Opioid-Induced Hyperalgesia: CPCP Review

We held a Clinical Problems in Consultation Psychiatry (CPCP) conference recently on Opioid-Induced Opioid Hyperalgesia (OIH), sometimes thought of as a controversial concept in the chronic pain management literature. Psychiatric consultants typically get called to see patients in the general hospital who complain bitterly of pain when they are being given high doses of opioid analgesics.

But it’s virtually impossible to tell, clinically, whether a particular patient in these situations has OIH. Many of us think we know OIH when we see it–but our diagnoses of it are pretty much based on anecdotal evidence and experience. We all would like to do much better than that.

The article we chose for discussion was the one by Lee and colleagues [1]. What I liked about this paper was the succinct definition and historical background:

Opioid-induced hyperalgesia (OIH) is defined as a state of nociceptive sensitization caused by exposure to opioids. The condition is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain could actually become more sensitive to certain painful stimuli. The type of pain experienced might be the same as the underlying pain or might be different from the original underlying pain. OIH appears to be a distinct, definable, and characteristic phenomenon that could explain loss of opioid efficacy in some patients.

A physician named Albutt was quoted who said in 1870, “At such times I have certainly felt it a  great responsibility to say that pain, which I know is an evil, is less injurious than morphia, which may be an evil.” “Does morphia tend to encourage the very pain it pretends to relieve?” “Experience is needed”…”in the cases in question, I have much reason to suspect that a reliance upon hypodermic morphia only ended in that curious state of perpetuated pain.”

Another physician, Rossbach, also was quoted in 1880, “when dependence on opioids finally becomes an illness of itself, opposite effects like restlessness, sleep disturbance, hypesthesia, neuralgia, and irritability become manifest.”

Delirium can also ensue from the high doses of opioid used in a futile effort to manage the pain complaints.

Although Lee and colleagues wrote an extensive section on experimental evidence for and proposed mechanisms of OIH, I turned to another paper for additional guidance on the science of this condition. The paper by Brush gives us a basic overview of the experimental and clinical evidence for OIH [2]. What I got from this is that there is intriguing evidence from animal experimental models and basic science suggestive that OIH as an entity may exist, but almost no consistent human studies that unequivocally establish that it does.

Both Lee and Brush acknowledge the methodological limitations of the extant studies on OIH. So what does that leave us clinically? How do we help our patients? How do psychiatric consultants improve their effectiveness for helping to manage chronic pain?

How do we identify it in the first place? Is there a reliable way to distinguish OIH from tolerance, for example? The management decisions differ greatly between the two. If the increasing pain is from tolerance, the strategy is to increase the dose of opioid. The physician must also distinguish interval injury and clinical exacerbation of preexisting pain as well.

Lee and colleagues think that certain features help differentiate OIH from these other entities. In their view, OIH:

  • Typically presents as diffuse pain
  • Is less well-defined in quality
  • Tends to spread to other areas of distribution from preexisting pain
  • Seems to mimic opioid withdrawal including pain because the neurobiology of both is similar
  • If the preexisting pain is undertreated or tolerance exists, increasing the opioid dose would decrease pain; OIH would get worse.

What about management? Lee and Brush admit that simply decreasing the dose of or discontinuing opioids may not be the most attractive options to patients. They both say that opioid rotation may be helpful. This is substituting one opioid for another. Research indicates that NMDA receptors may be involved in the pathophysiology of OIH. In that case, methadone or even ketamine could be considered because they both antagonize NMDA receptors. However, there are problems with both of these agents in terms of the route of administration of the latter limiting it to use in the hospital rather than at home (as well as its abuse potential) and long-term treatment with methadone can lead to OIH as well.

According to Lee, a policy of “rational polypharmacy” could be adopted, which could help minimize exposure to opioids. I have seen a good deal of what some physicians might call “rational polypharmacy” landing in the ICU. There are definite medical risks associated with them, including delirium. Buprenorphine has also been used to treat chronic pain. It has been shown to be “intermediate in its ability to induce pain sensitivity in patients maintained on methadone and control patients not taking opioids.” It is a substance for which clinicians need a special educational program to obtain certification to dispense, though.

So how can the psychiatric consultant improve his or her effectiveness when called to help manage someone with chronic pain despite receiving large doses of opioid? I think it’s a good idea to cite our limited scope of practice and keep the pain medicine specialist in mind. However, people in pain frequently suffer from depression and anxiety, and improving the ways we manage that can be helpful for managing pain. That doesn’t always mean we must use antidepressants and anxiolytics, although they can be effective. Mindfulness and cognitive behavioral therapy approaches can also be applied, which can return a sense of efficacy to those afflicted with chronic pain.


1. Lee, M., et al. (2011). “A comprehensive review of opioid-induced hyperalgesia.” Pain Physician 14(2): 145-161.
Opioid-induced hyperalgesia (OIH) is defined as a state of nociceptive sensitization caused by exposure to opioids. The condition is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain could actually become more sensitive to certain painful stimuli. The type of pain experienced might be the same as the underlying pain or might be different from the original underlying pain. OIH appears to be a distinct, definable, and characteristic phenomenon that could explain loss of opioid efficacy in some patients. Findings of the clinical prevalence of OIH are not available. However, several observational, cross-sectional, and prospective controlled trials have examined the expression and potential clinical significance of OIH in humans. Most studies have been conducted using several distinct cohorts and methodologies utilizing former opioid addicts on methadone maintenance therapy, perioperative exposure to opioids in patients undergoing surgery, and healthy human volunteers after acute opioid exposure using human experimental pain testing. The precise molecular mechanism of OIH, while not yet understood, varies substantially in the basic science literature, as well as clinical medicine. It is generally thought to result from neuroplastic changes in the peripheral and central nervous system (CNS) that lead to sensitization of pronociceptive pathways. While there are many proposed mechanisms for OIH, 5 mechanisms involving the central glutaminergic system, spinal dynorphins, descending facilitation, genetic mechanisms, and decreased reuptake and enhanced nociceptive response have been described as the important mechanisms. Of these, the central glutaminergic system is considered the most common possibility. Another is the hypothesis that N-methyl-D-aspartate (NMDA) receptors in OIH include activation, inhibition of the glutamate transporter system, facilitation of calcium regulated intracellular protein kinase C, and cross talk of neural mechanisms of pain and tolerance. Clinicians should suspect OIH when opioid treatment’s effect seems to wane in the absence of disease progression, particularly if found in the context of unexplained pain reports or diffuse allodynia unassociated with the original pain, and increased levels of pain with increasing dosages. The treatment involves reducing the opioid dosage, tapering them off, or supplementation with NMDA receptor modulators. This comprehensive review addresses terminology and definition, prevalence, the evidence for mechanism and physiology with analysis of various factors leading to OIH, and effective strategies for preventing, reversing, or managing OIH.

2. Brush, D. E. (2012). “Complications of long-term opioid therapy for management of chronic pain: the paradox of opioid-induced hyperalgesia.” J Med Toxicol 8(4): 387-392.
While opioids remain a valid and effective analgesic strategy for patients suffering from a wide variety of painful conditions, they are not a panacea. Increasingly, physicians must balance patient expectations of adequate pain control with known limitations of opioid pharmaceuticals including adverse effects, tolerance, addiction, withdrawal, and drug diversion. Further complicating the issue over the last decade is a growing body of evidence suggesting chronic opioid use may unexpectedly worsen the perception of pain in some individuals. This syndrome, termed opioid-induced hyperalgesia (OIH), fundamentally changes our understanding of opioid pharmacodynamics and may influence our approach to management of chronic pain. This manuscript describes the concept OIH and provides an overview of basic science and clinical research to date attempting to characterize this syndrome, as well as ascertain its clinical relevance. The potential existence of OIH in humans is framed within the context of our current understanding of opioids and our prescribing patterns so that physicians may begin to incorporate these ideas into their philosophy of pain management as further information develops. Animal studies reliably validate OIH in controlled models. Rigorous research protocols in humans are lacking, and we cannot yet confidently conclude that OIH manifests in clinically significant ways. However, clinicians should consider the possibility of OIH when evaluating outcomes of patients on chronic opioid therapy.



  1. Great post Jim. I have seen many pain crises that are triggered by OIH. A purely subjective analogy seems to be the common phenomenon of benzodiazepine tolerance where the panic attacks are about as bad as baseline, but the patient insists that the dose needs to be increased and that seems to work until the tolerance recurs. In the case of OIH, the recurrent pain seems to be much worse – often resulting in hospitalization. By the time psychiatry is consulted the pain is even worse as a result of additional opioid being given by the treating team. In my current work setting, we take patient off opioids who have chronic pain associated with their use. Most are surprised that the pain relief from non-opioid medications and therapy produce a superior result for them.

    More work needs to be done on the front end. This excellent work by NICE is a good example of type of education that all physicians need: http://www.nice.org.uk/nicemedia/live/12948/47936/47936.pdf


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