To characterize the comorbidities, pain-related pharmacotherapy, and healthcare resource use among older patients with fibromyalgia (FM) newly prescribed pregabalin in clinical practice.
Methods: Using the PharMetrics database, patients with FM aged 65 or more years (International Classification of Diseases, Ninth Revision, Clinical Modification code 729.1X) who were newly prescribed pregabalin (index event) on or after July 1, 2007, were identified (N = 98, mean age 72.4 ± 6.4 years; 81.6% female). Prevalence of comorbidities, pharmacotherapy, and healthcare resource use/costs (pharmacy, outpatient, inpatient, total) were examined during the 6-month preindex and postindex periods.
Results: Patients had a variety of comorbidities including various disorders generally associated with an older population, such as hypertension (41.8%), diabetes (22.5%), and coronary artery disease (15.3%). On average, patients received 3.3 ± 2.3 pregabalin prescriptions; the average number of days of therapy was 121 ± 88.9. Patients had a high medication burden in both the pre- and postindex periods; opioids were the most commonly prescribed medications (54.1% vs 59.2%); combination therapy was also common, with opioids and antidepressants the most frequent (35% in both periods). Except for the use of selective serotonin reuptake inhibitors, which decreased significantly in the postindex period (24.5% vs 19.4%, P = .0253), there were no changes in use of any of the other medications, including nonsteroidal anti-inflammatory drugs (36.7% vs 32.7%), tramadol (17.4% vs 24.5%), muscle relaxants (18.4% vs 21.4%), tricyclic antidepressants (21.4% vs 18.4%), serotonin and norepinephrine reuptake inhibitors (10.2% vs 12.2%), and anticonvulsants (17.4% vs 21.4%) after initiation of pregabalin therapy. There were decreases in the number of physician office visits and total outpatient visits (both P <.01) and in the proportion of patients with visits to physical therapists (21.4% vs 12.2%, P = .0201); however, there were no changes in healthcare costs (pharmacy, outpatient, inpatient, or total) from the pre- to postindex period.
These results suggest a substantial medication and comorbidity burden in older patients with FM. Although it is not possible to establish cause-and-effect relationships in claims database studies, results also suggest that the initiation of pregabalin was cost-neutral. Further evaluation is warranted to characterize FM and determine appropriate management strategies in this fragile population.
(Am J Manag Care. 2010;16:S144-S153)
Fibromyalgia (FM) is a chronic pain condition that, by recent estimates, affects 5 million individuals in the United States, primarily women, among whom the prevalence is 6 to 9 times higher than in men.1 Although FM is characterized by persistent and recurring widespread musculoskeletal pain, tenderness, and fatigue, patients frequently report a constellation of other symptoms, including sleep and mood disturbances as well as cognitive effects.2,3 This combination of pain and accompanying symptoms contributes to the reduced function and quality of life as well as the increased costs that are responsible for the substantial socioeconomic burden associated with FM.4
Many of the symptoms of FM are potentially amenable to pharmacologic therapy. However, in the absence of a clearly identified underlying etiology, current treatment strategies are primarily aimed at alleviating pain and improving functional status, although guidelines published by the American Pain Society (APS) focus on both pain and sleep disturbance.5 These guidelines recommend that nonpharmacologic therapies such as cardiovascular fitness and/or cognitive behavioral therapy be incorporated into patient management strategies along with the use of pharmacologic agents, including low-dose tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), benzodiazapines, dopa-replenishing agents, and tramadol, reserving the use of strong opioids when other therapies have failed.
Although the APS recommendations were developed prior to approval of any drugs for FM, they suggested that there was moderate evidence of efficacy for all 3 of the drugs that are currently approved: pregabalin, duloxetine, and milnacipran. More recently, the European League Against Rheumatism developed evidencebased guidelines for the management of patients with FM that include recommendations for the use of tramadol, TCAs, the SSRI tropisetron, the dopamine agonist pramipexole, and the anticonvulsant pregabalin.6
Despite the documented socioeconomic burden of FM and the issuance of treatment guidelines, information on pain-related treatment patterns and the presence of comorbid conditions in patients with FM in usual care settings is limited. Moreover, to date, no study has examined treatment patterns among older patients with FM. Indeed, although it has been reported that the prevalence of FM peaks in the 70- to 79-year-old age group, with the 60- to 69-year-old age group having the next highest prevalence,7 there have been only 2 publications specifically addressing FM in older individuals. One was a study that compared symptoms between older and younger FM patients, which suggested that there may be some differences in symptoms and aggravating factors,8 and the other was a review of diagnosis and treatment of FM in the geriatric population.9 Both of these were published more than 20 years ago, and both also highlighted that nonrecognition and/or misdiagnosis of FM was common in this population because of the presence of other musculoskeletal conditions and comorbidities.
This lack of information is disconcerting, since treatment of FM among older patients may be particularly challenging given the presence of multiple chronic conditions and use of multiple medications in this population. Additionally, the high probability of drug interactions that has already been reported to be present in older patients because of their use of multiple prescription and over-the-counter medications10 may be further compounded when a new therapy is added to a patient's existing treatment regimen. Therefore, the goal of the present study is to characterize the prevalence of comorbidities, patterns of pain-related pharmacotherapy, and resource utilization among older patients (>65 years old) with FM initiated on pregabalin.
Data were obtained from the PharMetrics Patient-Centric Database, which is comprised of adjudicated medical and pharmaceutical claims data from a systematic sample of over 95 commercial managed care health plans throughout the United States (Midwest 34%, Northeast 22%, South 29%, West 15%). This database covers more than 57 million individuals, and includes information on patient demographics and enrollment, inpatient and outpatient diagnoses (ICD-9-CM format [International Classification of Diseases, Ninth Revision, Clinical Modification]), and retail and mail order prescription records. Available data on prescriptions include the National Drug Code numbers, days supply, and quantity dispensed. Medical records for each patient can be linked using a unique encrypted patient identifier (thereby maintaining patient confidentiality) to create a longitudinal record of an individual's healthcare claims during a specified time period. The database is in compliance with the Health Insurance Portability and Accountability Act of 1996.
Patients 65 years of age or older who had 2 or more healthcare encounters with an associated diagnosis of FM (ICD-9-CM code 729.1X) on or after January 1, 2006, were selected, and a cohort of patients who were newly prescribed pregabalin (index event) after July 1, 2007, were identified; patients had to be naïve to pregabalin during the 6-month pretreatment period. Reasons for exclusion included missing data for age or sex, or lack of continuous enrollment for a period of 6 months prior to (preindex) and 6 months following (postindex) the date of their first prescription.
Measures and Analyses
Basic demographic and clinical characteristics of the patients prescribed pregabalin for FM were determined, including average age, sex distribution, and coprevalence ofselected chronic conditions, including mental disorders, sleep disorders, digestive disorders, musculoskeletal pain conditions (eg, arthritis and arthropathies, lumbago, low back pain, osteoarthritis), and neuropathic pain conditions. Comorbidities evaluated were those considered to have significant coprevalence in patients with rheumatic diseases such as cardiovascular-related disorders,11 or to be associated with FM or pain (eg, anxiety, depression, sleep disorders). 12,13 The prevalence of comorbidities was determined based on the presence of 2 or more healthcare encounters with an associated diagnosis code for the comorbidity during the 6-month preindex period. ICD-9-CM diagnoses codes used to define comorbidities examined in this study are described in .
Pain-related medication exposure was determined based on the proportion of patients who received 1 or more prescriptions during the pre- and postindex periods for the various medications and medication classes recommended and/or used for the treatment of FM or pain in clinical practice.14-24 These medications included short-acting opioids (SAOs [eg, oxycodone, hydrocodone, morphine sulfate]); long-acting opioids (LAOs [eg, controlled-release oxycodone, transdermal fentanyl]); anticonvulsants other than pregabalin and gabapentin (eg, lamotrigine); TCAs (eg, amitriptyline, desipramine); SSRIs (eg, citalopram, paroxetine); selective serotonin and norepinephrine reuptake inhibitors (SNRIs [eg, duloxetine, venlafaxine]); cyclooxygenase (COX)-2 specific and nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs); tramadol; tetracyclic and miscellaneous antidepressants (eg, bupropion, trazodone); topical agents approved for neuropathic pain (eg, capsaicin, lidocaine); topical corticosteroids (eg, betamethasone, desoximetasone); injectables (eg, bupivacaine, lidocaine); triptans and other antimigraines; and attention-deficit/hyperactivity disorder drugs. Additionally, exposure to benzodiazepines, sedatives/hypnotics, and muscle relaxants was evaluated, since these may be used adjunctively to treat pain-related mood and sleep disorders, which are frequently reported in patients with FM.
Use of opioid analgesics was examined on an aggregate basis (ie, any opioid) and separately by the type of formulation and duration of action (ie, SAOs and LAOs). Because opioid analgesics are often prescribed and used as rescue pain medications or on an "as needed" basis, evaluation of opioid use was stratified by patients who received 1 or more, only 1 or 2 or more opioid prescriptions in the pre- and postindex periods, respectively.
The direct medical costs associated with healthcare resources, including physician office visits, emergency department visits, hospitalizations, and other outpatient services (eg, labs, radiology, imaging), were examined for the pre- and postindex periods. The average number of prescriptions, days of therapy, and the time (days) between prescription refills were determined. The average daily dose was calculated as strength in milligrams multiplied by the quantity prescribed divided by days supply. Several methods were used to evaluate average daily dose. First, the average daily dose was calculated for the index pregabalin prescription as well as across all pregabalin prescriptions during the followup period. Second, the proportion of patients who received a dose within specific predetermined dose levels was evaluated among patients who received only 1, 2, and 3 or more consecutive prescriptions, respectively. A consecutive prescription was defined as a prescription whose "start date" was no later than 15 days after the "end date" of the previous prescription. Patient adherence was determined based on a surrogate outcome, the medication possession ratio (MPR). The MPR evaluates the persistency of medication availability over time in the form of prescription refills, and has been widely used as a measure of adherence when using administrative claims databases. The MPR was calculated as the total days supply (excluding day supply of last prescription) divided by the total number of days between the first and last prescriptions.
All study analyses were conducted using the SAS software system, PC version 8.0 (SAS Institute Inc, Cary, NC). Since the same subjects were included in the pre- and postindex periods (ie, matched pairs), McNemar tests were used to assess the statistical significance of changes in proportions of patients who received the various classes of study medications between these periods. Wilcoxon signed rank tests were used to calculate the statistical significance of differences between the number of prescriptions patients received for the various study medication classes in the pre- and postindex periods, and for any differences in costs between these periods. An alpha value <.05 was considered statistically significant.
Demographic and Clinical Characteristics
The identified population (N = 98) was predominantly female (81.6%), with a mean age of 72.4 ± 6.4 years and a range of 65 to 98 years. The Midwest was the region with greatest representation (70.4%), followed by the East (19.4%), and low proportions from the South (6.1%) and West (4.1%). The most frequent type of insurance was indemnity (38.8%), although health maintenance organization (11.2%), point of service (22.5%), preferred provider organization (15.3%) were also represented, and 12.2% of patients had multiple types of plans. The payer type was predominantly commercial (69.4%), with the balance being Medicare risk.
As shown in, these patients were characterized by the presence of a wide range of comorbidities, including a variety of comorbid musculoskeletal conditions, of which the most common were rheumatism excluding the back (35.7%) and back and neck pain other than low back pain (34.7%). One quarter of the patients had a neuropathic pain condition, with back and neck pain with neuropathic involvement most frequently reported (17.4%). Depression was the only neuropsychiatric disorder that was reported by multiple patients (15.3%), and hypertension was the most frequently reported cardiovascular comorbidity, occurring in 41.8% patients, followed by hyperlipidemia in 20.4%. Diabetes was present in 22.5% of patients, and neoplasms in 12.2% of patients. A high proportion of patients (71.4%) reported unattributed symptoms, signs, and ill-defined conditions.
Coprevalence of the examined comorbidities was high; 94% of patients had at least 1 of the listed comorbidities and more than half of the patients (57.1%) had 5 or more of the listed comorbidities.
In both the pre- and postindex periods, patients were characterized by a high burden of medications that are generally prescribed for the treatment of different types of pain () including traditional analgesics such as NSAIDs, COX-2 inhibitors, SAOs, LAOs, antidepressants, and anticonvulsants. Opioids were the most frequently prescribedmedication (54.1%), especially SAOs (52.0%), followed by NSAIDs (36.7%). Adjunctive medications including benzodiazepines, muscle relaxants, and sedatives/hypnotics that are often used to treat conditions associated with pain, such as depression, anxiety, and insomnia, were prescribed in 20% to 32% of patients. Other than a small but significant decrease in the proportion of patients prescribed SSRIs in the postindex period, from 24.5% to 19.4% (P = .0253), there were no changes in the use of any of the medication classes examined in this study, including opioids.
Multiple medication classes were commonly prescribed, with approximately 80% of patients prescribed 2 or more classes, and more than 30% of patients prescribed 5 or more classes in both the pre- and postindex periods. Overall, there was no difference from the pre- to postindex period in the proportion of patients prescribed multiple medication classes (P = .9096). Similarly, as shown in , there was no overall difference between the 2 periods in the proportion of patients who were prescribed combination therapies (P = .9608); approximately 54% of patients in both periods were prescribed at least 1 combination. The most frequent combination therapy was antidepressants plus opioids, prescribed to 35% of patients in each period, followed by sedatives/hypnotics plus opioids (16% and 17% for the pre- and postindex periods, respectively).
When medications identified in the APS recommendations were evaluated, there were no changes between the 2 treatment periods in the proportion of patients who received any of these medications (), the number of prescriptions for these medications, or the days of therapy with these medications (data not shown). Tramadol was the medication prescribed to the greatest proportion of patients during the pretreatment and follow-up periods, 17.4% and 24.5%, respectively.
Dosing and Adherence to Pregabalin
The average number of pregabalin prescriptions over the 6-month period was 3.3 ± 2.3, with an average of 121 ± 88.9 days of therapy. The average daily dose of the first pregabalin prescription in the postindex period was 149.7 ± 79.8 mg/ day, and the average dose across all prescriptions was 168.9 ± 104.4 mg/day. When dosing was evaluated by consecutive prescriptions, of the patients who received 1 (n = 24), 2 (n = 15), or 3 or more (n = 19) prescriptions, only 8.3%, 13.3%, and 21.1%, respectively, received a dose within the therapeutic range for FM (300-450 mg/day) by their first, second, or third prescription.
Patient adherence to pregabalin was high; 63.5% of patients achieved an MPR in excess of 80%, and the average MPR was 78.9% ± 25.2%. The median time between prescription refills was 1 day (interquartile range of -8 to 8 days).
Resource Use, Nonpharmacologic Therapies, and Costs
Results suggested substantial healthcare resource use in both the pre- and postindex periods. There were no differences between the 2 treatment periods in the proportion of patients using the different categories of healthcare resources (physician office visits, emergency department visits, other outpatient visits, and hospitalizations). Almost all of the study patients (99%) visited a physician at least once during both treatment periods; general/family practitioners and internists were the specialists most frequently consulted (40%-45% of patients), with consultations with rheumatologists (21%-22%) or neurologists also common (20%-22%) in the pre- and postindex periods. Chiropractors were consulted by approximately 15% of patients, and less frequent consultations were reported with psychiatrists (6%-8%) and psychologists (1%-2%).
When physician visits were stratified by specialty, there were no differences in frequency of visits between the 2 treatment periods except for physical therapists, which decreased by almost half, from 21.4% to 12.2% (P = .020). However, significant differences were observed in the number of physician office visits and the total number of outpatient visits, with fewer visits reported in the postindex period ().
When nonpharmacologic therapies identified in the APS recommendations were evaluated, few patients received these therapies. In the preindex period, therapeutic exercises/strength training was only used by 15% of patients and cognitive behavioral therapy was used by only 10%, with slight but nonsignificant decreases to 11% (P = .285) and 7% (P = .083), respectively, in the postindex period.
Total median healthcare costs were $6493 (interquartile range $3863-$12,095) and $5607 (interquartile range $35,901-$12,643) for the pre- and postindex periods, respectively. This difference was not significant (P = .634), and neither were significant differences observed between the 2 treatment periods for either the cost of any of the individual healthcare resource categories or for individual medications.
Previous burden of illness studies have shown that patients with FM are characterized by a high prevalence of comorbid conditions and by a substantial medication burden.23-26 The current study, which is the first to report on the presence of comorbidities and patterns of pharmacologic therapy among older patients who had a clinical diagnosis of FM, shows that the burden in these patients is at least as great as in a younger FM population.
Not surprisingly, given the age of this population (mean 72.4 ± 6.4), multiple comorbidities were common, with the presence of 5 or more comorbid conditions reported in more than half of the patients. Although the prevalence of many of these conditions was comparable to what has previously been reported in similar types of studies in more general, younger FM populations,23,25 the prevalence of other comorbidities that may be expected in an older population were higher. In particular, the prevalence of diseases such as diabetes, osteoarthritis, and a variety of cardiovascular conditions (eg, hypertension, congestive heart failure, peripheral vascular disease) was 2- to 10-fold higher than reported in younger FM populations.23,25,26 It is also interesting to note that among older individuals, the prevalence of anxiety as well as migraine/tension headaches was lower than reported in the studies of younger populations, consistent with what was observed in an early comparison of young and old patients with FM.8
A substantial medication burden was observed in both treatment periods, with the only significant difference in medication use an observed reduction in SSRIs during the postindex period. However, few patients received the 300- to 450-mg/day dose of pregabalin that is recommended for the management of patients with FM.27 While the low number of patients in this study may preclude a more accurate assessment of changes in medications from the pre- to the postindex periods, the suboptimal dosing of pregabalin may also have contributed to a less than optimal reduction in pain. Despite the high treatment burden, few patients were prescribed the individual medications recommended in the APS guidelines for the treatment of pain related to FM.5 However, some of the recommended medications that were prescribed are contraindicated in an older population, according to the modified Beers criteria.28
In particular, amitriptyline, fluoxetine, and cyclobenzaprine were prescribed to 6% to 14% of these individuals.
Opioids were the most frequently prescribed medication, and in particular, there was a high rate of prescription of SAOs, consistent with other studies that have evaluated FM treatment patterns23-25; SAOs are often prescribed and used as rescue pain medications or on an "as needed" basis. Also consistent with other studies,23-25 the most frequent combination therapy was opioids plus antidepressants. This finding is not surprising because depression is also commonly reported in patients with FM and was diagnosed in 15% of the present population. While this combination is not necessarily associated with greater side effects than opioids alone even among older individuals,29 the general recommendation is for the cautious use of opioids in older patients.30 These recommendations are based on age-related decreases in hepatic, renal, and gastrointestinal function that may exacerbate issues of safety and tolerability, as well as on the increased presence of polypharmacy and the occurrence of side effects such as drowsiness, dizziness, and motor imbalance that may have more serious consequences in this population relative to younger individuals.30
There were few changes in resource use between the treatment periods, with only postindex reductions in the number of physician office visits and the total number of outpatient visits showing significance. The overall health resource costs were similar in the 2 treatment periods, suggesting that addition of pregabalin was cost-neutral.
The results of this study are subject to several limitations, including the small sample size. Furthermore, this study was based on individuals with FM who were initiated on pregabalin, and it is possible that the characteristics of these patients may be different from those of FM patients in the database who were not initiated on this therapy. Retrospective database analyses are also potentially prone to errors in coding and recording, which may be especially compounded in FM due to the lack of a specific ICD-9-CM diagnosis code for FM.
Importantly, it cannot be ascertained from the available data if the prescriptions for pregabalin, or for any of the other medications evaluated in this study, were prescribed for pain related to FM or for other indications. Nevertheless, the information obtained in this study with regard to which medications are being prescribed in older patients with FM can inform future treatment decisions. An additional consideration is that the prescribing of a particular medication does not necessarily imply that the patient filled the prescription or used the medication. However, it should be noted that patient adherence to pregabalin was high, and the MPRs among patients prescribed pregabalin were generally comparable to those reported in the literature for medications used to treat other chronic conditions such as hypertension, hyperlipidemia, and diabetes.
This study confirms the substantial comorbidity and medication burden among patients with FM, and suggests that this burden may be higher in older individuals with this disease. While few differences in resource utilization and treatment patterns were observed between the 6-month periods before and after the initiation of pregabalin therapy, the initiation of pregabalin therapy itself appeared to be cost-neutral. The lack of information on FM in older individuals suggests that the current study is an important step in characterizing the burden and needs of this population. Further evaluation of the characteristics of older patients with FM and the challenges associated with their treatment may not only add to our knowledge of this disease, but can improve management strategies in this fragile population, especially related to reducing polypharmacy.
The authors would like to thank E. Jay Bienen for editorial assistance in the preparation of this manuscript, which was funded by Pfizer, Inc.
Author Affiliations: From Avalon Health Solutions, Inc (MG ), Philadelphia, PA; Pfizer, Inc.-Global Outcomes Research (AS, GZ), New York, NY; and Department of Anesthesiology (DC), University of Michigan, Ann Arbor, MI.
Funding Source: This supplement was funded by Pfizer, Inc.
Author Disclosures: Dr Gore is principal consultant at Avalon Health Solutions, Inc, who were paid consultants to Pfizer in connection with the development and execution of both this manuscript and the research it describes. Dr Gore also owns stock in Pfizer. Drs Sadosky and Zlateva are employees of Pfizer and own stock in Pfizer. Dr Clauw was not compensated for his participation in this research or for the preparation of this article. Dr Clauw has performed consulting for Cypress Bioscience, Forest, Lilly, Pfizer, Pierre Fabre, and UCB, and has received research funding support from Forest and Pfizer, Inc.
Authorship Information: Concept and design (MG, AS, GZ, DC); acquisition of data (MG); analysis and interpretation of data (MG, AS, GZ); drafting of the manuscript (MG, AS, DC); critical revision of the manuscript for important intellectual content (MG, AS, GZ, DC); statistical analysis (MG); obtaining funding (MG, AS, GZ); administrative, technical, or logistic support (GZ); and supervision (MG, AS, GZ).
Address correspondence to: Mugdha Gore, PhD, BPharm, Avalon Health Solutions, Inc, 1518 Walnut St, Ste 1507, Philadelphia, PA 19102.
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