The Problems with Fibromyalgia and its Drug Trials

Winfried Häuser, MD

Fibromyalgia (FM) is a controversial condition. There are ongoing debates on the classification of FM (pain disorder, small fiber neuropathy, rheumatic disease, functional somatic syndrome, somatoform pain disorder, affective spectrum syndrome disorder). Some physicians even question its existence or the utility of the diagnostic label „FM“.

However, in 1994, the tenth revision of the International Classification of Diseases (ICD‑10) listed FM under ‘diseases of the musculoskeletal system and connective tissue’. There are national and European guidelines on the management of FM available.

FM is frequently associated with other chronic pain conditions (e.g. tension headache, irritable bowel syndrome), „rheumatic“ diseases (e.g. osteoarthritis, inflammatory rheumatic diseases) and mental disorders (anxiety and depressive disorders, posttraumatic stress disorder). „FM only“ is very rare. The strict exclusion criteria strongly limit the external validity of the drug studies available.

On average, the results of drug trials in FM are disappointing. Only a minority of patients experienced a substantial relief of symptoms with good tolerability of the drugs. In addition, the drop our rates in clinical studies were high. The EMA refused the approval of duloxetine, milnacipran and pregabalin for FM, because the single European study with each of these drugs missed to meet the primary endpoint, namley the superiority over placebo in the reduction of mean pain intensity from baseline to the end of treatment. However, the drugs were superior to placebo if responder rates of moderate and substantial pain relief were analysed. Average values are not appropriate outcomes in FM.

If pain reduction is an appropriate outcome in chronic pain trials in general and in FM in particular is under debate. Improvement of physical function, life satisfaction and pain acceptance might be more apporpriate outcomes.

In my lecture, I will discuss consequences of these problems for the design of future studies, e.g. block randomization of patients stratified to comorbidities and dichotomous outcomes for the key symptoms of FM.