nsaids and opiods in pmr

role of nsaids and opiods

1. ROLE OF OPIOIDS and NSAIDS IN PMR MODERATOR: Dr Sandeep Kumar Gupt Assisstant prof DEPT OF PMR KGMU PRESENTED BY: Dr Joe Antony JR1 DEPT OF PMR KGMU

2. Contents Opiods Classification Moa Pharmacological action Specific opiods Nsaids Classification Moa Pharmacological action Specific drugs Who pain ladder

3. OPIODS Opiod analgesics are one of the oldest remedies for relief pain. Op i um is obtained t h e d a r k b r o w n from the poppy g u m my capsule exu d a t e (p a p a ver somniferum) Opium has been in use since 4000BC.

4. CLASSIFICATION Based on r eceptor occupation 1.Agonists A.Natural opium alkaloids Morphine ,codeine, B.Synthetic opioids Pethidine,Methadone 2.Antagonists Naloxone,naltrexone 3.Mixed agonist antagonists Pendazocine,nalpurine,butorphanol,Buprenorphine,nalorphine

5. M ORP H I N E In CNS mu (  ),kappa( k)and delta(  ) receptors Stimulation of opioid receptors (Morphine) Decrease the Intra cellular Calcium Level Decrease the release of Neurotransmitter It decreases the visceral Pain

6. Pharmacological action 1.Analgesia: Morphine is a potent analgesic and relieves pain without loss of consciousness.in higher doses it relieves severe pain as that of biliary colic . 2.Euphoria ,sedation and hypnosis Rapid IV inj of morphine produces a warm flushing of the skin and an immensely pleasurable sensatio n . I t also produces drowsiness

7. 3.Respiration Morphine produce respiratory depression. It directly depresses the respiratory center in the brain stem 4.Cough center It directly depress the cough center and thereby suppress cough.opioids should be used as antitussive only in the dry cough

8. 5.Nausea and emesis Morphine directly stimulates the CTZ in the medula causing nausea and vomitting.in higher doses it depress the vomitting center and hence there is no vomitting in poisoning . 6.pupil Morphine produces miosis resulting in a characteristic pinpoint pupil in high doses. 7.vagus Morphine stimulates vagal center causing bradycardia.

9. 8.Heat regulation Opioids shift the equlibirium point of heat regulating center so that body temperature falls slightly. 9.Truncal rigidity Higher dose of fentanyl found to enhance the tone of the large trunk muscles by acting at supraspinal levels. 10.Excitatory effect In high doses opioids produce convulsion

10. In t h era p eutic d o se mor p hi n e p r o d uces hypotension by; Direct peripheral vasodilatation. Inhibition of baroreceptor reflexes. In higher doses ,it causes depression of vasomotor center and histamine release both contributing to a fall in BP. Cardiovascular system

11. GIT Opioids decrease the motility of the gut. Stomach Gasric motility is decreased resulting in increased gastric empting time.gastric acid secretion is reduced. Intestine : Morphine diminises all secretions,delays digestion of food in the small intestine . Other Smooth Muscles Biliary tract – Morphine causes spasm of the sphincter of Oddi . Atrophine partially antagonise this . Urinary Bladder and Ureter – Opioids inhibit urinary voiding reflex, as a result of this urinary retention occurs especially in the elderly males with Prostatic hypertrophy. Bronchi –Morphine causes release of histamine from the mast cells leads to broncho constriction.

12. Adverse effects Nausea, Vomiting Respiratory Depression D y sph o ri a (S t a t e of be i n g U nha p p y) Dizziness Hypotension Skin Rashes Contraindications Respiratory insufficiency Head injury Undiagnosed acute abdomen Elderly males

13. Dosage 10-50mg 5 times daily No respiratory depression until pain relief is there Routes Oral Sc Intrathecal iv

14. TOLERANCE T oler a nce i s defined a s the ca p a city o f the b o d y to endure or become less responsive to a substance. Lethal dose of Morphine is 250 mg, addict can tolerate morphine in gm s .

15. DEPENDENCE Its ability to produce euphoria, makes it a drug of addiction. Op i o i ds p r o d uce bot h p s ych o l o gi c al and p h y s ical dependence.

16. OTHER OPIOIDS Heroin I t is c o n v er t ed t o mor p hin e i n the body . It has higher lipid solubility. I t g i v es euphoric ef f ects fas t er and greater. It is used as analgesics and banned in most countries.

17. OTHER OPIOIDS Codiene - It is Commonly used anti tussives. It is also available with Paracetamol f or anal g es i a. Dexomethorphan - It acts centrally to elevate the threshold f or c ou g hin g . I t i s e f f ect i v e a s c od e in e .

18. F entanyl It is about 100 times more potent than morphine. It is highly lipid soluble and fast acting. Epi d u r al f ent a n y l is us e d for pos t o p e r a t i v e a n d obstetric analgesia I t ca n a l so used in ch r onic pai n . Routes – transdermal patches ADVERSE EFFECT Cough muscle rigidity, Nausea & Vomiting Respiratory Depression

19. Tramadol Centrally acting atypical opiod it inhibits reuptake of NA and 5-HT, increases 5-HT release, and thus activates monoaminergic spinal inhibition of pain i . v. I 00 mg tramadol is equianalgesic to IO mg i.m. morphine.

20. Oral bioavailability of tramadol is good The t½ is 5-6 hours and effects last for 4-6 hrs . Tramadol causes insignificant respiratory depression , sedation, constipation or urinary retention . nausea and dizziness may be prominent . sleepiness , dry mouth, sweating lowering of seizure threshold, therefore contraindicated in epileptics risk of 'serotonin syndrome‘ in patients on ssri

21. Tramadol is indicated for mild-to-moderate short-lasting pain due to diagnostic procedures, injury , surgery, etc, as well as for chronic pain including cancer pain, but is not effective in severe pain. Little tendency to dose escalation by chronic users is seen and abuse potential is low. Dose: 50---100 mg oral/ i.m ./slow i.v . infusion (children I 2 mg/kg ) 4 6 hourly.

22. Roll in PMR Both nociceptive and neuropathic pain Chronic non malignant low back pain ( resistent to nsaids ) treating post herpetic neuralgia, phantom limb pain, diabetic neuropathy, and polyneuropathy of various etiologies American College of Rheumatology (ACR) recommends tramadol for OA patients who failed to achieve adequate benefit from nonnarcotic analgesic medications

23. Tapentadol Newer atypical opiod Similar mechanism to tramadol useful alternative to tramadol for acute as well as chronic pain of moderate severity . With less nausea Dose· 50 I 100 mg 2-4 times/day .

24. Specific roll of opiods in PMR Post op analgesia- transdermal patches 2 nd and 3 rd line drugs for neuropathic pain syndromes- phantom limb pain, diabetic neuropathy Procedural pain Non productive cough suppression ( which disturbs sleep) Diarrhoea treatment

25. NSAIDS Inflammation is the immediate response of our body in response of harmful stimulus. The treatment of patients with inflammation involves two primary goals Relief of symptoms and the maintenance of function: usually the major continuing complaints of the patient; Slowing or arrest of the tissue-damaging process. Reduction of inflammation with NSAIDs often results in relief of pain for significant periods

26. N S AID Aspirin, the original NSAID, has a number of adverse effects. Many other NSAIDs have been developed in attempts to improve upon aspirin’s efficacy and decrease its toxicity. Although there are many differences in the kinetics of NSAIDs, they have some general properties in common Most are well absorbed, and food does not substantially change their bioavailability. Most are highly metabolized, some by Phase I followed by phase II mechanisms others by direct glucuronidation (phase II) alone

27. Pharmacokinetics NSAID metabolism proceeds, in large part, by way of the CYP3A or CYP2C families of P450 enzymes in the liver. While renal excretion is the most important route for final elimination Nearly all undergo varying degrees of biliary excretion and re-absorption Most of the NSAIDs are highly protein-bound ( ∼ 98%), usually to albumin All NSAIDs can be found in synovial fluid after repeated dosing

28. Pharmacodynamics Mediated chiefly through inhibition of prostaglandin biosynthesis Various NSAIDs have additional possible mechanisms of action inhibition of chemotaxis, down-regulation of interleukin-1 production, decreased production of free radicals and superoxide interference with calcium-mediated intracellular events NSAID’s may be either non-selective COX inhibitor or preferentially/selective COX-2 inhibitor

29. Cyclooxygenase (COX)Pathway

30. Classification Non-selective COX inhibitors Salisylates Aspirin Propionic Acid derivatives: ibuprofen naproxen ketoprefen flurbiprofen Anthranilc acid derivative: mephanamic acid Aryl-acetic acid derivative : Diclofenac aceclofenac Oxicam: piroxicam tenoxicam Pyrolo-pyrolle derivative: ketorolac Indole derivative: indomethacin Pyrozolone derivative: phenylbutazone oxyphenbutazone Preferentical COX-2 inhibitors Nimesulide, meloxicam, nabumetone Selective COX-2 inhibitors: Celecoxib Etoricoxib parecoxib Analgesic-antipyretics Paraminophenol: Paracetamol Pyrozolone derivative: metamizol, propiphenazone

31. Prefferential/selective COX-2 inhibitors Do not affect platelet function at their usual doses. Efficacy of COX-2-selective drugs equals that of the older NSAIDs, while GI safety may be improved. Selective COX-2 inhibitors may increase the incidence of edema and hypertension . – Only celecoxib has FDA approval

32. Adverse Effect Central nervous system: Headaches, tinnitus, and dizziness. Cardiovascular: Fluid retention, hypertension, edema, and rarely, myocardial infarction, and congestive heart failure. Gastrointestinal: Abdominal pain, dysplasia, nausea, vomiting, and rarely, ulcers or bleeding. – all NSAID are gastric irritants and can be associated with GI ulcers to some extent Hematologic: Rare thrombocytopenia, neutropenia, or even aplastic anemia. Hepatic: Abnormal liver function tests and rare liver failure. Pulmonary: Asthma. Skin: Rashes, all types, pruritus. Renal: Renal insufficiency, renal failure, hyperkalemia, and proteinuria

33. Asp i rin Rarely used as an anti- inflammatory medication But it has proved to be beneficial for CVS patient in terms of its anti-platelet effects

34. Other uses of Salicylates Salicylates are used to treat: rheumatoid arthritis juvenile arthritis osteoarthritis other inflammatory disorders 5-Amino salicylates (mesalamine, sulfasalazine): Crohn's disease. Salicylic acid is used topically to treat: plantar warts fungal infections Corns

35. Adverse Effect Common side effects listed earlier Adverse effects at antithrombotic doses are gastric upset (intolerance) and gastric and duodenal ulcers Hepatotoxicity , asthma, rashes, GI bleeding, and renal toxicity rarely if ever occur at antithrombotic doses. Contraindicates its use by patients with hemophilia

36. Adverse effects The use of aspirin and other salicylates to control fever during viral infections in children and adolescents is totally contraindicated Is associated with an increased incidence of Reye's syndrome , characterized by vomiting, hepatic disturbances, Encephalopathy that has a 35% mortality rate.

37. PROPIONIC ACID DERIVATIVES - Ibuprofen Better tolerated alternative to aspirin All have similar pharmacodynamic properties But differ considerably in potency and to some extent in duration of action. The analgesic, antipyretic and anti-inflammatory efficacy is rated somewhat lower than high dose of aspirin All inhibit PG synthesis : Naproxen being the most potent Inhibition of platelet aggregation is short-lasting with ibuprofen , but longer lasting with naproxen.

38. Clinical Use: Ibuprofen Available as an 'over-the-counter’ drug as 200 mg, 400 mg, 600 mg Used as a simple analgesic and antipyretic Effective in dysmenorrhoea Ibuprofen and its congeners are widely used in rheumatoid arthritis, osteoarthritis and other mucoskeletal disorder indicated in soft tissue injuries, fracture , tooth extraction and to relieve post- partum pain

39. Clinical Use: Ibuprofen oral and intravenous routes are equally effective Topical cream preparation appears to be absorbed into fascia and muscle; – Relieve joint pain in osteoarthritis A liquid gel preparation 400 mg, provides prompt relief and good overall efficacy in postsurgical mucosal pain .

40. Adverse Effect Common adverse effects are already listed Contraindicated in individuals with nasal polyps, angioedema, and bronchospastic reactivity to aspirin Aseptic meningitis (particularly in patients with systemic lupus erythematosus), and fluid retention have been reported Concomitant administration of ibuprofen and aspirin – Antagonistic effect

41. Diclofenac Phenylacetic acid derivative that is relatively non- selective as a COX inhibitor. Its available as diclofenac sodium salt. Antiplatelet action is short lasting. T 1/2 : 2 hrs Good tissue penetrability

42. Diclofenac – Clinical Use Most extensively used NSAID Combination of diclofenac and omeprazole : effective with respect to the prevention of recurrent bleeding but renal adverse effects were common in high-risk patients. Dosage above 150 mg/d : impair renal blood flow and glomerular filtration rate Other combination includes ibuprofen+diclofenac : excellent pain management

43. Diclofenac – Clinical Use Can be used after intraocular lens implantation and strabismus surgery . Rectal suppository form can be considered for preemptive analgesia and postoperative nausea Also available as an oral mouthwash and for intramuscular administration osteoarthritis, bursitis, ankylosing spondylitis, toothache, dysmenorrhoea - quick relief of pain Td patches- 1/3% diclofenac epolamine - used for minor soft tissue injuries

44. KETOROLAC Novel NSAID with potent analgesic and moderate anti-inflammatory effect. In post operative pain it has equivalent efficacy of morphine – But it does not interact with opoid receptors and is free of opioid side effect

45. KETOROLAC Rapidly absorbed after oral and i.m. administration. T 1/2 5-7 hrs, highly plasma bound and 60% excreted unchanged. Metabolic pathway is glucuronidation conjugation Clinical use frequently used in postoperative pain management: dental and acute musculoskeletal pain When used with an opioid, it may decrease the opioid requirement by 25–50 %. inflammatory conditions.

46. KETOROLAC – Clinical Use renal colic and pain due to bony metastasis Orally it is used in a dose of 10-20mg Rated superior to aspirin, paracetamol (600 mg) and equivalent to ibuprofen (400 mg) Continuous use for more than 5 day is not recommended - renal toxicity

47. P a r ace t amol Acetaminophen: de-ethylated active metabolite of phenacetin Central analgesic action of paracetamol is like aspirin, i.e. it raises pain threshold It is a poor inhibitor of PG synthesis in peripheral tissues , but more active on COX in the brain. Its a good and promptly acting antipyretic, but negligible anti-inflammatory action

48. Pha r ma c ol o gy Analgesic action of aspirin and paracetamol is additive. Well tolerated orally, but only about 1/4th is protein bound It is uniformly distributed in the body Metabolism occurs mainly by conjugation of glucuronic acid and sulfate Plasma t 1/2 2-3 hrs, effects after an oral dose last for 3-5 hours

49. Routes Oral –tablet, syrup, suspension Dose 10-15 mg/kg 6 th hourly for pain.

50. Clinical Use One of the most commonly OTC drug for analgesic: headache, migraine, musculoskeletal pain , dysmenorrhea But is relatively ineffective when inlflamation is prominent. First choice analgesic for osteoarthriti s Drug of choice: as antipyretic, especially in children (no risk of Reye's syndrome )

51. Clinical Use Equally efficacious as aspirin for non- inflammatory conditions, without its side effect Insignificant gastric irritation, mucosal erosion and bleeding Occurs rarely in overdose. does not affect platelet function, clotting factors Used in combination with opiods Decrease dose requirement of both

52. Adverse Effect Safe and well tolerated Nausea and rashes occur occasionally and other side effects are similar to other NSAID Analgesic nephropathy: after years of heavy use Personality defect. Pathological lesions like necrosis, tubular atrophy followed by renal fibrosis Acute paracetamol poisoning : especially in small children who have low hepatic glucuronide conjugating ability. If a large dose > 150 mg/kg or > 10 g in an adult: serious toxicities Fatality is common > 250 mg/kg.

53. Celecoxib selective COX-2 inhibitor—about 10–20 times more selective for COX-2 than for COX-1 associated with fewer GI ulcers than most other NSAIDs Probably because it is a sulfonamide, celecoxib may cause rashes does not affect platelet aggregation at usual doses. It interacts occasionally with warfarin Adverse effects are the common toxicities listed above . Use – in patients with concomitant use of other anticoagulants, before spinal or intra articular injections

54. Who pain ladder

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