By Scott Millard
Executive Director, Strategic Development Department, Analgesia
Premier Research

It’s hard to fault fibromyalgia patients for feeling ignored and underserved. For years, many health professionals doubted and discounted their symptoms, even labeling them as malingerers. Physicians and researchers cannot easily or directly observe fibromyalgia’s manifestations, but must rely on patient reports of pain and a range of other symptoms. What’s more, no clear biomarkers are available to guide the condition’s management or measure response to treatment.

It wasn’t until the early 2000s that the affliction became more generally accepted as a syndrome, paving the way for FDA approval of three therapies: the anti-seizure medicine pregabalin and the serotonin and norepinephrine reuptake inhibitors duloxetine and milnacipran. But after that burst of activity, fibromyalgia largely fell off the pharmaceutical map until a rebirth of interest in 2012.

Research has since taken a diverse range of approaches. At one time, we had four programs running in entirely different methods of action: traditional approaches (serotonin-norepinephrine reuptake inhibitors, sedatives, muscle relaxants, and new chemical entities), antiviral products, electromagnetic and cranial stimulation devices, and behavioral therapy. Multiple new drugs are under study today, though none has yet received regulatory approval.

As the field has matured, it has become increasingly clear that fibromyalgia is a complex condition whose definition and measurement extend far beyond charting patient-reported pain levels on a numeric scale. While pain remains the condition’s primary symptom, improving quality of life requires more than just mitigating discomfort. Indeed, the FDA increasingly seeks evidence of overall benefit and functional improvement — and an online survey of nearly 2,600 patients revealed that the fatigue, sleep disturbance, and cognitive dysfunction are often more severe and problematic symptoms than pain.1

Six assessment domains

When characterizing fibromyalgia, we must look at six assessment domains:2

  • Pain
  • Comorbidities
  • Affective vulnerability
  • Beliefs and attitudes
  • Behavior
  • Environmental and social factors

Pain. The only measure of pain considered in early fibromyalgia trials was intensity. But there are other relevant aspects, such as quality, location and distribution, interference with functional status, and temporality.

Comorbidities. Conditions and symptoms that tend to accompany chronic pain include fatigue, sleep disturbance, and cognitive dysfunction.3 The National Institutes of Health now recognize fibromyalgia as a chronic overlapping pain condition, one of a set of co-aggregating disorders that share symptomatology and common mechanisms despite residing in anatomically distinct parts of the body.

Affective vulnerability. Emotion is considered to be central to experiencing pain, and historically, the phenotype of fibromyalgia included a high prevalence of comorbid affective disorders.4 As diagnosing fibromyalgia does not require diagnosis of a comorbid affective disorder, continuous measurement of emotion is useful when assessing the role of affect in this or any other chronic pain condition.

Beliefs and attitudes. Patients’ beliefs and attitudes about pain can directly influence their affect and functional status.5 This is especially true with fibromyalgia, whose sufferers may have a tendency to catastrophize their pain.

Behavior. Of the many behavioral domains that may be relevant for patients, physical functioning may be the most common.6 The Medical Outcomes Study Short Form Health Survey-36 and versions of it have been used to assess physical and mental function in multiple fibromyalgia studies. Sleep quality and lack thereof (indicated by waking unrefreshed), fatigue, depression, and cognitive functioning have become increasingly prominent criteria.

Environmental and social factors. The quality and quantity of social support at initial diagnosis often predict patients’ pain and functional status three to five years later.7 Therefore, social factors are often considered in the phenotypic assessment of fibromyalgia.

Patient characteristics

Patients in fibromyalgia trials are different from those you might in counter when studying other chronic pain indications. One obvious distinction is that they are overwhelmingly female, in part a holdover from the 1990 American College of Rheumatology diagnostic criteria — still used today alongside the ACR’s updated 2010 criteria — that showed a much higher incidence of the condition in women.

Regardless of gender, fibromyalgia patients are, as a rule, highly compliant with their ePRO diaries. Remember, these people suffer from a condition many in the medical profession did not take seriously until a few years ago. After facing diagnostic dead ends, or worse being dismissed (“it’s all in your head”), they value the opportunity to participate in drug trials and tend carefully to their diaries.

These patients also can pose significant challenges:

  • You need to carefully detail their medical history when screening. There are, without exaggeration, 50 to 60 potential symptoms that can vary throughout a trial. They’ll have good and bad days, spiking up on one condition and going down on another. And they’re often big self-medicators, presenting a list of 20 medications they’re taking. Even if they’re mostly supplements and other over-the-counter drugs, you’ll need to spend time sifting through the list and asking why they’re taking them.
  • This population can be, for lack of a more scientific term “needy.” Some patients, having been paid scant attention, so appreciate their role in the study that they get attached to the site staff and may seek to please them, even subconsciously, by showing improvement. We remedy this, in part, by switching up staff to keep familiarity at a minimum.
  • Placebo response may be higher in fibromyalgia trials than in other indications. How high? Pregabalin, one of the three currently approved drugs, had a 36 percent placebo response versus 61 percent for patients who received the drug.8 Reasons include that desire to please study staffers, misunderstanding of the assessment criteria, and — especially in today’s trials — inflated expectations in an environment where patients see the search for treatments as finally coming into its own.
  • There’s a lot of overlap between fibromyalgia symptoms and those experience by patients with a ride range of other disorders. These include regional pain syndromes like irritable bowel, interstitial cystitis, and temporomandibular joint dysfunction, and such psychiatric disorders as major depression, bipolar disorder, OCD, the post-traumatic stress disorder.

Picking study sites

Growth in fibromyalgia drug research over the past five years has made site selection a far less taxing prospect. There are now hundreds of sites capable of performing this research, and the challenge is to gather current feedback on them. You want to work with a CRO or other party that has performed multiple studies across numerous sites and has close connections with the fibromyalgia consultant community.

Look for competing fibromyalgia trials at the site (you don’t want to get locked in a competition for patients and staff time), examine database availability and willingness to work with central recruiting agencies, and evaluate the staff for objectivity of research versus patient care. It’s a bit like picking stocks — past performance does not guarantee future success — and site turnover is always high, so you have to continually study their data, looking at separation, data quality, and all the other things that might derail your research.


  1. Bennet RM, et al. An internet survey of 2,596 people with fibromyalgia. BMC Musculoskeletal Disorders. 2007;8:27.
  2. Williams DA, Kratz AL. Patient reported outcomes and fibromyalgia. Rheum Dis Clin North Am. 2016;42(2):317-332.
  3. Aaron LA, Buchwald D. A review of the evidence for overlap among unexplained clinical conditions. Ann Int Med. 2001;134:868-881.
  4. Goldenberg DL. Psychological symptoms and psychiatric diagnosis in patients with fibromyalgia. J 1989;19(Suppl):127-130
  5. Turner JA, Jensen MP, Roman JM. Do beliefs, coping, and catastrophizing independently predict functioning in patients with chronic pain? Pain. 2000;85(1-2):115-125.
  6. Williams DA, Kratz AL. Patient reported outcomes and fibromyalgia. Rheum Dis Clin North Am. 2016;42(2):317-332.
  7. Evers AW. Pain coping and social support as predictors of long-term functional disability and pain in early rheumatoid arthritis. Behavior Res Ther. 2003;41(11):1295-1310.
  8. Arnold LM, et al. Pain Ther 2013;2:65-71.