Sleep loss raises pain sensitivity; rest and caffeine may work better than painkillers.
Chronic sleep loss increases pain sensitivity, according to a new mouse study from Harvard Medical School researchers at Boston Children’s Hospital and Beth Israel Deaconess Medical Center.

The study suggests that chronic pain sufferers can get relief by getting more sleep, or, short of that, by taking medications to promote wakefulness, such as caffeine.

Both approaches performed better than standard painkillers in a rigorous study in mice, described in the journal Nature Medicine on 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 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.

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 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 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.”

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.