August 10th, 2015

Opioid-induced Hyperalgesia In Opioid Treatment Patients: Is It Opioid-Induced?

Editor’s Note: I believe that the better we understand the causes of addiction, the more likely we will be able to facilitate recovery. This week’s guest writer, Dr. Peggy Compton, is eminently qualified to advance this effort. She has done important research in the area of pain and addiction at the UCLA and Georgetown University Schools of Medicine and is the author of a chapter on this subject in the textbook of the American Society of Addiction Medicine. Anything our readers can do to help her find subjects to answer the questions she raises here about opioid-induced hyperalgesia would be very much appreciated.

By: Peggy Compton, RN, PhD

Robust evidence exists to show that patients on methadone or buprenorphine maintenance treatment are less tolerant of certain types of experimental pain than are healthy, opioid-free control patients matched on age, gender, and ethnicity. Over the course of multiple studies, opioid-maintained patients have been shown to be 42 to 76 percent more sensitive to cold pressor pain than others, which has important implications for the management of their pain in the clinical setting. As opposed to being less valid (and too often perceived as “drug-seeking”), their complaints of pain must be taken seriously and managed thoughtfully.

This relative pain intolerance has been ascribed to the phenomenon of opioid-induced hyperalgesia, which is a condition of generalized increased sensitivity to pain and is readily induced in laboratory animals with the chronic administration of opioids. Unfortunately, a causal role for opioids in producing hyperalgesia has yet to be conclusively demonstrated in patients, both those receiving opioids for the treatment of addiction or chronic pain. The data reflecting hyperalgesia in opioid-dependent patients at this time are cross-sectional only, comparing opioid-dependent and opioid-free samples, but not comparing the same individuals before and after opioid administration. For compelling clinical and ethical reasons, it is near impossible to design such a pre-post study, leaving open the question of whether the hyperalgesia suffered by methadone and buprenorphine patients is, in fact, opioid-induced.

Countering evidence suggests that rather than being opioid-induced, people who develop opioid use problems are relatively pain sensitive persons by nature and perhaps more likely to find the drugs rewarding. It is known that on experimental pain testing, people vary widely in their pain tolerance responses, with a subgroup being very sensitive to pain. Could it be that people in this subgroup are more likely to find themselves in opioid maintenance treatment than others? Animal data show that strains of mice that have poor pain tolerance are also likely to find opioids highly reinforcing, supporting this hypothesis. It is possible that this increased sensitivity to discomfort makes the opioid withdrawal experience more distressing for those dependent on opioids and therefore seekers of opioid maintenance treatment.

Another approach to testing the causal role of opioids in the hyperalgesia noted in opioid treatment patients is to follow their pain responses as they gradually withdraw from opioids. If opioids induce hyperalgesia, it follows that removing them should improve pain responses. A single, small study by Dorit Pud and colleagues1 almost a decade ago showed that experimental pain tolerance did not improve over the course of a 30-day inpatient detoxification, suggesting a trait, not state, mechanism. These findings require replication in larger samples to be supported and most likely will require a longer follow-up period to detect pain response changes. Growing evidence in the pain field supports an opioid-induced hyperalgesia component to chronic pain, such that taking patients off opioids improves their overall pain outcomes.

To test the causal nature of opioid-induced hyperalgesia in opioid dependent patients, our research team is actively looking for clinical partners who offer opioid discontinuation treatment to enable examination of patients’ pain responses as they become drug-free, and (as possible) at 3, 6 and 12 months post-discharge. It is anticipated that this prospective empirical approach will better help determine if the opioid-induced hyperalgesia identified in opioid dependent patients is, in fact, opioid induced.


1Pud et al., Drug Alcohol Depend. 2006 May 20;82(3):218-23

Peggy Compton, RN, PhD, is a professor and associate dean for research, evaluation and graduate programs at Georgetown University’s School of Nursing & Health Studies.

Contact us to learn more about opioid-induced hyperalgesia.


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