Background
HIV-associated distal sensory polyneuropathy (HIV-DSP) is the most frequently reported neurologic complication associated with HIV infection. It can be caused by the virus itself [
1] or by the use of antiretroviral drugs; for example, some nucleoside reverse transcriptase inhibitors have been shown to have a dose-dependent toxic effect in 15–30% of patients [
1]. The clinical presentation of HIV-DSP is similar regardless of whether it is caused by HIV itself or is due to the toxicity of antiretroviral drugs.
HIV-DSP presents with predominantly symmetrical signs of distal sensory loss and reduction or loss of ankle reflexes. Symptomatic HIV-DSP reflects the involvement of both small and large sensory nerve fibers and includes distal painful dysesthesias, allodynia, severe burning pain, pins and needles, and numbness [
1,
2]. These symptoms usually begin in the feet and may progress bilaterally up the legs and to the arms in severe HIV-DSP.
In a recent US study, 881 of 1,539 (57%) individuals infected with HIV showed evidence of HIV-sensory neuropathy, which encompasses HIV-DSP caused by the virus and toxic DSP due to dideoxynucleoside antiretroviral therapy [
3]. Of those with DSP, 38% reported neuropathic pain [
4]. Very few neuropathic pain treatments, however, have demonstrated efficacy in clinical trials for patients with HIV-associated neuropathy. For example, the tricyclic antidepressant amitriptyline [
5], the anticonvulsant pregabalin [
6], and topical treatments such as lidocaine [
7] and low-dose (0.075%) capsaicin cream [
8] have all failed to show significant pain relief when compared with controls. By contrast, three small, randomized, placebo-controlled studies showed that smoking cannabis reduced daily pain compared with smoking identical placebo cigarettes from which the cannabinoids had been removed [
9‐
11]. Other neuropathic pain therapies such as duloxetine and venlafaxine have not been studied in patients with HIV-DSP [
12] while the results of a single published study investigating opioid use among patients with HIV suggested those receiving opioids experienced more pain than those patients who did not receive opioids [
13]. Furthermore, many of these agents, which are not approved by the Food and Drug Administration or the European Medicines Agency, are associated with unwanted side effects and burdensome treatment regimens [
12]. Sedation and dizziness are common adverse events (AEs) associated with gabapentin and pregabalin, whereas nausea can be common with duloxetine [
12]. Gabapentin and pregabalin also require slow dose titration, as does amitriptyline [
12]. In addition, cumbersome regimens must be followed for treatment with lidocaine patches and low-dose capsaicin creams; the lidocaine patch is licensed to be worn for 12 hours followed by a 12-hour treatment break [
12], and capsaicin cream requires application several times a day [
8]. A recent systematic review of randomized controlled studies concluded that evidence of efficacy exists only for capsaicin 8%, smoked cannabis, and recombinant-human nerve growth factor (rhNGF) [
14]. However, rhNGF did not demonstrate evidence for the expected nerve fiber regeneration [
15] and was not developed further for clinical use.
NGX-4010 is a capsaicin 8% (w/w) dermal patch licensed in 2009 in the EU for the treatment of peripheral neuropathic pain in non-diabetic adults either alone or in combination with other medicinal products for pain; and indicated in the US for the management of neuropathic pain associated with post-herpetic neuralgia. NGX-4010 was developed to rapidly deliver a high dose of capsaicin directly to the source of pain with a single application. Capsaicin is a highly selective agonist for the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor, which is a ligand-gated non-selective cation channel that is highly expressed in nociceptors and is critical for pain transmission and modulation [
16]. As a component of small nerve fibers, C fibers are involved in HIV-DSP [
17] and, as TRPV1 expression is altered on C fibers following nerve injury [
18], these fibers may play a role in the neuropathic pain experienced by individuals with HIV-DSP. TRPV1 is therefore a logical target for treating neuropathic pain. Exposure of TRPV1 receptors to high concentrations of capsaicin initially causes depolarization, action potential initiation, and burning pain [
19,
20]. This is followed by a defunctionalization and reduction in the density of epidermal nerve fibers, resulting in inhibition of pain transmission [
19‐
21]. The effect is reversible, with regrowth of epidermal nerve fibers evident 12 weeks after exposure to capsaicin [
21].
Two similarly designed phase III, double-blind, controlled studies have investigated the efficacy of NGX-4010 in patients with HIV-DSP. These studies demonstrated that treatment with NGX-4010 was well tolerated and resulted in a reduction in pain over 12 weeks [
22,
23] (Table
1). Study C107 investigated the efficacy of NGX-4010 applied for 30, 60, or 90 minutes and demonstrated that the 30-minute NGX-4010 application resulted in a statistically significant reduction in pain; there was no evidence of increased efficacy with longer application durations [
22]. Study C119 investigated the efficacy of NGX-4010 applied for 30 or 60 minutes and demonstrated a greater pain reduction in the 30-minute NGX-4010 group
versus the 30-minute control group. Although this did not attain statistical significance using a prespecified analysis of covariance (ANCOVA) model, it did show a significant difference (p = 0.035) when a post hoc non-parametric test was used [
23]. In neither study did the 60-minute treatment group show a significant difference as compared with control.
Table 1
Summary of randomized, double-blind, controlled trials of NGX-4010 in patients with HIV-DSP
| 225 | 82 | Single 30-, 60-, or 90-minute application of NGX-4010 patch versus low-concentration (0.04%) capsaicin control patch | 30 minutes | −27.7 |
(p = 0.0007†versus control) |
60 minutes | −15.8 |
(p = 0.291†versus control) |
90 minutes | −24.7 |
(p = 0.0046†versus control) |
Pooled | −22.8 |
(p = 0.0026†versus control) |
| 332 | 162 | Single 30- or 60-minute application of NGX-4010 patch versus low-concentration (0.04%) capsaicin control patch | 30 minutes | −26.2 |
(p = 0.1031‡versus control) |
60 minutes | −32.8 |
(p = 0.4884‡versus control) |
Pooled | −29.5 |
(p = 0.0967‡versus control) |
To analyze in more detail the efficacy and safety of NGX-4010 in patients with HIV-DSP, an integrated analysis of the 30- and 60-minute NGX-4010 applications from the two double-blind, controlled HIV-DSP studies was performed. This integrated analysis also investigated the effects of demographic factors, disease duration and severity, and the use of concomitant neuropathic pain medication, which are often difficult to evaluate in individual studies due to the limited sample size.
Discussion
The similarity of the demographic and baseline characteristics of the patients from the two multicenter, randomized, double-blind, controlled phase III studies (Table
2), together with comparable study designs, enrollment, and assessment criteria allowed data from the two studies to be combined. The integrated analyses from the two phase III studies demonstrated that a single 30-minute application of NGX-4010 provides significant pain relief — as demonstrated by a decrease in NPRS score — for patients with HIV-DSP for at least 12 weeks. This decrease in the NPRS score of patients receiving a 30-minute NGX-4010 application was supported by the analysis of patient-reported outcomes using the PGIC. The PGIC provides a global assessment of patient improvement that is independent of NPRS score collection. This measurement is recommended in chronic pain studies by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials [
25] and is more sensitive to treatment effects in neuropathic pain than pain intensity measurements [
26]. Using the PGIC, 12 weeks after a single application of NGX-4010, 65% of patients felt slightly, much, or very much improved compared with 41% of control patients.
The reduction in NPRS score following the 60-minute application of NGX-4010 was not significantly different from control. This is likely due to the large effects of the control patch observed in study C119 [
23]. Interestingly, there was a significant improvement using the PGIC in the 60-minute treatment compared with the control group.
The data presented here show no evidence of increased efficacy with increased NGX-4010 treatment duration and support the selection of the 30-minute dose for treatment of peripheral neuropathic pain in patients with HIV-associated neuropathy. By contrast, for patients with post-herpetic neuralgia who typically experience neuropathic pain on the torso as opposed to the extremities, treatment duration is 60 minutes [
27,
28].
A transient increase in pain compared with baseline was seen on Day 0 in patients receiving NGX-4010, due to the treatment procedure. However, treatment-related pain was short-lived, with NPRS scores for patients treated with NGX-4010 for 30 minutes returning to baseline by Day 2. Thereafter, NPRS scores in patients receiving a 30-minute NGX-4010 application continued to decline and NGX-4010-treated patients achieved a greater pain reduction than those in the control group by Day 5 and on each subsequent day through Day 84. Weekly NPRS scores demonstrated significantly greater reductions in pain for NGX-4010-treated patients compared with controls each week from Week 2 to study completion (Week 12).
Subgroup analyses showed greater pain reduction in patients treated with NGX-4010 compared with those treated with control in all subgroups regardless of gender, baseline pain score, concomitant neuropathic pain medication, and HIV-DSP duration. However, NGX-4010 was more effective in patients not using concomitant neuropathic pain medications compared with those using concomitant neuropathic pain medications. This result is not unexpected as it has been shown previously that the additional reduction of neuropathic pain obtained with an add-on drug is generally not as large as the benefit obtained with monotherapy [
29,
30]. This may be because some of the pathophysiologic mechanisms implicated in the generation and maintenance of neuropathic pain overlap or converge to a common pathway, resulting in a less than additive effect even for medications that act via different mechanistic pathways. Furthermore, patients already taking several concomitant neuropathic pain medications may be more treatment resistant or more difficult to treat. It is therefore important to note that a significant treatment effect was seen with NGX-4010 compared with control, despite two-thirds of the patients using concomitant neuropathic pain medication at study entry and during the study (Table
2). Gender, baseline pain score, and the duration of HIV-DSP did not influence NGX-4010 efficacy, indicating that pain relief can be achieved with NGX-4010 treatment even in those patients with high pain levels or long disease duration.
Although NGX-4010 application does cause some treatment-related pain, it is generally mild or moderate and transient. The vast majority of patients were able to tolerate >90% of the intended NGX-4010 application. Most common treatment-related AEs were application-site reactions; systemic effects were limited to small, transient elevations in mean systolic and diastolic blood pressure shortly after NGX-4010 application due to treatment-associated increases in pain.
Methods
Enrollment
Details of each of the studies included in this analysis have been reported previously [
22,
23]. Both studies were approved by institutional review boards/independent ethics committees and conducted in accordance with the ethical principles of the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable regulatory requirements.
Both studies recruited patients who were ≥18 years of age with a diagnosis of HIV-DSP for ≥2 months and an average baseline NPRS score [
34] of 3–9. Patients taking other pain medications such as anticonvulsants, non-selective serotonin reuptake inhibitor (non-SSRI) antidepressants (e.g., tricyclic antidepressants, serotonin–norepinephrine reuptake inhibitors), opioids, non-steroidal anti-inflammatory drugs, salicylates, or acetaminophen had to be on stable doses for ≥21 days before patch application and remain on stable doses throughout the study period. Exclusion criteria in both studies included the prior use of NGX-4010 and use of a topical medication on the painful area within 21 days before the NGX-4010 application day.
Treatment
Patients were randomly assigned to receive treatment with an NGX-4010 (QUTENZA™/Qutenza®) patch (capsaicin 640 μg/cm2, 8% w/w; NeurogesX, Inc., San Mateo, CA, USA) or a low-concentration control patch (capsaicin 3.2 μg/cm2, 0.04% w/w). The control patch produced local erythema and a burning sensation to provide effective blinding in the studies.
Patients were pre-treated with a topical local anesthetic cream (L.M.X.4 lidocaine 4%; Ferndale Laboratories, Inc., Ferndale, MI, USA) for 60 minutes before patch application. Both the NGX-4010 and control patches were applied for 30, 60, or 90 minutes in study C107 [
22] and for 30 or 60 minutes in study C119 [
23]. After patch removal, the treatment area was cleansed with a proprietary cleansing gel (NeurogesX, Inc.) formulated to remove residual capsaicin. A rapid-onset, opioid-based oral pain medication (e.g., oxycodone hydrochloride oral solution, 1 mg/ml) could be administered at the onset of treatment-associated discomfort and as needed while in the clinic. Following patch removal, local cooling could be used. Patients could also take a short-term regimen of an opioid-based oral pain medication (e.g., hydrocodone bitartrate/acetaminophen 5 mg/500 mg) for treatment-related discomfort for up to 5 or 7 days post treatment, depending on the study.
Assessments
The studies included either a ≥5 day [
22] or ≥14 day [
23] baseline screening period. Assessments were also carried out on the day of treatment (Day 0), at the termination visit (Week 12), and, depending on the study, at interim visits at Weeks 1 and 4 or 4 and 8 during the 12-week blinded observation period. The primary efficacy endpoint was the mean percent change from baseline in NPRS scores for “average pain for the past 24 hours” from Weeks 2–12. Patients recorded their “average pain for the past 24 hours” every evening at 9:00 pm in paper pain diaries from the baseline screening period until the evening before the termination visit.
Other efficacy measurements included the percentage of patients with ≥30% mean decrease in NPRS score from baseline during Weeks 2–12 and the percentage of those feeling improved according to the PGIC at Week 12. In this assessment patients reported how they felt after treatment compared with before treatment on a 7-point scale with −3 indicating “very much worse” to +3 indicating “very much improved” and 0 indicating “no change”.
Safety and tolerability assessments included AEs, vital signs, clinical laboratory tests, physical examination, dermal assessment (0- to 7-point severity score) [
24], “pain now” NPRS scores during and after patch application, early patch removal, and use of medication for treatment-related discomfort during Days 0 to 5.
Efficacy analyses
Data from patients receiving NGX-4010 and control patches for 30 or 60 minutes were integrated from both phase III HIV-DSP studies. The 90-minute NGX-4010 dose was not included in these analyses as it was not evaluated in study C119 [
23]. Intent-to-treat efficacy analyses consisted of all patients who received any study treatment and had at least 3 days of available NPRS scores during the baseline period. The primary efficacy endpoint was the percent change in NPRS scores from baseline during Weeks 2–12. Changes in NPRS scores from baseline to Weeks 2–12 were compared between treatment groups using a pre-specified gender-stratified ANCOVA model with baseline pain score, pre-topical anesthetic pain score, and percent change in pain score after topical anesthetic treatment as covariates. To avoid the potentially confounding effect of opioid medications allowed during Days 0–5, Week 1 NPRS scores were not included in the primary endpoint analysis. In addition, least square means of the difference between treatment groups and the 95% confidence interval (CI) were calculated.
Missing post-treatment NPRS scores were imputed using a modified last observation carried forward approach. If the NPRS score was missing on post-treatment Days 0–8 or on Day 8 and one or more consecutive days, then the baseline score was imputed for those days. If the NPRS score was missing for any day after Day 8, then the missing score was imputed by the last available non-imputed score recorded before that day. If all post-treatment NPRS scores were missing (including Day 0), all scores were imputed using the baseline score. NPRS baseline scores were calculated using all available screening scores that were not biased by pain medication changes [
22] or using all available screening scores between Day −14 and Day −1 [
23]. For the weekly and the daily NPRS scores, missing scores were not imputed.
The percentage of responders (classified as those achieving ≥30% reduction in NPRS score from baseline) was compared between groups using logistic regression analyses, with baseline pain score, gender, pre-topical anesthetic pain score, and percent change in pain score after topical anesthetic treatment as covariates. In addition, odds ratios and the 95% CI of observing responses in the NGX-4010 group compared with the control group were estimated. The percentage of patients reporting improvements according to the PGIC was compared between treatment groups using Fisher’s exact test. For both the primary endpoint and responder analysis, the treatment effect was assessed by gender, baseline pain score (median NPRS score of < and ≥6.07), HIV-DSP duration (median of < and ≥5.2 years), and concomitant neuropathic pain medication use at study entry (defined as receiving an anticonvulsant, non-SSRI antidepressant or opioid on Day −1 and for at least 7 consecutive days) in patients treated for 30 minutes.
Safety and tolerability analyses
AEs were coded using the Medical Dictionary for Regulatory Activities version 9.0. Medication use for treatment-related discomfort (from Days 0–5) and the percentage of patients completing the intended patch duration were compared using Fisher’s exact test. The percentages of patients reporting each level of dermal response were compared using the Cochran–Mantel–Haenszel test. The maximum changes in “pain now” NPRS score from the pre-topical anesthetic time point during and after patch application were summarized and compared using the Wilcoxon rank sum test.
Patients were analyzed as randomized for the efficacy analyses and as treated for the safety analyses.
Competing interests
DMS has received consultancy fees and/or honorarium or speaker fees from NeurogesX, Astellas Pharma Europe Ltd., Eli Lilly and Pfizer. DMS’s institute has received grants from NeurogesX, Astra Zeneca and Pfizer. MF has received speaker fees and funding to attend a conference from Astellas. SB’s institute, AIDS Research Alliance, received grants to conduct the research. GS received funds as site investigator. JKT and GFV are former employees of NeurogesX and still own stock in NeurogesX.
Authors’ contributions
SB, DMS, GM, BJB, GS, NL, CO, and MF conducted the study, interpreted the data, and edited the manuscript. GFV and JKT designed the study, analyzed and interpreted the data, and prepared the manuscript. All authors read and approved the final manuscript.