Pregabalin

Pregabalin is an anticonvulsant drug, which has been shown to have analgesic and anxiolytic effects. Similarly to gabapentin, it is a derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and it was approved by the European Agency for Evaluation of Medicinal Products as an analgesic for peripheral neuropathic pain in 2004. Epidemiological data suggest that up to one-third of community-based patients with diabetes suffer from peripheral neuropathic symptoms and these can be difficult to treat. NICE recommends the use of pregabalin as first-line for people with non-diabetes related neuropathic conditions, but as a second-line treatment for painful diabetic peripheral neuropathy (PDPN). Figure 1 outlines the pharmacological action of pregabalin. It binds selectively to the alpha-2-delta protein subunit of pre-synaptic voltage-gated calcium channels in the central nervous system. This reduces calcium influx into the synapse, thereby diminishing the release of several neurotransmitters. Although its exact analgesic mechanism is not known, rat studies have shown that administration of pregabalin into inflammation-sensitised spinal tissue suppresses the release of neuropeptides from sensory neurons and the nociceptive effect of pregabalin may be a result of this action. Pharmacological action of pregabalin Pregabalin exhibits linear pharmacokinetics and has an oral bioavailability of over 90%. It is not protein bound so it readily crosses the blood brain barrier. It is exclusively renally excreted and therefore a dose adjustment is required in patients with a creatinine clearance of <60ml/min because of the reduction in its clearance and increase in its elimination half-life. Pregabalin has been studied in patients with epilepsy, PDPN, post-herpetic neuralgia, generalised anxiety disorder and social anxiety disorder. In a 12-week, multicentre, randomised controlled trial (RCT) evaluating the efficacy and safety of pregabalin in neuropathic pain in patients with post-herpetic neuralgia and PDPN, patients (n=338) were randomised to placebo (n=65) or pregabalin, either as a flexible schedule of 150, 300, 450 and 600mg/day with weekly dose titration according to response (n=141), or as a fixed schedule of 300mg/day for one week followed by 600mg/day for 11 weeks (n=132).1 The primary outcome measure was a reduction in pain scores and, in comparison to placebo, both dosing regimens reduced mean pain scores (p=0.002, p<0.001) by the end of the study. In all, 66.3% of subjects in the treatment arm experienced more than one adverse event. Out of 62 (18.3%) patients who discontinued the study due an adverse event, five (7.7%) were placebo-treated and 57 (20.9%) were pregabalin-treated. Numbers needed to harm for the most common adverse events were: dizziness 5.2; peripheral oedema 11.6; weight gain 10.3; somnolence 8.5; and nausea 16.2. Dizziness and somnolence were transient effects and the median duration of any adverse events in the treatment group was 1.0 day (apart from weight gain). The rates of adverse events in the fixed-dose treatment arm were higher when compared to the flexible-dose arm suggesting better tolerability of the drug with a stepwise approach to dose titration in response to pain relief. There are five RCTs that have assessed the efficacy of pregabalin in the treatment of PDPN. In one of these, patients (n=228) were randomised to receive pregabalin 75, 300 or 600 mg/day or placebo.2 Patients had a one- to five-year history of PDNP and average weekly pain scores of ≥4 on an 11-point numeric pain-rating scale. The primary efficacy measure was an improvement in the endpoint mean pain scores after five weeks. Patients in the 300 and 600mg/day pregabalin cohorts showed significant improvements in endpoint mean pain score versus placebo (p=0.0001). Other outcome measures of weekly pain score, sleep interference score, patient global impression of change, clinical global impression of change, SF-McGill Pain Questionnaire (SF-MPQ), and multiple domains of the SF-36 Health Survey also showed improvement in the pregabalin-treated group. Patients were classified as ‘responders’ if they had a ≥50% reduction in pain from baseline and in this were included 46% (300mg/day), 48% (600mg/day) and 18% (placebo) of each cohort by the end of the five weeks. In another study, with the same inclusion criteria and primary endpoint measure, 146 patients were randomised to receive placebo or pregabalin 300mg/day (divided doses of 100mg three times daily).3 At the end of eight weeks, pregabalin produced significant improvements versus placebo (p<0.0001) with pain relief beginning to be noticed during week 1 and remaining significant throughout the study (p<0.03). This study also showed improvements with pregabalin in SF-MPQ scores, sleep interference scores, SF-36 health survey scores and profile of mood states scores. A study of 246 people with PDPN showed similar results. This six-week, double-blind RCT randomised patients to receive pregabalin (150 or 600mg/day) or placebo. Pregabalin 600mg/day decreased the mean pain score to 4.3 versus 5.6 for placebo (p=0.0002).4 Pregabalin 150mg was no different to placebo in the results. A longer, 12-week, double-blind, placebo controlled trial investigated the safety and efficacy of pregabalin in 395 adults with PDPN for over a year by randomising them to receive placebo, 150, 300 or 600mg/day pregabalin.5 Forty-six percent of patients in the 600mg/day group showed ≥50% improvement in mean pain scores from baseline versus 30% of the placebo group (p=0.036). The number needed to treat to achieve this result was 6.3. One small study used nerve conduction studies as an objective safety measure while evaluating the efficacy of pregabalin 600mg/day (300mg twice daily).6 Along with assessing the endpoint mean pain score, they also looked at nerve conduction velocities and sensory and motor amplitudes at baseline, endpoint and end of follow up (two weeks post-treatment). In their cohort, patients had diabetes for over 10 years and PDPN for about five years; 82 received pregabalin while 85 received placebo. At the end, mean difference in pain scores in the two groups was 1.28 (p<0.001). There was no significant difference in amplitude and velocity from baseline to endpoint and baseline to follow up in the nerve conduction tests in between the two cohorts. The rate of adverse events with pregabalin was similar in all studies, with transient dizziness and somnolence being the most common. Despite this, discontinuation rates for pregabalin were low. An RCT of 83 subjects, conducted over a four-week period, has compared the effectiveness of amitriptyline, duloxetine and pregabalin.7 It did not find any significant difference in analgesic efficacy but found that pregabalin enhanced sleep continuity while duloxetine caused sleep fragmentation. Pregabalin at higher doses is effective in reducing diabetic peripheral neuropathic pain and is generally well tolerated. In addition, pregabalin also improves quality of life and reduces sleep disturbance. However, the studies published for this indication are of a relatively short duration with small patient numbers. Further studies are needed to confirm long-term effectiveness and safety, including clinical trials with head-to-head comparisons of pregabalin with other oral analgesics used for PDPN, as well as trials on the efficacy of pregabalin in combination with other analgesics. There are no conflicts of interest declared. References are available online at www.practicaldiabetes.com. Painful diabetic peripheral neuropathy is common in people with diabetes, and is a cause of much morbidity Pregabalin is effective at reducing symptoms of pain, so improving quality of life There is a need for studies comparing pregabalin with other treatments for painful peripheral neuropathy, either as a single drug or combined with other therapies

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