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Opioid Risk:Benefit Issues

Opioid Risk:Benefit Issues. U.S. Food and Drug Administration Anesthetic and Life Support Drugs Advisory Committee Bethesda MD September 9. 2003 Arthur G. Lipman, PharmD Professor of Pharmacotherapy, College of Pharmacy Director of Clinical Pharmacology, Pain Management Center

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Opioid Risk:Benefit Issues

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  1. Opioid Risk:Benefit Issues U.S. Food and Drug Administration Anesthetic and Life Support Drugs Advisory Committee Bethesda MD September 9. 2003 Arthur G. Lipman, PharmD Professor of Pharmacotherapy, College of Pharmacy Director of Clinical Pharmacology, Pain Management Center Pain Medicine & Palliative Care Advisory Group, Huntsman Cancer Institute Investigator, Pharmacotherapy Outcomes Research and Pain Research Centers University of Utah Health Sciences Center Editor, Journal of Pharmaceutical Care in Pain & Symptom Control Salt Lake City, Utah

  2. We are appalled by the needless pain • that plagues the people of the world - • in rich and poor nations alike. By any reasonable code, freedom from pain should be a basic human right limited only by our ability to achieve it. • Liebeskind J, Melzack R. Pain 1987;30:1

  3. U.S. News & World Report March 17, 1997 Old Thinking New Science

  4. AHCPR Clinical Practice Guideline Full Guideline Available in searchable format on the WWW at www.ahrq.gov 1992

  5. AHCPR Clinical Practice Guideline Full Guideline Available in searchable format on the WWW at www.ahrq.gov 1994

  6. American Pain Society Clinical Practice Guideline Released March 15, 2002 Available through the American Pain Society Website www.ampainsoc.org

  7. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer PainFifth Edition, 2003 Available from American Pain Society 4700 West Lake Avenue Glenview IL 60025-1485 Phone: 847 375-4715 Fax: 847 375-6315 E-mail: info@ampainsoc.org Web Site:www.ampainsoc.org

  8. Physiological Effects of Pain • increased catabolic demands poor wound healing, weakness, muscle breakdown • increased risk of thromboembolic event • respiratory effects shallow breathing, tachypnea (acutely), cough suppression increasing risk of atelectasis and pneumonia • increased sodium and water retention (renal) • decreased gastrointestinal motility • tachycardia and elevated blood pressure sympathetic autonomic activation AHCPR Acute & Cancer Pain Guidelines: www.ahrq.gov

  9. Psychological Effects of Pain • negative emotions anxiety depression • sleep deprivation • existential suffering may cause patients to seek end of life AHCPR Acute & Cancer Pain Guidelines: www.ahrq.gov

  10. Immunological Effects of Pain • impaired immune response decreased natural killer (NK) cell count AHCPR Acute & Cancer Pain Guidelines: www.ahrq.gov. Fakata KL, Lipman AG, Mullin S. APS Annual Meeting Abstracts, 2002.

  11. Correlation of of Pain Intensity and ImpactActivities Impaired by Increasing Pain on a Pain intensity Scale of 1-10 Relate Walk Walk Sleep Sleep Sleep Active Active Active Active Mood Mood Mood MoodWork Work Work Work Work Enjoy Enjoy Enjoy Enjoy Enjoy Enjoy 3 4 5 6 7 8 >>>>> >>>>> >>> Worst Pain Rating >>> >>>>> >>>>> Cleeland CS, Ryan KM. Ann Acad Med Singapore. 1994;23:129-138.

  12. Therapeutic Interventions Must Have Favorable Risk:Benefit Ratios • The risk of pain is >> than is generally appreciated • More aggressive analgesia often is needed • There is inherent risk in all pharmacotherapy • Every drug is a poison • Opioid risks must be contrasted to: • Risks of alternative pharmacotherapy • Risks of nonpharmacological therapy

  13. Treatment Alternatives for Moderate –Severe Pain • Oral NSAIDs • Oral Opioids • Invasive procedures • CNS stimulators • Spinal alnalgesia

  14. NSAIDs • Over 125,000,000 NSAID prescriptions written in U.S. annually in 1998 • Gastroduodenal and platelet effects problematic • Toxicities limit usefulness • Effects decrease adherence (compliance)

  15. FDA NSAID Class Warning “Risk of GI ulceration, bleeding, and perforation with NSAID: Serious GI toxicity such as bleeding, ulceration, and perforation can occur at any time, with or without warning symptoms, in patients treated chronically with NSAID…symptomatic upper GI ulcers, gross bleeding, or perforation appear to occur in approximately 1% of patients treated for 3–6 months and in about 2%–4% of patients treated for 1 year…”

  16. NSAID Gastrointestinal ToxicityUlcers and Complications of Ulcers • 107,000 hospitalizations and 16,500 deaths in U.S. reported in 1998 • Endoscopically documented lesions • Over three-quarters of patients were asymptomatic prior to N+SAID-induced bleeds • COX-1 vs. COX-2 Singh G Recent considerations in nonsteroidal anti-inflammatory drug gastropathy.Am J Med. 1998 Jul 27;105(1B):31S-38S. 1998

  17. Invasive Procedures • Generally not supported by evidence • Very expensive • highly profitable • seldom questioned by insurers • Often must be repeated • Adverse sequelae

  18. Opioid Concerns • physical dependence • psychological dependence - addiction • tolerance • cognitive impairment • respiratory depression • psychomotor impairment • legal sanction risks • therapeutic efficacy

  19. Opioid Addiction Addiction in the context of pain treatment with opioids is characterized by a consistent pattern of dysfunctional opioid use that may involve: adverse consequences associated with the use of opioids • loss of control over the use of opioids • preoccupation with obtaining opioids despite the presence of adequate analgesia American Society of Addiction Medicine Public Policy Statement, April, 1997

  20. American Society of Addiction Medicine Public Policy Statement “...Individuals who have severe, unrelieved pain may become intensely focused on finding relief for their pain. Sometimes, such patients may appear to observers to be preoccupied with obtaining opioids, but the preoccupation is with finding relief of pain, rather than using opioids, per se. This phenomenon has been termed ‘pseudoaddiction’…” April, 1997

  21. Distinct Types of Opioid Tolerance • Tolerance to Analgesia may occur in first days to weeks of therapy; rare after pain relief achieved with consistent dosing without increasing or new pathology. • Tolerance to Respiratory Depression, Confusion, Sedation, and Nausea predictable after 5-7 days of consistent opioid administration • Tolerance to Constipation does not occur; scheduled stimulating laxatives are indicated with regularly scheduled opioids Lipman AG, Jackson KC. Opioids. In C. Warfield and Z Bajwa, Eds, Principles and Practice of Pain Management, 2nd edition, NY, McGraw Hill, 2003

  22. Diamorphine Use: 62 YO Man with Lung Cancer Twycross, RG. Int J Clin Pharmacol 9:184-98

  23. Myth: Opioids Always Depress Respiration • Acutely, opioids can be profound respiratory depressants opioid-naïve patients • After 5-7 days of continuous opioids, patients predictably become tolerant to respiratory effects opioid-tolerant patients • pain is a powerful analeptic in awake patients

  24. Myth: Patients in Pain Don’t Skip Analgesic Doses • Once pain is controlled for a few days, patients often skip doses, especially with short acting opioids that must be taken several times a day • fear of adverse drug effects • family and friends who fear drug effects • Long term compliance is aided by less frequent dosing

  25. Physiological Responses to Repetitive Nociceptive Input • Windup highly augmented response to repetitive afferent (C-fiber) input • Neuronal plasticity changes in the CNS in response to repetitive afferent nociceptive input Herrero JF et al. Wind-up of spinal cord neurons and pain sensation: much ado about something? Prog Neurobiol. 2000;61:1690203. Mao J, Mayer DJ. Spinal cord neuroplasticity following repeated opioid exposure and its relation to pathological pain. Ann N Y Acad Sci. 2001;933:175-84.

  26. Pharmacologically Long Acting methadone levorphanol Pharmaceutically Long Acting morphine Oramorph SR, MS Contin, Kadian, Avinza Morphine ER oxycodone OxyContin Oral Long Acting Opioid Dosage Forms

  27. Methadone • Biphasic elimination • alpha (analgesic) T1/2 8-12 hours • beta T1/2 24-36 hours - protects against withdrawal • Risk of accumulation toxicity

  28. Methadone Biphasic Elimination Therapeutic window Therapeutic window Analgesic onset ~ 1 h Analgesic offset ~ 8 h Lipman AG. Oncology. 1999;13:(9):1275-82

  29. Plot of Methadone Accumulation(dosed q 8 h over 6 days) Lipman AG. Oncology. 1999;13:(9):1275-82

  30. Myth: Patients Taking Opioids Cannot Drive Safely • Opioids impair cognition and psychomotor coordination initially • patients should not drive for 5-7 days after starting opioids or a dose increase • After 5-7 days of continuous opioids, tolerance to these effects develops predictably • studies show no increase in MVA in patients taking chronic opioids Vainio A et al. Lancet 1995;346:667-70 Fishbain D et al. J Pain Palliative Care Pharmacotherap 2002;16(1):9-28.

  31. Myth: Opioids Cause End Organ Toxicity • Respiratory and CNS toxicity do occur with high opioid doses in opioid-naïve patients • Long term opioid therapy does not produce reported end-organ toxicity in patients who are titrated to response and monitored correctly • Long term NSAIDs may cause GI and renal toxicity • High acetaminophen doses can cause hepatotoxicity

  32. Myth: Opioids Cause End Organ Toxicity • Respiratory and CNS toxicity have occurred with high opioid doses in opioid-naïve patients • Long term opioid therapy does not produce reported end-organ toxicity in patients who are titrated to response and monitored correctly • Long term NSAIDs may cause GI and renal toxicity • High acetaminophen doses can cause hepatotoxicity

  33. Some Pain Management Guidelines and Statements that Advocate Opioids for Safe and Effective Analgesia • AHCPR Acute Pain Guideline 1992 • AHCPR Cancer Pain Guideline 1994 • ASA Cancer Pain Guidelines 1996 • AAPM-APS Opioids in Chronic Pain 1997 • ASAM Public Policy Statement 1997 • APS Sickle Cell Pain Guidelines 1999 • APS OA and RA Pain Guideline 2001 • AGS Persistent Pain in Elderly Guidelines 2002 • APS Acute and Cancer Principles, 5th ed 2003

  34. All this needless pain and suffering impoverishes the quality of life of those afflicted and their families; it may even shorten life by impairing recovery from surgery or disease. People suffering severe or unrelenting pain become depressed. They may lose their will to live and fail to take normal health preserving measures; some commit suicide. Liebeskind J, Melzack R. Pain 1987;30:1

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