Management of persistent unresponsive constipation in adults

INTRODUCTION — 

Chronic idiopathic constipation may be associated with defecatory dysfunction (pelvic floor dysfunction), slow colonic transit, or both. Most patients with chronic idiopathic constipation improve with lifestyle modification, fiber supplementation, and traditional stimulant and osmotic laxative therapy. Patients who experience persistent symptoms despite an adequate trial (usually at least one month or more) of these initial measures warrant additional testing and/or therapy.

This topic will review the management of chronic constipation that is nonresponsive to initial management. The approach to diagnosis and initial management of constipation in adults, as well as management of opioid-related constipation and irritable bowel syndrome with predominant constipation, are presented separately:

●(See "Etiology and evaluation of chronic constipation in adults".)

●(See "Management of chronic constipation in adults".)

●(See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Opioid bowel dysfunction'.)

●(See "Treatment of irritable bowel syndrome in adults".)

GENERAL APPROACH — 

The approach to a patient with persistent chronic idiopathic constipation depends on whether there is defecatory dysfunction, and whether there is normal or slowed colonic transit. The specific choice of agents and order of their introduction varies with the etiology of the condition.

●Management of defecatory dysfunction involves suppositories or biofeedback.

●Treatment for normal or slow transit constipation includes pharmacotherapy with secretagogues, prucalopride, or tenapanor (algorithm 1). Severe, intractable, slow transit constipation is rare and may be treated with surgery, but with extreme caution; patients should be referred to specialized centers for a comprehensive evaluation prior to surgery. This typically includes testing for defecatory dysfunction and assessment of colonic transit. (See "Etiology and evaluation of chronic constipation in adults", section on 'Subsequent evaluation for persistent symptoms'.)

Many patients have both defecatory dysfunction and slow transit; in these situations, patients should first be treated for defecatory dysfunction and then reevaluated to determine if additional therapy for slow transit constipation is necessary.

We advise patients to continue dietary and other lifestyle measures to support healthy bowel movements even when additional therapy is necessary. This includes 20 to 35 g daily fiber intake (unless there is slow transit constipation), adequate hydration, and regular physical activity. (See "Management of chronic constipation in adults", section on 'Initial measures for all patients'.)

In general, we continue osmotic and stimulant laxatives as we introduce additional treatments; these agents can be titrated down or stopped entirely once constipation is successfully treated. They can continue to be used for rescue therapy if needed.

DEFECATORY DYSFUNCTION — 

For patients who have defecatory dysfunction confirmed with anorectal manometry and balloon expulsion test or defecography, we advise treatment with suppositories and biofeedback. Patients with a structural defect leading to defecatory dysfunction (eg, rectocele or rectal prolapse) may require additional management for the underlying condition if biofeedback is not effective. The diagnosis and evaluation of defecatory dysfunction is reviewed separately. (See "Etiology and evaluation of chronic constipation in adults", section on 'Assessment for a defecation disorder'.)

Suppositories — We prefer an initial trial of suppositories (glycerin or bisacodyl) for treatment of defecatory dysfunction. Suppositories can be effective in liquifying stool and thereby overcoming anatomic obstruction (eg, rectocele) or pelvic floor dyssynergia. (See "Etiology and evaluation of chronic constipation in adults", section on 'Defecatory dysfunction'.).

Biofeedback — We suggest biofeedback for the management of most patients with defecatory dysfunction, particularly those with dyssynergic defecation. (See "Etiology and evaluation of chronic constipation in adults", section on 'Defecatory dysfunction'.)

Patients with dyssynergic defecation have pelvic floor dysfunction and inappropriate contraction of the puborectalis and external anal sphincter muscles. Biofeedback is a painless, noninvasive means of cognitively retraining these muscles to correct inappropriate contraction during defecation [1,2]. It is effective for patients with pelvic floor dysfunction and provides the potential for treatment without laxatives.

●Description – An instrument such as an anal plug or anorectal manometer is placed in the rectum to monitor external anal sphincter pressures. The patient attempts to expel the apparatus and watches the recordings of electromyography activity or sphincter pressure responses. They are able to observe whether they are generating sufficient pressure and appropriately relaxing the anal sphincter during expulsion. Over time, they are able to modify inappropriate responses through trial and error.

●Efficacy – The efficacy of biofeedback for dyssynergic defecation has been demonstrated in multiple studies [2-7]. In two randomized trials, biofeedback was more effective than laxatives in patients with pelvic floor dyssynergia [2,6]. Approximately two-thirds of patients with dyssynergic defecation have coexisting slow transit constipation. In this group of patients, biofeedback improves bowel function, dyssynergia, and colonic transit by improving outlet dysfunction [1]. Home biofeedback therapy may be as effective as office biofeedback therapy, but no commercial device is currently available [8].

●Limitations – Biofeedback has not been well standardized, and results may vary at different centers. In addition, biofeedback may not be widely available. In these situations, when possible, we refer patients to centers in which biofeedback is available.

Surgery in selected patients with underlying structural abnormalities — For patients with defecatory dysfunction associated with specific anatomic causes (eg, rectocele, rectal prolapse) who do not respond to suppositories and biofeedback, surgical correction may be required. Specific management and surgical techniques are reviewed in detail elsewhere:

●Rectocele (see "Posterior vaginal defects (eg, rectocele): Clinical manifestations, diagnosis, and nonsurgical management", section on 'Management' and "Surgical management of posterior vaginal defects")

●Rectal prolapse (see "Overview of rectal procidentia (rectal prolapse) in adults", section on 'Treatment' and "Surgical approach to rectal procidentia (rectal prolapse) in adults")

Additional laxative therapy for persistent symptoms — For patients with persistent defecatory dysfunction despite suppositories, biofeedback, and/or surgical correction of anatomic causes, we offer treatment with additional laxatives as described below for normal or slow transit constipation (algorithm 1) (see 'Pharmacologic therapy' below). Additional laxatives can be helpful by improving stool consistency and making stool passage easier. However, laxatives should be increased cautiously, as patients with defecatory dysfunction may be particularly prone to fecal incontinence if the stool consistency becomes too loose.

NORMAL OR SLOW TRANSIT CONSTIPATION — 

Patients with chronic idiopathic constipation who do not have defecatory dysfunction have either normal or slow transit constipation.

Optional testing — Although colonic motility studies can differentiate between these conditions, this testing does not alter treatment options and is not necessary unless surgical management is being considered. (See "Etiology and evaluation of chronic constipation in adults", section on 'Assessment of colonic transit'.)

Pharmacologic therapy — We initiate pharmacotherapy with secretagogue agents for patients with persistent normal or slow transit constipation that is unresponsive to dietary changes and osmotic and stimulant laxatives (table 1). There are no comparison trials between these agents, and treatment choice is dependent on patient and clinician preference as well as cost (algorithm 1).

Colonic secretagogues — We use guanylate cyclase-C receptor agonists (ie, linaclotide or plecanatide) as initial secretagogue therapy. Although comparative trials are not available, these agents may have a more favorable side effect profile compared with lubiprostone.

Guanylate cyclase-C receptor agonists — We prefer a guanylate cyclase-C receptor agonist as the initial agent for patients with constipation resistant to traditional osmotic and stimulant laxatives. These agents are minimally absorbed peptide agonists of the guanylate cyclase-C receptor that stimulate intestinal fluid secretion and transit [9,10]. Both have been found to be effective and well-tolerated in randomized trials; direct comparison trials are not available.

●Linaclotide – We start linaclotide at a dose of 145 mcg daily. For patients who develop diarrhea, decreasing the dosage to 72 mcg daily or 145 mcg every other day may increase tolerability [11].

For patients with an inadequate response after one month on 145 mcg daily, the dose may be increased to 290 mcg daily. If the response is inadequate after an additional two weeks at the maximum tolerated dose, linaclotide should be discontinued (it can be simply stopped) and an alternative treatment started. Although there are no data to guide which agent to switch to, we generally switch to tenapanor or prucalopride.

If symptoms are improving, it is reasonable to extend the trial up to 8 to 12 weeks before deciding whether to continue with linaclotide or switch to a different treatment.

•Efficacy – In two randomized trials evaluating patients with chronic constipation, patients who received linaclotide (at 145 mcg and 290 mcg) were more likely to achieve the primary composite endpoint (improvement in complete spontaneous bowel movements [CSBMs] ≥1 per week with ≥3 CSBMs per week for at least 75 percent of weeks in a 12-week trial of therapy) compared with placebo (145 mcg: 21 and 16 percent; 290 micrograms: 19 and 21 percent; versus placebo: 3 and 6 percent) [12]. Both linaclotide-treated groups reported an improvement in number of weekly bowel movements, improvement in stool consistency, and a reduction in straining, bloating, and abdominal discomfort. The most common adverse event was diarrhea, leading to discontinuation in approximately 4 percent of patients.

●Plecanatide – Plecanatide is also an appropriate option for initial secretagogue therapy. The starting dose is 3 mg daily. If there is no response after four weeks, the dose can be increased to 6 mg daily.

•Efficacy – In a randomized trial of almost 1400 patients with chronic idiopathic constipation, those who received plecanatide (3 or 6 mg) were more likely to achieve an improvement in the primary composite endpoint (improvement in CSBMs ≥1 per week with ≥3 CSBMs per week for at least 75 percent of weeks in a 12-week trial of therapy, including three of the final four weeks) compared with placebo (21 percent in 3 mg group, 20 percent in 6 mg group, 10 percent in placebo group) [10]. Plecanatide also improved stool consistency and constipation-related symptoms (straining, abdominal bloating, and abdominal discomfort) compared with placebo. The most common side effect was diarrhea, which led to treatment discontinuation in approximately 2.5 percent of patients in each plecanatide-treated group.

In a subsequent meta-analysis, patients who received plecanatide at 3 mg and 6 mg were more likely to achieve the composite endpoint (improvement in CSBMs ≥1 per week with ≥3 CSBMs per week for at least 75 percent of weeks in a 12-week trial of therapy, including three of the final four weeks) compared with placebo (odds ratio [OR] for 3 mg 1.99, 95% CI 1.57-2.51; OR for 6 mg 1.90, 95% CI 1.46-2.47) [13].

Lubiprostone — Lubiprostone is an alternative for patients in whom guanylate cyclase-C receptor agonists are not effective. We use 24 mcg twice daily. This agent is a locally acting chloride channel activator that enhances chloride-rich intestinal fluid secretion [14]. There have been no comparisons with other options for treatment of severe constipation, and its long-term safety is not yet established. Until further data are available (and because it is expensive compared with other options and induces nausea), it is best reserved for patients with severe constipation in whom other approaches have been unsuccessful.

Multiple studies have demonstrated the efficacy of lubiprostone compared with placebo in the treatment of chronic constipation [15,16]. As an example, in one randomized trial of over 240 patients with chronic constipation, lubiprostone 24 mcg twice daily increased the frequency of spontaneous bowel movements (SBMs) compared with placebo (mean weekly number of SBMs after one week was 5.7 in the lubiprostone group compared with 3.5 in the placebo group) [15]. In the lubiprostone group, 57 percent of patients reported a SBM within 24 hours, and 80 percent within 48 hours (compared with 37 percent at 24 hours and 61 percent within 48 hours in the placebo group). Patients in the lubiprostone group also reported improvements in stool consistency, straining, and constipation severity. The most common side effect was nausea, which led to treatment discontinuation in 5 percent of patients.

Additional options — For those who do not respond to secretagogue therapy, alternative agents include prucalopride and tenapanor. Misoprostol is an additional option for patients with persistent symptoms who are otherwise considering surgical management.

Prucalopride (prokinetic agent) — Prucalopride is an alternative agent for patients with chronic idiopathic constipation in whom secretagogues are not effective. We usually discontinue secretagogues and start prucalopride at 2 mg daily, titrating up to 4 mg or down based on clinical response. Prucalopride is a selective high-affinity 5HT₄ receptor agonist that stimulates the peristaltic reflex, intestinal secretions, and gastrointestinal motility.

Multiple trials have demonstrated the efficacy of prucalopride in chronic constipation compared with placebo [17-20]. As an example, in one randomized trial of over 600 patients with chronic constipation, patients who received prucalopride (2 mg or 4 mg) were more likely to achieve three or more CSBMs per week compared with placebo (31 percent in 2 mg group and 28 percent in 4 mg group, compared with 12 percent in placebo group) [20]. Both prucalopride-treated groups reported reduced severity of symptoms (reduction in straining and improvement in stool consistency) compared with placebo. The most frequently reported side effects were headache, nausea, abdominal pain, and diarrhea, leading to treatment discontinuation in approximately 8 percent of patients in each prucalopride-treated group. In a subsequent study evaluating the long-term efficacy of prucalopride, the improvement in quality-of-life scores seen with prucalopride was maintained for up to 18 months [21].

Tenapanor — Tenapanor can be used in the treatment of chronic idiopathic constipation refractory to standard therapies. We use 50 mg twice daily.

Tenapanor is a sodium/hydrogen exchanger 3 inhibitor. It reduces the absorption of sodium and phosphate and enhances intestinal fluid volume and transit. Although it has not yet been studied specifically for the treatment of chronic idiopathic constipation, it has demonstrated efficacy in the treatment of irritable bowel syndrome with predominant constipation. (See "Treatment of irritable bowel syndrome in adults", section on 'Tenapanor'.)

It does not currently have regulatory approval in the United States for use in chronic idiopathic constipation, although in the author's experience, it is safe and effective for this condition.

Misoprostol — Misoprostol can be used in the treatment of chronic idiopathic constipation refractory to standard therapies in whom surgery is otherwise being considered. We use 400 mcg daily or every other day and increase by 200 mcg daily to every other day at weekly intervals as tolerated. In our experience, it is most effective when used with polyethylene glycol in doses ranging from 17 to 34 g daily.

Misoprostol is a prostaglandin analog that stimulates intestinal transit. Although data are limited to very small trials [22,23], in our experience it can be effective for patients for whom other agents have not been beneficial. Misoprostol should not be used in women who could become pregnant since it induces labor and can lead to loss of the fetus. It can also increase menstrual bleeding.

Nonpharmacologic options for selected patients with severe symptoms

Vibrating capsule — Treatment with vibrating capsules has demonstrated efficacy in chronic idiopathic constipation. The mechanism of constipation improvement is through mechanical stimulation of the intestinal wall and augmentation of the circadian rhythm of colonic contractile activity. It appears to be safe and effective, but it is not yet widely available or frequently used. Although optimal patient groups who might benefit from this have not been established, it may be a particularly good option for those with side effects to pharmacologic therapy.

In one randomized trial, patients with chronic idiopathic constipation who received the vibrating capsule were more likely to achieve an increase in weekly CSBMs compared with placebo (39 percent achieved an increase of one or more CSBM per week compared with 22 percent in the placebo group) [24]. They also reported improvements in straining, stool consistency, and quality of life measures compared with placebo. In a subsequent analysis of 175 patients with severe constipation (defined as zero CSBMs during a two-week baseline period), those who received the vibrating capsule were more likely to achieve an increase in weekly CSBMs compared with placebo (45 percent achieved an increase of one or more CSBM per week compared with 21 percent in the placebo group) [25]. Patients receiving the vibrating capsule also reported improvement in straining effort and stool consistency compared with placebo.

Surgical treatment — We reserve surgical management for patients with severe symptoms who do not respond to medical management. At least five criteria should be met prior to consideration of surgery:

●Chronic, severe, and disabling symptoms from constipation that are unresponsive to medical therapy.

●Abdominal pain is not a prominent symptom. Surgical treatment can improve frequency of defecation but does not usually improve (and may worsen) abdominal pain and bloating.

●Slow colonic transit of the inertia pattern. (See "Etiology and evaluation of chronic constipation in adults".)

●Intestinal pseudoobstruction has been excluded by radiologic or manometric studies.

●Pelvic floor dysfunction has been excluded with anorectal manometry, balloon expulsion testing, or defecography.

In carefully selected patients, subtotal colectomy with ileorectal anastomosis can dramatically ameliorate incapacitating constipation [26-28]. In one study of 74 patients with severe, refractory slow transit constipation who underwent colectomy and ileorectostomy, 97 percent were satisfied with the results of the surgery, and 90 percent reported a good or improved quality of life over a mean follow-up period of 56 months [27]. Postoperative complications included small bowel obstruction (9 percent) and prolonged ileus (12 percent).

Treatment with limited evidence — Additional nonpharmacologic therapies are under investigation for the treatment of persistent nonresponsive constipation; there is currently inadequate evidence to recommend these therapies.

●Fecal microbiota transplant (FMT) – FMT has been proposed as a treatment option for constipation because of a possible role of the gut biome in regulating colonic motility. FMT involves delivering donor fecal matter into the patient's gastrointestinal tract, thus altering their microbiota. In one small, randomized trial of patients with slow transit constipation, FMT improved constipation endpoints compared with usual care during the 12-week observation period (clinical cure rate 36.7 versus 13.3 percent) [29]. However, long-term efficacy has not been established [30].

●Electrical stimulation – Studies evaluating electrical stimulation in the treatment of constipation have had mixed results [31,32]. Although one meta-analysis found that noninvasive electrical neuromodulation led to improvements in several constipation-related endpoints, the optimal patient population and most efficacious modality of electrical stimulation have not been established, and this treatment is not routinely used in clinical practice [32].

SPECIAL POPULATIONS

Opioid-induced constipation — Several additional treatment options exist for patients with constipation related to opioid use. Peripherally acting mu-opioid receptor antagonists (PAMORAs) including methylnaltrexone, and naloxegol can be used to manage treatment-resistant, opioid-induced constipation. As these opioid receptor antagonists act peripherally and do not cross the blood-brain barrier, they do not impair the analgesic effects of opioids. Treatment of refractory opioid-induced constipation is discussed in detail elsewhere. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Management of refractory opioid-induced constipation'.)

Neurogenic constipation — Neurologic causes of constipation include spinal cord injury, Parkinson disease, and multiple sclerosis. Symptoms can be treatment-resistant and may require secretagogues and other specific therapies (eg, ENT-01 in Parkinson disease-associated constipation, spinal electrical stimulation in spinal cord injury). These are reviewed in detail elsewhere:

●Spinal cord injury and disease (see "Chronic complications of spinal cord injury and disease", section on 'Gastrointestinal complications')

●Parkinson disease (see "Management of nonmotor symptoms in Parkinson disease", section on 'Constipation')

●Multiple sclerosis (see "Symptom management of multiple sclerosis in adults", section on 'Bowel dysfunction')

Chemotherapy-related constipation — Constipation in patients receiving chemotherapy is often multifactorial due to poor oral intake and medication side effects, including opioid analgesics and antiemetic agents. Specific cancer medications associated with constipation and the treatment of chemotherapy-associated constipation is reviewed in detail elsewhere. (See "Clinical presentation and risk factors for chemotherapy-associated diarrhea, constipation, and intestinal perforation", section on 'Constipation'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Constipation".)

SUMMARY AND RECOMMENDATIONS

●Treatment strategy – In patients with chronic constipation unresponsive to initial therapies, we first evaluate and treat defecatory dysfunction. For patients without defecatory dysfunction and those with ongoing symptoms after treatment for this, we initiate a secretagogue agent (table 1). We advise patients to continue dietary and lifestyle changes to support bowel health (eg, fiber intake, adequate hydration) as new treatments are initiated. We generally advise them to continue osmotic and stimulant laxatives at the onset of therapy, but we decrease or stop these if able once a more effective treatment regimen is established. (See 'General approach' above.)

●Defecatory dysfunction – For patients with defecatory dysfunction, we suggest biofeedback for initial treatment (Grade 2C). Biofeedback is most effective in patients with dyssynergic defecation; successful treatment can help avoid the need for long-term laxatives. We also suggest symptomatic treatment with suppositories (Grade 2C), which can help liquefy stools and thus make stool passage easier. Surgical correction of anatomic abnormalities (eg, rectocele, rectal prolapse) is generally reserved for patients in whom conservative treatment is not effective. (See 'Defecatory dysfunction' above.)

●Normal or slow transit constipation – Patients without defecatory dysfunction have either normal or slow transit constipation. For these patients, we suggest initial treatment with a guanylate cyclase-C receptor agonist (eg, linaclotide or plecanatide) (algorithm 1) (Grade 2C). If this therapy is not effective, alternative options include tenapanor, prucalopride, or lubiprostone. Misoprostol is usually reserved for patients with persistent symptoms who are otherwise considering surgical management. (See 'Normal or slow transit constipation' above.)

●Additional nonpharmacologic options – Vibrating capsules can alleviate constipation in some patients with symptoms that do not respond to medical management. They may be particularly helpful for patients who have side effects to pharmacologic options. In addition, surgical treatment can be helpful for patients with severe, persistent slow transit constipation refractory to medical management. (See 'Nonpharmacologic options for selected patients with severe symptoms' above.)

●Special populations – Patients with opioid-induced constipation, those with neurogenic constipation, and those with chemotherapy-related constipation may have particularly severe symptoms; management of constipation in these patient populations is discussed separately. (See 'Special populations' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Satish SC Rao, MD, PhD, FRCP, who contributed to earlier versions of this topic review.