When I was finishing my neurology residency, a junior professor in internal medicine asked me if I'd like to create a research project with him. I told him I didn't have a subject in mind. He replied, "No problem. We'll find a group of people with a common ailment and run all the lab tests imaginable. Something abnormal is bound to turn up and we can cash in on being the first to discover it."
I thought of this conversation the other evening when, for what seemed like the hundredth time, I saw Pfizer's most recent TV commercial for Lyrica, a drug to treat the chronic-pain syndrome, fibromyalgia. I can tolerate Pfizer's endless ads for Lipitor, the cholesterol-lowering drug, because the ad is doing a public service. High cholesterol is a serious health problem. But watching the kindly middle-age actress interrupt the evening news to tell me that "my fibromyalgia is real" raises serious medical issues and underscores the ruthless drive of Big Pharma.
Since its original description in the late '70s, experts have held widely divergent views about the cause of fibromyalgia; some even doubt that it is a real condition. Recently, though, with the advent of fMRI scans, researchers have shown that patients with fibromyalgia have different responses to pain than the "normal" population. This discovery holds out "proof" that fibromyalgia is a definitive organic condition requiring specific treatment. That may be good news for people who suffer from the mysterious condition, but it's great news for the pharmaceutical industry, which can march to the U.S. Food and Drug Administration and seek authorization for a drug to cure the now official disease. Which is exactly what Pfizer did in 2007, earning approval to treat fibromyalgia with Lyrica, already a blockbuster drug.
But hold on. Is that possible? Can an fMRI scan determine the presence or absence of disease? To date, no evidence convincingly shows that fMRI, designed to measure cerebral metabolism, is sufficient to diagnose a specific underlying disease. So what's going on here?
Let's begin with a closer look at fibromyalgia itself. Despite strong convictions on all sides, nobody knows whether fibromyalgia is a primary medical condition, part of a larger constellation of other ill-defined conditions, such as chronic fatigue or irritable bowel syndrome, or a label given to a variety of physical complaints that arise out of various mental states, such as anxiety and depression. There haven't been any reproducible and clear-cut objective findings, such as blood and lab tests, X-rays or anatomical abnormalities on biopsy, to provide a satisfactory understanding of the disease. Even the 1990 American College of Rheumatology diagnostic criteria -- widespread muscle pain of more than three months, unassociated with other known illnesses, and the presence of at least 11 tender points over 18 muscle groups -- are nothing more than subjective patient descriptions.
By the way, I don't mean to denigrate patients who experience pain associated with fibromyalgia. My concern is the notion that an fMRI can distinguish between psychological states and so-called "organic" processes that affect how we experience pain. And how patients and physicians respond to the uncertainty of fibromyalgia is often dependent on how they think about "real" vs. "imagined." Popular mythology has it that if you have physical complaints that arise out of worry and anxiety, the symptoms aren't as "real" as if they are caused by disease. But this distinction between "real" and "imagined" is both philosophically naive and unfair to patients with psychological conditions.
If you think an inert sugar pill (placebo) is a powerful analgesic, taking it can reduce your level of pain from, say, a dental procedure or wear-and-tear arthritis. Conversely, if you are given the same sugar pill and told it is a new untested drug and might make your pain worse, you might experience more pain (nocebo effect). Your imagined expectation of what the pill might do will affect both your pain perception and what changes will be seen on functional brain imaging. Nowhere in this schema is there any suggestion that changes in pain perception arising out of imagination aren't real. Placebo-induced relief of pain is clinically identical to pain relief from standard analgesics such as morphine.
Now consider one of the central features of fibromyalgia -- an increased number of areas sensitive to ordinary pressure. If you believe you have a condition that makes you more sensitive to painful stimuli, you may well experience more pain than those who believe they aren't sensitive to painful stimuli. This difference in pain appreciation or description, and the attendant brain changes on fMRI, will not reflect any underlying disease; both will be the reflections of your own self-perception. Even such personality traits such as optimism or pessimism (half-empty vs. half-full), or one's attitudes toward the medical establishment, can make critical differences.
With this basic principle in mind, let's look at what fMRI studies are telling us about fibromyalgia. In 2002, Georgetown University researchers compared how 16 women with fibromyalgia and 16 pain-free control subjects responded to both painful and nonpainful stimuli (a small piston generating various amounts of pressure to a thumbnail bed). They found that control subjects required more than twice the amount of pressure to elicit the same degree of pain and fMRI activation as fibromyalgia patients.
The authors concluded: "These results, combined with other work done by our group and others, have convinced us that some pathologic process is making these patients more sensitive. For some reason, still unknown, there's a neurobiological amplification of their pain signals."
Perhaps that is true, but amplification of pain signals can also occur simply from imagining an increased pain, as seen with the nocebo effect. So can simple anxiety.
In a subsequent 2007 study, the researchers used the same pain-eliciting techniques but different functional brain scans to look for differences between fibromyalgia patients and controls. This time they found a single region of altered activity between fibromyalgia patients and control subjects -- in the right thalamus. The severity of this difference correlated with the degree of fibromyalgia symptoms; the greater the difference, the worse the patient's symptoms were likely to be. The authors speculate that the findings "are likely the result of neuronal dysfunction."
But a closer look at this study suggests an alternative interpretation, one more consistent with the notion of how anticipation and expectation can alter brain function.
The researchers found fibromyalgia patients who believe their pain is the result of some external factor, such as a prior injury or exposure to toxic chemicals, experience a higher degree of altered activity on imaging studies. That belief also leads to a higher depression rating on the study questionnaire. The authors comment that attributing clinical symptoms to an external source, even in the absence of clear-cut evidence, is a characteristic feature of chronic pain patients who don't respond well to treatment.
In short, the described functional imaging findings correlate with patient expectation and belief. What we can't know is whether the beliefs cause the functional change or are the result of the alleged change. And, more important, there is nothing on the scan to point to whether this activity is or isn't "normal." Nevertheless, the authors conclude, "there is really something wrong going on in the brains of the patients with fibromyalgia."
Of course there is a physiological explanation for the pain of fibromyalgia. Ultimately there is a physiological explanation for all experience, whether it be pain, love or the hallucinations of acute psychosis. The issue isn't whether a condition is associated with "brain changes" on functional imaging, but whether such changes reflect a specific organic disease as opposed to a psychological state of mind.
And let's not kid ourselves. Researchers at big pharmaceutical companies are fully aware of the subtleties of how fMRI is performed and what interpretations can be drawn from even questionable studies. They realize that studies on chronic pain are notoriously difficult to interpret and prone to faulty interpretations. They understand overall results can be skewed by underestimating or misassigning the placebo effect. But the stakes are enormous; finding medical literature to support a claim that will dramatically boost sales is like striking gold.
Once a condition has been "authenticated," it's only a matter of time before Big Pharma steps in with a treatment. Armed with such "objective" fMRI evidence that fibromyalgia is a bona fide condition, Pfizer undertook a series of clinical studies that showed that some patients with fibromyalgia did experience at least partial relief of symptoms with Lyrica. (On a scale of 1 to 10, the fibromyalgia patients achieved an average reduction in symptoms of 2, whereas the controls given placebo had a 1 point reduction.)
As the result of these studies, in 2007, the FDA approved the use of Lyrica for the treatment of fibromyalgia. (Since the approval in 2007, it has been estimated that worldwide sales of Lyrica have increased 30 percent, to well over $2 billion annually.) Without making specific claims about what fibromyalgia is or how Lyrica works, Pfizer, on its Web site, states that "recent research suggests that changes in the central nervous system may be responsible for the chronic pain that comes with fibromyalgia." It adds that nerve damage may occur because of an infection or injury.
Suggesting that patients with fibromyalgia might have altered or damaged brain cells is based in part on fMRI studies. From there it's a short commercial step to suggesting that there could be an underlying infection or injury to fibromyalgia, for which there is no convincing evidence to date.
What isn't mentioned on the Pfizer's fibromyalgia Web site is that Lyrica has been approved in Europe for the treatment of generalized anxiety. Lyrica was shown to be effective in providing relief of both emotional symptoms, such as depressive symptoms and panic, as well as physical symptoms, including headaches and muscle aches. Yes, another way of thinking about the benefit of Lyrica is that it helps relieve the muscle aches and pains associated with generalized anxiety and that these may be the same aches and pains as described by patients diagnosed with fibromyalgia. (Without objective lab studies, this distinction is impossible to make.)
Now, perhaps a counterargument could be made that the fMRI changes in fibromyalgia are different than those with generalized anxiety. But to make this argument, we would need to have clear-cut and reproducible findings specific to fibromyalgia, and we should know precisely what such specific regional differences mean, from what the brain is doing to how accurately these changes predict both behavior and what the person is experiencing. So far, we have none of the above.
The fMRI is a wonderful, rapidly evolving technology; much of the research is in its infancy and will undoubtedly change as both the machinery and our understanding of the techniques improve. Meanwhile, the follies of bad and excessive interpretations continue to be both well documented and generally overlooked in the popular press. Of these excesses, I can imagine none with more potential for harm than "objectifying" a clinical syndrome without good peer-reviewed additional data.
The primary tenet of medicine is to do no harm. Everyone involved in the study of controversial conditions such as fibromyalgia -- physicians, researchers, pharmaceutical companies and the FDA -- has a huge moral obligation to be sure that questionable conclusions aren't foisted on the public as the final word, particularly without a clear understanding of whether such claims have their own adverse side effects. If beliefs change brain function, false beliefs in the mechanism of a condition can have real and lasting adverse effects.
If a patient believes that there is something "wrong with my brain," the effects can be disastrous. Anyone who has been told of a possible abnormality on a lab test knows how hard it is to shake off that disturbing knowledge even when repeat studies turn out to be normal. If a single lab test result can generate persistent anxiety despite contrary evidence, imagine the degree of negative expectation generated in those with fibromyalgia when they watch the woman in the Pfizer TV ad claim "my fibromyalgia is real." If negative expectation (the belief that you are more sensitive to pain than others because of a condition that has altered your pain perception) plays a significant role in the production of fibromyalgia symptoms, Pfizer runs the risk of creating or augmenting the very symptoms it is trying to treat. Talk about a vicious feedback loop!
Before jumping to conclusions about diseases and their causes, we need a more comprehensive and philosophical approach to how we integrate new technologies with basic understanding of human nature. We need to look at how thoughts, beliefs and expectations can generate or affect physical symptoms, and vice versa. And we need to abandon concepts like "real" and "all in your head" once and for all.