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MPharm Programme

PAIN & ANALGESIA

Dr Abdel Ennaceur

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Terminology
•Tract: collection of axons in
the CNS
•Nucleus:(nuclei, plural)
collection of neuron cell bodies
in the CNS
•Ganglion:(ganglia, plural)
collection of neuron cell bodies
in the PNS; There are however
some in the brain (example:
basal ganglia)
•Nerve: collection of axons in
the PNS
– Cranial nerves
– Spinal nerves

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 Terminology

Descending or Efferent pathway is made of one or a series of neurons projecting from

the brain toward the periphery. Ascending or Afferent pathway is made of one or a
series of neurons projecting from the brain toward the periphery.
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Neurons communicate with each other

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Neurons communicate with each other through
neurotransmitter release

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Pain

Pain is “an unpleasant sensory and emotional experience

associated with actual or potential tissue damage”

Pain is a perception; it is rooted in sensation, and on the

biological level, in the stimulation of receptor neurons.

Like other forms of perception, pain is sometimes experienced

when there is no corresponding biological basis.

Pain is the single most common reason for patients to seek

medical attention.

Pain is the perception of nociception, which occurs in the brain

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Sensory receptors
The nervous system has many types of sensory neurons.
Nerve endings on one end of each neuron are encased in a
special structure to sense a specific stimulus.

• Chemoreceptors: sense chemicals.

• Mechanoreceptors: sense touch, pressure and distortion
(stretch).
• Photoreceptors: sense light, are found in the retinas.
• Thermoreceptors: sense temperature.
• Auditory receptors: sense vibrations from sound waves.

• Nociceptors are free nerve endings that sense pain. They

respond to a variety of stimuli (heat, pressure, chemicals)
and sense tissue damage.

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Nociceptors
• A nociceptor is a sensory receptor specialized in informing
the CNS about the presence of a tissue threatening stimulus.

• It has the remarkable ability to detect a wide range of

stimulus modalities, including those of a physical and
chemical nature.

• Different chemical (capsaicin and acid) or physical (heat)

stimuli can excite nociceptors by activating a single receptor.

• Nociceptors are excitatory neurons and release glutamate as

their primary neurotransmitter.

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Nociceptors

• A nociceptor has an elevated stimulation threshold just

below the noxious level.

• In addition to an elevated stimulation threshold, a nociceptor

has to be able to encode the intensity of a stimulus within the
noxious range, i.e. it must not saturate when a stimulus
reaches noxious levels.

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Nociceptors

Nociceptors are found in any area of the body.

Nociceptors are found throughout all tissues except the brain

[Crit Care Nurse December 2008 vol. 28 no. 6 38-49].

Not all internal organs are sensitive to pain.

- Many diseases of the liver, the lungs or the kidneys are
completely painless.
- the stomach, the bladder or the ureters can produce
excruciating pain.

There are tissues that contain nociceptors which do not lead to

pain. In the lungs, for example, there are "pain receptors"
which cause you to cough, but do not cause you to feel pain.

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Nociceptors

There are different types of nociceptors:

• Thermal nociceptors.

• Mechanical nociceptors.

• Chemical nociceptors.

• Polymodal nociceptors.

• Silent (or sleeping) nociceptors

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Nociceptors
Pain sensory neurons: Three
types of sensory neurons are found
in the skin.

• Aδ ("A-delta") nerve fibers:

related to pain and temperature.

• C nerve fibers: related to pain,

temperature and itch.

• Aβ ("A-beta") fibers: related to

touch.

• A- ("A-Alpha"): related to muscle

sense (proprioception).

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Characteristics of primary afferent fibres
Aβ fibres Aδ fibres C fibres

Diameter Large Small 2-5μm Smallest <2μm

Myelination Highly Thinly Unmyelinated

Conduction > 40 ms-1 5-15ms-1 < 2ms-1

velocity

Receptor Low High and low High

activation
thresholds

Sensation on Light touch, Rapid, sharp, Slow, diffuse, dull

stimulation non-noxious localised pain pain

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Nociceptors

Aδ ("A-delta") fibers. These are thinly-myelinated. They are

responsible for the sensation of a quick shallow pain that is
specific to on one area.

C fibers are thin, unmyelinated, and tell about a much larger

area of skin. They conduct impulses slowly. They are
considered polymodal because they can react to various
stimuli.

Aβ ("A-beta") fibers are thickly-myelinated fibers. They mostly

respond to painless stimuli such as light touch.

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Types of sensory neurons
Comparative properties of primary afferent fibers
Fibre Threshold Main Main Laminar Normal Pathological
class afferents transmitters receptor location sensation sensation
activated
C Peptides NK1,2 I-II, V Slow pain Hyperalgesia

High
A EAA NMDA Fast pain Allodynia
AMPA
mGlu
Aβ Low EAA AMPA III-VI Touch Mechanical
vibration allodynia
pressure

EAA= Excitatory amino acids; NK= neurokinin (peptide) receptor; NMDA, AMPA, mGlu.

Low threshold afferents are myelinated fibers with specialized nerve endings
that convey innocuous sensations such as light touch, vibration, pressure (all
Aβ) and proprioception (A).
High threshold afferents are thinly-myelinated (A) or unmyelinated (C)
fibers located in the dermis and epidermis, which convey
pain and temperature.
Allodynia is a pain due to a stimulus which does not normally provoke pain

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Pain Pathways

Nociceptors have both a peripheral connection that innervates

muscles, tendons, organs, and epithelia, and a centrally
projecting axon that enters the CNS.

This central axon conveys “nociceptive” information to second-

order neurons in the dorsal horn of the spinal cord.

Neural connections pass from the dorsal horn to the thalamus,

and from there to the cortex (conscious experience).

The central axons of primary afferent nociceptive neurons also

provide information to polysynaptic spinal cord interneurons,
which are essential for the initiation of the nociceptive
withdrawal reflex (motor reflexes).

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Pain Pathways
The cell bodies of nociceptive afferents (ascending) that
- innervate the trunk, limbs and viscera are found in the
dorsal root ganglia (DRG),
- innervate the head, oral cavity and neck are in the
trigeminal ganglia (Gasserian ganglion), and project to the
brainstem trigeminal nucleus.

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Pain Pathways
The ascending neurons
(anterolateral system) transmits
nociceptive, thermal, and
nondiscriminatory touch
information to higher brain
centers, generally by a sequence
of 3 neurons and interneurons.

1st order neurons whose cell

bodies are located in a dorsal root
ganglion. They transmits sensory
information from peripheral
structures to the dorsal (posterior)
horn of the spinal cord.

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Pain Pathways
There are two main pathways that carry nociceptive signals
to higher centers in the brain.
• The spinothalamic tract
• The spinoreticular tract

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Pain Pathways: the spinothalamic tract
2nd order neurons: their cell bodies are located within the
dorsal horn of the spinal cord, and their axon usually
decussates a few segments of the level of entry into the
spinal cord, and ascend in the contralateral spinothalamic
tract to nuclei within the thalamus.

3rd order neurons: their cell body is located in the

thalamus, and their axon ascends ipsilaterally (same side) to
terminate in the somatosensory cortex.

There are also projections to the periaqueductal grey matter

(PAG).

The spinothalamic tract transmits signals that are important

for pain localization.

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Pain Pathways: the spinoreticular tract

The spinoreticular tract: axons

also decussate and ascend the
contralateral cord to reach the
brainstem reticular formation,
before projecting to the
thalamus and hypothalamus.

There are many further

projections to the cortex.

This spinoreticular tract is

involved in the emotional
aspects of pain.

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Descending pathways
The descending pain
pathways descend from the
cortical structures,
hypothalamus and
brainstem, and modulate
sensory input from primary
afferent fibers and
projection neurons in the
dorsal horn of the spinal
cord.

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Descending pathways

The best characterized descending analgesic pathways are the

serotonergic-noradrenergic pathway and the opioidergic
pathway.

These pathways lead to the release of 5-HT, NE and

endogenous opioids, which inhibit the release of excitatory
neurotransmitters such as glutamate and substance P.

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The periaqueductal gray (PAG)
PAG plays a crucial role in
endogenous pain attenuation
mechanisms of the CNS. It is
the primary control center for
descending pain modulation. Midbrain
It has enkephalin-producing
cells that suppress pain.
Pons

It is located in the midbrain. It

projects to the nucleus raphe
Spinal cord
magnus, and also contains
descending autonomic tracts.

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The periaqueductal gray
• Electrical or chemical stimulation of
the PAG suppresses a number of
nociceptive reflexes, and results in a
profound analgesia.

• PAG is the target for brain-stimulating

implants in patients with chronic pain.

• PAG exerts its inhibitory effect on

spinal nociceptive functions through
the activation of descending
serotonergic and noradrenergic
pathways that arise from the rostral
ventromedial medulla and pontine
noradrenergic nuclei.

Slide 26 of 78 M14 Pain Lecture notes

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Pain pathways
Neurons in the PAG of the
midbrain communicate with
the nucleus raphe magnus in
the medulla and lateral
reticular formation.

Neurons from these areas

descend the spinal cord and
synapse with inhibitory
interneurons that release
enkephalin.

These in turn synapse with

the axon terminals of
afferent neurons to decrease
the release of substance P.

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Locus coeruleus (LC)

LC is the major site of noradrenergic cell bodies in the brain.

Noradrenergic neurons project directly to the spinal cord and

inhibit spinal cord activity via 2-adrenoreceptors.

2-adrenoceptor mediated effects are mediated via inhibition

of adenylyl cyclase as a consequence of interaction of the
agonist-receptor complex with Gi.

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Raphe nucleus
Raphe nucleus is the major site of
serotonergic cell bodies in the brain.

Descending serotonergic RVM cells and

spinal serotonin (5-HT) receptors
contribute to the antinociception
induced by RVM or PAG stimulation.

Several studies reported that

descending serotonergic pathways
mediate antinociception through
activation of spinal 2A-adrenoceptor,
5-HT1A (Gi), 5-HT1B/D (Gi) and 5-HT7
(Gs) receptors.

The effect of spinal serotonin can be either inhibitory or

facilitatory, depending on the receptor subtype activated .
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Descending pathways

ACC=Anterior cingulate cortex

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Gate control theory of pain

The gate control theory suggested that previous experience,

thoughts and emotions influence pain perception.

The gate control theory of pain (Melzack and Wall 1965)

describes a process of inhibitory pain modulation at the spinal
cord level.

It tries to explain why when we bang our head, it feels better

when we rub it.

By activating Aβ fibres with tactile, non-noxious stimuli,

inhibitory interneurons in the dorsal horn are activated leading
to inhibition of pain signals transmitted via C fibres.

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Neuropathic pain
Pain that follows direct injury to a peripheral nerve is called
neuropathic pain.

Neuropathic pain results from damage to or dysfunction of the

peripheral or CNS, rather than stimulation of pain receptors.

Neuropathic pain is characterized by

- partial or complete damage to or dysfunction of the
somatosensory pathways in the peripheral or CNS, and
- the occurrence of pain and hypersensitivity phenomena
within the denervated zone and its surroundings.

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Neuropathic pain
Diabetic neuropathy, or nerve damage caused by diabetes, is
one of the most common known causes of neuropathy.

The first sign of diabetic neuropathy is usually numbness,

tingling or pain in the feet, legs or hands.

Over a period of several years, the neuropathy may lead to

muscle weakness in the feet, and a loss of reflexes, especially
around the ankle.

The progression of nerve damage

leads to the loss of sensation in the
feet and reduce a person's ability to
detect temperature or to notice pain.
The person can no longer notice when
his/her feet become injured.

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Neuropathic pain

Neuropathic pain is insensitive to morphine as well as other

opioid drugs, and is currently best treated with
antidepressants and antiepileptics.

Neuropathic pain may be insensitive to morphine because

damage of primary afferent nerves results in decreased
expression of mu-opioid on nociceptors and spinal neurons in
the pain pathway, thus reducing the efficacy of morphine.

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Neuropathic pain
Neuropathic pain can be significantly relieved with tricyclic
antidepressants (e.g. amitryptiline) or anticonvulsant agents
(e.g. carbamazepine).

Carbamazepine can also be used to treat the paroxysmal pain

experienced by patients who suffer from trigeminal neuralgia
(episodes of intense pain in the face).

Corticosteroids (e.g. dexamethasone) may produce

substantial improvement in some cases in neuropathic pain
associated with cancer.

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Trigeminal neuralgia
Trigeminal nerve is the chief nerve
of sensation for the face, which is
also the motor nerve that controls
the muscles used for chewing.

Problems with the sensory part of

the trigeminal nerve result in pain
or loss of sensation in the face.

Trigeminal neuralgia is severe

paroxysmal, lancinating facial pain
due to a disorder of the 5th cranial
nerve (trigeminal nerve).

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Trigeminal neuralgia
The trigeminal nerve is the 5th (V) cranial nerve, which arises
from the brainstem inside the skull. It divides into 3 branches
and then exits the skull to supply feeling and movement to
the face:
• Ophthalmic division (V1) provides
sensation to the forehead and eye.

• Maxillary division (V2) provides

sensation to the cheek, upper lip,
and roof of the mouth.

• Mandibular division (V3) provides

sensation to the jaw and lower lip;
it also provides movement of the
muscles involved in biting, chewing,
and swallowing

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Trigeminal neuralgia
Trigeminal neuralgia is usually
caused by an intracranial artery
or, less often, a venous loop
that compresses the 5th cranial
(trigeminal) nerve at its root
entry zone into the brain stem
[The brain stem consists of the
midbrain, pons, and medulla
oblongata].

Pain occurs along the

distribution of one or more
sensory divisions of the
trigeminal nerve, most often
the maxillary.

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Trigeminal neuralgia

Treatment
• Carbamazepine

If carbamazepine is ineffective or has adverse effects, one of

the following may be tried:
• Oxcarbazepine
• Gabapentin
• Phenytoin
• Baclofen
• Amitriptyline

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Chemicals involved in pain
When there is significant damage to tissue, several chemicals
are released into the area around the nociceptors.

This develops into what is called the "inflammatory soup", an

acidic mixture that stimulates and sensitizes the nociceptors
into a state called hyperalgesia, which is Greek for "super
pain".
Substance Source
Potassium Damaged cells
Serotonin Platelets
Bradykinin Plasma
Histamine Mast cells
Prostaglandins Damaged cells

Leukotrienes Damaged cells

Substance P Primary afferent fibers

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Naturally Occurring Agents That Activate or
Sensitize Nociceptors

Kininogens are proteins that are defined by their role as precursors for kinin.
Kallikrein is a hypotensive protease that liberates kinins from blood plasma
proteins and is used for vasodilation.
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WHO's pain ladder
The severity and response to other medication determines the choice
of an analgesic.

If pain occurs, there should be prompt oral administration of drugs in

the following order:
-1- non-opioids (aspirin and paracetamol);
-2- then, as necessary, mild opioids (codeine);
-3- then strong opioids such as morphine, until the patient is free of
pain.

To calm fears and anxiety, additional drugs – “adjuvants” – should be

used.

To maintain freedom from pain, drugs should be given “by the clock”,
that is every 3-6 hours, rather than “on demand”.

This three-step approach of administering the right drug in the right

dose at the right time is inexpensive and 80-90% effective.

Surgical intervention on appropriate nerves may provide further pain

relief if drugs are not wholly effective.

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Neurochemicals in pain
Several different neurotransmitters have been implicated in
pain pathways. Three of them:

Glutamate. This seems to be the dominant neurotransmitter

when the threshold to pain is first crossed. It is associated
with acute ("good / warning“) pain.

Substance P. This peptide (containing 11 amino acids) is

released by C fibers. It is associated with intense, persistent,
chronic ("bad/damage, injury“) pain.

Prostaglandins potentiate the pain of inflammation by blocking

the action of glycine [inhibitory in the CNS, especially in the spinal cord,
brainstem, and retina. It suppresses the transmission of pain signals in the
dorsal root ganglion].

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Systems of pain relief. Some agents act at the level of the presynaptic receptor of the
primary afferent fiber, or nociceptor; others operate at the postsynaptic receptor in
the dorsal horn of the spinal cord; and some work at both sites
(SP = substance P; GLU = glutamate; NO = nitrous oxide).
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Pain receptor targets

Opioid analgesics such as morphine are universally regarded as

the most powerful pain-relieving drugs.
Morphine acts through the μ-opioid receptor to inhibit signals that
transmit pain.
Intrathecal opioids work primarily at pre-synaptic levels to
reduce the transmission of painful stimuli, prevents the release of
substance P.
Release of substance P is inhibited by opioid agonists (μ, κ, and δ
agonist types).
This inhibition of Substance P release is a probable mechanism
for opioid analgesia.

Intrathecal means something introduced into or occurring in the space under the
arachnoid membrane of the brain or spinal cord.

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Pain receptor targets
Three known kinds of opioid receptors have been identified:

• mu (μ) receptors (μ1, μ2 and μ3): present in the brainstem

and the thalamus. Stimulation of these receptors can result
in analgesia, sedation and euphoria as well as respiratory
depression, constipation and physical dependence.

• kappa (κ) receptor: present in the diencephalon, the brain

stem and spinal cord. Stimulation of thid receptor produces
analgesia, sedation, loss of breath and dependence.

• delta (δ) receptor: widely distributed in the brain, and also

present in the spinal cord and digestive tract. Stimulation of
this receptor leads to analgesic and antidepressant effects,
may also cause respiratory depression.

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Pain receptor targets
Synthetic opioid and opioid-derivative drugs activate opioid
receptors (possibly by acting on the PAG directly, where these
receptors are densely expressed) to produce analgesia.

These drugs include:

- morphine,
- heroin (diacetyl-morphine),
- pethidine,
- hydrocodone,
- oxycodone, and
- similar pain-reducing compounds

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Opioids
Opioids bind to receptors on interneurons
in the pain pathways in the CNS.
The natural ligands for these receptors are
two enkephalins [endorphins]:
• Met-enkephalin (Tyr-Gly-Gly-Phe-Met)
• Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu)

The two enkephalins are released at

synapses on neurons involved in
transmitting pain signals back to the brain.
Enkephalin synapse close to the terminal of
a pain-signaling neuron.
Enkephalins hyperpolarize the postsynaptic
membrane thus inhibiting it from
transmitting these pain signals.

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Opioids
Morphine and other opioids bind opioid receptors.

- excellent pain killers.

- highly addictive.
- produces tolerance, the need for higher doses to achieve
the prior effect.

Morphine can be used via oral, intravenous, intramuscular or

subcutaneous route. It is also available as slow-release
preparations.

Morphine has poor oral bioavailability due to a significant first-

pass effect by the liver.

If taken orally, only 40–50% of the dose reaches the CNS.

IV injection is the most common method of administration.

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Opioids

Morphine-6-glucuronide (M6G) is an active metabolite with a

higher potency than morphine.

M6G is analgesic in its own right.

It is responsible for much of the pain-relieving effects of

morphine.

M6G can accumulate following chronic administration or in

renally impaired individuals.

Morphine has a short half-life of 1.5 - 7 hours.

M6G half-life is 4 +/- 1.5 hours

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Opioids

Morphine induces significant analgesia, but also a host of

other effects:
- respiratory depression,
- euphoria and sedation,
- nausea/vomiting,
- constipation,
- pupillary constriction,
- histamine release (leading to broncho-constriction and
itching).

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Opioids
Heroin (diamorphine) – is a pro-drug. It has an extremely
rapid half-life of 2-6 minutes, and is metabolized to 6-
acetylmorphine and morphine.

The half-life of 6-acetylmorphine is 6-25 minutes.

Both heroin and 6-acetylmorphine are more lipid soluble than

morphine and enter the brain more readily =>rapid onset
after intramuscular administration.

Heroin properties make it particularly suitable for epidural

administration, to relieve postoperative pain after major
surgery.

Heroin higher solubility also constitutes an advantage for

continuous subcutaneous infusion.

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Opioids

Codeine – is an analgesic with lower efficacy than morphine.

Its analgesic effect is due to demethylation in the liver to
morphine.

It may be used in combination with aspirin or paracetamol.

It has also a significant antitussive effect.

Like morphine, it induces constipation.

Pethidine – is a synthetic substance, which is more sedative

and has a more rapid onset and a shorter duration of action
than morphine.

Its metabolite, norpethidine, is active and may accumulate to

toxic levels in patients with renal impairment.
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Opioids

Methadone – is a synthetic compound with a half-life of >24

hours.
It leads to a much milder physical abstinence syndrome than
morphine but can induce psychological dependence.
It is used in maintenance programs for morphine and heroin
addicts.

Fentanyl – is a highly potent compound, with a half-life of 1-2

hours.
It can be used for severe acute pain and during anesthesia.

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Opioids

Buprenorphine – is a very lipid soluble compound, which acts

as a partial agonist at mu receptors.

Buprenorphine is a potent compound but has less efficacy

than morphine. Consequently, it may lead to a re-emergence
of pain in patients who have received more efficacious opioids,
such as morphine.

It can be used sublingually. It has a longer duration of action

than morphine, but is more emetic.

It may induce dysphoria.

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Pain receptor targets - Adrenoceptors
• 2 adrenergic agonists can enhance analgesia provided by
traditional analgesics, such as opiates.

• Activation of 2-adrenoceptors directly reduces pain

transmission by reducing transmitter release of substance P
and glutamate.

• Clonidine, 2 adrenergic agonist, is thought to produce

analgesia at the spinal level through stimulation of
cholinergic interneurons in the spinal cord by preventing pain
signal transmission to the brain.

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Pain receptor targets - Adrenoceptors

• It produces analgesia when administered by the epidural or

intrathecal route. Oral administration is not associated with
such relief.

• Epidurally administered clonidine produces dose-dependent

analgesia not antagonized by opiate antagonists.

The analgesia is limited to the body regions innervated by the

spinal segments where analgesic concentrations of clonidine
are present.

(Epidurally means situated upon or outside the dura mater)

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Pain receptor targets - Muscarinic

•Activation of spinal muscarinic receptors produces analgesia

and inhibits dorsal horn neurons through potentiation of
GABAergic inputs.

• Muscarinic receptors (M2, M4) exist in the dorsal horn and

are associated with inhibiting interneurons.

• M1, M3, M5 muscarinic receptors couple to stimulate

phospholipase C, while M2 and M4 inhibit adenylyl cyclase.

• Activation of M2 and M4 receptors induces analgesia, this was

shown by the injection of neostigmine [M2 and M4, likely
located on glutamatergic neurons].

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Pain receptor targets – Adenosine

Adenosine is an endogenous purine nucleotide that modulates

many physiological processes.

Adenosine nucleotides are involved in the energy metabolism

of all cells.

Activation of the A1 and A3 receptors causes inhibition of

adenylate cyclase and phospholipase C, which inhibits
neurotransmission.

Activation of the A2A and A2B receptors causes activation of

adenylate cyclase and phospholipase C, resulting in the
stimulation of neurotransmission.

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Pain receptor targets – Adenosine

• Adenosine is used for the treatment of paroxysmal

supraventricular tachycardia. It has an inhibitory effect on
the atrioventricular node (AV node).

• A2A stimulation is reported to have anti-inflammatory. A2A

agonists cause profound vasodilatation, with a corresponding
increase in plasma renin activity.

• Adenosine produces anti-nociceptive effects via adrenergic

mechanisms.

• Adenosine acts additively with clonidine.

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Pain receptor targets – NSAIDs
Inflammation is caused by tissue damage and, among other
things, causes pain.

Damaged tissue releases prostaglandins and these are potent

triggers of pain.

There are at least 3 key enzymes that synthesize

prostaglandins:
• Cyclooxygenase 1 (Cox-1)
• Cyclooxygenase 2 (Cox-2)
• Cyclooxygenase 3 (Cox-3)

Most NSAIDs block the action of all three cyclooxygenases.

They include aspirin, ibuprofen (Advil, Motrin), naproxen
(Aleve), and many others.

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Pain receptor targets – NSAIDs
Aspirin – analgesic and anti-inflammatory. This is due to the
irreversible inhibition of the synthesis of prostaglandins
peripherally, at the site of injury.

Ibuprofen – has analgesic and anti-inflammatory properties. It

may cause less gastric irritation than other NSAIDs.

Paracetamol – is antipyretic and analgesic, but with negligible

anti-inflammatory effects.

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Pain receptor targets – Acetaminophen

Acetaminophen (Paracetamol) is also considered as NSAID but

its mode of action is different from the others.

The onset of analgesia is approximately 11–29.5 minutes after

oral administration of paracetamol, and its half-life is 1–4
hours.

The efficacy of paracetamol is attributed to its specific

inhibition of COX-3 which is thought to be involved in
temperature regulation and fever.

The role of COX-3 in inflammation and pain is still disputed.

Acetaminophen is particularly useful for

• people allergic to aspirin and its relatives
• in order to avoid the risk of Reye's syndrome that has been
associated with giving aspirin to children with viral infections.

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Pain receptor targets – Calcium channels
Drugs used in the treatment of angina (chest pain) are used
to treat the pain.

• N-type calcium channels in nociceptors are located in the

dorsal horn.
• Ziconotide (Conotoxins) blocks the N-Type calcium channels
on the primary nociceptor (pain signal) nerves in the spinal
cord.
• Ziconotide inhibits the release of neurochemicals like
glutamate and substance P in the brain and spinal cord,
resulting in pain relief.

• Ziconotide is used to treat severe chronic pain in people who

cannot use or do not respond to standard pain-relieving
medications.

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Pain receptor targets – Sodium channels

Voltage-gated sodium channels are a crucial component of

action potentials.

Peripheral sensory neurons can become hyperexcitable after

nerve injury or in response to inflammation.

This hyperexcitability can contribute to pain.

Local anesthetics act mainly by inhibiting voltage-gated

sodium channels.

Bupivacaine blocks sodium influx into nerve cells, which

prevents depolarization.

In low concentrations, bupivacaine provides a sensory-

selective block.

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Pain receptor targets – Sodium channels

Local anaesthetics (e.g. lidocaine, amethocaine, bupivacaine,

prilocaine) are used for pain associated with localized surgery,
childbirth or in dentistry, and in the treatment of inflammatory
and neuropathic pain.

However, sodium channel therapeutics are often associated

with undesirable cardiac and CNS side effects as the drugs
target sodium channels in multiple tissues.

For many individuals with chronic or neuropathic pain, the

currently available treatments are not effective.

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Pain receptor targets – Sodium channels
Lidocaine is one of the most widely used local anesthetics.

It is used to numb tissue in a specific area, and to treat

ventricular tachycardia.

It can also be used for treating neuropathic pain.

It has proven very versatile and can be delivered in a variety

of ways.

The lidocaine patch (5%) is one of the more effective

treatments for: postherpetic neuropathic pain, allodynic pain,
or ongoing pain

Lidocaine patches might also be effective at treating painful

diabetic neuropathy and painful idiopathic distal
polyneuropathy.

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Pain receptor targets – Sodium channels

The primary reported adverse effect of Lidocaine is mild skin

irritation at the site of the patch.

Lidocaine has also been given systemically to treat

neuropathic pain.

The main problem associated with local anaesthetics is the

risk of systemic toxicity (e.g. hypotension, bradycardia and
respiratory depression).

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Pain receptor targets – Potassium channels

Numerous studies have demonstrated that the opening of

some of potassium channel plays an important role in the anti-
nociception induced by

- agonists of many G-protein-coupled receptors (2-

adrenoceptors, opioids, GABAB, muscarinic M2, adenosine A1,
5-HT1A and cannabinoid receptors),

- as well as by other anti-nociceptive drugs (NSAIDs, TCAs,

etc.) and natural products.

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Pain receptor targets – Potassium channels

Flupirtine is a centrally acting K+ channels opener with weak

NMDA antagonist properties.

It is used for moderate to strong pain and migraine, and for its
muscle relaxant properties.

It has no anticholinergic properties and is believed be devoid of

any activity on dopamine, serotonin or histamine receptors.

It is not addictive and tolerance does not develop.

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Pain receptor targets – Ketamine

Ketamine is a fast/short-acting anesthetic and painkiller used

primarily in veterinary surgery.

Ketamine is classified as an NMDA receptor antagonist.

At high, fully anesthetic level doses, it has been found to bind

to opioid µ and σ (Σ, sigma) receptors.

Ketamine has a wide range of effects in humans, including

analgesia, anesthesia, hallucinations, elevated blood pressure,
and bronchodilation.

Ketamine is primarily used for the induction and maintenance

of general anesthesia, usually in combination with a sedative.

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Pain receptor targets – Ketamine

Other uses of ketamine include sedation in intensive care,

analgesia (particularly in emergency medicine), and treatment
of bronchospasm.

Ketamine is usually used in pain that has failed to respond fully

to opioids despite escalating doses and combination with
appropriate adjuvants.

It may be particularly helpful in neuropathic pain.

Ketamine has been shown to be effective in treating

depression in patients with bipolar disorder who have not
responded to other anti-depressants.

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Pain receptor targets – Ketamine
Side effects:
- dysphoria, hallucinations and nightmares may occur
- Tolerance.

Tolerance can be reduced by concurrent treatment with

haloperidol or a benzodiazepine.

Other side effects includes sedation, confusion, increased

muscle tone, disorientation, delirium and dizziness, and if
encountered require patients reassurance.

There are side effects associated with higher doses which may
warrant dose reduction. These include:
- tachycardia,
- hypertension,
- diplopia [double vision] and
- nystagmus [involuntary eye movements].

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Pain receptor targets – Cannabinoids
Tetrahydrocannabinol (THC) is the primary psychoactive
component of the cannabis plant. It appears to ease moderate
pain (analgesic) and to be neuroprotective.

THC binds CB1 and CB2 receptors.

CB1 receptors are primarily located at central and peripheral

nerve terminals.

CB2 receptors are predominantly expressed in non-neuronal

tissues, particularly immune cells and microglial cells.

Cannabinoid receptors inhibit the enzyme adenylate cyclase

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Pain receptor targets – Cannabinoids
Cannabinoid receptors:
- localized in areas that control movement (basal ganglia,
cerebellum), cognition (cerebral cortex), and attention and
memory (hippocampus).
- sparse in areas that control heart rate and respiration
(medulla).
- localized in areas that control emesis (nucleus of the solitary
tract) and pain (spinal cord).
- not localized on ventral forebrain dopamine neurons that are
implicated in abuse potential of psychoactive drugs.

-Endocannabinoids are released upon electrical stimulation of

PAG, and in response to inflammation in the extremities.
-Cannabinoids produce their analgesic effects due to
suppression of spinal and thalamic nociceptive neurons.
-Sativex and other cannabinoids are used for neuropathic pain
and spasticity.

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Pain receptor targets – Cannabinoids
Therapeutic effects of cannabinoids

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Migraine
The management of pain associated with migraine consists of
the management of acute attacks, and prophylaxis.

Acute attacks may respond to NSAIDs such as aspirin and

paracetamol, or to agonists at 5-HT1D receptors, such as
sumatriptan.

Prophylaxis may be achieved by use of 5-HT2 receptor

antagonists (methysergide, cyproheptadine), calcium channel
blockers (e.g. verapamil), or tricylic antidepressants (e.g.
amitriptyline).

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