Experience and Challenges Presented by a Multicenter Crossover Study of Combination Analgesic Therapy for the Treatment of Painful HIV-Associated Polyneuropathies

Abstract

Objective There is limited evidence for efficacy of analgesics as monotherapy for neuropathic pain associated with HIV-associated polyneuropathies, in spite of demonstrated efficacy in other neuropathic pain conditions. We evaluated the tolerability and analgesic efficacy of duloxetine, methadone, and the combination of duloxetine-methadone compared to placebo. Design This study was a phase II, randomized, double blind, placebo-controlled, four-period crossover multi-center study of analgesic therapy for patients with at least moderate neuropathic pain due to HIV-associated polyneuropathy. Duloxetine, methadone, combination duloxetine-methadone, and placebo were administered in four different possible sequences. The primary outcome measure was mean pain intensity (MPI) measured daily in a study-supplied pain diary. Results A total of 15 patients were enrolled from 8 study sites and 8 patients completed the entire trial. Study treatments failed to show statistically significant change in MPI compared to placebo. Adverse events were frequent and associated with high rates of drug discontinuation and study drop-out. Conclusions Challenges with participant recruitment and poor retention precluded trial completion to its planned targets, limiting our evaluation of the analgesic efficacy of the study treatments. Challenges to successful completion of this study and lessons learned are discussed.

Pharmacologic and Non-Pharmacologic Interventions for HIV-Neuropathy Pain. A Systematic Review and a Meta-Analysis

“…Among these studies, 6 were evaluated non-pharmacologic techniques for HIV neuropathy pain (Sandoval et al [26], Paice et al [27], Mkandla et al [28], Maharaj et al [29], Evans et al [30], Anastasi et al [31]), one examined a combination of pharmacologic and non-pharmacologic intervention (Shlay et al [32]). 20 up to 27 studies examined pharmacologic administration in HIV neuropathy (Simpson et al [33], Simpson et al [34], Abrams et al [35], Ellis et al [36], Clifford et al [37], Simpson et al [38], Paice et al [39], Simpson et al [40], Simpson et al [41], Dinat et al [42], Kieburtz et al [43], Kemper et al [44], Hanh et al [45], McArthur et al [46], Youle et al [47], Estanislao et al [48], Simpson et al [49], Evans et al [50], Shiffito et al [51], Harrison et al [16]).…”

“…The follow up period varied from 5 days to 18 weeks. Among 20 included pharmacologic studies, five followed a cross-over design (Estanislao et al [48], Ellis et al, Dinat et al [42], Kemper et al [44] and Harrison et al [16]) and the remaining a parallel design. Despite the fact that review attempted to include only ITT patients' data, it wasn't always possible for these data to be retrieved.…”

“…The studies performed by Ellis et al [36] and Shiffito et al [51] didn't include ART therapy status in the inclusion criteria. Regarding missing data management only one study followed a baseline observation carried forward practice (Simpson et al [54]), while last observation carried forward method was used in 9 studies (Clifford et al [37], Simpson et al [33], Simpson et al [38], Evans et al [50], Youle et al [47], Simpson et al [40], McArthur et al [46], Kieburtz et al [43], Simpson et al [49]) and a per protocol analysis in 5 (Dinat et al [42], Harrison et al [16], Abrams et al [35], Simpson et al [41], Kemper et al [44]).…”

“…During the time period from 2010 till know new randomized trials have been published examining the efficacy of various pharmacologic treatments [16,17] Furthermore studies on non-pharmacological treatments for HIV painful neuropathy are often seen in the literature. From this perspective, we conducted a systematic review and meta-analysis of the literature in order to evaluate the efficacy and safety of various pharmacologic and non-pharmacologic treatments in the alleviation of painful symptoms in patients with HIV neuropathy.…”

Back to the future: The need to resolve analgesic efficacy in human immunodeficiency virus neuropathy

“…The quality of the data from such a trial would be of paramount importance, so participants could be selected for their commitment to the trial objectives and ability to conscientiously evaluate their pain. In any such effort, it would be critically important to address poor study accrual and retention, which contributed to the premature termination of a recent painful HIV neuropathy trial [13]. Concerted efforts to engage the collaborative partnership of the HIV community and potential participants in clinical trial design and execution could increase enrollment, facilitate retention, and enhance assay sensitivity [16].…”