Elsevier

Addictive Behaviors

Volume 29, Issue 7, September 2004, Pages 1311-1324
Addictive Behaviors

Pleasure into pain: The consequences of long-term opioid use

https://doi.org/10.1016/j.addbeh.2004.06.007Get rights and content

Abstract

One consequence of repeated drug administration is the development of adaptations in the nervous system, sometimes termed ‘drug-opposite’ responses. During administration, the effects of the drug are diminished by these adaptations (tolerance), while cessation of drug use results in the emergence of these drug-opposite responses as the withdrawal syndrome. Recent evidence on pain responses challenges this simple notion of withdrawal and suggests that aversive drug-opposite states may play a more important role in drug dependence than previously thought. While opioids such as heroin produce analgesia, people with a history of opioid self-administration are hypersensitive to certain kinds of pain during the time they are under the influence of the analgesic drug. This suggests that in pain systems, the drug-opposite response exceeds the pain inhibiting effect of the drug itself. This hyperalgesia is evident in people with a history of heroin use and is not modified by methadone or buprenorphine treatment but is reduced by long-term abstinence from opioids. This same pattern of the drug-opposite response exceeding the drug effect may also occur for mood. While opioids cause elevation of mood, commonly described as euphoria and reduction of emotional distress, methadone maintenance participants show significant negative mood disturbance relative to controls. Thus, for pain and mood, the chronic opioid user under the influence of the drug does not experience an opioid effect diminished by tolerance but a state opposite to the effect of the drug. Increases in drug concentration arising from administration serve only to reduce the degree of pain and mood disturbance. These aversive pain and mood states may contribute to the motivation for continued drug use and the dysfunction associated with drug dependence.

Section snippets

Tolerance to opioid effects in methadone maintenance patients

People who are heroin dependent show marked tolerance to the effects of all opioid drugs. This is evident from the doses of heroin they typically administer; these doses would produce respiratory depression, vomiting, sedation, and possibly coma in a nontolerant person. When such people elect to participate in methadone maintenance programs, their tolerance and physical dependence are maintained but with a controlled, regular dosing regimen. Tolerance can be inferred where the effects of

Pain responses in methadone maintenance patients

One of the original measures used to evaluate opioid effects over the 24-h methadone dosing interval was response to pain produced by electrical stimulation. This produced results very similar to those described above for respiration; that is, methadone patients exhibited pronounced tolerance, but there was a residual analgesic effect of methadone at time of trough concentration with an increase in the effect at time of peak concentration (Dyer et al., 1999). Like the other measures, electrical

Hyperalgesia in methadone maintenance patients: cause and consequence

The evidence from our group and others that methadone patients are hyperalgesic to cold-pressor pain when compared to controls raises the issue of the generality of this phenomenon. Subsequent to the study reported above, we have observed hyperalgesia in patients maintained on buprenorphine (Compton, Charuvastra, & Ling, 2001) and slow-release oral morphine (Bochner, Mitchell, White, & Somogyi, 2003) and in heroin-dependent patients entering treatment (Ling et al., 2003). Hyperalgesia is

Mechanisms of opioid-induced hyperalgesia

In contrast to the model of tolerance and withdrawal presented in Fig. 1, pain responsiveness (as measured by the cold-pressor test in humans) is better represented by the model in Fig. 2. Here the adaptational response is of greater magnitude than the direct response to the drug so that there is a net decrease in response below baseline or control level. The term hyperadaptation may best describe adaptational responses that exceed the original drug response in magnitude.

The difference from

Mood states and withdrawal in methadone maintenance patients

In the case of pain, we have good evidence that the model of hyperadaptation fits the data and we also have potential mechanisms underlying the exaggerated drug-opposite response. If respiration, pupillary response, and electrical stimulation pain exhibit conventional tolerance, the question of the uniqueness or generality of the cold-pressor response arises. Does the hyperadaptation model apply to other drug effects or is it unique to certain kinds of pain response only and therefore of little

Implications for theory and practice

These findings have very important implications for understanding both the nature of dependence and the functional state of opioid-dependent people on admission to and during treatment. The suggestion that adaptation may be exaggerated for some responses leading to a drug-opposite or withdrawal-like state during drug administration is similar, in some respects, to the notion of hedonic homeostatic dysregulation. Koob and Le Moal (1997) characterized addiction in terms of a cycle of spiraling

Acknowledgements

Preparation of this paper was supported by NIDA grant RO1 DA 13706-01.

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