Pharmacologic Management of Chronic Constipation

Chronic constipation is a common digestive problem in North America, with significant psychosocioeconomic implications. Dietary and lifestyle measures and low-cost traditional over-the-counter laxatives are usually the first line of therapy but help only half of the patients. Several newer agents that act by increasing colonic peristalsis, altering colonic secretion, and/or antagonizing enteric opioid receptors have been developed that are effective in treating constipation and its related symptoms as well as improving quality of life. This article focuses on the pharmacology of traditional and newer agents for the treatment of constipation.

Chronic constipation (CC) affects 20% of the population, has a significant effect on quality of life and use of health care resources including drug therapy, and causes significant psychological distress. Almost 85% of physician visits for constipation result in a prescription for laxatives, and $821 million is spent annually on over-the-counter laxatives.

Constipation comprises many symptoms such as hard stools, excessive straining, infrequent bowel movement, feeling of incomplete evacuation, and abdominal bloating; its treatment largely encompasses relieving these symptoms and restoring a normal bowel habit. An essential component of management of CC is identification and management of secondary causes such as drug-induced constipation, for example opioid-induced constipation or an obstructive lesion in the colon, the management of which usually results in resolution of constipation.

If excluded, primary constipation consists of 3 overlapping subtypes : (1) slow transit constipation, characterized by prolonged transit through the colon owing to a primary dysfunction of colonic smooth muscle (myopathy) or its nerve innervations (neuropathy)—this usually requires aggressive medical management but may need surgical intervention ; (2) dyssynergic defecation, a disorder of impaired abdominal, rectoanal, and pelvic floor muscle coordination that requires both medical management and biofeedback treatment ; (3) constipation-predominant irritable bowel syndrome (IBS-C), seen in patients in whom abdominal pain or discomfort is the predominant symptom with usually normal colonic transit and pelvic floor function, and thought to be a result of an interaction of genetic, environmental, social, biologic, and psychological factors. IBS-C is managed medically, using a wide variety of medications.

The treatment of constipation should be customized for each individual considering the cause of constipation, patient’s age, comorbid conditions, underlying pathophysiology, and the patient’s concerns and expectations. Lifestyle changes such as an adequate fluid intake, increased dietary fiber intake, regular nonstrenuous exercise, and dedicated time for passing bowel movements can be useful, but there is limited evidence to support these measures. This article focuses on the pharmacologic management of constipation, not related to IBS, with special emphasis on newer agents.

Present treatment options for chronic constipation

Several over-the-counter laxatives are available for the management of CC. However, studies using conventional laxatives were not well designed and have been summarized previously.

Bulk (Fiber) Laxatives

Bulking agents are organic polymers that increase the weight and water-absorbent properties of stool. The efficacy and side effects of bulking agents are shown in Table 1 .

Table 1

Summary of the pharmacologic properties of conventional laxatives used in the treatment of constipation and evidence-based medicine recommendation

Laxative Class	Medications	Mechanism of Action	Side Effects	Level of Evidence	Grade of Recommendation
Bulk (fiber) laxatives	Psyllium, calcium polycarbophil, methylcellulose, bran	Retaining water in stool, increasing stool bulk, and improving consistency	Flatulence, bloating, abdominal distension, rarely causing mechanical obstruction of esophagus and colon	Psyllium II; Others III	B/C
Stool softeners or wetting agents	Docusate sodium, docusate calcium	Promoting luminal water binding by detergent-like action, increasing stool bulk	Intestinal cramping, irritation of throat (liquid formulation)	III	C
Stimulant laxatives	Senna, aloe, bisacodyl, sodium picosulfate	Increasing intestinal peristalsis by acting on myenteric nerve plexus; decreasing large intestinal water absorption	Abdominal discomfort, rarely electrolytes disturbance, melanosis coli	Sodium picosulfate II; Others III	A/C
Osmotic laxatives	PEG, lactulose, sorbitol, milk of magnesia, magnesium citrate	Osmotic water binding	Bloating, flatulence, abdominal cramping, in rare instances, electrolytes disturbances	PEG I	A
				Lactulose I	A
				Sorbitol/Milk of Magnesia III	B/C
Mixed laxatives	Dried plums	Stool bulking and osmotic action	Flatulence, bloating	II	B

Level of Evidence – Level I (Good evidence): consistent evidence from well-designed, well-conducted studies; Level II (Fair evidence): results show benefit, but strength is limited by the number, quality or consistency of the individual studies; Level III (Poor evidence): insufficient because of limited number or power of studies, flaws in their design or conduct; Grade of Recommendation – Grade A: good evidence in support of use of a modality in the treatment of constipation, Grade B: moderate evidence in support of use of a modality in the treatment of constipation, Grade C: poor evidence in support of use of a modality in the treatment of constipation.

Abbreviation: PEG, polyethylene glycol.

Stool Softeners or Wetting Agents

Stool softeners are surface-acting agents that function primarily as detergents, that is, they allow water to interact more effectively with solid stool, thereby softening the stool, and include dioctyl sodium sulfosuccinate/docusate sodium (Colace) and docusate calcium (Surfak). The efficacy and side effects are shown in Table 1 .

Stimulant Laxatives

Stimulant laxatives increase intestinal motility by stimulating the colonic myenteric plexus on their contact with the colonic mucosa, and by inhibiting water absorption. Both bisacodyl and sodium picosulfate (SPS) are prodrugs that are converted in the gut into the same active metabolite, bis-( p -hydroxyphenyl)-pyridyl-2-methane, which causes the desired laxative effect. There is limited evidence to support their use. In a recent 4-week, double-blind, placebo-controlled trial using SPS, there was a significant increase in number of complete spontaneous bowel movements (CSBMs) per week (SPS: 0.9 ± 0.1 to 3.4 ± 0.2; placebo: 1.1 ± 0.1 to 1.7 ± 0.1; P <.0001), constipation-related symptoms, and quality of life. These agents have often been used as rescue therapy in many constipation and IBS-C trials, and their chronic use may induce tolerance. Abdominal discomfort and cramps are well-known side effects. Senna may cause melanosis coli or hepatotoxicity.

Osmotic Laxatives

Osmotic laxatives contain poorly absorbed ions or molecules, which create an osmotic gradient within the intestinal lumen, thereby retaining water in the lumen, leading to softer stools and improved propulsion. Polyethylene glycol (PEG) is a nonabsorbable, nonmetabolized osmotic agent. Electrolyte-free PEG has been used for the management of constipation. In 5 high-quality, placebo-controlled trials, PEG consistently increased stool frequency and improved stool consistency. PEG was shown to be more effective than tegaserod, with a favorable adverse effect profile. An open-labeled study of PEG, 17 g/d for 12 months, demonstrated that it was safe and effective for adults and elderly patients with CC. PEG may be associated with diarrhea, nausea, abdominal bloating, cramping, and flatulence, especially in nursing home residents. Rarely, electrolyte abnormalities may occur. A decision analysis model suggests that PEG is more cost-effective than lactulose. Three placebo-controlled randomized controlled trials (RCTs) have demonstrated that lactulose is safe and effective. Magnesium hydroxide and other similar salts (magnesium citrate, magnesium sulfate, sodium phosphate) act as osmotic agents. Hypermagnesemia has been reported in patients with renal impairment.

Dried plums and prune juice have been traditionally used for the treatment of constipation. Their effects may be caused by fiber, sorbitol, and phenolic compounds. In a recent 8-week, randomized crossover trial, dried plums was more efficacious than psyllium, with significant improvement in the number of CSBMs per week and stool consistency.

The aforementioned approaches are usually the first-line agents used in the management of constipation, owing to their low cost and wide availability. However, 50% of CC patients report dissatisfaction with these therapies and concerns include unpredictability (71%–75%), bloating (52%–67%), poor symptom relief (44%–50%), or inability to improve quality of life (44%–68%). Hence, several new pharmacologic classes of medications have been developed that are reviewed later ( Tables 2 and 3 ).

Table 2

Summary of the major newer classes of medications for CC including their indications, doses, mechanism of action, side effects, and EBM recommendations

Pharmacologic Class	Drug	Mechanism of Action	Indication	Usual Dose and Route of Administration	Dose Adjustment	Side Effects	Special Populations	Cost	Level of Evidence	Grade of Recommendations
Chloride channel activators	Lubiprostone (Amitiza)	Selective activation of intestinal epithelial chloride channel 2, increasing chloride secretion	Chronic idiopathic constipation, IBS-C	24 μg BID, orally	Not studied in hepatic and renal disease	Nausea, diarrhea, headache	Pregnancy Class C, avoid during breast feeding	$178/month	I	A
Guanylate cyclase C activators	Linaclotide	Activation of GC-C receptor on enterocytes, increasing cGMP, activating CFTR, increasing luminal chloride/bicarbonate secretion; ameliorating visceral hypersensitivity	Chronic idiopathic constipation, IBS-C	75–600 μg/d, orally	Not studied in hepatic and renal disease	Diarrhea	Class C, not studied in breast feeding	?	I	A
Opioid receptor antagonists	Methylnaltrexone (Relistor)	Enteric opioid receptor antagonism, with minimal absorption and not crossing blood-brain barrier	Opiate-induced constipation, postoperative ileus, chronic methadone users	8–12 mg (0.15–0.3 mg/kg) every other day as needed, subcutaneously	Half dose in severe renal and hepatic impairment	Abdominal cramping, flatulence, nausea	Class B, use with caution during breast feeding	$40/injection	I	A
Opioid receptor antagonists	Alvimopan (Entereg)		Postoperative ileus, opiate-induced constipation	6–12 mg BID, 30–300 min before surgery, then BID for 7 d	Avoid in severe renal and hepatic impairment	Nausea, vomiting	Class B; avoid during breast feeding	$700 per Tx course	I	A
Serotonergic agonists	Prucalopride (Resolor), Tegaserod, TD-5108, ATI-7505	Selective 5-HT ₄receptor activation with enhancement of gut motility by contraction of proximal smooth muscles and relaxation of distal smooth muscles; cAMP mediated colonic chloride secretion	Chronic idiopathic constipation, IBS-C	Prucalopride: 2 mg daily, Tegaserod: 2–6 mg BID	Dose adjustment in severe renal and hepatic impairment	Headache, nausea, diarrhea, abdominal pain, tegaserod with unfounded concerns for ischemic colitis	Class C, avoid during breast feeding	Prucalopride (?), Tegaserod: $100–199 per month	I	A

Abbreviations: BID, twice a day; cAMP, cyclic adenosine monophosphate; CFTR, cystic fibrosis transmembrane regulator; cGMP, cyclic guanosine monophosphate; GC-C, guanylate cyclase C; IBS-C, constipation-predominant irritable bowel syndrome.

Table 3

Summary of major clinical trials evaluating the efficacy of newer agents in the treatment of CC and other constipation-related symptoms

	Study Type		Patients
	Design	Duration	N	Mean Age	Females (%)	Interventions	Key Results
Lubiprostone
Johanson et al	Randomized, double-blind, placebo-controlled, multicenter, phase 3 trial	4 wk	242	48.6	90	Group 1: Lubiprostone 24 μg BID; Group 2: Placebo, BID	1. Increased SBMs/wk (Group 1 vs Group 2; 5.69 vs 3.46; P <.001); 2. SBM within 24 and 48 h (Group 1 vs Group 2; 56.7% vs 36.9%, 80.0% vs 60.7%; P <.01); 3. Improved symptom scores for stool consistency, straining, constipation scores, abdominal bloating, and discomfort
Johanson et al	3 open-label, long-term trials	24–48 wk	880 (308 + 248 + 324)	N/A	N/A	Lubiprostone 24 μg BID	Significant and persistent improvement in constipation severity [29% at 24 wk (n = 512); 28% at 48 wk (n = 281)], bloating [20% at 48 wk], abdominal discomfort [17% at 48 wk]
Linaclotide
Lembo et al	Randomized, double-blind, placebo-controlled, multicenter, phase 2b trial	4 wk	310	47.3	92	Group 1: Placebo; Group 2–5: Linaclotide 75 μg/d, 150 μg/d, 300 μg/d, 600 μg/d, respectively	1. Increased mean weekly CSBM frequency with increases of 1.5, 1.6, 1.8, and 2.3 for groups 2–5, compared with 0.5 for placebo ( P <.01); 2. Higher rate of SBM within 24 h (Groups 2–5 vs group 1: 14.3%–35.5% vs 7.4%; P <.05); 3. Improved symptom scores for stool consistency, straining, constipation scores, abdominal bloating and discomfort, and quality of life
Prucalopride
Camilleri et al	Randomized, double-blind, placebo-controlled, multicenter, phase 3 trial	12 wk	620	48.3	87.9	Group 1: Placebo; Group 2/3: Prucalopride 2 mg/4 mg QID	1. Increased proportion of patients with ≥3 CSBMs/wk (Group 1 vs Group 2/3: 12.0% vs 28.4%–30.9%; P <.001); 2. Higher proportion of patients with improved symptom scores for straining and stool consistency; 3. Improved patient perceived satisfaction with bowel function and constipation symptoms
Quigley et al	Randomized, double-blind, placebo-controlled, multicenter, phase 3 trial	12 wk	641	47.9	86.6	Group 1: Placebo; Group 2/3: Prucalopride 2 mg/4 mg QID	1. Increased proportion of patients with ≥3 CSBMs/wk (Group 1 vs Group 2/3: 12.1% vs 23.5–23.9%; P <.01); 2. Increased proportion of patients with increase from baseline of ≥1 CSBM/wk (Group 1 vs Group 2/3: 27.5% vs 42.6–46.6%; P <.001); 3. Improved patient perceived satisfaction as well as quality of life assessment
TD-5108 (Velusetrag)
Theravance press release	Randomized, double-blind, placebo-controlled, phase 2 trial	4 wk	400	N/A	N/A	Group 1: Placebo; Group 2–4: TD-5108 15/30/50 mg QID	1. Increased proportion of patients with ≥3 CSBMs/wk (Group 1 vs Group 2–43: 22% vs 42%–61%; P <.001); 2. Significant reduction in time to first SBM
Methylnaltrexone
Thomas et al	Randomized, double-blind, placebo-controlled, multicenter, phase 3 trial	2 wk	133 (on opiates for ≥2 wk and on stable dose of opiates and laxatives for ≥3 d with no benefit	71	57	Group 1: Placebo; Group 2: 0.15 mg/kg methylnaltrexone, SC, every other day, for 2 wk	1. Higher likelihood of laxation within 4 h of first dose (Group 1 vs Group 2; 15% vs 48%; P <.01); 2. Short median time to laxation (Group 1 vs Group 2; >48 h vs 6.3 h; P <.001); 3. Improved scores on stool consistency, constipation distress scores; 4. Stable pain scores and no symptoms of opioid withdrawal
Alvimopan
Büchler et al	Randomized, double-blind, placebo-controlled, multicenter, phase 3 trial	7 d	911 (undergoing small or large bowel resection)	64	45	Group 1: Oral Placebo; Group 2/3: Alvimopan 6/12 mg BID administered 2 h before surgery, then BID until discharge or for 7 d; opiates administered for pain via PCA or boluses	1. Quicker time to recovery of gastrointestinal function (Group 1 vs Group 2 vs Group 3: 92.6 h vs 84.2 h vs 87.8 h; P <.05 for group 2 vs 1); 2. In post hoc analysis of patients who received PCA, significantly quicker time to recovery for groups 2/3 as compared with group 1; 3. No reversal of analgesia
Ludwig et al	Randomized, double-blind, placebo-controlled, multicenter, phase 3 trial	7 d	654 (undergoing laparotomy for partial small- or large-bowel resection, with IV PCA opiates	59	50	Group 1: Oral placebo; Group 2: Alvimopan 12 mg BID PO administered 30–90 min before surgery, then BID until discharge or for 7 d	1. Hazard ratio of time to gastrointestinal recovery compared with group 1: 1.5 (1.29–1.82) [ P <.001]; 2. Mean postoperative LOS 1 d less for group 2 vs group 1 (5.2 d vs 6.2 d; P <.001)
NKTR-118
Webster et al	Randomized, double-blind, placebo-controlled, multicenter, phase 2 trial	4 wk	208 (being treated for moderate to severe pain with 30–1000 morphine equivalent units)	N/A	N/A	Group 1: Placebo; Group 2: NKTR-118 5 mg PO QID Group 3: NKTR-118 25 mg PO QID; Group 4: NKTR-118 50 mg PO QID	1. Mean increase in the mean number of SBMs/wk as compared with baseline (Group 1 vs Group 3: 1.9 vs 3.6, P <.005; Group 1 vs Group 4: 1.9 vs 4.4, P <.001); 2. Shorter median time to first BM (Group 1 vs Group 3: 48.6 h vs 6.6 h, P = .001; Group 1 vs Group 4: 44.9 h vs 2.9 h, P <.002; 3. No reversal of opioid-mediated analgesia
Neurotrophin-3
Parkman et al	Randomized, double-blind, placebo-controlled, dose- and dose-interval ranging study, multicenter, phase 2 trial	4 wk	107	43.5	91	Group 1: Placebo TTW; Group 2: NT-3 3 mg QW; Group 3: NT-3 3 mg TTW; Group 4: NT-3 9 mg QW Group 5: NT-3 9 mg TTW Group 6: NT-3 9 mg TTW × 1 wk followed by 9 mg QW × 3 wk	1. Significant increase in mean weekly CSBM frequency in a dose-dependent manner, with increase of 5.7 CSBMs/ wk with group 5; 2. Trend toward improvement (softening) of stool form, ease of stool passage, and in other constipation-related symptoms, as well as in colonic transit