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Opioid Toxicity

Opioid Toxicity. Nathaniel Katz, MD Harvard Medical School Boston, MA. Opioid Treatment of Chronic Pain: Major Concerns. Addiction Tolerance Neuropsychological effects Symptoms Nausea, vomiting, constipation Dizziness, sweating Itching, etc. Definitions.

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Opioid Toxicity

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  1. Opioid Toxicity Nathaniel Katz, MD Harvard Medical School Boston, MA

  2. Opioid Treatment of Chronic Pain: Major Concerns • Addiction • Tolerance • Neuropsychological effects • Symptoms • Nausea, vomiting, constipation • Dizziness, sweating • Itching, etc.

  3. Definitions • Addiction (also dependence, abuse) • Loss of control over drug use • Compulsive drug use • Continued use despite harm • Physical Dependence • Stopping the drug leads to a withdrawal syndrome • Tolerance • Less effect after prolonged use; dose escalation required to maintain effect

  4. Historical Perspectives • “It is better to suffer pain than to become dependent upon opium” • Diagoras of Melos, 3rd Cent. B.C. • “Opium should be completely avoided [due to risk of dependence]” • Erasistratus of Chios, 5th Cent. B.C.

  5. Drugs with High Abuse Potential Mentions Other Narcotic Analgesics Antidepressants Benzodiazepines Marijuana Heroin Cocaine Alcohol-in-combination Source: Drug Abuse Warning Network

  6. Studies demonstrating rarity of addiction in patients treated with opioids • Medina JL, Diamond S. Drug dependency in patients with chronic headaches. Headache 1977 Mar;17(1):12-4 • Porter J, Jick H. Addiction rare in patients treated with narcotics. N Engl J Med 1980 Jan 10;302(2):123 • Perry S, Heidrich G. Management of pain during debridement: a survey of U.S. burn units. Pain 1982 Jul;13(3):267-80 • Several retrospective survey studies

  7. No published study of opioids for chronic pain has prospectively evaluated the incidence of addiction, by any definition.

  8. Good Outcome (11) Primarily alcohol Good family support Membership in AA or similar groups Bad Outcome (9) Polysubstance Poor family support No membership in support groups Which Population?Chronic opioid therapy for patients with history of substance abuse (n=20) Dunbar & Katz, 1996

  9. Which Instrument?DSM-IV Substance Use Disorder and the Typical Pain Patient on Opioids A maladaptive pattern of substance use leading to significant impairment or distress as manifested by 3 or more of the following 9 symptoms: • Need for markedly increased doses to achieve effect • Diminished effect with same dose • Withdrawal syndrome • Taking substance to relieve or avoid withdrawal symptoms • Dose escalation or prolonged use • Persistent desire or unsuccessful efforts to cut down or control substance use • Excessive time spent obtaining, using or recovering from use of the substance • Activities abandoned because of substance use • Use despite harm

  10. Self-report-based measures?Four studies demonstrating unreliability of patient self-report • Ready LB, Sarkis E, Turner JA. Self-reported vs. actual use of medications in chronic pain patients. Pain 1982;12:285-94 • Fishbain DA, Cutler RB, Rosomoff HL, et al. Validity of self-reported drug use in chronic pain patients. Clin J Pain 1999;15:184-91. • Katz NP, et al. Behavioral Monitoring and Urine Toxicology Testing in Patients on Long-Term Opioid Therapy. APS Abstract, 2001 • Belgrade M. Non-compliant drug screens during opioid maintenance analgesia for chronic non-malignant pain. APS Abstract, 2001

  11. Tolerance A. B. T.I. Side Effects Dose Required Dose Required T.I. Analgesia Time Time C. D. T.I. Dose Required Dose Required T.I. Time Time T.I. = Therapeutic Index

  12. Daily Dose Requirements in Long-Term Follow-Up Study (N = 150)

  13. Mean Daily Dose of Study Medication: Change From Baseline to Week 4 P = 0.025 Comparison of Change From Baseline to Week 4 Change 16 mg Mean Daily Opioid Dose Change 1.6 mg

  14. The phenomenon of tolerance to opioids in the treatment of chronic pain has not been systematically investigated in published medical literature.

  15. Neuropsychological Function • Concerns: psychomotor performance, cognitive function, affective disturbance

  16. No published prospective controlled trial on opioids for chronic non-cancer pain has evaluated neuropsychological function.

  17. Opioids and Endocrine Function • Opioids lower testosterone levels in animals, heroin addicts, methadone maintenance pts, and intrathecal opioid pts. • Opioids anecdotally produce loss of libido and impotence in men; amenorrhea and infertility in women. • Low testosterone: fatigue, loss of muscle mass, mood disturbances, osteoporosis

  18. Endocrine Function in Males with Chronic Pain on Opioid Therapy • All patients on opioid therapy underwent endocrine testing • Data available on N=25 males • Free testosterone below reference range in 63% of patients aged 25-49 • Free testosterone below reference range in 88% of patients aged 50-75 • Mean LH, FSH values below normal Katz N et al, submitted for publication

  19. Opioid-Related Symptoms • Nausea, vomiting, dizziness, itching, sweating, dysphoria, constipation • Passive side effects capture inadequate • Dropouts due to symptomatic side effects substantial in acute and chronic pain trials of opioids (10-50% in chronic pain) • Active “symptom distress” assessment, especially for dropouts, necessary for risk-benefit and quality of life assessment

  20. Symptom Distress Checklist in Opioid Analgesia Jamison, Katz, 1998

  21. Opioid Sparing as Outcome Measure • Decreased opioid requirements in patients on study drug may be due to: • Study drug has analgesic activity in the model (NSAID) • Study drug enhances opioid analgesia (?NMDA antagonists) • Study drug enhances opioid side effects, patients use less (e.g. a drug that causes nausea)

  22. Is Opioid Sparing Meaningful? • Yes, if the scientific question is whether the drug has analgesic activity in the model (given pain & side effects no worse) • No, if the scientific question is whether the treatment helps the patients (need to show clinical benefit, e.g. decreased pain, side effects)

  23. Conclusions • Opioids are generally safe medications. • Treatment response appears durable in a subgroup; however, tolerance has not been systematically investigated. • Symptom distress or toxicity scales (esp. in dropouts) must be used to assess overall treatment effect. • Addiction, the major concern in chronic treatment, has not been investigated using legitimate methods. • Endocrinopathies may be a major organ toxicity of opioids.

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