The ongoing opioid epidemic underscores the dire need for new pain medications that aren’t addicting. New research published today in Nature Medicine suggests a possible avenue of relief for people with chronic pain: simply getting more sleep, or, failing that, taking medications to promote wakefulness.
In an unusually rigorous mouse study, either approach relieved pain better than ibuprofen or even morphine. The findings reveal an unexpected role for alertness in setting pain sensitivity.
Modeling everyday sleep deprivation
Pain physiologist Alban Latremoliere, PhD, of Boston Children’s Hospital and sleep physiologist Chloe Alexandre, PhD, of Beth Israel Deaconness Medical Center precisely measured the effects of acute or chronic sleep loss on sleepiness and on sensitivity to both painful and non-painful stimuli.
The husband-wife team started by measuring normal sleep cycles in the mice, using tiny headsets that took electroencephalography (EEG) and electromyography (EMG) readings. “For each mouse, we have exact baseline data on how much they sleep and what their sensory sensitivity is,” says Latremoliere, who works in the lab of Clifford Woolf, PhD, in the F.M. Kirby Neurobiology Center at Boston Children’s.
Then, unlike other studies that force mice to stay awake walking treadmills or falling from platforms, the researchers deprived mice of sleep in a way that echoes the human experience: They entertained them.
“We developed a protocol to chronically sleep-deprive mice in a non-stressful manner, by providing them with toys and activities at the time they were supposed to go to sleep, thereby extending the wake period,” says Alexandre, who works in the lab of Thomas Scammell, MD, at BIDMC. “This is similar to what most of us do when we stay awake a little bit too much watching late-night TV each weekday.”
To keep the mice awake, the researchers kept vigil, gently distracting them with new, custom-made toys when they became drowsy. This meant getting to know the individual mice very well, and being careful not to overstimulate them.
“Mice love nesting, so we would give them materials like a wipe or cotton ball,” says Latremoliere. “Rodents also like chewing, so we introduced a lot of activities based around chewing, for example, having to chew through something to get to a cotton ball.”
In this way, they kept groups of six to 12 mice awake for as long as 12 hours in one session (acute sleep loss), or six hours for five consecutive days (chronic sleep loss). Along the way, they monitored the animals’ sleepiness and stress hormones (to make sure they weren’t stressed).
Analgesics vs. wake-promoting agents
Alexandre, Latromoliere and colleagues then tested standard pain medications, like ibuprofen and morphine, as well as wakefulness-promoting agents like caffeine and modafinil, a prescription medication for narcolepsy.
Team members who didn’t know what medication the mice had received measured their pain sensitivity. They exposed the mice to controlled amounts of heat, cold, mechanical pressure or capsaicin (the “heat” in hot chili peppers), then measured how long it took the animal to move away from (or lick away) the pain source.
For comparison, the team also tested responses to non-painful stimuli, like a sudden loud sound.
“We found that five consecutive days of moderate sleep deprivation can significantly exacerbate pain sensitivity over time in otherwise healthy mice,” says Alexandre. “The response was specific to pain, and was not due to a state of general hyperexcitability to any stimuli.”
Ibuprofen didn’t block this sleep-loss-induced pain hypersensitivity, and even morphine lost most of its efficacy in sleep-deprived mice. But both caffeine and modafinil did block pain hypersensitivity caused by both acute and chronic sleep loss. Interestingly, these compounds had no analgesic properties in mice that weren’t sleep deprived.
“This represents a new kind of analgesic that hadn’t been considered before, one that depends on the biological state of the animal,” says Woolf, director of the Kirby Center at Boston Children’s. “Such drugs could help disrupt the chronic pain cycle, in which pain disrupts sleep, which then promotes pain, which further disrupts sleep.”
A new approach to chronic pain?
Rather than just taking painkillers, patients with chronic pain might benefit from better sleep habits and/or taking sleep-promoting medications at night, the investigators conclude. These efforts could be coupled with daytime alertness-promoting agents to try to break the pain cycle.
“This study suggests a novel approach to pain management that would be relatively easy to implement in clinical care,” says Kiran Maski, MD, a Boston Children’s specialist in sleep disorders who was not part of the study. “Many patients with chronic pain suffer from poor sleep and daytime fatigue, and some pain medications themselves can contribute to these co-morbidities.”
Maski adds that clinical studies are needed to understand what sleep duration people would need to ameliorate their pain and to test the efficacy of wake-promoting medications. It’s also still not clear how these medications work, though it’s known that both caffeine and modafinil boost dopamine circuits in the brain.
The study was funded by the National Institutes of Health, with support from the Neurodevelopmental Behavior Core and Pharmacokinetics Core at Boston Children’s and the metabolic Physiology Core at BIDMC.