Opioid induced constipation in cancer patients: pathophysiology, diagnosis and treatment

Figures & data

Table 1. Pathophysiology and clinical manifestations of opioid-induced bowel dysfunction.

Target organ	Motor and physiologic effects	Clinical effects
Esophagus	Dysmotility of LES [17,18] EGJ outflow obstruction [18,19]	GERD, and rarely dysphagia Nausea, vomiting
Stomach	Decreased gastric motility [18] Decreased pyloric tone [20]	Nausea, vomiting, anorexia, abdominal discomfort
Pancreas and biliary system	Decreased pancreatic secretions [21] Decreased biliary secretions [21] Biliary contraction [22]	Impaired digestion, abdominal discomfort Maldigestion, malabsorption Right upper quadrant pain
Small bowel	Reduced propulsive peristalsis [23] Enhanced fluid absorption [24]	Delayed absorption Hard, dry stools
Colon	Reduced propulsive peristalsis [25,26] Enhanced fluid absorption [24] Nonpropulsive contractions [22,27]	Constipation Hard, dry stools Spasms, abdominal pain
Rectum and anus	Decreased rectal sensitivity [28] Increased anal sphincter tone [29]	Incomplete evacuation, straining

LES: Lower esophageal sphincter; EGJ: Esophageo-gastric junction; GERD: Gastroesophageal reflux disease.

Table 2. Pharmacologic options for the treatment and prevention of opioid-induced constipation and their motor and physiologic effects.

Class agents	Mechanism of action	Motor and physiologic effect
Stimulant laxatives Senna Bisacodyl	Anti-absorptive, secretory, and prokinetic effects on colon	Improved stool consistency and enhanced colonic motility
Osmotic laxatives Magnesium hydroxide PEG3350 Lactulose	Poorly absorbable substances that serve as osmotic agents to draw water into the intestinal lumen	Improved stool consistency and increased stool water content
Stool softener Docusate Mineral oil	Anionic surfactants with an emulsifying detergent-like property that increase the content of water in stool	Increased stool weight and improved stool consistency
Bulk-forming agents Psyllium fiber	Fluid retention in stool	Increased stool weight and improved stool consistency
Prokinetics Prucalopride	5-HT4 receptor agonist	Enhanced colonic contractility
Secretagogues Lubiprostone Linaclotide	Chloride channel-2 agonist Guanylate cyclase C agonist	Stimulation of intestinal fluid secretion, lubrication of stool, and enhanced motility
Peripheral mu-opioid receptor antagonists Methylnaltrexone Alvimopan	Antagonize gut mu-opioid receptors. Due to inability to cross blood–brain barrier, they do not affect central mu-opioid receptors	Analgesia with minimal disruption of bowel motility, mucosal transport, or defecation reflexes
Opioid receptor agonist and antagonist combination tablets  Oxycodone–naloxone	Antagonize gut mu-opioid receptors. Due to inability to cross blood–brain barrier, they do not affect central mu-opioid receptors	Analgesia with minimal disruption of bowel motility, mucosal transport or defecation reflexes

Penagini R, Bianchi PA. Effect of morphine on gastroesophageal reflux and transient lower esophageal sphincter relaxation. Gastroenterology. 1997;113:409–414.

 PubMed Web of Science ®Google Scholar

Ratuapli SK, Crowell MD, DiBaise JK, et al. Opioid-Induced Esophageal Dysfunction (OIED) in patients on chronic opioids. Am J Gastroenterol. 2015;110:979–984.

 PubMed Web of Science ®Google Scholar

Kraichely RE, Arora AS, Murray JA. Opiate-induced oesophageal dysmotility. Aliment Pharmacol Ther. 2010;31:601–606.

 PubMed Web of Science ®Google Scholar

Yuan CS, Foss JF, O’Connor M, et al. Effects of low-dose morphine on gastric emptying in healthy volunteers. J Clin Pharmacol. 1998;38:1017–1020.

 PubMed Web of Science ®Google Scholar

Turnberg LA. Antisecretory activity of opiates in vitro and in vivo in man. Scand J Gastroenterol Suppl. 1983;84:79–83.

 PubMedGoogle Scholar

Kromer W. Endogenous opioids, the enteric nervous system and gut motility. Dig Dis. 1990;8:361–373.

 PubMed Web of Science ®Google Scholar

Sobczak M, Salaga M, Storr MA, et al. Physiology, signaling, and pharmacology of opioid receptors and their ligands in the gastrointestinal tract: current concepts and future perspectives. J Gastroenterol. 2014;49:24–45.

 PubMed Web of Science ®Google Scholar

Wood JD, Galligan JJ. Function of opioids in the enteric nervous system. Neurogastroenterol Motil. 2004;16(Suppl 2):17–28.

 PubMed Web of Science ®Google Scholar

Holzer P. Treatment of opioid-induced gut dysfunction. Expert Opin Investig Drugs. 2007;16:181–194.

 PubMed Web of Science ®Google Scholar

Kaufman PN, Krevsky B, Malmud LS, et al. Role of opiate receptors in the regulation of colonic transit. Gastroenterology. 1988;94:1351–1356.

 PubMed Web of Science ®Google Scholar

Holzer P. Opioids and opioid receptors in the enteric nervous system: from a problem in opioid analgesia to a possible new prokinetic therapy in humans. Neurosci Lett. 2004;361:192–195.

 PubMed Web of Science ®Google Scholar

Kurz A, Sessler DI. Opioid-induced bowel dysfunction: pathophysiology and potential new therapies. Drugs. 2003;63:649–671.

 PubMed Web of Science ®Google Scholar

Pappagallo M. Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg. 2001;182:11S–18S.

 PubMed Web of Science ®Google Scholar