It’s 3 a.m. on another sleepless night. What will it take to finally catch some Zs? For most, a jolt of caffeine is the worst possible option, but at least for the mice in a recent Nature Medicine study, who suffered from a certain type of sleeplessness, it actually the tonic that eventually helped them get to bed. They were forced to stay awake so the researchers could study how sleep deprivation affects their sensitivity to pain — which it did, a lot. And because the mice were in pain, they couldn’t sleep.

The vicious pain-sleeplessness cycle, which many humans experience, is what the research team, from the Boston Children’s Hospital, wanted to investigate. They already knew that people living with chronic pain conditions had trouble sleeping at night and that feeling tired the next morning only made the pain feel worse. In the study they published Monday, they investigated what they could use to treat that pain and break the cycle.

Normally, doctors turn to painkillers, like ibuprofen or morphine, to do the trick. But the problem with these is that they seem to be less effective when they’re given to sleep-deprived patients. In the study, they didn’t make the tired mice (who were kept up for hours on end with mouse “entertainment,” like chew toys and nesting objects) any less sensitive to pain, which the researchers measured by analyzing how long it took for them to respond to heat, cold, pressure, and a pain-inducing chemical (capsaicin, from chili peppers) compared to their healthy, well-rested control counterparts. The researchers reasoned that a larger dose of painkillers must be needed for treating sleep-deprived patients, which can have scary side effects.

What did make the mice less sensitive to pain, however, were drugs that increased their alertness, like the ubiquitous caffeine and the narcolepsy-turned-“smart”-drug modafinil. And by making the mice less sensitive to pain, these wakefulness drugs, counterintuitively, were thought to lead to a better sleep.

Chronic pain and sleeplessness
Caffeine and modafinil promoted better sleep in mice with chronic pain.

“This represents a new kind of analgesic that hadn’t been considered before, one that depends on the biological state of the animal,” said Clifford Woolf, Ph.D., director of the Kirby Center at Boston Children’s Hospital, in a statement. “Such drugs could help disrupt the chronic pain cycle, in which pain disrupts sleep, which then promotes pain, which further disrupts sleep.”

The idea that alertness drugs can help treat pain isn’t totally new. Researchers have known since the 1960s that caffeine can act as an adjuvant — a compound that’s administered with another to boost its effects — when paired with analgesics. For that reason, common painkillers, like aspirin, acetaminophen, and other NSAIDs, are sometimes sold in caffeinated forms.

However, it’s been less clear that alertness drugs have any painkilling ability on their own. In this particular study, caffeine and modafinil seemed to do just that. But more surprisingly, giving the sleep-deprived mice these drugs dulled their pain sensitivity “without affecting sleep debt.” Strangely, the drugs didn’t have the same effect on well-rested mice: They felt the same level of pain with or without them.

Scientists still don’t know why wakefulness drugs have an effect on pain sensitivity — in the paper, they speculate that it might have something to do with their involvement with the dopamine system — but they do know that they’re effective enough to start trying on humans. While they’re not suggesting that chronic pain sufferers make the twilight coffee a habit, they’re saying that these people could break the pain-sleeplessness cycle with a one-two punch — wakefulness drugs and analgesics to kill pain during the day, coupled with sleep-promoting drugs at night.