It’s long been a mystery why one of the most basic human experiences—feeling physical pain—fluctuates in intensity throughout the day. Since the early days of medicine, doctors and patients have noticed that many types of pain tend to get worse at night. Most research so far has tried to link mounting nighttime pain to sleep deprivation or disrupted sleep, but with limited success.
In a recently published study, scientists led by Claude Gronfier at the Lyon Neuroscience Research Centre in France have finally shed light on changing pain sensitivity, suggesting that our circadian clock strongly shapes these shifts, with a characteristic peak and trough of intensity at different times of day.
Even people who can’t dance have internal rhythms thrumming through every system in their body. Known as circadian rhythms, these biological processes tune their activity to rise and fall at precise times across the day, driven by the body’s internal clock. They influence pretty much every bodily system, exerting control over “almost all aspects of our physiology and behavior,” says Lance Kriegsfeld, a circadian biologist at the University of California, Berkeley.
The work by Gronfier and his team revealed the influence of these rhythms on pain by showing that a short, painful heat stimulus was perceived to be most painful around 3 am and least painful at approximately 3 pm. “It’s very exciting,” says Nader Ghasemlou, a pain scientist at Queens University in Kingston, Canada, who wasn’t involved in the research. “It is one of these studies that is answering questions that we’ve had for a long time.”
Uncertainties have persisted for so long because proving that anything is driven by the body’s internal clock is difficult and requires a grueling study design. Researchers must put participants in a controlled laboratory setting where they can rule out any environmental or behavioral factors that could also cause a rhythmic fluctuation. This approach is called a “constant routine protocol,” where everything is kept constant—lighting, temperature, access to food—and it’s impossible to tell what time it is. Participants must lie down in a semi-recumbent position in a dimly lit room for at least 24 hours. They’re not allowed to sleep, leave, or stand to use the bathroom. Food is given only as small snacks every hour. Participants can chat with study team members, but staff are strictly forbidden from mentioning anything related to the time. Under the protocol, nothing in the environment or the participants’ behavior is rhythmic anymore, Gronfier explains. So if the researchers spot a biological measure that has a 24-hour rhythm, that pattern “emanates from within, and precisely from the circadian timing system.”
To uncover pain’s rhythmic nature, Gronfier’s team found 12 healthy young men who agreed to undergo the protocol for 34 hours. Every two hours, the team tested their pain sensitivity using a device placed on the forearm that slowly increased in temperature by one degree Celsius until they reported pain. Participants usually stopped the device before it reached around 46 degrees Celsius (115 degrees Fahrenheit). The participants were also tested with the device set at specific temperatures (42, 44, and 46 degrees Celsius), and then asked to rate on a visual scale the level of pain they felt.
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Before the team could look for rhythms in this data, they had to get a measure of each person’s body clock. While everyone’s rhythms follow a daily cycle, some are skewed earlier or later in the day—leading to “morning larks,” “night owls,” and everyone in between. The team did this by collecting hourly saliva samples to evaluate the rise of melatonin, a hormone released about two hours before someone’s normal bedtime, and then used this information to synchronize everyone’s rhythms against a single 24-hour clock. A clear cycle of pain then emerged. On average, sensitivity peaked between 3 am and 4 am on this standardized measure before reaching its lowest point about 12 hours later.
The team also showed that these rhythms were specific to painful stimuli. Participants also performed a task where the temperature slowly rose until they detected warmth, but at these non-painful thresholds, there wasn’t any rhythmic pattern to the intensity of what people felt.
“It makes so much sense, and yet it is relatively non-intuitive—because if it were so obvious, it would have been proven a long time ago,” says Beth Darnall, director of the Pain Relief Innovations Lab at Stanford University. “This is so novel, but it has so much face validity.”
Since the participants weren’t allowed to sleep through the night, the researchers were also able to tease out whether any rises in pain were related to sleep deprivation—the prevailing theory before the new paper. The study team reasoned that any increased pain sensitivity caused by sleep deprivation would slowly build up linearly across the night as pressure to sleep increased. This would contrast with a waxing and waning pattern driven by the circadian system, and so the researchers used mathematical modeling to see to what extent the changes in participants’ pain perception appeared to be explained by a slow increase versus a rhythmic change. The results were an impressive win for the circadian system: 80 percent of the data could be explained by the circadian drive, with just 20 percent explained by the sleep drive.
“We were surprised by that ratio. Indeed, I was thinking that we would have much more drive-by sleep,” says Gronfier. “But it doesn’t mean that sleep isn’t important, because we did our study in very good sleepers.” Repeating the study in people who are chronically sleep-deprived or have a sleep disorder, he adds, might show that the need for sleep has a much larger impact on pain for some.
It will be necessary to repeat the study in a sample of women, too. Because hormones like estrogen are known to affect circadian rhythms, it’s possible researchers won’t find the same pattern of pain rhythmicity. “We see sex differences every time we do anything with men and women,” says Debra Skene, a circadian biologist at the University of Surrey in England who wasn’t involved in the research. “But to me, I think it would be about the amplitude—or how big that curve is—I don’t think it’s going to change the time that we’re most sensitive.”
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And though the study was small, with a sample of just 12 men, the rhythmic effects were so strong that researchers like Skene are confident the team uncovered a true circadian influence on pain, which can now be studied in older populations and people of different ethnicities.
In the future, Darnall hopes that studying the circadian nature of pain caused by health conditions—say cancer or shingles—will have an impact on how that pain is treated. “Circadian pathology may be a more important therapeutic target than has been appreciated before,” she says. It might be that it’s better to give pain treatments based on the body’s internal clock rather than the one on the wall. That’s just one of the things researchers like John Hogenesch, a circadian biologist at Cincinnati Children’s Hospital, are now pushing for.
In 2019, Hogenesch and his colleagues published a paper showing that hospital prescriptions for pain medications surged in the morning and dwindled at night. In other words, the hospital had its own 24-hour rhythm—but not one accurately reflecting the needs of its patients. “We know that pain is reported most often in the night, and despite that, the pain wasn’t really treated until the next day,” Hogenesch says. He’s hopeful the new paper from Gronfier’s lab will be read by clinicians, who may then decide to prescribe painkillers overnight. He also hopes the findings will encourage more research on the topic of pain fluctuation.
But as more work starts to trickle in, we can’t assume it will show that every type of pain reaches its apex at night. Some people with inflammatory pain conditions like migraines and arthritis report more pain in the morning, so it’s possible that variation depends on the type of tissue or bodily system involved. And of course, looking at different groups of people could reveal unique rhythms.
As for what’s causing the rise and fall of pain, scientists still aren’t sure. But there are clues. Nearly every cell in your body has its own molecular clock that listens to signals from the master pacemaker in our brain. So Zameel Cader, a neuroscientist and neurologist at the University of Oxford, and his colleagues hypothesized that the amount of pain we feel might be due to the rhythm of the cells detecting the pain. A recent preprint (an early piece of research still awaiting review by independent scientists) from his lab supports this—pain fluctuations over 24 hours in mice were shown to rely on the molecular clocks found in nerve cells activated by a painful stimulus. When they used a technique that deleted the molecular clocks in the mice’s peripheral nerve cells, the rodents’ pain levels were stable throughout the day.
Perhaps the biggest takeaway for now is that whenever pain strikes, the role of the circadian system means that what goes up must come down. On the slow roller-coaster ride of pain perception, you might be just a few hours away from relief without popping a single pill. Then again, it might be about to get worse.