Lacosamide in Painful Diabetic Neuropathy: An 18-Week Double-Blind Placebo-Controlled Trial

The efficacy and tolerability of oral lacosamide (200, 400, and 600 mg/day) was evaluated in patients with painful diabetic neuropathy in a double-blind, randomized, placebo-controlled trial. The primary target dose to be confirmed was lacosamide 400 mg/day. Efficacy was assessed by changes in pain scale scores from baseline, with changes over the last 4 weeks of the 12-week maintenance period regarded as the primary endpoint. Endpoint reductions in mean pain score were higher with all doses of lacosamide, reaching the level of significance with 400 mg/day (P = .05). Over the treatment period (titration + maintenance), pain relief was significantly higher than placebo with lacosamide 400 (P = .02) and 600 mg/day (P = .03). Lacosamide had an early-onset effect with significant reductions over placebo during the titration period. Nonparametric and mixed-model analysis approaches gave similar results, supporting significant efficacy at 400 mg/day. Secondary criteria such as Patient's Global Impression of Change, responder rates, and pain-free days provided additional support. Adverse events included dizziness, nausea, and headache. Incidence of cognitive and behavioral adverse events was low. This trial suggests that lacosamide has beneficial effects and may be a suitable treatment option for patients with diabetic neuropathic pain.PerspectiveThis study presents efficacy and safety results of a phase 3, double-blind, placebo-controlled trial of the anticonvulsant drug lacosamide in patients with painful diabetic neuropathy. Lacosamide treatment at a dose of 400 mg/day reduced diabetic neuropathic pain with a favorable safety and tolerability profile that may be suitable for patients with diabetes.     

Long‐term oral lacosamide in painful diabetic neuropathy: A two‐year open‐label extension trial

Objectives: This open‐label follow‐on trial aimed to investigate long‐term safety and efficacy of lacosamide in patients with painful diabetic neuropathy. Methods: After 1‐week baseline period, lacosamide 100mg/day was started. Each week, based on pain and safety assessments, doses were escalated by 100mg/day to an optimal level, up to a maximum of 400mg/day. Patients then entered the 20‐week maintenance period (dose adjusted as needed). Thereafter, patients could opt to continue lacosamide up to about 2.5 years (extension period). Results: Of the 69 enrolled patients, 47 (68%) completed the 20‐week maintenance period and elected to continue into the extension period; 37/69 (54%) patients were in the extension period for more than one year and 34/69 (49%) continued until study termination. The modal lacosamide dose in most patients (54%) was 400mg/day. Headache, upper respiratory tract infection, arthralgia, sinusitis, nasopharyngitis, and back pain were the most frequently reported adverse events (≥10% of patients). Significant reductions from baseline in Likert pain scores began during dose titration and were sustained throughout the study. Significant improvements were also seen in Neuropathic Pain Scale, Quality of Life scores, and Patient's Global Impression of Change assessment. Of 34 patients at study termination, 32 (90%) elected to continue with lacosamide treatment in another long‐term open‐label trial (NCT00235443). Conclusion: The long‐term safety profile and sustained efficacy of lacosamide observed in this trial support its continued development for treatment of painful diabetic neuropathy.     

Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies

To assess the efficacy and tolerability of lamotrigine in pain associated with diabetic neuropathy, two replicate randomized, double-blind, placebo-controlled studies were conducted. Patients (n=360 per study) with painful diabetic neuropathy were randomized to receive lamotrigine 200, 300, or 400 mg daily or placebo during the 19-week treatment phase, including a 7-week dose-escalation phase and a 12-week, fixed-dose maintenance phase. The mean reduction in pain-intensity score from baseline to week 19 (primary endpoint) was greater (p < or = 0.05) in patients receiving lamotrigine 400 mg than placebo in Study 2 (observed scores, -2.7 versus -1.6 on a 0- to 10-point scale). This finding was not replicated in Study 1. Lamotrigine 200 and 300 mg did not significantly differ from placebo at week 19 in either study. Lamotrigine 300 and 400 mg were only occasionally more effective than placebo for secondary efficacy endpoints. The 200-mg dose did not separate from placebo. In a post hoc analysis of pooled data including only patients who reached their target dose, lamotrigine 400 mg conferred greater (p0.05) mean reduction in pain-intensity score from baseline to week 19 than placebo (-2.5 for 300 mg and -2.7 for 400mg versus -2.0 for placebo). Adverse events were reported in 71-82% of lamotrigine-treated patients compared with 63-70% of placebo-treated patients. The most common adverse events with lamotrigine were headache and rash. Compared with placebo, lamotrigine (300 and 400 mg daily) was inconsistently effective for pain associated with diabetic neuropathy but was generally safe and well tolerated.     

Gabapentin vs. amitriptyline in painful diabetic neuropathy: an open-label pilot study

The objective of this study was to compare the efficacy and tolerability of gabapentin and amitriptyline monotherapy in painful diabetic neuropathy. This was a 12-week, open-label, prospective, randomized trial. Twenty-five type-II diabetic patients with pain attributed to diabetic neuropathy and a minimum score of 2 on a pain intensity scale ranging from 0 (no pain) to 4 (excruciating pain) were randomized to receive either gabapentin, titrated from 1,200 mg/day to a maximum of 2,400 mg/day, or amitriptyline, titrated from 30 mg/day to a maximum of 90 mg/day. Both drugs were titrated over a 4-week period and maintained at the maximum tolerated dose for 8 weeks. The main outcome measures were weekly pain intensity and paresthesia intensity, measured on two categorical scales. Thirteen patients received gabapentin and 12 received amitriptyline. All 25 patients completed the trial. Gabapentin produced greater pain reductions than amitriptyline (mean final scores were 1.9 vs. 1.3 points below baseline scores; P = 0.026). Decreases in paresthesia scores also were in favor of gabapentin (1.8 vs. 0.9 points; P = 0. 004). Adverse events were more frequent in the amitriptyline group than in the gabapentin group: they were reported by 11/12 (92%) and 4/13 (31%) of patients, respectively (P = 0.003). Side effects were the main limiting factor preventing dose escalation. Gabapentin produced greater improvements than amitriptyline in pain and paresthesia associated with diabetic neuropathy. Additionally, gabapentin was better tolerated than amitriptyline. Further controlled trials are needed to confirm these preliminary results.     

Efficacy and Safety of Lacosamide in Painful Diabetic Neuropathy

OBJECTIVE

To evaluate efficacy and safety of lacosamide compared with placebo in painful diabetic polyneuropathy.

RESEARCH DESIGN AND METHODS

Diabetic patients with at least moderate neuropathic pain were randomized to placebo or lacosamide 400 (in a slow or standard titration) or 600 mg/day over 6-week titration and 12-week maintenance periods. Primary efficacy criterion was intra-individual change in average daily Numeric Pain Rating Scale score from baseline to the last 4 weeks.

RESULTS

For the primary end point, pain reduction was numerically but not statistically greater with lacosamide compared with placebo (400 mg/day, P = 0.12; 600 mg/day, P = 0.18). Both doses were significantly more effective compared with placebo over the titration (P = 0.03, P = 0.006), maintenance (P = 0.01, P = 0.005), and entire treatment periods (P = 0.03, P = 0.02). Safety profiles between titration schemes were similar.

CONCLUSIONS

Lacosamide reduced neuropathic pain and was well tolerated in diabetic patients, but the primary efficacy criterion was not met, possibly due to an increased placebo response over the last 4 weeks.Up to one in four patients with diabetes may be affected by chronic diabetic painful neuropathy (DPN) (1,2) and suffer substantial morbidity and impaired quality of life (3). Because the current treatment options are limited, there is continued need for new therapeutic approaches (3,4). Lacosamide is an anticonvulsant with a unique mode of action, selectively enhancing slow inactivation of voltage-gated sodium channels (5–8). This trial was one of three similarly designed placebo-controlled, parallel-group trials to evaluate the efficacy of lacosamide in DPN (9,10) using 400 mg/day (two titration schemes) and 600 mg/day.     

Oxcarbazepine in painful diabetic neuropathy: a randomized, placebo-controlled study.

In this multicentre, placebo-controlled, 16-week trial, the efficacy and safety of oxcarbazepine monotherapy in patients with neuropathic pain of diabetic origin was evaluated. Eligible patients had a 6-month to 5-year history of neuropathic pain symptoms of diabetic origin and a pain rating of > or =50 units on the visual analogue scale (VAS). Oxcarbazepine was initiated at a dose of 300 mg/day and titrated to a maximum dose of 1800 mg/day. In total, 146 patients (oxcarbazepine, n=69; placebo, n=77) were randomized. After 16 weeks, oxcarbazepine-treated patients experienced a significantly larger decrease in the average change in VAS score from baseline compared with placebo (-24.3 vs. -14.7 units, respectively; p=0.01). The reduction from baseline in mean VAS score for oxcarbazepine-treated patients was of a greater magnitude than placebo as early as week 2 (-8.0 vs. -4.7; p<0.05). A significantly greater proportion of oxcarbazepine-treated patients experienced a >50% reduction from baseline in VAS score at the end of treatment compared with placebo (35.2% vs. 18.4%, respectively; p=0.0156; number needed to treat=6.0). Global assessment of therapeutic effect rating was improved in more oxcarbazepine patients than placebo patients (48% vs. 22%, respectively; p=0.0025). Patients on oxcarbazepine were awakened less frequently due to pain than patients on placebo. Most adverse events were mild to moderate in severity, transient, and in line with the known tolerability profile of oxcarbazepine. These observations suggest that oxcarbazepine monotherapy, pending additional trials, may be efficacious and may provide clinically meaningful pain relief in patients with neuropathic pain of diabetic origin.     

Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial.

This was a 6-week, randomized, double-blind, multicenter study evaluating the efficacy of pregabalin in the treatment of painful diabetic neuropathy. Two hundred forty-six men and women with painful diabetic neuropathy received pregabalin (150 or 600 mg/day by mouth) or placebo. The primary efficacy variable was mean pain score at the end of treatment. Efficacy results indicate that pregabalin 600 mg/day significantly decreased mean pain score to 4.3 (vs 5.6 for placebo, P = .0002) and increased the proportion of patients who had a > or =50% decrease from baseline pain (39% vs 15% for placebo, P = .002). Pregabalin also significantly reduced sleep interference, past week and present pain intensity, sensory and affective pain scores, and bodily pain and decreased by > or =50% the number of patients describing their pain as gnawing, sickening, fearful, and punishing-cruel. More patients receiving pregabalin 600 mg/day than placebo showed improvement, as rated on the Clinical and Patient Global Impression of Change scales, 73% vs 45% and 85% vs 47%, respectively. Pregabalin 150 mg/day was essentially no different from placebo. Dizziness was the most common side effect. These study results show pregabalin 600 mg/day to be safe and effective in reducing the pain and other associated symptoms of painful diabetic neuropathy. PERSPECTIVE: Painful diabetic peripheral neuropathy is a challenging neuropathic pain syndrome. This randomized controlled trial demonstrates that pregabalin, a new drug that interacts with the alpha2-delta protein subunit of the voltage-gated calcium channel, is an efficacious and safe treatment for the pain of this condition.     

文拉法辛和卡马西平治疗痛性糖尿病周围神经病变的随机双盲双模拟多中心临床试验

目的评价文拉法辛和卡马西平治疗痛性糖尿病周围神经病变的疗效和安全性。方法本试验是一个随机双盲双模拟多中心临床试验。3个临床中心共纳入132例患者。随机分为试验组,文拉发辛胶囊,25mg,每日2次,66例和阳性对照组,卡马西平片,0.1g,每日2次,66例,疗程为14天。主要的疗效指标为数字强度分级法评价疼痛强度。次要指标为生活质量评价。结果共119例患者完成试验。在试验的第5、7、10和14天时,文拉法辛组较卡马西平组明显改善疼痛强度(各组的P值分别为:P=0.02,P=0.03,P=0.003,P=0.001)。在治疗的第10天和第14天文拉法辛较卡马西平明显改善生活质量评价的总分(P=0.02;P=0.01)。文拉法辛和卡马西平都能明显改善患者的睡眠和情绪,但文拉法辛的效果优于卡马西平。文拉法辛最常见的不良反应是胃肠道不适、头昏和嗜睡。文拉法辛组的不良反应发生率为43.90%(4例患者因为不良反应退出试验);卡马西平组的不良反应发生率为25.76%(2例患者因为不良反应退出试验)。结论文拉发辛和卡马西平均有减轻糖尿病神经病变性疼痛以及改善患者生活质量的作用,但文拉发辛在减轻疼痛、改善生活质量方面的作用优于卡马西平,两组的不良反应和不良事件均相似,主要的不良事件是胃肠道不适,头昏和嗜睡。     

Duloxetine vs. placebo in patients with painful diabetic neuropathy

The aim of this study was to examine the efficacy and safety of duloxetine, a balanced and potent dual reuptake inhibitor of serotonin and norepinephrine, in the management of diabetic peripheral neuropathic pain. Serotonin and norepinephrine are thought to inhibit pain via descending pain pathways. In a 12-week, multicenter, double-blind study, 457 patients experiencing pain due to polyneuropathy caused by Type 1 or Type 2 diabetes mellitus were randomly assigned to treatment with duloxetine 20 mg/d (20 mg QD), 60 mg/d (60 mg QD), 120 mg/d (60 mg BID), or placebo. The diagnosis was confirmed by a score of at least 3 on the Michigan Neuropathy Screening Instrument. The primary efficacy measure was the weekly mean score of the 24-h Average Pain Score, which was rated on an 11-point (0-10) Likert scale (no pain to worst possible pain) and computed from diary scores between two site visits. Duloxetine 60 and 120 mg/d demonstrated statistically significant greater improvement compared with placebo on the 24-h Average Pain Score, beginning 1 week after randomization and continuing through the 12-week trial. Duloxetine also separated from placebo on nearly all the secondary measures including health-related outcome measures. Significantly more patients in all three active-treatment groups achieved a 50% reduction in the 24-h Average Pain Score compared with placebo. Duloxetine treatment was considered to be safe and well tolerated with less than 20 percent discontinuation due to adverse events. Duloxetine at 60 and 120 mg/d was safe and effective in the management of diabetic peripheral neuropathic pain.     

Prolonged-release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients

Background: Neuropathic pain remains one of the most challenging pain syndromes; under‐diagnosed, poorly managed and associated with significant co‐morbidity. With standard therapeutic treatments, responders rarely exceed 50% pain relief and the majority suffer from residual pain. Titration to optimum dose is often limited by dose‐related adverse events. Aims: This randomized, double‐blind, placebo‐controlled study assessed the potential benefit of adding oxycodone (OxyContin® tablets) to gabapentin. The primary endpoint was to evaluate the analgesic efficacy of co‐administration of gabapentin and prolonged‐release oxycodone, whilst also evaluating the use of escape medication, sleep quality and global assessment of pain. Methods: Three hundred and thirty eight patients with moderate to severe painful diabetic neuropathy despite receiving their maximum tolerated dose of gabapentin, had oral prolonged‐release oxycodone or placebo tablets added to their therapy for up to 12weeks. Results: Oxycodone–gabapentin reduced pain score by 33% from baseline to end of treatment. The overall treatment effect was greater with oxycodone–gabapentin than with placebo–gabapentin (P=0.007). Oxycodone–gabapentin also significantly improved pain relief vs gabapentin alone (P=0.003). Oxycodone–gabapentin co‐administration was associated with less escape medication use (P=0.03) and fewer nights of disturbed sleep (P<0.05). Discontinuations due to lack of therapeutic effect were much lower (14% vs 54%) with oxycodone–gabapentin. The commonly seen opiate‐induced adverse events were not exacerbated by the combination of oxycodone and gabapentin. Conclusions: This study provides the first evidence that co‐administration of prolonged‐release oxycodone and existing gabapentin therapy has a clinically meaningful effect in painful diabetic neuropathy.     

Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens

Pregabalin binds with high affinity to the alpha2-delta subunit protein of voltage-gated calcium channels and, thereby, reduces release of excitatory neurotransmitters. This 12-week randomised, double-blind, multicentre, placebo-controlled, parallel-group study evaluated the efficacy and safety of pregabalin in patients with chronic postherpetic neuralgia (PHN) or painful diabetic peripheral neuropathy (DPN). Patients were randomised to placebo (n=65) or to one of two pregabalin regimens: a flexible schedule of 150, 300, 450, and 600 mg/day with weekly dose escalation based on patients' individual responses and tolerability (n=141) or a fixed schedule of 300 mg/day for 1 week followed by 600 mg/day for 11 weeks (n=132). Both flexible- and fixed-dose pregabalin significantly reduced endpoint mean pain score (primary outcome) versus placebo (P=0.002, P<0.001) and were significantly superior to placebo in improving pain-related sleep interference (P<0.001). The most common adverse events (AEs) for pregabalin-treated patients were dizziness, peripheral oedema, weight gain (not affecting diabetes control), and somnolence. These results are consistent with previous studies' demonstrating pregabalin's efficacy, tolerability, and safety for treatment of chronic neuropathic pain associated with DPN or PHN. Pregabalin dosing aimed at optimal balance of efficacy and tolerability provides significant pain relief and may reduce risks for AEs and therapy discontinuation.     

Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial

A randomized, double-blind, placebo-controlled, parallel-group, multicenter, 8-week trial (with subsequent open-label phase) evaluated the effectiveness of pregabalin in alleviating pain associated with diabetic peripheral neuropathy (DPN). For enrollment, patients must have had at baseline: 1- to 5-year history of DPN pain; pain score ≥40 mm (Short-Form McGill Pain Questionnaire [SF-MPQ] visual analogue scale); average daily pain score of ≥4 (11-point numerical pain rating scale [0=no pain, 10=worst possible pain]). One hundred forty-six (146) patients were randomized to receive placebo (n=70) or pregabalin 300 mg/day (n=76). Primary efficacy measure was endpoint mean pain score from daily patient diaries (11-point numerical pain rating scale). Secondary measures included SF-MPQ scores; sleep interference scores; Patient and Clinical Global Impression of Change (PGIC and CGIC); Short Form-36 (SF-36) Health Survey scores; and Profile of Mood States (POMS) scores. Safety assessment included incidence and intensity of adverse events, physical and neurological examinations, and laboratory evaluations. Pregabalin produced significant improvements versus placebo for mean pain scores (P<0.0001); mean sleep interference scores (P<0.0001); total SF-MPQ score (P<0.01); SF-36 Bodily Pain subscale (P<0.03); PGIC (P=0.001); and Total Mood Disturbance and Tension–Anxiety components of POMS (P<0.03). Pain relief and improved sleep began during week 1 and remained significant throughout the study (P<0.01). Pregabalin was well tolerated despite a greater incidence of dizziness and somnolence than placebo. Most adverse events were mild to moderate and did not result in withdrawal. Pregabalin was safe and effective in decreasing pain associated with DPN, and also improved mood, sleep disturbance, and quality of life.     

Double-blind, placebo-controlled trial of lamotrigine in combination with other medications for neuropathic pain

This randomized, double-blind, placebo-controlled study was undertaken to evaluate the efficacy and tolerability of lamotrigine added to gabapentin, a tricyclic antidepressant, or a nonopioid analgesic in patients whose neuropathic pain was inadequately controlled with these medications. Patients with neuropathic pain from diabetic peripheral neuropathy, postherpetic neuralgia, traumatic/surgical nerve injury, incomplete spinal cord injury, trigeminal neuralgia, multiple sclerosis, or HIV-associated peripheral neuropathy, who had a mean weekly pain score > or =4 on an 11-point numerical rating scale, were randomized to receive a flexible dose of lamotrigine 200, 300, or 400mg daily (n=111) or placebo (n=109) for up to 14 weeks (including eight weeks of dose escalation) in addition to their prestudy regimen of gabapentin, a tricyclic antidepressant, or a nonopioid analgesic. No statistically significant difference in the mean change in pain-intensity score from baseline to Week 14 (primary endpoint) was detected between lamotrigine and placebo (P=0.67). Differences between lamotrigine and placebo were not statistically significant for secondary efficacy assessments, including mean changes from baseline in the Short-Form McGill Pain Questionnaire, the Neuropathic Pain Scale, rescue medication use, and the percentages of patients rated as much improved or very much improved at the end of treatment on the Clinician Global Impression of Change scale and the Patient Global Impression of Change scale. Lamotrigine was generally well tolerated. Lamotrigine (up to 400 mg/day) added to gabapentin, a tricyclic antidepressant, or a nonopioid analgesic did not demonstrate efficacy as an adjunctive treatment of neuropathic pain but was generally safe and well tolerated.     

Transdermal clonidine compared to placebo in painful diabetic neuropathy using a two-stage ‘enriched enrollment’ design

Because a variety of mechanisms may generate pain in neuropathic pain syndromes, conventional clinical trial methods may fail to identify some potentially useful drugs; a drug affecting just a single mechanism may work in too few patients to yield a statistically significant result for the trial. To test a previous clinical observation that approximately one-quarter of patients with painful diabetic neuropathy appear responsive to clonidine, we conducted a formal clinical trial of transdermal clonidine in painful diabetic neuropathy patients using a 2-stage enriched enrollment design. In the first stage (study I), 41 patients with painful diabetic neuropathy completed a randomized, 3-period crossover comparison of transdermal clonidine (titrated from 0.1 to 0.3 mg/day) to placebo patches. Twelve apparent responders from study I were entered into the ‘enriched enrollment’ second stage (study II), consisting of an additional 4 double-blind, randomized, 1-week treatment periods with transdermal clonidine and placebo. Study I showed that in the overall group of 41 patients, pain intensity differed little during clonidine and placebo treatment. In study II, however, the 12 apparent responders from study I had 20% less pain with clonidine than placebo (95% confidence interval (CI): 4–35% pain reduction; P = 0.015), confirming that their pain was responsive to clonidine. None of the 3 consistent clonidine responders who were tested with the -adrenergic blocker phentolamine had relief of pain, suggesting that clonidine's pain relief is not mediated by a decrease in sympathetic outflow. A post-hoc analysis of many variables suggested that patients who described their pain as sharp and shooting may have a greater likelihood of responding to clonidine. The results of this study support the hypothesis that there is a subset of patients with painful diabetic neuropathy who benefit from systemic clonidine administration and illustrate the value of an enriched enrollment technique in analgesic trials.     

Tramadol 37.5-mg/acetaminophen 325-mg combination tablets added to regular therapy for rheumatoid arthritis pain: a 1-week, randomized, double-blind, placebo-controlled trial

OBJECTIVE: This study evaluated the efficacy and tolerability of tramadol 37.5-mg/acetaminophen 325-mg combination tablets (tramadoUAPAP) as add-on therapy in subjects with rheumatoid arthritis (RA) pain that was inadequately controlled by NSAIDs and disease-modifying antirheumatic drugs alone. METHODS: Subjects in this multicenter, double-blind trial were randomized in a 3:1 ratio to receive 1 tramadol/ APAP tablet TID or a matching placebo for 1 week. Stable doses of previous medications were continued during the study. The primary efficacy variable was the mean daily pain relief score over 1 week, measured on a 6-point scale (4 = complete; ' = a lot; 2 = some; 1 = a little; 0 = none; -1 = worse). Secondary outcomes included the mean daily pain intensity score, measured on a 100-mm visual analog scale (VAS) (from 0 mm = no pain to 100 mm = extreme pain); pain intensity and pain relief at day 7; subjects' and investigators' mean overall assessments of study drug, measured on a Likert scale (from 2 = very good to -2 = very poor); and subjects' assessments of 8 aspects of physical function (measured on the Health Assessment Questionnaire). RESULTS: Of 277 subjects randomized to treatment, 267 (201 tramadol/APAP, 66 placebo) were included in the intent-to-treat population. Mean (SD) daily pain relief scores at the end of 1 week were significantly greater in the tramadol/APAP group compared with the placebo group (1.04 [0.89] vs 0.78 [0.80], respectively; P = 0.037), and mean daily pain intensity scores at the end of 1 week were significantly lower (47.23 [19.96] vs 53.81 [16.59]; P = 0.018). Physical function at the end of 1 week did not differ significantly between tramadol/APAP and placebo. Two hundred seventy-two subjects (205 tramadol/APAP, 67 placebo) were evaluable for tolerability. One hundred thirty-three of these subjects had at least 1 adverse event. The incidence of adverse events was significantly higher in the tramadol/APAP group than in the placebo group (57.6% vs 22.4%; P < 0.001). Discontinuations due to adverse events occurred in 19.0% of the tramadol/APAP group and 3.0% of the placebo group (P = 0.001). Of 213 treatment-related adverse events in tramadol/APAP subjects, nausea (34.1%) was the most frequent, followed by dizziness (20.0%) and vomiting (15.6%). One serious adverse event--chest discomfort, nausea, and vomiting after taking study medication-occurred in a subject receiving tramadol/APAP The symptoms resolved 1 day after discontinuing tramadol/APAP. CONCLUSIONS: In this study, tramadol/APAP used as add-on therapy in subjects with symptomatic RA was associated with a significant improvement in pain relief and a significant reduction in pain intensity compared with placebo, with no improvement in physical function. Use of tramadol/APAP may be considered when analgesics are needed in addition to conventional NSAIDs and disease-modifying antirheumatic drugs in subjects with RA.     

Patient compliance with SSRIs and gabapentin in painful diabetic neuropathy

BACKGROUND: Anticonvulsants are widely used for treatment of painful diabetic neuropathy. Selective serotonin reuptake inhibitors (SSRIs) are not first-line drugs but are commonly prescribed medicines for chronic pain. The majority of patients are hesitant to use these drug groups, thus their compliance remains an issue. OBJECTIVE: To compare patient compliance and the effectiveness of 2 SSRIs (paroxetine or citalopram) and 1 anticonvulsant (gabapentin) in patients with painful diabetic neuropathy. METHODS: This was a 6 months prospective trial in 101 patients with painful diabetic neuropathy and minimum score of 2 on a pain intensity scale ranging of 0 to 4. Compliance was assessed with patient interviews and pill counts. Adverse events, early discontinuation or satisfaction with treatment were also evaluated. RESULTS: Patients receiving SSRIs reported greater satisfaction and fewer concerns of the side-effects with their treatment (P<0.05) compared with the patients taking gabapentin. There was statistically significant better mood in the SSRI group (P<0.05). Overall, 43.5% of those taking SSRIs noticed no effect on the pain control, 50% felt better, and 6.5% felt worse. Among the patients taking gabapentin, 51% felt better, 40.5% noticed no effect, and 8.5% felt worse. Finally, on the pill count, more patients on SSRIs (93.5%) than on gabapentin (82.9%) were taking over the 75% of their medication (P<0.05). CONCLUSIONS: The lack of negative effects on quality of life, the better compliance, and the comparable efficiency of SSRIs suggest that these drugs may be considered as alternative to gabapentin in painful diabetic neuropathy.     

Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial

OBJECTIVE: The aim of this trial was to evaluate the effects of alpha-lipoic acid (ALA) on positive sensory symptoms and neuropathic deficits in diabetic patients with distal symmetric polyneuropathy (DSP). RESEARCH DESIGN AND METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 181 diabetic patients in Russia and Israel received once-daily oral doses of 600 mg (n = 45) (ALA600), 1,200 mg (n = 47) (ALA1200), and 1,800 mg (ALA1800) of ALA (n = 46) or placebo (n = 43) for 5 weeks after a 1-week placebo run-in period. The primary outcome measure was the change from baseline of the Total Symptom Score (TSS), including stabbing pain, burning pain, paresthesia, and asleep numbness of the feet. Secondary end points included individual symptoms of TSS, Neuropathy Symptoms and Change (NSC) score, Neuropathy Impairment Score (NIS), and patients' global assessment of efficacy. RESULTS: Mean TSS did not differ significantly at baseline among the treatment groups and on average decreased by 4.9 points (51%) in ALA600, 4.5 (48%) in ALA1200, and 4.7 (52%) in ALA1800 compared with 2.9 points (32%) in the placebo group (all P < 0.05 vs. placebo). The corresponding response rates (>/=50% reduction in TSS) were 62, 50, 56, and 26%, respectively. Significant improvements favoring all three ALA groups were also noted for stabbing and burning pain, the NSC score, and the patients' global assessment of efficacy. The NIS was numerically reduced. Safety analysis showed a dose-dependent increase in nausea, vomiting, and vertigo. CONCLUSIONS: Oral treatment with ALA for 5 weeks improved neuropathic symptoms and deficits in patients with DSP. An oral dose of 600 mg once daily appears to provide the optimum risk-to-benefit ratio.     

A randomized, double-blind, placebo-controlled, two-period, crossover, pilot trial of lamotrigine in patients with central pain due to multiple sclerosis

BACKGROUND: Approximately 30% of patients with multiple sclerosis (MS) have central pain (CP). The anticonvulsant lamotrigine has been shown to be efficacious in some types of CP, but its efficacy in MS-related CP has not been confirmed. OBJECTIVE: The aim of this pilot trial was to provide preliminary data for a planned larger trial. METHODS: A randomized, double-blind, placebo-controlled, 2-period, crossover pilot study was conducted in a sample of patients aged > or =18 years with CP due to MS. The 2 treatment periods began with an 8-week, double-blind titration period, during which the number of pills of study drug was increased until either total pain relief was achieved, 1 or more unmanageable adverse events were reported, or a maximum of 16 pills (400 mg of lamotrigine) were used daily. A 3-week maintenance period at the final prescribed amount was followed by a 2-week tapering period; there was a 2-week washout between the 2 treatment periods, after which patients were administered the alternate drug. Outcomes before, during, and after each study period were assessed using validated measures of pain and quality of life (the Brief Pain Inventory [BH], the Neuropathic Pain Scale [NPS], and the 54-item MS Quality of Life [MSQOL-54] questionnaire). Throughout the trial, patients completed a daily diary consisting of questions from the BPI-Short Form, as well as questions about the use of other analgesic drugs, changes in health, and the occurrence of adverse events. The BPI and NPS were completed weekly during telephone calls with the research coordinator, and the MSQOL-54 was administered during clinic visits (ie, visits at screening, baseline, end of period 1, and termination). The primary outcome measure was the mean pain intensity score during the final maintenance week of each of the 2 study periods. RESULTS: A total of 12 patients were enrolled and completed at least the first period of the study. Ten patients were women. The mean (SD) age was 49.3 (11.7) years, and the mean (SD) weight was 76.5 (19.9) kg. The analysis revealed no significant differences between the lamotrigine and placebo periods in any of the study outcomes related to pain or quality of life. Regarding adverse events, 1 patient developed a moderate rash during the study, but the physician attributed this lesion to herpes zoster; this patient completed the study. While other adverse events were mild, 2 patients were withdrawn from the study after experiencing adverse events during the first study period; 1 had been receiving lamotrigine and the other placebo. CONCLUSION: The results from this pilot trial did not support either the use of lamotrigine in patients with MS-related CP or the need for a larger trial.     

Efficacy of desipramine in painful diabetic neuropathy: a placebo-controlled trial

Although amitriptyline relieves pain in many patients with painful diabetic neuropathy, side effects often preclude effective treatment. Desipramine has the least anticholinergic and sedative effects of the first generation tricyclic antidepressants. We compared a 6 week course of desipramine (mean dose, 201 mg/day) to active placebo in 20 patients with painful diabetic neuropathy in a double-blind crossover trial. Pain relief with desipramine was statistically significant in weeks 5 and 6. Eleven patients reported at least moderate relief with desipramine, compared to 2 with placebo. Pain relief tended to be greater in depressed patients, but relief was also observed in patients who did not show an antidepressant effect. We conclude that desipramine relieves pain in many patients with painful diabetic neuropathy, offering an alternative for patients unable to tolerate amitriptyline. Blockade of norepinephrine reuptake, an action shared by desipramine, amitriptyline, and other antidepressants proven effective in neuropathic pain, may mediate this analgesic effect.