Pharmacologic Treatments

Pharmacologic interventions include both Food and Drug Administration (FDA) approved medications specifically for the treatment of fibromyalgia and other FDA approved drugs not specifically approved for the management of fibromyalgia symptoms in the United States.

FDA-Approved Drugs for Fibromyalgia

Three oral medications have been FDA approved for fibromyalgia since 2007: duloxetine and milnacipran (serotonin-norepinephrine reuptake inhibitors [SNRIs]) and pregabalin (a gamma-aminobutyric acid agonist).

Pregabalin was the first FDA approved medication for fibromyalgia. Antiepileptic drugs, such as pregabalin, are commonly used to treat neuropathic pain.²² Although its exact mechanism of action is unknown, pregabalin acts on neurons and results in analgesic, anxiolytic, and antiepileptic effects in animal studies.²²

Newer SNRIs, such as duloxetine and milnacipran, differ from selective serotonin reuptake inhibitors (SSRIs) because of their reuptake inhibition of both norepinephrine and serotonin neurotransmitters.²³ SNRIs were designed to have superior efficacy in treating depression than SSRIs, and with fewer side effects than tricyclic antidepressants,²² but evidence for this claim is not persuasive.²⁴ Duloxetine was the first SNRI that demonstrated efficacy for reducing pain in patients with fibromyalgia, although the exact mechanism of action on the perception of pain is unknown. Milnacipran was approved after demonstrating efficacy in concurrent improvements in pain, physical function, and global impression of disease. Additional information about these medications is listed in Table 1.

Table 1

FDA-approved drugs for the treatment of fibromyalgia.

Nonpharmacologic Treatments for Fibromyalgia

A wide array of nondrug treatments is used to manage pain and other symptoms associated with fibromyalgia, often in combination. Treatment goals are to reduce pain, improve physical function and endurance, and foster self-efficacy in fibromyalgia management, both short and long-term. Common therapies are listed in Table 2.

Table 2

Nonpharmacologic treatments for fibromyalgia.

Rationale for Review

Many clinical trials suggest a modest benefit from treatments for a general population of fibromyalgia patients.^1,20 Although clinicians believe that treatment effectiveness may vary in subgroups,^25-27 less is known about the efficacy and comparative effectiveness of these treatments for subgroups of adults (defined by number and type of coexisting syndromes or conditions, severity of pain or impairment at baseline,¹³ presence of a mood or other mental health disorder, primary complaint at baseline, or demographic or other related factors). Understanding subgroup treatment effects might help to inform clinical decisions. For example, moderate to severe depression affects 20 to 40 percent of fibromyalgia patients in clinical trials,^3,27-29 and approximately 10 percent have anxiety disorders.³⁰

This systematic review provides information for both patients and providers on treatment outcomes in fibromyalgia subgroups; such patients typically present with multiple, chronic symptoms and/or conditions and pose significant treatment dilemmas for providers.

Selection of Patient Subgroups

Certain subgroups of patients have a higher prevalence of fibromyalgia, are more clinically complex or challenging to treat, and/or have historically unsatisfactory treatment outcomes.^10,31 The patient subgroups were chosen a priori from the literature and with input from experts and other stakeholders, including: women,^32-36 older^37,38 or obese³⁹ adults, individuals with coexisting mental health conditions,^{5,10,29,40,41} those with high severity^41-44 or longer fibromyalgia duration,⁴⁵ multiple medical comorbidities,^5,45,46 or other chronic pain conditions.^{5,10,20,29,47}

• Women: Population-based prevalence estimates of fibromyalgia in women are two to seven times higher than those of males.^11,48 Women comprise the majority of fibromyalgia patients seen in clinical practice⁴⁹ and many studies were conducted exclusively in women. Women with fibromyalgia tend to have higher tender point counts, lower pain thresholds (per dolorimeter), and report more fibromyalgia symptoms (such as all-over pain, sleep disturbance, fatigue, and irritable bowel syndrome) than men.⁵⁰ Recent studies also identified differences by sex in depression, somatic symptoms, modes of treatment used, and patterns of health care service use.^32-36 More information is needed about how outcomes differ between men and women for the same modes and intensities of treatment and which treatment modes best benefit men or women.
• Individuals with coexisting mental health conditions: Coexisting mental health disorders are particularly common in fibromyalgia patients, especially depression and/or anxiety (which occurs in more than one-third of fibromyalgia patients) and substance abuse.^5,10,29,40 Traumatic or stressful events and post-traumatic stress disorder may trigger or exacerbate fibromyalgia.^5,51 Simultaneous treatment of co-occurring mental health disorders has been advised, especially in severe cases.⁴¹
• Individuals with high fibromyalgia symptom severity (Fibromyalgia Impact Questionnaire (FIQ) 59-100):⁴² Patients with high FIQ scores report greater functional limitations, higher overall impairment, and more severe symptoms; typical treatments may be less effective⁴³ or not feasible and may require adaptation to severity.^41,44 These highly-affected individuals present special treatment and management challenges for providers.
• Older adults: Older adults may have higher comorbidity burden, functional limitations, or altered renal clearance that require treatment modifications compared with middle-aged adults. More frequent and more severe medical comorbidities in older adults may increase the likelihood of adverse effects, drug interactions, and altered drug tolerance from pharmaceutical therapies for fibromyalgia, increasing the risk for falls, fractures, and other injuries from standard treatments. Recent information shows less impact of fibromyalgia on health-related quality of life (HRQoL) in older women³⁷ and less fibromyalgia symptomatology in older adults compared with middle-age adults.³⁸ However, feasible modes of treatment and outcomes may vary in this subgroup.
• Obese adults: Obese adults with fibromyalgia report greater fibromyalgia symptoms (pain, stiffness, depression) and poorer physical function³⁹ and may have differential treatment responses compared with nonobese adults with fibromyalgia.^52,53 High rates of obesity (45 percent) and overweight (27 percent) are reported in patients with fibromyalgia, and severe obesity is particularly associated with greater fibromyalgia symptoms and lower quality of life.³⁹
• Individuals with multiple medical comorbidities:⁴⁵
  • Concurrent rheumatic disease: rheumatoid arthritis (RA), lupus (SLE), ankylosing spondylitis (AS), etc., including osteoarthritis (OA). At least one-third of patients with rheumatic conditions also have fibromyalgia.^5,46
  • Other comorbidities
• Persons with other significant chronic pain conditions: The presence of other somatic syndromes with fibromyalgia complicates treatment and compromises outcomes.⁴⁷
  • Migraine or tension headaches affect up to than half of patients.^5,10,29
  • Somatic syndromes (e.g., irritable bowel syndrome, chronic fatigue syndrome, temporomandibular joint dysfunction, low back pain, and others) are associated with fibromyalgia.^5,20
• Individuals with longer duration of fibromyalgia symptoms: Longer duration of symptoms is associated with poorer outcomes. Initial assessment values are predictive of longer-term outcomes in fibromyalgia patients seen in rheumatology centers.⁴⁵

Scope of the Review

This systematic review examined whether specific subgroups would benefit from being treated differently from the general fibromyalgia patient population.

Unlike most systematic reviews that compare average treatment effects for average patients with a specific condition, the goal of this report is to provide summary information on the evidence to date to support patient and provider treatment choices when comorbid or complex clinical situations are present in adults with fibromyalgia. The subgroups, chosen a priori, reflect medically and/or psychologically complex patients or those who reported greater impairment or less responsiveness to treatments. Additional subgroups were included as found in the literature.

We limited this systematic review to subgroup treatment effects because McMaster University in Canada is currently conducting a comprehensive systematic review of randomized controlled trials (RCTs) on interventions for fibromyalgia in adults.⁵⁴ Our systematic review complements the McMaster work by examining outcomes in fibromyalgia patient subgroups and by including observational literature.

Because fibromyalgia is largely a chronic condition in adults, we limited our analysis to studies of individuals age 18 or older that compared treatments for fibromyalgia in subgroups of adults and reported outcomes at least 3 months after treatment initiation.

Key Questions

The following two Key Questions were the focus of this systematic review:

Key Question 2 (KQ 2) What are the harms of treatments for fibromyalgia in specific adult subpopulations?

• Women
• Individuals with coexisting mental health conditions
• Individuals with high fibromyalgia symptom severity (FIQ 59-100)
• Older adults
• Obese adults
• Individuals with multiple medical comorbidities
  • Concurrent rheumatic disease: rheumatoid arthritis (RA), lupus (SLE), ankylosing spondylitis (AS) etc., including osteoarthritis (OA)
  • Other comorbidities
• Individuals with other significant chronic pain conditions (low back pain, headache, irritable bowel syndrome (IBS), etc.)
• Individuals with longer duration of fibromyalgia symptoms

Components of the PICOTS framework to answer the Key Questions on fibromyalgia for this review are described in Table 3.

Table 3

PICOTS framework.