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3873 S1 08 Katz

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3873 S1 08 Katz

  1. 1. Opioid Toxicity Nathaniel Katz, MD Harvard Medical School Boston, MA
  2. 2. Opioid Treatment of Chronic Pain: Major Concerns <ul><li>Addiction </li></ul><ul><li>Tolerance </li></ul><ul><li>Neuropsychological effects </li></ul><ul><li>Symptoms </li></ul><ul><ul><li>Nausea, vomiting, constipation </li></ul></ul><ul><ul><li>Dizziness, sweating </li></ul></ul><ul><ul><li>Itching, etc. </li></ul></ul>
  3. 3. Definitions <ul><li>Addiction (also dependence, abuse) </li></ul><ul><ul><li>Loss of control over drug use </li></ul></ul><ul><ul><li>Compulsive drug use </li></ul></ul><ul><ul><li>Continued use despite harm </li></ul></ul><ul><li>Physical Dependence </li></ul><ul><ul><li>Stopping the drug leads to a withdrawal syndrome </li></ul></ul><ul><li>Tolerance </li></ul><ul><ul><li>Less effect after prolonged use; dose escalation required to maintain effect </li></ul></ul>
  4. 4. Historical Perspectives <ul><li>“ It is better to suffer pain than to become dependent upon opium” </li></ul><ul><ul><li>Diagoras of Melos, 3 rd Cent. B.C. </li></ul></ul><ul><li>“ Opium should be completely avoided [due to risk of dependence]” </li></ul><ul><ul><li>Erasistratus of Chios, 5 th Cent. B.C. </li></ul></ul>
  5. 5. Drugs with High Abuse Potential Cocaine Heroin Marijuana Benzodiazepines Antidepressants Narcotic Alcohol-in-combination Other Analgesics Source: Drug Abuse Warning Network Mentions
  6. 6. Studies demonstrating rarity of addiction in patients treated with opioids <ul><li>Medina JL, Diamond S. Drug dependency in patients with chronic headaches. Headache 1977 Mar;17(1):12-4 </li></ul><ul><li>Porter J, Jick H. Addiction rare in patients treated with narcotics. N Engl J Med 1980 Jan 10;302(2):123 </li></ul><ul><li>Perry S, Heidrich G. Management of pain during debridement: a survey of U.S. burn units. Pain 1982 Jul;13(3):267-80 </li></ul><ul><li>Several retrospective survey studies </li></ul>
  7. 7. No published study of opioids for chronic pain has prospectively evaluated the incidence of addiction, by any definition.
  8. 8. Which Population? Chronic opioid therapy for patients with history of substance abuse (n=20) <ul><li>Good Outcome (11) </li></ul><ul><li>Primarily alcohol </li></ul><ul><li>Good family support </li></ul><ul><li>Membership in AA or similar groups </li></ul><ul><li>Bad Outcome (9) </li></ul><ul><li>Polysubstance </li></ul><ul><li>Poor family support </li></ul><ul><li>No membership in support groups </li></ul>Dunbar & Katz, 1996
  9. 9. Which Instrument? DSM-IV Substance Use Disorder and the Typical Pain Patient on Opioids <ul><li>Need for markedly increased doses to achieve effect </li></ul><ul><li>Diminished effect with same dose </li></ul><ul><li>Withdrawal syndrome </li></ul><ul><li>Taking substance to relieve or avoid withdrawal symptoms </li></ul><ul><li>Dose escalation or prolonged use </li></ul><ul><li>Persistent desire or unsuccessful efforts to cut down or control substance use </li></ul><ul><li>Excessive time spent obtaining, using or recovering from use of the substance </li></ul><ul><li>Activities abandoned because of substance use </li></ul><ul><li>Use despite harm </li></ul>A maladaptive pattern of substance use leading to significant impairment or distress as manifested by 3 or more of the following 9 symptoms:
  10. 10. Self-report-based measures? Four studies demonstrating unreliability of patient self-report <ul><li>Ready LB, Sarkis E, Turner JA. Self-reported vs. actual use of medications in chronic pain patients. Pain 1982;12:285-94 </li></ul><ul><li>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. </li></ul><ul><li>Katz NP, et al. Behavioral Monitoring and Urine Toxicology Testing in Patients on Long-Term Opioid Therapy. APS Abstract, 2001 </li></ul><ul><li>Belgrade M. Non-compliant drug screens during opioid maintenance analgesia for chronic non-malignant pain. APS Abstract, 2001 </li></ul>
  11. 13. Tolerance Dose Required Time Side Effects Analgesia T.I. A. Dose Required Time T.I. B. Dose Required Time T.I. C. Dose Required Time T.I. D. T.I. = Therapeutic Index
  12. 14. Pain and dose stable in the completers (48% at 30 weeks) OA, n=295, Avinza 30qd vs. MSContin 15 bid vs. placebo, 4 wks, OL ext. *Caldwell, 2002 No info on tolerance. Mixed CP, MS-CR vs. active placebo, 9wks, x-over, n=61 Moulin, 1996 Dose, pain stable after initial escalation. LBP, RCT, MS-CR vs. oxy vs. naprox; 3-mo tx, titration; n=36 *Jamison, 1998 Dose stable in subgroup. PHN, Oxycontin vs. placebo, 4 wks, n=50, OL ext. *Watson, 1998 Diminution of analgesia in all 3 groups; worst in placebo. OA, RCT, enriched, Oxycontin vs. oxy/APAP vs. placebo, fixed, 4 wks, n=167 *Caldwell, 1999 Dose tripled over 4 wks. OA, CR codeine vs. placebo, titration, 4 wks, n=66 *Peloso, 2000 Pain relief, dose stable in 58/106 (6 mo), 15/106 (18 mo) OA, n=133, Oxycontin 10 vs 20 bid vs. placebo; fixed, 2wks, OL *Roth, 2000 Pain scores, dose stable over 6 mo. Only 4/117 DOLE Diabetic neuropathy, n=117, tramadol vs. placebo RCT, OL ext. this report *Harati, 2000 Pain at 19 wks stable. Mixed CP, n=46, CR codeine vs. placebo, 1 wk, 28 in OL ext. *Arkinstall, 1995 Published, Non-Opioid-Controlled RCTs of Opioids for Chronic Non-Cancer Pain, With at Least One Month Observation
  13. 15. Daily Dose Requirements in Long-Term Follow-Up Study (N = 150)
  14. 16. Mean Daily Dose of Study Medication: Change From Baseline to Week 4 Mean Daily Opioid Dose P = 0.025 Comparison of Change From Baseline to Week 4 Change 16 mg Change 1.6 mg
  15. 17. The phenomenon of tolerance to opioids in the treatment of chronic pain has not been systematically investigated in published medical literature.
  16. 18. Neuropsychological Function <ul><li>Concerns: psychomotor performance, cognitive function, affective disturbance </li></ul>
  17. 19. No published prospective controlled trial on opioids for chronic non-cancer pain has evaluated neuropsychological function.
  18. 20. Opioids and Endocrine Function <ul><li>Opioids lower testosterone levels in animals, heroin addicts, methadone maintenance pts, and intrathecal opioid pts. </li></ul><ul><li>Opioids anecdotally produce loss of libido and impotence in men; amenorrhea and infertility in women. </li></ul><ul><li>Low testosterone: fatigue, loss of muscle mass, mood disturbances, osteoporosis </li></ul>
  19. 21. Endocrine Function in Males with Chronic Pain on Opioid Therapy <ul><li>All patients on opioid therapy underwent endocrine testing </li></ul><ul><li>Data available on N=25 males </li></ul><ul><li>Free testosterone below reference range in 63% of patients aged 25-49 </li></ul><ul><li>Free testosterone below reference range in 88% of patients aged 50-75 </li></ul><ul><li>Mean LH, FSH values below normal </li></ul>Katz N et al, submitted for publication
  20. 22. Opioid-Related Symptoms <ul><li>Nausea, vomiting, dizziness, itching, sweating, dysphoria, constipation </li></ul><ul><li>Passive side effects capture inadequate </li></ul><ul><li>Dropouts due to symptomatic side effects substantial in acute and chronic pain trials of opioids (10-50% in chronic pain) </li></ul><ul><li>Active “symptom distress” assessment, especially for dropouts, necessary for risk-benefit and quality of life assessment </li></ul>
  21. 23. Symptom Distress Checklist in Opioid Analgesia Jamison, Katz, 1998 Drowsiness Dizziness Vomiting Nausea Severe Moderate Mild None Symptom
  22. 24. Opioid Sparing as Outcome Measure <ul><li>Decreased opioid requirements in patients on study drug may be due to: </li></ul><ul><ul><li>Study drug has analgesic activity in the model (NSAID) </li></ul></ul><ul><ul><li>Study drug enhances opioid analgesia (?NMDA antagonists) </li></ul></ul><ul><ul><li>Study drug enhances opioid side effects, patients use less (e.g. a drug that causes nausea) </li></ul></ul>
  23. 25. Is Opioid Sparing Meaningful? <ul><li>Yes, if the scientific question is whether the drug has analgesic activity in the model (given pain & side effects no worse) </li></ul><ul><li>No, if the scientific question is whether the treatment helps the patients (need to show clinical benefit, e.g. decreased pain, side effects) </li></ul>
  24. 26. Conclusions <ul><li>Opioids are generally safe medications. </li></ul><ul><li>Treatment response appears durable in a subgroup; however, tolerance has not been systematically investigated. </li></ul><ul><li>Symptom distress or toxicity scales (esp. in dropouts) must be used to assess overall treatment effect. </li></ul><ul><li>Addiction, the major concern in chronic treatment, has not been investigated using legitimate methods. </li></ul><ul><li>Endocrinopathies may be a major organ toxicity of opioids. </li></ul>