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Effects on Spasticity and Neuropathic Pain of an Oral Formulation of Δ9-Tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis.

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Journal Clinical therapeutics
Year 2018
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This article is included in 10 Systematic reviews Systematic reviews (10 references)

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PURPOSE: The aim of the present study was to evaluate the efficacy of an oral formulation of Δ9-tetrahydrocannabinol (ECP002A) in patients with progressive multiple sclerosis (MS). METHODS: This accelerated proof-of-concept study consisted of 2 phases: a crossover challenge (dose-finding) phase and a 4-week, parallel, randomized, placebo-controlled treatment phase. Twenty-four patients with progressive MS and moderate spasticity were enrolled. During the treatment phase, biomarkers for efficacy and secondary pharmacodynamic effects were measured at baseline and after 2 and 4 weeks of treatment. Serum samples were collected to determine pharmacokinetic properties and perform population modeling. Safety and tolerability profiles were assessed based on adverse events and safety measurements. FINDINGS: Pain was significantly reduced when measured directly after administration of ECP002A in the clinic but not when measured in a daily diary. A similar pattern was observed in subjective muscle spasticity. Other clinical outcomes were not significantly different between active treatment and placebo. Cognitive testing indicated that there was no decline in cognition after 2 or 4 weeks of treatment attributable to ECP002A compared with placebo. Implications This study specifically underlines the added value of thorough investigation of pharmacokinetic and pharmacodynamic associations in the target population. Despite the complex interplay of psychoactive effects and analgesia, the current oral formulation of Δ9-tetrahydrocannabinol may play a role in the treatment of spasticity and pain associated with MS because it was well tolerated and had a stable pharmacokinetic profile.

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Tetrahydrocannabinol Does Not Reduce Pain in Patients With Chronic Abdominal Pain in a Phase 2 Placebo-controlled Study.

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Journal Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
Year 2017
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This article is included in 1 Broad synthesis Broad syntheses (1 reference) 10 Systematic reviews Systematic reviews (10 references)

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BACKGROUND & AIMS: Delta-9-tetrahydrocannabinol (THC) is the most abundant cannabinoid from the plant Cannabis sativa. There is only equivocal evidence that THC has analgesic effects. We performed a phase 2 controlled trial to evaluate the analgesic efficacy, pharmacokinetics, safety, and tolerability of an oral tablet containing purified THC in patients with chronic abdominal pain. METHODS: Sixty-five patients with chronic abdominal pain for 3 months or more (numeric rating scale scores of 3 or more) after surgery or because of chronic pancreatitis were randomly assigned to groups given the THC tablet or identical matching placebos for 50-52 days. Subjects in the THC group were given the tablet first in a step-up phase (3 mg 3 times daily for 5 days and then 5 mg 3 times daily for 5 days), followed by a stable dose phase (8 mg 3 times daily until days 50-52). Preceding and during the entire study period, patients were asked to continue taking their medications (including analgesics) according to prescription. Patients reported any additional pain medications in a diary. Efficacy and safety assessments were conducted preceding medication intake (day 1), after 15 days, and at 50-52 days. Plasma samples were collected on study days 1, 15, and 50-52; mean plasma concentration curves of THC and 11-OH-THC were plotted. The primary end point was pain relief, which was measured by a visual analogue scale (VAS) of the mean pain (VAS mean scores) on the basis of information from patient diaries. Secondary end points included pain and quality of life (determined from patient questionnaires), pharmacokinetics, and safety. RESULTS: At days 50-52, VAS mean scores did not differ significantly between the THC and placebo groups (F1,46 = 0.016; P = .901). Between the start and end of the study, VAS mean scores decreased by 1.6 points (40%) in the THC group compared with 1.9 points (37%) in the placebo group. No differences were observed in secondary outcomes. Oral THC was generally well-absorbed. Seven patients in the THC group stopped taking the tablets because of adverse events, compared with 2 patients in the placebo group. All (possibly) related adverse events were mild or moderate. CONCLUSIONS: In a phase 2 study, we found no difference between a THC tablet and a placebo tablet in reducing pain measures in patients with chronic abdominal pain. THC, administered 3 times daily, was safe and well-tolerated during a 50-day to 52-day treatment period. ClinicalTrials.gov number: NCT01562483 and NCT01551511.

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Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies

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Journal British Journal of Pain
Year 2017
Links Pubmed DOI PubMed Central

This article is included in 1 Broad synthesis Broad syntheses (1 reference) 8 Systematic reviews Systematic reviews (8 references)

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Background: Opioids are critical for managing cancer pain, but may provide inadequate relief and/or unacceptable side effects in some cases. Objective: To assess the analgesic efficacy of adjunctive Sativex (Δ9-tetrahydrocannabinol (27 mg/mL): cannabidiol (25 mg/mL)) in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy. Methods: This report describes two phase 3, double-blind, randomized, placebo-controlled trials. Eligible patients had advanced cancer and average pain numerical rating scale (NRS) scores ≥4 and ≤8 at baseline, despite optimized opioid therapy. In Study-1, patients were randomized to Sativex or placebo, and then self-titrated study medications over a 2-week period per effect and tolerability, followed by a 3-week treatment period. In Study-2, all patients self-titrated Sativex over a 2-week period. Patients with a ≥15% improvement from baseline in pain score were then randomized 1:1 to Sativex or placebo, followed by 5-week treatment period (randomized withdrawal design). Results: The primary efficacy endpoint (percent improvement (Study-1) and mean change (Study-2) in average daily pain NRS scores) was not met in either study. Post hoc analyses of the primary endpoints identified statistically favourable treatment effect for Sativex in US patients <65 years (median treatment difference: 8.8; 95% confidence interval (CI): 0.00–17.95; p = 0.040) that was not observed in patients <65 years from the rest of the world (median treatment difference: 0.2; 95% CI: −5.00 to 7.74; p = 0.794). Treatment effect in favour of Sativex was observed on quality-of-life questionnaires, despite the fact that similar effects were not observed on NRS score. The safety profile of Sativex was consistent with earlier studies, and no evidence of abuse or misuse was identified. Conclusions: Sativex did not demonstrate superiority to placebo in reducing self-reported pain NRS scores in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy, although further exploration of differences between United States and patients from the rest of the world is warranted.

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An exploratory human laboratory experiment evaluating vaporized cannabis in the treatment of neuropathic pain from spinal cord injury and disease.

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Journal The journal of pain : official journal of the American Pain Society
Year 2016
Links Pubmed DOI PubMed Central

This article is included in 1 Broad synthesis Broad syntheses (1 reference) 8 Systematic reviews Systematic reviews (8 references)

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Using 8-hour human laboratory experiments, we evaluated the analgesic efficacy of vaporized cannabis in patients with neuropathic pain related to injury or disease of the spinal cord, most of whom were experiencing pain despite traditional treatment. After obtaining baseline data, 42 participants underwent a standardized procedure for inhaling 4 puffs of vaporized cannabis containing either placebo, 2.9%, or 6.7% delta 9-THC on 3 separate occasions. A second dosing occurred 3 hours later; participants chose to inhale 4 to 8 puffs. This flexible dosing was used to attempt to reduce the placebo effect. Using an 11-point numerical pain intensity rating scale as the primary outcome, a mixed effects linear regression model showed a significant analgesic response for vaporized cannabis. When subjective and psychoactive side effects (eg, good drug effect, feeling high, etc) were added as covariates to the model, the reduction in pain intensity remained significant above and beyond any effect of these measures (all <i>P</i> &lt; .0004). Psychoactive and subjective effects were dose-dependent. Measurement of neuropsychological performance proved challenging because of various disabilities in the population studied. Because the 2 active doses did not significantly differ from each other in terms of analgesic potency, the lower dose appears to offer the best risk-benefit ratio in patients with neuropathic pain associated with injury or disease of the spinal cord. PERSPECTIVE: A crossover, randomized, placebo-controlled human laboratory experiment involving administration of vaporized cannabis was performed in patients with neuropathic pain related to spinal cord injury and disease. This study supports consideration of future research that would include longer duration studies over weeks to months to evaluate the efficacy of medicinal cannabis in patients with central neuropathic pain. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

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Single dose delta-9-tetrahydrocannabinol in chronic pancreatitis patients: Analgesic efficacy, pharmacokinetics and tolerability

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Journal British journal of clinical pharmacology
Year 2016
Links Pubmed DOI PubMed Central

This article is included in 1 Broad synthesis Broad syntheses (1 reference) 5 Systematic reviews Systematic reviews (5 references)

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Aim We aimed to assess the analgesic efficacy, pharmacokinetics, tolerability and safety of a single dose of Δ9-THC in patients with chronic abdominal pain resulting from chronic pancreatitis (CP). Methods This was a randomized, single dose, double-blinded, placebo-controlled, two way crossover study in patients suffering from abdominal pain as result of CP (n = 24), post hoc subdivided into opioid and non-opioid users. Δ9-THC (8 mg) or active placebo (5 mg/10 mg diazepam) was administered orally in a double dummy design. Results No treatment effect was shown for delta VAS pain scores after Δ9-THC compared with diazepam. Δ9-THC was well absorbed with a mean tmax of 123 min. No significant differences were found between Δ9-THC vs. Diazepam for alertness, mood, calmness or balance. Feeling anxious and heart rate were significantly increased after Δ9-THC compared with diazepam. The most frequently reported adverse events (AEs) after Δ9-THC administration were somnolence, dry mouth, dizziness and euphoric mood. Conclusions A single dose of Δ9-THC was not efficacious in reducing chronic pain resulting from CP, but was well tolerated with only mild or moderate AEs. The PK results in CP patients showed delayed absorption and an increased variability compared with healthy volunteers.

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A preliminary evaluation of the relationship of cannabinoid blood concentrations with the analgesic response to vaporized cannabis

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Journal Journal of pain research
Year 2016
Links Pubmed DOI PubMed Central

This article is included in 1 Broad synthesis Broad syntheses (1 reference) 2 Systematic reviews Systematic reviews (2 references)

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A randomized, placebo-controlled crossover trial utilizing vaporized cannabis containing placebo and 6.7% and 2.9% delta-9-tetrahydrocannabinol (THC) was performed in 42 subjects with central neuropathic pain related to spinal cord injury and disease. Subjects received two administrations of the study medication in a 4-hour interval. Blood samples for pharmacokinetic evaluation were collected, and pain assessment tests were performed immediately after the second administration and 3 hours later. Pharmacokinetic data, although limited, were consistent with literature reports, namely dose-dependent increase in systemic exposure followed by rapid disappearance of THC. Dose-dependent improvement in pain score was evident across all pain scale elements. Using mixed model regression, an evaluation of the relationship between plasma concentrations of selected cannabinoids and percent change in items from the Neuropathic Pain Scale was conducted. Changes in the concentration of THC and its nonpsychotropic metabolite, 11-nor-9-carboxy-THC, were related to percent change from baseline of several descriptors (eg, itching, burning, and deep pain). However, given the large number of multiple comparisons, false-discovery-rate-adjusted P-values were not significant. Plans for future work are outlined to explore the relationship of plasma concentrations with the analgesic response to different cannabinoids. Such an appraisal of descriptors might contribute to the identification of distinct pathophysiologic mechanisms and, ultimately, the development of mechanism-based treatment approaches for neuropathic pain, a condition that remains difficult to treat.

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Efficacy of inhaled cannabis on painful diabetic neuropathy.

Journal The journal of pain : official journal of the American Pain Society
Year 2015
Links Pubmed DOI PubMed Central

This article is included in 14 Systematic reviews Systematic reviews (14 references) 3 Broad syntheses Broad syntheses (3 references)

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A randomized, double-blinded, placebo controlled crossover study was conducted in 16 patients with painful diabetic peripheral neuropathy to assess the short-term efficacy and tolerability of inhaled cannabis. In a crossover design, each participant was exposed to 4 single dosing sessions of placebo or to low (1% tetrahydrocannabinol [THC]), medium (4% THC), or high (7% THC) doses of cannabis. Baseline spontaneous pain, evoked pain, and cognitive testing were performed. Subjects were then administered aerosolized cannabis or placebo and the pain intensity and subjective “highness” score was measured at 5, 15, 30, 45, and 60 minutes and then every 30 minutes for an additional 3 hours. Cognitive testing was performed at 5 and 30 minutes and then every 30 minutes for an additional 3 hours. The primary analysis compared differences in spontaneous pain over time between doses using linear mixed effects models. There was a significant difference in spontaneous pain scores between doses (<i>P</i> &lt; .001). Specific significant comparisons were placebo versus low, medium, and high doses (<i>P</i> = .031, .04, and &lt;.001, respectively) and high versus low and medium doses (both <i>P</i> &lt; .001). There was a significant effect of the high dose on foam brush and von Frey evoked pain (both <i>P</i> &lt; .001). There was a significant negative effect (impaired performance) of the high dose on 2 of the 3 neuropsychological tests (Paced Auditory Serial Addition Test, Trail Making Test Part B. PERSPECTIVE: This small, short-term, placebo-controlled trial of inhaled cannabis demonstrated a dose-dependent reduction in diabetic peripheral neuropathy pain in patients with treatment-refractory pain. This adds preliminary evidence to support further research on the efficacy of the cannabinoids in neuropathic pain. (PsycInfo Database Record (c) 2022 APA, all rights reserved)

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A double‐blind, randomized, placebo‐controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment.

Journal European journal of pain (London, England)
Year 2014
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This article is included in 23 Systematic reviews Systematic reviews (23 references) 1 Broad synthesis Broad syntheses (1 reference)

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BACKGROUND: Peripheral neuropathic pain (PNP) associated with allodynia poses a significant clinical challenge. The efficacy of Δ⁹‐tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray, a novel cannabinoid formulation, was investigated in this 15‐week randomized, double‐blind, placebo‐controlled parallel group study. METHODS: In total, 303 patients with PNP associated with allodynia were screened; 128 were randomized to THC/CBD spray and 118 to placebo, in addition to their current analgesic therapy. The co‐primary efficacy endpoints were the 30% responder rate in PNP 0–10 numerical rating scale (NRS) score and the mean change from baseline to the end of treatment in this score. Various key secondary measures of pain and functioning were also investigated. RESULTS: At the 30% responder level, there were statistically significant treatment differences in favour of THC/CBD spray in the full analysis (intention‐to‐treat) dataset [<i>p</i> = 0.034; 95% confidence interval (CI): 1.05–3.70]. There was also a reduction in mean PNP 0–10 NRS scores in both treatment groups that was numerically higher in the THC/CBD spray group, but which failed to reach statistical significance. Secondary measures of sleep quality 0–10 NRS score (<i>p</i> = 0.0072) and Subject Global Impression of Change (SGIC) (p = 0.023) also demonstrated statistically significant treatment differences in favour of THC/CBD spray treatment. CONCLUSIONS: These findings demonstrate that, in a meaningful proportion of otherwise treatment‐resistant patients, clinically important improvements in pain, sleep quality and SGIC of the severity of their condition are obtained with THC/CBD spray. THC/CBD spray was well tolerated and no new safety concerns were identified. (PsycInfo Database Record (c) 2022 APA, all rights reserved)

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A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain

Journal Journal of pain and symptom management
Year 2014
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This article is included in 26 Systematic reviews Systematic reviews (26 references) 1 Broad synthesis Broad syntheses (1 reference)

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Context. Neuropathic pain caused by chemotherapy limits dosing and duration of potentially life-saving anti-cancer treatment and impairs quality of life. Chemotherapeutic neuropathy responds poorly to conventional treatments, and there is an urgent medical need for new treatments. Recent preclinical studies demonstrate that cannabinoid agonists suppress established chemotherapy-evoked neuropathy. Objectives. This was a pilot trial to begin to investigate a currently available cannabinoid agent, nabiximols (oral mucosal spray containing cannabinoids), in the treatment of chemotherapy-induced neuropathic pain. Methods. A randomized, placebo-controlled crossover pilot study was done in 16 patients with established chemotherapy-induced neuropathic pain. A 0-10 point numeric rating scale for pain intensity (NRS-PI) was used as the primary outcome measure. Results. When examining the whole group, there was no statistically significant difference between the treatment and the placebo groups on the NRS-PI. A responder analysis demonstrated that there were five participants who reported a two-point or greater reduction in pain that trended toward statistical significance and the number needed to treat was five. Conclusion. Chemotherapy-induced neuropathic pain is particularly resistant to currently available treatments. This pilot trial found a number needed to treat of five and an average decrease of 2.6 on an 11-point NRS-PI in five "responders" (as compared with a decrease of 0.6 with placebo) and supports that it is worthwhile to study nabiximols in a full randomized, placebo-controlled trial of chemotherapy-induced neuropathic pain. © 2014 U.S. Cancer Pain Relief Committee.

Primary study

Unclassified

Low-dose vaporized cannabis significantly improves neuropathic pain.

Journal The journal of pain : official journal of the American Pain Society
Year 2013
Links Pubmed DOI PubMed Central

This article is included in 23 Systematic reviews Systematic reviews (23 references) 2 Broad syntheses Broad syntheses (2 references)

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We conducted a double-blind, placebo-controlled, crossover study evaluating the analgesic efficacy of vaporized cannabis in subjects, the majority of whom were experiencing neuropathic pain despite traditional treatment. Thirty-nine patients with central and peripheral neuropathic pain underwent a standardized procedure for inhaling medium-dose (3.53%), low-dose (1.29%), or placebo cannabis with the primary outcome being visual analog scale pain intensity. Psychoactive side effects and neuropsychological performance were also evaluated. Mixed-effects regression models demonstrated an analgesic response to vaporized cannabis. There was no significant difference between the 2 active dose groups' results (<i>P</i> &gt; .7). The number needed to treat (NNT) to achieve 30% pain reduction was 3.2 for placebo versus low-dose, 2.9 for placebo versus medium-dose, and 25 for medium- versus low-dose. As these NNTs are comparable to those of traditional neuropathic pain medications, cannabis has analgesic efficacy with the low dose being as effective a pain reliever as the medium dose. Psychoactive effects were minimal and well tolerated, and neuropsychological effects were of limited duration and readily reversible within 1 to 2 hours. Vaporized cannabis, even at low doses, may present an effective option for patients with treatment-resistant neuropathic pain. PERSPECTIVE: The analgesia obtained from a low dose of delta-9-tetrahydrocannabinol (1.29%) in patients, most of whom were experiencing neuropathic pain despite conventional treatments, is a clinically significant outcome. In general, the effect sizes on cognitive testing were consistent with this minimal dose. As a result, one might not anticipate a significant impact on daily functioning. (PsycInfo Database Record (c) 2022 APA, all rights reserved)