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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Gastrointestinal adverse effects of varenicline at maintenance dose: a meta-analysis

LK Leung, FM Patafio, and WW Rosser.

Review published: 2011.

CRD summary

The authors concluded that use of varenicline at maintenance dose of 1mg twice a day for longer than six weeks was associated with adverse gastrointestinal effects. Despite limited search terms and unnecessary exclusion of potentially relevant studies, the authors' conclusions are likely to be reliable.

Authors' objectives

To examine the relative risks of nausea, constipation and flatulence due to maintenance dose of varenicline (1mg twice a day for at least six weeks) in the context of smoking cessation.


PubMed (from 1947 to December 2010), EMBASE (from 1947 to December 2010) and EBM Reviews were searched without language restrictions. Limited search terms were reported. Reference lists of identified studies and relevant review articles were searched.

Study selection

Randomised double-blind placebo-controlled trials with comparable sample sizes and a satisfactory score from the Cochrane Risk of Bias assessment tool were eligible for inclusion. Trials with a duration of less than six weeks and those with fewer than 40 participants were excluded. Eligible studies used one week titrated dose (0.5mg) of varenicline prior to maintenance dose (1mg twice a day) reported at least one extractable adverse gastrointestinal event of nausea, constipation or flatulence.

All of the studies recruited participants from the general population, except one study that recruited the patients with chronic obstructive pulmonary disease (COPD). All trials except one recruited participants who used any types of tobacco.

Mean age of participants ranged from 38.7 to 57.2 years and 48.6% to 96.7% were male. Intervention duration ranged from six weeks to 52 weeks.

Two reviewers performed the study selection.

Assessment of study quality

Two reviewers extracted methodological details and assessed the quality of the studies using the six-item Cochrane Risk of Bias tool. The authors used this information to give each trial a quality score out of 6 points (1 was low risk and zero was high or unknown risk).

Data extraction

Outcomes data of nausea, constipation and flatulence were extracted from each study and used to calculate odd ratios (ORs) with corresponding 95% confidence intervals (CIs).

Two reviewers extracted data and resolved any disagreement by mutual consensus.

Methods of synthesis

A random-effects meta-analysis was undertaken to calculate pooled odd ratios and 95% confidence intervals. Number needed to harm (NNH) was calculated to give an idea of the likelihood of adverse effect. Statistical heterogeneity was assessed using the Cochrane Q-statistic and Ι² (Q<0.10 and Ι²>50% were considered evidence of heterogeneity). Publication bias was assessed with funnel plots.

Results of the review

Twelve RCTs were included in the review (5,114 participants, range 248 to 714). All studies achieved a score of at least 4 out of 6 for the Cochrane Risk of Bias assessment.

Meta-analysis of varenicline versus placebo showed a statistically significant increased risk of gastrointestinal adverse effects such as nausea (OR 4.45, 95% CI 3.79 to 5.23, Ι²=0.06%; 12 RCTs), constipation (OR 2.45, 95% CI 1.61 to 3.72, Ι²=34.09%; eight RCTs) and flatulence (OR 1.74, 95% CI 1.23 to 2.48, Ι²=0%; five RCTs) in the varenicline group compared to placebo. The number needed to harm was five for nausea, 24 for constipation and 35 for flatulence.

Authors' conclusions

Use of varenicline at maintenance dose of 1mg twice per day for longer than six weeks was significantly associated with adverse effects of nausea, constipation and flatulence.

CRD commentary

The review question and inclusion criteria were clear. Relevant databases were searched, but the authors did not appear to have made attempts to locate unpublished data. The authors used limited search terms which may have omitted potentially relevant studies. No language restrictions were applied, which reduced potential for language bias. Two authors were involved in study selection, data extraction and quality assessment, which minimised potential for error and bias. It was unclear why studies with a sample size less than 40 were excluded, but this would not necessarily alter the conclusions of the review. Inclusion of only full-length published trials risked publication bias.

Quality assessment using the Cochrane Risk of Bias tool indicated the generally good quality of the included trials. Trials were pooled by meta-analysis. Statistical heterogeneity was assessed and the authors acknowledged subjective outcome assessment as an issue that could have contributed to heterogeneity in the meta-analyses.

Although there were some limitations (limited search terms and unnecessary exclusion of potentially relevant studies), the authors' conclusions reflected the evidence presented and are likely to be reliable.

Implications of the review for practice and research

Practice: The authors stated that clinicians should inform patients of the risk of gastrointestinal adverse effects of varenicline such as nausea, constipation and flatulence during their maintenance therapy.

Research: The authors did not state any implications for further research.


Not stated.

Bibliographic details

Leung LK, Patafio FM, Rosser WW. Gastrointestinal adverse effects of varenicline at maintenance dose: a meta-analysis. BMC Clinical Pharmacology 2011; 11(15) [PMC free article: PMC3192741] [PubMed: 21955317]

Indexing Status

Subject indexing assigned by NLM


Benzazepines /administration & dosage /adverse effects; Double-Blind Method; Gastrointestinal Diseases /chemically induced; Humans; Maintenance Chemotherapy; Nicotinic Agonists /administration & dosage /adverse effects; Placebos; Quinoxalines /administration & dosage /adverse effects; Randomized Controlled Trials as Topic; Smoking /drug therapy; Smoking Cessation /methods



Database entry date


Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 21955317