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Opioid-induced Hyperalgesia

What is opioid-induced hyperalgesia?

Algesia means pain. Hyper means over or above or heightened. Opioid-induced means caused by opioid pain medication.

We all have normal levels of heightened sensitivity to various stimuli. For example, you may have a favorite smell. Perhaps, it is cigar smoke because it fondly reminds you of your grandfather. A slight whiff of cigar smoke makes you think of your grandfather and gives you pleasant feelings. This experience is in response to a simple smell, which to others, leads to no such connotations. Or, perhaps, you have a favorite song. You may find yourself on an elevator and upon hearing the elevator music, you recognize the song and it feels good. No one else in the elevator even notices the song until you say, "Oh, that’s my favorite song." To take yet another example, you might be able to readily pick out your spouse in a large crowd and subsequently come to feel a sense of warmth and joy at simply your spouse’s presence. To others, however, your spouse may simply be an invisible stranger among others in the crowd. These kinds of normal sensitivity can be present in any and all of the senses, including touch, sight, smell, taste, and hearing.

We can also develop abnormally heightened sensitivities to various stimuli. For example, normally, lights and sounds don't hurt, but during certain types of migraine headache these normally innocuous or non-painful stimuli can become painful. The experience of stressful events can lead to an abnormally heightened sensitivity as well. Let's say that you were involved in a motor vehicle accident at a particular intersection some time ago. At the time of the accident, it was dark out. There were many cars on the road. There was snow and sleet and you did not have control over your vehicle. You were injured in the accident. Now, say, a year later, your injuries are healed. You are driving towards the same intersection. There is no snow. It is light out. There are no other cars on the road. Yet still, you feel nervous and tense as you get closer to the intersection. What is this about? You have an abnormally heightened sensitivity with respect to this intersection, this particular stimulus. Although this type of phenomenon is common, it is not normal to be afraid of a run-of-the-mill intersection. Your nervous system, including the brain, is reacting as if you are in danger even though you are now in no more danger than you are in at any other intersection. In other words, you have developed an abnormally heightened sensitivity to a particular stimulus, in this case, a particular intersection.

As with other stimuli, we can develop a heightened sensitivity to the stimulus of pain. Hyperalgesia is a heightened sensitivity, or hyper-sensitivity, to pain. It occurs due to changes in the nervous system. These changes can occur in the peripheral nervous system, the central nervous system, and/or the autonomic nervous system. An example of the changes in the peripheral nervous system might be what occurs when you have a sun burn. With sun burn, simple touch can become painful. An example of the changes in the central nervous system, which is the brain and spinal cord, might be a phenomenon such as phantom limb pain. When a limb is amputated there are changes that occur in the brain and spinal cord that can lead to continued pain in the limb that is no longer there. With various pain problems there may also be changes in the autonomic nervous system. This is part of the nervous system does things automatically, without you having to think about it. Muscle tightness, such as what happens in myofascial pain and/or fibromyalgia, might occur because of sensitization of the autonomic nervous system. While sometimes muscles automatically tighten in order to guard or protect an underlying injury, they can also contract for no distinct or clear-cut protective reason. It might be that the nervous system has become abnormally sensitive to even minimal stimuli. People with fibromyalgia commonly experience such pain when, for example, even mild touch or gentle hugs can cause pain.

Pain is a subjective experience that is a function of the nervous system in its interaction with some sort of stimuli. As we see, the nervous system can become hyper-sensitive and hyper-reactive to any stimuli, even the product of the nervous system itself – i.e., pain.

Moreover, the nervous system can become abnormally sensitive to even certain medications used to alleviate pain. That is to say, opioid medications can become the stimuli to which the nervous system becomes abnormally sensitized. It can occur for a number of reasons, but one of them is when the use of opioids, particularly high doses of opioids, occurs over a long period of time.

An early study titled Morphine-induced Hyperalgesia in Rats Tested on the Hot Plate was very informative and thought provoking. In this study on opioid-induced hyperalgesia, Kayan, Woods and Mitchell1 measured rats’ responses to heat before and after they were provided with morphine for a length of time. Morphine is an opioid pain medication. They found that the mice actually responded more rapidly and intensely to the heat following the use of morphine. In other words, the mice were more sensitive and more responsive to the heat. The investigators concluded that the morphine caused the abnormally heightened sensitivity to the painful stimuli. As such, it was a demonstration of the development of opioid-induced hyperalgesia.

Unlike animal studies the evidence of the existence of this phenomenon in humans is less obvious. There is controversy concerning the existence of this phenomenon, its clinical expression and impact in humans. However, there are a number of studies that describe this phenomenon in humans. A nice review of animal and human studies is an article published in 2012 titled: The Paradoxical Phenomenon of Opioid-induced Hyperalgesia by Dolnikov, et al.2 It discusses the controversy about this condition but also describes research concerning its existence and effects in humans as well as other animals.

As indicated, since the early study on mice, opioid-induced hyperalgesia has been demonstrated in studies with humans. For instance, Chen, et al.,3 compared pain sensitivity in three groups of people: one group who had no pain and did not take opioids; one group that had chronic pain and did not take opioid medications; and one group who had chronic pain and did take opioids. On two out of three types of pain sensitivity, the third group was significantly more sensitive to pain.

In a study of 81 cancer patients who received IV morphine for exacerbations of their cancer pain, Mercandante, et al.4 found that 12 of the subjects experienced more pain when they were treated with the morphine.

Using sophisticated measures of the nervous system’s innate ability to inhibit pain signals (i.e. diffuse noxious inhibitory control), Ram, et al.5 Ram, compared two groups of chronic pain patients – one group that was treated with oral opioids and one group that was not treated with opioids. They found that the nervous systems of those who were treated with opioids exhibited less capacity to inhibit pain signals. They inferred that this factor can subsequently lead to greater pain, at least in response to certain types of stimuli.

In a small, prospective, yet uncontrolled study of six patients with chronic low back pain who had not previously been treated with opioids, all six exhibited opioid-induced hyperalgesia after one month of morphine use.6 

While acknowledging some continued controversy about opioid-induced hyperalgesia, as well as many questions about its nature or even how to measure it, numerous reviews of the experimental literature have all concluded that opioids can induce a heightened sensitivity to pain in patients receiving opioids for chronic pain, post-operative pain, or cancer pain.7, 8, 9, 10 

These reviews basically suggest that a number of clinical factors may tend to bring on opioid-induced hyperalgesia. Among others, these factors are:

  • how fast an opioid is titrated upwards
  • being maintained on high doses of opioids
  • an extended duration of opioid use

Some articles indicate that there may also be genetic factors which leave certain individuals more prone to opioid-induced hyperalgesia once exposed to opioids.

Some articles also suggest that opioid-induced hyperalgesia might be suspected when, despite increasing doses of opioids over time, patients experience either:

  • an increasing sensitivity to tactile stimulation in areas of the body beyond the original site of pain
  • increasing intensity of pain in the absence of any progression of the underlying cause of pain
  • increasingly widespread location of pain in the absence of any progression of the underlying cause of pain

Opioid-induced hyperalgesia is not fully understood. It is a phenomenon that needs further study. Clinicians and patients should be aware of its manifestations, risks, and implications when using opioids. While how often the phenomenon occurs remains uncertain, it is apparent that a person can become hypersensitive and hyper-responsive to painful stimuli due to the use of opioids.


Jay Tracy, PA-C, PsyD, is a clinical psychologist and a physician's assistant who has practiced within the field of chronic pain rehabilitation most of his career. He has worked as both a clinician and a director of various chronic pain rehabilitation programs. Dr. Tracy recently retired from Pain Services at Courage Kenny Rehabilitation Institute in Golden Valley, MN. He is also an adjunct professor in the counseling psychology program at Bethel University in St. Paul, MN, where he teaches graduate level neuropsychology and biological bases of behavior courses. He is the author of two books, Pain: It's Not All In Your Head; The Test Don't Show Everything, and Pain: Nerves On Fire; Changing Neuropathic Pain.


1. Kayan, S., Woods, L. A., Mitchell, C. L. (1971). Morphine-induced hyperalgesia in rats tested on the hot plate. Journal of Pharmacology & Experimental Therapeutics, 177, 509-13.

2. Dolnikov, E., Pud, D., & Eisenberg, E. (April, 2012). Israeli Journal of Pain and Palliative Care.

3. Chen, L., Malarick, C., Seefeld, L., Wang, S., Houghton, M., & Mao, J. (2009). Altered quantitative sensory testing outcome in subjects with opioid therapy. Pain, 143(1-2), 65-70.

4. Mercandante, S., Ferrera, P., Arcuri, E., & Casuccio, A. (2012). Opioid-induced hyperalgesia after rapid titration with intravenous morphine: Switching and re-titration to intravenous methadone. Annals of Palliative Medicine, 1(1), 10-13. doi: 10.3978/j.issn.2224-5820.2012.01.02

5. K. C., Eisenberg, E., Haddad, M., & Pud, D. (2008). Oral opioid use alters DNIC but not cold pain perception in patients with chronic pain – new perspective of opioid-induced hyperalgesia. Pain, 139(2), 431-438. doi: 10.1016/j.pain.2008.05.015

6. Chu, L. F., Clark, D, J., & Angst, M. S. (2006). Opioid tolearnce and hyperalgesia in chronic patients after one month of oral morphine therapy: A preliminary prospective study. Journal of Pain, 7(1), 43-48.

7. Angst, M. S. & Clark, J. D. (2006). Opioid-induced hyperalgesia: A qualitative systematic review. Anesthesiology, 104(3), 570-587.

8. Chu, L. F., Angst, M. S. & Clark, D. (2008). Opioid-induced hyperalgesia in humans: Molecular mechanisms and clinical considerations. Clinical Journal of Pain, 24(6), 479-496.

9. Kopert, W. (2007). The impact of opioid-induced hyperalgesia for postoperative pain. Best Practice & Research: Clinical Anaesthesiology, 21(1), 65-83.

10. Lee, M., Silverman, S., Hansen, H., Patel, V., & Manchikanti, L. (2011). A comprehensive review of opioid-induced hyperalgesia. Pain Physician, 14(2), 145-161.

11. Mitra, S. (2008). Opioid-induced hyperalgesia: Pathophysiology and clinical implications. Journal of Opioid Management, 4(3), 123-130.

Date of publication: April 25, 2014

Date of last modification: May 21, 2017

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