Concomitant Use of Prescription-Based Agents for Chronic Constipation: A Single-Center Retrospective Study

Authors: Tushar Khanna, MariaLisa Itzoe, Josh Mukherjee, Nitin K. Ahuja

Symptoms of chronic constipation (CC) characterize a variety of clinical diagnoses including chronic idiopathic constipation (CIC), irritable bowel syndrome with constipation (IBS-C), and others. Among these conditions, symptom etiology and severity can vary widely. When considered in aggregate, though, CC is a common ambulatory complaint that is often difficult to treat, associated with impaired quality of life and significant health-care utilization, particularly when over-the-counter measures prove ineffective.^1^

Over the past 2 decades, several medications have entered the market for CC management, usually with explicit approval for use in CIC, IBS-C, or both. Society-based guidelines offer disease-specific recommendations on the use of these medications but do not advise providers how to choose among them, nor how to proceed among the remaining options if the first-choice agent fails.^2^^,^^3^ Meta-analyses have attempted to rank these agents’ effectiveness by disease and symptom domain, while cost-effectiveness analyses have attempted to establish priority based on patient and payor perspectives.4, 5, 6 Despite these efforts, data are limited on real-world prescribing patterns for the pharmacologic treatment of refractory CC.

In this retrospective study, we aimed to analyze outpatient prescription patterns for CC treatment within a single high-volume, tertiary-care center. Our particular interest was in the concomitant use of multiple prescription agents, an anecdotally common strategy in subspecialty care rarely discussed in the published literature to date. We also selectively queried the use of older drugs with off-label effects on bowel function for the treatment of refractory CC.^7^^,^^8^

Patients met inclusion criteria if they carried at least one of 13 constipation diagnosis codes (see Supplementary Material) and were seen in office by one of six neurogastroenterology providers between January 1 and December 31, 2023. We performed individual chart review to query the use of 6 prescription-based therapies for IBS-C and/or CIC (linaclotide, lubiprostone, plecanatide, prucalopride, tenapanor, and tegaserod) as well as 2 off-label treatments for refractory constipation (pyridostigmine and colchicine). Office notes were reviewed to confirm therapeutic intention to manage CC with one or more of these agents. We also collected data on patient demographics, medication initiation and discontinuation dates, and prescriber identity.

A total of 405 patients met the inclusion criteria (median age 54 [range 19–94], 78% female), of whom 138 (34%) received at least one prescription-based medication for CC (median age 52 [range 19–87], 81% female). Of these, 110 patients (79.7%) were treated with a single agent at a time, 23 (16.6%) received two concomitant prescription therapies, 4 (2.9%) received 3 simultaneous medications, and 1 (0.7%) was treated simultaneously with 4 prescription agents. (Figure). CIC was the most common diagnosis code for patients receiving any prescription-based therapy (n = 54, 31%).Figure 1Distribution of chronic constipation patients by number of medications prescribed.

For patients receiving monotherapy, linaclotide (n = 52, 49%) and prucalopride (n = 39, 37%) were the most commonly prescribed agents. Prucalopride (n = 19, 82%) and linaclotide (n = 16, 69%) were also the most likely agents to be prescribed in conjunction with another medication. The most common dual therapy regimen was prucalopride and linaclotide (n = 14, 61%) followed by prucalopride and lubiprostone (n = 3, 13%) (Figure A1). Patients on 1–2 medications had a varied distribution of diagnosis codes relative to patients on 3-4 concomitant prescriptions (Table A1). There were no statistically significant differences in prescribing trends across providers.

To our knowledge, this study is among the first to systematically describe the concomitant use of prescription medications for CC management in a referral-based subspecialty clinic. Most patients in this series were managed with single-agent therapy, a testament to the aggregate efficacy of the current suite of pharmacologic CC treatment options. That said, a notable minority (one-fifth) were treated with multiple agents simultaneously, most often with agents with discrete mechanisms of action. While these findings only apply to a single center, they formalize a pattern anecdotally shared among comparable tertiary-care settings. Recognizing this pattern invites further inquiry into these agents’ potential for additive or even synergistic effect.

By virtue of its design, this study has several limitations. Our methodology could not capture specific reasons governing therapy selection (for example out-of-pocket costs, foregut dysmotility, prior treatment failure, etc.) Past or current over-the-counter medication use was not reliably captured, nor was the use of constipating medications (eg opioids, glucagon-like peptide-1 receptor agonists) apart from specific diagnosis codes that may not have been systematically applied. We were unable to query temporal patterns of fluctuation among monotherapeutic or combination treatment regimens (eg length of time spent with therapeutic regimens ultimately deemed ineffective, number of agents tried as monotherapy before pursuing multi-agent regimens, frequency of patients returning to therapies previously deemed ineffective, etc.), which might hold relevance for potential drug-specific mechanisms of treatment failure. Non-pharmacologic approaches to CC management (eg physical therapy, vibrating capsules, dietary interventions) also could not be reliably queried via chart review. While our group regularly assesses for pelvic floor dysfunction in clinical practice, it is a common and dynamic entity, such that missed or refractory cases in this cohort may have biased toward observations of multimodal pharmacologic therapy and/or treatment failure.^9^

Among the current study’s strengths are its focus on CC symptoms rather than a specific CC diagnosis, inviting inquiry into the practical reality of off-label prescriptions as well as reflection on alternative ways to phenotype patients beyond the presence or absence of abdominal pain. Future research might also include a survey of patient variables associated with need for and benefit from multimodal CC pharmacotherapy. As the suite of medical options for CC management continues to mature, data-driven efforts to aid in medical decision-making will become increasingly useful as an adjunct to the industry-sponsored trials leading to drug approval. While current expert guidance dwells on the utility of these agents as monotherapies, future practice may entrench combination therapy within that suite of options for refractory symptoms.