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Opioid-Induced Hyperalgesia

An important and under-appreciated side effect of exposure to opioids

A man holding his knee in pain near a bottle of pills.

What is opioid-induced hyperalgesia?

“Hyper” comes from the Greek word for “over,” and “algesia” from “algos” meaning “pain.” “Hyperalgesia” is an increased sensation of pain. At first glance, it seems paradoxical that opioids, medications which are so good at relieving pain, can in some cases actually increase it. This can be confusing, but a closer look at how these medications work can help us understand the dramatic positive and negative effects that they have on the body.

How do opioids change our perception of pain?

Our bodies are adapted to maintain a stable internal environment, which is called “homeostasis.” Except in the case of illness, we do not generally need to spend time worrying about what our blood pressure is, how fast we are breathing, or what our blood sugar is. If we maintain our health, our bodies have resilient and elegant ways to do this for us. 

Pain regulation, the way in which the body detects threats, is no different, and our body uses something called the endorphin system to do this. Our brain has receptors for naturally produced opioid-like chemicals called “endorphins,” and in the normal state they help regulate our sense of well-being. When we use opioid pain medications, which can be much better at occupying the receptors in this system than the chemicals our body makes itself, this equilibrium (homeostasis) is disrupted. The brain senses that too much endorphin is circulating and does its job of trying to adapt: It makes less of its own endorphins. The receptor system senses that too many are occupied and adapts too, by producing more open receptors.

What are the symptoms of opioid-induced hyperalgesia?

A lot is going on in the body when we are injured. Simultaneously, our bodies are trying to repair the damaged tissue, stop bleeding, prevent infection, and keep us moving and safe from other threats. When used carefully, opioid pain medications can be very beneficial in recovery from injury, and in fact, modern anesthesia and surgery would not have been possible without them.

Because of the overwhelming effect that injury can have on the body, and how well opioids can work to make us seem well during recovery, the symptoms of opioid-induced hyperalgesia can be subtle and hard to notice. Sometimes it is the development of tolerance to the effect of the opioid: the dose which initially worked is no longer helping and more is needed to achieve the same effect. It can also seem that the pain from the original injury does not seem to improve or can actually feel worse. Other areas of the body which were not painful before can sometimes begin to hurt, including old injuries that we had already adapted to.

How can we treat opioid-induced hyperalgesia?

We do not yet know how to reliably predict the likelihood that someone will develop opioid-induced hyperalgesia. There are genetic, behavioral, and circumstantial factors that play a role in estimating the risks of opioid exposure. In some people, these effects seem minimal and take a long time to develop. However, we know that in others the endorphin system is changing due to opioid exposure even within a few hours. Certain kinds of opioids that have a direct effect on the opioid receptor (called “agonists”), especially those with a rapid onset and offset, may be more likely to produce hyperalgesia. This group includes some of the most commonly used opioid pain medications such as oxycodone, hydrocodone, morphine, hydromorphone, and fentanyl.

The most important way to treat opioid-induced hyperalgesia is to begin with a healthy respect for just how potent these medications can be. We are often aware aware of the most common and dangerous side-effects such as overdose, addiction, nausea, and constipation, but pay less attention to the other ways in which they can impact our health. It is important to use opioid pain medications only when necessary, at the lowest effective dose, and for as short a period of time as possible.

When someone is suspected to have developed an increase in pain due to opioid-induced hyperalgesia, the most important treatment is, when possible, to taper off the medication completely. After a period of abstinence, depending on the individual and the length of their exposure, the brain changes induced by the medication should resolve. When that occurs, individuals who have developed hyperalgesia often find that their pain has improved, and in many cases resolves. During this time, other non-opioid pain medications can be used safely, including acetaminophen, non-steroidal anti-inflammatory, or adjunctive pain medications such as anticonvulsants like gabapentin or pregabalin (Lyrica ).

It is important for patients on opioid pain medications to discuss the possibility of opioid-induced hyperalgesia with their doctor, and not to make sudden changes in their regimen without medical guidance.


Seth A. Waldman, MD
Assistant Attending Anesthesiologist, Hospital for Special Surgery
Clinical Assistant Professor of Anesthesiology, Weill Cornell Medical College

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