Lecture 15 - Pain & Analgesia 3 PDF

Lecture summary Pain and nociception Detection of noxious stimuli Transmission of noxious information to spinal cord and brain Sensitization and modulation of nociceptors Transmission at spinal level Regulation of nociception Opioid analgesia NSAIDS analgesia Other analgesics Analgesic dru...

Lecture summary Pain and nociception Detection of noxious stimuli Transmission of noxious information to spinal cord and brain Sensitization and modulation of nociceptors Transmission at spinal level Regulation of nociception Opioid analgesia NSAIDS analgesia Other analgesics Analgesic drugs Sensation of pain Descending inhibition of nociception - BOOST Spinal cord INHIBIT INHIBIT + Central Peripheral sensitization sensitization + Nociceptive stimuli  Analgesic drugs Opiate drugs NSAIDs (non-steroidal anti-inflammatory drugs) Other analgesics – already used, and in the pipeline  Opiate drugs Opiates act on opioid receptors mimic endogenous opioids Morphine Heroin (Diamorphine) Codeine Methadone Pethidine (Etorphine) Fentanyl Remifentanyl Butorphanol Buprenorphine Naloxone , ,  antagonist  World Health Organisation Pain Ladder Mild pain – NSAIDs e.g. aspirin, ibuprofen Moderate pain – codeine, buprenorphine Severe pain – morphine, fentanyl  Central sites of analgesia opiates + midbrain periaqueductal grey + locus coeruleus medulla nucleus raphe magnus noradrenaline 5HT spinal cord dorsal horn + Periphery opiates opiates  Peripheral modulation of nociception TrkA nerve growth factor (NGF) Potassium channels Prostanoid receptor prostaglandins K+ + + + + VGNa + + Inhibitory Opioid/cannabinoid receptor + VR-1 Morphine/anandamide BK2 H1 bradykinin histamine  Opioid receptors and sites of analgesia Receptor    Site of analgesia supraspinal +++ - - spinal ++ ++ + peripheral ++ - ++  Opioid receptors and drugs Receptor    Drug Morphine +++ + + Methadone +++ - - Fentanyl +++ + + Codeine - + - Buprenorphine  Behavioural responses of opiate drugs  receptor  receptor  receptor analgesia analgesia analgesia euphoria dysphoria - respiratory no respiratory no respiratory depression depression depression constipation diuresis proconvulsant Behavioural responses of -opioid receptor activation Desirable effects Undesirable effects Respiratory depression Euphoria Analgesia Constipation (methylnaltrexone) Euphoria Sedation Constipation Nausea & vomiting Sedation Tolerance Cough suppression Itching Psychological dependence Physical dependence  Tolerance Continued use of a drug requires increased doses for equivalent effect Forrest Smith, Richmond VA, USA  Routes of administration: opiates "For children teething. Greatly facilitates the process of Teething, by softening the gums, reducing all inflammation; will allay ALL PAIN and spasmodic action, and is SURE TO REGULATE THE BOWELS. Depend on it, Mothers, it will give rest to yourselves and Opiate drugs (narcotics)  Routes of administration: opiates Pills morphine / codeine Intravenous injection patient controlled injection morphine / diamorphine / fentanyl Epidural fentanyl / pethidine Transdermal patch fentanyl Lollipop fentanyl  World Health Organisation Pain Ladder Mild pain – NSAIDs e.g. aspirin, ibuprofen Moderate pain – codeine, buprenorphine Severe pain – morphine, fentanyl Non-steroidal anti-inflammatory drugs (NSAIDS) Most widely used therapeutic agents Over 50 types available eg. aspirin, ibuprofen, diclofenac, paracetamol Anti-inflammatory Anti-pyretic Analgesic All effects related to decreased prostaglandin synthesis Non-steroidal anti-inflammatory drugs (NSAIDS) Most widely used therapeutic agents Over 50 types available eg. aspirin, ibuprofen, diclofenac, paracetamol Anti-inflammatory - ‘acetaminophen’ in USA Anti-pyretic - More details (if interested; NOT tested in exam) can Analgesic be found on moodle All effects related to decreased prostaglandin synthesis Non-steroidal anti-inflammatory drugs (NSAIDS) Most widely used therapeutic agents Over 50 types available eg. aspirin, ibuprofen, diclofenac, paracetamol Anti-inflammatory Anti-pyretic Analgesic All effects related to decreased prostaglandin synthesis Non-steroidal anti-inflammatory drugs (NSAIDS) Most widely used therapeutic agents Over 50 types available eg. aspirin, ibuprofen, diclofenac, paracetamol Anti-inflammatory Anti-pyretic Analgesic All effects related to decreased prostaglandin synthesis  Modulation of nociception Potassium channels Prostanoid receptor prostaglandins K+ + + + VGNa + VR-1 Opioid/cannabinoid receptor Morphine/anandamide BK2 bradykinin  NSAIDs are COX inhibitors Phospholipid Phospholipase A2 Arachidonic acid NSAIDs x Cyclo-oxygenase-1 or -2 (COX-1 or COX-2) Prostaglandin H2 PGE synthase prostanoid Prostaglandin E2 (PGE2) receptor  Modulation of nociception NSAIDS Prostanoid receptor prostaglandins X + X + VGNa + VR-1 BK2 bradykinin Disadvantages of NSAIDS PGs involved in many processes multiple side effects severe gastric irritation kidney disorders paracetamol overdose Specific COX-2 inhibitors Less side effects. But……..  Specific COX-2 inhibitors Traditional NSAID (e.g. aspirin) Rofecoxib (vioxx) Celecoxib (celebrex) COX-1 COX-2 COX-1 COX-2 COX-2 specific inhibitor COX-1 is widespread throughout the body COX-2 is just involved in the inflammatory response  World Health Organisation Pain Ladder Mild pain – NSAIDs e.g. aspirin, ibuprofen Moderate pain – codeine, buprenorphine Severe pain – morphine, fentanyl  Neuropathic pain Pain unrelated to peripheral nociception Sometimes called pathological pain – serves no purpose Peripheral nerve damage (eg. Diabetic neuropathy) Peripheral nerve terminal damage or infection (eg. Post-herpetic neuralgia) Spinal damage Thalamic stroke Generally don’t respond to opioids / NSAIDs (see notes under slide for link to one example of someone with chronic neuropathic pain) Other analgesic approaches Tricyclic antidepressants (e.g. imipramine) Antiepileptic drugs (e.g. gabapentin) Neuropathic pain Unknown mode of action Cannabinoid receptor agonists Central and peripheral effects Neuropathic pain (esp. multiple sclerosis) Glutamate receptor blockers (MK801) Block afferent transmission Severe side effects Neurokinin receptor blockers Block central sensitization In development Nociceptor blockers (TRPV1, P2X3, sodium channel) Block detection of noxious signals In development  Lecture summary Pain and nociception Detection of noxious stimuli Transmission of noxious information to spinal cord and brain Sensitization and modulation of nociceptors Transmission at spinal level Regulation of nociception Opioid analgesia NSAIDS analgesia Other analgesics