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This document provides an overview of pain physiology and pharmacology, focusing on opioids. It defines pain and describes nociceptors and pain pathways in the body. It then discusses the mechanism of action of opioid analgesics like morphine, including their effects on opioid receptors in the brain and spinal cord. The document outlines both the analgesic effects of morphine and its potential adverse effects like tolerance, dependence, and withdrawal symptoms.
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- 1. Physiology and Pharmacology of Pain
- 2. But pain is a perfect misery The worst of evils Excessive overturns All patience John Milton In Paradise Lost
- 3. Objectives Definition of pain Nociceptors : Location, types Types of pain Pathway of Pain Opioid analgesics Mechanism of action Morphine Other opioid analgesics
- 4. Pain Unpleasant sensory and emotional experience associated with actual or potential damage Pain is redefined as a perception instead of a sensation because it is always a psychological state. Latin word "peona " meaning punishment Pain is always subjective It is differently experienced by each individual.
- 5. Nociception Coined by Sherrington Latin: noxa means injury it means the 卒perception of noxious stimuli卒 Mechanism by which noxious peripheral stimuli are transmitted to the central nervous system to elicit a mechanical response .
- 6. Pain - Receptors Specialized naked nerve endings found in almost every tissue of the body. Activated by stimuli (mechanical, thermal, chemical) Distinguished from other receptors by their higher threshold, and they are normally activated only by stimuli of noxious intensity-sufficient to cause some degree of tissue damage. A隆: Myelinated C: Unmyelinated
- 7. Characteristic features of A隆 & C fibres Feature A隆 fibre C fibre Number Less More Myelination Myelinated Unmyelinated Diameter 2-5 袖m 0.4-1.2 袖m Conduction velocity 12-30 m/s 0.5 -2 m/s Specific stimulus Most sensitive to pressure Most sensitive for chemical agents Impulse conduction Fast component of pain Slow component of pain
- 8. Location of nociceptors Superficial skin layers Deeper tissues Periosteum, joints, arterial wall, liver capsule, pleura Other deeper tissues Sparse pain nerve endings But wide spread tissue damage results in pain
- 9. Types of Nociceptors Somatic Free nerve endings of A隆 & C fibres Unimodal, polymodal, silent Visceral Wide spread inflammation, ischemia, mesentric streching , spasm or dilation of hollow viscera produces pain Probably strech receptors
- 10. Pain stimuli Mechanical / thermal stimuli Fast pain: Sharp well localized , pricking type Chemical stimuli Slow pain: poorly localized, dull, throbbing K+, ADP, ATP Bradykinin, histamine Serotonin, Prostaglandins Substance P, CGRP
- 11. Clinical types of pain Somatic Visceral Referred pain Convergence & facilitation theory Projected pain Radiating Pain Hyperalgesia
- 12. Pathway of pain sensation
- 17. Analgesics Drugs which relieve pain due to multiple causes with out causing loss of consciousness Drugs which relieve pain due to single causes or specific pain syndromes (ergotamine, carbamazepine, nitrates) are not classified as analgesics Corticosterroids also not classified as analgesics
- 18. Analgesics Opioid analgesics Morphine and morphine like drugs Non steroidal anti-inflammatory drugs Paracetamol, diclofenac, ibuprofen etc
- 19. Mechanism of action of Opioids
- 20. Opioid Receptors Opioid receptors found in the brain, spinal cord and peripheral nervous system Mu (亮1 and 亮2 ) Kappa (k1 & k3) Delta (隆) Nociceptin/Orphanin (N/OFQ)
- 21. Opioid Receptors Inhibitory action; coupled to Go & Gi Structure of the opioid receptor
- 22. Mu-Receptor: Two Types 亮1 Located outside spinal cord Higher affinity for morphine Supraspinal analgesia Selectively blocked by naloxone 亮2 Located throughout CNS Responsible for spinal analgesia, Respiratory depression, constipation physical dependence, and euphoria
- 23. Kappa Receptor Only modest analgesia(spinal 虜1 and supraspinal 虜3) Little or no respiratory depression Little or no dependence Dysphoric effects Miosis Reduced GI motility
- 24. Delta Receptor High affinity for Leu/Met enkephalins endogenous ligands. The 隆 mediated analgesia is mainly spinal Affective component of supraspinal analgesia appears to involve 隆 receptors as these receptors are present in limbic areasalso responsible for dependence and reinforcing actions. The proconvulsant action is more prominent in 隆 agonists.
- 25. Spinal sites of opioid action. reduce transmitter release from presynaptic terminals of nociceptive primary afferents hyperpolarize second-order pain transmission neurons by increasing K+ conductance, evoking an inhibitory postsynaptic potential
- 26. The descending control system, showing the main sites of action of opioids on pain transmission
- 27. Analgesic features of Morphine
- 28. Efficacy Morphine is a strong analgesic. Higher doses can mitigate even severe pain Degree of analgesia increasing with dose. Simultaneous action at spinal and supraspinal sites greatly amplifies the analgesic action.
- 29. Selectivity Suppression of pain perception is selective No affect on other sensations proportionate generalized CNS depression (contrast general anaesthetics).
- 30. Type of pain Dull, poorly localized visceral pain is relieved better than sharply defined somatic pain Nociceptive pain arising from stimulation of peripheral pain receptors is relieved better than neuritic pain due to inflammation or damage of neural structures
- 31. Mood and subjective effects Morphine has a calming effect. The associated reactions to intense pain apprehension, fear, autonomic effects are also depressed. Perception of pain and reaction to it are both altered so that pain is no longer as unpleasant or distressing, i.e. patient tolerates pain better.
- 32. Other effects include feeling of detachment, Lack of initiative, limbs feel heavy and body warm, mental clouding and inability to concentrate. In normal people, in the absence of pain or apprehension, these are generally appreciated as unpleasant Mood and subjective effects
- 33. Patients in pain or anxiety and addicts specially perceive it as pleasurable Refer it as 'high'. Rapid IV injection by addicts - gives them a 'kick' or 'rush' which is intense, pleasurableakin to orgasm. Thus one has to learn to perceive the euphoric effect of morphine. Mood and subjective effects
- 34. Mood and subjective effects In normal persons Dependence and Addiction In patients - Pain relief No addiction
- 35. Other pharmacological actions Gastrointestinal system : Increase in tone , reduced motility , contraction of sphincters , decrease of G.I. secretions leading to constipation .( , k , receptors ).
- 36. Other effects Respiratory centre Morphine depresses respiratory centre in a dose dependent manner Rate and tidal volume are both decreased Death in poisoning is due to respiratory failure Neurogenic, hypercapnoeic and later hypoxic drives are suppressed in succession
- 37. C.V.S. : Vasodilatation due to direct decrease of tone of blood vessels Shift of blood from pulmonary to systemic circuit histamine release and depression of vasomotor centre Urinary bladder Detrusor contraction leading to urgency . Sphincter contraction leading to retention of urine Other effects
- 38. Bronchoconstriction due to histamine release by morphine . Uterus may be relaxed . Mild hyperglycemia due to central sympathetic stimulation . It has weak anticholinesterase action . Other effects
- 39. Endocrine Growth hormone and prolactin and ADH levels are increased . FSH ,LH and ACTH levels are decreased . Other effects
- 40. Pharmacokinetic features Oral absorption is unreliable Metabolized by glucuronide conjugation. Morphine-6-glucuronide is an active metabolite (more potent than morphine) freely crosses placenta t1/2of morphine averages 2-3 hours Effect of a parenteral dose lasts 4-6 hours
- 41. ADVERSE EFFECTS The toxic effects of morphine are an extension of their pharmacological effects Idiosyncrasy and allergy Urticaria, itch,swelling of lips. A local reaction at injection site may occur due to histamine release. Allergy is uncommon and anaphylactoid reaction is rare.
- 42. Apnoea This may occur in new born when morphine is given to mother during labour. The BBB of foetus is undeveloped, morphine attains higher concentration in foetal brain Naloxone 10 袖g/kg injected in chord is the treatment of choice. ADVERSE EFFECTS
- 43. Tolerance Onset Tolerance to morphine develops rapidly and can be detected within 12 14 hours of morphine administration within 3 days the equianalgesic dose is increased 5 fold .
- 44. Tolerance - effects Tolerance extends to most actions of morphine analgesia , euphoria , respiratory depression not to the constipation miosis and convulsions Cross tolerance occurs between drugs acting at the same receptor , but not drugs acting on different receptor
- 45. Tolerance - Mechanism The tolerance is not pharmacokinetic but due to the true cellular adaptive response Two proposed mechanisms upregulation of cAMP system Downregulation of 亮 receptors Recent research suggests tolerance results due to uncoupling between 亮 receptor and G proteins Leading to reversal of second messenger (cAMP) and ion channel system
- 46. Recently the NMDA antagonists and nitric oxide synthase inhibitors have been found to block morphine tolerance and dependence in animals. Thus, analgesic action of morphine can be dissociated from tolerance and dependence which contribute to its abuse by NMDA receptor antagonists Agents that recouple 亮 receptor and G proteins Tolerance - Mechanism
- 47. Dependence Dependence comprises two components Physical dependence - associated with the withdrawal syndrome, lasting for a few days Psychological dependence - associated with craving, lasting for months or years.
- 48. Withdrawal symptoms Withdrawal of the drug causes significant distress to cause a drug seeking behavior manifested by sweating ,lacrimation, dehydration,fear anxiety , restlessness , mydriasis , tremor , colic hypertension , tachycardia and weight loss . Weak long acting receptor agonist methadone used to relieve withdrawal syndrome.
- 49. Psychological dependence Opioids facilitate DA transmission in mesolimbic /mesocortical pathways and activate endogenous reward pathways in brain. Important in intiating and mantaining drug seeking behaviour Psychological dependence rarely occurs in patients being given opioids as analgesics
- 50. Acute morphine poisoning 50 mg morphine i.m. produces serious toxicity. lethal dose : 250 mg. Manifestations are extension of pharm. action. Stupor, flaccidity, shallow breathing, cyanosis, miosis, BP & shock. Convulsions, pulmonary edema,coma occur at terminal stages Death is due to respiratory failure.
- 51. Treatment Respiratory support Maintenance of BP Gastric lavage with pot. Permanganate Naloxone 0.4-0.8 mg i.v. repeated every 2-3 min till respiration picks up. Repeat every 1- 4 hrs later on, according to response. preferred specific antagonist : does not have any agonistic action and resp. depression
- 52. Precautions and C/I Infants and the elderly Patients with respiratory insufficiency Bronchial asthma Head injury Hypotensive states and hypovolemia Undiagnosed acute abdominal pain Elderly male Hypothyroidism, liver and kidney disease Unstable personalities
- 53. Drug interactions Drugs which poteniate morphine Phenothiazines, TCA, MAO inhibitors, Amphetamine and Neostigmine Morphine retards absorption of many orally administered drugs by delaying gastric emptying..
- 54. Dose 10-50 mg oral, 10-15 mg i.m. or s.c. or 2-6 mg i.v. 2-3 mg epidural/intrathecal; children 0.1-0.2 mg/kg
- 55. Therapeutic uses Morphine / parenteral congeners indicated as analgesic in traumatic, visceral, ischaemic (myocardial infarction), postoperative, burns, cancer pain. Relieves anxiety and apprehension in serious and frightening disease accompanied by pain: myocardial infarction,
- 56. Acute left ventricular failure (cardiac asthma) Morphine rapid i.v. affords dramatic relief by preload and peripheral pooling of blood. shift blood from pulmonary to systemic circuit relieves pulmonary congestion and edema. Allays air hunger by depressing respiratory centre. Cuts down sympathetic stimulation by calming the patient, reduces cardiac work. Therapeutic uses
- 57. Epidural and intrathecal injection of Morphine It is being used for analgesia in abdominal, lower limb and pelvic surgeries labour, postoperative, cancer and other intractable pain. Preanaesthetic medication produces segmental analgesia for 12 hour without affecting sensory, motor or autonomic modalities. Resp. depression occurs after delay due to ascent through subarachnoid space to the resp. centre.
- 58. Codiene (Methyl Morphine) low-efficacy opioid a prodrug (t1/2 3 h). lacks efficacy for severe pain most of its actions 1/10th those of morphine. Large doses cause excitement. Dependence much less than with morphine. principal use: mild to moderate pain & cough 60 mg coeine = 600 mg aspirin
- 59. Pethidine Pethidine differs from morphine in that it: does not usefully suppress cough less likely to constipate less likely to cause urinary retention & prolong childbirth little hypnotic effect shorter duration of analgesia (2-3 h). Dose: 50-100mg SC or IM
- 60. Methadone principal feature of methadone is long duration, analgesia may last for 24 h. If used for chronic pain in palliative care (12- hourly) an opioid of short t 遜 should be provided for breakthrough pain rather than an extra dose of methadone. Also used in opioid withdrawal Dose: 2.5 mg to 10 mg oral or IM
- 61. Fentanyl Pethidine congener 80-100 times potent than morphine in analgesia and resp. depression High lipid solubility peak effect in 5 min Duration of action 30-40 min Injectable form exclusively used in anaesthesia Transdermal patch available used in cancer or other types of chronic pain Dose: 25-75 袖g /hr acts for 72 hours
- 62. Patient controlled analgesia (PCA) An attractive technique of postoperative pain control patient himself regulates the rate of i.v. fentanyl infusion according to intensity of pain felt. Transdermal fentanyl is a suitable option for chronic cancer and other terminal illness pain
- 63. Dextropropoxyphene Less analgesic, antitussive, and less dependence Its analgesic usefulness equal to codeine. Commonly combined with paracetamol Dextropropoxyphene interacts with warfarin, enhancing its anticoagulant effect. Dose= 60-120 mg
- 64. Tramadol Relieves pain by opioid as well as other mechanisms 100 mg IV Tramadol = 100 mg IM morphine Dose: 50-100 mg TDS Less respiratory depression, sedation, constipation, urinary retention, intrabiliary pressure & dependence than morphine As effective as pethidine for postoperative pain and as morphine for moderate chronic pain.
- 65. Pentazocine Weak 袖 antagonist action and marked 虜 agonist action Analgesia is primarily spinal (K1) can cause a withdrawal syndrome in addicts Dose= 30-60 mg IM OR 50 -100 mg oral shorter duration of pain relief 4-6 hrs, less dependence, sedation & resp. depression Use: post operative, moderately severe burns
- 66. Butorphanol K analgesic like pentazocine but more potent Psychomimetic effects less marked Neither substitute nor antagonize morphine Dose: 1-4 mg IM / IV Use: Post operative Short lasting painful conditions (renal colic)
- 67. Buprenorphine High-efficacy partial agonist of 袖 receptor and an antagonist of the K-receptor. Less liability to induce dependence and respiratory depression than pure agonists Duration of action = 6-8hrs Dose: 0.3-0.6 mg IM, SC, 0.2 -0.4 mg SL Use: cancer, MI, Post Operative, morphine dependence Contraindiacted In labour pain
- 69. A- Nonselective COX inhibitors (conventional NSAIDs) Salicylates: Aspirin, Diflunisal. Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone. Indole derivatives: Indomethacin, Sulindac. Propionic acid derivatives: Ibuprofen, Naproxen, ketoprofen, Flurbiprofen. Anthranilic acid derivative: Mephenamic acid. Aryl-acetic acid derivatives: Diclofenac. Oxicam derivatives: Piroxicarn, Tenoxicam. Pyrrole-pyrrole derivative: Ketorolac.
- 70. B- Preferential COX-2 inhibitors Nimesulide, Meloxicam, Nabumetone C- Selective COX-2 inhibitors Celecoxib, Rofecoxib, Valdecoxib D- Analgesic- antipyretics with poor antiinflammatory action Paraaminophenol derivative: Paracetamol (Acetaminophen). Pyrazolone derivatives: Metamizol (Dipyrone), Propiphenazone. Benzoxazocine derivative: Nefopam.
- 71. Benefits due to PG Synthesis inhibition Analgesia: prevention of pain nerve ending sensitization Antipyretic Anti-inflammatory Antithrombotic Closure of ductus arteriosus
- 72. Toxicities due to PG synthesis inhibition Gastric mucosal damage Bleeding: inhibition of platelet function Limitation of renal blood flow : Na and water retention Delay/prolongation of labour Asthma and anaphylactoid reactions in susceptible individuals
- 73. Adverse effects of NSAIDs Gastrointestinal- Gastric irritation, erosions, peptic ulceration, gastric bleeding/perforation, esophagttis Renal Na and water retention, chronic renal failure, interstitial nephritis, papillary necrosis (rare) Hepatic Raised transaminases, hepatic failure (rare)
- 74. CNS Head ache, mental confusion. Behavioural disturbances, Seizure precipitation. Haematological Bleeding, thrombocytopenia, haemolytic anaemia, agranulocytosis Others Asthma exacerbation, nasal polyposis skin rashes, pruritis, angioedema.
- 75. USES Analgesic- headache, backache, myalgia, joint pain, dysmenorrhoea; Antipyretic-fever of any origin; paracetamol being safer. Acute rheumatic fever- the first drug to be used
- 76. Rheumatoid arthritis - Aspirin in a dose of 3-5 g/day is effective in most cases; produces relief of pain, swelling and morning stiffness. Osteoarthritis - It affords symptomatic relief only; paracetamol is the first choice analgesic Post myocardial infarction and post stroke patients By inhibiting platelet aggregation it lowers the incidence of reinfarction.
- 77. Other uses are: Pregnancy induced hypertension and pre eclampsia. To delay labour Patent ductus arteriosus
- 79. Better tolerated than aspirin. The analgesic, antipyretic and antiinflammatory efficacy is lower than high dose of aspirin. All inhibit PG synthesis- naproxen being most potent; They inhibit platelet aggregation and prolong bleeding time.
- 80. Potent antiinflammatory drug comparable to phenylbutazone. Potent and promptly acting anti-pyretic. Analgesic action is better than phenylbutazone, but it relieves only inflammatory or tissue injury related pain. highly potent inhibitor of PG synthesis and suppresses neutrophil motility. Indomethacin
- 81. Uses Rheumatoid arthritis not controlled by aspirin; Ankylosing spondylitis, acute exacerbations of destructive arthropathies and psoriatic arthritis. It acts rapidly in acute gout. Malignancy associated fever refractory to other antipyretics. Medical closure of patent ductus arteriosus
- 82. MEPHENAMIC ACID Analgesic, Antipyretic and Anti-inflammatory drug which inhibits COX & antagonizes actions of PGs. Exerts peripheral & central analgesic action.
- 83. Uses analgesic in muscle, joint and soft tissue pain - strong anti-inflammatory action is not needed. It is quite effective in dysmcnorrhoea. useful in some cases of rheumatoid and osteoarthritis
- 84. ARYL-ACETIC ACID DERIVATIVE DICLOFENAC SODIUM
- 85. DICLOFENAC SODIUM An analgesic-antipyretic-antiinflammatory drug similar in efficacy to naproxen. short lasting antiplatelet action. Neutrophil chemotaxis and superoxide production at the inflammatory site are reduced.
- 86. USE most extensively used in rheumatoid and osteoarthritis, bursitis, ankylosing spondylitis, dysmenorrhoea, post-traumatic and postoperative inflammatory conditions affords quick relief of pain and wound edema.