Opioid analgesics remain the primary treatment for moderate to severe pain, but often cause behavioral impairment that constrains their therapeutic utility. Preclinical antinociception assays in animals have been indispensable in the development of analgesic medications, but have not typically provided concurrent assessment of behaviorally disruptive effects. To address this shortcoming, Sarah Withey and colleagues Carol Paronis and Jack Bergman of the Preclinical Pharmacology Laboratory of McLean Hospital, Harvard Medical School modified a previously validated warm-water tail withdrawal assay to measure tail withdrawal latencies (antinociception) concurrently with disruption of food-reinforced operant responding (behavioral impairment). A total of six different opioids were tested, and each resulted in dose-dependent antinociception and varying degrees of behavioral impairment. The researchers used a preclinical therapeutic ratio as a measure of a drug’s behavioral selectivity, which was defined as the ED50 for behavioral impairment divided by the ED50 for antinociception. The preclinical therapeutic ratio differed widely among the drugs. Nalbuphine had the highest therapeutic ratio (4.88) indicating significant antinociception at doses that did not cause behavioral impairment, whereas butorphanol had the lowest therapeutic ratio (0.17) indicating significant behavioral impairment at doses that were not sufficient to produce antinociception. Other opioids, including oxycodone, heroin, buprenorphine and methadone, had therapeutic ratios approaching 1.0, indicating that the antinociceptive and behaviorally impairing effects were produced by similar doses. These results are important because they demonstrate the utility of this animal model to concurrently measure antinociception and behavioral impairment, which may provide a useful technique for predicting the selectivity with which novel analgesics exert their therapeutic effects. Dr. Withey is new to the CPDD family; Dr. Bergman has been a member of CPDD since 1993 and currently serves as the Treasurer of the organization; Dr. Spealman has been a member of CPDD since 1992 and served as a Board of Director from 2010-2013. By Roger Spealman, Ph.D., Animals in Research Committee Member This research is published in The Journal of Pain.
