Pain and Analgesia Lecture Notes PDF

PAIN Professor Arthur Butt School of Pharmacy and Biomedical Science 1 Structure of Lecture. 1. Introduction 2. Pain: Perception and Sensation 3. The Pain Pathway 4. The Analgesic Ladder 5. Opioid Analgesics ...

PAIN Professor Arthur Butt School of Pharmacy and Biomedical Science 1 Structure of Lecture. 1. Introduction 2. Pain: Perception and Sensation 3. The Pain Pathway 4. The Analgesic Ladder 5. Opioid Analgesics  Sensory system Sensory receptors Transmit sensory information into – mechanoreceptors the spinal cord and to sensory – thermoreceptors areas of the brain – chemoreceptors – Proprioceptors – nociceptors Structure of Lecture. 1. Introduction 2. Pain: Perception and Sensation 3. The Pain Pathway 4. The Analgesic Ladder 5. Opioid Analgesics  2 Pain: Perception and Sensation Pain = perception – subjective response – to a noxious stimulus Sensation = nociception – Nociceptors – free nerve endings  Different kinds of pain DIFFERENT KINDS OF PAIN: – Acute (physiological) – Inflammatory (pathological) – Neuropathic Acute (physiological) Pain Acute pain is a physiological response that warns us of danger. Nociception - normal processing of pain and the responses to noxious stimuli that are damaging or potentially damaging to normal tissue. Inflammatory Pain } Inflammatory Pain } Tissue damage } release of inflammatory mediators such as prostaglandins and bradykinin } increase the sensitivity of nocipetors to noxious stimuli } Sensitization in the pain pathway } hyperalgesia - hypersensitivity to a noxious stimulus (hypersensitive nociceptors) } allodynia - pain that results from a non-noxious stimulus (low-threshold mechanoreceptors and thermoreceptors) } NSAIDs reduce production of prostaglandins Neuropathic Pain } Neuropathic Pain is caused by damage or injury to the nociceptive nerves – peripherally or centrally. } The pain is usually described as a burning sensation and affected areas are often sensitive to the touch.  Nociceptors Nociceptors are free nerve endings in the skin Many stimuli have been found to activate ion channels present on nociceptor terminals Act as molecular transducers to depolarize these neurons Thereby setting off nociceptive impulses along the pain pathways Blocked by local anaesthetics, e.g. lidocaine  Signal transduction in nociceptors Clinical Significance Antagonists block TRPV1 activity, thus reducing pain TRPV1 antagonists have been developed - efficacy in reducing nociception from inflammatory and neuropathic pain models in rats In humans, major side-effect is hyperthermia restricted usefulness of these drugs TRPVI TRPV1 – transient receptor potential cation channel vanilloid 1 (TRPV1) receptor – cation channel, activation results in sodium influx - activated by noxious heat, also low pH - leads to painful, burning sensation - sensitised by inflammatory agents  Signal transduction in nociceptors Clinical Significance upregulated in patients with painful bladder syndrome may be a target in prostate cancer TRPV1 –noxious heat TRPM8 – TRP subfamily M member 8 (TRPM8) - cation channel - sodium influx in response to cold  Signal transduction in nociceptors TRPV1 – noxious heat TRPM8 (CMR1) – cold ENaC/Degenerin family – activated by mechanical stimuli  Signal transduction in nociceptors TRPV1 - noxious heat TRPM8 (CMR1) - cold ENaC/Degenerin family - mechanical stimuli ASIC – acid sensing ion channel – belongs to the same family as ENaC - sodium channel activated by protons - acid  ASICs - Mamba Venom Mamba venom is made up mostly of dendrotoxins (dendrotoxin-k, -1, -3, and Black mamba venom is 'better -7, among others) painkiller' than morphine mambalgins – potent analgesic as strong as morphine – without most of the side-effects. – Block acid-sensing ion channels Black mamba venom peptides target acid-sensing ion channels to abolish pain Diochot et al. (2012) Nature Structure of Lecture. 1. Introduction 2. Pain: Perception and Sensation 3. The Pain Pathway 4. The Analgesic Ladder 5. Opioid Analgesics The Pain Pathway Perception of pain throughout the body arises when neural signals transmitted to specific higher order brain areas Cingulate Cortex mediates the emotional component of pain  Descending Pain Control Circuit Opioids } Opiates decrease pain by modulating the descending pain pathway in a complex manner Opioids  Pain transmission in the spinal cord } Nociceptive axons synapse with second order neurons in lamina I, II, and V of the dorsal horn in the spinal cord } Transmission ◦ for moderate pain axons release glutamate, with fast action ◦ stronger pain: axons release glutamate and substance P (and ATP), with slower sustained actions  Pain transmission in the spinal cord } Nociceptive axons synapse with second order neurons in lamina I, II, and V of the dorsal horn in the spinal cord } Transmission ◦ for moderate pain axons release glutamate, with fast action ◦ stronger pain: axons release glutamate and substance P (and ATP), with slower sustained actions carbamazepine – NaCh Sodium channel blocker Ziconotide - conotoxin from cone snail Voltage gated calcium blocker ketamine Decrease of glutamate  Pain transmission in the spinal cord } Nociceptive axons synapse with second order neurons in lamina I, II, and V of the dorsal horn in the spinal cord } Transmission ◦ for moderate pain axons release glutamate, with fast action ◦ stronger pain: axons release glutamate and substance P (and ATP), with slower sustained actions } Local inhibitory interneurons release GABA and glycine gabapentin pregabalin  Pain transmission in the spinal cord } Nociceptive axons synapse with second order neurons in lamina I, II, and V of the dorsal horn in the spinal cord } Transmission ◦ for moderate pain axons release glutamate, with fast action ◦ stronger pain: axons release glutamate and substance P (and ATP), with slower sustained actions } Local inhibitory interneurons release GABA and glycine } Descending pain control fibres release opioids to inhibit pain  Descending Pain Control Circuit } Opiates decrease pain by modulating the descending pain pathway in a complex manner Noradrenergic and Serotonergic Antidepressants - Tricyclics Treatment of neuropathic pain e.g. amitriptyline, doxepin, imipramine) inhibit reuptake of norepinephrine and serotonin Structure of Lecture. 1. Introduction 2. Pain: Perception and Sensation 3. The Pain Pathway 4. The Analgesic Ladder 5. Opioid Analgesics  The analgesic ladder Mirrors the pain pathway Step one - non-opioid analgesics (eg aspirin, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs).  The analgesic ladder Mirrors the pain pathway Step one - non-opioid analgesics (eg aspirin, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs). Step two - mild opioids (eg codeine) with or without non-opioid: Step three - strong opioids with or without non- opioid; useful for moderate-to-severe pain  The analgesic ladder Mirrors the pain pathway Step one - non-opioid analgesics (eg aspirin, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs). Step two - mild opioids (eg codeine) with or without non-opioid: Step three - strong opioids with or without non- opioid; useful for moderate-to-severe pain Neuropathic Pain - Antidepressants (5-HT), anticonvulsants (carbamazepine – NaCh and GABA-R), gabapentin and pregabalin (GABA), ketamine (NMDA receptors)  Summary - Targetting Pain The analgesic ladder mirrors the pain pathway (1) NSAIDs - site of injury/painful stimulus – inflammatory pain, e.g. NSAIDS – Cox inhibitors (inhibit production of prostaglandins) - ibuprofen, Naproxen, Diclofenac (contraindicated in asthmatics and those with gastric problems). Also in this group have one specific for certain things eg mefenamic acid for period pain(menorrhagia) (2) Analgesia – descending control - Paracetamol, Codeine based- co-codamol, Tramadol (very weak μ-opioid receptor agonist), Morphine (3) Neuropathic pain – spinal (dorsal horn neurons) - Amitriptyline, gabapentin, Pregabalin Structure of Lecture. 1. Introduction 2. Pain: Perception and Sensation 3. The Pain Pathway 4. The Analgesic Ladder 5. Opioid Analgesics  OPIATES versus OPIOIDS OPIOID - encompasses all drugs that act on opioid receptors - synthetic, semi- synthetic, or naturally occurring. OPIATE - subset of opioids that are either derived directly from poppy or synthesized from one.  Opioid Receptors ↑ Endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin G protein-coupled receptors with opioids as ligands - Mu µ opioid receptor (MOR) – activated by morphine, b endorphin and enkephalins - Delta d opioid receptors (DOR) activated by enkephalins and b endorphin - Kappa k opioid receptor (KOR) activated by dynorphin Receptor Activation - Opens K+ channels – makes neurons less excitable - Inhibits Ca2+ channels – decreases neurotransmitter release  MoR DOR ROR Morphine B. Endorphin Dynorphine B endorphin En Rephalins En Kephalins  Addiction Reward centre of the brain - DOPAMINE  Tolerance Receptor Desensitization  Peripheral Effects } GI motility } Decreased propulsive peristaltic waves } Tone is increased to the point of spasm } Tone of anal sphincter is greatly increased, reflex relaxation response to rectal distention is reduced } Ureter and urinary bladder } Increase tone and amplitude of contraction of ureter, response quite variable } Inhibit urinary voiding reflex, catheterisation may be required  Some OPIOIDS } Diamorphine (heroin) - Very lipid soluble - Pass through BBB readily so fast onset - Within body rapidly deacetylated to morphine } Codeine - 20% analgesic efficacy of morphine - Mainly used as oral analgesic fo - mild type of pain (headache, backache etc ) - Causes constipation - Has antitussive activity so often used in cough mixtures } Nalorphine - Opioid antagonist, high first-pass metabolism so has to be given by injection - Use for reversing respiratory depression, haemorrhagic shock } Naloxone - Opioid antagonist, orally active and longer acting - Use in treatment of opioid addiction  Some OPIOIDS } Pethidine Insomnia - Virtually identical to morphine but tends to cause restlessness rather than sedation Relax - Additional anti-muscarinic action (dry mouth and blurred vision) - Partly N-demethylated in liver to norpethidine which has a hallucinogenic and convulsant effect , XSI - Preferred to morphine for analgesia during labour, because it is shorter acting } Methadone - Main difference from morphine is oral efficacy and considerably longer duration of action - Used in treatment of opioid addiction The End – Thank you