seminar analgesics

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  • T:M = 11-12:1 (IM/IV)vs. codeine: single dose, post-op
  • seminar analgesics

    1. 1. ANALGESICS RAJESH SARDANA PG 1ST YR.
    2. 2. CONTENTS • • • • • • • PHASES OF PAIN METHODS IN PAIN CONTROL WHO LADDER ANALGESICS REGIME CLASSIFICATION OF ANALGESICS APPLICATION OF ANALGESICS IN OMFS RECENT ADVANCES IN PAIN CONTROL REFERENCES
    3. 3. Pain Derived from Greek ”Poin”; meaning penalty. • Derived from Latin punishment from God “Poena”; meaning
    4. 4. PHASES OF PAIN • A) Phases I (Acute nociceptive pain ) : • brief noxious stimuli--fairly simple & direct route-- centrally towards the thalamus & cortex --- conscious perception of pain-- possibility for modulation -- synaptic relays along the way • Close correlation the discharges in peripheral nociceptors & subjective expression pain
    5. 5. B) Phase 2 ( Inflammatory pain ) • Noxious stimulus very intense or prolonged • tissue damage & inflammation . Increased activity and responsiveness of sensitized nociceptors. • Increased afferent inflow to CNS from injured area • Nociceptive neurons in spinal cord modify their responsiveness.
    6. 6. C) Phase 3(NEUROPATHIC PAIN) • Symptom of neurological disease •Lesions of peripheral nerves or damage to any portion of somatosensory system within the CNS. • Spontaneous pain ,triggered by innocuous stimuli or are exaggerated responses to minor noxious stimuli. •Probable reason 1) Pathological changes in damaged neurons 2) Reactive changes in response to nociceptive afferent input and to loss of portions of the normal afferent inputs
    7. 7. Pain is perfect misery, the worst of evils, and excessive, overturns all patience”. John Milton (1608- 1674) Paradise Lost. One of the greatest services doctors can do their patients is to acquire skill in the management of pain.
    8. 8. THEORIES OF PAIN 1.THEORY OF SPECIFICITY 2.PATTERN THEORY 3 GATE CONTROL THEORY
    9. 9. Methods of pain control • • • • • Removing the cause. Blocking the pathway of painful impulses. Raising the pain threshold. Preventing pain reaction by cortical depression. Using psychosomatic methods.
    10. 10. Removing the cause • It is the desirable method of controlling pain. • If it is accomplished, the environmental change in tissue would be eliminated. • Free nerve endings would not be excited and no impulses would be initiated. • This method clearly affects pain perception.
    11. 11. Blocking the pathway of painful impulses • It is the most widely used method in dentistry for controlling pain. • A suitable drug, possessing local anesthetic properties is injected into the tissues in proximity to the nerves involved. • It prevents depolarization of the nerve fibers at the area of absorption, thus preventing those fibers from conducting any impulses beyond that point. • This method of pain control is possible by interfering with pain perception.
    12. 12. Raising the pain threshold • It depends on the pharmacologic actions of the drugs possessing analgesic properties. • These drugs raise the pain threshold centrally and therefore interfere with pain reaction. • The cause of the organic stimulus may still be present. • Pain perception is unaffected, but pain reaction is decreased and thus pain reaction threshold is raised, but it is impossible to eliminate all pain of the most severe nature.
    13. 13. Preventing pain reaction by cortical depression • Eliminating pain by this method by general anesthesia and general anesthetic agents. • The agent, by increasing depression of the CNS, prevents any conscious action to a painful stimulus.
    14. 14. • Using psychosomatic methods • Relaxation Training Relaxation involves concentration and slow, deep breathing to release tension from muscles and relieve pain. Learning to relax takes practice, but relaxation training can focus attention away from pain and release tension from all muscles. Relaxation tapes are widely available to help you learn these skills. • Biofeedback Biofeedback is taught by a professional who uses special machines to help you learn to control bodily functions, such as heart rate and muscle tension. As you learn to release muscle tension, the machine immediately indicates success. Biofeedback can be used to reinforce relaxation training. Once the technique is mastered, it can be practiced without the use of the machine. • Visual Imagery and Distraction
    15. 15. The WHO advocates “This stepped approach of administering the right drug in the right dose at the right time is inexpensive and generally effective in managing acute pain. Simplicity, Flexibility to a large variety of pain situations and also to prescribers globally. Emphasis on multimodal analgesia. Its disadvantages include: It may be too simplistic for management of certain types of pain, especially neuropathic pain or for those who are opioid dependant. References Organisation W. Analgesic Ladder. World Health Organization; 1986.
    16. 16. NSAIDS
    17. 17. PROSTANOIDS (PGs & Txs) PGI2 (prostacyclin) is located predominantly in vascular endothelium. Main effects: •vasodilatation •inhibition of platelet aggregation TxA2 is found in the platelets. Main effects: •platelet aggregation •vasoconstriction
    18. 18. PGE2 causes: • inhibition of gastric acid secretion •contraction of pregnant uterus •contraction of GI smooth muscles PGF2α – main effects: •contraction of bronchi •contraction of miometrium
    19. 19. Cyclooxygenase (COX) is found bound to the endoplasmatic reticulum. It exists in 3 isoforms: • COX-1 (constitutive) acts in physiological conditions. • COX-2 (inducible) is induced in inflammatory cells by pathological stimulus. • COX-3 (in brain).
    20. 20. Inflammatory stimulus (+) Ex Phospholipids Phospholipase A2 In Arachidonic acid Cyclooxy genase (COX) 5-lipoxygenase Leucotrienes 15-lipoxygenase Lipoxins Endoperoxides PGs TxA2
    21. 21. Essential of Medical Pharmacology – 5st Ed. (2003)
    22. 22. COX inhibitors Nonselective COX-1/COX-2 inhibitors NSAIDs COX-2 inhibitors COX-3 inhibitors • Selective (coxibs) •Antipyretic analgesics • Preferential
    23. 23. COX-2 inhibitors (1) Selective COX-2 inhibitors (Coxibs) • Celecoxib • Etoricoxib • Parecoxib (2) Preferential COX-2 inhibitors • Meloxicam • Nimesulide • Nabumetone
    24. 24. NSAIDs
    25. 25. NSAIDs Classifications • Mild to moderate anti-inflammatory action propionic acid derivatives ibuprofen, naproxen fenamic acids mefanamic acid • Marked anti-inflammatory action salicylic acids aspirin pyrazolone derivatives azapropazone, phenylbutazone acetic acid derivatives diclofenac, indomethacin oxicam derivatives piroxicam • Selective COX2 inhibitors celecoxib, rofecoxib
    26. 26. NSAIDs Main actions 1.) Analgesic -effective against mild to moderate pain, do not cause dependence 2.) Anti-inflammatory 3.) Anti-pyretic 4.)Anti-platelet- prevent thromboxane production, derived from prostaglandins and cause platelet aggregation Others 5.) Useful in treatment of dysmenorrhea, associated with increased prostaglandin synthesis and increased uterine contractility 6.) Used to close the patent ductus arteriosus
    27. 27. NSAIDs Adverse effects 1.) Gastric or intestinal mucosal damage - mucosal prostaglandins inhibit acid secretion, promote mucus secretion, prevent back diffusion of acid into the gastric submucosa - Inhibition thus results in erosions, ulceration, bleeding, perforation 2.) Disturbances of fluid and electrolyte balance - inhibition of renal prostaglandin production results in sodium retention and oedema, possible hyponatraemia, hyperkalaemia, antagonism of antihypertensive agents 3.) Analgesic nephropathy - due to long term ingestion of mixtures of agents - chronic interstitial nephritis, renal papillary necrosis, acute renal failure
    28. 28. NSAIDs Acetaminophen • equivalent analgesic efficacy to aspirin • no useful anti-inflammatory action used for mild to moderate pain, but aspirin is preferred if due to inflammatory process Metabolism • is conjugated in the liver as the inactive glucuronide and sulphate • a number of minor oxidation products inc. N-acetylbenzoquinoneimine (NABQI) are also formed • NABQI is highly chemically reactive and is usually inactivated by conjugation with SH (thiol) groups of glutathione • Supply of glutathione is limited and exhausted in overdose NABQI then reacts with cellular macromolecules and causes cell death Adverse effects • rare in therapeutic usage • occasional skin rash and allergy • Overdose can result in fulminant hepatic necrosis and liver failure
    29. 29. Paracetamol overdose • Ingestion of >4g of paracetamol may be fatal • may be lower in chronic alcoholics or subjects with underlying liver disease. Clinical features In severe poisoning • up to 24 hours none or nausea and vomiting • > 24 hoursnausea and vomiting, right upper quadrant pain, jaundice, encephalopathy
    30. 30. Rang et al. Pharmacology – 6th Ed. (2007)
    31. 31. Metabolism of Basic & Clinical Pharmacology – 10th Ed. (2007) paracetamol to hepatotoxic metabolites (NABQI etc.) (GSH – glutathione; SG – glutathione moiety) Daily dose > 4gm hepatotoxicity and nephrotoxicity NB: Acetylcysteine and GSH contain –SH groups. NABQI
    32. 32. Management • Blood for paracetamol at 4 hours post ingestion • Check treatment curve for N-acetylcysteine infusion ( if in doubt of severe poisoning, don’t delay) • Check prothrombin time and plasma creatinine, pH • acute renal (due to acute tubular necrosis) and hepatic failure and occur at 36-72 hours after ingestion • Indications for referral to liver unit are - rapid development of Grade 2 encephalopathy - PTT >45 secs at 48 hours or >50 secs at 72 hours - rising plasma creatinine - Arterial pH <7.3 more than 24 hours after ingestion
    33. 33. Bark of willow tree was used in folk medicine for years for mild pain and fever. Salicylic acid was obtained by hydrolysis of the bitter glycoside obtained from this plant. Acetylsalicylic acid was synthesized in 1853 1875 sodium salicylate was used in fever and pain. 1899 it was found to be effective in arthritis and was well tolerated.
    34. 34. Aspirin (acetyl salicylate) Actions • Analgesic - central and peripheral action • Antipyretic - act in hypothalamus to lower the set point of temperature control elevated by fever, also causes sweating • anti-inflammatory - inhibition of peripheral prostaglandin synthesis • respiratory stimulation direct action on respiratory centre, indirectly by ↑ CO2 production
    35. 35. Effects of NSAIDs 1. Analgesic and antipyretic action Aspirin is a weaker analgesic than morphine-type drugs Aspirin 600 mg < Codeine 60 mg < 6 mg Morphine Aspirin relieves inflammatory, tissue injury related, connective tissue and integumental pain but is relatively ineffective in severe visceral and ischemic pain. The analgesic action is mainly due to obtunding peripheral pain receptors and prevention of PG mediated sensitization of nerve endings. A central subcortical action, raising threshold to pain perception also contri- butes. No sedation, tolerance, and dependence are produced.
    36. 36. Aspirin (acetyl salicylate) • Metabolic effects i.) ↑ peripheral O2 consumption (uncoupled oxidative phosphorylation) hence ↑CO2 production with ↑ respiration, and direct analeptic action - respiratory alkalosis ii) renal loss of bicarbonate with sodium, potassium water iii) dehydration iv) metabolic acidosis - effects on Krebs cycle, ↑ ketone body, salicylic acid in blood, renal insufficiency due to vascular collapse, dehydration v) hypoglycaemia or even hyperglycaemia can occur
    37. 37. Aspirin (acetyl salicylate) • Uricosuric effects reduces renal tubular reabsorption of urate but treatment of gout requires 5-8g/d, < 2g/d may cause retention of urate. antagonises the uricosuric action of other drugs • Reduced platelet adhesion- irreversible inhibition of COX by acetylation, prolongs bleeding time, useful in arterial disease Note: low doses are adequate for this purpose since the platelet has no biosynthetic capacity and can not regenerate the enzyme • Hypothrombinaemia : occurs with large doses ie >5g/day
    38. 38. Alcohol increases GI toxicity of NSAIDs. . Urate excretion. Aspirin in high dose reduces renal tubular excretion of urate (both substances are transported by the same mechanism).
    39. 39. . GIT. Aspirin and its metabolite salicylic acid irritate gastric mucosa and cause epigastralgia, nausea, and vomiting. In higher doses it also stimulates CTZ. Aspirin (pKa 3.5) remains unionized and diffusible in the acid gastric juice, but on entering the mucosal cell (pH 7.1) it ionizes and becomes indiffusible. This “ion trapping” in the gastric mucosal cell enhances gastric toxicity.
    40. 40. Uses of Aspirin® (Bayer, 1899) As analgesic (300 to 600 mg during 6 to 8 h) for headache, backache, pulled muscle, toothache, neuralgias. As antipyretic in fever of any origin in the same doses as for analglesia. . Acute rheumatic fever. Aspirin is the first drug of choice. Other drugs substitute aspirin only when it fails or in severe cases. Antirheumatic doses are 75 to 100 mg/kg/24 h (resp. 4–6 g daily) in the first weeks . Rheumatoid arthritis. Aspirin a dose of 3 to 5 g/24 h after meal is effective in most cases. Since large doses of aspirin are poorly tolerated for a long time, the new NSAIDs (diclofenac, ibuprofen, etc.)
    41. 41. Aspirin (acetyl salicylate) OVERDOSAGE • Ingestion of > 10 g can cause moderate/severe poisoning in an adult • Clinical features - ‘salicylism’ tremor, tinnitus, hyperventilation, nausea, vomiting, sweating • Management- mainly supportive
    42. 42. Aspirin therapy in children with rheumatoid arthritis has been found to raise serum concentration transaminases, indicating liver damage. Most cases are asymptomatic but it is potentially dangerous. An association between salicylate therapy and “Reye’s syndrome”, a rare form of hepatic encephalopathy seen in children, having viral infection (varicella, influenza), has been noted. Aspirin should not be given to children under 15 years unless specifically indicated, e.g. for juvenile arthritis (paracetamol is preferred). Postmyocardial infarction and poststroke patients. By inhibiting platelet aggregation in low doses (100 mg daily) aspirin decreases the incidence of reinfarction.
    43. 43. Arachidonic acid Cyclooxygenase (COX) (-) >1 g/24 h Aspirin Endoperoxides (-) 100 mg/24 h Thromboxane A2 synthase PGs TxA2
    44. 44. Drug interactions with NSAIDs Drugs Diuretics Beta-blockers ACE inhibitors Anticoagulants Sulfonylurea Cyclosporine Alcohol Result Decrease diuresis Decrease antihypertensive effect Decrease antihypertensive effect Increase of GI bleeding Increase hypoglycemic risk Increase nephrotoxicity Increase of GI bleeding
    45. 45. Ibuprofen is a derivative of phenylpropionic acid. In doses of 2.4 g daily it is is equivalent to 4 g of aspirin in anti-inflammatory effect. Oral ibuprofen is often prescribed in lower doses (< 2.4 g/d), at which it has analgesic but not antiinflammatory efficacy. A topical cream preparation is absorbed into fascia and muscle. A liquid gel preparation of ibuprofen provides prompt relief in postsurgical dental pain. It is effective in closing ductus arteriosus in preterm infants, with much the same efficacy as indometacin.
    46. 46. Ketoprofen is a propionic acid derivative that inhibits both COX (nonselectively) and lipoxygenase. Concurrent administration of probenecid elevates ketoprofen levels and prolongs its plasma half-life. The effectiveness of ketoprofen at dosages of 100–300 mg/d is equivalent to that of other NSAIDs in the treatment of rheumatoid arthritis, osteoarthritis, gout, dysmenorrhea, and other painful conditions. In spite of its dual effect on prostaglandins and leukotrienes, ketoprofen is not superior to other NSAIDs. Its major adverse effects are on the GIT and the CNS. Phenylbutazone is a derivative of pyrazolidinedione with a high GI toxicity. It is rarely used now.
    47. 47. Indomethacin is a potent nonselective COX inhibitor and may also inhibit phospholipase A and C, reduce neutrophil migration, and decrease T cell and B cell proliferation. Probenecid prolongs indometacin's half-life by inhibiting both renal and biliary clearance. Indometacin is indicated for use in juvenile rheumatoid arthritis, gout and ankylosing spondylitis, etc. It has been used to treat patent ductus arteriosus. An ophthalmic preparation seems to be efficacious for conjunctival inflammation and to reduce pain after traumatic corneal abrasion. Gingival inflammation is reduced after administration of indometacin oral rinse. A high incidence (up to 50%) of GI and CNS side effects is produced: GI bleeding, diarrhoea, frontal headache, mental confusion, etc.
    48. 48. Diclofenac is a phenylacetic acid derivative. A 0.1% ophthalmic preparation is recommended for prevention of postoperative ophthalmic inflammation and can be used after intraocular lens implantation and strabismus surgery. A topical gel containing 3% diclofenac is effective for solar keratoses. Diclofenac in rectal suppository form can be considered a drug of choice for analgesia and postoperative nausea. It is also available for intramuscular and oral administration (Voltaren® and Feloran® – SR tablet: 100 mg/24 h). Side effects occur in approximately 20%: GI distress and occult bleeding, gastric ulceration. A preparation combining diclofenac and misoprostol (PGE1) decreases upper GI ulceration but may result in diarrhoea.
    49. 49. • Postoperative analgesia in orthognathic surgery patients: diclofenac sodium or paracetamol ? • • Ayşegül Mine Tüzüner Öncül, Emre Çimen, , Zuhal Küçükyavuz, Mine Cambazoğlu Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Ankara University, Besevler, Pe • . Thirty patients were randomly allocated into two groups (n = 15 in each) using sealed envelopes. The first group was given paracetamol 1 g intravenously and the second diclofenac sodium 75 mg intramuscularly. The analgesics were given during the last 15 min of the operation while the mucosa was being sutured. The number of requests for further analgesia, and the amount of analgesia given postoperatively (as diclofenac sodium) were recorded. The intensity of postoperative pain was recorded on a visual analogue scale (VAS), and postoperative requests for analgesia, haemodynamic variables (systolic blood pressure and heart rate), and complications were compared. The groups were comparable. A single dose of diclofenac or paracetamol effectively decreases the intensity of postoperative pain after bimaxillary osteotomy. British Journal of Oral and Maxillofacial Surgery Volume 49, Issue 2, March 2011,
    50. 50. PYRROLO-PYRROLE DERIVATIVE (Ketorolac) Ketorolac A novel NSAID with potent analgesic and modest anti-inflammatory activity. In postoperative pain it has equaled the efficacy of morphine no interaction with opioid receptors and is free of respiratory depressant, dependence producing, hypotensive and constipating side effects.
    51. 51. Pharmacokinetics Ketorolac is rapidly absorbed after oral and i.m. administration. It is highly plasma protein bound and 60% excreted unchanged in urine. Major metabolic pathway is glucuronidation; plasma t1/2 is 5-7 hours.
    52. 52. Adverse effects Nausea, abdominal pain, dyspepsia, ulceration, loose stools, drowsiness, headache, dizziness, nervousness, pruritus, pain at injection site, rise in serumtransaminase and fluid retention have been noted.. No significant drug interactions have been reported and it has been used concurrently with morphine. However, it should not be given to patients on anticoagulants. .
    53. 53. Piroxicam, an oxicam (enolate derivative), is a nonselective COX-1/COX-2 inhibitor that at high concentrations also inhibits polymorphonuclear leukocyte migration, decreases oxygen radical production, and inhibits lymphocyte function. Its long half-life permits once-daily dosing. Toxicity includes GI symptoms (20% of patients), dizziness, tinnitus, headache, rash. When piroxicam is used in dosages higher than 20 mg/d, an increased incidence of peptic ulcer and bleeding is encountered. This risk is as much as 10 times higher with piroxicam than with other NSAIDs.
    54. 54. Inhibiting activity rate (COX-2/COX-1) •Aspirin •Indometacin •Meloxicam (Preferential COX-2 inhibitor) 155 60 0,8 Classical NSAIDs
    55. 55. • Coxibs are selective COX-2 inhibitors. They exert • antiinflammatory, analgesic, and antipyretic action • with low ulcerogenic potential. Coxibs can cause • infertility. They have prothrombotic cardiovascular • risk. The ulcerogenic potential of preferential • COX-2 inhibitors Meloxicam, Nabumetone, and • Nimesulide (Aulin®) is significant
    56. 56. SULFONANILIDE DERIVATIVE (Nimesulide ) Nimesulide- this newer NSAID is a relatively weak inhibitor of PG synthesis (may be somewhat selective for COX-2); appears to exert its effects by other mechanisms like reduced generation of superoxide by neutrophils, inhibition of PAF synthesis and TNF release, free radical scavanging, inhibition of metalloproteinase activity in cartilage.
    57. 57. HEPATOTOXICITY
    58. 58. Celecoxib is as effective as other NSAIDs in the treatment of rheumatoid arthritis and osteoarthritis, and in trials it has caused fewer endoscopic ulcers than most other NSAIDs. Probably because it is a sulfonamide, celecoxib may cause rashes. It does not affect platelet aggregation at usual doses.
    59. 59. Meloxicam is an enolcarboxamide related to piroxicam that has been shown to preferentially inhibit COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d. It is not as selective as the other coxibs and may be considered “ preferentially" selective rather than “highly” selective. The drug has been approved for the treatment of osteoarthritis and rheumatoid arthritis. It is associated with fewer clinical GI symptoms and complications than piroxicam, diclofenac, and naproxen. Other toxicities are similar to those of other NSAIDs.
    60. 60. NSAIDs Non selective Vs selective COX2 inhibitors ↑ risk of cardiovascular adverse events with COX 2 inhibitors • Rofecoxib was withdrawn from the market • Higher BP, incidence of myocardial infarction, stroke • Mechanism _ ? Unopposed effect of cox 1 action - ? Block protective effect of COX2 on ishaemic myocardium or atherogenesis
    61. 61. Comparative action between COX inhibitors COX-1/COX-2 inhibitors COX-2 inhibitors 1. Analgesic action (+) (+) (+) 2. Antipyretic action (+) (+) 3. Antiinflammatory action (+) (+) (+) 4. Antiplatelet aggregatory (+) (-) 5. Gastric mucosal damage (+) (+) (+) (+) 6. Renal salt / water retention (+) (+) 7. Delay/prolongation of labor 8. Infertility (+) (+) (-) (+) (+) (+) 9. Ductus arteriosus closure (+) ? 10. Aspirin-like asthma 11. Cardiotoxicity (+) (-) ? (+) (+)
    62. 62. ® Bextra (Valdecoxib): Pfizer (penalty!) Many severe side effects •Infertility (> PGF2α) •Thrombosis (< PGI2; > TxA2)
    63. 63. Nonselective COX-1/COX-2 inhibitors DERIVATIVES OF ACIDS Salicylates Acetylsalicylic acid (Aspirin®, 1899), Diflunisal Methyl salicylate (revulsive drug) Phenylacetates: Acelcofenac, Diclofenac Indolacetates: Indometacin, Sulindac Enolates (oxicams) Piroxicam, Piroxicam beta-cyclodextrin (prodrug), Lornoxicam, Tenoxicam Propionates Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen OTHERS (with less application) Pyrazolones: Phenazone, Propyphenazone, etc. Pyrazolidinediones: Oxyphenbutazone, Phenylbutazone
    64. 64. Beneficial actions of NSAIDs due to prostanoid synthesis inhibition 1. Analgesia prevention of pain nerve ending sensitization 2. Antipyresis connected with influence of thermoregulatory centre in the hypothalamus 3. Antiinflammatory action mainly antiexudative effect 4. Antithrombotic action in very low daily doses 5. Closure of ductus arteriosus
    65. 65. Shared toxicities of NSAIDs due to prostanoid synthesis inhibition 1. Gastric mucosal damage connected with PGE inhibition 2. Bleeding: inhibition of platelet function (TxA2 synthesis) 3. Limitation of renal blood flow Na+ and water retention 4. Delay / prolongation of labour connected with PGF2α inhibition 5. Asthma and anaphylactoid reactions connected with PGF2α inhibition
    66. 66. Mechanisms by which NSAIDs may induce mucosal injury Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
    67. 67. Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
    68. 68. Brain’s opiate system Endorphin & Enkephalin • multiple areas of brain show opiate receptors • Enkephalin and Leu-Enkephalin---Brain stem and spinal cord • -Endorphine—Hypothalamus and spinal cord • Dynorphin-- Brain stem and spinal cord
    69. 69. Endorphins • Behave like morphine & bind to opiate receptors to obtund pain Like morphine • B – endorphin closely related to pituitary function • May act like hormone. • The Enkephalin & endorphins have antinociceptive effects, • Underlying mechanism not fully analyzed
    70. 70. Brain’s Opiate system • • 3 major components 1. Periaqueductal gray and periventricular nucleus— Enkephalinergic fibers • 2. Raphe Magnus nucleus,—Serotonergic fibers • 3. A pain inhibitory complex located in dorsal horns of spinal cord—Enkephalinergic fibers At this point, the analgesia signals can block the pain before it is relayed to the brain. •
    71. 71. Opioids NSAIDS
    72. 72. OPIATE ANALGESICS Classification • Low efficacy Codeine Dihydrocodeine Dextropropoxyphene • Medium efficacy Bupranorphine • High efficacy Morphine Diamorphine pethidine
    73. 73. OPIATE ANALGESICS Routes of administration • Oral • Parenteral • Suppositories • Transdermal- Patch • s/c Syringe driver
    74. 74. OPIATE ANALGESICS Mechanism of action • Bind to CNS opioid receptors whose natural ligands are endorphins and encephalins.
    75. 75. OPIATE ANALGESICS Actions • CNS Depression Analgesia Respiratory depression Depression of cough reflex sleep Stimulation vomiting miosis ↑ spinal reflexes (convulsions) mood changes- Euphoria Dependence – also affects other systems
    76. 76. OPIATE ANALGESICS • Smooth muscle stimulation GI muscle spasm causing delayed transit and constipation Biliary spasm Bronchospasm • Cardiovascular Dilation of resistance vessels (arterioles) and capacitance vessels (veins)
    77. 77. OPIATE ANALGESICS Dependence • Up to 8 h- Mild psychological withdrawal stress • 8-12 h - increasing nervousness, restlessness and anxiety • 12-24h - yawning, sweating, runny eyes and nose • 24 h - pupils dilate, waves of goose flesh • 36 h - twitching of muscles, leg & abdominal cramps vomiting and diarrhoea and anorexia, insomnia tachypnoea, ↑ BMR and mild pyrexia • 48-72 h - peak withdrawal symptoms • up to 10 d- symptoms gradually subside • Complete recovery requires 3-6 months • Note : Withdrawal syndrome can be in part alleviated by long acting opioid such as methadone
    78. 78. OPIATE ANALGESICS Opioid overdose • Death usually due to respiratory depression • Cardiovascular function usually well preserved unless severe anoxia • Treatment with iv naloxone • May need infusion - naloxone has shorter t1/2 (1h), particularly for opioids with long t1/2 – (methadone) and tight binding (bupranorphine)
    79. 79. Morphine is naturally occurring substance of the juice in the unripe seedpods of the opium poppy. It is a potent narcotic analgesic, and its primary clinical use is for moderately severe and severe pain. After heroin, morphine has the greatest dependence liability of the narcotic analgesics in common use.
    80. 80. It is legally available only in the form of water-soluble salts, such as Morphine sulfate and Morphine hydrochloride. taken orally, injected or Morphine is inhaled, or taken through rectal suppositories.
    81. 81. Morphine is so effective because it acts directly at pain-modulating receptors in the nervous system, termed opioid receptors. The receptors respond to natural compounds built by our bodies to control the level of pain experienced at different times.
    82. 82. Although morphine remains the most effective drug for pain relief, it is far from perfect. Morphine’s pharmacological effect is on the nervous system and the gastrointestinal tract. Morphine is highly addictive and tolerance and physical and psychological dependence develop quickly.
    83. 83. TRAMADOL
    84. 84. Acute Pain • Many small studies vs. opioids – Likley = morphine in equi-analgesic doses (T:M = ~10:1) up to 400 – 600mg/day maximum • Many small studies vs. non-opioids – Similar analgesia compared to NSAIDs postoperatively in a variety of doses Grond S, et al. Clin Pharmacokin 2004;43:879-923.
    85. 85. How does it work? • Weak -opioid receptor effects – Structurally related to morphine and codeine • ~10-fold less affinity for  receptor than codeine and up to 6000-fold less than morphine • Metabolized to highly active M1 300-fold greater affinity than parent compound – Analgesia only partially blocked by naloxone (~33%) • Serotonin and norepinephrine reuptake inhibition Grond S, et al. Clin Pharmacokin 2004;43:879-923. Raffa RB. J Clin Pharm Therap 2008;33:101-8.
    86. 86. • • • • • • • Analgesic and adjuvant anesthetic effect of submucosal tramadol after mandibular third molar surgery Marcelo Minharro Ceccheti University of Sao Paulo, São Paulo, Brazil( ORAL SURG ORAL PATHOL.ORAL RADIO 2012) The aim of this study was to assess analgesic and adjuvant anesthetic effects of submucosal tramadol after third molar extraction. . Submucosal tramadol injection after oral surgery improved postoperative analgesia, but did not extend duration of anaesthesia
    87. 87. Pre-Emptive Analgesic Effectiveness of Meloxicam Versus Tramadol After Mandibular Third Molar Surgery: A Pilot Study Mario A. Isiordia-Espinoza, DDS, MS,* Martín Sánchez-Prieto, DDS,† Francisco Tobías-Azúa, DDS,‡ and Juan G. Reyes-García, PhD§© 2012 American Association of Oral and Maxillofacial Surgeons 70;31-36.2012 To compare the pre-emptive analgesic effectiveness of 15 mg of meloxicam and 50 mg of tramadol after mandibular third molar surgery. Conclusion: The patients receiving 15 mg of preoperative meloxicam had less pain intensity and total analgesic consumption than those receiving 50 mg of preoperative tramadol.
    88. 88. RECENT TRENDS OF ANALGESIA
    89. 89. Acupuncture and Electroacupuncutre 1. Needle acupuncture 2. Electroacupuncutre .release of B- endorphin into Peripheral circulation .current applied at specific site where Deeper nociceptors available to be stimulated .profound analgesic effect for 1 hr
    90. 90. Pain – Gene THERAPY • Gene transfer technology to manipulate specific, localized biochemicalpathways involved in pain generation. • useful in ch.pain • viral mediated transfer of genes encoding opiate peptides to peripheral and central neurons
    91. 91. ELECTRONIC ANALGESIA • History in 46 AD, Scribonius Largus, physician to emperor Claudius, used the torpedo fish to relieve the pain of gout.
    92. 92. Mechanism of action (TENS ) • At the low frequency of 2Hz ,which is most often used in management of pain, TENS produces measurable changes in the blood levels of 1tryptophan, serotonin, and beta endorphins. • Serotonin possess analgesic actions, elevating the pain reaction threshold • Simultaneously levels of beta endorphins and encephalin increases in the cerebral circulation
    93. 93. CONSCIOUS SEDATION • Conscious sedation is a minimally depressed level of consciousness that retains the patient’s ability to maintain an airway independently and respond appropriately to physical stimulation and / or verbal command, such as ―open your eyes‖. Pharmacological behaviour managment 102
    94. 94. Nitrous oxide • Non- irritant, sweet smelling and colorless gas, not inflammable, not explosive but support combustion. • Concentrations of 35% to 40% enhance the sedative effects and have the degree of analgesia equivalent of 15mg of morphine. • It attains its peak effect in 3-5 min, first symptom appearing in less than 1 min. • It does not combine with any body tissue and is eliminated unchanged through the lungs in less than 5 min.
    95. 95. DRUG ROUTE OF ADMINSTRATION DOSAGE MIDAZOLAM ORAL INTRAMUSCULAR INTRAVENOUS INTRANASAL Oral Dosage in children under 25 kg of weight--0.3-0.5 mg/kg Maximum dose 12 mg. Children over 25kg of weight-12mg 1 to 0.15 mg/kg to a maximum dose of 10 mg Slow IV titration It produces sedative effect within 5 mins of administration. FLUMAZENIL (ROMAZICON) INTRAVENOUS 0.01mg/kg upto 0.2mg maximum dose of 1mg CHORAL HYDRATE (Noctec, Aquachloral Supprettes) ORAL RECTAL 25 to 50 mg/kg to a maximum of 1 gm 325, 500 and 650 mg. Pharmacological behaviour managment 104
    96. 96. NSAIDS IN PREGNANCY
    97. 97. • ANALGESICS: - Codeine causes fetal toxicity (FDA-C)in 1st trimester can use in 2nd or 3rd trimester. - Morphine & Meperidine is safe for short period, chronic use causes fetal toxicity (FDA-B). - NSAID: Inhibition of prostaglandin synthesis can cause premature closure of fetal ductus arteriosus constricture which will induce primary pulmonary hypertension and fetal bleeding tendencies. Aspirin—not used (FDA-C/D). Acetaminophen (FDA-B).-safe in all trimesters Ibuprofen (FDA-B)- avoid in third trimester can close the pda. Cox-2 inhibitors (FDA-C) avoid in third trimester can close the pda.
    98. 98. • BEST ANALGESICS EVER DISCOVERED OR INVENTED TILL DATE !!!!!! HEALTHY SMILES NURTURING OUR NEURONS
    99. 99. REFERENCES • KD TRIPATI, ESSENTIALS OF MEDICAL PHARMACOLOGY • LIPPINCOTT • WWW. SCIENCE DIRECT.COM • Selzer—Pain control and diagnosis in dentistry • Guyton—Textbook of physiology

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