doi: 10.1016/j.ibneur.2021.01.004. eCollection 2021 Jun.
- PMID: 34179865
- PMCID: PMC8211923
- DOI: 10.1016/j.ibneur.2021.01.004
Abstract
Human immunodeficiency virus (HIV) infection and antiretroviral therapy can independently induce HIV-associated neuropathic pain (HIV-NP). There is a dearth of drugs or therapeutic modalities that can alleviate HIV-NP. Smoked cannabis has been reported to improve pain measures in patients with neuropathic pain. Cannabis, phytocannabinoids, and the endocannabinoids such N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), produce some of their effects via cannabinoid receptors (CBRs). Endocannabinoids are degraded by various enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase. We searched PubMed, Google Scholar, clinicaltrials.gov and clinicaltrialsregister.eu using various key words and their combinations for published papers that studied HIV-NP and cannabis, cannabinoids, or endocannabinoids up to 27th December 2020. All original research articles that evaluated the efficacy of molecules that modulate the endocannabinoid system (ECS) for the prevention and/or treatment of pain in HIV-NP animal models and patients with HIV-NP were included. The PubMed search produced a total of 117 articles, whereas the Google Scholar search produced a total of 9467 articles. Amongst the 13 articles that fulfilled the inclusion criteria 11 articles were found in both searches whereas 2 articles were found in Google Scholar only. The clinicaltrials.gov and clinicaltrialsregister.eu searches produced five registered trials of which three were completed and with results. Ten preclinical studies found that the endocannabinoids (2-AG and AEA), synthetic mixed CB1R/CB2R agonist WIN 55,212-2, a CB2R-selective phytocannabinoid β-caryophyllene, synthetic CB2R-selective agonists (AM1710, JWH015, JWH133 and Gp1a, but not HU308); FAAH inhibitors (palmitoylallylamide, URB597 and PF-3845) and a drug combination of indomethacin plus minocycline, which produces its effects in a CBR-dependent manner, either prevented the development of and/or attenuated established HIV-NP. Two clinical trials demonstrated greater efficacy of smoked cannabis over placebo in alleviating HIV-NP, whereas another clinical trial demonstrated that cannabidivarin, a cannabinoid that does not activate CBRs, did not reduce HIV-NP. The available preclinical results suggest that targeting the ECS for prevention and treatment of HIV-NP is a plausible therapeutic option. Clinical evidence shows that smoked cannabis alleviates HIV-NP. Further research is needed to find out if non-psychoactive drugs that target the ECS and are delivered by other routes than smoking could be useful as treatment options for HIV-NP.
Keywords: 2-AG, 2-arachidonoylglycerol; ABHD12, α-β-hydrolase domain-containing 12; ABHD6, α-β-hydrolase domain-containing 6; AEA, N-arachidonoylethanolamine; AEs, adverse effects; Antiretroviral; BCP, β-caryophyllene; CB1R, cannabinoid type 1 receptor; CB2R, cannabinoid type 2 receptor; CBD, cannabidiol; CBDV, cannabidivarin; CBRs, cannabinoid receptors; CINP, chemotherapy-induced neuropathic pain; CNS, central nervous system; COX, cyclooxygenase; Cannabinoid; Cannabis; DAG, diacylglycerol; DAGL, DAG lipase; DDS, descriptor differential scale; DSP, distal symmetric polyneuropathy; ECS, endocannabinoid system; Endocannabinoid; FAAH, fatty acid amide hydrolase; FDA, Food and Drug Administration; GPCRs, G protein-coupled receptors; HIV, human immunodeficiency virus; HIV-DSP, HIV-distal symmetric polyneuropathy; HIV-NP, HIV-associated neuropathic pain; Human immunodeficiency virus; IPM, indomethacin plus minocycline; L-29, palmitoylallylamide; MAGL, monoacylglycerol lipase; MAIDS, murine acquired immunodeficiency syndrome; NAPE, N-acyl-phosphatidylethanolamine; NAPE-PLD, NAPE-specific phospholipase D; NP, neuropathic pain; NSAIDs, non-steroidal anti-inflammatory drugs; Neuropathic pain; OTC, over the counter; PLWH, people living with HIV; PNP, peripheral neuropathic pain; RCTs, randomised clinical trials; SAMRC, South African Medical Research Council; TRPA, transient receptor potential ankyrin; TRPV, transient receptor potential vanilloid; WHO, World Health Organization; ddC, 2′-3′-dideoxycytidine; delta-9-THC, delta-9-tetrahydrocannabinol; gp, glycoprotein.
© 2021 The Authors.
Conflict of interest statement
The authors have no conflicts of interest.
