Feeling true pain

Fibromyalgia is a condition that even after its classification as a 'true' illness by the American Medical Association (AMA) in 1987 is still not recognised by all physicians as a legitimate disorder.

Many doctors claim that complaints of fibromyalgia are simply manifestations of depression. Research funding in this area has therefore been limited.

However, this debilitating condition, with its significant effects on quality of life, is slowly making its way into the everyday workbook of the average physician. Patients frequently complain of diffuse, widespread pain including headaches and facial pain, fatigue and sleep disturbances, heightened sensitivity to odours, noises and bright lights, and symptoms of irritable bowel syndrome.

The specific etiology of this condition is as yet unknown, but several theories have been formulated. Alterations in neurotransmitter regulation, particularly serotonin and substance P, are suspected to play a major role in the pathology of fibromyalgia.

Serotonin has been linked to many conditions that represent symptoms of fibromyalgia, particularly depression, migraines and gastrointestinal distress. In turn, substance P has long been linked to pain, anxiety and stress, as well as being thought to play a part in depression.

Some researchers also consider sleep disturbances to be more than a symptom of the condition, but also a precipitating factor that is the result of a sleep disorder known as alpha-wave interrupted sleep pattern. Studies have shown that disturbances in sleep can trigger inflammatory immunological processes that in turn lead to fatigue, pain and a decrease in the pain threshold. This is supported by evidence that volunteers subjected to disrupted deep sleep report fibromyalgia-like pain symptoms.

Other experts in the field have suggested that factors such as injury of the upper spinal region, infections, and pathological changes in autonomic nervous system or muscle metabolism can trigger the onset of fibromyalgia.

While fibromyalgia is not a progressive disorder with extensive medical complications, it can be very debilitating and impacts negatively on patients' quality of life.

The current pharmaceutical approach to treatment aims to reduce pain and improve sleep patterns with the use of analgesics such as paracetamol and antidepressants, particularly amitriptyline, nortriptyline and doxepin. In the short term, muscle relaxants such as cyclobenzaprine, administered at bedtime, can be useful to alleviate muscle pain and spasms.

While this is not an indication that is characterised by heavy development, there are several up-and-coming treatments that will make an important difference to the lives of patients, and will offer clinicians a greater choice of available treatments.

Developments at Pfizer
Pfizer's Lyrica (pregabalin) is a structural analogue of the neurotransmitter GABA (gamma-amino-butyric acid) that modulates the activity of voltage-gated calcium channels in the central nervous system, thus presenting a potential treatment for a range of neurological, pain and psychiatric conditions.

This compound is approved as a treatment for epilepsy, neuropathic and postherpetic pain and is in preregistration for generalised anxiety disorder. Phase III development is currently ongoing in Canada, the US and Europe for fibromyalgia.

Two large randomised trials conducted by researchers at Pfizer Global Research and Development in the US, one published in April 2005 and another in November 2006, randomised more than 500 patients each to treatment with pregabalin at a dosage range of 150-600mg/day or placebo for eight weeks. Both trials found pregabalin to be statistically superior to placebo with regard to scores on various pain-related measures and, importantly, quality of life.

The study published in 2005 found a higher rate of dizziness, somnolence and dry mouth in pregabalin recipients compared with placebo-treated subjects, however most adverse events were mild or moderate in severity and the frequency of events leading to withdrawal was similar between the treatment groups.

Pfizer is currently recruiting patients with fibromyalgia into another large, randomised, double-blind, placebo-controlled trial of pregabalin initiated in June 2006. This trial is being held across centres in Europe, the US, Canada and Australasia and aims to recruit 740 patients, to ascertain more clearly the effects of this treatment on pain, sleep outcomes and patient quality of life.

Milestone for Jazz
Xyrem (sodium oxybate) from Jazz Pharmaceuticals is a medically-formulated gamma hydroxybutyrate (GHB)-based compound that is a precursor of GABA in the central nervous system, thus its premise is similar to that of Pfizer's pregabalin. Because of this compound's potential for misuse, sodium oxybate is a schedule III controlled substance and its distribution is governed by the Subpart H regulations of the US Food and Drug Administration (FDA).

A significant development milestone was reached in 2002 when sodium oxybate was the first treatment to become available in the US for cataplexy, a sudden loss of muscle tone associated with narcolepsy. Since then, sodium oxybate has been undergoing heavy development, and studies demonstrating the benefit of this new therapy in fibromyalgia have made an impact at conferences over the past year.

The drug, administered in dosages of 4,500 or 6,000mg/day, has demonstrated significant improvements in Visual Analogue Scale pain scores and Fibromyalgia Impact Questionnaire scores, and patients have experienced dose-dependent improvements on measures of sleep, tender points and joint tenderness.

Jazz Pharmaceuticals is currently conducting a phase III trial of sodium oxybate in patients with fibromyalgia across multiple centres in the US that is due for completion in December 2008. This randomised, double-blind, placebo-controlled trial is expected to provide supporting evidence of the clinical efficacy of this emerging therapy.

After years of suffering, there is hope for patients with fibromyalgia. The next few years will see the emergence of these and other treatments that are in the development pipeline, finally bringing optimal disease management to the ongoing chronic pain of fibromyalgia.

The author
Pipeline was written by Anna Mett of Adis International, using data derived from Adis Clinical Trials Insight and R&D Insight.