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The Effect of Repeated Intramuscular Alfentanil Injections on Experimental Pain and Abuse Liability Indices in Healthy Males

Tompkins, David Andrew MD*; Smith, Michael T. PhD; Bigelow, George E. PhD*; Moaddel, Ruin PhD; Venkata, Swarajya Lakshmi Vatem PhD; Strain, Eric C. MD*

doi: 10.1097/AJP.0b013e3182851758
Original Articles

Objective: Opioid-induced hyperalgesia (OIH), increased sensitivity to noxious stimuli after repeated opioid exposures, has been demonstrated in preclinical studies. However, there is no accepted, prospective model of OIH after repeated opioid exposures currently available in humans. This study assessed a potential prospective OIH model.

Methods: Double-blind intramuscular injections of a short-acting opioid (alfentanil 15 mcg/kg; N=8) were compared to active placebo (diphenhydramine 25 mg; N=3) on cold and pressure pain testing and standard abuse liability measures in eight 10-hour sessions (1 injection/session) over 4 to 5 weeks in healthy, pain-free males. Decreases from session baseline pain threshold (PThr) and tolerance (PTol) were calculated to represent hyperalgesia, and were assessed both within and across sessions.

Results: Mean decreases in cold PTol were seen in the alfentanil group at 180 minutes (−3.8 s, ±26.5) and 480 minutes (−1.63 s, ±31.5) after drug administration. There was a trend for differences between conditions on cold PThr hyperalgesia but not for pressure PThr. Alfentanil participants had greater mean ratings on Liking and High visual analog scales at peak effects (30 min), but these scores did not change across sessions.

Discussion: Repeated alfentanil exposures over 4 to 5 weeks resulted in within session decreases in cold pain tolerance from baseline but these differences were not substantially different from diphenhydramine controls. The results did not support the phenomenon of OIH in this model, although definitive conclusions regarding the existence of OIH in humans likely requires a larger sample size or an alternative model.

Supplemental Digital Content is available in the text.

Departments of *Psychiatry and Behavioral Sciences, Behavioral Pharmacology Research Unit

Psychiatry and Behavioral Sciences, Behavioral Sleep Medicine Program, Johns Hopkins University School of Medicine

Intramural Research Program, National Institute on Aging, Baltimore, MD

This study was performed at Johns Hopkins University School of Medicine, Baltimore, MD.

Preliminary analyses in this manuscript were presented at the 2010 American Pain Society and 2011 College on Problems of Drug Dependence annual meetings.

The authors declare no conflict of interest. Supported by grants from NIDA: 5T32 DA07209 and 1K24DA023186. Supported in part by the Intramural Research Program of the NIH, National Institute on Aging, Baltimore, MD.

Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website,

Reprints: David Andrew Tompkins, MD, Johns Hopkins Bayview Medical Campus, 5510 Nathan Shock Drive, Baltimore, MD 21231 (e-mail:

Received March 10, 2012

Accepted December 27, 2012

© 2014 by Lippincott Williams & Wilkins