IN this issue of Anesthesiology, Martin et al.  1take on some vexing issues surrounding analgesic evaluation and opioid management of chronic pain. Although there are many interesting facets to their studies, it is the issue of interaction between pain and opioid self-administration that lies at the heart of their contribution. The data provided are not only relevant to the treatment of neuropathic pain, which is modeled in their studies, but also to understanding how pain might modify susceptibility to the development of opioid addiction.

One motivation for undertaking these studies was that we normally measure analgesic effects against nociceptive responses evoked when “neuropathic” tissue is stimulated. Thus, the hind paws of animals sensitized by virtue of some type of nerve injury are typically prodded with mechanical devices or heated with focused light to cause readily quantifiable withdrawal responses. These methods are robust, easy to learn, and generally reproducible between laboratories. Therefore, journals are filled with reports of reductions in allodynia or hyperalgesia used as evidence of a drug's analgesic potential. Unfortunately, it may be the spontaneous or continuous aspects of the human pain experience that lead patients to seek treatment for their chronic neuropathic pain as opposed to the evoked pain more commonly modeled in animals.2Similarly, reductions in the area of allodynia or hyperalgesia surrounding surgical wounds does not consistently correlate with lower overall postoperative pain scores.3,4We also need to recognize soberly that robust antiallodynic effects of test compounds in animals have not always correlated well with useful analgesic effects in humans. Unfortunately, there are many fewer methods described for quantifying the relatively subtle spontaneous behaviors, and the measurements themselves can be very time-consuming.

In their report, Martin et al.  show that nerve-ligated but otherwise unperturbed rats self-administered a range of opioids in a manner consistent with providing analgesia. Self-administration was measured using an apparatus that delivered an intravenous dose of opioid when the rats pushed a lever placed above their enclosure's floor. The investigators based their conclusions on both the size of the doses required for maintained self-administration and the measured duration of effect of those doses. In essence, it seemed that the nerve-ligated rats would bolus themselves with opioid only if the dose delivered provided analgesia, and would redose when the effect wore off. The self-administration of opioids by sham operated rats followed a different pattern. Self-administration in the absence of pain is commonly used as an index of abuse liability of a drug.

Although the study might not be judged conclusive, it is exciting to think that we may be able to evaluate pain and analgesic effects based on a complex self-administration behavior rather than by poking a sensitized hind paw with a stiff piece of monofilament. The presumption is, of course, that whatever motivates the rat's self-administration behavior better reflects human pain than the evoked responses typically used. Time and a good deal of additional experimentation will tell.

Another key observation in these studies was that nerve-ligated rats showed less evidence of positive opioid reinforcement than the sham-operated controls. Although it had been observed previously that nerve-ligated animals showed less positive opioid reinforcement using the conditioned place preference testing paradigm, the more sophisticated self-administration approach had not been used.5,6Specifically, after nerve ligation, doses of heroin, morphine, and other opioids previously capable of supporting self-administration became less effective. It was not until the rats were given analgesic range doses that the nerve-ligated rats would self-administer opioid. Furthermore, when the neuropathic sensitization was reduced with intrathecal clonidine, heroin was poorly reinforcing even at high doses.

These observations may have important implications regarding the ongoing controversy about opioid abuse potential when these drugs are administered for pain. Although the existing literature is incomplete, opioid treatment for chronic pain seems to have a relatively low likelihood of leading to opioid addiction in patients without substance abuse histories.7–9Prescription opioids, however, are commonly abused substances, and the rate of prescription opioid abuse is increasing.10It is possible that the methodology introduced by Martin et al.  could help us to understand whether there is in fact some form of protection from opioid abuse conferred by chronic pain, and under what circumstances that protection exists. At the very least, this research group has provided another piece of evidence that systems related to pain and addiction share some common ground.

Department of Anesthesiology, Stanford University, Palo Alto, California, and Veterans Affairs Palo Alto Health Care System, Palo Alto, California.

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