1. Pharmacological Approaches in Pain Management Ryan J. Bickel, Pharm.D., BCPS updated by David G. Curry, PhD, APRN for NUR344, Fall, 2009 Used with permission

2. Learning Objectives Review common non-opioid, opioid, and adjuvant analgesic medications Discuss and apply equianalgesic dosing concepts to selected case studies

3. WHO Pain Ladder http://erlewinedesign.com/end-of-life-care/gfx/who_ladder.gif

4. Non-Opioid Medications “Ceiling effect” to analgesia Do not produce tolerance or physical dependence Exhibit antipyretic properties Ref. 1

5. Acetaminophen (APAP) Mechanism of action unclear No anti-inflammatory effects Causes liver toxicity at high doses –Max dose: 4 gm/day, if no liver disease –Newest recommendation 2.6 gm/day Decreases opioid requirements Ref. 1,2

6. Salicylates Aspirin (ASA) Effective as APAP for acute pain at similar doses Worse side effect profile than APAP Salicylate Salts Safer than ASA No platelet effects Examples: –Diflunisal (Dolobid) –Magnesium salicylate (Doan’s) Ref. 1,3

7. NSAIDs Efficacy is similar amongst NSAIDs Differences in potency, time of onset, & duration of action Side effects: –GI bleeding –renal dysfunction –platelet dysfunction Ref. 1,3

8. NSAIDs Ibuprofen (Motrin) initial choice for acute pain due to cost & safety GI safety profile similar to placebo in doses of <1200 mg/day Maximum daily dose ~ 3200 mg/day Now available in IV form (Caldolor) Ketorolac (Toradol) first parenteral NSAID available in U.S. use limited to <5 days due to side effects Ref. 2,3

9. COX-2 Inhibitors Selectively inhibit cyclooxygenase-2 –less GI irritation; less platelet effects –other side effects similar to NSAIDs Celecoxib (Celebrex) –Role: patients with low cardiovascular risk who require NSAID therapy & are at increased risk for GI toxicity Ref. 4

10. Opioids Originally derived from poppies Body possesses endogenous opioids –enkephalins –endorphins Opiate Receptors –mu (  ) –delta (  ) –kappa (  ) –sigma (  ) Papaver somniferum Ref. 2,5

11. Pharmacology of Opioids  1: inhibit transmission of pain  2: respiratory depression, euphoria, constipation, physical dependence  : inhibit transmission of pain  : inhibit transmission of pain  : autonomic effects, dysphoria, hallucinations Ref. 5

12. Common Side Effects of Opioids Constipation very common, tolerance is unlikely stool softeners + stimulant +/- metoclopramide Nausea/Vomiting tolerance usually develops pretreat with prochlorperazine Ref. 6

13. Common Side Effects of Opioids Urticaria/Pruritis due to histamine release treat with antihistamine Sedation tolerance usually develops Delirium rare in patients with normal renal function Ref. 6

14. Side Effects of Opioids Respiratory Depression preceded by somnolence tolerance develops use caution in patients with underlying pulmonary dysfunction if RR <8 bpm, consider naloxone (Narcan) Ref. 6

15. Morphine Gold standard of opioid therapy Half-life: 1.5 -2 hrs Duration: 3 - 5 hrs Metabolized to a renally excreted active metabolite –dose adjustment may be needed in renal failure Ref. 7

16. Morphine Multiple dosage forms available –extended-release cap/tab Avinza: once daily dosing Kadian: daily or q12h dosing MSContin, Oramorph SR: q8-12h dosing –Immediate-release tab –oral suspension (Roxanol) –suppository (RMS) –parenteral injection (Duramorph, Infumorph) Ref. 7,8

17. Hydromorphone (Dilaudid) Alternative to morphine –safe in renal failure –more soluble than morphine Good choice when opioid volume is an issue –opioid tolerant patients –cachectic patients Forms: parenteral, tab, suppository Ref. 7,9

18. Oxymorphone (Opana) Highly selective for mu receptor More potent than morphine Forms: –immediate release tab do not take with meals –extended-release tab do not take with meals or alcohol –parenteral Ref. 8,9

19. Codeine Indicated for mild-moderate pain –weak opioid activity itself –usually combined with acetaminophen Metabolized to morphine by the liver (2D6) –poor metabolizers (lack 2D6) –ultra-rapid metabolizers (2D6 gene duplication) Side effects limit use –Primarily nausea/vomiting or constipation Ref. 2,10

20. Codeine Derivatives Used in moderate-severe pain Hydrocodone –combined with acetaminophen (Lorcet, Lortab, Norco, Vicodin, Zydone) –watch amount of acetaminophen (max: 4 gm/day) Oxycodone –extended-release tabs (OxyContin) –immediate release caps/tabs (OxyIR, Roxicodone) –oral solution (Oxyfast, Roxicodone) –combination products (Percocet, Percodan, Tylox) Ref. 1,2,8

21. Meperidine (Demerol) Not a first line agent! Variable oral bioavailability Short duration of action Relatively low potency Neurotoxic metabolites –Normeperidine has very long half-life! Multiple drug interactions Ref. 11,12

22. Meperidine Borgess Usage Guidelines –Do not use for over 48 hrs –Maximum dose: 600 mg/24 hr period –Avoid in patients with renal dysfunction or a history of seizures Oral use discouraged

23. Fentanyl Highly lipophilic Causes less histamine release than other opioids Unique dosage forms/delivery devices –buccal tablet (Fentora) –lozenge (Actiq) –transmucosal film (Onsolis) – restricted use in US at the present time –transdermal patch (Duragesic) Ref. 7-9

24. Fentanyl Transdermal Patch Advantages: –sustained-release opioid –good in patients with poor compliance –good choice if concerned about drug abuse Disadvantages –delay in onset –residual activity after patch removed – must remove old patch!! –expensive Note: Heat increases rate of release from patch Ref. 2,13

25. Methadone (Dolophine) Not a first-line opioid Non-opioid actions provide additional analgesia Half-life: 22 hrs Duration: 3-6 hrs (initial) ;8-12 hrs (chronic) Pros: cheap; good for refractory pain Cons: unpredictable; difficult to dose; drug interactions Ref. 12,14

26. Propoxyphene (Darvon) Not a first line agent! Neurotoxic metabolite Long half-life Propoxyphene-APAP (Darvocet) –not much more efficacious than APAP alone Ref. 2,3

27. Mixed Agonist-Antagonists Not a first line agent –causes withdrawal in patients on opioids –ceiling effect on analgesia –psychotomimetic adverse effects Lower abuse potential Examples: Butorphanol (Stadol) Pentazocine (Talwin, Talwin NX) Buprenorphine (Buprenex) Ref. 7

28. Tramadol (Ultram) Dual mechanism of action Used for moderate pain Less respiratory depression than opioids May enhance risk of seizures –max dose: 400 mg/24 hrs –decrease dose in elderly & renally impaired Ref. 5,8

29. Adjuvant Pain Medications “drugs that are used primarily for treating conditions other than pain, but may be analgesic in selected circumstances” -AMA Ref. 1

30. Common Adjuvant Medications Antidepressants Anticonvulsants Corticosteroids Topical Anesthetics Calcitonin Bisphosphonates Ref. 1

31. Pharmacokinetics of Routes Ref. 6

32. Equianalgesic Table OpioidIM/IV (mg) Oral (mg) Morphine1030 OxycodoneNot Available20 Oxymorphone110 Hydromorphone1.57.5 Fentanyl0.1Not Available Meperidine75300 HydrocodoneNot Available20 Codeine120200 Ref. 8,15

33. Equianalgesic Dosing Methodology Total the 24-hour dose of current opioid usage including prn doses Convert for drug & route using table Reduce calculated dosage 30-50% Calculate breakthrough pain dose, if converting long-acting opioids –5 – 15% of total daily opioid dose Ref. 15,16

34. Equianalgesic Case 1 MJ is a 56 YOM with prostate cancer admitted to hospital for pain control. He was started on a morphine PCA. In the last 24 hours the patient has received 34 mg and his pain has been adequately control. The physician discontinued the PCA and started the patient on MSContin 30 mg PO BID. Is this an equivalent regimen?

35. Equianalgesic Case 1 Table IV dose Pt 24 hr IV dose Table PO dose X amount of PO =

36. Equianalgesic Case 1 OpioidIM/IV (mg) Oral (mg) Morphine1030 OxycodoneNot Available20 Oxymorphone110 Hydromorphone1.57.5 Fentanyl0.1Not Available Meperidine75300 HydrocodoneNot Available20 Codeine120200 Ref. 8,15

37. Equianalgesic Case 1 Set up proportion Cross multiply 10 mg IV 34 mg IV = 30 mg PO X 10 mg IV 34 mg IV = 30 mg PO X

38. Equianalgesic Case 1 10X = 1020 Divide each side by the number in front of X: 10X 1020 10 10 Select Reasonable Regimen MS Contin 45 mg PO BID X = 102=

39. Equianalgesic Case 1 Calculate the oral morphine dose needed for breakthrough pain Answer: Morphine 5 – 15 mg PO every 4 hours prn pain

40. Equinalagesic Case 2 PJ is a 47 YO female who is receiving morphine 2-6 mg IV q2h prn post-op. In the last 24 hours, the patient has received 24 mg IV morphine. Surgery just dc’d the morphine & ordered Lortab 5/500 mg 1-2 tabs PO q6h PRN pain. What do you think of this regimen?

41. Equinalagesic Case 2 Convert to oral morphine: 10 mg IV 24 mg IV = 30 mg PO X 10X = 720 X = 72 mg PO morphine

42. Equinalagesic Case 2 Convert to hydrocodone: 30 mg MS 72 mg MS = 20 mg HC X 30X = 1440 X = 48 mg hydrocodone

43. Equinalagesic Case 2 Dose Reduction –Suggested daily hydrocodone dose for BR 24 – 36 mg/day Assessment –BR’s current hydrocodone dose if given q6h scheduled = 20 – 40 mg

44. Questions

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