Trial Design and Oversight

In this randomized, double-blind, placebo-controlled trial, we compared pregabalin with placebo for the treatment of sciatica. The trial was conducted in accordance with the Consolidated Standards of Reporting Trials guidelines.19 The trial protocol20 and statistical analysis plan21 have been published previously and are available with the full text of this article at NEJM.org. Ethics approval for the trial was granted by the University of Sydney Human Research Ethics Committee. The authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. The trial was initiated by the investigators and was funded by the National Health and Medical Research Council of Australia. Pfizer Australia supplied the pregabalin capsules and matching placebo capsules at no cost and reviewed the manuscript before it was submitted; Pfizer Australia had no other involvement in either the conduct or the reporting of the trial. The investigators maintained full autonomy in the design, conduct, and reporting of the trial.

Eligibility and Recruitment

Patients who visited a trial clinician as an outpatient in New South Wales, Australia, for moderate-to-severe sciatica were considered for trial recruitment. Potential participants could also be screened by clinicians who were not involved in the trial (e.g., physiotherapists) and would then be referred to a trial clinician. Sciatica was defined in this trial as radiating pain into one leg below the knee, accompanied by nerve-root or spinal-nerve involvement as indicated by the presence of at least one of the following clinical features: dermatomal leg pain, myotomal weakness, sensory deficits, or diminished reflex, as determined by the trial clinician. Eligibility criteria also included a current episode of sciatica that had been present for a minimum of 1 week and a maximum of 1 year, leg pain that had been at least moderate in intensity or had resulted in at least moderate interference with daily activities during the previous week (as measured by modifications of items 7 and 8 in the Medical Outcomes Study 36-Item Short-Form Health Survey22), an age of at least 18 years, and either an adequate understanding of English or the availability of interpretation services for the participant to complete the trial.

Patients were excluded from participation in the trial if they had a known or suspected serious pathologic condition of the spine (e.g., the cauda equina syndrome); if they were pregnant, were breast-feeding, or were planning conception (men [with their partners] and women) during the first 8 weeks of the trial; if they were considering or planning to undergo spinal surgery or other interventional procedures (e.g., a glucocorticoid injection) for sciatica during the first 8 weeks of the trial; if they had contraindications to pregabalin; if they were taking medication for neuropathic pain, antiepileptic medication, antidepressant medication, or sedative medication and were unable to cease taking such medications; or if they had severe depression or suicidal thoughts (a score of ≥20 on the Patient Health Questionnaire [scores range from 1 to 27, with scores of ≥20 indicating severe depression]23 or a score of 2 or 3 on question 9 [regarding suicidal thoughts] of the questionnaire). Trained trial clinicians explained the trial to each patient, obtained written informed consent from each patient, advised the research team that patients had been enrolled, and provided pregabalin or placebo to the patient.

Randomization and Blinding

The randomization schedule was generated by an independent investigator by means of a computer-derived random-number sequence. Pregabalin capsules and matching placebo capsules were packaged in white, opaque, sealed containers at a central pharmacy according to the randomization schedule and were then supplied to the trial clinicians. All the research staff, statisticians, trial clinicians, and patients were unaware of the trial-group assignments during recruitment, data collection, and analysis.

Trial Regimen and Procedures

The trial regimen consisted of pregabalin or placebo as well as medical advice (e.g., advice to patients to avoid bed rest and to remain active and reassurance regarding the cause of symptoms and that symptoms usually diminish over time).24 Each patient received up to nine weekly consultations with the trial clinician to begin taking the assigned regimen, to monitor progress, and to adjust the dose of pregabalin or placebo over the course of the first 8 weeks of the trial. The starting dose was 150 mg of pregabalin per day (75 mg twice daily) or matching placebo. The dose was adjusted to a maximum of 600 mg per day (300 mg twice daily), depending on the patient’s progress and the side effects at each dose level as assessed by the trial clinician. In the standard trial regimen, the dose was increased each week for 3 weeks, from the starting dose of 150 mg per day to 300 mg per day, then to 450 mg per day, and then to a maintenance phase that was initiated at a dose of 600 mg per day for 4 weeks; subsequently, over the course of 1 week, the dose was gradually decreased and the regimen discontinued. If an adequate decrease in leg pain (e.g., leg pain rated as 0 or 1 for a minimum of 72 hours) was reported before the 8-week period was completed, the decrease in dose to subsequent cessation of the trial regimen could take place earlier.

Patients could receive additional medical care if it was considered to be suitable by the trial clinician. Such care could include physical therapies and could also include other analgesic medications (except for adjuvant analgesic agents), which would ideally be prescribed in accordance with the World Health Organization pain ladder.25 Trial clinicians were asked not to prescribe certain medicines (antiepileptic medications, selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, tricyclic antidepressants, topical lidocaine, and benzodiazepines) or to schedule interventional procedures. If the use of such medications or procedures was unavoidable, patients were permitted to stop taking pregabalin or placebo but could remain in the trial.

Outcomes and Data Collection

The primary outcome was the average leg-pain intensity score over the course of the previous 24 hours (on a numerical pain-rating scale from 0 to 10, with 0 indicating no pain and 10 the worst possible pain; clinically important difference, 1.5 points), as assessed at 8 weeks; the leg-pain intensity score was also evaluated at week 52, a secondary time point for the primary outcome. Secondary outcomes were the extent of disability as measured on the Roland Disability Questionnaire for Sciatica (scores range from 0 to 23, with higher scores indicating greater disability; clinically important difference, 3 points), back-pain intensity (on a scale from 0 to 10, with higher scores indicating more pain), global perceived effect (current symptoms as compared with baseline, on a scale from −5 [vastly worse] to 0 [unchanged], to +5 [completely recovered]), quality of life as measured on the Short Form Health Survey 12, version 2 (on a scale from 0 to 100, with higher scores indicating better quality of life), workplace absenteeism, and health care utilization (i.e., the use of health services and medicines).

Data on serious adverse events and adverse events were collected. A serious adverse event was defined as any adverse event or reaction, regardless of causality, that resulted in death, was life-threatening, necessitated hospitalization, or was considered to be an important medical event. Other data that were collected included baseline demographic information, the PainDETECT score to screen for neuropathic pain,26 satisfaction with the trial regimen, adherence to the prescribed doses of the trial regimen, and awareness of the trial-group assignment (patients were asked to report the trial group to which they believed they had been assigned). Outcomes were assessed at weeks 2, 4, 8 (primary time point of the primary outcome), 12, 26, and 52 (secondary time point of the primary outcome) either by means of telephone contact with the patients by trained trial researchers or by means of questionnaires that were completed by the patients directly through a secure online database.

Statistical Analysis

We determined that a minimum sample of 204 patients (102 per group) would be required to provide the trial with 90% power to detect a clinically important between-group difference of 1.5 points in the leg-pain intensity score on the 10-point numerical pain-rating scale at week 8 and to detect a clinically important between-group difference of 3 points out of 23 in the extent of disability on the Roland Disability Questionnaire for Sciatica21 at week 8. Assumptions for the leg-pain intensity score and the extent of disability included a two-sided alpha level of 0.05 and a mean standard deviation of 2.5 points.27 The estimated sample size would also allow for a withdrawal rate of 10% and a rate of nonadherence to the trial regimen of 20%.

Analyses were performed independently by two statisticians by means of dummy-group assignment and were based on the intention-to-treat principle. Two-sided P values of less than 0.05 were considered to indicate statistical significance. The primary outcome was analyzed with the use of repeated-measure linear mixed models that included all the leg-pain scores that were reported after randomization, with the baseline leg-pain score and the duration of leg pain as covariates. Adjusted mean differences were tested at week 8 (primary time point for the primary outcome) and at week 52 (secondary time point for the primary outcome). Within-patient correlations were modeled with the use of a compound symmetry covariance matrix. Similar analyses were applied to the secondary outcomes of extent of disability, back-pain intensity, global perceived effect, and quality of life. Unadjusted means and standard deviations were calculated for the primary outcome and for the secondary outcomes of extent of disability, back-pain intensity, global perceived effect, and quality of life.

Workplace absenteeism and health care utilization were calculated as the cumulative number of hours and the cumulative number of health services reported, respectively, between baseline and week 52, and were analyzed by means of analysis of covariance, with adjustment for the duration of leg pain at baseline. The use of medicines (excluding the trial regimen) was calculated as the percentage of patients who were reported to be taking at least one medicine for their leg pain and was compared between the trial groups with the use of Fisher’s exact test. The number and incidence of serious adverse events and adverse events were reported descriptively, and the percentages of patients in each trial group who had at least one event were compared with the use of Fisher’s exact test. Demographic and clinical characteristics at baseline, adherence to the trial regimen, assessment of awareness of the trial-group assignment, and satisfaction with the trial regimen were reported descriptively. Multiple imputations were not required because less than 10% of the primary-outcome data were missing.

Sensitivity analyses of the primary outcome and secondary outcomes (extent of disability, back-pain intensity, global perceived effect, and quality of life) were conducted by means of repeated-measure linear models with the use of heterogeneous compound symmetry and spatial power covariance. A subgroup analysis was conducted to assess whether the presence of neuropathic pain features, which had been identified by means of the PainDETECT questionnaire at baseline, was a modifier of treatment effect. In-depth statistical methods have been presented in the published statistical analysis plan.21 Post hoc analyses included the addition of sex as a covariate to the main model and the analysis of workplace absenteeism in only those patients who had been employed at baseline. Analyses were performed with the use of SAS software, version 9.4 (SAS Institute).