Effect of pregabalin on sleep in patients with fibromyalgia and sleep maintenance disturbance: A randomized, placebo-controlled, 2-way crossover polysomnography study

Authors

  • Thomas Roth,

    Corresponding author
    1. Sleep Disorders and Research Center, Henry Ford Health System, Detroit, Michigan
    • Sleep Disorders and Research Center, Henry Ford Health System, 2799 West Grand Boulevard, Detroit, MI 48202
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    • Dr. Roth has received research funding from Aventis, Cephalon, GlaxoSmithKline, Merck, Neurocrine, Pfizer, Sanofi-Aventis, Schering-Plough, Sepracor, Somaxon, Somnus, Syrex, Takeda, TransOral, Ventus, Wyeth, and XenoPort; has acted as a consultant or serves on an advisory board for Abbott, Acadia, Acologix, Acorda, Actelion, Addrenex, Alchemers, Alza, Ancel, Arena, AstraZeneca, Aventis, Aver, Bayer, BMS, BTG, Cephalon, Cypress, Dove, Eisai, Elan, Eli Lilly, Evotec, Forest, GlaxoSmithKline, Hypnion, Impax, Intec, Intra-Cellular, Jazz, Johnson & Johnson, King, Lundbeck, McNeil, MediciNova, Merck, Neurim, Neurocrine, Neurogen, Novartis, Ocera, Orexo, Organon, Otsuka, Prestwick, Procter & Gamble, Pfizer, Purdue, Resteva, Roche, Sanofi-Aventis, Sepracor, Servier, Shire, Somaxon, Somnus, Steady Sleep Rx, Syrex, Takeda, Transcept, TransOral, Vanda, Ventus, VivoMetrics, Wyeth, XenoPort, and Yamanouchi; and has received speaking fees from Cephalon, Sanofi-Aventis, and Sepracor.

  • D. Alan Lankford,

    1. Sleep Disorders Center of Georgia, Atlanta
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    • Dr. Lankford has received research funding from Actelion, Arena, Cephalon, Evotec, Fisher & Paykel, GlaxoSmithKline, Lilly, Merck, Neurim, Neurocrine, Neurogen, Organon, Pfizer, Respironics, Sanofi-Aventis, Schering-Plough, Sepracor, Somaxon, Takeda, Transcept, Vanda, and Ventus; has acted as a consultant or served on an advisory board for Actelion, Apnicure, Cephalon, Pfizer, and Somaxon; and has received speaking fees from Jazz Pharmaceuticals and Sanofi-Aventis.

  • Pritha Bhadra,

    1. Pfizer Inc, New York, New York
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    • Drs. Bhadra, Whalen, and Resnick own stock or stock options in Pfizer.

  • Ed Whalen,

    1. Pfizer Inc, New York, New York
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    • Drs. Bhadra, Whalen, and Resnick own stock or stock options in Pfizer.

  • E. Malca Resnick

    1. Pfizer Inc, New York, New York
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    • Drs. Bhadra, Whalen, and Resnick own stock or stock options in Pfizer.


  • ClinicalTrials.gov identifier: NCT00883740.

Abstract

Objective

To assess the effect of pregabalin on polysomnographic (PSG) measures of sleep and patient-rated sleep, tiredness, and pain in fibromyalgia patients.

Methods

We performed a randomized, double-blind, placebo-controlled, 2-period crossover PSG study. Patients ages ≥18 years with fibromyalgia satisfied subjective and objective sleep disturbance criteria prior to randomization. Eligible patients were randomized (1:1) to pregabalin (300–450 mg/day) or placebo for crossover period 1, and vice versa for period 2. Each crossover period comprised a dose-adjustment and dose-maintenance phase, with a 2-week taper/washout between periods. In-laboratory PSGs were recorded during 2 consecutive nights at screening and at the end of each crossover period. The primary end point was the difference in sleep maintenance defined by PSG-recorded wake after sleep onset (WASO; minutes) between 4 weeks of treatment with pregabalin and with placebo. Other PSG measures; patient-rated sleep, tiredness, and pain; and tolerability were assessed.

Results

Of 119 patients randomized (103 women [86.6%], mean age 48.4 years), 102 (85.7%) completed both periods. Patients treated with pregabalin showed a reduction in PSG-determined WASO versus treatment with placebo (week 4 difference: −19.2 minutes [95% confidence interval (95% CI) −26.7, −11.6]; P < 0.0001). Pain score improved (decreased) with pregabalin versus placebo treatment at all 4 weeks (week 4 difference: −0.52 [95% CI −0.90, −0.14]; P = 0.0084). Modest (ρ = <0.3) but significant correlations were found between PSG sleep assessments and ratings of pain and sleep quality. Frequently reported all-causality adverse events (pregabalin versus placebo) were: dizziness (30.4% versus 9.9%), somnolence (20.5% versus 4.5%), and headache (8.9% versus 8.1%).

Conclusion

Patients with fibromyalgia treated with pregabalin had statistically significant and meaningful improvements in sleep, as assessed by PSG. Patients with fibromyalgia also reported decreased daily pain. Pregabalin was well tolerated.

INTRODUCTION

Multifocal muscle pain and tenderness are key components in the diagnosis of fibromyalgia (FM) (1, 2); in addition, many patients report light disrupted sleep, daytime tiredness, and fatigue. Pain and sleep disturbance exhibit a bidirectional relationship, where pain interferes with sleep, and sleep disturbance can increase a patient's experience of pain (3–5), even in patients without underlying FM (6, 7). However, the specific sleep abnormality associated with pain in patients with FM has not been fully elucidated. In recognition of the high prevalence and important nature of sleep disturbance as a clinical problem in FM and the impact of sleep disruption on pain, it has been suggested that the presence of sleep disturbances be part of the diagnostics for FM (2).

Although the complexities are still under investigation, specific changes in sleep characteristics have been reported for patients with FM (8–10). For example, patients with FM have delayed sleep onset, decreased sleep efficiency, more frequent transient arousals, and sleep-disordered breathing compared with healthy controls (8, 9, 11). Interestingly, the degree to which stage 2 sleep was decreased correlated with self-reported pain in 1 sleep laboratory study (8), in line with other observations that fragmentation of sleep contributes to pain in FM (3–5). Collectively, data indicate that improving sleep in patients with FM may reduce daily pain.

Despite affecting at least 5 million Americans, only 3 treatments are specifically indicated for FM in the US (duloxetine, milnacipran, and pregabalin) (12). Treatment with pregabalin, an α2-δ ligand and the first compound to receive Food and Drug Administration approval for FM, improves core symptoms of FM, including pain, daytime tiredness, and patient-reported sleep disturbance (13–16). No studies to date have been specifically designed to determine the effect of pregabalin on objective measures of sleep in patients with FM. A double-blind polysomnographic (PSG) study in healthy volunteers has reported that pregabalin treatment increases slow-wave sleep (SWS) as a proportion of the total sleep time (TST) when compared with either placebo or the benzodiazepine, alprazolam (17). In addition, a pilot PSG study demonstrated improvements in sleep with pregabalin treatment in patients with epilepsy (18).

Taken together, these data indicate that in addition to reducing pain, treatment with pregabalin may improve sleep as measured both with PSG and patient reports in healthy patients and some patient populations. A specifically designed and adequately powered sleep laboratory study would allow objective validation of the patient-reported benefits of pregabalin in patients with FM. This study was undertaken to evaluate the efficacy of pregabalin on PSG measures of sleep in patients with FM and sleep maintenance disturbance (i.e., increased wake after sleep onset [WASO]), and to investigate covariation among pain and sleep measures.

Significance & Innovations

  • This is the first placebo-controlled polysomnographic study, using a crossover design to control for variability, to investigate the efficacy of pregabalin for improving objective measures of sleep, alongside subjective measures of sleep and daily pain, in patients with fibromyalgia and existing sleep difficulties.

  • Patients with fibromyalgia treated with pregabalin for a 4-week treatment period had statistically significant and meaningful improvements in sleep as assessed by polysomnography, compared with when treated with placebo.

  • Patients with fibromyalgia also reported (via daily diary) improved sleep duration and sleep quality, and reported decreased daily pain when treated with pregabalin versus placebo.

  • Pregabalin was well tolerated.

PATIENTS AND METHODS

Study design.

This randomized, double-blind, placebo-controlled, 2-treatment, 2-period, crossover PSG study was conducted at 19 sites across the US, Canada, and Germany (see Supplementary Figure 1, available in the online version of this article at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658). Patients participated from June 2009 to June 2010. The study was conducted in compliance with the Declaration of Helsinki (revised Edinburgh, 2000) and the International Conference on Harmonisation Guidelines for Good Clinical Practice. The final protocol and informed consent documentation were reviewed and approved by the institutional review board(s) and/or independent ethics committee(s) at each study center. Written informed consent was received from all eligible patients before the trial procedures were initiated.

Patients (see below) entered a single-blind placebo run-in period and were required to satisfy subjective and objective sleep disturbance criteria to be eligible for randomization (at day 0). The study comprised 2 double-blind crossover treatment periods, each having dose-adjustment (up to day 14 of a given period) and treatment-maintenance (to day 29 of a given period) phases. A 2-week taper and/or washout (where washout was applicable) period between completion of period 1 and the start of period 2 was required.

Randomization.

A computer-generated method of random-permutated blocks and a telerandomization system were used for enrollment and allocation to sequence (1:1): pregabalin → placebo or placebo → pregabalin. All randomized patients initiated double-blind therapy at 75 mg of pregabalin twice a day (150 mg/day) or matching placebo on day 0 (in period 1) and cumulative day 44 (start of period 2). The evening dose was taken 1 hour prior to habitual bedtime. On day 4, patients were up-titrated to 150 mg twice a day (300 mg/day). On day 8, patients who tolerated 300 mg/day were up-titrated to 225 mg twice a day (450 mg/day). Patients unable to tolerate dose up-titration continued on the pretitration dose until the end of the study. The target dosage was 300–450 mg/day. All patients were allocated to receive pregabalin and placebo.

Concomitant medications.

Patients were allowed to remain on concomitant medication(s) if they were stable for 30 days prior to screening and not indicated for FM, and if the medication(s) had no known effect on sleep and was not otherwise prohibited. Patients were allowed ≤4 gm/day of acetaminophen as a rescue analgesic. Selective serotonin reuptake inhibitors were allowed as antidepressants if stable for >2 months prior to screening, not prescribed as a sleep aid, and sleep disturbance preceded or did not initiate with antidepressant treatment. Prohibited medications included, but were not limited to, tricyclic antidepressants, benzodiazepines, anxiolytics, other anticonvulsants, antipsychotics, narcotic analgesics, H1 receptor antagonists, systemic corticosteroids, and barbiturates. The medication washout period was the longer of 7 days or 5 half-lives.

Study population..

Inclusion criteria.

Male or female patients ages ≥18 years were eligible for the study if they had been diagnosed with FM as defined by the American College of Rheumatology (1990 criteria [1]) and had a history of disturbed sleep on the screening interview, reflected by difficulty in maintaining sleep for ≥3 nights/week for ≥1 months prior to screening interview. Patients had to maintain a normal daytime/awake nighttime/asleep schedule (bedtime between 9:00 PM and midnight), with 6.5–8.5 hours in bed each night and <3 hours of variation in the night-to-night bedtime. Subjective sleep entry criteria, recorded during screening and prior to randomization via an interactive voice recognition system (IVRS) for a minimum of 5 daily IVRS diary data points after visit 2, were subjective TST ≤6 hours and subjective WASO ≥60 minutes for ≥3 nights/week during the screening period. PSG entry criteria (conducted on 2 consecutive nights at visit 3) included the average of 2 PSG nights of WASO >45 minutes and TST of 3.0–6.5 hours.

Exclusion criteria.

Patients were excluded if they had a history of any circadian rhythm sleep disorder or a primary sleep disorder (other than diagnosed insomnia disorder) in the past 5 years, including restless legs syndrome, narcolepsy, sleep apnea, and phase advance or delay syndromes; had any condition that could confound assessment of sleep or FM symptoms, including significant depression, or other psychiatric disorder or severe medical condition as judged by the investigator to make the patient inappropriate for the clinical trial; were taking any medications known to affect sleep–wake function; or had participated in a pregabalin clinical study. PSG exclusion criteria consisted of periodic extremity movement with arousal index >10 on either night of PSG, apnea/hypopnea index >10 on either night of PSG, and latency to persistent sleep (LPS) of <10 minutes on either PSG night. As pregabalin clearance is directly related to creatinine clearance, patients with a creatinine clearance ≤60 ml/minute were excluded, as were patients with any other clinical laboratory abnormality that was considered relevant. Patients were also excluded if they had an abnormality deemed clinically relevant on 12-lead electrocardiogram recorded at screening or any medical condition(s) considered by the investigator as significant. Patients were also excluded if they had any pending worker's compensation, civil litigation, or disability claims pertinent to FM; had current involvement in out-of-court settlements for claims pertinent to their FM; or were currently receiving monetary compensation as a result of any of the preceding.

Efficacy assessments.

PSG assessments.

The primary efficacy end point was the difference in WASO (in minutes) assessed at the end of period 1 (day 31) and at the end of period 2 (cumulative day 73) between treatment with pregabalin and treatment with placebo. PSG assessments were recorded for 8 hours, starting 1-hour postmedication, on 2 consecutive nights in the study center at the end of each crossover period (cumulative days 28–30 and days 71–73, respectively). The PSG recording and scoring were carried out in accordance with the Rechtschaffen and Kales manual (1968). A central laboratory was utilized, and PSG technologists from this central PSG laboratory scored all PSG recordings in a blinded fashion. Variables determined from PSG included: WASO; TST; number of awakenings after sleep onset (NAASO), defined as awake for ≥2 consecutive epochs; wake time during sleep, defined as the amount of time awake after the onset of persistent sleep and prior to the final awakening, or end of the 8-hour recording; wake time after sleep, defined as the amount of time awake after the final awakening until the end of the 8-hour recording; and LPS.

Patient-rated measures of sleep and tiredness.

Patients completed a daily diary throughout the study from visit 2 until the end point and including the mornings following the PSG recordings 30–60 minutes after waking. Patient-rated measures of sleep recorded daily via an IVRS included: subjective TST, subjective WASO, number of awakenings, and latency to sleep onset (LSO). Patients rated the quality of their sleep from the past night, daily on waking from 0 (“very poor”) to 10 (“excellent”), and tiredness in the past 24 hours due to FM from 0 (“not tired”) to 10 (“extremely tired”).

Daily pain due to FM.

Patients rated pain due to FM during the previous 24 hours by selecting the most appropriate number (30–60 minutes after waking) from 0 (“no pain”) to 10 (“worst possible pain”) as part of the daily IVRS.

Safety and tolerability.

Patients taking ≥1 doses of study medication were included in safety analyses. Adverse events (AEs) were reported by patients and their relationship to the study drug was based on the opinion of the investigator.

Statistical analysis.

Assuming the true mean treatment difference (pregabalin − placebo) in WASO is 20 minutes, between-subject variance is 412 minutes, and within-subject variance is 1,207 minutes, an estimated sample size of 100 patients (50 per treatment arm) was required to achieve at least 70 completers per treatment arm to provide ≥90% power for a 2-sided 5% statistical test comparing pregabalin with placebo with respect to the primary efficacy end point (WASO by PSG assessment). The primary efficacy analysis was performed on the per-protocol population who completed the study taking 300–450 mg/day with no major protocol violations (specified prior to unblinding). All randomized patients who received ≥1 doses of the study medication and had ≥1 postbaseline efficacy measurements were included in the intent-to-treat (ITT) population, used for all secondary efficacy assessments. For each subjective end point, the mean of 2 consecutive measurements was used. For patients who did not complete the study or for missing data, the last observation carried forward while receiving the study medication was used for end point analyses. The last observation carried forward approach was used for each crossover period separately. If only 1 of the 2 consecutive measurements was available, the available measurement was used. If both measurements were missing, the mean value for that end point was treated as missing.

PSG and patient-rated end points were analyzed using a linear mixed-effects model, including sequence, period, and treatment as fixed variables and subject within-sequence and within-subject error as random factors. The point estimate for mean treatment difference (pregabalin − placebo) and 95% confidence intervals (95% CIs) for the true mean treatment difference are reported. Descriptive statistics are reported for the primary end point by visit and treatment group.

A fixed-effects crossover model (variable = sequence + subject [sequence] + period + treatment) was used to assess potential correlation between PSG-recorded outcomes and patient-rated variables of pain, tiredness, and sleep quality, where “variable” is 1 of 3 diary variables or a PSG measure (WASO, TST, SWS, LPS, stage 1 sleep, total wake time [TWT]) and sequence is either pregabalin → placebo or placebo → pregabalin. Spearman's correlations coefficients (ρ) were calculated and compared using a t-test for rank-order correlations, where P values less than 0.05 were considered significant. Patients experiencing all-causality and treatment-related AEs were compared using a chi-square analysis. Data were analyzed using SAS statistical software, version 8.

RESULTS

Patient disposition and characteristics.

A total of 557 patients were screened, of whom 119 (21.4%) were randomized to receive study medication and took ≥1 doses of medication (59 pregabalin → placebo sequence and 60 placebo → pregabalin sequence) (Figure 1). Patients were predominantly women (103 [86.6%] of 119) and white (104 [87.4%] of 119), with a mean age of 48.4 years (range 27–77 years) and a mean weight of 75.6 kg (166.3 lb). The mean duration of FM was 4.2 years. Mean ± SD daily pain at baseline was 6.7 ± 1.6 overall and similar between treatment sequence arms (placebo → pregabalin: 6.7 ± 1.6 and pregabalin → placebo: 6.6 ± 1.6). Patients in the 2 randomization sequences had similar sleep characteristics recorded at screening (Table 1).

Figure 1.

Flow of patients through the study. AE = adverse event; ITT = intent-to-treat; PP = per protocol.

Table 1. PSG-recorded sleep characteristics of the patient population with fibromyalgia and sleep disturbance in the 2 randomization sequences recorded during 2 nights of PSG during screening (visit 3)*
 All (n = 115)Placebo → pregabalin sequence (n = 59)Pregabalin → placebo sequence (n = 56)
  • *

    Values are the mean ± SD. PSG = polysomnography; WASO = wake after sleep onset; TST = total sleep time; LPS = latency to persistent sleep; SWS = slow-wave sleep.

  • SWS is defined as stage 3 + 4 sleep.

WASO, minutes108.3 ± 29.7108.8 ± 28.0107.8 ± 31.5
TST, minutes320.6 ± 35.6321.4 ± 35.0319.8 ± 36.4
Sleep efficiency, %66.8 ± 7.4167.0 ± 7.2966.6 ± 7.59
Number of awakenings27.8 ± 11.026.9 ± 10.728.7 ± 11.3
LPS, minutes59.1 ± 29.156.7 ± 23.861.7 ± 33.7
SWS, % of TST15.3 ± 10.416.2 ± 11.014.3 ± 9.62

Similar numbers of patients discontinued from pregabalin (9 [8.0%]) and placebo (8 [7.2%]) treatment. Three discontinued due to AEs (2 pregabalin, 1 placebo), 10 had protocol violations (7 pregabalin, 3 placebo), 3 no longer wished to participate (3 placebo), and 1 was lost to followup (1 placebo). In total, 108 (96.4%) in the sequence pregabalin → placebo and 109 (98.2%) in the sequence placebo → pregabalin were included in the ITT population; 4 patients were randomized and treated at 2 different study centers and data from the second randomization were excluded from the ITT population. The majority of patients in each period (48 [87.3%] of 55 and 42 [79.2%] of 53 in periods 1 and 2, respectively) were up-titrated to pregabalin 300 or 450 mg/day, with more than half in each period (54.6% in period 1 and 66.0% in period 2) maintained on 450 mg/day. In total, 83 (69.7%) of 119 patients, comprising 41 in the pregabalin → placebo and 42 in the placebo → pregabalin sequence, were taking 300–450 mg/day of pregabalin and were included in the per-protocol analysis for assessment of the primary end point (WASO). Median treatment exposure for pregabalin was 32 days (range 2–41 days).

Efficacy analyses.

PSG assessments.

Treatment with pregabalin for 4 weeks reduced WASO by 19 minutes compared with treatment with placebo (week 4 WASO: 51.5 versus 70.7 minutes) (Table 2). The mean difference in WASO between pregabalin- and placebo-treated patients was smaller for the first crossover period (pregabalin 61.7 versus placebo 69.4 minutes) than the second crossover period (pregabalin 41.4 versus placebo 72.0 minutes).

Table 2. Analysis of PSG-recorded sleep measures after patients with fibromyalgia were treated for 4 weeks with pregabalin and with placebo*
 Value
  • *

    P value is based on a linear mixed-effects model including sequence, period, and treatment as fixed factors and patient within-sequence and within-subject error as random factors. PSG = polysomnography; WASO = wake after sleep onset; LS = least squares; 95% CI = 95% confidence interval; TST = total sleep time; LPS = latency to persistent sleep; NAASO1 = number of awakenings after sleep onset (wake period of at least 1 epoch duration); NAASO2 = NAASO (wake period of at least 2 epochs' duration); SWS = slow-wave sleep; WTDS = wake time during sleep; WTAS = wake time after sleep.

  • The primary efficacy analyses (WASO) were performed on the per-protocol population that completed the study taking 300–450 mg/day with no major protocol violations. All patients who were randomized and received ≥1 doses of study medication and had ≥1 postbaseline efficacy measurements were included in the intent-to-treat population, used to analyze all secondary efficacy assessments (TST, LPS, sleep efficiency, NAASO, SWS, WTDS, and WTAS).

  • Higher LS mean values and positive LS mean differences indicate improved sleep.

  • §

    Lower LS mean values and negative LS mean differences indicate improved sleep.

  • SWS is defined as stage 3 + 4 sleep. Higher LS mean values and positive LS mean differences indicate improved sleep.

WASO, minutes 
 Placebo (n = 83), LS mean (SE)70.7 (3.8)
 Pregabalin (n = 83), LS mean (SE)51.5 (3.8)
 LS mean difference (95% CI) from placebo−19.2 (−26.7, −11.6)
 P< 0.0001
TST, minutes 
 Placebo (n = 109), LS mean (SE)370.6 (4.7)
 Pregabalin (n = 108), LS mean (SE)396.2 (4.7)
 LS mean difference (95% CI) from placebo25.5 (17.5, 33.6)
 P< 0.0001
LPS, minutes§ 
 Placebo (n = 109), LS mean (SE)41.6 (3.7)
 Pregabalin (n = 108), LS mean (SE)34.5 (3.7)
 LS mean difference (95% CI) from placebo−7.18 (−14.2, −0.17)
 P0.0447
Sleep efficiency, % 
 Placebo (n = 109), LS mean (SE)77.2 (0.97)
 Pregabalin (n = 108), LS mean (SE)82.6 (0.98)
 LS mean difference (95% CI) from placebo5.42 (3.74, 7.11)
 P< 0.0001
NAASO1, no.§ 
 Placebo (n = 109), LS mean (SE)26.9 (1.0)
 Pregabalin (n = 108), LS mean (SE)24.5 (1.0)
 LS mean difference (95% CI) from placebo−2.41 (−4.31, −0.51)
 P0.0135
NAASO2, no.§ 
 Placebo (n = 109), LS mean (SE)10.2 (0.44)
 Pregabalin (n = 108), LS mean (SE)8.63 (0.45)
 LS mean difference (95% CI) from placebo−1.53 (−2.41, −0.66)
 P0.0008
SWS, % of TST 
 Placebo (n = 109), LS mean (SE)15.0 (1.0)
 Pregabalin (n = 108), LS mean (SE)17.2 (1.0)
 LS mean difference (95% CI) from placebo2.14 (0.78, 3.50)
 P0.0024
WTDS, minutes§ 
 Placebo (n = 109), LS mean (SE)63.4 (2.9)
 Pregabalin (n = 108), LS mean (SE)45.8 (2.9)
 LS mean difference (95% CI) from placebo−17.5 (−23.3, −11.8)
 P< 0.0001
WTAS, minutes§ 
 Placebo (n = 109), LS mean (SE)9.19 (1.6)
 Pregabalin (n = 108), LS mean (SE)7.38 (1.6)
 LS mean difference (95% CI) from placebo−1.81 (−5.92, 2.30)
 P0.3841

Secondary PSG end points relating to sleep are shown in Table 2. PSG-recorded TST increased by >25 minutes after 4 weeks of pregabalin treatment compared with placebo treatment (week 4 TST: 396.2 versus 370.6 minutes). Other measures of sleep (LPS, sleep efficiency, NAASO, and SWS) also improved after 4 weeks of pregabalin treatment compared with placebo treatment (Table 2).

Patient-reported measures of sleep, tiredness, and pain.

Improvements in patient-rated sleep outcomes were reported over 4 weeks of treatment with pregabalin compared with placebo (Figure 2). Subjective WASO and subjective LSO were reduced during all 4 treatment weeks with pregabalin versus placebo treatment (week 4 difference: subjective WASO −10.3 minutes and subjective LSO −6.2 minutes). Similar to PSG-recorded TST, subjective TST increased by >25 minutes after 4 weeks of pregabalin versus placebo treatment. In addition, pregabalin treatment was associated with an improvement in patient-rated sleep quality (week 4 difference: +0.89 [95% CI 0.51, 1.26]; P < 0.0001) and a decrease in FM-related tiredness (week 4 difference: −0.70 [95% CI −1.08, −0.33]; P = 0.0003). As would be expected, daily pain decreased (improved) for patients treated with pregabalin versus treatment with placebo during all treatment weeks (week 4 difference: −0.52 [95% CI −0.90, −0.14]; P = 0.0084) (Figure 2F).

Figure 2.

Patient-rated assessment of sleep, tiredness, and pain during 4-week treatment with pregabalin and with placebo. Data are shown as the least-squares (LS) mean (95% confidence interval), with the LS mean difference (pregabalin − placebo) with the 95% confidence interval given below the data. sWASO = subjective wake after sleep onset; sTST = subjective total sleep time; LSO = latency to sleep onset; FM = fibromyalgia.

Association between PSG measures of sleep and patient-rated sleep, tiredness, and pain.

Exploratory analyses found a modest but significant correlation (ρ = <0.3) between certain PSG-recorded sleep measures and patient-rated pain and sleep quality (Table 3). Specifically, daily pain was negatively correlated with TST (−0.24) and positively correlated with LPS (+0.25) and TWT (+0.27). Sleep quality was negatively correlated with LPS (−0.26) and TWT (−0.21). Interestingly, no significant correlation was observed between PSG-recorded sleep stage and patient-rated pain, tiredness, or sleep quality.

Table 3. Spearman's correlation coefficients (ρ) between patient-rated pain, tiredness, and sleep quality and polysomnographic measures of sleep*
 Daily painTirednessSleep quality
  • *

    Patient-rated measures were scored on individual 10-point rating scales (n = 107) and are detailed in the Methods. WASO = wake after sleep onset; TST = total sleep time; LPS = latency to persistent sleep; TWT = total wake time; SWS = slow-wave sleep.

  • Significant correlations.

  • TWT = LPS + wake time during sleep + wake time after sleep.

  • §

    SWS = stage 3 + 4 sleep.

WASO0.125−0.029−0.040
 P0.1990.7670.683
TST−0.236−0.1380.159
 P0.0140.1560.101
LPS0.2490.268−0.256
 P0.0100.00520.008
TWT0.2700.169−0.214
 P0.0050.0830.027
Stage 1 sleep0.0520.002−0.080
 P0.5930.9800.412
SWS§−0.012−0.081−0.039
 P0.9020.4090.694

Safety and tolerability.

Overall, 106 patients reported 229 all-causality AEs during the study, 174 of which were reported by 73 patients (65.2%) when treated with pregabalin, and 55 were reported by 33 patients (29.7%) when treated with placebo (Table 4). No serious AEs were reported during the study. Patients treated with pregabalin had similar patterns of AEs considered treatment related compared with placebo, but more patients experienced treatment-related AEs with pregabalin compared with placebo (57.1% versus 20.7%; P < 0.01). One patient receiving placebo reported 1 severe AE (dizziness), which resulted in withdrawal; all other AEs were mild or moderate in intensity. Treatment-related AEs reported by ≥5% of patients while receiving pregabalin included dizziness (32 [28.6%] of 112), somnolence (23 [20.5%] of 112), headache (8 [7.1%] of 112), and nausea (7 [6.3%] of 112), compared with when receiving placebo: dizziness (11 [9.9%] of 111), somnolence (5 [4.5%] of 111), headache (7 [6.3%] of 111), and nausea (2 [1.8%] of 111).

Table 4. Overview of treatment-emergent AEs for the safety population (n = 119)*
 Pregabalin (n = 112)Placebo (n = 111)
  • *

    Values are the number (percentage) unless otherwise indicated. The sample size of 119 indicates all randomized patients who took ≥1 doses of study medication. AE = adverse event; SAE = serious AE.

  • P < 0.01 by chi-square analyses.

All causality  
 Number of AEs17455
 Patients with:  
  AEs73 (65.2)33 (29.7)
  SAEs00
  Severe AEs01 (0.9)
  Discontinuations due to AEs2 (1.8)1 (0.9)
  Dose reductions/temporary discontinuations due to AE28 (25.0)10 (9.0)
Treatment related  
 Number of AEs14037
 Patients with:  
  AEs64 (57.1)23 (20.7)
  SAEs00
  Severe AEs01 (0.9)
  Discontinuations due to AEs2 (1.8)1 (0.9)
  Dose reductions/temporary discontinuations due to AE28 (25.0)10 (9.0)

DISCUSSION

Disrupted sleep, daytime sleepiness, and tiredness are recognized and well-documented common features of FM (8–10). In the current study, patients with FM showed statistical and meaningful improvements in sleep maintenance, as demonstrated by a PSG-measured reduction in WASO of 19 minutes when treated with pregabalin (300–450 mg/day) for 4 weeks compared with treatment with placebo. Consistent with previous studies (14, 15, 19) and the use of pregabalin in the management of FM, patients also reported an improvement (0.5-point reduction) in daily pain when treated with pregabalin versus placebo. Patients also reported improvements in ratings of sleep and tiredness. This simultaneous improvement in sleep and pain over 4 weeks of treatment in patients with FM may contribute toward an overall improvement in patients' daily symptoms.

Fragmented sleep is an essential feature of FM (20–22), and the interrelationship between disrupted sleep and chronic pain (5, 23–25) is complex and poorly understood. The present study is the first to demonstrate that pregabalin treatment decreases PSG-measured sleep disruption, as measured by WASO, in patients with FM and sleep maintenance difficulties. Alongside this improvement in WASO are other objective and subjective measures of sleep as well as improvements in pain status. More specifically, the overall improvement in wake time during sleep but not wake time after sleep for patients treated with pregabalin further suggests the improvement primarily occurred during nighttime sleep, rather than through a reduction in early morning awakenings. Disruption in SWS has been a proposed etiology contributing to pain in FM for many years (25), as has disruption in sleep continuity via frequent arousals (9, 10, 20, 26). These are common in FM and may have an influence on bodily hypersensitivity (27, 28) and pain. In this study, treatment with pregabalin increased both TST and SWS while reducing sleep disruption (i.e., arousals) versus placebo treatment, consistent with pregabalin treatment in healthy subjects (17). It is possible that a decrease in SWS is mediated by increased sleep fragmentation, and similarly the SWS-enhancing effect of pregabalin may be an indirect effect of sleep consolidation. Sleep disturbance in FM is highly complex, and a number of other abnormalities have been reported in the literature, such as reduced stage 2 sleep spindles (29), a shorter duration of stage 2 sleep (8), and a high frequency of a cyclical alternating pattern (11, 30). Future studies are needed to measure more precisely the microstructure of sleep (e.g., spectral analyses, brief arousals) to understand the interrelationship between the myriad sleep abnormalities seen in FM. How these sleep measures are interrelated, as well as how they relate to pain and daytime fatigue and possibly even depression, also needs further investigation.

Subjective improvements in sleep using sleep quality diaries and sleep scales, such as the Medical Outcomes Study sleep subscale, alongside clinically meaningful improvements in pain have previously been reported by patients with FM treated with pregabalin (14–16). Post hoc analyses were carried out to explore any correlations between PSG recordings of sleep and patient estimates of pain and sleep quality. A modest but significant correlation was found between PSG-recorded measures of sleep and patient estimates of sleep quality, and also pain. Pain was correlated with TST, LPS, and TWT, although not with WASO. Our exploratory data also indicate that an improvement in sleep quality is modestly correlated with LPS and TWT, in line with 1 study of self-rated sleep quality in FM patients and certain PSG measures, including TST, sleep efficiency, and SWS (10). Given the exploratory nature of these correlations and the complex interactions between chronic pain and disturbed sleep (5, 23–25), further research is required before firm conclusions can be made and any clinical significance determined.

The AEs reported in this study are consistent with the known tolerability profile of pregabalin (14, 16, 19). The most frequently reported AEs (dizziness, somnolence, headache, and nausea) for patients receiving pregabalin were also frequently reported for patients receiving placebo. As would be expected, however, more AEs were reported with pregabalin treatment compared with placebo, although discontinuations due to AEs were similar. As reported in previous studies (14, 15), the sleep benefits associated with pregabalin did not countermand the AE of somnolence (reported by 20.5% of pregabalin-treated patients). Therefore, the extent to which somnolence (or sedative effects) of pregabalin influenced sleep when patients were taking pregabalin is unknown. Indeed, the incidence of dizziness and somnolence with pregabalin treatment despite reported benefits to sleep quality and duration has led other authors to speculate that patients with FM may be more sensitive to central nervous system–related AEs (14). Given the objective improvements in sleep duration and the small albeit statistically significant reduction in LSO recorded in the present study, it seems unlikely that increased somnolence alone can explain the beneficial effects of pregabalin on different measures of sleep.

The strict criteria used for the per-protocol primary end point analyses could be a limitation of the study; however, analyses of the ITT population recorded similar improvements in WASO (week 4 difference of −19.3 versus −19.2 minutes for per protocol). Daily dairies are sometimes considered unreliable, given problems with recall and compliance. However, compliance with daily diary recording was high (>90%) in the present study and data recorded were consistent with sleep and pain ratings recorded in similar patient populations (14, 15). We also found patient-rated variables of sleep to be consistent with PSG measures in this patient population, suggesting that patients' perceptions of sleep recorded in diaries were reliable for comparison with objective measures of sleep recorded in the laboratory. Treatment was only for 4 weeks, and although subjective benefits on sleep have been demonstrated over a longer time horizon by others (14, 15), longer-term PSG studies would be needed to determine if tolerance to the beneficial effects of pregabalin occurs on sleep measures in this population of patients. Finally, given that medications with a known influence on sleep were disallowed per the study protocol, further studies would be needed to determine if pregabalin provides additional improvements to sleep duration and quality for FM patients taking concomitant somnolence-inducing medications, such as those commonly used to treat insomnia.

In conclusion, this is the first PSG study to show that FM patients treated with pregabalin for 4 weeks at doses approved for the management of FM showed statistical and meaningful improvements in sleep duration compared with placebo treatment. Patients also reported decreased pain and tiredness during the same treatment period. Improvement in sleep and pain in patients with FM may together contribute toward an overall improvement in patients' daily symptoms and quality of life.

AUTHOR CONTRIBUTIONS

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. Roth 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. Roth, Bhadra, Whalen, Resnick.

Acquisition of data. Roth, Lankford, Bhadra.

Analysis and interpretation of data. Roth, Bhadra, Whalen, Resnick.

ROLE OF THE STUDY SPONSOR

This study was sponsored by Pfizer Inc. Pfizer Inc was involved in the design of the study and data analyses in collaboration with Dr. Roth. Listed authors from Pfizer Inc were involved in the drafting of the manuscript and approval of the final content. Publication of the article was not dependent on the approval of Pfizer, but on the approval of all the listed coauthors.

Acknowledgements

Medical writing support was provided by Karen Burrows, MPhil, of UBC Scientific Solutions. We also thank the investigators: Drs. Charles Samuels, Mohamed R. G. Hussain, Colin Shapiro, Andrei Khariouzov, Heike Benes, Andreas Winkelmann, Jonathan Flescher, Larry Grant Willis, Beth Emmie Safirstein, Bruce Glenn Rankin, Alan Jan Kivitz, David Joshua Seiden, Howard I. Schwartz, Brett Plyler, Tram K. Tran-Johnson, David W. Mayleben, Daniel Mark Gruener, and John Kyle Schwab.

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