Cannabis sativa subsp. sativa’s pharmacological properties and health effects: A scoping review of current evidence

Introduction Hemp (Cannabis sativa subsp. sativa), commonly used for industrial purposes, is now being consumed by the public for various health promoting effects. As popularity of hemp research and claims of beneficial effects rises, a systematic collection of current scientific evidence on hemp’s health effects and pharmacological properties is needed to guide future research, clinical, and policy decision making. Objective To provide an overview and identify the present landscape of hemp research topics, trends, and gaps. Methods A systematic search and analysis strategy according to the preferred reporting items for systematic review and meta-analysis-ScR (PRISMA-ScR) checklist on electronic databases including MEDLINE, OVID (OVFT, APC Journal Club, EBM Reviews), Cochrane Library Central and Clinicaltrials.gov was conducted to include and analyse hemp research articles from 2009 to 2019. Results 65 primary articles (18 clinical, 47 pre-clinical) were reviewed. Several randomised controlled trials showed hempseed pills (in Traditional Chinese Medicine formulation MaZiRenWan) improving spontaneous bowel movement in functional constipation. There was also evidence suggesting benefits in cannabis dependence, epilepsy, and anxiety disorders. Pre-clinically, hemp derivatives showed potential anti-oxidative, anti-hypertensive, anti-inflammatory, anti-diabetic, anti-neuroinflammatory, anti-arthritic, anti-acne, and anti-microbial activities. Renal protective effects and estrogenic properties were also exhibited in vitro. Conclusion Current evidence on hemp-specific interventions are still preliminary, with limited high quality clinical evidence for any specific therapeutic indication. This is mainly due to the wide variation in test item formulation, as the multiple variants of this plant differ in their phytochemical and bioactive compounds. Future empirical research should focus on standardising the hemp plant for pharmaceutical use, and uniformity in experimental designs to strengthen the premise of using hemp in medicine.

Naldemedine for the treatment of opioid-induced constipation in adults with chronic noncancer pain

This review aims to summarize the efficacy data for naldemedine, a member of the novel peripherally acting μ-opioid receptor antagonists (PAMORAs), which gained US FDA approval for the treatment of opioid-induced constipation in adults with chronic noncancer pain-related syndromes in 2017. In Phase III trials, patients receiving naldemedine were significantly more likely to meet the primary end point ≥3 spontaneous bowel movements/week and an increase of ≥1 spontaneous bowel movement/week from baseline for at least 9/12 weeks compared to placebo (p < 0.0001). The most frequent adverse events were abdominal pain (8%) and diarrhea (7%). Based on available data, naldemedine appears to be an effective and safe first-line therapy for the treatment of opioid-induced constipation in adults with chronic noncancer pain.

Safety and efficacy of naldemedine in cancer patients with opioid-induced constipation: a pooled, subgroup analysis of two randomised controlled studies

ObjectiveThis post hoc, pooled, subgroup analysis of two randomised studies evaluated baseline characteristics that may influence the efficacy and safety of naldemedine in patients with opioid-induced constipation (OIC) and cancer.MethodsData for patients who received 0.2 mg naldemedine or placebo were pooled from randomised, placebo-controlled, phase IIb and phase III studies. Proportions of spontaneous bowel movement (SBM) responders and patients with diarrhoea were assessed for each treatment group. For the patient subgroups with or without possible blood–brain barrier (BBB) disruptions, changes in Numerical Rating Scale (NRS) and Clinical Opioid Withdrawal Scale (COWS) scores were assessed.ResultsA total of 307 patients were included in this analysis (naldemedine: n=155; placebo: n=152). The pooled proportion of SBM responders was 73.5% with naldemedine versus 35.5% with placebo. There was a significant increase in the proportion of SBM responders with naldemedine versus placebo (38.0% (95% CI 27.6% to 48.4%); p<0.0001). Greater proportions of SBM responders and patients who experienced diarrhoea were observed with naldemedine versus placebo in all subgroups. Changes from baseline in NRS and COWS scores were similar with naldemedine or placebo in patients with or without brain metastases.ConclusionsAlthough not powered to detect statistically significant differences in treatment effect among subgroups, this study demonstrated that naldemedine appeared to benefit patients with OIC and cancer, irrespective of baseline characteristics, and did not seem to affect analgesia or withdrawal–even in patients with potential BBB disruptions. Baseline characteristics did not appear to affect the incidence of diarrhoea in patients who received naldemedine.Trial registration numbersJapicCTI-111510 and JapicCTI-132340.

Naldemedine for opioid-induced constipation in patients receiving palliative care: A real-world registry study (Phase-R OIC Study).

11582 Background: Although naldemedine, a new peripherally-acting mu-opioid receptor antagonist, was approved for the management of opioid-induced constipation (OIC), its safety and effectiveness in real world clinical practice is unknown. Methods: We conducted a real world registry study in 14 hospital palliative care teams and inpatient palliative care units in Japan between April and December 2018. Consecutive cancer patients who received naldemedine for OIC were enrolled in a 7-day observational study. All treatment and assessment procedures were performed according to the accepted clinical practice. The primary outcome of the study was the proportion of patients who experienced spontaneous bowel movement within 24 hours after the initial administration of naldemedine. Adverse events, which indicated a possible or stronger causal relationship with naldemedine treatment, were reported according to the Common Terminology Criteria for Adverse Events (CTCAE) ver 4.0. Results: Overall, 204 patients were enrolled in the study. The mean age of the patients was 63±14 years, and 103 (50.5%) were male. The most common primary cancer site was lung (23.5%), followed by gastrointestinal (13.7%), and urological organs (9.3%). The proportion of patients undergoing active cancer treatment was 59.9%. Oxycodone was the most frequently used regular opioid (n = 115, 56.4%), and the median oral morphine-equivalent daily dose of opioids was 30 mg (interquartile range: 20-60 mg). Magnesium oxide (64.2%) and Senna (17.2%) were used as concomitant laxatives. All patients received 0.2 mg of naldemedine orally once daily. Most patients (90.2%) completed the 7-day observation. In 146 patients, spontaneous bowel movement was observed within 24 hour after the first administration of naldemedine (71.6%, 95% confidence interval 65.4-77.8%). Nearly two-thirds of the patients experienced increased frequency of spontaneous bowel movement in the week after naldemedine administration. The most prevalent adverse events were diarrhea (CTCAE grade 1-2, 35 cases; grade 3, 1 case) and abdominal pain (CTCAE grade 1-2, 10 cases; grade 3, 1 case). No serious adverse events including gastrointestinal perforation were reported. Conclusions: Naldemedine for opioid-induced constipation is safe and effective in the real world oncology and palliative care settings. Clinical trial information: UMIN000031381.

Efficacy of Naldemedine for the Treatment of Opioid-Induced Constipation: A Meta-Analysis

Background & Aim: Opioid induced constipation (OIC) is the most common side effect of opioid therapy. It can lead to a decreased quality of life. Naldemedine is a peripherally acting μ-opioid receptor antagonist that has been recently studied in randomized controlled trials (RCTs) for the management of OIC. The aim of this study is to perform a meta-analysis of existing clinical trials to estimate the efficacy and safety of naldemedine in opioid-induced constipation.Methods: A systematic search of PubMed, CINAHL, Scopus, Cochrane database of systematic reviews, and ClinicalTrials.gov registry was performed in March 2018. Two independent reviewers systematically identified prospective RCTs published in the English language that compared the effect of oral naldemedine versus placebo in adults with OIC. Meta-analysis was performed using a random effects model to assess the primary outcome: spontaneous bowel movement (SBM) responder rates. Assessed secondary outcomes were: a change in SBM frequency per week from baseline during the treatment period, change from baseline in the frequency of complete SBM and incidence of treatment-emergent adverse events. Review Manager 5.3 software program was utilized for statistical analysis.Results: Six RCTs met the inclusion criteria. A total of 2,762 patients were included in the meta-analysis. The proportion of SBM responders was significantly higher in the naldemedine group compared to the placebo group (56.4%, vs. 34.7%, p<0.00001). There was no statistically significant difference in treatment-emergent adverse events between naldemedine group and placebo group (mean odds ratio=1.18, p = 0.25, 95% CI: 0.89-1.55). Change in SBM frequency was higher in the naldemedine group versus placebo group (p<0.00001), as well as the change in complete SBM frequency.Conclusions: Naldemedine 0.2 mg daily significantly improved symptoms in patients with opioid-induced constipation and was generally well tolerated. These results support the use of naldemedine for the treatment of opioid-induced constipation.

EFFICACY AND SAFETY OF INTESTINAL SECRETAGOGUES FOR CHRONIC CONSTIPATION: A SYSTEMATIC REVIEW AND META-ANALYSIS

ABSTRACT BACKGROUND: Intestinal secretagogues have been tested for the treatment of chronic constipation and constipation-predominant irritable bowel syndrome. The class-effect of these type of drugs has not been studied. OBJECTIVE: To determine the efficacy and safety of intestinal secretagogues for the treatment of chronic constipation and constipation-predominant irritable bowel syndrome. METHODS: A computer-based search of papers from 1966 to September 2017 was performed. Search strategy consisted of the following MESH terms: intestinal secretagogues OR linaclotide OR lubiprostone OR plecanatide OR tenapanor OR chloride channel AND chronic constipation OR irritable bowel syndrome. Data were extracted as intention-to-treat analyses. A random-effects model was used to give a more conservative estimate of the effect of individual therapies, allowing for any heterogeneity among studies. Outcome measures were described as Relative Risk of achieving an improvement in the symptom under consideration. RESULTS: Database Search yielded 520 bibliographic citations: 16 trials were included for analysis, which enrolled 7658 patients. Twelve trials assessed the efficacy of intestinal secretagogues for chronic constipation. These were better than placebo at achieving an increase in the number of complete spontaneous bowel movements per week [RR 1.87 (1.24-2.83)], at achieving three or more spontaneous bowel movements per week [RR 1.56 (1.31-1.85)] and at inducing spontaneous bowel movement after medication intake [RR 1.49 (1.07-2.06)]. Similar results were observed when assessing the efficacy of intestinal secretagogues on constipation-predominant irritable bowel syndrome based on the results of six trials. CONCLUSION: Intestinal secretagogues are useful and safe therapeutic alternatives for the treatment of constipation-related syndromes.

Home-Based Transcutaneous Neuromodulation Improved Constipation via Modulating Gastrointestinal Hormones and Bile Acids

This study aims to investigate the role of transcutaneous neuromodulation (TN) on the regulation of gastrointestinal hormones and bile acids in patients with functional constipation (FC). Twenty FC patients were treated with TN for four weeks. The effects of TN on symptoms were evaluated by questionnaires. Plasma levels of serotonin (5-HT), motilin, somatostatin, and vasoactive intestinal peptide (VIP) were measured by ELISA and 12 individual bile acids assayed by liquid chromatography tandem mass spectrometry. Results were as follows. (1) TN treatment increased the frequency of spontaneous bowel movement, improved the Bristol Stool Score, and reduced Patient Assessment of Constipation Symptom score and Patient Assessment of Constipation Quality of Life score. (2) FC patients showed decreased plasma levels of 5-HT, motilin, and VIP and an increased plasma level of somatostatin (P<0.05). Four-week TN treatment increased plasma levels of 5-HT and motilin and decreased the plasma level of somatostatin in the FC patients (P<0.05). (3) Taurocholic deoxycholate, taurocholic acid, and taurocholic lithocholic acid were increased in the FC patients (P<0.005) but reduced by TN treatment (P<0.05). This study has suggested that the therapy may improve the symptoms of FC by alleviating the disorders of gastrointestinal hormones and bile acids.

Plecanatide: a new guanylate cyclase agonist for the treatment of chronic idiopathic constipation

Chronic constipation affects millions of Americans, consumes significant healthcare resources, and significantly affects quality of life (QOL). Recently, several new treatment options have become available for the treatment of constipation, including intestinal secretagogues such as lubiprotone, and linaclotide, prokinetics such as prucalopride, and bile acid transporter antagonists. Plecanatide is the newest of the secretagogue class of compounds that has been approved by the US Food and Drug Administration for the treatment of adults with chronic idiopathic constipation (CIC) in the USA. It is a guanylate cyclase agonist, and a 16 amino acid synthetic peptide that is a structural analog of human uroguanylin. Two large randomized, double-blind, placebo-controlled studies assessed the efficacy and safety of plecanatide in CIC patients (Rome III). Both doses of plecanatide, 3 mg and 6 mg resulted in a significantly greater percentage of patients who were durable overall complete spontaneous bowel movement (CSBM) responders (primary endpoint) compared with those who received placebo (plecanatide 3 mg, 21.0%; plecanatide 6 mg, 19.5%; placebo, 10.2%; p < 0.001 for each drug dose versus placebo). Plecanatide treatment also significantly reduced the severity of other CIC symptoms (straining effort, stool consistency, bloating). Also, plecanatide-treated patients reported high levels of satisfaction and improved QOL and desire to continue treatment. The rate of treatment-emergent adverse events with plecanatide was low, including rates of diarrhea (5%). Plecanatide is a luminally acting secretagogue that is efficacious and safe for the treatment of CIC. This article provides an overview of plecanatide in the management of adults with CIC.