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BMC Neurology Jun 2023Many drugs are prescribed in relieving acute migraine attacks, we aim to compare metoclopramide with other antimigraine drugs. (Meta-Analysis)
Meta-Analysis
The efficacy and safety of metoclopramide in relieving acute migraine attacks compared with other anti-migraine drugs: a systematic review and network meta-analysis of randomized controlled trials.
BACKGROUND
Many drugs are prescribed in relieving acute migraine attacks, we aim to compare metoclopramide with other antimigraine drugs.
METHODS
We searched online databases like PubMed, Cochrane Library, Scopus, and Web of Science till June 2022 for RCTs that compared metoclopramide alone with placebo or active drugs. The main outcomes were the mean change in headache score and complete headache relief. The secondary outcomes were the rescue medications need, side effects, nausea and recurrence rate. We qualitatively reviewed the outcomes. Then, we performed the network meta-analyses (NMAs) when it was possible. which were done by the Frequentist method using the MetaInsight online software.
RESULTS
Sixteen studies were included with a total of 1934 patients: 826 received metoclopramide, 302 received placebo, and 806 received other active drugs. Metoclopramide was effective in reducing headache outcomes even for 24 h. The intravenous route was the most chosen route in the included studies and showed significant positive results regarding headache outcomes; however, the best route whether intramuscular, intravenous, or suppository was not compared in the previous studies. Also, both 10 and 20 mg doses of metoclopramide were effective in improving headache outcomes; however, there was no direct comparison between both doses and the 10 mg dose was the most frequently used dosage. In NMA of headache change after 30 min or 1 h, metoclopramide effect came after granisetron, ketorolac, chlorpromazine, and Dexketoprofen trometamol. Only granisetron's effect was significantly higher than metoclopramide's effect which was only significantly higher than placebo and sumatriptan. In headache-free symptoms, only prochlorperazine was non-significantly higher than metoclopramide which was higher than other medications and showed significantly higher effects only with placebo. In rescue medication, metoclopramide's effect was only non-significantly lower than prochlorperazine and chlorpromazine while its effect was higher than other drugs and showed higher significant effects only than placebo and valproate. In the recurrence rate, studies showed no significant difference between metoclopramide and other drugs. Metoclopramide significantly decreased nausea more than the placebo. Regarding side effects, metoclopramide showed a lower incidence of mild side effects than pethidine and chlorpromazine and showed a higher incidence of mild side effects than placebo, dexamethasone, and ketorolac. The reported extrapyramidal symptoms with metoclopramide were dystonia or akathisia.
CONCLUSION
A dose of 10 mg IV Metoclopramide was effective in relieving migraine attacks with minimal side effects. Compared to other active drugs, it only showed a lower significant effect compared with granisetron regarding headache change while it showed significantly higher effects only with placebo in both rescue medication needs and headache-free symptoms and valproate in only rescue medication need. Also, it significantly decreased headache scores more than placebo and sumatriptan. However, more studies are needed to support our results.
Topics: Humans; Metoclopramide; Sumatriptan; Network Meta-Analysis; Prochlorperazine; Chlorpromazine; Granisetron; Valproic Acid; Ketorolac; Randomized Controlled Trials as Topic; Migraine Disorders; Nausea; Headache
PubMed: 37291500
DOI: 10.1186/s12883-023-03259-7 -
Journal of Applied Toxicology : JAT Apr 2023In this review, we summarized the current literature on the impact of phenothiazine derivatives on autophagy in vitro. Phenothiazines are antipsychotic drugs used in the... (Review)
Review
In this review, we summarized the current literature on the impact of phenothiazine derivatives on autophagy in vitro. Phenothiazines are antipsychotic drugs used in the treatment of schizophrenia, which is related to altered neurotransmission and dysregulation of neuronal autophagy. Thus, phenothiazine derivatives can impact autophagy. We identified 35 papers, where the use of the phenothiazines in the in vitro autophagy assays on normal and cancer cell lines, Caenorhabditis elegans, and zebrafish were discussed. Chlorpromazine, fluphenazine, mepazine, methotrimeprazine, perphenazine, prochlorperazine, promethazine, thioridazine, trifluoperazine, and novel derivatives can modulate autophagy. Stimulation of autophagy by phenothiazines may be either mammalian target of rapamycin (mTOR)-dependent or mTOR-independent. The final effect depends on the used concentration as well as the cell line. A further investigation of the mechanisms of autophagy regulation by phenothiazine derivatives is required to understand the biological actions and to increase the therapeutic potential of this class of drugs.
Topics: Animals; Antipsychotic Agents; Zebrafish; Promazine; Phenothiazines; Chlorpromazine; Mammals
PubMed: 36165981
DOI: 10.1002/jat.4397 -
Journal of Dental Anesthesia and Pain... Oct 2021Migraine headaches are the second leading cause of disability worldwide and are responsible for significant morbidity, reduction in the quality of life, and loss of... (Review)
Review
BACKGROUND
Migraine headaches are the second leading cause of disability worldwide and are responsible for significant morbidity, reduction in the quality of life, and loss of productivity on a global scale. The purpose of this systematic review and meta-analysis was to evaluate the efficacy of ketamine on migraines and other primary headache disorders compared to placebo and other active interventions, such as midazolam, metoclopramide/diphenhydramine, and prochlorperazine/diphenhydramine.
METHODS
An electronic search of databases published up to February 2021, including Medline via PubMed, EMBASE, Web of Science, and Cochrane Library, a hand search of the bibliographies of the included studies, as well as literature and systematic reviews found through the search was conducted to identify randomized controlled trials (RCTs) investigating ketamine in the treatment of migraine/headache disorders compared to the placebo. The authors assessed the risk of bias according to the Cochrane Handbook guidelines.
RESULTS
The initial search strategy yielded 398 unduplicated references, which were independently assessed by three review authors. After evaluation, this number was reduced to five RCTs (two unclear risk of bias and three high risk of bias). The total number of patients in all the studies was 193. Due to the high risk of bias, small sample size, heterogeneity of the outcomes reported, and heterogeneity of the comparison groups, the quality of the evidence was very low. One RCT reported that intranasal ketamine was superior to intranasal midazolam in improving the aura attack severity, but not duration, while another reported that intranasal ketamine was not superior to metoclopramide and diphenhydramine in reducing the headache severity. In one trial, subcutaneous ketamine was superior to saline in migraine severity reduction; however, intravenous (I.V.) ketamine was inferior to I.V. prochlorperazine and diphenhydramine in another study.
CONCLUSION
Further double-blind controlled studies are needed to assess the efficacy of ketamine in treating acute and chronic refractory migraines and other primary headaches using intranasal and subcutaneous routes. These studies should include a long-term follow-up and different ketamine dosages in diagnosed patients following international standards for diagnosing headache/migraine.
PubMed: 34703891
DOI: 10.17245/jdapm.2021.21.5.413 -
Therapeutic Advances in... 2021Antipsychotic agents (APS) are widely used drugs to treat psychotic symptoms and can effectively reduce both positive and negative symptoms of schizophrenia. For...
BACKGROUND
Antipsychotic agents (APS) are widely used drugs to treat psychotic symptoms and can effectively reduce both positive and negative symptoms of schizophrenia. For decades, some studies suggested that there is a relationship between using APS and the risk of venous thromboembolism (VTE) and pulmonary embolism (PE). However, results remain inconclusive.
METHOD
This review has been registered in International Prospective Register of Systematic Reviews (PROSPERO, ID: CDR42020155620). Relevant studies were identified among observational studies published up to 1 October 2019 in the databases MEDLINE, EMBASE, and Cochrane Library. Random or fixed-effects models were used to calculate the pooled odds ratio (OR).
RESULTS
In total, 28 observational studies were included. The results showed that compared with non-users, current APS users have significantly increased risks of VTE [OR 1.55 95% confidence interval (CI) 1.36, 1.76] and PE (OR 3.68, 95% CI 1.23, 11.05). Subgroup analyses suggested that new users were associated with a higher risk of VTE (OR 2.06, 95% CI 1.81, 2.35). For individual drugs, increased risk of VTE and PE was observed in taking haloperidol, risperidone, olanzapine, prochlorperazine but not in chlorpromazine, quetiapine or aripiprazole. However, careful interpretation is needed because of high heterogeneity among studies and scarce data.
CONCLUSION
The present comprehensive meta-analysis further indicates a significantly increased risk of VTE and PE in current APS users compared with non-users. Subgroup analyses suggest that new users are more likely to develop VTE. However, due to significant heterogeneity among studies, conclusions should be considered with caution.
PubMed: 33505665
DOI: 10.1177/2045125320982720 -
Headache May 2019The aim of this review was to evaluate the efficacy and safety of prochlorperazine (PCP) in patients with acute migraine headache in the emergency department (ED). (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The aim of this review was to evaluate the efficacy and safety of prochlorperazine (PCP) in patients with acute migraine headache in the emergency department (ED).
METHODS
Electronic databases (Medline, Scopus, Web of Science, and Cochrane) were searched for randomized clinical trials that investigated the effect of PCP on headache relief. The outcomes were the number of patients without headache or with reduced headache severity, the number of adverse events, and the need for rescue analgesia.
RESULTS
From 450 citations, 11 studies (n = 771) with 15 comparison arms met the inclusion criteria. Overall, PCP was more effective than placebo (OR = 7.23; 95% CI = 3.82-3.68), metoclopramide (OR = 2.89; 95% CI = 1.42-5.86), and other active comparators (OR = 3.70; 95% CI = 2.41-5.67) for headache relief. The odds ratio of experiencing adverse events with PCP compared with placebo was 5.79 (95% CI = 2.43-13.79). When PCP compared with other active comparators, no statistical difference was found regarding the overall number of adverse events (OR = 1.88; 95% CI = 0.99-3.59). However, PCP significantly increased the odds of akathisia/dystonia (OR = 2.55; 95% CI = 1.03-6.31). The request for rescue analgesia was significantly lower in the PCP group compared with other groups (16% vs 84%; OR = 0.16; 95% CI = 0.09-27).
CONCLUSIONS
For adult patients with acute migraine, PCP could effectively abort the acute attack and reduce the request for rescue analgesia in the ED. However, compared with placebo, PCP could increase the risk of adverse events.
Topics: Acute Disease; Akathisia, Drug-Induced; Dopamine Antagonists; Drug Therapy, Combination; Emergency Service, Hospital; Humans; Hypotension, Orthostatic; Migraine Disorders; Prochlorperazine; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 30990883
DOI: 10.1111/head.13527 -
Sao Paulo Medical Journal = Revista... 2018The therapeutic effects of cannabinoid compounds have been the center of many investigations. This study provides a synthesis on all Cochrane systematic reviews (SRs)...
BACKGROUND
The therapeutic effects of cannabinoid compounds have been the center of many investigations. This study provides a synthesis on all Cochrane systematic reviews (SRs) that assessed the use of cannabinoids as a therapeutic approach.
DESIGN AND SETTING
Review of SRs, conducted in the Discipline of Evidence-Based Medicine, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP).
METHODS
A broad search was conducted in the Cochrane Database of Systematic Reviews to retrieve any Cochrane SRs that assessed the efficacy and safety of cannabinoids as a therapeutic approach. The results and key characteristics of all reviews included were summarized and discussed.
RESULTS
Eight SRs were included. They assessed the use of cannabinoids for the following types of conditions: neurological (two SRs), psychiatric (two SRs), rheumatological (one SR), infectious (one SR) and oncological (two SRs). There was moderate-quality evidence showing that the use of cannabinoids reduced nausea and vomiting among adults, compared with placebo. Additionally, there was moderate-quality evidence showing that there was no difference between cannabinoids and prochlorperazine regarding the number of participants who reported vomiting, in this same population.
CONCLUSIONS
This review identified eight Cochrane systematic reviews that provided evidence of unknown to moderate quality regarding the use of cannabinoids as a therapeutic intervention. Further studies are still imperative for solid conclusions to be reached regarding practical recommendations.
Topics: Cannabinoids; Dementia; Epilepsy; Evidence-Based Medicine; Fibromyalgia; HIV Infections; Humans; Nausea; Schizophrenia; Systematic Reviews as Topic; Tourette Syndrome; Vomiting
PubMed: 30365598
DOI: 10.1590/1516-3180.2018.0313210818 -
Phytotherapy Research : PTR Apr 2018Nausea and vomiting are common and distressing adverse events of chemotherapy. This review focuses on the findings and quality of systematic reviews (SRs) of... (Review)
Review
Nausea and vomiting are common and distressing adverse events of chemotherapy. This review focuses on the findings and quality of systematic reviews (SRs) of cannabinoids for chemotherapy-induced nausea and vomiting (CINV). Review of SRs, a systematic literature search, was conducted in several electronic databases and included SRs evaluating cannabinoids for CINV in cancer patients. Methodological quality and quality of reporting were evaluated by AMSTAR and PRISMA, respectively. Initial search retrieved 2,206 records, and 5 SRs were included. On the basis of findings of the sole SR judged as high methodological quality, cannabinoids seem to be more effective than placebo, equal to prochlorperazine for reducing CINV, and to be preferred by patients. The response to different combinations of antiemetic agents seems to be equal to 1 antiemetic alone. The average of AMSTAR score was 5, and the average of PRISMA score was 13.2. Cannabinoids represent a valuable option for treating CINV, despite the adverse events related to treatment, such as drowsiness and cognitive impairment. There is no good quality evidence to recommend or not the use of cannabinoids for CINV. More studies are still needed to evaluate the effectiveness of cannabinoids when compared with modern antiemetics.
Topics: Antiemetics; Antineoplastic Agents; Cannabinoids; Humans; Nausea; Neoplasms; Vomiting
PubMed: 29168289
DOI: 10.1002/ptr.5975 -
Drug Safety Jun 2016Prochlorperazine is recommended for adults with breakthrough or refractory chemotherapy-induced nausea and vomiting (CINV). The objective of this review was to describe... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Prochlorperazine is recommended for adults with breakthrough or refractory chemotherapy-induced nausea and vomiting (CINV). The objective of this review was to describe its safety in children when given for any indication to help define its role for CINV control in children.
METHODS
Electronic searches of MEDLINE, EMBASE, PsycINFO, and the Cochrane Central Register of Controlled Trials were performed as of 9 March 2015. All studies in English reporting adverse effects (AEs) associated with prochlorperazine in children (≤18 years) were included. AEs were synthesized for prospective studies.
RESULTS
Forty-nine (15 prospective) studies evaluating the use of prochlorperazine in 758 children were included. The most commonly reported AEs in prospective studies of prochlorperazine in children were sedation (multiple-dose studies: 10 %, 95 % CI 5-21) and extrapyramidal symptoms (EPS) (single-dose studies: 9 %, 95 % CI 3-29; multiple-dose studies: 4 %, 95 % CI 1-11). Serious AEs (seizure, neuroleptic malignant syndrome, autonomic collapse, tardive dyskinesia) were rarely associated with prochlorperazine use in children. Five fatalities were reported in children receiving prochlorperazine.
LIMITATIONS
The limitations of this systematic review and meta-analysis were that the AEs reported in the included studies were heterogeneous, the prospective use of systematic clinical tools to identify AEs was rare, and the risk of bias in most prospective studies was moderate.
CONCLUSIONS
The most common AEs reported with the pediatric use of prochlorperazine are EPS and sedation. Fatalities, life-threatening, and persistent AEs have also been reported.
Topics: Antiemetics; Antineoplastic Agents; Chemotherapy-Induced Febrile Neutropenia; Child; Child Health Services; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Nausea; Prochlorperazine; Risk Assessment; Vomiting
PubMed: 26884326
DOI: 10.1007/s40264-016-0398-9 -
Headache Jan 2016We sought to conduct a qualitative systematic review to evaluate the safety and efficacy of available treatments for pediatric patients with migraine or benign primary... (Review)
Review
OBJECTIVE
We sought to conduct a qualitative systematic review to evaluate the safety and efficacy of available treatments for pediatric patients with migraine or benign primary headache in the emergency department, in an effort to inform future practice.
METHODS
Scopus, Medline, and PubMed databases were searched for randomized controlled trials retrospective reviews, review articles, and case studies discussing migraine or benign primary headache management that were conducted in the emergency room or outpatient acute care setting in pediatric patients (less than 18-years old). Meeting abstracts and cited references within articles were also evaluated. Multiple variables were recorded, including type of treatment, study design, dosing, primary outcome, and side effects. Therapeutic gain was calculated in studies with a placebo arm. Treatments were subjectively assessed based on methodology and number of trials for a particular therapy.
RESULTS
Thirty-one studies were included in the final analysis. Of these, 17 were randomized controlled trials, 9 were retrospective reviews, and 5 were prospective chart review studies. One pertained to IV fluids, 2 to nonspecific analgesic use, 5 to dopamine receptor antagonists, 2 to valproic acid, 1 to propofol, 1 to magnesium, 1 to bupivicaine, 13 to triptan medications, and 3 to dihydroergotamine (DHE). Treatments considered effective for acute migraine or benign primary headache in the analgesic category include ibuprofen, and to a lesser degree acetaminophen. Ketorolac was not compared to other NSAIDs, but was found to be less effective than prochlorperazine. Of the phenothiazines, prochlorperazine was considered most effective. Of the triptan medications, almotriptan, rizatriptan, zolmitriptan nasal spray, sumatriptan nasal spray, and combination sumatriptan/naproxen are effective agents for acute treatment. Treatments considered probably effective included IV fluids, chlorpromazine, valproate sodium, injectable sumatriptan, and IV DHE. Treatments with oral zolmitriptan showed inconsistent results, while treatments considered ineffective included isolated oral sumatriptan and oral DHE. There is insufficient evidence to comment on propofol, magnesium, and bupivicaine efficacy.
CONCLUSIONS
Of the available evidence, ibuprofen, prochlorperazine, and certain triptan medications are the most effective and safe agents for acute management of migraine and other benign headache disorders in the pediatric population. Additional studies in this population are needed, and should take into consideration variables such as dosing, co-administered medications, treatment duration, and length of treatment effect.
Topics: Child; Child, Preschool; Emergency Service, Hospital; Humans; Migraine Disorders; Pediatrics; Treatment Outcome
PubMed: 26790849
DOI: 10.1111/head.12746 -
The Cochrane Database of Systematic... Nov 2015Cannabis has a long history of medicinal use. Cannabis-based medications (cannabinoids) are based on its active element, delta-9-tetrahydrocannabinol (THC), and have... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cannabis has a long history of medicinal use. Cannabis-based medications (cannabinoids) are based on its active element, delta-9-tetrahydrocannabinol (THC), and have been approved for medical purposes. Cannabinoids may be a useful therapeutic option for people with chemotherapy-induced nausea and vomiting that respond poorly to commonly used anti-emetic agents (anti-sickness drugs). However, unpleasant adverse effects may limit their widespread use.
OBJECTIVES
To evaluate the effectiveness and tolerability of cannabis-based medications for chemotherapy-induced nausea and vomiting in adults with cancer.
SEARCH METHODS
We identified studies by searching the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO and LILACS from inception to January 2015. We also searched reference lists of reviews and included studies. We did not restrict the search by language of publication.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that compared a cannabis-based medication with either placebo or with a conventional anti-emetic in adults receiving chemotherapy.
DATA COLLECTION AND ANALYSIS
At least two review authors independently conducted eligibility and risk of bias assessment, and extracted data. We grouped studies based on control groups for meta-analyses conducted using random effects. We expressed efficacy and tolerability outcomes as risk ratio (RR) with 95% confidence intervals (CI).
MAIN RESULTS
We included 23 RCTs. Most were of cross-over design, on adults undergoing a variety of chemotherapeutic regimens ranging from moderate to high emetic potential for a variety of cancers. The majority of the studies were at risk of bias due to either lack of allocation concealment or attrition. Trials were conducted between 1975 and 1991. No trials involved comparison with newer anti-emetic drugs such as ondansetron. Comparison with placebo People had more chance of reporting complete absence of vomiting (3 trials; 168 participants; RR 5.7; 95% CI 2.6 to 12.6; low quality evidence) and complete absence of nausea and vomiting (3 trials; 288 participants; RR 2.9; 95% CI 1.8 to 4.7; moderate quality evidence) when they received cannabinoids compared with placebo. The percentage of variability in effect estimates that was due to heterogeneity rather than chance was not important (I(2) = 0% in both analyses).People had more chance of withdrawing due to an adverse event (2 trials; 276 participants; RR 6.9; 95% CI 1.96 to 24; I(2) = 0%; very low quality evidence) and less chance of withdrawing due to lack of efficacy when they received cannabinoids, compared with placebo (1 trial; 228 participants; RR 0.05; 95% CI 0.0 to 0.89; low quality evidence). In addition, people had more chance of 'feeling high' when they received cannabinoids compared with placebo (3 trials; 137 participants; RR 31; 95% CI 6.4 to 152; I(2) = 0%).People reported a preference for cannabinoids rather than placebo (2 trials; 256 participants; RR 4.8; 95% CI 1.7 to 13; low quality evidence). Comparison with other anti-emetics There was no evidence of a difference between cannabinoids and prochlorperazine in the proportion of participants reporting no nausea (5 trials; 258 participants; RR 1.5; 95% CI 0.67 to 3.2; I(2) = 63%; low quality evidence), no vomiting (4 trials; 209 participants; RR 1.11; 95% CI 0.86 to 1.44; I(2) = 0%; moderate quality evidence), or complete absence of nausea and vomiting (4 trials; 414 participants; RR 2.0; 95% CI 0.74 to 5.4; I(2) = 60%; low quality evidence). Sensitivity analysis where the two parallel group trials were pooled after removal of the five cross-over trials showed no difference (RR 1.1; 95% CI 0.70 to 1.7) with no heterogeneity (I(2) = 0%).People had more chance of withdrawing due to an adverse event (5 trials; 664 participants; RR 3.9; 95% CI 1.3 to 12; I(2) = 17%; low quality evidence), due to lack of efficacy (1 trial; 42 participants; RR 3.5; 95% CI 1.4 to 8.9; very low quality evidence) and for any reason (1 trial; 42 participants; RR 3.5; 95% CI 1.4 to 8.9; low quality evidence) when they received cannabinoids compared with prochlorperazine.People had more chance of reporting dizziness (7 trials; 675 participants; RR 2.4; 95% CI 1.8 to 3.1; I(2) = 12%), dysphoria (3 trials; 192 participants; RR 7.2; 95% CI 1.3 to 39; I(2) = 0%), euphoria (2 trials; 280 participants; RR 18; 95% CI 2.4 to 133; I(2) = 0%), 'feeling high' (4 trials; 389 participants; RR 6.2; 95% CI 3.5 to 11; I(2) = 0%) and sedation (8 trials; 947 participants; RR 1.4; 95% CI 1.2 to 1.8; I(2) = 31%), with significantly more participants reporting the incidence of these adverse events with cannabinoids compared with prochlorperazine.People reported a preference for cannabinoids rather than prochlorperazine (7 trials; 695 participants; RR 3.3; 95% CI 2.2 to 4.8; I(2) = 51%; low quality evidence).In comparisons with metoclopramide, domperidone and chlorpromazine, there was weaker evidence, based on fewer trials and participants, for higher incidence of dizziness with cannabinoids.Two trials with 141 participants compared an anti-emetic drug alone with a cannabinoid added to the anti-emetic drug. There was no evidence of differences between groups; however, the majority of the analyses were based on one small trial with few events. Quality of the evidence The trials were generally at low to moderate risk of bias in terms of how they were designed and do not reflect current chemotherapy and anti-emetic treatment regimens. Furthermore, the quality of evidence arising from meta-analyses was graded as low for the majority of the outcomes analysed, indicating that we are not very confident in our ability to say how well the medications worked. Further research is likely to have an important impact on the results.
AUTHORS' CONCLUSIONS
Cannabis-based medications may be useful for treating refractory chemotherapy-induced nausea and vomiting. However, methodological limitations of the trials limit our conclusions and further research reflecting current chemotherapy regimens and newer anti-emetic drugs is likely to modify these conclusions.
Topics: Adult; Antiemetics; Antineoplastic Agents; Cannabinoids; Chlorpromazine; Dizziness; Domperidone; Euphoria; Humans; Metoclopramide; Nausea; Neoplasms; Prochlorperazine; Randomized Controlled Trials as Topic; Vomiting
PubMed: 26561338
DOI: 10.1002/14651858.CD009464.pub2