This article from NYTimes.com
January 12, 2003
By SANDEEP JAUHAR
Three years ago a strange cycle of headaches started to grip Linda Norton. In July 1999, after her husband received a promotion, she moved from a cozy house in the woods of New Hampshire to an upscale development in Hackettstown, N.J. A few days after the move, while unpacking boxes, she felt a mild throbbing in her head. Norton, a 42-year-old mother of three with glossy blond hair and a winsome smile, didn’t make much of it; she hadn’t had a headache since she was a teenager. She took some Tylenol, and the headache went away. But a few days later the pain came back – it felt like a vise clamped around the back of her head – and returned again a few days after that. It had to be the stress of moving, Norton concluded, figuring that her headaches would disappear once her family settled into their new home. But her headaches multiplied, and within a month she was having them every day. Over-the-counter medication provided temporary relief, yet the headaches kept coming back. At first Norton suspected the house and had it professionally cleaned several times. When that didn’t help, she sought medical advice. ”I wanted to figure out what was causing the headaches,” she told me recently at the Jefferson Headache Center in Philadelphia, one of the country’s best headache clinics. ”I thought, something has to be causing this.” She first went to an internist, who sent her for various brain scans. The scans were normal: there was no tumor. Then an ear, nose and throat specialist put her on anti
biotics and flushed out her sinuses. That had no effect, so Norton started consulting self-help books. She read that nuts, chocolate, aged cheeses and wine could trigger headaches, so she eliminated them from her diet. She started exercising and tried yoga and relaxation therapy. She even moved to a new town, hoping a change in environment would help. ”I did the whole gamut,” she said. ”I did anything and everything I could do to get rid of my headaches.” That included taking over-the-counter drugs. ”Tylenol was probably the first thing I tried, because it was the easiest thing for me to buy,” she said. Within weeks she was taking about eight pills a day. Then she tried Excedrin Migraine (a combination of acetaminophen, aspirin and caffeine) every six hours, as instructed on the bottle, but her headaches persisted. Eventually she tried other over-the-counter analgesics: Advil, Aleve, Sine-Off, Midrin. She didn’t want to take prescription drugs, because she was afraid she might ”get hooked.” Still in constant pain, Norton became a patient of Dr. Stephen Silberstein, director of the Jefferson Headache Center. His diagnosis stunned her. The probable cause of her headaches, he told her, was her headache medicine. Taking all those pills had thrown her body’s natural pain-control system out of whack, causing headaches to return as soon as the latest round of medication wore off. A tall man with an intimidating air of authority and a staccato speaking style, Silberstein is one of the country’s leading headache experts and the senior editor of the most authoritative book in the field. On a recent morning he led me into his cluttered office, where, from atop a bookshelf, a human skull grimaced at us.
Norton’s problem, Silberstein told me, is one he sees surprisingly often. ”Over-the-counter medication overuse is one of the leading causes of chronic daily headache,” he said. Chronic daily headaches are believed to affect 4 to 5 percent of Americans, including perhaps 10 percent of women over 30. (About four times as many women as men are afflicted.) Roughly half of chronic daily headache patients, Silberstein estimates, developed the problem from medication overuse. In fact, the majority of people who seek clinical treatment for daily headaches are found to be taking five or more doses of headache medication a day –often on a preventive basis.
Some of these patients were no doubt taking more pills than is recommended. But a German study published this year suggested that the ”critical intake frequency” for developing medication-overuse headaches was only three to four pills a day. Other research has shown that over-the-counter analgesics taken even five times a week can transform an episodic headache into a chronic one. Despite such troubling findings, the ”rebound headache,” as it is known, has yet to be widely discussed. ”Most people are not even aware of this,” Silberstein said. ”It is a silent epidemic.”
Most Americans had a headache last year. In fact, Americans appear to have more headaches than other people. Studies in Africa and Japan have shown headache rates one-third and half, respectively, that of the United States. Every year in this country headaches are the primary reason for at least 10 million doctor visits, more than any other pain symptom. Although stress is a leading trigger of headaches – which may explain why overworked, multitasking Americans suffer disproportionately from them – almost anything can cause one. Bright light, a lack of sleep and food allergies are all known triggers. Sometimes, however, the pain seems to be brought on by nothing at all.
Of all the different kinds of headaches, the migraine, from which at least 28 million Americans suffer, is one of the worst. When a person gets a classic migraine, a noxious stimulus – a bright light, a loud noise or an unfamiliar taste – sets off a wave of electrical excitation across the brain. In its wake, chemicals are released that stimulate the trigeminal nerve, which is responsible for transmitting head pain. (The trigeminal nerve extends across the face, crosses over the eyes and ventures into the center of the brain.) The nerve releases small molecules, including one called substance P (for ”pain”), that sensitize the nerve and cause neighboring blood vessels to dilate. These vessels then pulsate against the sensitized nerve endings, causing pain. ”It’s like hives of the lining of the brain,” Silberstein said. In the late 17th century, an English physician named Thomas Willis, considered by many to be the father of neurology, postulated that dilated blood vessels in the head were responsible for migraines. By the Victorian era, drugs had become popular treatments for headaches and migraines. In ”War and Peace,” Tolstoy describes a headache-suffering countess who puts vinegar compresses on her forehead. Other drugs that enjoyed spells of popularity include cyanide, arsenic, mercury, morphine, quinine, amyl nitrite, chloroform and tobacco. None of these particularly worked, of course. In the latter part of the 19th century, physicians in the United States and Europe started using ergot, a rye fungus that constricts blood vessels, to treat migraines. Aspirin was invented in 1899 and soon became the most popular treatment – until 1961, when a drug named Tylenol started being sold over the counter in drugstores. Throughout the 20th century, headache drugs became increasingly effective but were also increasingly abused. In a 1972 survey in Britain, 41 percent of adults reported having taken an analgesic within two weeks of being interviewed, half of them for headaches. By the early 1980’s, experts were warning that the frequent use of non-narcotic analgesics could, paradoxically, sustain chronic pain. Worse, daily consumption appeared to inspire a vicious cycle of tolerance and withdrawal, leading to even more use.
But only recently, as scientists have begun to elucidate the way the human brain reacts to pain, has a neurological explanation for ”over-the-counter headaches” begun to emerge. Recent studies, for example, suggest that a constant intake of analgesics lowers the brain’s level of serotonin, a neurotransmitter that inhibi
ts pain-conducting cells. Another study showed that even a two-week course of Tylenol causes a drop in serotonin-receptor density in rat brains; the effect is reversed when the drug is stopped. Much of this science remains to be worked out, but it is becoming increasingly clear that seemingly benign drugs like Tylenol and Advil can have profound effects on the brain’s pain-control pathways. ”People often ask me, ‘Why doesn’t my headache go away?”’ Silberstein said. ”A better question is, ‘Why does a headache ever stop?’ That, to me, is the crucial issue.”
Not too long ago, Andrea Nass, a psychology researcher who lives in Philadelphia, felt as if her headaches never stopped. She started getting migraines 15 years ago, when she was 13. Her attacks had classic features: nausea and vomiting, a strong aversion to light and sound, dizziness. Nass, who has bright blond hair and deep blue eyes, started taking Tylenol three or four times a week, but by her late teens, she told me, she felt she had become ”immune” to the drug and switched to Advil, which she took as directed, up to six pills on the days she had migraines.
In her mid-20’s, Nass developed a different kind of headache. She was still getting migraines about once a week, but she also started getting dull headaches, less intense than her migraines and more gradual in their onset, almost every afternoon. To control them she took more Advil, though she was careful not to take more than six pills a day. The Advil helped for a while, keeping her headaches ”mildly annoying” but ”tolerable.” Prescription drugs, she found, had too many side effects.
The daily headaches got worse, eventually causing her to withdraw socially. ”I was so afraid of getting into a situation with a headache and feeling trapped and being a burden on the people I was with,” she told me one morning at the Jefferson clinic. ”Friends get frustrated, boyfriends get frustrated — and you end up being even more of a hermit.”
In the summer of 2002 she went to Silberstein’s clinic. A doctor there immediately diagnosed drug-induced headaches and told her to stop taking Advil. He said it might take several months to break the rebound-headache cycle. At the clinic, I asked Nass how she felt when she learned that by taking Advil she was probably causing her own headaches. ”Angry and frustrated,” she replied. ”I have seen many neurologists over the years, and everyone always said, ‘Shame, shame, shame, you shouldn’t be taking so much Advil,’ but because of how it might affect my stomach or my liver. No one ever mentioned anything about the fact that it could be causing my headaches.”
Nass’ doctor suggested a short hospitalization to help her detoxify, but she decided to go ”cold turkey” on her own. ”It’s ridiculous to even have to use addiction lingo,” she said, ”but basically, I developed an addiction to Advil and had to try to stop.”
When I spoke with Nass, she said she hadn’t taken Advil for two months, trying alternative remedies like vitamins instead. ”I’m definitely using the grin-and-bear-it method right now,” she said, her face tightening into a half-smile. ”I’m trying to rid my system of everything.”
Her chronic headaches were abating, she reported. Instead of daily bouts of pain, she was now getting about three a week. She was still getting episodic migraines, however; her doctors told her those probably wouldn’t go away.
”I wish I had known about drug-induced headaches earlier,” Nass said. ”I turned to what seemed like the safest thing, over-the-counter medications, to control a painful situation. The next thing I know, I have an addiction that left me with more pain than I started with. The ironic thing is, in trying to be so safe, I got myself into more trouble.
”I don’t know how much I truly believed that if I just stopped taking Advil these headaches would go away,” Nass went on. ”My status quo was headaches on a daily basis. I found it hard to believe that anything was really going to make that much of a difference.” Does she believe it now? ”I’m starting to,” she said.
The leading theory of drug-induced headaches is based in part on an interesting experiment that Dr. Rami Burstein and his colleagues at Harvard Medical School performed in 1999. The scientists attached a tiny metal disc with an adjustable temperature to the forearms and to the skin around the eyes of 42 migraine patients and tested pain thresholds before and after the onset of a migraine attack. (They also tickled these areas with tiny plastic filaments.) Burstein’s group found that during a migraine attack four out of five patients had significantly reduced pain thresholds for heat, col
d and pressure. They termed the effect ”cutaneous allodynia.” (Allodynia is pain that comes from non-noxious stimuli.)
Burstein and his colleagues interpreted their results in the following way: when pain signals on the trigeminal nerve travel into the brain, they encounter special neurons that also receive signals from non-painful stimuli. Barraged with pain signals, these neurons become hyperactive, causing the brain to interpret otherwise tolerable sensations, like light pressure or heat from a warm metal disc, as agonizing. Patients with migraines often say that their hair hurts or that their scalp is tender or that it hurts to brush their teeth. This concept, called ”central sensitization” (because it occurs in the central nervous system), is now considered the backbone of the theory of chronic daily headaches and other such pain syndromes, like fibromyalgia.
In a follow-up experiment, Burstein’s group studied the effects of triptans, a kind of prescription migraine medication, given early and late in an attack. They found that when a triptan is given early, before cutaneous allodynia develops, it effectively terminates the migraine. But if given late in the attack, it provides little or no pain relief.
In another seminal paper, published in the journal Nature Medicine in 1995, researchers in London used P.E.T. brain scanning to show that during and after a migraine attack, blood flow increases to parts of the brain stem. They thought that activation of the brain stem might play a role in the onset of migraine pain. Later work suggested that one particular area of the brain stem, the periaqueductal gray, might inhibit migraine pain and prevent central sensitization. In 2001, Dr. K. Michael Welch, a migraine expert, and his colleagues at the University of Kansas showed that patients with chronic daily headaches have increased amounts of iron – a sign of neuronal damage – in the periaqueductal gray. (Silberstein referred to it as ”brain rust.”) Welch speculated that this area of the brain stem, when damaged, could function as a ”migraine generator.” Since then, Burstein’s group has shown that stopping the chronic consumption of painkillers can help normalize function in some areas of the brain stem.
Scientists are now largely convinced that the overuse of medication can interfere with the brain’s own pain-control system, paving the way for chronic headache syndromes. It’s ”like a mouse chasing its own tail,” Silberstein said – headaches lead to drugs, drugs lead to headaches, and only when the cycle is broken can the brain’s pain-damping mechanism re-establish itself. I asked Silberstein if this meant that the brain’s natural painkillers were better than ones bought over the counter. ”What I’m arguing is that you have to combine the body’s natural pain-inhibition system with appropriate use of drugs,” he said. ”You shouldn’t tough a headache out, but the process has to be treated early and appropriately. If you treat it late, with more and more drugs, all you’re going to do is interfere with the recovery process.” In the age of the quick fix, drug-induced headaches are a reminder that quick fixes don’t always work. Though medicine helps, medicine also disrupts. Popping a pill can make things better in the short term, but in the long term, drugs, even supposedly ”benign” drugs at recommended doses, can have strange, paradoxical effects. Laxative overuse, for example, often worsens constipation. Sleeping pills can cause insomnia.
This sort of lesson is appealing to people like my father, who have never trusted medicines to keep them well. Five years ago my father started having daily headaches that were probably triggered by job stress but became chronic because of medication overuse. Over the course of a year and a half he took megadoses of Tylenol, aspirin, Advil and Aleve. He then moved on to prescription medication: Flexeril (a muscle relaxant), Fiorinal, Imitrex, amitriptyline, Paxil and prednisone. During that period he was seen by three internists, two neurologists, two rheumatologists, an anesthesiologist and an ophthalmologist. No one could tell him what was wrong. Then one day, totally fed up, my father stopped all his medications. Two weeks later his headaches were gone.
”It was the medicine that was causing the headaches,” he sometimes tells me, still incredulous. But what is incredible to me is that my father got hooked on something like Tylenol in the first place. It is a sentiment that was also expressed by Linda Norton. ”You think it’s O.K. because you’re taking Tylenol,” she told me. ”You think, this is safe because I can buy it without a prescription.” Late this summer, after enjoying almost a month free of headaches, Norton inexplicably started taking Duradrin, which contains acetaminophen, the active ingredient in Tylenol. Pretty soon, her headaches came back, more severe than ever. ”It’s like a vicious cycle starting all over again,” Norton said sadly. ”I can’t decide if the headaches are from the medications. It’s like, ‘Am I doing it?”’
I asked Dr. Anthony Temple, vice-president for medical affairs at McNeil Consumer and Specialty Pharmaceuticals, the company that manufactures Tylenol, about Norton’s problem. He pointed out that acetaminophen does not meet the standard chemical definition of an addictive substance. ”There are no data that conclusively demonstrate that the routine use of acetaminophen by itself leads to chronic headaches,” he added. ”Virtually all of the data in patients with chronic headache is confounded by the mixed use of analgesics, m
aking careful consideration of actual cause and effect virtually impossible to assess.”
Whatever the technical definitions might be, Linda Norton’s own experience leads her to one unavoidable conclusion. ”I hate to say it, but I’m a Tylenol addict,” she told me. ”I was an Excedrin Migraine addict before, because I thought those were safe drugs, and they’re not. I didn’t think you could abuse them. But you definitely can.”