Analgesics

analgesics, pain killers in dentistry

1. ANALGESICS 1

2. CONTENTS INTRODUCTION HISTORICAL BACKGROUND CLASSIFICATION PHARMACOLOGICAL ACTIONS ADVERSE EFFECTS USES ADDICTION CONCLUSION 2

3. etymology The word analgesic derived from Greek words. “An”-without “ Algos ”-pain 3

4. INTRODUCTION An analgesic or pain killer is any member of the group of drugs used to achieve analgesia, relief from pain. Analgesia simply means the absence of pain without losing consciousness. 4

5. Historical background Opiates, originally derived from the opium poppy, have been used for thousands of years for both recreational and medicinal purposes. 5

6. The most active substance in opium is morphine—named after Morpheus , the Greek god of dreams . 6 Historical background...

7. In the sixteenth century, laudanum , opium prepared in an alcoholic solution, was used as a painkiller. It was used widely as a painkiller during the American Civil War, and many soldiers became addicted. 7 Historical background...

8. Throughout the early 19 th century, the recreational use of opium grew and by 1830, the British dependence on the drug reached an all-time high. So, the British government banned opioids in their country but started exporting it to China. The Chinese also got addicted to it, and started doing crime activities. 8 Historical background...

9. So, the Chinese emperor requested the British Government to stop the opium trade, but they refused. The British sent warships to the coast of China in 1839 in response to China’s attempt to suppress the opium trade, here begins the “First Opium War.” The British won the war, conquered areas of China and started expanding the trade of opium. 9 Historical background...

10. classification ANALGESICS NARCOTIC/OPIOID DRUGS NON-NARCOTIC DRUGS 10

11. Opioid anal g esi c s Natural alkaloids M o rph i ne Codeine Semi s y n t h e tic opiates Heroin Pholcodeine H y d r o c odone Oxycodone Synthetic opioids P e th i dine Fentanyl T r ama dol 11

12. MORPHINE Morphine is the principal alkaloid in opium and is widely used till today. Therefore, it is described as prototype. Dose : 10-50mg oral, i.m , s.c (4hourly)......2-6mg i.v Children 0.1-0.2mg/kg i.m or s.c MORPHINE SULPHATE 10mg/ml inj. MORCONTIN 10, 30, 60, 100 mg tab RILIMORF 10, 20mg tabs 12

13. Pharmacological actions On central nervous system 13

14. Pharmacological actions... Neuro -endocrine Weakens hypothalamic influence on pituitary. ACTH. FSH, LH levels fall GH, Prolactin levels increases. In heavy abusers, impotence, menstrual irregularities and infertility are seen. 14

15. Pharmacological actions... On cardio vascular system Morphine causes vasodilatation due to Histamine release Depression of vasomotor centre Decreasing tone of blood vessels On GIT Constipation 15

16. pharmacokinetics It is primarily metabolized in liver Plasma t1/2 of morphine—2-3hours Elimination is almost complete in 24 hours Small amounts may persist. Adverse effects Sedation, mental clouding, lethargy Vomiting, constipation Blurring of vision, fall in BP, urinary retention 16

17. Acute morphine poisoning >50mg of morphine i.m produces serious toxicity. Respiration is slow and depressed. Cyanosis , sweating. Pinpoint pupil Coma Treatment: Gastric lavage with potassium permanganate 0.2% Artificial respiration with O 2 – CO 2 mixture Specific antidotes: Naloxone (0.4-0.8mg i.v for every 2-3 mins till respiration picks up) 17

18. Tolerance Tolerance: (failure of responsiveness to the usual dose of the drug) Tolerance develops to the analgesic and respiratory depressant actions of morphine after 10-14 days. But no tolerance develops to the constipating and miotic actions of morphine. Morphine addict always has constipation . Cross-tolerance occurs between morphine and various other narcotic analgesics. 18

19. dependence 19 Dependence is the subjective feeling that the user needs the drug to maintain a feeling of well-being.

20. addiction Opium or Morphine Addiction: Repeated administration of morphine leads to psychological as well as physiological dependence. 20

21. Adverse effects of drug addiction Inattentiveness Euphoria Poor performance Depressed consciousness Impaired respiration Decreased sexual interest Vision problems Collapsed veins Coma Death 21

22. withdrawal symptoms The withdrawal symptoms are characterized by: Rhinorrhea . Lacrimation . Restless sleep and insomnia. Dilated pupils. Vomiting. Diarrhea . 22

23. Severe muscle cramps. Severe headache. Patient refuses food leading to dehydration and acidosis. Treatment of Morphine Addiction: Withdrawal of morphine and substitution therapy with methadone Then, methadone is withdrawn gradually over a period of 3-5 days. It is an addicting drug but the withdrawal symptoms of methadone are less than those of morphine. 2. Sedatives to help sleeping. 23

24. Precautions, contraindications & interactions Infants and elderly are more susceptible to the respiratory depressant action of morphine. Morphine is risky in patients with respiratory insufficiency. Morphine can precipitate asthmatic attack by its histamine releasing action. Contraindicated in patients with head injury. 24

25. Precautions, contraindications & interactions... Elderly male: chances of urinary retention are high. Hypothyroidism, liver and kidney disease patients are more sensitive to morphine. Unstable personalities: are liable to continue with its use and become addicted. 25

26. codeine It is methyl-morphine, occurs naturally in opium, and is partly converted in the body to morphine. Cannot relieve severe pain. Cough suppressant. Single oral dose acts for 4-6hours. Constipation is prominent. Dose : 7.5-30mg (every 6 hours) for cough 15-60mg (every 6hours) for pain 26

27. Semi-synthetic opioids HEROIN (Diacetylmorphine) It is 3times more potent than morphine. Enters brain more rapidly. More euphorient and highly addicting. No therapeutic advantage over morphine 27

28. Brown sugar Brown sugar (an adulterated form of heroin), also called smack, junk, dope, and chaw . Brown sugar accounts for only 20% of the Pure heroin drug; the remaining 80% comes in the form of chalk powder, zinc oxide, and even strychinine . Because of this adulteration, it is very cheap and more dangerous 28

29. Methods of Use Users prefer to sniff, smoke Heat the powder and inhale the fumes Inject 29

30. Effects of heroin 30

31. Synthetic opioids PETHIDINE Pethidine was synthesized as an atropine substitute in 1939. Morphine-like action (analgesic). To relieve labour pain. As pre- anesthetic medication instead of morphine. Better than morphine in renal and biliary colics . 31

32. PETHIDINE... Difference from morphine : Its analgesic action is 1/10 that of morphine. It does not depress cough. It does not depress respiration in therapeutic doses. It does not cause constipation . Has atropine-like action . Pupil is dilated . Tolerance and addiction are less than with morphine. Dose : 50-100 mg orally or parenterally (S.C. or I.M). 32

33. Fentanyl Analgesic potency is 80 times that of morphine. Duration of action shorter than morphine and pethidine . Uses: As analgesic alone. With a tranquillizer to produce Neuroleptanalgesia (a state of sedation and analgesia) which is used in minor procedures e.g. bronchoscopy or in obstetrics. 33

34. methadone A potent analgesic. With long duration of action. Depresses respiratory and cough centers . Causes addiction but the withdrawal symptoms are milder than morphine. Dose: 60mg daily Uses: Analgesic. Treatment of opium (morphine) addiction. 34

35. tramadol Dose : 50-100mg oral/ i.m (every 4-6hours) CONTRAMAL,DOMADOL,TRAMAZAC 50mg cap,50mg/ml inj 1ml Used to treat short–lasting pain due to dental problems, visceral illness. Abuse potential is low 35

36. Opioid antagonists NALOXONE Drug of choice for morphine poisoning and reversing neonatal asphyxia due to opioid use during labor Injected intravenously (0.4-0.8 mg every 2-3mins, max 10mg) it promptly antagonizes all actions of morphine. It is inactive orally because of high first pass metabolism in liver. 36

37. naltrexone NALTIMA, NALTROX 50mg tab Chemically related to naloxane . Differs from naloxane in being orally active. Alcohol craving also reduced by naltrexone and used to prevent relapse of heavy drinking. 37

38. Opioids in dental pain Dental pain is mostly associated with inflammation. NSAIDS are more effective than opioids. Occasionally employed as additional drugs with paracetomol, ibuprofen to boost the analgesic effect. 38

39. Opioids in dental pain... Codeine, tramadol are used as additional drugs. The place of analgesics in dental pain is secondary to treatment of the cause of pain by appropriate local (antiseptics, root canal therapy)and systemic(antibiotics) measures. 39

40. In india ....in individual medical practitioner... Morphine formulations–total quantity not > 500 mg Codeine formulations not > 2000mg Hydrocodone -­‐total quantity not > 320 mg Fentanyl –2 TD patches one each of 12.5 µg / hour and 25 µg / hour Oxycodone -­‐total quantity not > 250 mg Methadone –the upper limit of quantity is not yet mentioned in the Rules. Guidelines for Stocking and Dispensing Essential Narcotic Drugs in Medical Institutions NCG Palliative Care Committee August 2017 40

41. In palliative care Palliative care is specialized medical care for people with a serious illness. This type of care is focused on providing relief from the symptoms and stress of a serious illness. The goal is to improve quality of life for both the patient and the family.‎ 41

42. 42 In palliative care... ANALGESIC LADDER BY WHO 1986

43. Offer a typical total daily starting dose schedule of 20–30 mg of oral morphine (for example, 10–15 mg oral sustained-release morphine twice daily), plus 5 mg oral immediate release morphine. If oral opioids are not suitable– transdermal patches, 43 In palliative care...

44. A transdermal fentanyl 12 microgram patch equates to approximately 45 mg oral morphine daily. Inform about constipation, nausea and drowsiness due to morphine and manage accordingly. 44 In palliative care...

45. N S A I DS Non selective COX inhibitors Aspirin I ndom e t h acin Ibuprofen Diclofenac Piroxicam Ketorolac Preferential COX 2 inhibitors Nimesulide Meloxicam Na b um e t one Selective COX 2 inhibitors Celecoxib R o f e c o xib Analgesics with poor anti-inflammatory action Ac et ami nop hen Nefopam 45 CLASSIFICATION OF NON-OPIOID ANALGESICS

46. History of nsaid s By 1897, German chemist Felix Hoffman and the Bayer company prompted a new age of pharmacology by introducing aspirin. Other NSAIDs were developed from the 1950s. 46

47. Mechanism of action of nsaid s 1971,Vane and coworkers made the landmark observation that NSAIDs blocked prostoglandin (PG) generation. Prostaglandins are produced from arachidonic acid( abudant in brain) by the enzyme cyclo-oxygenase . 47

48. Two main forms of Cyclooxygenases (COX) Cyclooxygenase-1 (COX-1) Cyclooxygenase-2 (COX-2) Produces prostaglandins that mediate inflammation, pain, and fever. Induced mainly in sites of inflammation by cytokines Pathologic Inflammation Pain Fever Produces prostaglandins that mediate homeostatic functions Constitutively expressed Homeostatic Protection of gastric mucosa Platelet activation Renal functions Macrophage differentiation 48

49. Beneficial actions of pg synthesis inhibition 49

50. Shared toxicities due to pg synthesis inhibition Gastric mucosal damage Bleeding Limitation of renal blood flow Delay/prolongation of labor Asthma and anaphylatic reactions 50

51. NON-SELECTIVE COX INHIBITORS(traditional nsaid s ) SALICYLATES Salicylic acid was prepared by hydrolysis of the bitter glycoside obtained from the plant Salix alba. Sodium salicylate was used for fever and pain in 1875. Its great success lead to the introduction of acetylsalicylic acid( ASPIRIN ) in 1897. 51

52. aspirin Aspirin is acetylsalicylic acid. Rapidly converted in the body to salicylic acid, which is responsible for most of its pharmacological actions. 52

53. TRADE NAMES Colsprin 100,325,650 mg tabs Ecosprin 75,150,325 mg tabs Dispirin 350mg tab. SALICYLATES - ASPIRIN 53

54. Pharmacological actions Aspirin has Analgesic, antipyretic and anti-inflammatory action. It interferes with platelet aggregation and bleeding time is prolonged to nearly twice the normal value. It effectively relieves inflammatory, tissue injury related, connective tissue and integumental pain. 54

55. pharmacokinetics Aspirin is rapidly de-acetylated in the gut wall, liver, plasma and other tissues to release salicylic acid which is the major circulating and active form. Entry into brain is slow, but aspirin freely crosses placenta. The metabolites are excreted by glomerular filtration as well as tubular secretion. 55

56. The plasma t1/2 of aspirin as such is 15-20min, but taken together with that of released salicylic acid, it is 3-5 hours. t1/2 of anti-inflammatory doses may be 8-12 hours. Thus, elimination is dose dependent. 56

57. Adverse effects At analgesic dose(0.3-1.5g/day) Nausea Vomiting Epigastric distress Increased occult blood loss in stools Rashes Rhinorrhoea 57

58. At inflammatory dose(3-5 g/day) Acute salicylate poisoning Adverse effects..... Salicylism —dizziness, tinnitus, vertigo, reversible impairment of hearing and vision, excitement and mental confusion, hyperventilation and electrolyte imbalance. vomiting, dehydration, electrolyte imbalance, acidotic breathing, petechial hemorrhages , restlessness, delirium, hallucinations, hyperpyrexia, convulsions, coma and death. Treatment- i.v fluid with Na, K, HCO 3 and glucose 58

59. Precautions & contradictions Contradicted in patients with peptic ulcer, bleeding tendencies In chronic liver disease, aspirin precipitate hepatic necrosis. Should be avoided in diabetics, congestive heart failure, pregnancy and breast feeding mothers. Should be stopped 1week before dental extraction and elective surgery. 59

60. interactions Aspirin displaces warfarin , naproxen, sulfonylureas , phenytoin and methtrexate from binding sites on plasma proteins. Aspirin also blunts diuretic action of furosemide and thiazides . 60

61. Propionic acid derivatives IBUPROFEN analgesic and antipyretic Rheumatoid arthritis, osteoarthritis Very popular in dentistry. Suppress post-operative swelling . Dose: 400-600mg TDS BRUFEN,EMFLAM,IBUSYNTH 200,400,600mg tab IBUGESIC 100mg/5ml syrup 61

62. pharmacokinetics Well absorbed orally, highly bound to plasma proteins. They enter brain, synovial fluid and cross placenta. They are largely metabolized in liver and excreted in bile as well as urine interactions Similar to other NSAIDs decrease actions of thiazides , furosemide and beta blockers 62

63. Fenamate ( anthranilic acid derivative) Dose 250-500mg TDS MEDOL 250,500mg cap MEFTAL 200,500mg tab,100mg/5ml susp PONSTAN 125,250,500mg tab, 50mg/ml syrup Analgesic, antipyretic Diarrhoea is the most important side effect. Hemolytic anaemia is rare but serious complication. 63

64. Enolic acid derivative PIROXICAM Dose 20mg BD for 2days followed by 20mg OD DOLONOX, PIROX 10, 20mg cap, 20mg/ml inj PIRICAM 10,20mg cap Used as long term anti-inflammatory drug in arthritis, relatively more toxic. Heart burn, nausea, anorexia are the common side effects 64

65. Acetic Acid derivatives KETOROLAC Dose: 15-30mg i.m or i.v (every 4-6hrs) orally 10-20mg (every 6hrs) 0.5mg/kg for children KETOROL, ZOROVON,TOROLAC 10mg tab Analgesic and anti-inflammatory Adverse effects-nausea, abdominal pain, ulceration, dyspesia , drowsiness 65

66. Acetic Acid derivatives... INDOMETHACIN Dose : 25-50mg BD IDICIN, INDOCAP 25mg cap,75mg cap INDOFLAM 25,75 mg caps,1% eyedrop . Anti-inflammatory and anti-pyretic Gastric irritation, nausea, anorexia, diarrhoea, head ache, hallucinations are prominent 66

67. pyrazolones Analgesic and antipyretic METAMIZOL(ANALGIN)- widely used in India but banned since JUNE 2013 due to its high gastric and CNS toxicity. Dose: 150-300mg TDS In SARIDON, ANAFEBRIN: Propyphenazone150mg+paracetamol 250mg Taken as self medication for headache, toothache, bodyache , fever, etc. 67

68. Preferential cox-2 inhibitors DICLOFENAC SODIUM Dose : 50mg TDS, then BD VOVERAN, DICLONAC 75mg deep i.m Used in arthritis, tooth ache, dysmenorrhoea Afford quick relief of pain Adverse effects: nausea, headache, dizziness, rashes, gastric pain. ACECLOFENAC- similar properties, tolerance is better with diclofenac Dose : 100mg BD ACECLO, DOLOKIND 100mg tab,200mg tab 68

69. Selective cox-2 inhibitors Currently 3 selective COX-2 inhibitors available in India- Celecoxib , Etoricoxib and Paracoxib . Do not inhibit platelet aggregation or prolong bleeding time. Used for dental pain, arthritis without affecting platelet function Dry mouth, apthous ulcers, taste disturbances, abdominal pain, rise in BP and paresthesias are its adverse effects. 69

70. Para-amino phenol derivatives PARACETAMOL (ACETAMINOPHEN) Dose : Adults 325-650mg Children 10-15mg/kg. CROCIN 0.5,1.0g tabs, METACIN, PARACIN 500mg tab, CALPOL 500mg tab, 125mg /5ml syrup. It is the de-ethylated active metabolite of phenacetin , was introduced in the last century but has come into common use only since 1950. 70 3-4 times/day

71. PARACETAMOL... Analgesic for headache, toothache, musculoskeletal pain, etc. Best anti-pyretic. Can be used in all age groups, pregnant/lactating women. Does not have significant drug interactions. Preferred over aspirin. 71

72. pharmacokinetics Paracetomol is well absorbed orally, plasma t1/2 is 2-3hours, effects after an oral dose last for 3-5hours. It is conjugated with glucuronic acid and sulfate Excreted rapidly in urine. 72

73. Acute paracetomol poisoning It occurs specially in small children who have low hepatic glucuronide conjugating ability. If a large dose(>10g) is taken, serious toxicity can occur. Early----Nausea, vomiting, abdominal pain, liver tenderness with no loss of consciousness. After 12-18 hours, hepatic and renal tubular necrosis Leading to coma and death. 73

74. Acute paracetomol poisoning... If the levels are lower-recovery obtained with supportive treatment. Antidote---N acetylcysteine infused i.v It is practically ineffective if started 12-16 hours or more after paracetomol ingestion. 74

75. Nsaid s IN DENTISTRY NSAIDs are the main stay for the management of acute dental pain. Mild-moderate pain with little inflammation- paracetomol or ibuprofen. Postextraction - diclofenac or ibuprofen or ketorolac 75

76. Nsaid s IN DENTISTRY... Patients with Gastric intolerance- paracetamol History of asthma or anaphylactic reaction to aspirin- diclofenac Pediatric patients- paracetamol , ibuprofen Pregnancy- paracetamol , low dose aspirin 76

77. conclusion Before prescription of any analgesic, the dental practitioner should have a clear idea on its advantages and disadvantages, mechanism of action, pharmacokinetics ,adverse effects in general and in relation to that individual patient, whilst reducing the risks and providing a streamlined treatment. A clinicians goal should be, to avoid chronic use of any analgesic whenever possible. 77

78. references Essentials of Medical Pharmacology-6 th edition- KD Tripathi Goodman & Gilman's The Pharmacological Basis Of Therapeutics - 11th Ed. (2006) Opioids in palliative care: full guideline (May 2012) Raymond ‘s The Essence of Analgesia and Analgesics-2 nd edition. Lynch ME, Watson CP (2006) The pharmacotherapy of chronic pain: a review. Pain Res Manag 11: 11-38. 78

79. Dionne RA, Berthold CW (2001) Therapeutic uses of non-steroidal anti-inflammatory drugs in dentistry. Crit Rev Oral Biol Med 12: 315-330. Haas DA (2002) Opioid agonists and antagonists, Pain and anxiety control in dentistry. Philadelphia, USA 114-128. . Thapa D, Rastogi V, Ahuja V (2011) Cancer pain management-current status. J Anaesthesiol Clin Pharmacol 27: 162-168 79

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