Mark Hutchinson could read the anguish on the participants' faces in seconds. As a graduate student at the University of Adelaide in Australia in the late 1990s, he helped with studies in which people taking methadone to treat opioid addiction tested their pain tolerance by dunking a forearm in ice water. Healthy controls typically managed to stand the cold for roughly a minute. Hutchinson himself, "the young, cocky, Aussie bloke chucking my arm in the water," lasted more than 2 minutes. But the methadone patients averaged only about 15 seconds.
"These aren't wimps. These people are injecting all sorts of crazy crap into their arms. … But they were finding this excruciating," Hutchinson says. "It just fascinated me." The participants were taking enormous doses of narcotics. How could they experience such exaggerated pain?
The experiment was Hutchinson's first encounter with a perplexing phenomenon called opioid-induced hyperalgesia (OIH). At high doses, opioid painkillers actually seem to amplify pain by changing signaling in the central nervous system, making the body generally more sensitive to painful stimuli. "Just imagine if all the diabetic medications, instead of decreasing blood sugar, increased blood sugar," says Jianren Mao, a physician and pain researcher at Massachusetts General Hospital in Boston who has studied hyperalgesia in rodents and people for more than 20 years.
But how prevalent hyperalgesia is, and whether it plays a role in the U.S. epidemic of opioid abuse and overdose, is unclear. A lack of reliable testing methods and a series of contradictory papers have created believers and skeptics. A few researchers, like Mao, think hyperalgesia is an underappreciated puzzle piece in the opioid epidemic—a force that can pile on pain, drive up doses, and make it harder for chronic users to come off their drugs. Some of those researchers are looking for ways to turn down hyperalgesia, to help patients function on lower doses of their oxycodone, for example, or make it easier to taper off it altogether. Others see OIH as an oddity in the literature—real, and a powerful clue to the workings of pain pathways, but unlikely to tighten the grip of opioids on most patients. Hutchinson thinks the majority of physicians are either unaware of hyperalgesia or unconvinced of its importance. "I think if you surveyed prescribers of opioids, they would be divided probably 60–40."