Dr. Satyavan is a critical care clinical pharmacist at Capital Health Fuld Campus, Trenton, New Jersey. Dr. Barna is a clinical assistant professor at Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey.
Opioid analgesic medications are widely used in the treatment of acute and chronic pain. Optimal pain relief and therapeutic efficacy of these agents are sometimes limited by their numerous adverse effects, the most common being those related to gastrointestinal (GI) tract functioning. Although a variety of GI complaints—including nausea, vomiting, and gastric reflux—may occur in patients receiving opioid treatment, opioid-induced constipation (OIC) is the most common, debilitating side effect of therapy.
Unlike other GI adverse effects of opioids, patients rarely become tolerant of the constipation associated with their use.1,2 Underrecognition and failure to prevent OIC can lead to adverse impacts on the patient’s underlying disease state (eg, cancer-related pain), health-related quality of life, worsening discomfort, and ultimately may lead to discontinuing opioid therapy to avoid OIC. Although OIC is often a difficult topic for patients to bring up, the pharmacist needs to be versed on both the pharmacologic and nonpharmacologic interventions that may benefit this patient population.
Just as the analgesic effects of opioids are mediated by specific opioid receptors, the GI adverse effects also are related to opioid receptor effects. The 3 major opioid receptors in the enteric nervous system are mu, delta, and kappa. The primary mediator involved in the development of OIC is the muopioid receptor. The inhibition of excitatory and inhibitory neurotransmitters occurs when opioid agonists bind to this receptor, causing inhibition of gastric emptying, reduction of mucosal secretions, and decrease in peristalsis throughout the GI tract.
All these factors, including increased reabsorption of fluid from the gut, cause stool to become dry and hard and ultimately lead to constipation.1 Signs and symptoms associated with the broader condition of opioid-induced bowel dysfunction (of which constipation is a major component) include cramping, dry, hard stools, straining, abdominal distension and pain, nausea, vomiting, and gastric reflux.
The mainstay of OIC treatment revolves around preventing the constipation preemptively to ensure adherence to analgesic regimens and maintenance of patient dignity and quality of life. Nonpharmacologic interventions can be as simple as encouraging patients to practice good toileting habits, including not suppressing the urge to defecate. Additionally, provision of adequate privacy for toileting may be of consideration in the acute care and long-term care settings.
Unlike constipation associated with other conditions or causes, OIC is unlikely to respond to increased dietary fiber, fluid intake, or physical activity levels. Use of bulk-forming laxatives (eg, psyllium, methylcellulose) and excessive dietary fiber intake are not likely to relieve symptoms of OIC and may even be detrimental, as these agents can cause bowel obstruction and worsen fecal impaction.
In patients whose diets are deemed to be deficient in fiber or whose constipation is related to decreased fluid intake and dehydration, counseling should center around these conditions as possibly contributing to OIC, although increasing fiber and fluid intake alone is unlikely to relieve symptoms adequately.3 Modest physical activity may alleviate symptoms of mild constipation, although the role of physical activity for the prevention of OIC has not been investigated.
To prevent OIC, scheduled laxative regimens should be considered for patients prescribed long-term courses of opioid treatment,4 and a wide variety of laxatives are available (Table). Bulk laxatives, as previously mentioned, are usually considered to be safe for chronic use; however, they are not recommended in OIC, as these agents may increase the risk of bowel obstruction in patients with impaired GI motility.5
Mineral oil eases passage of stool by decreasing water absorption, lubricating the intestine, and retarding colonic absorption of water. Mineral oil has many safety issues, including possible aspiration due to failure to stimulate the cough reflex, drug interactions, and decreased absorption of fat-soluble vitamins A, D, E, and K with prolonged use. To avoid aspiration, patients must ingest mineral oil while upright and remain that way for 30 to 60 minutes postingestion.6
Three different types of osmotics/hyperosmotics are available: saline, sugar alcohols, and macrogols. All 3 have similar mechanisms of drawing fluid into the bowel by being hyperosmotic/ hypotonic. Orally, these laxatives are not absorbed and will hold dietary fluids in the intestinal tract during their transit. Rectally, these laxatives hydrate hardened stool in the distal colon allowing for easier passage.7 Saline laxatives should be used judiciously, as many adverse effects are associated with it, including—but not limited to—the following: electrolyte abnormalities, excessive fluid loss, and dehydration. These agents should be avoided in patients with congestive heart failure, edema, cirrhosis, kidney disease, heart disease, or dehydration.6
Stimulant laxatives are the most commonly used laxatives to treat OIC. Stimulant laxatives induce peristalsis by directly irritating the smooth muscle of the intestine and, possibly, the colonic plexus. Stimulant laxatives are not associated with abuse over time, but it is known to cause a brown–black discoloration of the colonic lumen known as pseudomelanosis coli or melanosis coli.8,9 It resolves once the stimulant is discontinued.
Stool softeners exert their effect by reducing surface tension of the oil– water interface of the stool, resulting in stool softening through enhanced incorporation of water and fat. Adverse effects are minimal. These agents are particularly useful in patients with hard, desiccated stools in the distal colon. Patients should be counseled to avoid administration of stool softeners with mineral oil, as it enhances the systemic absorption of mineral oil.
Methylnaltrexone (Relistor) is a newer agent on the market for the treatment of OIC in the palliative care population with constipation refractory to standard laxative use. It is a peripherally acting opioid antagonist that preferentially blocks opioid binding at the mu receptor. Due to its high polarity and low lipid solubility, methylnaltrexone does not cross the blood–brain barrier. It has no intrinsic opioid agonist properties, does not affect opioid analgesic effects, and does not induce opioid withdrawal symptoms.10,11 Methylnaltrexone is administered as a subcutaneous injection and is dosed based on body weight.
The Pharmacist’s Role
Constipation is an expected side effect of opioid analgesic medication use, and all patients receiving opioids should be reminded of this before beginning therapy. OIC can be debilitating and associated with negative effects on quality of life and adherence to treatment; thus, treatment goals should be aimed at prevention, including counseling about lifestyle habits and use of laxatives.
1. Panchal SJ, Muller-Schwefe P, Wurzelmann. Opioid-induced bowel dysfunction: prevalence, pathophysiology and burden. Int J Clin Pract. 2007:61(7):1181-1187.
2. Pappagallo M. Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg. 2001;182(5A Suppl):11S-18S.
3. Muller-Lissner SA, Kamm MA, et al. Myths and misconceptions about chronic constipation. Am J Gastroenterol. 2005;100(1):232-242.
4. Hanks G, Cherny N. Opioid analgesic therapy. In: Doyle D, Hanks GWC, and MacDonald N, eds. Oxford Textbook of Palliative Medicine, 3rd ed. Oxford, UK: Oxford University Press; 2003. http://fds.oup.com/www.oup.co.uk/pdf/medicine/otpm3chapter8_2_3.pdf. Accessed August 2, 2009.
5. Fakata KL, Cole BE. Peripheral opioid antagonists: a therapeutic advance for optimizing opioid gastrointestinal tolerability. J Fam Pract. 2007;56(suppl 6):S3-S12.
6. Fakata KL, Tuteja AK, Lipman AG. Opioid bowel dysfunction in acute and chronic nonmalignant pain. In: Yuan C-S, ed. Handbook of Opioid Bowel Syndrome. Binghamton, NY: Haworth Medical Press; 2005:101-118.
7. Pray WS. Nonprescription Product Therapeutics, 2nd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006:142-167.
8. Bastistou A, Panelos J, Agnantis NJ. Melanosis intestini: case report. Diagn Pathol. 2006;1(1):3.
9. Villanacci V, Bassotti G, Cathomas G, et al. Is pseudomelanosis coli a marker of colonic neuropathy in severely constipated patients? Histopathology. 2006;49(2):132-137.
10. Yuan CS. Methylnaltrexone mechanisms of action and efficacy on opioid bowel dysfunction and other opioid adverse effects. Ann Pharmacother. 2007;41(6):984-993.
11. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med. 2008;358(22):2332-2343.
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