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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES

Objective

To evaluate the efficacy, tolerability, and safety of multiple fixed dosages of esreboxetine for the treatment of fibromyalgia.

Methods

Patients meeting the American College of Rheumatology criteria for fibromyalgia were randomized to receive esreboxetine at dosages of 4 mg/day (n = 277), 8 mg/day (n = 284), or 10 mg/day (n = 283) or matching placebo (n = 278) for 14 weeks. The primary efficacy outcomes were the weekly mean pain score and the Fibromyalgia Impact Questionnaire (FIQ) total score at week 14. Secondary efficacy measures included scores for the Patient's Global Impression of Change (PGIC) scale, the Global Fatigue Index (GFI), and the 36-item Short-Form health survey (SF-36; physical function scale only) at week 14. The safety profile of esreboxetine was evaluated based on adverse events and other safety measures.

Results

Patients receiving all dosages of esreboxetine demonstrated statistically significant improvements in the pain score (P ≤ 0.025), the FIQ score (P ≤ 0.023), and the PGIC score (P ≤ 0.007) compared with patients in the placebo group. Additionally, patients receiving esreboxetine at dosages of 4 mg/day and 8 mg/day showed statistically significant improvements in the GFI score compared with those receiving placebo (P = 0.001). No significant differences in SF-36 physical function scores were observed between patients receiving esreboxetine (any dosage) and those receiving placebo. Adverse events were mostly mild to moderate in severity; insomnia, constipation, dry mouth, nausea, dizziness, hot flush, headache, hyperhidrosis, and palpitations were reported most frequently.

Conclusion

Esreboxetine was generally well tolerated and was associated with significant improvements in pain, FIQ, PGIC, and fatigue scores compared with placebo. The lack of a dose-response relationship in both the efficacy and safety analyses suggests that esreboxetine at a dosage of 4 mg/day would offer clinical benefit with the least risk of drug exposure.

Fibromyalgia is a chronic pain condition that affects ∼2% of the adult population in the US (1), with worldwide prevalence estimates in adults ranging from 0.5% to 5.0% (2). The prevalence rates are substantially higher in women (3.4%) than in men (0.5%) (1). Although fibromyalgia is defined by the American College of Rheumatology (ACR) as at least a 3-month history of widespread pain, with pain on digital palpation of ≥11 of 18 specified tender point sites (3), it is also associated with other symptoms, including sleep disturbance, fatigue, anxiety, depression, and memory/cognitive problems (1–3). The range and severity of these symptoms profoundly impact a patient's overall quality of life (4, 5). Consequently, treatment typically involves a combination of pharmacologic and nonpharmacologic approaches (6, 7).

The underlying etiology of fibromyalgia remains unclear, although evidence suggests that associated pain is mediated in part by dysregulated signaling in the descending analgesic systems of the brain and spinal cord (8, 9). As such, 2 key neurotransmitters in this pain-inhibitory pathway, serotonin and norepinephrine, have been targeted in the management of fibromyalgia (6, 7). The dual-specific serotonin–norepinephrine reuptake inhibitors duloxetine (10–14) and milnacipran (10, 15–18) are approved by the US Food and Drug Administration for the management of fibromyalgia. In addition, tricyclic antidepressants that work to enhance serotonin- and norepinephrine-mediated signaling have exhibited moderate efficacy for the pain, fatigue, and sleep disturbance associated with fibromyalgia (19, 20). However, serotonin may have both antinociceptive and pronociceptive activity in the descending analgesic pathway (21). Indeed, the efficacy of selective serotonin reuptake inhibitors has been less consistent than that of the dual-specific serotonin–norepinephrine reuptake inhibitors for the treatment of fibromyalgia (22–26). In contrast, norepinephrine is believed to have predominantly pain-inhibitory actions in the descending analgesic pathway (21), and the antinociceptive properties of norepinephrine reuptake inhibitors have been demonstrated in preclinical models of pain (27, 28). Therefore, norepinephrine reuptake inhibitors such as reboxetine (29) are promising therapeutic agents for the management of fibromyalgia.

Recently, a proof-of-concept clinical study in fibromyalgia demonstrated significant and clinically meaningful treatment effects for esreboxetine, a highly selective norepinephrine reuptake inhibitor and the active enantiomer of racemic reboxetine (30). Patients receiving flexible-dosage esreboxetine (2–8 mg/day) demonstrated improvements in pain, fatigue, and functioning compared with those receiving placebo (30). The purpose of the current study was to further evaluate the efficacy, tolerability, and safety of esreboxetine for the treatment of fibromyalgia, by comparing multiple fixed dosages in an expanded patient population.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES

This 14-week, randomized, double-blind, multiple-dose, placebo-controlled, parallel-group study was conducted from December 2006 to May 2009 at 129 centers in the US and 9 centers in Canada. The study protocol was approved by the appropriate institutional review board or independent ethics committee at each participating investigational center, and all patients provided written informed consent before entering the study. This study was conducted in compliance with the Declaration of Helsinki, and all International Conference on Harmonisation Good Clinical Practice Guidelines.

Entry criteria.

Patients who were at least 18 years of age and met the ACR 1990 criteria for fibromyalgia (3) were eligible for inclusion in the study. Patients were required to have a score of ≥40 mm on the 100-mm visual analog scale (VAS; 0 = no pain, 100 = worst possible pain) of the short-form McGill Pain Questionnaire (SF-MPQ) (31) at the time of screening.

Patients were excluded if they had other severe pain (e.g., diabetic neuropathy or postherpetic neuralgia) that could have confounded assessment of the pain associated with fibromyalgia. Other exclusion criteria included previous treatment with esreboxetine; current treatment with reboxetine; rheumatic disease; active infection; untreated endocrine disorder; significant hepatic impairment; urinary retention; clinically relevant abnormal 12-lead electrocardiogram; unstable cardiovascular disease; postural hypotension; transient ischemic attack or stroke; recurrent syncope or low blood pressure; uncontrolled narrow-angle glaucoma; pregnancy, breastfeeding, or the use of an unacceptable mode of contraception; a current or recent diagnosis (last 6 months) or episode of major depressive disorder or dysthymia (as diagnosed by the Mini-International Neuropsychiatric Interview [MINI] [32]); serious suicide risk; history of mania, hypomania, or psychotic disorder as diagnosed by the MINI; drug or alcohol abuse within the last 2 years; seizure disorder; human immunodeficiency virus or recent hepatitis virus infection; malignancy within the last 2 years; significant or unstable medical or psychologic conditions; or involvement in workers' compensation claims, disability claims, or civil litigation related to fibromyalgia.

Patients were required to discontinue 1) tender point injections or treatment with opioids at least 30 days before completion of the first visit; 2) thioridazine or effectors of cytochrome P450 3A4 at least 14 days prior to completion of the first visit; 3) muscle relaxants, antidepressants, anticonvulsants, oral steroids, mexiletine, dopamine agonists, long-acting benzodiazepines, acupuncture, or transcutaneous electrical nerve stimulation at least 7 days prior to completion of the first visit; and 4) diphenhydramine or melatonin at least 1 day before completion of the first visit. Treatment with simple analgesics (nonsteroidal antiinflammatory drugs, aspirin, cyclooxygenase 2 inhibitors) and hypnotics (short- and medium-acting benzodiazepines, nonbenzodiazepines), rescue pain therapy with acetaminophen (≤4 gm/day), and current stable nonpharmacologic therapies were permitted during the study.

Study design.

The study was composed of 4 phases: a 1-week screening period; a 2-week, single-blind, placebo-treatment period; a 14-week, randomized, placebo-controlled treatment period; and a 2-week followup period. At the end of the single-blind placebo period, patients were required to have a score of ≥40 mm on the SF-MPQ 100-mm VAS and a weekly mean score of ≥4 on an 11-point pain scale (0 = no pain and 10 = worst possible pain) (33) in the week before randomization. Eligible patients were then randomized, according to a computer-generated pseudorandom code, in a 1:1:1:1 ratio to receive esreboxetine at a dosage of 4 mg/day, 8 mg/day, or 10 mg/day, or matching placebo, in a double-blinded manner. Patients in all of the esreboxetine groups initially received 4 mg/day for 2 weeks, followed by dosages of 4 mg/day, 8 mg/day, or 10 mg/day for 12 weeks, according to their randomization. All patients underwent a followup visit 2 weeks after the end of the double-blind treatment period.

Patients received esreboxetine or matching placebo once daily in the form of round, light grey tablets; all of the tablets were identical in appearance, to preserve blinding. A centralized telerandomization system was used to manage the allocation of treatment. Treatment compliance was based on returned tablet counts at each visit, and compliance of <80% was a potential cause for discontinuation.

Outcome measures.

The primary efficacy outcomes were the weekly mean pain score and the Fibromyalgia Impact Questionnaire (FIQ) (34) total score at week 14. Each morning, patients rated the intensity of their fibromyalgia-associated pain during the previous 24 hours on an 11-point scale via telephone, using an interactive voice response system. The end point of mean pain score was defined as the mean of all available pain scores during the final week the patient was receiving study medication. The FIQ is a self-administered questionnaire designed to assess the symptoms of fibromyalgia, and their effect on the patient, over the previous week (34). Ten subscales provide information on physical functioning, difficulty working, pain, fatigue, stiffness, morning tiredness, anxiety, and depression. The total score (range 0–100) provides an estimation of the impact of fibromyalgia, with higher scores indicating greater severity.

Secondary efficacy measures included scores for the Patient's Global Impression of Change (PGIC) scale (35), the Global Fatigue Index (GFI), and the 36-item Short-Form health survey (SF-36; physical function scale only) at week 14 (36). The PGIC is a self-administered survey that measures changes in a patient's condition on a scale from 1 (very much improved) to 7 (very much worse). The GFI score is derived from the Multidimensional Assessment of Fatigue (MAF) scale, a self-administered questionnaire survey that assesses the degree to which fatigue interferes with the activities of daily living. The GFI score is calculated from the scores for fatigue severity (mean of scores for items 1 and 2), distress (score for item 3), degree of interference in activities of daily living (mean of scores for items 4, 5, and 8–15), and timing (score for item 15 multiplied by 2.5) on the MAF. The final score is the mean of these calculations and ranges from 0 (no fatigue) to 10 (severe fatigue) (37). The SF-36 assesses health-related quality of life over the previous week and provides information on physical functioning, limitations due to physical problems, social functioning, body pain, mental health, limitations due to emotional problems, vitality, and general health perception. The scores for each scale range from 0 to 100, with higher scores indicating greater health. Patients completed the FIQ (weeks 0, 2, 6, 10, and 14 [all visits]), the PGIC (weeks 2, 6, 10, and 14), the MAF (all visits), and the SF-36 (weeks 0 and 14) during the randomized double-blind treatment period.

Safety and tolerability measures.

The safety profile of esreboxetine was assessed based on observed and reported adverse events (AEs), which were evaluated by the investigator for severity and relationship to study treatment. Additional safety measures included clinical laboratory tests (hematology, chemistry, urinalysis), vital signs (blood pressure, pulse rate), and 12-lead electrocardiogram.

Statistical analysis.

Sample size calculation was based on both primary end points, and estimates of variability were based on those observed in a proof-of-concept study of esreboxetine treatment in patients with fibromyalgia (30). Using the predefined testing strategy described below to account for multiple treatment comparisons/end points and assuming mean ± SD improvements of esreboxetine over placebo of 0.6 ± 1.85 and 7.0 ± 18.5 on the 11-point pain scale and the FIQ, respectively, a sample size of 1,108 randomized patients would provide ∼90% power at a 2-sided significance level of 5% for both primary end points. In the original protocol, a sample size of 1,040 patients was calculated based on pain and GFI as the co-primary outcome end point. This sample size was adjusted to 1,148 patients following an amendment to the protocol that changed the co-primary end point into 2 separate primary end points. An amendment to the protocol assigning pain and FIQ scores as the primary end points resulted in the final sample size of 1,108 patients.

The predefined testing strategy to account for multiple end points and treatment comparisons was as follows: all doses of esreboxetine demonstrating statistical significance for the primary pain score end point were then assessed for the primary FIQ score end point; all doses of esreboxetine demonstrating statistical significance for both primary end points were then assessed for secondary end points. The step-down order for secondary end points was PGIC, GFI, and SF-36 physical function scores. Each end point in the step-down procedure was analyzed using Hochberg's adjustment (38) for multiple treatment comparisons, and statistical significance could be concluded based only on this testing strategy. Namely, the P values for the 3 treatment comparisons were ranked from larger (P1) to smaller (P3). If P1 (least significant of the P values) was less than 0.05, then all comparisons were declared significant. If that failed, the remaining 2 comparisons were declared significant if P2 was less than or equal to 0.025. If that failed, the final comparison was considered significant if P3 was less than or equal to 0.017.

All analyses were based on the full analysis set, which included all randomized patients who received at least 1 dose of study medication and were tested according to the strategy described above. In the case of patients who were withdrawn, data collected up to the time of withdrawal were included in all analyses according to the intent-to-treat principle.

The primary efficacy measures (mean pain and FIQ scores) were analyzed using a mixed-effects model repeated- measures (MMRM) analysis (39), with baseline score, week, and treatment as covariates together with a treatment-by-week interaction. The primary treatment comparisons were the 3 esreboxetine dosages versus placebo at week 14, using the treatment-by–week 14 interaction. In this analysis, there was no imputation for missing values. However, analysis of covariance (ANCOVA) (40) was applied for sensitivity analyses of both primary end points, and missing data were imputed using the last observation carried forward (LOCF) and baseline observation carried forward (BOCF) approaches.

The PGIC score at the end point was analyzed using a proportional odds logistic regression model (41) with a LOCF approach for imputation of missing values. GFI and SF-36 physical function scores at the end point were analyzed using MMRM and ANCOVA (using an LOCF approach for missing data) models, respectively. Additional supportive analyses examining mean pain and FIQ scores at each time point were performed using an MMRM model. Pain responses (≥30% and ≥50% decreases from baseline in the mean pain score) were analyzed using a proportional odds logistic regression model with an LOCF approach to account for missing data. AEs, laboratory data, and other safety data were clinically reviewed, recorded, and summarized. Mean changes in heart rate and blood pressure were calculated from baseline to the end of the study.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES

Patient disposition and characteristics.

Of the 2,958 patients screened, 1,438 entered the 2-week single-blind placebo phase, 1,122 were randomized to receive treatment, and 716 completed the study (Table 1). Treatment-related AEs were the most common cause for discontinuation, particularly in the esreboxetine groups.

Table 1. Flow of patients through the trial*
AssignmentNo. of patients
  • *

    A total of 2,958 patients entered the 1-week screening phase. Of these, 1,438 entered the 2-week, single-blind placebo phase, and 1,122 patients were randomized to the 14-week, double-blind treatment phase. Patients received esreboxetine at a dosage of 4 mg/day for the first 2 weeks of the 14-week, double-blind, treatment period.

  • Events that were deemed to be related to the study treatment.

Placebo 
 Assigned278
 Treated277
 Discontinued76
  Adverse event18
  Lack of efficacy12
  Noncompliance10
  Lost to followup16
  Other20
 Completed201
Esreboxetine 4 mg/day 
 Assigned277
 Treated274
 Discontinued103
  Adverse event46
  Lack of efficacy11
  Noncompliance4
  Lost to followup16
  Other26
 Completed171
Esreboxetine 8 mg/day 
 Assigned284
 Treated282
 Discontinued111
  Adverse event62
  Lack of efficacy8
  Noncompliance6
  Lost to followup12
  Other23
 Completed171
Esreboxetine 10 mg/day 
 Assigned283
 Treated281
 Discontinued108
  Adverse event58
  Lack of efficacy6
  Noncompliance4
  Lost to followup18
  Other22
 Completed173

The baseline characteristics of the patients were comparable in all treatment groups (Table 2). The majority of patients were white (88.1%) and female (90.6%) with a mean age of ∼50 years (range 19–84 years) and a mean duration of fibromyalgia of ∼7 years (range 0–55 years). The use of concomitant drug treatments was similar in the placebo group (91%) and the esreboxetine groups (89–90%), and the most common treatments were analgesics such as ibuprofen and acetylsalicylic acid. The mean duration of treatment in all groups was 97 days.

Table 2. Baseline characteristics of the patients*
CharacteristicPlacebo (n = 277)Esreboxetine
4 mg/day (n = 274)8 mg/day (n = 282)10 mg/day (n = 281)
  • *

    Except where indicated otherwise, values are the number (%). BMI = body mass index.

  • For placebo and esreboxetine 4 mg/day, 8 mg/day, and 10 mg/day, n = 274, n = 273, n = 278, and n = 279, respectively, due to height values that were missing (n = 4) or were excluded due to assumed measurement errors (n = 6); heights for these patients were recorded as 60–70 cm, but weights were in the normal range.

  • The lower end of the range (0.0) represents patients with newly diagnosed fibromyalgia.

Sex    
 Female255 (92.1)245 (89.4)254 (90.1)255 (90.7)
 Male22 (7.9)29 (10.6)28 (9.9)26 (9.3)
Age, mean ± SD years49.9 ± 11.850.6 ± 10.951.6 ± 11.950.4 ± 12.1
Weight, mean ± SD kg81.0 ± 19.583.8 ± 20.382.3 ± 18.082.1 ± 19.9
BMI, mean ± SD kg/m230.4 ± 7.031.0 ± 7.530.7 ± 6.630.7 ± 7.6
 ≥25 kg/m2217 (79)204 (75)218 (78)217 (78)
 ≥30 kg/m2124 (45)134 (49)138 (50)138 (49)
Race    
 White250 (90.3)241 (88.0)239 (84.8)251 (89.3)
 Black16 (5.8)21 (7.7)24 (8.5)14 (5.0)
 Asian2 (0.7)1 (0.4)2 (0.7)4 (1.4)
 Other9 (3.2)11 (4.0)17 (6.0)12 (4.3)
Duration of fibromyalgia, years    
 Mean6.97.06.86.4
 Range0.0–54.50.0–37.40.0–30.80.0–37.4

Primary efficacy outcomes.

According to the predefined testing strategy and primary MMRM analysis, a significant reduction in the mean pain scores in the groups receiving all dosages of esreboxetine compared with the placebo group was observed at the study end point (Table 3). Evidence of improvement compared with placebo, as suggested by P values less than 0.05, began at week 2, and this improvement was sustained throughout the trial for patients receiving esreboxetine at dosages of 4 mg/day and 8 mg/day (Figure 1A). In contrast, P values less than 0.05 were evident only at weeks 12 and 14 for the group receiving esreboxetine at a dosage of 10 mg/day.

Table 3. Summary of primary analyses of primary and secondary efficacy outcomes*
 PlaceboEsreboxetine
4 mg/day8 mg/day10 mg/day
  • *

    All values for the treatment difference (and for the number of patients improved) are versus placebo. 95% CI = 95% confidence interval; FIQ = Fibromyalgia Impact Questionairre; PGIC = Patient's Global Impression of Change; GFI = Global Fatigue Index; SF-36 = 36-item Short-Form health survey.

  • Response of much improved or very much improved.

  • Not statistically significant using the predefined testing strategy.

Pain score (range 0–10)  
 No. of patients276273279280
 Baseline, mean ± SEM6.52 ± 0.096.44 ± 0.086.50 ± 0.096.54 ± 0.09
 Week 14, mean ± SEM estimate5.41 ± 0.134.68 ± 0.144.65 ± 0.144.99 ± 0.14
 Treatment difference −0.74−0.76−0.42
  95% CI −1.10, −0.37−1.13, −0.04−0.79, −0.05
  P <0.001<0.0010.025
FIQ score (range 0–100)    
 No. of patients262237249250
 Baseline, mean ± SEM54.93 ± 0.8554.04 ± 0.9755.27 ± 1.0056.38 ± 0.91
 Week 14, mean ± SEM estimate48.52 ± 1.1641.41 ± 1.2541.85 ± 1.2544.65 ± 1.24
 Treatment difference −7.12−6.67−3.88
  95% CI −10.47, −3.76−10.02, −3.33−7.21, −0.54
  P <0.001<0.0010.023
PGIC score    
 No. of patients275264272275
 No. (%) improved80 (29.1)110 (41.7)116 (42.6)110 (40.0)
  OR (95% CI) 1.74 (1.22, 2.49)1.81 (1.27, 2.58)1.62 (1.14, 2.32)
  P 0.0020.0010.007
GFI score (range 0–10)    
 No. of patients262237248248
 Baseline, mean ± SEM6.83 ± 0.116.62 ± 0.126.85 ± 0.127.00 ± 0.10
 Week 14, mean ± SEM estimate6.06 ± 0.125.42 ± 0.135.48 ± 0.135.76 ± 0.13
 Treatment difference −0.64−0.59−0.30
  95% CI −1.00, −0.28−0.94, −0.23−0.66, 0.05
  P 0.0010.0010.093
SF-36 physical function score (range 0–100)    
 No. of patients255241247250
 Baseline, mean ± SEM36.32 ± 0.5435.92 ± 0.5934.28 ± 0.6335.03 ± 0.57
 Week 14, mean ± SEM estimate38.19 ± 0.4638.49 ± 0.4839.51 ± 0.4738.28 ± 0.47
 Treatment difference 0.301.320.10
  95% CI −1.01, 1.600.02, 2.62−1.20, 1.39
  P 0.6530.0470.884
thumbnail image

Figure 1. Mean ± SEM pain scores (A) and Fibromyalgia Impact Questionnaire (FIQ) scores (B) according to study week. † = Adjusted for the mean score at baseline. ∗ = P < 0.05 versus placebo.

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Sensitivity analyses of the primary pain end point provided supporting evidence (P < 0.05) for improvements over placebo for esreboxetine at dosages of 4 mg/day (LOCF and BOCF) and 8 mg/day (LOCF) at week 14. Using a LOCF approach, the adjusted mean treatment differences compared with placebo were –0.55 (95% confidence interval [95% CI] –0.85, –0.24 [P < 0.001]), –0.55 (95% CI –0.85, –0.25 [P < 0.001]), and –0.22 (95% CI –0.53, 0.08 [P = 0.146]) for esreboxetine at dosages of 4 mg/day, 8 mg/day, and 10 mg/day, respectively. Using a BOCF approach, the adjusted mean treatment differences compared with placebo were –0.36 (95% CI –0.65, –0.08 [P = 0.013]), –0.26 (95% CI –0.54, 0.03 [P = 0.075]), and –0.12 (95% CI –0.41, 0.16 [P = 0.407]) for esreboxetine at dosages of 4 mg/day, 8 mg/day, and 10 mg/day, respectively.

A ≥30% decrease from baseline to end point in the mean pain score at week 14 was reported by 37.0%, 39.4%, and 33.9% of patients in the groups receiving esreboxetine at dosages of 4 mg/day (odds ratio [OR] 1.51, 95% CI 1.06, 2.17 [P = 0.024]), 8 mg/day (OR 1.68, 95% CI 1.18, 2.40 [P = 0.004]), and 10 mg/day (OR 1.33, 95% CI 0.93, 1.91 [P = 0.123]), respectively, compared with 27.9% of patients receiving placebo. In addition, a ≥50% decrease at week 14 was reported by 17.9%, 20.1%, and 15.0% of patients in the groups receiving esreboxetine at dosages of 4 mg/day (OR 1.60, 95% CI 0.99, 2.58 [P = 0.053]), 8 mg/day (OR 1.85, 95% CI 1.16, 2.95 [P = 0.010]), and 10 mg/day (OR 1.30, 95% CI 0.80, 2.13 [P = 0.291]), respectively, compared with 12.0% of patients receiving placebo.

According to the predefined testing strategy and primary MMRM analysis, all dosages of esreboxetine also demonstrated statistically significant improvement compared with placebo in the FIQ total score at week 14 (Table 3). Evidence of improvement compared with placebo, as suggested by P values less than 0.05, was present at all time points for the groups receiving esreboxetine at dosages of 4 mg/day and 8 mg/day, while the P value was less than 0.05 only at week 14 for the group receiving esreboxetine at a dosage of 10 mg/day (Figure 1B).

The results of a sensitivity analysis of the FIQ scores at week 14 were similar to those for the primary MMRM analysis when using an LOCF approach for missing data; the adjusted mean treatment differences compared with placebo were –5.27 (95% CI –8.20, –2.34 [P < 0.001]), –4.25 (95% CI –7.16, –1.34 [P = 0.004]), and –3.07 (95% CI –5.97, –0.17 [P = 0.038]) for the groups receiving esreboxetine at dosages of 4 mg/day, 8 mg/day, and 10 mg/day, respectively. Supporting evidence for improvements compared with placebo (P < 0.05) in the groups receiving esreboxetine at dosages of 4 mg/day and 8 mg/day also was obtained using a BOCF approach; the adjusted mean treatment differences compared with placebo were –3.86 (95% CI –6.42, –1.30 [P = 0.003]), –3.44 (95% CI –5.98, –0.90 [P = 0.008]), and –1.76 (95% CI –4.30, 0.79 [P = 0.176]) for esreboxetine dosages of 4 mg/day, 8 mg/day, and 10 mg/day, respectively.

Secondary efficacy outcomes.

According to the PGIC, the percentage of patients who reported that their condition was much or very much improved at week 14 was statistically significantly higher in the groups receiving esreboxetine (4 mg/day, 8 mg/day, and 10 mg/day) compared with the placebo group (Table 3). The groups receiving esreboxetine at dosages of 4 mg/day and 8 mg/day also demonstrated statistically significant improvements compared with the placebo group in the MAF-derived GFI score at week 14 (Table 3). Taking into account the predefined testing strategy, none of the esreboxetine groups demonstrated a statistically significant improvement compared with placebo group in the SF-36 physical function score at week 14 (Table 3).

Safety and tolerability.

Table 4 summarizes the treatment-related AEs in the 1,114 patients who received at least 1 dose of study treatment. The severity of most treatment-related AEs was considered mild to moderate. The incidence of severe treatment-related AEs was higher in the esreboxetine groups (∼10%) compared with the placebo group (∼3%). The most common treatment-related AEs were insomnia, constipation, dry mouth, nausea, dizziness, hot flush, headache, hyperhidrosis, and palpitations. Each of these events occurred more frequently and with greater severity in the esreboxetine groups compared with the placebo group (Table 4). There were no dose-related trends with respect to the severity of these events, and only dry mouth and dizziness occurred slightly more frequently with increasing doses of esreboxetine.

Table 4. Incidence of the most common treatment-related AEs*
 Placebo (n = 277)Esreboxetine
4 mg/day (n = 274)8 mg/day (n = 282)10 mg/day (n = 281)
  • *

    Values are the number (%). Adverse events (AEs) are those occurring in ≥5% of patients in any treatment group. SAE = serious adverse event.

Patients with ≥1 AE85 (30.7)158 (57.7)157 (55.7)162 (57.7)
Patients with ≥1 SAE02 (0.7)1 (0.4)2 (0.7)
Patients with ≥1 severe AE9 (3.2)26 (9.5)27 (9.6)27 (9.6)
Discontinuations due to AE17 (6.1)43 (15.7)57 (20.2)51 (18.1)
Deaths0000
Insomnia16 (5.8)33 (12.0)55 (19.5)39 (13.9)
Constipation4 (1.4)52 (19.0)37 (13.1)36 (12.8)
Dry mouth7 (2.5)28 (10.2)37 (13.1)42 (14.9)
Nausea15 (5.4)29 (10.6)30 (10.6)25 (8.9)
Dizziness11 (4.0)16 (5.8)22 (7.8)29 (10.3)
Hot flush5 (1.8)21 (7.7)20 (7.1)22 (7.8)
Headache8 (2.9)17 (6.2)20 (7.1)19 (6.8)
Hyperhidrosis1 (0.4)19 (6.9)15 (5.3)16 (5.7)
Palpitations7 (2.5)10 (3.6)10 (3.5)14 (5.0)

The treatment-related AEs most often reported as moderate to severe were insomnia, constipation, dry mouth, and nausea. The incidence of moderate-to-severe treatment-related insomnia was 10.7% among patients receiving esreboxetine compared with 2.6% among those receiving placebo. The incidences of moderate-to-severe treatment-related constipation (7.8% versus 0.4%), dry mouth (5.6% versus 0.4%), and nausea (4.8% versus 1.1%) were also higher among esreboxetine-treated patients compared with placebo-treated patients.

The most common treatment-related AE leading to discontinuation was moderate-to-severe insomnia; 22 patients (2.6%) discontinued esreboxetine treatment due to moderate-to-severe insomnia compared with 1 patient (0.4%) receiving placebo. Three patients (1 receiving placebo and 1 each in the groups receiving esreboxetine at dosages of 8 mg/day and 10 mg/day) discontinued the study due to an exacerbation of fibromyalgia. Treatment-related serious AEs leading to discontinuation included urinary retention and gastroesophageal reflux disease in the group receiving esreboxetine at a dosage of 4 mg/day (1 patient each), and chest pain and unstable angina in the group receiving esreboxetine at a dosage of 10 mg/day (1 patient each). All patients recovered upon discontinuation. One patient, who discontinued treatment with esreboxetine at a dosage of 8 mg/day because of insomnia, experienced a serious arrhythmia 16 days after cessation of treatment and, as of his/her last visit, had not recovered.

The cardiovascular changes observed in this study are summarized in Table 5. All esreboxetine groups had a greater proportion of patients with standing pulse rates of ≥100 beats per minute at week 14 compared with placebo group (16.5%, 17.0%, and 17.4% in the groups receiving esreboxetine at dosages of 4 mg/day, 8 mg/day, and 10 mg/day, respectively, versus 3.0% in the placebo group). The groups receiving esreboxetine at dosages of 4 mg/day and 10 mg/day also had an increased proportion of patients (8.2% and 4.7%, respectively) with supine pulse rates ≥100 beats per minute at week 14 compared with placebo (0.5%). A higher incidence of treatment-related cardiac palpitations also was present in the esreboxetine groups (4.1%) compared with the placebo group (2.5%) (Table 4). Aside from increased heart rates, no notable or consistent changes in cardiac rhythm were observed by electrocardiography.

Table 5. Cardiovascular changes observed during the study*
 PlaceboEsreboxetine
4 mg/day8 mg/day10 mg/day
  • *

    Results are presented as the mean value at baseline/mean change from baseline at week 14, except for postural changes, which are presented as the mean change observed at baseline/mean change observed at week 14. BP = blood pressure; bpm = beats per minute.

  • Upon going from supine to standing position.

Systolic BP, mm Hg  
 Supine121.7/–0.2123.0/0.9122.5/2.4122.6/0.5
 Standing121.9/0.6123.0/0.4123.5/0.2123.6/–1.5
Diastolic BP, mm Hg    
 Supine75.2/0.376.3/2.875.5/4.376.7/2.3
 Standing77.5/0.979.3/1.978.2/2.979.5/0.6
Pulse rate, bpm    
 Supine72.0/–1.072.5/8.271.6/9.872.3/8.6
 Standing76.7/0.078.3/7.676.5/10.177.1/7.9
Postural changes    
 Systolic BP, mm Hg–0.2/–0.90.0/0.5–1.0/2.3–0.9/2.0
 Diastolic BP, mm Hg–2.3/–0.6–3.0/0.8–2.8/1.4–2.7/1.7
 Pulse rate, bpm–4.6/–1.1–5.8/0.6–4.8/–0.4–4.9/0.7

Decreases in body weight of 1.0 kg, 0.7 kg, and 1.0 kg were observed in the groups receiving esreboxetine at dosages of 4 mg/day, 8 mg/day, and 10 mg/day, respectively, compared with an increase of 0.2 kg in the placebo group.

The number of clinically significant laboratory abnormalities that met the criteria for an AE was low and not indicative of a trend with esreboxetine treatment. No deaths were reported in this study.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES

In this 14-week trial of esreboxetine in fibromyalgia, esreboxetine monotherapy was associated with statistically significant analgesic effects at the end point for all dosages evaluated compared with placebo. Evidence of improvements compared with placebo became apparent at week 2, and improvement was sustained throughout the treatment period for esreboxetine at dosages of 4 mg/day and 8 mg/day. Additionally, a greater proportion of patients receiving esreboxetine at a dosage of 4 mg/day or 8 mg/day experienced pain reduction of ≥30% from baseline compared with placebo, a standard believed to represent a clinically important improvement (42).

The analgesic effect of esreboxetine treatment was accompanied by a general improvement in fibromyalgia status, as evidenced by statistically significant improvement in both FIQ and PGIC scores at end point for all dosages compared with placebo. Evidence of improvement compared with placebo in the FIQ score became apparent at week 2, and this improvement was sustained throughout the treatment period for esreboxetine dosages of 4 mg/day and 8 mg/day. The minimal clinically important difference in the FIQ score has been estimated as a 14% decrease from baseline (43), and the groups that received each dosage of esreboxetine had a greater percentage of patients (51%) who achieved this target compared with the placebo group (39%). All dosages of esreboxetine produced a statistically significantly greater proportion of patients, compared with placebo, who reported on the PGIC that their fibromyalgia was at least “much improved” over the course of treatment. These improvements in the FIQ and PGIC scores suggest that esreboxetine treatment reduced the impact of fibromyalgia and provided global and recognizable benefits to patients.

Esreboxetine treatment (4 mg/day and 8 mg/day) also was associated with statistically significant improvements in the GFI score, a patient-related measure of fatigue, compared with placebo. This is an important finding, because fatigue is one of the most common and disabling symptoms of fibromyalgia (5). Esreboxetine treatment did not result in a statistically significant improvement compared with placebo with respect to the SF-36 physical function score; this result differs from that in a previous trial of esreboxetine in fibromyalgia, in which significant improvement in the SF-36 physical function score was observed in the esreboxetine group relative to the placebo group (30). Therefore, further study is needed to assess the effects of esreboxetine on physical functioning.

Overall, these findings demonstrated a significant and clinically meaningful effect of esreboxetine in the management of pain and fatigue and in the overall impact of fibromyalgia, extending the findings of the previous 8-week flexible-dose clinical trial of esreboxetine (2–8 mg/day) (30). In the current study, higher doses of esreboxetine did not appear to yield more efficacious results in patients. Generally, the primary and secondary outcome results were similar for the groups receiving esreboxetine at dosages of 4 mg/day and 8 mg/day and lower in magnitude for the group receiving a dosage of 10 mg/day. This suggests a nonmonotone dose-response relationship for esreboxetine efficacy.

Treatment-related AEs, the most frequent of which were insomnia, constipation, dry mouth, nausea, and dizziness, were more common with esreboxetine than with placebo (∼57% versus ∼31%). These events were mostly mild to moderate in severity and reflected AEs that are commonly associated with drugs with significant noradrenergic activity. In addition, more patients in the esreboxetine groups discontinued the study because of treatment-related AEs (∼18% versus ∼6% of the placebo group), with the most common cause being moderate-to-severe insomnia. Generally, however, no dose-response relationship was evident with respect to the incidence and severity of treatment-related AEs within the esreboxetine groups. These safety findings are consistent with those from the previous trial of esreboxetine in fibromyalgia, in which patients most commonly reported mild-to-moderate constipation, insomnia, and dry mouth (30).

Cardiovascular changes associated with esreboxetine treatment in this study included an increase in both standing and supine pulse rates. Patients also experienced increased blood pressures in response to esreboxetine treatment. Overall, these cardiovascular changes are generally consistent with those in previous studies of esreboxetine (30) and the effects of reboxetine in healthy adults (44). The clinical relevance of such increases is unknown and requires further study.

Obesity is commonly observed in the population of patients with fibromyalgia. In this study, 45–50% of patients in all treatment arms had a body mass index of ≥30 kg/m2 at baseline (Table 2). Esreboxetine treatment, however, was associated with only a modest weight decrease at the end point.

A few limitations of this study should be considered. Because this was a trial of esreboxetine monotherapy, patients were required to discontinue medications used to treat fibromyalgia. This approach may have excluded patients with more severe fibromyalgia, although baseline demographics indicated that patients in the trial had moderate-to-severe levels of pain and a mean duration of fibromyalgia of ∼7 years. Fibromyalgia typically requires continuous therapy to manage the chronic pain and other associated symptoms. The results of this 14-week trial, however, may not generalize to longer periods of treatment. Finally, the inclusion and exclusion criteria limit the ability to extrapolate the results beyond the population studied. For example, the results of this trial may not extend to patients with comorbid pain disorders or psychiatric disorders, because such patients were excluded from the trial.

Overall, the results of this study support the safety and efficacy of esreboxetine for the treatment of fibromyalgia, and, based on a benefit–risk assessment, the lack of a dose-response relationship in both the efficacy and safety analyses suggests that esreboxetine at a dosage of 4 mg/day would offer clinical benefit with the least risk of drug exposure. Lower doses of esreboxetine may also offer benefit, although further research is needed to explore this possibility. Esreboxetine was discontinued from clinical development for fibromyalgia as part of an overall portfolio review and was not discontinued for safety reasons or for lack of efficacy. In a broader sense, the findings from this study suggest that other selective norepinephrine reuptake inhibitors may be useful therapeutic agents for the management of fibromyalgia.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Arnold had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Ellis, Hughes.

Acquisition of data. Arnold.

Analysis and interpretation of data. Arnold, Hirsch, Sanders, Ellis, Hughes.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES

This study was funded by Pfizer. Medical writing support for the preparation of this manuscript was provided by Matt Soulsby, PhD, of UBC Envision group and was funded by Pfizer. Publication of this manuscript was not contingent on approval by Pfizer.

REFERENCES

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  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. REFERENCES
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