Pain 2_2022_Student(2) (1).pptx

Physiology of pain 2 Professor Andrew Dilley Previous lecture • Nociceptors and their responses to noxious stimuli • Transduction of painful stimuli • Role of tissue injury and inflammation • Hypersensitivity (hyperalgesia and allodynia) • Peripheral sensitisation (mechanism of hyperalgesia) • As...

Physiology of pain 2 Professor Andrew Dilley Previous lecture • Nociceptors and their responses to noxious stimuli • Transduction of painful stimuli • Role of tissue injury and inflammation • Hypersensitivity (hyperalgesia and allodynia) • Peripheral sensitisation (mechanism of hyperalgesia) • Ascending pain pathways • Descending inhibition of pain and role of opioids Clinical pain • Clinical pain is seen in clinics • Associated with damage to tissues, including the nervous system • Mechanisms can be nociceptive and/or neuropathic Nociceptive Normal functioning of nociceptors In response to tissue injury Neuropathic Pain in response to injury to the nervous system How long does clinical pain last? • Clinical pain can be acute or chronic International Association for the Study of Pain: Pain <3 months = Acute Pain >3 months = Chronic Acute pain Acute pain • Due to tissue injury or inflammation • E.g. following surgery, musculoskeletal injury, burn, headache, visceral pain Nociceptive Normal functioning of nociceptors In response to tissue injury Injury site recovers Pain stops Acute pain mechanisms • Acute pain is due to the excitation of nociceptors by tissue injury and inflammatory products Direct activation E.g. ATP H+ Serotonin Acute pain mechanisms • Acute pain is due to the excitation of nociceptors by tissue injury and inflammatory products Peripheral sensitisation Leads to hyperalgesia Bradykinin NGF Reduce the threshold of heatactivated channels (TRPV1) Prostaglandins Reduce the threshold of sodium and TRPV1 channels Acute pain treatments • Lots of acute pain treatments • Very effective • Sites of action are: 1. PNS (e.g., at the site of injury) 2. CNS 3. Or both Local anaesthetics • Examples include lidocaine, lignocaine • Act in periphery Topically applied to skin or injected Mechanism of action: Prevents nociceptor firing by blocking sodium channels Lidocaine Nociceptor Na+ channel Non-steroidal anti-inflammatory drugs • Examples include aspirin, ibuprofen • Act in periphery Mechanism of action: Cyclooxygenase (COX) inhibitors Reduce the inflammatory response by inhibiting prostaglandin synthesis Reduces peripheral sensitisation X X COX inhibited Prostaglandin synthesis reduced X Prevents decrease in Na+ and TRPV1 channel threshold Paracetamol / acetaminophen • Paracetamol is not a NSAID (no anti-inflammatory properties) • Acts within the central nervous system Mechanism of action: Exact mechanism not known Inhibits cyclooxygenase enzymes Acts on descending serotonergic pathway Activation of cannabinoid receptors Topical capsaicin treatment • Component of chili peppers • Acts in periphery Topically applied to skin Mechanism of action: TRPV1 agonist Persistent opening of TRPV1 Calcium overload Nociceptor stops working Anand & Bley 2011 Opioids • Examples include morphine, codeine, tramadol • Most effective pain relief but numerous side effects • Acts centrally and peripherally Opioid - X PAG Agonists of the endogenous opioid system Brainstem (Disinhibition) Spinal cord Peripheral (inhibits channels on nociceptors) Spinothalamic tract Mechanism of Action Inhibitory pathway - X RVM Dorsal horn - - Nociceptor Gate control theory • Gently rubbing or blowing on painful area can reduce pain I.e., Pain evoked by nociceptors can be reduced by the simultaneous activation of low threshold mechanoreceptors Mechanism of Action Gate control theory - Modulation at spinal level • Ab-fibre stimulation at injury site activates interneurons in dorsal horn, which inhibit spinothalamic neurons C fibres inhibit inhibitory interneurons – Opens gate Aβ fibres activate inhibitory interneurons – Closes gate X X Chronic pain - Mechanisms Chronic pain • Pain persists (>3 months) Very common - Affects 20-50% of population Lots of examples: Chronic back pain, cancer, carpal tunnel syndrome, arthritis, fibromyalgia, diabetes, migraine, post-surgery, postherpetic neuralgia (shingles), phantom limb pain, multiple sclerosis, trigeminal neuralgia Chronic pain • Chronic pain can be nociceptive or neuropathic Nociceptive In response to tissue injury (persistent inflammation) e.g. Osteoarthritis Neuropathic Pain in response to injury to the nervous system Neuropathic pain • Nerve injury may be a compression, traction, sever, hypoxia, demyelination, tumour or neuroinflammation • Affects 8% of the population However, a nerve injury may not always be obvious on clinical examination Symptoms of neuropathic pain Neuropathic pain mechanisms Mechanisms are complex, involving both peripheral and central nervous systems Peripheral mechanisms Main peripheral mechanisms: 1. Peripheral sensitization (Covered in previous lecture) 2. Increased firing of primary afferents Increased firing of primary afferents • At nerve injury sites, the damaged tips of nociceptors fire spontaneously Intact nociceptor: Severed nociceptor: E.g., Knife injury or amputation Neuroma forms (i.e., tangle of regenerating nerve fibre endings) Tips of the regenerating nerve endings are excitable • Responsible for spontaneous pain and also phantom limb pain • Underlies central neuropathic pain mechanisms Central mechanisms Main central mechanisms: 1. Central sensitization – within spinal cord 2. Changes in activation patterns/cortical remapping – within brain (Not covered in lecture) Central sensitization • Increase in the responsiveness of the spinothalamic neurons within the central nervous system Normal inputs begin to produce abnormal responses Due to the reduced threshold for activation (similar to LTP) Reduced threshold for activation Constant firing of axons from the periphery (following injury) Sustained release of glutamate Prolonged depolarisation of the postsynaptic membrane Massive influx of Ca2+ through NMDA receptors Secondary order neuron of spinothalamic tract Activation of kinases Phosphorylation of NMDA/AMPA receptors Channel protein synthesis Alters kinetics of channels and causes insertion of more channels “Neuron fires more easily” Allodynia mechanism • Non-noxious Aβ fibres also synapse onto 2nd order spinothalamic neurons Normally these are non-functional Following central sensitization: • Non-noxious afferents activate sensitized 2nd order neurons = Woolf, 2011 Allodynia Problem with central changes Not easily reversible Chronic pain - Treatments Chronic pain treatments • Difficult to treat Acute pain treatments often do not work • Good individual patient management is critical • Important to manage primary condition as well as other associated symptoms Depression Sleep disturbances Fatigue Current neuropathic pain treatments • Drugs: Tricyclic antidepressants Anticonvulsants Have analgesic properties • Acupuncture • Physical therapies – e.g. manipulation of tissues, pacing • Psychological therapies – e.g. cognitive behavior therapy • Surgery – e.g. spinal cord stimulator Tricyclic antidepressants • Examples include amitriptyline and duloxetine • Act centrally Spinothalamic tract Mechanism of action: Act on descending inhibitory pathways Inhibits reuptake of serotonin (and noradrenalin) RVM Serotonergic neuron - Inhibitory interneuron Dorsal horn Nociceptor Anticonvulsants • Examples include pregabalin, gabapentin and carbamazepine • Act centrally Mechanism of action: (proposed) Act in spinal cord to reduce excitability Blocks calcium (pregabalin) and sodium (carbomazepine) channels Pregabalin blocks presynaptic voltage-gated Ca2+ channels Prevent release of glutamate X Nociceptor Spinothalamic tract NICE guidelines on treatment of neuropathic pain • First-line of treatment: Amitriptyline, duloxetine, pregabalin or gabapentin • Second-line of treatment: Switch drugs or combine • Third-line of treatment: Refer patient to a specialist pain service and consider oral tramadol (opioid) or in combination with the second-line treatment consider topical lidocaine Placebo and complimentary alternative medicines • Important to consider the placebo effect Placebo analgesia has been demonstrated for the treatment of neuropathic pain Due to activation of descending inhibitory pathways • Many Complementary Alternative Medicines Examples include acupuncture, massage therapy, homeopathy, hypnosis The effectiveness of many CAMS is still inconclusive [Exceptions include acupuncture] What’s gone wrong in chronic pain? Peripheral terminals Peripheral sensitization Axon Increased firing of primary afferent neurons Dorsal root ganglia Changes in protein synthesis Dorsal horn/spinal cord Central sensitization Brain Changes in brain activation patterns Summary • Acute pain - Mechanisms - Treatments • Chronic pain - Mechanisms - Treatments