Cannabinoids, cannabis, and cannabis-based medicines for pain management: an overview of systematic reviews

Cannabinoids, cannabis, and cannabis-based medicines (CBM) are increasingly used to manage pain, with limited understanding of their efficacy and safety. We assessed methodological quality, scope, and results of systematic reviews of randomised controlled trials of these treatments. Several search strategies sought self-declared systematic reviews. Methodological quality was assessed using both AMSTAR-2 and techniques important for bias reduction in pain studies. Of the 106 articles read, 57 were self-declared systematic reviews, most published since 2010. They included any type of cannabinoid, cannabis, or CBM, at any dose, however administered, in a broad range of pain conditions. No review examined the effects of a particular cannabinoid, at a particular dose, using a particular route of administration, for a particular pain condition, reporting a particular analgesic outcome. Confidence in the results in the systematic reviews using AMSTAR-2 definitions was critically low (41), low (8), moderate (6), or high (2). Few used criteria important for bias reduction in pain. Cochrane reviews typically provided higher confidence; all industry-conflicted reviews provided critically low confidence. Meta-analyses typically pooled widely disparate studies, and, where assessable, were subject to potential publication bias. Systematic reviews with positive or negative recommendation for use of cannabinoids, cannabis, or CBM in pain typically rated critically low or low (24/25 [96%] positive; 10/12 [83%] negative). Current reviews are mostly lacking in quality and cannot provide a basis for decision-making. A new high-quality systematic review of randomised controlled trials is needed to critically assess the clinical evidence for cannabinoids, cannabis, or CBM in pain

Multiple Components of the VHL Tumor Suppressor Complex Are Frequently Affected by DNA Copy Number Loss in Pheochromocytoma

Pheochromocytomas (PCC) are rare tumors that arise in chromaffin tissue of the adrenal gland. PCC are frequently inherited through predisposing mutations in genes such as the von Hippel-Lindau (VHL) tumor suppressor. VHL is part of the VHL elongin BC protein complex that also includes CUL2/5, TCEB1, TCEB2, and RBX1; in normoxic conditions this complex targets hypoxia-inducible factor 1 alpha (HIF1A) for degradation, thus preventing a hypoxic response. VHL inactivation by genetic mechanisms, such as mutation and loss of heterozygosity, inhibits HIF1A degradation, even in the presence of oxygen, and induces a pseudohypoxic response. However, the described <10% VHL mutation rate cannot account for the high frequency of hypoxic response observed. Indeed, little is known about genetic mechanisms disrupting other complex component genes. Here, we show that, in a panel of 171 PCC tumors, 59.6% harbored gene copy number loss (CNL) of at least one complex component. CNL significantly reduced gene expression and was associated with enrichment of gene targets controlled by HIF1. Interestingly, we show that VHL-related renal clear cell carcinoma harbored disruption of VHL alone. Our results indicate that VHL elongin BC protein complex components other than VHL could be important for PCC tumorigenesis and merit further investigation

Cannabinoids, cannabis and cannabis-based medicine for pain management: a systematic review of randomised controlled trials

ABSTRACT: Cannabinoids, cannabis, and cannabis-based medicines (CBMs) are increasingly used to manage pain, with limited understanding of their efficacy and safety. We summarised efficacy and adverse events (AEs) of these types of drugs for treating pain using randomised controlled trials: in people of any age, with any type of pain, and for any treatment duration. Primary outcomes were 30% and 50% reduction in pain intensity, and AEs. We assessed risk of bias of included studies, and the overall quality of evidence using GRADE. Studies of &lt;7 and &gt;7 days treatment duration were analysed separately. We included 36 studies (7217 participants) delivering cannabinoids (8 studies), cannabis (6 studies), and CBM (22 studies); all had high and/or uncertain risk of bias. Evidence of benefit was found for cannabis &lt;7 days (risk difference 0.33, 95% confidence interval 0.20-0.46; 2 trials, 231 patients, very low-quality evidence) and nabiximols &gt;7 days (risk difference 0.06, 95% confidence interval 0.01-0.12; 6 trials, 1484 patients, very low-quality evidence). No other beneficial effects were found for other types of cannabinoids, cannabis, or CBM in our primary analyses; 81% of subgroup analyses were negative. Cannabis, nabiximols, and delta-9-tetrahydrocannabinol had more AEs than control. Studies in this field have unclear or high risk of bias, and outcomes had GRADE rating of low- or very low-quality evidence. We have little confidence in the estimates of effect. The evidence neither supports nor refutes claims of efficacy and safety for cannabinoids, cannabis, or CBM in the management of pain.</p

The Effect of Gamma Irradiation on the Physiochemical Properties of Caesium-Selective Ammonium Phosphomolybdate–Polyacrylonitrile (AMP–PAN) Composites

Managing certain by-products of the nuclear fuel cycle, such as the radioactive isotopes of caesium: 134Cs, 135Cs and 137Cs is challenging due to their environmental mobility and radioactivity. While a great many materials can isolate Cs+ ions from neutral or basic aqueous solutions via ion exchange, few of these, with the exception of ammonium phosphomolybdate (AMP), function effectively in acidic media. The use of AMP, and its porous composite in polyacrylonitrile (PAN) for management of Cs radioisotopes in various nuclear wastes have been known for decades and are well studied, yet the effects of radiation on the physiochemical properties of such composites have only received limited attention to date. In a previous publication, we demonstrated that a 100 kGy gamma irradiation dose has negligible effect on the ion exchange performance of AMP and AMP−PAN with respect to capacity or kinetics under the Cs+ concentrations and acidity found in spent nuclear fuel (SNF) recycling. As a continuation of this prior study, in this publication we explore the effects of gamma irradiation on the physiochemical properties of AMP and AMP−PAN using a range of characterisation methods. The effects of the same gamma dose on the oxidation state of Mo in AMP and AMP−PAN, the thermal degradation of both AMP and AMP−PAN, combined with a first study into the high-temperature degradation AMP, are reported. The implications of irradiation, its possible mechanism, the conditions present in SNF recycling, and for the end-of-life disposal or recycling of these materials are also discussed

Multiple Components of the VHL Tumor Suppressor Complex Are Frequently Affected by DNA Copy Number Loss in Pheochromocytoma

Pheochromocytomas (PCC) are rare tumors that arise in chromaffin tissue of the adrenal gland. PCC are frequently inherited through predisposing mutations in genes such as the von Hippel-Lindau (VHL) tumor suppressor. VHL is part of the VHL elongin BC protein complex that also includes CUL2/5, TCEB1, TCEB2, and RBX1; in normoxic conditions this complex targets hypoxia-inducible factor 1 alpha (HIF1A) for degradation, thus preventing a hypoxic response. VHL inactivation by genetic mechanisms, such as mutation and loss of heterozygosity, inhibits HIF1A degradation, even in the presence of oxygen, and induces a pseudohypoxic response. However, the described &lt;10% VHL mutation rate cannot account for the high frequency of hypoxic response observed. Indeed, little is known about genetic mechanisms disrupting other complex component genes. Here, we show that, in a panel of 171 PCC tumors, 59.6% harbored gene copy number loss (CNL) of at least one complex component. CNL significantly reduced gene expression and was associated with enrichment of gene targets controlled by HIF1. Interestingly, we show that VHL-related renal clear cell carcinoma harbored disruption of VHL alone. Our results indicate that VHL elongin BC protein complex components other than VHL could be important for PCC tumorigenesis and merit further investigation

The ACTTION-APS-AAPM Pain Taxonomy (AAAPT) Multidimensional Approach to Classifying Acute Pain Conditions.

Objective: With the increasing societal awareness of the prevalence and impact of acute pain, there is a need to develop an acute pain classification system that both reflects contemporary mechanistic insights and helps guide future research and treatment. Existing classifications of acute pain conditions are limiting, with a predominant focus on the sensory experience (e.g., pain intensity) and pharmacologic consumption. Consequently, there is a need to more broadly characterize and classify the multidimensional experience of acute pain. Setting: Consensus report following expert panel involving the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), American Pain Society (APS), and American Academy of Pain Medicine (AAPM). Methods: As a complement to a taxonomy recently developed for chronic pain, the ACTTION public-private partnership with the US Food and Drug Administration, the APS, and the AAPM convened a consensus meeting of experts to develop an acute pain taxonomy using prevailing evidence. Key issues pertaining to the distinct nature of acute pain are presented followed by the agreed-upon taxonomy. The ACTTION-APS-AAPM Acute Pain Taxonomy will include the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Future efforts will consist of working groups utilizing this taxonomy to develop diagnostic criteria for a comprehensive set of acute pain conditions. Perspective: The ACTTION-APS-AAPM Acute Pain Taxonomy (AAAPT) is a multidimensional acute pain classification system designed to classify acute pain along the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Conclusions: Significant numbers of patients still suffer from significant acute pain, despite the advent of modern multimodal analgesic strategies. Mismanaged acute pain has a broad societal impact as significant numbers of patients may progress to suffer from chronic pain. An acute pain taxonomy provides a much-needed standardization of clinical diagnostic criteria, which benefits clinical care, research, education, and public policy. For the purposes of the present taxonomy, acute pain is considered to last up to seven days, with prolongation to 30 days being common. The current understanding of acute pain mechanisms poorly differentiates between acute and chronic pain and is often insufficient to distinguish among many types of acute pain conditions. Given the usefulness of the AAPT multidimensional framework, the AAAPT undertook a similar approach to organizing various acute pain conditions