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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURE
  10. Acknowledgments
  11. REFERENCES
  12. Supporting Information

Objective

To compare the efficacy, discontinuation rates, and safety of once nightly versus twice daily dosing of pregabalin in a community-based trial.

Methods

This multicenter, double-blind, 8-week randomized clinical trial compared the effects of 300-mg daily doses of pregabalin given either twice daily or once nightly for the treatment of fibromyalgia in 177 patients. The primary outcome was the comparison of end point mean pain scores derived from a daily diary.

Results

Both twice daily (88 patients randomized) and once nightly (89 patients) pregabalin significantly reduced the average severity of pain experienced by patients (P < 0.001 for both). Treatment-emergent adverse events were reported by significantly more patients in the twice daily group than those in the once nightly group (P = 0.023). There were no significant differences between the groups for the frequencies of individual adverse events (P > 0.05 for all). There was no significant difference in adverse events or efficacy in patients taking both pregabalin and a selective serotonin and norepinephrine reuptake inhibitor or selective serotonin uptake inhibitor.

Conclusion

While a nightly dosing schedule of pregabalin has been used by clinicians hoping to improve treatment, this study showed no significant difference (either beneficial or detrimental) between either treatment option. While there was a decrease in total patient-reported adverse events in the once nightly arm, the lack of specificity in relation to a particular adverse event suggested no real difference in adverse events.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURE
  10. Acknowledgments
  11. REFERENCES
  12. Supporting Information

Fibromyalgia affects between 3 million and 6 million people in the US, with a prevalence rate estimated between 1–2.1% ([1-3]). Fibromyalgia is more common among women, with a 6:1 ratio of affected women to men ([4]). Fibromyalgia is characterized by chronic widespread pain, disordered sleep, and fatigue. Since 1990, the American College of Rheumatology (ACR) has defined fibromyalgia as widespread pain for >3 months with pain on palpation at ≥11 of 18 specified tender points ([5]). The 2010 ACR preliminary diagnostic criteria for fibromyalgia consider both widespread pain and the severity of concomitant symptoms (fatigue, cognitive symptoms, waking unrefreshed, and amount of other symptoms) to determine a fibromyalgia diagnosis ([6]).

The current treatment for fibromyalgia is symptom based and aims to alleviate pain, increase restorative sleep, and improve physical function. Nonpharmacologic therapies include education, exercise, and psychological treatments ([7]). Pharmacologic treatment commonly includes pregabalin, duloxetine, and milnacipran among other serotonin norepinephrine uptake inhibitors (SNRIs), selective serotonin uptake inhibitors (SSRIs), muscle relaxants, hypnotics, and analgesics ([7, 8]). No single agent has consistently demonstrated efficacy across all symptom domains ([8]), and almost all patients experience adverse events ([9]).

Pregabalin is an α2δ ligand approved by the US Food and Drug Administration (FDA) for the treatment of fibromyalgia. Pregabalin is a dose-dependent medication where 300 mg to 600 mg per day can only achieve a ≥50% responder rate. In clinical trials, most people taking pregabalin and those in placebo groups experienced adverse events. This is not surprising considering the large range of symptoms often associated with fibromyalgia. The most common adverse events included somnolence, dizziness, and weight gain ([9]).

The package insert information for pregabalin recommends fixed dosing beginning at 75 mg twice daily, increasing to 150 mg twice daily over 1 week, and increasing to 225 mg twice daily. Flexible dosing of pregabalin in postherpetic neuralgia reduced discontinuation, allowed higher dosing, and resulted in slightly greater pain relief ([10]). Clinicians are commonly using a go low, go slow approach in their patients, which may improve tolerability and adherence ([11]). Clinicians are also using nightly dosing, hoping to reduce the impact of the pregabalin-induced somnolence and possibly improving sleep.

It has been proposed that nightly dosing would have similar pain relief to twice daily dosing, decrease early terminations (defined as increased course completion or reduced early termination), have fewer side effects, and be more likely to improve sleep ([12]). This study aimed to explore the efficacy and safety of a 300 mg/day dosage of pregabalin administered once nightly and titered slowly compared with a similar total dose of 150 mg taken twice daily per the package insert instructions.

Box 1. Significance & Innovations

  • Clinicians in the community often consider a go low, go slow approach to fibromyalgia medications such as pregabalin. This community-based trial showed comparable safety and efficacy to the twice daily approach suggested in the package insert.
  • This trial showed the safety of combined pharmacotherapy with pregabalin and a selective serotonin uptake inhibitor or a serotonin norepinephrine uptake inhibitor for fibromyalgia. There were insufficient numbers to study efficacy with combined pharmacotherapy.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURE
  10. Acknowledgments
  11. REFERENCES
  12. Supporting Information

Study design

This 9-week multicenter, randomized, double-blind study was conducted between May 2010 and July 2012 at 9 study centers across the US. The study was conducted in accordance with the Declaration of Helsinki and received central institutional review board approval by Western Institutional Review Board.

The patients were randomly assigned to receive either a twice daily or once nightly dose of pregabalin (supplied by Pfizer). Patients were randomized using a random number generator to assign patients to either group. Each group entered a 1-week screening phase in which they recorded daily pain scores via a numerical rating scale (NRS) to establish a baseline measure. The patients had office visits at the screening, baseline (week 0), week 2, week 4, week 8, and week 9 (if applicable).

At baseline, the twice daily group received the following dosing schedule: 75 mg twice daily during week 1, 150 mg twice daily during weeks 2–8, and a 75-mg twice daily taper dose during week 9. The once nightly group was given a placebo pill for morning doses and received a nightly dose of 75 mg during week 1, 150 mg during week 2, 225 mg in week 3, 300 mg for weeks 4 through 8, and taper doses of 150 mg during days 57–60 and 75 mg during days 61–63. The week 9 period was used solely for tapering medication. Patients wishing to continue receiving pregabalin to treat fibromyalgia after the study ended their study participation at week 8 and were not required to taper medication during week 9. No outcome information was collected during week 9.

Study patients

Women ages ≥18 years who met the 1990 ACR criteria for fibromyalgia syndrome (FMS) ([5]) were eligible to enter the study. The eligible women were required to have a score of ≥4 on an NRS for pain (NRS-pain) at both the screening and baseline visits and were also required to complete at least 5 NRS-pain daily diary entries during the screening week. Patients with a history of pregabalin use were excluded if their discontinuation of pregabalin was a result of an adverse reaction to pregabalin. Patients who discontinued pregabalin for other reasons were allowed to enter the study, provided they had been discontinued for at least 30 days.

The enrolled patients underwent a physical examination, blood tests, and a urine pregnancy test, if applicable. Patients were excluded if they were not ambulatory, had an estimated creatinine clearance rate of ≤60 ml/minute (using the Cockroft-Gault equation), were pregnant, or had significant kidney or liver disease (patients with other chronic pain conditions were allowed to enroll). Women who were not postmenopausal were tested to confirm that they were not pregnant. Women of childbearing potential were required to use at least 1 method of appropriate contraception (including barrier or hormonal) as discussed with their study doctor. All patients gave written and informed consent. All consent documents and outcome tools were provided in English or Spanish.

Patients were prohibited from using opioids or gabapentin during the study; tramadol was permitted. Patients were allowed to concomitantly use at most 1 class of medication specifically used to treat fibromyalgia-related pain. Medications used for anything other than analgesic purposes were allowed, provided that the patient had been taking a stable dose for at least 30 days. Patients were not allowed to initiate a new medication regimen during the course of the study and were instructed to maintain their normal daily routines.

Efficacy assessments

The schedule of outcome assessments is shown in Supplementary Appendix A (available in the online version of this article at http://onlinelibrary.wiley.com/doi/10.1002/acr.22111/abstract). At the end of each day, the patients rated the intensity of FMS pain during the prior 24 hours in a daily paper diary using an 11-point NRS, where 0 = no pain and 10 = intolerable pain. Patients also completed the NRS-pain questionnaires at the screening, baseline, and each day during the week-long screening period. The daily NRS-pain score was used as the primary measure.

To more fully describe the core symptoms of FMS, a number of secondary measures were used. At the end of each week, in addition to the daily NRS-pain score, patients completed an extended questionnaire that included a visual analog scale (VAS) for determining pain, fatigue, trouble sleeping, and waking unrefreshed over the prior week. The patients also completed a morning stiffness scale that categorically lists the duration of morning stiffness as no stiffness, <30 minutes, 30 minutes to 1 hour, 1 to 2 hours, 2 to 4 hours, 4 to 8 hours, and >8 hours.

Patients completed the Revised Fibromyalgia Impact Questionnaire (FIQR) ([13]) during randomization and at week 8. The Patient Global Impression of Change (PGIC) was measured on a scale ranging from no change to a great deal better and was rated at week 4 and at the end point. The Manual Tender Point Survey ([14]) was administered by a physician at the screening and end point.

Tolerability and safety assessments

All spontaneously reported or observed treatment-emergent adverse events were recorded at each study visit. The dates the adverse event began and ended were recorded, as were the seriousness, severity, and frequency of the adverse event and the relationship to the study drug and the action taken by the subject and physician.

Statistical analysis

The sample sizes for this study were determined assuming a noninferiority equivalence design, which requires 86 subjects per treatment group for 90% power and an effect size of 0.5 to determine the significance between means. The primary outcome is the least square mean of the daily NRS-pain scores. Analysis of covariance models were used to compare changes in pain, fatigue, sleep, waking unrefreshed, and morning stiffness from baseline between the 2 treatment groups. The models had effects for the treatment, center, and baseline scores. Categorical end points (≥30% and ≥50% responder rates, percentages with improved PGIC) were analyzed using Cochran-Mantel-Haenszel or logistic regression methods with the treatment, center, and baseline pain scores as covariates. All patients who received at least 1 dose of the study medication were included in the intent-to-treat analysis. End point analyses were based on the last observation carried forward (LOCF) method to impute missing values. Data were not imputed for patients who did not have any postbaseline data for a given variable; rather, such subjects were treated as missing in the analysis.

Subjects who received at least 1 dose of pregabalin were included in the safety evaluation. Safety data were described using descriptive statistics. The descriptive analyses included here characterize the study population in terms of all key dependent, independent, and control variables (Table 1). Categorical variables are shown as the percentage and number of patients in each category. Continuous variables are summarized by providing the mean ± SD for each. Statistical tests of significance for differences between baseline and the end point were performed for each arm and for differences in the end point score. A critical P value less than or equal to 0.05 was used as the threshold for statistical significance.

Table 1. Baseline characteristics of the patients*
 Twice daily group (n = 88)Once nightly group (n = 89)
  1. Values are the mean ± SD unless otherwise indicated. There was no statistical difference between the groups.

Age, years49.3 ± 12.949.8 ± 11.4
Race, no. (%)  
White87 (98.8)83 (93.3)
African American0 (0)4 (4.5)
Hispanic1 (1.2)2 (2.2)
Height, inches63 ± 464 ± 4
Weight, pounds191 ± 53189 ± 49
Body mass index, kg/m233.6 ± 9.732.7 ± 8.4
Fibromyalgia duration, months49 ± 6645 ± 52

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURE
  10. Acknowledgments
  11. REFERENCES
  12. Supporting Information

Patient characteristics

Of the 198 subjects who were screened, 177 were randomized and took at least 1 dose of study medication (Figure 1). A majority of screening failures were due to an inability to meet the inclusion or exclusion criteria, in particular the use of or refusal to withdraw from prohibited medications. Withdrawing consent during the screening period was another significant contributor. The baseline characteristics were similar across the treatment groups (Table 1). Most study participants were white (96%), with only 4 African American and 3 Hispanic participants. Participants in this study were relatively overweight, with a median body mass index within the moderate obesity range (33.2 kg/m2). The mean duration of FMS was ∼4 years, with over 53% of subjects having been diagnosed within 2 years of entering the study.

image

Figure 1. Diagram of patient flow. The diagram represents the outcome of all patients entered into the screening. BID = twice daily; HS = once nightly; AE = adverse event.

Download figure to PowerPoint

Tolerability and safety

A total of 124 patients (70.0%) completed the 8-week study (Figure 1). In the twice daily treatment arm, 64 patients completed the study and 24 patients withdrew early. Adverse events were the reason given for 20 withdrawals, with withdrawal of consent (2 patients), lack of transportation (1 patient), and lack of efficacy (1 patient) being the other reasons for withdrawal. In the once nightly treatment arm, 60 patients completed the study and 29 patients withdrew. The primary reasons for withdrawal included adverse events (21 patients), lost to followup (4 patients), withdrawal of consent (2 patients), lack of efficacy (1 patient), and protocol violations (1 patient). The comparison of completion rates between the 2 arms showed no significant difference in either the number of patients completing the study or the number withdrawing because of adverse events (P > 0.05 for both).

A comparison of the most common adverse events is shown in Table 2. Treatment-emergent adverse events were reported by most patients in each group (84% in the twice daily group and 70% in the once nightly group), but significantly more patients in the twice daily group experienced adverse events (P = 0.023). Dizziness was the most common adverse event, occurring in 36 patients overall (20.3%; 18 patients in each trial arm). Fatigue, cognitive difficulties (including brain fog, memory loss, and confusion), and edema were also among the most common adverse events. The adverse event of weight gain was self-reported by 11 patients, but an analysis of their weight at each visit showed that only 1 subject met the FDA criteria of a 7% gain in weight. The mean weight gain for all participants was 1.9 pounds (1.4% gain in weight for the twice daily group and 0.4% loss in weight for the once nightly group; P < 0.05). There were no significant differences between the arms for the frequencies of individual adverse events (P > 0.05 for all).

Table 2. Summary of the most frequently reported treatment-emergent adverse events*
 Twice daily group (n = 88)Once nightly group (n = 89)
  1. Values are the number of affected patients. Included are adverse events reported by at least 5% of patients in either arm. There was no significant difference in the frequency of individual adverse events (P > 0.05 for all).

Dizziness1818
Headache67
Blurred vision78
Fatigue1014
Edema117
Somnolence84
Cognitive1413
Nausea37
Euphoria51
Vertigo83

Concomitant medication use

The use of concomitant medication was evenly distributed between the 2 treatment arms. The most common medications taken were nonsteroidal antiinflammatory drugs (NSAIDs; 32% of subjects), SSRIs (23% of subjects), and SNRIs (17% of subjects). A total of 23 subjects (7 from the twice daily group and 16 from the once nightly group), representing 12.5% of the study population, were not taking any medications for the treatment of their fibromyalgia.

Because fibromyalgia has a range of concomitant symptoms, patients may often take multiple medications. Approximately 45% of the subjects were taking only 1 medication, with 22% taking 2 medications, and >21% taking ≥3 different classes of medications. There was no significant difference in efficacy or adverse event frequency among patients taking no concomitant medication, 1 therapy, or a combination of other therapies during the treatment period.

This study is one of the few controlled studies to permit the use of certain concomitant medications for the treatment of fibromyalgia, allowing us to follow the safety profile of possible drug–drug interactions. We compared the adverse event–related early terminations of patients not taking concomitant medications to those taking an additional SSRI or SNRI and to those taking an additional NSAID or cyclooxygenase 2 inhibitor. Even though the patient data for this comparison were limited, enough data points existed for a statistical comparison. There was a significant decrease in the risk of early termination due to NSAID use compared with those patients not taking other medications. There was no difference for those patients taking an SSRI or SNRI.

Efficacy

The primary efficacy assessment for this study was the daily NRS-pain score diary. Using the LOCF method to account for missing data and patient withdrawal, the mean ± SD pain score in the twice daily arm dropped from 7.14 ± 1.70 to 5.27 ± 2.7 (P < 0.001). In the once nightly arm, the mean ± SD baseline score dropped from 7.18 ± 1.76 to 4.96 ± 2.6 (P < 0.001). There was no significant difference between the mean scores at baseline and week 8 or the difference of the reduction from baseline to week 8 (Figure 2).

image

Figure 2. Daily numerical rating scale (NRS) pain score from the patient diaries. Using the last observation carried forward (LOCF) method to account for missing data and patient withdrawal, the mean ± SD pain score in the twice daily (BID) arm dropped from 7.14 ± 1.70 to 5.27 ± 2.7 (P < 0.001). In the once nightly (HS) arm, the mean ± SD baseline score dropped from 71.8 ± 1.76 to 4.96 ± 2.6 (P < 0.001).

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The responder analysis of the daily NRS-pain score was calculated using both the generally accepted improvement as ≥50% from baseline and a less stringent difference of ≥30% improvement from baseline, which has been shown to be a clinically meaningful improvement ([15]). The responder score was based on a continuous 7-day average. In the twice daily arm, 35 patients (39.7%) showed at least 30% improvement and 25 patients (28.4%) showed at least 50% improvement. In the once nightly arm, 41 patients (46.1%) showed at least 30% improvement and 27 patients (30.3%) showed at least 50% improvement. There was no statistical significance between either arm in the proportion of responders. In addition, on day 32, there was a drop in the number of patients responding to medication in both arms. Because the responder analysis was based on a 7-day average, the average scores for all patients from day 26 to day 32 increased. We offer no explanation for this event (Figure 3).

image

Figure 3. Results of the continuous responder analysis. The responder score was based on the difference of the average of the 7-day screening period and a continuous 7-day average during the study. A ≥30% reduction in mean pain score from baseline represents a clinically meaningful response. BID = twice daily; HS = once nightly.

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The mean scores in the FIQR were statistically similar between the twice daily and once nightly groups at baseline (P = 0.89). In the twice daily treatment arm, the mean ± SD score dropped significantly from 58.5 ± 20.8 at baseline to 46.5 ± 24.6 at week 8 or termination (P < 0.001). The once nightly treatment arm saw a similar mean ± SD drop from 59.5 ± 19.2 to 45.5 ± 24.5 (P < 0.001). The change in scores was similar in each group (P = 0.9), meaning that both treatment groups had the same overall reduction in the FIQR score. A responder analysis for the FIQR was also completed. Using the full FIQ, a drop in score of 14% indicates the minimum clinically important difference (MCID) ([16]). There are no published studies using the MCID for the FIQR, but because the tools have near identical properties, using 14% represents a reasonable measure. In the twice daily and once nightly groups, 44 subjects (51%) and 42 subjects (49%) were considered responders, respectively. The rates at which subjects responded were statistically similar (P = 0.82).

The weekly VAS scores for pain, fatigue, difficulty sleeping, and waking unrefreshed were obtained on a weekly basis. The results are shown in Table 3. In all instances, there was a significant drop in score from baseline to week 8 (P values are shown in Table 3). There was no statistical difference in the scores between each arm (P = 0.5 for VAS pain, P = 0.73 for VAS fatigue, P = 0.49 for VAS difficulty sleeping, and P = 0.64 for VAS waking unrefreshed).

Table 3. Baseline and end point values for outcome measures*
ParameterOverall mean ± SD at baselineTwice daily end pointOnce nightly end point
NValueNValue
  1. Values are the mean ± SD unless otherwise indicated. Lower numbers suggest improvement for all parameters except for Patient Global Impression of Change (PGIC), for which higher numbers suggest improvement. Baseline values were based on all patients included in each analysis. VAS = visual analog scale; FIQR = Revised Fibromyalgia Impact Questionnaire Revised; WPI = Widespread Pain Index; MTS = Manual Tender Point Survey.

  2. a

    Significant drop from baseline (P < 0.05); no significant difference between arms.

Pain diary (range 0–10)6.94 ± 1.54885.27 ± 2.7a864.97 ± 2.6a
VAS fatigue (range 0–100 mm)79.5 ± 18.88853.1 ± 30.1a8952.0 ± 30.2a
VAS sleep disturbance (range 0–100 mm)71.6 ± 24.38843.5 ± 33.0a8941.5 ± 33.6a
VAS waking unrefreshed (range 0–100 mm)78.5 ± 23.08848.6 ± 34.4a8948.2 ± 34.1a
FIQR (range 0–100)59.0 ± 19.98646.5 ± 24.6a8545.5 ± 24.5a
14% responders, no. (%)8644 (51)8542 (49)
WPI (range 0–19)12.0 ± 8.7809.0 ± 4.6a808.4 ± 4.8a
Symptom severity (range 0–12)8.9 ± 8.5806.5 ± 2.8a806.5 ± 3.1a
MTS (range 0–18)16.6 ± 7.98813.1 ± 4.9a8612.2 ± 5.3a
Morning stiffness (range 1–7)2.90 ± 1.36792.48 ± 1.5a802.2 ± 1.2a
PGIC (range 1–7)834.8 ± 1.5764.3 ± 1.8

The duration of morning joint stiffness was measured once weekly in the patients' diaries. The average score of the twice daily group decreased from 2.84 at baseline to 2.48 at week 8 (P = 0.045). The average score of the once nightly group decreased from a baseline score of 2.98 to 2.20 (P = 0.0002). Significance was measured using Wilcoxon's signed rank test. There was no significant difference when comparing the difference between the twice daily and once nightly groups.

The PGIC data were collected from each patient during the week 4 visit and during the week 8/early termination (ET) visit. At the week-4 visit, 63.9% of patients in the twice daily group and 64.6% of patients in the once nightly group reported that their condition was “moderately better,” “better,” or “a great deal better.” At week 8, the patient responses were 50.6% and 53.9% in the twice daily and once nightly groups, respectively. At week 4, 41.9% of patients in the twice daily group and 40% of patients in the once nightly group described their condition as either “better” or “a great deal better.” These proportions dropped to 27.7% and 28.9% in the twice daily and once nightly groups, respectively, at the week 8/ET visit. This decrease from week 4 to week 8/ET was expected because the week 8 data included early termination patients who did not make it to week 8 due to adverse events and a lack of efficacy. The week 4 data did not include data from patients that terminated early, unless they remained in the trial through the week 4 visit before leaving the study. Wilcoxon's rank sum test showed no significant difference between the 2 groups.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURE
  10. Acknowledgments
  11. REFERENCES
  12. Supporting Information

This study aimed to compare the effects of the recommended dosing instructions of twice daily administration of pregabalin on patient outcomes compared with once nightly dosing. In both the twice daily and once nightly treatment arms, patients showed significant improvements in pain relief, as measured by a daily NRS-pain score diary. Significant improvements were also seen for pain, fatigue, sleep disturbance, and waking unrefreshed. Patients experienced a significant improvement when measuring their quality of life using the FIQR. There was no reduction in the number of patients withdrawing from treatment in the twice daily group compared with the once nightly group because both arms had a similar number of patients withdraw from the trial due to adverse events.

There was a significant decrease in risk of early termination due to NSAID use compared with those patients taking no other medications. It is possible that NSAID use mitigated the effect of common adverse events, but the exact nature of this cause was unknown. Even though the numbers were large enough for significant measurement, larger studies specifically examining this effect may be useful for our understanding of its occurrence.

The only measured difference between the trial arms was in the total number of patients experiencing an adverse event. The once nightly arm had significantly fewer patients experience treatment-related adverse events; however, there was no specific reduction in a particular adverse event. While there was a decrease in total patient-reported adverse events in the once nightly arm, the nonspecificity in relation to a particular adverse event suggested no real difference in adverse events.

The study object and hypothesis were that once nightly treatment with pregabalin would reduce early termination, have fewer side effects, and be more likely to improve sleep compared with the recommended twice daily dosing schedule. While there was no improvement in continuation rates and in the sleep score, there was a measurable difference in the number of patients experiencing adverse events.

Because a host of randomly controlled clinical trials have been published, specifically at the 300 mg/day dosage, we were able to compare some basic study results with a meta-analysis of 5 studies performed in 2010. The current study results for trial completion, withdrawal due to adverse events, mean difference in daily diary score, and the rate of ≥30% and ≥50% responders all compared similarly to the meta-analysis values. Weight gain is one of the more frequent patient concerns about pregabalin. Other studies have shown that ∼10% of patients experience a 7% increase in weight gain ([9]); in the current study, while 11 patients (6%) self-reported weight gain, only 1 patient met the defined 7% criteria. There was a statistical significance in the amount of weight gained in the twice daily group compared with the once nightly group, a possible consideration when prescribing for patients also in need of weight management.

This was an investigator-initiated community-based trial that tried to mimic the situations that physicians face in daily practice and was one of the few studies that allowed concomitant medication use. However, the study was limited because there was no true placebo arm for comparisons and there was only an 8-week observation window. Because 96% of the patients were white, this study may not be widely applicable to other racial or ethnic groups. Additionally, the timeframe of this study overlapped with the introduction of the 2010 ACR criteria for diagnosing fibromyalgia. While this information was included as a secondary outcome, only 86% of the subjects would have met the new definition for fibromyalgia. With the recent introduction of the 2010 criteria, data are limited in comparison, making it difficult to compare our study data to published data. Studies have published conflicting results in indicating either an overestimation ([17]) or underestimation ([18]), with anecdotal clinical experience suggesting overestimation. More thorough and larger-scale studies examining the relationship between the 1990 and 2010 criteria need to be undertaken to understand our results in context.

While a nightly dosing schedule of pregabalin has been used by clinicians hoping to improve treatment, this study showed no significant difference (either beneficial or detrimental) between either treatment option. While there was a decrease in patient-reported adverse events in the once nightly arm, the nonspecificity in relation to a particular adverse event makes the claim that once nightly treatment reduces adverse events a dubious one.

There is no comparable difference when treating fibromyalgia with 300 mg of pregabalin either twice daily or once nightly. Because the cost of treatment of pregabalin is usually determined by the number of pills and not the dose dispensed, once nightly dosing may reduce the cost. These study results give clinicians and patients options when choosing a personalized dosing schedule.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURE
  10. Acknowledgments
  11. REFERENCES
  12. Supporting Information

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. Silverman 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. Nasser, Silverman.

Acquisition of data. Nasser, Kivitz, Maricic, Silver, Silverman.

Analysis and interpretation of data. Nasser, Silverman.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURE
  10. Acknowledgments
  11. REFERENCES
  12. Supporting Information

Pfizer participated in the study design. Pfizer did not participate in the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit the manuscript for publication. Publication of this article was not contingent upon approval by Pfizer.

Acknowledgments

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURE
  10. Acknowledgments
  11. REFERENCES
  12. Supporting Information

The authors would like to thank Jim Mirocha for his statistical analysis and data interpretation. We thank Mila Manajan for contributions to the design, study management, and data collection. We thank the following investigators who participated and contributed to this trial: Nazanin Firooz, MD (West Hills, California), Wesley Mizutani, MD (Huntington Beach, California), Richard Olson, MD (Rockford, Illinois), Ronald Rapoport, MD (Fall River, Massachusetts), and William Shergy, MD (Huntsville, Alabama).

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURE
  10. Acknowledgments
  11. REFERENCES
  12. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. ADDITIONAL DISCLOSURE
  10. Acknowledgments
  11. REFERENCES
  12. Supporting Information

Additional Supporting Information may be found in the online version of this article.

FilenameFormatSizeDescription
ACR_22111_sm_SupplAppA.docx14KSupplementary Appendix A: study schedule of outcome questionnaires

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.