The paradox of opioid-induced hyperalgesia

Something has clearly gone awry with our efforts to manage chronic non-cancer pain. Emergency departments in the U.S. are facing an epidemic of opioid overdoses. Deaths from opioid overdoses now exceed those from motor vehicle accidents. Opioid prescribing is up 300% over the past decade and the U.S. now consumes 80% of the world’s prescription narcotics. And yet the problem of chronic pain seems to be increasing. Primary care clinicians and physicians in many other fields deal with chronic pain on a daily basis, and requests for continuing or increasing the doses of narcotics is a common part of these office visits.

Managing chronic non-malignant pain is not an easy task. And prescribing opioids effectively and safely is an even harder responsibility. This post looks briefly at one specific problem in safe opioid prescribing. I am not attempting a comprehensive review of the management of chronic non-malignant pain. Opioid prescribing is only one element in what should ideally be a multi-faceted approach to chronic pain management.

The issue I want to touch on is the phenomenon called opioid-induced hyperalgesia (OIH). This is a common but often-unappreciated problem in which high doses of opioids can paradoxically create increased pain. When people take high doses of narcotics, they tend to have increased pain sensitivity, and this increased pain awareness tends to improve when their narcotic dose is tapered.

There are at least three proposed biological explanations for OIH. (1) Opioids inhibit glutamate transporters, leading to higher glutamate levels and therefore higher stimulation of glutamate receptors, which can increase pain awaremeness. (2) Opioids increase spinal dysnorphins, and this leads to increased pain sensitization. (3) Opioids impact cells in the rostral ventromedial medulla of the spinal cord in a way that increases pain sensitivity.

Not every individual on high dose narcotics will experience OIH, but it is a common problem. We have all seen patients who are on high-dose prescription opioids but who state their pain is just getting worse, leading them to request even higher doses of opioids. While increasing the narcotic dose may provide some temporary relief, it actually fuels the pain problem and will make the pain get even worse. For patients on high dose opioids complaining of worsening pain, the best response may actually be to start tapering the narcotics, rather than increasing them. To take this approach requires a lot of time and discussion with the patient, and is easier to accomplish if other treatment modalities are available (e.g. physical therapy, exercise, acupuncture, behavioral counseling, etc.)

It is worth noting that OIH is biochemically different than tolerance, though both phenomena yield a similar outcome, which is that high doses of narcotics lose their effectiveness in controlling pain.

As the phenomenon of opioid-induced hyperalgesia becomes more widely understood, national experts in pain management are increasingly encouraging clinicians to limit total daily opioid doses to 120 mg of morphine equivalents per day for non-cancer pain. Doses higher than this level have a greater tendency to lead to OIH and the downward spiral of continually escalating narcotic doses. Many calculators are available on-line which enable clinicians to convert different narcotics to morphine equivalents. A good one can be found at

Treating chronic non-malignant pain is very tough. It is hard not to increase a patient’s narcotic dose further when they are reporting significant pain. But if they are already on a high dose of opioids, the best approach may be to take the time required to educate the patient about OIH, and the related phenomenon of tolerance. By acceding to the patient’s heartfelt request, or urgent demand, to increase their narcotic dose, we may actually be creating even more pain in the not-too-distant future.

Richard Fleming, MD

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