Capsaicin 8% patch repeat treatment plus standard of care (SOC) versus SOC alone in painful diabetic peripheral neuropathy: a randomised, 52-week, open-label, safety study.

BACKGROUND: 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). METHODS: 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. RESULTS: 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%). CONCLUSION: 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. TRIAL REGISTRATION: ClinicalTrials.gov registration: NCT01478607 . Date of registration November 21, 2011; retrospectively registered.

Are treatment benefits in neuropathic pain reflected in the Self Assessment of Treatment questionnaire?

BACKGROUND/OBJECTIVE: The Self Assessment of Treatment (SAT) questionnaire was developed to reflect key patient reported outcomes of Neuropathic Pain (NP) treatments. This study aimed to understand how patients perceived the relevance and ease of understanding of the questions in the SAT and to recommend modifications based on patient and clinician interviews. METHODS: Semi-structured interviews were conducted with clinicians and NP patients to provide information regarding treatment attributes and the impact of pain. Patients were debriefed on the SAT, a 5-item scale evaluating pain, activity level, quality of life (QoL) and satisfaction with treatment (recommend treatment and undergo treatment again). The SAT has a recall period reflecting back to the start of treatment. The qualitative analysis software ATLAS.ti 5.0 was used to analyze patient transcripts. Changes to the SAT were integrated into the questionnaire for a second round of debriefing interviews. RESULTS: Three NP clinicians and 44 patients (20 painful diabetic neuropathy, 16 HIV-associated neuropathy and 8 post herpetic neuralgia) with a mean age of 60.3 (12.3) years and an even gender distribution were interviewed. Patient treatment experience included anticonvulsants (73%), antidepressants (34%), opioids (25%), and topical medications (41%). Pain descriptors and treatment attributes were similar across the three NP groups. Pain relief was judged the most important treatment attribute, followed by ability to undertake activities. Sleep improvement was another important attribute. Activity limitations and QOL were perceived as too broad and non-specific, and were split into 3 concepts each (activity limitations was split into self care, daily and physical activities and QOL was split into sleep, emotions, and social function). A 7-day recall period was introduced. The item stem and response options were made consistent, and a baseline and follow-up questionnaires were developed (except for the satisfaction items) to enable monitoring onset of treatment benefit and change over time. CONCLUSIONS: The content validity of the revised SAT was improved by the qualitative research, and NP treatment benefits are reflected in a more consistent fashion by the changes. Baseline and follow-up versions make it possible to perform assessments of change over time.

Capsaicin 8% Patch Versus Oral Neuropathic Pain Medications for the Treatment of Painful Diabetic Peripheral Neuropathy: A Systematic Literature Review and Network Meta-analysis.

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.

Capsaicin 8% Patch Repeat Treatment in Nondiabetic Peripheral Neuropathic Pain: A 52-Week, Open-Label, Single-Arm, Safety Study.

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.

Capsaicin 8% Patch in Painful Diabetic Peripheral Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Study.

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. PERSPECTIVE: 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.

Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13-week, randomized trial.

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.

Predictors of Response in Patients With Postherpetic Neuralgia and HIV-Associated Neuropathy Treated With the 8% Capsaicin Patch (Qutenza).

OBJECTIVES: Qutenza is a high-dose capsaicin patch used to relieve neuropathic pain from postherpetic neuralgia (PHN) and HIV-associated neuropathy (HIV-AN). In clinical studies, some patients had a dramatic response to the capsaicin patch. Our objective was to determine the baseline characteristics of patients who best benefit from capsaicin patch treatment. METHODS: We conducted a meta-analysis of 6 completed randomized and controlled Qutenza studies by pooling individual patient data. Sustained response was defined as>50% decrease in the mean pain intensity from baseline to weeks 2 to 12, and Complete Response as an average pain intensity score≤1 during weeks 2 to 12. Logistic regression was used to identify predictors of response and Complete Response, and subgroups of patients who respond best to the capsaicin patch. RESULTS: Baseline pain intensity score (BPIS)≤4 was a predictor of Sustained and Complete Response in PHN and HIV-AN patients; absence of allodynia and presence of hypoesthesia, and a McGill Pain Questionnaire (MPQ) sensory score <22 were predictors of Sustained Response in PHN patients; female sex was a predictor of Sustained and Complete Response in HIV-AN patients. Thus, characteristics associated with the highest chance of responding to the capsaicin patch were, for PHN, BPIS≤4, MPQ sensory score≤22, absence of allodynia, and presence of hypoesthesia; for HIV-AN, they were female sex and BPIS≤4. Patients with these characteristics had a statistically significantly greater chance of responding to the capsaicin patch than other patients. DISCUSSION: We identified subpopulations of PHN and HIV-AN patients likely to benefit from the capsaicin patch.

Humanistic and economic burden of painful diabetic peripheral neuropathy in Europe: A review of the literature.

AIMS: Painful diabetic peripheral neuropathy (PDPN) is a common complication of diabetes mellitus. A systematic literature review was conducted to provide an overview of published literature in the last 10-years on the epidemiology, humanistic burden and economic burden of PDPN in Europe. METHODS: A search was performed according to pre-defined strategy and review criteria in Embase, Pubmed, and conference proceedings databases from 2003 till December 2012. In total, 30 publications written in English covering the relevant patient population and topics of interest. RESULTS: European prevalence ranges from 6% to 34% in diabetes mellitus patients. PDPN has a significant humanistic and economic impact. Patients are limited in their general functioning and their ability to sleep and often experience anxiety and depression. Not surprisingly, PDPN is associated with reduced Health-Related-Quality-of-Life (HRQoL). PDPN patients incur high health care costs due to hospitalizations and outpatient visits. In addition, the painful symptoms cause impaired work productivity. Studies suggest both humanistic and economic burden increase with higher pain severity. CONCLUSIONS: The burden from PDPN appears to be higher with increasing pain severity. More severe pain leads to a higher impairment in daily functioning, sleep and HRQoL. Higher pain intensity also leads to increasing healthcare costs and work productivity losses.

Qutenza (capsaicin) 8% patch onset and duration of response and effects of multiple treatments in neuropathic pain patients.

INTRODUCTION: Qutenza (capsaicin) 8% patch is used to treat various neuropathic indications, including postherpetic neuralgia (PHN) and human immunodeficiency virus-associated neuropathy (HIV-AN). OBJECTIVES: We conducted a meta-analysis of Qutenza studies to describe clinical phenomena of effects of Qutenza treatment better, such as onset and duration of pain relief, and the need for retreatments. METHODS: The meta-analyses combined individual patient data (1313 participants with PHN and 801 with HIV-AN) from 7 completed randomized, double-blind, controlled studies. Studies had similar designs, and all used the Qutenza patch (8% capsaicin) and a low-dose control patch (0.04% capsaicin). A 30% response was defined as a ≥30% decrease in mean pain intensity score during week 2 to end of follow-up; complete pain relief was defined as an average pain intensity ≤1 during week 2 to end of follow-up. Duration of response was calculated using the data from long-term studies as the time from onset of response to offset of response, retreatment, or end of follow-up (whichever occurred first). RESULTS: Overall 44% of PHN and 41% of HIV-AN patients had a 30% response, and 11% and 7%, respectively, had complete pain relief 2 to 12 weeks after treatment with Qutenza. The mean (median) onset of response to Qutenza was 3.4 (1) days for PHN and 6.5 (4) days for HIV-AN (delayed due to an initial increase in discomfort). The mean (median) duration of response after 1 Qutenza treatment was 5 (3) months. Of the patients followed-up for 12 months, 40% PHN and 36% HIV-AN patients had a 30% response, and 9% and 10%, respectively, had complete pain relief from week 2 to end of follow-up. CONCLUSIONS: Qutenza is effective in a high proportion of patients. In patients who respond to Qutenza, analgesia starts within a few days of treatment and lasts on average 5 months.

Efficacy of Qutenza® (capsaicin) 8% patch for neuropathic pain: a meta-analysis of the Qutenza Clinical Trials Database.

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.

Validation of the Self-Assessment of Treatment Questionnaire among Patients with Postherpetic Neuralgia.

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.

Safety and efficacy of esreboxetine in patients with fibromyalgia: An 8-week, multicenter, randomized, double-blind, placebo-controlled study.

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.