Comparing pregabalin and gabapentin for persistent neuropathic pain: A protocol for a pilot N-of-1 trial series.

BACKGROUND: Evidence-based management of neuropathic pain is commonly ineffective due to the large variability in response between cases. Patients often have to trial several drugs before finding one that provides adequate relief, leading to increased costs and worsened outcomes. There is thus a need for tools to guide and streamline prescribing decisions in neuropathic pain. N-of-1 trials provide a potentially precise and economical method of selecting between multiple interventions in an individual patient, and merit a feasibility assessment for use in clinical pain practice. AIMS: We aim to evaluate the feasibility of N-of-1 trials to compare pregabalin and gabapentin for individual presentations of neuropathic pain. METHODS: This is a double-blinded multiple crossover study, with recruitment from existing patients at an outpatient pain clinic in New South Wales, Australia. Participants will undergo three 4-week treatment pairs, comprising 2 weeks of pregabalin (150-600 mg/day) and 2 weeks of gabapentin (900-3600 mg/day), in an individually randomised order. Intervention doses will be derived from participants' existing treatment dose. Medications will be taken orally three times daily. The primary outcome will be pain intensity; measures will be self-reported daily in patient diaries. After completing all three cycles, participants and their physicians will be presented with the results of the trial to form an informed decision about their treatment. DISCUSSION: As a stable yet debilitating condition, neuropathic pain is especially amenable to an N-of-1 study design. A successful trial would represent a significant quality of life improvement for the patient, possibly extending over the course of their lifetime.

Determining level of care appropriateness in the patient journey from acute care to rehabilitation.

BACKGROUND: The selection of patients for rehabilitation, and the timing of transfer from acute care, are important clinical decisions that impact on care quality and patient flow. This paper reports utilization review data on inpatients in acute care with stroke, hip fracture or elective joint replacement, and other inpatients referred for rehabilitation. It examines reasons why acute level of care criteria are not met and explores differences in decision making between acute care and rehabilitation teams around patient appropriateness and readiness for transfer. METHODS: Cohort study of patients in a large acute referral hospital in Australia followed with the InterQual utilization review tool, modified to also include reasons why utilization criteria are not met. Additional data on team decision making about appropriateness for rehabilitation, and readiness for transfer, were collected on a subset of patients. RESULTS: There were 696 episodes of care (7189 bed days). Days meeting acute level of care criteria were 56% (stroke, hip fracture and joint replacement patients) and 33% (other patients, from the time of referral). Most inappropriate days in acute care were due to delays in processes/scheduling (45%) or being more appropriate for rehabilitation or lower level of care (30%).On the subset of patients, the acute care team and the utilization review tool deemed patients ready for rehabilitation transfer earlier than the rehabilitation team (means of 1.4, 1.3 and 4.0 days from the date of referral, respectively). From when deemed medically stable for transfer by the acute care team, 28% of patients became unstable. From when deemed stable by the rehabilitation team or utilization review, 9% and 11%, respectively, became unstable. CONCLUSIONS: A high proportion of patient days did not meet acute level of care criteria, due predominantly to inefficiencies in care processes, or to patients being more appropriate for an alternative level of care, including rehabilitation. The rehabilitation team was the most accurate in determining ongoing medical stability, but at the cost of a longer acute stay.To avoid inpatients remaining in acute care in a state of 'terra nullius', clinical models which provide rehabilitation within acute care, and more efficient movement to a rehabilitation setting, is required. Utilization review could have a decision support role in the determination of medical stability.

Safety and efficacy of pregabalin in patients with central post-stroke pain.

Pregabalin has demonstrated efficacy in several forms of neuropathic pain, but its long-term efficacy in central post-stroke pain (CPSP) is unproven. We evaluated the efficacy and safety of pregabalin versus placebo in patients with CPSP. A 13-week, randomized, double-blind, multicenter, placebo-controlled, parallel group study of 150 to 600 mg/day pregabalin was conducted in patients aged ≥18 years with CPSP. The primary efficacy endpoint was the mean pain score on the Daily Pain Rating Scale over the last 7 days on study drug up to week 12 or early termination visit. Secondary endpoints included other pain parameters and patient-reported sleep and health-related quality-of-life measures. A total of 219 patients were treated (pregabalin n=110; placebo n=109). A mean pain score at baseline of 6.5 in the pregabalin group and 6.3 in the placebo group reduced at endpoint to 4.9 in the pregabalin group and 5.0 in the placebo group (LS mean difference=-0.2; 95% CI=-0.7, 0.4; P=0.578). Treatment with pregabalin resulted in significant improvements, compared with placebo, on secondary endpoints including MOS-sleep, HADS-A anxiety, and clinician global impression of change (CGIC) P<0.05. Adverse events were more frequent with pregabalin than with placebo and caused discontinuation in 9 (8.2%) of pregabalin patients versus 4 (3.7%) of placebo patients. Although pain reductions at endpoint did not differ significantly between pregabalin and placebo, improvements in sleep, anxiety, and CGIC suggest some utility of pregabalin in the management of CPSP.

Using N-of-1 trials to improve patient management and save costs.

BACKGROUND: N-of-1 trials test treatment effectiveness within an individual patient. OBJECTIVE: To assess (i) the impact of three different N-of-1 trials on both clinical and economic outcomes over 12 months and (ii) whether the use of N-of-1 trials to target patients' access to high-cost drugs might be cost-effective in Australia. DESIGN: Descriptive study of management change, persistence, and costs summarizing three N-of-1 trials. PARTICIPANTS: Volunteer patients with osteoarthritis, chronic neuropathic pain or ADHD whose optimal choice of treatment was uncertain. INTERVENTIONS: Double-blind cyclical alternative medications for the three conditions. MEASURES: Detailed resource use, treatment and health outcomes (response) data collected by postal and telephone surveys immediately before and after the trial and at 3, 6 and 12 months. Estimated costs to the Australian healthcare system for the pre-trial vs. 12 months post-trial. RESULTS: Participants persisting with the joint patient-doctor decision 12 months after trial completion were 32% for osteoarthritis, 45% for chronic neuropathic pain and 70% for the ADHD trials. Cost-offsets were obtained from reduced usage of non-optimal drugs, and reduced medical consultations. Drug costs increased for the chronic neuropathic pain and ADHD trials due to many patients being on either low-cost or no pharmaceuticals before the trial. CONCLUSIONS: N-of-1 trials are an effective method to identify optimal treatment in patients in whom disease management is uncertain. Using this evidence-based approach, patients and doctors tend to persist with optimal treatment resulting in cost-savings. N-of-1 trials are clinically acceptable and may be an effective way of rationally prescribing some expensive long-term medicines.

N-of-1 randomized trials to assess the efficacy of gabapentin for chronic neuropathic pain.

OBJECTIVE: The objective of this study was to compare the efficacy of gabapentin with placebo for neuropathic pain at the individual and population levels. DESIGN: This study used an n-of-1 trial methodology with three double-blind, randomized, crossover comparisons of gabapentin with placebo. SETTING: This study was carried out at specialist outpatient clinics at two Australian hospitals. Patients. The patients are adults with chronic neuropathic pain. INTERVENTIONS: Following a dose-finding period, participants underwent three comparisons of 2-week periods on gabapentin (600-1,800 mg per day) and placebo. The dose-finding period was commenced by 112 patients, of whom 39 had no response so they did not enroll, leaving 73 trial participants. Of these, 48 completed and 7 partially completed their trials, and 18 withdrew. OUTCOME MEASURES: The five outcome measures were the visual analog scale (0-10) of pain, sleep interference and functional limitation; frequency of adverse events and medication preference. The aggregate response was determined by weighting the response to each measure equally. RESULTS: Of the 55 participants who completed at least one cycle, the aggregate response to gabapentin was better than placebo in 16 (29%), of whom 15 continued gabapentin posttrial. No difference was shown in 38 (69%), and 1 (2%) showed a better response to placebo. Fifteen of these 39 continued gabapentin posttrial. Meta-analysis of the mean scores showed lower mean (standard deviation) scores for gabapentin by 0.8 (0.2) for pain, 0.6 (0.2) for sleep interference, and 0.6 (0.2) for functional limitation. CONCLUSIONS: The response rate and mean reduction in symptoms with gabapentin were small. Gabapentin prescribing posttrial was significantly influenced by the trial results.

Developing prosthetic weight bearing in a knee disarticulation amputee.

An essential component of prosthetic training in amputees is to achieve full weight bearing through the prosthesis. The end-bearing nature of the intact femur in an individual with a knee disarticulation amputation (KDA) offered a rare opportunity to examine this component. The purpose of this case study was to describe the weight-bearing development in a temporary prosthesis. Longitudinal measurement of gait and balance parameters offer objective data to assess this component of amputee rehabilitation. It was concluded that (1) the temporary prosthesis for a KDA was a successful treatment option in the rehabilitation of a KDA; (2) full weight bearing was achieved in four weeks; and (3) the longitudinal objective measures identified unexpected results.