The effect of intravenous hyoscine butylbromide on slow progress in labor (BUSCLAB): A double-blind randomized placebo-controlled trial.

BACKGROUND: Prolonged labor is a common condition associated with maternal and perinatal complications. The standard treatment with oxytocin for augmentation of labor increases the risk of adverse outcomes. Hyoscine butylbromide is a spasmolytic drug with few side effects shown to shorten labor when used in a general population of laboring women. However, research on its effect on preventing prolonged labor is lacking. We aimed to assess the effect of hyoscine butylbromide on the duration of labor in nulliparous women showing early signs of slow labor. METHODS AND FINDINGS: In this double-blind randomized placebo-controlled trial, we included 249 nulliparous women at term with 1 fetus in cephalic presentation and spontaneous start of labor, showing early signs of prolonged labor by crossing the alert line of the World Health Organization (WHO) partograph. The trial was conducted at Oslo University Hospital in Norway from May 2019 to December 2021. One hundred and twenty-five participants were randomized to receive 1 ml hyoscine butylbromide (Buscopan) (20 mg/ml), while 124 received 1 ml sodium chloride intravenously. Randomization was computer-generated, with allocation concealment by opaque sequentially numbered sealed envelopes. The primary outcome was duration of labor from administration of the investigational medicinal product (IMP) to vaginal delivery, which was analyzed by Weibull regression to estimate the cause-specific hazard ratio (HR) of vaginal delivery between the 2 treatment groups, with associated 95% confidence interval (CI). A wide range of secondary maternal and perinatal outcomes were also evaluated. Time-to-event outcomes were analyzed by Weibull regression, whereas continuous and dichotomous outcomes were analyzed by median regression and logistic regression, respectively. All main analyses were based on the modified intention-to-treat (ITT) set of eligible women with signed informed consent receiving either of the 2 treatments. The follow-up period lasted during the postpartum hospital stay. All personnel, participants, and researchers were blinded to the treatment allocation. Median (mean) labor duration from IMP administration to vaginal delivery was 401 (440.8) min in the hyoscine butylbromide group versus 432.5 (453.6) min in the placebo group. We found no statistically significant association between IMP and duration of labor from IMP administration to vaginal delivery: cause-specific HR of 1.00 (95% CI [0.77, 1.29]; p = 0.993). Among 255 randomized women having received 1 dose of IMP, 169 women (66.3%) reported a mild adverse event: 75.2% in the hyoscine butylbromide group and 57.1% in the placebo group (Pearson's chi-square test: p = 0.002). More than half of eligible women were not included in the study because they did not wish to participate or were not included upon admission. The participants might have represented a selected group of women reducing the external validity of the study. CONCLUSIONS: One intravenous dose of 20 mg hyoscine butylbromide was not found to be superior to placebo in preventing slow labor progress in a population of first-time mothers at risk of prolonged labor. Further research is warranted to answer whether increased and/or repeated doses of hyoscine butylbromide might have an effect on duration of labor. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03961165) EudraCT (2018-002338-19).

Selective inhibition of overactive warmth-sensitive Ca2+-permeable TRPV3 channels by antispasmodic agent flopropione for alleviation of skin inflammation.

The temperature-sensitive Ca2+-permeable TRPV3 ion channel is robustly expressed in the skin keratinocytes, and its gain-of-function mutations are involved in the pathology of skin lesions. Here, we report the identification of an antispasmodic agent flopropione that alleviates skin inflammation by selective inhibition of TRPV3. In whole-cell patch clamp recordings, flopropione selectively inhibits macroscopic TRPV3 currents in a concentration-dependent manner with an IC50 value of 17.8 ± 3.5 µM. At the single-channel level, flopropione inhibits TRPV3 channel open probability without alteration of its unitary conductance. In an in vivo mouse model of skin inflammation induced by the skin sensitizer DNFB, flopropione also alleviates dorsal skin lesions and ear skin swelling. Further molecular docking combined with site-directed mutagenesis reveals that two residues E501 and I505 in the channel S2-helix are critical for flopropione-mediated inhibition of TRPV3. Taken together, our findings demonstrate that the spasmolytic drug flopropione as a selective inhibitor of TRPV3 channel not only provides a valuable tool molecule for understanding of TRPV3 channel pharmacology but also holds repurposing potential for therapy of skin disorders, such as dermatitis and pruritus.

Pharmacotherapy for gastric and intestinal cramping pain: current and emerging therapies.

INTRODUCTION: Acute gastrointestinal cramping pain (GICP) is a debilitating condition that affects many people worldwide, significantly reducing their quality of life. As such, prompt treatment is crucial. AREAS COVERED: This article will explore relevant literature from databases such as PubMed, Scopus, Google Scholar, Cochrane Library, and Web of Science. Additionally, we searched ClinicalTrials.gov and the WHO ICTRP database for the latest clinical trials. EXPERT OPINION: Consensus dictates that antispasmodics such as hyoscine-N-butyl bromide and mebeverine should be the primary treatment for GICP. If these prove ineffective, patients can switch to an antispasmodic with a different mode of action or add acetaminophen/NSAIDs for more severe cases. Currently, several antispasmodics are undergoing clinical trials, including drotaverine, alverine, pinaverium, otilonium bromide, fenoverine, tiropramide, otilonium bromide, trimebutine, and peppermint oil. Well-designed head-to-head studies are necessary to evaluate current antispasmodics' safety, efficacy, pharmacokinetic, and pharmacoeconomics profiles. Recent studies have shown that fixed-dose combinations of antispasmodics + NSAIDs or two different antispasmodics can improve patient compliance and synergistically reduce GICP. Therefore, it is recommended that the global availability and accessibility of these products be enhanced.

Ethnopharmacological basis and pharmacodynamics prospectives for folkloric claims of Rosa webbiana wall. Ex. Royle in diarrhea and asthma via In vitro, In vivo and In silico techniques.

ETHNOPHARMACOLOGICAL RELEVANCE: Rosa webbiana (Family: Rosaceae) is used by South Asian herbalists to treat gastrointestinal and respiratory disorders. AIM OF THE STUDY: This research aimed at multiple targets to verify R. webbiana for treating diarrhea and asthma. In vitro, in vivo, and in silico experiments were planned to demonstrate the antispasmodic and bronchodilator potential of R. webbiana. MATERIALS AND METHODS: The bioactive compounds of R. webbiana were identified and quantified through LC ESI-MS/MS and HPLC. These compounds were predicted for muti-mechanisms of bronchodilator and antispasmodic potential in network pharmacology and molecular docking. In vitro methods (isolated rabbit trachea, bladder, and jejunum tissues) confirmed these multi-mechanisms for antispasmodic and bronchodilator effects. Antiperistalsis, antidiarrheal, and antisecretory experiments were conducted in in-vivo experiments. RESULTS: The phytochemical analysis indicates the presence of rutin (742.91 µg/g), kaempferol (726.32 µg/g), and quercitrin (688.20 µg/g) in Rw. EtOH. These bioactive compounds in network pharmacology interfere with the pathogenic genes of diarrhea and asthma, which are the members of calcium-mediated signaling pathways and showed the stronger binding affinity towards voltage-gated L-type calcium channels, myosin light chain-kinase, Calcium calmodulin-dependent-kinase, Phosphodiesterase-4, and phosphoinositide phospholipase-C in molecular docking. Rw. EtOH elicited a spasmolytic response in isolated jejunum, trachea, and urine preparations by relaxing K+ (80 mM) and CCh (1 µM) spastic contractions. Additionally, it suppressed calcium concentration-response curves to the right, like verapamil. Like dicyclomine, it caused a rightward parallel shift of the CCh curves, followed by a non-parallel shift at higher concentrations with suppression of the maximal response. Like papaverine, it also caused isoprenaline-induced inhibitory CRCs to shift to the left. Verapamil did not potentiate isoprenaline-induced inhibitory CRCs, although it was more efficacious against K+ (80 mM) than CCh (1 µM)-induced contractions. R. webbiana EtOH extract exhibited complete antiperistalsis (21.55%), antidiarrheal (80.33%), and antisecretory (82.59±0.60) activities in vivo experiments at the dose of 300 mg/kg. CONCLUSION: Thus, Rw. EtOH modulated multiple pathways, produced calcium antagonistic, anticholinergic, and phosphodiesterase inhibitory actions, and had antidiarrheal and bronchodilator effects.

Investigations of plausible pharmacodynamics supporting the antispasmodic, bronchodilator, and antidiarrheal activities of Berberis lycium Royle. Via in silico, in vitro, and in vivo studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Berberis lycium Royle, a member of the Berberidaceae family, is a high-value medicinal plant with a documented history of usage in traditional medicine and has demonstrated significant therapeutic results among local populations throughout the globe. It is used traditionally in many parts of Pakistan to treat diarrhea, abdominal spasms, coughs, and chest problems. AIM OF THE STUDY: To investigate the antispasmodic, bronchodilator, and antidiarrheal effects of B. lycium and its possible underlying mechanisms through in silico, in vitro, and in vivo studies. MATERIALS AND METHODS: LC ESI-MS/MS analysis was used to identify bioactive components within the hydromethanolic extract of B. lycium. In silico studies, including network pharmacology and molecular docking, were utilized to investigate the antispasmodic and bronchodilator properties of the extract's bioactive components. In vitro pharmacological studies were conducted using isolated rabbit jejunum, trachea, urinary bladder, and rat ileum preparations. In vivo antidiarrheal activities were conducted in mice, including castor oil-induced diarrhea, intestinal transit, and castor oil-induced enteropooling. RESULTS: The LC ESI-MS/MS analysis of the hydromethanolic extract of B. lycium identified 38 bioactive compounds. Network pharmacology study demonstrated that the mechanism of BLR for the treatment of diarrhea might involve IL1B, TLR4, PIK3R1, TNF, PTPRC, IL2, PIK3CD, and ABCB1, whereas, for respiratory ailments, it may involve PIK3CG, TRPV1, STAT3, ICAM1, ACE, PTGER2, PTGS2, TNF, MMP9, NOS2, IL2, CCR5, HRH1, and VDR. Molecular docking research revealed that chlorogenic acid, epigallocatechin, isorhamnetin, quinic acid, gallic acid, camptothecin, formononetin-7-O-glucoside, velutin, caffeic acid, and (S)-luteanine exhibited a higher docking score than dicyclomine with validated proteins of smooth muscle contractions such as CACB2_HUMAN, ACM3_HUMAN, MYLK_HUMAN, and PLCG1_HUMAN. In vitro investigations demonstrated that Blr.Cr, Blr.EtOAc, and Blr.Aq relaxed spontaneously contracting jejunum preparations; carbachol (1 µM)-induced and K+ (80 mM)-induced jejunum, trachea, and urinary bladder contractions in a concentration-dependent manner, similar to dicyclomine. Moreover, Blr.Cr, Blr.EtOAc, and Blr.Aq exhibited a rightward shift in Ca+2 and carbachol cumulative response curves, similar to dicyclomine, demonstrating the coexistence of antimuscarinic and Ca+2 antagonistic mechanisms due to the presence of alkaloids and flavonoids. In vivo antidiarrheal activities showed that the hydromethanolic extract was significantly effective against castor oil-induced diarrhea and castor oil-induced enteropooling, similar to loperamide, and charcoal meal intestinal transit, similar to atropine, in mice at doses of 50, 100, and 200 mg/kg body weight, which supports its traditional use in diarrhea. CONCLUSION: The dual blocking mechanism of muscarinic receptors and Ca+2 channels behind the smooth muscle relaxing activity reveals the therapeutic relevance of B. lycium in diarrhea, abdominal spasms, coughs, and chest problems.

Hyoscine butylbromide mode of action on bowel motility: From pharmacology to clinical practice.

BACKGROUND: Hyoscine butylbromide (HBB) has been available for use as an antispasmodic since 1951 and is indicated for the treatment of abdominal pain associated with cramps. A previous review in 2007 summarized the evidence on the mode of action of HBB in vitro and in vivo in both animal and human studies. However, since then, novel publications have appeared within the literature and also our knowledge of what represents normal motility in humans has evolved. PURPOSE: This review is the result of the collaboration between a basic scientist and clinicians with the aim of providing an updated overview of the mechanisms of action of HBB and its clinical efficacy to guide not only use in clinical practice, but also future research.

[The effectiveness of a probiotic containing Bifidobacterium longum BB-46 and Enterococcus faecium ENCfa-68 in the treatment of post-infectious irritable bowel syndrome. Prospective randomized comparative study].

BACKGROUND: In the treatment of post-infectious irritable bowel syndrome (PI-IBS), the leading role belongs to the normalization of the composition of the intestinal microbiome, the disturbances of which are associated with previous intestinal infections. AIM: To study the effectiveness of the drug Bifiform in the treatment of PI-IBS. MATERIALS AND METHODS: An open, prospective, comparative, randomized study included 62 patients with PI-IBS. The diagnosis was confirmed by the results of clinical, laboratory and endoscopic examination of the intestine and met the diagnostic criteria for IBS of the Rome Consensus IV. The patients were randomized into 2 groups depending on the therapy. The patients of the main group received an antispasmodic drug (mebeverin 200 mg 2 times a day or trimebutin 200 mg 3 times a day for 4 weeks), an antibiotic (rifaximin 400 mg 3 times a day or nifuroxazide 400 mg 2 once a day for 1 week), a drug that normalizes the consistency of feces (dioctahedral smectite or macrogol 4000) and Bifiform 2 capsules 2 times a day for 2 weeks. For patients of control group similar therapy was performed without the Bifiform. Evaluation of the effectiveness of treatment was carried out at the end of the course of therapy and 6 months after its termination. RESULTS: All included patients with PI-IBS had abdominal pain, flatulence and tenderness to palpation along the bowel, most of them had diarrhea. Disorders of the intestinal microbiota were detected in 77.4% of patients, while excessive bacterial growth in the small intestine occurred in 72.6%, disorders of the colon microbiocenosis with the presence of opportunistic bacteria in 62.9% of patients. A significant part of the patients had a combination of small and large intestinal dysbiosis. Histological examination of the colon mucosa showed signs of low degree of inflammation activity in all patients. The moderate increase in the level of fecal calprotectin was found in 62.2% of patients with colonic dysbiosis. The majority of patients in the main group showed a pronounced positive dynamics of clinical manifestations of the disease, restoration of the normal composition of the intestinal microbiota and normalization of the content of fecal calprotectin at the end of the course therapy. The good result was observed much more often in the main group at the end of the course of treatment and 6 months after its termination. CONCLUSION: The inclusion of Bifiform in the complex therapy of PI-IBS significantly increases its effectiveness both in arresting the clinical manifestations of the disease, and in restoring the normal composition of the intestinal microbiome and reducing the inflammatory process in the intestinal mucosa. In the majority of patients receiving Bifiform, the remission of the disease achieved at the end of the course of treatment and persisted even 6 months after its termination.

Thymol has anticancer effects in U-87 human malignant glioblastoma cells.

BACKGROUND: Thymol (2-isopropyl-5-methylphenol) is a colorless crystalline derivative of cymene, that possesses pleotropic pharmacological properties, including analgesic, antibacterial, antispasmodic, and anti-inflammatory activities. Thymol has also been recognized for its beneficial effect as an anti-tumor agent, but the precise mechanism for this has not been fully elucidated. We aimed to identifying whether thymol exerts anti-cancer activity in human U-87 malignant glioblastoma (GB) cells (U-87). METHODS AND RESULTS: Cell viability and apoptosis was evaluated in U-87 cells treated with thymol at different concentrations. Reactive oxygen species (ROS) production, mRNA expressions of apoptosis-related genes and cell cycle characteristics were assessed. The cytotoxic activity of the co-exposure of thymol and temozolomide (TMZ) was also evaluated. The half-maximal inhibitory concentration (IC50) of thymol in the U-87 cells was 230 µM assessed at 24 h after exposure. Thymol did not exhibit any cytotoxic effects on normal L929 cells at this concentration. Thymol treatment increased the expression of Bax and p53, and also increased apoptotic cell death, and excessive generation of ROS. Moreover, the cytotoxic activity of thymol on the U-87 cells may be related to the arrest of the cell cycle at the G0/G1 interface. Combination therapy showed that the cytotoxic effects of thymol synergized with TMZ, and combined treatment had more cytotoxic potential compared to either of the agents alone. CONCLUSIONS: Our data indicate the potential cytotoxic activities of thymol on U-87 cells. Further studies are required to evaluate the spectrum of the antitumor activity of thymol on GB cells.

AGA Clinical Practice Guideline on the Pharmacological Management of Irritable Bowel Syndrome With Constipation.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction associated with significant disease burden. This American Gastroenterological Association guideline is intended to support practitioners in decisions about the use of medications for the pharmacological management of IBS-C and is an update of a prior technical review and guideline. METHODS: The Grading of Recommendations Assessment, Development and Evaluation framework was used to assess evidence and make recommendations. The technical review panel prioritized clinical questions and outcomes according to their importance for clinicians and patients and conducted an evidence review of the following agents: tenapanor, plecanatide, linaclotide, tegaserod, lubiprostone, polyethylene glycol laxatives, tricyclic antidepressants, selective serotonin reuptake inhibitors, and antispasmodics. The Guideline Panel reviewed the evidence and used the Evidence-to-Decision Framework to develop recommendations. CONCLUSIONS: The panel agreed on 9 recommendations for the management of patients with IBS-C. The panel made a strong recommendation for linaclotide (high certainty) and conditional recommendations for tenapanor, plecanatide, tegaserod, and lubiprostone (moderate certainty), polyethylene glycol laxatives, tricyclic antidepressants, and antispasmodics (low certainty). The panel made a conditional recommendation against the use of selective serotonin reuptake inhibitors (low certainty).

Antisecretory and Spasmolytic Activities of Aqueous and Ethanolic Stem Bark Extracts of Nauclea diderrichii in Wistar Rats.

Background: Diarrheal diseases are a major cause of morbidity and mortality throughout the world and particularly in developing countries. Nauclea diderrichii is a plant used in traditional medicine in the treatment of anemia, fever, gastric ulcer, malaria, abdominal pain, skin infections, and diarrhea. The present work is aimed at evaluating the antisecretory and spasmolytic activities of aqueous and ethanolic stem bark extracts of Nauclea diderrichii in Wistar rats. Methods: The effect of aqueous and ethanolic extracts of Nauclea diderrichii was tested at doses of 100, 200, and 300 mg/kg on castor oil-induced secretory diarrhea, misoprostol-induced fluid accumulation, and the effect of pretreatment with yohimbine and glibenclamide. They were also tested on normal motility and castor oil- and carbachol-induced hypermotility. Results: The results showed that the aqueous and ethanolic extracts of Nauclea diderrichii significantly (p < 0.001) inhibited castor oil-induced secretory diarrhea at all the doses. Both extracts significantly (p < 0.001) inhibit fluid accumulation induced by misoprostol. The pretreatment with glibenclamide reduced the antidiarrheal activity of aqueous extract of Nauclea diderrichii. The pretreatment with yohimbine did not alter the effect of the aqueous extract of Nauclea diderrichii. On intestine transit as on castor oil- and carbachol-induced motility, the aqueous and ethanolic extracts at doses of 100 and 200 mg/kg reduced significantly (p < 0.05, p < 0.01, and p < 0.001) the travelled distance by charcoal and peristaltic index. Conclusions: The study demonstrated that the aqueous and ethanolic extracts of Nauclea diderrichii possess antisecretory and antispasmolytic properties hence its use in traditional medicine against diarrhea.

Pain in irritable bowel syndrome: Does anything really help?

Pain relief remains a significant challenge in the management of irritable bowel syndrome (IBS): "Does anything really help relieve the pain in patients with IBS?". Interventions aimed at pain relief in patients with IBS include diet, probiotics or antibiotics, antidepressants, antispasmodics, and drugs targeting specific gastrointestinal receptors such as opioid or histamine receptors. In the systematic review and meta-analysis published in this journal, Lambarth et al. examined the literature on the role of oral and parenteral anti-neuropathic agents in the management of pain in patients with IBS. This review article appraises their assessment of the efficacy of the anti-neuropathic agents amitriptyline, pregabalin, gabapentin, and duloxetine in the relief of abdominal pain or discomfort, and impact on overall IBS severity and quality of life. This commentary provides an update of current evidence on the efficacy of the dietary and pharmacological treatments that are available or in development, as well psychological and cognitive behavioral therapy for pain in IBS. Advances in recent years augur well for efficacious treatments that may expand the therapeutic arsenal for pain in IBS.

A Mini Review on Characteristics and Analytical Methods of Otilonium Bromide.

Irritable bowel syndrome (IBS) is a world-wide disease prevalently in Western nations. It influences about 15% of the western populace, with a negative effect on the quality of life and furthermore on medical services costs. Anticholinergic antispasmodics are first line of treatment for discomfort or abdominal pain, particularly if unrelieved after alleviation of stoppage or antidiarrheal treatment. Otilonium bromide (OTB) is quaternary ammonium compound with action on distal GI tract as antispasmodic. It is utilized in the treatment of patients influenced by Irritable inside disorder (IBS) because of its particular pharmacokinetic and pharmacodynamic properties. OTB is poorly absorbed systematically was viable in contrast with different medications used for same purpose, for example, pinaverium bromide and mebeverine, with a good tolerability profile. The effects are long lasting, even after stopping the dosage regime for reduction of abdominal pain. In this review, an overview of mechanism of action, pharmacologic action, synthesis and particularly various analytical and bioanalytical methods are discussed. The analytical methods discussed are spectrophotometry including Near Infrared Spectroscopy (NIRS), chromatography and capillary electrophoresis methods are described with the range, limit of detection and quantification. The paper also provides details of scope of further extension of analytical methods. It was found that most of the analytical methods involves usage of toxic solvents e.g., methanol, acetonitrile, chloroform etc. posing risk to the analyst as well as environment.

Efficacy of phloroglucinol in shortening the first stage of labor: systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Protracted labor is associated with an elevated risk of maternal and fetal complications. Results of randomized controlled trials on the efficacy in labor of phloroglucinol (PHL), a pure antispasmodic drug, are uncertain. OBJECTIVES: To evaluate whether PHL is effective in shortening the first stage of labor. SEARCH STRATEGY: MEDLINE, EMBASE, LILACS, Scopus, ClinicalTrials.gov, and the Cochrane Library were searched from inception to July 2020. SELECTION CRITERIA: Randomized controlled trials (RCTs) concerning women with a singleton vertex pregnancy at term who were treated with PHL. DATA COLLECTION AND ANALYSIS: Relevant data were extracted and tabulated. Review Manager 5.3 was used for data analysis. Primary outcome evaluated was the mean reduction of the first stage of labor. MAIN RESULTS: Five RCTs, including 487 pregnant women, were analyzed. The first stage of labor duration was significantly shorter in the treatment arm compared to the control group [MD-113.21 min (95% CI-119.63,-106.79)]. A significant shortening of the second stage was achieved in the PHL group [MD-11.12 min (95% CI-12.64,-9.75)] while no differences were reported for the third stage. CONCLUSIONS: PHL might represent an effective treatment to shorten the duration of the first and second stage of labor. SYNOPSIS: A meta-analysis of 5 trials found that Phloroglucinol favorably impacts on the total duration of the labor in primiparae and multiparae women with a singleton pregnancy.

A trial-based economic evaluation of peppermint oil for the treatment of irritable bowel syndrome.

BACKGROUND: Irritable Bowel Syndrome (IBS) is a prevalent, chronic gastrointestinal disorder that imposes a substantial socioeconomic burden. Peppermint oil is a frequently used treatment for IBS, but evidence about cost-effectiveness is lacking. OBJECTIVE: We aimed to assess cost-effectiveness of small-intestinal release peppermint oil versus placebo in IBS patients. METHODS: In a multicenter randomized placebo-controlled trial, cost-effectiveness was evaluated from a societal perspective. The incremental cost-effectiveness ratios (ICERs) were expressed as (1) incremental costs per Quality Adjusted Life Years (QALY), and (2) incremental costs per successfully treated patient, that is per abdominal pain responder (according to FDA definitions), both after an eight-week treatment period with placebo versus peppermint oil. Cost-utility and uncertainty were estimated using non-parametric bootstrapping. Sensitivity analyses were performed. RESULTS: The analysis comprised 126 patients (N = 64 placebo, N = 62 small-intestinal release peppermint oil). Peppermint oil was a dominant treatment compared to placebo in 46% of bootstrap replications. Peppermint oil was also more effective but at higher cost in 31% of replications. The net-benefit acceptability curve showed that peppermint oil has a 56% probability of being cost-effective at a conservative willingness-to-pay threshold of €10.000/QALY. Peppermint oil was also a dominant treatment per additional successfully treated patient according to FDA definitions, that is in 51% of replications. In this case, the acceptability curve showed an 89% probability of being cost-effective. CONCLUSIONS: In patients with IBS, small-intestinal release peppermint oil appears to be a cost-effective treatment although there is uncertainty surrounding the ICER. When using abdominal pain responder as outcome measure for the ICER, peppermint oil has a high probability of being cost-effective. The use of peppermint oil, which is a low-cost treatment, can be justified by the modest QALY gains and slightly higher proportion of abdominal pain responders. More research and long-term data are necessary to confirm the cost-effectiveness of peppermint oil. NCT02716285.

Cannabinoid Activity-Is There a Causal Connection to Spasmolysis in Clinical Studies?

Cannabinoid drugs are registered for postoperative nausea and emesis, Tourette syndrome and tumor-related anorexia, but are also used for spasticity and pain relief, among other conditions. Clinical studies for spasmolysis have been equivocal and even conclusions from meta-analyses were not consistent. This may be due to uncertainty in diagnostic criteria as well as a lack of direct spasmolytic activity (direct causality). In this review we used the Hill criteria to investigate whether a temporal association is causal or spurious. METHODS: A systematic literature search was performed to identify all clinical trials of cannabinoids for spasticity. Studies were evaluated for dose dependency and time association; all studies together were analyzed for reproducibility, coherence, analogy and mechanistic consistency. A Funnel plot was done for all studies to identify selection or publication bias. RESULTS: Twenty-seven studies were included in this meta-analysis. The spasmolytic activity (effect strength) was weak, with a nonsignificant small effect in most studies and a large effect only in a few studies ("enriched" studies, low patient numbers). No dose dependency was seen and plotting effect size vs. daily dose resulted in a slope of 0.004. Most studies titrated the cannabinoid to the optimum dose, e.g., 20 mg/d THC. The effect decreased with longer treatment duration (3-4 months). The spasmolytic effect is consistent for different European countries but not always within a country, nor is the effect specific for an etiology (multiple sclerosis, spinal cord injury, others). For other criteria like plausibility, coherence or analogous effects, no data exist to support or refute them. In most studies, adverse effects were frequently reported indicating a therapeutic effect only at high doses with relevant side effects. CONCLUSIONS: Current data do not support a specific spasmolytic effect; a general decrease in CNS activity analogous to benzodiazepines appears more likely. Whether individual patients or specific subgroups benefit from cannabinoids is unclear. Further studies should compare cannabinoids with other, nonspecific spasmolytic drugs like benzodiazepines.

Efficacy, acceptability, and safety of muscle relaxants for adults with non-specific low back pain: systematic review and meta-analysis.

OBJECTIVE: To investigate the efficacy, acceptability, and safety of muscle relaxants for low back pain. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: Medline, Embase, CINAHL, CENTRAL, ClinicalTrials.gov, clinicialtrialsregister.eu, and WHO ICTRP from inception to 23 February 2021. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised controlled trials of muscle relaxants compared with placebo, usual care, waiting list, or no treatment in adults (≥18 years) reporting non-specific low back pain. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently identified studies, extracted data, and assessed the risk of bias and certainty of the evidence using the Cochrane risk-of-bias tool and Grading of Recommendations, Assessment, Development and Evaluations, respectively. Random effects meta-analytical models through restricted maximum likelihood estimation were used to estimate pooled effects and corresponding 95% confidence intervals. Outcomes included pain intensity (measured on a 0-100 point scale), disability (0-100 point scale), acceptability (discontinuation of the drug for any reason during treatment), and safety (adverse events, serious adverse events, and number of participants who withdrew from the trial because of an adverse event). RESULTS: 49 trials were included in the review, of which 31, sampling 6505 participants, were quantitatively analysed. For acute low back pain, very low certainty evidence showed that at two weeks or less non-benzodiazepine antispasmodics were associated with a reduction in pain intensity compared with control (mean difference -7.7, 95% confidence interval-12.1 to-3.3) but not a reduction in disability (-3.3, -7.3 to 0.7). Low and very low certainty evidence showed that non-benzodiazepine antispasmodics might increase the risk of an adverse event (relative risk 1.6, 1.2 to 2.0) and might have little to no effect on acceptability (0.8, 0.6 to 1.1) compared with control for acute low back pain, respectively. The number of trials investigating other muscle relaxants and different durations of low back pain were small and the certainty of evidence was reduced because most trials were at high risk of bias. CONCLUSIONS: Considerable uncertainty exists about the clinical efficacy and safety of muscle relaxants. Very low and low certainty evidence shows that non-benzodiazepine antispasmodics might provide small but not clinically important reductions in pain intensity at or before two weeks and might increase the risk of an adverse event in acute low back pain, respectively. Large, high quality, placebo controlled trials are urgently needed to resolve uncertainty. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019126820 and Open Science Framework https://osf.io/mu2f5/.

Successful treatment of idiopathic Harlequin Syndrome with oxybutynin and propranolol.

Harlequin syndrome (HS) is a rare entity derived from the dysfunction of the sympathetic nervous system. It is characterised by unilateral facial flushing and sweating induced by exercise, heat and emotion. Most cases are primary with an unknown pathogenic mechanism. In these cases, the prognosis is favourable. Medical or surgical treatments are not usually required for idiopathic HS. However, symptomatic treatment may be indicated when symptoms affect the quality of life of patients. We present the case of a patient with idiopathic HS successfully treated with oxybutynin and propranolol. In this patient, a marked improvement in both hyperhidrosis and facial erythema was noted with this combined therapy. We consider it of interest to highlight the response of our patient to the treatment employed, which may be advantageous in future cases of this rare disorder.

Antispasmodics for Chronic Abdominal Pain: Analysis of North American Treatment Options.

Chronic abdominal pain is a common gastrointestinal (GI) symptom that characterizes many functional GI disorders/disorders of gut-brain interaction, including irritable bowel syndrome, functional dyspepsia, and centrally mediated abdominal pain syndrome. The symptoms of abdominal pain in these highly prevalent disorders are often treated with antispasmodic agents. Antispasmodic treatment includes a broad range of therapeutic classes with different mechanisms of action, including anticholinergic/antimuscarinic agents (inhibition of GI smooth muscle contraction), calcium channel inhibitors (inhibition of calcium transport into GI smooth muscle), and direct smooth muscle relaxants (inhibition of sodium and calcium transport). The aim of this review article was to examine the efficacy and safety of antispasmodics available in North America (e.g., alverine, dicyclomine, hyoscine, hyoscyamine, mebeverine, otilonium, pinaverium, and trimebutine) for the treatment of chronic abdominal pain in patients with common disorders of gut-brain interaction. For the agents examined, comparisons of studies are limited by inconsistencies in treatment dosing and duration, patient profiles, and diagnostic criteria employed. Furthermore, variability in study end points limits comparisons. Risk of selection, performance, detection, attrition, and reporting bias also differed among studies, and in many cases, risks were considered "unclear." The antispasmodics evaluated in this review, which differ in geographic availability, were found to vary dramatically in efficacy and safety. Given these caveats, each agent should be considered on an individual basis, rather than prescribed based on information across the broad class of agents.