Several of my friends swear that a daily dose of glucosamine sulfate -- a dietary supplement prepared from the shells of crabs and other shellfish -- reduces their arthritis-related knee pain and improves their overall mobility. Yet despite annual U.S. sales of $200 million and decades of medical trials, it remains unclear if glucosamine offers any significant benefit other than that derived from the placebo effect, commonly defined as an inert medication or treatment that can have a therapeutic effect if a patient believes he or she is receiving a beneficial treatment.
The popular glucosamine is only a tip of the complementary and alternative medicine (CAM) iceberg. Health-conscious consumers now spend more than $30 billion a year on CAM therapies. But as a growing body of medical research and the convincing recent book, "Snake-Oil Science: The Truth About Complementary and Alternative Medicine," by R. Barker Bausell, former research director of the National Institutes of Health-funded National Center for Complementary and Alternative Medicine, point out, the primary benefit of CAM therapies is a result of placebo.
Before jumping to the conclusion that I'm on the anti-CAM bandwagon, be assured that the placebo effect is equally prominent in conventional medical therapy. Consider the previously well-accepted surgical procedure for incapacitating wear-and-tear osteoarthritis of the knee -- removal of the bony spurs and degenerated cartilage.
In a landmark 2002 study of 180 patients with demonstrable knee osteoarthritis, patients who had "sham" arthroscopic surgery (general anesthesia was given and superficial incisions were made in the skin, but no actual surgical repair was performed) reported as much pain relief and improved mobility as patients who underwent the actual procedure. At the time of the study, more than 650,000 knee operations had been performed annually at a cost of $5,000 each.
In other words, billions were spent on a surgical procedure that hadn't undergone a decent controlled study against placebo -- the same criticism often leveled by CAM skeptics. At least glucosamine doesn't have the known serious side effects associated with unnecessary surgery.
The placebo effect has maddened the medical world for generations. But recent advances in brain imaging emphasize for me that “placebo” should not be regarded a dirty word. In fact, it is time to give placebo a new image and update its beneficial role in our modern medical armamentarium.
Folk psychology tells us that the placebo effect is, in large part, a function of patient suggestibility and that some of us are clearly more suggestible than others. For centuries, physicians have handed out inert colored water and sugar pills with the full knowledge that approximately a third of their patients will report feeling better. We assume that the degree of response is somehow a reflection of the psychological state of the patient -- the greater the degree of gullibility, the more likely he or she is to believe that a sugar pill will relieve aches and pains. But there's an unanticipated side effect of this assumption.
Attributing the placebo effect to gullibility is a subtle accusation of a patient's weakness and lack of sophistication. I suspect that many of us consciously or unconsciously look down upon those who are good placebo responders, as though you have to be a real dummy to believe everything the doctor tells or gives you.
But placebo serves a very real evolutionary function. At a time when there were no medicines, the placebo effect was all that stood between primitive humans and the agonies of injuries and illnesses. A look at the functional imaging scans shows how truly robust are the involved brain systems. These systems are here to stay. Even given our advanced state of medical knowledge, much of routine medical care -- from treating backaches to the common cold -- relies primarily upon reassurance and hope, not disease-specific treatments.
Given the choice, we'd all prefer to be placebo responders, though none of us want to be categorized as rubes. We complain about not getting enough quality time with our doctors, yet would never dream of directly asking for a prescription for a placebo. Instead, if we believe in conventional (allopathic) medicine, we might ask for an antibiotic for the common cold, with the rationale that, yes, it's only a virus, but perhaps the antibiotic will help. If we are inclined toward alternative medical treatments, we will plunk down a few bucks for a bottle of echinacea or a pack of zinc lozenges. To the extent that we feel better, we have invoked the placebo effect.
Keep in mind that whenever there is no specific well-substantiated treatment for a condition, the only alternative to glum acceptance and the proverbial stiff upper lip is to seek out a placebo. But don't tell us it's a placebo. Don't even hint that we are self-deluded suckers who might spring for a case of snake oil or a six-pack of eye of newt. Just as religion softens the blow of facing death, placebo softens the blow of facing life.
It's no wonder that CAM is so popular. In her recent book, "The Cure Within: A History of Mind-Body Medicine," Harvard chairwoman of history of science Anne Harrington outlines the various narratives that have historically contributed to the placebo response's role in CAM. She points out that the belief in positive thinking and maintaining personal self-control push us into making our own health choices, irrespective of their scientific validity.
She also emphasizes another increasingly popular Western narrative -- the "broken by modern life" tale of woe, anger and rebellion. It cannot be overstated that a medical system that feels and appears unfriendly will be abandoned in favor of one that does not, even if the supporting evidence isn't there. The urge for comfort is greater than an insistence upon objectivity. Even if glucosamine isn't demonstrably helpful for garden-variety arthritis, it will be a bestseller until a real treatment is found.
Again and again, the same problem applies to conventional medicine. Even some of the best-designed trials run headlong into the hidden power of the placebo. Consider the data from a 2002 review of trials on the six leading antidepressants, including Prozac, Zoloft and Effexor. Of the 47 trials, 27 showed the antidepressants to have no greater benefit than the placebo control group. According to the lead author, Irving Kirsch of the University of Connecticut, the remaining 20 showed improvements of dubious clinical significance.
In fact, evaluating any new treatment for a condition that must be subjectively evaluated -- pain, mood change, quality of life -- runs into the same problem. Whether looking at drugs for attention-deficit hyperactivity disorder or for mental illnesses such as bipolar disorder and schizophrenia, or simply determining if a drug can modify the behavioral manifestations of Alzheimer's disease, we are at the mercy of how to adequately contain and measure the placebo effect -- an impossibly complex task with serious ethical implications.
To get a sense of how far off-base our ideas about placebo often are, consider the latest deliciously amusing if it weren't so serious controversy. Not long ago, a chewable, cherry-flavored dextrose tablet, Obecalp (placebo spelled backward), went on sale online; bottles of 50 tablets sell for $5.95. The manufacturer clearly explains that the pills are inert. The rationale of the developer for offering commercial placebo tablets for children is "to empower parents to do something tangible for minor ills and reduce the unnecessary use of antibiotics and other medicines," as the New York Times reported. Needless to say, there has been a great deal of concern about the ethics of marketing medical deception to children, including teaching children that pills can be the solution for whatever ails them.
No matter how you feel about such products, you have to tip your hat to the utter ingenuity of the marketers who are knowingly pushing an inert pill that has an already-proven effect. The truth is, many of the standard ailments of childhood, such as the cough associated with the common cold, have a decent placebo response rate. In attempting to boycott the sale of placebos for children, the opposition has, inadvertently, with tortured logic worthy of Alice in Wonderland, revealed how poorly understood the placebo effect can be.
For instance, according to Daniel Fabricant, science and regulatory affairs vice-president at the Washington, D.C.-based Natural Products Association, "This is not a lawfully marketed product, and it shouldn't be on the shelves at all. By calling a product a placebo you are indicating that you're treating something. It is consumer fraud."
But ask the approximately 30 percent of those who will respond to the sugar pills if the treatment is a fraud or a "real" benefit. At the heart of the widely held misunderstanding of the placebo effect is that the benefits are "imaginary," as opposed to "real." I've put imaginary and real in quotes to indicate the folly of discussing subjective benefits as though they don't count if they can't be objectively observed. Subjective improvement is still real improvement.
To clarify this point, let's look at a couple of studies on the biological effects of inert substances. To date, the most robust and best-studied placebo effect is its ability to reduce pain. In a classic study from University of California at San Francisco dental school in the late '70s, postoperative dental surgery patients were given either I.V. saline or morphine for pain relief. Those receiving saline after being told that the injection was a new, powerful analgesic achieved the same level of relief as those receiving morphine. The tentative conclusion was that the placebo effect worked by triggering the release of the brain's own (endogenous) opiatelike hormones (endorphins) that reduce pain levels.
Recent functional brain imaging by University of Michigan researchers, headed by neuroscientist Jon-Kar Zubieta, has confirmed this finding. Their model is straightforward. Healthy young volunteers agreed to receive a painful injection into a jaw muscle. Prior to the injection, the volunteers were asked to gauge how much pain reduction they would experience if they were also administered a painkiller. Would they feel a 20 percent reduction in pain? Fifty percent? Then, simultaneously, they received the painful jaw muscle injection and a painkiller injection -- only the "painkiller" was a placebo -- an inert saline solution.
In patients reporting pain relief, PET scans showed an activation of their opioid receptors, where both narcotics and endorphins ply their trade, and a decrease in activity in several brain regions vital for feeling pain. The scans also showed that the placebo effect isn't confined to endorphin release; the neurotransmitter dopamine receptor sites critical for the brain's primary reward system also lighted up.
In an elegant follow-up study, Zubieta and colleagues looked at how subject expectation of pain relief was associated with a more generalized expectation of good results. The volunteers were invited to play a game; if they won, they'd get a small monetary reward. Before playing the game, they were asked to estimate their chances of winning. The study showed that those who felt they were most likely to win were the same folks who predicted the greatest relief from their "painkiller" injection. Scans confirmed that the activation of brain reward regions correlated with both general anticipation of winning and degree of expectation of pain relief.
As a result of such imaging studies, the placebo effect is presently thought to involve several distinct but overlapping mechanisms: expectation of pain relief, direct modification of pain perception and a differential degree in reporting the actual experience of pain. In short, the placebo response is complex, with multiple brain systems and neurotransmitters orchestrating the effect.
The University of Michigan researchers conclude: "There is substantial evidence that the placebo effect has strong biological underpinnings, and that some individuals are more likely than others to demonstrate this effect." Just watching the dopamine receptors light up in those expecting positive results raises the impossibly complex question of how much of a placebo response is related to cultural and personal narratives and how much might be due to one's individual biology.
Already, genetic variations in dopamine receptor responsiveness have been associated with a wide variety of behaviors, such as ADHD, risk-taking behavior, even pathological gambling. If so, how one responds to the site of a needle containing a placebo injection will itself be modified by genetic differences. Just as we are beginning to understand how certain genetic populations respond differentially to various drugs, it's likely that we will see placebo response in the same light.
Ultimately, we need a more level-headed, scientific and empathetic view of placebo. After all, we are built to seek out placebo in the same way that we try to avoid touching a hot stove or are biologically primed for lust and greed. Ironically, CAM is so hugely popular in large part because its advocates vehemently deny that CAM's primary benefit is pure placebo effect. It is their noncritical insistence upon the specificity of their herbs, supplements, devices and manipulations that provides believers with real benefits (and real risks, ranging from cost and potential side effects to delay in the diagnosis and treatment of serious conditions). The same goes for many conventional medical therapies. Keep in mind that sham surgery made a significant percentage of arthritis sufferers feel better and that the majority of the benefits of major antidepressants can be duplicated with sugar pills augmented by the cultural belief in antidepressants as effective specific treatments.
As a matter of public policy, we should seriously debate what it means to spend such huge sums on inert conventional and alternative treatments that provide real relief. Ideally, we would have perfect specific treatments for whatever ails us. Until then, we need to reconsider how to facilitate the placebo effect with minimal risk and cost, and without deception -- a paradoxical set of conditions that is unlikely to satisfy anyone. No explanation will be entirely sugarcoated, but perhaps that's not necessary if the real sweetness is magically tucked away inside our own deviously evolved minds.
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