Pill Pushing©

Laxatives - The end is near - (4/1/2017)

By Dr. Ron Gasbarro

Society at the (beginning of) time
The year was 10,002,017 BC. Fred Flintstone, a big fan of pterodactyl barbeque and Tyrannosaurus rex stew, found himself constipated. Wilma did not know what to do to relieve his pain so she asked Barney Rubble to help. Barney suggested he go to the quarry and swallow pebbles (the rocks, not the baby). All that did was create flatulence that was faster than a speeding bullet. The next idea was for Fred to stand under a waterfall with his mouth open. Sort of like a super-flush. But that method has a 98.5% fatality rate (P<.001). Then Barney goes through some reference books, specifically Encyclopedia Brontosaurus where he reads about other ways to solve Fred’s intestinal irregularity. Dynamite? Patient Zero died. Milk of Miasma? Killed patient and several bystanders.  Suction worked well but also liberated several internal organs. The rectal hook method? It worked but the funeral afterward had to be closed-coffin. 

Fred eventually solved his problem with a mixture of fossil bird egg powder and triceratops tea. Constipation can be comical up to a point. Constipation can not only be uncomfortable and even painful, it can be life-threatening too.   

The good, the bad, and the ugly. 
Constipation is the most common digestive complaint in the United States. It is a symptom rather than a disease. Despite its frequency, it often remains unrecognized until the patient develops sequelae, such as anorectal disorders or diverticular disease. 

Here are some US statistics on chronic constipation:
Prevalence: 63 million people (2000)[CDC, 2010]
Ambulatory care visits: 4.0 million (2009) [Peery, 2012]
Hospitalizations: 1.1 million (2010) [CDC/NCHS, 2010]
Mortality: 132 deaths (2010) [Everhart, 2008] 
Prescriptions: 5.3 million (2004) [Cullen, 2009] 

According to the Rome III criteria for constipation, a patient must have experienced at least 2 of the following symptoms over the preceding 3 months:
Fewer than 3 bowel movements per week
Straining
Lumpy or hard stools
Sensation of anorectal obstruction
Sensation of incomplete defecation
Manual maneuvering required to defecate
A constipated patient may be otherwise totally asymptomatic or may complain of 1 or more of the following:
Abdominal bloating
Pain on defecation
Rectal bleeding
Spurious diarrhea
Low back pain

According to the Mayo Clinic, the frequency of your bowel movements vary, but people normally have as many as 3 bowel movements a day to as few as 3 a week. You may be constipated if you have fewer bowel movements than are normal for you. In addition, constipation may involve stools that are difficult to pass because they're hard, dry or small.

However, before turning to laxatives, try these lifestyle changes to help with constipation:
Eat fiber-rich foods, such as wheat bran, fresh fruits and vegetables, and oats. 
Drink plenty of fluids daily. 
Exercise regularly.
Lifestyle improvements relieve constipation for many people, but if problems continue despite these changes, your next choice may be a mild laxative.

TNT for your colon
Laxatives work in different ways, and the effectiveness of each laxative type varies with each individual. Generally, bulk-forming laxatives, also referred to as fiber supplements, are the gentlest on your body and safest to use long term. Metamucil and Citrucel fall into this category. Stimulant laxatives, such as Dulcolax and Senokot, are the harshest and should be used only occasionally. Some examples of laxatives are presented in the table below. Even though many laxatives are available over-the-counter, it is best to talk to your pharmacist or doctor about 
laxative use and which type may be best. 

Type of laxative (brand examples)

How they work

Side effects

Oral osmotics (Milk of Magnesia, Miralax)

Draw water into the colon from surrounding body tissues to allow easier passage of stool

Bloating, cramping, diarrhea, nausea, gas, increased thirst

Oral bulk formers (Benefiber, Citrucel, FiberCon, Metamucil)

Absorb water to form soft, bulky stool, prompting normal contraction of intestinal muscles

Bloating, gas, cramping or increased constipation if not taken with enough water

Oral stool softeners (Colace, Surfak)

Add moisture to stool to allow strain-free bowel movements

Electrolyte imbalance with prolonged use

Oral stimulants (Dulcolax, Senokot)

Trigger rhythmic contractions of intestinal muscles to eliminate stool

Belching, cramping, diarrhea, nausea, urine discoloration

Rectal stimulants (Bisacodyl, Pedia-Lax, Dulcolax)

Trigger rhythmic contractions of intestinal muscles to eliminate stool

Rectal irritation, stomach discomfort, cramping


Oral laxatives may interfere with your body's absorption of some medications and nutrients. Some laxatives can lead to an electrolyte imbalance, especially after prolonged use. Electrolytes — which include calcium, chloride, potassium, magnesium and sodium — regulate a number of body functions. An electrolyte imbalance can cause abnormal heart rhythms, weakness, confusion, and seizures [Mayo Clinic, 2017].

Laxative abuse 
Laxative abuse occurs when a person attempts to get rid of unwanted calories, lose weight, “feel thin,” or “feel empty” through the repeated, frequent use of laxatives. Often, laxatives are misused following eating binges, when the individual mistakenly believes that the laxatives will work to rush food and calories through the gut and bowels before they can be absorbed. But that does not really happen. Unfortunately, laxative abuse is serious and dangerous – often resulting in a variety of health complications and sometimes causing life-threatening conditions. 

Laxatives have been used for over 2,000 years, and for much of that time abuse or misuse of laxatives has occurred [Roerig, 2010]. Individuals who abuse laxatives can generally be categorized as falling into 1 of 4 groups: 
Eating disorders: By far the largest group is made up of individuals suffering from an eating disorder such as anorexia or bulimia nervosa. The prevalence of laxative abuse has been reported to range from approximately 10% to 60% of individuals in this group. 
Increasing age: Individuals who are generally middle aged or older who begin using laxatives when constipated but continue to overuse them. This pattern may be due to certain beliefs that daily bowel movements are necessary for good health. 
Athletes: Individuals engaged in certain types of athletic training, including sports with set weight limits. 
Secret abusers: Surreptitious laxative abusers who use the drugs to cause factitious diarrhea and may have a factitious disorder. Hypochondria? 

The laxative myth 
The belief that laxatives are effective for weight control is a myth. In fact, by the time laxatives act on the large intestine, most foods and calories have already been absorbed by the small intestine. Although laxatives artificially stimulate the large intestine to empty, the “weight loss” caused by a laxative-induced bowel movement contains little actual food, fat, or calories. Instead, laxative abuse causes the loss of water, minerals, electrolytes and indigestible fiber and wastes from the colon. This “water weight” returns as soon as the individual drinks any fluids and the body re-hydrates.  If the chronic laxative abuser refuses to re-hydrate, she or he risks dehydration, which further taxes the organs and which may ultimately cause death.

According to the National Eating Disorders Association, laxative abuse has serious metabolic consequences. The body's electrolytes and minerals that are present in very specific amounts are necessary for proper functioning of the nerves and muscles, including those of the colon and heart. Upsetting this delicate balance can cause improper functioning of these vital organs. Severe dehydration may cause tremors, weakness, blurry vision, fainting, kidney damage, and, in extreme cases, death. Dehydration often requires medical treatment. Laxative dependency occurs when the colon stops reacting to usual doses of laxatives so that larger and larger amounts of laxatives may be needed to produce bowel movements. Internal organ damage may result, including stretched or “lazy” colon, colon infection, irritable bowel syndrome, and, rarely, liver damage. Chronic laxative abuse may contribute to the risk of colon cancer.
 
Where the drugs are today
Laxatives are more targeted and more expensive than ever before. You have probably seen their “pricey to produce” ads on TV and they are mostly for opioid-induced constipation (OIC). Opioids are a major class of analgesics often used to relieve pain [Vanegas, 1998]. One of the most common side effects of opioids is constipation, with incidences ranging from 40% to 80% [Sharma, 2013; Bell, 2009; Kalso, 2004]. In a patient survey, 81% of patients taking oral opioids experienced constipation [Bell, 2009]. In a meta-analysis of 18 clinical trials, 41% of patients receiving oral opioids for chronic non-cancer pain reported constipation [Kalso, 2004]. Therefore, the market is rife with new products. 

The osmotic agent lubiprostone (Amitiza®) is FDA-approved for constipation caused by irritable bowel syndrome (IBS) [FDA, 2008] and OIC [Jeffrey, 2013] in adults with chronic, non-cancer pain. Cost ~$175/month without insurance.
Several peripherally-acting mu-opioid receptor antagonists (PAMORA) have been approved by the FDA for OIC in adults with chronic non-cancer pain and/or for palliative care such as naloxegol (Movantik®). Cost ~$400/month without insurance. 
Methylnaltrexone (Relistor®) is a PAMORA indicated for OIC in adults with chronic non-cancer pain or those with advanced illness who are receiving palliative care, when responses to laxative therapy has been insufficient. Cost ~$350 for a 2-week supply without insurance; subcutaneous formulation. 
Linaclotide (Linzess®) [Pharmaceutical, 2010] and plecanatide (Trulance®) [Plecanide PI, 2017] are guanylate cyclase C (GC-C) agonists; they are indicated for chronic idiopathic constipation. Additionally, linaclotide is indicated for constipation caused by IBS in adults. Both cost ~$375/month without insurance. Currently, not approved for OIC. 

Running to the ER
Meanwhile, emergency room (ER) visits because of painful constipation are on the rise. Although constipation is typically managed in an outpatient setting, there is an increasing trend in the frequency of constipation-related hospital visits in the US. A 2015 study demonstrated that between 2006 and 2011, the frequency of constipation-related ER visits increased by 41.5%, from 497,034 visits to 703,391 visits, whereas the mean cost per patient rose by 56.4%, from $1,474 in 2006 to $2,306 in 2011 [Sommers, 2015]. The aggregate national cost of constipation-related ER visits increased by 121.4%, from $733 million in 2006 to $1.6 billion in 2011. Infants (<1-year-old) had the highest rate of constipation-related ER visits in both 2006 and 2011. The late elders (85+ years) had the second highest constipation-related ER visit rate in 2006; however, the 1- to 17-year-old age group experienced a 50.7% increase in constipation-related ER visit rate from 2006 to 2011 and had the second highest constipation-related ER visit rate in 2011. The study investigators could not explain why people come to the ER with constipation. However, they speculated on the reasons why people did. First, the person may have severe abdominal pain. Second, there has been an increase in the number of people on government-funded insurance, notably Medicaid. Those people may be more likely to seek treatment at an ER and less likely to purchase over-the-counter treatments for constipation, wrote the researchers.

Ron Gasbarro, PharmD, is a registered pharmacist, medical writer, and principal at Rx-Press.com. Visit him at www.rx-press.com

References 
Andrews CN, Storr M. The pathophysiology of chronic constipation. Can J Gastroenterol. 2011;25(suppl B):16B-21B.

Bell TJ, Panchal SJ, Miaskowski C, Bolge SC, Milanova T, Williamson R. The prevalence, severity, and impact of opioid-induced bowel dysfunction: results of a US and European patient survey (PROBE 1). Pain Med. 2009;10:35-42.

CDC/NCHS national hospital discharge survey: United States, 2010. Centers for Disease Control and Prevention website. Available at: https://www.cdc.gov/nchs/nhds/about_nhds.htm

Centers for Disease Control and Prevention, National Center for Health Statistics. Underlying cause of death, detailed mortality, 2010, sorted by diseases of the digestive system (K00–K92). CDC WONDER online database. http://wonder.cdc.gov/ 

Cullen KA, Hall MJ, Golosinskiy A. Ambulatory surgery in the United States, 2006. Natl Health Stat Report. 2009;11:1–25.

Everhart JE, ed. The Burden of Digestive Diseases in the United States. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases, US Department of Health and Human Services; 2008. NIH Publication 09–6433.

Jeffrey S. FDA approves Amitiza for opioid-induced constipation [press release]. Medscape Medical News. Available at http://www.medscape.com/viewarticle/802953. April 23, 2013.

Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain. 2004;112:372-80.

Lembo A, Camilleri M. Chronic constipation. N Engl J Med. 2003;349:1360-8.

Peery AF, Dellon ES, Lund J, et al. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology. 2012;143:1179–87.

Pharmaceutical Business Review. Ironwood Pharma, Forest Labs Present Linaclotide Phase 3 Trial Results. pharmaceutical-business-review.com. Available at http://clinicaltrials.pharmaceutical-business-review.com/news/ironwood_pharma_forest_labs_present_linaclotide_phase_3_trial_results_

Plecanatide (Trulance) [prescribing information]. New York, NY: Synergy Pharmaceuticals Inc. 2017. 

Roerig JL, Steffen KJ, Mitchell JE, Zunker C. Laxative abuse: epidemiology, diagnosis and management. Drugs. 2010;70:1487-503. 

Sharma A, Jamal MM. Opioid induced bowel disease: a twenty-first century physicians' dilemma. Curr Gastroenterol Rep. 2013;15:334.

Sommers T, Corban C, Sengupta N, et al. Emergency department burden of constipation in the United States from 2006 to 2011. Am J Gastroenterol. 2015;110:572-9.

US Food and Drug Administration. FDA approves Amitiza for IBS-C [press release]. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116889.htm. April 29, 2008.

US Food and Drug Administration. FDA approves Trulance for chronic idiopathic constipation. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm537725.htm. January 19, 2017.

Vanegas G, Ripamonti C, Sbanotto A, De Conno F. Side effects of morphine administration in cancer patients. Cancer Nurs. 1998;21:289-97.


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