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Patrick D. Meek, Michael R. Brodeur
Albany College of Pharmacy and Health Sciences, Albany, New York 12208, USACorrespondence to: Patrick D. Meek, PharmD, MSPH, Associate Professor of Pharmacy Practice. Albany College of Pharmacy and Health Sciences, 106 New Scotland Avenue, Albany, New York 12208, USA. Email: [email protected]; Michael R. Brodeur, PharmD, CGP, FASCP, Associate Professor of Pharmacy Practice. Albany College of Pharmacy and Health Sciences, 106 New Scotland Avenue, Albany, New York 12208, USA. Email: [email protected].
Abstract: Constipation and diarrhea are common symptoms in palliative medicine that could have a significantly negative impact on the quality of life of patients suffering from serious and chronic illnesses. This chapter provides an overview of drug-related risk factors, frequency and clinical characteristics, and therapeutic options for the management of constipation as well as diarrhea in the context of palliative medicine. Effective treatment of constipation and diarrhea should target the underlying cause, provide supportive care, aim to alleviate troublesome symptoms, and prevent recurrence. Patients should be monitored for improvement in bowel function, quality of life, and activities of daily living. Keywords: Constipation; diarrhea; risk factors; management strategies; palliative care Received: 09 May 2016; Accepted: 04 August 2016; Published: 18 August 2016.
doi: 10.21037/xym.2016.08.08
View this article at: http://dx.doi.org/10.21037/xym.2016.08.08
Risk factors for constipation Constipation and diarrhea are common symptoms in Opioid effects in the colon result in reduced motility palliative medicine that could have a significantly negative and decreased propulsive migrating contractions, and an impact on the quality of life of patients suffering from increased risk of constipation, acute abdomen, paralytic serious and chronic illnesses. A common risk factor for ileus, and obstruction. OIC is a direct consequence of drug constipation in the setting of palliative care is the use of binding to peripheral mu receptors located in the enteric opioid analgesics (1-4). Opioid-induced constipation (OIC) nervous system (ENS) (6). The ENS coordinates normal and narcotic bowel syndrome (NBS) are two preventable gastrointestinal (GI) function and is composed of the conditions caused by opioids that should be considered myenteric plexus, which coordinates motor function, and when evaluating patients with constipation in this setting. the submucosal plexus, which is responsible for secretory Diarrhea, although less common than constipation, is seen and absorptive functions. Opioids augment GI function in about 10% of patients, and can lead to serious fluid through several mechanisms within the ENS and colon: and electrolyte disturbances, and nutrient deficiencies (5). (I) inhibition of acetylcholine release decreases longitudinal The most common causes of diarrhea in palliative care are smooth muscle contractions, which decreases peristalsis and laxative use, side effects of medications, radiotherapy, and forward movement of stool, and an increased segmental specific disease processes, including AIDS/HIV infection, contraction leads to stasis; (II) inhibition of vasoactive enteric infection, pancreatic and biliary conditions, intestinal polypeptide (VIP) and prostaglandin E1 release; inflammatory bowel disease, and celiac disease. This chapter combined with (III) enhanced norepinephrine and serotonin provides an overview of drug-related risk factors, frequency release, decreases secretions and desiccates the stool; and and clinical characteristics, and therapeutic options for (IV) decreases in intestinal stasis enhance passive absorption the management of constipation as well as diarrhea in the of water and electrolytes.
context of palliative medicine.
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agents (i.e., tramadol and codeine) at lower equivalent Table 1 Risk factors for constipation and diarrhea in palliative care
daily doses of oral morphine (7). However, patient factors such as immobility, may contribute heavily to the risk of Opioid therapy for treatment of pain constipation, and therefore, opioid dose should not be Concomitant treatment with drugs that independently increase considered independently of other factors (8). In terms the risk of constipation (anticholinergics, antihypertensive (calcium of the method of administration, transdermal fentanyl channel blockers, diuretics), aluminum-containing antacids, causes less OIC than morphine (9), and may be a preferred calcium, and iron supplements) agent in patients whose opioid requirements are stable. In contrast, evidence supporting an effect of switching from oral to a parenteral route of administration is inconclusive (10-12).
Lack of physical activity Frequency and characterization of OIC Endocrine or neuromuscular disorder History of constipation in childhood In a survey, performed in the United States and Europe (PROBE 1) (13), of 322 patients taking daily oral opioids and laxatives, 45% of respondents reported fewer than three Depression or anxiety bowel movements per week, 81% reported constipation, Family history of cancer and 58% reported straining. Symptoms were most often History of pelvic surgery reported as severe, and had at least a moderate negative impact on overall quality of life and activities of daily living.
Unlike other opioid-induced adverse effects (i.e., Laxative therapy for prevention or treatment of constipation respiratory depression, nausea, sedation), tolerance Chemotherapy (5-fluorouracil, irinotecan, capecitabine, and to constipation will rarely develop and is often cited docetaxel, in particular) as the most common dose-limiting adverse effect that Targeted cancer therapies (erlotinib, gefitinib, and sorafenib) may prevent adequate pain control. Clinically, OIC is a constellation of symptoms, including hard/dry stools, Concomitant medications that independently increase the risk of diarrhea [antibiotics, promotility drugs, proton pumps straining, feeling of incomplete evacuation, bloating inhibitors, magnesium-containing antacids, misoprostol, and abdominal distention. These symptoms are similar digoxin, anti-arrhythmic agents, oral hypoglycemic drugs to those seen in chronic constipation, but patients with (biguanides, alpha-galactocidase inhibitors)] OIC may also experience decreased appetite, dyspepsia/ heartburn, and gastroesophageal reflux. Uncontrolled OIC can lead to complications, including fecal impaction with overflow diarrhea, pseudo-obstruction of the bowel causing AIDS/HIV infection anorexia, nausea, vomiting, inadequate absorption of oral Clostridium difficile associated diarrhea medications, urinary retention and incontinence, and Comorbid conditions in the elderly (inflammatory bowel disease, pancreatic or biliary disease, celiac disease) In a meta-analysis of 11 randomized studies of opioid therapy for nonmalignant pain, constipation affected an average of 41% of patients taking opioids for 8 weeks (14). of exposure, including opioid dose (based on equivalent In terms of the burden of symptoms in advanced illness, daily doses of oral morphine), route of administration, and OIC can rival the distress caused by pain. Since tolerance presence of concomitant causes of constipation (Table 1). to this side effect does not develop, constipation is unlikely High-potency opioids (i.e., morphine, oxycodone, and to improve over time, and therefore must be anticipated, fentanyl) at higher equivalent daily doses of oral morphine monitored, and addressed throughout the opioid treatment may cause OIC more often than low- or medium-potency Xiangya Medicine. All rights reserved.
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Table 2 Laxative categories
Absorbs liquids in the intestines and swells to form a soft, bulky stool Osmotic laxatives Lactulose, sorbitol, polyethylene glycol (PEG), Draws water into the bowel from surrounding body tissues providing magnesium citrate, magnesium hydroxide a soft stool mass Stimulants/irritants Bisacodyl, senna Encourage bowel movements by acting on the intestinal wall Coats the bowel and the stool mass with a waterproof film so stool remains soft Helps liquids mix into the stool and prevent dry, hard stool masses Chloride channel Increases fluid secretion in the intestine, which increases intestinal Combinations containing more than 1 type of laxative Therapeutic options for management of products containing two or more laxatives is generally not advised except in refractory patients, as combination products may cause more side effects.
Nonpharmacologic management of constipation
A variety of nonpharmacologic options are available for Management of OIC
the general management of chronic constipation. Lifestyle measures such as increasing fluids, increasing dietary fiber When routine prophylactic laxatives are insufficient (17,18), intake, or initiating an exercise regimen are often the first- treatment with subcutaneous methylnaltrexone should be line approach, but studies evaluating the effects of these considered. Methylnaltrexone is a quaternary N-methyl measures have yielded mixed results, and patients have likely derivative of the opioid antagonist naltrexone, an opioid already tried many of these measures prior to reporting antagonist similar to naloxone, but is less lipid soluble so it symptoms to their clinicians.
is less likely to cross the blood brain barrier and reverse the Although a diet low in fiber can lead to constipation, a palliative effects of opioids or cause withdrawal reactions. high-fiber diet will not necessarily benefit all patients with The efficacy of methylnaltrexone was evaluated in a study constipation, especially patients with an underlying motility of 134 patients with advanced illness receiving opioids for disorder. The American Gastroenterological Association ≥2 weeks and laxatives for ≥3 days without relief of OIC does, however, recommend a gradual increase in fiber intake who were randomized to methylnaltrexone 0.15 mg/kg vs. in either dietary or supplement form as a first-line approach placebo subcutaneously every other day for 2 weeks (19). to management of chronic constipation (15). Supplemental When comparing methylnaltrexone vs. placebo, bowel fiber should be introduced gradually to avoid significant movement without laxative occurred more often within bloating and cramps, and patients should be advised that 4 hours of the first dose in 48% vs. 15% (P<0.001, they may experience an increase in gaseousness.
NNT 3). The range of response with individual doses of Exercise has not been shown to be an effective stand- methylnaltrexone was 37–48% vs. 7–15% with placebo. alone therapy for chronic constipation, but may help to More patients treated with methylnaltrexone had three improve bowel function as part of a broader rehabilitation or more laxative-free bowel movements per week in 68% program for elderly patients with constipation (16). If vs. 45% (P=0.009, NNT 5). There were no significant nonpharmacologic approaches prove insufficient, laxative differences in scores of withdrawal or changes in pain. A therapy is typically the next step. Commonly used products similar response rate persisted in the 3-month open-label include bulking agents, stool softeners, osmotic laxatives, extension trial. Adverse effects were more common with and stimulant laxatives (Table 2). Use of combination methylnaltrexone vs. placebo (Table 3).
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Table 3 Methylnaltrexone-related adverse effects (19)
Number needed to treat to treated group (%) placebo group (%) Increased body temperature While opioid side effects such as constipation and nausea a patient's medication profile (GI drugs, cardiovascular are common and anticipated during palliative care, other drugs, oral hypoglycemic drugs). The risk of diarrhea is less common adverse events may occur that may not be compounded whenever multiple medications with different attributed to opioid therapy, even though opioids are the mechanisms for causing diarrhea are used concurrently.
root cause. This is the case for NBS, which has several unique characteristics that differentiate it from OIC and warrant a much different approach to treatment.
NBS is characterized by chronic recurring abdominal Diarrhea associated with misuse of laxatives in the
pain that worsens with continued or escalating doses of narcotics (20). Other symptoms of NBS include: Elderly patients who use laxatives chronically may intermittent vomiting, weight loss and occasional ileus- experience diarrhea, and incontinence. Habitual laxative like symptoms. The recurrence or persistence of painful use in this population is well documented (22), and may NBS symptoms leads to additional use of narcotics. After be a potential cause of unexplained diarrhea despite a a short period of relief, pain typically recurs, despite comprehensive diagnostic workup. An alternating pattern narcotics, and is stronger. These symptoms lead to of constipation and diarrhea, and persistent electrolyte additional narcotics, yet again. Until it is recognized, NBS disturbance should increase the level of suspicion in laxative symptoms will persist and continue to worsen. Treatment misuse. Diarrhea caused by stimulant laxatives may be of NBS involves early diagnosis, and gradual withdrawal of accompanied by colic and urgency, while osmotic laxatives narcotics (21). Benzodiazepines and clonidine are useful in and stool softeners often cause stool fecal leakage. Persistent the management of withdrawal symptoms as the patient is hypokalemia and melanosis coli may result from chronic use titrated off the narcotic. of Senna (an anthraquinone laxative). Diarrhea associated with laxatives or methylnaltrexone
Risk factors for diarrhea The next section reviews risk factors for diarrhea in The risk of diarrhea is significantly increased during palliative medicine (Table 1), with an emphasis on drug- pharmacologic treatment for OIC. In a meta-analysis related causes. Subsequent sections cover frequency of 11 placebo-controlled trials of mu-opioid receptor and characterization, and therapeutic options for the antagonist therapy for OIC, diarrhea was reported by an management of diarrhea. average of 8.4% of patients in the active treatment groups, Drug-induced diarrhea is the most common cause of compared with an average of 4.7% in the placebo groups diarrhea in palliative care. Certain medication classes may (RR =1.61, 95% CI, 1.21–2.13; NNH 33) (23). Likewise, be obvious candidates when considering diarrhea as an diarrhea is one of the most common side effects reported in adverse drug event (laxatives, specific chemotherapeutic comparative trials of laxative therapy for OIC (24). Bowel drugs, and antibiotics), while other classes may be less function should be closely monitored during OIC therapy prominent and potentially overlooked during a review of to minimize the risk of diarrhea.
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breast, head and neck, squamous cell disease, non-small cell lung cancer, advanced gastric cancer, and hormone Over 20% of cancer patients receive chemotherapy or other refractory prostate cancer. Diarrhea from docetaxel is forms of aggressive cancer care near the end of life (25,26). typically mild and is caused by the drug's cytotoxic activity 5-fluorouracil, irinotecan, capecitabine, and docetaxel are in the mucosal lining of the GI tract. As a result of reduced notable examples. These drugs are associated with high GI mucosal defenses, patients are predisposed to enteritis rates of diarrhea ranging in severity from mild to moderate, and colitis. Severe cases of neutropenic enterocolitis, a in 20% to 50% of patients, to severe, in 5% to 10% of life-threatening complication of chemotherapy, have been patients (27-31).
reported in patients receiving high doses of docetaxel 5-Fluorouracil is approved by the U.S. Food and Drug when administered along with myeloablative therapies that Administration (FDA) for palliative treatment of breast, deplete bone marrow cells (32,33). pancreatic, colorectal and gastric cancer. Diarrhea from High rates of diarrhea are also associated with targeted 5-Fluorouracil is caused by the drug's antimitotic effects cancer therapies, such as the epidermal growth factor on intestinal crypt cells and villous enterocytes that leads receptor tyrosine kinase inhibitors; erlotinib, gefitinib, to a reduced surface area for absorption in the GI tract. It and vascular endothelial growth factors; sorafenib. Close is more common at higher (bolus) doses, and during co- inspection of a patient's medication profile in an effort treatment with leucovorin.
to identify drugs with the potential to cause diarrhea will Irinotecan is FDA approved as first-line treatment facilitate the development of a specific treatment plan for of metastatic colorectal cancer in combination with drug-induced diarrhea in patients with cancer.
5-fluorouracil and leucovorin, or as single-agent treatment of metastatic colorectal cancer that has recurred or progressed after 5-fluorouracil-based therapy. Diarrhea from irinotecan can be either early-(during or shortly after While chemotherapy and other cancer treatments should infusion) or late-onset (usually 24 hours or longer after be considered a probable cause of diarrhea in cancer infusion). Most early onset adverse events from irinotecan patients, several other drugs should also be recognized for are caused by the drug's activation of cholinergic receptors their potential contribution to the prevalence of diarrhea in that result in diarrhea, abdominal cramping, flushing, palliative care (Table 1) (34). lacrimation, salivation and other cholinergic symptoms. Late onset diarrhea from irinotecan is unpredictable, and can occur at any dose of the drug. However, lower rates Antibiotics can cause diarrhea through a variety of of diarrhea are seen when irinotecan is administered every mechanisms. Most cases of diarrhea are mild and transient. 3 weeks, instead of a weekly basis.
However, pseudomembranous colitis is a well-known Capecitabine is FDA approved for metastatic breast complication of diarrhea from antibiotic therapy and is most or colorectal cancer. It is an orally administered prodrug closely associated with clindamycin, amoxicillin, ampicillin, of 5-Fluorouracil that is transformed to the active drug and cephalosporins, but may also occur with erythromycin, by enzymatic conversion at the site of the tumor. Like fluoroquinolones, cotrimoxazole, suflamethoxazole, and 5-Fluorouracil, capecitabine reduces the villous enterocyte penicillin. Fatty diarrhea may occur with aminoglycoside, population, which predisposes individuals to an imbalance or tetracycline antibiotics.
between absorption and secretion in the small bowel, and increases the risk of diarrhea. Lower rates of diarrhea are reported with oral capecitabine compared to infusion In addition to laxatives, several other types of GI drugs are regimens of 5-Fluorouracil, especially when capecitabine is known to increase the risk of diarrhea. Promotility drugs administered as single-agent chemotherapy. Capecitabine- (cisapride, domperidone, metoclopramide, prucalopride) can induced diarrhea is more common in the United States, cause diarrhea due to a direct effect on GI transit. The only which may indicate the potential influence of genetic drug in this category with FDA approval is metoclopramide. polymorphisms, or variation in dietary intake of folic acid, Diarrhea may also be seen in patients receiving a proton which is required for 5-Fluorouracil activation.
pump inhibitor (omeprazole, lansoprazole, pantoprazole, Docetaxel is FDA approved for locally advanced/metastatic rabeprazole, esomeprazole, dexlansoprazole), although this Xiangya Medicine. All rights reserved.
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Table 4 Antidiarrheal drugs
Psyllium, methylcellulose 3.4 gram psyllium orally two to three times Bulking agent for control of mild diarrhea daily or 1 teaspoonful methylcellulose orally up to three times daily 30 to 60 mL every 4 hours Adsorbent/absorbent combination for control of mild diarrhea 4 mg orally, then 2 to 4 mg orally every 4 to Opioid agonist for control of mild to moderate Diphenoxylate/atropine (2.5/0.025 mg 2.5/0.025 mg to 5.0/0.05 mg diphenoxylate/ Combination of opioid agonist with anticholinergic per tablet or per teaspoonful) atropine orally every 4 to 6 hours drug for control of mild diarrhea 15 to 60 mg orally every 4 to 6 hours Opioid agonist for control of refractory diarrhea Deodorized tincture of opium (10%) 0.6 to 1.2 mL orally every 4 to 6 hours Opioid agonist for control of refractory diarrhea adverse effect occurs in only 2–5% of patients receiving fecal incontinence, dehydration, fluid and electrolyte one of these drugs. Magnesium-containing antacids are disturbances, and nutritional deficiencies (36), each of which poorly absorbed substances that draw fluid into lumen of could lead to serious outcomes such as hospitalization and the bowel can cause an osmotic diarrhea. Misoprostol, death (37). Early recognition and appropriate therapy can a gastroprotectant for prevention of nonsteroidal anti- minimize the impact of diarrhea on a patient's quality of inflammatory drug-induced gastropathy, is also associated life, and activities of daily living.
with a high rate of diarrhea. Therapeutic options for management of diarrhea Cardiovascular drugs and oral hypoglycemic drugs
Diarrhea may be a concerning side effect of drugs used to
The goal of therapy for diarrheal conditions is to address treat cardiovascular disease or diabetes. Digoxin, quinidine, the underlying cause with specific interventions, and and procainamide each have rates of diarrhea less than 5%. manage symptoms with appropriate nonpharmacologic Although the rates are low, this side effect could be dose- and pharmacologic antidiarrheal treatments (Table 4). limiting or lead to treatment nonadherence. In patients with Therefore, the first step in treatment is to identify the diabetes, oral hypoglycemic drugs, especially biguanides underlying cause. Bulking agents may provide relief for mild (metformin), alpha-galactocidase inhibitors (acarbose, diarrhea, especially in patients with low dietary fiber intake. and miglitol), are associated with high rates of diarrhea. Laxative- or methylnaltrexone-induced diarrhea can be Reported rates of diarrhea for these agents during clinical managed by reducing the dose or discontinuing the culprit trials are 53%, 31%, and 28%, for metformin, acarbose, and drug. Management of chemotherapy-induced diarrhea will depend on the mechanism of diarrhea. Aggressive oral rehydration and electrolyte replacement may be necessary as supportive care for some patients with severe diarrhea. Mild Frequency and characterization of diarrhea to moderate diarrhea from 5-Fluorouracil, capecitabine, The overall rate of diarrhea in palliative care may be as docetaxel, and early- and late-onset diarrhea from irinotecan high as 10–20% (35), and will depend on the prevalence of can be managed with loperamide or diphenoxylate-atropine. risk factors in a given population. The onset and worsening Early-onset cholinergic symptoms from irinotecan may of drug-induced diarrhea may correlate with periods of be prevented or treated with intravenous or subcutaneous intensification of therapy. This is particularly true with atropine. Adsorbent/absorbent combinations may also laxative therapy for OIC and chemotherapy during cancer be used as adjunctive agents for additional relief from care. Complications of poorly controlled diarrhea include chemotherapy-induced diarrhea. Xiangya Medicine. All rights reserved.
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doi: 10.21037/xym.2016.08.08
Cite this article as: Meek PD, Brodeur MR. Constipation/
diarrhea. Xiangya Med 2016;1:24.
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