1 This Clinical Resource gives subscribers additional insight related to the Recommendations published in April 2017 ~ Resource # Treatment of Constipation in Adults Use this document as a stepwise guide to managing in nonpregnant adults. For information regarding the treatment of in children and pregnant women, see our charts, Treatment of Constipation in Children and GI Med Use in Pregnancy and Lactation. We also have a chart, Treatments for Irritable Bowel Syndrome, which includes meds useful for -predominant IBS (IBS-C). Step 1: Assess for symptoms of 1,2 Difficulty passing stool Incomplete passage of stool Reduced frequency of bowel movements (e.g., <3x/week) Step 2: If constipated patients have alarm symptoms, recommend colon cancer screening 1,3,4 Change in bowel habits after 50 years of age Blood in stool Weight loss of 5 kg (10 lbs) or more in past six months Anemia Family history of colon cancer Refractory Step 3: Assess for underlying causes of 1,3-6 Evaluate for medications that can cause 1. Is the patient taking any of the following? Antacids with aluminum or calcium, anticholinergics (e.g., tricyclic antidepressants, antihistamines, antipsychotics), antidiarrheals, beta-blockers, calcium channel blockers, calcium supplements, nonpotassium sparing diuretics, NSAIDs, oral iron supplements, opioids, 5-HT3 receptor antagonists (e.g., ondansetron). 2. If yes, consider reducing the dose or switching to another medication if risks of the med outweigh its benefits. Evaluate for disease states or metabolic abnormalities that can cause 1. Does the patient have any of the following? Anxiety, autonomic neuropathy, chronic kidney disease, colorectal cancer, dementia, depression, diabetes, diverticulitis, hemorrhoids, hypercalcemia, hypokalemia, hypothyroidism, irritable bowel syndrome, multiple sclerosis, Parkinson s disease, rectal prolapse, stroke, systemic sclerosis (scleroderma). 2. If yes, treat the underlying cause if possible.
2 (Clinical Resource #330407: Page 2 of 6) Step 4: Recommend first-line treatment options Assess for special considerations Patients who have difficulty swallowing, are on fluid restriction, or are immobile: avoid bulk laxatives. 2 Patients with intestinal obstruction: avoid oral laxatives, use enemas or suppositories for patients with fecal impaction. 2,7 Patients taking opioids: use a bowel regimen of an osmotic laxative (PEG 3350, etc) or a stimulant laxative while patients are taking opioids (i.e., initiate bowel regimen at start of opioid therapy). 2 (Note that adding a stool softener [docusate] to a stimulant laxative is widely recommended, although small studies show that adding docusate is not beneficial.) 11 Patients who should avoid straining after surgery, heart attack, etc: use an osmotic laxative (PEG 3350, etc). 13 Patients at risk for electrolyte abnormalities, such as the elderly, those with renal failure or heart failure, and those who take diuretics: avoid osmotic saline laxatives (e.g., magnesium-containing, oral sodium phosphate). 1,2 Implement appropriate lifestyle changes (may take days to weeks for results) Increase dietary fiber to a total of 20 to 25 g per day, via fiber-rich foods such as whole grains, wheat bran, or vegetables. Encourage a target fluid intake of 1.5 to 2 L per day. Start slowly and titrate up over one to two weeks to improve tolerance. 2,4,8 Consider increased physical activity if possible. 8 Counsel on toileting habits such as not holding it, not rushing on the toilet, sitting on the toilet about 30 minutes after breakfast, and sitting on the toilet in a position where the knees are at least as high as the hips. 1,2 Recommend OTC meds if necessary, titrating dose to soft stools 1. Consider a two- to four-week trial of a laxative the patient previously found to be effective Consider a two- to four-week trial of fiber (e.g., psyllium, methylcellulose) or an osmotic laxative, such as PEG 3350 (preferred because of good evidence and good tolerability), sorbitol, lactulose (Rx in U.S.), or magnesium hydroxide. 1,9 3. Consider switching to or adding a stimulant laxative such as bisacodyl or senna if additional effects are needed. 4,9 4. Consider a stimulant laxative as a rescue method with other laxatives if the patient has not had a bowel movement for two days or longer. 3 Step 5: If lifestyle changes and OTC options are not effective after a trial period, consider diagnostic tests (e.g., anorectal manometry, rectal balloon expulsion, etc) to determine cause of 9 Continue to the next section for general information about laxatives and prescription medications for
3 (Clinical Resource #330407: Page 3 of 6) Step 6: Consider therapies targeted to specific diagnoses, including Rx therapies as indicated Rx Therapy Cost* Indication Therapeutic Considerations (Adults Only) Linaclotide 14,15 (Linzess [U.S.]; Constella [Canada]) ~$12/day (U.S.) Chronic idiopathic Do not crush or chew; can sprinkle contents on applesauce or water (can give via nasogastric tube) Give on an empty stomach, 30 minutes Lubiprostone 17 (Amitiza-U.S. only) Methylnaltrexone (Relistor) 18,19 ~$4 to $6/day (Canada) ~$12/day ~$55/day (oral; U.S.) $109/ 12 mg (injectable, U.S.) ~$40/ 12 mg (injectable, Canada; oral not available in Canada) IBS with Chronic idiopathic IBS (women) with Opioid-induced in pain Opioid-induced in pain (U.S.) or with advanced illness, receiving palliative care before first meal of the day Minimal absorption, interactions unlikely Expect improvement in week 1 for bowel symptoms; longer onset for abdominal symptoms. Keep this in mind if treatment delayed (e.g., during transitions of care). No adjustments needed for renal or Protect from moisture; keep in original container with supplied desiccant Swallow whole, do not break or chew No known drug interactions Reduce dose for moderate and severe May not be effective in patients taking methadone. In vitro and preliminary data 26 suggest methadone may interfere with lubiprostone s activation of GI chloride channels. No known drug interactions Reduce dose for moderate and severe Reduce oral (U.S.) and injectable dose for renal impairment Adjust dose for under- or overweight Stop other laxatives; can restart if needed after 3 days (U.S.) May see less response in those on opioids for less than 4 weeks Monitor for opioid withdrawal Oral Give on an empty stomach, at least 30 minutes prior to first meal Subcutaneous Injection Works within 4 hours of injection in up to 50% of patients (median 24 minutes); advise patients to stay close to the toilet Give injection while seated or lying down Protect from light Consider stopping if no response after 4 doses (Canada)
4 Rx Therapy Cost* Indication (Adults Only) Naldemedine 25 ~$11/day Opioid-induced (Symproic-U.S. in only) pain (Clinical Resource #330407: Page 4 of 6) Therapeutic Considerations Take with or without food Avoid with strong CYP3A inducers and other opioid antagonists; monitor with moderate and strong CYP3A4 inhibitors and P-gp inhibitors Avoid with severe May see less response in those on opioids for less than 4 weeks Monitor for opioid withdrawal Naloxegol 20,21 (Movantik) ~$11/day (U.S.) ~$7/day (Canada) Opioid-induced in pain Can crush tablet; mix powder with water for oral or nasogastric tube use Give on an empty stomach, 1 hour prior to first meal or 2 hours after Contraindicated with strong CYP3A4 inhibitors; avoid with moderate inhibitors (if possible) and grapefruit juice Reduce dose for moderate to severe renal impairment, with weak CYP3A4 inhibitors (Canada), with moderate CYP3A4 inhibitors (if use can t be avoided), or if not tolerated Avoid with severe May see less response in those on opioids for less than 4 weeks Stop other laxative therapy; may restart in 3 days if needed Monitor for opioid withdrawal Oxycodone/ naloxone 16 (Targin-Canada only) Plecanatide 22 (Trulance-U.S. only) ~$2 to $6/day ~$12/day Oxycodone for treatment of severe pain (similar pharmacokinetics to OxyContin) Naloxone for relief of opioid-induced Chronic idiopathic Controlled release; swallow whole High first pass metabolism of naloxone results in almost no systemic action Contraindicated in severe renal impairment and moderate to severe Remnants of capsule may appear in stool Holding oxycodone (e.g., during transitions of care) could result in withdrawal symptoms Swallow whole; can crush in applesauce or water (can give via nasogastric tube) Give with or without food Negligible absorption; no expected drug interactions Protect from moisture; keep in original bottle with desiccant * Medication pricing by Elsevier, accessed November 2017 (for U.S. pricing). Cost listed is wholesale acquisition cost (WAC) in U.S. and Canada.
5 Mechanisms of Action of Laxatives:* (Clinical Resource #330407: Page 5 of 6) Osmotic agents (e.g., lactulose [Rx in U.S.], PEG 3350 [Miralax-U.S., RestoraLAX-Canada, others], sorbitol, and saline laxatives [see below]) promote secretion of water into the lumen of the colon and stimulate movement of the bowel. 1,2 The main side effect is diarrhea. Onset is typically from 12 to 96 hours. 2 Glycerin suppository onset is usually within 15 to 60 minutes. 23 Fiber/Bulk agents (e.g., methylcellulose-u.s. only [Citrucel, etc], calcium polycarbophil [FiberCon-U.S., Prodiem Fibre Therapy-Canada, etc], psyllium [Metamucil, etc]) hold water in stool, increase stool weight, increase colonic distension, and improve frequency of bowel movements. 1 The main side effects are bloating and cramping. Onset is typically from 12 to 72 hours. 2 Stimulant laxatives (e.g., bisacodyl [Dulcolax, etc], sennoside [Senokot, etc]) increase intestinal motility and colonic secretions. 1,4 The usual onset with oral formulations is six to ten hours, possibly up to 24 hours. The onset with rectal suppositories is 15 to 60 minutes. The main side effect is cramping. 2 Stool softeners (e.g., docusate [Colace, etc]) improve the interaction of water and solid stool. 1 See our commentary, Docusate: Is It Effective?, for more about the role of docusate. Saline laxatives, (a type of osmotic laxative; e.g., magnesium hydroxide, magnesium citrate, oral sodium phosphate liquid) draw water into intestines and colon by osmosis to increase motility. 2,3 Major side effects are cramping, dehydration, and electrolyte disturbances. 2,12 Onset is 30 minutes to six hours (magnesium hydroxide) and 30 minutes to three hours (magnesium citrate, oral sodium phosphate). 10 The onset of sodium phosphate enema (Fleet, etc) is usually within one to five minutes. 24 *OTC unless otherwise indicated. Be aware of the possibility for confusion due to brand name extensions, and generally recommend that patients choose a product based on generic rather than brand name. Users of this resource are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication. Project Leaders in preparation of this clinical resource (330407): Stacy A. Hester, R.Ph., BCPS, Associate Editor (Original); Annette Murray, BScPharm (November 2017 update) References 1. Gandell D, Straus SE, Bundookwala M, et al. Treatment of in older people. CMAJ 2013;185: Weitzel KW, Goode JR. Constipation. In: Krinsky DL, Ferreri SP, Hemstreet B, et al, Eds. Handbook of Nonprescription Drugs. 18 th ed. Washington, DC: American Pharmaceutical Association, Bharucha AE, Pemberton JH, Locke GR 3rd. American Gastroenterological Association technical review on. Gastroenterology 2013;144: Lembo A, Camilleri M. Chronic. N Engl J Med 2003;349: Gras-Miralles B, Cremonini F. A critical appraisal of lubiprostone in the treatment of chronic in the elderly. Clin Interv Aging 2013;8: Meek PD, Evang SD, Tadrous M, et al. Overactive bladder drugs and : a meta-analysis of randomized, placebo-controlled trials. Dig Dis Sci 2011;56: Ford AC, Talley NJ. Laxatives for chronic in adults. BMJ 2012;345:e Ternent CA, Bastawrous AL, Morin NA, et al. Practice parameters for the evaluation and management of. Dis Colon Rectum 2007;50: Bharucha AE, Dorn SD, Lembo A, Pressman A. American Gastroenterological Association medical position statement on. Gastroenterology 2013;144: Clinical Resource, Medications for Constipation. Pharmacist s Letter/Prescriber s Letter. May Tarumi Y, Wilson MP, Szafran O, Spooner GR. Randomized, double-blind, placebo-controlled trial of oral docusate in the management of in hospice patients. J Pain Symptom Manage 2013;45: FDA. Drug safety communication: FDA warns of possible harm from exceeding recommended dose of over-the-counter sodium phosphate products to treat. Updated January 15, tm?source=govdelivery&utm_medium= &utm_ source=govdelivery. (Accessed November 3, 2017). 13. McGraw T. Polyethylene glycol 3350 in occasional : a one-week, randomized, placebocontrolled, double-blind trial. World J Gastrointest Pharmacol Ther 2016;7:
6 (Clinical Resource #330407: Page 6 of 6) 14. Product information for Linzess. Allergan USA, Inc. Irvine, CA March Product monograph for Constella. Forest Laboratories Canada, Inc. Markham, ON L6G 0B5. July Product monograph for Targin. Purdue Pharma. Pickering, ON L1W 3W8. May Product information for Amitiza. Takeda Pharmaceuticals America, Inc. Deerfield, IL August Product information for Relistor. Salix Pharmaceuticals, Inc. Bridgewater, NJ August Product monograph for Relistor. Salix Pharmaceuticals, Inc. Raleigh, NC February Product information for Movantik. AstraZeneca Pharmaceuticals LP. Wilmington, DE August Product monograph for Movantik. Knight therapeutics, Inc. Montreal, QC H3Z 3B8. July Product information for Trulance. Synergy Pharmaceuticals, Inc. New York, NY February Product information for glycerin suppository. G & W Labs. South Plainfield, NJ January Product information for enema saline laxative. AmerisourceBergen. Chesterbrook, PA June Product information for Symproic. Purdue Pharma LP. Stamford, CT August Spierings EL, Drossman DA, Cryer B, et al. Efficacy and safety of lubiprostone in opioid-induced : phase 3 study results and pooled analysis of the effect of concomitant methadone use on clinical outcomes. Pain Med 2017 Jul 17. doi: /pm/pnx156. Cite this document as follows: Clinical Resource, Treatment of Constipation in Adults. Pharmacist s Letter/Prescriber s Letter. April Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA ~ TEL (209) ~ FAX (209) Copyright 2017 by Therapeutic Research Center Subscribers to the Letter can get clinical resources, like this one, on any topic covered in any issue by going to PharmacistsLetter.com, PrescribersLetter.com, PharmacyTechniciansLetter.com, or NursesLetter.com