We are all ignorant- just on different subjects.

1. We are all ignorant- just on different subjects. - Will Rogers

2. Managing Chronic Pain Hospice of St. Tammany Palliative Care Institute of Southeast Louisiana Covington, LA

3. Introduction • 50 million people suffer from chronic pain • Treatment with opioids is safe and effective • New understanding of CNS changes in chronic pain provides rationale for treatment • Relief from suffering is our goal

4. How to Manage Pain Effectively and Efficiently • Assessing Pain • Difference between Acute and Chronic • Treatment of Pain • Specific Opioids • Adjuvants for Pain • Side-effects • Importance of Teamwork

5. Assessing Pain • Detailed description of pain • What makes it better or worse • Effect on emotional, social status • Do a physical assessment • Review diagnostic and lab data • Reassess often to adjust treatment

6. Acute Pain • Pathway for acute pain perception is conventional • Duration is short • Endorphins and enkephalins are released by CNS to block pain perception • Opioids are effective for acute pain

7. Chronic Pain • Prolonged pain impulses cause “burn-out” of the AMPA receptors involved in pain transmission in the spinal cord • Endorphins become less effective • NMDA receptors, normally quiescient, are ACTIVATED, causing changes in pain transmission and behavior

8. NMDA Effects in Chronic Pain • Windup • Neural remodeling • Activation of NK-1 receptors • Afferent becomes efferent • Neurogenic inflammation

9. Treating Pain with Opioids • Nociceptive(Somatic and Visceral) and Neuropathic Pain • WHO 3-step analgesic ladder • Step 1: Mild analgesics: APAP, Propoxyphene, NSAIDS • Step 2: Moderate analgesics: Codeine, Hydrocodone/APAP, Oxycodone/APAP, Tramadol • Step 3: Strong Opioids

10. Prescribing Opioids for Chronic Pain- General Principles • Use WHO pain ladder to select analgesic • Around-the-clock, q. 3-4 hr. • Assess frequently, adjust dose • Add up total opioid taken q. 24hr. • Select long-acting opioid q. 12 hr. • Use short-acting opioid for breakthrough pain prn. • Use one short- and one long-acting • Reassess to titrate dose

11. Equianalgesic Doses if Morphine = 10 mg p.o. • Dilaudid(hydromorphone= 2mg • Oxycodone = 5-10 mg • Hydrocodone =15 mg • Codeine = 60mg • Ultram(tramadol) =50 mg • Demerol(merperidine) =50 mg • Fentanyl(duragesic)=see slide 16 • Levorphanol = 1-2 mg

12. Number of Analgesic Prescriptions: United States est. 2002(millions) Step 3 WHO Stepladder Total 13.03 Morphine 3.67 Fentanyl 4.35 Meperedine 1.78 Hydromorphone .77 Methadone 1.66 All others .08 Step 2 Total 173.32 Propoxyphene 28.94 Hydrocodone 91.83 Oxycodone 28.95 Codeine* 22.61 Dihydrocodeine 0.32 Pentazocine 0.67 Step 1 Total 135.30 COX-2 52.94 Other NSAIDs 65.98 Tramadol 16.38 *Includes Fiorinal with codeine combinations Source: IMS Health’s National Prescription Audit (NPA) Retail Phcy., LTC & M.O.

13. Step 3 Strong Opioids • Morphine • Oxycodone • Dilaudid (Hydromorphone) • Fentanyl • Methadone • Levorphanol

14. Morphine • Usual 1st. choice for moderate, severe pain. Begin low, 15mg q 3-4 hr. Titrate ,reassess often. • No ceiling • Resp. depression rare in chronic pain patients. • High doses: metabolites = nausea,dysphoria, muscle jerks

15. Dilaudid- hydromorphone • Beginning dose 2-4 mg q 3-4 hr. Very effective, similar to MS. • Less nausea. No ceiling. Often used orally for breakthrough pain and i.v. • No sustained-release form. • 2 mg = 10 mg MS

16. Oxycodone • Starting oral dose 5-10 mg q 3-4 hr. Very effective • Less nausea, less troublesome metabolites.Combined with ASA and APAP (Percocet,etc.), limits ceiling. • Expensive sustained-release form (Oxycontin), no ceiling. Watch for illegal diversion. Oxycontin 10,20,40,80mg. • Liquid concentrate 20mg/ml useful buccally in the dying, as is MS(Roxanol).

17. Duragesic (Fentanyl) • Duragesic patch: use care in opioid- naïve patient-use 25 mcg/hr first, after pain controlled by short-acting opioid. • To calculate dose, convert any and all opioids to their morphine-equivalent/24 hr first. • 12 hr delay in onset and offset due to skin reservoir absorption.

18. Duragesic (cont’d) • Fever increases absorption rate. Avoid skin with scant subcut. fat. • 25mcg patch= 50 mg MS /24 hrs • 50 ‘ ‘ = 100 mg “ • 75 “ “ = 150 mg “ • 100 “ “ = 200mg “ • (approx.)

19. Methadone and Levorphanol • Under-used, not marketed • NMDA receptor-blocking activity makes these, especially methadone, the best choice for neuropathic and complex chronic pain • Levorphanol is 4-8x stronger than MS: longer ½ life (q 6 hrs)

20. Advantages of Methadone • Long duration of action • Short initial distribution half-life • No active metabolites • No ceiling dose • NMDA receptor-blocker action in spinal cord (important in neuropathic and chronic pain) • Cost: approx. $20-25/month( vs. $200-500/mo. for hydromorphone,sust.act. morphine,oxycodone,fentanyl patch.

21. Advantages (cont’d) Potency at least equal to morphine • Oral, rectal absorption excellent • Low incidence of side-effects • Less constipating • Lower incidence of tolerance • Available for iv infusion use • Most important,methadone is both a mu opioid agonist and an NMDA receptor antagonist as it relates to pain relief

22. Disadvantages • Stigma and association with substance-abuse • Accumulation due to long and variable elimination half-life in some persons • Said to be hard to convert to and from other opioids • Fear of regulators • Lack of education and experience

23. Cost Comparison of Opioids ( 30 day supply) • Duragesic Patch 25mcg/hr $ 140 • Duragesic Patch 100 mcg/hr $ 430 • Oxycontin 40 mg q 12 hr $ 250 • MS contin 60 mg q 12 hr $ 210 • Dilaudid 4 mg q 4 hr ATC $ 118 • Percocet 5 mg q 4 hr ATC $ 210 • Levorphanol 2 mg q 6 hr $ 120 • Methadone 10 mg q 8 hr $ 20

24. 108 outpatients with cancer pain on opioids 103 successfully switched to methadone – oral q 8 hrs with significant reduction of pain • Bruera E et al, Proceeding of the 9th World Congress on Pain, 2000, p. 957

25. 52 prospective, consecutive patients with either uncontrolled cancer pain on opioids or intolerable side effects switched to methadone. All had significant reduction of pain and significantly less nausea, vomiting, constipation and drowsiness.• Mercandante S et al, Journal of Clinical Oncology. 2001; 19:2898- 2904

26. Personal experience: Prescribing Methadone 2001-2003 • Palliative Care Consults(total) 140: • Methadone for Chronic pain: 88 • Excellent relief( pain reduced from 7-10 to 0-3) : 50 • Fair relief (pain reduced to 4-6): 18 • No benefit or side-effects: 20 ( Nausea 6, Sedation 12, Depression 2)

27. Adjuvants for Pain • For Neuropathic pain: Tricyclic antidepressants Anticonvulsants • For bone and soft-tissue pain: NSAIDs,corticosteroids,palliative radiation,biphosphonates, tricyclics For visceral pain: corticosteroids,H-2 blockers,metoclopropamide

28. The doctor is themost powerful adjuvant.

30. DOCTOR AND PATIENT WORK TOGETHER TO ACHIEVE INCREMENTAL IMPROVEMENT • Good sleep • Pain free at rest • Pain free during activities

31. Nociceptive pain • Tissue damage • Neuropathic pain • Nerve damage

32. 65% nociceptive 5% neuropathic 30% mixed CANCER PATIENTS

33. TCA • Tertiary amine • Amytriptaline (Elavil) • Impramine (Tofranil) • Secondary amine • Nortriptyline (Pamelor) • Desipramine (Norprimine) • Secondary amines have equal 5HT, NE potency • Secondary amines have half the side effects

34. One adjuvant at a time, targeted to the specific symptom Tricyclic antidepressants (amitriptyline, nortriptyline, desipramine, venlafaxine) for pain described as “constant burning pain” Anticonvulsants (Gabapentin, valproate, carbamazepine, clonazepam) for pain described as “shooting, stabbing, electric shock pain” ADJUVANTS

35. WHY AED? • Inhibit excessive neuronal activity • Na channel blockade • Inhibit excitatory systen • glutamate • Activate inhibitory • GABA

36. GABAPENTIN:CANCER PAIN • N = 22 cancer patients with refractory pain • Gabapentin was added to opioid treatment • 800 mg to 1800 mg/day • Results • Pain decreased from 6.4 to 2.1 (0 - 10 scale) • Burning pain decreased from 5.1 to 2.0 • Shooting pain decreased from 7.2 to 2.2 • Allodynia disappeared in 7 0f 9 • Caraceni et al j Pain Sympt Manag 1999; 17:441-445

37. DIABETIC PERIPHERAL NEUROPATHY PAIN GABAPENTIN VS. AMITRIPTYLINE • N = 28, double-blind, cross-over • Gabapentin 900-1800 mg/day • Amitriptyline 25-75 mg/day • Results: No difference in pain relief or global pain score data • Moderate or greater pain relief in 52% of GBP vs. 67% (AMT) • Arch Intern Med 1999;159:1931-1937

38. TCA – 10 - 100 mg AED – full dose, except Valproic acid(usually 250 mg once daily hs.)

39. Side-effects of Treatment • Opioid adverse effects: nausea,constipation,somnolence, dysphoria, muscle jerks, itching, respiratory depression • Neuropathic adjuvant side-effects: dizziness ,sleepiness, low BP, liver toxicity(uncommon) • NSAID side-effects: nausea, GI ulcer or bleeding, edema,decreased renal function

40. Importance of Teamwork • Complex chronic pain, especially if caused by life-threatening disease, is best treated by a team. • The diverse talents of physician, nurse, social worker, chaplain, working together offers comprehensive control of physical, emotional, and spiritual pain. • Palliative care is for ALL patients who are suffering.