Clinical characteristics and medication uses among fibromyalgia patients newly prescribed amitriptyline, duloxetine, gabapentin or pregabalin

Abstract

Background

Fibromyalgia is a common chronic pain disorder with unclear etiology. No definitive treatment is available for fibromyalgia and treatment with antidepressants or antiepileptics is often used for symptom management.

Methods

Using US health care utilization data, a large population-based cohort study was conducted to describe clinical characteristics and medication use patterns in patients diagnosed with fibromyalgia who newly started amitriptyline, duloxetine, gabapentin or pregabalin.

Results

There were 13,404 amitriptyline, 18,420 duloxetine, 23,268 gabapentin, and 19,286 pregabalin starters. The mean age ranged from 48 to 51 years and 72% to 84% were women in each group. Back pain was the most frequent comorbidity in all four groups (48%-64%) and hypertension, headache, depression, and sleep disorder were also common. Median daily dose at the start of follow-up was 25mg for amitriptyline, 60mg for duloxetine, 300mg for gabapentin, and 75mg for pregabalin and more than 60% of patients remained on the same dose throughout the follow-up period. Only one fifth of patients continued the treatment started for at least one year. The mean number of different prescription drugs at baseline ranged from 8 to 10 across the groups. More than a half of patients used opioids and a third used benzodiazepines, sleep disorder drugs and muscle relaxants.

Conclusion

Patients who started one of the four common drugs for fibromyalgia similarly had multiple comorbidities and other fibromyalgia-related drug use, but continued the treatment only for a short time. The dose of the four drugs was not increased in most patients during the follow-up.

INTRODUCTION

Fibromyalgia is a common chronic pain disorder with unclear definitive etiology and pathophysiology, affecting more than 2% of the adult population [1, 2]. According to the 2010 American College of Rheumatology preliminary diagnostic criteria for fibromyalgia, a patient has fibromyalgia if they have widespread musculoskeletal pain involving more than 7 areas with a symptom severity scale score indicating moderate to severe fatigue, sleep disturbance or cognitive symptoms for more than three months and have no other disorder that could explain the symptom.[3] Patients with fibromyalgia commonly have joint stiffness, fatigue, sleep disturbance, depression, frequent headache, dizziness, numbness, weakness, and gastrointestinal or genitourinary irritability [4].

Currently, there is no definitive treatment available for fibromyalgia; various non-pharmacological and pharmacological treatment options are targeted toward patients’ specific symptoms [4]. Several studies show effectiveness of antidepressants, such as tricyclic and tetracyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors, in reducing pain, depression, and fatigue and improving sleep quality and health-related quality of life in patients with fibromyalgia.[5] Antiepileptics such as gabapentin and pregabalin were also found to be effective for symptoms related to pain, anxiety and fatigue and to improve overall health-related quality of life in fibromyalgia.[5]

As the cardinal symptom of fibromyalgia is widespread pain, use of analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics, is very common among these patients [6-10]. In a previous large U.S.-based study, more than 50% of newly diagnosed and established fibromyalgia patients were on either NSAIDs or opioid drugs [10]. Approximately 30% received sedatives or anxiolytic agents [10]. However, limited data is available whether specific treatments for fibromyalgia could decrease the use of analgesic drugs as well as muscle relaxants, sedatives and anxiolytic agents. A previous epidemiologic study observed a significant decrease in the proportion of patients receiving nonselective NSAIDs, but a significant increase in the proportion of patients receiving long-acting opioids during the 6-month period after starting therapy with pregabalin compared to the pre-treatment period [7]. No decrease in the proportion of patients receiving any type of analgesics was noted in the gabapentin group [7].

Over the last decade, two highly selective SNRIs, duloxetine and milnacipran, and the alpha-2-delta ligand, pregabalin, have been approved by the U.S. Food and Drug Administration for the treatment of fibromyalgia symptoms. The objective of this study was to describe clinical characteristics and medication use patterns in patients with fibromyalgia who started one of the four commonly prescribed drugs for fibromyalgia -- amitriptyline, duloxetine, gabapentin and pregabalin -- using claims data from a large population-based commercial health insurance plan.

METHODS

Data Source

We conducted a cohort study using the claims data from the ‘Innovus InVision Data Mart’, a commercial U.S. health plan which insures primarily working adults and their family members for the period January 1, 2007 to December 31, 2009. This database contains longitudinal claims information including medical diagnoses, procedures, hospitalizations, physician visits, and pharmacy dispensing on more than 14 million fully-insured subscribers with medical and pharmacy coverage at any particular time point across the United States. Personal identifiers were removed from the dataset before the analysis to protect subject confidentiality. Patient informed consent was therefore not required. The study protocol was approved by the Institutional Review Board of Brigham and Women’s Hospital.

Study Cohort

Adult patients who had at least one dispensing for a study drug, amitriptyline, duloxetine, gabapentin, or pregabalin, any time during the study period were identified. Patients who had a dispensing for amitriptyline, duloxetine, gabapentin or pregabalin, after a visit coded with the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD 9-CM) code, 729.1×, for fibromyalgia were eligible for the study cohort. At least 180 days of continuous health plan eligibility before receiving the first prescription of a study drug was required. To ensure that we only included new users of the study drugs, patients who used any of the four drugs during the 180-day baseline period and were prescribed more than one drugs at the same index date were excluded. Patients were followed from the dispensing date of the first study drug defined as the index date to the first of any of the following censoring events: discontinuation of study drugs, loss of health plan eligibility, end of study database, or death.

Data Analysis

Variables potentially related to fibromyalgia or initiation of the study drugs were assessed using data from the 180 days before the index date and during the follow-up period. These variables included demographic factors (age and sex), fibromyalgia-related comorbidities (back pain, chronic headache, depression, anxiety, chronic pain, fatigue, sleep disorder, and abdominal pain condition), other comorbidities (hypertension, diabetes, stroke, cardiovascular disease, chronic kidney disease, malignancy, smoking, obesity, and inflammatory arthritis), and use of fibromyalgia-related medications (opioids, benzodiazepines, anticonvulsants, antidepressants, migraine drugs, muscle relaxants, non-benzodiazepine sleep disorder drugs, topical analgesics, oral glucocorticoids, gastrointestinal drugs, non-selective NSAIDS and selective cyclooxygenase -2 inhibitors). Appendix 1 lists the diagnosis codes that were used to determine comorbidities and Appendix 2 shows the name of medications in each category. To quantify patients’ comorbidities, we also calculated the Deyo-adapted Charlson Comorbidity Index based on ICD-9-CM.[11, 12] The Comorbidity Index is a summative score, based on 19 major medical conditions including myocardial infarction, congestive heart failure, peripheral vascular disease, dementia, cerebrovascular disease, pulmonary, renal, hepatic disease, diabetes, ulcer, connective tissue disease, cancer, and human immunodeficiency virus infection. A score of 0 represents absence of comorbidity and a higher score indicates a greater number of comorbid conditions.

To examine the patterns of medication use over time, we collected data on duration of treatment with the study drugs, changes in the daily doses, and proportion of patients who continued the study drugs, used fibromyalgia-related medications during the follow-up period, and started another study drug during the follow-up period. The duration of study drug use was calculated as the number of days from the index date to the last drug available date, which is the last dispensing date plus the number of days’ supply.

Multinomial logistic regression models were used to assess the association between baseline clinical characteristics and initiation of amitriptyline, duloxetine or pregabalin using gabapentin as reference. All analyses were done using SAS 9.3 Statistical Software (SAS Institute Inc., Cary, NC).

RESULTS

Cohort Selection

Between 2007 and 2009, there were 116,183 patients had at least one diagnosis of fibromyalgia. After applying the inclusion and exclusion criteria, we identified 74,378 patients who had at least one diagnosis of fibromyalgia and received the first prescription for amitriptyline, duloxetine, gabapentin, or pregabalin after the 180-day eligibility period free of any of the study drugs. Of these, 13,404 initiated amitriptyline, 18,420 duloxetine, 23,268 gabapentin, and 19,286 pregabalin. Figure 1 displays our cohort selection process.

Figure 1. Selection of Study Cohort.

Our final study cohort included 13,404 amitriptyline, 18,420 duloxetine, 23,268 gabapentin, and 19,286 pregabalin initiators with fibromyalgia.

Patient Characteristics

Baseline characteristics of the study cohort were presented in Table 1. The mean (SD) age of patients ranged from 47.5 (12.7) to 50.8 (12.8) years and 72% to 84% were women in each group. 63% of amitriptyline, 76% of duloxetine, 62% of gabapentin, and 66% of pregabalin initiators had two or more diagnoses code for fibromyalgia during the study period. The longest mean (SD) duration of follow-up was 195 (206) days in duloxetine initiators and the shortest 141 (180) days in gabapentin initiators. The mean (SD) Comorbidity Index was similar across the four groups ranging from 0.5 (1.0) to 0.8 (1.3). Back pain was the most common comorbidity affecting 48% to 64% of patients across the groups, followed by headache (22%-30%) and sleep disorder (16%-19%).

Table 1.

Baseline characteristics of study cohort

	Amitriptyline (n=13,404)	Duloxetine (n=18,420)	Gabapentin (n=23,268)	Pregabalin (n=19,286)
% or mean ± SD
Demographic characteristic
Age	47.5±12.7	47.6±11.7	50.8±12.8	50.0±11.8
Female	81	84	72	78
Follow-up period (d)	156 (198)	195 (206)	141 (180)	153 (187)
Fibromyalgia-related conditions
Back pain	48	53	64	63
Headache	30	23	22	22
Depression	11	24	12	12
Anxiety	13	21	14	13
Abdominal Pain	5	4	3	4
Sleep disorder	16	19	16	17
Other comorbidities
Comorbidity Index	0.5±1.0	0.5±1.0	0.8±1.3	0.7±1.2
Diabetes	10	11	18	14
Hypertension	29	30	38	35
Cardiovascular disease	5	5	8	7
Stroke	3	3	5	4
Inflammatory arthritis	10	12	12	15
Smoking	6	6	8	6
Obesity	5	6	7	6
Chronic kidney disease	2	2	3	2
Malignancy	4	4	7	6

After adjusting for patients’ demographic factors, fibromyalgia-related conditions and other comorbidities at baseline, multinomial logistic regression analysis (Table 2) showed that older patients, female, smokers, and those with a higher Comorbidity Index and a diagnosis of back pain and diabetes were more likely to be started on gabapentin compared to the other three drugs. Patients with headache, abdominal pain, and sleep disorders at baseline were more likely to be started on amitriptyline compared to gabapentin. Depression and anxiety were significant factors for initiating duloxetine compared to gabapentin. A diagnosis of abdominal pain, sleep disorder, and inflammatory arthritis significantly increased the probability of getting treated with pregabalin compared to gabapentin. Appendix 3 shows the results from the multinomial logistic regression analysis using pregabalin as a reference drug.

Table 2.

Adjusted odds ratio and 95% confidence intervals for initiating amitriptyline, duloxetine, and pregabalin compared to initiating gabapentin

Parameter	Initiating amitriptyline vs. gabapentin	Initiating duloxetine vs. gabapentin	Initiating pregabalin vs. gabapentin
Demographic
Age *	0.99 (0.98-0.99)	0.99 (0.98-0.99)	1.00 (0.99-1.00)
Male	0.72 (0.68-0.76)	0.60 (0.57-0.63)	0.78 (0.74-0.82)
Fibromyalgia-related conditions
Back pain	0.51 (0.49-0.53)	0.61 (0.59-0.64)	0.92 (0.88-0.96)
Headache	1.49 (1.42-1.57)	0.93 (0.89-0.98)	0.97 (0.93-1.02)
Depression	0.86 (0.80-0.92)	2.14 (2.02-2.23)	1.01 (0.95-1.08)
Anxiety	0.86 (0.80-0.92)	1.32 (1.25-1.40)	0.89 (0.84-0.94)
Abdominal pain	1.46 (1.31-1.64)	1.18 (1.06-1.31)	1.19 (1.07-1.32)
Sleep disorder	1.10 (1.03-1.16)	1.26 (1.20-1.33)	1.13 (1.07-1.19)
Other comorbidities
Comorbidity Index*	0.92 (0.89-0.95)	0.90 (0.88-0.93)	0.99 (0.97-1.02)
Diabetes	0.69 (0.64-0.75)	0.80 (0.75-0.86)	0.84 (0.79-0.89)
Hypertension	0.95 (0.90-1.00)	0.97 (0.92-1.01)	0.99 (0.95-1.04)
Cardiovascular disease	0.88 (0.80-0.97)	0.92 (0.84-1.00)	1.01 (0.93-1.09)
Stroke	0.96 (0.85-1.08)	0.87 (0.77-0.97)	0.94 (0.85-1.04)
Inflammatory arthritis	0.91 (0.85-0.98)	1.07 (1.00-1.14)	1.32 (1.24-1.40)
Smoking	0.83 (0.76-0.91)	0.63 (0.58-0.68)	0.84 (0.78-0.90)
Obesity	0.89 (0.81-0.98)	0.95 (0.87-1.03)	0.95 (0.87-1.03)
Chronic kidney disease	1.00 (0.85-1.18)	0.89 (0.77-1.04)	0.91 (0.80-1.04)
Malignancy	0.82 (0.73-0.93)	0.90 (0.80-1.00)	0.84 (0.76-0.93)

^*Modeled as a continuous variable.

Treatment Pattern for Fibromyalgia

The most commonly prescribed starting dose per day was 25mg for amitriptyline, 60mg for duloxetine, 300mg for gabapentin, and 75mg for pregabalin. Figure 2 shows the proportion of patients who continued the fibromyalgia treatment in each group. Only 42% of amitriptyline, 57% of duloxetine, 40% gabapentin, and 45% pregabalin initiators remained on the treatment for 3 months or more. 28% of amitriptyline, 38% of duloxetine, 25% gabapentin, and 28% pregabalin initiators continued the treatment for at least 6 months. Less than 20% of patients across the four groups were treated for at least one year.

Figure 2. Proportion of patients remaining on fibromyalgia treatment over time.

Approximately 40% of patients started amitriptyline, gabapentin, and pregabalin and 60% of patients started duloxetine continued the treatment for more than 3 months. Less than 20% of patients across the four drug groups remained on the treatment for more than 1 year.

The majority of patients remained on the same dose throughout the follow-up period. Among the patients who continued the treatment for at least 6 months, 77% of amitriptyline, 66% of duloxetine, 70% gabapentin, and 52% of pregabalin initiators had no change in the dosage of the drugs. Among the gabapentin and pregabalin initiators whose dose was never changed during the follow-up, 20% of gabapentin and 22% of pregabalin initiators continued the treatment for at least 6 months.

At the end of the follow-up period, only 7% of amitriptyline initiators received a daily dose higher than 50mg, 3% of gabapentin received a daily dose greater than 600mg, and 4% pregabalin initiators were prescribed a daily dose higher than 150mg. Among the gabapentin and pregabalin initiators whose dose was increased during the follow-up, 45% of gabapentin and 52% of pregabalin initiators continued the treatment for at least 6 months.

A combination therapy with another fibromyalgia drugs was noted but not common. During the follow-up, 8.5% of amitriptyline, 10.4% of duloxetine, 8.1% of gabapentin and 10.4% of pregabalin initiators started at least one or more drugs for fibromyalgia.

Use of Other Fibromyalgia-related Drugs

Many patients used at least one of the fibromyalgia-related drugs in the baseline period. More than a half of patients across the four group used opioids and approximately a third used benzodiazepines, sleep disorder drugs and muscle relaxants (Table 3). The mean (SD) number of different prescription drugs used in the baseline period was generally high: 7.9 (6.7) in amitriptyline, 9.6 (7.8) in duloxetine, 9.3 (7.6) in gabapentin and 8.7 (7.1) in pregabalin initiators. Figure 3 shows the change in the proportion of patients who used opioids, NSAIDs, benzodiazepines, and muscle relaxants before and after starting amitriptyline, duloxetine, gabapentin, or pregabalin. These changes were all statistically significant.

Table 3.

Fibromyalgia-related drug use at baseline (%)

	Amitriptyline (n=13,404)	Duloxetine (n=18,420)	Gabapentin (n=23,268)	Pregabalin (n=19,286)
Topical analgesics	3	4	6	7
Opioids	54	56	67	69
Benzodiazepines	30	39	34	36
Anti-convulsants	10	13	40	39
TCAs	39	4	4	5
SSRIs	19	20	21	22
SNRIs	6	47	8	9
COX2/NSAIDs	34	33	38	42
Sleep disorder drugs*	19	25	19	23
Other antidepressants	10	19	14	16
Migraine drugs	10	8	6	8
Muscle relaxants	30	31	36	40
Oral steroids	26	26	30	32
GI protective drugs	22	23	24	26

TCA: Tricyclic antidepressants, SSRI: selective serotonin reuptake inhibitor, SNRI: serotonin and noradrenaline reuptake inhibitor, COX2: cyclooxygenase -2 inhibitor, NSAID: non-steroidal antiinflammatory drug, GI: gastrointestinal

^*: non-benzodiazepines

Figure 3. Use (in percentage) of analgesics, sedatives, and muscle relaxants before and after the index date.

NSAID: non-steroidal anti-inflammatory drugs including cyclooxygenase -2 inhibitors, BZD: benzodiazepines, M Relax: muscle relaxants

DISCUSSION

This large population-based study illustrates that many patients newly prescribed amitriptyline, duloxetine, gabapentin, or pregabalin for fibromyalgia similarly had a high number of fibromyalgia-related conditions and other comorbidities. These fibromyalgia patients also used various different prescription drugs. Notably, the dosage of these fibromyalgia drugs was not titrated up over time and the use of these drugs were generally short in most patients.

This study has several important findings that might have implications in clinical practice or future research. First, we conducted a cohort study that included new users of four commonly used fibromyalgia drugs. To reduce confounding, the patients were required to be free of any of the drugs 180 days prior to the index date.[13] Patients’ baseline characteristics across the four groups were generally similar. The largest group in this study was for gabapentin initiators, although fibromyalgia or chronic pain is one of the unlabeled uses of both amitriptyline and gabapentin. Second, we assessed association between baseline clinical characteristics and treatment that patients received, simultaneously adjusting for demographic factors and other comorbidities in multinomial regression. Factors significantly associated with getting started on gabapentin were older age, female, smokers, higher Comorbidity Index, and a diagnosis of back pain and diabetes. Third, the majority of patients across all groups used a high number of other prescription drugs at baseline with the mean number of prescription drugs ranging from 8 to 10. Opioids, benzodiazepines, sleep disorder drugs, and muscle relaxants were commonly used, consistent with the results of previous studies.[14, 15] To date, limited data is available with regard to comparative effectiveness and safety of FDA-approved drugs versus unapproved drugs in fibromyalgia. Further research using an appropriate methodology to minimize confounding by indication in an observational study setting is needed on comparative effectiveness of these fibromyalgia treatments in reducing use of pain-related medications or health care resources.[16]

Third, most patients started low dosage of these agents and generally remained on the same dose throughout the follow-up period. Furthermore, only one fifth of patients continued the treatment for at least one year. Amitriptyline, gabapentin, and pregabalin have a wide range of recommended dosage and a dose escalation should be considered if tolerated, before stopping the drug for inefficacy.[17-19] The most commonly used daily dose for amitriptyline in a meta-analysis of randomized clinical trials was between 12.5mg and 50mg.[20] In this study, 36% of amitriptyline initiators were on less than 12.5mg a day during the follow-up. A previous randomized placebo-controlled clinical trial showed that gabapentin 1,200 to 2,400mg per day was more effective in control of pain and other fibromyalgia related symptoms compared to placebo.[19] In a systematic review and meta-analysis of four clinical trials, pregabalin at doses of 300mg, 450mg, and 600mg daily, but not 150mg daily, produced useful benefits in patients with fibromyalgia.[18] Only 3% of gabapentin initiators received a dose higher than 600mg a day and 4% of pregabalin initiators were on a dose higher than 150mg a day during the follow-up in this study. These findings suggest that the majority of fibromyalgia patients prescribed gabapentin and pregabalin were on an inadequate dose before they stopped the drugs.

There are, however, limitations to our study. First, since we mainly relied on the diagnosis codes to select patients with fibromyalgia and identify their comorbidities, a potential for misclassification bias should be noted. Second, we relied on prescription dispensing records in the database to determine patients’ exposure to all the drugs. This may not be the most accurate way to verify individuals’ daily drug intake and use of over-the-counter pain medications, but it has been recognized as a valid way to ascertain drug exposure status in non-experimental settings.[21] Third, data on the reasons for discontinuation of the study drugs were not available. Some patients might have discontinued treatment due to various reasons including side effects, lack of efficacy, medication costs, non-compliance, or switching to non-pharmacologic treatment.[22, 23] Fourth, we did not assess whether patients were receiving non-pharmacologic treatment in addition to the study drugs. Further research on comparative effectiveness/safety of pharmacologic and non-pharmacologic management for fibromyalgia would help clinicians optimize the management of fibromyalgia patients. Lastly, we assessed a number of variables potentially related to initiating amitriptyline, duloxetine, gabapentin, or pregabalin using the data from the 6 months prior to the index date, but this time period might not be long enough to capture all the information on important clinical factors associated with fibromyalgia.

In conclusion, patients who started one of the four common drugs, amitriptyline, duloxetine, gabapentin, and pregabalin, for fibromyalgia similarly had multiple comorbidities and other fibromyalgia-related drug use. Most patients in this study remained on the same daily dose of the fibromyalgia drugs and continued the treatment only for a short time. These findings highlight the need for improving overall management of fibromyalgia with regard to patient education, appropriate dose titration for pharmacologic treatments, and non-pharmacologic management strategies such as aerobic exercise.

Significance and Innovation.

• -Patients who started amitriptyline, duloxetine, gabapentin or pregabalin for fibromyalgia similarly had multiple comorbidities and other fibromyalgia-related drug use.
• -The majority of patients continued the treatment only for a short period of time.
• -The dose of amitriptyline, duloxetine, gabapentin or pregabalin was not changed in most patients during the follow-up.