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Cannabis in painful HIV-associated sensory neuropathy
Abstract
To determine the effect of smoked cannabis on the neuropathic pain of HIV-associated sensory neuropathy and an experimental pain model.
Prospective randomized placebo-controlled trial conducted in the inpatient General Clinical Research Center between May 2003 and May 2005 involving adults with painful HIV-associated sensory neuropathy. Patients were randomly assigned to smoke either cannabis (3.56% tetrahydrocannabinol) or identical placebo cigarettes with the cannabinoids extracted three times daily for 5 days. Primary outcome measures included ratings of chronic pain and the percentage achieving >30% reduction in pain intensity. Acute analgesic and anti-hyperalgesic effects of smoked cannabis were assessed using a cutaneous heat stimulation procedure and the heat/capsaicin sensitization model.
Fifty patients completed the entire trial. Smoked cannabis reduced daily pain by 34% (median reduction; IQR = -71, -16) vs 17% (IQR = -29, 8) with placebo (p = 0.03). Greater than 30% reduction in pain was reported by 52% in the cannabis group and by 24% in the placebo group (p = 0.04). The first cannabis cigarette reduced chronic pain by a median of 72% vs 15% with placebo (p < 0.001). Cannabis reduced experimentally induced hyperalgesia to both brush and von Frey hair stimuli (p < or = 0.05) but appeared to have little effect on the painfulness of noxious heat stimulation. No serious adverse events were reported.
Smoked cannabis was well tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy. The findings are comparable to oral drugs used for chronic neuropathic pain.
... However, the use of opioids can pose significant risks, including drug dependence and incorrect dosing, especially when considering variations based on individual genetics or state regulations. Cannabinoids have long been recognized for their potential in pain management, with emerging research indicating their involvement in modulating nociceptive transmission [2,11,12,59,[69][70][71][72][73][74][75][76][77][78][79]. Recent studies have underscored the widespread activity of the endocannabinoid system in pain regulation, particularly targeting the affective aspects of pain, attributed to the distribution of cannabinoid receptors in regions of the brain associated with emotions and cognition. ...
... The report emphasized that cannabis holds significant promise for pain relief, particularly in neuropathic pain conditions like HIV-related peripheral neuropathy. Encouragingly, a trial involving vaporized cannabis in diabetic neuropathy yielded positive results [2,11,12,59,[69][70][71][72][73][74][75][76][77][78][79]. ...
... Overall, while randomized controlled trials pose challenges in evaluating cannabis as a Schedule 1 botanical, observational studies and ongoing clinical trials provide valuable insights into its potential therapeutic role in pain management, particularly in cancer care. Previous studies, as indicated in the text, have shown promising results regarding the efficacy of cannabinoids in managing pain, including chemotherapy-induced peripheral neuropathy, and their potential to reduce opioid use in cancer patients (Table 3) [2,11,12,59,[69][70][71][72][73][74][75][76][77][78][79][80][81]. Table 3. Summary table of studies exploring cannabis in pain management. ...
Simple Summary
Cancer is a major disease and a leading cause of death worldwide. Improving treatment and management strategies for cancer is critical. This article explores cannabis and its pharmacological properties as a promising tool in cancer care, especially in easing symptoms like appetite loss, pain, nausea, vomiting, and insomnia. Moreover, it examines the anti-tumor properties of cannabis, highlighting that, although some evidence suggests benefits, more research is necessary to confirm these effects. The article addresses the evidence concerning the clinical challenges of using cannabis, such as its psychoactive effects, and potential side effects. The article aims to clarify the current understanding of cannabis use in cancer care, helping healthcare professionals and patients make better-informed decisions and improve treatment outcomes.
Abstract
As the legalization of medical cannabis expands across several countries, interest in its potential advantages among cancer patients and caregivers is burgeoning. However, patients seeking to integrate cannabis into their treatment often encounter frustration when their oncologists lack adequate information to offer guidance. This knowledge gap is exacerbated by the scarcity of published literature on the benefits of medical cannabis, leaving oncologists reliant on evidence-based data disheartened. This comprehensive narrative article, tailored for both clinicians and patients, endeavors to bridge these informational voids. It synthesizes cannabis history, pharmacology, and physiology and focuses on addressing various symptoms prevalent in cancer care, including insomnia, nausea and vomiting, appetite issues, pain management, and potential anti-cancer effects. Furthermore, by delving into the potential mechanisms of action and exploring their relevance in cancer treatment, this article aims to shed light on the potential benefits and effects of cannabis in oncology.
... Due to its antiemetic qualities, it can help reduce nausea and vomiting brought on by some medical procedures, like chemotherapy [63]. A randomized controlled trial (RCT) was carried out by Abrams et al. (2007) to look at the analgesic effects of smoked cannabis on patients with neuropathic pain.The findings suggest that Δ9-THC possesses analgesic properties. The study provided evidence for the analgesic effect of Δ9-THC by showing a substantial decrease in the level of pain in the cannabis group relative to the placebo group [64]. ...
... A randomized controlled trial (RCT) was carried out by Abrams et al. (2007) to look at the analgesic effects of smoked cannabis on patients with neuropathic pain.The findings suggest that Δ9-THC possesses analgesic properties. The study provided evidence for the analgesic effect of Δ9-THC by showing a substantial decrease in the level of pain in the cannabis group relative to the placebo group [64]. ...
... CBD has medicinal benefits without the euphoric symptoms that THC is commonly associated with, it is frequently considered to be the more adaptable and advantageous of the two [66]. CBD, widely acknowledged for its potential therapeutic applications, finds use in treating diverse medical conditions, including epilepsy, anxiety, pain management, and inflammation [62,64]. An essential distinction lies in the fact that CBD does not induce intoxication, making it suitable for patients seeking relief without experiencing the psychoactive high associated with THC [67]. ...
... [74] Cannabis has also demonstrated efficacy for the control of neuropathic pain in randomized placebo-controlled human studies. [75] Over the past 30 years, there have been a growing number of jurisdictions legalizing access to medicinal cannabis, with most of the states in the USA legalizing medical marijuana or CBD use. [76] Since the concern regarding the increased use of cannabis with marijuana legalization is after all unsupported, [76] the medicinal potentials for cannabis-based analgesia would unravel as more jurisdictions approve a legal framework for its use. ...
... Medicinal cannabis Abrams et al. [75] Randomized controlled trial ...
Conventional analgesics have traditionally been the mainstay of pain management, but unsatisfactory pain relief and troubling side effects
have led to continuing search for more efficacious and safer remedies. Adjuvant analgesics are drugs with beneficial analgesic effects despite
not having been developed as analgesics. Adjuvants facilitate better pain control with a reduction in analgesic consumption, as well as the
concomitant side effects. The opioid epidemic, deaths from opioid overdose, and several other complications of opioid‑based analgesia have
led to increasing interrogation of its use in both acute and chronic pain settings. The current trends in surgical practice, especially ambulatory
surgery and enhanced recovery after surgery/fast‑track care pathways have profoundly impacted the choices for acute pain management,
with an increasing role for adjuvants. Medicinal cannabis and other adjuvants have also become increasingly popular for the management of
intractable chronic pain and neuropathic pain owing to the inadequacy of conventional analgesics in these pain states. As clinical and research
interest in patient safety and patient satisfaction evolve further development of adjuvant analgesics will be expected to fill the existing gaps
in pain management. This review aims to examine the expanding role of analgesic adjuvants in the management of acute and chronic pains,
and in the prevention of the transition to chronic pain. In doing so, we conducted an online search primarily on the PUBMED database using
the term “analgesic adjuvant” for human studies published in peer‑reviewed journals from 2000 to 2022.
Keywords: Ambulatory surgery, analgesic adjuvant, cannabis, neuropathic pain, opioids
... The medicinal benefits of cannabis in treating peripheral neuropathy have been evidenced in cases related to diabetes and HIV, showing a reduction in daily pain by as much as 34% following cannabis use [42][43][44]. Furthermore, studies have been carried out to investigate the impact of cannabis on relieving chemotherapy-induced peripheral neuropathy in laboratory mice. ...
Cannabinoids, the active constituents of Cannabis sativa, replicate the effects of endogenous cannabinoids
by engaging specific cannabinoid receptors, notably the CB1 receptor predominantly located in the
central nervous system and the CB2 receptor primarily associated with immune function. Delta-9-
tetrahydrocannabinol, the principal bioactive cannabinoid in this plant has been approved as a prescription
medication for managing chemotherapy-induced nausea and vomiting as well as anorexia. Furthermore,
cannabinoids may provide relief in cancer-related pain due to a potential synergistic effect with opioid
analgesics. They have also demonstrated efficacy in alleviating peripheral neuropathy resulting from
chemotherapy. While cannabinoids possess a favorable safety profile, their therapeutic application is often
constrained by their psychoactive properties and limited bioavailability. This review aimed to explore the
application of medicinal cannabis in alleviating symptoms experienced by cancer patients.
... The medicinal benefits of cannabis in treating peripheral neuropathy have been evidenced in cases related to diabetes and HIV, showing a reduction in daily pain by as much as 34% following cannabis use [42][43][44]. Furthermore, studies have been carried out to investigate the impact of cannabis on relieving chemotherapy-induced peripheral neuropathy in laboratory mice. ...
... The sensitivity and specificity of the PSQI was 80-89.6% and 86.5-86.6%, respectively [24][25][26]. ...
Background: Sleep difficulty is common in the current society. Poor sleep has a significant influence on health, social interactions and even mortality; therefore, maintaining good sleep is of prime importance. Cannabidiol (CBD), a cannabis-derived compound, is known for its medical significance with many positive effects in humans, including decreasing anxiety and improving sleep for those with sleep disorders. Objective: However, whether CBD skin absorption results in similar effects is unknown. Therefore, examining CBD-coated fabric as a pillow cover to improve sleep quality in duty shift nurses is the purpose of this paper. Methods: This study recruited 55 duty shift nurses as participants to evaluate sleep patterns and quality using the Pittsburgh Sleep Quality Index (PSQI) and a consumer-grade tracker (Fitbit Charge 3). Data were collected over three phases: a one-week baseline period, a two-week intervention period using a CBD-coated pillow cover and a one-week follow-up period, referred to as the post-intervention phase, during which the use of CBD-coated pillow cover was continued. Results: Of the 55 participants, 10 were men (18.2%) and 45 were women (81.8%). At baseline, all participants exhibited poor sleep quality (PSQI ≥ 5). However, after three weeks of using CBD-coated pillow covers, subjective sleep quality significantly improved, with 7.3% of participants achieving PSQI scores <5. Additionally, slight changes in sleep patterns were observed, with increases in both light sleep and deep sleep durations. Light sleep duration increased from a baseline of 196.21 ± 65.28 to 206.57 ± 59.15 min two weeks after intervention (p = 0.337). Similarly, deep sleep duration showed a modest increase from 61.97 ± 21.01 min to 64.35 ± 22.19 min (p = 0.288). Furthermore, a significant reduction in anxiety levels was reported (p < 0.005). Conclusions: Using a CBD-coated pillow cover was found to enhance sleep duration in healthy individuals experiencing poor sleep. Consequently, for adults struggling with sleep difficulties, incorporating a CBD-coated pillow cover may serve as an effective aid in improving sleep quality.
... Clinical evidence supports the use of cannabis for various conditions, including neuropathic pain of HIV-associated sensory neuropathy [6] or spasticity associated with multiple sclerosis [7]. MC treatment demonstrates both efficacy and tolerability in adult patients with Tourette Syndrome [8], and has shown promise in reducing the severity of self-reported headache and migraine [9]. ...
Background
Despite its increasing prevalence among the public, cannabis use is still perceived as deviant behavior and consequently stigmatized. However, there remains a paucity of understanding regarding the impact of this stigma on patients employing cannabis for therapeutic purposes. This qualitative research endeavored to explore the stigma experiences of medical cannabis (MC) users in Germany, aiming to discern challenges that may impede their daily lives and healthcare access. The primary objective of this study was to identify instances of stigma associated with MC usage across various spheres.
Methods
We conducted semistructured interviews with 15 individuals prescribed MC across diverse regions and occupational backgrounds in Germany. Interviews explored personal experiences with MC use, interactions with healthcare professionals, and stigma-related challenges. Data collection adhered to the COREQ guidelines. Transcribed interviews underwent systematic qualitative content analysis using MAXQDA software, with coding developed iteratively through researcher discussions. Communicative validation and inter-coder comparison enhanced analytical robustness.
Results
Despite participants exhibiting a positive attitude towards the therapeutic effects and benefits of MC, stereotypes and prejudices persist. Participants highlighted the role of media portrayals and a lack of public awareness as central barriers to broader societal acceptance. Personal experiences with MC were marked by improved quality of life but also internalised stigma and external challenges, including interactions with law enforcement and difficulties with healthcare access.
Conclusion
This qualitative study suggests that the utilisation of MC remains inadequately normalised in Germany. Our findings indicate that MC users experience both substantial benefits and persistent challenges, with stigma remaining a key issue. While participants reported improvements in quality of life, barriers such as bureaucratic hurdles and knowledge gaps among healthcare professionals hinder access to appropriate care. The findings underscore the imperative for enhanced education among healthcare professionals.
... For the management of neuropathic pain, results have been both promising and inconsistent. A randomized placebo-controlled trial of patients suffering from HIV-associated sensory neuropathy demonstrated more than 30% reduction in pain was reported by 52% in the inhaled cannabis group and by 24% in the placebo group [53]. Similarly, a meta-analysis by Andreae et al. [54] confirmed the efficacy of inhaled THC, showing dose-dependent pain relief in patients, reporting a reduction in pain scores in one out of every five to six patients with nerve-related pain. ...
Background/Objectives: Chronic pain remains a pervasive and challenging public health issue, often resistant to conventional treatments such as opioids, which carry substantial risks of dependency and adverse effects. Cannabinoids, bioactive compounds derived from the Cannabis sativa plant and their synthetic analogs, have emerged as a potential alternative for pain management, leveraging their interaction with the endocannabinoid system to modulate pain and inflammation. Methods: The current, evolving literature regarding the history, efficacy, applications, and safety of cannabinoids in the treatment of chronic pain was reviewed and summarized to provide the most current review of cannabinoids. Results: Evidence suggests that cannabinoids provide moderate efficacy in managing neuropathic pain, fibromyalgia, cancer-related pain, and multiple sclerosis-related spasticity. Patient-reported outcomes further indicate widespread perceptions of cannabinoids as a safer alternative to opioids, with potential opioid-sparing effects. However, the quality of existing evidence is limited by small sample sizes and methodological inconsistencies. Regulatory barriers, including the classification of cannabis as a Schedule I substance in the United States, continue to hinder robust research and clinical integration. Moreover, the risks associated with cannabinoids, such as psychiatric effects, addiction potential, and drug interactions, necessitate cautious application. Conclusions: Cannabinoids represent a promising, albeit complex, alternative for chronic pain management, particularly given the limitations and risks of traditional therapies such as opioids. However, significant deficiencies remain in the research. While smaller trials and systematic reviews indicate therapeutic potential, the quality of evidence is often low due to limited sample sizes, short study durations, and methodological inconsistencies. Large-scale, randomized controlled trials with long-term follow-up are urgently needed to confirm efficacy and safety across diverse patient populations and pain etiologies.
... Cannabis consumption is increasing and debates about the legalisation of the recreational use of cannabis are ongoing in numerous countries. Medical applications of cannabis and its active compounds delta-9-tetrahydrocannabinol (d-9-THC or THC) and cannabidiol have been studied [1][2][3][4][5], particularly for control of pain [1,6,7], spasticity [8][9][10], neurological [11][12][13] as well as gastrointestinal disorders [14] and nausea and vomiting [15,16]. Similarly, subjective effects of THC have increasingly become a focus of academic interest [17,18]. ...
Background
Cannabis is increasingly used and debates about the legalisation of the recreational use of cannabis are ongoing. In this prospective, placebo-controlled study in healthy volunteers not regularly consuming cannabis, subjective psychotropic and somatic effects after a single dose of intravenous THC were assessed and quantified over 48 h.
Methods
Twenty-five healthy volunteers received a single IV bolus of THC and 6 received normal saline. Psychotropic and somatic effects of THC were assessed by two questionnaires that were completed at up to 14 timepoints from shortly before drug administration to 48 h later.
Results
Demographic data did not differ between groups. Differences between THC and placebo for all assessed effects, except for euphoria, irritation and headache, were clearly discernible. Subdimensions related to positive mood were less and those related to negative mood were more pronounced in the THC group. Peak plasma concentrations were observed at 1 to 5 min after THC administration while peak effects occurred between 45 and 60 min. Differences between THC and placebo were pronounced and seen for up to 90 to 120 min for most effects, except for “sleepiness” and “deactivation”, where the effect of THC was discernible for up to 5 h. At 24 and 48 h, there were no statistically significant difference between THC and placebo group.
Conclusions
THC triggers a large range of psychotropic and somatic effects with peak effects at 45 to 60 min after IV administration of THC, much later than plasma peak levels. Most effects are short-lasting with a duration of up to 2 h, but some effects like sleepiness and deactivation can be longer-lasting and persist for 5 h or longer in cannabis-naïve or cannabis-abstinent individuals. Since effects of THC demonstrate a time course that differs from the time course of plasma concentrations it might be important to base the judgment of a possible impairment related to THC consumption on clinical or behavioral tests in addition to THC plasma levels.
Trial registration
www.isrctn.com; registration number ISRCTN53019164.
... 64 In our review, we identified 14 studies investigating chronic neuropathic pain in a total of 506 patients. [65][66][67][68][69][70][71][72][73][74][75][76][77][78] Seven studies reported satisfactory results, 65-71 1 study showed unfavorable results, 72 and the remaining 6 studies reported inconsistent results after treatment with THC and CBD. [73][74][75][76][77][78] Table 6 presents the list of studies on chronic neuropathic pain. ...
Chronic pain affects up to 40% of adults, contributing to high medical expenses, the loss of productivity, reduced quality of life (QoL), and disability. Chronic pain requires detailed diagnostic assessment, treatment and rehabilitation, yet approx. 80% of patients report inadequate pain management. As new treatment options are needed, we aimed to explore the effectiveness of medical cannabis-based products in managing chronic pain, with a particular focus on treatment patterns.We searched the PubMed, Scopus and Web of Science databases using keywords related to cannabinoids and chronic pain syndromes. In total, 3,954 articles were identified, and 74 studies involving 12,562 patients were included. The effectiveness of cannabis-based products varied across studies. Cannabinoids were most effective in treating chronic secondary headache and orofacial pain, chronic secondary musculoskeletal pain, chronic secondary visceral pain, and chronic neuropathic pain. Properly qualifying patients is the first crucial step in managing chronic pain, considering pain characteristics, comorbidities and other treatment options. Treatment should start with low doses of cannabinoids, which are then increased to achieve the desired therapeutic effect while minimizing adverse effects.This narrative review revealed significant gaps in the evidence regarding precise treatment patterns, particularly for the long-term maintenance treatment needed by patients with chronic pain. Medical cannabis can be considered an option for carefully selected patients with chronic pain syndromes when other treatment options fail to achieve an adequate response, and when the potential benefits outweigh the risks. However, there is still a need for well-designed clinical research to establish the long-term efficacy and safety of cannabinoids.
... Cannabis plants with concentrations higher than 0.2 % Δ 9 -THC are considered illegal, and their owners can be prosecuted according to national laws. The cannabis drug type, also known as marijuana, is used for medical purposes (Abrams et al., 2007;Corey-Bloom et al., 2012) and for its psychotropic effect (Baker et al., 2003;Ben Amar, 2006;Leung, 2011;Borgelt et al., 2013). On the other hand, hemp, the non-drug strain, is used in the food-fiber industry (Duque Schumacher et al., 2020;Nissen et al., 2010). ...
... Cannabis use in PWH has previously shown therapeutical potential in managing HIV-associated complications [49]. Recent studies have reported that PWH using cannabis have less immune cell activation compared to PWH that do not use cannabis [50,51]. ...
(1) Background: Triggering receptor expressed on myeloid cells 2 (TREM2) is involved in neu-roinflammation and HIV-associated neurocognitive impairment (NCI). People with HIV (PWH) using cannabis exhibit lower inflammation and neurological disorders. We hypothesized TREM2 dysfunction mediates HIV neuropathogenesis and can be reversed by cannabinoids. (2) Methods: EcoHIV-infected wildtype (WT) and TREM2R47H mutant mice were used to study HIV's impact on TREM2 and behavior. TREM2 and related gene expressions were examined in mono-cyte-derived macrophages (MDMs) from PWH (n=42) and people without HIV (PWoH; n=19) with varying cannabis use via RNA sequencing and qPCR. Differences in membrane-bound and soluble TREM2 (sTREM2) were evaluated using immunocytochemistry (ICC) and ELISA. (3) Results: EcoHIV increased immature and C-terminal fragment forms of TREM2 in WT mice but not in TREM2R47H mice, with increased IBA1 protein in TREM2R47H hippocampi, correlating with worse memory test performance. TREM2 mRNA levels increased with age in PWoH but not PWH. Cannabidiol (CBD) treatment increased TREM2 mRNA alone and with IL1β. RNA-seq showed upregulation of TREM2-related transcripts in cannabis-using PWH compared to naïve controls. IL1β increased sTREM2 and reduced membrane-bound TREM2, effects partially re-versed by CBD. (4) Conclusions: These findings suggest HIV affects TREM2 expression modu-lated by cannabis and CBD, offering insights for therapeutic strategies.
... People with HIV (PWH) continue to experience neurological disorders even with the widespread implementation of suppressive antiretroviral therapy (ART). Despite the therapeutic success of ART in PWH, HIV-associated neuroinflammation can persist and Cannabis use in PWH has previously shown therapeutical potential in managing HIVassociated complications [50]. Recent studies have reported that PWH using cannabis have less immune cell activation compared to PWH that do not use cannabis [51,52]. ...
Triggering receptor expressed on myeloid cells 2 (TREM2) is involved in neuroinflammation and HIV-associated neurocognitive impairment (NCI). People with HIV (PWH) using cannabis exhibit lower inflammation and neurological disorders. We hypothesized that TREM2 dysfunction mediates HIV neuropathogenesis and can be reversed by cannabinoids. EcoHIV-infected wildtype (WT) and TREM2R47H mutant mice were used to study HIV’s impact on TREM2 and behavior. TREM2 and related gene expressions were examined in monocyte-derived macrophages (MDMs) from PWH (n = 42) and people without HIV (PWoH; n = 19) with varying cannabis use via RNA sequencing and qPCR. Differences in membrane-bound and soluble TREM2 (sTREM2) were evaluated using immunocytochemistry (ICC) and ELISA. EcoHIV increased immature and C-terminal fragment forms of TREM2 in WT mice but not in TREM2R47H mice, with increased IBA1 protein in TREM2R47H hippocampi, correlating with worse memory test performance. TREM2 mRNA levels increased with age in PWoH but not in PWH. Cannabidiol (CBD) treatment increased TREM2 mRNA alone and with IL1β. RNA-seq showed the upregulation of TREM2-related transcripts in cannabis-using PWH compared to naïve controls. IL1β increased sTREM2 and reduced membrane-bound TREM2, effects partially reversed by CBD. These findings suggest HIV affects TREM2 expression modulated by cannabis and CBD, offering insights for therapeutic strategies.
... Alleviating chronic inflammation could potentially help to prevent the onset of non-AIDS-related comorbidities in PWH on ART [5][6][7][8]. Furthermore, cannabis is often used by PWH for both medical reasons such as chronic pain, anxiety and depression, but also for recreational reasons, and to improve quality of life [9][10][11][12][13]. The primary cannabinoids in the cannabis plant, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), demonstrate potent anti-inflammatory and anti-fibrotic effects in both experimental models [14][15][16][17][18][19][20][21][22], as well as in human studies [23][24][25]. ...
Cannabis-based medicines (CBMs) could help reduce systemic inflammation in people with HIV (PWH). In a prospective, randomized pilot study we enrolled participants from August 2021–April 2022 with HIV, aged ≥18 and on antiretroviral therapy and randomly assigned them to cannabidiol (CBD) ± Δ9-tetrahydrocannabinol (THC) capsules for 12 weeks with the primary objective being to assess safety and tolerability. Here we report on timeliness to study initiation, enrolment, compliance and retention rates. The target sample size was not reached. Two hundred and five individuals were approached, and 10 consented and were randomized; the rest refused (reasons: cannabis-related stigma/discomfort; too many study visits/insufficient time; unwillingness to undergo a “washout period” for three weeks) or were not eligible. The age of those randomized was 58 years (IQR 55–62); 80% were male. Only three met all criteria (30% enrolment compliance); seven were enrolled with minor protocol deviations. Compliance was excellent (100%). Eight (80%) participants completed the study; two (20%) were withdrawn for safety reasons (transaminitis and aggravation of pre-existing anemia). Time to study initiation and recruitment were the most challenging aspects. Ongoing work is required to reduce stigma related to CBMs. Future studies should find a balance between the requirements for safety monitoring and frequency of study visits.
... The therapeutic role of cannabinoids for peripheral neuropathy has been previously explored for diabetes, HIV-related neuropathy, and, more recently, for taxane-related CIPN [36,37]. To our knowledge, only three studies (one pilot study, one retrospective analysis, and one observational study) have assessed the clinical effect of medicinal cannabis (MC) in CIPN [38,39]. ...
Chemotherapy-induced peripheral neuropathy (CIPN) remains a clinical challenge for up to 80% of breast cancer survivors. In an open-label study, participants underwent three interventions: standard care (duloxetine) for 1 month (Phase 1), oral cannabidiol (CBD) for 2 months (Phase 2), and CBD plus multi-modal exercise (MME) for another 2 months (Phase 3). Clinical outcomes and gut microbiota composition were assessed at baseline and after each phase. We present the case of a 52-year-old female with a history of triple-negative breast cancer in remission for over five years presenting with CIPN. She showed decreased monocyte counts, c-reactive protein, and systemic inflammatory index after each phase. Duloxetine provided moderate benefits and intolerable side effects (hyperhidrosis). She experienced the best improvement and least side effects with the combined (CBD plus MME) phase. Noteworthy were clinically meaningful improvements in CIPN symptoms, quality of life (QoL), and perceived physical function, as well as improvements in pain, mobility, hand/finger dexterity, and upper and lower body strength. CBD and MME altered gut microbiota, showing enrichment of genera that produce short-chain fatty acids. CBD and MME may improve CIPN symptoms, QoL, and physical function through anti-inflammatory and neuroprotective effects in cancer survivors suffering from long-standing CIPN.
... In medical investigations Sativex and smoked cannabis greatly decreased pain feeling in neuropathic patients [180][181][182]. In another study, cannabis substantially demoted pain in patients with distal symmetrical polyneuropathic disorder [183]. Additional studies reinforced that cannabis-based medicine significantly decreases chronic pain intensity in patients with neurological disorders [8]. ...
Identification and development of pharmaceuticals for neurological disorders is associated with several unique challenges. The primary weakness of candidate neurological compounds is the poor penetration efficacy across the blood-brain barrier (BBB). The BBB is the bottleneck in nervous system drug development and is the paramount factor that limits success in neurotherapeutics. Findings suggest cannabinoids might overcome the limiting effects of the BBB and play a key role in improving neurological dysfunctions. This supports the therapeutic potential of cannabidiol for the treatment of ischemic and inflammatory diseases of the central nervous system (CNS). The potential application of cannabinoids for Parkinson’s disease, Autism, and childhood Epilepsy is explored in this chapter.
... Using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), the following lipids were quantified: the two main endocannabinoids N-arachidonoylethanolamine (AEA/anandamide) and 2-arachidonoylglycerol (2-AG), two related eicosanoids N-oleoyl ethanolamide (OEA) and N-palmitoyl ethanolamide (PEA), and arachidonic acid (AA). Details on the extraction and quantification of endocannabinoids and related lipids have been described previously (Abrams et al., 2007;League et al., 2021) and are outlined in Supplementary Methods. ...
Background
Some evidence suggests that cannabidiol (CBD) has potential to help alleviate HIV symptoms due to its antioxidant and anti-inflammatory properties. Here we examined acute CBD effects on various behaviors and the endocannabinoid system in HIV Tat transgenic mice.
Methods
Tat transgenic mice (female/male) were injected with CBD (3, 10, 30 mg/kg) and assessed for antinociception, activity, coordination, anxiety-like behavior, and recognition memory. Brains were taken to quantify endocannabinoids, cannabinoid receptors, and cannabinoid catabolic enzymes. Additionally, CBD and metabolite 7-hydroxy-CBD were quantified in the plasma and cortex.
Results
Tat decreased supraspinal-related nociception and locomotion. CBD and sex had little to no effects on any of the behavioral measures. For the endocannabinoid system male sex was associated with elevated concentration of the proinflammatory metabolite arachidonic acid in various CNS regions, including the cerebellum that also showed higher FAAH expression levels for Tat(+) males. GPR55 expression levels in the striatum and cerebellum were higher for females compared to males. CBD metabolism was altered by sex and Tat expression.
Conclusion
Findings indicate that acute CBD effects are not altered by HIV Tat, and acute CBD has no to minimal effects on behavior and the endocannabinoid system.
... Clinical investigations have demonstrated that cannabis, particularly THC, has therapeutic effects in various conditions, such as spasticity caused by multiple sclerosis (Grant et al., 2012;Hill, 2015), HIV-associated sensory neuropathy (Ellis et al., 2009;Larriviere, 2014), and chronic neuropathic pain (Wilsey et al., 2008). In a clinical treatment for neuropathic pain, marijuana cigarettes containing 4−32 mg of THC substantially decreased pain intensity (Abrams et al., 2007). Other randomized controlled trials have indicated that THC (up to 25 mg daily) can considerably reduce pain compared with placebo (Svendsen et al., 2004;Zajicek et al., 2003). ...
... The debate around legalization of marijuana has been an important yet controversial policy issue. Marijuana has been proved to be effective in treatment of several diseases and a wealth of new scientific understanding regarding its medicinal benefits are documented in Berman et al. (2004), Wilsey et al. (2013), Abrams et al. (2003Abrams et al. ( , 2007, Ellis et al. (2009), Johnson et al. (2010), McAllister et al. (2011), Guzmán (2003, Duran et al. (2010). 2 However, despite the medicinal benefits, smoking or consumption of marijuana is not completely benign and may cause harmful effects, especially associated with respiratory illnesses and cognitive development (Kalant 2004;Polen et al. 1993;Meier et al. 2012). 3 As a result, several surveys have been conducted to assess public opinion on the matter. ...
This chapter presents an overview of a specific form of limited dependent variable models, namely, discrete choice models, where the dependent (response or outcome) variable takes values which are discrete and inherently ordered. Within this setting, the dependent variable may take only two values (such as 0 and 1) giving rise to binary models (e.g., probit and logit) or more than two values (say , where J is a small integer) giving rise to ordinal models (e.g., ordinal probit and ordinal logit). In these models, the primary goal is to model the probability of responses/outcomes conditional on the covariates. We connect the outcomes of a discrete choice model to the random utility framework in economics, discuss estimation techniques, and present the calculation of covariate effects and measures to assess model fitting. Some recent advances in discrete data modeling are also discussed. Following the theoretical overview, we utilize the binary and ordinal models to analyze public opinion on marijuana legalization and the extent of legalization in the United States. All computations are done in MATLAB. We obtain several interesting results including that past use of marijuana, belief about legalization and political partisanship are important factors that shape public opinion.
... 85 Several studies have assessed the use of medical cannabis for neuropathic pain conditions. In a randomized, placebocontrolled trial by Abrams et al, 86 50 patients with HIV-associated peripheral neuropathy were randomly assigned to smoke cannabis (3.56% THC) or placebo cigarettes 3 times a day for 5 days. Overall, 52% of patients in the cannabis group reported a greater than 30% reduction in pain, whereas 24% of those in the placebo group had a greater than 30% pain reduction. ...
Cannabinoids have recently gained a renewed interest due to their potential applicability to various medical conditions, specifically the management of chronic pain conditions. Unlike many other medications, medical cannabis is not associated with serious adverse events, and no overdose deaths have been reported. However, both safety and efficacy data for medical cannabis treatment of chronic, nonmalignant pain conditions are lacking. Therefore, representatives from the American Society of Pain and Neuroscience summarize the evidence, according to level and grade, for medical cannabis treatment of several different pain conditions. Treatment of cancer-related pain has prospective evidentiary support for the use of medical cannabis. Although 3 large and well-designed randomized controlled trials investigated cannabis treatment of cancer-related pain, the evidence yielded only a grade D recommendation. Neuropathic pain has been investigated in prospective studies, but a lack of high-quality evidence renders cannabis treatment for this indication a grade C recommendation. Both safety and efficacy data are lacking for use of medical cannabis to treat chronic nonmalignant pain conditions.
... Otherwise, plants with higher than 0.3 % levels of THC are illegal, and considered drugs. The cannabis drug type, also known as marijuana, is used for its psychotropic effect [10][11][12][13] and for different medical purposes [14,15]. On the other hand, hemp, the non-drug strain, is used in fiber and food industries [16], as well as for oil production and skin cream treatments [17]. ...
... To our knowledge, cannabidiol's effects on pain have not been studied in PLWH and/or neuroHIV mouse models, including the Tat transgenic mouse model. However, it has been reported that cannabis use in PLWH improves nerve pain [59], shrinks the area of painfully sensitive skin [110], and can relief neuropathic pain [111]. Further, CBD has been shown to be necessary for THC-related antinociception in some human trials [112]. ...
(1) Background: Some evidence suggests that cannabidiol (CBD) has potential to help alleviate HIV symptoms due to its antioxidant and anti-inflammatory properties. Here we examined acute CBD effects on various behaviors and the endocannabinoid system in HIV Tat transgenic mice. (2) Methods: Tat transgenic mice (female/male) were injected with CBD (3,10,30 mg/kg) and assessed for antinociception, activity, coordination, anxiety, and recognition memory. Brains were taken to quantify endocannabinoids and related lipids. Additionally, CBD and metabolite 7-hydroxy-CBD were quantified in the plasma and cortex. (3) Results: Tat decreased striatal-related nociception and locomotion, with some sex-dependent effects on coordination. CBD had no effect on nociception and coordination, but increased locomotor activity. For anxiety, differential CBD effects were noted for sex, with decreasing anxiety-like behavior in males only. In the striatum and spinal cord, male sex was associated with lower 2-arachidonoylglycerol and with elevated concentrations of its proinflammatory metabolite arachidonic acid. CBD metabolism was altered by sex and Tat. (4) Conclusion: Findings indicate that acute CBD effects are not altered by HIV Tat, and CBD has minimal effects on behavior and the endocannabinoid system. Interestingly, sex-dependent alterations were noted for endocannabinoids and related lipids, which may be of relevance in view of potential CBD-based treatment options for people living with HIV.
... Smoked cannabis has been shown to reduce pain intensity scores to a greater extent than placebo cigarettes in individuals suffering from HIV-associated, diabetic, post-surgery/traumatic and other unspecified forms of neuropathic pain (Abrams et al., 2007;Corey-Bloom et al., 2012;Ellis et al., 2009;Finnerup et al., 2015;Ware et al., 2005Ware et al., , 2010Wilsey et al., 2008). Vapourised cannabis has also been reported to significantly improve symptoms in various forms of neuropathic pain (Eisenberg et al., 2014;Wilsey et al., 2013Wilsey et al., , 2016. ...
Chronic neuropathic pain is a debilitating pain syndrome caused by damage to the nervous system that is poorly served by current medications. Given these problems, clinical studies have pursued extracts of the plant Cannabis sativa as alternative treatments for this condition. The vast majority of these studies have examined cannabinoids which contain the psychoactive constituent delta‐9‐tetrahydrocannabinol (THC). While there have been some positive findings, meta‐analyses of this clinical work indicates that this effectiveness is limited and hampered by side‐effects. This review focuses on how recent preclinical studies have predicted the clinical limitations of THC‐containing cannabis extracts, and importantly, point to how they might be improved. This work highlights the importance of targeting channels and receptors other than cannabinoid CB1 receptors which mediate many of the side‐effects of cannabis.
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... Second, as referred to earlier, another novel therapy outlined by Wilson et al. involves decreasing microbial translocation through cannaboids [93]. Cannabis is established as an effective therapy for symptoms PLWH and people with cancer frequently experience [109][110][111][112]. Indeed, the literature suggests cannabis is effective for pain and nausea management related to HIV [112]; however, additional research is needed to build the evidence-base regarding the cannabis and gut-brain axis relationship [93]. ...
Mild to moderate forms of neurocognitive impairment persist among people living with HIV (PLWH), despite being virally suppressed on antiretroviral therapy. PLWH are disproportionally impacted by physiological and psychosocial comorbidities compared to those without HIV. As adults live longer with HIV, the neurocognitive burden of physiological and psychosocial stressors can impair everyday functioning and may contribute to the development of neurodegenerative diseases such as Alzheimer’s disease. This article outlines neurocognitive consequences of everyday stressors in PLWH. While some lifestyle factors can exacerbate inflammatory processes and promote negative neurocognitive health, novel interventions including the use of cannabinoids may be neuroprotective for aging PLWH who are at risk for elevated levels of inflammation from comorbidities. Studies of integrated neurocognitive rehabilitation strategies targeting lifestyle factors are promising for improving neurocognitive health, and may over time, reduce the risk of Alzheimer’s disease in PLWH.
... Neuropathic Pain ▪ General: Start with 2.5 mg CBD inhaled or PO TID and titrate to 25 mg over a 3-hr period [94]. ▪ HIV-associated: Start with 5 mg inhaled or PO CBD TID for 5 days [95] or 2.5-10.0 mg CBD and Δ-9-THC QID for 5 days [96]. ...
Background
The opioid crisis continues in full force, as physicians and caregivers are desperate for resources to help patients with opioid use and chronic pain disorders find safer and more accessible non-opioid tools.
Main body
The purpose of this article is to review the current state of the opioid epidemic; the shifting picture of cannabinoids; and the research, policy, and current events that make opioid risk reduction an urgent public health challenge. The provided table contains an evidence-based clinical framework for the utilization of cannabinoids to treat patients with chronic pain who are dependent on opioids, seeking alternatives to opioids, and tapering opioids.
Conclusion
Based on a comprehensive review of the literature and epidemiological evidence to date, cannabinoids stand to be one of the most interesting, safe, and accessible tools available to attenuate the devastation resulting from the misuse and abuse of opioid narcotics. Considering the urgency of the opioid epidemic and broadening of cannabinoid accessibility amidst absent prescribing guidelines, the authors recommend use of this clinical framework in the contexts of both clinical research continuity and patient care.
We aimed to describe long-term use trajectories and predictors prior to recreational cannabis legalization in people with HIV in Ontario, Canada. We analysed interview data from the prospective Ontario HIV Treatment Network Cohort Study from 2008 to 2017. We conducted Latent Class Growth Analyses to describe cannabis use trajectories and chi-square tests to identify trajectory group predictors. Most participants (N = 3,299) were male (81%), gay (57%), current/former tobacco smokers (58%), and many had significant symptoms of depression (43%). Four cannabis use trajectory groups were identified (Low/No Use (67%); Increased Use (4%); Decreased use (2%); High Use (26%)). Relative to the Low/No Use group, membership in the High Use group was associated with several predictors such as being older age, completing university, smoking tobacco, and significant depressive symptoms. Future research should explore the relationship between cannabis use and depressive symptoms, outcomes associated with trajectory groups and changes in use trajectories following recreational legalization.
Background
Cannabis use is increasing in the United States, including among liver transplant candidates. Although the anesthesia literature suggests an association between cannabis use and increased post-operative pain, the impact of cannabis use on post-liver transplant (LT) opioid use remains unknown. This study investigates changes in cannabis use at a transplant center over time, as well as the impact of cannabis use on post-LT opioid use, healthcare utilization, and mortality.
Methods
We included 4,236 patients evaluated for LT at our institution between January 2013 and July 2023. Our primary risk factor was cannabis use, defined as urine toxicology (UTox) positive for cannabis within 90 days of LT evaluation. Our primary outcome was post-LT opioid use, including oral morphine equivalents (OME) received during the LT hospitalization and discharge opioid prescriptions. We used multivariable logistic and quantile regression to compare post-LT opioid use, healthcare utilization outcomes, and mortality between cannabis users and nonusers.
Results
Cannabis use was associated with higher OME use in the 48 hours post-LT ( p =0.04). There were no statistically significant differences between groups in 72-hour ( p =0.07) or 7-day cumulative OME ( p =0.33), opioid prescriptions on discharge ( p =0.25), hospital length of stay (LOS, p =0.69), intensive care unit LOS ( p =0.94), 90-day readmission ( p =0.66), or 90-day mortality ( p =0.96).
Conclusions
While cannabis use pre-LT was associated with significantly higher opioid use in the immediate postoperative period, this did not translate to differences in opioid use beyond 48 hours post-LT, or short-term healthcare utilization or clinical outcomes. These findings should help set provider expectations for immediate post-LT pain control. Our findings support the growing body of literature that fails to identify an association between pre-LT cannabis use and post-LT outcomes.
Medical cannabis holds immense therapeutic potential, offering significant advantages as either a palliative or direct treatment for a wide range of health conditions. Yet this promise is often overshadowed by a web of misconceptions that impede scientific progress and delay its integration into healthcare systems. The pervasive myths surrounding medical cannabis create significant obstacles for research, clinical practice, and public health. These myths obstruct progress by delaying advancements in medical science, restricting access to treatments, and perpetuating stigma, which discourages informed discussions. Addressing these barriers is essential to realizing the full potential of medical cannabis and improving healthcare outcomes.
Background: Emerging evidence supports cannabidiol (CBD) as a promising therapeutic compound for various health conditions, despite its approval as a medication (product for medical purposes) remaining restricted to a limited range of clinical indications. Simultaneously, the regulation of cannabis-derived products for medicinal and recreational use has expanded their global market availability to meet local community demands. This scenario presents a complex challenge for clinicians, researchers, and industry, as the global appeal of therapeutic uses of CBD is growing more rapidly than the scientific evidence supporting its safety and effectiveness. Outcomes: A narrative review was conducted to discuss the best evidence regarding the pharmacological profile of CBD, its efficacy, and safety within the context of regulation and perspectives on the development of new cannabinoid-based drugs. Key articles addressing the various facets of this issue were selected for comprehensive analysis. Conclusions: Clinicians and researchers may face unique challenges in understanding the pharmacological profile of CBD and the prospects for developing its clinical indications, given the heterogeneity of clinical terminologies and the quality and composition of cannabis-based medical products available on the market. More basic and clinical research that complies with regulatory agencies’ testing guidelines, such as good manufacturing practices (GMPs), good laboratory practices (GLPs), and good clinical practices (GCPs), is needed to obtain approval for CBD or any other cannabinoid as a therapeutic for broader clinical indications.
The rate at which cannabis has been utilized by youths is becoming alarming and predominants of them who are being asked reported that it helps them to deal with pains. Therefore, the study was aimed at investigating the effect of cannabis extract on pain sensitivity using rat. A total of 24 consisting of 12 male and 12 female albino Wistar rats of weight 100 gm were used in a completely randomized design (CRD) experiment. They were maintained in the animal house unit of the Department of Pharmacy and Toxicology, University of Uyo, Nigeria, at a temperature of 30 ± 2°C and 12 hr light/dark cycles with free access to food and water. Cannabis sativa was purchased with the approval of the office of the National Drug Law Enforcement Agency (NDLEA), Uyo, Akwa-Ibom State and homogenized using the manual blender. There were three treatments of eights mice each replicated three times with three rats per replicate. Thomas scientific hot plate (author regulated) and Object recognition test were used to test pain sensitivity and memory recognition respectively. The study utilized a pretest-posttest design and the statistics used in analyzing the result in the study was Analysis of Variance (ANOVA). Result revealed that Cannabis significantly affects pain sensitivity. Result also revealed that sex significantly affect pain sensitivity. It was therefore concluded that cannabis have significant effect on pain sensitivity. The study recommend that little or low dose of cannabis use with doctors’ supervision may be helpful to people who go through severe pain.
Background
Patients with chronic kidney disease experience high burden of symptoms, negatively affecting their quality of life. Medication therapy is often initiated to address these symptoms but is limited by variable efficacy and high pill burden. There is interest among clinicians and patients to explore cannabis and cannabinoids as an alternative treatment to manage symptoms related to kidney disease.
Objective
The objectives were to characterize cannabis use among patients receiving maintenance hemodialysis (HD), to describe patient perspectives on cannabis, and to explore patient experiences with their kidney health care team related to cannabis.
Design
This was a descriptive, cross-sectional paper-based patient survey.
Setting/Participants
Patients receiving maintenance HD at Toronto General Hospital in the ambulatory setting between July and August 2020 were included.
Methods
A 33-item questionnaire was developed to address the study questions based on existing cannabis questionnaires and input from kidney specialist physicians, pharmacists, kidney nurse practitioners, and patients. The questionnaire was distributed to patients during their in-center HD session. Patients who chose to participate in the study completed the questionnaire and returned it to the study team.
Results
In total, there were 52 respondents, of which 11 (21%) reported cannabis use in the preceding 3 months, and 23 (44%) reported historical cannabis use. Baseline characteristics were similar between those who used cannabis and those who did not, with a possible trend of cannabis users being younger. The most commonly reported reasons for using cannabis were recreation and symptom management. Those who reported using cannabis for symptom management were doing so without medical authorization or documentation. Common symptoms that cannabis was used to self-treat were insomnia, anxiety, and/or non-neuropathic pain. Dried flower was the most common type of product used, and smoking was the most common route. Care gaps and opportunities to improve patient care related to cannabis use were identified, related to monitoring and management of adverse effects, management of drug interactions, harm reduction strategies, informed decision-making, and prescriber education.
Limitations
The overall participation rate was low, at approximately 17%, possibly related to the COVID-19 pandemic, lack of interest, or fear of revealing cannabis use. Non-response bias is a possible limitation as this was a voluntary survey. The questionnaire was limited to multiple-choice and Likert scale questions, therefore limiting the depth of patient responses.
Conclusions
Our study showed that cannabis use among patients receiving HD is common and comparable with the general population. Patients may be using cannabis to self-manage symptoms related to kidney disease, without the involvement of the health care team. Multiple opportunities to improve patient care related to cannabis use were identified.
Cannabis A Novel (Old) Herbal with many applications, the dried leaves to be used for medicinal purposes is derived from the hemp plant marijuana and has been considered a wonder weapon in all diseases. purpose of this review is to look at the current scientific literature on marijuana and its overall effects in different medical areas (neurological disorders, psychiatric conditions, pain management/cancer-related symptoms/cardiovascular/metabolic diseases). While we know that compounds like THC and CBD interact with the endocannabinoid system in ways which produce positive outcomes, their complete impact on human health is a chapter of history still being written. However, there are also emerging concerns regarding adverse digestive effects and the regulatory headache around marijuana. Further work is needed to define appropriate safety profiles, optimal dosing, and successful integration into clinical practice. This review highlights marijuana's emergent role in contemporary medicine and the need for clinical trials to further its therapeutic use within patient safety and regulatory criterion.
Marijuana (cannabis), a naturally occurring herb with two active constituents, D9-tetrahydrocannabinol (THC) and cannabidiol (CBD), has been recognized for its medicinal properties for centuries. Marijuana is the most used of all illicit substances. Marijuana use is more common among people living with HIV/AIDS (PLWH) than the general population. It has been shown to have some therapeutic effects in PLWH, including stimulating appetite, reducing anxiety, providing analgesia, and mitigating neurologic and behavioral health symptoms. However, it also has many negative neurocognitive effects.
Here, we describe how THC/CBD interacts with human metabolic and immunologic pathways and affect the efficiency of acquiring HIV infection, persistence of viral load, and chronic inflammation. We also discuss therapeutic applications of THC/CBD to several syndromes common in HIV patients, including HIV-associated neurologic decline, liver fibrosis and co-infection with viral hepatitis, cardiovascular disease, and behavioral health symptoms. Finally, we review the evidence of marijuana’s impact on patient’s adherence to their antiretroviral medications and the likelihood of achieving process measures along the HIV care continuum.
Psychiatric factors play a significant role in the ongoing human immunodeficiency virus (HIV) pandemic. In less than four decades, advances in HIV medical care and research have transformed acquired immune deficiency syndrome (AIDS) from a rapidly fatal illness of unknown cause into a chronic, manageable illness. Vast strides have been made in clinical care and pathogenesis research in the fields of HIV prevention and psychiatric care, including pre- (PreP) and and post-exposure (PEP) prophylaxis. Although AIDS is an entirely preventable infectious illness, HIV transmission continues throughout the world. Transmission of HIV continues to be fueled by many factors, including stigma of HIV and mental illness as well as discrimination, criminalization, and risky behaviors. A comprehensive biopsychosocial approach to sexual health and mental health and diminution of stigma are key to both HIV prevention and HIV care. Integration of psychiatric care into HIV prevention and treatment entails use of a biopsychosocial approach that maintains a view of each individual with HIV as a member of a family, community, and society who deserves to be treated with dignity and compassion. This textbook provides an update on HIV medicine and psychiatry; introduces the concept of HIV/AIDS as “the great magnifier of maladies”; explores the paradoxes and disparities of HIV care; explains how HIV psychiatry is a paradigm for the psychiatric care of the medically ill (psychosomatic medicine); and sets the stage for an understanding of how integrated care can prevent transmission of HIV and reduce morbidity and mortality in persons with HIV.
The pharmacologic management of neuroma and neuropathic pain has a long history with suboptimal results in many cases. Effective treatment remains challenging due to the diverse pain etiologies and mechanisms at play. These include structural and functional changes that occur peripherally within neuromas, as well as alterations that occur centrally within the brain and spinal cord. While surgical management is beginning to show promise, pharmacological management remains indispensable. Although different medications may alleviate specific subtypes of neuropathic pain, no single medication has demonstrated consistent and superior efficacy. A multimodal approach with a combination of different classes of medications is likely to be optimal, with the goal to minimize opioid use and to capitalize on synergistic effects of nonopioid medications. Finally, there are experimental agents (e.g., 4-AP and EPO) demonstrating promise in management of these difficult clinical situations.
Medical cannabis has potential therapeutic benefits in managing pain, anxiety, depression, and neurological and movement disorders. Phytocannabinoids derived from the cannabis plant are responsible for their pharmacological and therapeutic properties. However, the complexity of cannabis components, especially cannabinoids, poses a challenge to effective medicinal administration. Even with the increasing acceptance of cannabis-based medicines, achieving consistent bioavailability and targeted distribution remains difficult. Conventional administration methods are plagued by solubility and absorption problems requiring innovative solutions. After conducting a thorough review of research papers and patents, it has become evident that nanotechnology holds great promise as a solution. The comprehensive review of 36 research papers has yielded valuable insights, with 7 papers reporting enhanced bioavailability, while others have focused on improvements in release, solubility, and stability. Additionally, 19 patents have been analyzed, of which 7 specifically claim enhanced bioavailability, while the remaining patents describe various formulation methods. These patents outline effective techniques for encapsulating cannabis using nanocarriers, effectively addressing solubility and controlled release. Studies on the delivery of cannabis using nanocarriers focus on improving bioavailability, prolonging release, and targeting specific areas. This synthesis highlights the potential of nanotechnology to enhance cannabis therapies and pave the way for innovative interventions and precision medicine.
Background: Patients have been known to use cannabinoids for treating established chemotherapy-induced peripheral neuropathy (CIPN) based on anecdotal information and retrospective reports suggesting that such might be beneficial. In response, a double-blinded, placebo-controlled, randomized, pilot clinical trial was developed to evaluate whether resultant data would support a phase III trial for testing whether a cannabidiol (CBD) cream might improve CIPN. Methods: Forty patients with established CIPN were randomized, in a double-blinded manner, to topical CBD or a placebo cream. The study product was applied for 2 weeks, followed by a crossover for 2 weeks. Neuropathy was evaluated using the European Organization of Research and Treatment of Cancer (EORTC)-CIPN20, the Chemotherapy-Induced Peripheral Neuropathy Assessment Tool, and the Global Impression of Change instruments. Side effects were recorded by symptom diaries. Results: The EORTC-CIPN20 scores were similar in the patients receiving CBD versus the placebo. Likewise, the toxicity scores were similar in patients who received the CBD versus the placebo. Conclusions: This pilot trial did not support that the studied CBD isolate cream improved painful established CIPN. It was well tolerated overall. Clinical Trial Registration Number: NCT05388058.
Postoperative pain (POP) is a challenging clinical phenomenon that affects the majority of surgical patients and demands effective management to mitigate adverse outcomes such as persistent pain. The primary goal of POP management is to alleviate suffering and facilitate a seamless return to normal function for the patient. Despite compelling evidence of its drawbacks, opioid analgesia remains the basis of POP treatment. Novel therapeutic approaches rely on multimodal analgesia, integrating different pharmacological strategies to optimize efficacy while minimizing adverse effects. The recognition of the imperative role of the endocannabinoid system in pain regulation has prompted the investigation of cannabinoid compounds as a new therapeutic avenue. Cannabinoids may serve as adjuvants, enhancing the analgesic effects of other drugs and potentially replacing or at least reducing the dependence on other long-term analgesics in pain management. This narrative review succinctly summarizes pertinent information on the molecular mechanisms, clinical therapeutic benefits, and considerations associated with the plausible use of various cannabinoid compounds in treating POP. According to the available evidence, cannabinoid compounds modulate specific molecular mechanisms intimately involved in POP. However, only two of the eleven clinical trials that evaluated the efficacy of different cannabinoid interventions showed positive results.
Los ensayos randomizados, doble ciegos, controlados con placebo sobre el dolor neuropático son cada vez más comunes y por ende se necesita una revisión actualizada de la evidencia disponible. Los estudios fueron identificados por medio de búsquedas en MEDLINE y EMBASE. Los valores del número necesario a tratar (NNT) y número necesario a dañar (NND) se utilizaron para comparar la eficacia y seguridad de los diferentes tratamientos para un número de condiciones dolorosas neuropáticas. Se incluyeron ciento setenta y cuatro estudios, lo que representa un 66% de incremento en los ensayos randomizados, controlados con placebo publicados en los últimos 5 años. Se examinó la polineuropatía dolorosa (más comúnmente debida a diabetes) en 69 estudios, neuralgia post-herpética en 23, mientras que la injuria nerviosa periférica, dolor central, neuropatía por HIV, y neuralgia de trigémino fueron estudiados con menor frecuencia. Los antidepresivos tricíclicos, los inhibidores de la recaptación de serotonina y noradrenalina, los anticonvulsivantes gabapentina y pregabalina, y los opioides son las clases de drogas para las cuales existe la mejor evidencia de un efecto clínico relevante. A pesar del 66% de incremento en los ensayos publicados, sólo se obtuvo una limitada mejoría en el tratamiento del dolor neuropático. Una amplia proporción de pacientes con dolor neuropático permanece con un insuficiente alivio del dolor. Este hecho exige otras opciones de tratamiento para abordar el dolor neuropático crónico. Para evaluar la hipótesis de que una clasificación basada en el mecanismo puede ayudar a mejorar el tratamiento de pacientes individuales, se necesitan ensayos farmacológicos de gran escala que apunten a identificar los posibles subgrupos de pacientes que tengan probabilidades de responder a drogas específicas.
Cannabinoid use has surged in the past decade, with a growing interest in expanding cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) applications into special populations. Consequently, the increased use of CBD and THC raises the risk of drug–drug interactions (DDIs). Nevertheless, DDIs for cannabinoids, especially in special populations, remain inadequately investigated. While some clinical trials have explored DDIs between therapeutic drugs like antiepileptic drugs and CBD/THC, more potential interactions remain to be examined. This review summarizes the published studies on CBD and THC–drug interactions, outlines the mechanisms involved, discusses the physiological considerations in pharmacokinetics (PK) and DDI studies in special populations (including pregnant and lactating women, pediatrics, older adults, patients with hepatic or renal impairments, and others), and presents modeling approaches that can describe the DDIs associated with CBD and THC in special populations. The PK of CBD and THC in special populations remain poorly characterized, with limited studies investigating DDIs involving CBD/THC in these populations. Therefore, it is critical to evaluate potential DDIs between CBD/THC and medications that are commonly used in special populations. Modeling approaches can aid in understanding these interactions.
Endometriosis, a chronic condition affecting around 10–14% of women, is challenging to manage, due to its complex pathogenesis and limited treatment options. Research has suggested a potential role of the gut microbiota and the endocannabinoid system in the development and progression of endometriosis. This narrative review aims to explore the role of, and any potential interactions between, the endocannabinoid system (ECS) and the gut microbiota in endometriosis. This review found that both the ECS and microbiota influence endometriosis, with the former regulating inflammation and pain perception and the latter influencing immune responses and hormonal balance. There is evidence that a dysregulation of the endocannabinoid system and the gut microbiota influence endometriosis symptoms and progression via changes in CB1 receptor expression and increased circulating levels of endocannabinoids. Microbial imbalances in the gut, such as increases in Prevotella, have been directly correlated to increased bloating, a common endometriosis symptom, while increases in E. coli have supported the bacterial contamination hypothesis as a potential pathway for endometriosis pathogenesis. These microbial imbalances have been correlated with increases in inflammatory markers such as TNF-α and IL-6, both often raised in those with endometriosis. Protective effects of the ECS on the gut were observed by increases in endocannabinoids, including 2-AG, resulting in decreased inflammation and improved gut permeability. Given these findings, both the ECS and the gut microbiota may be targets for therapeutic interventions for endometriosis; however, clinical studies are required to determine effectiveness.
Mounting evidence suggests safety and tolerability of cannabis-derived and psychedelic drugs as potential novel therapeutics for psychiatric, as well as sleep and pain disorders. Evidence concerning the therapeutic efficacy of these compounds remains controversial, although some promising preliminary results are available for them in specific disorders. For example, CBD is approved as medication for treatment-refractory epilepsy, while MDMA and psilocybin are being tested in phase 3 clinical trials respectively for treatment-refractory PTSD and MDD. Despite encouraging preliminary results, further preclinical and clinical trials are required to validate these findings. Most importantly, more systematic research is required to assess the potential long-term side effects that might arise following the use of cannabinoids and psychedelic compounds in psychiatric settings.
Neuropathic pain is a disabling condition caused by various diseases and can profoundly impact the quality of life. Unfortunately, current treatments often do not produce complete amelioration and can be associated with potential side effects. Recently, herbal drugs have garnered more attention as an alternative or a complementary treatment. In this article, we summarized the results of randomized clinical trials to evaluate the effects of various phytomedicines on neuropathic pain. In addition, we discussed their main bioactive components and potential mechanisms of action to provide a better view of the application of herbal drugs for treating neuropathic pain.
Context.—
Peripheral neuropathy is common in persons infected with the human immunodeficiency
virus (HIV) but few data on symptomatic treatment are available.Objective.—
To evaluate the efficacy of a standardized acupuncture regimen (SAR)
and amitriptyline hydrochloride for the relief of pain due to HIV-related
peripheral neuropathy in HIV-infected patients.Design.—
Randomized, placebo-controlled, multicenter clinical trial. Each site
enrolled patients into 1 of the following 3 options: (1) a modified double-blind
2 × 2 factorial design of SAR, amitriptyline, or the combination compared
with placebo, (2) a modified double-blind design of an SAR vs control points,
or (3) a double-blind design of amitriptyline vs placebo.Setting.—
Terry Beirn Community Programs for Clinical Research on AIDS (HIV primary
care providers) in 10 US cities.Patients.—
Patients with HIV-associated, symptomatic, lower-extremity peripheral
neuropathy. Of 250 patients enrolled, 239 were in the acupuncture comparison
(125 in the factorial option and 114 in the SAR option vs control points option),
and 136 patients were in the amitriptyline comparison (125 in the factorial
option and 11 in amitriptyline option vs placebo option).Interventions.—
Standarized acupuncture regimen vs control points, amitriptyline (75
mg/d) vs placebo, or both for 14 weeks.Main Outcome Measure.—
Changes in mean pain scores at 6 and 14 weeks, using a pain scale ranging
from 0.0 (no pain) to 1.75 (extremely intense), recorded daily.Results.—
Patients in all 4 groups showed reduction in mean pain scores at 6 and
14 weeks compared with baseline values. For both the acupuncture and amitriptyline
comparisons, changes in pain score were not significantly different between
the 2 groups. At 6 weeks, the estimated difference in pain reduction for patients
in the SAR group compared with those in the control points group (a negative
value indicates a greater reduction for the "active" treatment) was 0.01 (95%
confidence interval [CI], −0.11 to 0.12; P
=.88) and for patients in the amitriptyline group vs those in the placebo
group was −0.07 (95% CI, −0.22 to 0.08; P=.38).
At 14 weeks, the difference for those in the SAR group compared with those
in the control points group was −0.08 (95% CI, −0.21 to 0.06; P=.26) and for amitriptyline compared with placebo was
0.00 (95% CI, −0.18 to 0.19; P=.99).Conclusions.—
In this study, neither acupuncture nor amitriptyline was more effective
than placebo in relieving pain caused by HIV-related peripheral neuropathy.
Figures in this Article
PERIPHERAL NEUROPATHIES are diagnosed in 30% to 35% of patients with
human immunodeficiency virus (HIV) and cause pain and dysesthesias.1- 2 Symptomatic treatment includes antidepressants,
nonnarcotic and narcotic analgesics, anticonvulsants, and acupuncture.2- 3 The use of these treatments is based
on anecdotal4 information and trials in other
disease conditions.5
We chose to examine the efficacy of 2 commonly used treatments, amitriptyline
hydrochloride and acupuncture, for HIV-related peripheral neuropathy. Amitriptyline
is frequently prescribed for neuropathic pain and has been shown to be an
effective treatment for diabetic, hereditary, toxic, and idiopathic neuropathies.6- 7
Although several trials that reported examining acupuncture for chronic
painful conditions claim efficacy,8- 9
these studies have methodological limitations, including small sample sizes
and inadequate controls for the nonspecific effects of acupuncture.9- 11 Meta-analyses of studies
of acupuncture for chronic pain show a response rate of approximately 70%
for acupuncture, 50% for "sham" acupuncture (needling points not considered
effective), and 30% for control treatments, such as sham transcutaneous electrical
nerve stimulation.9- 10,12- 13
To evaluate the effect of both a nonstandard and standard medical therapy
for peripheral neuropathy, we performed a multicenter, modified double-blind,
randomized, placebo-controlled study of the separate and combined efficacy
of a standardized acupuncture regimen (SAR) and amitriptyline for the relief
of pain caused by HIV-related peripheral neuropathy.
The discovery of cannabinoid receptors and their putative endogenous ligands raises questions as to the nature of the effects produced by cannabinoids on neural circuits that mediate pain and whether endogenous cannabinoids produced by the brain or in the periphery serve naturally to modulate pain. A sizable body of previous work showed that cannabinoid agonists suppress pain behavior in a variety of models of acute and chronic pain. However, at appropriate doses, cannabinoids also profoundly suppress motor behavior (see Sañudo-Peña et al., this volume), which complicates the interpretation of behavioral analgesia since a motor response is the endpoint of virtually all such studies. Studies conducted in this laboratory used biochemical and neurophysiological measures to determine whether cannabinoids suppress nociceptive neurotransmission. The results showed that cannabinoids suppress nociceptive neurotransmission at the level of the spinal cord and the thalamus. These effects are reversible, receptor mediated, selective for painful as opposed to nonpainful somatic stimuli and track the behavioral analgesia both in time course and potency.
Pain is the most disturbing symptom of diabetic peripheral neuropathy. As many as 45% of patients with diabetes mellitus develop peripheral neuropathies.
To evaluate the effect of gabapentin monotherapy on pain associated with diabetic peripheral neuropathy.
Randomized, double-blind, placebo-controlled, 8-week trial conducted between July 1996 and March 1997.
Outpatient clinics at 20 sites.
The 165 patients enrolled had a 1- to 5-year history of pain attributed to diabetic neuropathy and a minimum 40-mm pain score on the Short-Form McGill Pain Questionnaire visual analogue scale.
Gabapentin (titrated from 900 to 3600 mg/d or maximum tolerated dosage) or placebo.
The primary efficacy measure was daily pain severity as measured on an 11-point Likert scale (0, no pain; 10, worst possible pain). Secondary measures included sleep interference scores, the Short-Form McGill Pain Questionnaire scores, Patient Global Impression of Change and Clinical Global Impression of Change, the Short Form-36 Quality of Life Questionnaire scores, and the Profile of Mood States results.
Eighty-four patients received gabapentin and 70 (83%) completed the study; 81 received placebo and 65 (80%) completed the study. By intent-to-treat analysis, gabapentin-treated patients' mean daily pain score at the study end point (baseline, 6.4; end point, 3.9; n = 82) was significantly lower (P<.001) compared with the placebo-treated patients' end-point score (baseline, 6.5; end point, 5.1; n = 80). All secondary outcome measures of pain were significantly better in the gabapentin group than in the placebo group. Additional statistically significant differences favoring gabapentin treatment were observed in measures of quality of life (Short Form-36 Quality of Life Questionnaire and Profile of Mood States). Adverse events experienced significantly more frequently in the gabapentin group were dizziness (20 [24%] in the gabapentin group vs 4 [4.9%] in the control group; P<.001) and somnolence (19 [23%] in the gabapentin group vs 5 [6%] in the control group; P = .003). Confusion was also more frequent in the gabapentin group (7 [8%] vs 1 [1.2%]; P = .06).
Gabapentin monotherapy appears to be efficacious for the treatment of pain and sleep interference associated with diabetic peripheral neuropathy and exhibits positive effects on mood and quality of life.
To report a case of antiretroviral therapy failure caused by an interaction between carbamazepine and indinavir.
A 48-year-old HIV-positive white man was treated with antiretroviral triple therapy, consisting of indinavir, zidovudine, and lamivudine. His HIV-RNA (viral load) became undetectable (<400 copies/mL) less than two months after this therapy was started; this was confirmed one month later. Shortly after the start of antiretroviral therapy, the patient developed herpes zoster, which was treated with famciclovir. Tramadol was initially prescribed for postherpetic neuralgia; however, this was substituted with carbamazepine due to insufficient analgesic effect. Indinavir plasma concentrations decreased substantially during carbamazepine therapy. Carbamazepine was stopped after 2.5 months and, two weeks later, the HIV-RNA was detectable (6 x 103 copies/mL). Resistance for lamivudine was observed in that blood sample; resistance for zidovudine might have been present, and resistance to indinavir was not detected. A few months later, a further increase of the HIV-RNA occurred (300 x 103 copies/mL), after which the therapy was switched to a new antiretroviral regimen containing nevirapine, didanosine, and stavudine.
Physicians may prescribe carbamazepine for HIV-infected patients to treat seizures or postherpetic neuralgia, which are complications of opportunistic infections such as herpes zoster or toxoplasmosis. Carbamazepine is a potent enzyme inducer, predominantly of the CYP3A enzyme system, while HIV-protease inhibitors such as indinavir are substrates for and inhibitors of CYP3A. Therefore, an interaction between these drugs could be expected. A low dose of carbamazepine (200 mg/d) and the usual dose of indinavir (800 mg q8h) in our patient resulted in carbamazepine concentrations within the therapeutic range for epilepsy treatment; indinavir concentrations dropped substantially. The virologic, resistance, and plasma drug concentration data, as well as the chronology of events, are highly indicative of antiretroviral treatment failure due to the interaction between carbamazepine and indinavir.
Concomitant use of carbamazepine and indinavir may cause failure of antiretroviral therapy due to insufficient indinavir plasma concentrations. Drugs other than carbamazepine should be considered to prevent this interaction. Amitriptyline or gabapentin are alternatives for postherpetic neuralgia; valproic acid or lamotrigine are alternatives for seizures. When alternate drug therapy is not possible, dosage adjustments, therapeutic drug monitoring, and careful clinical observation may help reduce adverse clinical consequences.
We investigated the effects of i.v. magnesium on secondary hyperalgesia following heat/capsaicin stimulation in human volunteers.
Twenty‐five volunteers were included in this double blind, randomized, crossover study. Sensitization was induced in the volunteers,
who were then subjected to either i.v. saline or magnesium sulphate. No analgesic or antihyperalgesic effect could be demonstrated
in sensitized skin during infusion of magnesium. In contrast, painfulness of thermal stimulation was increased in normal skin.
These results suggest that i.v. magnesium has no important analgesic effects in clinically relevant doses.
Br J Anaesth 2001; 86: 871–3
Although opioids are commonly used to treat chronic neuropathic pain, there are limited data to guide their use. Few controlled trials have been performed, and many types of neuropathic pain remain unstudied.
Adults with neuropathic pain that was refractory to treatment were randomly assigned to receive either high-strength (0.75-mg) or low-strength (0.15-mg) capsules of the potent mu-opioid agonist levorphanol for eight weeks under double-blind conditions. Intake was titrated by the patient to a maximum of 21 capsules of either strength per day. Outcome measures included the intensity of pain as recorded in a diary, the degree of pain relief, quality of life, psychological and cognitive function, the number of capsules taken daily, and blood levorphanol levels.
Among the 81 patients exposed to the study drug, high-strength levorphanol capsules reduced pain by 36 percent, as compared with a 21 percent reduction in pain in the low-strength group (P=0.02). On average, patients in the high-strength group took 11.9 capsules per day (8.9 mg per day) and patients in the low-strength group took close to the 21 allowed (18.3 capsules per day; 2.7 mg per day). Affective distress and interference with functioning were reduced, and sleep was improved, but there were no differences between the high-strength group and the low-strength group in terms of these variables. Noncompletion of the study was primarily due to side effects of the opioid. Patients with central pain after stroke were the least likely to report benefit.
The reduction in the intensity of neuropathic pain was significantly greater during treatment with higher doses of opioids than with lower doses. Higher doses produced more side effects without significant additional benefit in terms of other outcome measures.
Cannabinoid use could potentially alter HIV RNA levels by two mechanisms: immune modulation or cannabinoid-protease inhibitor interactions (because both share cytochrome P-450 metabolic pathways).
To determine the short-term effects of smoked marijuana on the viral load in HIV-infected patients.
Randomized, placebo-controlled, 21-day intervention trial.
The inpatient General Clinical Research Center at the San Francisco General Hospital, San Francisco, California.
67 patients with HIV-1 infection.
Participants were randomly assigned to a 3.95%-tetrahydrocannabinol marijuana cigarette, a 2.5-mg dronabinol (delta-9-tetrahydrocannabinol) capsule, or a placebo capsule three times daily before meals.
HIV RNA levels, CD4+ and CD8+ cell subsets, and pharmacokinetic analyses of the protease inhibitors.
62 study participants were eligible for the primary end point (marijuana group, 20 patients; dronabinol group, 22 patients; and placebo group, 20 patients). Baseline HIV RNA level was less than 50 copies/mL for 36 participants (58%), and the median CD4+ cell count was 340 x 109 cells/L. When adjusted for baseline variables, the estimated average effect versus placebo on change in log10 viral load from baseline to day 21 was -0.07 (95% CI, -0.30 to 0.13) for marijuana and -0.04 (CI, -0.20 to 0.14) for dronabinol. The adjusted average changes in viral load in marijuana and dronabinol relative to placebo were -15% (CI, -50% to 34%) and -8% (CI, -37% to 37%), respectively. Neither CD4+ nor CD8+ cell counts appeared to be adversely affected by the cannabinoids.
Smoked and oral cannabinoids did not seem to be unsafe in people with HIV infection with respect to HIV RNA levels, CD4+ and CD8+ cell counts, or protease inhibitor levels over a 21-day treatment.
To evaluate the effect of the oral synthetic delta-9-tetrahydrocannabinol dronabinol on central neuropathic pain in patients with multiple sclerosis.
Randomised double blind placebo controlled crossover trial.
Outpatient clinic, University Hospital of Aarhus, Denmark.
24 patients aged between 23 and 55 years with multiple sclerosis and central pain.
Orally administered dronabinol at a maximum dose of 10 mg daily or corresponding placebo for three weeks (15-21 days), separated by a three week washout period.
Median spontaneous pain intensity (numerical rating scale) in the last week of treatment.
Median spontaneous pain intensity was significantly lower during dronabinol treatment than during placebo treatment (4.0 (25th to 75th centiles 2.3 to 6.0) v 5.0 (4.0 to 6.4), P = 0.02), and median pain relief score (numerical rating scale) was higher (3.0 (0 to 6.7) v> 0 (0 to 2.3), P = 0.035). The number needed to treat for 50% pain relief was 3.5 (95% confidence interval 1.9 to 24.8). On the SF-36 quality of life scale, the two items bodily pain and mental health indicated benefits from active treatment compared with placebo. The number of patients with adverse events was higher during active treatment, especially in the first week of treatment. The functional ability of the multiple sclerosis patients did not change.
Dronabinol has a modest but clinically relevant analgesic effect on central pain in patients with multiple sclerosis. Adverse events, including dizziness, were more frequent with dronabinol than with placebo during the first week of treatment.
In the United States, an estimated 2 million persons have neuropathic pain that is often resistant to therapy. The use of opioids for neuropathic pain remains controversial, in part because studies have been small, have yielded equivocal results, and have not established the long-term risk-benefit ratio of this treatment.
To assess the efficacy and safety of opioid agonists for the treatment of neuropathic pain based on published randomized controlled trials (RCTs).
We searched MEDLINE (1966 to December 2004) and the Cochrane Central Register of Controlled Trials (fourth quarter, 2004) for articles in any language, along with reference lists of reviews and retrieved articles, using a combination of 9 search terms for RCTs with 32 terms for opioids and 15 terms for neuropathic pain.
Trials were included in which opioid agonists were given to treat central or peripheral neuropathic pain of any etiology, pain was assessed using validated instruments, and adverse events were reported. Studies in which drugs other than opioid agonists were combined with opioids or opioids were administered epidurally or intrathecally were excluded.
Data were extracted by 2 independent investigators and included demographic variables, diagnoses, interventions, efficacy, and adverse effects.
Twenty-two articles met inclusion criteria and were classified as short-term (less than 24 hours; n = 14) or intermediate-term (median = 28 days; range = 8-56 days; n = 8) trials. The short-term trials had contradictory results. In contrast, all 8 intermediate-term trials demonstrated opioid efficacy for spontaneous neuropathic pain. A fixed-effects model meta-analysis of 6 intermediate-term studies showed mean posttreatment visual analog scale scores of pain intensity after opioids to be 14 units lower on a scale from 0 to 100 than after placebo (95% confidence interval [CI], -18 to -10; P<.001). According to number needed to harm (NNH), the most common adverse event was nausea (NNH, 3.6; 95% CI, 2.9-4.8), followed by constipation (NNH, 4.6; 95% CI, 3.4-7.1), drowsiness (NNH, 5.3; 95% CI, 3.7-8.3), vomiting (NNH, 6.2; 95% CI, 4.6-11.1), and dizziness (NNH, 6.7; 95% CI, 4.8-10.0).
Short-term studies provide only equivocal evidence regarding the efficacy of opioids in reducing the intensity of neuropathic pain. Intermediate-term studies demonstrate significant efficacy of opioids over placebo for neuropathic pain, which is likely to be clinically important. Reported adverse events of opioids are common but not life-threatening. Further RCTs are needed to establish their long-term efficacy, safety (including addiction potential), and effects on quality of life.
Context:
Pain is the most disturbing symptom of diabetic peripheral neuropathy. As many as 45% of patients with diabetes mellitus develop peripheral neuropathies.
Objective:
To evaluate the effect of gabapentin monotherapy on pain associated with diabetic peripheral neuropathy.
Design:
Randomized, double-blind, placebo-controlled, 8-week trial conducted between July 1996 and March 1997.
Setting:
Outpatient clinics at 20 sites.
Patients:
The 165 patients enrolled had a 1- to 5-year history of pain attributed to diabetic neuropathy and a minimum 40-mm pain score on the Short-Form McGill Pain Questionnaire visual analogue scale.
Intervention:
Gabapentin (titrated from 900 to 3600 mg/d or maximum tolerated dosage) or placebo.
Main outcome measures:
The primary efficacy measure was daily pain severity as measured on an 11-point Likert scale (0, no pain; 10, worst possible pain). Secondary measures included sleep interference scores, the Short-Form McGill Pain Questionnaire scores, Patient Global Impression of Change and Clinical Global Impression of Change, the Short Form-36 Quality of Life Questionnaire scores, and the Profile of Mood States results.
Results:
Eighty-four patients received gabapentin and 70 (83%) completed the study; 81 received placebo and 65 (80%) completed the study. By intent-to-treat analysis, gabapentin-treated patients' mean daily pain score at the study end point (baseline, 6.4; end point, 3.9; n = 82) was significantly lower (P<.001) compared with the placebo-treated patients' end-point score (baseline, 6.5; end point, 5.1; n = 80). All secondary outcome measures of pain were significantly better in the gabapentin group than in the placebo group. Additional statistically significant differences favoring gabapentin treatment were observed in measures of quality of life (Short Form-36 Quality of Life Questionnaire and Profile of Mood States). Adverse events experienced significantly more frequently in the gabapentin group were dizziness (20 [24%] in the gabapentin group vs 4 [4.9%] in the control group; P<.001) and somnolence (19 [23%] in the gabapentin group vs 5 [6%] in the control group; P = .003). Confusion was also more frequent in the gabapentin group (7 [8%] vs 1 [1.2%]; P = .06).
Conclusion:
Gabapentin monotherapy appears to be efficacious for the treatment of pain and sleep interference associated with diabetic peripheral neuropathy and exhibits positive effects on mood and quality of life.
• We prospectively studied 40 hospitalized patients who had well-established diagnoses of acquired immunodeficiency syndrome. Patients with confounding risk factors for neuropathy were excluded; none of the study patients had known vitamin deficiency, alcoholism, or any metabolic, drug, or toxic factor. Clinical and electrophysiologic evidence of a distal symmetric polyneuropathy was found in 35% (13/37) of the patients. Symptoms and signs of neuropathy were usually mild, and painful dysesthesias were uncommon. Amplitude reduction of sural nerve action potentials distinguished all patients with from those without clinical neuropathy. Results of other electrophysiologic studies of sural, peroneal, and median nerves were typically normal. These results provide evidence of distal axonal degeneration. Neuropathy occurred only in patients with systemic illness longer than five months' duration. When compared with patients without neuropathy, these patients had more severe weight loss and a higher incidence of clinical dementia. Follow-up evaluation showed no evidence of clinical progression over a six-month period. The pathogenesis of this common distal axonal polyneuropathy is unknown and warrants further investigation.
An analysis of the analgesic activity of δ
9-tetrahydrocannabinol (δ
9-THC) was carried out in rats and mice using both the hot plate and tail flick tests. In the rat, the dose-effect curve of δ
9-THC was comparable to that of morphine in both tests. In the mouse, however, the THC dose-effect curves were more variable and less steep than the morphine dose-effect curves. THC was less potent than morphine in both tests in mice. THC analgesia reached its peak at one hour and had a longer duration of action than morphine.
The administration of single oral doses of delta-9-tetrahydrocannabinol (THC) to patients with cancer pain demonstrated a mild analgesic effect. At a dose of 20 mg, however, THC induced side effects that would prohibit its therapeutic use including somnolence, dizziness, ataxia, and blurred vision. Alarming adverse reactions were also observed at this dose. THC, 10 mg, was well tolerated and, despite its sedative effect, may analgesic potential.
The effect of marijuana and placebo on pain tolerance was compared in cannabis-experienced and naive subjects. A statistically significant increase in tolerance was observed after smoking marijuana. Although there was no statistically significant interaction between the drug effect and having had previous cannabis experience, there was a definite trend towards a greater increase for the experienced (16%) compared to the naive group(8%).
We prospectively studied 40 hospitalized patients who had well-established diagnoses of acquired immunodeficiency syndrome. Patients with confounding risk factors for neuropathy were excluded; none of the study patients had known vitamin deficiency, alcoholism, or any metabolic, drug, or toxic factor. Clinical and electrophysiologic evidence of a distal symmetric polyneuropathy was found in 35% (13/37) of the patients. Symptoms and signs of neuropathy were usually mild, and painful dysesthesias were uncommon. Amplitude reduction of sural nerve action potentials distinguished all patients with from those without clinical neuropathy. Results of other electrophysiologic studies of sural, peroneal, and median nerves were typically normal. These results provide evidence of distal axonal degeneration. Neuropathy occurred only in patients with systemic illness longer than five months' duration. When compared with patients without neuropathy, these patients had more severe weight loss and a higher incidence of clinical dementia. Follow-up evaluation showed no evidence of clinical progression over a six-month period. The pathogenesis of this common distal axonal polyneuropathy is unknown and warrants further investigation.
Six adult male research volunteers, in two groups of three subjects each, lived in a residential laboratory for 13 days. All contact with the experimenter was through a networked computer system and subjects' behaviors, including food intake, were continuously recorded. During the first part of the day, subjects remained in continuously recorded. During the first part of the day, subjects remained in their private rooms doing planned work activities, and during the remainder of the day, they were allowed to socialize. Two cigarettes containing active marijuana (2.3% delta 9 THC) or placebo were smoked during both the private work period and the period of access to social activities. Smoked active marijuana significantly increased total daily caloric intake by 40%. Increased food intake was evident during both private and social periods. The increase in caloric intake was due to an increased consumption of snack foods as a consequence of an increase in the number of snacking occasions. There was no significant change in caloric consumption during meals. The principal increase within the category of snack foods was in the intake of sweet solid items, e.g., candy bars, compared to sweet fluid, e.g., soda, or savory solid items, e.g., potato chips. Increases in body weight during periods of active marijuana smoking were greater than predicted by caloric intake alone.
Pathological alterations associated with adjuvant-induced arthritis in rats, including paw volume and temperature and decreased pain threshold, become increasingly severe throughout the course of development of the disease (21 days). Acetyl salicylic acid and indomethacin produced significant in swelling and pyresis observed in both hind paws, with little or no effect on pain threshold. Conversely, d-propoxyphene·HCl produced analgesia in both hind paws even though inflammation and increased paw temperature were not significantly reduced.
After oral administration to mice, pethidine, Δ ⁸ ‐tetrahydrocannabinol (THC), Δ ⁹ ‐THC, a cannabis extract and cannabinol had a dose‐dependent antinociceptive effect when measured by the hot‐plate method. Cannabidiol was inactive at 30 mg/kg. Δ ⁸ ‐THC, Δ ⁹ ‐THC and pethidine did not differ significantly in potency, but Δ ⁹ ‐THC was 6·5 times more active than cannabinol.
After oral administration, three different cannabis extracts, Δ ⁸ ‐THC, Δ ⁹ ‐THC and morphine produced dose‐dependent depressions of the passage of a charcoal meal in mice. Δ ⁸ ‐THC and Δ ⁹ ‐THC were equipotent and were about five times less potent than morphine. Cannabidiol was inactive up to 30 mg/kg. The effect of the three cannabis extracts on intestinal motility could be accounted for by their Δ ⁹ ‐THC content.
The antinociceptive effect of pethidine and the effect of morphine on intestinal motility were antagonized by nalorphine whilst the effects of the cannabis extracts and the pure cannabinoids were not.
From these results it is concluded that although cannabis and the narcotics share several common pharmacological properties, the mode of action of each is pharmacologically distinct.
1.The psychopharmacological activity of ?1-tetrahydrocannabinol, (I); ?1(6)-tetrahydrocannabinol (4' hexyl), (II); ?1(6)-tetrahydrocannabinol, (III); 1-ethoxyhexahydrocannabinol, (IV); 8-ethoxy-iso-hexahydrocannabinol, (V); ?1(6)-tetrahydrocannabinolic acid Me ester, Isomer I, (VI); ?1(6)-tetrahydrocannabinolic acid Me ester, Isomer II, (VII); cannabigerol, (VIII); ?1(6)-tetrahydrocannabinol (3' hexyl), (IX); cannabichromene, (X); has been examined in a variety of animal species.2.Compounds (I) and (III) caused severe motor disturbances and a stuporous state in dogs and ptosis, “tameness” and peculiar postural changes in monkeys. In the latter animal, compound (II) elicited similar effects.3.Compounds (I) and (III) after intraperitoneal but not subcutaneous administration, suppressed the gerbil digging activity; reduced the rat conditioned avoidance response and induced a cataleptoid reaction in mice, rats and gerbils. In addition, compound (I) reduced the performance of mice on the rotating-rod. Both compounds, administered subcutaneously, induced a measurable ataxic gait in rats.4.Amphetamine reversed the behavioural changes elicited by compounds (I) and (III) in monkeys, as well as the cataleptoid reaction in rats.5.None of the other compounds provoked observable changes in any of the species studied.6.It is suggested that Rhesus monkeys might serve as a suitable model for assessing the psychopharmacological activity of active cannabinoids.
The analgesic effects of delta 9-tetrahydrocannabinol (THC), the psychoactive component of marihuana, were tested using the formalin test. Rats were treated with either THC (5 mg/kg or 10 mg/kg) or a placebo by gavage 4 h before the formalin test for analgesia was initiated. THC produced a highly significant analgesic effect against both phasic pain and tonic pain. THC is discussed as a model for the development of new analgesics or as a suitable analgesic if used with another potentiating drug.
To assess the safety and efficacy of Peptide T in the treatment of painful distal symmetrical polyneuropathy (DSP) associated with human immunodeficiency virus (HIV) infection.
Painful DSP is a frequent complication of HIV infection, although its etiology and optimal treatment are unknown. Peptide T (D-(alpha 1)-Peptide T-amide) has been found in phase I trials and anecdotal reports to relieve neuropathic pain in AIDS patients.
In this multicentered, double-blind, randomized study, subjects received intranasal Peptide T 6 mg/day or placebo for 12 weeks. The primary outcome measure was change in the modified Gracely pain score. Secondary efficacy variables were results of neurologic examination, neuropsychological and electrophysiologic studies, global evaluation, and CD4 lymphocyte counts.
Of 81 evaluable subjects, 40 received Peptide T and 41 received placebo. The change in pain scores was not significantly different (p = 0.32) in the Peptide T group (-0.24) as compared to placebo (-0.39). Group comparisons were not significantly different for change in any clinical examination or neuropsychologic measure, sural nerve amplitude or conduction velocity, or CD4 lymphocyte count. No significant drug-related adverse effects occurred in either group.
Intranasal Peptide T is safe but ineffective in the treatment of painful DSP associated with AIDS.
The effects of a high affinity cannabinoid receptor agonist were evaluated in rats subjected to chronic constriction injury of the sciatic nerve (CCI) or a sham operation. Intraperitoneal (i.p.) injections of the active, but not the inactive enantiomer, alleviated the pain behavior exhibited by CCI animals in a dose dependent manner. Moreover, at doses ranging from 0.43 to 4.3 mg/kg effects on sensitivity to a heat stimulus were observed neither in the paw contralateral to the sciatic ligation, nor in animals subjected to sham surgery. Animals subjected to CCI and treated with 4.3 mg/kg exhibited hypoalgesia in the paw ipsilateral to the ligated sciatic, i.e. heat hypoalgesia was completely reversed. The hypoalgesia is presumed to be the results of unmasking of a sensory deficit reflecting the known loss of C and A delta with CCI. Although side effects were present in some CCI animals subjected to the high dose (4.3 mg/kg), a moderate dose (2.14 mg/kg) completely alleviated the thermal and mechanical hyperalgesia, and mechanical allodynia without side effects. In addition to identifying a potential drug treatment for painful neuropathy, this study suggests that changes in cannabinoid receptors occurs in nerve injured animals.
The potent analgesic effects of cannabis-like drugs and the presence of CB1-type cannabinoid receptors in pain-processing areas of the brain and spinal cord indicate that endogenous cannabinoids such as anandamide may contribute to the control of pain transmission within the central nervous system (CNS). Here we show that anandamide attenuates the pain behaviour produced by chemical damage to cutaneous tissue by interacting with CB1-like cannabinoid receptors located outside the CNS. Palmitylethanolamide (PEA), which is released together with anandamide from a common phospholipid precursor, exerts a similar effect by activating peripheral CB2-like receptors. When administered together, the two compounds act synergistically, reducing pain responses 100-fold more potently than does each compound alone. Gas-chromatography/mass-spectrometry measurements indicate that the levels of anandamide and PEA in the skin are enough to cause a tonic activation of local cannabinoid receptors. In agreement with this possibility, the CB1 antagonist SR141716A and the CB2 antagonist SR144528 prolong and enhance the pain behaviour produced by tissue damage. These results indicate that peripheral CB1-like and CB2-like receptors participate in the intrinsic control of pain initiation and that locally generated anandamide and PEA may mediate this effect.
Peripheral neuropathy is common in persons infected with the human immunodeficiency virus (HIV) but few data on symptomatic treatment are available.
To evaluate the efficacy of a standardized acupuncture regimen (SAR) and amitriptyline hydrochloride for the relief of pain due to HIV-related peripheral neuropathy in HIV-infected patients.
Randomized, placebo-controlled, multicenter clinical trial. Each site enrolled patients into 1 of the following 3 options: (1) a modified double-blind 2 x 2 factorial design of SAR, amitriptyline, or the combination compared with placebo, (2) a modified double-blind design of an SAR vs control points, or (3) a double-blind design of amitriptyline vs placebo.
Terry Beirn Community Programs for Clinical Research on AIDS (HIV primary care providers) in 10 US cities.
Patients with HIV-associated, symptomatic, lower-extremity peripheral neuropathy. Of 250 patients enrolled, 239 were in the acupuncture comparison (125 in the factorial option and 114 in the SAR option vs control points option), and 136 patients were in the amitriptyline comparison (125 in the factorial option and 11 in amitriptyline option vs placebo option).
Standardized acupuncture regimen vs control points, amitriptyline (75 mg/d) vs placebo, or both for 14 weeks.
Changes in mean pain scores at 6 and 14 weeks, using a pain scale ranging from 0.0 (no pain) to 1.75 (extremely intense), recorded daily.
Patients in all 4 groups showed reduction in mean pain scores at 6 and 14 weeks compared with baseline values. For both the acupuncture and amitriptyline comparisons, changes in pain score were not significantly different between the 2 groups. At 6 weeks, the estimated difference in pain reduction for patients in the SAR group compared with those in the control points group (a negative value indicates a greater reduction for the "active" treatment) was 0.01 (95% confidence interval [CI], -0.11 to 0.12; P=.88) and for patients in the amitriptyline group vs those in the placebo group was -0.07 (95% CI, -0.22 to 0.08; P=.38). At 14 weeks, the difference for those in the SAR group compared with those in the control points group was -0.08 (95% CI, -0.21 to 0.06; P=.26) and for amitriptyline compared with placebo was 0.00 (95% CI, -0.18 to 0.19; P=.99).
In this study, neither acupuncture nor amitriptyline was more effective than placebo in relieving pain caused by HIV-related peripheral neuropathy.
Although mexiletine, an antiarrhythmic with local anesthetic properties, has been reported to relieve discomfort in diabetic neuropathy, its usefulness in the treatment of HIV-related painful peripheral neuropathy (PPN) has not been determined. The tolerance and effectiveness of mexiletine in HIV-related PPN were assessed in 22 patients who were randomized to receive mexiletine (maximum dose, 600 mg/day) or placebo for 6 weeks, followed by the alternative intervention for 6 weeks after a 1-week washout period. The daily pain response was assessed using a visual analogue scale card in 19 patients who received at least 2 weeks of the drug, 16 of whom were crossed-over to receive the alternate agent. No statistically significant difference was found between the mean daily pain scores for patients receiving mexiletine versus placebo, irrespective of the order in which the agents were received. Comparing the mean individual daily pain scores for each phase of study, 5 patients (31%) had significantly less pain while receiving mexiletine compared with their response to placebo, 5 patients (31%) had significantly less pain while receiving placebo, and no difference was noted in 6 patients (38%). Crossover and multivariate analyses for repeated measures showed no apparent difference in the response to mexiletine versus placebo. Dose-limiting adverse events occurred in 39% of those receiving mexiletine, but only 1 patient (5%) discontinued placebo. Mexiletine was only modestly well tolerated despite its relatively brief period of administration, and no evidence was found to support its benefit in HIV-related PPN. Although a first-drug effect was not demonstrated, a powerful placebo effect was seen in some patients.
Postherpetic neuralgia (PHN) is a syndrome of often intractable neuropathic pain following herpes zoster (shingles) that eludes effective treatment in many patients.
To determine the efficacy and safety of the anticonvulsant drug gabapentin in reducing PHN pain.
Multicenter, randomized, double-blind, placebo-controlled, parallel design, 8-week trial conducted from August 1996 through July 1997.
Sixteen US outpatient clinical centers.
A total of 229 subjects were randomized.
A 4-week titration period to a maximum dosage of 3600 mg/d of gabapentin or matching placebo. Treatment was maintained for another 4 weeks at the maximum tolerated dose. Concomitant tricyclic antidepressants and/or narcotics were continued if therapy was stabilized prior to study entry and remained constant throughout the study.
The primary efficacy measure was change in the average daily pain score based on an 11-point Likert scale (0, no pain; 10, worst possible pain) from baseline week to the final week of therapy. Secondary measures included average daily sleep scores, Short-Form McGill Pain Questionnaire (SF-MPQ), Subject Global Impression of Change and investigator-rated Clinical Global Impression of Change, Short Form-36 (SF-36) Quality of Life Questionnaire, and Profile of Mood States (POMS). Safety measures included the frequency and severity of adverse events.
One hundred thirteen patients received gabapentin, and 89 (78.8%) completed the study; 116 received placebo, and 95 (81.9%) completed the study. By intent-to-treat analysis, subjects receiving gabapentin had a statistically significant reduction in average daily pain score from 6.3 to 4.2 points compared with a change from 6.5 to 6.0 points in subjects randomized to receive placebo (P<.001). Secondary measures of pain as well as changes in pain and sleep interference showed improvement with gabapentin (P<.001). Many measures within the SF-36 and POMS also significantly favored gabapentin (P< or =.01). Somnolence, dizziness, ataxia, peripheral edema, and infection were all more frequent in the gabapentin group, but withdrawals were comparable in the 2 groups (15 [13.3%] in the gabapentin group vs 11 [9.5%] in the placebo group).
Gabapentin is effective in the treatment of pain and sleep interference associated with PHN. Mood and quality of life also improve with gabapentin therapy.
Painful sensory neuropathy is a common complication of HIV infection. Based on prior uncontrolled observations, we hypothesized that amitriptyline or mexiletine would improve the pain symptoms.
A randomized, double-blind, 10-week trial of 145 patients assigned equally to amitriptyline, mexiletine, or matching placebo. The primary outcome measure was the change in pain intensity between baseline and the final visit.
The improvement in amitriptyline group (0.31+/-0.31 units [mean+/-SD]) and mexiletine group (0.23+/-0.41) was not significantly different from placebo (0.20+/-0.30). Both interventions were generally well tolerated.
Neither amitriptyline nor mexiletine provide significant pain relief in patients with HIV-associated painful sensory neuropathy.
Although it is well known that cannabinoids produce antinociception in acute pain models, there is less information on the ability of cannabinoids to alleviate hyperalgesia. In the present study, we determined whether cannabinoids attenuated the development of hyperalgesia produced by intraplantar injection of capsaicin in rats. In normal, untreated animals, intraplantar injection of 10 microg capsaicin produces nocifensive behavior (elevation of the injected paw) suggestive of pain, an increase in the frequency of withdrawal from punctate mechanical stimuli applied to the paw (mechanical hyperalgesia) and a decrease in the latency of withdrawal from noxious heat (heat hyperalgesia). Separate groups of animals were pretreated intravenously with vehicle, the cannabinoid receptor agonist WIN 55,212-2 at doses of 1, 10, 100 or 200 microg/kg, or the enantiomer WIN 55,212-3 (100 microg/kg) 5 min before intraplantar injection of capsaicin into one paw. The duration of nocifensive behavior was measured during the first 5 min after capsaicin injection. Withdrawal responses to mechanical and heat stimuli applied to the plantar surface of both hindpaws were measured before and at 5 and 30 min after capsaicin. Pretreatment with WIN 55,212-2 produced a dose-dependent decrease in nocifensive behavior and in hyperalgesia to mechanical and heat stimuli produced by capsaicin, as compared with vehicle pretreatment. Doses of 100 and 200 microg/kg WIN 55,212-2 completely blocked the development of hyperalgesia to mechanical and heat stimuli without altering withdrawal responses on the contralateral control paw. Furthermore, these doses of WIN 55,212-2 had no effect on basal withdrawal responses to heat in animals that did not receive capsaicin. The inactive enantiomer WIN 55,212-3 did not alter the development of capsaicin-evoked pain or hyperalgesia. These data suggest that low doses of cannabinoids, which do not produce analgesia or impair motor function, attenuate chemogenic pain and possess antihyperalgesic properties.
The heat/capsaicin sensitization model is a new human experimental pain model that synergistically combines non-invasive physical and chemical methods of nociceptor stimulation to produce stable and long-lasting hyperalgesia with a low potential for skin injury. In 10 healthy volunteers the forearm was stimulated with a 45 degrees C thermode for 5 min to produce an area of secondary hyperalgesia. Applying capsaicin cream for 30 min further expanded the area of secondary hyperalgesia. Periodically heating the treated skin with a previously non-painful temperature of 40 degrees C re-kindled the sensitization enough to maintain stable areas of secondary hyperalgesia for 4h. The evoked pain was moderate and well tolerated. The heat/capsaicin sensitization model should be well suited for studying pain mechanisms and testing new analgesics.
Distal symmetrical peripheral neuropathy (DSPN) is a particularly distressing pain syndrome associated with human immunodeficiency virus (HIV) disease. Capsaicin has been found to be effective in relieving pain associated with other neuropathic pain syndromes, and is mentioned as a possible topical adjuvant analgesic for the relief of DSPN. This multicenter, controlled, randomized, double-masked clinical trial studied patients with HIV-associated DSPN and compared measures of pain intensity, pain relief, sensory perception, quality of life, mood, and function for patients who received topical capsaicin to the corresponding measures for patients who received the vehicle only. Twenty-six subjects were enrolled in the study. At the end of 1 week, subjects receiving capsaicin tended to report higher current pain scores than did subjects receiving the vehicle (Mann-Whitney test; P = 0.042). The dropout rate was higher for the capsaicin group (67%) than for the vehicle group (18%) (chi 2 test of association; P = 0.014). There were no other statistically significant differences between the capsaicin and vehicle groups with respect to current pain, worst pain, pain relief, sensory perception, quality of life, mood, or function at study entry or at any time during the 4-week trial. These results suggest capsaicin is ineffective in relieving pain associated with HIV-associated DSPN.
To investigate the analgesic efficacy of lamotrigine in the treatment of painful HIV-associated distal sensory polyneuropathy (DSP).
The pathogenesis of HIV-associated DSP is unknown and there is no effective treatment. A novel anticonvulsant, lamotrigine, blocks voltage-sensitive sodium channels and inhibits the release of glutamate and aspartate. There have been anecdotal reports of efficacy of lamotrigine in the treatment of painful neuropathy and trigeminal neuralgia.
In a multicenter, randomized, double-blind, placebo-controlled study, lamotrigine was initiated at 25 mg per day and slowly titrated over 7 weeks to 300 mg per day. Study duration was 14 weeks. The primary outcome measure was change in pain on the modified Gracely scale with secondary outcome measures including change in neurologic examination, use of concomitant analgesic medications, and global pain relief.
Of 42 enrolled subjects, 13 did not complete the 14-week study endpoint. In five of these, rash was the cause for dropout. In the remaining 29 evaluable subjects, 20 patients received placebo and 9 received lamotrigine. The pain scores at baseline were not significantly different. The reduction in average pain from baseline to week 14 was greater (p = 0.03) in the lamotrigine group (-0.55) than in the placebo group (-0.18), adjusting for baseline levels of pain. There was no difference between the groups on the change in peak worst pain.
In this small trial, lamotrigine showed promise in the treatment of pain associated with HIV-related DSP. The frequency of rash was greater than in lamotrigine studies in epilepsy. A larger controlled study of lamotrigine is warranted.
The heat--capsaicin sensitization model was developed as a noninvasive and noninjurious human experimental pain model. The sequential application of moderate intensity thermal and topical chemical stimuli produces stable and long-lasting areas of cutaneous secondary hyperalgesia. The aim of the present study was to validate the heat--capsaicin sensitization model as a tool for testing analgesic drug efficacy. Responsivity of model-associated measures was tested with remifentanil, a potent and ultrashort acting mu-opioid agonist.
Sensitization was induced by heating forearm skin with a thermode at 45 degrees C for 5 min, immediately followed by application of 0.075% capsaicin cream for 30 min. Sensitization was rekindled four times at 40-min intervals with the thermode at 40 degrees C for 5 min. After each rekindling, areas of secondary hyperalgesia were measured, and the painfulness of thermal stimulation in normal skin with 45 degrees C for 1 min (long thermal stimulation [LTS]) was rated. Before and during the second rekindling, remifentanil 0.10 microg x kg(-1) x min(-1) or saline-placebo was infused for 35 min.
Infusion of remifentanil reduced the areas of secondary hyperalgesia to 29--30% of baseline size compared with 75--83% during placebo. Similarly, remifentanil reduced the painfulness of LTS to 29% of baseline severity compared with 84% during placebo. Areas of secondary hyperalgesia and LTS painfulness returned to baseline levels by the time of the third rekindling, demonstrating rapid disappearance of remifentanil analgesia and possibly transient spontaneous opioid withdrawal hyperalgesia.
Using the heat-capsaicin sensitization model, opioid analgesia and suppression of secondary hyperalgesia was reliably demonstrated without skin injury.
Pain intensity is frequently measured on an 11-point pain intensity numerical rating scale (PI-NRS), where 0=no pain and 10=worst possible pain. However, it is difficult to interpret the clinical importance of changes from baseline on this scale (such as a 1- or 2-point change). To date, there are no data driven estimates for clinically important differences in pain intensity scales used for chronic pain studies. We have estimated a clinically important difference on this scale by relating it to global assessments of change in multiple studies of chronic pain. Data on 2724 subjects from 10 recently completed placebo-controlled clinical trials of pregabalin in diabetic neuropathy, postherpetic neuralgia, chronic low back pain, fibromyalgia, and osteoarthritis were used. The studies had similar designs and measurement instruments, including the PI-NRS, collected in a daily diary, and the standard seven-point patient global impression of change (PGIC), collected at the endpoint. The changes in the PI-NRS from baseline to the endpoint were compared to the PGIC for each subject. Categories of "much improved" and "very much improved" were used as determinants of a clinically important difference and the relationship to the PI-NRS was explored using graphs, box plots, and sensitivity/specificity analyses. A consistent relationship between the change in PI-NRS and the PGIC was demonstrated regardless of study, disease type, age, sex, study result, or treatment group. On average, a reduction of approximately two points or a reduction of approximately 30% in the PI-NRS represented a clinically important difference. The relationship between percent change and the PGIC was also consistent regardless of baseline pain, while higher baseline scores required larger raw changes to represent a clinically important difference. The application of these results to future studies may provide a standard definition of clinically important improvement in clinical trials of chronic pain therapies. Use of a standard outcome across chronic pain studies would greatly enhance the comparability, validity, and clinical applicability of these studies.
The anticonvulsant gabapentin, proven effective for neuropathic pain in two large, placebo-controlled clinical trials, is widely used for treatment of chronic pain. Preclinical studies have demonstrated analgesic and antiallodynic effects in models involving neuronal sensitization and nerve injury, without affecting acute pain transmission. The aim of the present study was to link data from animal models and clinical trials for chronic pain by investigating the effect of gabapentin on acute nociception and experimentally induced cutaneous hyperalgesia in healthy volunteers.
The human experimental hyperalgesia model, the heat-capsaicin sensitization model, was induced in 25 healthy male volunteers. Subjects received oral gabapentin (1,200 mg) or placebo after heat-capsaicin sensitization was established on the forearm. The primary outcome measures were the sizes of the areas of secondary hyperalgesia to von Frey hair and brush stimulation on the forearm. Secondary outcome measures were as follows: (1) size of secondary hyperalgesia area in response to brief thermal sensitization procedure on the thigh; (2) heat pain detection thresholds in normal and sensitized skin; and (3) painfulness of 1 min of 45 degrees C stimulation in normal skin.
Oral gabapentin profoundly suppressed established cutaneous sensitization on the forearm and prevented development of cutaneous sensitization on the thigh. Thermal nociception in normal skin was unchanged. Side effects were modest.
The results link preclinical findings with results from clinical trials of neuropathic pain. The results further suggest that gabapentin may prove effective in acute pain disorders involving neuronal sensitization, such as postoperative pain and acute herpetic pain, and could prove effective in prevention of chronic pain.
During the last decade, rigorous scientific methods have been applied to determine the effects of cannabinoids on nociceptive neurotransmission. Cannabinoids have been observed to markedly decrease signalling in specific neural pathways that transmit messages about pain. These effects were found to be due to the suppression of spinal and thalamic nociceptive neurons, and independent of any actions on either the motor system or sensory neurons that transmit messages related to non-nociceptive stimulation. Spinal, supraspinal, and peripheral sites of cannabinoid analgesia have been identified. The discovery of endocannabinoids raised the question of their natural role in pain. Multiple lines of evidence indicate that endocannabinoids serve naturally to suppress pain. While it is now clear that cannabinoids suppress nociceptive neurotransmission, more work is needed to establish the clinical utility of these compounds. The few human studies conducted to date produced mixed results, with more promising findings coming from studies of clinical pain as compared with experimental pain. The therapeutic potential of cannabinoids remains an important topic for future investigations.
Highly active antiretroviral therapy (HAART) is effective in suppressing systemic human immunodeficiency virus (HIV) viral load and has decreased mortality rates and the incidence of systemic opportunistic infections in patients with acquired immunodeficiency syndrome (AIDS). Multiple studies now suggest that the incidence rates of HIV-associated neurological disease and central nervous system (CNS) opportunistic infections also are decreasing. Since the introduction of HAART in 1996, the incidence of HIV dementia has decreased by approximately 50%. The mean CD4 cell count for new cases of HIV dementia is increasing, but it remains as a complication of moderate-advanced immunosuppression. The incidence of HIV-associated distal sensory polyneuropathy has decreased, although the incidence of antiretroviral drug-induced toxic neuropathy has increased. However, as patients with AIDS live longer as a result of HAART, the prevalence of peripheral neuropathy in HIV-seropositive patients may be increasing. The incidence rates of CNS opportunistic infections (cryptococcal meningitis, toxoplasmosis, progressive multifocal leukoencephalopathy) and primary CNS lymphoma have decreased since the introduction of HAART. As patients develop increasing resistance mutations to antiretroviral drugs and with subsequent decline in CD4 cell counts, in the near future, the incidence of HIV-associated neurological disease may begin to rise.
To evaluate the efficacy and tolerability of lamotrigine (LTG) for the treatment of pain in HIV-associated sensory neuropathies.
In a randomized, double-blind study, patients with HIV-associated distal sensory polyneuropathy (DSP) received LTG or placebo during a 7-week dose escalation phase followed by a 4-week maintenance phase. Randomization was stratified according to whether or not patients were currently using neurotoxic antiretroviral therapy (ART).
The number of patients randomized was 92 (62 LTG, 30 placebo) in the stratum receiving neurotoxic ART and 135 (88 LTG, 47 placebo) in the stratum not receiving neurotoxic ART. Mean change from baseline in Gracely Pain Scale score for average pain was not different between LTG and placebo at the end of the maintenance phase in either stratum, but the slope of the change in Gracely Pain Scale score for average pain reflected greater improvement with LTG than with placebo in the stratum receiving neurotoxic ART (p = 0.004), as did the mean change from baseline scores on the Visual Analogue Scale for Pain Intensity and the McGill Pain Assessment Scale and patient and clinician ratings of global impression of change in pain (p </= 0.02). The incidence of adverse events, including rash, was similar between LTG and placebo.
Lamotrigine was well-tolerated and effective for HIV-associated neuropathic pain in patients receiving neurotoxic antiretroviral therapy. Additional research is warranted to understand the differing response among patients receiving neurotoxic antiretroviral therapy compared with those not receiving neurotoxic antiretroviral therapy.
In this randomized double-blind placebo-controlled study, the analgesic effect of oral lamotrigine (400 mg) on cutaneous sensitization induced with the heat/capsaicin sensitization model was compared with the effect of oral hydromorphone (8 mg) in healthy volunteers. In a separate session, intravenous remifentanil (0.10 microg.kg(-1).min(-1)) and placebo were administered. This session was used as an additional reference comparator. Outcome measures were the areas of secondary hyperalgesia to brush and von Frey hair stimulation and the painfulness of noxious thermal stimulation in nonsensitized skin. Compared with placebo, both intravenous remifentanil and oral hydromorphone significantly suppressed secondary hyperalgesia and acute thermal nociception. Oral lamotrigine did not reduce secondary hyperalgesia or acute thermal nociception but produced side effects of severity comparable with that of oral hydromorphone. Although lamotrigine is efficacious in the management of some types of chronic neuropathic pain, the lack of effect of this agent on human experimental pain suggests that its analgesic effects depend on nerve injury-associated abnormalities, which cannot be simulated in healthy human volunteers.
Painful HIV-associated sensory neuropathies (HIV-SN) are a common complication of HIV infection. The pathogenesis is unknown and the treatment very limited. Gabapentin (GBP) is effective in painful diabetic neuropathy and postherpetic neuralgia and its effectiveness on painful HIV-SN has been reported anecdotally.
Multicenter, prospective, randomised, double-blind, placebo-controlled study.
Patients were followed for a 1-week screening, a 4-week double-blind and a 2-week open treatment phase. GBP was initiated at 400 mg/d, titrated over 2 weeks to 1200 mg/d, and then either maintained at this level or-if not beneficial-titrated to 2400 mg/d. After 4 weeks the medication was unblinded and the patient had the choice to begin, to maintain or to increase GBP to 3600 mg/d. The primary outcome measure was an improvement in median pain on the Visual Analogue Scale (VAS) from the screening week compared to the 4(th) treatment week. A secondary efficacy measure was the median sleep score (VAS).
15 patients received GBP and 11 placebo. In each group one patient dropped out during the doubleblind phase. Median pain (GBP 5.1; placebo 4.7) and sleep score (GBP 4.5; placebo 5.6) did not differ between both groups at baseline. In the GBP-group there was a significant decrease of the pain to 2.85 (-44.1 %) as well as of the sleep VAS to 2.3 (-48.9 %). No significant decrease in the pain (median VAS=3.3, -29.8 %) as well as in the sleep score (median VAS=4.95, -11.6 %) was observed in the placebo-group. GBP was generally well tolerated. The most frequent side effect was somnolence reported in 80% of GBP-treated patients.
GBP was more effective than placebo in reducing pain and sleep interference in patients with HIV-SN.
Despite the major benefits of antiretroviral therapy on survival during HIV infection, there is an increasing need to manage symptoms and side effects during long-term drug therapy. Cannabis has been reported anecdotally as being beneficial for a number of common symptoms and complications in HIV infections, for example, poor appetite and neuropathy. This study aimed to investigate symptom management with cannabis. Following Ethics Committee approval, HIV-positive individuals attending a large clinic were recruited into an anonymous cross-sectional questionnaire study. Up to one-third (27%, 143/523) reported using cannabis for treating symptoms. Patients reported improved appetite (97%), muscle pain (94%), nausea (93%), anxiety (93%), nerve pain (90%), depression (86%), and paresthesia (85%). Many cannabis users (47%) reported associated memory deterioration. Symptom control using cannabis is widespread in HIV outpatients. A large number of patients reported that cannabis improved symptom control.
Cognitive disorders, vacuolar myelopathy, and sensory neuropathies associated with HIV are the most common disorders in patients with HIV AIDS, and are the focus of this review. These disorders are treatable and of those associated with HIV AIDS the pathogenic mechanisms are the most understood. Although triggered by productive HIV macrophage infections, aberrant immune activation plays a major role in inducing the CNS disorders. Novel therapies aimed at these inflammatory mechanisms can be effective. The sensory neuropathies associated with HIV infection are a major cause of morbidity; incidence may be increased by the toxic effects of specific antiretroviral drugs within the peripheral nervous system.
Central pain in multiple sclerosis (MS) is common and often refractory to treatment.
We conducted a single-center, 5-week (1-week run-in, 4-week treatment), randomized, double-blind, placebo-controlled, parallel-group trial in 66 patients with MS and central pain states (59 dysesthetic, seven painful spasms) of a whole-plant cannabis-based medicine (CBM), containing delta-9-tetrahydrocannabinol:cannabidiol (THC:CBD) delivered via an oromucosal spray, as adjunctive analgesic treatment. Each spray delivered 2.7 mg of THC and 2.5 of CBD, and patients could gradually self-titrate to a maximum of 48 sprays in 24 hours.
Sixty-four patients (97%) completed the trial, 34 received CBM. In week 4, the mean number of daily sprays taken of CBM (n = 32) was 9.6 (range 2 to 25, SD = 6.0) and of placebo (n = 31) was 19.1 (range 1 to 47, SD = 12.9). Pain and sleep disturbance were recorded daily on an 11-point numerical rating scale. CBM was superior to placebo in reducing the mean intensity of pain (CBM mean change -2.7, 95% CI: -3.4 to -2.0, placebo -1.4 95% CI: -2.0 to -0.8, comparison between groups, p = 0.005) and sleep disturbance (CBM mean change -2.5, 95% CI: -3.4 to -1.7, placebo -0.8, 95% CI: -1.5 to -0.1, comparison between groups, p = 0.003). CBM was generally well tolerated, although more patients on CBM than placebo reported dizziness, dry mouth, and somnolence. Cognitive side effects were limited to long-term memory storage.
Cannabis-based medicine is effective in reducing pain and sleep disturbance in patients with multiple sclerosis related central neuropathic pain and is mostly well tolerated.
New studies of the treatment of neuropathic pain have increased the need for an updated review of randomized, double-blind, placebo-controlled trials to support an evidence based algorithm to treat neuropathic pain conditions. Available studies were identified using a MEDLINE and EMBASE search. One hundred and five studies were included. Numbers needed to treat (NNT) and numbers needed to harm (NNH) were used to compare efficacy and safety of the treatments in different neuropathic pain syndromes. The quality of each trial was assessed. Tricyclic antidepressants and the anticonvulsants gabapentin and pregabalin were the most frequently studied drug classes. In peripheral neuropathic pain, the lowest NNT was for tricyclic antidepressants, followed by opioids and the anticonvulsants gabapentin and pregabalin. For central neuropathic pain there is limited data. NNT and NNH are currently the best way to assess relative efficacy and safety, but the need for dichotomous data, which may have to be estimated retrospectively for old trials, and the methodological complexity of pooling data from small cross-over and large parallel group trials, remain as limitations.