Chronic Opioid Use in Fibromyalgia Syndrome

A Clinical Review

Jacob T. Painter, PharmD, MBA, PhD; Leslie J. Crofford, MD


J Clin Rheumatol. 2013;19(2):72-77. 

In This Article

Pharmaceutical Treatment Alternatives

Treatment of FM typically focuses on the 2 most troublesome aspects of the syndrome: pain and lack of restorative sleep. Treatment is generally multimodal, consisting of pharmacologic agents and nonpharmacologic therapies. According to a 2004 review published in the Journal of the American Medical Association, pharmacologic therapies for FM can be divided according to the level of existing efficacy evidence: strong, modest, weak, or none.[26] Since the publication of this review in 2004, 3 other clinical reviews focusing on the treatment of patients suffering from FM have been published.[31–33] Guidelines generally agree on appropriate agents for pharmacologic intervention, although since the first guideline published in 2004, 3 medications have obtained Food and Drug Administration (FDA) approval, and each is considered a preferred medication for treatment of this syndrome (Table 2).

In 2004, only a very limited number of medications were considered to have strong evidence for efficacy in FM. These included amitriptyline, a tricyclic antidepressant, and cyclobenzaprine, a muscle relaxant. Amitriptyline has been shown to be effective at reducing pain, fatigue, and sleep disturbances, each with large effect sizes in FM patients.[34] A meta-analysis of cyclobenzaprine use in patients with FM showed significant short-term benefit, although a troublesome adverse effect profile hampers increased use of this medication.[35] More recent guidelines prefer the use of amitriptyline to cyclobenzaprine and include medications introduced after 2004. Three medications have now been approved for use in the United States for treatment of FM syndrome. In 2007, the FDA approved pregabalin, an [alpha]2 delta ligand that reduces calcium influx at nerve terminals and therefore reduces the release of several relevant neurochemicals.[36] Pregabalin has been shown to be superior to placebo in reducing pain and fatigue, improving sleep index scores, improving both patient and clinician global impression of change, and improving 4 of 8 SF-36 domains.[37] One year following the approval of pregabalin, the FDA approved duloxetine for treatment of FM. Duloxetine, a balanced serotonin-norepinephrine reuptake inhibitor, has been shown in 2 randomized placebo-controlled trials to improve FM symptoms across many domains in women with and without major depressive disorder.[38] In 2009, the FDA approved a third drug, milnacipran, for use in FM. Milnacipran is another balanced serotonin-norepinephrine reuptake inhibitor, which was shown to be superior to placebo in pain response, patient global impression of change, fatigue, cognition, and several SF-36 domains.[39]

Many medications have shown modest evidence of efficacy in FM. Among these are some of the selective serotonin reuptake inhibitors and tramadol. Selective serotonin reuptake inhibitors, particularly fluoxetine and paroxetine, have been shown to be effective in reducing pain associated with FM; however, no significant effect on mood or fatigue has been demonstrated.[40] Although pure analgesics in general have not proven efficacious in the treatment of FM, tramadol has shown efficacy for FM in 2 randomized controlled trials.[41,42] The efficacy of tramadol may be due to its complicated mechanistic action combining μ-opioid receptor agonistic activity with serotonin and norepinephrine reuptake inhibition. Despite the efficacy evidence supporting the use of tramadol for treatment of FM, recent warnings from the FDA concerning suicide risk associated with the use of this medication suggest that other treatment alternatives may be preferable.[43]

Reviews and treatment guidelines have also made note of medications with no evidence for efficacy. Included in this class were corticosteroids and nonsteroidal anti-inflammatory drugs, although these types of medications may be useful for concomitant conditions including various types of immune-inflammatory disorders or mechanical derangements. Opioid analgesics have no evidence for efficacy in FM, and each guideline has reiterated the inappropriateness of opioids for the treatment of this syndrome or has reserved their use for a small subset of patients as a last-line therapy.[31–33] In 2005, the American Pain Society states that opioids should only be considered after "all other pharmacologic and nonpharmacologic therapies have been exhausted."[33] Three years later, the European League Against Rheumatism wrote more simply "…opioids are not recommended."[32] Finally, the latest review, which comes from the Association of Scientific Medical Societies in Germany in 2009, makes no mention of opioids, but recommends only amitriptyline, pregabalin, duloxetine, or milnacipran for use.

Despite recommendations against the use of opioids for the treatment of FM, evidence suggests widespread and increasing clinical utilization.[18] Recent evidence shows that more than four-fifths of FM patients receive opioid therapy and that treatment using approved medications not only does not reduce this trend but also tends to increase opioid utilization rates.[44] The treatment of central pain such as that seen in FM is a complicated endeavor; drugs that have been submitted to clinical trials are at best 50% effective at controlling pain, resulting in a number needed to treat of 2.[45] Unfortunately, medications approved for use in FM are not even this effective. Numbers needed to treat seen for a 30% reduction in pain in FM patients are 7.2 for duloxetine, 8.6 for pregabalin, and 19 for milnacipran.[46]

In addition to the modest effect sizes seen for treatment of central pain associated with FM, there is also a problem with the perception of efficacy among patients. An Internet survey of more than 2500 FM patients in 2007, before widespread use of any FDA-approved medication, showed that the most commonly used medications included over-the-counter therapies (acetaminophen, ibuprofen, and naproxen) and medications considered to have evidence of efficacy (amitriptyline and cyclobenzaprine).[47] Despite these being the most highly utilized medications, patients reported the most effective medications were those that both had no evidence of efficacy and had a high potential for abuse, including hydrocodone, alprazolam, oxycodone, zolpidem, and clonazepam.[47] These findings should trigger concern for practitioners dealing with FM, as the perceived benefit of these medications may be the result of central reward effects rather than the relief from the syndrome itself and reflective of the abuse liability properties of these drugs. The possible dependence and adverse effects seen with 2 of these medications (hydrocodone and oxycodone) are of particular concern as the consequence of chronic use of these drugs is many and severe.