Pharmacology of Analgesia (Pharmacological Classes and Agents) Lecture Notes PDF

Pharmacology of analgesia (pharmacological classes and agents) PHS310 Week 11 Dr. Fatemah Alherz 1 Objectives Review basic principles of Analgesia in relation to the physiology of pain transmission Review the classif...

Pharmacology of analgesia (pharmacological classes and agents) PHS310 Week 11 Dr. Fatemah Alherz 1 Objectives Review basic principles of Analgesia in relation to the physiology of pain transmission Review the classification of Analgesics Explain mechanisms of action of Analgesics Describe major features of Analgesics 2 What is Pain Pain: An unpleasant sensory and emotional experience associated with actual or potential tissue damage. Hyperaesthesia (hypersensitivity): Increased sensitivity to stimulation, excluding the special senses Hyperalgesia: Increased pain in response to a noxious stimulus Allodynia: Pain due to a stimulus that does not normally produce pain From the International Association for the Study of Pain (IASP) definitions (Merskey, and Bogduk 1994) 3 Categories of pain Physiologic: experienced pain in response to an intense or noxious stimulus. Inflammatory : Under circumstances where tissue injury and inflammation are present, noxious stimuli elicit more severe pain than normal because of increases in the excitability of the somatosensory system, and stimuli that would not normally cause pain become painful. such as rheumatoid arthritis 4 Categories of pain cont. Neuropathic: nerve injury produced by disease or trauma—as in amputation, HIV infection, varicella zoster (VZV) infection, cytotoxic treatment, and diabetes mellitus—evokes pain that persists long after the initiating cause has disappeared. In these conditions, pathologic and sometimes irreversible alterations in the structure and function of the nervous system lead to severe and intractable pain. Dysfunctional: some patients experience considerable pain in the absence of noxious stimuli, inflammation, or lesions to the nervous system. This dysfunctional pain, as in tension-type headache, fibromyalgia, or irritable bowel syndrome, results from an abnormal function of the nervous system. 5 Mechanism of pain  Activation of the peripheral terminal by a noxious stimulus leads to the generation of action potentials (Na+ ion channel) These are conducted to the dorsal horn of the spinal cord (N-type voltage-gated calcium channels control neurotransmitter release. From synaptic vesicles) Neurotransmission in the dorsal horn relays the signal to CNS neurons, which send the signal to the brain. This circuit is also subject to descending modulatory control. 7 Neurotransmission in the spinal cord dorsal horn. 8  Descending and Local Inhibitory Regulation in the Spinal Cord Synaptic transmission in the spinal cord is regulated by the actions of both local inhibitory interneurons and projections that descend from the brainstem to the dorsal horn. Because these systems can limit the transfer of incoming sensory information to the brain, they represent an important site for pharmacologic intervention. The major inhibitory neurotransmitters in the dorsal horn of the spinal cord are opioid peptides, norepinephrine, serotonin (5-HT), glycine, and GABA 10 Pain management Non-steroidal anti-inflammatory drugs (NSAIDs) 14  Non-steroidal anti-inflammatory drugs (NSAIDs) Salicylate Propionic acid Phenylacetic acid Selective COX-2 derivatives derivatives inhibitors -Acetylsalicylic acid (aspirin) Ibuprofen Diclofenac Celecoxib Naproxen Ketorolac Analgesic-antipyretic drug: Acetaminophen  Non-steroidal anti-inflammatory Drugs (NSAIDs ) Mechanism of action NSAIDs inhibit the activity of cyclooxygenase enzymes (COX-1 and COX-2) that are required for the production of prostaglandins  Non-steroidal anti-inflammatory Drugs (NSAIDs ) Mechanism of action cont. NSAIDs affect pain pathways in at least three different ways. 1) Prostaglandins reduce the activation threshold at the peripheral terminals of primary afferent nociceptor neurons. NSAIDs decrease inflammatory hyperalgesia and allodynia by reducing prostaglandin synthesis. 2) NSAIDs decrease the recruitment of leukocytes and, thereby, the production of leukocyte-derived inflammatory mediators. 3) NSAIDs that cross the blood-brain barrier prevent the generation of prostaglandins that act as pain-producing neuromodulators in the spinal cord dorsal horn. 19  NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) Therapeutic actions: Reduce inflammation (anti-inflammatory) Reduce pain (analgesic effect) Reduce fever (antipyretic effect) Adverse effects: Non-selective COX inhibitors: injury to gastric mucosa and kidneys. Salicylates (Acetylsalicylic acid - aspirin) Rarely used in pain management>>it exhibits anti-inflammatory activity only at relatively high dose MOA; covalently acetylates COX-1 and COX-2. Irreversible inactivation of COX-1 (COX1 mediate TXA2 production) Adverse Effects. Gastric irritation, hemorrhage, vomiting, renal tubular necrosis. 21 Dose dependent effects of Aspirin Toxic levels High Levels COX-2 Inhibitors Selective COX-2 inhibitors Rofecoxib and valdecoxib – withdrawn (increased risk of adverse CV effects and skin reactions). Celecoxib >>>still in use For patients who required NSAIDs but were at high risk for developing gastrointestinal (GI), renal, or hematologic adverse effects. Adverse effects less GI adverse effects compared to non-selective NSAID Potential to increase myocardial infarctions and strokes 23  Ibuprofen Analgesic, anti-inflammatory, antipyretic. Lower incidence of adverse effects than aspirin. Propionic acid derivatives Naproxen More potent and longer t1/2 than ibuprofen, prescribed less frequently Adverse effects similar to ibuprofen>>dyspepsia to gastric bleeding. 24 Phenylacetic acid derivatives Diclofenac and ketorolac Moderate to severe pain Risk of severe adverse effects : anaphylaxis, acute renal failure, Stevens-Johnson syndrome, GI bleeding. Ketorolac- for short-term pain control in place of opioids. 25  Analgesic-antipyretic Acetaminophen (paracetamol) Reduces PG synthesis in the CNS. Produces analgesia and antipyresis but has little anti-inflammatory efficacy. Acetaminophen is frequently combined with weak opioids for the treatment of moderate pain, and preparations are available featuring acetaminophen combined with codeine or hydrocodone. A major concern with acetaminophen use is its low therapeutic index; overdose can result in liver failure. 26 Mechanism of action 27  NSAIDS NSAIDs and COX-2 inhibitors act centrally and peripherally. (Unlike acetaminophen which acts only centrally). (NSAID + opioids) or (Opioids + Acetaminophen). → synergistic effect 28  Neuropathic Pain Nerve injury involve both functional and structural alterations in the nervous system and occur in both primary afferent neurons and the CNS In the periphery, changes in primary afferent sensory neurons occur after nerve damage, contributing to neuropathic pain. These alterations are induced by combinations of : Positive signals: such as inflammatory cytokines released by macrophages and Schwann cells Negative signals: such as the loss of peripheral support from neurotrophic factors. In addition, the expression pattern of sodium channels changes in injured primary sensory neurons 29  TCAs Treatment options for Dual NE/serotonin reuptake inhibitors neuropathic pain Antiepileptics 30  Analgesic Use of Antidepressants Used as adjuvants in chronic pain management. MOA: analgesic action appears to be mediated mainly in the spinal cord and to involve the reduction of central sensitization 31 Analgesic Use of Antidepressants (cont..) TCAs (amitriptyline) Increase the activity of antinociceptive noradrenergic and serotonergic projections descending from the brain to the spinal cord. Dual NE/serotonin reuptake inhibitors (Venlafaxine) Useful in the treatment of neuropathic pain and fibromyalgia. 32 Analgesic use of Antiepileptics Based on their ability to reduce neuronal excitability, these agents have been used to manage some chronic pain conditions. Gabapentin, pregabalin, and carbamazepine 36 Gabapentin Structural GABA analogue “no effect on GABA receptor” MOA: binds to the α2δ subunit of voltage-dependent calcium channels and inhibits the release of excitatory neurotransmitters in the presynaptic area (reduces the trafficking of the channel to the membrane). Useful in trigeminal neuralgia, diabetic neuropathy, and post- operative pain reduction Adverse effects: dizziness, somnolence, confusion and ataxia 37 38 Pregabalin Substituted GABA analogue More potent, faster onset and more predictable bioavailability than gabapentin. Similar effect as gabapentin in neuropathic pain and fibromyalgia. Similar but less dose-related CNS adverse effects than gabapentin 39 Carbamazepine Blocks Na+ channels Used primarily to treat trigeminal neuralgia. Oxcarbazepine: derivative of carbamazepine, with altered liver metabolism and reduced risk of aplastic anemia 40 Severe acute pain or chronic malignant or nonmalignant pain 41  Opioid receptor Full Agonists Partial and mixed Antagonists Strong Moderate agonists Morphine Codeine Buprenorphine Naloxone Meperidine Butorphanol Naltrexone Methadone Nalbuphine Fentanyl 10/28/2024 42 Opioid receptor agonists Primary class in acute management of moderate to severe pain. Act on µ opioid receptor Sites of analgesic action include: the brain, brainstem, spinal cord, and primary afferent peripheral terminals. 43 Mechanism of action of μ-opioid receptor agonists in the spinal cord: Activation of both presynaptic and postsynaptic μ-opioid receptors by descending and local circuit inhibitory neurons inhibits central relaying of nociceptive stimuli. In the presynaptic terminal, μ-opioid receptor activation decreases Ca+2 influx in response to an incoming action potential Postsynaptic μ-opioid receptor activation increases K+ conductance, decreasing the postsynaptic response to excitatory neurotransmission. 44 Adverse Effects of Opioids ◼ CVS– decrease sympathetic tone → orthostatic hypotension, bradycardia. ◼ Respiratory: causes respiratory suppression by acting on the medullary respiratory control center to blunt respiratory response to CO2 and cause apnea. ◼ GI: by acting on the medullary CTZ, and the GIT → nausea, vomiting, and constipation ◼ CNS; sedation, dizziness, confusion, euphoria & myoclonus. ◼ Tolerance, Physical dependence, Addiction 45  Morphine: The reference opioid Various routes of administration Hydromorphone Morphine derivative with higher potency (approximately 5 to 10 times higher potency) Opioids Codeine (methylmorphine) Greater oral availability, less analgesic potency than morphine Antitussive, and antidiarrheal The analgesic action of codeine results largely from its hepatic demethylation to morphine, which has substantially greater μ- agonist activity. Oxycodone & hydrocodone–more potent than codeine, widely used in combination with acetaminophen. 46  Methadone: Long half life 25-34 hr Sustained relief of chronic pain μ-opioid agonist, and a low-potency effect as an NMDA receptor antagonist. Fentanyl: Opioids Short-acting synthetic opioid agonist that is 75–100 times more potent than morphine (cont.) Used for intraoperative and periprocedural analgesia Meperidine: μ-agonist with analgesic efficacy similar to morphine but lower potency Due to its serotonergic effect combination with MAOI, SSRI is contraindicated Causes mydriasis (rather than miosis) Toxic metabolite “normeperidine”- CNS excitability, seizures 47  Butorphanol and Buprenorphine Partial µ-receptor agonists Partial and produce morphine-like analgesia with milder euphoric effects. Mixed Used in opioid addiction treatment Opioid Nalbuphine: Agonists a K-agonist with µ-receptor antagonist activity Reverse the pruritus induced by neuraxial opioid administration 48  µ-receptor antagonists: to reverse life- threatening adverse effects (respiratory depression) of opioids. Opioid Naloxone: parenteral; shorter half life antagonists than morphine Naltrexone :orally; used in out-patient settings for detoxification in opioid addicts 49 Migraine Therapy 50 Migraine Migraine headache is a disorder consisting of headache attacks that last for up to 3 days, typically associated with light and sound avoidance and nausea. Some migraines are accompanied by aura, in which transient neurologic symptoms are associated with the migraine. 51 Migraine Therapy Tryptan serotonin receptor agonists: Selectively act on 5HT-1B and 5HT-1D o 5-HT1B receptors are located on vascular endothelial cells, smooth muscle cells, and neurons, including trigeminal nerves. o 5-HT1D receptors are present on the trigeminal nerves that innervate meningeal blood vessels. Reduce both sensory activation in the periphery and nociceptive transmission in the brainstem trigeminal nucleus, where they diminish central sensitization. Cause vasoconstriction (could be dangerous in patients with coronary heart disease) Routes: Subcutaneous, oral, and nasal inhalation →reduced toxicity E.g Sumatriptan Other vasoconstrictive agent like, ergotamine is used in the treatment of migraine. 52 Migraine (contd…) Tryptans, NSAIDs, Opioids, Caffeine, Antiemetic: for acute migraine attacks. Prophylaxis: drugs are used to reduce the frequency of attacks β-blockers, valproic acid, serotonin antagonists, Ca+ channel blockers, TCAs like amitriptyline (1). (1) Jessica Ailani MD,Rebecca C. Burch MD,Matthew S. Robbins MD,on behalf of the Board of Directors of the American Headache Society. The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. https://doi.org/10.1111/head.14153. 53  Summary Because of the limited efficacy of any single drug, it is common in clinical practice to use a polypharmacy approach to manage pain. Most of the currently available analgesics have been identified by empirical observation (opioids, NSAIDs, and local anesthetics) or serendipity (antiepileptic drugs). Now that the mechanisms responsible for pain are being explored at a molecular level, many new targets are being revealed that are likely to lead to new and different classes of analgesics. It is hoped that drugs active at these targets will achieve higher efficacy and have fewer adverse effects than current therapies. Effective pain management approaches must not rely only on pharmacologic intervention; physical therapy and rehabilitation and, in some situations, surgical approaches may also have a role. 54  Case JD, a 15-year-old boy, is severely burned while escaping from a building fire. The extensive burns include first- and second-degree burns covering much of his body and a local, full-thickness burn on his right forearm. He reaches the emergency department in severe pain and is treated with intravenous morphine in increasing quantities until he reports that the pain has subsided. This dose of morphine is then maintained. The next day, he has surgical debridement of his burn wounds and a skin graft to his right forearm. During the operation, an anesthesiologist provides a continuous intravenous infusion of remifentanil, with a bolus dose of morphine added near the end of the operation. At the end of the operation, and for 4 days thereafter, JD receives intravenous morphine through a patient-controlled analgesia device. As the burns heal, the morphine dose is tapered and eventually replaced with an oral oxycodone/acetaminophen combination tablet. Three months later, JD reports severe loss of sensation to touch in the area of the skin graft. He also describes a persistent tingling sensation in this area, with occasional bursts of sharp, knife-like pain. After referral to a pain clinic, JD is prescribed oral gabapentin, which partially reduces his symptoms. However, he reports to the pain clinic again 2 months later, still in severe pain. At this time, amitriptyline is added to the gabapentin, and the pain is further relieved. Three years later, JD’s lingering pain has resolved and he no longer requires medication, but the lack of forearm sensation persists. 55 Questions 1. What mechanisms produced and sustained the pain that lasted from JD’s exposure to the fire until his initial treatment? 2. What was the rationale for the sequence of medications used during the skin debridement operation? 3. Explain the mechanisms that could produce spontaneous pain in the region of the full-thickness burn months to years after healing of the skin and the rationale for using gabapentin to treat JD’s chronic pain. 4.Why was morphine tapered gradually and replaced with a combination oxycodone/acetaminophen tablet? 56 Questions 57