Physiology andPharmacology of Pain
“But pain is a perfect misery     The worst of evils    Excessive overturns       All patience”          John Milton      ...
Objectives•   Definition of pain•   Nociceptors : Location, types•   Types of pain•   Pathway of Pain•   Opioid analgesics...
Pain• Unpleasant sensory and emotional experience  associated with actual or potential damage• Pain is redefined as a perc...
Nociception  – Coined by Sherrington  – Latin: noxa means injury  – it means the ´perception of noxious stimuli´• Mechanis...
Pain - Receptors• Specialized naked nerve endings found in almost every  tissue of the body.• Activated by stimuli (mechan...
Characteristic features of Aδ & C fibresFeature       Aδ fibre            C fibreNumber        Less                MoreMye...
Location of nociceptors• Superficial skin layers• Deeper tissues  – Periosteum, joints,    arterial wall, liver    capsule...
Types of Nociceptors• Somatic  – Free nerve endings of Aδ & C fibres  – Unimodal, polymodal, silent• Visceral  – Wide spre...
Pain stimuli• Mechanical / thermal stimuli  – Fast pain: Sharp well localized , pricking type• Chemical stimuli  – Slow pa...
Clinical types of pain• Somatic• Visceral• Referred pain  – Convergence & facilitation theory• Projected pain• Radiating P...
Pathway of pain sensation
Modulation of pain
Gate control system
Supra spinalpain supression    system
Analgesics• Drugs which relieve pain due to multiple  causes with out causing loss of consciousness• Drugs which relieve p...
Analgesics• Opioid analgesics  – Morphine and morphine like drugs• Non steroidal anti-inflammatory drugs  – Paracetamol, d...
Mechanism of action of Opioids
Opioid Receptors• Opioid receptors found in the brain, spinal cord and  peripheral nervous system• Mu (μ1 and μ2 )• Kappa ...
Opioid Receptors• Inhibitory action; coupled to Go & Gi              Structure of the opioid receptor
Mu-Receptor: Two Typesμ1                              μ2     – Located outside spinal        – Located throughout CNS     ...
Kappa Receptor• Only modest analgesia(spinal κ1 and  supraspinal κ3)• Little or no respiratory depression• Little or no de...
Delta Receptor• High affinity for Leu/Met enkephalins endogenous  ligands.• The δ mediated analgesia is mainly spinal• Aff...
Spinal sites of opioid action.                    hyperpolarizesecond-order pain transmission neurons by increasing       ...
The descending control system, showing the main  sites of action of opioids on pain transmission
Analgesic features of Morphine
Efficacy•   Morphine is a strong analgesic.•   Higher doses can mitigate even severe pain•   Degree of analgesia increasin...
Selectivity• Suppression of pain perception is selective• No affect on other sensations• proportionate generalized CNS dep...
Type of pain• Dull, poorly localized visceral pain is relieved  better than sharply defined somatic pain• Nociceptive pain...
Mood and subjective effects• Morphine has a calming effect.• The associated reactions to intense pain  – apprehension,  – ...
Mood and subjective effects• Other effects include  – feeling of detachment,  – Lack of initiative,  – limbs feel heavy an...
Mood and subjective effects• Patients in pain or anxiety and addicts  – specially perceive it as pleasurable  – Refer it a...
Mood and subjective effectsIn patients - Pain relief   In normal persons                             Dependence and     No...
Other pharmacological actionsGastrointestinal system :  – Increase in tone ,  – reduced motility ,  – contraction of sphin...
Other effectsRespiratory centre• Morphine depresses respiratory centre in a  dose dependent manner• Rate and tidal volume ...
Other effects• C.V.S. :   – Vasodilatation due to direct decrease of tone of     blood vessels   – Shift of blood from pul...
Other effects• Bronchoconstriction  – due to histamine release by morphine .• Uterus may be relaxed .• Mild hyperglycemia ...
Other effects• Endocrine  – Growth hormone and prolactin and ADH levels    are increased .  – FSH ,LH and ACTH levels are ...
Pharmacokinetic features• Oral absorption is unreliable• Metabolized by glucuronide conjugation.• Morphine-6-glucuronide i...
ADVERSE EFFECTS• The toxic effects of morphine are an extension  of their pharmacological effects• Idiosyncrasy and allerg...
ADVERSE EFFECTS• Apnoea This may occur in new born when  morphine is given to mother during labour.• The BBB of foetus is ...
ToleranceOnset• Tolerance to morphine develops rapidly and  can be detected within 12 – 14 hours of  morphine administrati...
Tolerance - effects• Tolerance extends to most actions of  morphine  – analgesia ,  – euphoria ,  – respiratory depression...
Tolerance - Mechanism• The tolerance is not pharmacokinetic but due  to the true cellular adaptive response• Two proposed ...
Tolerance - Mechanism• Recently the NMDA antagonists and nitric  oxide synthase inhibitors have been found to  block morph...
DependenceDependence comprises two components• Physical dependence - associated with the  withdrawal syndrome, lasting for...
Withdrawal symptoms• Withdrawal of the drug causes significant  distress to cause a drug seeking behavior  manifested by  ...
Psychological dependence• Opioids facilitate DA transmission in  mesolimbic /mesocortical pathways and  activate endogenou...
Acute morphine poisoning• 50 mg morphine i.m. produces serious toxicity.• lethal dose : 250 mg.• Manifestations are extens...
Treatment• Respiratory support• Maintenance of BP• Gastric lavage with pot. Permanganate• Naloxone 0.4-0.8 mg i.v. repeate...
Precautions and C/I•   Infants and the elderly•   Patients with respiratory insufficiency•   Bronchial asthma•   Head inju...
Drug interactions• Drugs which poteniate morphine  – Phenothiazines, TCA, MAO inhibitors,  – Amphetamine and Neostigmine• ...
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...
Therapeutic uses• Morphine / parenteral congeners indicated as  analgesic in  – traumatic, visceral, ischaemic (myocardial...
Therapeutic usesAcute left ventricular failure (cardiac asthma)• Morphine rapid i.v. affords dramatic relief by  – ↓ prelo...
Epidural and intrathecal injection of               Morphine• It is being used for   – analgesia in abdominal, lower limb ...
Codiene (Methyl Morphine)•   low-efficacy opioid a prodrug (t1/2 3 h).•   lacks efficacy for severe pain•   most of its ac...
Pethidine• Pethidine differs from morphine in that it:• does not usefully suppress cough• less likely to constipate• less ...
Methadone• principal feature of methadone is long  duration, analgesia may last for 24 h.• If used for chronic pain in pal...
Fentanyl• Pethidine congener 80-100 times potent than  morphine in analgesia and resp. depression• High lipid solubility p...
Patient controlled analgesia (PCA)• An attractive technique of postoperative pain  control• patient himself regulates the ...
Dextropropoxyphene• Less analgesic, antitussive, and less  dependence• Its analgesic usefulness equal to codeine.• Commonl...
Tramadol• Relieves pain by opioid as well as other  mechanisms• 100 mg IV Tramadol = 100 mg IM morphine• Dose: 50-100 mg T...
Pentazocine• Weak µ antagonist action and marked κ  agonist action• Analgesia is primarily spinal (K1)• can cause a withdr...
Butorphanol•   K analgesic like pentazocine but more potent•   Psychomimetic effects less marked•   Neither substitute nor...
Buprenorphine• High-efficacy partial agonist of µ receptor and  an antagonist of the K-receptor.• Less liability to induce...
NON STEROIDALANTIINFLAMMATORY DRUGS               DR.AYESHA
A- Nonselective COX inhibitors (conventional  NSAIDs)• Salicylates: Aspirin, Diflunisal.• Pyrazolone derivatives: Phenylbu...
B- Preferential COX-2 inhibitors           Nimesulide, Meloxicam, NabumetoneC- Selective COX-2 inhibitors          Celecox...
Benefits due to PG Synthesis inhibition• Analgesia: prevention of pain nerve ending  sensitization• Antipyretic• Anti-infl...
Toxicities due to PG synthesis inhibition• Gastric mucosal damage• Bleeding: inhibition of platelet function• Limitation o...
Adverse effects of NSAIDsGastrointestinal-• Gastric irritation, erosions, peptic ulceration, gastric bleeding/perforation,...
CNS• Head ache, mental confusion. Behavioural  disturbances, Seizure precipitation.Haematological• Bleeding, thrombocytope...
USES• Analgesic- headache, backache, myalgia, joint  pain, dysmenorrhoea;• Antipyretic-fever of any origin; paracetamol  b...
• Rheumatoid arthritis - Aspirin in a dose of 3-5  g/day is effective in most cases; produces  relief of pain, swelling an...
Other uses are:• Pregnancy induced hypertension and    pre eclampsia.• To delay labour• Patent ductus arteriosus
PROPIONIC ACID DERIVATIVES        Ibuprofen
• Better tolerated than aspirin.• The analgesic, antipyretic and  antiinflammatory efficacy is lower than high  dose of as...
IndomethacinPotent antiinflammatory drug comparable to  phenylbutazone.Potent and promptly acting anti-pyretic.Analgesic a...
Uses• Rheumatoid arthritis not controlled by aspirin;• Ankylosing spondylitis, acute exacerbations of  destructive arthrop...
MEPHENAMIC ACID• Analgesic, Antipyretic and Anti-inflammatory  drug which inhibits COX & antagonizes actions  of PGs.• Exe...
Uses• analgesic in muscle, joint and soft tissue pain  - strong anti-inflammatory action is not  needed.• It is quite effe...
ARYL-ACETIC ACID DERIVATIVE      DICLOFENAC SODIUM
DICLOFENAC SODIUM• An analgesic-antipyretic-antiinflammatory  drug similar in efficacy to naproxen.• short lasting antipla...
USE• most extensively used in rheumatoid and  osteoarthritis, bursitis, ankylosing spondylitis,  dysmenorrhoea, post-traum...
Physiology and pharmacology of pain
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Physiology and pharmacology of pain

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describes physiology of pain and pharmacotherapy of pain with description of drugs

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Physiology and pharmacology of pain

  1. 1. Physiology andPharmacology of Pain
  2. 2. “But pain is a perfect misery The worst of evils Excessive overturns All patience” John Milton In Paradise Lost
  3. 3. Objectives• Definition of pain• Nociceptors : Location, types• Types of pain• Pathway of Pain• Opioid analgesics – Mechanism of action – Morphine – Other opioid analgesics
  4. 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. 5. Nociception – Coined by Sherrington – Latin: noxa means injury – it means the ´perception of noxious stimuli´• Mechanism by which noxious peripheral stimuli are transmitted to the central nervous system to elicit a mechanical response .
  6. 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.• Aδ: Myelinated• C: Unmyelinated
  7. 7. Characteristic features of Aδ & C fibresFeature Aδ fibre C fibreNumber Less MoreMyelination Myelinated UnmyelinatedDiameter 2-5 µm 0.4-1.2 µmConduction 12-30 m/s 0.5 -2 m/svelocitySpecific Most sensitive to Most sensitive forstimulus pressure chemical agentsImpulse Fast component of Slow componentconduction pain of pain
  8. 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. 9. Types of Nociceptors• Somatic – Free nerve endings of Aδ & C fibres – Unimodal, polymodal, silent• Visceral – Wide spread inflammation, ischemia, mesentric streching , spasm or dilation of hollow viscera produces pain – Probably strech receptors
  10. 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. 11. Clinical types of pain• Somatic• Visceral• Referred pain – Convergence & facilitation theory• Projected pain• Radiating Pain• Hyperalgesia
  12. 12. Pathway of pain sensation
  13. 13. Modulation of pain
  14. 14. Gate control system
  15. 15. Supra spinalpain supression system
  16. 16. 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
  17. 17. Analgesics• Opioid analgesics – Morphine and morphine like drugs• Non steroidal anti-inflammatory drugs – Paracetamol, diclofenac, ibuprofen etc
  18. 18. Mechanism of action of Opioids
  19. 19. Opioid Receptors• Opioid receptors found in the brain, spinal cord and peripheral nervous system• Mu (μ1 and μ2 )• Kappa (k1 & k3)• Delta (δ)• Nociceptin/Orphanin (N/OFQ)
  20. 20. Opioid Receptors• Inhibitory action; coupled to Go & Gi Structure of the opioid receptor
  21. 21. Mu-Receptor: Two Typesμ1 μ2 – Located outside spinal – Located throughout CNS cord – Responsible for – Higher affinity for • spinal analgesia, morphine • Respiratory – Supraspinal analgesia depression, – Selectively blocked by • constipation naloxone • physical dependence, and euphoria
  22. 22. Kappa Receptor• Only modest analgesia(spinal κ1 and supraspinal κ3)• Little or no respiratory depression• Little or no dependence• Dysphoric effects• Miosis• Reduced GI motility
  23. 23. Delta Receptor• High affinity for Leu/Met enkephalins endogenous ligands.• The δ mediated analgesia is mainly spinal• Affective component of supraspinal analgesia appears to involve δ receptors as these receptors are present in limbic areas—also responsible for dependence and reinforcing actions.• The proconvulsant action is more prominent in δ agonists.
  24. 24. Spinal sites of opioid action. hyperpolarizesecond-order pain transmission neurons by increasing K+ conductance, evoking an inhibitory postsynaptic potential reduce transmitter release from presynaptic terminals of nociceptive primary afferents
  25. 25. The descending control system, showing the main sites of action of opioids on pain transmission
  26. 26. Analgesic features of Morphine
  27. 27. 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.
  28. 28. Selectivity• Suppression of pain perception is selective• No affect on other sensations• proportionate generalized CNS depression (contrast general anaesthetics).
  29. 29. 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
  30. 30. 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.
  31. 31. Mood and subjective effects• 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
  32. 32. Mood and subjective effects• 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, pleasurable—akin to orgasm.• Thus one has to learn to perceive the euphoric effect of morphine.
  33. 33. Mood and subjective effectsIn patients - Pain relief In normal persons Dependence and No addiction Addiction
  34. 34. Other pharmacological actionsGastrointestinal system : – Increase in tone , – reduced motility , – contraction of sphincters , – decrease of G.I. secretions – leading to constipation .( , k , receptors ).
  35. 35. Other effectsRespiratory 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
  36. 36. Other effects• 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
  37. 37. Other effects• Bronchoconstriction – due to histamine release by morphine .• Uterus may be relaxed .• Mild hyperglycemia due to central sympathetic stimulation .• It has weak anticholinesterase action .
  38. 38. Other effects• Endocrine – Growth hormone and prolactin and ADH levels are increased . – FSH ,LH and ACTH levels are decreased .
  39. 39. 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
  40. 40. 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.
  41. 41. ADVERSE EFFECTS• 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 µg/kg injected in chord is the treatment of choice.
  42. 42. ToleranceOnset• 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 .
  43. 43. 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
  44. 44. Tolerance - Mechanism• The tolerance is not pharmacokinetic but due to the true cellular adaptive response• Two proposed mechanisms – upregulation of cAMP system – Downregulation of μ receptors• Recent research suggests tolerance results due to uncoupling between μ receptor and G proteins• Leading to reversal of second messenger (cAMP) and ion channel system
  45. 45. Tolerance - Mechanism• 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 μ receptor and G proteins
  46. 46. DependenceDependence 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.
  47. 47. 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.
  48. 48. 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
  49. 49. 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.
  50. 50. 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
  51. 51. 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
  52. 52. 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..
  53. 53. 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
  54. 54. 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,
  55. 55. Therapeutic usesAcute 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.
  56. 56. 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.
  57. 57. 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
  58. 58. 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
  59. 59. 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 ½ 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
  60. 60. 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 µg /hr acts for 72 hours
  61. 61. 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
  62. 62. 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
  63. 63. 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.
  64. 64. Pentazocine• Weak µ antagonist action and marked κ 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
  65. 65. 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)
  66. 66. Buprenorphine• High-efficacy partial agonist of µ 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
  67. 67. NON STEROIDALANTIINFLAMMATORY DRUGS DR.AYESHA
  68. 68. 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.
  69. 69. B- Preferential COX-2 inhibitors Nimesulide, Meloxicam, NabumetoneC- Selective COX-2 inhibitors Celecoxib, Rofecoxib, ValdecoxibD- Analgesic- antipyretics with poor antiinflammatory action Paraaminophenol derivative: Paracetamol (Acetaminophen). Pyrazolone derivatives: Metamizol (Dipyrone), Propiphenazone. Benzoxazocine derivative: Nefopam.
  70. 70. Benefits due to PG Synthesis inhibition• Analgesia: prevention of pain nerve ending sensitization• Antipyretic• Anti-inflammatory• Antithrombotic• Closure of ductus arteriosus
  71. 71. 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
  72. 72. Adverse effects of NSAIDsGastrointestinal-• Gastric irritation, erosions, peptic ulceration, gastric bleeding/perforation, esophagttisRenal• Na and water retention, chronic renal failure, interstitial nephritis, papillary necrosis (rare)Hepatic• Raised transaminases, hepatic failure (rare)
  73. 73. CNS• Head ache, mental confusion. Behavioural disturbances, Seizure precipitation.Haematological• Bleeding, thrombocytopenia, haemolytic anaemia, agranulocytosisOthers• Asthma exacerbation, nasal polyposis skin rashes, pruritis, angioedema.
  74. 74. 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
  75. 75. • 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.
  76. 76. Other uses are:• Pregnancy induced hypertension and pre eclampsia.• To delay labour• Patent ductus arteriosus
  77. 77. PROPIONIC ACID DERIVATIVES Ibuprofen
  78. 78. • 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.
  79. 79. IndomethacinPotent 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.
  80. 80. 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
  81. 81. MEPHENAMIC ACID• Analgesic, Antipyretic and Anti-inflammatory drug which inhibits COX & antagonizes actions of PGs.• Exerts peripheral & central analgesic action.
  82. 82. 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
  83. 83. ARYL-ACETIC ACID DERIVATIVE DICLOFENAC SODIUM
  84. 84. 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.
  85. 85. 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.

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