Friday, Mar. 11, 2011

Beyond Drugs

It wasn't but a few minutes after an alligator the size of an outboard motorboat tore off Don Goodman's right arm that he began to feel a curious pain. As he waited for an ambulance, the bloody stump above his now missing elbow didn't hurt much. Instead, he felt burning pain in his right hand — which was, of course, inside the 11-ft. (3.4 m) alligator, a monster he and his staff at Kanapaha Botanical Gardens in Gainesville, Fla., had named Mojo. "I could feel every finger of the hand that had served me for 59 years and which now lay in the belly of an alligator 200 yards away," wrote Goodman, a zoologist, in his 2007 memoir, Summer of the Dragon. "And they all hurt!"

The attack occurred on Sept. 23, 2000. Within a couple of hours, Mojo was dispatched with a 12-gauge shotgun. But he exacts revenge every day: since the incident, Goodman has had to endure a particular agony known as phantom-limb pain. He described it to me this way: "It's a sensation of pressure, as if I had my right hand in a steel glove that's one size too small. And then that's overlaid by the type of tingling you get when a limb falls asleep — multiplied by about 10." Goodman dulls the pain with his prescribed 5 mg of methadone three times a day. But the underlying hurt never really stops, and if he is idle, it's virtually all he thinks about.

How to manage chronic pain — whether it's the exotic variety in the form of an agonizing phantom limb or the more familiar ache of lower-back pain — is one of medicine's oldest puzzles. For much of the 19th and 20th centuries, opioids like morphine were the only weapons for killing serious pain. But opioids have many downsides, particularly for chronic-pain patients expected to live for years or decades. "They make people sleepy. They impair mentation. They're constipating. They deaden life in lots of ways," says Dr. Josephine Briggs, director of the National Center for Complementary and Alternative Medicine (NCCAM, pronounced N-cam) at the National Institutes of Health. "In addition, they're addictive."

Acetaminophen (now best known as Tylenol) came along in the 1950s, and ibuprofen (marketed as Advil) followed in the '60s. Both drugs are non-narcotic, but using them in large doses to treat chronic pain carries serious risks: high-dose acetaminophen is a leading cause of liver failure, and ibuprofen and other anti-inflammatories (including aspirin) can literally burn a hole in your stomach.

That's why, over the past three decades, pain specialists have begun investigating nondrug treatments for chronic pain. Massage, acupuncture, yoga, herbal remedies, meditation, tai chi, mindfulness-based psychotherapy and even mineral baths are being tested in clinical trials as treatments for chronic pain. So far the results are mixed, but the science is lagging well behind everyday use.

In 2007, the most recent year the federal government conducted its National Health Interview Survey of more than 20,000 Americans, nearly 40% of those responding reported using complementary or alternative medicine (CAM) in the previous 12 months. The distinction between complementary and alternative therapies lies in whether they are used in concert with mainstream medicine or instead of it. In the 1960s and '70s, physicians and nonmainstream practitioners viewed one another with deep suspicion. Today many physicians recommend nondrug approaches like massage and meditation. Similarly, most CAM practitioners recognize the need for medical intervention in serious cases.

In the National Health Interview Survey, pain was the most common reason cited for seeking CAM therapies. According to the survey, more than 8% of Americans said they had gotten a massage in the past year (usually for back or neck pain). Approximately 11% had used meditation or deep-breathing exercises for physical (and emotional) pain. And some 3.1 million Americans (1.4% of the population) had undergone acupuncture — by far the highest proportion ever reported.

In other words, even in a world where we touch screens more often than we do people, we seem to be reaching back to rediscover folk remedies for pain. The encouraging news is that rigorous science is now showing that CAM therapies can work well to treat pain. In some cases, trials are demonstrating that CAM therapies reduce pain more effectively than standard drug treatments do.

With new NCCAM funding, researchers are learning more about how mind-body practices like yoga and acupuncture can instruct the brain to dial down pain signals. Founded just over 10 years ago, NCCAM spent much of its first half-decade debunking claims about the supposed healing power of supplements like echinacea and ginkgo. But in the past five years the center has begun to shift more of its $100 million grant budget to pain studies. Today about half of its grants go toward investigating mind-body practices, most of which are targeted at pain.

But how does something like massage actually reduce pain? Why does acupuncture pacify some people and not others? And what can we do about central pain, the name for the kind of torment that Goodman and many amputees suffer every day: pain that has no localized cause, no lesion to suture or sprain to wrap? Other central-pain sufferers include those with fibromyalgia and complex regional pain syndrome, an excruciating yet mysterious pain that persists long after the original injury heals. What's exciting about CAM therapies is that they offer solutions for even these intractable and puzzling kinds of agony. In pain treatment, the only way forward may be to look back.

The Healing Power of Touch
On Nov. 1, 1985, a 56-year-old woman who had lived in the English countryside around Oxford for most of her life arrived in distress at the Radcliffe Infirmary, the hospital that first began treating Oxford's ill in the 1700s. The woman, known as Mrs. Headley, had suffered a terrible stroke. When physicians looked at a scan of her brain, they found that its right hemisphere had infarcts, areas of tissue that was dead because of a failure of blood supply.

Because the brain's right hemisphere controls the left side of the body, Headley couldn't move her left arm or hand. She was transferred to Rivermead Rehabilitation Centre, but its staff could do little for her. And yet an experimental psychologist from Oxford University, Lawrence Weiskrantz, took an interest in her case.

Most of the time, stroke patients are given a simple stimulation test to measure how much feeling remains. A little fibrous device called von Frey hairs is applied to the skin; Headley, like most severe-stroke patients, didn't feel the von Frey hairs on her left side at any level of intensity.

But then, during a break between tests, Weiskrantz noticed that Headley was rubbing her insensate hand with her normal right hand. When asked why, she quietly — but insistently — said that even though no other object produced sensation in her left hand, she could feel her right hand when it touched the left. The doctors tested her by pretending her right hand was touching the left when it wasn't. Throughout the testing, Headley knew more often than not when her right hand was returning sensation to her left.

The 1987 paper that Weiskrantz and his colleague Daren Zhang wrote about Headley has become a seminal document in the emerging science of nondrug healing. This science can be said to begin with a simple question: What's the first thing you do when you burn your hand on the stove? Put it under a faucet? Reach for ice? Actually, the first thing most people do is reflexively grasp the hurt hand with the other one. Scientists have known since at least the '60s that this kind of self-touch reduces pain. If you try to keep your other hand away, you will hurt a lot more.

Last year, researchers in three countries demonstrated in a Current Biology paper that simple touch can minimize complex central pain. They used a method called the thermal-grill illusion to prove their point.

The thermal-grill illusion was a quirky choice because it is best known as a 19th century carnival act. Subjects are asked to touch a very warm object — say, a heated but not scorching grill — and then, right afterward, a cool or room-temperature grill. Quite reliably, the participants' brains fool them into believing the second object is excruciatingly hot, even though nothing has happened to their flesh. Today we know that burning sensation as central pain.

The Current Biology team replicated the illusion in a lab experiment using water. Study participants immersed their index and ring fingers in 109°F (39°C) water and their middle fingers in 57°F (14°C) water. As in the original illusion, their middle fingers felt significantly hotter than they really were. The scientists then had participants repeat the experiment with their right fingers only. Immediately after, the subjects used the same three fingers on their left hand to touch the wet fingers on the right hand. This mere touch caused a 64% reduction in self-reported pain scores on a scale of 1 to 100.

Touch is at the core of many CAM therapies, but scientists aren't sure exactly how it works. One theory is that the healing power of touch is an evolutionary response: our ancestors had few remedies for a cut hand other than grasping it until their fellow hunter-gatherers could fashion a poultice from mud or yak dung. This evolutionary impulse may have encoded a placebo response in later generations: we came to expect that touch would reduce pain, and so we report less pain. It's also possible that evolution encoded an actual decrease in pain signals — either the number of signals or their intensity (or both) — when touch is applied to a wound.

The biological mechanics of how touch might work to reduce pain were explored in a compelling study published in September in the Journal of Alternative and Complementary Medicine. The lead author, Dr. Mark Hyman Rapaport, chief of psychiatry and behavioral neurosciences at Cedars-Sinai Medical Center in Los Angeles, found that even a single deep-tissue Swedish-massage session resulted in a significant decrease in the hormone arginine vasopressin (AVP). AVP constricts blood vessels and raises blood pressure, both of which can cause agitation and spikes in pain. The study also showed that either massage or light-touch therapy produced reductions in levels of cortisol, a hormone associated with higher levels of pain that is released when people are stressed.

Intrigued that massage could have such immediate biological effects, I asked Rapaport if I could undergo the same procedure as the 53 study participants. After giving two samples of blood to serve as a baseline, I was worked over (not too strenuously) by a massage therapist for 45 minutes. A sound machine issued the gentle music of ocean waves. And then the bad part: six more blood draws over one hour.

I found the whole experience stressful, partly because I was reporting but mostly because a large needle was shoved into the soft crease of my arm the whole time. That's why my results surprised me: my levels of cortisol declined by a stunning 56%. The massage therapist also rubbed away a huge amount of my AVP; it went from 85 picograms per milliliter to 59. Not bad for 45 minutes of massage — although without follow-up tests, it's not clear how long the benefits lasted.

Does this mean we should get a massage every day? Every week? "The jury is still out on dosage," Rapaport told me. But he recommends "occasional" massages.

His study needs to be replicated, but it offers an explanation for why so many people seek massage to reduce neck, back and joint pain. Other studies are finding that other kinds of touch — even just placing both hands on different areas of a patient's body — can reduce pain. A 2008 Annals of Internal Medicine paper reported the results of a trial involving 380 advanced-cancer patients with moderate-to-severe pain. The authors — a team from Florida Atlantic University and the University of Colorado Denver — randomly assigned participants to receive either six 30-minute massages over two weeks or six control sessions in which a therapist placed both hands on 10 different areas of the body for three minutes each.

The study found that touch of either kind was associated with statistically significant improvements in pain reports with very few side effects. The authors point out that one reason pain may decline with touch is that healthy people have an aversion to touching sick people, so those who are ill get fewer hugs and less hand holding. Under this theory, isolation literally hurts, and though it's a bit treacly to say, a hug can heal.

A Little Pain, Some Gain
I've always been puzzled by acupuncture, because it's supposed to help by hurting. When I underwent acupuncture for the first time a couple of weeks ago, my right ear and left foot bled where the needles were inserted. However — perhaps because the acupuncturist suggested the session would ease my chronic insomnia — I slept eight hours that night, longer than I have slept in a single night since the early '90s.

What can needles do to alleviate pain? A remarkable study published in 2009 in the journal Acupuncture in Medicine found that in four trials involving more than 1,000 subjects with osteoarthritis, 46% of those who got 10 acupuncture sessions over six weeks responded with a decline in lower-back pain. Only 27% of those who received standard treatment — anti-inflammatory drugs, exercise and physical therapy — enjoyed pain relief. (A subsequent study found that anti-inflammatories are only about 5% better than sugar pills in relieving osteoarthritis pain.)

Twelve other studies, involving 3,172 patients with knee osteoarthritis, found that acupuncture reduced self-reported pain by 7.4% — a modest figure but still better overall than the alleviation produced by standard-care control therapies involving drugs. Similarly, a 2009 paper by scientists in four countries found that acupuncture managed migraine pain only slightly better than drugs did, but with far fewer side effects. Sufferers who got acupuncture also had fewer migraines than those who got prophylactic pain medications. Finally, the multinational group of scientists found that even nine months after acupuncture treatment ended, patients who had been randomly assigned to the needle therapy were doing better than those treated with routine care.

The mechanism by which acupuncture works remains murky, but according to a 2010 study released by the Cochrane Collaboration, a health-research group, positron-emission-tomography scans have shown that needle pricks "can stimulate regions of the brain associated with natural opiate production." These naturally occurring painkillers come to the rescue when aroused by the needle pricks and then stay active for at least a few hours. Another theory is that acupuncture tamps down both inflammation and the nervous-system pathways that control pain, but how it might accomplish these tasks isn't clear.

One virtual certainty about acupuncture: it generates a strong placebo response. As the Cochrane Collaboration put it, acupuncture's "repeated sessions, intense provider contact, slightly painful procedure, an often 'exotic' model of symptom explanation and associated relaxation during sessions" all maximize sufferers' expectation that it will help. And unlike drugs — which many patients fear will carry side effects like nausea or dependency — acupuncture produces little or no "nocebo" response, the phantom pain that patients sometimes feel merely because they expect negative side effects.

A final interesting finding in many acupuncture studies: it's not the precise placement of needles along supposed meridians in the body that makes a difference in pain levels. Rather, a great deal of research has found that random placement of needles around the body works so well that its benefits are statistically indistinguishable from those of traditional acupuncture. In other words, it's the needle punctures that help reduce pain, not the shamanistic rituals.

At this point, a caveat is in order: all but the most ideological proponents of CAM therapies advocate a multidisciplinary approach to treating pain, rather than attacking it with only acupuncture or herbs or relaxation techniques like yoga (which is thought to reduce pain by inducing a calmer state and stimulating natural opioids that ease postyoga soreness). "I would never want it to be put forward that people with serious pain should not have access to effective pharmacology," says NCCAM's Briggs. "But the more the patients know they have a variety of things that can help, the more control they will feel over the pain." And the less pain they will experience: powerlessness and other negative emotions have been shown to increase aches in those with chronic pain.

Do Herbs Work?
Some of the names evoke The Shire: Bilberry, cat's claw, chasteberry, feverfew, evening primrose oil, goldenseal and, my favorite, thunder god vine. If massage, acupuncture and yoga are the mechanical, corporeal methods of nondrug treatment, herbal remedies are the earthy, mystical variety. Trouble is, few of them actually ease pain.

According to NCCAM's Quick Guide to Herbal Supplements, chasteberry (the fruit of the shrublike chaste tree, which is found in Central Asia and the Mediterranean) may help a bit to reduce breast pain of any origin, but the evidence is spotty. Some research shows that feverfew — a short, flowering bush found in the Americas and in Europe — helps prevent migraines, but again, the data are mixed. Ginkgo is thought to reduce claudication (exercise-induced leg cramps), but the benefits are modest at best. Similarly, turmeric, a spice you might have in the back of a cabinet, may have anti-inflammatory properties that soothe joint pain, but most studies on the spice are small and inadequately designed.

The only really successful herbal treatment for pain is thunder god vine. A perennial vine native to East Asia, thunder god has been used in Chinese medicine for at least four centuries. A large study funded by the National Institutes of Health's clumsily named National Institute of Arthritis and Musculoskeletal and Skin Diseases compared a root extract of thunder god vine with a common conventional drug used to treat rheumatoid arthritis, delayed-release sulfasalazine. The study found that participants' joint pain declined significantly more with the root extract than with the medication. Score one for the Shire.

A few nonherbal supplements, particularly the combination of glucosamine and chondroitin, are also used for pain relief in those who suffer from osteoarthritis. But NCCAM says there is, at best, limited evidence to support nonherbal supplements' use. The same goes for prolotherapy, injections of dextrose and other naturally occurring chemicals that are thought to ease the pain caused by ligament and tendon injuries. Prolotherapy reduces inflammation but no more so than saline control injections do. Similarly, there is virtually no evidence that mineral baths and tai chi help reduce pain — probably because, unlike yoga, they do not cause that almost pleasant postworkout soreness that sparks the release of natural opioids.

Finally, there are so-called biofield therapies — therapeutic touch, spiritual healing (think Pentecostal laying on of hands), qigong (the name for a variety of Chinese physical and mindfulness practices) and johrei (the Japanese equivalent of qigong, more or less). A study published last year in the International Journal of Behavioral Medicine reviewed 66 studies of such therapies. The authors — Shamini Jain of the UCLA Division of Cancer Prevention and Control Research and P.J. Mills, a psychiatrist at the University of California — found "strong evidence" that biofield therapies can reduce pain intensity. But of the 66 studies, only seven controlled for placebo response. Jain and Mills suggest one mechanism by which qigong and johrei could work: like yoga, those practices call for controlled, sometimes stressful whole-body movement, which, as a result, may release naturally occurring opioids.

So we are left with massage, acupuncture, yoga, maybe qigong and thunder god vine. But how do we help Goodman and his phantom limb? How do you massage or needle or exercise a limb that's gone?

A Mirror as Medicine
The most intriguing cam therapy is the newest. It's called mirror therapy. Well over half of amputees suffer from phantom-limb pain because, roughly speaking, their brains are confused. The motor-command center in the frontal lobe doesn't register that a limb (or an ear or the nose) is gone. Consequently, it keeps sending nerve signals down the spine to the appendage. These signals can't be received, of course, and the missing body part can't transmit its customary neuronal cues back to the brain. The brain then responds by firing "pay attention to me" signals in its areas that control the arms or legs or ear and so on. These signals are interpreted as pain in the phantom limb.

Phantom-limb pain was recognized at least as far back as the 1870s, when many Civil War veterans complained that they were disturbed by "sensory ghosts." Few treatments other than great gobs of opiates existed for phantom-limb pain until Vilayanur Ramachandran, a neuroscientist at the University of California, San Diego, took an interest in the subject a few years ago. And few neurologists and psychiatrists paid attention to Ramachandran's work until thousands of U.S. service members began returning from Afghanistan and Iraq without all their limbs.

As Ramachandran writes in his new book, The Tell-Tale Brain: A Neuroscientist's Quest for What Makes Us Human, when an arm is amputated, "there is no longer an arm, but there is still a map of the arm in the brain. The job of this map, its raison d'être, is to represent its arm. The arm may be gone; but the brain map, having nothing better to do, soldiers on."

And so, in order to treat chronic phantom pain, one must trick this map into believing that a new road has been constructed. Because they deaden the senses, pain medications are the worst way to construct a new map. Psychotherapies — particularly mindfulness-based practices that urge patients to accept that they have lost a limb and learn to live without it — can change the brain's map over weeks or months through rigorous cognitive therapy combined with behavioral therapy that focuses on recognizing that a limb is missing and strengthening other parts of the body to compensate.

But Ramachandran devised a way to trick the brain much more efficiently. Struck by the simplicity of his theory that phantom-limb pain was merely a symptom of brain confusion, Ramachandran reasoned that if the brain could be convinced the missing limb still existed, the central pain resulting from its loss would ease. So he placed an upright mirror between the two "hands" or two "legs" of an amputee. He faced the reflecting side of the mirror toward the whole hand — let's say it's the right one — which created the illusion that the left hand was still there. When Ramachandran tried mirror therapy with his patients, the results were so immediate as to be shocking. Patients who had suffered abominable agony for years suddenly "saw" their amputated limb and could move it naturally. The brain convinced itself that neurons were once again firing in the missing limb, so it finally dialed down its pain signals. Since then, other teams — including one from the Walter Reed Army Medical Center — have replicated Ramachandran's case studies in (rather small) placebo-controlled clinical studies.

Not long ago, I visited New York University's Rusk Institute of Rehabilitation Medicine, where I met Mark Constantino, 65, who lost his right leg below the knee to Type 2 diabetes last year. His doctor, Jeffrey Cohen, who directs the limb-loss program at Rusk, used mirror therapy to help Constantino get back to normal functioning. For 15 minutes each day, five days a week for four weeks, Constantino would watch his left foot move — and, in the mirror, "see" his right foot also moving.

Constantino told me that the mirror-therapy sessions helped reduce the pain in his phantom limb from a fairly bad 7 (on a scale of 1 to 10) to an annoying but tolerable 2 to 3. The remarkable part: the benefit from four weeks of mirror therapy has lasted for months. Except for demonstrating the therapy for me, Constantino hasn't used it since last fall.

Goodman, the alligator victim, sometimes uses mirror therapy by himself at home, but his doctor — Robert Hurley, director of the University of Florida's pain medicine program — doesn't employ mirror therapy in his practice. Hurley told me the therapy doesn't have a strong enough basis in evidence quite yet.

And that's where many CAM therapies stand: they show only promising anecdotal results. But research scientists and everyday pain specialists recognize that a combination of traditional therapies like acupuncture must work in concert with new drugs and psychotherapies in order to advance the fight against pain.