Clinical Evidence for OTC Products for Constipation

This article was sponsored by Bayer, maker of MiraLAX (PEG 3350) and Phillips' laxatives.

Constipation is a widespread condition that affects an estimated 16% of all adults in the United States.¹ Chronic constipation is defined by the ROME IV criteria, and it is characterized by symptoms such as infrequent bowel movements, difficult passage of stool, straining, and the feeling of incomplete evacuation.^1,2 There is no formal definition for occasional constipation, although the symptoms of occasional and chronic constipation are common to both conditions. The differences between occasional constipation (an acute condition) and chronic constipation are the underlying cause and the length of time for which symptoms have existed.^1,2

The burden of constipation symptoms can substantially affect quality of life and cause the interruption of daily activities.³ Unresolved constipation can lead to various consequences, such as hemorrhoids, anal fissures, rectal prolapse, and fecal impaction.²

THERAPEUTIC CLASSES OF OTC OPTIONS AVAILABLE

There are many OTC products with different mechanisms of action and formulations available for the management of occasional constipation. Laxatives are a popular selection for the relief of occasional constipation; in fact, approximately 40% of Americans self-treat with OTC laxatives.⁴ It is important to increase awareness of effective and safe options available to those in the pharmacy to aid consumers in choosing among the available OTC products and provide pharmacists' evidence-based recommendations if requested.

Five OTC classes of treatment options commonly used to treat constipation include osmotic laxatives, saline laxatives, stimulant laxatives, bulk-forming (fiber) laxatives, and stool softeners.^2,4 Notably, there is variability in both the quality and quantity of evidence supporting the use of these various agents (Table).^2,5-14

As there may be mixed perceptions regarding the relative evidence supporting the different OTC options,⁴ pharmacists have an important opportunity to familiarize themselves with the levels of evidence supporting the use of each so that they can educate both patients and health care practitioners.

AN UPDATED SYSTEMATIC REVIEW: EVIDENCE SUPPORTING THE USE OF OTC PRODUCTS

A systematic review published in 2005 evaluated the efficacy and safety of treatment options available for the management of constipation based on data published between 1966 and 2004.⁵ The review provided evidence-based recommendations for the use of these agents; however, it identified a lack of robust supporting evidence for many agents.⁵

Polyethylene glycol (PEG) was the sole OTC preparation that received a strong recommendation based on high levels of evidence.⁵ PEG 3350, marketed in the United States under the brand name MiraLAX, is an osmotic laxative FDA approved for the treatment of occasional constipation.⁷ Within the 15 years since the initial review, additional high-quality trial data have been published for many of the agents.

An updated systematic review of efficacy and safety data generated in the 15 years since the initial analysis was published in the American Journal of Gastroenterology in March 2021.This analysis was designed to review the body and quality of evidence of all classes of OTC agents to provide up-to-date treatment recommendations.⁶

The analysis included 41 studies published between 2004 and 2020 that evaluated 8 classes of OTC products for constipation.⁶ Updated evidence-based recommendations were provided and graded from A (good evidence in support) to I (insufficient evidence) based on the level of evidence from I (good) to III (poor).⁶ Refer to the Table ­for a summary of the evidence-based recommendations.^2,6-14

Osmotic laxatives

The osmotic laxative, PEG, had the most robust clinical evidence supporting its efficacy and safety. PEG received a grade A recommendation for its use based on level I evidence that was evaluated from 9 trials, of which 3 were placebo controlled. PEG also demonstrated high levels of tolerance across the studies reviewed. Most adverse events (AEs) were mild to moderate in severity and included abdominal distention, diarrhea, loose stools, flatulence, and nausea.⁶

Stimulant laxatives

The only other OTC agent with a similar level of evidence and recommendation (see TABLE) was the stimulant laxative senna, based on the results from 2 short-term placebo-controlled trials.It should be noted that 1 of those trials used substantially higher doses of senna than normally used in clinical practice. Of the other stimulant laxatives assessed, bisacodyl received a grade B recommendation based on the results from 3 trials, 1 of which was placebo controlled.⁶

Based on the safety data, bisacodyl and sennosides are both associated with the potential for dose reduction and intolerance due to AEs. Common gastrointestinal-related AEs reported in clinical studies were diarrhea and abdominal pain, which are believed to be due to the mechanism of action of the stimulant class.⁶

Bulk-forming agents

Bulk-forming (fiber-containing) agents demonstrated more modest efficacy based on the findings from placebo-controlled and comparative studies. In 2 trials, the soluble fiber psyllium did not show a significant benefit compared with placebo, and head-to-head trials revealed that psyllium is less effective than several comparator agents, including PEG. This yielded psyllium a grade B recommendation based on level II evidence. Other fibers (polydextrose and inulin) showed inconsistent benefits over placebo, and no trials were identified that assessed the efficacy of methylcellulose for the treatment of constipation.⁶

Saline laxatives

There were no studies evaluating the efficacy of magnesium hydroxide that were published after 2004, which met the inclusion criteria for this review. A single trial demonstrated the superiority of magnesium oxide over placebo and noninferiority versus senna (level I evidence, Grade B recommendation). Magnesium-rich water preparations received a similar recommendation. However, the lack of standardized preparations and dosages evaluated in the studies were noted as limitations of the review.⁶

Stool softeners

Docusate is an OTC stool softening agent that is frequently used for relief of constipation; however, its efficacy has been questioned previously due to inconsistent clinical data. Despite docusate being one of the most used agents for constipation, no studies conducted after 2004 were identified for inclusion in this analysis. The authors concluded that there is insufficient evidence to make a recommendation to support its use.⁶

Overall, a substantial amount of higher-quality evidence is currently available to support the use of OTC products in the treatment of constipation; however, there remains considerable variability in clinical trial design and the clinical definitions of constipation and efficacy end points.⁶ Based on the findings of this review, the authors concluded that there was good evidence to recommend PEG and senna as first-line options for the treatment
of constipation.⁶

EFFICACY OF PEG 3350 USING MODERN CONSTIPATION END POINTS

Given the lack of evidence assessing the response to OTC laxative treatment using modern, standardized end points, a reanalysis of previously published data from a 6-month double-blind, placebo-controlled trial evaluating the efficacy of PEG 3350 was conducted using the FDA–recommended end point for chronic idiopathic constipation (CIC) treatment response.^15,16 This stringent end point is more relevant to today’s clinicians. It is generally recognized within the medical community that a laxative product that provides relief from chronic constipation will also be effective in occasional constipation. There is also the problem of feasibility in conducting research in subjects with occasional constipation. Thus, it is sensible to conduct trials in the CIC population and extrapolate the results to occasional constipation.

The reanalysis focused on the current FDA-recommended CIC responder end point, defined as at least 3 complete spontaneous bowel movements (CSBMs) per week and an increase of at least 1 CSBM from baseline during at least 9 of 12 treatment weeks, including 3 of the last 4 weeks of this period. Patients with CIC, as defined by modified ROME I criteria, who had fewer than 3 satisfactory bowel movements per week during the 14-day baseline observation period were randomized (2:1) to receive 17 g of PEG 3350 or placebo daily for 24 weeks. CSBMs and spontaneous bowel movements (SBM) responses were evaluated weekly throughout the study period.¹⁶

In the reanalysis, the weekly CSBM response rate defined by the FDA-recommended end point indicated a more than 3-fold increased likelihood of response to PEG 3350 compared with placebo (42% vs 13% CSBM response rate; P < .0001), which was durable over 6 months of treatment. Multiple additional analyses evaluating CSBMs and SBMs demonstrated substantial efficacy in patients with CIC, and responses were sustained throughout the 6-month study period.¹⁶

To assess the efficacy of PEG during its FDA-approved duration of use (7 days), CSBM and SBM data were also analyzed over the first week of treatment. After initiation of treatment, the number of CSBMs and SBMs increased rapidly in the PEG 3350 group. PEG 3350 increased the mean number of CSBMs from baseline by more than 2.5 times that observed with placebo (2.1 vs 0.8 CSBM increase; P < .0013).^16,17

The significant efficacy observed across multiple time intervals for multiple end points demonstrates the overall consistency in the clinical benefits of PEG 3350 for patients with constipation.¹⁶

ROLE OF THE PHARMACIST

As pharmacists are readily accessible health care professionals in community settings, they are a helpful resource to provide additional education for consumers with constipation symptoms, and they can support physicians with questions about treatment options for optimal management.⁴ Pharmacists can recognize common OTC, complementary, and prescription medications that may potentially cause or worsen constipation symptoms (eg, antipsychotics, diuretics, opioids, antihypertensives, iron supplements).^1,2

When educating on available OTC agents, pharmacists should highlight the body of evidence supporting the relative effectiveness among different options to support selection. PEG and senna are the only OTC laxatives with substantially favorable evidence to support their use in occasional constipation. However, only PEG is supported by robust short-term and long-term clinical evidence, including the evaluation of treatment response using stringent, standardized trial end points. Moderate evidence supports the use of psyllium, bisacodyl, and magnesium for the treatment of constipation. Docusate lacks well-controlled trials demonstrating its efficacy and thus has poor evidence to support its use in clinical practice.⁶

REFERENCES

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13. Phillips’ Caplets Laxative Dietary Supplement (facts). Bayer HealthCare, Consumer Care. Accessed May 7, 2021. https://www.phillipsdigestive.com/sites/g/files/vrxlpx15496/files/2021-03/phillips-caplets_0.pdf
14. Colace-docusate sodium capsule (drug facts). Avrio Health L.P.Updated November 2020. Accessed May 7, 2021. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=7793fced-e8ee-44e2-b212-dd2a59a5f462&type=display
15. Di Palma JA, Cleveland MV, McGowan J, Herrera JL. A randomized, multicenter comparison of polyethylene glycol laxative and tegaserod in treatment of patients with chronic constipation. Am J Gastroenterol. 2007;102(9):1964-1971. doi:10.1111/j.1572-0241.2007.01365.x
16. Menees SB, Lembo AJ, Chey WD. Six-month efficacy of polyethylene glycol (PEG) 3350 in the treatment of chronic idiopathic constipation: analysis using FDA endpoints. P1094 (S0457).Poster presented at: American College of Gastroenterology Annual Meeting; October 23-28, 2020; virtual. Accessed May 12, 2021. https://www.eventscribe.com/2020/ACG/fsPopup.asp?efp=RElCSUFHUk02NDI2%20&PosterID=298978%20&rnd=0.6476836&mode=posterinfo
17. Data on File. Bayer Consumer Health.