Long-term Evaluation of Opioid Treatment in Fibromyalgia
The Clinical Journal of Pain
Objectives: In a 12-month observational study, we evaluated the effect of opioid use on outcomes in 1700 adult patients with fibromyalgia (FM). Methods: Data were evaluated using propensity-score-matching after patients were divided into cohorts based on their baseline medication use:1) taking an opioid (concurrent use of tramadol was permitted); (2) taking tramadol (but no opioids); and (3) not taking opioids or tramadol. Changes in outcomes were assessed using the Brief Pain Inventory for
... n Inventory for severity and pain-related interference (BPI-S, BPI-I), Fibromyalgia Impact Questionnaire (FIQ), Patient Health Questionnaire for depression , Insomnia Severity Index (ISI), Sheehan Disability Scale (SDS), 7-item Generalized Anxiety Disorder scale (GAD-7) and economic factors. Time to opioid or tramadol discontinuation was analyzed using Kaplan-Meier survival analyses. Results: Compared with the opioid cohort, the non-opioid cohort demonstrated significantly greater reductions (P<0.05) in BPI-I, FIQ, PHQ-8, SDS and ISI; the tramadol cohort compared with the opioid group showed greater reductions on FIQ and ISI. Reductions in BPI-S and GAD-7 did not differ significantly among cohorts. Compared with the opioid cohort, patients in the tramadol cohort had fewer outpatient visits to healthcare providers. Few significant differences were found between the tramadol and non-opioid cohorts across outcomes. Discussion: While pain severity was reduced over time in all cohorts, opioid users showed less improvement in pain-related interference with daily living, functioning, depression, and insomnia. Overall, the findings show little support for the long-term use of opioid medications in patients with FM given the poorer outcomes across multiple assessment domains associated with this cohort. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of the article is prohibited. synthetic opioid analgesic with activity on mµ receptors and serotonin and norepinephrine reuptake inhibition, we categorized tramadol separately from opioids or non-opioids. A meta-analysis of studies examining the effectiveness and adverse effects of opioids for non-malignant chronic pain, including FM-related pain, showed that opioids were generally effective for pain relief and improving functional outcomes across a range of chronic conditions, and that this may be a reason some practitioners turn to opioid treatment for FM. 7 However, the Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of the article is prohibited. 4 lack of scientific support of opioid use in this patient population remains a concern in terms of physiological factors (e.g., side effects) and the risks of abuse, addiction, or overdose associated with opioid use. 3, 7, 12, 13 Evidence-based recommendations from the European League Against Rheumatism released in 2008 suggested that weak opioids may be considered for treatment of FM syndrome, but strong opioids were not recommended. 16 Despite these recommendations and a lack of scientific support, many patients with FM are being prescribed and are taking opioid medications. 17 In our 12-month, prospective observational study, identified as REFLECTIONS (Real World Examination of Fibromyalgia: Longitudinal Evaluation of Costs and Treatments) two of the most commonly reported medications used for FM were opioids (24.2%) and tramadol (15.3%). 18 For the overall sample in that study, opioids had the highest mean medication possession ratio (defined as the number of days that supply of medication was supplied to number of days in the 12-month study) at 0.27. Among patients who had any opioid use at baseline (36.5%), the ratio was particularly high at 0.72. 18 The purpose of this analysis was to evaluate the effects of long-term opioid treatment relative to tramadol or non-opioids on outcomes of relevance to FM and on the length of time patients remained on these treatments in the REFLECTIONS study. 19 Methods Study Setting and Participants The study methodology has been described in detail by Robinson et al. 18, 19 In brief, study participants were enrolled in various regions throughout the United States (northeast, north central, southeast, south central, west) and in Puerto Rico by their treating physicians (n=91) at 58 health care settings, including outpatient practices of rheumatology (59.3%), primary care (37.4%), neurology (2.2%), psychiatry (3.3%), pain specialties (3.3%), physical medicine (2.2%), obstetrics and gynecology (1.1%), and osteopathy (1.1%). Minimal inclusion and exclusion criteria were used to increase the degree to which our sample represented patients with FM who are seen in real-world practice (ie, study generalizability); to be eligible, patients were ≥18 years of age and agreed to participate in the study for 12 months. Eligible patients were initiating a "new" treatment for FM (ie, were naive to FM treatment over the last 6 months), starting a new therapy to replace a previously used therapy, or adding a new therapy to their current FM treatment regimen. The treating physicians' decisions regarding the proper FM diagnosis, treatment, and care of the patients were made in the course of normal clinical practice. This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and was consistent with good clinical practices and applicable local laws and regulations. The ethical review boards of each investigator's institution approved the protocol and informed consent was obtained from each patient prior to study participation. This study was registered in ClinTrials.gov (identifier: NCT00725101). Study Design and Measures Study data were collected via a physician survey and patient visit form at baseline, and via computer-assisted telephone interviews at baseline, and 1, 3, 6, and 12 months postbaseline. Patients were invited to participate during a regular outpatient visit in which pharmacologic treatment for FM was prescribed, including but not limited to pain medications, antidepressants, anticonvulsants, stimulants, sleep agents, and anxiolytics. Information about the type of medications used by patients was collected at each data collection wave from baseline to 12 months, including all concurrent medications, as well as which medications were discontinued during the study and reasons for discontinuation (multiple responses were allowed, including "felt better," "didn't help," "adverse events," "too costly," and "other"). The computer-assisted telephone interviews included the following outcome measures: Brief Pain Inventory (BPI) average pain severity (BPI-S; range 0 to 10) and average pain interference (BPI-I; range 0 to 10); 20 the total Sheehan Disability Scale total score, which incorporates disability across domains of work/school, social life, and family life/home responsibilities (SDS; range 0 to 30); 21 Fibromyalgia Impact Questionnaire total score across items of physical functioning; number of days the patient felt well; number of days the patient felt unable to work due to FM symptoms; and patient ratings of work difficulty, pain intensity, fatigue, morning tiredness, stiffness, anxiety, and depression (Fibromyalgia Impact Questionnaire [FIQ]; range 0 to 80); 22 Patient Health Questionnaire 8-item depression severity measure (PHQ-8, range 0 to 24); 23,24 PHQ physical symptoms measure (PHQ-15; range 0 to 30); 24,25 7-Item Generalized Anxiety Disorder scale of anxiety disorder severity (GAD-7; range: 0 to 21); 24,26 Insomnia Severity Index (ISI; range 0 to 28); 27 and Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH-CPFQ; range 7 to 42). 28 For all of these measures, higher scores indicated worse status. To minimize patient burden, at the 1-month and 6-month visits, only the BPI-S, BPI-I, and PHQ-8 were administered. The computer-assisted telephone interviews also assessed health care utilization measures, including the number of outpatient and hospital visits, over the 12 months. Statistical Analysis Patients were hierarchically classified into 3 mutually exclusive cohorts based on their baseline medication use: (1) opioids: currently taking an opioid (concurrent use of tramadol was permitted); (2) tramadol: currently taking tramadol but not opioids; and (3) non-opioid: not currently taking opioids or tramadol. Concurrent use of non-opioids was allowed in each cohort. The list of opioid medications reported included: bezitramide, buprenorphine, butorphanol, codeine, codeine plus N-acetyl-p-aminophenol (APAP), dextropropoxyphene, dextropropoxyphene napsilate, doxyphene, fentanyl, fortagesic, hydrocodone, hydrocodone plus APAP, hydromorphone, levorphanol, methadone, morphine, opioids (not specified), oxycodone, oxycodone plus APAP, oxymorphone, pentazocine, pethidine, phenazocine, propoxyphene, propoxyphene plus APAP, thebaine, and tilidine. Descriptive statistics were used to characterize patients' demographic and baseline clinical characteristics, physician characteristics, baseline outcome measures, and economic measures. Summary statistics were calculated for all enrolled patients (N =1700), and for patients in each of the 3 cohorts. Overall P values were provided with chi-square test for categorical variables and F test (analysis of variance) for continuous variables. The propensity score matching method was used to construct matched-cohorts with similar demographics, and clinical and economic characteristics, for 3 pairwise cohort Chen is an employee of PharmaNet/i3. Bill McCarberg is an advisor for NeurogesX. Philip Mease receives research funding and consulting fees and is an honoraria speaker for Eli Lilly and Company, Forest Pharmaceuticals, and Pfizer. Danette Hann is a medical writer with INC Research. The REFLECTIONS study was sponsored by Eli Lilly and Company or one of its subsidiaries.