The document discusses several major concerns regarding the long-term use of opioids to treat chronic pain, including addiction, tolerance, and neuropsychological and endocrine effects. It notes that while some retrospective studies have suggested addiction is rare, no published studies have prospectively evaluated addiction rates using standardized definitions. It also summarizes several studies that have investigated tolerance, side effects, and endocrine impacts but have not systematically addressed these issues. The document concludes that while opioids may be generally safe, more research is still needed to fully understand long-term risks and benefits.

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

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

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

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

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

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

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

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

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

23. Symptom Distress Checklist in Opioid Analgesia Jamison, Katz, 1998 Drowsiness Dizziness Vomiting Nausea Severe Moderate Mild None Symptom