Highlights • A formal review was conducted for painful diabetic peripheral neuropathy (PDPN). • European PDPN prevalence ranges from 6% to 34% in diabetic patients. • PDPN is associated with reduced ...HRQoL as a result of the symptoms. • PDPN patients incur high health care costs and have impaired work productivity. • The burden from PDPN appears to be higher with increasing pain severity.
Abstract Purpose A network meta-analysis (NMA) was performed, aiming to assess the relative efficacy and tolerability of the capsaicin 179-mg (8% weight for weight) cutaneous patch (capsaicin 8% ...patch) compared with oral, centrally acting agents (ie, pregabalin, gabapentin, duloxetine, amitriptyline) in patients with painful diabetic peripheral neuropathy (PDPN). Methods A systematic search of EMBASE/MEDLINE, Cochrane Library, and the National Health Service Centre for Reviews and Dissemination Database of Abstracts of Reviews of Effects was conducted to identify all randomized controlled trials. Data from eligible studies according to predefined inclusion and exclusion criteria were extracted, and analyses were based on aggregate-level data. Efficacy outcomes were the proportions of patients with ≥30% and ≥50% reductions in pain, and tolerability outcomes were somnolence, dizziness, nausea, diarrhea, constipation, headache, fatigue, insomnia, and rate of discontinuation due to adverse events (AEs). Data were analyzed by using a Bayesian NMA. Fixed and random effects models were estimated. Relative treatment effect was presented as odds ratios (ORs) with 95% CIs. Sources of heterogeneity were assessed. Findings The NMA included 25 randomized controlled trials. For ≥30% pain reduction, the capsaicin 8% patch was significantly more effective than placebo (OR, 2.28 95% CI, 1.19–4.03), exhibited a numerical advantage compared with pregabalin (OR, 1.83 95% CI, 0.91–3.34) and gabapentin (OR, 1.66 95% CI, 0.74–3.23), and had similar efficacy compared with duloxetine (OR, 0.99 95% CI, 0.5–1.79). The evidence available was not sufficient to assess the relative efficacy of amitriptyline. In the NMA for tolerability, the capsaicin 8% patch was only included for headache because the incidence was 0% for the other outcomes. Oral, centrally acting agents had a significantly elevated risk compared with placebo for somnolence (pregabalin, gabapentin, duloxetine, and amitriptyline), dizziness (pregabalin, gabapentin, duloxetine, and amitriptyline), nausea (duloxetine), diarrhea (duloxetine), fatigue (duloxetine), and discontinuation because of AEs (pregabalin, gabapentin, and duloxetine). Compared with pregabalin and gabapentin, duloxetine had a significantly lower risk of dizziness but a significantly higher risk of nausea. Implications This NMA suggests that the efficacy observed with the capsaicin 8% patch is similar to that observed with oral agents (ie, pregabalin, duloxetine, gabapentin) in patients with PDPN. The oral agents were associated with a significantly elevated risk of somnolence, dizziness, fatigue, and discontinuation because of AEs compared with placebo. The capsaicin 8% patch was as effective as oral centrally acting agents in these patients with PDPN but offers systemic tolerability benefits.
ABSTRACT
Objective: This trial evaluated the efficacy and safety of pregabalin dosed twice daily (BID) for relief of neuro-pathic pain associated with postherpetic neuralgia (PHN).
Research design ...and methods: The 13‐week, double-blind, placebo-controlled study randomized 370 patients with PHN to pregabalin (150, 300, or 600 mg/day BID) or placebo.
Main outcome measures: Primary efficacy measure was endpoint mean pain score from daily pain diaries. Secondary efficacy measures included endpoint mean sleep-interference score from daily sleep diaries and Patient Global Impression of Change (PGIC). Safety evaluations included adverse events (AEs), physical and neurologic examinations, 12-lead ECG, vital signs, and laboratory testing.
Results: Pregabalin provided significant, dose-proportional pain relief at endpoint: difference from placebo in mean pain score, 150 mg/day, –0.88, p = 0.0077; 300 mg/day, –1.07, p = 0.0016; 600 mg/day, –1.79, p = 0.0003. Weekly mean pain scores significantly improved as early as week 1. Sleep interference in all pregabalin groups was also significantly improved at endpoint, compared with placebo ( p < 0.001), beginning at week 1 ( p < 0.01). At study termination, patients in the 150 (p = 0.02) and 600 mg/day (p = 0.003) groups were more likely to report global improvement than were those in the placebo group.
Most AEs were mild or moderate. Among pregabalin-treated patients, 13.5% withdrew due to AEs, most commonly for dizziness (16 patients, 5.8%), somnolence (8, 2.9%), or ataxia (7, 2.5%).
Conclusions: Pregabalin, dosed BID, reduced neuropathic pain associated with PHN and was well tolerated. It also reduced the extent to which pain interfered with sleep. Pregabalin's effects were seen as early as week 1 and were sustained throughout the 13‐week study.
Abstract Background: Esreboxetine is an investigational, highly selective norepinephrine reuptake inhibitor that has been reported to have antinociceptive effects in preclinical pain models. ...Objective: This study assessed the efficacy and safety profile of esreboxetine in the management of fibromyalgia. Methods: This was a multicenter, randomized, double-blind, placebo-controlled trial in patients aged ≥18 years who met American College of Rheumatology criteria for fibromyalgia. Eligible patients were required to have a score ≥40 mm on the 100-mm visual analog scale of the Short-Form McGill Pain Questionnaire at screening and randomization, and a mean score ≥4 on an 11-point pain rating scale (from 0 = no pain to 10 = worst possible pain) based on the weekly mean pain score in the week before randomization. After a 1-week baseline period and a 2-week, single-blind, placebo run-in period, patients were randomized to receive esreboxetine or placebo for 8 weeks, followed by a 1-week follow-up period. Esreboxetine dosing was started at 2 mg/d and was escalated by 2 mg/d every 2 weeks until attainment of a dose of 8 mg/d or the maximum tolerated dose. The primary efficacy outcome was the change from baseline to week 8 in weekly mean pain scores, as derived from patients' daily pain ratings on the 11-point scale. Additional primary efficacy outcomes included changes in the Fibromyalgia Impact Questionnaire (FIQ) total score and the Patient Global Impression of Change (PGIC). The safety profile was evaluated based on observed and spontaneously reported adverse events, laboratory tests, and other safety measures. Results: One hundred thirty-four patients were randomized to each study group, but 1 patient in the placebo group did not receive treatment. Thus, the study population consisted of 267 patients (89.5% female; 88.4% white; mean age, ∼50 years range, 20–84 years). Twenty-seven patients in each group discontinued the study. Adverse events were the most common reason for discontinuation in the esreboxetine group (11 patients), compared with 3 discontinuing due to adverse events in the placebo group. Patient default (withdrawal of consent and loss to follow-up) was the most common reason for discontinuation in the placebo group (13 patients), compared with 10 in the esreboxetine group. The esreboxetine group had significantly greater improvement in the weekly mean pain score compared with the placebo group (mean SE change from baseline: −1.55 0.16 vs −0.99 0.16, respectively; P = 0.006). A significantly greater percentage of patients in the esreboxetine group reported a ≥30% reduction in pain scores compared with the placebo group (37.6% 50/133 vs 22.6% 30/133; P = 0.004). Esreboxetine was associated with significant improvement compared with placebo in the FIQ total score (mean change from baseline: −15.63 1.56 vs −8.07 1.54; P < 0.001). On the PGIC, significantly more patients in the esreboxetine group than in the placebo group reported their condition much or very much improved (odds ratio = 2.42; 90% CI, 1.549-3.786; P < 0.001). Esreboxetine also was associated with significant improvements in secondary outcomes compared with placebo. These included fatigue, as reflected in scores on the Multidimensional Assessment of Fatigue (mean SE change from baseline: −6.39 0.75 vs −2.82 0.75, respectively; P < 0.001), and scores on measures of patient function and health-related quality of life, including the 36-item Short Form Health Survey (SF-36) Physical Component Summary (mean change from baseline: 4.36 0.59 vs 1.86 0.59; P = 0.002), the SF-36 Mental Component Summary (mean change from baseline: 4.25 0.83 vs 1.81 0.83; P = 0.019), and the Sheehan Disability Scale total score (mean change from baseline: −6.50 0.64 vs −2.79 0.61; P < 0.001). Numerically more patients in the esreboxetine group than in the placebo group reported at least one adverse event (71.6% vs 57.1%), most commonly constipation (17.2% vs 5.3%), insomnia (15.7% vs 3.0%), dry mouth (15.7% vs 2.3%), and headache (10.4% vs 2.3%). Conclusions: In this 8-week trial in patients with fibromyalgia, esreboxetine was associated with significant reductions in pain scores compared with placebo. It was also associated with improvements in outcomes relevant to fibromyalgia, including the PGIC, function, and fatigue. ClinicalTrials.gov identifier: NCT00357825.
Qutenza is effective for the treatment of both postherpetic neuralgia and human immunodeficiency virus-associated neuropathy compared to low-dose control patch.
Qutenza® is a capsaicin patch used to ...treat peripheral neuropathic pain, including postherpetic neuralgia (PHN) and human immunodeficiency virus-associated neuropathy (HIV-AN). The Qutenza Clinical Trials Database has been assembled to more fully characterize the effects of Qutenza. We conducted a within-subject meta-analysis of Qutenza studies to further define the medication’s efficacy profile across studies. The meta-analysis combined individual patient data from randomized, controlled studies of Qutenza in peripheral neuropathic pain (1458 subjects treated with approved doses of Qutenza or control patches; 1120 with PHN and 338 with HIV-AN). These 7 studies had similar designs and were performed with the high-dose 8% capsaicin Qutenza patch and a 0.04% low-dose control patch. The difference between treatment groups for the primary efficacy end point of percentage change from baseline to weeks 2 to 12 on pain intensity score was calculated. Response was defined as a ⩾30% decrease in mean pain intensity score during weeks 2 to 12. The overall between-group difference in percentage change from baseline in pain intensity was 8.0% (95% confidence interval 4.6, 11.5; P<.001), which statistically significantly favored Qutenza over low-dose control. Qutenza superiority was demonstrated for both PHN and HIV-AN patients for the primary end point and the end point proportion of 30% pain reduction response, and for PHN patients for the end point of proportion of 50% pain reduction response. These results confirm that Qutenza is effective for the treatment of both PHN and HIV-AN compared to low-dose control patch.
This 12-week study evaluated the efficacy and safety of capsaicin 8% patch versus placebo patch in painful diabetic peripheral neuropathy (PDPN). Patients aged 18 years or older with PDPN were ...randomized (1:1) to one 30-minute treatment (capsaicin 8% patch or placebo patch) to painful areas of the feet. Overall, 369 patients were randomized (capsaicin 8% patch, n = 186; placebo patch, n = 183). Percentage reduction in average daily pain score from baseline to between weeks 2 through 8 (the primary end point) was statistically significant for capsaicin 8% patch versus placebo (−27.4% vs −20.9%; P = .025); improvements in pain were observed from week 2 onward. Versus placebo, patients treated with capsaicin 8% patch had a shorter median time to treatment response (19 vs 72 days) and modest improvements in sleep interference scores from baseline to between weeks 2 through 8 (P = .030) and weeks 2 through 12 (P = .020). Apart from application site reactions, treatment-emergent adverse events were similar between groups. No indications of deterioration in sensory perception of sharp, cold, warm, or vibration stimuli were observed. In patients with PDPN, capsaicin 8% patch treatment provided modest pain relief and sleep quality improvements versus a placebo patch, similar in magnitude to other treatments with known efficacy, but without systemic side effects or sensory deterioration.
To our knowledge, this is the first study of the capsaicin 8% patch versus placebo in patients with PDPN to show that one 30-minute capsaicin treatment provides modest improvements in pain and sleep quality. Results confirm the clinical utility of the capsaicin 8% patch in the diabetic population.
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•Capsaicin 8% patch provided effective relief in painful diabetic peripheral neuropathy.•Improvements in sleep quality were modest and significant with capsaicin 8% patch.•Capsaicin 8% patch was well tolerated with no deterioration in sensory perception.•Safety and tolerability were in line with previous studies of capsaicin 8% patch.
Introduction. A five-item Self-Assessment of Treatment (SAT) was developed to assess improvement and satisfaction with treatment associated with the application of a novel high concentration 8% ...capsaicin topical patch in clinical trials in patients with postherpetic neuralgia (PHN). This study evaluated the item performance and psychometric properties of the SAT. Methods. The SAT, Brief Pain Inventory, SF-36v2, Short-Form McGill Pain Questionnaire, and Patient and Clinician Global Impression of Change (PGIC; CGIC) scores were measured in two 12-week Phase 3 clinical trials. Factor analysis assessed the underlying factor structure, followed by examination of the reliability and validity of the multi-item domain. Results. Pooled data from 698 patients completing SAT after 12 weeks of treatment were analyzed. A one-factor model combining three of the five items emerged as the optimal solution. Internal consistency reliability of this treatment efficacy factor was high (Cronbach's alpha = 0.89). Construct validity was demonstrated by moderate to high correlations with change in other study endpoints. SAT mean scores consistently discriminated between patient change groups defined by PGIC and CGIC. Conclusions. The measurement properties of the three-item version of SAT are valid and reliable for assessment of treatment with a high concentration capsaicin patch among patients with PHN.
OBJECTIVES:To investigate the long-term safety and tolerability of capsaicin 8% patch repeat treatment in nondiabetic patients with peripheral neuropathic pain.
METHODS:A prospective, open-label, ...observational study in patients with postherpetic neuralgia, posttraumatic or postsurgical nerve injury, HIV-associated distal sensory polyneuropathy, or other peripheral neuropathic pain, and average daily pain score ≥4, who received ≤6 capsaicin 8% patch treatments over 52 weeks according to clinical need (retreatment at 9 to 12 wk intervals). Sensory testing and analgesic effectiveness were assessed using “bedside tests” and Brief Pain Inventory (question 5).
RESULTS:Overall, 306 patients received treatment. Treatment-emergent adverse events (TEAEs) and drug-related TEAEs were reported by 252 (82.4%) and 207 (67.6%) patients. Application site pain was the most common drug-related TEAE (n=112, 36.6%); no drug-related serious TEAEs were reported. Sensory category shift analyses from baseline to end of study (EoS) in patients attending at least 2 sensory visits (n=278 for all tests except warm, n=277) found sensory deterioration/loss in at least 1 modality in 50.4% (n=140); deterioration/loss in 1, 2, 3, 4, or 5 modalities occurred in 26.6% (n=74), 14.0% (n=39), 5.8% (n=16), 2.5% (n=7), and 1.4% (n=4) cases. Newly emergent hyperesthesia or allodynia was apparent in 1.1% to 3.6% of the cases (depending on modality) by EoS. Between 25.2% and 32.0% of patients reported improvement in a sensory modality by EoS. Average daily pain was 6.6 and 4.7 at baseline and month 12.
CONCLUSIONS:Generally, capsaicin 8% patch repeat treatment over 52 weeks was well tolerated, with variable alteration in sensory function and minimal chance of complete sensory loss.
This 52-week study evaluated the long-term safety and tolerability of capsaicin 8% w/w (179 mg) patch repeat treatment plus standard of care (SOC) versus SOC alone in painful diabetic peripheral ...neuropathy (PDPN).
Phase 3, multinational, open-label, randomised, controlled, 52-week safety study, conducted in Europe. Patients were randomised to capsaicin 8% patch repeat treatment (30 or 60 min; 1-7 treatments with ≥ 8-week intervals) to painful areas of the feet plus SOC, or SOC alone. The primary objective was the safety of capsaicin 8% patch repeat treatment (30 min and 60 min applications) plus SOC versus SOC alone over 52 weeks, assessed by changes in Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) total score from baseline to end of study (EOS). Secondary safety endpoints included Utah Early Neuropathy Scale (UENS) assessments and standardised testing of sensory perception and reflex function.
Overall, 468 patients were randomised (30 min plus SOC, n = 156; 60 min plus SOC, n = 157; SOC alone, n = 155). By EoS, mean changes in Norfolk QOL-DN total score from baseline estimated mean difference versus SOC alone; 90% CI for difference were: 30 min plus SOC, -27.6% -20.9; -31.7, -10.1; 60 min plus SOC, -32.8% -26.1; -36.8, -15.4; SOC alone, -6.7%. Mean changes difference versus SOC alone in UENS total score by EoS versus baseline were: 30 min plus SOC, -2.1 -0.9; -1.8, 0.1; 60 min plus SOC, -3.0 -1.7; -2.7, -0.8; SOC alone, -1.2. No detrimental deterioration was observed in any of the Norfolk or UENS subscales by EoS with capsaicin. Also, no worsening in sensory perception testing of sharp, warm, cold and vibration stimuli was found with capsaicin by EoS. Capsaicin treatment was well tolerated and the most frequent treatment-emergent adverse events were application site pain (30 min, 28.2%; 60 min, 29.3%), burning sensation (30 min, 9.0%; 60 min, 9.6%) and application site erythema (30 min, 7.7%; 60 min, 8.9%).
In patients with PDPN, capsaicin 8% patch repeat treatment plus SOC over 52 weeks was well tolerated with no negative functional or neurological effects compared with SOC alone.
ClinicalTrials.gov registration: NCT01478607 . Date of registration November 21, 2011; retrospectively registered.
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