Literature Search

To identify articles relevant to each key question we searched MEDLINE, Embase, The Cochrane Library, and the International Pharmaceutical Abstracts; we used either Medical Subject Headings (MeSH or MH) as search terms when available or key words when appropriate. We combined terms for selected indications (chronic constipation, irritable bowel disorder), drug interactions, and adverse events with a list of seven specific constipation drugs (docusate calcium, docusate sodium, lactulose, lubiprostone, polyethylene glycol, psyllium, tegaserod) and their trade names. We limited the electronic searches to "human" and "English language"; we searched sources from 1985 to 2007 (April) to delimit literature relevant to the scope of our topic.

We used the National Library of Medicine publication type tags to identify reviews, randomized controlled trials (RCTs), and meta-analyses; we also manually searched reference lists of pertinent review articles and letters to the editor. All citations were imported into an electronic database (EndNote, version X). Additionally, we hand-searched the Center for Drug Evaluation and Research (CDER) database to identify unpublished research submitted to the FDA.

Further, the Center for Evidence-based Policy at the Oregon Health and Science University (OHSU) contacted pharmaceutical manufacturers and invited them to submit dossiers, including citations, using a protocol available at www.ohsu.edu/drugeffectiveness. We received dossiers from two pharmaceutical companies (Novartis and Takeda Pharmaceuticals).

Our searches found 434 citations, unduplicated across databases; we found an additional 89 articles from manually reviewing the reference lists of pertinent review articles and an additional 12 articles in the pharmaceutical dossiers. The total number of citations included in the database was 535. For further details on the search strategy, see Appendix A.

Study Selection

Two people independently reviewed each abstract; if both reviewers agreed that the study did not meet eligibility criteria, it was excluded. We obtained the full text of all remaining articles. Records were considered for exclusion if they did not meet pre-established eligibility criteria with respect to study design, patient population, interventions, outcomes, and comparisons to medications outside our scope of interest.

All controlled, prospective studies were eligible for inclusion, regardless of sample size or study duration. For adverse events we also included case series and retrospective studies. Eligibility criteria and outcomes of interest are presented in Table 5.

Table 5

Eligibility criteria.

Data Abstraction

We designed and used a structured data abstraction form to ensure consistency in appraisal for each study. Trained reviewers abstracted data from each study and assigned an initial quality rating. A senior reviewer read each abstracted article and evaluated the completeness of the data abstraction. We abstracted the following data from included trials: study design, eligibility criteria, intervention (drugs, dose, duration), additional medications allowed, methods of outcome assessment, population characteristics, sample size, loss to follow-up, withdrawals attributed to adverse events, results, and adverse events reported. We recorded intention-to-treat results if available.

Quality Assessment

We assessed the internal validity (quality) of trials based on predefined criteria (Appendix B) developed by the US Preventive Services Task Force (ratings: good-fair-poor)¹³ and the National Health Service Centre for Reviews and Dissemination.¹⁴ External validity (generalizability) was assessed¹⁵ and reported but did not influence quality ratings. We did not rate the quality of descriptive studies (case series).

Two independent reviewers assigned quality ratings; they resolved any disagreements by discussion and consensus or by consulting a third, independent party. Elements of internal validity assessment for RCTs included, among others, randomization and allocation concealment, similarity of compared groups at baseline, use of intention-to-treat analysis, and overall and differential loss to follow-up.

To assess the quality of observational studies, we used criteria outlined by Deeks et al.¹⁶ Items assessed included selection of cases or cohorts and controls, adjustment for confounders, methods of outcomes assessment, length of follow-up and statistical analysis.

Loss to follow-up was defined as the number of persons randomized who did not reach the endpoint of the study,¹⁷ independent of the reason and the use of intention-to-treat analysis. Appendix C describes our procedure for assessing quality in greater detail.

Trials that had a fatal flaw in one or more categories were rated poor quality; trials that met all criteria were rated good quality. Because of the lack of studies for this drug class we included poor quality studies in the synthesis of the evidence. For studies rated as poor, we provide the main reason for the poor rating in the in-text tables. Greater details about methodological shortcomings can be found in the evidence tables.

Data Synthesis

Throughout this report we synthesized the literature qualitatively. Because of the small number of studies and heterogeneous outcomes, no quantitative analyses were possible.

Rating the Strength of a Body of Evidence

We rated the strength of the available evidence in a three-part hierarchy based on an approach devised by the GRADE working group.¹⁸ Developed to grade the quality of evidence and the strength of recommendations, this approach incorporates four key elements: study design, study quality, consistency of results, and directness. Directness refers to the availability of data on outcomes or populations of interest. GRADE also considers the presence of imprecise or sparse data, high probability of publication bias, evidence of a dose gradient, and magnitude of the effect.

As shown in Table 6, we used three grades: high, moderate, and low (combining the GRADE category of very low with low).¹⁹ Grades reflect the strength of the body of evidence to answer key questions on the general and comparative efficacy and harms of drugs to treat chronic constipation or IBS-C; the critical element is the extent to which new evidence might alter the confidence we would have in our findings. Due to the lack of evidence and heterogeneous outcomes, we were unable to rate the strength of the evidence for individual outcomes; instead, we provided summary ratings on the general and the comparative efficacy and harms.

Table 6

Definitions of the grades of the overall strength of evidence.

This approach does not incorporate other factors that might be relevant to assess reliably the comparative efficacy, effectiveness, and harms such as funding sources and comparable dosing. We have assessed these additional factors and highlighted issues that could potentially bias our assessments (e.g., all studies funded by the same manufacturer).