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Opioid Use in Fibromyalgia

A Cautionary Tale

      Abstract

      Multiple pharmacotherapies are available for the treatment of fibromyalgia (FM), including opioid analgesics. We postulate that the mechanism of action of traditional opioids predicts their lack of efficacy in FM. Literature searches of the MEDLINE and Cochrane Library databases were conducted using the search term opioid AND fibromyalgia to identify relevant articles, with no date limitations set. Citation lists in returned articles and personal archives of references were also examined for additional relevant items, and articles were selected based on the expert opinions of the authors. We found no evidence from clinical trials that opioids are effective for the treatment of FM. Observational studies have found that patients with FM receiving opioids have poorer outcomes than patients receiving nonopioids, and FM guidelines recommend against the use of opioid analgesics. Despite this, and despite the availability of alternative Food and Drug Administration–approved pharmacotherapies and the efficacy of nonpharmacologic therapies, opioids are commonly used in the treatment of FM. Factors associated with opioid use include female sex; geographic variation; psychological factors; a history of opioid use, misuse, or abuse; and patient or physician preference. The long-term use of opioid analgesics is of particular concern in the United States given the ongoing public health emergency relating to excess prescription opioid consumption. The continued use of opioids to treat FM despite a proven lack of efficacy, lack of support from treatment guidelines, and the availability of approved pharmacotherapy options provides a cautionary tale for their use in other chronic pain conditions.

      Abbreviations and Acronyms:

      BPI-I (Brief Pain Inventory-Interference), BPI-S (Brief Pain Inventory-Severity), FDA (Food and Drug Administration), FIQ (Fibromyalgia Impact Questionnaire), FM (fibromyalgia), HAQ (Health Assessment Questionnaire), ISI (Insomnia Sleep Index), MPQ (McGill Pain Questionnaire), OIH (opioid-induced hyperalgesia), PGA (patient global assessment), PHQ-8 (8-item Patient Health Questionnaire), SDS (Sheehan Disability Scale), VAS (visual analog scale)
      Article Highlights
      • There is no clinical or real-world evidence demonstrating the efficacy or effectiveness of opioids in the treatment of fibromyalgia (FM).
      • Despite this, and despite treatment guidelines recommending against the use of long-term opioids for FM, opioid use is very common in patients with FM.
      • The rate of opioid prescribing is high in FM despite the availability of guideline-recommended and Food and Drug Administration–approved medications for FM.
      • Excess opioid prescription by physicians and opioid consumption by patients with FM may be contributing to the ongoing opioid epidemic in the United States and provides a valuable lesson for other chronic pain disorders.
      The cardinal symptom of fibromyalgia (FM) is chronic widespread pain.
      • Wolfe F.
      • Ross K.
      • Anderson J.
      • Russell I.J.
      • Hebert L.
      The prevalence and characteristics of fibromyalgia in the general population.
      • Wolfe F.
      • Michaud K.
      • Li T.
      • Katz R.S.
      Chronic conditions and health problems in rheumatic diseases: comparisons with rheumatoid arthritis, noninflammatory rheumatic disorders, systemic lupus erythematosus, and fibromyalgia.
      • Lachaine J.
      • Beauchemin C.
      • Landry P.A.
      Clinical and economic characteristics of patients with fibromyalgia syndrome.
      • Clauw D.J.
      Fibromyalgia: a clinical review.
      Fibromyalgia is a prototypical central pain disorder, and it has been used as a model to study related chronic pain disorders. It is also associated with multiple somatic symptoms, including fatigue, sleep disturbances, mood and cognitive disturbances, and headache, as well as bowel and bladder irritability.
      • Wolfe F.
      • Ross K.
      • Anderson J.
      • Russell I.J.
      • Hebert L.
      The prevalence and characteristics of fibromyalgia in the general population.
      • Wolfe F.
      • Michaud K.
      • Li T.
      • Katz R.S.
      Chronic conditions and health problems in rheumatic diseases: comparisons with rheumatoid arthritis, noninflammatory rheumatic disorders, systemic lupus erythematosus, and fibromyalgia.
      • Lachaine J.
      • Beauchemin C.
      • Landry P.A.
      Clinical and economic characteristics of patients with fibromyalgia syndrome.
      • Clauw D.J.
      Fibromyalgia: a clinical review.
      It has an estimated prevalence of approximately 1.1% to 5.4% in the general population,
      • Wolfe F.
      • Ross K.
      • Anderson J.
      • Russell I.J.
      • Hebert L.
      The prevalence and characteristics of fibromyalgia in the general population.
      • Branco J.C.
      • Bannwarth B.
      • Failde I.
      • et al.
      Prevalence of fibromyalgia: a survey in five European countries.
      • Vincent A.
      • Lahr B.D.
      • Wolfe F.
      • et al.
      Prevalence of fibromyalgia: a population-based study in Olmsted County, Minnesota, utilizing the Rochester Epidemiology Project.
      • Jones G.T.
      • Atzeni F.
      • Beasley M.
      • Fluss E.
      • Sarzi-Puttini P.
      • Macfarlane G.J.
      The prevalence of fibromyalgia in the general population: a comparison of the American College of Rheumatology 1990, 2010, and modified 2010 classification criteria.
      and it often coexists with other pain conditions. Of patients with rheumatic diseases, including osteoarthritis, rheumatoid arthritis, and systemic lupus erythematosus, 10% to 20% have FM, as do 30% to 70% of individuals with chronic pain disorders, such as irritable bowel syndrome and temporomandibular joint disorder.
      • Clauw D.J.
      Fibromyalgia: a clinical review.
      There is strong evidence for the efficacy of nonpharmacologic therapies, including patient education, cognitive behavior therapy, and exercise, in FM.
      • Clauw D.J.
      Fibromyalgia and related conditions.
      Pharmacologic treatments with demonstrable efficacy in FM include tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (eg, duloxetine and milnacipran), and alpha-2-delta ligands (gabapentin and pregabalin).
      • Hauser W.
      • Walitt B.
      • Fitzcharles M.A.
      • Sommer C.
      Review of pharmacological therapies in fibromyalgia syndrome.
      Duloxetine, milnacipran, and pregabalin are approved by the US Food and Drug Administration (FDA) for the treatment of FM. Opioid analgesics continue to be commonly used for the treatment of FM.
      • Ngian G.S.
      • Guymer E.K.
      • Littlejohn G.O.
      The use of opioids in fibromyalgia.
      • Painter J.T.
      • Crofford L.J.
      Chronic opioid use in fibromyalgia syndrome: a clinical review.
      However, medical guidelines, including those of the American Pain Society and the American Academy of Pain Medicine,
      • Chou R.
      • Fanciullo G.J.
      • Fine P.G.
      • et al.
      Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.
      the American Academy of Neurology,
      • Franklin G.M.
      Opioids for chronic noncancer pain: a position paper of the American Academy of Neurology.
      the European League Against Rheumatism,
      • Carville S.F.
      • Arendt-Nielsen S.
      • Bliddal H.
      • et al.
      EULAR evidence-based recommendations for the management of fibromyalgia syndrome.
      the Canadian Pain Society and the Canadian Rheumatology Association,
      • Fitzcharles M.A.
      • Ste-Marie P.A.
      • Goldenberg D.L.
      • et al.
      2012 Canadian guidelines for the diagnosis and management of fibromyalgia syndrome: executive summary.
      and the British Pain Society,
      • Lee J.
      • Ellis B.
      • Price C.
      • Baranowski A.P.
      Chronic widespread pain, including fibromyalgia: a pathway for care developed by the British Pain Society.
      recommend against the use of long-term opioids in FM. There is evidence that tramadol may be effective in the treatment of FM,
      • Bennett R.M.
      • Kamin M.
      • Karim R.
      • Rosenthal N.
      Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study.
      • Biasi G.
      • Manca S.
      • Manganelli S.
      • Marcolongo R.
      Tramadol in the fibromyalgia syndrome: a controlled clinical trial versus placebo.
      • Russell I.J.
      • Kamin M.
      • Bennett R.M.
      • Schnitzer T.J.
      • Green J.A.
      • Katz W.A.
      Efficacy of tramadol in treatment of pain in fibromyalgia.
      but it is considered a weak opioid receptor agonist, and its efficacy in FM is likely related to its other mechanism of action as a serotonin-norepinephrine reuptake inhibitor.
      • Arnold L.M.
      Biology and therapy of fibromyalgia: new therapies in fibromyalgia.
      • Desmeules J.A.
      • Piguet V.
      • Collart L.
      • Dayer P.
      Contribution of monoaminergic modulation to the analgesic effect of tramadol.
      This review is, therefore, limited to traditional opioid analgesics, and tramadol is not included. Moreover, use of the terms strong and weak opioids can be misleading because definitions are inconsistent and it is the duration of opioid treatment that is key. We deliberately do not use these terms unless individual studies have given specific definitions.
      The widespread use of opioid analgesics for chronic pain disorders is of particular concern given the ongoing public health emergency in the United States relating to prescription opioid use.
      • Chen L.H.
      • Hedegaard H.
      • Warner M.
      Drug-poisoning deaths involving opioid analgesics: United States, 1999-2011.
      This review examines the place of opioids in the treatment of FM by assessing the physiologic and clinical evidence supporting opioid use, their use and outcomes in real-world FM populations, and factors that may influence their use in FM. Because FM is considered the prototypical centralized pain state,
      • Clauw D.J.
      Fibromyalgia and related conditions.
      this information has implications for other chronic pain disorders, in particular those with a centralized component.

      Methods

      Literature searches of the MEDLINE and Cochrane Library databases were conducted using the search term opioid AND fibromyalgia to identify relevant articles. No date limitations were set, and no other filters were applied. As of September 4, 2015, 190 articles were returned from MEDLINE and 2 from the Cochrane Library. Citation lists in returned articles and personal archives of references were also examined for additional relevant items. The selection of articles for inclusion in this review was based on the expert opinions of the authors.

      Evidence of Altered Opioid Activity in FM

      Many studies have suggested altered baseline opioidergic activity in FM. Although the peripheral actions of opioids are poorly understood and are unlikely to directly reflect central activity, nearly all studies examining peripheral opioid activity to date show fairly striking differences between patients with FM and controls. Reduced concentrations of endogenous opioids in peripheral blood mononuclear cells were found in patients with both FM and chronic fatigue syndrome but not in depressed individuals.
      • Panerai A.E.
      • Vecchiet J.
      • Panzeri P.
      • et al.
      Peripheral blood mononuclear cell beta-endorphin concentration is decreased in chronic fatigue syndrome and fibromyalgia but not in depression: preliminary report.
      Another study demonstrated markedly increased μ- and δ-opioid receptor expression in the skin of patients with FM.
      • Salemi S.
      • Aeschlimann A.
      • Wollina U.
      • et al.
      Up-regulation of delta-opioid receptors and kappa-opioid receptors in the skin of fibromyalgia patients.
      Using radioimmunoassay, Vaeroy et al
      • Vaeroy H.
      • Helle R.
      • Forre O.
      • Kass E.
      • Terenius L.
      Cerebrospinal fluid levels of beta-endorphin in patients with fibromyalgia (fibrositis syndrome).
      • Vaeroy H.
      • Nyberg F.
      • Terenius L.
      No evidence for endorphin deficiency in fibromyalgia following investigation of cerebrospinal fluid (CSF) dynorphin A and Met-enkephalin-Arg6-Phe7.
      examined levels of several endogenous opioids, including β-endorphin and Met-enkephalin, in the cerebrospinal fluid of patients with FM and found these to be normal. However, early radioimmunoassay investigations showed extensive cross-reactivity between endogenous opioids and other ligands. A more recent radioimmunoassay study demonstrated increased endogenous opioid levels in the cerebrospinal fluid of patients with FM vs controls.
      • Baraniuk J.N.
      • Whalen G.
      • Cunningham J.
      • Clauw D.J.
      Cerebrospinal fluid levels of opioid peptides in fibromyalgia and chronic low back pain.
      In a subsequent positron emission tomography imaging study, [11C]-carfentail, a μ-opioid receptor selective tracer, was used to quantify μ-opioid receptor availability in patients with FM.
      • Harris R.E.
      • Clauw D.J.
      • Scott D.J.
      • McLean S.A.
      • Gracely R.H.
      • Zubieta J.K.
      Decreased central mu-opioid receptor availability in fibromyalgia.
      Receptor availability was reduced in several pain-processing and modulatory regions, including the dorsal cingulate, amygdala, and nucleus accumbens, compared with controls. Moreover, reduced receptor availability was associated with greater clinical pain in the FM group, as reported at the time of the positron emission tomography experiment.
      There are 2 possible interpretations of these data that are not mutually exclusive. First, individuals with FM may have a more activated opioid system at rest, reflecting increased release of endogenous opioids and reduced receptor availability. Second, patients with FM may have fewer opioid receptors, which could lead to elevated pain. Regardless of the operative mechanism, both outcomes would predict that individuals with lowered receptor availability have a diminished response to opioid analgesics. Perhaps the strongest data supporting a state of excess endogenous opioid activity in FM comes from studies that showed that low doses of naltrexone, an opioid receptor antagonist, may be effective in FM.
      • Younger J.
      • Mackey S.
      Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study.
      • Younger J.
      • Noor N.
      • McCue R.
      • Mackey S.
      Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels.
      Although the use of opioid antagonists requires further study, these data emphasize the notion that opioid analgesics are not likely to be effective in FM.
      The hypothesis of aberrant endogenous opioid-related pain processing is supported by indirect evidence from patient phenotypic characteristics and opioid analgesic consumption. In a prospective, observational cohort study in 519 patients who underwent lower-extremity joint arthroplasty, those with higher preoperative FM survey scores used more opioid medication and reported higher pain severity.
      • Brummett C.M.
      • Janda A.M.
      • Schueller C.M.
      • et al.
      Survey criteria for fibromyalgia independently predict increased postoperative opioid consumption after lower-extremity joint arthroplasty: a prospective, observational cohort study.
      Moreover, FM survey score and preoperative opioid use were highly predictive of postoperative opioid consumption. For each 1-point increase in FM survey score, patients used 9 mg more of oral morphine equivalents in the perioperative period. The authors concluded that the higher pain sensitivity, preoperative opioid use, and postoperative opioid consumption in patients with higher FM survey scores may reflect aberrant opioid-related central pain processing. These findings have been replicated in a different surgical cohort of women undergoing hysterectomy.
      • Janda A.M.
      • As-Sanie S.
      • Rajala B.
      • et al.
      Fibromyalgia survey criteria is associated with increased postoperative opioid consumption in women undergoing hysterectomy.
      In this study, each 1-point increase in FM survey score was associated with the use of 7 mg more of oral morphine equivalents. In a separate study of 582 patients taking opioid medication for pain relief, 49% continued to report severe pain.
      • Wasserman R.A.
      • Brummett C.M.
      • Goesling J.
      • Tsodikov A.
      • Hassett A.L.
      Characteristics of chronic pain patients who take opioids and persistently report high pain intensity.
      Among phenotypic characteristics, higher FM survey scores and more neuropathic pain symptoms were associated with higher levels of pain, suggesting that patients with persistently high pain scores despite opioid therapy were more likely to present with characteristics of centralized pain, typified by FM.
      Further supporting evidence for involvement of the central opioid system in FM is the phenomenon known as opioid-induced hyperalgesia (OIH), identified as a paradoxical increase in pain sensitivity on exposure to opioids.
      • Brush D.E.
      Complications of long-term opioid therapy for management of chronic pain: the paradox of opioid-induced hyperalgesia.
      • Smith H.S.
      Opioids and neuropathic pain.
      • Angst M.S.
      • Clark J.D.
      Opioid-induced hyperalgesia: a qualitative systematic review.
      • Lee M.
      • Silverman S.M.
      • Hansen H.
      • Patel V.B.
      • Manchikanti L.
      A comprehensive review of opioid-induced hyperalgesia.
      The exact mechanisms are unknown, but multiple hypotheses have been suggested that lead to sensitization of central pronociceptive pathways.
      • Lee M.
      • Silverman S.M.
      • Hansen H.
      • Patel V.B.
      • Manchikanti L.
      A comprehensive review of opioid-induced hyperalgesia.
      Opioid-induced hyperalgesia has yet to be directly demonstrated in patients with FM but has been suggested in patients with other chronic pain conditions.
      • Chu L.F.
      • Clark D.J.
      • Angst M.S.
      Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: a preliminary prospective study.
      • Hay J.L.
      • White J.M.
      • Bochner F.
      • Somogyi A.A.
      • Semple T.J.
      • Rounsefell B.
      Hyperalgesia in opioid-managed chronic pain and opioid-dependent patients.
      In addition, OIH has been reported in healthy volunteers receiving opioid infusions,
      • Brush D.E.
      Complications of long-term opioid therapy for management of chronic pain: the paradox of opioid-induced hyperalgesia.
      • Fishbain D.A.
      • Cole B.
      • Lewis J.E.
      • Gao J.
      • Rosomoff R.S.
      Do opioids induce hyperalgesia in humans? an evidence-based structured review.
      and there is also good evidence of OIH from a variety of animal studies.
      • Angst M.S.
      • Clark J.D.
      Opioid-induced hyperalgesia: a qualitative systematic review.
      Therefore, OIH may be an iatrogenic phenomenon that leads to a centralized pain state, analogous to the centralized pain in patients with FM that is caused by an aberrant endogenous central opioid system, both of which result in elevated pain.

      Current Use of Opioid Analgesics for FM

       Clinical Trials of Opioid Analgesics for FM

      There is no evidence from clinical trials to support the efficacy and safety of opioids in FM. Two pilot studies evaluating a single morphine infusion in patients with FM reported mixed results.
      • Sorensen J.
      • Bengtsson A.
      • Backman E.
      • Henriksson K.G.
      • Bengtsson M.
      Pain analysis in patients with fibromyalgia: effects of intravenous morphine, lidocaine, and ketamine.
      • Sorensen J.
      • Bengtsson A.
      • Ahlner J.
      • Henriksson K.G.
      • Ekselius L.
      • Bengtsson M.
      Fibromyalgia: are there different mechanisms in the processing of pain? a double blind crossover comparison of analgesic drugs.
      The lack of supporting data on the use of opioids in FM is reflected by a Cochrane systematic review of oxycodone for the treatment of neuropathic pain or FM.
      • Gaskell H.
      • Moore R.A.
      • Derry S.
      • Stannard C.
      Oxycodone for neuropathic pain and fibromyalgia in adults.
      This review was unable to identify any relevant studies for FM. Moreover, a recent systematic review found insufficient evidence to support the use of long-term (>1 year) opioid therapy for the treatment of any form of chronic pain.
      • Chou R.
      • Turner J.A.
      • Devine E.B.
      • et al.
      The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health pathways to prevention workshop.

       Real-world Data on the Use of Opioid Analgesics for FM

       Opioid Analgesic Use Is Common in Real-world Studies

      The widespread, real-world use of opioids in patients with FM has been comprehensively demonstrated in several large retrospective health claims database studies (Table 1). These studies documented opioid use in large numbers of patients with FM.
      • Berger A.
      • Dukes E.
      • Martin S.
      • Edelsberg J.
      • Oster G.
      Characteristics and healthcare costs of patients with fibromyalgia syndrome.
      • White L.A.
      • Robinson R.L.
      • Yu A.P.
      • et al.
      Comparison of health care use and costs in newly diagnosed and established patients with fibromyalgia.
      • Palacio A.
      • Uribe C.L.
      • Li H.
      • et al.
      Financial and clinical characteristics of fibromyalgia: a case-control comparison.
      • Berger A.
      • Sadosky A.
      • Dukes E.M.
      • Edelsberg J.
      • Zlateva G.
      • Oster G.
      Patterns of healthcare utilization and cost in patients with newly diagnosed fibromyalgia.
      • Painter J.T.
      • Crofford L.J.
      • Talbert J.
      Geographic variation of chronic opioid use in fibromyalgia.
      • Kim S.C.
      • Landon J.E.
      • Solomon D.H.
      Clinical characteristics and medication uses among fibromyalgia patients newly prescribed amitriptyline, duloxetine, gabapentin, or pregabalin.
      • Halpern R.
      • Shah S.N.
      • Cappelleri J.C.
      • Masters E.T.
      • Clair A.
      Evaluating guideline-recommended pain medication use among patients with newly diagnosed fibromyalgia.
      Rates of opioid use ranged from 11.3% to 69%, including short- and long-acting opioids. Two recent studies assessed opioid use in relation to the use of approved or recommended nonopioid treatment options. In patients with FM who had been newly prescribed amitriptyline, duloxetine, pregabalin, or gabapentin, opioid use was greater than 50% during the baseline period and significantly decreased during the 3 years after treatment initiation, but opioids were still being used by more than 45% of patients in each cohort.
      • Kim S.C.
      • Landon J.E.
      • Solomon D.H.
      Clinical characteristics and medication uses among fibromyalgia patients newly prescribed amitriptyline, duloxetine, gabapentin, or pregabalin.
      In the second study, opioid use decreased in the first year of treatment in patients prescribed opioids alone or with an approved FM treatment, but 38.5% were still using an opioid in the fourth quarter after diagnosis.
      • Halpern R.
      • Shah S.N.
      • Cappelleri J.C.
      • Masters E.T.
      • Clair A.
      Evaluating guideline-recommended pain medication use among patients with newly diagnosed fibromyalgia.
      Once patients received opioids after the diagnosis of FM, the likelihood of receiving guideline-recommended medications was small.
      • Halpern R.
      • Shah S.N.
      • Cappelleri J.C.
      • Masters E.T.
      • Clair A.
      Evaluating guideline-recommended pain medication use among patients with newly diagnosed fibromyalgia.
      The availability and use of FDA-approved and guideline-recommended nonopioid treatment options, therefore, does not eliminate the widespread use of opioid analgesics.
      Table 1Rates of Opioid Analgesic Use in Patients With FM From Retrospective Health Claims Database Studies
      FM = fibromyalgia.
      DatabaseSample (No.)Study duration (y)Rate of opioid use (%)Reference, year
      PharMetrics Patient-Centric Database, a US health insurance database of >85 health plans covering ∼11 million persons33,176 newly diagnosed as having FM337.8 (37.1 short acting, 6.8 long acting)Berger et al,
      • Berger A.
      • Dukes E.
      • Martin S.
      • Edelsberg J.
      • Oster G.
      Characteristics and healthcare costs of patients with fibromyalgia syndrome.
      2007
      Ingenix employer database, a large administrative claims database of 31 self-insured US companies27,947 newly diagnosed as having FM; 13,588 with established FM2 (newly diagnosed) and 1 (established)39.5
      In the 1 year before diagnosis in newly diagnosed patients.


      43.5
      In the 1 year after diagnosis in newly diagnosed patients.


      43.9
      In the 1 year after the most recent FM diagnosis in established patients.
      White et al,
      • White L.A.
      • Robinson R.L.
      • Yu A.P.
      • et al.
      Comparison of health care use and costs in newly diagnosed and established patients with fibromyalgia.
      2009
      Humana's commercial and Medicare populations9988240.8
      In the 12 months before diagnosis.


      46.7
      In the 12 months after diagnosis.
      Palacio et al,
      • Palacio A.
      • Uribe C.L.
      • Li H.
      • et al.
      Financial and clinical characteristics of fibromyalgia: a case-control comparison.
      2010
      Medstat MarketScan Health and Productivity Management Database, a large health insurance claims database of 80 US health plans covering ∼28 million persons1803 newly diagnosed as having FM251.3 (51.1 short acting, 5.5 long acting)
      In the 12 months before diagnosis.


      55.9 (55.5 short acting, 7.7 long acting)
      In the 12 months after diagnosis.
      Berger et al,
      • Berger A.
      • Sadosky A.
      • Dukes E.M.
      • Edelsberg J.
      • Zlateva G.
      • Oster G.
      Patterns of healthcare utilization and cost in patients with newly diagnosed fibromyalgia.
      2010
      Nationally representative US data set of 15 million commercially insured individuals245,758 across 48 states311.3 (range, 4.0-20.2)Painter et al,
      • Painter J.T.
      • Crofford L.J.
      • Talbert J.
      Geographic variation of chronic opioid use in fibromyalgia.
      2013
      Innovus InVision Data Mart, a commercial US health plan of 14 million subscribers74,378 newly prescribed amitriptyline, duloxetine, pregabalin, or gabapentin for FM354-69
      At baseline. The rate of opioid use depended on which approved FM-related medication (amitriptyline, duloxetine, pregabalin, or gabapentin) was newly prescribed.


      >45
      In the 3 years after the study index date.
      Kim et al,
      • Kim S.C.
      • Landon J.E.
      • Solomon D.H.
      Clinical characteristics and medication uses among fibromyalgia patients newly prescribed amitriptyline, duloxetine, gabapentin, or pregabalin.
      2013
      Large US health plan96,175155.4
      In the first quarter after FM diagnosis. Includes patients prescribed opioids alone or opioids plus an approved FM treatment.


      38.5
      In the fourth quarter after FM diagnosis. Includes patients prescribed opioids alone or opioids plus an approved FM treatment.
      Halpern et al,
      • Halpern R.
      • Shah S.N.
      • Cappelleri J.C.
      • Masters E.T.
      • Clair A.
      Evaluating guideline-recommended pain medication use among patients with newly diagnosed fibromyalgia.
      2015
      a FM = fibromyalgia.
      b In the 1 year before diagnosis in newly diagnosed patients.
      c In the 1 year after diagnosis in newly diagnosed patients.
      d In the 1 year after the most recent FM diagnosis in established patients.
      e In the 12 months before diagnosis.
      f In the 12 months after diagnosis.
      g At baseline. The rate of opioid use depended on which approved FM-related medication (amitriptyline, duloxetine, pregabalin, or gabapentin) was newly prescribed.
      h In the 3 years after the study index date.
      i In the first quarter after FM diagnosis. Includes patients prescribed opioids alone or opioids plus an approved FM treatment.
      j In the fourth quarter after FM diagnosis. Includes patients prescribed opioids alone or opioids plus an approved FM treatment.
      In addition to data from health claims databases, other studies have examined the prevalence of opioid use in patients with FM in a real-world setting. A 7-year prospective study of 538 patients from 6 rheumatology centers with an interest and expertise in FM identified opioid use in 7% of patients,
      • Wolfe F.
      • Anderson J.
      • Harkness D.
      • et al.
      A prospective, longitudinal, multicenter study of service utilization and costs in fibromyalgia.
      whereas in an 11-year longitudinal study of 3123 US adult patients, 46.7% of patients were using opioids at the end of the study.
      • Wolfe F.
      • Walitt B.T.
      • Katz R.S.
      • Lee Y.C.
      • Michaud K.D.
      • Hauser W.
      Longitudinal patterns of analgesic and central acting drug use and associated effectiveness in fibromyalgia.
      During the 11-year study period, severity-adjusted use of any opioid increased from 40.0% to 46.6%. It is notable that opioid use increased during this period even though use of the FDA-approved FM treatments duloxetine, milnacipran, and pregabalin increased from less than 10% to 39% during the same period.
      In a separate 12-month, prospective, observational study of 1700 participants, opioid use was 24.2% at baseline.
      • Robinson R.L.
      • Kroenke K.
      • Mease P.
      • et al.
      Burden of illness and treatment patterns for patients with fibromyalgia.
      At any time during the 12 months of follow-up, opioids were used by 36.5% of patients.
      • Robinson R.L.
      • Kroenke K.
      • Williams D.A.
      • et al.
      Longitudinal observation of treatment patterns and outcomes for patients with fibromyalgia: 12-month findings from the reflections study.
      A total of 61.4% of patients used an opioid at any time during the study.

       Impact of Opioid Analgesic Use in FM

      There is evidence that the use of opioids in FM may have a negative effect on patient outcomes compared with other therapies (Table 2), extending findings from clinical studies that demonstrate a lack of proven efficacy. A 2-year longitudinal analysis of 43 opioid and 88 nonopioid users documented improved pain severity scores and patient function in both groups but significantly greater improvement in nonopioid users.
      • Fitzcharles M.A.
      • Faregh N.
      • Ste-Marie P.A.
      • Shir Y.
      Opioid use in fibromyalgia is associated with negative health related measures in a prospective cohort study.
      Similarly, in a 12-month observational study, improvements in pain severity scores were not statistically different between 412 opioid users (concurrent use of tramadol was permitted) and 1056 patients not taking opioids.
      • Peng X.
      • Robinson R.L.
      • Mease P.
      • et al.
      Long-term evaluation of opioid treatment in fibromyalgia.
      However, patients not taking opioids showed statistically significant improvements in scores for pain interference and patient function, as well as measures of insomnia, disability severity, and depression severity, vs the opioid cohort. The authors concluded that the results showed little support for the long-term use of opioids in patients with FM.
      • Peng X.
      • Robinson R.L.
      • Mease P.
      • et al.
      Long-term evaluation of opioid treatment in fibromyalgia.
      Table 2Outcome Data on the Use of Opioid Analgesics in Fibromyalgia
      Study designSample (No.)Regimen, type of opioid(s), and number of patientsStudy duration (y)Main outcomesReference, year
      Single center, prospective, longitudinal13143 opioid users and 88 nonopioid users2Pain severity scores at 2 y were significantly better in nonopioid vs opioid users, as measured by VAS (P<.05) and MPQ (P<.01)

      Scores for measures of patient function, including PGA, FIQ, and HAQ, were all significantly better (P<.05) in nonopioid vs opioid users at 2 y
      Fitzcharles et al,
      • Fitzcharles M.A.
      • Faregh N.
      • Ste-Marie P.A.
      • Shir Y.
      Opioid use in fibromyalgia is associated with negative health related measures in a prospective cohort study.
      2013
      Multicenter, prospective, observational1700412 opioid users (including concurrent tramadol) and 1056 nonopioid users1Improvements in BPI-S scores not significantly different between cohorts

      Significant improvements in scores for BPI-I, FIQ, ISI, SDS, and PHQ-8 (all P<.05) for nonopioid vs opioid cohorts
      Peng et al,
      • Peng X.
      • Robinson R.L.
      • Mease P.
      • et al.
      Long-term evaluation of opioid treatment in fibromyalgia.
      2015
      BPI-I = Brief Pain Inventory-Interference; BPI-S = Brief Pain Inventory-Severity; FIQ = Fibromyalgia Impact Questionnaire; HAQ = Health Assessment Questionnaire; ISI = Insomnia Sleep Index; MPQ = McGill Pain Questionnaire; PGA = patient global assessment; PHQ-8 = 8-item Patient Health Questionnaire; SDS = Sheehan Disability Scale; VAS = visual analog scale.

       Factors Associated With the Use of Opioids in FM

      A retrospective medical record review of 457 patients referred to a Canadian tertiary care pain center clinic with a diagnosis of FM found opioid use by 31.5%.
      • Fitzcharles M.A.
      • Ste-Marie P.A.
      • Gamsa A.
      • Ware M.A.
      • Shir Y.
      Opioid use, misuse, and abuse in patients labeled as fibromyalgia.
      Use of weak opioids, ie, codeine and tramadol, occurred in 8.5% of patients, whereas 23.0% used strong opioids, ie, all other opioids available in Canada at that time. Use of opioids was associated with lower educational status, unemployment, disability, unstable mental illness, a history of substance abuse, and previous suicide attempts. Unemployment, unstable mental illness, and substance abuse were more common in patients using strong opioids than in those using weak opioids.
      Patient preference for opioids has varied. An Internet survey conducted before the FDA approvals of duloxetine, milnacipran, and pregabalin asked 2569 patients which different medications they had tried for relief of FM symptoms and whether they considered each to be helpful.
      • Bennett R.M.
      • Jones J.
      • Turk D.C.
      • Russell I.J.
      • Matallana L.
      An internet survey of 2,596 people with fibromyalgia.
      A total of 44% of patients had ever used hydrocodone plus acetaminophen, and 32% had used oxycodone plus acetaminophen. Of the patients who had used each treatment, 75% considered hydrocodone plus acetaminophen to be helpful, and 67% considered oxycodone plus acetaminophen to be helpful. Of all the medications used, including nonopioids, hydrocodone preparations were considered to be the most helpful. The duration of opioid therapy was not noted. In contrast, results from a German consumer survey of 1661 patients demonstrated that patients considered treatment with strong opioids to be the most harmful management strategy in terms of adverse effects, and the use of strong opioids did not feature in the top 10 most effective management strategies.
      • Hauser W.
      • Jung E.
      • Erbsloh-Moller B.
      • et al.
      The German fibromyalgia consumer reports: a cross-sectional survey.
      This study did not report which opioids were classified as strong or weak.
      Physiologic and psychological factors seem to be important in the use of opioids in FM. In a cohort of women undergoing hysterectomy, higher FM survey scores were associated with higher levels of pain in patients taking opioids who continued to report severe pain.
      • Wasserman R.A.
      • Brummett C.M.
      • Goesling J.
      • Tsodikov A.
      • Hassett A.L.
      Characteristics of chronic pain patients who take opioids and persistently report high pain intensity.
      In a comparison of patients with FM who were either taking (n=19) or not taking (n=25) opioids, those taking opioids had significantly lower self-efficacy ratings, a measure of patients' confidence in accomplishing specific tasks despite concurrent pain, and significantly higher pain catastrophizing scores, a measure of negative thoughts experienced during pain, with no apparent difference in pain severity between groups.
      • Adu J.
      • Chung C.P.
      • Alemo Munters L.
      • et al.
      Fibromyalgia patients taking opioids have low self-efficacy and high pain catastrophizing but no reduction in pain or improvement in activity.
      In a large health database study that reported chronic opioid use in 11.3% of 245,758 patients with FM in the United States, demographic and geographic factors were important determinants of opioid use.
      • Painter J.T.
      • Crofford L.J.
      • Talbert J.
      Geographic variation of chronic opioid use in fibromyalgia.
      The authors identified a 5-fold difference in long-term opioid use in the 48 different states assessed, ranging from approximately 4% to approximately 20%. Female sex and previous illicit opioid use were associated with higher rates of use, whereas physician prevalence and FM prevalence were associated with lower rates of use. There was also a significantly negative association between opioid use and the prevalence of the use of code 729.1 of the International Classification of Diseases, Ninth Revision, Clinical Modification, the code used to identify FM, in a given geographic area.
      McNett et al,
      • McNett M.
      • Goldenberg D.
      • Schaefer C.
      • et al.
      Treatment patterns among physician specialties in the management of fibromyalgia: results of a cross-sectional study in the United States.
      in a cross-sectional study of treatment patterns among physician specialties in the management of FM, reported different rates of opioid prescription across different specialties. In a sample of 203 patients, the rate of opioid prescription was 54.4% by primary care physicians, 44.0% by psychiatrists, 39.1% by rheumatologists, and 36.8% by neurologists.

      Discussion

      These findings suggest that the use of long-term opioid therapy in FM should be discouraged and that it is the duration of opioid treatment rather than the use of strong or weak opioids that is important. There are no randomized clinical trials of opioids in FM, but large population-based surveys and results from tertiary pain clinics have shown no evidence that long-term opioid treatment is effective for FM. Indeed, long-term opioid use in FM has been associated with poorer outcomes than in individuals who are not receiving opioids.
      • Fitzcharles M.A.
      • Faregh N.
      • Ste-Marie P.A.
      • Shir Y.
      Opioid use in fibromyalgia is associated with negative health related measures in a prospective cohort study.
      • Peng X.
      • Robinson R.L.
      • Mease P.
      • et al.
      Long-term evaluation of opioid treatment in fibromyalgia.
      Furthermore, mechanisms of altered pain processing in FM are not likely to be improved with opioids. In fact, the aggregate studies suggest that the endogenous opioid system may contribute to the hyperalgesia seen in FM, akin to OIH.
      Despite these facts, opioids have been prescribed for 10% to 60% of patients with FM in large database sets (Table 1). It might be expected that the more recent availability of 3 FDA-approved medications for FM would diminish earlier reliance on opioids. However, in reports of patients with FM receiving the FDA-approved medications duloxetine, milnacipran, or pregabalin, more than 45% of these patients were still taking opioids.
      • Kim S.C.
      • Landon J.E.
      • Solomon D.H.
      Clinical characteristics and medication uses among fibromyalgia patients newly prescribed amitriptyline, duloxetine, gabapentin, or pregabalin.
      Furthermore, after opioids are prescribed, the likelihood of a patient receiving one of the FDA-approved medications is small.
      • Halpern R.
      • Shah S.N.
      • Cappelleri J.C.
      • Masters E.T.
      • Clair A.
      Evaluating guideline-recommended pain medication use among patients with newly diagnosed fibromyalgia.
      These findings suggest that although the use of FDA-approved medications is increasing, there is sustained or even increasing use of opioids. This may be due to several factors, such as patient demand because they believe that opioids are a stronger or better analgesic
      • Bennett R.M.
      • Jones J.
      • Turk D.C.
      • Russell I.J.
      • Matallana L.
      An internet survey of 2,596 people with fibromyalgia.
      or because the FDA-approved medications are not effective for many patients.
      • Hauser W.
      • Walitt B.
      • Fitzcharles M.A.
      • Sommer C.
      Review of pharmacological therapies in fibromyalgia syndrome.
      • Arnold L.M.
      • Cappelleri J.C.
      • Clair A.
      • Masters E.T.
      Interpreting effect sizes and clinical relevance of pharmacological interventions for fibromyalgia.
      There has also been suboptimal use of effective nonpharmacologic therapies.
      • Clauw D.J.
      Fibromyalgia and related conditions.
      Opioids, especially for short-term use, may be recommended for carefully selected patients with FM, particularly those with severe FM. The use of opioids in these circumstances is broadly supported by current medical guidelines.
      • Chou R.
      • Fanciullo G.J.
      • Fine P.G.
      • et al.
      Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.
      • Carville S.F.
      • Arendt-Nielsen S.
      • Bliddal H.
      • et al.
      EULAR evidence-based recommendations for the management of fibromyalgia syndrome.
      • Fitzcharles M.A.
      • Ste-Marie P.A.
      • Goldenberg D.L.
      • et al.
      2012 Canadian guidelines for the diagnosis and management of fibromyalgia syndrome: executive summary.
      Fibromyalgia is the prototype for most chronic pain conditions, typically accompanied by sleep disturbances, depression and anxiety, and catastrophizing.
      • Clauw D.J.
      Fibromyalgia: a clinical review.
      Higher scores on FM criteria surveys characterize a central pain phenotype and have been associated with adverse analgesic outcomes. For example, higher FM scores were associated with increased postoperative opioid consumption and poorer long-term pain reduction after total hip or knee replacement.
      • Brummett C.M.
      • Janda A.M.
      • Schueller C.M.
      • et al.
      Survey criteria for fibromyalgia independently predict increased postoperative opioid consumption after lower-extremity joint arthroplasty: a prospective, observational cohort study.
      • Brummett C.M.
      • Urquhart A.G.
      • Hassett A.L.
      • et al.
      Characteristics of fibromyalgia independently predict poorer long-term analgesic outcomes following total knee and hip arthroplasty.
      Physicians in the United States frequently prescribe opioids as part of chronic pain management. In 2012, 82.5 opioid analgesic prescriptions per 100 people were written in the United States.
      • Paulozzi L.J.
      • Mack K.A.
      • Hockenberry J.M.
      Vital signs: variation among states in prescribing of opioid pain relievers and benzodiazepines: United States, 2012.
      The apparent overreliance on opioids as part of the armamentarium for chronic pain disorders, such as FM, may, in part, be due to the complexity of managing chronic pain conditions
      • Fishman S.M.
      • Young H.M.
      • Lucas Arwood E.
      • et al.
      Core competencies for pain management: results of an interprofessional consensus summit.
      and the limited education available to health care professionals.
      Institute of Medicine (IOM)
      Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research.
      • Mezei L.
      • Murinson B.B.
      Pain education in North American medical schools.
      • Morley-Forster P.K.
      • Pergolizzi J.V.
      • Taylor Jr., R.
      • Axford-Gatley R.A.
      • Sellers E.M.
      Mitigating the risk of opioid abuse through a balanced undergraduate pain medicine curriculum.
      The FM phenotype is prominent in most chronic pain disorders, including low back pain and chronic headaches.
      • Clauw D.J.
      Fibromyalgia: a clinical review.
      • Kindler L.L.
      • Bennett R.M.
      • Jones K.D.
      Central sensitivity syndromes: mounting pathophysiologic evidence to link fibromyalgia with other common chronic pain disorders.
      Psychiatric comorbidity, an important factor in FM and in most chronic pain disorders, predicts the risk of opioid use and misuse.
      • Jamison R.N.
      • Mao J.
      Opioid analgesics.
      For example, depression was associated with chronic opioid use irrespective of pain severity or physical function.
      • Goesling J.
      • Henry M.J.
      • Moser S.E.
      • et al.
      Symptoms of depression are associated with opioid use regardless of pain severity and physical functioning among treatment-seeking patients with chronic pain.
      Cautioning health care providers about the misuse of opioids in FM may be the best approach to changing current practice habits. The study by Painter et al
      • Painter J.T.
      • Crofford L.J.
      • Talbert J.
      Geographic variation of chronic opioid use in fibromyalgia.
      reporting significant geographic variation in opioid prescribing for FM suggests an important role for physician education. This study also found a negative correlation of opioid use with a greater regional International Classification of Diseases FM diagnosis. The lessons learned from FM suggest that health care providers should stratify patients at risk for chronic pain and avoid opioids in those high-risk individuals.

      Conclusion

      The mechanism of action of traditional opioids predicts their lack of efficacy in FM, and there is no evidence from clinical trials that opioids are effective for the treatment of FM. Moreover, FM guidelines recommend against the use of opioid analgesics. Observational studies indicate that patients who receive opioids have poorer outcomes than those who do not. Nonopioid pharmacologic and nonpharmacologic therapies with demonstrable efficacy are available. In addition, the United States is in the grip of an ongoing public health emergency relating to excess and long-term opioid analgesic use. Despite these issues, opioids are still commonly used to treat FM. Targeting health care providers to change their current practice habits regarding FM may be the best approach to reduce the overuse of opioids, suggesting an important role for physician education. Educating patients about the lack of benefit and potential risks associated with opioid use would also be beneficial. The example of FM provides a cautionary tale for the use of opioids in other chronic pain conditions.

      Acknowledgments

      Medical writing support was provided by David Cope, PhD, of Engage Scientific Solutions and was funded by Pfizer .

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