Ae Pain Lect Week16 141117 .pdf

WEEK 16

MPharm Programme PAIN & ANALGESIA

Dr Abdel Ennaceur Slide 1 of 78

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Pain Lecture notes

Terminology

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•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. Slide 13 of 78

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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 velocity

> 40 ms-1

5-15ms-1

< 2ms-1

Receptor activation thresholds

Low

High and low

High

Sensation on stimulation

Light touch, non-noxious

Rapid, sharp, localised pain

Slow, diffuse, dull 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 class

Threshold afferents

C

Main transmitters

Main receptor activated

Laminar location

Normal sensation

Pathological sensation

Peptides

NK1,2

I-II, V

Slow pain

Hyperalgesia

EAA

NMDA AMPA mGlu

Fast pain

Allodynia

EAA

AMPA

Touch vibration pressure

Mechanical allodynia

High A

Aβ

Low

III-VI

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 Slide 11 of 78

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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 secondorder 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. It has enkephalin-producing cells that suppress pain.

Midbrain Pons

It is located in the midbrain. It projects to the nucleus raphe magnus, and also contains descending autonomic tracts.

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Spinal cord

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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.

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Efferent (Descending) | Afferent (Ascending)

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 . Slide 29 of 78

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Descending pathways

ACC=Anterior cingulate cortex Slide 30 of 78

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(Efferent)

(Afferent)

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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 midbrain, pons, oblongata].

consists and

of the medulla

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. Slide 42 of 78

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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). Slide 45 of 78

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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. Slide 46 of 78

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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 firstpass 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 6acetylmorphine 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 prostaglandins: • Cyclooxygenase • Cyclooxygenase • Cyclooxygenase

least

3

key

enzymes

that

synthesize

1 (Cox-1) 2 (Cox-2) 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, selective block.

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bupivacaine

provides

Pain Lecture notes

a

sensory-

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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. Slide 68 of 78

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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 neuropathic pain.

been

given

systemically

to

treat

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 Lecture notes

WEEK 16

Pain receptor targets – Potassium channels Numerous studies have demonstrated that the opening of some of potassium channel plays an important role in the antinociception induced by - agonists of many G-protein-coupled receptors (2adrenoceptors, 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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M14

Pain Lecture notes

WEEK 16

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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M14

Pain Lecture notes

WEEK 16

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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M14

Pain Lecture notes

WEEK 16

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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M14

Pain Lecture notes

WEEK 16

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 Lecture notes

WEEK 16

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 Lecture notes

WEEK 16

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 Lecture notes

WEEK 16

Pain receptor targets – Cannabinoids Therapeutic effects of cannabinoids

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Pain Lecture notes

WEEK 16

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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Pain Lecture notes