STOWE, VT—Neurologists and headache specialists have probably all seen patients who say that their headaches are linked to sleep, either when they go to sleep or when they wake up. Data suggest that roughly 50% of patients with obstructive sleep apnea will have headaches, and up to 80% of patients with narcolepsy will also have headaches. So what’s the connection? Speaking at the Headache Cooperative of New England’s 20th Annual Headache Symposium, Brian W. Smith, MD, said there is marked overlap between sleep and headaches. Dr. Smith is Co-Director of Sleep Medicine Services of Western Massachusetts in Amherst.
Anatomically, migraine headaches and sleep start down in the brainstem and spread up the thalamus, hypothalamus, and cortex. The pathways are very similar. A lot of migraine disorders and sleep seem to have the same mechanisms. But what’s really going on?
REM and Headache
REM sleep is also called paradoxical sleep, because the brain is actually more active during REM sleep than it is during wakefulness. “Cerebral glucose metabolism increases in REM versus during wakefulness,” Dr. Smith said. “At the same time the body is paralyzed.” So what is the relationship? Why does REM cause more headaches? “It might be a few things,” Dr. Smith speculated. “One is during REM sleep, serotonin is shut off.” The dorsal raphe nucleus, which secretes serotonin, is quiescent during REM. “We all know that we use serotonergic agents to treat headaches. So is it this withdrawal of serotonin that occurs during REM sleep that causes headache?”
Regarding the body paralysis seen during sleep, Dr. Smith points out that airways become more collapsible. “We see worsening of sleep apnea,” he said. “And we also see decreased respiratory capabilities during REM sleep, more hypoxia, and hypercapnia. And these too may cause headache. During REM sleep, is it this trigger of the withdrawal of serotonin that causes headaches? Or is it a little bit of hypoxemia/hypocarbia that then results in cerebrovasal dilation?” These are all possibilities, Dr. Smith said, and there is overlap in those areas.
Melatonin is frequently used to treat headache. There are data suggesting that patients, especially those with cluster headaches, have decreased melatonin secretion and delayed melatonin secretion. Patients with menstrual migraine probably also have decreased melatonin secretions. “So we see some efficacy at times using melatonin to treat various headache disorders,” Dr. Smith said. He noted that melatonin is synthesized from serotonin. So this may tie in to the serotonin withdrawal theory of sleep-related headache.
There are two things that control the sleep/wake cycle. “One is our circadian rhythm and the other is our homeostatic sleep drive. The longer you’re awake, the sleepier you get,” Dr. Smith said. This sleep drive appears to correlate with accumulation of adenosine in the brain.
“Adenosine is ubiquitous. It’s a breakdown product of ATP, and its effect depends on what organ is involved and what receptors,” he explained. “In the basal forebrain, if you accumulate adenosine it promotes sleepiness. How does that correlate with headache? Well, there are four primary adenosine receptors in the brain, and they’re basically pain modulators. So some will inhibit pain, and some will actually have an activating effect on pain.” And this, he said, is evident when treating headache patients.
“If you think about what we use for some of our headache patients, one thing is caffeine,” Dr. Smith commented. “Caffeine is a major inhibitor of adenosine. So when we’re giving caffeine for headaches, part of its effect may be related to inhibition of adenosine. When patients go through caffeine withdrawal, the increase we see in headaches may again be associated with a relative increase in adenosine levels.”
Dr. Smith also pointed to another drug on the market—dipyridamole, which is part of Aggrenox for stroke prophylaxis.
“Dipyridamole is an adenosine reuptake inhibitor,” he noted. “And Aggrenox’s major side effect is headache. Almost 40% of people get headache.”
Orexin/hypocretin are excitatory neuropeptide hormones that promote wakefulness and inhibit REM sleep. A deficit of orexin/hypocretin is associated with narcolepsy. “When people have narcolepsy, one of the symptoms is cataplexy, in which they develop muscle weakness. It’s just an intrusion of REM sleep,” Dr. Smith said. How does that correlate with headache disorders? “The data suggest that up to 80% of people with narcolepsy will have headache,” he noted. Research suggests that orexin/hypocretin is involved in modulation of pain activity, including the trigeminal nucleus caudalis. Further evidence links orexin/hypocretin receptor 2 gene polymorphisms to cluster headache.
“So if we look at all of these varied overlaps between [sleep and headache] it just makes us think, well, if we have patients with headaches should we think about further workups? Should we think about sleep and what’s happening with that patient. What is this patient’s sleep hygiene?” According to Dr. Smith, a lot of data suggest that patients with chronic headaches are not great sleepers. Decreased total sleep time and complaints about poor sleep are common among headache patients. “If you’re not comfortable dealing with their sleep issues, then maybe refer them to a sleep clinic,” Dr. Smith suggested.