HIV-associated Neuropathic Pain Research Articles

Health-Related Quality of Life ‘Well-Being' in HIV Distal Neuropathic Pain is More Strongly Associated with Depression Severity than with Pain Intensity

Despite modern antiretroviral treatment, HIV-associated distal neuropathic pain (DNP) remains one of the most prevalent and debilitating complications of HIV disease. Neuropathic pain is often accompanied by depressed mood, and both pain and depression have been associated with decreased health-related quality of life (HRQOL) well-being. The relative contribution of depression and pain to worse life quality has not been addressed, however, even though a better understanding might sharpen intervention strategies. We used the Medical Outcomes Study HIV (MOS-HIV) Health Survey and the Beck depression inventory-II and linear regression models to investigate HRQOL well-being in HIV-infected patients with DNP (n = 397) participating in an observational cohort study at six U.S. sites (CNS HIV Antiretroviral Treatment Effects Research Study, CHARTER). For this sample of patients with HIV DNP, severity of depressed mood was more highly correlated with HRQOL well-being than was pain intensity. These results suggest that interventions to improve HRQOL well-being in individuals with HIV-associated DNP may need to address not only pain intensity but mood state as well.

A pilot study of the effects of cannabis on appetite hormones in HIV-infected adult men

Rationale The endocannabinoid system is under active investigation as a pharmacological target for obesity management due to its role in appetite regulation and metabolism. Exogenous cannabinoids such as tetrahydrocannabinol (THC) stimulate appetite and food intake. However, there are no controlled observations directly linking THC to changes of most of the appetite hormones. Objectives We took the opportunity afforded by a placebo-controlled trial of smoked medicinal cannabis for HIV-associated neuropathic pain to evaluate the effects of THC on the appetite hormones ghrelin, leptin and PYY, as well as on insulin. Methods In this double-blind cross-over study, each subject was exposed to both active cannabis (THC) and placebo. Results Compared to placebo, cannabis administration was associated with significant increases in plasma levels of ghrelin and leptin, and decreases in PYY, but did not significantly influence insulin levels. Conclusion These findings are consistent with modulation of appetite hormones mediated through endogenous cannabinoid receptors, independent of glucose metabolism.

In Vivo Evidence that Truncated Trkb.T1 Participates in Nociception

Brain-Derived Neurotrophic Factor (BDNF) is a central nervous system modulator of nociception. In animal models of chronic pain, BDNF exerts its effects on nociceptive processing by binding to the full-length receptor tropomyosin-related kinase B (trkB.FL) and transducing intracellular signaling to produce nocifensive behaviors. In addition to trkB.FL, the trkB locus also produces a widely-expressed alternatively-spliced truncated isoform, trkB.T1. TrkB.T1 binds BDNF with high affinity; however the unique 11 amino acid intracellular cytoplasmic tail lacks the kinase domain of trkB.FL. Recently, trkB.T1 was shown to be specifically up-regulated in a model of HIV-associated neuropathic pain, potentially implicating trkB.T1 as a modulator of nociception. Here, we report that trkB.T1 mRNA and protein is up-regulated in the spinal dorsal horn at times following antiretroviral drug treatment and hind paw inflammation in which nocifensive behaviors develop. While genetic depletion of trkB.T1 did not affect baseline mechanical and thermal thresholds, the absence of trkB.T1 resulted in significant attenuation of inflammation- and antiretroviral-induced nocifensive behaviors. Our results suggest that trkB.T1 up-regulation following antiretroviral treatment and tissue inflammation participates in the development and maintenance of nocifensive behavior and may represent a novel therapeutic target for pain treatment.

Comparison of dorsal root ganglion gene expression in rat models of traumatic and HIV-associated neuropathic pain

To elucidate the mechanisms underlying peripheral neuropathic pain in the context of HIV infection and antiretroviral therapy, we measured gene expression in dorsal root ganglia (DRG) of rats subjected to systemic treatment with the anti-retroviral agent, ddC (Zalcitabine) and concomitant delivery of HIV-gp120 to the rat sciatic nerve. L4 and L5 DRGs were collected at day 14 (time of peak behavioural change) and changes in gene expression were measured using Affymetrix whole genome rat arrays. Conventional analysis of this data set and Gene Set Enrichment Analysis (GSEA) was performed to discover biological processes altered in this model. Transcripts associated with G protein coupled receptor signalling and cell adhesion were enriched in the treated animals, while ribosomal proteins and proteasome pathways were associated with gene down-regulation. To identify genes that are directly relevant to neuropathic mechanical hypersensitivity, as opposed to epiphenomena associated with other aspects of the response to a sciatic nerve lesion, we compared the gp120 + ddC-evoked gene expression with that observed in a model of traumatic neuropathic pain (L5 spinal nerve transection), where hypersensitivity to a static mechanical stimulus is also observed. We identified 39 genes/expressed sequence tags that are differentially expressed in the same direction in both models. Most of these have not previously been implicated in mechanical hypersensitivity and may represent novel targets for therapeutic intervention. As an external control, the RNA expression of three genes was examined by RT-PCR, while the protein levels of two were studied using western blot analysis.

A Randomized Trial Evaluating Prosaptide™ for HIV-Associated Sensory Neuropathies: Use of an Electronic Diary to Record Neuropathic Pain

ObjectivesTo examine the efficacy and safety of Prosaptide™ (PRO) for the treatment of painful HIV-associated sensory neuropathies (HIV-SN).DesignA randomized, double-blind, placebo-controlled, multicenter study in participants with sensory neuropathy. Pain modulating therapy was discontinued prior to baseline. Participants were stratified by sural sensory nerve action potential (SNAP) amplitude. Participants were trained to use an electronic diary (ED) to record pain.SettingPeripheral neuropathies are common complications of HIV infection. The pathogenesis is unknown and currently treatments are restricted to symptomatic measures. We examined PRO against placebo (PBO) for treatment of painful HIV-SN and performed a post-hoc evaluation of an electronic diary (ED) to record HIV-associated neuropathic pain.ParticipantsEligible participants included adults with neurologist-confirmed painful HIV-SN.Interventions2, 4, 8, or 16 mg/d PRO or PBO administered via subcutaneous (SC) injection for six weeks. Neurotoxic antiretroviral drug usage was held constant.Outcome MeasuresChanges from baseline in the weekly average of evaluable daily random prompts measuring pain using the Gracely pain scale and adverse events.Results237 participants were randomized. The study was stopped after a planned futility analysis. There were no between-group differences in the frequency of adverse events or laboratory toxicities. The 6-week mean (sd) Gracely pain scale changes were −0.12 (0.23), −0.24 (0.35), −0.15 (0.32), −0.18 (0.34), and −0.18 (0.32) for the 2, 4, 8, 16 mg, and PBO arms respectively. A similar variability of pain changes recorded using the ED were noted compared to previous trials that used paper collection methods.Conclusions6-week treatment with PRO was safe but not effective at reducing HIV-associated neuropathic pain. Use of an ED to record neuropathic pain is novel in HIV-SN, resulted in reasonable compliance in recording pain data, but did not decrease the variability of pain scores compared to historical paper collection methods.Trial RegistrationCurrent Controlled Trials NCT00286377

Pharmacological, behavioural and mechanistic analysis of HIV-1 gp120 induced painful neuropathy

A painful neuropathy is frequently observed in people living with human immunodeficiency virus type 1 (HIV-1). The HIV coat protein, glycoprotein 120 (gp120), implicated in the pathogenesis of neurological disorders associated with HIV, is capable of initiating neurotoxic cascades via an interaction with the CXCR4 and/or CCR5 chemokine receptors, which may underlie the pathogenesis of HIV-associated peripheral neuropathic pain. In order to elucidate the mechanisms underlying HIV-induced painful peripheral neuropathy, we have characterised pathological events in the peripheral and central nervous system following application of HIV-1 gp120 to the rat sciatic nerve. Perineural HIV-1 gp120 treatment induced a persistent mechanical hypersensitivity (44% decrease from baseline), but no alterations in sensitivity to thermal or cold stimuli, and thigmotactic (anxiety-like) behaviour in the open field. The mechanical hypersensitivity was sensitive to systemic treatment with gabapentin, morphine and the cannabinoid WIN 55,212-2, but not with amitriptyline. Immunohistochemical studies reveal: decreased intraepidermal nerve fibre density, macrophage infiltration into the peripheral nerve at the site of perineural HIV-1 gp120; changes in sensory neuron phenotype including expression of activating transcription factor 3 (ATF3) in 27% of cells, caspase-3 in 25% of cells, neuropeptide Y (NPY) in 12% of cells and galanin in 13% of cells and a spinal gliosis. These novel findings suggest that this model is not only useful for the elucidation of mechanisms underlying HIV-1-related peripheral neuropathy but may prove useful for preclinical assessment of drugs for the treatment of HIV-1 related peripheral neuropathic pain.

HIV-Associated Neuropathic Pain

Peripheral neuropathy is associated with numerous systemic illnesses including HIV infection. Neuropathic pain constitutes approximately 25-50% of all pain clinic visits. Distal symmetrical polyneuropathy (DSP) is the most common form of peripheral neuropathy in individuals with HIV infection. DSP is distinguished from other forms of neuropathy on the basis of history and neurological examination. The pain associated with DSP can be debilitating. Therefore, it is important to diagnose HIV-associated DSP properly and treat the neuropathic pain in order to improve quality of life. We review the clinical manifestations, epidemiology, pathophysiology and management strategies for HIV-associated DSP.

Efficacy of a vibratory stimulus for the relief of HIV-associated neuropathic pain

Pain related to HIV disease is frequently debilitating. Of the many pain syndromes that occur in persons with HIV, distal symmetrical polyneuropathy (DSPN) is particularly devastating. Because DSPN often responds, at best, only partially to available pharmacologic interventions, non-pharmacologic interventions need to be investigated. Vibration has been suggested to be effective for reducing pain in other populations with chronic pain. This randomized, sham-controlled, double-masked study tested the short-term efficacy of a 45-min vibration treatment for DSPN foot pain in persons infected with HIV. Vibration therapy was delivered using a portable platform foot vibrator that provided stimulation at a frequency of 60 Hz. For all patients, the control box for the vibrator emitted an audible hum and part of the control box lit up during treatment, but only patients randomized to active treatment received vibration. Pain intensity (0–10) was measured immediately prior to and after treatment. Subjects were also questioned regarding pain relief (0–100%) immediately after the treatment. The mean percentage pain relief was 61.0±33.1% (median 70.0; range 0–100) for all patients, 67.3±34.0% (median 80.0; range 0–100) for vibration patients, and 55.0±32.0% (median 60.0; range 0–100) for sham patients. No statistically significant differences were found between the vibration and sham groups with respect to percentage pain relief (Mann–Whitney test; P=0.19) or the pre- and post-treatment current-pain difference (Mann–Whitney test; P=0.92). These results underscore the necessity for control groups in studies of non-pharmacologic therapies for pain.