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Mongering Diseases to Hawk Pills: The Case of Fibromyalgia

Worst Pills, Best Pills Newsletter article November, 2008

Over three centuries ago, English physician Thomas Sydenham established a system of disease classification based on observing the progress of specific illnesses and their symptoms. This scheme, premised on the idea that disease was a real entity separate from the patient, marked a turning point in the history of medicine. It counteracted the prevailing theological view that disease was the result of karma or punishment for sin, associated with an ethical or spiritual reason. Sydenham’s views...

Over three centuries ago, English physician Thomas Sydenham established a system of disease classification based on observing the progress of specific illnesses and their symptoms. This scheme, premised on the idea that disease was a real entity separate from the patient, marked a turning point in the history of medicine. It counteracted the prevailing theological view that disease was the result of karma or punishment for sin, associated with an ethical or spiritual reason. Sydenham’s views helped launch the bacteriological revolution and the doctrine of specific etiology, which assume that there is a particular pathogenic agent or causal entity associated with each disease. But this view also undermined other concepts such as multiple causality, and the role of the host-agent-environment triad in defining disease. It also led to the medicalization of health conditions, with doctors becoming the arbiters of who is ill and in what way they should be treated.

More recent thinkers and holistic theorists have questioned whether diseases are discrete entities apart of the patient. Many agree with William Osler that “it is much more important to know what sort of a patient has a disease than to know what sort of a disease a patient has.” Still, the urge to label symptoms has led to new disease entities, which in turn fuel the quest for specific pharmaceutical interventions. These often focus on the physical pathology of the conditions and not on the psychosocial aspects that affect how patients cope with their symptoms. The following article addresses the latter issue, and how it is affecting the diagnosis and treatment of fibromyalgia.

The author Nortin M. Hadler, MD, is a Professor of Medicine and Microbiology/Immunology at the University Of North Carolina School Of Medicine and an Attending Rheumatologist at the University of North Carolina Hospitals. He is the author of several books, including Occupational Musculoskeletal Disorders; The Last Well Person: How to stay well despite the health-care system, a treatise on medicalization of illness; Worried Sick: A prescription for health in an overtreated America; and Backbone: Personal, social and policy consequences of low back pain that will be published in early 2009.

The Annals of Internal Medicine is an august journal published by the American College of Physicians. The cover of the July 1, 2008 issue had a 2-page “advertisement” paid for by Pfizer showing the profile of a young woman, face glowing but skull revealing a magenta image of her brain. No drug is mentioned; the stated intent is to inform as to the “evolving view of a controversial condition.” In bold print, the header announces “Fibromyalgia: ‘Neurotic’ or Neurologic?” The text goes on to infer that the problem is the latter, that “pain is amplified” by “pain-processing areas of the brain.” This header begs close attention. It offers as much insight into the way we think of health as it does into why Pfizer is attempting to influence that thinking. Why should any person, patient, physician or pharmaceutical marketing agency think we would consider “neurologic” better than, or even different from, “neurotic”?

“Neurosis” is an antiquated term, expunged from the psychiatric lexicon but not from parlance. Sigmund Freud and Carl Jung used the term to denote psychiatric illnesses in which anxiety-provoking emotional distress leads to physical and mental symptoms. These range from normal human experiences all the way to phobias, hysteria and depression (but not to disordered thought processes). The notion and term subsequently became an accusation of weakness rather than an assertion that one’s coping style needs correction. The current psychiatric terminology would label those with a “neurosis” manifested as physical symptomatology as having a “somatoform” disorder, a rubric that I find as confusing as “neurosis” and that most sufferers find equally insulting.

This is not to say there are no such sufferers. These are subsets of people who tend to combine depression with psychosocial and socioeconomic challenges, and are more likely to seek care, but otherwise they are just people doing the best they can to cope with physical symptoms. The physical symptoms are myriad and often coincident, notably persistent widespread pain, bowel concerns and a lack of energy, let alone joie d’vivre. For most, these symptoms wax and wane over years. Those who go to a specialist are less likely to perceive their symptoms as improving over time. They will acquire the labels that medicalize their chief complaint: fibromyalgia, irritable bowel syndrome and chronic fatigue syndrome in the examples above. However, they are no more likely than others their age to develop any important damaging systemic disease such as Crohn’s, rheumatoid arthritis or lupus. They just never again view themselves as well, let alone feel well.

In my view, they should feel relief in knowing that they are not facing some lurking catastrophe. To my way of thinking, they are suffering from a very bad idea and they need to be taught a better idea (i.e. cognitive behavior therapy, in today’s jargon). More importantly, anyone with a tendency toward such a bad idea needs to be forewarned, and deserves to be offered alternatives long before the bad idea becomes an obsession.

My views stand unshaken in the light of contemporary science. Studies on the biochemistry and physiology of those with this obsession have discerned the most subtle of differences at best. These differences are more likely a consequence of life under a pall than they are the reason for such a life. Most differences are irreproducible or non-specific, and have therefore been abandoned by researchers committed to finding the required though elusive underlying “disease.” Many have also dismissed the fibromyalgia label as meaningless, rejected the criteria for the disease established by the American College of Rheumatology as circular reasoning, and considered the “diagnostic tender points” as simply a measure of distress in life.

The evidence for using the label of “neurologic disorder in pain amplification” is another exercise in circular reasoning, to my way of thinking. It is based on functional magnetic resonance imaging. MRI is a cutting edge technique, but the edge is awfully blunt. Our brains react differently depending on the task at hand: pain, happiness and moral dilemmas light up these images differently. The brain of a Shakespearean scholar will react differently whether she reads a comedy or a tragedy. Patients who have adopted a specific disease label seem to mobilize an image that is distinctive, particularly when faced with a painful stimulus. The differences are subtle, not particularly reproducible or specific, and are readily perturbed by stimuli such as having an empathic family member present. The fibromyalgists, the patients, and the support groups are leaping to this new “disease.” Their enthusiasm has substantial underwriting from pharmaceutical firms: Pfizer, Lilly and the upstart Cypress Bioscience.

This is not the first time the pharmaceutical industry has tried to establish a foothold for the benefit of all the people faced with persistent physical symptoms of unknown cause. Merck tried to co-opt this market for cyclobenzaprine (Flexeril), its first generation tricyclic anti-depressant, over 20 years ago. At the time, the drug was not touted as an anti-depressant since the implication would be offensive to these patients. Rather it was marketed as a muscle relaxant which might be useful in fibromyalgia. In trying to educate all involved, Merck underwrote the American Rheumatism Association Committee that crafted the now discredited American College of Rheumatology Criteria for Fibromyalgia. Cyclobenzaprine never captured this market; few patients persisted in taking an agent that made them groggier than they already perceived themselves to be. But the market potential is enormous, and the quest to serve it has never died. It is now coming to harvest.

In June 2007 pregabalin (Lyrica) became the first drug ever to be licensed by the Food and Drug Administration (FDA) specifically for the treatment of “fibromyalgia.” Pregabalin is one of many compounds in search of clinical utility resulting from the molecular biology revolution. This one alters calcium channels in nerve cells and seemed to have tranquilizing and anticonvulsant activity in animal models. Pfizer convinced the FDA that the drug had a role to play in the treatment of seizures and diabetic neuropathy, and then convinced physicians to write about 600,000 prescriptions for these indications, with the average patient footing a monthly bill approaching $150.

This approval is a testimony to the mindset of the FDA when faced with the perseverance of Pfizer in sponsoring multiple trials with marginal if not disappointing results. In the first trial, published in 2005 by the 1008-105 study group, there was less than a point improvement on a 10-point scale for pain, and this change was statistically significant only at the highest dose studied. However, “dizziness” and “somnolence” was the price paid by over half exposed to this dose. Interestingly, only 10 percent of those on placebo experienced “dizziness” and 5 percent experienced “somnolence.” This makes me wonder how the effects were monitored, since “non-restorative sleep” is nearly ubiquitous in this patient population and neurological symptoms such as lightheadedness are nearly as prevalent. How were half the subjects on pregabalin able to distinguish the adverse event of “somnolence” given their prevalence of “non-restorative sleep”? It is therefore not surprising that licensing was withheld pending firmer evidence. This resulted in the “Freedom Trial.” In this randomized clinical trial, twice as many “unblinded” patients (who knew what they were taking) found the benefit of pregabalin to be worthwhile compared to their blinded counterparts, who were unaware of the drug. The Freedom Trial also showed that more of those who were randomized to take a placebo relapsed in the withdrawal phase. I can’t imagine that blinding was possible in this design given the high likelihood of drug related adverse events. By the end of five months, fully a third of the pregabalin patients had reverted to their baseline symptoms. But the FDA was convinced of the drug’s efficacy and licensed it. Pfizer has been rewarded handsomely. I have no doubt that pregabalin will rapidly fall out of favor but not before it has further cemented the obsession of these patients, and lined the coffers of the stakeholders.

A year later, duloxetine (Cymbalta) followed pregabalin as the second drug to be approved by the FDA specifically for fibromyalgia. Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) that was already licensed for the treatment of depression and diabetic neuropathy. The theory underlying the use of duloxetine in fibromyalgia is contrived; in the trial published in 2005 the rationale was that “central monoaminergic neurotransmission may play a role in its etiology.” This leap was enough for Eli Lilly and Company to sponsor the several trials that lead to licensure, after which the company embarked on an aggressive marketing campaign to sell the expensive drug. The trials have much in common with the pregabalin trials. Many patients, as many as half, drop out of the trial early on. Of those who persist, the difference in efficacy between drug and placebo over six months is underwhelming. There is about a 10 percent absolute difference in the many outcome measures purporting to assess pain and other components of the illness experience. Furthermore, this small difference results in considerable nuisance. In the duloxetine trials nearly half the subjects on the agent (vs. less than 15 percent of those on placebo) tolerate nausea caused by the treatment. Duloxetine also has considerable potential for liver toxicity. My prediction is that duloxetine is not likely to survive as a therapy for fibromyalgia any longer than pregabalin.

And there are other drugs in the pipeline. Milnacipran is a variation on the SNRI theme, a norepinephrine serotonin reuptake inhibitor (NSRI) which has been marketed for depression in Europe as Ixel for the past decade. Cypress Bioscience bought the exclusive rights for approval and marketing of this drug in the U.S. and Canada in 2003 and partnered with Forest Pharmaceuticals in January 2006 to undertake a Phase III trial (following preliminary tests in which the drug has been proved to be efficacious in at least some patients). This multicenter trial involves 1200 patients labeled with “fibromyalgia.” In a press release dated May 22, 2007, these companies announced “positive results…statistically significant therapeutic effects” and predicted the submission of a new drug application before long. The results of the trial have not been published. I was invited as one of a “group of expert physicians from across the United States” to a confidential meeting to be hosted by Forest Pharmaceuticals, Inc and Cypress Bioscience, Inc. in October at which they would “present clinical trial data and the clinical features of milnacipran.” I do not attend such industry-sponsored meetings; I prefer to review the data myself once published. I would need to see clear evidence that milnacipran is any more than a duloxetine wannabe, and I’m not impressed with duloxetine. But much money is being expended in the lead-up to approval and I anticipate more will be spent should marketing follow.

I am impressed with the industry agenda – impressed by its tenacity in undertaking and underwriting so many trials, its use of composite objectives and other examples of data massaging, and its recruitment of fellow-traveling rheumatologists. The same handful of names appears on the masthead of the papers reporting the trials regardless of the drug or sponsor; the list is always accompanied by revelatory statements concerning paid consultancies and board memberships. This is one happy, conspiratorial family trying to convince these sad patients that “it’s in your mind” is a new-age disease requiring pharmaceutical intervention.