2,4-difluoro-
and pain indications including musculoskeletal, phenyl)phenol. Finally this compound is carbox-
soft-tissue and joint disorders, headache, dys- ylated with K2 CO3 and CO2 at 175 ◦ C and 90
menorrhoea, and fever [50]. In addition acetyl- bar, followed by an acidification.
salicylic acid is used as an antiplatelet drug
for the prevention of myocardial infarction and
stroke [44] and in combination with thrombolyt-
ics in the acute treatment of myocardial infarc-
tion.
Depending on the assay system, acetylsali-
cylic acid shows a balanced inhibition of COX-1
and COX-2 [23] or a selectivity towards COX-1
[22]. In addition to COX inhibition acetylsal-
icylic acid modulates the activities of several
cellular kinases [51], which may contribute to
its anti-inflammatory effects.
The inhibition of COX-1 and COX-2 by
acetylsalicylic acid does not follow a competi-
tive mechanism like with other nonsteroidal anti-
inflammatory drugs but rather is due to a co-
valent enzyme inhibition via acetylation. After
absorption, acetylsalicylic acid is hydrolyzed to
salicylate which itself still shows some COX in-
hibition activity. Both compounds are bound to
plasma proteins to 80–90 %. The plasma elim-
ination half-life is about 15 min for acetylsal-
icylic acid and between 3 and 22 h for salicy-
late, depending on the dose [52]. Acetylsalicylic
acid is usually administered orally (0.5–8 g/d)
for pain and inflammation and for antiplatelet
8 Analgesics and Antipyretics

Clinical use: Diflunisal [60] is a nonsteroidal of mild pain conditions including musculoskele-
anti-inflammatory drug used in the treatment tal, soft-tissue, and joint disorders. It is now
of mild to moderate pain including osteoarthri- mostly substituted by newer COX inhibitors.
tis, rheumatoid arthritis, and primary dysmenor- Trade names: Percutalgine (France), Intral-
rhoea. It is used as base or lysine- or arginine-salt gin (UK), Anabar (USA).
for oral or parenteral application.
Diflunisal is a weak inhibitor of both COX-1
and COX-2 [61]. 2.2. para-Aminophenol Derivatives
Peak plasma concentrations are reached
within 2 to 3 h after oral dosing. Diflunisal is Paracetamol [103-90-2], acetaminophen,
strongly bound to plasma protein (> 99 %), has N-(4-hydroxyphenyl)acetamide, C8 H9 NO2 , M r
a long elimination half-life (8–12 h) and non- 151.16, mp 168–169 ◦ C.
linear elimination kinetics. Hence, it is used with Synthesis:
an initial loading dose (1000 mg) and a lower
maintenance dose (500–1000 mg/d). a) classical route [48, 64]:
The main side effects are gastrointestinal dis-
turbances, headache and rash.
Trade names: Dolobis (France), Dolobid
(Italy, UK, USA).

Ethenzamide [938-73-8], 2-ethoxybenz-

amide, C9 H11 NO2 , M r 165.19, mp 132–134 ◦ C.
Synthesis: Salicylamide is ethylated with di-
ethyl sulfate [48, 62].

b) Hoechst-Celanese process:

Clinical use: Ethenzamide is a nonsteroidal

anti-inflammatory drug used mainly in combina-
tion with other ingredients for the treatment of
mild to moderate pain including musculoskele-
tal and joint disorders.
Trade names: Trancalgyl (France).

Salicylamide [65-45-2], 2-hydroxybenz-

amide, C7 H7 NO2 , M r 137.14, mp 140 ◦ C.
Synthesis [48, 63]:

Clinical use [65]: Paracetamol has analgesic

Clinical use: Salicylamide shows analgesic
and antipyretic efficacy and was used in multi-
drug combinations for the treatment of a variety
and antipyretic properties, but no relevant anti-
inflammatory action. It is used for the treat-
ment of various mild to moderate pain con-
ditions and to reduce fever. Despite a long
therapeutic use, the mechanism of action of
paracetamol is unclear. The compound shows
some weak inhibition of COX-1 and COX-2,

and there are speculations that a third COX
isoenzyme, named COX-3, may be inhibited
[66]. Recently, a new and unexpected mech-
anism through which paracetamol could exert
its analgesic effect was detected [67, 68]. Fol-
lowing deacetylation to its metabolite p-amino-
phenol, paracetamol is conjugated with arachi-
donic acid to give a compound named AM404.
The metabolite AM404 affects several important
targets in the nervous system involved in pain.
AM404 inhibits purified COX-1 and COX-2 and
prostaglandin formation in lipopolysaccharide-
stimulated macrophages. AM404 is also a po-
tent activator of the ion channel TRPV1 (tran-
sient receptor potential cation channel, former
classified as the vanilloid receptor VR1 ) and has
an effect on cannabinoid CB1 receptors. Both
TRPV1 and CB1 receptors are involved in pain
and in thermoregulatory pathways.
Paracetamol is one of the most popular anal-
gesics as single drug or in multi-ingredient
preparations, often in combination with NSAIDs
or weak opioids. It is used orally or rectally as
suppositories, the oral dose range is 500–1000
mg every 4–5 h up to 4 g daily. Side effects are
rare and may include hematological reactions,
leucopenia, agranulocytosis and other hypersen-
sitivity reactions. Paracetamol has a narrow ther-
apeutic dose range and overdosage induces se-
vere liver and renal damage [69] via accumu-
lation of a toxic metabolite, N-acetylbenzoqui-
noneimine (NABQI). Acetylcysteine or methio-
Analgesics and Antipyretics 9
nine, which increase glutathione conjugation of
the metabolite, are used as antidote.
Paracetamol is not soluble in aqueous solu-
tions and cannot be given parenterally. A soluble
glycine prodrug derivative has been developed
for parenteral use (propacetamol, see below).
Trade names: Benuron (Germany, Switzer-
land), Dafalgan (France) Tylenol (Austria,
Canada, USA, Spain), Alvedon (Norway, Swe-
den, UK).
Combination with codeine: Co-Tylenol
(USA).
Combination with tramadol: Zaldiar (Ger-
many, Austria, France, Spain, Switzerland), Tra-
macet (UK), Ultracet (USA).
Paracetamol is also used in many generic for-
mulations.
Propacetamol [66532-85-2], 4-
(acetylamino)phenyl N,N-diethylglycinate,
C14 H2 ON2 O3 , M r 264.33, is a soluble glycine
prodrug derivative of paracetamol. It is used as
hydrochloride ([66532-86-3], C14 H2 ON2 O3 ·
HCl, M r 300.79), for intramuscular or intra-
venous application and is rapidly metabolized
to free paracetamol [70].
Trade name: Pro-Dafalgan (Belgium,
France), Pro-Efferalgan (Italy)
Phenidine [62-44-2], phenacetin, N-
(4-ethoxyphenyl)acetamide, C10 H13 NO2 , M r
179.22, mp 134–135 ◦ C.
Synthesis [48]:
10 Analgesics and Antipyretics
Clinical use: Phenidine is a weak anal-
gesic, antipyretic compound without anti-
inflammatory action. It has been used in com-
bination with other compounds like aspirin, caf-
feine, or codeine, but due to hematological and
nephrotoxic side effects [71] has been with-
drawn from the market and substituted by the
less toxic paracetamol.
2.3. Anthranilates
Etofenamate [30544-47-9], 2-(2-hydroxy-
ethoxy)ethyl 2-(3-trifluoromethylphenylamino)
benzoate, C18 H18 F3 NO4 , M r 369.34, pale yel-
low viscous oil, thermolabile at 180 ◦ C, bp
(133.32 Pa) 130–135 ◦ C.
Synthesis: Esterification of the potassium salt
of flufenamic acid (see page 10) with 2-(2-
chloroethoxy)ethanol in dimethyl formamide as
solvent yields etofenamate [48, 72].
Clinical use: Etofenamate [73] is a non-
steroidal anti-inflammatory drug which was
used mainly as a topical formulation (500–1300
mg/d) and by intramuscular injection (1 g/d) for
the treatment of joint, musculoskeletal and soft-
tissue disorders.
Flufenamic acid [530-78-9], flufe-
namate, 2-[3-(trifluoromethyl)phenyl]ami-
nobenzoic acid, C14 H10 F3 NO2 , M r 281.23,
mp 124-125 ◦ C (also reported as 134-
136 ◦ C); aluminum salt (3 : 1) [16449-54-0],
C42 H27 AlF9 N3 O6 , M r 867.66.
Synthesis: 2-Chlorobenzoic acid is reacted
with 3-trifluoromethylaniline in the presence of
copper and potassium carbonate [48, 74, 75].
Clinical use: Flufenamate is a nonsteroidal
anti-inflammatory drug used for the treatment of
mild to moderate pain of musculoskeletal, joint
or soft-tissue origin. It was marketed in a variety
of topical formulations alone or in combination
with other ingredients.
Flufenamate is not recommended in patients
with acute porphyria and was associated with
acute proctocolitis [76].
In addition to COX inhibition flufenamate
like other fenamates modifies several ion chan-
nel functions, e.g., inhibition of nonselec-
tive cation conductance [77], calcium-activated
chloride channels [78], voltage-gated calcium
channels and potassium channels [79, 80] and
induces blocking of gap junctions [81]. The rel-
evance of these activities for the analgesic and
anti-inflammatory potential of fenamates is un-
known.
Meclofenamic acid [644-62-2], meclofe-
namate, 2-[(2,6-dichloro-3-methylphenyl)ami-
no]benzoic acid, C14 H11 Cl2 NO2 , M r 296.15,
mp 257–259 ◦ C; monosodium salt monohy-
drate [6385-02-0], C14 H10 Cl2 NNaO2 · H2 O,
M r 336.15, mp 289–291 ◦ C.
Synthesis: Meclofenamic acid is obtained by
condensation of 2-bromobenzoic acid with 2,6-
dichloro-3-methylaniline using CuBr2 in dieth-
yleneglycol dimethyl ether containing N-ethyl-
morpholine, and heating at 145–155 ◦ C [48, 82–
84] .

Clinical use: Meclofenamate [85] is a non-
steroidal anti-inflammatory drug used for the
treatment of mild to moderate pain, muscu-
loskeletal, and joint disorders like rheumatoid
arthritis and osteoarthritis as well as dysmen-
orrhoea. Meclofenamate inhibits COX-1 and
COX-2 and modifies ion channels [86, 87] (see
page 10).
Meclofenamate is administered orally (300–
400 mg/d).
Trade names: Lenidolor (Italy), Meclomen
(Austria, Spain, Switzerland, USA).
Mefenamic acid [61-68-7], 2-
[(2,3-dimethylphenyl)amino]benzoic acid,
C15 H15 NO2 , M r 241.29, mp 230–231 ◦ C;
monosodium salt C15 H14 NNaO2 , M r 263.27.
Synthesis [48, 88]:
Clinical use: Mefenamic acid is a non-
steroidal anti-inflammatory drug which is used
for the treatment of mild to moderate pain con-
ditions, musculoskeletal and joint disorders like
rheumatoid arthritis and osteoarthritis, and dys-
menorrhoea. [89]. Mefenamic acid inhibits both
COX isoforms with some preference for COX-2
and modifies ion channels [90] (see page 10).
Mefenamic acid is given orally (1500 mg/d
maximal dose). The main side effects concern
Analgesics and Antipyretics 11
the gastrointestinal system and include diarrhea
[91].
Trade names: Ponstyl (France), Ponstan
(UK), Ponstel (USA).
Niflumic acid [4394-00-7], 2-(3-trifluoro-
methylphenylamino)nicotinic acid, 2-[[3-(tri-
fluoromethyl)phenyl]amino]-3-pyridinecarb-
oxylic acid, C13 H9 F3 N2 O2 , M r 282.22, mp
204 ◦ C.
Synthesis: Condensation of 2-chloronicotinic
acid with 3-trifluoromethylaniline or reaction of
2-aminonicotinic acid with 1-bromo-3-trifluoro-
methylbenzene yields niflumic acid [48, 92].
Clinical use: Niflumic acid [93] is a non-
steroidal anti-inflammatory drug used for the
treatment of inflammation and pain in muscu-
loskeletal and joint disorders like rheumatoid
arthritis as well as traumatic and postoperative
pain. Niflumic acid is used in oral, rectal, or top-
ical applications (up to 750 mg/d).
The morpholinoethyl ester morniflumate,
which is used in topical formulations, in-
hibits both cyclooxygenase and 5-lipoxygenase
which suggests an additional component of anti-
inflammatory activity [94].
Trade names: Niflurid, Niflugel (Belgium,
France, Switzerland), Actol (Austria, Sweden).
Tolfenamic acid [13710-19-5], 2-[(3-
Chloro-2-methylphenyl)amino]benzoic acid,
N-(3-chloro-o-tolyl)anthranilic acid; N-
(2-methyl-3-chlorophenyl)anthranilic acid,
C14 H12 ClNO2 , M r 261.70, mp 207.0–
207.5 ◦ C.
12 Analgesics and Antipyretics

Synthesis: Tolfenamic acid is obtained by

condensation of 2-chlorobenzoic acid with 3-
chloro-2-methyl-phenylamine using CuBr2 in
diethylenglycol dimethyl ether [95, 96].

Clinical use: Tolfenamic acid is a non-

steroidal anti-inflammatory drug [97] used for
the treatment of rheumatoid arthritis [98], os-
teoarthritis, ankylosing spondylitis, trauma pain,
and dysmenorrhoea [99]. It is also used for the
prophylactic and acute treatment of migraine
[100]. The compound is further marketed for
veterinary use.
Trade name: Clotam (Denmark).

2.4. Arylacetic Acids

Acemetacin [53164-05-9], carboxymethyl

[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-
1H-indol-3-yl]-acetate, C21 H18 ClNO6 , M r
415.82, mp 150–153 ◦ C (fine pale yellow crys-
tals).
Synthesis [48, 101] (see on top, right column).
In addition, the reaction product of in-
domethacin (see page 14) with benzyl bromoac-
etate can be hydrogenated to acemetacin.
Clinical use: Acemetacin [102] is a non-
steroidal anti-inflammatory drug acting directly
and via its major metabolite indomethacin.
Acemetacin is used in chronic joint pain as well
as in postoperative pain. Oral dosing is recom-
mended between 120 and 360 mg daily.
Trade names: Rantudil (Germany), Emflex
(UK).
Acemetacin is also used in several generic
formulations.
Proglumetacin [57132-53-3], 1-(4-
Chlorobenzoyl)-5-methoxy-2-methyl-1H-
indole-3-acetic acid 2-[4-[3[4-(benzoylamino)-
5-(dipropylamino)-1,5-dioxopentyl]oxy]pro-
pyl]-1-piperanzinyl]ethyl ester, rac-N-[2-
[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-
3-indolylacetoxy]ethyl]-N  -[3-(N-benzoyl-
N  ,N  -di-n-propyl-dl-isoglutaminoyl)oxypro-
pyl]piperazine, C46 H58 ClN5 O8 , Mr 844.43,
dimaleate, 4-Benzamido-5-(dipropylamino)-
5-oxopentanoic acid 3-[4-[2-[2-[1-(chloro-
benzoyl)-5-methoxy-2-methyl-1 H-indol-3-
yl]acetoxy]ethyl]piperazin-1-yl]propyl es-
ter dimaleate [59209-40-4], C46 H58 ClN5 O8
2C4 H4 O4 , Mr 1076.58, mp 146–148◦ C.
Synthesis: The reaction of N-benzoyl-N  ,

N -di-n-propyl-dl-isoglutamin (proglumide)
 Analgesics and Antipyretics 13

with 1-(3-chloropropyl)-4-(2-hydroxyethyl)-pi-
perazine obtained from 1-(2-hydroxyethyl)pi-
perazine and 1-bromo-3-chloropropane by
means of sodium methanolate in DMSO at
105◦ C gives N-[3-(N-benzoyl-N  , N  -di-n-
propyl-dl-isoglutaminyl)oxypropyl]-N  -(2-hy-
droxyethyl)piperazine, which is then conden-
sated with Indomethacin (1-(p-chlorobenzo-
yl)-5-methoxy-2-methylindole-3-acetic acid)
by means of dicyclohexylcabodiimide and
NaHCO3 in ethyl acetate [103, 104] (see on
top).
Proglumetacine is a prodrug of acemetacine
[105] and is used for the treatment of os-
teoarthritis, rheumatoid arthritis, gout, ankylos-
ing spondylitis, and pain [106].
Trade names: Protaxon (Gemany), Proxil
(Italy).

Bufexamac [2438-72-4], 2-(4-butoxy-

phenyl)-N-hydroxyacetamide, C12 H17 NO3 , M r
223.12, mp 153–155 ◦ C.
Synthesis [48, 107] (see right column).
14 Analgesics and Antipyretics
Clinical use: Bufexamac is a nonsteroidal
anti-inflammatory drug used in topical formula-
tions for mild skin disorders and as suppositories
(250–500 mg/d) for hemorrhoids.
Trade names: Duradermal (Germany), Par-
fenac (France, Germany).
Diclofenac [15307-86-5], [2-(2,6-
dichlorophenylamino)phenyl]acetic acid,
C14 H11 Cl2 NO2 , M r 296.15, mp 156–158 ◦ C;
sodium salt [15307-79-6], C14 H10 Cl2 NNaO2 ,
M r 318.13, mp 283–285 ◦ C.
Synthesis [108]:
Clinical use: Diclofenac [109] is a non-
steroidal anti-inflammatory drug with balanced
COX-1 and COX-2 inhibition [22]. It is com-
monly used for a variety of inflammatory and
pain conditions such as musculoskeletal and
joint disorders, periarticular disorders, soft-
tissue disorders, renal colic, acute gout, dysmen-
orrhoea, and postoperative pain.
The plasma protein binding of diclofenac is
greater than 99.5 % and the plasma elimination
half-life is between 1 and 2 h.
Diclofenac is used mainly as the sodium salt
orally or parenterally (75–150 mg/d) and as oph-
thalmic solution. Topical formulations may con-
tain the diethylammonium or epolamine salt. Di-
clofenac is combined with misoprostol to reduce
gastrointestinal side effects, which are the main
adverse events and with weak opioids (codeine)
to increase the analgesic potential.
Trade names: Allvoran (Germany), Diclac
(Germany), Voltaren (Germany, Italy, USA),
Voltarène (France), Voltarol (UK).
Combination with misoprostol: Arthotec
(Germany).
Combination with codeine: Combaren.
Diclofenac is also used in many generic for-
mulations.
Indomethacin [53-86-1], [1-(4-chloro-
benzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]-
acetic acid, C19 H16 ClNO4 , M r 357.79, mp 153–
154 ◦ C (crystals exhibiting polymorphism, mp
for another form is 162 ◦ C); sodium trihydrate
[74252-25-8], C19 H15 ClNNaO4 · 3H2 O, M r
433.82, pale yellow crystalline powder.
Synthesis [48, 110] (see next page).
Clinical use: Indomethacin is a nonsteroidal
anti-inflammatory drug commonly used for
the treatment of mild to moderate pain. In-
domethacin is used in acute and chronic pain
states like rheumatoid arthritis, osteoarthritis,
joint and soft-tissue pain, dental pain, postop-
erative pain and dysmenorrhoea. Indomethacin
is a COX-1 selective inhibitor with 10- to 60-
fold selectivity compared to COX-2 [22, 23]. It
is administered orally, rectally or topically (50–
150 mg/d, maximal daily dose 200 mg) as well
as ophthalmic solution.
The major side effects of indomethacin are
gastrointestinal irritations and inflammation and
central nervous system disturbances like depres-
sion, drowsiness, tinnitus, and convulsions. In-
domethacin is absorbed after oral application
reaching peak plasma concentrations after 2 h.
It is bound to about 99 % to plasma proteins and
shows a variable terminal half-life from 2.6 to
11.2 h in adults and up to 30 h in neonates.
Indomethacin is available as sodium, meg-
lumine, or l-arginine salt or as prodrug
(proglumetacin maleate).
Trade names: Elmetacin, Inflam, Wydora
(Germany), Indocid (France, UK), Indocin
(USA), Indolgina (Italy), Indocolir eye drops
(Germany).
Prodrugs of indomethacin are acemetacin
(see Section page 12) and proglumetacin
maleate: Protaxon (Germany).

a) Merck & Co. process [111]:
Lonazolac [53808-88-1], [3-(4-
chlorophenyl-1H-pyrazol-4-yl]acetic acid,
C17 H13 ClN2 O2 , M r 312.75, mp 150–
151 ◦ C; calcium salt (2 : 1) [75821-71-5],
C34 H24 CaCl2 N4 O4 , M r 663.57, mp 270–
290 ◦ C (decomp.).
Synthesis: The pyrazole-4-carbaldehyde syn-
thesized according to the Vilsmeier synthesis is
reduced to the alcohol, which is chlorinated. The
chloro derivative is reacted with sodium cyanide
to give the nitrile, which is hydrolyzed to lona-
zolac. The calcium salt, slightly soluble in water,
Analgesics and Antipyretics 15
b) Sumitomo process [112]:
is formed by adding calcium chloride to the free
acid [48, 113–115].
Clinical use: Lonazolac [85] is a nonsteroidal
anti-inflammatory drug used for the treatment of
acute inflammatory pain conditions of joint and
soft-tissue disorders as well as posttraumatic and
postoperative pain. Lonazolac is used as calcium
salt and is given orally (600 mg/d, initial dose up
to 900 mg/d) or rectally (800 mg/d).
Trade names: Argun (Germany), Irritren
(Austria, Belgium, Switzerland).
16 Analgesics and Antipyretics
Sulindac [38194-50-2], (Z)-5-fluoro-
2-methyl-1-[4-(methylsulfinyl)phenyl]methy-
lene-1H-indene-3-acetic acid, C20 H17 FO3 S,
M r 356.41, mp 182–185 ◦ C (decomp.).
Synthesis [48, 116, 117] (see right column).
Clinical use: Sulindac [118] is a nonsteroidal
anti-inflammatory drug used in the treatment of
mild to moderate pain including musculoskele-
tal and joint disorders like rheumatoid arthritis,
osteoarthritis, and gout. The main side effects are
gastrointestinal disturbances and kidney stones
[119]. Sulindac induces no relevant COX inhibi-
tion whereas the active metabolite sulindac sul-
fide inhibits both isoenzymes with some COX-1
preference [120], indicating that the pharmaco-
logical activity of sulindac probably results from
its sulfide metabolite. Another metabolite, sulin-
dac sulfone, induces apoptosis in tumor cells and
sulindac is extensively studied for cancer treat-
ment [121]. Sulindac is administered orally or
rectally (200–400 mg/d).
Trade names: Arthrocine (France), Clinoril
(Italy, UK, USA).
Tolmetin [26171-23-3], [1-methyl-5-(4-
methylbenzoyl)-1H-pyrrol-2-yl]acetic acid,
C15 H15 NO3 , M r 257.28, mp 155–157 ◦ C;
sodium salt [35711-34-3], C15 H14 NNaO3 , M r
279.27; sodium salt dihydrate [64490-92-2],
C15 H14 NNaO3 · 2 H2 O, M r 315.30.
Synthesis [48, 122, 123] (see next page, left
column).
Clinical use: Tolmetin [124] is a nonsteroidal
anti-inflammatory drug used for the treatment of
mild to moderate pain states in musculoskeletal,
soft-tissue, and joint disorders like rheumatoid
arthritis, osteoarthritis, and gout as well as juve-
nile rheumatoid arthritis. Tolmetin inhibits both
isoforms of cyclooxygenase with some prefer-
ence for COX-1 [125]. Tolmetin is administered
orally, rectally, or topically (600–1800 mg/d).
The peak plasma concentrations are reached
within 30 to 60 min. Tolmetin shows a high
plasma protein binding of 99 % and a biphasic
plasma half-life of 1 to 2 and 5 h, respectively.

Trade name: Tolectin (Austria, Switzerland,
UK, USA).
Amtolmetin guacil (AMG, ester pro-
drug of tolmetin) [87344-06-7], 2-[2-[1-
methyl-2-(4-methylbenzoyl)pyrrol-5-yl]acet-
amido]acetic acid 2-methoxyphenyl ester, 2-
[2-[1-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]-
acetamido]acetic acid 2-methoxyphenyl ester,
N-[(1-methyl-5-p-toluoylpyrrol-2-yl)acetyl]-
glycine 2-methoxyphenyl ester, 1-methyl-5-p-
toluoylpyrrole-2-acetamidoacetic acid guaicyl
ester, C24 H24 N2 O5 , M r 420.46, mp not re-
ported.
Synthesis: The condensation of 1-methyl-
5-(4-methylbenzoyl)pyrrole-2-acetic acid with
glycine ethyl ester in the presence of car-
bonyldiimidazole and triethylamine in tetra-
hydrofuran gives the corresponding ethyl 2-[2-
(1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-
yl)acetamido]acetate, which is hydrolyzed with
NaOH in tetrahydrofuran – water yielding 2-
[2-[1-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]-
acetamido]acetic acid. Finally, this compound is
esterified with 2-methoxyphenol (guaiacol) in
hot tetrahydrofuran with carbonyldiimidazole
as catalyst [126].
Analgesics and Antipyretics 17
Clinical use: Amtolmetin guacil (AMG) is
a non-steroidal anti-inflammatory drug devel-
oped by Sigma-Tau for the treatment of pain
and inflammation. It acts similarly to tolmetin,
and in preclinical trials displayed long-lasting
anti-inflammatory and analgesic activity. Am-
tolmetin has a good gastrointestinal tolerability
in humans [127] and does not induce gastric ul-
cers in the rat [128]. The good gastrointestinal
tolerability and even a gastroprotective effect
was related to an increase of endogenous NO
via stimulation of inducible NO synthase in the
gastric mucosa [129].
Trade name: Eufans (Italy).
Mofezolac [78967-07-4], 3,4-bis(4-meth-
oxyphenyl)-5-isoxazoleacetic acid, 3,4-di-
(p-methoxyphenyl)isoxazole-5-acetic acid,
C19 H17 NO5 , M r 339.35, mp 147.5 ◦ C.
18 Analgesics and Antipyretics
Synthesis:
a) The reaction of deoxyanisoin with hydroxyl-
amine in methanol gives the corresponding
1,2-bis(4-methoxyphenyl)ethanone oxime,
which is cyclized with ethyl acetate by means
of n-butyllithium in tetrahydrofuran yield-
ing 3,4-di(4-methoxyphenyl)-5-methylisox-
azole. Finally, this compound is condensed
with CO2 with n-butyllithium as catalyst
in tetrahydrofuran to yield mofezolac [130,
131]. The synthesis with ClCO2 C2 H5 in-
stead of CO2 is described in [132, 133].
b) Alternatively the corresponding 1,2-bis(4-
methoxyphenyl)ethanone oxime can be con-
densed with (E)-methyl 3-methoxyacrylate
with the aid of potassium tert-butyrate in
tert-butanol to yield (E)-methyl 4,5-bis(4-
methoxyphenyl)-5-oxopent-3-enoate, which
is cyclized with hydroxyl amine. Subsequent
treatment with oxygen in acetic acid yields
mofezolac [132–135].
Clinical use: Yoshitomi (now Mitsubishi
Pharma) has launched mofezolac, a COX-1 in-
hibitor [136] with preferential COX-1 inhibition
[137] for the treatment of arthritis-related pain
in Japan.
The compound is used in oral doses of 75 mg
for the treatment of periarthritis, lumbago, neck-
shoulder-arm syndrome and pain after surgery,
trauma, or dental extraction.
Trade name: Disopain (Japan).
Bromfenac [91714-94-2], 2-amino-3-
(4-bromobenzoyl)benzeneacetic acid, 2-[2-
amino-3-(4-bromobenzoyl)phenyl]acetic acid,
C15 H12 BrNO3 , M r 334.17, monosodium salt
[91714-93-1], C15 H11 BrNNaO3 , M r 356.15,
mp 284–286 ◦ C (dec.), monosodium salt sesqui-
hydrate [120638-55-3], C15 H11 BrNNaO3 3/2
H2 O, M r 766.35.
Synthesis: The cyclization of 2-amino-4’-
bromobenzophenone with ethyl 2-(methyl-
thio)acetate with tert-butyl hypochlorite as
catalyst in dichloromethane at 70 ◦ C gives 7-
(4-bromobenzoyl)-3-(methylthio)-2,3-dihydro-
1H-indol-2-one, which is desulfurized by treat-
ment with Raney nickel in THF yielding 7-(4-
bromobenzoyl)-2,3-dihydro-1H-indol-2-one.
Finally, this compound is hydrolyzed with re-
fluxing 3 M aqueous NaOH and acidified with
concentrated HCl [138–141].

Clinical use: Bromfenac, used as the sodium
salt, is a non-steroidal anti-inflammatory drug
acting via inhibition of COX-1 and COX-2. It
was launched in Japan in 2000 by Senju for
topical treatment of ocular inflammation [142]
and has been approved in the United States in
2006 for the treatment of pain following cataract
surgery. It was used for the short-term treatment
of acute pain, but it was withdrawn for this in-
dication in June 1998 because of several post-
marketing reports of severe hepatic failure [143–
145].
The drug is rapidly absorbed and excreted.
The drug’s long duration of anti-inflammatory
action despite its short half-life deserves further
investigation.
Trade name: Xibrom (Japan, USA).
Nabumetone [42924-53-8], 4-(6-methoxy-
naphthalen-2-yl)butan-2-one, C15 H16 O2 , M r
228.29, mp 80 ◦ C.
Synthesis: Condensation of 6-methoxy-2-
naphthaldehyde with acetone in an aque-
ous solution of NaOH gives 4-(6-methoxy-2-
naphthyl)-3-buten-2-one, which is reduced with
H2 over Pd-C in ethyl acetate [48, 146–149].
Analgesics and Antipyretics 19
Several additional ways for the synthesis of
nabumetone are described. A short, simple, and
economical process for large scale preparation
avoiding hazardous chemicals or tedious work
up procedures has been published [149].
Clinical use: Nabumetone [150] undergoes
rapid first-pass metabolism to the active metabo-
lite 6-methoxy-2-naphthylacetic acid (6-MNA).
6-MNA shows a balanced inhibition of both
COX-1 and COX-2 [22]. Nabumetone is used
for the treatment of pain and inflammation asso-
ciated with osteoarthritis and rheumatoid arthri-
tis. It shows a 99 % binding to plasma protein
and an elimination half-life of up to 22 h with
marked individual differences. Nabumetone is
given orally (500–2000 mg/d).
Trade names: Listran (Spain), Nabuser
(Italy), Relafen (USA), Relifex (UK).
2.5. Arylpropionic Acids
Flurbiprofen [5104-49-4], 2-(3 -
fluorobiphenyl-4-yl)propionic acid, 2-
fluoro-α-methyl[1,1 -biphenyl]-4-acetic acid,
C15 H13 FO2 , M r 244.26, mp 110–111 ◦ C;
sodium salt [56767-76-1], C15 H12 FNaO2 , M r
266.25.
Synthesis [48, 151–154]:
 20 Analgesics and Antipyretics

Clinical use: Flurbiprofen is a nonsteroidal

anti-inflammatory drug used for the treatment
of pain and inflammation associated with mus-
culoskeletal and joint disorders as well as neu-
ralgia, dysmenorrhoea, and postoperative pain.
Flurbiprofen is used as free acid or sodium
salt and given orally or rectally (150–200 mg/d,
max. 300 mg/d) and as ophthalmic solutions.
Peak plasma concentration appears 1 to 2 h after
oral application. The plasma protein binding is
about 99.5 % and the elimination half-life is in
the range of 3–5 h.
Use of flurbiprofen as antiplatelet agent after
myocardial infarction is discussed [155].
In addition to COX inhibition, flurbiprofen
induces weak inhibition of the transcription fac-
tors NFκ-B and AP-1 and inhibits cell prolifera-
tion, that is why its use in the treatment of cancer
has been investigated [156].
Trade names: Ansaid (USA), Antadys, Cebu-
tid (France), Dobedan (Germany), Froben (UK),
Ocufen (UK, USA). Ocuflur eye drops (Ger-
many)

Ibuprofen [15687-27-1], 2-(4-isobutyl-

phenyl)propionic acid, C18 H18 O2 , M r 206.28,
mp 75–77 ◦ C.
Synthesis [48, 157, 158] (see next page).
Several alternative processes are described in
the literature.
Clinical use: Ibuprofen [159] is a non-
steroidal anti-inflammatory drug, commonly
used for the treatment of mild to moderate
pain. It is used in conditions like rheumatoid
a) arthritis, osteoarthritis, joint and soft-tissue pain,
dental pain, postoperative pain, dysmenorrhoea,
and headache, including acute migraine attacks.
Ibuprofen is given by oral, rectal, or topical ad-
ministration (800–2400 mg/d) and with a lower
dose (40 mg kg−1 d−1 ) for the treatment of
fever in children.
Ibuprofen shows the typical side effects of
nonsteroidal anti-inflammatory drugs but seems
to be better tolerated than other nonsteroidal
anti-inflammatory drugs. This may be due to
the balanced inhibition of COX-1 and COX-2
as seen in cultured human cells [23].
Ibuprofen is absorbed within 1 to 2 h after
oral application, bound to plasma protein up to
99 % and shows a plasma half-life of about 2 h.
Ibuprofen is a racemate, the active enantiomer,
b) the S(+)-enantiomer, is available in some coun-
 Analgesics and Antipyretics 21
a) Boots process (industrial process): b) Boots-Hoechst-Celanese process:

Combination with hydrocodone: Vicoprofen

(USA).
Combination with oxycodone: Combunox
(USA).
Ibuprofen is also marketed in many generic
formulations.

Ketoprofen [22071-15-4], 2-(3-benzo-

ylphenyl)propionic acid, 3-benzoyl-α-methyl-
benzeneacetic acid, C16 H14 O3 , M r 254.28,
mp 94 ◦ C; lysine salt (1 : 1) [57469-78-0],
C16 H14 O3 · C6 H14 N2 O2 , M r 400.47; sodium
salt [57495-14-4], C16 H13 NaO3 , M r 276.27.
Synthesis [48, 160] (see next page).
Clinical use: Ketoprofen [161, 162] is a non-
steroidal anti-inflammatory drug used for the
treatment of a variety of acute and chronic
pain and inflammatory conditions including
rheumatoid arthritis, osteoarthritis, ankylosing
spondylitis, postoperative pain, and dysmenor-
rhoea. It is administered orally, rectally, topi-
cally, or intramuscular (100–200 mg/d, maxi-
mal dose 300 mg/d) as sodium or lysine salt.
Ketoprofen is given as racemate. The pharma-
tries (dexibuprofen). Ibuprofen is given as free
cologically active isomer is mainly the S(+)-
base or a variety of salts, esters, and other deriva-
enantiomer, which is available in some coun-
tives. Low-dose ibuprofen is available without
tries as the trometamol (2-amino-2-(hydroxy-
prescription and has become one of the most
methyl)-1,3-propanediol) salt. As compared to
popular OTC analgesics.
the racemate, absorption of the S(+)-isomer is
Trade names: Actren, Anco (Germany),
said to be faster, leading to an earlier onset of
Brufen (France, Italy, UK), Ibuprox (Spain), Im-
action [163].
bun (Germany), Motrin (USA).
22 Analgesics and Antipyretics

a) First large-scale manufacturing process of

Syntex [167]:

b) Stereospecific Syntex process [168]:

The stereospecific Syntex process is an example
The peak plasma concentration after oral ad- using chiral technology to produce enantiomer-
ministration occurs within 2 h. Ketoprofen is ically pure naproxen:
bound to plasma protein up to 99 % and shows
a plasma elimination half-life of 1.5 to 4 h.
Trade names: Ketocid (UK), Profénid
(France), Orudis (Germany, Italy, USA).
S(+)-ketoprofen: Keral (UK).
Naproxen [22204-53-1], (+)-(S)-2-
(6-methoxynaphthalen-2-yl)propionic acid,
C14 H14 O3 , M r 230.26, mp 155.3 ◦ C (also
reported as 152–154 ◦ C), [α]D + 66◦ (c
= 1, CHCl3 ); sodium salt [26159-34-2],
C14 H13 NaO3 , M r 252.25, mp 244–246 ◦ C, [α]D
− 11◦ (c = 1, CHCl3 ).
Synthesis [48, 164–166]:
For racemic resolution of naproxen the use of
cinchonidine, N-alkyl-d-glucamine, dehydroa-
bietylamine or (S)-α-phenylethylamine is de-
scribed. For enzymatic cleavage of esters of
racemic naproxen, cloned esterases, which are
cheap and easy to produce, have been developed
(production in a 100 t/a process is planned). Sev-
eral other synthetic routes exist.
 Analgesics and Antipyretics 23

The asymmetric hydrogenation of 2-(6-meth-

oxy-2-naphthyl)acrylic acid using ruthenium-
2,2 -bis(diphenylphosphino)-1,1 -binaphthyl
(BINAP) complexes yields also enantiomer-
ically pure naproxen.
Clinical use: Naproxen [169] is a non-
steroidal anti-inflammatory drug used for the
treatment of mild to moderate pain and inflam-
matory pain conditions like rheumatoid arthri-
tis, osteoarthritis, soft-tissue disorders, postop-
erative pain, and dysmenorrhoea. In contrast to
most other COX inhibitors, which are racemic
mixtures, naproxen has been developed and is
clinically used only as the (S)(+)-enantiomer.
Naproxen is given orally or rectally (up to 1250
mg/d). The major side effects are gastrointestinal
disturbances. To decrease gastrointestinal side
effects, fixed combinations wih the proton pump
inhibitor lansoprazole were developed.
Naproxen is available as free base, as sodium
salt, and in combination with misoprostol for the Zaltoprofen [7411-43-6], 2-(10-
reduction of the gastrointestinal side effects. For oxo-10,11-dihydrodibenzo[b,f ]thiepin-2-yl)-
topical use, morpholinyl- and methylpiperazi- propionic acid, α-methyl-10-oxo-10,11-di-
nylacyloxyalkyl prodrugs have been developed hydrodibenzo[b,f ]thiepin-2-acetic acid, 10,11-
[170]. dihydro-α-methyl-10-oxodibenzo[bf ]thiepin-
Trade names: Aleve (France, Germany), 2-acetic acid, C17 H14 O3 S, M r 298.36, mp
Anoprox (USA), Apranax (France, Germany), 131-133 ◦ C; (S)-enantiomer [89482-01-9], mp
Naprosyn (UK, USA), Proxen (Germany), Syn- 25
129.5-131 ◦ C), [α]D +32.4◦ (c = 1, chloroform).
flex (UK).
Synthesis: The cyclization of 5-(1-
Combination with lansoprazole: Prevacid,
cyanoethyl)-2-(phenylthio)phenylacetic acid in
NapraPAC (USA).
presence of polyphosphoric acid at 120 ◦ C gives
Naproxen is also marketed in several generic
2-(10-oxo-10,11-dihydrodibenzo[b,f ]thiepin-
formulations.
2-yl)propionitrile, which is then hydrolyzed
Tiaprofenic acid [33005-95-7], 2-(5-ben-
with KOH in refluxing ethanol – water to zalto-
zoylthiophen-2-yl)propionic acid, C14 H12 O3 S,
profen [174, 175].
M r 260.31, mp 96 ◦ C.
Synthesis [48, 171] (see right column, top).
Clinical use: Tiaprofenic acid [172] is a non-
steroidal anti-inflammatory drug used for the
treatment of mild to moderate pain states in mus-
culoskeletal, soft-tissue, and joint disorders as
well as for postoperative pain treatment. Tiapro-
fenic acid is given as oral or rectal administra-
tion (600 mg/d) and as intramuscular injection
of the trometamol (2-amino-2-(hydroxymeth-
yl)-1,3-propanediol) salt. The main side effects
are urinary tract symptoms like cystitis and blad-
der irritation [173].
Trade name: Surgam (France, Germany,
UK).
24 Analgesics and Antipyretics

Clinical use: Zaltoprofen is a non-steroidal yl)hydratropic acid, C13 H14 ClNO2 , M r 251.71,
anti-inflammatory drug originated by Nippon mp 98-100 ◦ C.
Chemiphar and jointly developed with Zeria. Synthesis:
It has been available on the market in Japan
a) Ethyl 4-nitrophenylacetate is methylated
since 1993 for the relief of pain and inflamma-
with NaH – CH3 I in dimethylformamide –
tion resulting from arthritis deformations, pe-
toluene to form ethyl 2-(4-nitrophenyl)-
riarthritis of the shoulder, neck-shoulder-arm
propionate, which is reduced with H2
syndrome, rheumatoid arthritis, lumbago, post-
over Pd/C in EtOH – H2 O to ethyl 2-(4-
surgery pain, trauma, and tooth extraction and
aminophenyl)propionate. This product is
used in oral doses of 80 mg [176]. According to
acetylated with acetic anhydride to yield
studies, the analgesic effects of zaltoprofen may
ethyl 2-(acetylaminophenyl)propionate. Al-
involve the inhibition of bradykinin-2 receptor-
ternatively, ethyl 4-aminophenylacetate can
mediated responses in primary afferent neurons
be acetylated with acetic anhydride to
[177, 178]. Although zaltoprofen is marketed as
ethyl 4-acetylaminophenylacetate followed
a racemate the anti-inflammatory activity resides
by methylation with CH3 I and sodium in
in the (S)-enantiomer.
liquid NH3 to give ethyl 2-(4-acetylami-
Trade name: Peon, Soleton (Japan).
nophenyl)propionate [179, 180]. Ethyl 2-(4-
acetylaminophenyl)propionate is chlorinated
Pirprofen [31793-07-4], rac-3-chloro-4-
with Cl2 in acetic acid to ethyl 2-(3-chloro-
(2,5-dihydro-1H-pyrrol-1-yl)-α-methylbenz-
4-acetylaminophenyl)propionate. This inter-
eneacetic acid, rac-3-chloro-4-(3-pyrrolin-1-
mediate is hydrolyzed with HCl in EtOH

to give ethyl 2-(3-chloro-4-aminophenyl)-
propionate hydrochloride. The last step is
the reaction of the preceding intermedi-
ate with cis-1,4-dichloro (or dibromo)-2-
butene in dimethylformamide and Na2 CO3
to ethyl 2-(3-chloro-4-(3-pyrrolinyl)phenyl)-
propionate, followed by hydrolysis with
KOH in EtOH – H2 O (see previous page).
b) 2,4-Dichloronitrobenzene is reacted with
sodium diethyl methylmalonate in dimeth-
ylformamide to yield diethyl 2-(4-nitro-3-
chlorophenyl)-2-methylmalonate, followed
by hydrolysis, decarboxylation and esteri-
fication to form ethyl 2-(3-chloro-4-nitro-
phenyl)propionate. The latter is reduced
as in route (a) to ethyl 2-(3-chloro-4-
aminophenyl)propionate hydrochloride. Al-
ternatively, diethyl 2-(4-nitro-3-chlorophe-
nyl)-2-methylmalonate can be hydrogenated
first to diethyl 2-(4-amino-3-chlorophenyl)-
2-methylmalonate, and then hydrolyzed,
decarboxylated and esterified again to form
ethyl 2-(3-chloro-4-aminophenyl)propionate
hydrochloride [179, 180] (see below).
Clinical use: Pirprofen is a nonsteroidal anti-
inflammatory drug [181] and can be used for
Analgesics and Antipyretics 25
the treatment of post-operative pain, oncolog-
ical pain, episodic headache attacks, and acute
migraine [182]. There are reports on hepatic and
renal intolerability [183–186] which precluded
the further use.
Trade names: Rengasil (France, Belgium,
Netherlands, Chile), Seflenyl.
Fenoprofen [31879-05-7], rac-α-meth-
yl-3-phenoxybenzeneacetic acid, rac-m-
phenoxyhydratropic acid, α-(d,l)-2-(3-phen-
oxyphenyl)propionic acid, C15 H14 O3 , M r
242.27, viscous oil, bp0.11 (0.147 hPa) 168-
171 ◦ C; calcium salt dihydrate, [53746-45-
5], C30 H26 CaO6 . 2H2 O, M r 558.64, mp 68-
171 ◦ C.
Synthesis: The condensation of 3-hy-
droxyacetophenone with bromobenzene yields
3-phenoxyacetophenone, which is reduced
with sodium borohydride to 1-(3-phenoxy-
phenyl)ethanol. Bromination with phos-
phorus(III)bromide yields 1-(1-bromoethyl)-
3-phenoxybenzene. After reaction with sodium
cyanide the resulting 2-(3-phenoxyphenyl)pro-
panenitrile is hydrolyzed to fenoprofen [187,
188]; for alternative syntheses see [189–191].
26 Analgesics and Antipyretics

by means of acetyl chloride. Methylation with

methyl iodide in the presence of n-butyllithium
yields the desired vedaprofen after the standard
work-up procedure [198].

Clinical use: Fenoprofen [192–194] is a non-

steroidal anti-inflammatory drug used in oral
doses of 300 mg as the calcium salt or in doses
of 200–400 mg as free base for the treatment of
moderate to severe pain and symptomatic treat-
ment of acute and chronic rheumatoid arthritis
and osteoarthritis. Enteric coated tablets of the
Ca salt were developed to reduce gastrointesti-
nal microbleeding [195]. The use of fenoprofen
was associated with renal impairment [196] and
allergic skin inflammation [197].
Trade names: Fepron (Italy), Nalfon (USA),
Nalgesic (France).
Clinical use: Vedaprofen is a nonsteroidal
Vedaprofen [71109-09-6], rac-4-cy- anti-inflammatory drug with antipyretic and
clohexyl-α-methyl-1-naphthaleneacetic acid, analgesic properties, based on inhibition of
rac-2-(4-cyclohexylnaphthalen-1-yl)propanoic prostaglandin synthesis. Both enantiomers con-
acid, C19 H22 O2 , M r 282.38, mp 150 ◦ C. tribute to the biological and therapeutic actions
Synthesis: The reaction of 1-cyclohexylnaph- of vedaprofen. Although vedaprofen was ini-
thalene and paraformaldehyde in the presence tially developed for human use, it is is now
of concentrated hydrochloric acid and H3 PO4 mainly used as a veterinary drug as oral gel [199]
at 85 ◦ C yields 1-chloromethyl-4-cyclohexyl- for the reduction of inflammation and pain asso-
naphthalene, which is transformed to (4-cy- ciated with musculo-skeletal disorders in dogs
clohexylnaphthalen-1-yl)-acetonitrile by means [200] and horses and parenterally as the meglu-
of sodium cyanide in water acetone mixture mine salt for the acute treatment of colic pain
as solvent. The hydrolysis of the nitrile with in horses [201]. In horses vedaprofen is admin-
potassium hydroxide yields the sodium salt of istered orally at an initial dose of 2 mg/kg, fol-
(4-cyclohexylnaphthalen-1-yl)-acetic acid. Af- lowed by 1 mg/kg every 12 h for up to 14 days.
ter treatment with hydrochloric acid the free Trade name: Quadrisol.
acid is converted to the corresponding (4-cyclo-
hexyl-naphthalen-1-yl)-acetic acid methyl ester

Nepafenac [78281-72-8], 2-(2-amino-3-
benzoylphenyl)acetamide, 2-amino-3-benzoyl-
benzeneacetamide, C15 H14 N2 O2 , M r 254.29,
mp 178.5-180 ◦ C.
Synthesis: The reaction of (2-aminophenyl)-
phenylmethanone and thiocarbamic acid S-
methyl ester in the presence of 2,2-di-
methylpropionyl chloride in methylene chloride
at -65 ◦ C and subsequent treatment with triethyl-
amine at the same temperature yields the cor-
responding condensation product 2-(2-amino-
3-benzoyl-phenyl)-2-methylsulfanylacetamide.
Finally, nepafenac is obtained by reduction with
Raney nickel in tetrahydrofuran [202, 203].
Clinical use: Nepafenac is a nonsteroidal an-
tiinflammatory drug, that was launched by Al-
con in 2005 for the treatment of pain and inflam-
mation associated with cataract surgery, because
it rapidly penetrates ocular tissues, and it is used
locally as 1 % ophthalmic suspensions [204].
Nepafenac is an amide analog and a pro-
drug of amfenac (2-amino-3-benzoylbenzene-
acetic acid), which is a COX-1 and COX-2 in-
hibitor [205]. Nepafenac is the first ophthalmic
NSAID prodrug to receive FDA approval. It had
originally been developed at Wyeth Consumer
Healthcare [204, 206, 207].
Trade name: Nevanac.
Amfenac [51579-82-9], 2-amino-3-ben-
zoylbenzeneacetic acid, 2-amino-3-benzoyl-
phenylacetic acid, C15 H13 NO3 , M r 255.28, mp
121-123 ◦ C (dec.); sodium salt monohydrate
[61618-27-7], C15 H12 NNaO3 H2 O, M r 295.27,
mp 254-255.5 ◦ C.
Synthesis: The reaction of 1-aminoindolin-
2-one with phenylacetone in presence of
Analgesics and Antipyretics 27
acetic acid in refluxing ethanol gives 1-(α-
methylphenethylidieneimino)indolin-2-one,
which by reaction with refluxing ethanolic
hydrogen chloride affords ethyl α-(2-methyl-
3-phenylindol-7-yl)acetate. The ozonolysis of
this intermediate in acetic acid yields ethyl 2-
acetamido-3-benzoylphenyl acetate, which is
cyclized by refluxing with HCl in acetic acid
to give 7-benzoylindolin-2-one. Alternatively,
the hydrolysis of the ester ethyl α-(2-methyl-3-
phenylindol-7-yl)acetate with KOH in refluxing
water affords the corresponding acid, which can
be ozonolyzed as before yielding 2-acetamido-
3-benzoylphenylacetic acid. This acid can be
cyclized to 7-benzoyl-1,3-dihydro-indol-2-one
by refluxing with HCl in acetic acid as before
[208–210].
2.6. Pyrazolinone Derivatives
Metamizol [50567-35-6], dipyrone[(1,5-
dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazol-4-yl)methylamino]-methanesulfonic
acid, C13 H17 N3 O4 S, M r 311.36; sodium
salt [68-89-3], C13 H16 N3 NaO4 S, M r 333.34;
sodium salt monohydrate [50567-35-6],
C13 H16 N3 NaO4 S · H2 O, M r 351.36.
Synthesis [48, 211, 212] (see next page).
Clinical use: Metamizol [213, 214] is the wa-
ter soluble sodium sulfonate of amidopyrine.
After oral application it is rapidly hydrolyzed
to 4-methylaminoantipyrine and metabolized to
various active metabolites [215]. Metamizol has
strong analgesic, spasmolytic, and antipyretic,
but no anti-inflammatory properties. The exact
mechanism of action is unknown but may in-
clude inhibition of prostaglandin synthesis. In-
hibition of both COX isoenzymes by metami-
zol has been demonstrated only when very high
concentrations of this drug were used, thus ques-
tioning the relevance of this activity.
COX inhibition may be induced by the
metabolites, but this is not yet systematically in-
vestigated. Metamizol is used for the treatment
of medium to severe pain, often in combina-
tion with opioids, for fever reduction and for
the treatment of colic pain. It is given by mouth
in doses of 500 mg up to 4 g daily, by intra-
venous or by rectal application. Metamizol is rel-
atively free of acute side effects but in rare cases
may cause severe and life-threatening allergic
28 Analgesics and Antipyretics

reactions like agranulocytosis, allergic skin re- Propyphenazone [479-92-5], 1,2-dihydro-

actions, and allergic shock. The compound is 1,5-dimethyl-4-(1-methylethyl)-2-phenyl-3H-
not used in the UK, USA, and in Scandinavian pyrazol-3-one, C14 H18 N2 O3 , M r 230.31, mp
countries. 103 ◦ C.
Synthesis [48, 216, 217]:

Clinical use: Propyphenazone [218, 219] is a

derivative of phenazone and has a similar anal-
gesic and antipyretic action. It is used as a mono-
compound as well as in multi-ingredient prepa-
rations.
Trade name: Demex (Germany).
Multi-ingredient preparation: Saridon (Ger-
many).

2.7. Acidic Enolic Compounds

2.7.1. Pyrazolidine-3,5-diones

Kebuzone [853-34-9], 4-(3-oxobutyl)-1,2-

Trade names: Analgin, Novalgin (Germany, diphenyl-pyrazolidine-3,5-dione, C19 H18 N2 O3 ,
Austria, Switzerland). M r 322.36, mp 115.5–116.5 ◦ C or 127.5–
Metamizol is also marketed in several generic 128.5 ◦ C, depending on crystal form.
formulations. Synthesis [158, 220, 221]:

Clinical use: Kebuzone [222] is a non-
steroidal anti-inflammatory drug used for the
treatment of acute and chronic pain and inflam-
mation states like musculoskeletal, joint, and
soft-tissue disorders. Kebuzone is administered
orally, rectally, or intramuscular (up to 1500
mg/d initial dose, 250–500 mg/d maintenance
dose).
Trade names: Ketazon (Austria), Chetopir
(Italy).
Mofebutazone [2210-63-1], 4-butyl-1-
phenylpyrazolidine-3,5-dione, C13 H16 N2 O2 ,
M r 232.28, mp 102–103 ◦ C; sodium salt
[41468-34-2], C13 H15 N2 NaO2 , M r 254.27.
Synthesis [48, 223, 224]:
Analgesics and Antipyretics 29
Clinical use: Mofebutazone [225] is a non-
steroidal anti-inflammatory drug used as sodium
salt for the treatment of mild to moderate
pain including inflammatory and degenerative
rheumatic disorders and musculoskeletal pain.
Mofebutazone can be given by oral, rectal
(900–1200 mg/d), or intramuscular administra-
tion (650 mg/d).
Trade name: Mofesal (Germany).
Oxyphenbutazone [129-20-4], oxyphenyl-
butazone, 4-butyl-1-(4-hydroxyphenyl)-2-
phenylpyrazolidine-3,5-dione, C19 H2 ON2 O3 ,
M r 324.37, mp 124–125 ◦ C; monohydrate
[7081-38-1], C19 H20 N2 O3 · H2 O, M r 342.40,
mp 96 ◦ C.
Synthesis [48, 226]:
Clinical use: Oxyphenbutazone is a non-
steroidal anti-inflammatory drug, which was
used by oral, rectal, or topical administration
(400 - 600 mg/d) for the acute treatment of anky-
losing spondylitis, chronic polyarthritis, and
gout. Because of a high incidence of severe side
effects including disturbances of the hematopoi-
etic system like agranulocytosis and aplastic
anemia [233] the compound is no longer used.
Oxyphenbutazone is a metabolite of phenyl-
butazone.
Phenylbutazone [50-33-9], 4-butyl-1,2-
diphenylpyrazolidine-3,5-dione, C19 H20 N2 O2 ,
30 Analgesics and Antipyretics

M r 308.37, mp 105 ◦ C; sodium salt [129-18-0], 335.34, mp 265–271 ◦ C (decomp.); sodium salt,
C19 H19 N2 NaO2 , M r 331.36; calcium salt (2 : 1) C14 H12 N3 NaO5 S, M r 343.29, mp 270–272 ◦ C.
[36298-23-4], C38 H36 CaN4 O4 , M r 656.83; pi- Synthesis [48, 231–233]:
perazine salt (1 : 1) [4985-25-5], C19 H20 N2 O2 ·
C4 H10 N2 , M r 395.51, mp 140–141 ◦ C.
Synthesis [48, 228]:

Clinical use: Phenylbutazone [229] is a

nonsteroidal anti-inflammatory drug used for
the acute treatment of ankylosing spondyli-
tis, chronic polyarthritis, and gout. Because of
severe side effects including disturbances of
the hematopoietic system like agranulocytosis
and aplastic anemia [230] the use is limited
to conditions in which other nonsteroidal anti-
inflammatory drugs do not show sufficient ef-
ficacy. Phenylbutazone is given as oral, rectal,
intramuscular or topical formulation (up to 600
mg/d initial dose, up to 400 mg/d maintenance
dose). The peak plasma concentration is reached
2 h after oral application. Phenylbutazone is
bound to 98 % to plasma protein. Oxyphenbuta- Clinical use: Isoxicam [234] is a nonsteroidal
zone is formed as an active metabolite of phenyl- anti-inflammatory drug withdrawn from the
butazone. market as a consequence of reports of fatal skin
Trade names: Butazolidin (France, Germany, reaction.
UK, USA), Ambene (Germany).
Lornoxicam [70374-39-9], 6-chloro-
4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-
2.7.2. Arylsulfonamides (Oxicames) 1λ6 -thieno[2,3-e][1,2]thiazine-3-carboxyl-
ic acid pyridin-2-ylamide, 6-chloro-4-hy-
The oxicams are a group of nonsteroidal droxy-2-methyl-N-(2-pyridyl)-2H-thieno[2,3-
anti-inflammatory agents containing a 2H-1,2- e]-1,2-thiazine-3-carboxamide 1,1-dioxide,
benzothiazine-3-carboxamide 1,1-dioxide moi- C13 H10 ClN3 O4 S2 , M r 371.81, mp 225–230 ◦ C
ety as common structural entity (for Meloxicam (decomp.).
see Section 2.9.1). Synthesis: Sulfonation of 2,5-di-
chlorothiophene with ClSO3 H/SOCl2 gives
Isoxicam [34552-84-6], 4-hy- 2,5-dichlorothiophene-3-sulfonyl chloride,
droxy-2-methyl-1,1-dioxo-1,2-dihydro-1λ6 - which by reaction with methylamine in
benzo[e][1,2]thiazine-3-carboxylic acid CHCl3 yields the corresponding methy-
isoxazo-3-ylamide, 4-hydroxy-2-methyl-N-(5- lamide. The carboxylation with butyl lithium
methyl-3-isoxazolyl)-2H-1,2-benzothiazine-3- and CO2 in ether affords 5-chloro-3-(N-
carboxamide 1,1-dioxide, C14 H13 N3 O5 S, M r methylsulfamoyl)thiophene-2-carboxylic acid,

which is esterified with PCl5 and metha-
nol to the methyl ester. Condensation with
methyl iodoacetate by means of NaH in
DMF gives methyl 5-chloro-3-[N-(methoxycar-
bonylmethyl)-N-methylsulfamoyl]thiophene-
2-carboxylate, which is cyclized with sodium
methoxide in methanol yielding methyl 6-
chloro-4-hydroxy-2-methyl-2H-thieno[2,3-e]-
1,2-thiazine-3-carboxylate-1,1-dioxide. Finally
this compound is treated with 2-aminopyridine
in refluxing xylene [235].
Clinical use: Lornoxicam [236] is a non-
steroidal anti-inflammatory drug with a strong
and balanced inhibition of COX-1 and COX-2 in
cultured human cells [23]. In addition, lornoxi-
cam inhibits inducible nitric oxide synthase and
Analgesics and Antipyretics 31
interleukin-6, both of which could contribute
to its potent anti-inflammatory and analgesic
action [237]. It is used orally (8–24 mg/d) for
the treatment of mild to moderate pain includ-
ing postoperative pain, rheumatoid arthritis, os-
teoarthritis, and ankylosing spondylitis [238].
Lornoxicam shows a high binding to plasma
protein and in contrast to other oxicams a short
plasma half-life of 3 to 5 h [236].
Trade names: Telos (Germany), Taigalor
(Italy), Xefo (Austria, Denmark, Italy, Switzer-
land, UK).
Piroxicam [36322-90-4], 4-hydroxy-
2-methyl-1,1-dioxo-1,2-dihydro-1λ6 -benzo-
[e][1,2]thiazine-3-carboxylic acid pyridin-2-
ylamide, 4-hydroxy-2-methyl-N-2-pyridinyl-
2H-1,2-benzothiazine-3-carboxamide 1,1-di-
oxide, C15 H13 N3 O4 S, M r 331.35, mp 198–
200 ◦ C.
Synthesis [239–243, 251]:
Clinical use: Piroxicam [244] is a non-
steroidal anti-inflammatory drug used for the
treatment of mild to moderate acute and chronic
pain and inflammation including musculoskele-
tal, soft-tissue, and joint disorders like ankylos-
ing spondylitis, chronic polyarthritis, and gout
[245]. Piroxicam shows a 600-fold selectivity
for COX-1 compared to COX-2 in cultured
animal cells [246]. Piroxicam is administered
orally, rectally, intramuscular, or topically (10–
30 mg/d, maximal initial dose 40 mg/d) as the
free base, as complex with beta-cyclodextrine,
and as cinnamate or pivalate. After oral admin-
istration, piroxicam reaches peak plasma con-
centration after 3 to 5 h, shows a 99 % binding
to plasma protein and a long half-life of about
50 h.
32 Analgesics and Antipyretics
Trade names: Brexidol (EU, USA), Brexin
(Franc, Italy), Feldéne (France), Felden (Ger-
many), Feldene (UK, USA).
Piroxicam is also marketed in several generic
formulations.
Tenoxicam [59804-37-4], 4-hydroxy-2-
methyl-1,1-dioxo-1,2-dihydro-1λ6 -thieno[2,3-
e][1,2]thiazine-3-carboxylic acid pyridin-2-
ylamide, 4-hydroxy-2-methyl-N-2-pyridinyl-
2H-thieno[2,3-e]-thiazine-3-carboxamide 1,1-
dioxide, C13 H11 N3 O4 S2 , M r 337.38, mp 209–
213 ◦ C (decomp.).
Synthesis: The reaction of methyl 3-hy-
droxythiophene-2-carboxylate with PCl5 in re-
fluxing CCl4 gives 3-chlorothiophene-2-car-
boxylic acid, which by treatment with NaHSO3
and Cu in aqueous alkaline solution at 143 ◦ C
in a pressure vessel is converted into 3-
sulfothiophene-2-carboxylic acid. Its esterifi-
cation with refluxing methanol affords methyl-
3-sulfothiophene-2-carboxylate, which by re-
action with refluxing SOCl2 yields methyl-
3-chlorosulfonylthiophene-2-carboxylate. The
following condensation with sarcosine ethyl
ester in hot CHCl3 gives 3-(N-ethoxycarbon-
ylmethyl-N-methylsulfamoyl)thiophene-2-car-
boxylate, which is cyclized by treatment with
sodium methoxide in refluxing methanol afford-
ing 3-ethoxycarbonyl-4-hydroxy-2-methyl-2H-
thieno-[2,3-e]-1,2-thiazine 1,1-dioxide. Finally
this compound is condensed with 2-aminopyri-
dine in refluxing toluene [48, 243, 247].
Clinical use: Tenoxicam [248] is a non-
steroidal anti-inflammatory drug used for the
treatment of mild to moderate pain states in
musculoskeletal, soft-tissue, and joint disorders
like rheumatoid arthritis, osteoarthritis and gout.
Tenoxicam shows a balanced inhibition of both
COX-1 and COX-2 in cultured human cells [23].
Tenoxicam is administered orally, rectally, or in-
tramuscular (20 mg/d, maximal dose 40 mg/d).
Peak plasma concentration appears within 1 to 6
h after administration depending on food intake.
Tenoxicam is bound to plasma protein to 98.5 %
and shows a long plasma elimination half-life of
70 to 90 h.
Trade names: Mobiflex (UK), Tilcotil
(France, Italy, Switzerland).
2.8. Other Structures
Ketorolac [74103-06-3], 5-benzo-
yl-2,3-dihydro-1H-pyrrolizine-1-carboxylic
acid, C15 H13 NO3 , M r 255.27, mp 160–
161 ◦ C; tromethamine salt (1 : 1) [74103-07-
4], C15 H13 NO3 · C4 H11 NO3 , M r 376.41, (+)-
form mp 174 ◦ C, [α]D + 173◦ (c = 1, CH3 OH),
(−)-form mp 169–170 ◦ C, [α]D − 176◦ (c =
1, CH3 OH); monosodium salt [110618-38-7],
C15 H12 NNaO3 , M r 277.26.
Synthesis: Benzoylation of 2-methyl-
thiopyrrole with N,N-dimethylbenzamide in the
presence of POCl3 in refluxing CH2 Cl2 gives
5-benzoyl-2-methylthiopyrrole, which is con-
densed with spiro[2,5]-5,7-dioxa-6,6-dimethyl-
octane-4,8-dione by means of NaH in DMF.
Oxidation of this product with m-chloroperben-
zoic acid in CH2 Cl2 affords the sulfone, which
is submitted to methanolysis with methanol and
HCl giving 1-(3,3-dimethoxycarbonylpropyl)-
2-methanesulfonyl-5-benzoylpyrrole. Cycliza-

tion with NaH in DMF yields dimethyl-5-benzo-
yl-1,2-dihydro-3H-pyrrolo[1,2-α]pyrrole-1,1-
dicarboxylate, which is finally hydrolyzed and
decarboxylated with KOH in refluxing methanol
[48, 249–253].
Clinical use: Ketorolac [254] is a non-
steroidal anti-inflammatory drug mainly used
for the treatment of moderate to severe post-
operative pain. Ketorolac shows a balanced in-
hibition of COX-1 and COX-2 in cultured hu-
man cells [23]. Ketorolac is mostly used as
Analgesics and Antipyretics 33
the tromethamine salt. Due to a number of se-
vere side effects including gastrointestinal dis-
turbances, impairment of liver functions, renal
failures, skin irritations, and other hypersensi-
tivity reaction it has been withdrawn in many
countries.
Trade names: Acular (UK, USA), Droal
(Spain), Tora-Dol (France, Italy), Toradol (UK,
USA).
Oxaprozine [21256-18-8], 3-(4,5-diphen-
yl-oxazol-2-yl)propionic acid, C18 H15 NO3 , M r
293.32, mp 160.5–161.5 ◦ C.
Synthesis [255–257]:
Clinical use: Oxaprozine [257] is a non-
steroidal anti-inflammatory drug used for the
treatment of mild to moderate pain includ-
ing rheumatoid arthritis and osteoarthritis.
Oxaprozine shows slow elimination kinetics
with an elimination half-life of about 24 h. It
is given orally (600–1200 mg/d, maximum dose
1800 mg/d).
Trade names: Deflam (South Africa), Daypro
(USA).
2.9. COX-2 Inhibitors
2.9.1. Nonselective COX-2 Inhibitors
Etodolac [41340-25-4], (1,8-diethyl-
1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)-
acetic acid, C17 H21 NO3 , M r 287.35, mp 145–
148 ◦ C.
Synthesis [258–261]:
34 Analgesics and Antipyretics
Clinical use: Etodolac [262] shows a ten-fold
selectivity for COX-2 compared to COX-1 in
human whole blood and belongs to the first gen-
eration of COX-2 inhibitors [22]. Etodolac is a
racemate with an active (S)-enantiomer and an
inactive (R)-enantiomer. It is used for the treat-
ment of mild to moderate acute and chronic pain
including rheumatoid arthritis and osteoarthri-
tis. Clinical data indicate fewer gastrointesti-
nal side-effects in comparison to naproxen [51,
264]. Etodolac is used in oral slow and immedi-
ate release preparations and applied in doses of
600–1200 mg/d. Peak plasma concentrations are
reached within 2 h. Etodolac shows a 99 % bind-
ing to plasma protein and an elimination half-life
of about 7 h.
Trade name: Lodine (USA, UK, France).
Meloxicam [71125-38-7], 4-hy-
droxy-2-methyl-1,1-dioxo-1,2-dihydro-1λ6 -
benzo[e][1,2]thiazine-3-carboxylic acid (5-
methyl thiazol-2-yl)amide, 4-hydroxy-
2-methyl-N-(5-methyl-2-thiazoyl)-2H-1,2-
benzothiazine-3-carboxamide 1,1-dioxide,
C14 H13 N3 O4 S2 , M r 351.40, mp 264 ◦ C (de-
comp.).
Synthesis: Reaction of benzothiazolo-3(2H)-
one-1,1-dioxide with methyl chloroacetate gives
the methyl 2(3H)-acetate derivative, which is
isomerized with sodium methoxide in toluene-
tert-butanol yielding methyl 4-hydroxy-2H-1,2-
benzothiazine-3-carboxylate-1,1-dioxide. Sub-
sequent methylation with methyl iodide in
methanol yields the 2-methyl compound. Fi-
nally this compound is treated with 2-amino-5-
methylthiazole in xylene [48, 265, 266].
Clinical use: Meloxicam [267] shows a ten-
fold selectivity for COX-2 compared to COX-
1 in human whole blood and belongs to the
first generation of COX-2 selective drugs [22].
Meloxicam is used for the acute and chronic
treatment of mild to moderate pain including
arthritis and ankylosing spondylitis. Meloxi-
cam shows central antinociceptive effects in rats
which seems to be independent from the COX
inhibiting properties [268].
Meloxicam is given by oral administration
(7.5–15 mg/d). It shows an elimination half-life
of 20 h.
Trade names: Mobec (Germany), Mobic
(Italy, UK, USA), Movalis (Spain).
Nimesulide [51803-78-2], N-(4-
nitro-2-phenoxyphenyl)methanesulfonamide,
C13 H12 N2 O5 S, M r 308.05, mp 143–144.5 ◦ C.
Synthesis [48, 269]:

Clinical use: Nimesulide [270] is a first-
generation COX-2 inhibitor with a 5- to 100-
fold selectivity for COX-2 compared to COX-1,
depending on the assay system [22, 23]. It is
used for the short-term treatment of inflamma-
tory conditions, fever, and pain, including mus-
culoskeletal and joint disorders. In addition to
COX inhibition nimesulide reduces the produc-
tion of the pro-inflammatory cytokine TNF-α
under inflammatory conditions [271].
Nimesulide is available in oral or rectal for-
mulations (up to 400 mg/d).
The use of nimesulide has been reported to
be associated in some cases with hepatic failure
[272, 273] and the compound was withdrawn
from the market in several countries.
Trade names: Aulin (Italy, Switzerland),
Nexen (France), Guaxan (Spain, withdrawn).
2.9.2. Selective COX-2 Inhibitors (Coxibs)
Celecoxib [169590-42-5], 4-(5-p-tolyl-
3-trifluoromethylpyrazol-1-yl)-benzenesulfon-
amide, C17 H14 F3 N3 O2 S, M r 381.37, mp 157–
159 ◦ C (pale yellow solid).
Synthesis: Condensation of 4-methylaceto-
phenone with ethyl trifluoroacetate in reflux-
Analgesics and Antipyretics 35
ing methanol using sodium methoxide as
catalyst gives 4,4,4-trifluoro-1-(4-methylphe-
nyl)butane-1,3-dione, which is cyclized with 4-
hydrazinophenylsulfonamide in refluxing etha-
nol [488, 493].
Clinical use: Celecoxib [166] is a second-
generation selective COX-2 inhibitor and was
the first drug of this group to reach the market.
The selectivity for COX-2 compared to COX-1
is about 375-fold in human recombinant enzyme
preparations and about eight-fold in a whole
blood assay. Celecoxib has been approved in
1999 in the USA and is now used for the treat-
ment of rheumatoid arthritis and osteoarthritis,
ankylosing spondylitis, acute pain and primary
dysmenorrhoea all over the world.
Celecoxib is further approved for the use in
familial adenomatous polyposis in the US and
leads to a reduction in the number of colorectal
polyps in these patients [276].
The use of celecoxib is associated with a
reduced incidence of gastroduodenal ulcers in
comparison to naproxen [277], ibuprofen, and
diclofenac [278] in arthritic patients. Because of
a greater COX-1 inhibiting component as com-
pared to the newer highly COX-2 selective com-
pounds such as valdecoxib, rofecoxib, and pari-
coxib, cardiovascular side effects of celecoxib
are less prominent and the compound avoided
withdrawal from the market [279]. Nevertheless
36 Analgesics and Antipyretics
celecoxib should be used with appropriate pre-
caution.
Plasma peak concentrations are achieved
within 2 h and the elimination half-life is about
12 h. Celecoxib is given orally (200–400 mg/d).
Trade names: Celebrex (EU, USA), Onsenal
(EU).
Etoricoxib [202409-33-4], [202409-40-
3] (mono HCl), 5-chloro-3-[4-(methyl-sul-
fonyl)phenyl]-2-(6-methylpyridin-3-yl)pyri-
dine, 5-chloro-6 -methyl-3-(4-[methylsulfo-
nyl)phenyl]-2,3 -bipyridine, C18 H15 ClN2 O2 S,
M r 358.848, crystals, mp 271.5-138.1 ◦ C
(136.7 ◦ C DSC onset).
Synthesis [280–284]:
a) Synthesis via dichloropyridine:
i) The bromination of 5-chloro-2-hy-
droxypyridine with Br2 in acetic acid
gives 3-bromo-5-chloro-2-hydroxypyri-
dine, which is treated with benzyl bro-
mide and Ag2 CO3 in hot benzene to
yield the benzyl ether 2-(benzyloxy)-3-
bromo-5-chloropyridine. Condensation of
2-(benzyloxy)-3-bromo-5-chloropyridine
with 4-(methylsulfanyl)phenylboronic
acid with the aid of Pd(PPh3 )4 and
Na2 CO3 in refluxing ethanol/benzene
affords 2-(benzyloxy)-5-chloro-3-[4-
(methylsulfanyl)phenyl]pyridine, which
is oxidized with OsO4 and sodium sul-
fite to furnish sulfone 2-(benzyloxy)-
5-chloro-3-[4-(methylsulfonyl)phenyl]-
pyridine. Treatment of 2-(benzyloxy)-5-
chloro-3-[4-(methylsulfonyl)phenyl]pyri-
dine with trifluoroacetic acid (TFA) pro-
vides the 2-hydroxypyridine derivative,
which is reacted with POCl3 to yield 2,5-
dichloro-3-[4-(methylsulfonyl)phenyl]-
pyridine.
ii) Bromination of 2-amino-5-chloropyr-
idine with Br2 in acetic acid pro-
vides 2-amino-3-bromo-5-chloropyr-
idine, which is condensed with 4-
(methylsulfanyl)phenylboronic acid in
the presence of Pd(PPh3 )4 and Na2 CO3
in refluxing ethanol/benzene to give 5-
chloro-3-[4-(methylthio)phenyl]pyridin-
2-amine. Oxidation of 5-chloro-3-[4-
(methylthio)phenyl]pyridin-2-amine with
OsO4 as before yields the sulfone
5-chloro-3-[4-(methylsulfonyl)phenyl]-
pyridin-2-amine, which is converted
into 2,5-dichloro-3-[4-(methylsulfo-
nyl)phenyl]pyridine by treatment first with
NaNO2 and HCl and then chlorination
with POCl3 [280, 281].
iii) 2,5-dichloro-3-[4-(methylsulfonyl)phenyl]-
pyridine is condensed with either trimeth-
yl(6-methyl-3-pyridyl)tin or the boronate
ester lithium salt by means of Pd(PPh3 )4 to
afford etoricoxib .The metalated pyridine
2-methyl-5-(trimethylstannyl)pyridine is
obtained by esterification of 3-hydroxy-6-
methylpyridine with trifluoromethanesul-
fonic (triflic) anhydride to give the corre-
sponding triflate 6-methylpyridin-3-yl tri-
fluoromethanesulfonate, which is treated
with hexamethylditin to afford the tar-
get tin intermediate 2-methyl-5-(trimeth-
ylstannyl)pyridine. The boronate lithium
salt is prepared by treatment of 5-bromo-
2-methylpyridine with n-butyl lithium fol-
lowed by addition of triisopropyl borate
[281] (see next page).
b) In addition, etoricoxib is obtained by sev-
eral related ways via the ketosulfone key
intermediate 1-(6-methylpyridin-3-yl)-2-
[4-(methylsulfonyl)phenyl]ethanone, which
can also be synthesized by several different
routes:
i) Reaction of ketosulfone 1-(6-
methylpyridin-3-yl)-2-(4-[methylsulfo-
nyl)phenyl]ethanone with 2-chloro-1,3-
bis(dimethylamino)trimethinium hexa-
fluorophosphate salt in the presence of
an equimolar amount of potassium tert-
butoxide, followed by treatment with
acetic/trifluoroacetic acid and then heating
at reflux with an excess of ammonium hy-
droxide. The 2-chloro-1,3-bis(dimethyl-
amino)trimethinium hexafluorophosphate
salt is obtained by reaction of chloroacetic
acid with hot dimethylformamide and
POCl3 , and then the reaction mixture
is treated with 5 N NaOH and hexa-
fluorophosphoric acid in water.
ii) Cyclization of ketosulfone 1-(6-
methylpyridin-3-yl)-2-(4-[methyl-
sulfonyl)phenyl]ethanone with 2-
chloromalondialdehyde (A: X=OH),
or by cyclization of ketosulfone 1-(6-
methylpyridin-3-yl)-2-[4-(methylsulfo-

nyl)phenyl]ethanone with aminoacrolein
(B: X=NH2 ) in the absence of am-
monium acetate. The cyclization of
the lithium enolate of ketosulfone
1-(6-methylpyridin-3-yl)-2-(4-(methyl-
sulfonyl)phenyl)ethanone with 2,3-di-
chloroacrolein (C: X=Cl) – obtained by
Analgesics and Antipyretics 37
treatment of chloromalondialdehyde with
oxalyl chloride and dimethyl formamide in
toluene – followed by reaction with am-
monium acetate or anhydrous ammonia
yield also the desired etoricoxib.
iii) Etoricoxib can also be obtained by cycliza-
tion of the aniline derivative 2-chloro-3-
38 Analgesics and Antipyretics
phenylaminopropenal and ammonium ac-
etate in hot propionic acid [280–284].
Clinical use: Etoricoxib [280, 285] is a third-
generation COX-2 inhibitor with a 100-fold se-
lectivity for COX-2 in a whole blood assay. The
selectivity ratio is higher than with other coxibs
such as rofecoxib, valdecoxib, or celecoxib.
The compound was shown to be active in
rheumatoid arthritis, osteoarthritis, ankylosing
spondylitis, postoperative pain, and in chronic
low back pain. Further positive results were seen
in patients with acute gout and against primary
dysmenorrhoea [286].
Etoricoxib is used in oral doses of 60–120
mg/d. The compound is rapidly absorbed and
peak plasma concentrations are achieved within
1.0 to 1.5 h after administration in healthy vol-
unteers [287]. The elimination half-life is about
15 h. Etoricoxib is metabolized to about 60 %
by members of the cytochrome P450 3A family
[288]. In vitro studies give no evidence for active
metabolites with respect to COX-1 and COX-2
inhibition [289].
Etoricoxib is generally well tolerated and in-
duces less gastrointestinal side effects than con-
ventional COX-1 inhibitors or non-COX selec-
tive NSAIDs [290]. Renal tolerability is simi-
lar to conventional COX-1 inhibitors [291]. Ac-
cording to its COX-2 selectivity, etoricoxib has
an increased risk of cardiovascular side effects
[292] and should only be used with appropriate
precautions.
Trade name: Arcoxia (EU, USA).
Lumiracoxib [220991-20-8], 2-[2-(2-
chloro-6-fluorophenylamino)-5-methylphe-
nyl]acetic acid, C15 H13 ClFNO2 , M r 293.72,
mp 158-159 ◦ C.
Synthesis [61, 294, 295]: The partial reduc-
tion of 4-methylanisole with sodium in liquid
ammonia/THF/ethanol gives the enol ether 3-
methoxy-6-methylcyclohexa-1,4-diene, which
is condensed with 2-chloro-6-fluoroaniline in
presence of TiCl4 in chlorobenzene/THF to
yield (E)-2-chloro-6-fluoro-N-(4-methylcyclo-
hex-2-enylidene)benzenamine, which, without
isolation, is aromatized with I2 in AcOH/THF
to provide N-(2-chloro-6-fluorophenyl)-N-(4-
methylphenyl)amine. The acylation of this
intermediate with 2-chloroacetyl chloride at
90 ◦ C affords the 2-chloro-N-(2-chloro-6-
fluorophenyl)-N-p-tolylacetamide, which is
cyclized by means of AlCl3 by heating at
160 ◦ C to afford 1-(2-chloro-6-fluorophenyl)-
5-methylindolin-2-one. Finally, this compound
is hydrolyzed with NaOH in refluxing etha-
nol/water and acidified with 1 N HCl to give
lumiracoxib. Alternatively, the intermediate
N-(2-chloro-6-fluorophenyl)-N-(4-methylphe-
nyl)amine can also be obtained by condensa-
tion of 2-chloro-N-(4-methylphenyl)acetamide
with 2-chloro-6-fluorophenol using K2 CO3 in
isopropanol to yield 2-(2-chloro-6-fluorophen-
oxy)-N-(4-methylphenyl)acetamide, which is
treated with MeONa in methanol to obtain the
target secondary amine Lumiracoxib [61, 294].

An alternative synthesis of lumiracoxib
involves the coupling of N,N-dimethyl-5-
methyl-2-iodophenylacetamide with 2-chloro-
6-fluoroaniline in the presence of copper pow-
der, copper(I) iodide and anhydrous potassium
carbonate, and refluxing in xylene for 48 h.
This synthetic route includes the following
steps: The reduction of 2-iodo-5-methylbenzo-
ic acid with BH3 /THF in THF gives 2-iodo-
5-methylbenzyl alcohol, which is treated with
refluxing 48 % HBr to yield the benzyl bro-
mide. Reaction of the benzyl bromide with
NaCN in ethanol/water affords the phenylace-
tonitrile, which is hydrolyzed with NaOH in
refluxing EtOH/water to provide the phenyl-
Analgesics and Antipyretics 39
acetic acid. Reaction of 2-(2-iodo-5-methylphe-
nyl)acetic acid with SOCl2 in refluxing dichloro-
methane gives the corresponding acyl chlo-
ride, which is treated with dimethylamine in
diethyl ether/THF to yield 2-(2-iodo-5-meth-
ylphenyl)-N,N-dimethylacetamide. Condensa-
tion of this intermediate with 2-chloro-
6-fluoroaniline by means of Cu powder,
Cu2 I2 and K2 CO3 in refluxing xylene af-
fords 2-[2-(2-chloro-6-fluorophenylamino)-5-
methylphenyl]-N,N-dimethylacetamide, which
is finally hydrolyzed with NaOH in refluxing bu-
tanol/water to give lumiracoxib [61, 294, 295].
Clinical use: Lumiracoxib [296] is a novel
COX inhibitor with the highest COX-2 selectiv-
ity of all coxibs. The compound is structurally
related to the phenylacetic acid COX inhibitors,
has weakly acidic properties and is devoid of
the sulfonamide or methylsulfone group of the
other coxibs. The compound showed clinical ef-
ficacy against osteoarthritis [297] and rheuma-
toid arthritis [298] and inhibited acute pain re-
lated to primary dysmenorrhoea, dental or ortho-
pedic surgery, or tension-type headache [299].
40 Analgesics and Antipyretics
The compound is well tolerated and gas-
trointestinal side effects were significantly lower
than after treatment with COX-1 inhibitors like
ibuprofen or naproxen [300, 301] The meta-
analysis of all clinical trials in osteoarthritis and
rheumatoid arthritis gave no indication of an in-
creased risk of cardiovascular side effects [302].
Liver function tests showed a moderate and re-
versible increase in liver enzymes [303].
Lumiracoxib has a high oral bioavailability
of about 74 %, is rapidly absorbed, reaches its
peak plasma concentrations within 2 h and is
strongly bound to plasma protein. The com-
pound is strongly metabolized, is devoid of ac-
tive metabolites and has a plasma elimination
half-life of about 4 h [304]. Despite the short
half-life, a once-daily administration in doses of
100–400 mg is recommended. A dose of 100 mg
is used for the symptomatic relief of osteoarthri-
tis and 400 mg for short-term relief of moderate
to severe pain, associated with dental or ortho-
pedic surgery. As with other COX-2 inhibitors,
the compound should be used with appropriate
precaution.
Trade name: Prexige (EU, USA).
Parecoxib [198470-84-7], (free acid)
[198470-85-8], N-(4-(5-methyl-3-phenyl-
isoxazol-4-yl)phen-ylsulfonyl)propionamide
sodium salt C19 H17 N2 O4 SNa, M r 392.409,
crystals, mp 271.5–272.7 ◦ C.
Synthesis: The acylation of 4-(5-methyl-
3-phenylisoxazol-4-yl)benzenesulfonamide
(valdecoxib), with propionic anhydride in a so-
lution of triethanolamine (TEA) and 4-dimeth-
ylaminophenol (DMAP) in tetrahydrofuran
gives N-[4-(5-methyl-3-phenylisoxazol-4-
yl)phenylsulfonyl]propionamide, which is
treated with NaOH in ethanol to give the sodium
salt of parecoxib [79, 306, 307].
Clinical use: Parecoxib [77, 78, 80] is a third-
generation COX-2 inhibitor. Parecoxib is a pro-
drug of valdecoxib with aqueous solubility suffi-
cient for the use in parenteral formulations. The
compound induced potent pain inhibition in den-
tal, gynecological and orthopedic surgery and
produced less gastrointestinal side effects than
conventional COX-1 inhibitors [81].
Parecoxib is rapidly hydrolyzed in the liver
to its active metabolite valdecoxib. Plasma
peak concentrations for valdecoxib are achieved
within 1.1 to 3.5 and 0.27 to 2 h after i.m.
and i.v. administration, respectively. The elim-
ination half-life for parecoxib is 15 to 35 min
and 5 min for i.m. and i.v. administration, re-
spectively. Metabolism of parecoxib follows the
metabolism of the active metabolite valdecoxib
which is a substrate for CYP3A4 and CYP2C9.
Parecoxib was used in doses of 20 and 40 mg
of its sodium salt in the short-term treatment of
postoperative pain.
Parecoxib together with valdecoxib was with-
drawn from the market because of an increased
risk of cardiovascular side effects [312, 313].
Trade names: Dynastat, Rayzon, Xapit (com-
pound withdrawn from EU and US markets).
Rofecoxib [162011-90-7], 4-[4-(methyl-
sulfonyl)phenyl]-3-phenylfuran-2(5H)-one,
C17 H14 O4 S, M r 314.36.
Synthesis: Condensation of phenylacetic
acid with ethyl bromoacetate in the pres-
ence of triethylamine in THF yields ethyl
2-(phenylacetoxy)acetate, which is cyclized
to the hydroxyfuranone using potassium
tert-butoxide in tert-butanol. The reaction
with trifluorosulfonyl anhydride and diiso-
propylethylamine in CH2 Cl2 affords the
corresponding trifluorosulfonate, which by
reaction with LiBr in hot acetone yields
the bromofuranone. The coupling with 4-
(methylsulfanyl)phenylboronic acid with
Na2 CO3 and Pd[(C6 H5 )3 P]4 as catalysts in hot
toluene gives 4-[4-(methylsulfanyl)phenyl]-3-
phenylfuran-2(5H)-one, which is finally oxi-

dized with 2KHSO5 · KHSO4 · K2 SO4 (oxone)
[314].
Rofecoxib can also synthesized by several
different routes [156]. In 2001 a highly ef-
ficient synthesis of rofecoxib was described
[316]. As illustrated in the following scheme,
the acetophenone (i) is prepared according
to the literature by Friedel–Crafts acylation
with thioanisole. Oxidation with magnesium
monoperoxyphthalate hexahydrate (MMPP) af-
fords the sulfone (ii), which is reacted with
bromine in chloroform in the presence of a trace
amount of AlCl3 to give (iii). Bromoketone (iii)
is then coupled and cyclized in a second step, in
a one-pot procedure with phenylacetic acid. The
mixture of bromoacetophenone (iii) and phenyl-
acetic acid in acetonitrile was then treated with
triethylamine at room temperature to provide the
ester intermediate, subsequent cooling and addi-
Analgesics and Antipyretics 41
tion of dibutylurea (DBU) effected the cycliza-
tion to provide rofecoxib as the final product.
Clinical use: Rofecoxib [156, 317, 318] is a
second-generation selective COX-2 inhibitor. It
was the second COX-2 selective drug to reach
the market in 1999. The selectivity for COX-2
compared to COX-1 is more than 800-fold in
cellular assays and more than 10-fold in whole
blood assays [319].
Rofecoxib is used for treatment of rheuma-
toid arthritis, osteoarthritis (12.5–25 mg/d) and
pain of different origin such as postoperative
pain, dental pain, and primary dysmenorrhoea
(50 mg/d).
Rofecoxib reaches peak plasma concentra-
tions between 2 to 9 h after oral administra-
tion. It is bound about 87 % to plasma protein
and has an elimination half-life of about 17 h.
Therefore a once daily dosing is appropriate.
The main metabolites formed in the liver are
the cis-dihydro and trans-dihydro derivatives of
rofecoxib. Rofecoxib is excreted in the form
of its metabolites mainly in the urine (72 %)
with some unchanged drug excreted in the fe-
ces (14 %).
Rofecoxib shows significantly less gastroin-
testinal toxicity than ibuprofen in studies with
osteoarthritis patients [320] and compared to
naproxen in patients with rheumatoid arthri-
tis [321]. Rofecoxib does not prolong bleeding
time.
Rofecoxib was withdrawn from the market at
the end of 2004 after it had been shown that use
for a period of more than 18 month increased
42 Analgesics and Antipyretics
the risk of heart attack and stroke [31]. It is be-
ing discussed with the health authorities that a
relaunch should be possible under appropriate
safety regulations [322].
Trade name: Vioxx (EU, USA; currently
withdrawn from the market).
Valdecoxib [181695-72-7], 4-(5-methyl-
3-phenylisoxazol-4-yl)benzenesulfonamide,
C16 H14 N2 O3 S, M r 314.366; mp 172-173 ◦ C.
Synthesis: Deoxybenzoin is converted to
the corresponding oxime by treatment with
hydroxylamine under basic conditions with
sodium acetate in aqueous ethanol or in toluene
in presence of potassium hydroxide in absolute
ethanol. The treatment of the oxime under nitro-
gen with two equivalents of butyllithium in tetra-
hydrofuran is followed by cyclization in ethyl
acetate or acetic anhydride to the isoxazoline
derivative. Finally, treatment of the isoxazoline
with cold chlorosulfuric acid followed by reac-
tion of the intermediate with aqueous ammonia
affords the desired product [79–81, 156, 316,
323].
Clinical use: Valdecoxib [79, 324–326] is
a third-generation COX-2 inhibitor. It shows
about 30-fold selectivity for COX-2 in a whole-
blood assay. The compound has a very low sol-
ubility in water and can only be administered
orally. For parenteral administration, a water-
soluble prodrug derivative, parecoxib, was de-
veloped in parallel. Valdecoxib showed strong
analgesic and anti-inflammatory properties and
was developed for the treatment of osteoarthritis,
rheumatoid arthritis [327] and acute and chronic
pain of various origin [328] including migraine
headache [329].
Valdecoxib is converted in rodents and dogs,
and in a low abundance in humans, by hy-
droxylation of the methyl group to an ac-
tive metabolite (4-(5-hydroxymethyl-3-phenyl-
isoxazol-4-yl)benzenesulfonamide).
Valdecoxib induced severe allergic skin re-
actions [330, 331] which, together with an in-
creased risk of cardiovascular side effects [332]
was the reason why the compound, together with
its prodrug derivative parecoxib, was withdrawn
from the market in 2004.
Trade name: Bextra (EU, USA; currently
withdrawn from the market).
3. Centrally Acting Analgesics
3.1. Opioids
The term “centrally acting analgesics” is used
for compounds which inhibit the pain reaction
predominantly within the central nervous sys-
tem. Most of them induce a very powerful pain
inhibition and are thus named synonymously
“strong analgesics”. The most important repre-
sentatives of this group are the opioids [333]. In
respect to structural features [334] opioids can
be separated into three groups:
• The first group contains the natural products
morphine, codeine, and thebaine, which are
isolated from opium. The group contains in
addition various semisynthetic derivatives of
the three compounds, which are prepared by
chemical modifications of these natural prod-
ucts.
• The second group encompasses fully syn-
thetic compounds which often have a to-
tal different chemical structure than the
semisynthetic analogues, but interact with
the same opioid receptors and show the same
spectrum of analgesia and side effects as the
natural compounds. For both groups together
the older name “opiates“ is still in use.
• The third group consists of naturally occur-
ring and synthetic peptides with opioid-like
properties. The opioid peptides were disco-
vered during the search for endogenous lig-
ands of the opioid receptors and share the
same action and side effect profile with the
nonpeptidic compounds, but they are not in
clinical use.

Opioids interact with specific receptors (re-
ceptor ligands) and they can act as pure agonists,
as partial agonists (agonists with a reduced in-
trinsic activity) or as antagonist (binding without
intrinsic activity). Only few compounds of the
opioid family are selective ligands for a single
type of opioid receptor (Table 3). Most of them
bind with similar or different affinities to more
than one receptor type and the pharmacological
effect is the result of the combined effects on all
receptors involved. Opioids may act as a full or
partial agonist on one receptor type and as an
antagonist on the other. These compounds are
named mixed agonist – antagonists and they are
an important subgroup of opioid analgesics (see
Section 3.1.2.1). Opioid analgesics are the most
important drugs for the treatment of moderate,
severe, and very severe pain.
Humans and most animal species are
equipped with opioid receptors and endogenous
ligands. This endogenous opioid system [336] is
widely distributed within the body, it is phyllo-
genetically very old and is expressed in all ver-
tebrates. A high density of opioid receptors is
found in the brain [337] and in the spinal cord,
where it is involved in pain inhibition and ad-
ditionally in many other central regulatory pro-
cesses. In addition to the CNS localization, opi-
oid receptors are expressed in many peripheral
organs [338]. Of great importance are the opioid
receptors of the gastrointestinal system, which
regulate stomach emptying, gut motility, and
intestinal fluid secretion. Opioid receptors are
found in cells of the immune system and periph-
eral opioids seem to be involved in the regulation
of inflammatory and immunological processes
[339]. In addition to the outstanding role in the
central pain inhibition, action at peripheral opi-
oid receptors, which are expressed in high quan-
tities during inflammation and immune stimula-
tion, may add to central pain inhibition [340].
Opioid Receptor Types. Differences in
analgesic activity and in the side effect pro-
file of synthetic opioids reinforced speculations
that more than one type of opioid receptor ex-
ists and is involved in the analgesic activity of
these compounds. Martin and coworkers inves-
tigated in 1960 these differences in a specially
developed test model, the chronic spinal dog
[341] and postulated three types of opioid recep-
tors, the µ-receptor (ligand = morphine), the κ-
Analgesics and Antipyretics 43
receptor (ligand= ketazocine) and the σ-receptor
(ligand = SKF 100 81). This was later confirmed
by binding experiments with radioactive-labeled
ligands and by the different binding and action
profiles of the endogenous opioid peptides, the
enkephalins and endorphines [342]. Up to now,
three types of receptors, the µ-, κ-, and δ-opioid
receptor have been confirmed [343, 344], the σ-
receptor is no longer considered to be an opioid
receptor.
More recently, a fourth opioid receptor type,
named opioid receptor like (ORL1) receptor has
been identified [345]. The receptor was detected
as a c-DNA, which coded for a protein with
opioid receptor-like properties. Within a short
time, the endogenous ligand, a peptide named
nociceptin, was isolated, which, depending on
the place and route of application, induced pro-
nociceptive or anti-nociceptive actions. The full
spectrum of biological activity of nociceptin and
the physiological role of the ORL-1 opioid re-
ceptor in pain processing is still under investi-
gation [367].
Subtypes of the Different Opioid Recep-
tors. Corresponding to other receptor systems,
binding studies and functional investigations in-
dicate that subtypes of opioid receptors exist
[346, 347]. Within the µ-receptor two subtypes,
the µ-1 and µ-2 receptor have been described.
It was postulated by some investigators [347]
that analgesia and opioid side effects are differ-
ently distributed between µ-receptor subtypes,
which should allow separation of analgesia from
the unwanted opioid side effects. According to
Pasternak and Wood [347], analgesia should be
mediated by the µ-1 receptor site, whereas res-
piratory depression and addiction is mediated
via the µ-2 receptor subtype. But in contrast to
binding experiments, the functional separation
of the µ-1 and µ-2 subtype is more equivocal
and a clear separation of analgesia from res-
piratory depression and addiction potential had
never been found within the µ-opioids. There-
fore, a differentiation of µ-opioid analgesics ac-
cording to subtype specificity is no longer main-
tained.
The subtypes of µ-opioid receptors could
not be confirmed in cloning experiments [348].
Therefore, possible heterogeneity of opioid re-
ceptor subtypes must result from a later modifi-
cation which is independent from the gene level.
44 Analgesics and Antipyretics
Possible variations could include splice variants,
receptor association, posttranslational modifica-
tions (e.g., glycosidation) or coupling with dif-
ferent transduction mechanisms.
Endogenous Opioid Peptides. For each
class of opioid receptors endogenous ligands
of peptidic structure exist, which show a dis-
tribution within the body corresponding to that
of the receptor. Three distinct families of lig-
ands with various members have been identi-
fied and named endorphins, enkephalins, and
dynorphins (Table 2). The opioid peptides are
split off in the organism from specific precursor
polypeptides. Enkephalins are derived from pro-
enkephalin and interact with µ- and δ-opioid re-
ceptors. The precursor molecule of endorphin is
pro-opiomelanocortin (POMC), which addition-
ally releases peptidic hormones such as α-MSH,
ACTH and β-LPH. Endorphins are specific lig-
ands of the µ-opioid receptor type. Dynorphins
interact with the κ-opioid receptor and are de-
rived from pro-dynorphin. ORL binding sites
have recently been identified together with its
endogenous peptidic ligand named nociceptin
(Table 2).
Various further natural and synthetic opioid
peptides, acting as agonists or antagonist at the
different opioid receptors have been discovered.
They have the same effect and side effect profile
as their nonpeptidic counterparts. Opioid pep-
tides are only used experimentally and no com-
pound has reached clinical application.
Molecular Pharmacology of Opioid Re-
ceptors. The first successfully cloned opioid re-
ceptor was the δ-opioid receptor of the mouse,
which was in parallel described by the groups
of Kieffer [349] and Evans [350]. Both used
neuroblastoma-glioma hybridoma cells which
expressed a high density of δ-receptors in their
membrane. The isolated receptor protein con-
sisted of 372 amino acids and had a mo-
lecular mass of 40 644. The amino acid se-
quence showed a partial overlap with the recep-
tors of somatostatin (37 %), angiotensin (31 %)
and interleukine-8 (22 %). Similar to the so-
matostatin receptor, seven hydrophobic domains
were identified by which the receptor is in-
serted into the lipid bilayer of the cell mem-
brane. Shortly thereafter the rat and human δ-
receptors were cloned. With the same technique
a novel opioid-like cDNA was isolated [351],
which coded for an unknown opioid receptor.
The new receptor had many similarities with the
classical opioid receptors [352] and was added
as the forth member to the opioid receptor family
under the name ORL-1. All four opioid recep-
tors have been identified in humans. All together,
they show a high degree of structural identity,
which corresponds to their widely overlapping
biological functions [348, 353].
All opioid receptors belong to the group
of pertussis toxin sensitive G-protein-coupled
receptors of the rhodopsin family with seven
transmembrane spanning hydrophobic domains.
The N-terminal part is oriented to the outer side
of the cell membrane and is involved in the selec-
tion and binding of the receptor specific ligands.
Studies with chimeric or point mutated recep-
tors indicate that predominantly the second and
third extracellular loop determines receptor se-
lectivity. The N-terminal sequence contains sev-
eral free amino groups which can be conjugated
with sugar residues. The carboxy-terminal is di-
rected into the inner part of the cell and is in-
volved in the signal transduction cascade. The
carboxy-terminal contains groups which can be
phosphorylated and which are involved in recep-
tor internalization and inactivation. The seven
transmembrane regions are connected by extra-
cellular and intracellular loop regions of differ-
ent length. Comparing the sequence of the µ-, δ-,
and κ-receptor reveals that the highest degree
of similarity is located in the transmembrane
regions and in the intracellular loop, whereas
the external loops and both terminal regions are
more heterogeneous. The external loops and the
terminal part are involved in the selection and
binding of the ligands and contain the structural
elements, which determine the receptor selectiv-
ity.
Transduction Mechanisms of Opioid Re-
ceptor Interaction. As described above, all
four receptor types belong to the group of G-
protein-coupled receptors (GPCRs) [354]. Ag-
onistic binding at the receptor induces associ-
ation of the α-, β-, and γ- subunit of the G-
protein which triggers several biochemical reac-
tions within the cell [355–358]. Most important
for the pharmacological effects of the opioids
are:

Table 2. Mammalian endogenous opioid peptides
Precursor Endogenous peptide
Pro-opiomelanocortin β-endorphin
Pro-enkephalin [MET]enkephalin
[LEU]enkephalin
Pro-dynorphin dynorphin A
dynorphin B
α-neoendorphin
β-neoendorphin
Pro-nociceptin/OFQ a Nociceptin
a
OFQ = orphanin FQ.
• Activation of a hyperpolarizing K+ channel
(inward rectifying K+ channel)
• Inactivation of voltage-dependent Ca2+
channels (N-, P- and R-type)
• Inhibition of adenylate cyclase
A further relevant mechanism involved in the
inhibition of synaptic transmission by opioids
is a direct impairment of the exocytotic release
of neurotransmitters, induced by stabilization of
the presynaptic membrane.
Additional actions with only partially un-
derstood relevance are activation of phospholi-
pases (PLH2, PLC7), activation of MAP kinases
and activation of some voltage dependent Ca2+
channels (L-type and T-type).
As a result of these actions opioids inhibit
neurotransmission at the presynaptic and post-
synaptic site. The presynaptic inhibition mostly
depends on the direct inhibitory effect on trans-
mitter exocytosis from membrane-associated
storage vessels. This direct effect is increased by
the inhibition of Ca2+ channels, since Ca2+ ions
trigger the transmitter release. Activation of K+
ions induces membrane hyperpolarization and
this is the most important action component for
postsynaptic inhibition.
Activation of K+ channels, inactivation of
2+
Ca channels and direct inhibition of neuro-
transmitter release are powerful mechanisms by
which opioids inhibit the neuronal transmission
of the pain signal.
Opioid receptors are not only located at ex-
citatory synapses, but are likewise expressed at
inhibitory neurons. At these synapses, opioids
inhibit the transmission of the inhibitory signal,
and this inhibition of inhibition as the result,
induces excitation and an increased release of
neurotransmitters in the innervated neuron.This
Analgesics and Antipyretics 45
Amino acid sequence
YGGFMTSEKSQTPLVTLFKNAIIKNAYKKGE
YGGFM
YGGFL
YGGFLRRIRPKLKWDNQ
YGGFLRRQFKVVT
YGGFLRKYPK
YGGFLRKYP
FGGFTGARKSARKLANQ
explains why opioids, in addition to their promi-
nent inhibitory actions, have some stimulant ef-
fects, too.
Relation of the Biological Effect to the Opi-
oid Receptor Type. The peptide structure of the
four different opioid receptors is very similar
[348] and this is the reason why most of the opi-
oid receptor ligands show affinity for more than
one type of receptor. In most cases, one type is
preferred and the action and side effect profile is
dominated by the properties of this receptor. A
huge chemical effort was necessary to develop
receptor-specific “selective“ ligands, but nowa-
days several selective agonists and antagonists
for each type of opioid receptor exist (Table 3).
µ-Opioid Receptors. Binding experiments
and investigations in pain models have shown
that predominantly the µ-receptor and to a lesser
degree the κ-and d-receptors mediate pain inhi-
bition. Most of the clinically used opioid anal-
gesics [359] have prevalence for the µ-opioid
receptor and this confirms that µ-receptor activa-
tion is the common pain inhibiting mechanism of
these compounds. Since morphine is the proto-
type, they are called “morphine-like”analgesics.
Their side effect profile includes respiratory de-
pression, constipation as well as addiction and
dependence. All these effects, corresponding to
analgesia, are mediated via µ-opioid receptor
activation. This is the reason why the primary
goal of the development of synthetic opioids, the
separation of analgesia from the addiction and
dependence potential, has never been achieved.
The involvement of the same receptor popu-
lation in analgesia and side effect profile of
morphine and morphine-like opioids was im-
pressively confirmed in µ-knockout mice [360,
46 Analgesics and Antipyretics
Table 3. Opioid receptor specifity
Receptor type Selective ligands
Agonist Antagonist
MOR morphine CTOP
µ- fentanyl
methadone
DAMGO
KOR enadoline nor-BNI
κ- U50,488
dynorphin
DOR DPDPE naltrindol
δ- SNC-80
MOR = mu-opioid receptor. KOR = kappa-opioid receptor. DOR = delta-opioid receptor. DAMGO = [d-Ala2 , MePhe4 ,
Gly(ol)5 ]enkephalin. Enadoline = (5R)-(5α,7α,8β-(-)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxaspiro[4,5]dec-8-yl)-4-benzofuranacetamide,
previously CI977. U50,488 = trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methanesulfonate. DPDPE
= [d-Pen2 , d-Pen5 ]enkephalin. SNC-80 =
(+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide. CTOP =
d-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 . nor-BNI = nor-binaltorphimine.
361]. In these animals, morphine did neither
show an analgesic effect nor side effects. There
was no respiratory depression and no inhibi-
tion of gastrointestinal motility and secretion.
In behavioral models in µ-knockouts, morphine
did not induce liking or any other signs of ad-
diction and repeated treatment with morphine
did not produce signs of tolerance and physical
dependence.
κ-Opioid Receptors. Activation of κ-
receptors induces a clinically relevant pain in-
hibition [362, 363], which seems to be less
efficacious than µ-receptor mediated analge-
sia. κ-Receptor interaction is a common action
component of the so-called partial opioid ago-
nists or agonists – antagonists, such as penta-
zocine, nalbuphine, and butorphanol (see Sec-
tion 3.1.1.1). The most prominent side effects of
κ-activation are sedation and diuresis. In con-
trast to µ-agonists, which induce well-being and
euphoria, activation of κ-receptors in the limbic
system induces dysphoria and other unpleasant
psychic effects, such as hallucinations and spa-
tial disorientation. The dose range of analgesia
and psychic side effects partly overlap and this
interferes with the medical use of κ-receptor ag-
onists. In compounds with a marked κ-agonistic
component (cyclazocine, nalorphine) the dys-
phoric side effects are so prominent that the
compounds could not be used for therapeu-
tic purposes. This may explain why despite an
intensive search for κ-selective analgesics, no
selective κ-agonist has ever reached the clinical
use.
Nonselective ligands
Agonist Antagonist
levorphanol naloxone
etorphine naltrexone
levorphanol naloxone
etorphine naltrexone
levorphanol naloxone
etorphine naltrexone
δ-Opioid Receptors. In contrast to µ- and κ-
receptors, indications for a prominent role of δ-
receptors in the pain process are less obvious
[364, 365]. There is a broad but still controversial
discussion concerning a genuine analgesic effect
mediated by δ-1 or δ-2 receptors, because anal-
gesia is scarcely observed in compounds with
pure δ-agonistic activity.
ORL-1 Receptors. The ORL-1 receptor [352,
366] differs in its peptide sequence from the clas-
sical opioid receptors. In contrast to these, ORL-
1 receptor activation at least at the supraspinal
level has a pronociceptive effect and induces
pain. Supraspinally induced release of spinal
CCK-8, NMDA or PGE-2 is discussed as the
mechanism of pronociceptive activity. Spinal
application of nociceptine incontrary induces
anti-nociception. With the aid of nonpeptidic
ORL-1 agonists and antagonists, which are cur-
rently under development, it will be possible to
elucidate the contribution of the ORL-1 opioid
system to pain processing and to other physio-
logical processes [367].
Location of Opioid Receptors in the Pain
Pathway. The endogenous opioid system [368]
is the most important component of the pain in-
hibitory system of the body. Opioids act at dif-
ferent levels of the pain pathway and their action
interferes with different aspects of the pain pro-
cessing [369, 370].
Opioids induce:
• Inhibition of the transmission of the pain sig-
nal

• Inhibition of the emotional aspect of pain
• Inhibition of pain realization
Pain processing is inhibited at the spinal and
supraspinal level. Spinal opioid receptors are lo-
cated pre- and postsynaptically at interneurons
of the substantia gelatinosa of the dorsal horn.
The opioid interneurons inhibit the release of
excitatory transmitters and reduce the transmis-
sion of the pain signal from the primary afferents
to the secondary neurons of the spinal ascending
pain pathway. Supraspinally, opioids are located
in different regions of the brainstem, in the peri-
aquaeductal grey matter, in the limbic system, in
the thalamic nuclei, in the basal ganglia, and in
the cortex. Cortical and thalamic localization is
involved in the perception of the pain stimulus,
cortical regions in addition in the localization of
the origin of the pain focus.
Opioids in the different parts of the limbic
system suppress the emotional component of
pain and the pain suffering. In the formatio retic-
ularis, they inhibit the pain induced activation of
autonomous functions, such as increase in respi-
ration, increase in blood pressure and sweating.
Inhibitory actions at the formatio reticularis are
the origin of the most prominent side effects of
the opioids, like respiratory depression, brady-
cardia and the centrally mediated part of the gas-
trointestinal inhibition.
In addition to the inhibitory effect at the as-
cending pain transmission, opioids activate a
descending pain inhibitory system, which orig-
inates from different centers of the pons and
medulla, such as nucleus coeruleus, areas of the
periaquaeductal grey matter, and areas of the
raphe nuclei. The descending nerve fibers termi-
nate at the spinal interneurons in noradrenergic
and serotoninergic inhibitory synapses, which
suppress the ascending pain signal. Thus, opi-
oids inhibit the spinal pain processing by two
mechanisms, one is a direct pre- and postsynap-
tic inhibition of the ascending pain pathway and
the other is a centrally-mediated activation of the
descending pain inhibitory system.
Use of Opioids in Pain Treatment. Opioids
are used for the treatment of moderate to se-
vere or very severe pain of acute or chronic type
[371]. Nearly all forms of pain are sensitive to
opioid treatment and in contrast to traditional
opinions even neuropathic pain is reasonably
sensitive to higher doses of opioids. This was
Analgesics and Antipyretics 47
clearly shown in well-controlled clinical stud-
ies [372]. The most important use of opioids
in acute pain treatment is postoperative pain,
whereas treatment of cancer pain, often accom-
panied by a neuropathic pain component, is the
classical domain of chronic opioid treatment.
Opioid Side Effects.
Respiratory Depression. Opioids induce
respiratory depression via inhibition of the res-
piratory center of the medulla oblongata, which
respond to the pCO2 content of the blood [373,
374]. The inhibitory effect is more prominent in
respect to the respiratory frequency than to the
volume of respiration. At higher opioid dosages,
respiration becomes irregular and grasping oc-
curs. In awake persons, respiratory depression
by opioids can be voluntarily compensated over
a broad dose range. Respiratory impairment is
not a prominent feature in awake pain patients,
because pain itself is a strong stimulus for res-
piration.
Opioid-induced respiratory depression is
augmented by other CNS-depressant com-
pounds such as sedatives and hypnotics. Res-
piratory depression becomes an important side
effect when opioids are used for postoperative
pain treatment, because the anesthetic agent and
most adjuncts of anesthesia induce a long last-
ing depressant effect on respiration, which can
increase the opioid effects up to respiratory ar-
rest. Therefore a careful supervision of respira-
tion during the postoperative period is manda-
tory [375]. Opioid-induced respiratory depres-
sion can be interrupted by the opioid antagonist
naloxone. Naloxone has a short duration of ac-
tion and repeated applications may be necessary
to successfully counteract the effect of longer
acting opioids. Highly potent opioids induce se-
vere respiratory depression in the higher dose
range. In addition, they induce a stiffness of the
chest musculature [376], called chest rigidity or
“wooden chest”, which is mediated via stimula-
tion of dopamine release in the nucleus cauda-
tus. Chest rigidity further increases the respira-
tion impairment by these compounds. Therefore
higher doses of potent opioids such as fentanyl
and analogues, as used for anesthesia, need arti-
ficial or at least assisted ventilation.
Cardiovascular Effects. Nearly all opioids
induce bradycardia [377], most likely mediated
48 Analgesics and Antipyretics
via central stimulation of the vagus nerve. The
cardiovascular depression of most opioids is
moderate and only the stronger opioids of the
fentanyl group induce a more prominent effect.
Morphine and some analogues induce a non-
opioid receptor mediated release of histamine,
which can result in a decrease in blood pressure
and a compensatory tachycardia.
Gastrointestinal Effects. Opioids induce an
inhibitory effect on gastrointestinal motility and
fluid secretion [378]. The effect is peripherally
and centrally mediated. The peripheral part is
related to µ- and κ-receptors at intestinal or-
gans, which are densely equipped with opioid
receptors. The receptors are located at parasym-
pathic ganglions and inhibit the release of acetyl-
choline, which stimulates the contraction of the
smooth muscles. Inhibition of the intestinal fluid
secretion is mediated via inhibition of adenylate
cyclase. The intestinal effects of opioids extend
to all parts of the gut and results in inhibition
of stomach emptying and inhibition of secretion
and motility in the duodenum, jejunum, colon,
and rectum.
Reduced motility and secretion can let to con-
stipation, which is the most prominent side ef-
fect of chronic opioid treatment [379]. Opioid-
induced constipation can increase up to mega-
colon or paralytic ileus. Therefore chronic opi-
oid treatment should be accompanied by con-
comitant use of laxatives. Besides their periph-
eral actions, opioids are involved in the central
regulation of intestinal functions which is lo-
cated in the formatio reticularis. This explains
why the intestinal side effects of opioids are not
restricted to the more hydrophilic compounds
such as morphine, but are seen likewise in the
more centrally active lipophilic analogues. Dur-
ing chronic opioid treatment a varying degree of
tolerance towards the intestinal side effects may
occur.
The intestinal inhibitory action of opioids can
be used for the treatment of diarrhea [380]. The
clinically most important antidiarrheal opioid is
loperamide [381]. After oral administration, lop-
eramide acts locally within the gastrointestinal
tract. After parenteral administration, the com-
pound is rapidly inactivated and does not reach
the CNS. Therefore loperamide does not show
the typical central opioid side effects, has no
analgesic action and has no abuse potential.
Emetic Activity. Nausea and emesis are com-
mon unpleasant side effects of opioids [382,
383]. They are most intensively experienced at
the beginning of the treatment. During chronic
application, tolerance may occur, which reduces
the emetic sequelae. Nausea and emesis are in-
duced via activation of chemoreceptors, which
are located in the trigger zone of the area
postrema of the formatio reticularis. The recep-
tors are located at the tissue surface and contact
the circulating blood. Thus the emetic effect of
opioids is not mediated centrally, which means
after penetration of the blood – brain barrier, but
rather peripherally via the part of the compound,
which is distributed in the circulating blood.
After passage through the blood – brain bar-
rier, opioids have an antiemetic effect [384]. The
emesis inhibition is induced via blockade of an
emesis center located in a more central area
of the formatio reticularis. This explains why
the emetic effect of opioids is most prominent
immediately after application, especially after
rapid intravenous administration and is reduced
or terminated when the compound has reached
the CNS. The more hydrophilic opioids such as
morphine have stronger emetic side effects than
lipophilic compounds like methadone or fen-
tanyl [385], which are rapidly transported into
the CNS.
Tolerance and Dependence. µ-Opioid com-
pounds induce a feeling of well being and eu-
phoria, which is mediated by the release of
dopamine within the limbic system. κ-Opioids
induce an opposite effect with dysphoria, dis-
orientation, and hallucinations [386]. Repeated
activation of the µ-opioid rewarding system
may induce a psychological dependence, which
leads to addiction and a compulsory behavior of
drug seeking [387]. In addition, higher opioid
dosages, as used for nonmedicinal purposes, in-
duces tolerance and as a consequence a further
increase of the dose to achieve the intended ef-
fect. In the course of the tolerance development
opioid users becomes physically dependent on
the supply of the compound [388] and suspen-
sion of the treatment or blocking of the opi-
oid receptors with an antagonist induces a with-
drawal reaction, characterized by strong dyspho-
ria, restlessness, pain, and various symptoms of
autonomic dysregulation, like diarrhea, shiver-
ing, chills and cardiovascular collapse.

The euphorigenic effect of opioids, the
“opioid kick”, is more intensely induced by
lipophilic compounds such as diacetylmorphine
(heroin), which rapidly penetrates into the CNS.
The feeling of euphoria on the one hand and the
absence of well-being on the other hand is more
prominent when brain concentrations of the opi-
oid change rapidly. This intensifies drug seeking
behavior and psychological as well as physical
dependence.
In contrast to recreational use, chronic pain
treatment with opioids afforts constant dosing
and has only a limited risk to induce psycho-
logical dependence and drug addiction [389]. A
proper dosing during chronic pain treatment can
often postpone tolerance development for longer
time periods. The most important precaution to
avoid tolerance and dependence development is
to ensure constant plasma levels of the opioid,
which have to be high enough to give complete
pain relief. This can be reasonably achieved by
oral administration of retarded formulations or
by an opioid patch [390]. Breakthrough pain,
which is often induced by a fluctuation in pain
intensity, should be rapidly compensated by ad-
ditional treatment with an immediate release for-
mulation of the same or a similar opioid.
3.1.1. Opioids in Clinical Use
3.1.1.1. Morphine and Morphinane
Derivatives
Morphine [57-27-2], (5α,6α)-7,8-di-
dehydro-4,5-epoxy-17-methylmorphinan-3,6-
diol, C17 H19 NO3 , M r 285.34, mp 254 ◦ C (de-
comp., 197 ◦ C is reported for a metastable
25
phase), [α]D −132◦ (c = 1, CH3 OH); hy-
drochloride [52-26-6], C17 H19 NO3 · HCl,
25
M r 321.80, mp 200 ◦ C (trihydrate), [α]D
◦
−113.5 (c = 2.2, water); sulfate (2 : 1) [64-
31-3], C17 H19 NO3 · 1/2 H2 SO4 , M r 668.76;
sulfate pentahydrate [6211-15-0], C17 H19 NO3 ·
1/2 H2 SO4 · 5H2 O, M r 758.85, mp 250 ◦ C (de-
25
comp.), [α]D −108.7◦ (c = 4, water). Mor-
phine is the main alkaloid of opium, isolated
from the milky liquid of the poppy seed capsule
[108].
Preparation: Morphine is obtained by extrac-
tion of poppy capsules or opium (opium contains
9–14 % morphine, depending on the source)
Analgesics and Antipyretics 49
with water, precipitation with aqueous Na2 CO3 -
solution, washing of the precipitate with ethanol
and dissolving in diluted acetic acid [392–395].
Morphine in the conventional presentation
(left) and in a stereoformula according to IU-
PAC rules (right)
The total synthesis of (-)-morphine had been a
challenging target for organic chemists for many
decades [316, 334, 396]. Although a number of
successful syntheses were developed, only a few
could produce the compound in an enantio- and
diastereo-controlled manner [397–399].
Morphine biosynthesis: The studies on the
biosynthesis of morphine have been performed
on cell cultures mainly of Coptis japonica and
species of Thalictrum. The overall biosynthetic
pathway from tyrosine to morphine is depicted
in Figure 3.
Opioid receptor binding: Morphine has a
high (nanomolar) binding affinity for the µ-
opioid receptor. The affinity for the δ- and κ-
opioid receptor is at least 10-fold lower.
Clinical use: Morphine is a very potent anal-
gesic and still the “gold standard” for the treat-
ment of severe, acute, and chronic pain [400].
The compound is used in various salt forms,
preferentially as the hydrochloride or sulfate.
Morphine can be administered orally or par-
enterally. Oral administration is preferred for
chronic pain treatment and various slow-release
forms have been developed to reduce the ap-
plication frequency to 1–2 times per day. Par-
enterally, morphine is used in doses of 10
mg mostly for postoperative pain and self-
administration devices have been developed for
patient-controlled analgesia (PCA).
Other morphine preparations are under eval-
uation for local administration, e.g., inhalation
via the broncho-pulmonal way.
Pharmacokinetic properties: Morphine is ex-
tensively metabolized by glucuronidation at
both hydroxyl groups at positions 3 and 6 and by
N-demethylation [401, 402]. The 3-glucuronide
has a minimal opioid receptor binding affinity
50 Analgesics and Antipyretics

Figure 3. The overall biosynthetic pathway from tyrosine to morphine


and is devoid of analgesic action, whereas the
morphine-6-glucuronide has a similar binding
affinity as morphine, is analgesically active and
seems to be involved in pain inhibition during
chronic oral treatment with morphine [403]. De-
spite the polar sugar residue the glucuronide can
pass the blood – brain-barrier. The morphine-
6-glucuronide is being tested as an indepen-
dent opioid analgesic. The N-demethyl deriva-
tive normorphine is analgesically active, but has
a lower µ-receptor affinity, a lower potency and
a shorter duration of action than morphine. Nor-
morphine is not in clinical use.
The main metabolites of morphine are shown
in Figure 4.
Figure 4. Metabolic pathway of morphine
Side effects: Morphine induces a variety of
centrally and peripherally mediated side effects.
Most important after parenteral administration
is respiratory depression, especially in the post-
operative situation. Chronic oral administration
induces constipation and chronic treatment with
oral morphine has to be supplemented with lax-
Analgesics and Antipyretics 51
atives. Other frequent side effects are nausea,
vomiting, dizziness, and sedation.
Morphine is a controlled substance. It has a
high euphorigenic potential and is liable to abuse
and dependence. The euphorigenic effect is less
expressed in the context of pain treatment and
tolerance and dependence can largely be avoided
by appropriate dosing and application intervals,
securing constant and pain-appropriate plasma
levels of the compound.
Trade names: M-Long (Germany), MST con-
tinuous (Germany, UK), Capros (Germany), Ka-
panol (Germany, USA), Moscontin (France), In-
fumorph (USA), Oxamorph (USA).
Morphine is also marketed in many generic
formulations.
Codeine [76-57-3], C18 H21 NO3 , M r
299.36, mp 154–156 ◦ C (monohydrate from wa-
ter or diluted alcohol), anhydrous form sublimes
25
at 140–145 ◦ C and 133.32 Pa, [α]D −136◦
(c = 2, CH3 CH2 OH); monohydrate [6059-47-
8], C18 H21 NO3 · H2 O, M r 317.38, mp 154–
156 ◦ C; hydrochloride dihydrate C18 H21 NO3 ·
HCl · 2 H2 O, M r 371.86, mp 280 ◦ C (decomp.),
[α]D − 108◦ ; hydrobromide dihydrate [125-25-
7], C18 H21 NO3 · HBr · 2 H2 O, M r 416.31, mp
190–192 ◦ C (anhydrous), [α]D − 96.6◦ ; phos-
phate [52-28-8].
Preparation: Codeine is extracted from
opium (concentration in opium 0.7 to 2.5 %, de-
pending on the source), but mostly prepared by
methylation of morphine in a phase transfer re-
action [404, 405].
52 Analgesics and Antipyretics

Opioid receptor binding: Codeine has a low

affinity at µ-, δ-, and κ-opioid receptors and the
in vivo effects are predominantly induced by me-
tabolization to morphine [55].
Clinical use: Codeine [407] is an O-methyl
analogue of morphine. It has a morphine-like
action profile but a 5–10 times lower potency.
Codeine has a good oral availability and oral
administration forms are used for the treatment
of mild to moderate pain and as antitussive (→
Cough Remedies, Section 2.1.1). In therapeu-
tic dosages, codeine produces fewer opioid-type
side effects than morphine and has only a low
risk of abuse. The lower abuse and dependence
can be explained by the fact that the opioid ac-
tion is only available after metabolic activation. Clinical use: Ethylmorphine (→ Cough
High codeine doses can induce excitement and Remedies, Section 2.1.1) is the ethyl congener
convulsions. of codeine and has a similar therapeutic applica-
The compound is extensively metabolized tion. It has a low opioid receptor affinity and is
by O- and N-demethylation followed by glu- metabolized to the active metabolites morphine
curonidation. The main metabolites are nor- and normorphine. Ethylmorphine can be used
codeine, morphine, and hydrocodeine and their as cough suppressant, medium-potent analgesic,
glucuronides. There are indications [408] that and anti-diarrheal agent. Today the compound is
the analgesic effect is reduced in poor metabo- widely out of therapeutic use, but is often used
lizers with a low CYP2D6 activity. as clinical reagent to characterize the metabolic
Codeine is used in the form of different salts N-dealkylation activity of CYP3A4 [411, 412].
like hydrochloride, phosphate and sulfate. To in- Trade names: Codethyline (Belgium), Tra-
crease the duration of action, slow-release prepa- chyl (France), Collins Elixir (UK).
rations have been developed. Codeine salts are
frequently combined with non-opioid analgesics Diacetylmorphine [561-27-2], diamor-
such as paracetamol, acetylsalicylic acid, or di- phine, heroin, C21 H23 NO5 , M r 369.41, mp
clofenac. 25
173 ◦ C, [α]D −166◦ (c = 1.49, CH3 OH);
Trade names: Codipront (Germany), Codi-
hydrochloride monohydrate [561-27-2],
caps (Germany), Codimal (USA).
C21 H23 NO5 · HCl · H2 O, M r 423.89, mp 243–
Combination with paracetamol: Co-Tylenol 25
(USA). 244 ◦ C, [α]D −156◦ (c = 1.044).
Combination with Diclofenac: Combaren Synthesis: Diamorphine is prepared by acety-
(USA). lation of morphine with acetic anhydride [413].
Codeine is also marketed in many generic for-
mulations.

Ethylmorphine [76-58-4], (5α,6α)-

7,8-didehydro-4,5-epoxy-3-ethoxy-17-methyl-
morphinan-6-ol, C19 H23 NO3 , M r 313.40, mp
199–201 ◦ C; hydrochloride dihydrate [6746-
59-4], C19 H23 NO3 · HCl · H2 O M r 385.89, mp
123 ◦ C (decomp.), anhydrous form melts at
170 ◦ C (decomp.). Opioid receptor binding: Diamorphine [414]
Synthesis: Ethylmorphine is synthesized by has a 10- to 100-fold lower µ-opioid receptor
ethylation of morphine with ethyl benzenesul- binding affinity than morphine. The relevant opi-
fonate [48, 409, 410]. oid properties originate from the high µ-receptor

affinity of the metabolites 6-acetylmorphine and
morphine [415].
Clinical use: Diamorphine [416] is a
lipophilic morphine derivative which rapidly
penetrates into the central nervous system,
where 6-acetylmorphine and morphine are re-
leased [417, 418]. The rapid brain access induces
an immediate onset of action and this seems to be
the reason for the strong euphorigenic effect and
the high abuse potential. Because of the wide-
spread abuse, therapeutic application is prohib-
ited in many countries including Germany and
the US. In other countries like the UK, parenteral
heroin is used for the relief of severe pain, espe-
cially in terminal illness. The compound is more
potent than morphine, but has a similar action
and opioid side effect profile.
Trade name: Diagesil (UK).
Dihydrocodeine [125-28-0], (5α,6α)-
4,5-epoxy-3-methoxy-17-methylmorphinan-6-
ol, C18 H23 NO3 , M r 301.38, mp 112–113 ◦ C;
tartrate (1 : 1) [5965-13-9], C18 H23 NO3 ·
C4 H6 O6 , M r 451.47, mp 192–193 ◦ C (com-
mercial medicinal grade usually melts at 186–
25
190 ◦ C, [α]D −72◦ to −75◦ (c = 1.0, water).
Synthesis: Hydrogenation of codeine yields
dihydrocodeine [48, 419, 420].
Opioid receptor binding: Dihydrocodeine
has a low µ-opioid receptor binding affin-
ity and opioid properties are mostly due to
metabolic activation to the demethyl derivative
dihydromorphine.
Clinical use: Dihydrocodeine has codeine-
like analgesic and antitussive properties and is
used for the treatment of moderate to severe pain
Analgesics and Antipyretics 53
[421] and as antitussive [422] (→ Cough Reme-
dies, Section 2.1.1). Dihydrocodeine is mostly
used as oral immediate- or sustained-release for-
mulations [423]. For pain treatment the dose
range is 30–80 mg, for cough inhibition doses
are in the range of 10 mg.
Dihydrocodeine induces morphine-like side
effects, but the intensity is less pronounced.
Chronic treatment may produce dependence,
and abuse by opioid addicts has been reported.
Trade names: Paracodin (Germany), Di-
codin (France), DHC Continus (UK), Synalgos
(USA).
Etorphine [14521-96-1], [5α,7α(R)]-4,5-
epoxy-3-hydroxy-6-methoxy-α,17-dimethyl-
α-propyl-6,14-ethenomorphinan-7-methanol,
C25 H33 NO4 , M r 411.53, mp 214–217 ◦ C; hy-
drochloride [13764-49-3], C25 H33 NO4 · HCl,
M r 447.99, mp 266–267 ◦ C.
Synthesis: Starting from thebaine etorphine
can be synthesized in a similar way as buprenor-
phine (see page 66) [424–427].
Opioid receptor binding: Etorphine [428] has
a high affinity and selectivity for the µ-opioid re-
ceptor.
Clinical use: Etorphine [429] is an extremely
strong and rapid-acting µ-opioid with a potency
400–1000-fold higher than morphine. The com-
pound is very rapidly absorbed through skin and
mucosa and extraordinary care is necessary to
avoid contamination during medical use. Nalox-
one or diprenorphine can be used as antago-
nist. Etorphine induces strong central nervous
depression and is mostly used in veterinary prac-
tice for immobilization or pain treatment of big
animals [430]. Etorphine is only used parenter-
ally.
Trade name: Immobilon (UK).
Hydrocodone [76-42-6], (5α)-4,5-
epoxy-3-methoxy-17-methylmorphinan-6-one,
54 Analgesics and Antipyretics
C18 H21 NO3 , M r 299.36, mp 198 ◦ C; hy-
drochloride [25968-91-6], C18 H21 NO3 · HCl,
M r 335.83; hydrochloride monohydrate [124-
90-3], C18 H21 NO3 · HCl · H2 O, M r 353.85,
27
mp 185–186 ◦ C (decomp.), [α]D −130◦ (c =
2.877); bitartrate hemipentahydrate [34195-34-
1], C18 H21 NO3 · C4 H6 O6 · 5/2 H2 O, M r 494.5,
mp 118–128 ◦ C.
Synthesis: Palladium or platinum catalyzed
isomerization of codeine yields hydrocodone
[48, 431, 432].
Opioid receptor binding: Hydrocodone has a
µ-opioid receptor binding affinity that is 10- to
100-fold higher than that of codeine [433]. In
contrast to codeine, the compound itself has a
relevant µ-opioid receptor affinity and is, in ad-
dition to the active metabolite hydromorphone,
responsible for analgesia and other opioid prop-
erties.
Clinical use: Hydrocodone [420] is an opioid
related to codeine with analgesic and marked an-
titussive properties. The compound is more po-
tent than codeine and is used in oral doses of 5
to 10 mg for the treatment of moderate to mod-
erately severe pain. Combinations with parac-
etamol or other COX inhibitors are common, as
well as multi-ingredient preparations as antitus-
sives. Hydrocodone induces side effects similar
to codeine and morphine and has an appreciable
abuse and dependence potential [434].
Trade names: Dicodid (Germany, UK), Vi-
codin (USA).
Combination with paracetamol: Zydone
(USA), combination with ibuprofen: Vicopro-
fen (USA).
Hydromorphone [466-99-9], (5α)-4,5-
epoxy-3-hydroxy-17-methylmorphinan-6-one,
C17 H19 NO3 , M r 285.34, mp 266–267 ◦ C;
monohydrochloride [71-68-1], C17 H19 NO3 ·
HCl, M r 321.80.
Synthesis [48, 435, 436]:
Morphine is hydrogenated over a palladium
catalyst, and the resulting dihydromorphine is
oxidized with benzophenone and potassium
tert-butoxide. Alternative oxidants are cyclo-
hexanone with aluminum tri(tert-butoxide) or
aluminum triphenoxide.
Opioid receptor binding: Hydromorphone
has a high affinity and selectivity for the µ-opioid
receptor, the µ-affinity is about 10-fold higher as
compared to morphine.
Clinical use: Hydromorphone [437] is a
morphine derivative with an analgesic potency
higher than morphine. It is used as hydrochloride
parenterally or orally in the dose range of 2–4
mg to treat moderate to severe pain [438] or as
a syrup for cough inhibition. Hydromorphone
shows the typical morphine-like side effect pro-
file and has a relatively high potential for addic-
tion and dependence [439].
Trade name: Dilaudid (Germany, UK, USA),
Palladone (USA).
Levorphanol [77-07-6], 17-methylmorphi-
nan-3-ol, (−)-3-hydroxy-N-methylmorphinan,
C17 H23 NO, M r 425.48, mp 198–199 ◦ C,
20
[α]D −56◦ (c = 3, CH3 CH2 OH); tartrate di-
hydrate [5985-38-6], C17 H23 NO · C4 H6 O6 · 2
H2 O, M r 257.37, mp 113–115 ◦ C (anhydrous
20
mp 206–208 ◦ C), [α]D −14◦ (c = 3, water).
Synthesis: The analgesic activity of racemor-
phan is due to the (−) isomer, levorphanol,
which is obtained by resolving the racemate
with (+)-d-tartaric acid. The resolution can also
be performed on the intermediate 1-(4-methoxy
benzyl)-1,2,3,4,5,6,7,8-octahydro isoquinoline
(1) prior to N-methylation [48, 440–443].

Opioid receptor binding: Levorphanol is a µ-
selective synthetic opioid with a higher receptor
affinity than morphine [225].
Clinical use: Levorphanol [445] is a strong
analgesic used as tartrate for parenteral and oral
administration. Parenterally, levorphanol is 4–
5 times more potent than morphine. After oral
administration, the compound has a long du-
ration of action (up to 8 h). Levorphanol has a
morphine-type side effect profile with prominent
respiratory depression in the high dose range.
Analgesics and Antipyretics 55
The compound induces morphine-type addic-
tion and dependence [446].
Trade name: Levo-Dromoran (USA).
Oxycodone [76-42-6], (5α)-4,5-epoxy-14-
hydroxy-3-methoxy-17-methylmorphinan-6-
one, 14-hydroxydihydrocodeinone, dihydrone,
dihydrohydroxycodeinone, C18 H21 NO4 , M r
315.36, mp 218-220 ◦ C; hydrochloride [124-
90-3], C18 H21 NO4 · HCl, M r 351.81, mp 270–
20
272 ◦ C (decomp.), [α]D −125◦ (c = 2.5, water).
Synthesis [48, 447, 448]: Thebaine is ox-
idized with hydrogene peroxide to 14-hy-
droxycodeinone [449, 450], which is hydro-
genated directly or via its oxime, or its bromi-
nation products to oxycodone. The reduction
of 14-hydroxycodeinone can also be performed
with sodium hydrosulfite. Alternatively, 14-hy-
droxycodeinone is prepared by oxidation of
codeine (see next page, top).
Opioid receptor binding: Oxycodone [433] is
a µ-selective opioid with a 10-fold higher recep-
tor affinity than codeine. Both the parent com-
pound and the high affinity metabolite oxymor-
phone mediate the opioid effects of the com-
pound [451].
Clinical use: Oxycodone [452] is an orally
active opioid analgesic for the treatment of mod-
erate to moderately severe pain. The compound
is used as hydrochloride in a dose range of 5–
10 mg and is often combined with paracetamol
or other COX-inhibitors. Higher dosages and
oral slow-release preparations [453] are used
for the control of severe pain. Oxycodone has
a morphine-like side effect profile. Respiratory
depression has been found in children. The com-
pound has a relevant abuse and dependence po-
tential and illicit use of the retarded prepara-
tions is reported. To obviate misuse, abuse deter-
rent formulations (ADF) and combinations with
naloxone and naltrexone are under development.
Trade names: Eukodal (Germany), Eubine
(France), Proladone (UK),Roxicodone, Oxy-
Contine (USA), Oxygesic (Germany)
Combination with ibuprofene: Combunox
(USA).
Oxymorphone [76-41-5], (5α)-4,5-
epoxy-3,14-hydroxy-17-methylmorphinan-
6-one, dihydrohydroxymorphinone, di-
hydro-14-hydroxymorphinone, 14-hydroxydi-
hydromorphinone, C17 H19 NO4 , M r 301.34, mp
56 Analgesics and Antipyretics

248–249 ◦ C (decomp.); hydrochloride [357-07- 3.1.1.2. Piperidine Derivatives

3], C17 H19 NO4 · HCl, M r 337.80.
Synthesis [454] Oxycodone is hydrolyzed
with boiling concentrated hydrobromic acid.
3.1.1.2.1. Meperidine and Congeners
(for Diphenoxylate, Loperamide, and Pir-
itramide see Section 3.1.1.4)

Pethidine [57-42-1], meperidine, ethyl

1-methyl-4-phenylpiperidine-4-carboxylate,
C15 H21 NO2 , M r 247.33; hydrochloride [50-
13-5], C15 H21 NO2 · HCl, M r 283.80, mp 186–
189 ◦ C.

Opioid receptor binding: Oxymorphone is a

µ-selective opioid with a binding affinity in the
range of morphine.
Clinical use: Oxymorphone is a synthetic
morphine derivative with a potency 5–10 times
higher than that of morphine. The compound
is used as hydrochloride in parenteral and rec-
tal application forms (suppositories) and as oral
sustained-release formulations to treat moder-
ate to severe pain [455]. Oxymorphone has no
cough suppressant activity. Oxymorphone has a
morphine-type side effect profile and can induce
addiction and dependence [456].
Trade name: Numorphan (USA, Canada).

Synthesis [48, 457–460]:
a) The original synthesis involved condensation
of benzyl cyanide with N,N-bis(2-chloro-
ethyl)-N-methyl-amine, which is a skin ir-
ritant and a carcinogen.
b) Another synthesis begins with pyridine-4-
carboxylic acid.
Opioid receptor binding: Pethidine is a µ-
selective synthetic opioid with an intermediate
receptor affinity [461].
Clinical use: Pethidine [462] is a synthetic
analgesic with µ-receptor preference similar to
morphine. Pethidine, introduced in 1939, was
the first fully synthetic analgesic with morphine-
like activity. It has a lower potency and a shorter
duration of action than morphine and is used as
hydrochloride for the treatment of moderate to
severe pain. It is preferentially used in parenteral
formulations, perioperative and obstetrical anal-
gesia and as adjunct to anesthesia.
Pethidine has a morphine-type side effect
profile with a lower incidence of constipation.
Higher doses induce central stimulation and an-
timuscarinic effects accompanied by pupil di-
latation. In even larger doses toxic symptoms
such as muscular twitching, tremor, mental con-
fusion, and convulsions occur, which are partly
attributed to the more toxic metabolite norpethi-
Analgesics and Antipyretics 57
dine [463]. Severe side effects including coma
and cyanosis have been observed in combina-
tion with MAO-inhibitors [464]. Pethidine in-
duces morphine-type tolerance and dependence
and addicts using high doses of pethidine have
an increased risk of excitatory side effects.
Due to the high risk of severe side effects the
clinical use of the compound has strongly de-
creased [465–467].
Trade names: Dolantin (Germany), Dolosal
(France), Demerol (USA).
Ketobemidone [469-79-4], N-(3-hy-
droxyphenyl)-N-(1-methylpiperidin-4-yl)-
propionamide, C15 H21 NO2 , M r 247.34,
mp 150–151 ◦ C; hydrochloride [5965-49-1],
C15 H21 NO2 · HCl, M r 283.80, mp 201–202 ◦ C.
Synthesis: The cyano group of 4-cyano-4-
(3-methoxyphenyl)-1-methylpiperidine is con-
verted into a ketoethyl group by reaction with
ethylmagnesium bromide. Subsequent ether
cleavage by means of HBr yields ketobemidone
[48, 459, 468, 469].
Opioid receptor affinity: Ketobemidone is
a µ-selective synthetic opioid with a receptor
affinity similar to morphine [470].
Clinical use: Ketobemidone is a synthetic
opioid of the pethidine group with an analgesic
potency in the range of morphine [471]. The
58 Analgesics and Antipyretics

compound has a weak NMDA blocking effect
[472], which may contribute to the analgesic ef-
ficacy. It can be given orally, by injection or rec-
tally; usual doses are 5–10 mg. Ketobemidone
has a morphine-like side effect and abuse and
dependence potential [473].
Trade names: Cliradon (Germany, out of
use), Ketogan (Sweden, Norway).
3.1.1.3. Fentanyl and Congeners
Fentanyl and fentanyl derivatives (so-called
designer drugs) have an essential abuse poten-
tial [477] and induce a morphine type of physical
dependence.
Trade names: Actic (USA), Duragesic
(USA), Durogesic, Durogesic-SMAT (Ger-
many), Durogesic-Dtrans (UK), Fentanyl
Janssen (Germany), Sublimaze (UK, USA).
Combination with Droperidol: Thalamonal.
Transdermal fentanyl patches are also mar-
keted in generic formulations.

Fentanyl [437-38-7], N-(1-phenethylpiperi-

din-4-yl)-N-phenylpropionamide, C22 H28 N2 O,
M r 336.47, mp 83–85 ◦ C; citrate (1 : 1) [990-
73-8], C22 H28 N2 O · C6 H8 O7 , M r 528.60, mp
149–151 ◦ C.
Synthesis [48, 474] (see right column).
Opioid receptor binding: Fentanyl is a µ-
selective potent opioid with a similar recep-
tor binding affinity as morphine. The higher in
vivo potency of fentanyl results from its higher
lipophilicity.
Clinical use: Fentanyl is a potent synthetic
opioid related to pethidine [475] and has an ac-
tion profile similar to morphine. Fentanyl citrate
is used for the inhibition of acute and chronic
severe pain, and especially as adjunct to anes-
thesia and as a primary anesthetic for induction
and maintenance of anesthesia [476]. In com-
bination with neuroleptics or tranquilizers it in-
duces a surgical state named neuroleptanalgesia
in which surgery can be performed in an awake,
but calm and pain-free status. Fentanyl is orally
bioavailable and can be administered orally (spe-
cial forms exist for the oral-transmucosal route),
parenterally, and transdermally as patch formu-
lations. A formerly used less safe reservoir patch
formulation has now been substituted by a new
matrix patch. Fentanyl is a highly lipophilic
compound and is bound to plasma proteins to
about 80 %. The compound has a rapid onset
and a relatively short duration of action, presum-
ably due to tissue redistribution. The elimination
half-life is longer than that of morphine.
The side effect profile is typical of potent µ-
opioids with respiratory depression, increased
muscle tone (chest wall rigidity during fentanyl
anesthesia), strong sedation, and emesis being
most prominent. Adverse reactions can be an-
tagonized with naloxone.
 Analgesics and Antipyretics 59

Alfentanil [71195-58-9], N-{1-[2-(4-ethyl-

5-oxo-4,5-dihydrotetrazol-1-yl)ethyl]-4-meth-
oxymethylpiperidin-4-yl}-N-phenylpropion-
amide, C21 H32 N6 O3 , M r 416,25; hydrochloride
monohydrate [70879-28-6], C21 H32 N6 O3 ·
HCl · H2 O, M r 470.99, mp 138.4–140.8 ◦ C.
Synthesis: The cyclization of ethyl isocy-
anate with sodium azide in the presence of
AlCl3 in refluxing THF gives 1-ethyl-1,4-di- Finally the tetrazole derivative 2 is condensed
hydro-5H-tetrazol-5-one, which is alkylated with the propionamide 3 in the presence of
with 1-chloro-2-bromoethane using Na2 CO3 Na2 CO3 and KI as catalysts in refluxing 4-
and KI in refluxing 4-methyl-2-pentanone to af- methyl-2-pentanone.
ford 1-ethyl-4-(2-chloroethyl)1,4-dihydro-5H-
tetrazol-5-one (2) [48, 478–480].

N-(4-methoxymethyl-4-piperidinyl)-N-
Opioid receptor binding: Alfentanil is a µ-
phenylpropionamide (3) is synthesized ac-
selective opioid [481] with a receptor affinity in
cording the following scheme starting from
the range of morphine and fentanyl.
1-benzyl-4-piperidone:
Clinical use: Alfentanil is a potent opioid
analgesic with a rapid onset and a shorter du-
ration of action than fentanyl [482]. The i. v.
formulation (dose range 1–4 mg) is mainly used
perioperatively as strong analgesic, supplement
to general anesthesia, or as a primary anesthetic
[483]. Alfentanil has a strong respiratory de-
pressant action and high doses induce chest wall
rigidity. The compound has a µ-type addiction
and dependence potential.
Trade names: Rapifen (Germany, France,
UK), Alfenta (USA).

Remifentanil [132875-61-7], methyl 1-(2-

methoxycarbonylethyl)-4-(phenylpropionylami-
no)piperidine-4-carboxylate, methyl 4-(meth-
oxycarbonyl)-4-[(1-oxopropyl)phenylamino]-
1-piperidinepropanoate, C20 H28 N2 O5 , M r
376.45; monohydrochloride [132539-07-2],
C20 H28 N2 O5 · HCl, M r 412.91; oxalate (1 :
1) [132875-62-8], C20 H28 N2 O5 · C2 H2 O4 , M r
466.49.
60 Analgesics and Antipyretics
Synthesis: Remifentanil is prepared by con-
densation of methyl 4-(phenylpropionylamino)
piperidine-4-carboxylate with methyl acrylate in
hot acetonitrile [48, 484–486].
Clinical use: Remifentanil [487, 488] is a
very short-acting and potent µ-opioid agonist
with strong analgesic and anesthetic properties.
It has been developed as an ultra-short anes-
thetic and adjunct to general anesthesia. [489,
490]. It affords potent intraoperative analgesia
and has a sparing effect on concomitantly used
sedatives and hypnotics [491]. Remifentanil is
given as intravenous short infusion in doses of
0.5–1 µg/kg or as continuous infusions in the
range of 0.0025–2 µg kg−1 min−1 . It is rapidly
inactivated by plasma and tissue esterases [492].
The terminal elimination half-life is 10–20 min.
Remifentanil has a µ-opioid type side effect
profile with strong CNS and respiratory depres-
sant properties and a morphine-like addiction
and dependence potential.
Trade name: Ultiva (Germany, UK, USA).
Sufentanil [56030-54-7], N-[4-(meth-
oxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperi-
dinyl]-N-phenylpropanamide, N-[4-methoxy-
methyl-1-(2-thiophen-2-yl-ethyl)piperidin-4-
yl]-N-phenylpropionamide, C22 H30 N2 O3 S, M r
386.56, mp 96.6 ◦ C; citrate (1 : 1) [60561-17-3],
C22 H30 N2 O3 S · C6 H8 O7 , M r 578.68.
Synthesis: Sufentanil is obtained by con-
densation of N-(4-methoxymethylpiperidin-4-
yl)-N-phenylpropionamide with 2-thiophen-2-
yl-ethyl methanesulfonate [48, 493–496].
Opioid receptor binding: Sufentanil is a µ-
selective opioid with an about 10-fold higher re-
ceptor affinity than fentanyl [497].
Clinical use: Sufentanil [498] is a very potent
and short-acting fentanyl derivative with pref-
erence for the µ-opioid receptor. It has strong
sedating and analgesic properties and is used
predominantly as an adjunct in anesthesia or
as a primary anesthetic. Anesthetic doses in-
duce respiratory depression and chest wall rigid-
ity [499] which requires assisted ventilation.
For pain treatment intravenous or epidural on-
demand procedures are in use and a patch for-
mulation for pain relief up to seven days is under
development. Following parenteral administra-
tion sufentanil has a rapid onset and a short dura-
tion of action. The compound is very lipophilic
and has a high plasma protein binding of ≈ 90 %.
The short duration of action is more dependent
on redistribution than on metabolic inactivation.
Doses up to 8 µg/kg are adequate for pain treat-
ment and higher doses up to 30 µg/kg for surgery
[500]. Sufentanil has a morphine-type side ef-
fect profile and induces severe respiratory de-
pression and chest wall rigidity in anesthetic
dosages [501]. High dose levels have been asso-
ciated with seizures. Prolonged use may induce
tolerance and dependence.
Trade name: Sufenta (Belgium, Germany,
France, Norway, USA).
3.1.1.4. Methadone and Congeners
Levomethadone [125-58-6], (R)-6-
dimethylamino-4,4-diphenylheptan-3-one,

C21 H27 NO, M r 309.45, mp 98–100 ◦ C (mp
20
racemic form [57-42-1] 78–79 ◦ C), [α]D −32◦
(c = 1.8, CH3 CH2 OH), hydrochloride [5967-
73-7], C21 H27 NO · HCl, M r 345.91, mp 240–
241 ◦ C (mp racemic form [1095-90-5] 231 ◦ C),
20
[α]D −169◦ (c = 2.0, water).
Synthesis [502–509]:
Opioid receptor binding: Levomethadone
is the µ-selective levorotatory enantiomer of
racemic methadone [510]. It has an opioid re-
ceptor affinity in the range of morphine.
Clinical use: Levomethadone [511] is similar
to morphine in potency and side effect profile.
The compound has a high oral availability and a
long duration of action [12, 513]. Methadone is
extensively protein-bound and accumulation can
occur during chronic administration. For pain
treatment, the active dose range is 2.5–10 mg.
Methadone can be given orally or by subcuta-
neous or intramuscular administration (2.5–10
mg in analgesia), but causes pain at the injection
site.
The long duration of action makes the com-
pound suitable for the substitution treatment of
opioid addiction [514]. Whereas levomethadone
is preferred for pain treatment, oral racemic
methadone is widely used for the substitution
treatment of opioid addiction [515].
Levomethadone has a morphine-like side ef-
fect profile with stronger respiratory depression
and less sedation than morphine [516]. The com-
pound has a morphine-type abuse and depen-
Analgesics and Antipyretics 61
dence potential. Because of its slow elimination
withdrawal reactions are more protracted and
less severe than with morphine [517].
Trade names: Eptadone (Italy), Dolophine
(USA), Metasedin (Spain),Physeptone (UK), l-
Polamidon (Germany).
Levomethadyl acetate [34433-66-4],
l-α-acetylmethadol (LAAM), 4-dimethyl-
amino-1-ethyl-2,2-diphenylpentyl acetate,
[S-(R*,R*)]-β-[2-(dimethylamino)propyl]-
α-ethyl-β-phenylbenzeneethanol acetate,
C23 H31 NO2 , M r 353.50; hydrochloride
C23 H31 NO2 · HCl, M r 389.96, mp 215 ◦ C,
25
[α]D −60◦ (c = 0.2, water).
Synthesis: Levomethadyl acetate is prepared
by reduction of dextromethadone and subse-
quent acylation [518].
Opioid receptor binding: Levomethadyl ac-
etate has a moderate affinity for opioid receptor
binding with selectivity for the µ-type. Higher
binding affinity is induced by the active metabo-
lites l-alpha-noracetylmethadol, normethadol
and methadol [519].
Clinical use: Levomethadyl acetate is an
orally active methadone derivative with a slow
onset and a long duration of action. The com-
pound is extensively metabolized and active
metabolites contribute to the long duration of
action. Levomethadyl acetate was used mainly
for substitution treatment of opioid dependence
[520]. Oral doses from 20 up to 140 mg are given
every 2–3 d. Supplementation with short acting
opioids is necessary during the first days because
of the delayed onset of action.
Levomethadyl acetate induces opioid-type
side effects with respiratory depression, brady-
cardia, and impairment of cardiac contractil-
ity [521]. The compound inhibits cardiac elec-
tric conductivity and increases the QT interval
in the electrocardiogram [522] and may induce
ventricular arrhythmias and Torsade de pointes
[523]. Because of the cardiovascular side effects
62 Analgesics and Antipyretics

(Q/T-interval prolongation), the compound was Dextropropoxyphene [469-62-5], 1-

recently withdrawn from the market. benzyl-3-dimethylamino-2-methyl-1-phenyl-
Trade name: Orlaam (USA). propionate, [S-(R*,S*)]-α-[2-(dimethylami-
no)-1-methylethyl]-α-phenylbenzeneethanol
Dextromoramide [357-56-2], (+)-(S)- propanoate (ester), C22 H29 NO2 , M r 339.47,
25
3-methyl-4-morpholin-4-yl-2,2-diphenyl-1- mp 75–76 ◦ C, [α]D +67.3◦ (c = 0.6, CHCl3 );
pyrrolidin-1-yl-butan-1-one, C25 H32 N2 O2 , M r hydrochloride [1639-60-7], C22 H29 NO2 · HCl,
25 25
392.55, mp 183–184 ◦ C, [α]D +25.5◦ (c = M r 375.93, mp 163–168.5 ◦ C, [α]D +59.8◦ (c
25 ◦
5, benzene), [α]D +16 (c = 5, ethanol), d- = 0.6, water).
tartrate [2922-44-3], C25 H32 N2 O2 · C4 H6 O6 , Synthesis: 4-Dimethylamino-3-methyl-1,2-
25
M r 542.64, mp 189–192 ◦ C, [α]D +25.5◦ (c = diphenyl-butan-2-ol is formed by Grignard
25 ◦ reaction of 3-dimethylamino-2-methyl-1-
5, water), [α]D +30.5 (c = 5, CH3 OH).
Synthesis [48, 524]: phenylpropan-1-one with benzylmagnesium
chloride. The preferred product is the α-
diastereomer (75 % α-form = 1SR,2RS isomer,
15 % β-form). The α-form crystallizes and the
diastereomeric β-form remains in solution, be-
cause of its better solubility. Racemic resolution
to obtain the analgetically (+)-enantiomer can
be performed on the pure α-Grignard product
via fractional crystallization of the salts with
d-camphorsulfonic acid. Alternatively the reso-
lution can be achieved by treating the racemic
Mannich product 3-dimethylamino-2-methyl-1-
phenylpropan-1-one with (−)-dibenzoyltartaric
acid in acetone as solvent [582, 585–587] .

Opioid receptor binding: Dextromoramide is

a µ-selective opioid with a higher receptor affin-
ity than morphine.
Clinical use: Dextromoramide tartrate [525]
is a strong opioid, structurally related to
methadone and is used in the treatment of severe
pain. Dextromoramide has a high oral availabil-
ity and is administered orally or rectally. The par-
enteral potency is in the range of morphine, but
the duration of action is shorter. The compound
has a morphine-type abuse and dependence po-
tential.
Trade name: Palfium (France, UK, Nether-
lands).

Opioid receptor binding: Dextropropoxy-
phene has a µ-opioid receptor binding affinity
lower than morphine. Binding at other opioid
receptors is even weaker.
Clinical use: Dextropropoxyphene is a mod-
erately potent opioid analgesic often combined
with paracetamol or acetylsalicylic acid. As hy-
drochloride or napsylate it is used orally for the
treatment of mild to moderate pain [529]. Ad-
verse reactions in the therapeutic range are mild
and include drowsiness, dizziness, sedation, and
nausea. Overdosage can induce serious adverse
events including profound sedation, respiratory
depression, cardiovascular disturbances, con-
vulsions, and psychotic reactions, often with fa-
tal outcome [530]. Dextropropoxyphene has a
relatively low abuse liability. Abuse by injection
is impeded by severe irritations at the injection
side.
Because of severe and often fatal intoxica-
tions the compound is more and more substituted
by other weak opioids.
Trade names: Antalvic (France), Darvon
(USA), Develin (Germany), Doloxene (UK).
Diphenoxylate [915-30-0], ethyl 1-
(3-cyano-3,3-diphenylpropyl)-4-phenylpiperi-
dine-4-carboxylate, C30 H32 N2 O2 , M r 452.59;
hydrochloride [3810-80-8], C30 H32 N2 O2 ·
HCl, M r 489.06, mp 220.5–222.0 ◦ C.
Synthesis: The reaction of ethyl 4-
phenylpiperidine-4-carboxylate with 4-bromo-
2,2-diphenylbutyronitrile yields diphenoxylate
[48, 531].
Analgesics and Antipyretics 63
Alternatively, diphenylacetonitrile can be
condensed with ethyl 1-(2-chloro-ethyl)-4-
phenylpiperidine-4-carboxylate in the presence
of sodium amide.
Opioid receptor binding: Diphenoxylate is
the active metabolite of difenoxine [532] and
has a high affinity and selectivity for the µ-type
of opioid receptor.
Clinical use: Diphenoxylate [533] is a syn-
thetic pethidine derivative with a limited ac-
cess to the brain and marginal analgesic activity.
After oral administration, it reduces intestinal
motility and secretion and is used for the treat-
ment of diarrhea. Side effects include dizziness,
drowsiness, euphoria, anorexia, intestinal paral-
ysis. Prolonged use of high dosages may induce
morphine-like physical dependence. To avoid
abuse, diphenoxylate is routinely combined with
small amounts of atropine.
The compound is now substituted by lop-
eramide, which has less CNS side effects.
Trade names: Reasec (Germany, Italy),
Diaserd (France), Tropergen (UK), Lomotil
(USA).
Loperamide [53179-11-6], 4-[4-(4-chloro-
phenyl)-4-hydroxypiperidin-1-yl]-N,N-dime-
thyl-2,2-diphenylbutyramide, 4-(4-chlorophe-
nyl)-4-hydroxy-N,N-dimethyl-α, α-diphenyl-
1-piperidinebutanamide, C29 H33 CIN2 O2 , M r
477.04; monohydrochloride [34552-83-5],
C29 H33 ClN2 O2 · HCl, M r 513.51, mp 222–
223 ◦ C (decomp.).
Synthesis [48, 534, 535] (see next page).
Opioid receptor binding: Loperamide has a
morphine-like affinity and selectivity for the µ-
opioid receptor [536].
Clinical use: Loperamide [537] is a syn-
thetic opioid subjected to extensive first-pass
metabolization after oral administration. There-
fore little intact drug reaches the systemic cir-
culation and the central nervous system. Lop-
eramide has no centrally mediated analgesic ef-
ficacy, but may have a clinically useful analgesic
64 Analgesics and Antipyretics
effect via peripheral opioid receptors [539]. Sys-
temic and central opioid side effects are widely
missing. Orally administered loperamide acts lo-
cally in the gut by inhibition of intestinal motil-
ity and secretion [540]. Besides the strong µ-
opioid action, calcium and calmoduline antag-
onism are involved in the antidiarrheal activ-
ity. The compound is used in doses of 4–8 mg
for the treatment of acute and chronic diarrhea
and for the management of colostomies and
ileostomies [538]. Adverse effects include nau-
sea, dry mouth, dizziness. High doses can induce
toxic megacolon and paralytic ileus. The com-
pound has no abuse and dependence potential
and is meanwhile available as over the counter
(OTC) product [542].
Trade names: Imodium (Germany, Belgium,
USA, France), Arret (UK).
Loperamide is also marketed in many generic
formulations.
Piritramide [302-41-0], 1 -(3-cyano-3,3-
diphenylpropyl)-[1,4 ]bipiperidinyl-4 -carbox-
amide, C27 H34 N4 O, M r 430.59, mp 149–
150 ◦ C.
Synthesis: Piritramide is prepared by conden-
sation of 4-piperidinopiperidine-4-carboxamide
with 3,3-diphenyl-3-cyanopropylbromide [48,
543].
Opioid receptor binding: Piritramide is a µ-
opioid with morphine-like affinity and receptor
selectivity.
Clinical use: Piritramide [544] is a synthetic
opioid analgesic used for the treatment of acute,
preferentially postoperative pain. It is given in
doses of 15 mg by the intramuscular, subcuta-
neous, or intravenous route. Piritramide has a
morphine-like effect – side effect profile.
Trade names: Dipidolor (Germany, Belgium,
Netherlands), Piridolan (Sweden).
3.1.2. Other Structures
Tilidine [51931-66-9], ethyl trans-
2-dimethylamino-1-phenylcyclohex-3-ene-
carboxylate, C17 H23 NO2 , M r 273.17, mp
34 ◦ C, bp (133.32 Pa) 95.5–96 ◦ C; hydro-
chloride [27107-79-5], C17 H23 NO2 · HCl, M r

309.84, mp 159 ◦ C; hydrochloride hemihydrate
C17 H23 NO2 · HCl · 1/2 H2 O, M r 318.80, mp
125 ◦ C.
Synthesis: Reaction of buta-1,3-dienyl-di-
methylamine 4 with ethyl atropate 5 yields ti-
lidine as a cis/trans mixture (trans : cis = 2 : 3).
Most of the analgetically inactive cis isomer is
separated as a zinc complex and the trans isomer
is isolated as the hydrochloride. The cis isomer
can be epimerized to the trans form by treating
the epimeric mixture with acid [48, 545–548].
Opioid Receptor Binding: Tilidine itself has
a low opioid receptor binding affinity, whereas
the active metabolites nortilidine and bisnortili-
dine have a high affinity and selectivity for the
µ-type of opioid receptor [549].
Clinical use: Tilidine [550] is rapidly me-
tabolized to the active metabolites nortilidine
and bisnortilidine. It can be given orally and
parenterally and is used in single doses of 50–
Analgesics and Antipyretics 65
75 mg for the treatment of moderate to severe
pain. Tilidine has a substantial abuse potential.
To avoid parenteral misuse, oral preparations
are combined in some countries with a small
amount of naloxone hydrochloride. This is in-
tended to induce withdrawal symptoms after il-
licit parenteral administration. After oral admin-
istration, the naloxone component is metabol-
ically inactivated and does not inhibit analge-
sia. After parenteral administration the naloxone
component is active and blocks the tilidine effect
and can induce withdrawal reactions [551]. The
combination with naloxone, in contrast to pure
tildine, is available under normal prescription.
Trade names: Valoron (Germany, Switzer-
land), Tilidate (Spain).
Combination with naloxone: Tilidin-N, Val-
oron N.
Tramadol [27203-92-5], cis-2-dimethyl-
aminomethyl-1-(3-methoxyphenyl)cyclohex-
anol, C16 H25 NO2 , M r 263.38; hydrochloride
[36282-47-0], C16 H25 NO2 · HCl, M r 299.84,
mp 180–181 ◦ C.
Synthesis: Grignard reaction of 2-(dimethyl-
aminomethyl)cyclohexanone (obtained by Man-
nich reaction of cyclohexanone, formaldehyde,
and dimethylamine hydrochloride) and the Grig-
nard reagent of 3-bromoanisole yields tramadol
as a cis/trans mixture (cis : trans = 85 : 15). Tra-
madol (cis isomer) is separated from the reaction
mixture by crystallization of the hydrochloride
66 Analgesics and Antipyretics
salt. A crystallization process of the hydrate or
hydrobromide salts is also described. The trans
isomer can be epimerized to the cis isomer by
strong acids [48, 552, 553].
Opioid receptor affinity: Tramadol [554] it-
self has a weak opioid receptor affinity, the ac-
tive metabolite O-demethyltramadol shows µ-
selective binding with an affinity about ten times
lower than morphine.
Clinical use: Tramadol hydrochloride [555]
is a centrally acting analgesic with a µ-opioid
and nonopioid action component [556]. The
nonopioid component acts spinally via inhibi-
tion of noradrenaline (NA) and serotonin (5HT)
reuptake. Tramadol is a racemic mixture of two
optical enantiomers and uptake inhibition and
opioid properties are differentially distributed
between the enantiomers [557]. Opioid recep-
tor affinity is low, but like codeine, tramadol
is biotransformed to the O-demethyl derivative
(M1), which has an essentially higher µ-opioid
receptor affinity and may be responsible for the
opioid properties of the compound. Tramadol
is marketed worldwide and has become one of
the most important centrally acting analgesics
[558]. It is used in single doses of 50–100 mg
for the treatment of acute and chronic medium
to severe pain. The compound has a high oral
bioavailability and can be given by mouth, rec-
tally, or by intramuscular, subcutaneous, or slow
intravenous injection or infusion. Typical side
effects are nausea, sweating, and dizziness. High
doses may have a pro-convulsive effect. Tra-
madol shows a reduced level of opioid side ef-
fects like respiratory depression and constipa-
tion. It has a very limited abuse potential and in
most countries is not subject to narcotic control.
Tramadol is used as a mono-compound or as
a combination with paracetamol [559].
Trade names: Adolonta (Spain), Contra-
mal (Belgium, France, Italy), Nobligan (Skan-
dinavia), Tramal, Tramal Long (Germany,
Switzerland, Austria), Tramacet (UK), Ultram
(USA), Ultracet (USA), Xprim (France), Zydol
(UK, Ireland).
Combination with paracetamol: Ultracet
(USA), Zaldiar (Germany, Austria, Switzer-
land).
Tramadol is also marketed in many generic
formulations.
3.1.2.1. Mixed Opioid Agonist – Antagonists
and Partial Agonists
Mixed agonist – antagonists are opioid com-
pounds that have in vivo relevant affinity for
more than one type of opioid receptors, com-
monly for the µ- and κ-types. The compounds
of this group are historically derived from the an-
tagonist nalorphine. At the µ-receptor they act as
antagonists or partial agonists with low intrinsic
activity. At the κ-receptor they act mostly as ag-
onists. These substances are used as analgesics
and the κ-agonistic effect and/or the partial µ-
agonistic effect is responsible for their analgesic
efficacy. The side effect profile and the misuse
potential depend on the relative prevalence of
either component in the individual compound.
The κ-component effects dysphoria, hallucina-
tions, and other psychotic reactions, but induces
a low level of respiratory depression and ad-
diction. Compounds with a marked κ-agonistic
component such as pentazocine are meanwhile
withdrawn from the market because of their un-
pleasant side effect profile. The µ-component is
responsible for respiratory depression, eupho-
ria, and dependence potential. Compounds with
a more µ-antagonistic profile have a low abuse
potential and are not under narcotic drug control,
compounds with a stronger µ-agonistic com-
ponent are scheduled. Application of a mixed
agonist-antagonist in an opioid pretreated pa-
tient may reduce analgesia and induce a with-
drawal reaction.
Buprenorphine [52485-79-7], 17-cy-
clopropylmethyl-α-(1,1-dimethylethyl)-4,5α-
epoxy-18,19-dihydro-3-hydroxy-6-methoxy-
α-methyl-6,14-ethanomorphinan-7-methanol,
C29 H41 NO4 , M r 467.30, mp 209 ◦ C; hydro-
chloride [53152-21-9], C29 H41 NO4 · HCl, M r
504.10.
Synthesis [48, 424–427] (see next page).
Opioid receptor binding: Buprenorphine
[560] has a mixed agonistic – antagonistic ac-
tion profile with a high affinity at the µ-, κ-, and
δ-opioid receptor. A ca. 100-fold lower affinity
was observed at the ORL1-receptor. The com-
pound shows a slow receptor dissociation which
can explain some peculiarities in the pharmaco-
logical actions [561].
Clinical use: Buprenorphine [562] is used
against moderate to severe pain, mostly for

chronic pain treatment. The potency is about 20–
30 times higher than that of morphine. Buprenor-
phine may be used for anesthesia premedication
or as adjunct to anesthetics. The compound has
a long duration and a slow offset of action and
is therefore suited for the substitution treatment
of opioid addiction [563, 564]. Due to its par-
tial agonistic properties buprenorphine can act in
combination with full agonists as an antagonist,
reducing their effect and precipitating a with-
drawal reaction in opioid dependent persons.
Antagonistic properties are seen in doses much
higher than the analgesic dose range. There-
fore no special precaution is necessary when
changing the treatment with a standard opioid
agonist to buprenorphine or vice versa [565].
Buprenorphine is given parenterally, orally (sub-
lingual), or by the transcutaneous route as a
patch. The doses for slow intravenous or in-
tramuscular administration are 300–600 µg, the
sublingual doses are 200–400 µg, both given ev-
ery 6–8 h. Buprenorphine patches are available
Analgesics and Antipyretics 67
as a matrix patch formulations with release rates
of 35, 52.5, and 70 µg/h.
The use of buprenorphine for opioid addic-
tion becomes more and more important. For this
indication, buprenorphine is used in doses up to
24 mg sublingually alone or in combination with
naloxone.
Adverse reactions of buprenorphine are typi-
cal of µ-opioids and include respiratory depres-
sion, drowsiness, nausea, and vomiting. Respi-
ratory depression often occurs delayed, is long
lasting, and may need higher doses of naloxone
[566, 567]. Buprenorphine has a limited abuse
potential and withdrawal reactions, due to slow
receptor dissociation, are mild and delayed.
Trade names: Buprenex (USA), Buprex,
Subutex (Germany, France, USA), Temgesic
(Germany, France, UK), Transtec (Germany,
Austria, Switzerland.
Combination with naloxone: Suboxone
(USA).
68 Analgesics and Antipyretics
Butorphanol [42408-82-2], 11-cyclobutyl-
methyl-1,2,3,4,9,10-hexahydro-4α,10-pro-
panophenanthrene-6,10α-diol, C21 H29 NO2 ,
M r 327.22, mp 215-217 ◦ C, [α]D − 70◦
(c = 0.1, CH3 OH); tartrate [58786-99-5],
C21 H29 NO2 · C4 H6 O6 , M r 477.55, mp 217–
219 ◦ C, [α]D − 64.0◦ (c = 0.4, CH3 OH).
Synthesis [48, 568–570] (see on top).
Opioid receptor binding: Butorphanol [571]
is a mixed agonist – antagonist opioid with high
µ- and κ-receptor affinity and full agonistic ac-
tivity at the κ-receptor and partial agonistic –
antagonistic effect at the µ-receptor.
Clinical use: Butorphanol [572, 573] is a
fairly potent opioid analgesic. It is used for the
treatment of moderate to severe pain, for mi-
graine and headache [574] and as an adjunct
to anesthesia. Butorphanol is orally inactive but
can be given by the nasal route [574]. The usual
administration is via the intramuscular or intra-
venous route. The intramuscular doses are 1–4
mg every 3–4 h, the intravenous doses are 0.5–2
mg. Nasal doses are ≈ 1 mg per spray in each
nostril.
The plasma elimination half-life of butor-
phanol is in the range of 3 h. Butorphanol [571]

has a side effect profile combining morphine-
and pentazocine-like symptoms. They include
drowsiness, weakness, sweating, feelings of
floating, and nausea. It has respiratory depres-
sant properties similar to morphine but with a
ceiling effect. As antidote naloxone can be used.
Overt hallucinations or other psychotic effects
are rare and less often reported than with penta-
zocine. The compound has a low abuse potential
and has not been submitted to narcotic control.
Trade name: Stadol (USA).
Dezocine [53648-55-8], 15-amino-1-
methyltricyclo[7.5.1.0127,255 ]pentadeca-2,4,6-
trien-4-ol, [5R-(5α,11α,13S*)]-13-amino-
5,6,8,9,10,11,12-octahydro-5-methyl-5,11-
methanobenzocyclodecen-3-ol, C16 H23 NO,
M r 245.36; hydrobromide [57236-36-9],
C16 H23 NO · HBr, M r 326.27, mp 269–270 ◦ C.
Synthesis [48, 575, 576]:
Opioid receptor binding: Dezocine [577] is
a mixed agonist – antagonist with binding affin-
ity to the µ-opioid receptor in the range of mor-
phine. The δ- and κ-affinity is 10–100-fold lower
[578].
Clinical use: Dezocine [579, 580] is a
medium-potent opioid and is suited for the treat-
Analgesics and Antipyretics 69
ment of moderate to severe pain. It is given by
injection in the dose range of 5–20 mg. Side ef-
fects include nausea, vomiting, and drowsiness.
Overdosing can be treated with naloxone. In opi-
oid pretreated patients, dezocine may precipitate
withdrawal symptoms.
Trade name: Dalgan (USA, no longer mar-
keted).
Meptazinol [54340-58-8], 3-(3-ethyl-
1-methylazepan-3-yl)phenol, 3-(3-ethyl-
hexahydro-1-methyl-1H-azepin-3-yl)phenol,
C15 H23 NO, M r 233.35, mp 127.5–133 ◦ C; hy-
drochloride [59263-76-2], C15 H23 NO · HCl,
M r 269.81.
Synthesis [48, 581, 582]:
Opioid receptor binding: Meptazinol [583] is
a partial µ-agonist with a high µ-receptor affin-
ity. A selective action at a special subtype of
µ-opioid receptor (µ-1 subtype, [584]) is con-
troversial.
70 Analgesics and Antipyretics
Clinical use: Meptazinol [585] is used par-
enterally (50–100 mg) or orally to treat moder-
ate or moderately severe pain. The compound
has a shorter duration of action than morphine.
The most common side effects are nausea, vom-
iting, and dizziness. Sweating and hypotension
can also occur. Meptazinol has opioid antago-
nistic properties and can induce withdrawal in
opioid-dependent persons. The compound has a
very low dependence potential and is not under
narcotic drug control. The compound is reported
to be relatively free of respiratory depressant ac-
tivity, which was attributed to selective binding
to a µ-1 subtype of the opioid receptor [584].
This is not confirmed by others and the effect
may be alternatively explained by a choliner-
gic action component [583] of the compound.
In accordance with a low κ-receptor affinity, the
incidence of psychotomimetic actions and hal-
lucinations is low.
Trade name: Meptid (Germany, UK).
Nalbuphine [20594-83-6], (5α6α)-17-(cy-
clobutylmethyl)-4,5-epoxymorphinan-3,6,14-
triol, C21 H27 NO4 , M r 357.44, mp 230.5 ◦ C; hy-
drochloride [23277-43-2], C21 H27 NO4 · HCl,
M r 393.91, mp 291–292 ◦ C (decomp.).
Synthesis: Starting material for the nal-
buphine synthesis is oxycodone (see page 55).
After ether cleavage to oxymorphone the prod-
uct is acylated and the N-methyl group is re-
moved by treatment with cyanogen bromide.
The acetyl groups are hydrolyzed with dilute
hydrochloric acid. The resulting 14-hydroxydi-
hydronormorphinone 6 is N-alkylated with cy-
clobutylmethyl bromide, and the carbonyl group
at C-6 is reduced [48, 586, 587].
Opioid receptor binding: Nalbuphine is a
mixed agonist – antagonist opioid with a high
affinity at the µ- and κ-opioid receptor. At the
κ-receptor the compound is an agonist, at the µ-
receptor a partial agonist with a very low intrin-
sic activity, thus acting more as a µ-antagonist
[588].
Clinical use: Nalbuphine [589, 590] is an opi-
oid analgesic with a mixed agonist – antagonist
action profile. Analgesia is limited by a “ceiling”
effect. The compound has a low oral availability
and is used as hydrochloride only for parenteral
application to treat moderate to severe pain and
as adjunct to anesthesia. The dose for pain re-
lief is 10–20 mg. The most frequent side effects
are drowsiness, sweating, nausea, and vomiting.
Hallucinations and psychotomimetic reactions
are less frequent than with pentazocine, reflect-
ing a relative weak κ-agonistic component of the
compound. Nalbuphine induced respiratory de-
pression is less severe than with morphine and is
limited by a ceiling effect [591]. The dependence
potential is low and nalbuphine is not subject to
narcotic control.
Trade name: Nubain (Germany, France, UK,
USA).
Nalorphine [62-67-9], (5α,6α)-7,8-dide-
hydro-4,5-epoxy-17-(2-propenyl)morphinan-
3,6-diol, C19 H21 NO3 , M r 311.38, mp 208–
25
209 ◦ C, [α]D −155.3◦ (c = 3, CH3 OH); hy-
drochloride [57-29-4], C19 H21 NO3 · HCl, M r
347.84, mp 260–263 ◦ C; hydrobromide [1041-
90-3], C19 H21 NO3 · HBr, M r 392.29, mp 258–
259 ◦ C (decomp.).
Synthesis: Diacetylmorphine (heroin) is
demethylated with cyanogen bromide and hy-
drolyzed to normorphine, which is alkylated
with allyl bromide to give nalorphine [48, 592].
 Analgesics and Antipyretics 71

enteral, and rectal formulations for the treatment

of moderate to severe pain. Pentazocine induces
morphine-type side effects like dizziness, nau-
sea, vomiting, sedation, and sweating. In ad-
dition, it can cause κ-agonist type psychoto-
mimetic effects like hallucinations, nightmares
and thought disturbances. Respiratory depres-
sion is weaker than with morphine and is subject
to a “ceiling” effect.
The compound has a relevant abuse potential
[597] and high doses may produce dependence
of the morphine type. Pentazocine effects can be
antagonized by naloxone.
Because of its side effect profile, the com-
pound is no longer used.

Opioid receptor binding: Nalorphine [113] is

a mixed agonist – antagonist with a high affinity
and low intrinsic action at the µ- and κ-opioid
receptors.
Clinical use: Despite a predominant antago-
nistic action profile nalorphine has substantial
analgesic activity and was the first opioid com-
bining analgesic activity with an antagonistic ac-
tion. The compound is no longer used because of
κ-agonistic type adverse reactions such as anx-
iety, hallucinations, and dysphoric mood alter-
ations.

Pentazocine [359-83-1], 6,11-di-

methyl-3-(3-methylbut-2-enyl)-1,2,3,4,5,6-
hexahydro-2,6-methanobenzo[d]azocin-8-ol,
(2α,6α,11R*)-1,2,3,4,5,6-hexahydro-6,11-di-
methyl-3-(3-methyl-2-butenyl)-2,6-methano-
3-benzazocin-8-ol, C19 H27 NO, M r 285.42,
mp 145–148 ◦ C; hydrochloride [2276-52-
0], C19 H27 NO · HCl, M r 321.89; lactate (1 :
1) [17146-95-1], C19 H27 NO · C3 H6 O3 , M r
375.51.
Synthesis [48, 594, 595] (see right column).
Opioid receptor binding: Pentazocine [596]
is a mixed opioid agonist – antagonist with ag-
onistic effects at the κ- and partial antagonistic
effects at the µ-type of opioid receptor.
Clinical use: Pentazocine is a potent anal-
gesic with therapeutic dosages in the range of
25–100 mg. It is orally bioavailable and was
used as hydrochloride or lactate in oral, par-
72 Analgesics and Antipyretics

3.1.2.2. Opioid Antagonists [598]

Opioid and narcotic antagonists (Table 2) are

compounds with binding affinity at opioid re-
ceptors, but without intrinsic activity. They only
block the receptor without inducing a genuine
effect but are able to inhibit or reverse the ac-
tions of opioid agonists or partial agonists. An-
tagonists may or may not be selective for one
opioid receptor type. Only antagonists with a
high affinity and/or selectivity for the µ-receptor
have clinical application. They are used to termi-
nate medically desired effects of µ-opioid such
as anesthesia, to reverse side effects like respira-
tory depression or to treat opioid intoxications.
Acute administration of antagonists precipitates
withdrawal reactions in opioid-dependent sub-
jects. In the course of long-term treatment orally
active antagonists are used for detoxification of
opioid addicts.
Antagonists with δ- or κ-receptor selectivity
have no clinical application but are widely used
in opioid research.

Levallorphan [152-02-3], 17-(2-propenyl)- Naloxone [465-65-6], (5α)-4,5-epoxy-

morphinan-3-ol, 1-N-allyl-3-hydroxymorphi- 3,14-dihydroxy-17-(2-propenyl)morphinan-6-
nane, C19 H25 NO, M r 283.42, mp 180–182 ◦ C, one, C19 H21 NO4 , M r 327.37, mp 184 ◦ C (also
25
[α]D −88.9 ◦ (CH3 OH); hydrogen tartrate (1 : 20
reported as 177–178 ◦ C), [α]D −194.5◦ (c
1) [71-82-9], C19 H25 NO · C4 H6 O6 , M r 433.50, = 0.93, CHCl3 ); hydrochloride [357-08-4],
25
mp 176–177 ◦ C, [α]D −39◦ (water). C19 H21 NO4 · HCl, M r 363.84, mp 200–205 ◦ C.
Synthesis: Starting material for the lev- Synthesis: 14-Hydroxydihydronormorphinone
allorphan synthesis is 1-(4-methoxybenzyl)- 6 (see page 70) is N-alkylated with allyl bro-
1,2,3,4,5,6,7,8-octahydro isoquinoline (1) mide [48, 606, 607].
(preparation see page 54) [48, 599–602].
Opioid receptor binding: Levallorphan has a
high binding affinity but a low intrinsic activity
at the µ-opioid receptor.
Analgesic efficacy and clinical use: Levallor-
phan [603] is an opioid antagonist with practi-
cally no analgesic action. It has been used as
one of the first relative pure antagonists for the
treatment of opioid overdosage, to reverse opi-
oid central depression and to antagonize opioid- Opioid receptor binding: Naloxone [608] is
induced respiratory impairment [604]. The com- a pure opioid antagonist with a high affinity and
pound is now replaced by naloxone [605]. a limited selectivity for the µ-receptor.
 Analgesics and Antipyretics 73

Efficacy and clinical use: Naloxone [609, b)

610] has no analgesic activity. The compound
is the standard antidote to treat opioid adverse
reactions, opioid overdoses, or to stop an in-
tended use of an opioid compound. Typical in-
dications are inhibition of opioid-induced res-
piratory depression, termination of opioid anes-
thesia or protection of neonates following opi-
oid treatment during labor. Naloxone has a short
duration of action and repetitive administration
may be necessary to antagonize longer acting
agonists. To avoid parenteral misuse of non-
scheduled oral opioid formulations (tilidine,
pentazcocine), a small amount of naloxone is
added which is orally inactivated, but is fully
active after parenteral administration.
Naloxone is orally inactive and is only used
parenterally in single or repetitive doses of 0.4–
2 mg up to a total dose of 10 mg, as an intra- Opioid receptor binding: Naltrexone has a
venous bolus injection or by infusion. The com- high affinity and selectivity for the µ-opioid re-
pound is more potent against pure opioid ag- ceptor [612].
onists than against mixed agonist – antagonists. Efficacy and clinical use: Naltrexone [613,
Caution should be used in opioid-dependent per- 614] is a pure opioid antagonist and has no
sons or in persons under high-dose opioid treat- analgesic activity. Naltrexone has a higher in-
ment, as naloxone may precipitate an acute with- travenous potency and longer duration of action
drawal reaction. Naloxone is relatively free of than naloxone. It has a higher oral bioavailability
side effects. Nausea, vomiting, and convulsions and is given by mouth to treat opioid dependence
have occasionally been reported. and to maintain abstinence during opioid detoxi-
Trade names: Narcan (France, UK, USA), fication [615]. In opioid-dependent persons, nal-
Narcanti (Germany, Austria). trexone induces an acute withdrawal reaction.
Trade names: Nalorex (France, UK), Ne-
Naltrexone [16590-41-3], (5α)-17-(cy- mexin (Germany), Revia (USA), Trexan (USA).
clopropylmethyl)-4,5-epoxy-3,14-dihydroxy
morphinan-6-one, C20 H23 NO4 , M r 341.40, N-Methylnaltrexone bromide [073232-
mp 168–170 ◦ C; hydrochloride [16676-29-2], 52-7], 17-(cyclopropylmethyl)-4,5a-epoxy-
C20 H23 NO4 · HCl, M r 377.87, mp 274–276 ◦ C. 3,14-dihydroxy-17-methyl-6-oxomorphi-
Synthesis: nanium bromide, C21 H26 BrNO4 , M r 436.34,
mp 251 ◦ C, [α]D25 - ?◦ (c = 1.49, CH3 OH);
a) Naltrexone is prepared in the same way as N-methylnaltrexone iodide [073232-53-8],
naloxone starting from oxycodone via the in- C21 H26 INO4 , M r 483.34.
termediate 6 except that the nitrogen atom Synthesis: Methylnaltrexone is obtained
is alkylated with cyclopropyl bromide [48, by quaternization of N-(cyclopropylmethyl)-
611]. noroxymorphone (naltrexone) with methyl bro-
mide in acetone/dimethylformamide [616]:
74 Analgesics and Antipyretics

Efficacy and intended clinical use: N-
Methylnaltrexone [617] is the polar derivative
of naltrexone, which does not reach the central
nervous system but can block intestinal opioid
receptors. The compound is under development
to counteract opioid induced bowel dysfunction
such as constipation and megacolon [618].
Nalmefene [055096-26-9], N-(cyclopro-
pylmethyl)-4,5α-6-methylenemorphinan-3,1β-
diol, C21 H25 NO3 , M r 339.43, mp 105–110 ◦ C;
hydrochloride [58895-64-0], C21 H26 ClNO3 ,
M r 375.89, mp 188–190 ◦ C.
Synthesis: Nalmefene is synthesized by a
Wittig reaction of naltrexone with triphenyl-
methylphosphonium bromide in DMSO under
neuropathic pain as pain initiated or caused by
a primary lesion or dysfunction in the nervous
system. This malfunction of the nervous system
can occur at any point along the sensory path-
way (peripheral nerve, dorsal root ganglion, and
CNS). The term peripheral neuropathic pain is
usually used to refer to abnormalities in the pe-
ripheral nervous system. Central pain is retained
as the term when the lesion or dysfunction oc-
curs in CNS.
Table 4. Etiological classification of neuropathic pain [623]
Injury Examples
Infection/inflammation
• postherpetic neuralgia
• HIV

basic catalysis of NaH. Trauma

• post-amputation phantom limb
pain
• spinal cord injury
• surgery

Ischemia
• diabetic neuropathy
• central post-stroke pain

Compression
Nalmefene is a 6-methylene analogue of nal- • sciatica
• carpal tunnel
trexone. It is a pure opioid receptor antagonist • trigeminal neuralgia
and has a high affinity for the κ-opioid receptor.
Nalmefene has a long duration of action and is Neoplasm
used in oral and parenteral formulations. • invasion of neural structures
Nalmefene is used to reverse opioid intoxica- • compression by tumor
expansion
tion [619] and for the treatment of opioid depen-
dence [620]. The compound is in clinical devel- Iatrogenic
opment for the treatment of alcoholism [621], to • vinca alkaloids
support smoking cessation and to control patho- • antiretrovirals
• post-irradiation
logical gambling [622].
Trade name: Revex (USA). Idiopathic
• multiple sclerosis
• trigeminal neuralgia
• complex regional pain
3.2. Antineuropathic Analgesics and syndrome
Other Non-opioid Compounds
Classification: Neuropathic pain has been
3.2.1. Neuropathic Pain Treatment
traditionally classified according to its etiology
[623–629, 658, 659]
(Table 1) and tends to be chronic and unremit-
ting. Patients with neuropathic pain are often dif-
Definition: Neuropathic pain results from dam-
ficult to treat, the pain is sometimes relatively un-
age to the nervous system due to many diverse
responsive to conventional analgesics and thus
processes. The damage causes persistent, dis-
a wide variety of drugs from many classes have
tressing pain, that is reputedly unresponsive to
been suggested for this indication. Table 4. indi-
conventional analgesics. The International As-
cates that neuropathic pain refers to a group of
sociation for the Study of Pain (IASP) defines
 Analgesics and Antipyretics 75

painful disorders characterized by pain due to
dysfunction or disease of the nervous system at
a peripheral level, a central level, or both. In con-
trast to nociceptive pain, which results from the
activation of pain receptors (nociceptors), neu-
ropathic pain is the result of injury to the pain-
conducting nervous system.
Symptoms: Neuropathic pain is a complex en-
tity with many symptoms and signs that fluctu-
ate, in number and intensity, with time. The de-
fer the best treatment options. Other interven-
tions such as stimulation, blockade, or destruc-
tion of nerves and psychological treatments are
also part of the armament for treating neuro-
pathic pain. Table 5. gives an overview on the
current available evidence-based treatment op-
tions for neuropathic pain.
Table 5. Evidence-based treatment options for neuropathic pain
[623]

scriptors associated with neuropathic pain have Drug class Proposed mechanism Examples
of action
been described qualitatively as burning, stab- Tricyclic
bing, shooting, aching and electric shock-like, antidepressants
• unspecific sodium • amitryptiline
amongst others. Pain may be continuous or channel blockade • nortriptyline
paroxysmal and felt superficially or deeply. It • inhibition of • desipramine
norepinephrine • imipramine
may also occur spontaneously, independent of a and serotonin
stimulus. Sensory changes in the injured area reuptake
are common. There may be areas of sensory • blockade of
α-adrenergic
loss but also of altered sensation to cutaneous receptors
stimuli. Non-noxious stimuli, e.g. stroking, may
elicit pain (allodynia). Mildly painful stimuli Serotonin and/or blockade of serotonin
norepinephrine and/or norepinephrine
may cause excessive pain (hyperalgesia) and reuptake inhibitors reuptake • duloxetine
• venlafaxine
repetitive stimulation can cause an explosive
build-up of pain that lasts well beyond the stim- Anticonvulsants
ulus (hyperpathia). These sensory abnormalities • unselective block • benzodiazepines
can be classified by type of stimulus – thermal, of sodium • carbamazepine
channels • oxacarbazepine
mechanical, and chemical. Mechanically evoked • phenytoin
events can be further subdivided into dynamic • lamotrigin
(brush-stroke evoked), static (pressure-evoked) • topiramate
• zonisamide
and punctate.
Anticonvulsants
Current Treatment Options in Neuro- • selective block of • gabapentin
pathic Pain. There are several rationales to calcium channels • pregabalin

guide treatment of patients with neuropathic Local anesthetics

pain. The most widely used at present is based on (type 1b
• unspecific sodium • lidocaine
antiarrythmic
the etiology and anatomical distribution of the drugs) (and/or calcium) • mexiletine
pain. Others have suggested a symptom-based channel blockade • bupivacaine
approach on the premise that certain symptoms Drugs for the
might respond best to specific classes of drugs. treatment of
neurological • antagonism of the • memantine
In clinical practise it is shown that one mecha- disorders NMDA receptor • dextromethorphan
nism may lead to different symptoms and that • ketamine
a similar pain symptom or deficit may be pro- Opioids
duced by several different underlying mecha-
• opioid agonism • blockade of
nisms. At present, there is no single treatment norepinephrine
that adequately and predictably controls neuro- reuptake
• increased
pathic pain, nor does there seem to be any way serotonin release
of preventing the development of neuropathic • morphine
pain following nerve injury. Management by a • tramadol
• methadone
combination of both pharmacological and non-
pharmacological approaches, ideally in a mul-
tidisciplinary pain clinic setting, seems to of-
76 Analgesics and Antipyretics

3.2.2. Individual Compounds

Baclofen [1134-47-0], β-(aminomethyl)-

4-chlorobenzenepropanoic acid, δ-(amino-
methyl)-p-chlorohydrocinnamic acid, γ-amino-
β-(p-chlorophenyl)butyric acid, C10 H12 ClNO2 ,
M r 213.66, mp 206-208 ◦ C; hydrochloride,
C10 H13 Cl2 N, M r 250.12, mp 179-181◦ C.
Synthesis:
a.) Baclofen is synthesized by reaction
of 4-chlorobenzaldehyde with ethyl aceton-
acetonate under catalysis of sodium ethoxide.
The resulting condensation product is hydro-
lyzed to 3-(4-chlorophenyl)glutaric acid. Cy-
clization to 3-(4-chlorophenyl)glutaric anhy-
dride and subsequent aminolysis yields 3-
(4-chlorophenyl)glutarimide, which is finally
transformed to baclofen [630, 631]
Clinical use: Baclofen, a GABAB agonist,
was initially launched in the 1970s for the oral or
parenteral treatment of voluntary muscle spas-
ticity due to cerebrovascular accidents, cere-
bral palsy, meningitis, multiple sclerosis (MS),
spinal lesions, and head injury. Baclofen medi-
ates its effect directly via the GABAB receptor.
An analgesic action of baclofen administered
systemically was first described more than 25
years ago and subsequently confirmed by many
different groups. Despite the large volume of
preclinical data that is now available, the use of
baclofen as an analgesic in humans has been lim-
ited owing, in part, to rapid tolerance and adverse
effects following systemic administration. Pos-
sibly, the only type of pain for which baclofen
can be used systemically is trigeminal neural-
gia. However, when administered intrathecally,
baclofen is able to reduce central pain such as
occurs in stroke [632].
Trade names: Gabalon, Lioresal (Germany,
UK, Italy), Liorésal (France).

Carbamazepine [298-46-4], dibenzo[b,f ]-

azepine-5-carboxamide, C15 H12 N2 O, M r
236.27, mp 204–206 ◦ C (also reported as 190–
193 ◦ C).
Synthesis [633]:

b.) Alternatively, baclofen can be obtained

by reaction of ethyl-4-chlorocinnamate with
nitromethane followed by hydrogenation and es-
ter cleavage [630, 631].

Alternatively, 5H-dibenzo[b,f ]azepine can
be treated directly with potassium cyanate yield-
ing carbamazepine [634].
Clinical use: Carbamazepine is an orally ac-
tive anticonvulsant. It is used additionally in the
treatment of manic depression and as an anal-
gesic in trigeminal neuralgia and other neuro-
pathic pain conditions [635]. Common side ef-
fects are dizziness, drowsiness, ataxia, visual
disturbances, dry mouth, abdominal pain, nau-
sea, and vomiting. Other adverse reactions in-
clude headache, arrhythmias, and heart block.
Trade names: Tegretal (Germany, Italy),
Tegretol (UK, France, USA).
Clonidine [4205-90-7], (2,6-dichloro-
phenyl)-(4,5-dihydro-1H-imidazol-2-yl)amine,
C9 H9 Cl2 N3 , M r 230.09, mp 139 ◦ C; monohyd-
rochloride [4205-91-8], C9 H9 Cl2 N3 · HCl, M r
266.55, mp 305 ◦ C.
Synthesis [48, 636, 637]:
Clinical use: Clonidine is an α2 -adrenergic
agonist and is primarily used in the cardiovas-
cular field for blood pressure reduction (→ An-
tihypertensives, Section 5.1.2) [638]. The com-
pound induces analgesia via central α2 -receptor
interaction and can be used orally, parenter-
ally or epidurally for pain treatment, often in
combination with opioids or local anesthetics
[639]. Epidural clonidine – opioid combinations
are preferentially used for neuropathically main-
tained cancer pain. The compound is addition-
ally used for migraine prophylaxis and to reduce
opioid and alcohol withdrawal symptoms [640].
Clonidine frequently induces side effects like
hypotension, sedation, drowsiness, dry mouth,
and constipation. The compound is well ab-
sorbed orally.
Trade names: Duraclon (USA), Catapresan
(Germany), Catapres (USA).
Analgesics and Antipyretics 77
Duloxetine [116539-59-4], (+)-(S)-
N-methyl-N-[3-(naphthalen-1-yloxy)-3-(2-
thienyl)propyl]amine, (S)-N-methyl-γ-(1-
naphthalenoxy)-2-thiophenepropanamine
C18 H19 NOS, M r 297.41, mp 118–122 ◦ C,
20
[α]D +122 ◦ (c = 1.0, CH3 OH); hydrochloride
[136434-34-9], C18 H20 ClNOS5 , M r 333.88,
mp 163–167 ◦ C.
Synthesis: Reaction of 2-acetylthiophene
with paraformaldehyde and dimethylamine in
ethanol gives 3-(dimethylamino)-1-(2-thienyl)-
1-propanone, which is enantioselectively re-
duced with a 2:1 complex of (2R,3S)-4-(di-
methylamino)-3-methyl-1,2-diphenyl-2-buta-
nol and LiAlH4 in toluene to yield (S)-3-(di-
methylamino)-1-(2-thienyl)-1-propanol. The
condensation of (S)-3-(dimethylamino)-1-(2-
thienyl)-1-propanol with 1-fluoronaphthalene
catalyzed by NaH in DMSO affords the corre-
sponding naphthyl ether (S)-N,N-dimethyl-3-
(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-
1-amine, which is finally monodemethylated
with 2,2,2-trichloroethyl chloroformate and zinc
in toluene and treated with oxalic acid [641,
642].
The ketone intermediate 3-(dimethylami-
no)-1-(2-thienyl)-1-propanone can also be re-
78 Analgesics and Antipyretics

duced with NaBH4 in ethanol to the racemic

alcohol 3-(dimethylamino)-1-(thiophen-2-yl)-
propan-1-ol, which is submitted to optical reso-
lution with (S)-(+)-mandelic acid to provide the
(S)-enantiomer [641, 642].

Reaction of thiophene-2-carboxylic acid with

oxalyl chloride and triphenylphosphine gives
the corresponding acyl chloride thiophene-2-
carbonyl chloride, which is condensed with
vinyltributylstannane, yielding 1-(2-thienyl)-2-
propen-1-one. The addition of HCl to the double
bond of 1-(2-thienyl)-2-propen-1-one affords
3-chloro-1-(2-thienyl)-1-propanone, which is
reduced with BH3 and the chiral (R)-
oxazaborolidine catalyst in THF to give (S)-3-
chloro-1-(2-thienyl)-1-propanol. Treatment of
(S)-3-chloro-1-(2-thienyl)-1-propanol with NaI
in acetone affords the (S)-3-iodopropanol Clinical use: Duloxetine hydrochloride is an
derivative, which is condensed with methy- inhibitor of 5-HT reuptake and norepinephrine
lamine in THF to provide (S)-3-(methylami- reuptake. The compound was launched in 2004
no)-1-(2-thienyl)-1-propanol. Finally, this com- by originator Lilly for the treatment of major de-
pound is condensed with 1-fluoronaphthalene by pression, urinary incontinence, and pain caused
means of NaH in DMA [641, 642]. by diabetic peripheral neuropathy [643–645].
The Friedel – Crafts condensation of thio- The drug is also undergoing phase III clini-
phene with 3-chloropropionyl chloride in pres- cal trials at Lilly for the treatment of generalized
ence of SnCl4 in benzene gives the afore- anxiety and fibromyalgia.
mentioned 3-chloro-1-(2-thienyl)-1-propanone, Trade names: Cymbalta (Eli Lilly, UK,
which is reduced with NaBH4 in ethanol to France, Italy, Germany), Yentrere (Eli Lilly,
yield the racemic alcohol 3-chloro-1-(thiophen- USA, UK, France, Italy, Germany), Arichaim
2-yl)propan-1-ol. Optical resolution of 3- (Boehringer Ingelheim, UK, France, Italy, Ger-
chloro-1-(thiophen-2-yl)propan-1-ol performed many), Xeristar (Boehringer Ingelheim, UK,
by means of immobilized CALB (Novozyme France, Italy, Germany).
435, Novo-Nordisk A/S) affords the enan-
tiomer (S)-3-chloro-1-(thiophen-2-yl)propan-1-
ol [643].

Flupirtine [56995-20-1], ethyl[2-ami-
no-6-(4-fluorobenzylamino)pyridin-3-yl]carb-
amate, C15 H17 FN4 O2 , M r 304.32, mp
115–116 ◦ C; monohydrochloride [33400-45-
2], C15 H17 FN4 O2 · HCl, M r 340.79, mp
214–215 ◦ C; maleate (1 : 1) [75507-68-5],
C15 H17 FN4 O2 · C4 H4 O4 , M r 420.39, mp
175.5–176 ◦ C.
Synthesis [48, 646–649]:
Clinical use: Flupirtine maleate [650] is an
analgesic with an unknown mode of action. It is
used in single doses of 100 mg orally and 150
mg rectally for the treatment of different pain
conditions.
Trade name: Katadolon (Germany).
Gabapentin
Synthesis [651, 653–655]: In the original syn-
thesis (Goedecke) cyclohexenone is reacted with
ethyl cyanoacetate in the presence of ammo-
nia to yield the Guareschi salt, which is hy-
drolyzed and decarboxylated to give 1,1-cyclo-
hexanediacetic acid which is transformed by to
the corresponding anhydride with acetic anhy-
dride. This anhydride is treated with methanol to
Analgesics and Antipyretics 79
yield the half ester 2-[1-(methoxycarbonyl)cy-
clohexyl]acetic acid, which is subjected to a Cur-
tius type rearrangement to give the isocyanate
2-[1-(isocyanatomethyl)cyclohexyl]acetic acid.
The desired compound is obtained by hydroly-
sis of 2-[1-(isocyanatomethyl)cyclohexyl]acetic
acid with HCl, followed by hydrochloric salt re-
moval via anion exchange [651, 652].
The anhydride can also be treated alter-
natively with N-hydroxylamine to afford the
N-hydroxyimide, which is converted to the
N-benzenesulfonyloxylimide by reaction with
benzenesulfonyl chloride. Subsequent reac-
tion of the N-benzenesulfonyloxylimide with
triethylamine in methanol gives the ure-
thane ester methyl 1-(methoxycarbonyl)cyclo-
hexanecarboxylate, which is submitted to HCl
hydrolysis to afford the hydrochloride of
gabapentin. The free amino acid is obtained from
the hydrochloride via anion exchange.
80 Analgesics and Antipyretics
The anhydride can also be treated with am-
monia to yield cyclohexane-1,1-diacetic acid
monoamide. In this route the compound is sub-
mitted to a Hoffman rearrangement to provide
the target amino acid.
The reaction of 2-[1-(carbamoylmethyl)cy-
clohexyl]acetic acid with NaOCl and NaOH
(a Hofmann rearrangement) gives the isocya-
nate intermediate, which without isolation hy-
drolyzes to the target gabapentin.
The condensation of cyclohexene-1-
carbaldehyde with benzoylhydrazide in
dichloromethane gives the correspond-
ing hydrazone (E)-N  -(cyclohexenylmethy-
lene)benzohydrazide, which is condensated un-
der reductive conditions with trichloroacetyl
chloride under catalysis of BH3 /(CH3 )2 NH and
Ms-OH (methanesulfonic acid) in diethyl ether
to yield the adduct N  -(cyclohexenylmethyl)-
N  -(2,2,2-trichloroacetyl)benzohydrazide. The
cyclization of this adduct by means of CuCl
and tetramethylenediamine (TMDA) in hot ace-
tonitrile affords the spiro pyrrolidone, which
is dechlorinated and debenzamidated by treat-
ment with wet Raney nickel in ethanol at 110 ◦ C
to provide 2-azaspiro[4,5]decan-3-one. Finally,
this compound is hydrolyzed with hot aqueous
HCl to form the target gabapentin [653–655].
Clinical use: Gabapentin was developed as
a structural GABA analogue but it has no di-
rect GABAergic action and it does not affect
GABA uptake or metabolism. Preliminary evi-
dence points to the possible effect of gabapentin
on the α2δ type of calcium channels.
The complex pharmacological mechanism
by which gabapentin and the related compound
pregabalin exert their clinical effect in epilepsy
and neuropathic pain, remains unclear [656,
657].
Gabapentin has a clearly demonstrated ef-
ficacy in relieving pain and associated symp-
 Analgesics and Antipyretics 81

toms in patients with postdiabetic and posther-

petic neuropathy. The starting dosage which can
be used is 300 mg three times a day. Increase
by 200 mg increments to 200–400 mg three to
four times a day is recommended. As main side
effects, sedation, dizziness, fatique, and pedal
edema are reported [658, 659].
Trade name: Neurontin (Germany).
Gabapentin is also used in many generic for-
mulations.

Lamotrigine [084057-84-1], 6-(2,3-di-

chlorophenyl)-1,2,4-triazine-3,5-diamine, 3,5-
Lamotrigine can also be obtained by the
diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine
following route: Hydrogenation of 2,3-di-
C9 H7 Cl2 N5 , M r 256.09, mp 216-218 ◦ C.
chloronitrobenzene with H2 over Raney nickel
Synthesis: The reaction of the Grignard com-
in methanol gives 2,3-dichloroaniline, which is
pound of 2,3-dichloroiodobenzene with CO2
diazotized with NaNO2 and HCl and treated
in diethyl ether gives 2,3-dichlorobenzoic acid,
with CuCN to yield 2,3-dichlorobenzonitrile.
which is converted to the corresponding acyl
Hydrolysis of the nitrile with NaOH in reflux-
chloride by refluxing with SOCl2 . The re-
ing methanol/water affords 2,3-dichlorobenzoic
action of 2,3-dichlorobenzoyl chloride with
acid, which is treated with hot SOCl2 to pro-
cuprous cyanide and KI in refluxing xylene
vide the corresponding acyl chloride. Reaction
yields 2,3-dichlorobenzoyl cyanide. Finally, this
of 2,3-dichlorobenzoyl chloride with CuCN and
compound is cyclized with aminoguanidine in
KI in refluxing chlorobenzene gives 2,3-dichlo-
DMSO to yield lamotrigine [660–663].
robenzoyl cyanide, which is condensed with
aminoguanidine by means of H2 SO4 /TsOH in
hot toluene to yield 2,3-dichlorobenzoyl cyanide
amidinohydrazone. Finally, this compound is
cyclized by treatment with NaOMe in refluxing
methanol to yield lamotrigine.

Condensation of 2,3-dichlorobenzoyl
cyanide with aminoguanidine in the presence
of polyphosphoric acid (PPA) as catalyst in hot
acetonitrile yields 2,3-dichlorobenzoylcyanide
amidinohydrazone, which is cyclized to the
target 1,2,4-triazine by heating in refluxing
propanol with or without DMSO.
82 Analgesics and Antipyretics

Clinical use: Lamotrigine is a phenyltriazine Alternative route:

derivative and one of the newer antiepilep-
tic agents, that stabilize neural membranes
by blocking the activation of voltage-sensitive
sodium channels and inhibiting the presynaptic
release of glutamate. Lamotrigine was initially
approved in the USA as add-on therapeutic for
partial complex seizures. At doses of 50 to 400
mg/d lamotrigine has demonstrated efficacy in
relieving pain in patients with trigeminal neu-
ralgia refractory to other treatments, such as
carbamazepine, phenytoin, or both. Pain reduc-
tion usually occurs at oral doses of more than 200
mg daily. However, lamotrigine must be dosed
very slowly during the first six weeks of treat-
ment to prevent a toxic rash. Recent negative
results from a clinical trial indicated that more
well-designed trials are needed to better define
the role of lamotrigine as an analgesic drug.
Main side effects are rash, dizziness, unsteadi-
ness, and drowsiness [658, 659, 664].
Trade name: Lamictal (Germany, UK,
France, Italy, USA).

Nefopam [13669-70-0], 5-methyl-1-

phenyl-3,4,5,6-tetrahydro-1H-benzo[f ][1,4]-
oxazocine, C17 H19 NO, M r 253.34; hydro-
chloride [23327-57-3], C17 H19 NO · HCl, M r
289.81, mp 238–242 ◦ C.
Synthesis [48, 665, 666]:

Clinical use: Nefopam [667] is a centrally

acting analgesic without opioid properties. It in-
duces inhibition of NA and 5-HT reuptake and
has antimuscarinic and sympatomimetic actions
which all might be relevant for its analgesic ac-
tion. Nefopam is used orally and parenterally for
the treatment of moderately severe pain. Side
effects are nausea, vomiting, sweating, nervous-
ness, tachycardia, and occasionally convulsions.
Nefopam should not be used in combination
with MAO inhibitors.
Trade names: Ajan (Germany), Acupan (Bel-
gium, France, Italy, UK).

Phenytoin [561-27-2], diphenylhydantoin,

5,5-diphenyl-2,4-imidazolidinedione
C15 H12 N2 O2 , M r 252.27, mp 295-298 ◦ C;
monosodium salt [690-93-3], C15 H11 N2 NaO2 ,
M r 274.26.

Synthesis:
a) Phenytoin is synthesized by cyclization of
benzil with urea [668, 670].
b) Alternatively phenytoin can also obtained by
using benzophenone as a starting material
[669, 670]:
Phenytoin
Clinical use: Phenytoin became the first anti-
convulsant to be used to treat neuropathic pain.
The first clinical trials started in 1977. Current
data indicate that the analgesic effect of pheny-
toin is achieved through the blockage of sodium
channels, inhibition of presynaptic glutamate re-
lease and suppression of spontaneous neuronal
ectopic discharges. Phenytoin is also used as
a co-analgesic in combination therapy. As an
oral starting dose, 200 mg at bedtime is recom-
mended. An increase by 100 mg increments to
300–400 mg daily divided in 1–2 doses is pos-
sible. Main side effects are slurred speech, rash,
unsteadiness, confusion, or blurry vision [658,
659].
Analgesics and Antipyretics 83
Trade names: Epanutin, Phenhydan, Zen-
tropil (Germany), Dihydan (France), Epanutin
(UK), Dilantin (USA).
Topiramate [097240-79-4], 2,3;4,5-bis-O-
(1-methylethylidene)-β-d-fructopyranose sulfa-
mate, 2,3;:4,5-bis-O-(1-methylethylidene)-1-O-
sulfamoyl-β-d-fructopyranose, C12 H21 NO8 S,
25
M r 339.36, mp 122-126 ◦ C, [α]D −34 ◦ (c =
0.4, CH3 OH).
Synthesis: Topiramate is synthesized by two
methods [671, 672]: d-Fructose is reacted with
acetone to produce the thermodynamically more
stable bisacetonide. This bisacetonide is then
condensed with sulfamoyl chloride in the pres-
ence of sodium hydride. Alternatively, the in-
termediate bisacetonide is reacted with sulfuryl
chloride and pyridine in methylene chloride and
then with sodium azide in acetonitrile to furnish
the azido sulfate, which is reduced with copper
powder in methanol [671, 672]
Alternatively the reaction of diacetone fruc-
tose with sulfamide in presence of of pyridine
in xylene at 128-133 ◦ C yields the target topira-
mate [673, 674].
84 Analgesics and Antipyretics
Clinical use: Topimarate is a sulfamate-
substituted derivative of d-fructose with the abil-
ity to block sodium channels, enhance GABA
activity by interacting with a nonbenzodiazepine
site of GABAA receptors, and selectively block
AMPA/kainate glutamate receptors [658].
The empirical use of topimarate as an
antinociceptive drug in humans was established
before systematic, planned research on animal
models of pain was initiated. Topiramate was
initially launched in 1995 as monotherapy and
adjunctive therapy for the treatment of epilepsy,
specifically for the treatment of partial seizures,
Lennox–Gastaut syndrome, and primary gen-
eralized tonic clonic seizures in patients inad-
equately controlled by other anticonvulsants.
Topiramate is also used for the prophylaxis of
migraine headaches.
The oral starting dose of topimarate is 25–
50 mg at bedtime and can be increased by 25
mg increments weekly to 100–200 mg twice a
day. Main reported side effects include confu-
sion, weakness, weight loss, and kidney stones.
The compound had been under development
for the treatment of neuropathic pain, bipolar
disorders, obesity, pathological gambling, abuse
and dependency, and for smoking cessation.
Trade names: Epitomax, Topamax, Topimax.
Ziconitide [097240-79-4], H-Cys-Lys-
Gly-Lys-Gly-Ala-Lys-Cys-Ser-Arg-Leu-Met-
Tyr-Asp-Cys-Cys-Thr-Gly-Ser-Cys-Arg-Ser-
Gly-Lys-Cys-NH2 cyclic S-3.1-S-3.16:S-
3.8-S-3.20:S-3-15-S-3.25-tris(disulfide),
omega-conotoxin MVIIA (reduced),
cyclic (1-16),(8-20),(15-25)-tris(disulfide),
C102 H172 N36 O32 S7 , M r 2639.14.
Synthesis: Ziconitide is the synthetic form of
the conotoxin ω-conopeptide MVIIA [675, 676]
(see below).
Clinical use: Ziconotide is the synthetic
equivalent of a naturally occurring conopeptide
found in the marine snail Conus magus. Zi-
conotide is an N-type calcium channel blocker,
that was launched in the USA by Elan in 2005 as
a solution for intrathecal infusion for the man-
agement of severe, chronic pain in patients who
are refractory to other treatments [675, 676].
Regulatory approval has been obtained for the
product in the EU. The drug is administered
through appropriate programmable microinfu-
sion pumps, that can be implanted or external,
and which release the drug into the fluid sur-
rounding the spinal cord.

Ziconotide binds to N-type calcium chan-
nels located on the primary nociceptive (Aγ and
C) afferent nerves in the superficial layers (rexed
laminae I and II) of the dorsal horn in the spinal
cord. Although the mechanism of action of the
drug has not been established in humans, results
in animals suggest that blocking of N-type cal-
cium channels leads to a blockade of excitatory
neurotransmitter release from the primary affer-
ent nerve terminals which induces antinocicep-
tion.
In July 2001, ziconotide received orphan drug
designation from the EMEA for the treatment
of chronic pain requiring intraspinal analgesia.
The compound had also been under evaluation
at Elan for the treatment of head injury.
Intended trade name: Prialt.
4. References
General References
1. J. G. Hardman (eds.) et al.: Goodman and
Gilman’s The Pharmacological Basis of
Therapeutics, 9th ed., McGraw Hill, New York
1995, pp. 521–555, 557–600, 617–657.
2. J. E. F. Reynolds (eds.) et al.: Martindale The
Extra Pharmacopoeia, 31st ed., The Royal
Pharmaceutical Society, London 1996.
3. A. Herz (ed.): Handbook of Experimental
Pharmacology, vol. 104/I, Opioids I., vol.
104/II, Opioids II, Springer Verlag, Berlin
1993.
4. T. Dickenson, J. Besson (eds.): Handbook of
Experimental Pharmacology. The
Pharmacology of Pain, vol. 130, Springer
Verlag, Berlin 1997.
5. M. Zenz, I. Jurna (eds.): Lehrbuch der
Schmerztherapie. Grundlage, Theorie und
Praxis für Aus- und Weiterbildung.
Wissenschaftliche Verlagsgesellschaft mbH,
Stuttgart 1993.
6. J. J. Bonica (ed.): The Management of Pain,
2nd ed., Lea & Febiger, 1990.
7. S. Budavari (ed.): The Merck Index, 12th ed.,
Merck & Co. Inc., 1996.
8. P. D. Wall, R. Melzack (eds.): Textbook of
Pain, 3rd ed., Churchill Livingstone, New
York 1994.
9. J. R. Vane et al., “Cyclooxygenases 1 and 2,”
Annu. Rev. Pharmacol. Toxicol. 38 (1998)
97–120.
10. C. J. Hawkey: “Cox-2 Inhibitors”, Lancet 353
(1999) 307–314.
Analgesics and Antipyretics 85
Specific References
11. J. R. Vane et al., Ann. Rev. Pharmacol. Toxicol.
38 (1998) 97 120.
12. K. L. Pierce et al., TIPS 16 (1995) 253 256.
13. C. D. Funk, et al., FASEB J. 5 (1991)
2304–2312.
14. D. A. Kujubu et al., J. Biol. Chem. 266 (1991)
12866–72.
15. T. Hla, K. Neilson, Proc. Natl. Acad. Sci. U S
A. 89 (1992) 7384–8.
16. M. K. O’Banion, et al., Proc. Natl. Acad. Sci.
U S A. 89 (1992) 4888–4892.
17. R. Langenbach et al., Ann. N. Y. Acad. Sci. 889
(1999) 52–61.
18. S. G. Morham et al., Cell 83 (1995) 473–482.
19. J. E. Dinchuk et al., Nature 378 (1995)
406–409.
20. D. Picot et al., Nature 367 (1994) 243–249.
21. J. R. Kiefer et al., Nature 405 (2000) 97–101.
22. J. R. Vane et al., Annu. Rev. Pharmacol.
Toxicol. 38 (1998) 97–120.
23. J. Berg et al., J. Pharmacol. Toxicol. Meth. 37
(1997) 179–186.
24. A. Graul et al., Drugs Future 22 (1997)
711–714.
25. L. J. Crofford et al., J. Clin. Invest. 93 (1994)
1095–101.
26. H. Sawaoka et al., Prostaglandins Leukot.
Essent. Fatty Acids 59 (1998) 313–316.
27. C. J. McCarthy et al., Am. J. Gastroenterol. 94
(1999) 1218–1223.
28. R. Langenbach et al., Ann. N.Y. Acad. Sci. 889
(1999) 52–61.
29. L. J. Crofford, Curr. Pharm. Des. 17 (2000)
1725–36.
30. C. Bombardier et al., N. Engl. J. Med. 343
(2000) 1520–1528.
31. R. S. Bresalier et al., N. Engl. J .Med. 352
(2005) 1092–1102.
32. S. D. Solomon et al., N. Engl. J. Med. 352
(2005) 1071–1180.
33. N. A. Nussmeier et al., N. Engl. J. Med. 352
(2005) 1081–1091.
34. B. F. McAdam et al., Proc. Natl. Acad. Sci.
U.S.A. 96 (1999) 272–277.
35. X. Leval et al., Curr. Med. Chem. 9 (2002)
941–962.
36. M. Inagaki et al., J. Med. Chem. 43
(2000)2040-2048.
37. S. Tries et al., Inflamm. Res. 51 (2002)
135–143.
38. S. Laufer et al., Arzneimittelforschung 44
(1994) 1329–1333.
39. B. Chin, J. Wallace, Curr. Opin. Investig.
Drugs 1 (1999) 148–152.
86 Analgesics and Antipyretics
40. C. Pisano et al., Dig. Dis. Sci. 44 (1999)
713–724.
41. S. Fiorucci, E. Antonelli, Curr. Top. Med.
Chem. 5 (2005) 487–492.
42. R. Scatena, Curr. Opin. Investig. Drugs 5
(2004) 551–556.
43. J. L. Wallace et al., Am. J. Physiol.
Gastrointest. Liver Physiol. 286 (2004)
G76–81.
44. C. Patrono, N. Engl. J. Med. 330 (1994)
1287–1294.
45. Patrignani et al., Br. J. Pharmacol. 118 (1996)
1285–1293.
46. R. G. Kurumbail et al., Nature 384 (1996)
644–648.
47. A. S. Kalgutkar et al. Science 280 (1998)
1268–1270.
48. A. Kleemann, J. Engel, B. Kutscher, D.
Reichert: Pharmaceutical Substances,
Synthesis, Patents, Applications, Thieme,
Stuttgart – New York,
1999 (available in print and CD-ROM).
49. N. Kuhnert, Chem. Unserer Zeit 33 (1999)
213–220.
50. Am. J. Med. 74 (1983) no. 6A, 1–109.
51. I. Tegeder et al., FASEB J. 15 (2001)
2057–2072.
52. C. J. Needs, P. M. Brooks, Clin.
Pharmacokinet. 10 (1985) 164–177.
53. R. J. Waldmann et al., JAMA 247 (1982)
3089–3094.
54. Merck & Co., US 4 225 730, 1980, (H. Jones,
R. Houser.
55. For alternative synthesis: US 3 992 495,
(Merck & Co.).
56. For alternative synthesis: US 4 131 618,
(Merck & Co.).
57. J. Hannah et al., J. Med. Chem. 21 (1978)
1093.
58. E. Arrigoni-Martelli, Drugs Future 3 (1978)
28–33.
59. J. Hannah et al., J. Med. Chem. 21 (1978)
1093–1100.
60. M. Cotton, R. A. Hux, Anal. Profiles Drug
Subst. 14 (1985) 491–526.
61. J.M. Young et al., Inflamm Res. 45 (1996)
246–253.
62. Lunbeck, GB 656 746, 1948.
63. D. S. Hoffenberg, C. R. Hauser, J. Org. Chem.
20 (1955) 1496–1500.
64. Warner-Lambert, US 2 998 450, 1961, (G.
Wilbert, J. De Angelis).
65. B. Ameer et al., Ann. Int. Med. 87 (1977)
202–209.
66. D. A. Willoughby et al., Lancet 355 (2000)
646–648.
67. P. Kirkpatrick, Nature Reviews Drug
Discovery 4 (2005) 883.
68. E. D. Hogestatt et al., J. Biol. Chem. 36 (2005)
31405–31412.
69. R. K. Lewis, F. P. Paloucek, Clin. Pharm. 10
(1991) 765–774.
70. M. Depre et al., Fundam. Clin.Pharmacol. 6
(1992) 259–262.
71. U. C. Dubach et al., N. Engl. J. Med. 308
(1983) 357–362.
72. K. H. Boltze, H. Kreisfeld,
Arzneim.-Forsch./Drug Res. 27 (1977) no. 1,
1300–1312.
73. R. Coletta et al., Int. J. Clin. Pharmacol. Res. 8
(1988) 295–298.
74. Parke Davis, FR 1 341 M, 1961.
75. R. B. Moffett, B. D. Aspergen, J. Am. Chem.
Soc. 82 (1960) 1605.
76. S. Ravi et al., Postgrad. Med. J. 62 (1986)
773–776.
77. H. Gögelein et al., FEBS Lett. 268 (1990)
79–82.
78. M. M. White et al., Mol. Pharmacol. 37 (1990)
720–724.
79. L. Sorbera et al., Drugs of the Future 26
(2001) 133–140.
80. G. J. Grover et al., J. Pharmacol. Exp. Ther.
269 (1994) 536–540.
81. Y. T. Lee, Q. Wang, Eur. J. Pharmacol. 378
(1999) 349–356.
82. Parke Davis, US 3 313 848, 1967;
DE 1 149 015, 1961.
83. P. F. Juby et al., J. Med. Chem. 11 (1968)
111–117.
84. E. Arrigoni-Martelli, Drugs Future 3 (1978)
307–310.
85. J. R. McLean, M. I. Geuckman,
Arzneimittel-Forsch. 33 (1983) 627–631.
86. A. Peretz et al. Mol. Pharmacol. 67 (2005)
1053–1066.
87. Y. T. Lee, Q. Wang, Eur. J. Pharmacol. 378
(1999) 349–356.
88. Parke Davis, US 3 138 636, 1964;
DE 1 163 846, 1961.
89. G. R. Singh, P. Choudhury, Indian Pediatr. 26
(1989) 577–579.
90. M. Ottolia, L. Toro, Biophys. J. 67 (1994)
2272–2279.
91. J. S. Marks, M. H. Gleeson, Br. Med. J. 4
(1975) 442.
92. Labs. U.P.S.A., US 3 415 834, 1968;
US 3 337 570, 1967.
93. J. Auclair et al., Curr. Ther. Res. 46 (1989)
782–788.

94. M. Civelli et al., Agents Actions 33 (1991)
233–239.
95. Park Davis, US 3313848 (A. Scherer, F. W.
Short), 1967
96. M. Zovko, B. Zorc, M. J.-M. Takac, B.
Metelko, P. Novac, Croatica Chemica Acta 76
(2003), 335–341.
97. T. Corell, Pharmacol. Toxicol. 75 Suppl 2
(1994) 14–21.
98. H. Isomaki, Pharmacol. Toxicol. 75 Suppl 2
(1994) 64–65.
99. J. Delgado et al. Pharmacol. Toxicol. 75 Suppl
2 (1994) 89–91.
100. P. E. Hansen, Pharmacol. Toxicol. 75 Suppl 2
(1994) 81–82.
101. K. H. Boltze et al., Arzneim.-Forsch./Drug
Res. 30 (1977) no. 2 1314–1325.
102. H. Jacobi, H. D. Dell, Arzneimittel-Forsch. 30
(1980) 1348–1362.
103. Rotta Research Lab., DOS 2 535 799, 1975.
104. Rotta Research Lab., US 3 985 878, 1974.
105. F. Makovec et al., Arzneimittelforschung 37
(1987) 806–813.
106. V. Fossaluzza et al., Minerva Med. 74 (1983)
723–726.
107. N. P. Buu-Hoi et al., Hebd. Seances Acad. Sci.
261 (1965) 2259.
108. P. Moser et al., J. Med. Chem. 33 (1990)
2358–2368. Link
109. P. A. Todd, E. M. Sorkin, Drugs 35 (1988)
244–285.
110. T. Y. Shen et al., J. Am. Chem. Soc. 85 (1963)
488–489.
111. Merck & Co., US 3 161 654, 1964,
DE 1 232 150, 1962.
112. H. Yamamoto et al., Chem. Pharm Bull. 16
(1968) no. 17, 647.
113. Byk Gulden, US 4 4 325 962, 1982;
DE 1 946 370, 1969.
114. G. Rainer et al., Arzneim.-Forsch./Drug Res.
31 (1981) 649–655.
115. B. Unterhalt, Drugs Future 7 (1982) 110–111.
116. Merck & Co., US 3 882 239, 1975;
DE 1 039 426, 1970.
117. R. F. Shuman et al., J. Org. Chem. 42 (1977)
1914–1919.
118. R. N. Brogden et al., Drugs 16 (1987) 97–114.
119. A. Whelton et al., JAMA 249 (1983) 2892.
120. T. D. Warner et al., Proc. Natl. Acad. Sci.
U.S.A. 96 (1999) 7563–7568.
121. C. Haanen, Curr. Opin. Investig. Drugs 2
(2001) 677–683
122. McNeil, US 3 752 826, 1973;
GB 1 428 272, 1973.
Analgesics and Antipyretics 87
123. J. R. Carson et al., J. Med. Chem. 14 (1971)
646–647.
124. R. N. Brogden, Drugs 15 (1978) 429–450.
125. C. Brideau et al., Inflamm Res. 45 (1996)
68–74.
126. E. Arrigoni-Martelli, J. Prous, J. Castaner,
Drugs of the Future 14 (1989) 963.
127. G. Biasi, R. Marcolongo, Minerva Med. 92
(2001) 315–324.
128. G. Coruzzi et al., Curr. Drug Targets Inflamm.
Allergy. 3 (2004) 43–61.
129. G. Coruzzi et al., Dig. Liver Dis. 34 (2002)
403–410.
130. J. Prous, J. Castaner, Drugs of the Future 13
(1988) 1050.
131. CDC Life Sciences Inc., US 4 327 222, 1982
(R. G. Micetich et al.).
132. Teiho Pharmaceuticals, EP 454 871, 1990 (H.
Tanaka, Y. Hagiwara, H. Kajitani, H.
Yasumoto).
133. Taiho Pharmaceuticals, EP 464 218, 1991 (H.
Tanaka, Y. Hagiwara, H. Kajitani, H.
Yasumoto).
134. CDC Life Science, EP 26928, 1981 (R. G.
Micetich et al.).
135. T. Ushio et al, Iykuhin Kenkyu 22 (1991) 892.
136. N. Ono et al., Nippon Yakurigaku Zasshi. 95
(1990) 63–81.
137. K. Goto et al., Prostaglandins Other Lipid
Mediat. 56 (1998) 245–254.
138. D. A. Walch et al., J. Med. Chem. 27 (1984)
1379–1388.
139. US 4 126 635, 1977 (H. Robins et al.).
140. A.H. Robinson Co., Inc. US 4 568 695, 1983
(H. Robins et al.).
141. J. Prous, J. Castaner, Drugs of the Future 13
(1988) 943.
142. T. Ogawa et al. Nippon Ganka Gakkai Zasshi
99 (1995) 406–411.
143. R. J. Fontana et al., Liver Transpl. Surg. 5
(1999) 480–484.
144. E. B. Hunter et al., Am. J. Gastroenterol. 94
(1999) 2299–2301.
145. P. L. Moses et al., Am. J. Gastroenterol. 94
(1999) 1393–1396.
146. Beecham, US 4 420 639, 1983;
DE 2 463 219, 1974.
147. A. C. Goudie et al., J. Med. Chem. 12 (1978)
1260–1264.
148. M. Neumann, Drugs Future 6 (1981) 35–36.
149. C. Prabhakar et al., Org. Process Res. Dev. 3
(1999) 121–125.
150. H. A. Friedel et al., Drugs 45 (1993) 131–156.
151. Degussa, US 3 513 171, 1970;
DE 1 670 522, 1966.
152. Drugs Future 8 (1983) 773–775.
88 Analgesics and Antipyretics
153. W. v. Bebenburg, et al., Chem. Ztg. 105 (1981)
217–219.
154. W. v. Bebenburg, G. Steinmetz, K. Thiele,
Chem. Ztg. 103 (1979) 387–399.
155. M. L. Brochier, Eur. Heart J. 14 (1993)
951–957.
156. W. J. Wechter et al., Cancer Res. 60 (2000)
2203–2208.
157. J. M. Mayer, B. Testa, Drugs Future 22 (1997)
1347–1366.
158. M. Cleij et al., J. Org. Chem. 64 (1999)
5029–5035.
159. M. Busson, J. Int. Med. Res. 14 (1986) 53–62.
160. Rhône-Poulence, US 3 641 127, 1972.
161. G. G. Liversidge, Anal. Profiles Drug Subst.
10 (1981) 443–471.
162. J. L. Hommeril et al., Br. J. Anaesth. 72 (1994)
383–387.
163. P. Patrignani et al., J Physiol. Pharmacol. 48
(1997) 623–631.
164. R. L. Dorfman, Arzneim.-Forsch./Drug Res. 25
(1975) 278–281.
165. T. Y. Shen, Angew. Chem. Int. Ed. Engl. 11
(1972) 460.
166. H. R. Bellur, J. R. Ahuja, D. G. Kulkarni,
Tetrahedron: Asymmetry 3 (1992) 163–192.
167. Syntex, US 3 663 584, 1972.
168. Syntex, US 4 605 758, 1986.
169. P. A. Todd, S. P. Clissold, Drugs 40 (1990)
91–137.
170. J. Rautio et al., J. Med. Chem. 43 (2000)
1489–1494.
171. Roussel-Uclaf, DOS 2 055 264, 1970.
172. G. L. Plosker, A. J. Wagstaff, Drugs 50 (1995)
1050–1075.
173. F. G. Mayall et al., Br. Med. J. 309 (1994)
599–600.
174. J. Prous, J. Castaner, Drugs of the Future 14
(1989) 302.
175. Nippon Chemiphar, US 4 247 706, 1981 (Y.
Fujimoto, S. Yamabe).
176. M. Hatori, S. Kokubun, Curr. Med. Res. Opin.
14 (1998) 79–87.
177. N. Murakami et al., Jpn. J. Pharmacol. 72
(1996) 29–37.
178. H. B. Tang et al., Neuropharmacology 48
(2005) 1035–1042.
179. R. W. Carney et al., Experientia 29 (1973),
938.
180. Ciba, US 3 641 040, 1972 (R. W. Carney, G.
DeStevens).
181. P. A. Todd, R. Beresford, Drugs. 32 (1986)
509–537.
182. M. Guidotti et al., J. Int. Med Res. 17 (1989)
48–54.
183. J. Pirotte et al., Gastroenterol. Clin. Biol. 11
(1987) 520.
184. J. R. Hannequin et al., Rev. Rheum. Mal.
Osteoartic. 55 (1988) 983–988.
185. A. C. Depla et al., Neth. J. Med. 37 (1990)
32–36.
186. M. Eugene et al., Rev. Med. Interna 8 (1987)
115.
187. Ely Lilly, DOS 1 941 625, 1969.
188. Ely Lilly, US 3 600 437, 1971 (W. S.
Marshall).
189. Mitsubishi Petrochemical, DOS 2 646 792,
1976 (M. Takeda, M. Uchide, H. Masayuka).
190. Nissin Flour Milling, US 4 016 196, 1977 (K.
Katsura Kogure, T. Noriyoshi Sueda, T.
Youziro Yoshino, K. Kunio Nakagawa).
191. Sagami, DAS 2 709 504, 1977 (G.
Tsuchihashi, K. Ogura).
192. C. M. Gruber Jr., J. Rheumatol. 2 (1976) 8–17.
193. R. N. Brogden et al., Drugs 13 (1977)
241–265.
194. R. N. Brogden et al., Drugs 21 (1981) 1–22.
195. J. R. Ryan et al., Clin. Pharmacol. Ther. 42
(1987) 28–32.
196. M. L. Wendland et al., Mayo Clin. Proc. 55
(1980) 103–107.
197. J. S. Stotts et al., J. Am. Acad. Dermatol. 18(4
Pt 1) (1988) 755–757.
198. CERM, US 4 218 473, 1980 (J. J. Godfroid, E.
Steiner).
199. M. Hoeijmakers et al., J. Vet. Pharmacol. Ther.
28 (2005) 305–312.
200. T. Nell et al., J. Small Anim. Pract. 43 (2002)
208–212.
201. P. Lees et al., J. Vet. Pharmacol. Ther. 22
(1999) 96–106.
202. D. A. Walsh et al., J. Med. Chem. 33 (1990),
2296–2304.
203. Alcon, WO 09932104, 2000 (J. H. Yanni, M.
R. Hellberg).
204. T. L. Ke et al., Inflammation 24 (2000)
371–384.
205. K. Takahashi et al., Invest. Ophthalmol. Vis.
Sci. 44 (2003) 409–415.
206. D. A. Gamache et al., Inflammation 24 (2000)
357.
207. R. Linstrom, T. Kim, Curr. Med. Res. Opin. 22
(2006) 397–404.
208. W. J. Welstead et al., J. Med. Chem. 22 (1979),
1074–1079.
209. Robins Co., Inc., DE 2 324 768, 1973 (W.
Welstead, H. W. Moran)
210. Robins Co., Inc., US 1972 254 285, 1972 (W.
Welstead, H. W. Moran)

211. G. Ehrhart, H. Ruschig: Arzneimittel,
Entwicklung, Wirkung, Darstellung, vol. 1,
Verlag Chemie, Weinheim 1972, pp. 171–172.
212. I.G. Farben, DRP 476 663, 1922.
213. Z. Fendrich, Cas. Lek. Cesk. 139 (2000)
440–444.
214. F. Arellano, J A. Sacristan, Eur. J. Clin.
Pharmacol. 38 (1990) 617–619.
215. M. Levy et al., Clin. Pharmacokinet. 28 (1995)
216–234.
216. Hoffmann-La Roche, DRP 565 799, 1931.
217. Riedel-deHaen, DE 962 254, 1954.
218. K. Brune, Agents Actions 25 Suppl. (1988)
9–19.
219. E. Gores et al., Med. Monatsschr. Pharm. 27
(2004) 72–76.
220. R. Denss et al., Helv. Chim. Acta 40 (1957)
402.
221. M. Kühn et al., J. Prakt. Chem. 156 (1940)
103.
222. Horakova et al., Pharmacotherapeutica (1963)
335–350.
223. J. Büchi et al., Helv. Chim. Acta 36 (1953) 75.
224. Comm. Farmaceutica Milanese, GB 839 057,
1957.
225. D. Loew et al., Z. Rheumatol. 44 (1985)
186–192.
226. Geigi, US 2 745 783, 1956.
227. L. E. Westerholm, Br. Med. J. 3 (1973)
339–343.
228. Geigi, US 2 562 830, 1951.
229. S. L. Ali, Anal. Profiles Drug Subs. 11 (1982)
483–521.
230. G. A. Faich, Pharmacotherapy 7 (1987)
25–27.
231. Warner-Lambert, DOS 2 208 351, 1972.
232. J. G. Lombardino, E. H. Wisemann, J. Med.
Chem. 14 (1971) 973.
233. H. Zinnes et al., J. Med. Chem. 25 (1982) 12.
234. W. W. Downie, Semin. Arthritis Rheum. 12
(1982) Suppl. 2, 170–174.
235. Drugs Future 17 (1992) 683–686.
236. T. Pruss et al., Postgrad. Med. J. 66 (1990)
Suppl. 4818–821.
237. T. Christoph et al., Inflamm. Res. 44 (1995)
Suppl. 3 Abstr. W16/17.
238. J. A. Balfour et al., Drugs 51 (1996) 639–657.
239. Pfizer, US 3 591 584, 1971;
US 4 469 866, 1984.
240. J. G. Lombardino et al., J. Chiaini, J. Med.
Chem. 5 (1973) 493–496.
241. E. H. Wisemann et al., Arzneim.-Forsch./Drug
Res. 26 (1976) 1300–1303.
242. L. Castaner, E. Arrigoni-Martelli, Drugs
Future 2 (1977) 124–127.
Analgesics and Antipyretics 89
243. Hoffmann-La Roche, DOS 2 537 070, 1975.
244. R. N. Brogden et al., Drugs 22 (1981)
165–187.
245. R. N. Brogden et al., Drugs 28 (1984)
292–323.
246. J. A. Mitchell et al., Proc. Natl. Acad. Sci. USA
90 (1993) 11693–11697.
247. E. Arrigoni-Martelli, Drugs Future 7 (1982)
493–494.
248. P. A. Todd, S. P. Clissold, Drugs 41 (1991)
625–646.
249. Synthex, US 4 347 186, 1982;
US 4 458 081, 1984;
US 4 873 340, 1989.
250. E. Arrigoni-Martelli, Drugs Future 8 (1983)
871–874.
251. A. Guzman et al., J. Med. Chem. 29 (1986)
589–591.
252. J. M. Muchowski et al., J. Med. Chem. 28
(1985) 1037–1049.
253. F. F. Franco et al., J. Org. Chem. 47 (1982)
1682–1688.
254. M. M. T. Buckley, R. N. Brogden, Drugs 39
(1990) 86–109.
255. John Wyeth and Brothers, Ltd, US 3578671,
1971 (K. Brown).
256. E. Arrigoni-Martelli, Drugs of the Future 3
(1978) 539–542.
257. L. G. Miller, Clin. Pharm. 11 (1992) 591–603.
258. American Home Products, US 3 843 681,
1974.
259. L. Castaner, E. Arrigoni-Martelli, Drugs
Future 2 (1977) 21–23.
260. C. A. Demerson, et al., J. Med. Chem. 19
(1976) 391–395.
261. C. A. Demerson et al., J. Med. Chem. 18
(1975) 189.
262. N. Bellamy, Inflammopharmacology 5 (1997)
139–152.
263. A. S. Taha et al., Gut 30 (1989) A751.
264. G. Bianchi Porro, et al., J. Intern. Med. 229
(1991) 5–8.
265. Thomae GmbH, DE 2 756 113, 1979.
266. G. Trummlitz, G. Engelhardt, U. Busch, Drugs
Future 14 (1989) 1047–1048.
267. G. Engelhardt et al., Inflamm. Res. 44 (1995)
423–433.
268. J. A. Lopez-Garcia et al., Neuroreport 9
(1998) 647–651.
269. Riker, US 3 840 597, 1974;
DOS 2 333 643, 1973.
270. R. Davis, R. N. Brogden, Drugs 48 (1994)
431–454.
271. A. Azab et al., Life Sci. 63 (1998) PL 323–327.
90 Analgesics and Antipyretics
272. P. A. McCormick et al., Lancet 353 (1999)
40–41.
273. C. Ferreiro et al., Gastroenterol. Hepatol. 23
(2000) 428–430.
274. Drugs Future 22 (1997) 711–714.
275. Searle & Co., US 5 521 207; EP 731 795; WO
9 515 316 (J. J. Talley, T. D. Penning, P. W.
Collins et al.).
276. G. Steinbach et al., N. Engl. J. Med. 342
(2000) 1946–1952.
277. J. L. Goldstein et al., Am. J. Gastroenterol. 96
(2001) 1019–1027
278. F. E. Silverstein et al., JAMA 284 (2000)
1247–1255.
279. J. M. Brophy, Expert Opin. Drug. Saf. 4 (2005)
1005–1015.
280. L.A. Sorbera et al., Drugs of the Future 26
(2001) 346–353.
281. R.W. Friesen et al., Biorg. Med. Chem. Lett. 8
(1999) 2777–2782.
282. I. W. Davies et al., J. Org. Chem. 65 (2000)
8415–8420.
283. I. W. Davies et al., J. Org. Chem. 65 (2000)
8571–8574.
284. J. F. Marcoux et al., Org. Lett. 2 (2000)
2339–2341.
285. A. Dallob et al., J Clin Pharmacol. 43 (2003)
573–585.
286. D. J. Cochrane et al., Drugs. 62 (2002)
2637–2651.
287. A. D. Rodrigues et al., Drug Metab. Dispos. 31
(2003) 224–232.
288. K. Kassahun et al., Drug Metab. Dispos. 29
(2001) 813–820.
289. N. Chauret et al., Bioorg. Med. Chem. Lett. 11
(2001) 1059–1062.
290. D. R. Ramey et al., Curr. Med. Res. Opin. 21
(2005) 715–722.
291. S. P. Curtis et al., Clin Ther. 26 (2004) 70–83.
292. S. Aldington et al., N. Z. Med. J. 118 (2005)
U1684.
293. L. A. Sorbera et al., Drugs of the Future 27
(2002) 740–747.
294. Novartis, WO 2001 023346, 2001 (M. Murat,
T. Allemendiger, J. Calienni, J. Cercus, O.
Loiseleur).
295. Novartis, WO 1999 011605, 1999 (L.
Mcquire, B. Mugrage, J. Van Duzer).
296. K. A. Lyseng-Williamson et al., Drugs 64
(2004) 2237–2246.
297. F. Berenbaum et al., J. Int. Med. Res. 33
(2005) 21–41.
298. P. Geusens et al., Int. J. Clin. Pract. 58 (2004)
1033–1041.
299. E. Packman et al., Headache 45 (2005)
1163–1170.
300. J. A. Rosenberg et al., Nat. Clin. Pract.
Gastroenterol. Hepatol. 2 (2005) 14–15.
301. C. J. Hawkey et al., Clin. Gastroenterol.
Hepatol. 4 (2006) 57–66.
302. P. Matchaba et al., Clin. Ther. 27 (2005)
1196–214.
303. H. Tannenbaum et al., Ann. Rheum. Dis. 63
(2004) 1419–1426.
304. C. M. Rordorf et al., Clin. Pharmacokinet. 44
(2005) 1247–1266.
305. Pfizer Inc., WO 2005123701, 2005 (L. J.
Letendre, C. K. Snoddy, G. H. Klemm, J. P.
Lawson, M. J. Bauer).
306. J. J. Talley et al., J. Med. Chem. 43 (2000)
1661–1663.
307. Searle & Co. WO 9515316;
US 5 521 207;
EP 731 795 1995 (J. J -Talley et al.).
308. S. M. Cheer, K. L. Goa, Drugs 61(2001)
1133–1141.
309. A. W Gotta, Idrugs 4 (2001) 939–944.
310. A. S. Dalpiaz, D. Peterson, Expert. Rev.
Neurother. 4 (2004) 165–177.
311. S. Aldington et al., N. Z. Med. J. 118 (2005)
U1755.
312. C. D. Furberg et al., Circulation 111 (2005)
249.
313. E. G. Harks et al., J. Pharmacol. Exp. Ther.
298 (2001) 1033–1041.
314. L. A. Sorbera et al. Drugs Future 23 (1998)
1287–1296.
315. L. A. Sorbera et al., Drugs of the Future 23
(1998) 1287–1296.
316. M. Therien et al., Synthesis (2001) 1778–1779.
317. L. J. Scott, H. M. Lamb Drugs. 58 (1999)
499–505.
318. A. J. Matheson, D. P. Figgitt, Drugs. 61 (2001)
833–865.
319. C. C. Chan et al., J. Pharmacol. Exp. Ther. 290
(1999) 551–560.
320. L. Laine et al., Gastroenterology 117 (1999)
776–783.
321. C. Bombardier et al., N. Engl. J. Med. 343
(2000) 1520–1528.
322. M. Wadman, Nature 433 (2005) 790.
323. J. J. Talley in F. D. King A. W. Oxford (eds.):
Progress in Medicinal Chemistry-Vol 36,
Elsevier, Amsterdam 1999.
324. D. Ormrod et al., Drugs 62 (2002) 2059–2071.
325. M. L. Chavez, C. J. De Korte Clin Ther. 25
(2003) 817–851.
326. C. Fenton et al. Drugs. 64 (2004)1231–1261.
327. J. E. Edwards et al. Pain 111 (2004) 286–296.

328. G. P.Joshi Expert Rev. Neurother. 5 (2005)
11–24.
329. D. Kudrow et al. Headache 45 (2005)
1151–1162.
330. C. Talhari et al., J. Allergy Clin. Immunol. 115
(2005) 1089–1090.
331. F. L. Byerly et al., Burns 31 (2005) 383–387.
332. N. A. Nussmeier et al. N. Engl. J. Med. 352
(2005) 1081–1091.
333. A. F. Casy, R. T. Parfitt: Opioid Analgesics,
Chemistry and Receptors, Plenum Press, New
York 1986.
334. A. F. Casy, R. T. Parfitt, Opioid Analgesics.
Chemistry and Receptors, Plenum Press, New
York -London 1986.
335. A. F. Casy, R. T. Parfitt, Opioid Analgesics.
Chemistry and Receptors, Plenum Press, New
York -London 1986.
336. H. Akil et al. Annu. Rev. Neurosci. 7 (1984)
223–255.
337. A. Mansour et al., Trends Neurosci. 18 (1995)
22–29.
338. A. Herz J. Neural. Transm. Suppl. 18 (1983)
227–233.
339. G. B. Stefano, et al. Crit. Rev. Immunol. 16
(1996) 109–144.
340. C. Stein et al.,in C. Stein (ed.): Opioids in Pain
Control. Basic and Clinical Aspects,
Cambridge University Press, Cambridge 1999,
pp. 96–108.
341. W.R. Martin et al., J. Pharmacol. Exp Ther.
197 (1976) 517–5132.
342. C. J. Fowler G. L. Fraser Neurochem. Int. 24
(1994) 401–426.
343. W. R. Martin, Pharmacol. Rev. 35 (1983)
283–323.
344. B. N. Dhawan et al., Pharmacol Rev. 48
(1996) 567–592.
345. J. C. Meunier et al., Nature 377 (1995)
532–535.
346. P. L. Wood, Neuropharmacology 21 (1982)
487–497.
347. G. W. Pasternak, P. J. Wood, Life Sci. 38
(1986) 1889–1898.
348. G. Gaveriaux-Ruff, B. Kieffer, in C. Stein,
(ed.): Opioids in Pain Control. Basic and
Clinical Aspects, Cambridge University Press,
Cambridge 1999, pp. 1–20.
349. B. L. Kieffer et al., Proc. Natl. Acad. Sci. U S
A. 89 (1992) 12048–12052.
350. C. J. Evans et al., Science, 258 (1992)
1952–1955.
351. R. K. Reinscheid et al. Science, 270 (1995)
792–794.
352. G. Calo’ et al. Peptides, 21 (2000) 935–947.
Analgesics and Antipyretics 91
353. R. J. Knapp et al., FASEB J. 9 (1995) 516–525.
354. S. R. Childers Life Sci. 48 (1991) 1991–2003.
355. I. McFadzean, Neuropeptides 11 (1988)
173–180.
356. W. F. Simonds, Endocr. Rev. 9 (1988) 200–212.
357. A. D. Blake et al. Channels 5 (1997) 231–235.
358. P. Y. Law, H. H. Loh, J. Pharmacol. Exp. Ther.
289 (1999) 607–624.
359. N. I. Cherny, Drugs 51 (1996) 713–737.
360. H. W. Matthes et al., Nature 383 (1996)
819–823.
361. B. L. Kieffer, Trends Pharmacol. Sci. 20
(1999) 19–26.
362. D. I. Scopes, Drug of the Future 18 (1993)
933–947.
363. A. Barber, R. Gottschlich, Exp. Opin. Invest.
Drugs 6 (1997) 1354–1368.
364. G. Dondio et al., Exp. Opin. Ther. Patents 7
(1997) 1075–1098.
365. M. A. Scheideler, Curr. Opin. CPNS Invest
Drugs 2 (2000) 171–177.
366. C. Mollereau, L. Mouledous, Peptides. 21
(2000) 907–917.
367. R. Bertorelli et al., Trends Pharmacol. Sci. 21
(2000) 233–234.
368. A. Mansour et al., Trends Neurosci. 18 (1995)
22–29.
369. J. Lipp, Clin. Neuropharmacol. 14 (1991)
131–147.
370. T. L Yaksh, Acta Anaesthesiol. Scand. 41
(1997) 94–111.
371. C. Stein, Opioids in Pain Control. Basic and
Clinical Aspects, Cambridge University Press,
Cambridge 1999.
372. C. P. Watson, Clin. J. Pain, 16 (2 Suppl.)
(2000) S49–55.
373. R. C. Etches et al., Can. J. Anaesth. 36 (1989)
165–185.
374. J. E. Shook et al., Am. Rev. Respir. Dis. 142
(1990) 895–909.
375. M. F. Mulroy, Reg. Anesth. 21 (6 Suppl.)
(1996) 89–93.
376. F. W. Jackson, Gastroenterology 106 (1994)
820–821.
377. T. A. Bowdle, Drug Saf. 19 (1998) 173–189.
378. W. Kromer, Dig. Dis. 8 (1990) 361–373.
379. I. Mancini, E. Bruera, Support Care Cancer 6
(1998) 356–364.
380. A. De Luca, I. M. Coupar, Pharmacol. Ther.
69 (1996) 103–115.
381. R. C. Heel et al. Drugs. 15 (1978) 33–52.
382. E. Campora et al., J. Pain Symptom Manage. 6
(1991) 428–430.
383. R. Aparasu et al., J. Pain Symptom Manage. 18
(1999) 280–288.
92 Analgesics and Antipyretics
384. J. P. Blancquaert et al. Eur. J. Pharmacol. 128
(1986) 143–150.
385. N. M. Barnes et al., Neuropharmacology 30
(1991) 1073–1083.
386. A. Pfeiffer et al., Science 233 (1986) 774–776.
387. R. Brown, R. Lo, Aust. N. Z. .J Ment. Health
Nurs. 9 (2000) 65–74.
388. D. A. Taylor, W. W. Fleming, Pharmacol. Exp.
Ther. 297 (2001) 11–18.
389. H. A. Heit, Eur. J. Pain 5 Suppl A (2001)
27–29.
390. R. F. Reder, Eur. J. Pain. 5 Suppl A (2001)
109–111.
391. F. J. Muhtadi, Anal. Profiles Drug Subs. 17
(1988) 259–366.
392. Knoll, DOS 2 726 925, 1977.
393. T. Hudlicky et al.: “A historical perspective of
morphine synthesis,” in: Atta-ur-Rahman
(ed.): Studies in Natural products Chemistry,
Elsevier, Amsterdam 1996, pp. 43–116.
394. D. Trauner et al., Synthesis 1983 203–204.
395. J. Mulzer, D. Trauner, Chirality 11 (1999)
475–482.
396. J. Frackenpohl, Chem. u. Zeit 34 (2000)
99–112.
397. G. J. Meuzelaar et al., Eur. J. Org. Chem.
(1999) 2315–2321.
398. J. Mulzer, D. Trauner, Chirality 11 (1999)
475–482.
399. H. Nagata, et al. Chem. Commun. (2001)
1094–1095.
400. H. J. McQuay, B. J. Anaest. 63 (1989)
213–226.
401. L L. Christrup, Acta Anaesthesiol. Scand. 41
(1997) 116–122.
402. R. Osborne et al., Clin. Pharmacol. Ther. 47
(1990) 12–19.
403. J. Lotsch, G. Geisslinger, Clin.
Pharmacokinet. 40 (2001) 485–499.
404. G. Ehrhart, H. Ruschig: Arzneimittel,
Entwicklung, Wirkung, Darstellung, vol. 1,
Verlag Chemie, Weinheim 1972, pp. 117–118.
405. Boehringer, DRP 247 180, 1912.
406. B. L. Posey, N. S. Kimble, J. Anal. Toxicol. 8
(1984) 68–74.
407. F. J. Muhtadi, M. M. A. Hassan, Anal. Profiles
Drug Subs. 10 (1981) 93–138.
408. Q. Y. Yue et al., Ther. Drug Monit. 19 (1997)
539–542.
409. G. Ehrhart, H. Ruschig: Arzneimittel,
Entwicklung, Wirkung, Darstellung, vol. 1,
Verlag Chemie, Weinheim 1972, 118.
410. E. Merck AG, DRP 131 980, 1902.
411. E. Tani et al., Arzneimittelforschung 39 (1989)
1399–1402.
412. V. Ozdemir et al., Pharmacogenetics 10
(2000) 373–388.
413. G. Ehrhart, H. Ruschig: Arzneimittel,
Entwicklung, Wirkung, Darstellung, vol. 1,
Verlag Chemie, Weinheim 1972, pp. 79, 115.
414. C.E. Inturrisi et al., Life Sci. 33 Suppl 1 (1983)
773–776.
415. J. G. Umans, C. E. Inturrisi, J. Pharmacol.
Exp. Ther. 218 (1981) 409–415.
416. D. K. Wyatt, L. T. Grady, Anal. Profiles Drug
Subst. 10 (1981) 357–403.
417. U. Boerner et al., Drug Metab. Rev. 4 (1975)
39–73.
418. C. E. Inturrisi et al., N. Engl. J. Med. 310
(1984) 1213–1217.
419. G. Ehrhart, H. Ruschig: Arzneimittel,
Entwicklung, Wirkung, Darstellung, vol. 1,
Verlag Chemie, Weinheim 1972, p. 180.
420. A. Stein, Pharmazie 10 (1955) 180–186.
421. J. E. Edwards et al. Cochrane Database Syst.
Rev. (2000) CD 2760.
422. H. Matthys et al., Schweiz. Med. Wochenschr.
115 (1985) 307–311.
423. R. S. Lloyd et al., Curr. Med. Res. Opin. 13
(1992) 37–48.
424. Reckitt & Colman, DE 1 620 206, 1966.
425. Reckitt & Sons Ltd., US 3 433 791, 1969.
426. K. W. Bentley, D. G. Hardy, Proc. Chem. Soc.
(London) 1963, 220.
427. W. G. Dorner, Chem. Unserer Zeit 15 (1986)
33–46.
428. K. O. Lee et al., Eur. J. Pharmacol. 378 (1999)
323–330.
429. G. F. Blane, J. Pharm. Pharmacol. 19 (1967)
367–373.
430. T. Alford et al., J. Am. Vet. Med. Ass. 164
(1974) 702–705.
431. G. Ehrhart, H. Ruschig: Arzneimittel,
Entwicklung, Wirkung, Darstellung, vol. 1,
Verlag Chemie, Weinheim 1972, pp. 119–120.
432. Knoll, DRP 607 931, 1935.
433. Z. R. Chen et al., Life Sci. 48 (1991)
2165–2171.
434. A. B. Morrison, Can. Med. Assoc J. 120
(1979) 1338.
435. Merck, US 2 715 626, 1955.
436. H. Rapoport, R. Naumann, E. R. Bissel, R. M.
Bonner, J. Org. Chem. 15 (1950) 1103–1107.
437. G. Lindena et al., Schmerz 12 (1998) 195–204.
438. D. E. Moulin et al., Lancet 337 (1991)
465–468.
439. J. L. Hill, J. P. Zacny, Psychopharmacology
(Berlin). 152 (2000) 31–39.

440. G. Ehrhart, H. Ruschig: Arzneimittel,
Entwicklung, Wirkung, Darstellung, vol. 1,
Verlag Chemie, Weinheim 1972, pp. 130–131.
441. O. Schnider, A. Grüssner, Helv. Chim. Acta 34
(1951) 2211–2217.
442. O. Schnider, J. Hellerbach, Helv. Chim. Acta
33 (1950) 1437–1448.
443. R. Grewe, Naturwissenschaften 33 (1946)
333–337.
444. S. R. Childers, Life Sci. 48 (1991) 1991–2003.
445. L. L. Randall, G. Lehmann, J. Pharmacol.
Exp. Ther. 99 (1950) 163.
446. S. W. Coniam, Anaesthesia 46 (1991) 518.
447. G. Ehrhart, H. Ruschig: Arzneimittel,
Entwicklung, Wirkung, Darstellung, vol. I,
Verlag Chemie, Weinheim 1972, 118.
448. E. Merck, DRP 411 530, 1925.
449. K. W. Bentley: The Chemistry of Morphine
Alkaloids, Oxford 1954.
450. F. M. Hauser et al., J. Med. Chem. 17 (1974)
1117.
451. J. Cleary et al., J. Pharmacol. Exp. Ther. 271
(1994) 1528–1534.
452. E. Kalzo, A. Vanino, Clin Pharmacol. Ther. 47
(1990) 639–646.
453. F. Kaiko et al., Clin. Pharmacol. Ther. 59
(1996) 52–61.
454. U. Weiss, J. Am. Chem. Soc. 77 (1955)
5891–5892.
455. R. S. Sinatra, D. M. Harrison, Clin. Pharm. 8
(1989) 541–544.
456. V. S. Copland et al., Am. J. Vet. Res. 48 (1987)
1626–1630.
457. Winthrop, US 2 167 351, 1939, (O. Eisleb).
458. I. G. Farben, DE 679 281, 1937.
459. O. Eisleb, Chem. Ber. 74 (1941) 1433–1450.
460. E. E. Smissman, G. Hite, J. Am. Chem. Soc. 81
(1959) 1201–1203.
461. C. B. Pert, S. H. Snyder, J. Med. Chem. 19
(1976) 1248–1250.
462. N. P. Fish, N. J. De-Angelis, Anal. Profiles
Drug Subs. 1 (1972) 175–205.
463. K. Jiraki, Am. J. Forensic Med. Pathol. 13
(1992) 42–43.
464. D. Meyer, V. Halfin, J. Clin.
Psychopharmacol. 1 (1981) 319–321.
465. C. F. Seifert, S. Kennedy, Pharmacotherapy 24
(2004) 776–783.
466. J. G. Stevenson et al., Jt. Comm. J. Qual. Saf.
30 (2004) 277–281, 233.
467. A. B. O’Connor, et al., Am. J. Med. 118 (2005)
885–889.
468. I.G. Farben, DRP 752 755, 1942.
469. H. Kägi, K. Miescher, Helv. Chim. Acta 32
(1949) 2489–2507.
Analgesics and Antipyretics 93
470. C. B. Christensen, Pharmacol. Toxicol. 73
(1993) 344–345.
471. L. Jylli et al., Acta Anaesthesiol. Scand. 48
(2004) 1256–1259.
472. S. Andersen et al., Pain 67 (1996) 369–374.
473. P. Peltola, P. Soisalo, AMA Arch Intern Med.
101 (1958) 741–746.
474. Janssen, US 3 164 600, 1965;
US 3 141 823, 1964.
475. R. Hess et al., J. Pharmacol. Exp. Ther. 179
(1971) 474–484.
476. M. A. Clotz, M. C. Nahata, Clin. Pharm. 10
(1991) 581–593.
477. J. F. Buchanan, C. R. Brown, Med. Toxicol. 3
(1988) 1–17.
478. Janssen, DE-OS 2 819 837, 1978.
479. F. Janssen et al., J. Med. Chem. 29 (1986)
2290–2297.
480. S. J. Hopkins, Drugs Future 6 (1981) 335–337.
481. R. F. Cookson et al., Br. J. Anaesth. 55 Suppl 2
(1983) 147S–155S.
482. C. J. E. Niemegeers, P. A. J. Janssen, Drug.
Dev. Res. 1 (1981) 83.
483. G. E. Larijani, M. E. Goldberg, Clin. Pharm. 6
(1987) 275–282.
484. Glaxo, EP 383 579, 1990.
485. Drugs Future 19 (1994) 1088–1092.
486. K. Flick et al., Arzneim.-Forsch./Drug Res. 28
(1978) no. 1, 107–113.
487. W. E. Hoffman et al., Anesthesiology 79
(1993) 107–113.
488. T. E. Egan, Clin. Pharmacokinet. 29 (1995)
80–94.
489. F. Servin, Eur. J. Anaesthesiol. 15
Suppl.(1997) 41–44.
490. C. G. Haigh, Minerva Anesthesiol. 66 (2000)
414–416.
491. J. Cohen, D. l. Royston, Curr. Opin. Crit. Care
7 (2001) 227–231.
492. L. G. Michelsen et al., J. Clin. Anesth. 8
(1996) 679–682.
493. Janssen, US 3 998 834, 1976.
494. L. Castaner, E. Arrigoni-Martelli, Drugs
Future 2 (1977) 334–337.
495. W. F. M. Van Bever, et al.,
Arzneim.-Forsch./Drug Res. 26 (1976)
1548–1556.
496. P. G. H. Van Daele et al.,
Arzneim.-Forsch./Drug Res. 26 (1976)
1521–1531.
497. J. E. Leysen et al., Eur. J. Pharmacol. 87
(1983) 209–225.
498. I. P. Monk et al., Drugs 36 (1988) 286–313.
499. M. Goldberg et al., Anesthesiology 63 (1985)
199–201.
94 Analgesics and Antipyretics
500. J. A. Grass, J. Pain Symptom Manage. 7
(1992) 271–286.
501. M. Goldberg et al., Anesthesiology 63 (1985)
199–201.
502. Farbw. Hoechst, DBP 865 314, 1941.
503. Merck & Co., US 2 644 010, 1953.
504. Abott, US 2 983 757, 1961.
505. E. M. Schultz et al., J. Am. Chem. Soc. 69
(1947) 2454–2459.
506. N. R. Easton et al., J. Am. Chem. Soc. 69
(1947) 2941–2942.
507. A. A. Larsen et al., J. Am. Chem. Soc. 70
(1948) 4195–4196.
508. E. E. Howe, M. Sletzinger, J. Am. Chem. Soc.
71 (1949) 2935.
509. M. Bockmühl, G. Ehrhart, Justus Liebigs Ann.
Chem. 561 (1948) 52–85.
510. S. K. Sim, Can. Med. Assoc. J. 109 (1973)
615–619.
511. R. H. Biskara, Anal. Profiles Drug Subs. 3
(1974) 365–439.
512. G. D. Olson et al., Clin. Pharmacol. Ther. 21
(1977) 147–157.
513. M. P.xs Davis, D. Walsh, Support Care Cancer
9 (2001) 73–83.
514. H. Joseph et al., Mt. Sinai J. Med. 67 (2000)
347–364.
515. M. Farell et al., Br. Med. J. 309 (1994)
997–1001.
516. M. J. Kreek, JAMA. 223 (1973) 665–668.
517. J. Lowinson et al., Curr. Psychiatr. Ther. 18
(1978) 165–172.
518. F. I. Carroll et al., J. Org. Chem. 41 (1950)
3521–3524.
519. S. A. Walczak et al., Eur. J. Pharmacol. 72
(1981) 343–349.
520. J. D. Blaine et al. Ann. N. Y. Acad. Sci. 362
(1981) 101–115.
521. A. Wolven et al., NIDA Res. Monogr. (1976)
29–38.
522. J. Kang et al., Eur. J. Pharmacol. 458 (2003)
25–29.
523. R. L. Deamer et al., J. Addict Dis. 20 (2001)
7–14.
524. Janssen, DE 1 117 126; 1956;
GB 822 055, 1956.
525. A. J. Grace, Br. Med. J. 281 (1980) 1285.
526. A. Pohland, H. R. Sullivan, J. Am. Chem. Soc.
75 (1953) 4458–4461; 77 (1955) 3400–3401.
527. A. Pohland et al., J. Org. Chem. 28 (1963)
2483–2484.
528. H. R. Sullivan et al., J. Org. Chem. 28 (1963)
2381–2385.
529. D. Boven et al., Hum. Toxicol. 3 (1984) Suppl.,
1S–238S.
530. A. A. Lawson, D. B. Northridge, Med. Toxicol.
Adverse Drug Exp. 2 (1987) 430–444.
531. Janssen, US 2 898 340, 1959;
Searle, US 4 086 234, 1978.
532. C. J. Niemegeers et al., Arzneimittelforschung
22 (1972) 516–518.
533. D. D. Hung, Anal. Profiles Drug. Subst. 7
(1978) 149–169.
534. Janssen, US 3 714 159, 1973;
ED-OS 2 126 559, 1971.
535. R. A. Stokbroekx et al., J. Med. Chem. 16
(1973) 782–786.
536. M. R. Dashwood et al., Prog. Clin. Biol. Res.
328 (1990) 165–169.
537. R. C. Heel et al., Drugs 15 (1978) 33–52.
538. R. C. Heel et al., Drugs. 15 (1978) 33–52.
539. D. L. DeHaven-Hudkins, et al., Life Sci. 71
(2002) 2787–2796.
540. F. Awouters et al., Dig. Dis. Sci. 38 (1993)
977–995.
541. R. C. Heel et al., Drugs. 15 (1978) 33–52.
542. C. D. Ericsson P. C. Johnson, Am. J. Med.
88(6A) (1990) 10S–14S.
543. Janssen, DE 1 238 472, 1961.
544. F. Weyne et al., Acta anaesth. belg. 19 (1968)
33–45.
545. Gödecke, DE 1 518 959, 1965;
Warner-Lambert, US 3 557 126, 1969.
546. L. E. Overman et al., J. Org. Chem. 44 (1979)
4183–4185.
547. G. Satzinger, Justus Liebigs Ann. Chem. 758
(1972) 43–64, 65–71; 728 (1969) 64–87.
548. G. Satzinger et al., Pharm. Ind. 40 (1978)
657–664.
549. R. Schulz et al., Naunyn Schmiedebergs Arch.
Pharmacol. 304 (1978) 89–93.
550. M. Hermann et al., Arzneimittel-Forsch. 20
(1970) 977–983.
551. K. O. Vollmer, Fortschr. Med. 106 (1988)
593–596.
552. Grünenthal, GB 997 399, 1964;
US 3 564 100, 1971 (E. Frankus, K. Flick).
553. K. Flick et al., Arzneim.-Forsch./Drug Res. 28
(1978) no. 1, 107–113.
554. M. C. Frink et al., Arzneimittelforschung 46
(1996) 1029–1036.
555. E. Friderichs et al., Arzneimittel-Forsch. 28
(1978) 122–134.
556. R. B. Raffa, E. Friderichs, Pain Rev. 3 (1996)
249–271.
557. R. B. Raffa et al., J. Pharmacol. Exp. Ther. 267
(1993) 331–340.
558. C. R. Lee et al., Drugs 46 (1993) 313–340.
559. K. McClellan, L. J. Scott, Drugs 63 (2003)
1079–1088.

560. P,Huang et al., J. Pharmacol. Exp. Ther. 297
(2001) 688–695.
561. B. Kögel et al. Eur. J. Pain. 9 (2005) 599–611.
562. R. C. Heel et al., Drugs. 17 (1979) 81–110.
563. J. Martin, J.Psychoactive Drugs Suppl 2
(2004) 129–137.
564. S. Sung, J. M. Conry, Ann. Pharmacother. 40
(2006) 501–505.
565. T. J. Gal, Clin. Pharmacol. Ther. 45 (1989)
66–71.
566. N. Griessinger et al., Curr. Med. Res Opin. 21
(2005) 1147–1156.
567. A. Dahan et al., Br. J. Anaesth. (2006) 96,
627–632.
568. Bristol-Myers, US 3 775 414, 1973.
569. J. Monkovic et al., J. Am. Chem. Soc. 95
(1973) 7910.
570. J. Monkovic et al., J. Am. Chem. Soc. 100
(1978) 4609–4610.
571. C. E. Rosow, Acute Care 12 Suppl 1 (1988)
2–7.
572. R. C. Heel et al., Drugs 16 (1978) 473–505.
573. B. Ameer, F. J. Salter, Am. J. Hosp. Pharm. 36
(1979) 1683–1691.
574. R. V. Homan, Am. Fam. Physician 49 (1994)
188–192.
575. American Home, BE 776 173, 1971;
DE 2 159 324, 1971.
576. M. E. Freed et al., J. Med. Chem. 16 (1973)
595–599.
577. J. C. Chen et al., Life Sci. 52 (1993) 389–396.
578. J. J. O’Brien, et al., Drugs 38 (1989) 226–248.
579. J. L. Malis, J. Pharmacol. Exp. Ther. 194
(1975) 488–498.
580. J. J. O’Brien, P. Benfield, Drugs 38 (1989)
226–248.
581. Wyeth, DE-OS 1 941 534, 1969;
GB 1 285 025, 1969.
582. G. Bradley et al., Eur. J. Med. Chem. 15 (1980)
375.
583. B. Holmes, A. Ward, Drugs 30 (1985)
285–312.
584. G. W. Pasternak et al., Postgrad. Med. J. 61
Suppl 2 (1985) 5–12.
585. B. Holmes, A. Ward, Drugs 30 (1985)
285–312.
586. Endo Laboratories, GB 1 119 270, 1968;
US 3 332 950, 1967.
587. L. Castaner, P. J. Roberts, Drugs Future 2
(1977) 613–615.
588. E. B. De Souza, et al., J. Pharmacol. Exp.
Ther. 244 (1988) 391–402.
589. J. K. Errick, R. C. Heel, Drugs 26 (1983)
191–211.
Analgesics and Antipyretics 95
590. W. K. Schmidt, Drug Alcohol Depend. 14
(1985) 339–362.
591. G. C. Pugh et al., Br. J. Anaesth. 62 (1989)
601–609.
592. Merck & Co., US 2 364 833, 1944;
US 2 891 954, 1959.
593. M. U. Zubair et al., Anal. Profiles Drug Subs.
18 (1989) 195–219.
594. Sterling Drug, BE 611 000, 1961.
595. S. Archer et al., J. Med. Chem. 7 (1964)
123–127.
596. R. N. Brogden et al., Drugs 5 (1973) 6–91.
597. D. A. Reed, S. H. Schnoll, JAMA 256 (1986)
2562–2564.
598. H. Schmidthammer, Prog. Med. Chem. 35
(1998) 83–132.
599. G. Ehrhart, H. Ruschig: Arzneimittel,
Entwicklung, Wirkung, Darstellung, vol.1,
Verlag Chemie, Weinheim 1972, pp. 131–132.
600. J. Hellerbach et al., Helv. Chim. Acta 39
(1956) 429–440.
601. O. Schnider, A. Grüssner, Helv. Chim. Acta 24
(1951) 2211–2217.
602. D. M. Paton, Drugs Future 4 (1979) 438–441.
603. W. Leimgruber et al., Adv. Biochem.
Psychopharmacol. 8 (1973) 45–50.
604. F. F. Foldes et al., Can. Anaesth. Soc. J. 16
(1969) 151–161.
605. J. M. Evans et al., Anaesthesia 29 (1974)
721–727.
606. US 3 254 088, 1966;
DE 1 183 508, 1962 (M. J. Lewenstein).
607. R. A. Olofson et al., Tetrahedron Lett. 1977
1567–1577.
608. R. Simantov, S. H. Snyder, Biochem. Soc.
Trans. 5 (1977) 62–65.
609. K. A. Handal et al., Ann. Emerg. Med. 12
(1983) 438–445.
610. P. M. Goodrich, AANA J. 58 (1990) 14–16.
611. Endo Laboratories, GB 1 119 270, 1968;
US 3 332 950, 1967.
612. V. Höllt, A. Herz, Fed. Proc. 37 (1978)
158–161.
613. B. L. Crabtree, Clin. Pharm. 3 (1984)
273–280.
614. J. P. Gonzalez, R. N. Brogden, Drugs 35
(1988) 192–213.
615. B. A. Judson et al., Drug Alcohol Depend. 7
(1981) 325–346.
616. Boehringer Ingelheim Pharma GmbH & Co.
KG, US 4176186, 1979 (L. Goldberg, H.
Merz, K. Stockhans).
617. C. S. Yuan, J. F. Foss, Neuropharmacology 38
(1999) 425–432.
618. C. S. Yuan et al., J. Pharmacol. Exp. Ther. 300
(2002) 118–123.
96 Analgesics and Antipyretics
619. D. S. Wang et al., J. Emerg. Med. 16
(1998):471–475.
620. H. E. Jones et al., Drug Alcohol Depend. 60
(2000) 29–37.
621. L. C. Costantini et al., Int. J. Pharm. 283
(2004) 35–44.
622. J. E. Grant et al., Am. J. Psychiatry 163 (2006)
303–312.
623. K. Hempenstall, A. S. Rice, Curr. Opin.
Investig. Drugs 3 (220) 441–448.
624. R. H. Dworkin et al., Arch. Neurol. 60 (2003)
1524–1534.
625. H. Ueda, Pharmacol Therap. 109 (2006)
57–77.
626. D. B. Gordon, G. Love, Pain Manage. Nurs. 5
(2004) 19–33.
627. G. T. Carter, M. D. Sullivan, Curr. Opin.
Investig. Drugs 3 (2002) 454–458.
628. J. Zhou, Drugs of the Future 29 (2004)
1235–1244.
629. J. Lai et al., Ann. Rev. Pharmacol. Toxicol. 44
(2004) 371–397.
630. Ciba, US 3 471 548. 1969.
631. Ciba, US 3 978 216, 1972.
632. N. G. Bowery, Curr. Opin. Pharmacol. 6
(2006) 37–43.
633. Geigi, US 2 948 718, 1960 (W. Schindler).
634. DD 133 052, 1977 (R. Müller).
635. D. Soyka et al., Schmerz 12 (1998) 419–427.
636. Boehringer Ingelheim, DE 1 303 141, 1961;
US 3 236 857, 1966.
637. VEB Arzneimittelwerke Dresden, DE-AS 1
770 874, 1968.
638. H. Schmitt, Handb. Exp. Pharmacol. 39
(1977) 299–396.
639. C. Lund et al., Br. J. Anaesth. 63 (1989)
516–519.
640. D. R. Jasinki et al., Arch. Gen. Psychiatry 42
(1985) 1063–1066.
641. J. Deeter et al., Tetrahedron Lett. 31 (1990)
7101.
642. L. A. Sorbera et al., Drugs of the Future 25
(2000) 907–916.
643. H. Liu et al., Chirality 12 (2000) 26–29.
644. S. Attila, E. Leinonen, Curr. Opin.
Investig.Drugs 3 (2002) 1217–1221.
645. N. Pitsikas, Curr. Opin. Investig. Drugs 1
(2000) 116–121.
646. Degussa, DE 1 795 858, 1968;
US 3 513 171, 1970.
647. Drugs Future 8 (1983) 773–775.
648. W. von Bebenburg et al., Chem. Ztg. 103
(1979) 387–399.
649. W. von Bebenburg et al., Chem. Ztg. 105
(1981) 217–219.
650. H. A. Friedel, A. Fitton, Drugs 45 (1993)
548–569.
651. Pfizer, US 4152326, (J. Hartenstein, G.
Satziger).
652. Pfizer, US 4024175, (G. Satzinger, J.
Hartenstein, M. Hermann, W. Heldt).
653. Zambon Group, WO 2005 044 779, 2005 (K.
Arrighi, F. Corcella, G. Marchioro, A. Nicoli,
M. Paiocchi, M. Villa).
654. Taro Pharmaceutical Industries Ltd., WO 2003
089403, 2003
655. R. Cagnoli et al., Tetrahedron 59 (2003) 9951.
656. G. J. Sills, Curr. Opin. Pharmacol. 6 (2006)
108–113.
657. J. K. Baille, I. Power Curr. Opin. Investig.
Drugs 7 (2006) 33–39.
658. I. W. Tremont-Lukats et al., Drugs 60 (2000)
1029–1052.
659. J. Devulder et al., Acta Neurol. Belg. 102
(2002) 97–103.
660. Wellcome Foundation, EP 21 12, 1981 (M. G.
Baxter, et al.).
661. Wellcome, US 4 560 687, 1985 (M. G. Baxter,
A. R. Elphick, A. A. Miller, D. A. Sawyer).
662. Wellcome, US 4 602 017, 1986 (M. G. Baxter,
A. R. Elphick, A. A. Miller, D. A. Sawyer).
663. E. Eisenberg et al., Rev. Neurotherapeutics 5
(2005) 729–735.
664. M. Guven, H. Bozdemir, J. Gunay, Y. Sarica, J.
Kahraman, F. Koc, The actions of lamotrigine
and levetiracetam on the conduction properties
of isolated rat sciatic nerve, Eur. J. Pharmacol.
553 (2006), 129–134.
665. Rexall, US 3 487 153, 1969.
666. Riker, US 3 830 803, 1974.
667. R. C. Heel et al., Drugs 19 (1980) 249–267.
668. Park Davis, US 2 409 754, 1946 (H. R. Henze).
669. H. Biltz et al., Ber. Dtsch. Chem. Ges. 41
(1908) 1391.
670. Warner-Lambert WO 99/48876, 1999 (R. L.
Bosch)
671. B. D. Maryanoff, B. L. Margul, Drugs of the
Future 14 (1989) 342.
672. B. E. Maryanoff, et al., Med. Chem. 30 (1987)
880–887.
673. Ortho-McNeil Pharmaceuticals Inc., US
4513006, 1985 (B. E. Maryanoff, J. F.
Gardocki).
674. Ortho-McNeil Pharmaceuticals Inc., WO 2004
078769, 2004 (J. E. Berkner, S. Duncan)
675. C. E. Heading, IDrugs 4 (2001) 339–350.
676. C. E. Heading, Curr. Opin. Investig. Drugs 3
(2002) 915–920.
677. S. Tries et al., Inflamm. Res. 51 (2002)
129–134.

678. J. J.Talley, .J Med. Chem. 43 (2000) 775–777.
679. US 2 806 033, 1955 (M. J. Lewenstein, U.
Weiss).
680. T. Appelboom, P. Franchimont, Adv. Therapy
11 (1994) 228–234.
Analgesics and Antipyretics 97
681. Troponwerke, US 3 692 818, 1972,
DE 1 939 112, 1969.
682. Syntex, US 3 896 157, 1975.
683. Geigi, US 3 558 690, 1971.