Clinical Pharmacology of Analgesic Medications & Non-Pharmacological Treatments

2. of Analgesic Medications & Non-Phramacologcial Treatments Clinical Pharmacology type in your name type inthe name ofyour institution

3. Contents of this Lecture (1) Clinical Pharmacology of: • Paracetamol (Acetaminophen) • Non-steroidal anti-inflammatory drugs (NSAIDS) / COX-2 specific inhibitors • Opioids • Ketamine • Drugs used for neuropathic pain • Local Anaesthetic agents • Others - Steroids (2) Non-drug treatments

4. Clinical Pharmacology includes • Mechanism of Action • Absorption / Elimination of the drug • Indication for use / dosage • Adverse / side effects • Any special precautions that should be taken

5. Paracetamol • Paracetamol has been in use for more than a century • It has both analgesic and antipyretic action • However, the exact mechanism of its action is unclear Absorption / Elimination from the body • It is well tolerated when taken orally. • On oral administration it is absorbed from the intestine (70%), stomach and colon (30%) • The rate of absorption is rapid and depends on the dose

6. Absorption / Elimination • The time taken to reach maximum plasma concentration (Tmax) is 15 - 30 minutes depends on the preparation • It is available as tablets (adults), suspension or syrup for children and suppositories • Tmax is 2 - 3 hours with suppositories • Bioavailability ranges from 60-90% Elimination • Paracetamol is metabolized in the liver and only 2 - 5% is excreted unchanged

7. Indications and dosages • It is used as an analgesic drug for mild to moderate pain • E.g. Tooth ache / teething pain in children, backpain, joint and muscle pain, headache, dysmenorrhoea • Relief of fever in adults and children Dosage • Adults – Up to 1g oral / rectal, every 6 hours ( 4g should not be exceeded / day • Children – Oral / rectal 20 mg / kg – every 6 hours

8. Side effects • Paracetamol is well tolerated and has no side effects at therapeutic doses • It has good haematological tolerability and does not alter haemostasis

9. Caution • Since it is metabolized in the liver it must be used with caution / or omitted in the presence of liver impairment • In patients with renal impairment, the dose of paracetamol should be reduced • Do not exceed 4g/day in adults and 125 mg/ kg in children

10. Adverse effects Hepatotoxicity with an overdose of paracetamol • This can occur when a patient does not get adequate relief with paracetamol and decides to take more than the prescribed dose of a maximum of 4g/day (8 - 10 g / day) • Intentional overdose (Paracetamol overdose / poisoning is the leading cause of acute liver failure in the US, UK and Australia) • Overdose causes acute liver failure, as the elimination pathways are saturated resulting in elevated levels of toxic metabolites

11. Adverse Effects • N-acetylcysteine (NAC) is the antidote for paracetamol poisoning and it is most effective when administered within 8 - 10 hours after ingestion • Renal toxicity – Overdose can cause severe kidney necrosis • Allergic reactions are rare

12. NSAIDs Non Steroidal Anti-inflammatory Drugs

13. History of Aspirin • Salicylate from the bark of the willow tree and was used to treat fever and rheumatism for centuries • In the late 19th century, salicylic acid and later acetylsalicylic acid was synthesized and called aspirin. • Aspirin was widely used to treat fever and pain till the availability of other drugs with similar mechanisms of action. It continues to be used in many parts of the world

14. Non-Steroidal Anti-inflammatory Drugs (NSAIDs) • They are diverse group of compounds which were later synthesized, with actions similar to that of aspirin and became known as NSAIDs • The mechanism of action of aspirin / NSAIDs was discovered in the 1960’s by Prof Vane, who was awarded a Nobel prize in Medicine in 1982

15. Non-steroidal Anti-inflammatory Drugs -NSAIDs • NSAIDs are widely used to treat pain and inflammation • They act through inhibition of the two isoforms of the enzyme cyclooxygenase (COX) – i.e. COX-1 and COX-2 • NSAIDs that act on both the enzymes are known as non-selective NSAIDs (ns-NSAIDs) • NSAIDs which act predominantly on the COX-2 enzyme are known as specific COX-2 inhibitors (also referred to as Coxibs)

16. The Two Isoforms of COX • COX-1 is a normal constituent in the body for homeostasis, such as in: • Gastric mucosa – gastric cytoprotection • Kidney – Sodium and water balance / renal perfusion • Platelets – for aggregation • COX-2 is induced in the presence of injury and inflammation • COX-2 is also a normal constituent in the many organs such as: Kidney, brain, endothelium, ovary and uterus

17. What happens when there is tissue injury? Cell wall injury Releases Membrane phospholipids Phospholipase A2 Arachidonic Acid COX-1 & COX-2 that is induced with injury and inflammation, cancer PGH2 (Prostaglandin H2) PGD2 PGI2 PGE2 PGF2 TXA2 Prostaglandins- PGE2 as the most significant Thromboxane

18. Arachidonic Acid Cascade Phospholipid from cell membrane Arachidonic Acid Cyclo-oxygenase Lipoxygenase PGH2 5-HPETE Thromboxane Prostaglandins Leukotrienes These inflammatory mediators activate the nociceptors on the Aδ and c fibres and result in pain and sensitization

19. Arachidonic Acid Cascade Phospholipid from cell membrane Arachidonic Acid NSAIDs / COX-2 inhibitors Cyclo-oxygenase Lipoxygenase PGH2 5-HPETE Thromboxane Prostaglandins Leukotrienes Reduce Prostaglandins and Thromboxane, resulting in reduced pain

20. COX-2 specific inhibitors (= Coxibs) ns-NSAIDs Acetylsalicylic acid (aspirin) • Tablet, suppository Ibuprofen • Tablet, suspension for children Indomethacin • Tablet Diclofenac • Oral tablet, suppositories, parenteral form available Mefenamic acid • Oral tablets Celecoxib • Oral capsules Etoricoxib • Oral tablets Parecoxib • parenteral

21. Anti-Pyretics / NSAIDs on the WHO essential drug list : • Acetylsalicylic acid (Aspirin) • Tablet 100 mg to 500 mg • Suppository 50 mg to 150 mg • Ibuprofen > 3 months in age • Tablet 200 mg; 400 mg • Oral liquid: 200 mg / 5 ml • Paracetamol • Tablet 100 mg to 500 mg • Suppository: 100mg, 250 mg • Oral Liquid: 125 mg / 5 ml

22. Absorption and Elimination • When administered orally, aspirin, ns-NSAIDs and Coxibs are well absorbed and reach therapeutic levels within 30 to 60 minutes.

23. Indications • Both the ns-NSAIDs and Coxibs have the same efficacy in postoperative analgesia • Sole analgesia for day surgery • Along with opioids for major surgery • Musculo-skeletal pain – e.g. back pain, joints, muscle sprains etc. • Osteoarthritis • Rheumatoid arthritis • Not indicated for neuropathic pain

24. Side effects / Adverse effects Gastrointestinal effects • The risk of erosions, ulcers and bleeding is higher with ns-NSAIDs compared to Coxibs. • This risk with ns-NSAIDs is also variable with some being less than others. • Risk is greater • In elderly patients • Those who are also taking aspirin • Risk can be reduced by adding a proton-pump inhibitor (e.g. omeprazole) to ns-NSAIDs. • H2 receptor blockers are not very effective.

25. Renal effects • Both COX-1 & 2 are constituent enzymes in the kidney • Maintain renal perfusion and sodium/water balance • Both ns-NSAIDs and Coxibs can cause • Hypertension, odema • Decrease in creatinine clearance that may be significant in patients with impaired renal function or transient hypotension / hypovolaemia in the postoperative period

26. Cardiovascular effects • Some studies have shown that there was a higher risk of thrombotic cardiovascular events (stroke, heart attack) when on Coxibs when compared to ns-NSAIDs such as naproxen • Other studies have shown that the cardiovascular events are similar • Nevertheless, current recommendations are that Coxibs should not be used in patients with active cardiovascular disease and a known thrombotic condition

27. Effect on platelets • ns-NSAIDs are able to prevent platelet aggregation as platelets do not have COX-2. There is therefore a potential for bleeding with ns-NSAIDs • Coxibs do not prevent platelet aggregation • ns-NSAIDs should be used with caution in patients who are already on aspirin

28. Others • Some ns-NSAIDs can precipitate asthma is aspirin sensitive asthmatic patients. • Coxibs are well tolerated by patients who have aspirin sensitive asthma

29. Summary (cont.) NS-NSAIDs / Coxibs • Both drugs are effective in providing pain relief for moderate pain • The mechanism of action of both groups of drugs is by inhibiting the COX-2 enzyme that is induced with injury, inflammation and cancer • Gastrointestinal side effects are less with coxibs

30. Summary NS-NSAIDs / Coxibs • Coxibs have no effect on platelet aggregation • Both drugs should be used with caution in patients with renal impairment and in the elderly • Coxibs should not be used in patients with active cardiovascular disease or known thrombotic effects • Coxibs can be given to patients with aspirin sensitive asthma • Both drugs should be used for the shortest period of time at the lowest dosage

31. Opioids

32. Opioids • Opium alkaloids derived from the opium poppy has been used for pain relief for centuries • Morphine was isolated by Sertuner in 1813 • The glass syringe was introduced in 1844 • Since then morphine has been the mainstay in the management of severe pain • The term “opioid” is referred to any drug, either natural, semi-synthetic or fully synthetic, which has actions similar to morphine

33. Available Opioids • Natural • Morphine • Codeine • Semi-Synthetic • Hydromorphone • Oxycodone • Diacetylmorphine(heroin) • Naloxone (antagonist) • Fully Synthetic • Pethidine (meperidine) • Tramadol • Nalbuphine • Methadone • Pentazocine • Fentanyl • Alfentanil • Sufentanil • Remifentanil • Opioids on the WHO essential drug list • Morphine • Codeine • Tramadol

34. Opioids can be classified as: • Strong opioids used for severe pain • Morphine, Oxycodone, Pethidine, Fentanyl • Weak Opioids used for moderate pain • Codeine, Tramadol

35. The analgesic ladder for acute pain management Strong opioids Weak opioids

36. Mechanism of Action • Opioids act by binding to opioid receptors (complex proteins embedded within the cell membrane of neurons) There are three different opioid receptors - µ, δ, κ µ - most relevant as all clinically used opioids exert their action via the µ -opioid receptor Opioid receptors are found in the brain and in the dorsal horn of the spinal cord

37. Mechanism of Action • Opioids bind to opioid receptors • Activate intracellular signaling events • Leading to reduction in excitability of neurons and inhibition of pain signals • Resulting in reduction of pain perception

38. Opioids can be administered via several routes Opioids produce potent analgesia when administered: • Systemically – oral, Intravenous, intramuscular, subcutaneous, transcutaneous, per rectal • Spinally – epidural, intrathecal, intraventricular Time to peak action and duration of action depends on the route and dose of the drug

39. Morphine • Is the most widely used opioid for the control of severe pain • It can be given by all the routes that was described in the previous slide. • It is well absorbed when given orally and has a bio-availability of around 30-35%. • Bio-availability means the amount of drug that is available in the systemic circulation after an oral dose is given.

40. Oral morphine Immediate release morphine • Aqueous / liquid morphine (usually prepared as 1-2 mg / ml) • Tablet morphine (10 mg) • Need to be given every four hours for continuous relief of severe pain Sustained Release (SR) Morphine Tablets • Morphine is released slowly over 12 hours • 10 mg, 30 mg, 60 mg • These tablets are given twice a day

41. Parenteral morphine (10 mg / I ml ampoule) Intramuscular / subcutaneous morphine • Onset of Analgesia 15 - 20 min • Peak action 45 - 90 min • Duration of action 4 hours Intravenous route is chosen when rapid control of severe pain is desired.

42. Metabolism The principle pathway of metabolism is conjugation with glucuronic acid in hepatic and extra-hepatic (kidney) sites • Morphine -3 and morphine -6 glucuronides that are excreted mainly by the kidneys • Morphine should be used with caution in patients with hepatic and renal impairment

43. Codeine phosphate – Weak opioid • Oral tablet 15mg; 30 mg • Is well absorbed and there is no first pass metabolism in the liver • Codeine is metabolized to morphine; which accounts for its analgesic effect • 60 mg of codeine has an equi-analgesic effect of 650 mg aspirin • Has an anti-tussive effect and is often used in cough mixtures • Is available in combination with paracetamol • Cause minimal sedation, nausea, vomiting and constipation

44. Tramadol – Weak opioid • This is also known as an “atypical opioid” • It has a dual mechanism of action: • weak opioid receptor binding properties • Inhibits the reuptake of serotonin and noradrenaline at the descending inhibitory pathway • It is available • Oral capsule (50 mg) • Injection – 50 mg / ml – in 2 ml ampoules • Due to its weak opioid activity it is not placed in the same schedule as the strong opioids such as morphine

45. Tramadol • It is well absorbed when given orally • Time to effect is around 30 minutes and can last 5 - 6 hours • Sedation is minimal • Can cause nausea, vomiting, dizziness • Abuse potential is minimal • Is used as a weak opioid, however as it has a dual mechanism of action – its analgesic efficacy is superior to codeine – Maximum daily dose is 400 mg

46. Metabolism • Tramadol is metabolized by the liver and excreted by the kidneys • Tramadol has an active metabolite (O-desmethyltramadol) – that is also excreted by the kidney • The daily dose should be reduced in the presence of chronic renal failure

47. Opioid related side effects • Gastrointestinal • Nausea and vomiting • Constipation • Sedation • Respiratory depression in overdose • Pruritus • Cough suppression (anti-tussive)

48. Opioid related side effects • On initiation of opioid therapy, patients frequently report acute side effects of sedation, dizziness, nausea and vomiting • After a few days these symptoms subside except for constipation • This is noted in patients with cancer pain

49. Opioids and Tolerance Patients can develop tolerance when opioids are used for an extended period • E.g. cancer pain; intensive care units Tolerance is defined as reduction of the pharmacological effect of an opioid: • When the same dose produces a lesser effect • Increasing doses of drug is required to produce the same effect • The mechanisms of the development of tolerance are complex

50. Physical Dependence and Addiction Physical dependence is a state of adaptation by the body with extended use of an opioid • It is manifested by withdrawal symptoms with abrupt cessation of the opioid, rapid dose reduction or administration of an opioid antagonist Addiction to opioids is drug seeking behaviourwhere the person is looking for opioids for its euphoric action rather than pain relief alone