The Strange Connection Between Opioid Addiction And Narcolepsy Might Help Us Treat Both

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A new study could revive an abandoned theory about how to treat narcolepsy, the thus-far incurable disorder that makes people chronically sleepy. And it could also provide a new lead on how to treat drug addiction.

The paper, published Wednesday in Science Translational Medicine, suggests that opioids can restore a narcoleptic person's ability to produce a neurotransmitter crucial to regulating sleep. And because that same neurotransmitter seems to play a role in making people without narcolepsy vulnerable to addiction, finding a way to create the opposite effect might just help treat addiction to boot.

Narcolepsy affects at least 200,000 Americans. People with the disorder feel perpetually exhausted, often dozing off throughout the day. But their fatigue isn't caused by a lack of sleep — on average, they sleep the same amount per day as anyone else. Instead, it's because they can't regulate their rapid eye movement (REM) sleep, an especially restorative stage of sleep (it's also when we most dream).

Because of this lack of control, narcoleptic people experience sleep paralysis, hallucinations, and sleepwalking, which are all signs of REM sleep bleeding over into their waking lives. Two-thirds of narcoleptic people also experience cataplexy, meaning they suddenly, unexpectedly lose control of their muscles while awake. The constant nodding off, coupled with cataplexy episodes, accounts for the stereotypical depiction of narcoleptics falling asleep at any moment.

The symptoms of narcolepsy, especially cataplexy, are caused by having incredibly low levels of hypocretin (also called orexin), a chemical produced in the brain that helps govern our sense of wakefulness, among other things. And the researchers of this current study had earlier found that the deceased brains of narcoleptics had 90 per cent fewer hypocretin-producing cells than healthy subjects.

One of the controls they used in that study as a comparison, however, turned out to be an interesting case themselves. The person, who had lived with heroin addiction, had much higher amounts of hypocretin-producing cells than the other controls. Building on that strange discovery, they decided to look at the brains of four people who had had with opioid addiction, finding the exact same pattern. These brains had more hypocretin-producing cells — an average of 54 per cent more — than control subjects.

"So it was natural to ask if opiates would reverse narcolepsy," senior author Jerry Siegel, a neuroscientist at the Brain Research Institute at the University of California, Los Angeles, told Gizmodo.

As it turned out, they did, at least in mice.

Narcoleptic mice dosed with morphine for at least two weeks had their level of hypocretin-producing cells brought back to normal, Siegel and his team found. They also had fewer episodes of cataplexy. And the effects seemed to last for weeks after the doses had stopped.

"In the past there were two studies showing that narcoleptics 'accidentally' prescribed opiates (for pain) had a reversal of symptoms, including cataplexy," Siegel said, referencing case reports published in the early 1980s. These studies prompted a trial of opioids (using the drug codeine) for narcolepsy patients published in 1986. Unfortunately, the trial was largely deemed a failure, since there were no objective changes in how sleepy people were after taking opioids.

At the time, Siegel says, doctors were understandably worried about unnecessarily giving addictive opioids to patients. That fear might have encouraged researchers to give up studying the connection between opioids and narcolepsy after a single poor study. But even in the "failed" study, he notes, patients who took opioids still reported feeling better than those who didn't. And his team's research suggests the full effects of opioids might simply take longer to show up than the study was allowed to run (patients were given only one week's worth of codeine).

People with narcolepsy have a dysfunctional immune system that kills off the cells responsible for making hypocretin. But opioids likely don't help the brain create more of these neurons, since Siegel's team found no evidence of new neuron growth in the mice. Instead, they seem to reawaken some of the surviving-but-dormant neurons' ability to produce the chemical.

"Understanding why opiates 'awaken' these cells is a task for the future," Siegel said.

Thomas Scammell, a narcolepsy expert at Harvard Medical School and Beth Israel Deaconess Medical Center, is encouraged by the findings, though he cautions reading too much into them.

"They do make a good case that opioids — at least in mice — can suppress cataplexy, but I'm not completely sold that it's due to an increase in hypocretin signalling," he told Gizmodo. Even if it was certain that opioids are reversing cataplexy, though, that doesn't mean we'll be able to use them as a narcolepsy treatment, given their risks.

"No mother of a 15-year-old with narcolepsy would sign onto us giving them several doses of morphine a day," he said, especially when there are other widely available and generally safe treatments around. And while some research has suggested that narcoleptics are known to be less likely to develop drug addiction than the general public, despite the fact they're often on powerful drugs such as stimulants to keep them awake, Scammell's own research has cast doubt on that theory.

While Scammell doesn't rule out the possibility that opioids could be used to help narcoleptic people who haven't responded to conventional treatments, he's much more excited by the implications Siegel's research could have for understanding and treating addiction.

"If chronic use of opioids is increasing hypocretin production — and the authors show that nicely — then that could amplify the rewarding aspects of these drugs, making addiction all that much worse," Scammell said. "I think that's actually the most interesting part of their research."

Plenty of research in animals and humans has indicated that hypocretin is an important cog in the reward system that gets hijacked by addictive drugs, alongside the neurotransmitter dopamine. So finding a way to safely reduce the number of hypocretin-producing cells or otherwise blocking its production, the team theorizes, might just short-circuit a person's cycle of addiction.

For now, Siegel and his team are once again looking to forge ahead with human trials of opioid therapy for narcoleptics, hoping to find the best dose and strength of opioid needed to reverse symptoms safely (the ideal goal would be to develop a drug with no addiction potential). In animals, they're also trying to find a way to reverse drug addiction through tweaking the hypocretin system.

[Science Translational Medicine]

This post has been updated.

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