Polyethylene glycol got a strong recommendation. So did three drugs that cost far more

The cheapest widely available treatment for chronic constipation carries the same strength of recommendation as the newest and most expensive ones. In the joint clinical practice guideline issued by the American Gastroenterological Association and the American College of Gastroenterology, polyethylene glycol sits in the strong-recommendation tier alongside sodium picosulfate, linaclotide, plecanatide and prucalopride [s1].

Fibre, lactulose, senna, magnesium oxide and lubiprostone received conditional recommendations [s1]. That is the whole distribution, and it is a useful thing for a reader to see laid out.

How the guideline was built

The two societies formed a multidisciplinary guideline panel that conducted systematic reviews of each agent: fibre; the osmotic laxatives polyethylene glycol, magnesium oxide and lactulose; the stimulant laxatives bisacodyl, sodium picosulfate and senna; the secretagogues lubiprostone, linaclotide and plecanatide; and the serotonin type 4 agonist prucalopride [s1].

The panel prioritised clinical questions and outcomes, used the GRADE framework to assess the certainty of evidence for each intervention, and applied an Evidence to Decision framework weighing desirable against undesirable effects, patient values, costs and health equity [s1]. Ten recommendations resulted [s1].

Cost being an explicit input into the framework matters here. A strong recommendation for polyethylene glycol is not merely a statement that it works; it is a statement that it works well enough, at a price and safety profile, to be recommended without reservation.

What the head-to-head evidence looks like

No head-to-head randomised trials of these drugs against each other exist, which is why a network meta-analysis was needed to rank them. One published in The Lancet Gastroenterology & Hepatology identified 33 eligible randomised controlled trials comprising 17,214 patients, all requiring at least four weeks of treatment [s2].

The rankings depended on the endpoint and the timepoint. Judged on failure to achieve three or more complete spontaneous bowel movements per week, the diphenyl methane stimulant laxatives bisacodyl and sodium picosulfate at 10 mg once daily ranked first at four weeks (relative risk 0.55, 95% CI 0.48 to 0.63, P-score 0.99), while prucalopride 2 mg once daily ranked first at 12 weeks (0.82, 0.78 to 0.86, P-score 0.96) [s2].

On the other endpoint — failure to achieve an increase of one or more complete spontaneous bowel movements per week from baseline — the diphenyl methane laxatives again ranked first at four weeks (0.44, 0.37 to 0.54, P-score 0.99), with prucalopride 4 mg once daily first at 12 weeks (0.74, 0.66 to 0.83, P-score 0.79), and linaclotide 290 μg once daily and prucalopride 2 mg once daily close behind at P-scores of 0.76 and 0.71 [s2].

The authors' own reading is more careful than the ranking implies. They note that patients with milder symptoms might have been included in the stimulant laxative trials, and that many of the prucalopride trials recruited patients who had previously failed laxatives — which is why they conclude prucalopride is likely to be the most efficacious for chronic idiopathic constipation despite the four-week ranking [s2]. Bisacodyl ranked last on safety, for both total adverse events and abdominal pain, with a P-score of 0.08 [s2].

Almost all drugs studied were superior to placebo on one endpoint or the other [s2]. And the authors flag the limit that matters most: because treatment duration in most trials was four to twelve weeks, the long-term relative efficacy of these drugs is unknown [s2].

The number that reframes everything above

Chronic constipation trials have a large placebo response, and knowing its size changes how the drug results read.

A meta-analysis of 23 placebo-controlled trials found the placebo response ranged from 4% to 44% depending on the endpoint used [s3]. Pooled, it was 13% (95% CI 11% to 16%) using the threshold of three or more complete spontaneous bowel movements per week, and 28% (95% CI 21% to 30%) using an increase of one or more per week compared with baseline [s3].

Higher baseline bowel movement frequency, older age, and trials with more male participants were all significantly associated with a stronger placebo response on both endpoints [s3]. Trial location — Europe against Asia and the United States — and drug class also produced differences [s3]. The placebo response was not significantly affected by number of study visits, study duration, year of publication, dropouts, or the likelihood of receiving active drug [s3].

That last list is the interesting one. Several of the things people assume drive placebo effects — more contact with researchers, longer trials, better odds of getting the real drug — did not [s3].

The honest summary

Nothing in this literature shows a newer agent decisively beating the cheap old options on the grounds a patient would care about. The guideline places polyethylene glycol in the same strong recommendation tier as three of the newest drugs [s1]. The network meta-analysis ranks stimulant laxatives first at four weeks and prucalopride first at twelve, on trials no longer than twelve weeks [s2]. And the pooled placebo response in this literature is 13% on one endpoint and 28% on the other [s3].

The guideline's own framing is that it provides a framework rather than an algorithm, and that clinicians should engage in shared decision-making based on patient preference as well as medication cost and availability [s1]. It also highlights limitations and gaps in the evidence explicitly, to guide future research [s1].

This article is informational and is not medical advice. Chronic constipation has serious differentials, and any new or changing bowel habit — particularly with bleeding, weight loss or pain — needs clinical assessment rather than a laxative bought on the strength of a guideline table.

Sources

• American Gastroenterological Association-American College of Gastroenterology Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation — Gastroenterology, 2023-05-19
• Efficacy of drugs in chronic idiopathic constipation: a systematic review and network meta-analysis — The Lancet Gastroenterology & Hepatology, 2019-08-29
• Placebo Response in Chronic Idiopathic Constipation: A Systematic Review and Meta-Analysis — American Journal of Gastroenterology, 2019-10-07