Open Access Open Access  Restricted Access Subscription or Fee Access

Defining clinical issues around tolerance, hyperalgesia, and addiction: A quantitative and qualitative outcome study of long-term opioid dosing in a chronic pain practice

Jennifer P. Schneider, MD, PhD, Kenneth L. Kirsh, PhD


Treatment with opioid medications has grown over the past decades, but has been surrounded by some ongoing controversy and debate to whether it is causing more harm than good for patients. To this end, the field of pain management has suffered from a lack of clarity about some basic definitions on concepts such as tolerance and hyperalgesia. Some characterize these issues as inevitable parts of opioid therapy while other schools of thought look at these issues as relatively rare occurrences. Unfortunately, most of the rhetoric around these topics has occurred with very little in the realm of real world data. To this end, the authors have reviewed the charts of 197 patients treated by a pain specialist for at least 1 year to better illustrate whether notions of tolerance and hyperalgesia are common occurrences and, more importantly, whether they occur within any type of specified timeframe. A total of 197 patient charts were reviewed. The sample had an average age of 49.39 years (range = 19-87 years; standard deviation [SD] = 12.48) and comprised 66 men (33.5 percent) and 131 women (66.5 percent). The patients were seen in the pain practice for an average of 56.52 months (range = 12-155 months; SD = 31.26). On average, the patients maintained an average daily dose of 180 mg morphine equivalents for a period of 35.1 months (range = 3-101 months; SD = 21.3). Looking at the pattern of medication usage change over time, 34.5 percent experienced dose stabilization after the initial titration, 13.2 percent had early dose stabilization within one dose change, and an additional 14.7 percent actually had dose decreases after surgeries or other interventional procedures. Only 6.6 percent of the sample had to be discharged or weaned from controlled substances over time in the clinic. Thus, it appears that tolerance and hyperalgesia are not foregone conclusions when considering placing a patient on long-term opioid therapy.


tolerance, dependence, opioids, hyperalgesia, long-term opioid therapy

Full Text:



Cicero TJ, Inciardi JA, Munoz A: Trends in abuse of oxycontin and other opioid analgesics in the United States: 2002-2004. J Pain. 2005; 6(10): 662-672.

Savage SR, Kirsh KL, Passik SD: Challenges in using opioids to treat pain in persons with substance use disorders. Addict Sci Clin Pract. 2008; 4(2): 4-25.

Fishbain DA, Cole B, Lewis JE, et al.: Do opioids induce hyperalgesia in humans? An evidence-based structured review. Pain Med. 2009; 10(5): 829-839.

Chou R, Ballantyne JC, Fanciullo GJ, et al.: Research gaps on use of opioids for chronic noncancer pain: Findings from a review of the evidence for an American Pain Society and American Academy of Pain Medicine Clinical Practice Guideline. J Pain. 2009; 10: 147-159.

Dole VP: Narcotic addiction, physical dependence and relapse. N Engl J Med. 1972; 286: 988-991.

Martin WR, Jasinski DR: Physiological parameters of morphine dependence in man—Tolerance, early abstinence, protracted abstinence. J Psychiatr Res. 1969; 7: 9-13.

American Academy of Pain Medicine, American Pain Society, and American Society of Addiction Medicine: Definitions Related to the Use of Opioids for the Treatment of Pain. AAPM, APS, and ASAM, 2001. Available at Accessed October 14, 2010.

Candiotti KA, Gitlin MC: Review of the effect of opioid-related side effects on the undertreatment of moderate to severe chronic non-cancer pain: Tapentadol, a step toward a solution? Curr Med Res Opin. 2010; 26(7): 1677-1684.

Noble M, Treadwell JR, Tregear SJ, et al.: Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev. 2010; (1): CD006605.

Bruera E, Macmillan K, Hanson JA, et al.: The cognitive effects of the administration of narcotic analgesics in patients with cancer pain. Pain. 1989; 39: 13-15.

Ling GSF, Paul D, Simantov R, et al.: Differential development of acute tolerance to analgesia, respiratory depression, gastrointestinal transit and hormone release in a morphine infusion model. Life Sci. 1989; 45: 1627-1641.

Foley KM: Clinical tolerance to opioids. In Basbaum AI, Besson J-M (eds.): Towards a New Pharmacotherapy of Pain. Chichester: Wiley, 1991: 181-187.

Portenoy RK: Opioid tolerance and efficacy: Basic research and clinical observations. In Gebhardt G, Hammond D, Jensen T (eds.): Proceedings of the VII World Congress on Pain. Progress in Pain Research and Management. Vol. 2. Seattle: IASP Press, 1994: 595-613.

Aronoff GM: Opioids in chronic pain management: Is there a significant risk of addiction? Curr Pain Rev. 2000; 4: 112-121.

McCarberg BH, Barkin RC: Long-acting opioids for chronic pain: Pharmacotherapeutic opportunities to enhance compliance, quality of life, and analgesia. Am J Ther. 2001; 8: 181-186.

Zenz M, Strumpf M, Tryba M: Long-term opioid therapy in patients with chronic nonmalignant pain. J Pain Symptom Manage. 1992; 7: 69-75.

Roth SH, Fleischman RM, Burch FX, et al.: Around-the-clock, controlled-release oxycodone therapy for osteoarthritis-related pain: Placebo-controlled trial and long-term evaluation. Arch Int Med. 2000; 160: 853-860.

Caldwell JR, Rapoport RJ, Davis JC, et al.: Efficacy and safety of a once-daily morphine formulation in chronic, moderate-to-severe osteoarthritis pain: Results from a randomized, placebo-controlled, double-blind trial and an open-label extension trial. J Pain Symptom Manage. 2002; 23(4): 278-291.

Ytterberg S, Mahowald ML, Woods SR: Codeine and oxycodone use in patients with chronic rheumatic disease pain. Arthritis Rheum. 1998; 41: 1603-1612.

Portenoy RK, Farrar JT, Bakonja M-M, et al.: Long-term use of controlled-release oxycodone for noncancer pain: Results of a 3-year registry study. Clin J Pain. 2007; 23: 287-299.

Guignard B, Bossard AE, Oste C, et al.: Acute opioid tolerance: Intraoperative remifentanil increased postoperative pain and morphine requirement. Anesthesiology. 2000; 93: 409-417.

Cohen SP, Christo PJ, Wang S, et al.: The effect of opioid dose and treatment duration on the perception of a painful standardized clinical stimulus. Reg Anesth Pain Med. 2008; 33: 199-206.

Hay JL, White JM, Bochner F, et al.: Hyperalgesia in opioid-managed chronic pain and opioid-dependent patients. J Pain. 2009; 10: 316-322.

Redmond DE, Krystal JH: Multiple mechanisms of withdrawal from opioid drugs. Ann Rev Neurosci. 1984; 7: 443-478.

American Psychiatric Association: Diagnostic and Statistical Manual for Mental Disorders-IV. Washington, DC: American Psychiatric Association, 1994.

World Health Organization: Youth and drugs, Technical Report No. 516. Geneva: World Health Organization, 1973.

Wikler A: Opioid Dependence: Mechanisms and Treatment. New York: Plenum Press, 1980.

Halpern LM, Robinson J: Prescribing practices for pain in drug dependence: A lesson in ignorance. Adv Alcohol Subst Abuse. 1985; 5: 184-191.

Dai S, Corrigal WA, Coen KM, et al.: Heroin self-administration by rats: Influence of dose and physical dependence. Pharmacol Biochem Behav. 1989; 32: 1009-1015.

Portenoy RK: Using opioids for chronic nonmalignant pain: Current thinking. Intern Med. 1996; 17 (Suppl): 25-31.

Passik SD, Kirsh KL: The interface between pain and drug abuse and the evolution of strategies to optimize pain management while minimizing drug abuse. Exp Clin Psychopharmacol. 2008; 16(5): 400-404.

Pasero C: Challenges in pain assessment. J Perianesth Nurs. 2009; 24(1): 50-54.

Smith HS, Kirsh KL, Passik SD: Chronic opioid therapy issues associated with opioid abuse potential. J Opioid Manage. 2009; 5(5): 287-300.

Schneider JP, Miller A: Urine drug tests in a private chronic pain practice. Practical Pain Manage. Jan/Feb 2008: 62-66.

Michna E, Jamison RN, Pham L-D, et al.: Urine toxicology among chronic pain patients on opioid therapy: Frequency and predictability of abnormal findings. Clin J Pain. 2007; 23: 173-179.



  • There are currently no refbacks.