HIV-associated Distal Sensory Polyneuropathy Research Articles

Neuroinflammation in the Dorsal Root Ganglia and Dorsal Horn Contributes to Persistence of Nociceptor Sensitization in SIV-Infected Antiretroviral Therapy-Treated Macaques

Despite the development of antiretroviral therapy (ART), HIV-associated distal sensory polyneuropathy remains prevalent. Using SIV-infected rhesus macaques, this study examined molecular mechanisms of peripheral and central sensitization to infer chronic pain from HIV infection. Previous studies identified atrophy in nociceptive neurons during SIV infection, which was associated with monocyte infiltration into the dorsal root ganglia (DRG). However, the sensory signaling mechanism connecting this pathology to symptoms remains unclear, especially because pain persists after resolution of high viremia and inflammation with ART. We hypothesized that residual DRG and dorsal horn neuroinflammation contributes to nociceptive sensitization. Using three cohorts of macaques [uninfected (SIV-), SIV-infected (SIV+), and SIV infected with ART (SIV+/ART)], this study showed an increase in the cellular and cytokine inflammatory profiles in the DRG of SIV+/ART macaques compared with uninfected animals. It found significant increase in the expression of nociceptive ion channels, TRPV1, and TRPA1 among DRG neurons in SIV+/ART compared with uninfected animals. SIV-infected and SIV+/ART animals showed reduced innervation of the nonpeptidergic nociceptors into the dorsal horn compared with uninfected animals. Finally, there were a significantly higher number of CD68+ cells in the dorsal horn of SIV+/ART macaques compared with uninfected animals. In summary, these data demonstrate that neuroinflammation, characteristics of nociceptor sensitization, and central terminal atrophy persists in SIV+/ART animals.

Stability of High Concentration Capsaicin in Transfersome Carriers in Gel Dosage Form

Topical capsaicin with high concentrations (8%) is effective in the treatment of pain in Post-Herpetic Neuralgia (PHN) and HIV-Associated Distal Sensory Polyneuropathy (HIV-DSP) patients. High concentrations of capsaicin encapsulated in transfersome nanovesicles aim to reduce the irritating ability of capsaicin when using as drugs. Gel preparations were chosen in the formulation because they are non-sticky, easy to wash, easy to apply, and more practical. The components contained in the gel affect the stability of the gel. Physical and chemical stability tests need to be carried out to ensure the quality, safety and efficacy of the gel so that it meets the expected specifications during its shelf life. This study aims to determine the stability of selected gel formulas containing high concentrations of transfersome capsaicin. The selected gel formula is a gel containing a mixture of phosphatidylcholine (Phospholiphon 90G®) and Tween 80 (80:20). Stability was carried out at high temperature (40±2oC), room temperature (30±2oC), low temperature (5±3oC), and cycling test. The stability parameters tested included organoleptic, pH, viscosity, and assay. The results of the transfersom capsaicin gel stability test showed no change in pH, viscosity, and assay in all storage conditions, but the gel showed a change in color, smell, and taste when stored at high temperatures (40 ± 2oC). It can be concluded that the resulting capsaicin transfersome gel formula with a phospholipid:tween ratio of 80 (80:20) was less stable during 12 weeks of storage at 40 oC

Association of painful human immunodeficiency virus distal sensory polyneuropathy with aberrant expectation of pain relief: functional magnetic resonance imaging evidence.

Mechanisms underlying chronic neuropathic pain associated with HIV-associated distal sensory polyneuropathy are poorly understood, yet 40% of those with distal neuropathy (or 20% of all people with HIV) suffer from this debilitating condition. Central pain processing mechanisms are thought to contribute to the development of HIV neuropathic pain, yet studies investigating central mechanisms for HIV neuropathic pain are few. Considering the motivational nature of pain, we aimed to examine the degree to which expectation of pain onset and expectation of pain offset are altered in sixty-one male patients with HIV-related distal sensory polyneuropathy with (N = 30) and without (N = 31) chronic neuropathic pain. By contrasting painful (foot) and non-painful (hand) sites between those with and without neuropathic pain, we could identify unique neural structures that showed altered activation during expectation of pain offset or relief. Our results showed no evidence for peripheral mechanisms evidenced by lack of significant between group differences in thermo-sensation, subjective pain response or epidermal nerve fibre density. Likewise, we found no significant differences between groups in subjective or brain mechanisms underlying the expectation of pain onset. Conversely, we found significant interaction within right anterior insula during expectation of pain offset in our study in that individuals in the pain group compared to the no-pain group exhibited increased anterior insula activation on the painful compared to the non-painful site. Our findings are consistent with abnormal processing of expectation of pain offset or abnormal pain relief-related mechanisms potentially due to increased emotional distress regarding the experience of chronic endogenous pain.

Prevention of HIV-1 TAT Protein-Induced Peripheral Neuropathy and Mitochondrial Disruption by the Antimuscarinic Pirenzepine.

HIV-associated distal sensory polyneuropathy (HIV-DSP) affects about one third of people with HIV and is characterized by distal degeneration of axons. The pathogenesis of HIV-DSP is not known and there is currently no FDA-approved treatment. HIV trans-activator of transcription (TAT) is associated with mitochondrial dysfunction and neurotoxicity in the brain and may play a role in the pathogenesis of HIV-DSP. In the present study, we measured indices of peripheral neuropathy in the doxycycline (DOX)-inducible HIV-TAT (iTAT) transgenic mouse and investigated the therapeutic efficacy of a selective muscarinic subtype-1 receptor (M1R) antagonist, pirenzepine (PZ). PZ was selected as we have previously shown that it prevents and/or reverses indices of peripheral neuropathy in multiple disease models. DOX alone induced weight loss, tactile allodynia and paw thermal hypoalgesia in normal C57Bl/6J mice. Conduction velocity of large motor fibers, density of small sensory nerve fibers in the cornea and expression of mitochondria-associated proteins in sciatic nerve were unaffected by DOX in normal mice, whereas these parameters were disrupted when DOX was given to iTAT mice to induce TAT expression. Daily injection of PZ (10 mg/kg s.c.) prevented all of the disorders associated with TAT expression. These studies demonstrate that TAT expression disrupts mitochondria and induces indices of sensory and motor peripheral neuropathy and that M1R antagonism may be a viable treatment for HIV-DSP. However, some indices of neuropathy in the DOX-inducible TAT transgenic mouse model can be ascribed to DOX treatment rather than TAT expression and data obtained from animal models in which gene expression is modified by DOX should be accompanied by appropriate controls and treated with due caution.

Predictive variables for peripheral neuropathy in treated HIV type 1 infection revealed by machine learning.

Peripheral neuropathies (PNPs) in HIV-infected patients are highly debilitating because of neuropathic pain and physical disabilities. We defined prevalence and associated predictive variables for PNP subtypes in a cohort of persons living with HIV. Adult persons living with HIV in clinical care were recruited to a longitudinal study examining neurological complications. Each patient was assessed for symptoms and signs of PNP with demographic, laboratory, and clinical variables. Univariate, multiple logistic regression and machine learning analyses were performed by comparing patients with and without PNP. Three patient groups were identified: PNP (n = 111) that included HIV-associated distal sensory polyneuropathy (n = 90) or mononeuropathy (n = 21), and non-neuropathy (n = 408). Univariate analyses showed multiple variables differed significantly between the non-neuropathy and PNP groups including age, estimated HIV type 1 (HIV-1) duration, education, employment, neuropathic pain, peak viral load, polypharmacy, diabetes, cardiovascular disorders, AIDS, and prior neurotoxic nucleoside antiretroviral drug exposure. Classification algorithms distinguished those with PNP, all with area under the receiver operating characteristic curve values of more than 0.80. Random forest models showed greater accuracy and area under the receiver operating characteristic curve values compared with the multiple logistic regression analysis. Relative importance plots showed that the foremost predictive variables of PNP were HIV-1 duration, peak plasma viral load, age, and low CD4+ T-cell levels. PNP in HIV-1 infection remains common affecting 21.4% of patients in care. Machine-learning models uncovered variables related to PNP that were undetected by conventional analyses, emphasizing the importance of statistical algorithmic approaches to understanding complex neurological syndromes.

Peripheral neuropathy in HIV patients on antiretroviral therapy: Does it impact function?

HIV-associated distal sensory polyneuropathy (DSP), with or without neuropathic symptoms, can develop after anti-retroviral therapy (ART). Symptoms frequently involve small fibres but reports on autonomic dysfunction in HIV-DSP are sparse. We studied an HIV-infected cohort after 5 years of ART, and report on the frequency and severity of autonomic symptoms and the impact of DSP on everyday function. This cross-sectional study comprised of participants from a community-based South African HIV-clinic. The Brief Peripheral Neuropathy Screen and reduced Total Neuropathy Score evaluated neuropathic symptoms/signs. DSP was defined as ≥2 symmetrical DSP-signs, and symptomatic DSP when accompanied by neuropathic symptoms. Autonomic symptoms questionnaires, heart rate variability and postural blood pressure changes were assessed. The Lower Extremity Functional Scale (LEFS) was completed. The 67 participants had a median age of 42 years and median ART exposure of 7 years with viral suppression in 84%. Most (81%) met our criteria for DSP and 36% had additional neuropathic symptoms. Autonomic symptoms and signs (above normative values) were present in 15% and more likely in those with symptomatic DSP (P < .001). Participants with DSP, even without symptoms, had lower LEFS scores (P ≤ .039) than those without. HIV-DSP is prevalent and impacts on daily living.

A randomized, double-blind, placebo-controlled trial and open-label extension study to evaluate the efficacy and safety of pregabalin in the treatment of neuropathic pain associated with human immunodeficiency virus neuropathy

The objective of these studies was to assess the efficacy and safety of pregabalin in the treatment of human immunodeficiency virus (HIV)–associated neuropathic pain. Patients with HIV-associated distal sensory polyneuropathy (DSP) were randomized to treatment with flexible-dose pregabalin (150–600mg/day) or placebo for 17weeks in a single-blind, placebo lead-in, randomized, double-blind, parallel-group, placebo-controlled multinational trial. The primary efficacy outcome was the change in mean pain score on an 11-point numeric rating scale (NRS) from baseline to study endpoint. Participants who completed this trial were invited to participate in a 6-month open-label extension study with pregabalin. Of the 377 patients enrolled in the randomized controlled trial (pregabalin, n=183; placebo, n=194), 68.4% completed treatment. In the open-label extension, 217 patients were treated and 59.4% completed treatment. Both studies were terminated by the sponsor after a preplanned interim analysis indicated trial futility. At endpoint, the change from baseline in least-squares mean NRS pain scores in the intent-to-treat population was −2.04 for pregabalin versus −2.11 for placebo (P=.709). There were no significant differences between the pregabalin and placebo groups in the secondary efficacy measures. Incidence of adverse events was lower than seen in previous pregabalin studies. Overall, this trial did not show pregabalin to be more efficacious than placebo in treating HIV-associated DSP. Studies such as these, which fail to support their primary hypotheses, may be important in informing the methodology of future trials, especially when novel approaches to limit variability in the control group are included.ClinicalTrials.gov identifiers: NCT01049217 and NCT01145417.

NGX-4010, a Capsaicin 8% Dermal Patch, for the Treatment of Painful HIV-associated Distal Sensory Polyneuropathy

To evaluate the efficacy, safety, and tolerability of repeated NGX-4010 treatments in the open-label extension phase of a 52-week study in patients with neuropathic pain due to HIV-associated distal sensory polyneuropathy (HIV-DSP). Patients completing the 12-week, randomized, double-blind phase of the study could enter a 40-week, open-label phase, and receive up to 3, 60-minute NGX-4010 treatments. Patients recorded their "average pain for the past 24 hours" daily using the Numeric Pain Rating Scale (NPRS). Efficacy assessment included the percentage NPRS score reduction from baseline to weeks 2 to 12 after the final treatment, and Patient Global Impression of Change (PGIC) and Clinician Global Impression of Change (CGIC) questionnaires at study termination. Of 307 patients randomized, 272 entered the open-label phase; 81, 90, 55, and 46 received 0, 1, 2, and 3 retreatments, respectively. The mean percentage decrease in NPRS score from baseline to weeks 2 to 12 after the final treatment was similar in patients receiving single or multiple NGX-4010 treatments (-25.8%, -27.1%, -24.6%, and -22.7% for 1, 2, 3, and 4 NGX-4010 treatments, respectively). PGIC and CGIC results demonstrated a benefit of NGX-4010 treatment through to the end of the study regardless of the number of treatments received. Transient local application site reactions were the most frequently reported adverse events, and were mainly mild to moderate, nonserious, and did not increase with repeated treatment. Repeated NGX-4010 treatments were generally well tolerated and resulted in consistent reductions in HIV-DSP-associated pain and improvement in patient-reported outcomes.

Physical Therapy Interventions for Individuals with HIV Associated Distal Sensory Polyneuropathy: A Systematic Review

Physical Therapy Interventions for Individuals with HIV Associated Distal Sensory Polyneuropathy: A Systematic Review

A review of the high-concentration capsaicin patch and experience in its use in the management of neuropathic pain

In the European Union, the high-concentration capsaicin patch is licensed for the management of neuropathic pain conditions in nondiabetic patients, including postherpetic neuralgia (PHN) and HIV-associated distal sensory polyneuropathy (HIV-DSP). However, in the USA, the Food and Drug Administration approved its use only in PHN patients. Capsaicin is a transient receptor potential vanilloid-1 agonist, which increases the intracellular calcium ion concentration. This triggers calcium-dependent protease enzymes causing cytoskeletal breakdown and leads to the loss of cellular integrity and 'defunctionalization' of nociceptor fibres. Efficacy and therapeutic effect has been shown in several clinical studies of PHN and HIV-DSP. The high-concentration capsaicin patch and its practical application are different from low-concentration creams; one application can help for up to 3 months. The process of setting up of a service to use the capsaicin 8% patch is also discussed.

NGX-4010, a capsaicin 8% patch, for the treatment of painful HIV-associated distal sensory polyneuropathy: integrated analysis of two phase III, randomized, controlled trials

BackgroundHIV-associated distal sensory polyneuropathy (HIV-DSP) is the most frequently reported neurologic complication associated with HIV infection. NGX-4010 is a capsaicin 8% dermal patch with demonstrated efficacy in the treatment of HIV-DSP. Data from two phase III, double-blind studies were integrated to further analyze the efficacy and safety of NGX-4010 and explore the effect of demographic and baseline factors on NGX-4010 treatment in HIV-DSP.MethodsData from two similarly designed studies in which patients with HIV-DSP received NGX-4010 or a low-concentration control patch (capsaicin 0.04% w/w) for 30 or 60 minutes were integrated. Efficacy assessments included the mean percent change from baseline in Numeric Pain Rating Scale (NPRS) scores to Weeks 2–12. Safety and tolerability assessments included adverse events (AEs) and pain during and after treatment.ResultsPatients (n = 239) treated with NGX-4010 for 30 minutes demonstrated significantly (p = 0.0026) greater pain relief compared with controls (n = 100); the mean percent change in NPRS scores from baseline to Weeks 2–12 was −27.0% versus −15.7%, respectively. Patients who received a 60-minute application of NGX-4010 (n = 243) showed comparable pain reductions (−27.5%) to patients treated for 30 minutes, but this was not statistically superior to controls (n = 115). NGX-4010 was effective regardless of gender, baseline pain score, duration of HIV-DSP, or use of concomitant neuropathic pain medication, although NGX-4010 efficacy was greater in patients not receiving concomitant neuropathic pain medications. NGX-4010 was well tolerated; the most common AEs were application-site pain and erythema, and most AEs were mild to moderate. The transient increase in pain associated with NGX-4010 treatment decreased the day after treatment and returned to baseline by Day 2.ConclusionsA single 30-minute application of NGX-4010 provides significant pain relief for at least 12 weeks in patients with HIV-DSP and is well tolerated.Trial registrationC107 = NCT00064623; C119 = NCT00321672

Screening Tools for Distal Sensory Polyneuropathy Associated with HIV Disease

Study Design: Literature review. Objective: Describe the clinical assessment tools that are available to use with people who have distal sensory polyneuropathy (DSP) associated with human immunodeficiency virus (HIV) disease. Methods: A review of English articles using the databases PubMed, Biological Sciences and EBSCO Host with Medline, CINAHL, Health Source, and Academic Search Premier were used to identify relevant screening tools. Search terms included HIV, sensory, peripheral, neuropathy, and screening. Results: Screening tools for DSP included the Total Neuropathy Score (TNS), Subjective Peripheral Neuropathy Screen (SPNS), Brief Peripheral Neuropathy Screen (BPNS), Neuropathy Severity Score (NSS), and Single Question Neuropathy Screen (SQNS). The TNS and SPNS displayed reliability of 0.96 and 0.60. The SPNS, BPNS, NSS, and SQNS demonstrated specificity of 84%, 88%, 91%, and 80% respectively. Conclusion: The clinical assessment tools reviewed symptoms of HIV-associated DSP and provide a diagnostic perspective, however, lack functional outcome measures. Further research is needed to combine assessment and functional based tools for a comprehensive approach to measuring progress over time in rehabilitation of HIV-associated DSP.

A Randomized, Double-Blind, Controlled Study of NGX-4010, a Capsaicin 8% Dermal Patch, for the Treatment of Painful HIV-Associated Distal Sensory Polyneuropathy

Effective treatment of HIV-associated distal sensory polyneuropathy remains a significant unmet therapeutic need. In this randomized, double-blind, controlled study, patients with pain due to HIV-associated distal sensory polyneuropathy received a single 30-minute or 60-minute application of NGX-4010--a capsaicin 8% patch (n = 332)--or a low-dose capsaicin (0.04%) control patch (n = 162). The primary endpoint was the mean percent change from baseline in Numeric Pain Rating Scale score to weeks 2-12. Secondary endpoints included patient global impression of change at week 12. Pain reduction was not significantly different between the total NGX-4010 group (-29.5%) and the total control group (-24.5%; P = 0.097). Greater pain reduction in the 60-minute (-30.0%) versus the 30-minute control group (-19.1%) prevented intended pooling of the control groups to test individual NGX-4010 treatment groups. No significant pain reduction was observed for the 30-minute NGX-4010 group compared with 30-minute control (-26.2% vs.-19.1%, respectively, P = 0.103). Pain reductions in the 60-minute NGX-4010 and control groups were comparable (-32.8% vs. -30.0%, respectively; P = 0.488). Posthoc nonparametric testing demonstrated significant differences favoring the total (P = 0.044) and 30-minute NGX-4010 groups (P = 0.035). Significantly, more patients in the total and 30-minute NGX-4010 group felt improved on the patient global impression of change versus control (67% vs. 55%, P = 0.011 and 65% vs. 45%, P = 0.006, respectively). Mild to moderate transient application site pain and erythema were the most common adverse events. Although the primary endpoint analyses were not significant, trends toward pain improvement were observed after a single 30-minute NGX-4010 treatment.

Schwann Cells as a Therapeutic Target for Peripheral Neuropathies

Schwann cells, the myelin forming cells in the peripheral nervous system, play a key role in the pathology of various inflammatory, metabolic and hereditary polyneuropathies. Advances in identifying growth factors and signaling molecules that are expressed by Schwann cells have paved the way for development of new treatment strategies that are aimed to improve the protective and regenerative properties of Schwann cells in peripheral nerve disorders. These include the exogenous application of growth factors and neurohormones which have been advanced into clinical trials in humans, and transplantation paradigms that have been moved into late stage preclinical models. In this review we will discuss the latest developments in these therapeutic approaches with special regard to peripheral nerve disorders, in which progress in basic research has already been translated into clinical trials, including HIV-associated distal sensory polyneuropathy and diabetic neuropathy.

HIV neuropathy in South Africans: Frequency, characteristics, and risk factors

The purpose was to estimate the frequency, characteristics, and risk factors of HIV-associated distal sensory polyneuropathy (DSP) among South Africans who attend an urban community-based clinic. In a cross-sectional study, neuropathy status was determined in 598 HIV-infected adults using validated tools (Brief Peripheral Neuropathy Screen and a modified version of the Total Neuropathy Score) to categorize subjects as DSP versus no DSP. Symptomatic DSP (SDSP) required the presence of at least two neuropathic signs together with symptoms. Clinical, anthropometric, and laboratory evaluations were prospectively performed. CD4 counts, antiretroviral therapy (ART), and questionnaires regarding previous tuberculosis (TB) and alcohol exposure were collected retrospectively. Approximately half (49%) of the study population were diagnosed with DSP, and 30% of the study population were diagnosed with SDSP. In multivariate analyses the odds ratio (OR) (95% confidence interval) of DSP were independently associated with ART use (OR 1.7, 1.0-2.9), age (per 10 year increment) (OR 1.7, 1.4-2.2), and prior TB (OR 2.0, 1.3-3.0). Pain or paresthesias were reported as moderately severe by 70% of those with SDSP. Stavudine use was significantly associated with DSP. DSP is a clinically significant problem in urban HIV-infected Africans. Our findings raise the possibility that the incidence of DSP may be reduced with avoidance of stavudine-containing regimens in older subjects, especially with a history of prior TB infection.

Prevalence and Risk Factors for HIV-associated Peripheral Sensory Neuropathy in HIV-infected Adults in Daegu, Korea

Peripheral neuropathies complicate all stages of HIV infection and cause considerable morbidity and disability in HIV-infected individuals. The aim of this study was to describe the prevalence and risk factors of HIV-associated symptomatic distal sensory polyneuropathy (HIV-DSPN) in the HAART era in Daegu, Korea. HIV-infected adults visiting two tertiary teaching hospitals in Daegu during a 2-month period (October 2008 to November 2008) were screened for HIV-DSPN. HIV-DSPN was defined as being present if the patient had neuropathic symptoms or abnormal neurologic signs. Demographic, clinical, laboratory, and treatment data were collected, and statistical analysis was done. One hundred fifty patients (136 patients in Kyungpook National University Hospital and 14 patients in Dongsan Medical Center) were screened. The prevalence of HIV-DSPN was 16.0% (24/150). In the univariate analysis, the statistically significant risk factors for symptomatic peripheral sensory neuropathy were older age [40.6±9.4 years in the DSPN(−) group vs. 46.2±9.5 years in the DSPN(+) group, p=0.009], diagnosis of AIDS [odds ratio: 4.605 (95% CI: 1.305∼16.256), p=0.011], and treatment of tuberculosis [odds ratio: 3.912 (95% CI: 1.352 ∼11.317), p=0.015]. In the multivariate analysis, older age (odds ratio: 1.082, 95% CI: 1.024∼1.143, p=0.005) and diagnosis of AIDS (odds ratio: 7.861, 95% CI: 1.330∼46.452, p=0.023) were still significant risk factors. HIV-DSPN was not uncommon among ambulatory patients (16.0% prevalence) in Daegu, Korea, and more careful history taking and physical examination for HIV-DSPN should be performed in the management of older AIDS patients.

Smoked Medicinal Cannabis for Neuropathic Pain in HIV: A Randomized, Crossover Clinical Trial

Despite management with opioids and other pain modifying therapies, neuropathic pain continues to reduce the quality of life and daily functioning in HIV-infected individuals. Cannabinoid receptors in the central and peripheral nervous systems have been shown to modulate pain perception. We conducted a clinical trial to assess the impact of smoked cannabis on neuropathic pain in HIV. This was a phase II, double-blind, placebo-controlled, crossover trial of analgesia with smoked cannabis in HIV-associated distal sensory predominant polyneuropathy (DSPN). Eligible subjects had neuropathic pain refractory to at least two previous analgesic classes; they continued on their prestudy analgesic regimens throughout the trial. Regulatory considerations dictated that subjects smoke under direct observation in a hospital setting. Treatments were placebo and active cannabis ranging in potency between 1 and 8% Delta-9-tetrahydrocannabinol, four times daily for 5 consecutive days during each of 2 treatment weeks, separated by a 2-week washout. The primary outcome was change in pain intensity as measured by the Descriptor Differential Scale (DDS) from a pretreatment baseline to the end of each treatment week. Secondary measures included assessments of mood and daily functioning. Of 127 volunteers screened, 34 eligible subjects enrolled and 28 completed both cannabis and placebo treatments. Among the completers, pain relief was greater with cannabis than placebo (median difference in DDS pain intensity change, 3.3 points, effect size=0.60; p=0.016). The proportions of subjects achieving at least 30% pain relief with cannabis versus placebo were 0.46 (95%CI 0.28, 0.65) and 0.18 (0.03, 0.32). Mood and daily functioning improved to a similar extent during both treatment periods. Although most side effects were mild and self-limited, two subjects experienced treatment-limiting toxicities. Smoked cannabis was generally well tolerated and effective when added to concomitant analgesic therapy in patients with medically refractory pain due to HIV DSPN.

Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy

HIV-associated distal sensory polyneuropathy (HIV-DSP) is a painful condition with limited effective treatment. Capsaicin desensitizes cutaneous nociceptors resulting in reduced pain. We report a placebo-controlled study of a high-concentration capsaicin dermal patch (NGX-4010) for the treatment of painful HIV-DSP. This double-blind multicenter study randomized 307 patients with painful HIV-DSP to receive NGX-4010 or control, a low-concentration capsaicin patch. After application of a topical anesthetic, NGX-4010 or control was applied once for 30, 60, or 90 minutes to painful areas on the feet. The primary efficacy endpoint was percent change in Numeric Pain Rating Scale (NPRS) from baseline in mean "average pain for past 24 hours" scores from weeks 2 to 12. A single NGX-4010 application resulted in a mean pain reduction of 22.8% during weeks 2 to 12 as compared to a 10.7% reduction for controls (p = 0.0026). Following a transient treatment-related pain increase, pain was reduced; significant improvement was apparent by week 2 and continued throughout the controlled 12-week observation period. Mean pain reductions in the NGX-4010 30-, 60- and 90-minute groups were 27.7%, 15.9%, and 24.7% (p = 0.0007, 0.287, and 0.0046 vs control). One third of NGX-4010-treated patients reported >or=30% pain decrease from baseline as compared to 18% of controls (p = 0.0092). Self-limited, mild-to-moderate local skin reactions were commonly observed. A single NGX-4010 application was safe and provided at least 12 weeks of pain reduction in patients with HIV-associated distal sensory polyneuropathy. These results suggest that NGX-4010 could provide a promising new treatment for painful HIV neuropathy.

(332) Hypnosis for treatment of HIV neuropathic pain

Over 30% of HIV patients suffer from symptomatic HIV-associated distal sensory polyneuropathy (HIV- DSP). The pain symptoms adversely affect patients’ quality of life and are often severe enough to diminish their capacity for independent self-care. HIV-DSP is not reversible. Current treatments are typically pharmacological palliation. None of these treatments are uniformly or consistently effective, and they sometimes have unacceptable side-effects. A behavioral intervention such as hypnosis, either alone or in combination with medication, could potentially decrease pill burden and provide another useful treatment.

An Open-Label Pilot Study of High-Concentration Capsaicin Patch in Painful HIV Neuropathy

Peripheral neuropathy is the most frequent neurological complication of human immunodeficiency virus (HIV)-1 infection and is commonly associated with the development of chronic pain. This open-label, 12-week pilot study assessed the efficacy, tolerability, and safety of a high-concentration capsaicin dermal patch (NGX-4010; capsaicin, 640 μg/cm 2, 8% w/w) to treat painful HIV-associated distal sensory polyneuropathy (DSP). Eligible patients had moderate-to-severe pain in both feet due to HIV-associated DSP or antiretroviral toxic neuropathy. Patients received a single 60-minute application of the investigational high-concentration capsaicin patch to the affected areas. The primary outcome measure was the mean percent change in numeric pain rating scale (NPRS) during weeks two to 12 postadministration. After a single 60-minute NGX-4010 application, the mean percent change from baseline in “average pain for past 24 hours” NPRS scores during weeks two to 12 was −40% (95% CI: −61%, −19%; P = 0.0020). Similar results were observed for “worst pain for past 24 hours” and “pain now” scores. Eight of 12 patients (67%) were treatment responders (≥30% pain decrease). Four of 12 patients (33%) experienced a ≥50% reduction in pain. Treatment was generally well tolerated. Treatment-associated pain was self-limited and could be managed with short-acting opioids. This study demonstrates that treatment of painful HIV-associated neuropathy with a single application of NGX-4010, a high-concentration capsaicin patch, was feasible, well tolerated, and associated with significant reduction in pain over the 12 weeks studied. No safety concerns were identified. Controlled studies of NGX-4010 for the treatment of painful HIV-associated neuropathy are warranted.