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.

Brief report: Characteristics of antidepressant use in patients with heart failure.

BACKGROUND: Depression is common in heart failure (HF), but there is little data on the characteristics of antidepressant use in patients with HF. OBJECTIVE: To survey basic information on antidepressant prescription characteristics, use, effectiveness, and follow-up. METHODS: Observational study in two outpatient cardiology clinics of 37 NYHA class I-IV HF patients taking antidepressant medication. RESULTS: Thirty-one percent of prescriptions for antidepressants were obtained from psychiatrists, 58% from primary care physicians, and 8% from cardiologists. The majority of patients (87%) reported regularly taking their antidepressant medication as prescribed, however 48% reported never having had the dosage of their antidepressant medication adjusted. Only 53% of the patients reported that the medication had helped their mood "almost entirely" or "mostly" back to normal since starting their antidepressants, while the remaining patients reported that their mood was only "halfway" or "somewhat" back to normal or that the medication had not helped their depression at all. Among a subset of 10 patients who completed the Beck Depression (BDI) inventory, 6 still had depressed mood (BDI >/= 10). CONCLUSION: The findings from this survey study provide insight into the characteristics of antidepressant use in patients with HF and argue for better follow up of HF patients who are prescribed antidepressants.

Lithium improves HIV-associated neurocognitive impairment.

OBJECTIVE: To determine the effects of low-dose oral lithium on the neuropsychological performance of individuals diagnosed with HIV-associated neurocognitive impairment. DESIGN AND METHODS: The project was a single-arm, open-label, 12-week pilot study at a university-based tertiary care center. The participants were adults who had been diagnosed with HIV-associated neurocognitive impairment and had been on stable antiretroviral therapy for at least 12 weeks. Conditions that could affect cognition, worsen adherence to study procedures, or increase the risk of lithium adverse reactions were excluded. Twenty-one individuals were screened and eight were enrolled, all of whom completed the study. Oral lithium was initiated at 300 mg daily and was titrated to maintain 12-h trough concentrations between 0.4 and 0.8 mEq/l. Global neuropsychological performance was assessed by the global deficit score. RESULTS: At baseline, all participants had impaired neuropsychological performance and most had reduced CD4 cell counts (median 292 cells/microl), and HIV RNA levels in plasma below 400 copies/mL (seven of eight). Titrated lithium doses ranged between 600 and 1200 mg/day. Performance improved in all eight individuals after 12 weeks, and became unimpaired in six. The study treatment was well tolerated with no grade 3 or 4 adverse events and no premature discontinuations. CONCLUSIONS: Lithium resulted in improved neuropsychological performance in antiretroviral-treated, impaired individuals in this small, open-label study. Based on published in vitro data, lithium may exert this effect by inhibiting neuronal glycogen synthase kinase-3beta.

Lopinavir concentrations in cerebrospinal fluid exceed the 50% inhibitory concentration for HIV.

INTRODUCTION: Lopinavir (LPV) is highly bound to plasma proteins and is a substrate for active drugs transporters, which may greatly limit the access of LPV to the central nervous system (CNS). However, even low lopinavir concentrations may be sufficient to inhibit HIV replication. Prior anecdotal reports indicated that lopinavir concentrations were below detection in cerebrospinal fluid (CSF). METHODS: LPV was measured by liquid chromatography/mass spectrometry in 31 CSF-plasma pairs from 26 HIV-infected individuals who were taking LPV-containing antiretroviral regimens. The lower limit of quantification was 3.7 microg/l. RESULTS: Seven of the sample pairs had very low plasma (and CSF) LPV concentrations, with a mean estimated plasma trough of 274 microg/l (range, < 3.7 to 608; typical trough values approximately 4000 microg/l), suggesting poor recent adherence. In the remaining 24 sample pairs, the median LPV concentration was 5889 microg/l [interquartile range (IQR), 4805-9620] and all CSF samples had measurable LPV concentrations: median 17.0 microg/l (IQR, 12.1-22.7). The median CSF-plasma ratio was 0.23% (range, 0.12-0.75). All CSF concentrations in these samples were more than double the 50% inhibitory concentration for wild-type HIV virus. CONCLUSIONS: In patients with typical plasma levels of LPV, the drug is detectable in the CSF at concentrations that exceed those needed to inhibit HIV replication. Despite being > 98% bound to plasma proteins, LPV penetrates into the CNS and may contribute to the control of HIV in this potential reservoir.