Super Bowl, Super Bowel, or Just More Turds?

And here it is folks, the moment you’ve all been waiting for – the softer version of our 2017 Super Bowel Blog following several editorial and constitutional considerations! This year, rather than justifiably attacking politicians, our intent was to crack you up a bit with some humor while providing updates and key learning points for the treatment and prevention of OIC.

Hats off to our two quest bloggers Matt Simpson and Erica Wegrzyn…

As we approach Super Bowl LI and impending showdown between The Patriots and Falcons, we are reminded of the controversy of last year’s Super Bowl. Not deflategate, as you might have assumed, but the controversy that stemmed from the airing of a commercial for Movantik (Naloxegol) for the treatment of opioid induced constipation (OIC). Then student, Dr. Kathleen Nicewicz outlined the controversy in previous blog post, Opportunistic Turds and Opioid Induced Constipation. Monetary and political double standards were obviously conflated, as OIC has nothing to do with the dangers of respiratory risks when prescribing opioids.  Simply put, Movantik and other PAMORAs are to treat a symptom of chronic opioid therapy – PAMORAs are not dangerous drugs by any stretch.  But, Movantik manufacturer Astra Zeneca’s message was clear (and safe) when compared to Anheuser-Busch and Coca Cola Co. The real facts are that both of these companies, unlike Astra Zeneca, are likely responsible for more worldwide deaths due to obesity, alcoholism, and diabetes, than all opioids combined, but that is a separate issue when considering the cold hard facts.

With the Super Bowl upon us, we wanted to take this opportunity to review OIC and here is to hoping this year is controversy free, sportsmanship-wise and OIC-wise.

Opioid medication therapy is an important tool for healthcare providers to have for treatment of pain. Patients on opioid therapy can experience nausea, vomiting, sedation, respiratory depression and constipation. OIC is the most common adverse effect of opioid therapy. Although tolerance may develop to the central nervous system (CNS) side effects, this does not occur with OIC. OIC occurs in a large percentage of patients who require chronic opioid therapy.¹ Specifically in patients being treated for noncancer pain, the prevalence of OIC is from 40% to 50%.¹

What is Opioid Induced Constipation (OIC)?

The American College of Gastroenterology defines constipation as unsatisfactory defecation with infrequent bowel movements, difficult stool passage, or both.² Gastroenterology journal defines OIC as a change from baseline bowel habits that can be characterized by any of the following: reduced bowel frequency, development or worsening of straining, a sense of incomplete evacuation or a patient’s perception of distress related to bowel habits.³ Diagnostic criteria for OIC as new or worsening symptoms of constipation when opioid therapy is initiated or current dosage is increased or when transitioning between opioid agents that includes any 2 of the following:

1. Straining during more than one fourth of defecations
   b. lumpy or hard stools more than one fourth of defecations
   c. sensation of incomplete evacuation more than one fourth of defecations
   d. sensation of anorectal obstruction/blockage more than one fourth of defecations
   e. manual maneuvers to facilitate more than one fourth of defecations
   f. fewer than three spontaneous bowel movements per week.³
   The single greatest risk factor for patients is duration of opioid therapy.⁴          

What is the Mechanism of Opioids Causing OIC?

Mu-opioid, kappa-opioid and delta opioid receptors are all located in the gastrointestinal tract, although Mu-receptors are the most abundant. OIC is caused when opioid agonists bind in peripheral tissues of the enteric nervous system. The activation of the opioid receptors in the gastrointestinal tract by oral opioids results in increased transit time, increased non-propulsive contractions and enhanced fluid absorption.¹ Transit time is increased via reduced smooth muscle tone and contractility in the bowel.^1,4

What are Current Treatment Options for OIC?

There are currently several non-pharmacological treatment options for OIC including increasing fluid and fiber intake as well as increasing physical activity.⁵ Traditional over-the-counter options include stool softeners, bulking agents, and laxatives. Among over the counter laxative options, no one choice is better than the other and require patients to find which one or combination works best for them. It is recommended that laxatives and stool softeners should be initiated at the start of opioid therapy.

Anti-Constipatory Agent	Mechanism of Action
Bulk-Producing Agents	Bulking agents work in both the small and large bowel, with an onset of action of 12 to 72 hours. They bulk up the stool so that it retains more water, making peristalsis easier. Examples include psyllium, methylcellulose and dietary fiber
Stool Softeners	Stool softeners soften stool and make it “slippery,” making the stool easier to pass. These work in the colon and take effect in 6 to 8 hours
Lubricants or Emollients	Lubricants/emollients, such as mineral oil, soften and coat the stool, thus preventing colonic water absorption. Vegetable-oil enemas act as lubricants.
Hydrating Agents	Hydrating Agents increase the water content in the stool, which makes the stool softer and easier to pass. Some of these work by increasing the bowel lumen osmolality. Examples include Fleet phospho-soda and Miralax.
Stimulants	Stimulants stimulate colonic contractions that propel stools forward. These agents irritate the lining of the intestines. Examples include cascara sagrada, bisacodyl and senna
Others	Prostaglandins, prokinetic drugs, and other agents change the way the intestine absorbs water and electrolytes, and increase the weight and frequency of stools while reducing transit time.

Above table is reformatted from Gudin J, Fudin J. Opioid-Induced Constipation: New and Emerging Therapies– Update 2016. Practical Pain Management. 2016 December; 16(10).

New developing therapies are designed to antagonize the gastrointestinal opioid receptors to reverse OIC. Peripherally acting mu-receptor antagonists (PARMORA) target the receptors that are the main cause of OIC. PAMORAs represent a unique solution to opioid induced constipation (OIC) by targeting opioid receptors in the GI tract directly. PAMORA agents on the market include Entereg (alvimopan), Movantik (naloxegel), and Relistor (methylnaltrexone). Also available is Amitza (lubiprostone) a chloride channel activator.

Entereg (alvimopan) is marketed by Merck&Co. Entereg is not FDA approved for OIC however it’s mechanism of action suggests it would be effective in this area. Entereg also has a REMS program called EASE due to increased risk of myocardial events which was discovered during a clinical trial of patients with chronic non-cancer pain. Suggested dosing is based on FDA approved use with postoperative ileus. Entereg is not recommended in renal or hepatic impairment.⁶

Movantik (naloxegel) is marketed by Daiichi-Sankyo and AstraZenaca. Movantik is administered as a 25mg tablet once daily every morning. Dosing is adjusted to 12.5 mg daily for CrCl <60 mL/min. Use of Movantik is not suggested in patients with hepatic impairment. When starting Movantik, all other maintenance laxatives should be discontinued. If there is suboptimal response after 3 days of therapy, the patient may resume use of laxatives. Adverse effects of using Movantik include abdominal pain, diarrhea, and nausea.⁷

Relistor (methylnaltrexone) is marketed by Salix and is available in two formulations, subcutaneous or oral. Relistor is given as 12 mg subcutaneously once daily or as 450 mg orally once daily in the morning. If CrCl <60 mL/min, the dose should be reduced to 6 mg subq or 150 mg orally. Relistor also must be dose adjusted for moderate to severe hepatic impairment. Adverse effects include abdominal pain, flatulence, and nausea. Also in rare but serious cases, GI perforation may occur. Similarly to Movantik, all maintenance laxatives must be discontinued when starting Relistor and may be restarted if there is unsatisfactory response after 3 days of therapy.⁸

Amitza (lubiprostone) is marketed by Takeda Pharmaceuticals. Unlike the above PAMORAs, Amitza is a chloride channel activator and functions by increasing intestinal fluid secretion to aid in motility. Amitza is available as a 24mcg capsule taken twice a day. Amitza requires dose adjustment for hepatic impairment. For Child Pugh Class B reduce initial dose to 16 mcg orally twice daily. For Child Pugh Class C reduce initial dose to 8 mcg orally twice daily. If tolerated and optimal response is not achieved the dose may be increased to 24 mcg. Most common adverse effects of Amitza include nausea and diarrhea. Dyspnea, syncope, and hypotension may occur with the first dose. Dyspnea usually resolves within 3 hours of taking the dose. If syncope and hypotension occur with additional doses, Amitza should be discontinued.⁹

Table 1 ^6,7,8,9

Medication	Mechanism	Side Effects	Dose Adjustment	Contraindications	Special Notes
Movantik (naloxegol) 25 mg orally once daily in the morning	A pegylated derivative of naloxone that targets peripheral tissue to antagonize the mu-opioid receptors.	Abdominal pain (21%), Diarrhea (12.9%), Nausea (9%)	Reduce dose to 12.5 mg once daily if CrCl <60 mL/min.   Avoid use in severe hepatic impairment	GI obstruction   Concomitant use with strong CYP 3A4 inhibitors   Hypersensitivity	Prior to initiation discontinue all maintenance laxative therapy, may resume 3 days later if there is suboptimal response
Entereg (alvimopan) 12 mg administered 30 minutes to 5 hours prior to surgery followed by 12 mg twice daily beginning the day after surgery for up to 7 days.	Selective antagonist of mu-receptor. Reverses the gastrointestinal motility and secretion effects caused by opioids	Dyspepsia (1.5%)	Not recommended in severe hepatic impairment. No dose adjustment for renal impairment	Patients who have taken therapeutic doses of opioids for more than 7 days prior	REMS- Hospital use only due to myocardial risk. Not approved for OIC
Relistor (methylnaltrexone) 12 mg subq once daily   450 mg orally once daily in the morning	Targets opioid receptor binding sites in peripheral tissues to decreased OIC without interfering with analgesic effects in CNS.	Abdominal pain (14-29%), flatulance (13%), nausea (12%), GI perforation (rare but serious)	Reduce oral dose to 150 mg and subq dose to 6 mg if CrCl <60 mL/min. Moderate- severe hepatic impairment, consult package insert for adjustment	GI obstruction	Prior to initiation discontinue all maintenance laxative therapy, may resume 3 days later if there is suboptimal response
Amitiza (lubiprostone) 24 mcg by mouth twice daily	Activates  type-2 chloride channels in epithelial cells that line the intestinal tract which increases intestinal fluid secretion and motility in the intestine.	Nausea  (11%), diarrhea (8%)	No renal adjustment. Hepatic impairment: Child Pugh Class B reduce initial dose to 16 mcg orally twice daily. Child Pugh Class C reduce initial dose to 8 mcg orally twice daily. If tolerated and optimal response is not achieved may increase dose to 24 mcg.	Known or suspected mechanical gastrointestinal obstruction. May interact with diphenylheptane opioids	Dyspnea: May occur within 1 hour of first dose. Generally resolves within 3 hours. Syncope and hypotension: May occur with first dose. Discontinue if occur with repeat dosing

OIC is the most common side effect of opioid therapy. When patients are started on opioid therapy they should also be started on a bowel regimen. Commonly, over the counter products such as laxatives, stool softeners, or bulk forming agents are selected as first line. PAMORAs offer a unique option by acting peripherally to reverse effects on the opioid receptors in the gut without interfering with the analgesic effect of the opioid. Other agents like Amitza (lubiprostone) function in unique ways to support normal bowel motility. OIC can be prevented and treated with these options, patients shouldn’t have to suffer from OIC.

So, this year when re-laxing in front of the television, remember that this sedentary activity may contribute to constipation, opioid-induced or otherwise.  Drink plenty of fluids (use your own discretion and be safe – don’t drive), don’t combine alcohol with opioids or other sedating drugs, binge on junk food moderately unless you have diabetes (sugar) or uncontrolled hypertension (salt), and enjoy the game!

As always, we welcome all comments, regardless of consistency!

This guest blog was collaboratively written by Mr. Simpson and Dr. Wegrzyn under the mentorship of and edited by Dr. Jeffrey Fudin.

Many thanks to our guest bloggers Matt and Erica!

Matthew Simpson is a Doctor of Pharmacy candidate in the 2017 class at
Albany College of Pharmacy and Health Sciences. He is interested in
cardiology and pain management. He is interested in pursuing a position in clinical or community pharmacy after graduation.

 

Dr. Erica Wegrzyn is currently completing a PGY-2 Pain and Palliative Care Residency at the
Stratton VA Medical Center, Albany NY. Dr. Wegrzyn received her PharmD from Western
New England University College of Pharmacy, Springfield MA and completed a PGY-1
residency at Maine General Medical Center, Augusta ME. Prior to completing her PharmD,
Dr. Wegrzyn also received her bachelors’ degrees in Biochemistry and Music (trombone) from Ithaca College.

 

 

References:

1. Gudin J, Fudin J. Opioid-Induced Constipation: New and Emerging Therapies- Update 2016. Practical Pain Management. 2016 December; 16(10).
2. Brandt LW, Prather CM, Quigley EMM, Et al.Sstematic review on the management of chronic constipation in North America. Am J Gastroenterol. 2005;100(1)S5-S22
3. Lacy B, Mearin F, Chang L, et al. Bowel Disorders. Gastroenterology 2016;150:1393-1407.
4. Argoff CE, Brennan MJ, Camilleri M, et al. Consensus recommendations on initiating prescription therapies for opioid-induced constipation. Pain Med. 2015;16(12):2324-2337.
5. Kumar L, Barker C, Emmanuel A. Opioid-induced constipation: pathophysiology, clinical consequences, and management. Gastroenterol Res Pract. 2014;1-6.
6. Entereg [package insert].Kenilworth (NJ):  Merck & CO; December 2016
7. Movantik [package insert]. Wilmington (DE): AstraZeneca Pharmaceuticals LP; September 2016
8. Relistor [package insert]. Raleigh (NC): Salix Pharmaceuticals; September 2016
9. Amitiza [package insert]. Deerfield (IL): Takeda Pharmaceuticals; September 2016