Pregabalin in patients with central neuropathic pain: A randomized, double-blind, placebo-controlled trial of a flexible-dose regimen

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Abstract
The effective treatment of patients suffering from central neuropathic pain remains a clinical challenge, despite a standard pharmacological approach in combination with anticonvulsants and antidepressants. A randomized, double-blinded, placebo-controlled trial evaluated the effects of pregabalin on pain relief, tolerability, health status, and quality of life in patients with central neuropathic pain caused by brain or spinal cord injuries. At baseline and 4 weeks after the start of treatment subjects were evaluated with standard measures of efficacy: pain intensity measured by visual analog scale, health status (Pain Disability Index and EQ-5D) and quality of life (SF-36). Forty patients received escalating doses of either pregabalin (150, 300, and 600 mg/day) or matching placebo capsules. In both groups, patients started with 1 capsule per day (either 150 mg of pregabalin or placebo). If pain relief was insufficient, patients were titrated to a higher dose. There was a statistically significant decrease in mean pain score at endpoint for pregabalin treatment, compared with placebo ( P = 0.016). Follow-up observation showed no significant difference in Pain Disability Index scores between the two groups. The pregabalin group, however, showed a statistically significant improvement for the EQ-5D. Pregabalin treatment led to a significant improvement in the bodily pain domain of the SF36. In the other domains, more favorable scores were reported without reaching statistical significance. Pregabalin, in a flexible-dose regime, produced clinically significant reductions in pain, as well as improvements in health status in patients suffering from severe central neuropathic pain. Keywords Pregabalin Central neuropathic pain Quality of life 1 Introduction Central neuropathic pain (pain associated with lesions of the central nervous system) has been estimated to occur in up to 8% of patients after stroke, and in about 40% of patients with spinal cord injury ( Siddall et al., 2003; Nicholson, 2004 ). The mechanisms underlying central neuropathic pain are not fully understood. A dominating feature of central pain, however, is an abnormal spinothalamic function with altered sensitivity to temperature and pinprick ( Finnerup and Jensen, 2004 ). Disruption of the spinothalamic pathways may contribute to neuronal hyperexcitability, loss of descending inhibitory control mechanisms in the spinal cord, and alterations in the processing of incoming noxious and non-noxious stimuli resulting in an abnormal pain perception ( Eide, 1998; Nicholson, 2004 ). In addition, loss of balance between noxious and non-noxious sensory inputs gives rise to neuronal reorganization in the thalamus contributing to the onward flow of nociceptive information to the postcentral gyrus of the cortex ( Millan, 1999 ). Despite recent advances in identification of peripheral and central sensitization mechanisms related to central nervous system injury, the effective treatment of patients suffering from central pain remains a clinical challenge. In spite of numerous treatment options (including opioids, anticonvulsants, antidepressants, baclofen, α-adrenergic agonists, and ketamine), some of these patients still experience severe neuropathic pain. In addition, the use of these agents is often limited by significant side effects. Recently, pregabalin was reported to possess antihyperalgesic and antiallodynic properties in various animal models. Moreover, pregabalin was shown to be effective in randomized clinical trials of nonmalignant chronic neuropathic pain (including postherpetic neuralgia, diabetic peripheral neuropathy, and neuropathic pain following spinal cord injury) ( Gilron and Flatters, 2006; Siddall et al., 2006 ). Additionally, this anticonvulsant has excellent bioavailability and a favorable safety profile with minimal concern for drug interactions and no interference with hepatic enzymes. Given the absence of other effective pharmacological treatments for central pain, any medication providing some benefit in terms of symptom amelioration and quality of life improvement in patients with neuropathic pain has to be evaluated. Therefore, we tested, in a randomized, double-blind, placebo-controlled trial, the effects of pregabalin on pain relief, tolerability, health status, and quality of life in patients with central neuropathic pain. 2 Methods 2.1 Patients The study was approved by the Medical Ethical Committee of our institution. Eligible patients visiting our outpatient hospital clinic (between January, 2006 and March, 2006) were recruited. Randomization took place after all patients were recruited (see below). Inclusion criteria: age 18 years or older; written informed consent; patients suffering from severe neuropathic pain, visual analog scale score more than six caused by lesion or dysfunction in the central nervous system. The pain had to persist continuously for at least 6 months, and had started after sustaining the lesion or dysfunction in the central nervous system. Neuropathic pain was described by at least one of the following: burning pain, paroxysmal episodes of shooting pain, or pain on light touch. Additionally, patients had to score above 12 on the Leeds Assessment of Neuropathic Symptoms and Signs questionnaire (LANSS) ( Bennett, 2001 ). Patients were not eligible or not recruited, if they: were pregnant; had a history of intolerance, hypersensitivity, or known allergy to pregabalin; had a known history of significant hepatic, renal, or psychiatric disorder; had a history of galactose intolerance, lactase deficiency, or glucose–galactose malabsorption syndrome. Subjects with a calculated creatinine clearance rate below 60 mL/min (estimated from serum creatinine using Cockroft–Gault equation) were also excluded. Patients taking concomitant analgesic medication were allowed to enter the study if neuropathic pain treatment was on a stable regimen at least 90 days before start of...