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The Effect of Opioid Dose and Treatment Duration on the Perception of a Painful Standardized Clinical Stimulus
  1. Steven P. Cohen, M.D.a,b,
  2. Paul J. Christo, M.D., M.B.A.a,
  3. Shuxing Wang, M.D., Ph.D.c,
  4. Lucy Chen, M.D.c,
  5. Milan P. Stojanovic, M.D.c,d,
  6. Cynthia H. Shields, M.D.b,
  7. Chad Brummett, M.D.e and
  8. Jianren Mao, M.D., Ph.D.c
  1. aDepartment of Anesthesiology & Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD
  2. bDepartment of Surgery, Walter Reed Army Medical Center, Washington, DC
  3. cDepartment of Anesthesiology & Critical Care, Massachusetts General Hospital, Boston, MA
  4. dDepartment of Anesthesiology & Critical Care, Harvard Medical School, Boston, MA
  5. eDepartment of Anesthesiology, University of Michigan School of Medicine, Ann Arbor, MI.


Background and Objectives: The concept of opioid-induced hyperalgesia has recently gained prominence as a contributing factor for opioid tolerance and long-term treatment failure. But whereas the preclinical data for this phenomenon are strong, the mixed clinical data derive primarily from experimental pain models conducted in volunteers and heroin addicts, and nonstandardized clinical stimuli, e.g., surgery. The primary objective of this study is to delineate the effect of opioid dose and treatment duration on pain intensity and unpleasantness ratings following a standardized clinical pain stimulus.

Methods: Three hundred and fifty-five patients, on a steady regimen of analgesic medications and scheduled for an interventional procedure, received a standardized subcutaneous injection of lidocaine prior to a full dose of local anesthetic. Before and immediately following the injection, subjects were asked to rate pain and unpleasantness intensity on a 0 to 10 numerical rating scale. Subjects were stratified into 6 groups based on opioid dosage. A control group of 27 volunteers who had no pain and were taking no analgesics were also injected.

Results: Both opioid dose and duration of treatment directly correlated with pain intensity and unpleasantness scores. Baseline pain intensity was also positively associated with both outcome variables. Gender was found to be associated with pain intensity and unpleasantness, with females scoring higher in both categories than males. Compared with patients not receiving opioid treatment, patients receiving opioid therapy were more likely to rate the standardized pain stimulus as being more unpleasant than painful.

Conclusions: The results of this study bolster preclinical and experimental pain models demonstrating enhanced pain perception in subjects receiving opioid therapy. This simple clinical model may provide a useful tool in examining opioid-induced hyperalgesia.

  • Hyperalgesia
  • Nerve block
  • Opioid
  • Pain perception
  • Tolerance

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  • Reprint requests: Steven P. Cohen, M.D., 550 North Broadway, Suite 301, Baltimore, MD 21029. E-mail: scohen40{at}

  • Funded in part by the John P. Murtha Neuroscience and Pain Institute, Johnstown, PA, and the Army Regional Anesthesia & Pain Medicine Initiative, Washington, DC. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.