Approved and commonly used drugs for chronic opioid-induced constipation

Class	Mechanism	Use	Problems
Bulk-forming laxatives (cellulose or psyllium seeds)	Increases mass and water content of stool Decreases transit time	Should always be considered; may be useful in changing character of the effluent from a functioning stoma	May worsen flatulence and distention Should be avoided in patients who are severely debilitated or suspected of early bowel obstruction
Osmotic cathartics (magnesium salts, sodium salts, lactulose, sorbitol, polyethylene glycol)	Increases water in the bowel Decreases transit time Lactulose/sorbitol attracts water into colon, acidifies contents Polyethylene glycol attracts water into the colon	Often used for bowel cleansing before medical procedures Lactulose and sorbitol have a slower onset and are commonly selected for long-term use; dose must be adjusted to effect Polyethylene glycol is not absorbed, has a slower onset, and the powder formulation also is commonly used for long-term therapy; dose must be adjusted to effect	Severe diarrhea and dehydration may occur with overuse Rarely, causes serious electrolyte disorders or volume overload Patients with renal insufficiency or cardiac failure must be carefully monitored if sodium or magnesium salts are used Use of phosphate containing laxatives has been associated with acute phosphate nephropathy (rare); risk factors include chronic kidney disease, frequent use, and advanced age Lactulose or sorbitol may increase flatulence Lactulose should be avoided in patients who are lactose-intolerant
Surfactants (docusate)	Facilitates mixture of fat and stool	Usually combined with a contact cathartic as a first-line therapy for opioid-induced constipation	Minimal risks
Contact cathartics diphenylmethane drugs (bisacodyl) Anthraquinone drugs (cascara, senna)	Increases peristalsis Reduces absorption of water and electrolytes from intraluminal contents	May be used for acute or chronic therapy Often a first-line approach for long-term management, including prophylaxis when opioid therapy is initiated	Risks associated with short-term use are minimal "Laxative bowel," a condition characterized by dependence on laxatives for bowel function has been reported but is presumably rare Allergies to these substances have been reported
Opioid antagonists	Opioid antagonist	Goal is "bowel withdrawal" without concurrent systemic withdrawal
Subcutaneous methylnaltrexone		Opioid-induced constipation in refractory cases; does not cause systemic withdrawal symptoms	Methylnaltrexone must be given subcutaneously; dose adjustment needed for renal impairment
Naloxegol		Opioid-induced constipation; does not cause systemic withdrawal symptoms	Naloxegol is metabolized by CYP3A4; numerous significant drug interactions are anticipated Dose adjustment needed for renal impairment
Oral naloxone		Opioid-induced constipation; parenteral formulation has been given orally, but the optimal dose and schedule are unknown	Limited evidence supporting efficacy of oral naloxone, and some patients will absorb sufficient naloxone to develop systemic withdrawal symptoms May cause abdominal cramping
Fixed combination of extended-release oral oxycodone and naloxone (2:1 ratio)		Chronic pain requiring around-the-clock opioid treatment and prevention or relief of opioid-induced constipation	Exceeding the maximum daily dose of 80 mg oxycodone/40 mg naloxone can cause systemic withdrawal symptoms Though systemic exposure of oral naloxone is low (≤3%) among patients with normal organ function, bioavailability increases in the setting of hepatic impairment and/or renal impairment Use is contraindicated in moderate to severe hepatic impairment Not recommended for perioperative use
Chloride channel activator Lubiprostone	Locally acting type 2 chloride channel (ClC-2) activator	Treatment of opioid-induced constipation	Can cause nausea and abdominal pain Some patients report dyspnea and/or chest tightness within 0.5-2 hours of taking the drug (mechanism unknown) Not studied in methadone-associated opioid-induced constipation and based upon in vitro data provided in the product label; it may not be effective for that use

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