Introduction
Neuropathic pain results from damage to the nervous system and may be classified as central or peripheral, depending on the site of the lesion. Central neuropathic pain is estimated to occur in approximately 40% of patients following spinal cord injury; 27% of patients with multiple sclerosis; and 8% of patients following stroke. Such pain is often severe, chronic, and refractory to pharmacologic treatment, which may include anticonvulsants, antidepressants, analgesics, and antispasticity medications. As a result, central neuropathic pain has a substantial negative impact on patient function and overall quality of life.
Pregabalin, an α2δ ligand, is approved for the treatment of peripheral neuropathic pain in the European Union and Japan, and for peripheral neuropathic pain due to diabetic peripheral neuropathy (DPN) or postherpetic neuralgia (PHN) in the United States.Pregabalin is also approved for the treatment of central neuropathic pain in the European Union and, more recently, for the treatment of neuropathic pain associated with spinal cord injury in the United States.
Studies of pregabalin for the treatment of central neuropathic pain, however, have been limited to double-blind studies of 4–17 weeks in duration. The purpose of the current 53-week, open-label study was to assess the long-term safety and tolerability of pregabalin in Japanese patients with central neuropathic pain due to spinal cord injury, multiple sclerosis, or cerebral stroke. The long-term efficacy of pregabalin in this population was also examined.
Patients and methods
inclusion and exclusion criteria
Patients with central neuropathic pain due to spinal cord injury were recruited from a previous short-term trial of pregabalin.
To be eligible for participation in the current 53-week study, patients must have completed all efficacy assessments upon conclusion of the previous short-term study. The previous study was conducted in ten countries, but only Japanese patients were recruited for the current study.
The results of this previous study, as well as a full list of inclusion/exclusion criteria, are published elsewhere.12 Patients aged ≥ 18 years, with central neuropathic pain of ≥ 6 months in duration due to cerebral stroke or multiple sclerosis were also eligible for the current study, provided they had a score of ≥40 mm on the 100 mm visual analog scale ([VAS] from 0= no pain to 100= worst possible pain) of the Short-Form McGill Pain Questionnaire (SF-MPQ) at screening and at the start of the treatment phase.
Post-stroke patients were also required to have involvement of the cutaneous sensory pathway in the stroke location, confirmed by computerized tomography or magnetic resonance imaging, and neuropathic pain developed at the site of the post-stroke sensory disturbance. Patients with multiple sclerosis had to be diagnosed according to the McDonald Diagnostic Criteria and were required to score ＜ 6.5 on the Expanded Disability Status Scale.
Key exclusion criteria included the following: having experienced a serious treatment-related adverse event (AE) during the previous randomized controlled trial (patients with spinal cord injury only); atrial fibrillation during 12-lead electrocardiogram (ECG) at the first visit (post-stroke patients only); uncontrolled diabetes, hypertension, or hyperlipidemia (post-stroke patients only); dementia, serious aphasia, or hemispatial neglect (post-stroke patients only); a diagnosis of neuromyelitis optica (patients with multiple sclerosis only);serious nociceptive pain, musculoskeletal pain, or painful tonic convulsion (patients with multiple sclerosis only); peripheral neuropathic pain or trigeminal neuralgia (patients with multiple sclerosis only); other severe pain that could confound the assessment of central neuropathic pain; participation in a previous trial of pregabalin (except patients with spinal cord injury); intolerance or hypersensitivity to pregabalin or gabapentin; and a documented retinal abnormality or use of a retinotoxic agent.
Patients were required to discontinue gabapentin or cannabinoids at least 7 days before screening, and pregabalin at least 60 days prior. Nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, and acetaminophen (≤ 1.5 g/day in Japan) were permitted as rescue therapy. Antidepressants were permitted if the patient was on a stable dose within 30 days prior to first visit.
study design
This 53-week, open-label study was conducted from 2010 to 2012 at 26 medical centers in Japan. 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 prior to entering the study. This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines.
The study was composed of three phases: a 2-week screening period for newly enrolled patients; a 52-week open-label treatment period; and a 1-week taper period. All patients received 75 mg of pregabalin on day 1 of the 52-week treatment period, and 150 mg/day for the remainder of the first week. Based on patient tolerability, the dose of pregabalin could be increased to 300 mg/day on day 8,450 mg/day on day 15, and 600 mg/day on day 22. Weekly dose adjustments were allowed from day 8 until day 29.
Ideally, after day 29, patients received their optimized dose of pregabalin until the end of the 52-week treatment period. However, in consideration of efficacy and safety, a single-level (±150 mg/day) dose adjustment was allowed at each visit during the dose maintenance period (weeks 4, 8, 12, 20, 28, 36, and 44). After the week 52 visit, patients were tapered off pregabalin over a 1-week period.
safety and tolerability measures
The primary endpoint of this study was to assess the safety and tolerability of pregabalin in patients with central neuropathic pain. The safety profile of pregabalin was assessed based on observed and reported AEs, which were evaluated throughout the study by the investigator for severity and relationship to treatment. Additional safety measures included ophthalmologic, neurologic, and physical examinations with assessment of vital signs; edema and deep vein thrombosis assessments; clinical laboratory testing; and 12-lead ECG.
Efficacy measures
A secondary endpoint of this study was to examine the efficacy of pregabalin patients with central neuropathic pain. Efficacy was assessed using the SF-MPQ16 and the ten-item modified Brief Pain Inventory (mBPI-10). The SF-MPQ is a patient-reported instrument that consists of 15 pain descriptors (eleven sensory and four affective), which are rated on a scale from 0–3. Composite SF-MPQ total score ranges from 0–45, while the sensory and affective scores range from 0–33 and 0–12, respectively.
The SF-MPQ also provides a present pain index (PPI) score that ranges from 0–5, and a VAS for pain that ranges from 0–100 mm. For all SF-MPQ items, higher scores indicate greater pain severity. The SF-MPQ was completed at each study visit. The mBPI-10 is a patient-reported instrument that assesses pain interference with functional activities over the previous week. Items are measured on a scale from 0–10, with higher scores indicating greater interference. Total score was calculated by averaging the ten individual items listed on the mBPI-10. The mBPI-10 was completed at week 1 and week 52, or at the time of study discontinuation.
statistical analysis
All subjects who received at least one dose of study medication were included in the safety analysis. The efficacy analyses included all subjects who received at least one dose of study medication and had both baseline and at least one post-baseline efficacy measurement. All safety and efficacy measures were summarized descriptively and no inferential testing was performed. A last-observation-carried-forward approach for missing values was used to summarize SF-MPQ scores at endpoint.
Results
Patients and treatment
A total of 112 patients were screened and 103 patients received pregabalin treatment (Figure 1). Of the patients receiving pregabalin, 60 had post-stroke pain, 38 had spinal cord injury-related pain, and five had pain related to multiple sclerosis (Table 1). Median (range) treatment duration for all patients combined was 367 (3–386) days. In total, 61.2% of patients received ≥ 365 days of study drug and 89.3% received ≥ 181 days of study drug. The mean (standard deviation [SD])/median (range) daily dose of pregabalin at final visit was 383 (158)/450 (150–600) mg/day.
Overall, 5.8% of patients received a maximum daily dose of pregabalin of 150–299 mg/day; 23.3% received 300–449 mg/day; 28.2% received 450–599 mg/day; and 42.7% received 600 mg/day. Common concomitant drug treatments are shown in Table 2. All patients received at least one concomitant treatment of any kind, while 81.6% received at least one concomitant drug treatment related to pain management. The most common concomitant pain medications were loxoprofen sodium and ketoprofen, which were received by 30% and 29% of patients, respectively.
safety and tolerability
A majority of patients (87.4%) experienced at least one treatment-related AE, most commonly somnolence, weight gain, dizziness, or peripheral edema (Tables 3).
However, most treatment-related AEs were mild-to-moderate in intensity and few patients discontinued due to an AE. Of the 229 treatment-related AEs reported, 204 (89.1%) were characterized as mild, 21 (9.2%) were characterized as moderate, and 4 (1.7%) were characterized as severe. Severe treatment-related AEs included one instance each of feeling abnormal (post-stroke patient), ataxia (post-stroke patient),cerebral hemorrhage (post-stroke patient), and somnolence (patient with spinal cord injury). The instance of cerebral hemorrhage was characterized as the only treatment-related serious AE reported in the study. No deaths were reported during the study.
The mean (SD) change in body weight from baseline was 1.7 (3.1) kg in all patients combined. Fourteen patients (13.6%) experienced clinically important weight gain at last observation, which was defined as an increase of ≥ 7% from baseline. In addition, 25 patients (24.3%) experienced clinically important weight gain at any point during the study, compared with only two patients (1.9%) who experienced clinically important weight loss (a decrease of ≥ 7%).
Clinically significant increase in systolic and diastolic blood pressures (both measured sitting) occurred in one patient each at endpoint. There was no change in pulse rate that was clinically significant. There were two patients with clinically significant abnormal ECG findings at endpoint. Atrial fibrillation was reported as a treatment-related AE at endpoint for one of these patients; however, the fibrillation was mild in terms of severity and resolved after cessation of treatment.
Major laboratory abnormalities (those with an incidence ≥ 10%, regardless of whether baseline levels were within the reference range) were increased triglycerides, increased low-density lipoprotein cholesterol, and urinary occult blood positive. There was no laboratory abnormality reported as a serious AE. There were no other clinically significant findings related to laboratory tests, vital signs, ECGs, or physical examinations during the study.
Efficacy
In all patients combined, pregabalin treatment was associated with improvements from baseline on all predefined efficacy measures at endpoint. Mean improvement in SF-MPQ total score was −4.6 at endpoint. Mean (SD) improvements in SF-MPQ sensory and affective scores were −3.6 (6.2) and −1.0 (2.7), respectively. SF-MPQ VAS pain score was improved by −20.1 (25.2) mm and the SF-MPQ PPI was improved by −0.7 (1.1) . Improvements in SF-MPQ VAS score were evident at week 2 and were sustained throughout the treatment period (Figure 2). Finally, a −1.4 (2.4) improvement was observed in mBPI-10 total score at endpoint.
Improvements in SF-MPQ total score, SF-MPQ sensory pain score, SF-MPQ affective pain score, and SF-MPQ PPI score were evident in patients with post-stroke pain or spinal cord injury-related pain, but not in patients with multiple sclerosis (Table 4). Improvements in SF-MPQ VAS score and mBPI-10 total score were evident in all patient populations, including those with pain due to multiple sclerosis(Tables 4).
Conclusion
Overall, our findings demonstrate that pregabalin is generally well tolerated over a 52-week treatment period in patients with chronic central neuropathic pain. Though descriptive in nature, our data also suggest that pregabalin is effective in the treatment of central neuropathic pain out to 1 year.
