Both approaches performed better than standard painkillers in a rigorous study described in Nature Medicineon May 8.
Pain physiologist Alban Latremoliere, HMS research fellow in neurology at Boston Children’s, and sleep physiologist Chloe Alexandre, HMS instructor in neurology at Beth Israel Deaconess, who were co-first authors of the study, precisely measured the effects of acute or chronic sleep loss on sleepiness and sensitivity to both painful and nonpainful stimuli.
They then tested standard pain medications such as ibuprofen and morphine, as well as wakefulness-promoting agents like caffeine and modafinil.
Their findings reveal an unexpected role for alertness in setting pain sensitivity.
The research was supported by a National Institutes of Health program that required a pain scientist to join a nonpain scientist to tackle a completely new area of research, said Thomas Scammell, HMS professor of neurology at Beth Israel Deaconess and co-senior author of the study.
“This cross-disciplinary collaboration enabled our labs to discover unsuspected links between sleep and pain, with actionable clinical implications for improving pain management,” Scammell said.
The team started by measuring normal sleep cycles, 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,” said Latremoliere, who works in the lab of Clifford Woolf, professor of neurology at HMS and Boston Children’s and co-senior author of the study.
Next, unlike other sleep studies that force mice to stay awake by walking treadmills or falling from platforms, Alexandre, Latremoliere and colleagues deprived mice of sleep in a way that mimics what happens with people: They entertained them.
“We developed a protocol to chronically sleep-deprive mice in a nonstressful manner by providing them with toys and activities at the time they were supposed to go to sleep, thereby extending the wake period,” said Alexandre, who works in the Scammell lab.
“This is similar to what most of us do when we stay awake a little bit too much watching late-night TV each weekday,” Alexandre said.
To keep the mice awake, researchers kept vigil too, providing the mice with custom-made toys as interest flagged, while being careful not to overstimulate them.
“Mice love nesting, so when they started to get sleepy, as seen by their EEG/EMG pattern, we would give them nesting materials like a wipe or cotton ball,” said 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, or six hours for five consecutive days, monitoring sleepiness and stress hormones (to make sure they weren’t stressed) and testing for pain along the way.
Pain sensitivity was measured in a blinded fashion by exposing mice to controlled amounts of heat, cold, pressure or capsaicin—the agent in hot chili peppers—and then measuring how long it took the animal to move away or lick away the discomfort caused by capsaicin. The researchers also tested responses to nonpainful stimuli, such as jumping when startled by 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,” said Alexandre. “The response was specific to pain, and was not due to a state of general hyperexcitability to any stimuli.”
Analgesics vs. wake-promoting agents
Common painkillers such as ibuprofen did not block the pain hypersensitivity induced by sleep loss. Even morphine lost most of its efficacy in sleep-deprived mice.
If similar results are observed in people, it would suggest that patients using these drugs for pain relief have to increase their dose to compensate for sleep loss, thereby increasing their risk for side effects.
In contrast, caffeine and modafinil, drugs used to promote wakefulness, successfully blocked the pain hypersensitivity caused by both acute and chronic sleep loss.
In non sleep-deprived mice, caffeine and modafinil had no painkilling properties.
“This represents a new kind of analgesic that hadn’t been considered before, one that depends on the biological state of the animal,” said Woolf, director of the F.M. Kirby Neurobiology 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?
Based on their findings in mice, the researchers hypothesize that rather than just taking painkillers, patients with chronic pain might benefit from better sleep habits or taking sleep-promoting medications at night, coupled with daytime alertness-promoting agents to try to break the pain cycle.
Some painkillers already include caffeine as an ingredient, although its mechanism of action isn’t yet known. Both caffeine and modafinil boost dopamine circuits in the brain, which may provide a clue.
“Many patients with chronic pain suffer from poor sleep and daytime fatigue, and some pain medications themselves can contribute to these co-morbidities,” said Kiran Maski, a specialist in sleep disorders at Boston Children’s. “This study suggests a novel approach to pain management that would be relatively easy to implement in clinical care.”
“Clinical research is needed to understand what sleep duration is required and to test the efficacy of wake-promoting medications in chronic pain patients,” Maski added.
This work was supported by grants from the National Institutes of Health (R01DE022912, R01NS038253). The Neurodevelopmental Behavior and Pharmacokinetics Cores at Boston Children’s Hospital, the Metabolic Physiology Core at Beth Israel Deaconess (P30DK057521) and P01HL09491 also supported this study.
Adapted from a joint Boston Children’s/Beth Israel Deaconess news release.