Medicating fibromyalgia in 2019: any news in the pipeline?

Piercarlo Sarzi-Puttini, Alberto Batticciotto, Daniela Marotto, Fabiola Atzeni
ASST Fatenebefratelli-Sacco University Hospital, Milan; Rheumatology Unit, Ospedale del Circolo Varese; Rheumatology, Department of Medical Sciences and Public Health Assl Olbia, Olbia; Rheumatology Unit , University of Messina, Messina, Italy

Fibromyalgia syndrome (FM) continues to pose an unmet need regarding pharmacological treatment and many patients fail to achieve sufficient relief from existing treatments (1).  Recently published guidelines recommend the adoption of a symptom-based approach to guide pharmacologic treatment. Emerging treatment options for FM may be best differentiated on the basis of their effect on comorbid symptoms that are often associated with pain (e.g. sleep disturbance, mood, fatigue) (2).  None of the currently available drugs are fully effective against the whole spectrum of FM symptoms, which seem to benefit from multidisciplinary management (3).

Various drugs have been recommended in the different guidelines, but none have been approved by the European Medicines Agency, and only three by the Food and Drug Administration (FDA): the serotonin and norepinephrine reuptake inhibitors (SNRIs) duloxetine and milnacipran, and pregabalin, which acts via the α2δ subunit of voltage-gated calcium channels. However, a significant number of patients do not respond adequately to these drugs or experience intolerable side effects (3).

The existence of subgroups of FM patients has been suggested by many studies and the heterogeneity of the condition may be responsible for the limited efficacy of pharmacological treatments(4,5).

In observational, prospective, and longitudinal studies, patients frequently require and take multiple prescription drugs, although monotherapy would clearly be the optimal approach to treating FM (6,7).  However, there is no evidence that patients actually benefit from drug combinations: only few trials have investigated the combination of pregabalin and antidepressants, as well as combined treatment with amitriptyline (8).  

The new formulations of older drugs include a controlled-release (CR) formulation of pregabalin, an extended-release (ER) formulation of gabapentin, and the sublingual TNX-102 tablet of low-dose cyclobenzaprine. Although evidence is scarce the once-daily formulations of these drugs are promising therapeutic options that should also improve patient compliance (9).

However, Tonix’s sublingual oral cyclobenzaprine (TNX-102) was disappointing.   Tonix evaluated TNX-102 in at least four FM trials and seven other studies.  The trials indicated that TNX-102 did have its benefits, but it failed to reduce pain significantly in at least 30% of the FM patients taking it.

Mirogabalin is  a gabapentinoid with significantly higher potency than pregabalin.  In the three, 13-week, double-blind, global, phase 3 ALDAY clinical trials evaluating mirogabalin for the treatment of pain associated with FM, mirogabalin did not meet the primary efficacy endpoint to demonstrate a statistically significant reduction in the weekly average of worst daily pain score from baseline to Week 13. In Japan, the company submitted a marketing application only for treatment of peripheral neuropathic pain. 

Ambroxol is a secretolytic substance, but may also potentially influence several pathophysiological mechanisms involved in fibromyalgia. First, ambroxol interferes with oxidative stress and influences cytokines and inflammation. Second, ambroxol blocks sodium channels, especially the tetrodotoxin-resistant (TTX-r) channel subtype Nav1.8, which is expressed particularly in spinal ganglion cells and in nociceptive, sensory neurons. Nevertheless, at this point the evidence basis for ambroxol is not strong enough for clinical recommendation (10).

There is no evidence that pure opioids are effective in fibromyalgia but there is some evidence that opioids with additional actions on the norepinephrine-related pain modulatory pathways, such as tramadol, can be clinically useful in some patients. Novel actions of low-dose opioid antagonists may lead to better understanding of the role of opioid function in fibromyalgia (11).

Even though current evidence is too scarce and weak to support the use of cannabinoids in FM, it would be interesting to investigate their potential role. The existing data are limited to the synthetic cannabinoids, nabilone, and dronabinol, but future studies should also investigate the role of the efficacy and long-term safety of other synthetic or natural cannabinoids (12).

Evidence-based interdisciplinary guidelines give a strong recommendation for aerobic exercise and cognitive behavioral therapies. Drug therapy is not mandatory. Only a minority of patients experience substantial symptom relief with duloxetine, milnacipran, and pregabalin or with a combination of different drugs (13).

References
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