- Based on a thorough assessment of the current evidence, the American Gastroenterological Association (AGA) strongly recommends traditional laxative therapy as first line agents given established efficacy and benefits of safety and cost.
- When an adequate trial of laxatives results in suboptimal symptom control, AGA recommends escalation of therapy to peripherally acting µ-opioid receptor antagonists (PAMORA) drugs with high or moderate quality evidence of efficacy, namely naldemedine and naloxegol.
- AGA also conditionally recommends use of methylnaltrexone for laxative-refractory opioid-induced constipation (OIC).
- Due to insufficient evidence, AGA did not issue a recommendation regarding use of either lubiprostone or prucalopride in OIC.
Three different classes of opioid receptors mediate the gastrointestinal effects of opioid medications: µ (mu), d (delta), and k (kappa). Opioids exert their GI effects via kappa receptors in the stomach and small intestine and mu receptors located in the small intestine and proximal colon. OIC occurs primarily via activation of enteric mu receptors, which results in increased tonic nonpropulsive contractions in the small and large intestine, increased colonic fluid absorption and stool desiccation. Opioids are also thought to increase the minimum sensory threshold of the rectum and increase anal sphincter tone. The sum of these effects results in harder stool and less frequent and less effective defecation. Because OIC results from the specific effects of opioids, it differs mechanistically from other forms of constipation, and therefore, medical management of this disorder deserves dedicated attention.
- It is estimated that 4–5% of the U.S. population use prescription opioids regularly, and opioid prescribing has increased over the past several decades, particularly for non-cancer pain.
- The true number of those affected by opioid dependence and opioid-induced side effects is larger due to nonmedical or illicit use, which is also on the rise.
- Opioid induced bowel dysfunction refers to the set of gastrointestinal adverse effects associated with opioid therapy, including constipation, gastroesophageal reflux disease, nausea and vomiting, bloating, and abdominal pain.
- Constipation is by far the most common and debilitating gastrointestinal effect of opioids, and some degree of constipation is near universal in patients taking opioid medications.
Table 1. Definitions
|Rome IV||A Consensus Definition|
|New or worsening symptoms of constipation when initiating, changing, or increasing opioid therapy that must include 2 or more of the following:||A change when initiating opioid therapy from baseline bowel habits that is characterized by any of the following:|
Summary of Recommendations of AGA Clinical Guidelines for the Medical Management of OIC
|Statement||Strength of recommendation||Quality of evidence|
|1. Traditional laxatives|
|In patients with OIC, AGA recommends use of laxatives as first-line agents||Strong||Moderate|
|2. Peripherally-acting µ-opioid receptor antagonists|
|In patients with laxative refractory OIC, AGA recommends naldemedine over no treatment||Strong||High|
|In patients with laxative refractory OIC, AGA recommends naloxegol over no treatment||Strong||Moderate|
|In patients with laxative refractory OIC, AGA suggests methylnaltrexone over no treatment||Conditional||Low|
|3. Intestinal secretagogues|
|In patients with OIC, AGA makes no recommendation for the use of lubiprostone||No Recommendation||Evidence gap|
|4. Selective 5-HT agonists|
|In patients with OIC, AGA makes no recommendation for the use of prucalopride||No Recommendation||Evidence gap|
Table 2. µ-Opioid Receptor Antagonists for OIC
|Tablets: 0.2 mg||0.2 mg once daily|
|Tablets: 12.5 mg and 25 mg||25 mg once daily. If not tolerated, reduce to 12.5 mg once daily.|
Renal impairment (CLcr <60 mL/min):
12.5 mg once daily; increase to 25 mg once daily; if tolerated, and monitor for adverse reactions
|Tablets: 150 mg|
|Tablets: 450 mg once daily in the morning|
Table 3. Different Classes of Agents for OIC and Mechanisms of Action
|Class/type||Examples||Mechanism of action|
|Osmotic||Polyethylene glycol (PEG), lactulose, magnesium citrate, magnesium hydroxide||Draw water into intestine to hydrate and soften stool|
|Stimulant||Bisacodyl, sodium picosulfate, senna||Irritate sensory nerve endings to stimulate colonic motility and reduce colonic water absorption|
|Detergent/surfactant stool softeners||Docusate||Allow water and lipids to penetrate the stool to hydrate and soften fecal material|
|Lubricant||Mineral oil||Lubricate the lining of the gut to facilitate defecation|
|Block μ-opioid receptors in the gut thereby effectively restoring the function of the enteric nervous system|
|Intestinal secretagogues||Lubiprostone||Act on chloride channels or guanylate cyclase receptors in enterocytes to stimulate fluid secretion into the intestinal lumen|
|Selective 5-HT agonists||Prucalopride||Activate 5-HT4 receptor, leading to increased colonic motility and accelerated transit|
Table 4. Bowel Function Index
|1||During the last 7 days, how would you rate your ease of defecation on a scale from 0 to 100?||0 = easy or no difficulty|
100 = severe difficulty
|2||During the last 7 days, how would you rate your feeling of incomplete bowel evacuation on a scale from 0 to 100?||0 = not at all|
100 = very strong
|3||During the last 7 days, how would you rate your constipation on a scale from 0 to 100?||0 = not at all|
100 = very strong
|Total score||Average of 3 scores|
Figure 1. Clinical Decision Support Tool for the Medical Management of Opioid-Induced Constipation — Footnotes1 OIC definition from Camilleri et al. Neurogastroenterol Motil. 2014.
2 Laxative refractory OIC defined as persistent constipation (e.g. Bowel Function Index score ≥30) despite scheduled use of at least 2 classes of laxatives for at least 2 weeks.