Tramadol in the treatment of neuropathic cancer pain: a double-blind, placebo-controlled study. Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo-controlled trial. The effect of tramadol in painful polyneuropathy in relation to serum drug and metabolite levels. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy.
To assess the efficacy, safety and impact on quality of life of tramadol in the treatment of neuropathic pain in patients with cancer.
                Patients with similar characteristics were grouped in pairs and randomised to receive either tramadol or placebo. The initial tramadol dosage was 1 mg/kg every 6 hours, increasing to 1.5 mg/kg every 6 hours if necessary to control pain.
                The study enrolled 36 patients (22 women, 14 men), with a mean age of 50 years. In the group receiving tramadol (n = 18), major improvements in pain intensity and Karnofsky scores occurred (p < 0.001), sleep quality improved by day 45 (p < 0.05) activities of daily living improved (p < 0.05), and use of analgesics that had been taken before the study was reduced (p < 0.05) compared with the placebo group. There was no difference between the groups with regard to changes in the Zung Depression Scale, Beck Anxiety Inventory scores and neurophysiological assessments. More patients in the tramadol group experienced adverse events (p < 0.05). The most common adverse events were nausea, vomiting and constipation.
                Tramadol is a therapeutic option for the control of neuropathic pain in patients with cancer, and appears to improve quality of life in these patients. The analgesic effect of tramadol is independent of changes in anxiety, depression and nervous system function. The efficacy and safety of sustained-release tramadol compared to placebo in the treatment of post-herpetic neuralgia were evaluated in a multicenter, randomized, double-blind, parallel-group study in 127 outpatients. Treatment was administrated for 6 weeks. The dose of tramadol could be increased from 100 mg/day to 400 mg/day (300 mg/day in patients more than 75 years old). Groups were compared on changes in pain intensity on a Visual Analogue Scale (VAS) between inclusion and the 6th week of treatment (covariance analysis as main analysis and repeated measures analysis as complementary analysis) in the per protocol (PP) population. The randomized population comprised 127 patients aged 35-85 years, mostly females (72.4%). Groups were comparable at inclusion both in the intent to treat (ITT) population (63 patients in the tramadol group and 62 patients in the placebo group) and in the PP population (53 patients in the tramadol group and 55 patients in the placebo group). Mean pain intensity on day 43 adjusted on day 1 (covariance analysis) was significantly lower in the tramadol group than in the placebo group in both the PP (P=0.0499), and the ITT (P=0.031) populations. The two groups significantly differed on change in pain intensity over time (repeated measures analysis) in the ITT population (P=0.012). The percentage of pain relief over the 6th week was significantly higher in the tramadol group than in the placebo group (P=0.017). During the 6th week, patients in the tramadol group required less rescue medication than patients in the placebo group (P=0.022). No significant difference was found between groups either in pain intensity on a 5-point Verbal Scale (VRS) or in quality of life measurements. Tramadol was administered at an average dosage of 275.5 (89.7) mg/day after a 1-week dose-adaptation period. Tramadol was well tolerated. No notable difference appeared between groups either in the percentage of patients with treatment-associated adverse events (TAAE) (29.7% in the tramadol group and 31.8% in the placebo group) or in the total number of TAAE (31 in the tramadol group and 28 in the placebo group). Tramadol is a racemic drug that may act through a monoaminergic effect of (+)- and (-)-tramadol and through an opioid effect of its metabolite (+)-Ml. The objective of this study was to investigate the relationship between relief of pain and serum concentrations of tramadol and Ml in tramadol treatment of painful polyneuropathy.
                In a randomized, double-blind, placebo-controlled trial of 200 to 400 mg/day tramadol, serum concentrations of (+)- and (-)-tramadol and (+)- and (-)-Ml were determined in 28 of 34 patients. Ongoing and touch-evoked pain was rated daily by the patients by use of 0- to 10-point numeric rating scales during two 4-week treatment periods.
                Tramadol significantly reduced both on-going (P = .002) and touch-evoked pain (P < .001). There was no relation between relief of on-going and touch-evoked pain and serum concentrations of (+)-tramadol, (-)-tramadol, (+)-M1, or (-)-M1 (P = .11 to P = .89). Seventeen of the patients were categorized as responders for on-going pain and 16 for touch-evoked pain. Responders for on-going pain tended to have higher serum concentrations of (+)-Ml than nonresponders (median, 27 nmol/L versus 16 nmol/L; P = .08). Isobolograms showed that the fraction of nonresponders was higher among patients with low concentrations of both tramadol and (+)-Ml both for on-going (P = .009) and touch-evoked (P = .02) pain.
                The opioid effect of (+)-Ml may be of importance for tramadol relief of on-going neuropathic pain but, in general, relief of neuropathic pain seems to depend on both the monoaminergic effect of (+)- and (-)-tramadol and the opioid effect of (+)-Ml. The objective of this study was to evaluate the efficacy and safety of tramadol in treating the pain of diabetic neuropathy.
                The pain of diabetic neuropathy is a major cause of morbidity among these patients and treatment, as with other small-fiber neuropathies, is often unsatisfactory. Tramadol is a centrally acting analgesic for use in treating moderate to moderately severe pain.
                This multicenter, outpatient, randomized, double-blind, placebo-controlled, parallel-group study consisted of a washout/screening phase, during which all analgesics were discontinued, and a 42-day double-blind treatment phase. A total of 131 patients with painful diabetic neuropathy were treated with tramadol (n=65) or placebo (n=66) tramadol, which were administered as identical capsules in divided doses four times daily. The primary efficacy analysis compared the mean pain intensity scores in the tramadol and placebo groups obtained at day 42 of the study or at the time of discontinuation. Secondary efficacy assessments were the pain relief rating scores and a quality of life evaluation based on daily activities and sleep characteristics.
                Tramadol, at an average dosage of 210 mg/day, was significantly (p < 0.001) more effective than placebo for treating the pain of diabetic neuropathy. Patients in the tramadol group scored significantly better in physical (p=0.02) and social functioning (p=0.04) ratings than patients in the placebo group. No statistically significant treatment effects on sleep were identified. The most frequently occurring adverse events with tramadol were nausea, constipation, headache, and somnolence.
                The results of this placebo-controlled trial showed that tramadol was effective and safe in treating the pain of diabetic neuropathy.
Tramadol is an effective treatment for neuropathic pain.