A motorcycle accident leaves you with a shattered leg. The pain is stabbing, intense and all-encompassing, like nothing you have experienced before. Your journey to recovery begins with a successful surgery, but you find that in order to cope with the pain and function day-to-day, you’re taking large amounts of opioid pain killers. Initially, they work well, and the pain subsides

After a while, though you notice that it’s back with a vengeance and has spread beyond your leg. Now, things that didn’t really bother you before—like splashing hot water on your hand or stubbing your toe—are excruciating. Shouldn’t the drugs be helping? Why are you feeling even more pain?

Opioids are the most powerful analgesic drugs at our disposal, helping millions cope with severe pain associated with surgery, broken bones and cancer. But instead of providing analgesia—that is, pain relief—opioids can sometimes actually make people more sensitive to pain, a condition known as opioid-induced hyperalgesia (OIH). English physician Clifford Allbutt first recognized this perplexing phenomenon in the 19th century. After observing his patients injecting themselves with morphine every day, he wondered: “Does morphia tend to encourage the very pain that it pretends to relieve?”

Today, opioid-induced hyperalgesia is a contentious issue amongst pain physicians in light of conflicting reports on its development in opioid users. Nevertheless, it can be an important factor in the diminishing effectiveness of continuous opioid use. In some cases, it can lead to a vicious cycle known as the paradox of dose escalation. Patients desperately seeking relief take more opioids, which serves only to aggravate the problem and worsen their underlying suffering.

“Opioid-induced hyperalgesia is a manifestation of opioid toxicity that is usually related to high dose and high potency opioids as well as long duration of usage” according to Jane Ballantyne, a professor of anesthesiology and pain medicine at the University of Washington, Seattle, who has studied opioids for over 25 years. “It’s similar to sunburn in that when somebody knocks against you it can be very painful. Typically, OIH patients can’t bear to be touched” she added. The prevalence of this rather alarming side effect of opioid use, or who exactly will suffer from it, is still poorly understood, although long-term opioid use does appear to be a significant risk factor.

The largest opioid-induced hyperalgesia study to date involved over 10,000 men and women. Participants were asked to place their hands in ice-cold water for as long as they could as a measure of their cold pain tolerance. Those who reported regular opioid were unable to tolerate the cold water for as long as an opioid nonuser could. The opioid users also had a lower cold pain tolerance compared to regular users of other pain drugs, such as acetaminophen. This suggests that opioid exposure can indeed heighten sensitivity to pain.

Another study of 187 adults with chronic pain reported an increased sensitivity to heat in patients regularly taking opioids compared to opioid nonusers. Other studies have examined the prevalence of opioid-induced hyperalgesia in smaller groups, ranging from healthy volunteers to patients who receive high opioid doses during surgery to former opioid addicts. Increased pain sensitivity is observed in all these groups, particularly after sustained or high dose opioid use. And anecdotal reports of patients on long-term opioid treatment complaining of inadequate pain relief and severe breakthrough pain add to the breadth of evidence supporting opioid-induced hyperalgesia. 

However, most of these studies are limited by having only small numbers of participants and relatively short investigation times, making their relevance to the clinic uncertain. In contrast, several reports have demonstrated no development of opioid-induced hyperalgesia in cancer pain patients and chronic low back pain patients who take opioids regularly, leading some to conclude that tolerance may be a more pressing concern for these patients. This is a common phenomenon in pharmacology, in which higher doses of a drug are needed to produce the same effect. Indeed, the difficulty in distinguishing opioid-induced hyperalgesia from tolerance makes it challenging to estimate the number of people who experience it.

Opioid-induced hyperalgesia and tolerance are intricately linked, however; both reduce the effectiveness of the drugs. “Theoretically,” says Ballantyne, “a reduction in dose should be sufficient to combat opioid-induced hyperalgesia, while an increase in dose should overcome tolerance. But often in practice we see that giving higher doses of opioids can also overcome the hyperalgesia. “However, this only serves to exacerbate the vicious cycle of taking more opioids to combat the hyperalgesia, along with increasing the risk of other serious side effects.”

The similarity to tolerance, difficulty in diagnosis and contradictory reports in the scientific literature, have all contributed to a level of skepticism of the importance of opioid-induced hyperalgesia in chronic pain patients. Some pain physicians argue that it's not a serious enough risk to stop opioid use. In 2017 The U.S. Food and Drug Administration sent a letter to drug companies with approved opioid medications, requiring them to conduct post-marketing studies to better assess the risks of opioid side effects including opioid-induced hyperalgesia—an indication of the growing awareness surrounding this issue.

By far, the most compelling evidence for opioid-induced hyperalgesia comes from animal studies, which have shed light on potential mechanisms. Countless studies show that giving rodents repeated doses of opioids will make them more sensitive in common pain tests, and that the neurotransmitter glutamate is likely a key culprit. Glutamate is the most abundant neurotransmitter in the brain, facilitating communication between nerves. Blocking the action of glutamate can diminish or prevent opioid-induced hyperalgesia.

In addition to glutamate, glial cells (star-shaped immune cells in the brain and spinal cord) may be another potential driver of opioid-induced hyperalgesia. When activated, glial cells can release proinflammatory substances that act on many different nerves, creating a hypersensitive environment that may account for the widespread and diffuse pain of opioid-induced hyperalgesia. The key to treating the increased pain sensitivity beyond stopping opioid treatment, which is impractical for many patients, will be to target this hypersensitive inflammatory state without interfering with the desirable analgesic properties of these drugs.

Although opioid-induced hyperalgesia can represent a serious problem for some, it is important to highlight that the pain-relieving effects of opioids generally override the pain-inducing ones and that these drugs can offer a lifeline to people suffering from unimaginable pain. More specifically, as opioid consumption has increased drastically in the U.S. in the past decade, Ballantyne believes that reducing opioid usage could have the biggest impact on opioid-induced hyperalgesia. “The greatest success with opioids appears to be with intermittent and not continuous use, but to empirically prove this remains a big research question,” she says. “Can you prevent opioid-induced hyperalgesia and the need for high doses by not using opioids continuously? Knowing this would help to avoid the destructive side effects seen with long-term opioid use and enable us to treat opioid patients better than we do now.”

For a deeper look at opioids and pain, see How to Break the Bonds of Opioids in our January 2020 issue.