4

Paracetamol and propacetamol for post-

operative pain: contrasts to traditional
NSAIDs

C. A L B R E C H T W I E B A L C K
HUGO VAN AKEN

Acute post-operative pain used to be a routine and relatively simple

problem to solve and the most commonly used agents for its control were
parenterally administered opioid analgesics. These drugs are potent and
extremely effective analgesics, and yet, the inadequate management of
post-operative pain is a ubiquitous problem that has continued for decades
despite advances in pharmaceutical agents and delivery systems, and new
insights into pain physiology (Papper et al, 1952; Keats, 1956; Marks and
Sachar, 1973; Cohen, 1980; Donovan et al, 1987; Dauber et al, 1993).
Nevertheless, the advantages of adequate pain relief are numerous: dimin-
ished morbidity and mortality have been repeatedly invoked (Cousins, 1989;
Moore, 1990; Ballantyne et al, 1993). The comfort of the patient is also
increased, and well-being seems to be one of the most important concerns
of our modem society. In addition, it gives the anaesthesiologist an unusual
degree of prestige and respect from patients and colleagues (Moore, 1990).
Pain should be regarded as only the visible part of an iceberg. Metabolic
changes and inflammatory reactions are the other consequences of surgical
procedures. Adequate pain relief should be an essential part of a broad
acute rehabilitation strategy. Problems that are encountered in realising
such a management of post-operative pain are related to the efficacy and
safety of drugs and appropriate application of methods. This includes the
diagnosis of pain and the assessment of its intensity which depends on the
surgical procedure and on the personality of the patient.
What is the role of paracetamol, propacetamol and non-steroidal anti-
inflammatory drugs (NSAIDs) in the management of post-operative pain?
What are the differences between these agents?

PARACETAMOL/PROPACETAMOL AND NSAIDs

PHARMACOLOGY

Paracetamol (acetaminophen), the oldest known synthetic analgesic-

antipyretic drug introduced in 1893 (Von Meyring), is one of the most
Batlh~re's Chnical Anaesthestology- 469
Vol. 9, No 3, September 1995 Copyright © 1995, by Bailli~re TmdaU
ISBN 0-7020-2070-2 All nghts of reproduction m any form reserved
470 C. A . W I E B A L C K A N D H . V A N A K E N

frequently used around the world. It is almost insoluble and for that reason
can not be used parenterally. In certain circumstances, for example after an
acute trauma or operation, intravenous administration is preferable because
of potential dysfunction of the gastro-intestinal tract and reduced time of
onset. Propacetamol is a water-soluble precursor of paracetamol with the
same properties. Plasma esterases act on propacetamol and release para-
cetamol rapidly and completely (Depr6 et al, 1992). One gram of propa-
cetamol is the equivalent of 500mg paracetamol. Depr6 et al (1992)
compared the pharmacokinetics of 500 mg paracetamol given orally with
1 g propacetamol given intravenously in a double-blind, placebo-
controlled, randomized, two-period cross-over study, Between 1 and 2
hours after administration, mean plasma concentrations of paracetamol
became practically identical. These authors also demonstrated that no sig-
nificant accumulation of paracetamol occurred even after five dosages of
2 g propacetamol/24 hours. Half-life was 3.6 hours and distribution volume
was 93 + 26 litres.
NSAIDs are widely used for their analgesic, anti-inflammatory and for
some agents antipyretic effects. As some of these drugs are non-prescrip-
tion or over-the-counter drugs, it is estimated that up to 2% of the North
American population use NSAIDs on a daily basis (Knodel et al, 1992).
NSAIDs consist of several chemical classes, which are shown in Table 1.
The NSAIDs differ from each other both based on their pharmacokinetics
and, at least to some extent, their pharmacodynamic profile. The mean
plasma elimination half-life ranges from 1 to 60 hours, but it may be that
other factors like differences in stereo selectivity, protein binding and kinet-
ics in connective tissue are equally important for the clinical efficacy
(Lapicque et al, 1993; Simkin et al, 1993). Nevertheless, NSAIDs have
much in common: good oral resorption, high protein binding (> 90%) and
a relatively small distribution volume, 0.1-0.2 l/kg.

MECHANISMS OF ACTION

A noxious stimulus to tissue initiates a cascade consisting of nociception,

inflammation, and hyperalgesia (Woolf, 1989; Dab1 and Kehlet, 1991,
1993). Sympathetic postganglionic neurons produce and release
prostaglandins, and primary afferent neuron endings release substance P
and related nociceptive peptides. The resultant process is a prostaglandin-
mediated inflammation with vasodilation and increased vascular per-
meability. Sensitization of nociception increases, indicating that the
functional state of the nervous system alters, the pain threshold decreases
and hyperalgesia results (Woolf, 1989). Primary hyperalgesia describes the
changes in pain threshold within the area of injury, while secondary hyper-
algesia refers to changes in the surrounding uninjured tissue as a result of
altered central processing of the nociceptive input from the periphery (Dahl
and Kehlet, 1991).
Secondary hyperalgesia is explained by expansion of the receptive fields
in the central nervous system. The normal pattern of afferent processing
P A R A C E T A M O L AND PROPACETAMOL 471

Table 1. NSAIDs and paracetamol: chemacal classes, dosages and avmlable preparations
Approximate
Single adult durationof action Preparataon
Chemical class Available agent dose (mg) (hours) available
Acetic acids Indomethacin 50-100 12 oral rectal
50 12 1.m, 1.v.
Carboxylic acids Aspmn (ASA) 500-1000 6-8 oral
Lysm acetylsallcylate 500-1000 6-8 av
Sallcylamide 500-1000 6-8 im
Enolic acids Oxyphenbutazone 100-200 8-12 oral, rectal
Phenylbutazone 200 12-24 oral, rectal
PlrOxlcam 10-20 24 oral, rectal
20--40 24 im
Tenoxlcam 20 24 oral, rectal
20 12 im,iv
Fenamle acids Flafenme 200 6 oral, rectal
Mefenamlc acid 250-500 6-8 oral
Niflumlc acid 250 8-12 oral
700 12 rectal
Para-amlnophenol Paracetamol 300-1000 4-6 oral, rectal
Propacetamol 1000-2000 4-6 Iv
Phenylacetic acids Aclofenac 500-600 8-12 oral, rectal
650 24 im
D~clofenac 100-150 8-12 oral, rectal
75 12 lm,lv
Fenclofenac 600 12 oral
Ketorolac 30 4-6 1.m, ~ v
Propionlc acids Flurbiprofen 50-100 6-8 oral, rectal
Ibuprofen 400-600 6-8 oral, rectal
Ketoprofen 100-200 8-12 oral, rectal
100 8-12 i m , i.v
Naproxen 250-500 12 oral, rectal

alters in terms of a decrease in the threshold of the dorsal horn neurons.

This change is thought to be mediated centrally by activation of N-methyl-
D-aspartate (NMDA) receptors in the dorsal horn of the spinal cord (Davies
and Lodge, 1987; Coderre and Melzack, 1992). Consequently, a 'wind-up'
phenomenon occurs which results in the formation of a positive feed-
forward circuit in which afferent sensory input, central sensitization, and
sympathetic outflow all contribute to the modulation of the pain response.
As a result, a hypersensitivity state may develop that can outlast the dura-
tion of the initial injury (Woolf, 1989).
For many years, the effects of the NSAIDs have been attributed only to
their action on the peripheral synthesis of prostaglandins. Most NSAIDs are
reversible inhibitors of cyclooxygenase (acetylsalicylic acid is an irre-
versible inhibitor). Analgesic effects of NSAIDs were interpreted as the
inhibition of prostaglandin synthesis, decreasing the inflammatory response
to surgical trauma and, hence, reduced peripheral nociception and pain per-
ception (McCormack and Brune, 1991).
However, there are some arguments against an exclusively peripheral
action of NSAIDs. They are analgesically effective in dosages too small by
472 C . A . WIEBALCK AND H. VAN AKEN

far to block prostaglandin synthesis. Moreover, paracetamol has analgesic

properties without affecting peripheral prostaglandin synthesis (Jurna,
1991). Animal studies suggest an effect on the central nervous system
caused by both paracetamol and NSAIDs. Firstly, paracetamol and NSAIDs
produce a dose-dependent depression of the rat thalamic response to periph-
eral nociceptor input (Carlsson et al, 1988; Juma and Brune, 1990). This
effect could not be reversed by naloxone. Secondly, paracetamol and
NSAIDs appear to prevent the rise of prostaglandins found in the cere-
brospinal fluid following activation of NMDA receptors (Sorkin, 1993;
Bj6rkman et al, 1994; Bj6rkman, 1995). Furthermore, intrathecal admini-
stration of ketorolac produces a dose-dependent inhibition of both the first
and second phase of the rat formalin test (Malmberg and Yaksh, 1992, 1993).
The first phase is thought to represent immediate pain, and the second relates
to delayed hyperalgesia (Malmberg and Yaksh, 1993). Therefore, it has been
suggested that paracetamol and NSAIDs can reduce both acute pain and the
subsequent hyperalgesic response by central mechanisms.
Finally, it has been suggested that ketorolac potentiates the anti-nocicep-
tire action of opioid analgesics. Using a visceral pain model (colonic dis-
tension in rats), ketorolac alone had no significant analgesic action,
whereas morphine had a potent effect (Mares et al, 1994). Moreover,
ketorolac potentiated the anti-nociceptive effect of morphine and this action
was completely reversed by naloxone, suggesting that ketorolac may exert
an effect at the opioid receptor.
Experimental studies suggest that indomethacin and some other NSAIDs
interact with the adenylate cyclase system by inhibition of phosphodi-
esterase, thereby increasing the intracellular concentration of cyclic adeno-
sine monophosphate (AMP) and reducing the release of enzymes known to
play a role in the inflammatory response (Benoist, 1988; Dahl and Kehlet,
1991).
Paracetamol has no significant influence on the peripheral synthesis of
prostaglandins. In vitro, however, it blocks the brain prostaglandin syn-
thetase, but not that of peripheral tissue. McCormack (1994) recently pub-
lished an extensive review on non-steroidal anti-inflammatory drugs and
spinal nociceptive processing. Paracetamol is antipyretic, anti-inflamma-
tory (Lekken et al, 1977; Skjelbred et al, 1977; Abbadie and Besson, 1994)
and it stimulates the degradation of endoperoxides. This suggests that
endoperoxides, and in particular prostaglandin endoperoxide PGG2, play a
major role in the pain generating impulses (Benoist, 1988; Moreau et al,
1990).

ANALGESIC EFFICACY

Paracetamol and NSAIDs have a considerable analgesic effect for post-

operative pain relief after minor procedures such as dental surgery (Garrec
et al, 1991; Hans et al, 1993). Compared with opioids, they have fewer side
effects, especially regarding drowsiness and respiratory depression, making
NSAIDs more appropriate for ambulatory surgery.
PARACETAMOL AND PROPACETAMOL 473

For certain types of surgery NSAIDs can provide excellent analgesia.

For laparoscopy, 800 mg ibuprofen provided better pain relief than 75 gg
fentanyl and caused less vomiting (Rosenblum et al, 1990). Furthermore,
clinical experience reveals that paracetamol and NSAIDs seem to be par-
ticularly efficient in relieving pain related to orthopaedic surgery (Dekens
et al, 1988). Hence, the aetiology of pain seems to be an important factor
for the effectivity of pain relief by a given drug.
Paracetamol and NSAIDs may be administered in patients undergoing
major surgery, but there is no reason to believe that these drugs given alone,
provide adequate or even better analgesia than opioids (Baude et al, 1991).
Opioids may be combined with paracetamol and NSAIDs as the different
working mechanisms result in additive analgesia. This is how paracetamol
and NSAIDs may contribute to pain relief after major surgery (Dahl and
Kehlet, 1991) in spite of their limited analgesic potency.
The combination of paracetamol and NSAIDs with opioids has been
shown to be effective (Rod et al, 1989; Moote, 1992; Wong et al, 1993;
Beaulieu, 1994). Several studies found about a 30% sparing effect on opi-
old consumption together with a reduction of opioid side effects such as
less respiratory depression (Dekens et al, 1988; Moffat et al, 1990; Watcha
et al, 1992; Grass et al, 1993; Vandermeulen et al, submitted for publica-
tion).
In spite of the widespread use of paracetamol and NSAIDs, there are
only a few controlled studies comparing the post-operative analgesic effi-
cacy of paracetamol with another NSAID (Table 2). These studies suggest
that pain relief after paracetamol is less than or equal to NSAIDs and of

Table 2. S u m m a r y of double-blind, controlled climcal trials comparing the post-operative analgesic

effectivity of paraeetamol and a N S A I D
No. of NSAID Alternative Analgesic
Reference Surgery patients treatment treatment effect Remedlcation
Flltzer (1980) Mixed Naproxen (N) Paracetamol (P) N>P N<P
McGaw et al Dental 150 Ibuprofen (I) Paracetamol (P) I>P
(1987) 200 mg p.o. 240/360 mg p.o
Ogunbode Obstetrics Plroxlcam Paracetamol (P) P1 = P
(1987) (P1)
Vargas Busquets Plastic Naproxen (N) Paracetamol (P) N=P
et al (1988)
Skovlund et al Obstetrics 56 Naproxen (N) Paracetamol (P) N=P
(1991) 2 x 500 mg 4 x 500 mg
Dolcl et al Dental 32 Plroxlcam Paracetamol (P) P1 > P > PI < P
(1993) (P0 20 mg 05g Placebo
Mornson and Ophthalmology 60 Ketorolac (K) Paracetamol (P) K>P=I
Repka 60 mg x v. 0 65 g p.o or
(1994) Ibuprofen (I)
600 mg p o.
Umbram et al Dental 71 Ketorolac (K) Propacetamol (P) K>P> K<P<
(1994) 30 mg x v 2giv Placebo Placebo
Hynes and Total hip 138 Dlclofenac Propacetamol (P) D=P> D=P<
McCaroll arthroplasty (D) 2 g 1 v. Placebo Placebo
(submitted 75 mg Lm.
for publication)
 474 C. A. W I E B A L C K A N D H . V A N A K E N

shorter duration than the commonly used NSAIDs naproxene, piroxicam,

diclofenac and ketorolac. However, interpretation of these results is diffi-
cult because of different methods of assessment and major differences in
surgical procedures between the patients studied.

DRUG ADMINISTRATION

The timing of drug administration may play an important role. A pre-oper-

atively given analgesic may prevent nociceptor sensitization and reduce
post-operative pain by modifying the response of the central nervous sys-
tem (CNS) and by reducing the inflammatory reaction normally observed
after surgical trauma (Moreau et al, 1990; Campbell and Kendrick, 1991).
Pre-operative versus post-operative treatment with NSAIDs has been
examined, unfortunately only in a few studies. One controlled study sug-
gested improved analgesia when flurbiprofen was given before rather than
after surgery (Dupuis et al, 1988) whereas oedema and inflammation have
been reduced with pre-operative administration of NSAIDs compared with
placebo after plastic and rheumatic surgery (Dahl and Kehlet, 1991). The
resuks, however, are controversial and interpretation is difficult.
The route of drug administration should also be considered. Most
NSAIDs are given orally, intramuscularly or rectally. Only recently, some
products have become available in a form for intravenous injection (tenoxi-
cam, ketorolac, indomethacin, diclofenac, ketoprofen, propacetamol).
These drugs appear to be significantly more effective with a more rapid
onset of action (Buckley and Brogden, 1990; Campbell and Kendrick,
1991; Laitinen and Nuutinen, 1992). This may be related to higher plasma
levels at the beginning with a more rapid and larger penetration of the
blood-brain barrier with a more pronounced CNS effect.

SIDE EFFECTS AND COMPLICATIONS OF NSAIDs

Side effects of NSAIDs may be due to inhibition of prostaglandin synthe-

sis (bleeding, gastric-duodenal adverse events, renal adverse events) or to
allergic, toxic or idiosyncratic reactions. They are infrequent (O'Brian,
1986), but nevertheless, they can cause severe complications in the post-
operative period. Dyspepsia, peptic ulceration, nausea, renal adverse
events, skin reactions, hepatic syndromes, neurological problems (e.g.
headache and dizziness) and bleeding disorders (Brooks and Day, 1991)
have been reported. Advanced age has emerged as one of the most striking
risk factors for all of these adverse effects (Sager and Benett, 1992).
Most of the described side effects were found during long-term use of
NSAIDs. Moreover, several studies suggest that the most dangerous
period concerning side effects is within the first few months of taking an
NSAID (Hawkey, 1990) but the data do not allow separation of risk
between the first 3-5 days and the following weeks. Hence, a few studies
with short-term administration of NSAIDs have been performed to evalu-
PARACETAMOL AND PROPACETAMOL 475

ate the adverse effects on gastro-intestinal tract, coagulation system and

kidneys.
Nausea, vomiting and dyspepsia were not found more often after admin-
istration of indomethacin, oxycodon and diclofenac (Laitinen et al, 1992).
There was no difference in the incidence of nausea between diclofenac- and
fentanyl-treated patients undergoing hip surgery (Laitinen and Nuutinen,
1992) whereas Cahadell-Carafi et al (1991) described these side effects as
a common feature of ketorolac treatment. While Parker et al (1994) found
a similar incidence of nausea and vomiting after ketorolac and opioid anal-
gesics, Ready et al (1994) showed a reduced incidence. Moreover, gastric
irritation was described after short-term use of diclofenac (Muller et al,
1989) and ketorolac when the daily dose exceeded 120 mg (Lanza et al,
1987). To summarize, the influence of NSAIDs on nausea and vomiting is
not easily described. Possibly different side effects of the various NSAIDs
and the incomparability of studies may explain contradictory results.
Nevertheless, no study (to the knowledge of the authors) demonstrates a
higher incidence of nausea and vomiting after NSAIDs than after opioids.
Bleeding time was slightly prolonged but still within the normal range in
most studies after a single dosage of indomethacin, diclofenac and ketoro-
lac (Nuutinen et al, 1993). The situation, however, was different after
administration of warfarin or low-dose acetylsalicylic acid for prophylaxis
against thrombosis after total hip replacement. Patients taking NSAIDs
until the time of operation had more post-operative bleeding complications,
including gastro-intestinal tract bleeding, compared with those not taking
NSAIDs (Connelly and Panush, 1991).
Renal function may be affected after short-term use of NSAIDs but this
impairment with decline of renal blood flow and glomerular filtration rate
is reversible after stopping NSAIDs administration. Controlled studies indi-
cated a temporary reduction of urine output (diclofenac) and, for ketorolac,
a potassium retention (Nuutinen et al, 1993). Hence, attention should be
paid in particular to patients with pre-existing risk factors for abnormal
renal function (Table 3).
One side effect of minor importance compared to those previously men-
tioned is the recently described disturbance of the normal sleeping patterns
(Murphy et al, 1994). The authors demonstrated, that patients after admin-
istration of acetylsalicylic acid and indomethacin were less refreshed and
recuperated in the morning than those after paracetamol and placebo, due
to delayed sleep and significantly more disruptions of sleep during the
night.
Referring to NSAID treatment in pregnant patients, there is no evidence
for teratogenicity of any NSAIDs in humans. However, due to inhibition of
prostaglandin synthesis, a shared property of all NSAIDs, adverse effects
such as constriction of the ductus arteriosus in utero, persistent pulmonary
hypertension in the neonate, intracranial haemorrhage, prolongation of
pregnancy and labour, and increased maternal blood loss associated with
delivery, are possible (~stensen, 1994).
Other side effects of NSAIDs may be related to drug interactions. The
relative frequency of drugs that may have adverse interactions with
476 C. A. WIEBALCK AND H. VAN AKEN

Table 3. Risk factors for possible NSAIDs-lnduced adverse events.

Risk factor Possible adverse event
Allergic con&tions Allergic reactmns
Asthma
Cross intolerance with aspmn
Alcohohsm Bleeding
Bleeding &sorders
Drug interactions with anticoagulants
Elderly patients
Gastroduodenopathy
Nasal polyps
Alcoholism Gastric adverse events
Drug interactmn with cort~colds,
anUcoagulants
Elderly patients
Gastroduodenopathy
Atherosclerosis Renal adverse events
Congestive heart failure
Drug interactions with diuretics,
[5-blockers and nephrotoxlc drugs
Elderly patients
Hypotonia
Hypovolaewaa
Liver cirrhosis
Renal failure
Sepsis
Atherosclerosls Disturbed control of blood pressure
Drug interactions w~th diuretics,
[5-blockers
Elderly patients
Hypovolaemia
Lxthium, Methotrexate, Cyclosporine, Drug interactions with potentially
oral hyperglycemic agents severe side effects
(Brouwers and De Smet, 1994)

NSAIDs is partially due to both properties of NSAIDs, the high percentage

bound to protein, and the small distribution volume. From a theoretical
point of view the toxicity of NSAIDs may be increased by coadministration
of interacting drugs, or by increasing the toxicity of coadministered drugs
(Table 3). The most important drugs are those affecting the coagulation sys-
tem, the renal function, some chemotherapeutica and antidiabetica. Drug
interactions in elderly people are not infrequent, they occurred two times
more often in NSAID users than in the control group of non-NSAID users
(Hogan et al, 1994). Reduction of the incidence may be possible because
Buchan and Bird (1991) identified drug interactions in half of the patients
being treated with NSAIDs for symptoms of arthritis, although only a
minority of these patients had clinical manifestations.
In summary, the well known side effects during prolonged use of
NSAIDs may limit their potential use in the peri-operative period.
However, data from prospective controlled studies do not suggest that
PARACETAMOL AND PROPACETAMOL 477

short-term NSAID treatment (< 1 week) may have clinically significant

adverse effects (Dahl and Kehlet, 1991). Thus the fear of side effects should
not limit use of NSAIDs in the healthy surgical patient but caution and
restrictive use are required in patients potentially at risk (Table 3).

SIDE EFFECTS AND COMPLICATIONS OF PARACETAMOL

There are very few drugs that have such a low intensity and frequency of
side effects and complications as paracetamol. Some case studies have
reported allergic reactions [cross allergy to acetylsalicylic acid (Ispano et
al, 1993)], also, during rapid injection, propacetamol may lead to a tempo-
rary decrease of blood pressure and a slight irritation at the site of injection.
Several drug interactions are theoretically possible, but they are clinically
irrelevant (Lechat and Kisch, 1989). Dosages should be reduced in patients
with severe renal insufficiency (creatinine clearance < 10 ml/min) and with
severe deficiency of liver cell glutathione which may occur in patients with
profound hepatocellular insufficiency, administration of antiepileptica and
premature babies. In summary, paracetamol may be administered in almost
all patients irrespective of age, underlying disease or pregnancy.

CLINICAL USE OF NSAIDs

The goal of post-operative pain relief is to allow the patient the quickest
and most convenient restoration of his normal functions, e.g. breathing,
coughing and mobility. This can be supported by the inhibition of trauma-
induced nociceptive impulses in order to blunt autonomic and somatic
reflex responses to pain (Kehlet, 1994).
Post-operative pain therapy should be structured. It should be based on
the general principles of pre-emptive analgesia and the multimodal
approach (Kehlet and Dalai, 1993). The value of pre-emptive analgesia is
limited at present (Dahl and Kehlet, 1993), but this principle may have
some implications in the future. The multimodal approach includes the
principle of balanced analgesia. The basic idea is to combine different anal-
gesic drugs and techniques to achieve an additive or synergistic analgesic
effect. So, the doses of the single drugs can be reduced and side effects are
limited. Another element is the assessment of pain and the choice of the
appropriate treatment.
The first step of the 'analgesic treatment ladder' is represented by para-
cetamol and NSAIDs which are the first line drugs for control of mild to
moderate pain. This has been recommended by many authors and the
World Health Organization (Rummans, 1994) as these analgesics have less
side effects than opioids. Patients treated with NSAIDs are less drowsy
than opioid-treated patients, although the incidence of nausea and vomit-
ing is similar with both treatments. No respiratory effects have been
observed after paracetamol/NSAIDs, in contrast, a decrease in respiratory
rate and an increase in arterial partial pressure of carbon dioxide may
478 C. A. W I E B A L C K A N D H . V A N A K E N

occur in opioid-treated patients. For minor surgery, paracetamol and

NSAIDs will minimize the need for opioid analgesics in the post-operative
period.
The second step of the 'analgesic treatment ladder' for the control of
more severe pain includes the combination of these drugs with opioids. As
already mentioned, paracetamol/NSAIDs have fewer side-effects than opi-
oids and by combination of both groups a low dose of opioids can be
administered (opioid sparing). It should be remembered that opioid sparing
produces reductions in nausea and vomiting, respiratory depression and
sedation.
A third step of the 'analgesic treatment ladder' might be necessary for
patients with severe pain. This step includes the use of local anaesthetics
and other adjuvant medications that can improve the pain treatment (cloni-
dine, corticoids, antispasmodics, neuroleptica, anticonvulsants, muscle
relaxants, antidepressants, etc). A conception for the realization of such a
post-operative pain management has been proposed by Wiebalck et al (sub-
mitted for publication).

DIFFERENCES IN USE AND INDICATIONS FOR

PARACETAMOL AND NSAIDs

Paracetamol and NSAIDs, both and even together are indicated for the
treatment of mild to moderate pain and for more severe pain, in combina-
tion with opioids, local anaesthetics and other adjuvant medications. The
most problematic side effects of NSAIDs are related to the inhibition of the
peripheral cyclooxygenase-system: bleeding, gastro-duodenal and renal
adverse events. The analgesic potential of paracetamol may be less pro-
nounced and of shorter duration, but there are almost no side effects.
As one of the highest commandments 'Nihil nocere.t' requires, NSAIDs
should be avoided if certain risk factors for NSAIDs-induced side effects
are present such as advanced age, gastroduodenopathy, bleeding diathesis,
renal insufficiency and other factors listed in Table 3. Today, it is recom-
mended that paracetamol alone represents the non-opioid background anal-
gesia.
In the future, a more rational choice of the optimal drug may be possible
as there are some differences among non-steroidal anti-inflammatory drugs
(Furst, 1994). Research on efficacy, tolerance, incidence of adverse effects,
optimal route of administration and dosage schedules will provide more
information. Then, the choice of a specifically indicated NSAID can be
based on (patient-related) efficacy, patients' concomitant medications and
diseases, and consideration of cost.

SUMMARY

Although less efficacious than opioid compounds, parenterally adminis-

tered NSAID and paracetamol are effective analgesics that have a clear role
PARACETAMOL AND PROPACETAMOL 479

in the management of post-operative pain. They should be considered as

part of a balanced approach to analgesia using a combination of different
drugs and techniques.
Pain therapy should be structured. Assessment of pain allows the finding
of appropriate measures of treatment. The first step of the 'analgesic treat-
ment ladder' is represented by paracetamol/NSAIDs (mild analgesics)
which are the first line drugs for control of mild to moderate pain. The
second step of the 'analgesic treatment ladder' for the control of more
severe pain includes the combination of these drugs with opioids.
Paracetamol/NSAIDs have fewer side effects than opioids and by combi-
nation of both groups a lower dose of opioids can be administered (opioid
sparing). A third step of the 'analgesic treatment ladder' might be necessary
for patients with severe pain. This step includes the use of local anaesthetics
and other adjuvant medications that can improve the pain treatment (Kehlet
and Dahl, 1993).
Paracetamol and NSAIDs, are indicated for the treatment of mild to
moderate pain and for more severe pain, in combination with opioids, local
anaesthetics and other adjuvant medications.
If a patient presents risk factors for NSAIDs-induced adverse events,
today it is recommended to achieve the regular background analgesia with
paracetamol alone. In the future, a more selective use of NSAIDs will pro-
vide more advantages. For this reason, more research is required to distin-
guish the differences between the various NSAIDs concerning efficacy,
tolerability, incidence of adverse effects, optimal route of administration
and dosage schedules.
Today, the optimal regimen for the peri-operative management of pain
would appear to involve primarily paracetamol, the selective use of
NSAIDs in low-risk patients in combination with opioid analgesics and
local anaesthetics whenever necessary.

REFERENCES
Abba&e C & Besson J-M (1994) Chronic treatment with aspirin and acetammophen reduce both the
development of polyarthntis and post Fos-hke immunoreactivity in rat lumbar spinal cord Pam
59:45-54
Ballantyne JC, Cart DB, Chalrners TC et al (1993) PostoperaUve patient-controlled analgesia Meta-
analyses of mmal randomized control trials Journal of Climcal Anesthesia 5: 182-193.
Baude C, Long D, Chabrol B e t al (1991) Postoperative analgesia for nephrectomy Cahters
d'Anesthgsiologw 39: 533-536.
Beanheu P (1994) Intravenous admimstratlon of paracetamol (Propacetamol) for postoperative anal-
gesia Anaesthesta 49:739-740
Benoxst JM (1988) Mamement des analgtslques antlpyrttiques In Boreau Fr (ed.) Prattque du
Traltement de la Douleur, pp 125-143. Paris- Dora Editeurs.
Bjorkman R (1995) Central antinoclceptive effects of non-steroidal anla-inflammatory drugs and
paracetamol. Acta Anaesthestologwa Scandmavtca 39 (supplement 103): 1M-4
Bjtrkman R, Hallman K, Hedner J e t al (1994) Acetammophen blocks spinal hyperalgesla induced
by NMDA and substance P Pare 57: 259-264.
Brooks PM & Day RO (1991) Nonsteroldal anU-mflammatory drugs~&fferences and slrrulantles
New England Journal of Medicine 324:1716--1725
 480 C.A. WIEBALCK AND H. VAN AKEN

Brouwers JRBJ & De Smet AGM (1994) Pharmacokinetlc-pharmacodynamic drug interactions with
nonsteroidal anti-inflammatory drugs Chntcal Pharmacoktnetws 27: 462-485.
Buchan IE & Bird HA (1991) Drug interactions in arthritic patients. Annals of the Rheumatic Diseases
50:680-681
Buckley MM-T & Brogden RN (1990) Ketorolac A review of its pharmacodynamic and pharmaco-
kinetic properties, and therapeutic potential. Drugs 39: 86--109.
Cahadell-Carafi J, Moreno-Londono A & Conzales-Caudevllla B (1991) Ketorolac, a new non-oplmd
analgesic: a single blind trial versus buprenorphine in pain after orthopaedic surgery Current
Medtcal Research and Opmton 12:343-349
Campbell WI & Kendrick R (1991) Intravenous &clofenac sodium. Does its administration before
operation suppress postoperative pain? Anaesthesia 4: 763-766.
Carlsson KH, Mouzel W & Jurna I (1988) Depression by morphine and the non-oploid analgesic
agents, metamizol (&pyrone), lyslne acetylsahcylate, and paracetamol of activity in rat thalamus
neurons evoked by electrical stimulation of nociceptive afferents Pam 32: 313-326.
Coderre TJ & Melzack R (1992) The contribution of excitatory ammoacids to central sensitization
and perslstant nociceptIon after formalin induced tissue injury Journal of Neurosctence 12:
3665-3670.
Cohen FL (1980) Postsurgical pain relief Patients' status and nurses' medication choices. Pain 9:
265-274.
Connelly CS & Panush RS (1991) Should non-steroidal anti-inflammatory drugs be stopped before
elective surgery? Archives of Internal Medtcine 151: 1963-1966.
Cousins MJ (1989) Acute pain and the injury response: immediate and prolonged effects Regwnal
Anesthesta 14:162-179
Dahl J & Kehlet H (1991) Non-steroidal anti-inflammatory drugs, rationale for use in severe postop-
erative pain. British Journal of Anaesthesia 66: 703-712.
Dahl J & Kehlet H (1993) The value of preemptive analgesia in the treatment of postoperative pain.
Brlttsh Journal of Anaesthesta 70: 434-439.
Dauber A, Ure BM, Neugebauer E et al (1993) Zur Inzidenz postoperativer Schmerzen auf chlrurgis-
chen Normalstatlonen. Anaestheszst 42:448-454
Davies SN & Lodge D (1987) Evidence for involvement of N-methyl-D-aspartate receptors in 'wind
up' of class 2 neurones in the dorsal horn of the ~at Bram Research 424: 402--406.
Dekens J, Lepomte F, Besserve P et al (1988) Analg6sie postop6ratotre en chn-urgle ost6oarticulaire
par le k6toprof'ene en perfuslon Cahters d'Anesth3slologze 36:25-27
Depr6 M, Van Hecken A, Verbesselt R et al (1992) Tolerance and phannacokinetics of propacetamol,
a paracetamol formulation for intravenous use. Fundamentals of Clinical Pharmacology 6:
259-262.
Dolcl G, Ripari M, Pacificl L e t al (1993) Analgesic efficacy and the tolerance for plroxlcam-beta-
cyclodextrin compared to plroxlcam, paracetamol and placebo m the treatment of postextractlon
dental pare Mmerva-Stomatologlca 42: 235-241.
Donovan M, Dillon P & McGmre L (1987) Incidence and characteristics of pain in a sample of med-
xcal-surglcal mpatlents. Pain 30: 69-78.
Dupms R, Lemay H, Bushnelle MC et al (1988) Preoperatwe flarbiprofen in oral surgery a method
of choice m controlhng postoperative pain. Pharmacotherapeutwa 8:193-200
Ffltzer HS (1980) Double-bhnd randomized comparison of naproxen sodium, acetaminophen and
pentazocine m postoperative pare. Current Therapeutic Research, Clinical and Experimental 27:
293-302
Furst DE (1994) Are there differences among non-steroidal anti-inflammatory drugs? Arthrttls and
Rheumattsm 37:1-9
Garret F, Chupm AM & Souron R (1991) Analgesle postop6ratoire par le propacetamol. Cahters
d'Anesthgsiologte 39:333-335
Grass JA, Sakima NT, Valley Met al (1993) Assessment of ketorolac as an adjuvant to fentanyl patient-
controlled epldurai analgesia after radical retropubic prostatectomy. Anesthestology 78:642-648
Hans P, Brichant JF, B onhomme V e t al (1993) Analgesic efficiency of propacetamol hydrochlonde
after lumbar &sc surgery Acta Anaestheslologica Belgica 44: 129-133.
Hawkey CJ (1990) Non-steroidal anta-inflammatory drugs and peptic ulcers. British Medical Journal
300:278-284
Hogan DB, Campbell NR, Crutcher R et al (1994) Prescription of nonsteroldal anti-inflammatory
drugs for elderly people in Alberta. Canadzan Medical Assoctatton Journal 151: 315-322.
Ispano M, Fontana A, Scibiha Jet al (1993) Oral challenge with alternative nonsteroldal anti-inflam-
PARACETAMOL AND PROPACETAMOL 481

matory drugs and paracetamol m patients intolerant to these agents. Drugs 46 (supplement 1P):
253-256.
Juma I (1991) Central analgesic effects of non-steroidal anti-rheumatic agents, Zettschrift fur
Rheumatologte 50 (supplement 1): 7-13
Jurna I & Brune K (1990) Central effect of the nonsteroldal ants-inflammatory agents lndomethacln,
ibuprofen and diclofenac, determined in C fiber-evoked activity m single neurons of the rat thal-
amus Pare 41:71-80
Keats AS (1956) Postoperative pain research and treatment Journal ofChromc Dtseases 4:72-83
Kehlet H (1994) Postoperative pare relief--what is the issuer Brttish Journal of Anaesthesta 72:
375-378.
Kehlet H & Dahl JB (1993) The value of 'multimodal' or 'balanced analgesia' in postoperative pain
treatment Anesthesta and Analgesta 77:1048-1056
Knodel LC, Rousch MK & Barton TL (1992) Nonsteroldai anti-inflammatory drugs Chnical
Pedtatric Medtcal Surery 9:301-325
Laitinen & Nuutlnen L (1992) Intravenous &clofenac coupled with PCA fentanyl for pain relief after
total hip replacement Anesthestology76:194-198
Lmtmen J, Nuutmen LS, Kliskil~t EL et al (1992) Comparison of intravenous diclofenac,
lUdomethacin and oxycodon as postoperative analgesics in pataents undergoing knee-surgery
European Journal of Anaesthestology 9:29-34
Lanza FL, Karlln DA & Yee JP (1987) A double bhnd, placebo-controlled endoscopic study corn-
panng the mucosal injury seen with an orally and parenteralty administered new nonsteroldal
analgesic' ketorolac thromethamine at therapeutic and supratherapeutlc doses AmericanJournal
of Gastroenterology 82:939
Lapicque F, Muller N, Payan E et al (1993) Protein-binding and stereoselectivity of nonsteroldal anti-
inflammatory drugs. Chnwal Pharmacokmetws 25:115-125
Lechat P & Kisch R (1989) Le parac6tamol. Actualisatlon des connalssances en 1989. Thdrapte 44:
337-354
Lckken P, Skoglund LA & Skjelbred P (1977) Anti-Inflammatory efficacy of treatments with aspirin
and acetammophen Pare 60: 231-232.
Malmberg AB & Yaksh TL (1992) Antmociceptor actions of spinal non-steroidal anti-inflammatory
agents on the formalin test m the rat. Journal of Pharmacology and Experimental Therapeutics
263: 136-146.
Maimberg AB & Yaksh TL (1993) Pharmacology of the spinal action ot ketorolac, morphine,
US0488H, and L-PIA on the formalin test and an lsobolographlc analysis of the NSAID interac-
tion Anesthestology79:270-281
Marks RM & Sachar EJ (1973) Undertreatment of medical inpatients with narcotic analgesics Annals
of Internal Medwme 78:173-181
Maces TJ, Pechman PS, Meller ST et al (1994) Ketorolac potentiates morphine antinociception dur-
ing visceral nocicepaon m the rat. Anesthestology 80:1094-1101
McCormack K (1994) Nonsteroidal antiinflammatory drugs and spinal nocicepave processing Pare
59:9-43
McCormack K & Brune K (1991) Dissociation between the antlnoclceptlve and antllnflammatory
effects of the non-steroidal antiinflammatory drugs. Drugs 41:533-547
McGaw T, Raboru W & Grace M (1987) Analgesics in pediatric dental surgery relative efficacy of
aluminium ibuprofen suspension and acetammophen ehxlr. Journal of Denttstryfor Children 54:
106-109.
Moffat AC, Kenny GNC & Prentice JW (1990) Postoperative nefopam and dlclofenac evaluation of
their morphine-sparing effect after upper abdominal surgery. Anaesthesia 45: 302-305.
Moore DC (1990) The role of the anesthesiologist in managing postoperative pain Regtonal
Anesthesia 15: 223-231.
Moote C (1992) Efficacy of non-steroidal anti-inflammatory drugs in the management of postopera-
tive pain Drugs 44 (supplement 5): 14-30
Moreau X, Cottmeau C, Cocaud J et al (1990) Analg6sie pedoperatolre en chirurgle vemeuse
p6nph6dque Cahtersd'Anesth~siologie 38: 403-407.
Morrison NA & Repka NX (1994) Ketorolac versus acetammophen or lbuprofen in controlling post-
operaUve pain in patients with strabismus. Ophthalmology 101:915-918
Muller P, Dammann HG, Leucht U & Simon B (1989) Comparison of the gastrodnodenal tolerance
of tenoxicam and diclofenac Na a double-blind, endoscopically controlled study in healthy
volunteers. European Journal of Chmcal Pharmacology36:419-421.
482 C.A. WIEBALCK AND H. VAN AKEN

Murphy PJ, Ba&a P, Myers BL et al (1994) Nonstermdal anti-inflammatory drugs affect normal sleep
patterns in humans Phystology and Behavtor 55:1063-1066
Nuutinen LS, Lmtmen JO & Salomaki TE (1993) A risk-benefit appraisal of inJectable NSAIDs m the
management of postoperaUve pain. Drug Safety, 9:380-393
O'Brian W (1986) Adverse reactions to nonsteroldal antHnflammatory drugs Dlclofenac compared
with other nonsteroldal anta-mflammatory drugs. American Journal of Medtcme 80 (supplement
4B): 70-80
Ogunbode O (1987) A comparative trial of plroxlcam and paracetmnol after eplslotomy wound repair
Current Therapeutic Research, Climcal and Expertmenta141: 89-94
Ostensen M (1994) Optimlsatlon of antirheumatlc drug treatment in pregnancy. Chmcal
Pharmacokmetws 27:486-503
Papper EM, Bro&e BB & Rovenstme EA (1952) Postoperative pain' Its use in comparatwe evalua-
tion of analgesics Surgery 32:107-109
Parker RK, Holtman B, Smith I & White PF (1994) Use of ketorolac after lower abdominal surgery
Anesthestology 80: 6-12.
Ready KB, Brown CR, Stahlgren LH et al (1994) Evaluation of intravenous ketorolac administered
by bolus or infusion for treatment of postoperative pmn Anesthestology 80:1277-1286
Rod B, Monrlgal JP, Lepoittevin Let al (1989) Traitement de la douleur postoperatoare chez l'enfant
en salle de reveille Utillsatlon de la morphine et du propacetamol par voie intraveneuse Cahters
d'Anesth~szologte 37:525-530
Rosenblum M, Weller RS, Conrad P e t al (1990) Ibuprofen provides better analgesm than fentanyl
following laparascopic surgery Anesthestology 73:A778
Rummans TA (1994) Nonopmld agents for treatment of acute and subacute pmn Mayo Chmc
Proceedings 69:481-490
Sager DS & Benett RM (1992) Indivlduallsmg the risk/benefit ratao of NSAIDs m older patients
Gerlatrtcs 47:24-31
Slmkin PA, Mary PW & Foster DM (1993) Articular pharmacokmeUcs of protein bound
antlrheumatlc agents. Chmcal Pharmacokmetics 25:342-350
Skjelbred P, Album P & LOkken P (1977) Acetylsabcylic acid vs paracetamol: effects on postopera-
tlve course European Journal of Clmtcal Pharmacology 12:257-264
Skovlund E, Fylhngen G, Landre H et al (1991) Comparison of postpartem pare treatments using a
sequential trial design" naproxen versus paracetamol European Journal of Chntcal
Pharmacology 40: 539-542.
Sorkin LS (1993) IT ketorolac blocks NMDA-evoked spinal release of prostaglandm E2 (PGE2) and
thromboxane B2 (TXB2) Anesthesiology 79: A909.
Umbrmn V, Moerman I & Camu F (1994) Postoperative analgestafor dental surgery: a double bhnd
compartson Abstract for Congress 6-11 November 1994 in Bangkok, Thailand
Vargas Busquets MA, Keoshlan LA, Kellemer R et al (1988) Naproxen sodium versus aceta-
mmophen-codeine for pmn following plastic surgery Current Therapeuttc Research, Clmtcal
and Expertmenta143: 311-316
Von Meynng J (1893) Beltrage zur Kenntnis der AntipyreUka Therapeuttsche Monatsschrtft 7:577
Watcha MF, Jones MB, Lagueruela RG et al (1992) Comparison of ketorolac and morphine as adju-
vants during paediatnc surgery Anesthestology 76: 368-372.
Wong HI, Carpenter RL, Popazc DJ et ai (1993) A randomized double-blind evaluation of ketorolac
trlmethamine for postoperative analgesia in ambulatory surgery patients Anesthestology 78"
6-14.
Woolf CJ (1989) Recent advances m the pathophysiology of acute pain. Brmsh Journal of
Anaesthesta 63:139-146.