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Combating Opioid-Induced Constipation: New and Emerging Therapies

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Combating Opioid-Induced Constipation: New and Emerging Therapies FEATURE Combating Opioid-Induced Constipation: New and Emerging Therapies Jeffrey Gudin, MD Jeffrey Fudin, BS, PharmD, FCCP Director Clinical Pharmacy Specialist Pain and Palliative Care Director Englewood Hospital and Medical Center PGY2 Pain and Palliative Care Pharmacy Residency Englewood, New Jersey Stratton VA Medical Center Clinical Instructor of Anesthesiology Albany, New York Mt Sinai University School of Medicine New York, New York Adam Laitman, MD Courtney Kominek, PharmD, BCPS Clinical Pharmacy Specialist in Pain Management Medical Graduate Harry S. Truman Memorial Veterans’ Hospital Xavier University School of Medicine, Aruba Columbia, Missouri Research Associate Pain and Palliative Care Englewood Hospital and Medical Center Englewood, New Jersey ain is a significant and prevalent public health Almost all patients requiring chronic opioid therapy problem that costs society approximately develop side effects, the most common of which affect the $560 to $635 billion annually, an amount gastrointestinal (GI) and central nervous systems (CNS).3,4 equal to about $2,000.00 for every person Although tolerance develops to many of the CNS side effects living in the US.1 As a result of the number over time (ie, sedation), resolution of opioid-induced bowel of individuals experiencing persistent pain, dysfunction (OIBD), and more specifically opioid-induced P the National Institute of Health reported that constipation (OIC), does not occur with continued use.3 approximately 200 million prescriptions for opioids were How prevalent is OIC? The numbers vary widely based dispensed in 2013, a trend that has grown by more than on study design and patient populations. Based on an anal- 50% over the last 10 years, and by nearly 100% since 2000.2 ysis of 16 clinical trials and observational studies, OIC November/December 2014 | PracticalPainManagement.com 41 Combating Opioid-Induced Constipation: New and Emerging Therapies Table 1. Commonly Used Definition of Opioid-Induced Constipation lost productivity per week), and 38% activity impairment.8 Additionally, Diagnosis of Opioid-Induced Constipation participants in a recent OIC study 1. Fewer than 3 bowel movements per week commonly reported that their con- 2. Hard or lumpy stools stipation interfered with the ability 3. Sensation of incomplete evacuation of their opioid medication to control 4. Sensation of anorectal obstruction pain, with 49% reporting moderate or complete interference, and 8% report- 5. Straining with defecation ing that they changed how they used 6. Bloating and abdominal pain relieved with bowel movements their opioid in order to have a bowel 7. Small stools movement.9 8. GERD (potentially) Effect of Opioids on GI Tract GERD, gastroesophageal reflux disease Based on references 11 and 17. Multiple mechanisms influence the occurrence of OIC. In fact, the very Table 2. Categories of Anti-constipatory Agents mechanisms that allow opioids to be Category Mechanisms of Action effective pain medications are also involved in causing OIC. Opioid ago- Bulking agents work in both the small and large bowel, nists mitigate pain by binding to opi- with an onset of action of 12 to 72 hours. They bulk up Bulk-producing Agents the stool so that it retains more water, making peristalsis oid receptors that are located in the easier. Examples include psyllium, methylcellulose, and central and peripheral nervous sys- dietary fiber. tems. Mu-opioid receptors, and to a Stool softeners soften stool and make it “slippery,” making lesser extent kappa- and delta-opioid Stool Softeners the stool easier to pass. These work in the colon and take receptors, are located throughout the from 6 to 8 hours to take effect. GI tract. Here opioids reduce contrac- tility and tone leading to increased Lubricants/emollients, such as mineral oil, soften and 3 Lubricants or Emollients coat the stool, thus preventing colonic water absorption. transit time. Specifically, they exert Vegetable-oil enemas act as lubricants. their effects in the neuronal plexi, located between the longitudinal Hydrating agents increase the water content in the stool, which makes the stool softer and easier to pass. Some and circular muscle layers (myenteric Hydrating Agents of these work by increasing the bowel lumen osmolality. plexus) and within the submucosa Examples include Fleet phospho-soda and Miralax. (submucosal plexus),9 and indirectly through the central nervous system via Stimulants stimulate colonic contractions that propel stools Stimulants foward. These agents irritate the lining of the intestines. intrathecal administration of opioids, Examples include cascara sagrada, bisacodyl, and senna. decreasing GI motility and intestinal secretion.10 Prostaglandins, prokinetic drugs, and other agents change the way the intestine absorbs water and electrolytes, and Passive absorption of fluids is Others increase the weight and frequency of stools while reducing increased and intestinal secretions transit time. are reduced in the GI tract with opi- oids due to increased frequency and strength of circular muscle contrac- has been reported to occur in 15% to side effect, OIC significantly affects tions that cause non-propulsive con- 90% of patients.5 When these stud- a patient’s quality of life.7 A study tractions.3 Within the myenteric ies are qualified according to type of of work productivity in patients on plexus, opioids stimulate relaxation of chronic pain, estimates from observa- chronic opioid therapy found that the longitudinal smooth-muscle layer, tional studies in the United States sug- OIC impacted productivity and thus increasing tonicity in the circu- gested that the prevalence of OIC in activity levels. Specifically, the study lar smooth-muscle layer. The mecha- patients with non-cancer pain ranged found that patients reported 9% work nism of this action is believed to occur between 40% and 50%.6 time missed, 32% impairment while through inhibition of acetylcholine In addition to being a common working (equivalent of 14 hours of release and inhibition of vasoactive 42 PracticalPainManagement.com | November/December 2014 Combating Opioid-Induced Constipation: New and Emerging Therapies intestinal peptide and nitric oxide Table 3. Current and Emerging Treatments for Opioid-Induced Constipation release. Ultimately, this results in an increase in segmental contraction, Agent (Brand) Company Status while peristaltic activity is decreased, PAMORAs 6 inducing constipation. Reduced pro- GlaxoSmithKline FDA approved for postoperative pulsive contractions of longitudinal Alvimopan (Entereg) ileus; results in OIC were muscles also contributes to hard and equivocal 4 dry stools. Rectal stool evacuation Axelopran Theravance, Inc. In Phase 3 clinical trials is decreased by an increased thresh- (formerly TD 1211) old for triggering of the anorectal Cubist In Phase 3 clinical trials 3,11 Bevenopran reflex. Pharmaceuticals Salix Pharmaceuticals FDA approved for OIC in Diagnosis of OIC Methylnaltrexone advanced illness in palliative care (Relistor) Opioids affect the entire gut, from the and CNCP mouth to the anus, and OIBD refers to the constellation of GI effects.4 This Naldemedine (S-297995) Shionogi Inc. In Phase 3 clinical trials includes gastroparesis, gastroesopha- Naloxegol (Movantik) AstraZeneca FDA approved for OIC in CNCP geal reflux disease (GERD), and other Chloride Channel Activator GI-related disorders.12 Although no delineation for constipation has been Lubiprostone (Amitiza) Sucampo/Takeda FDA approved for OIC in CNCP universally accepted, various defini- CNCP, chronic non-cancer pain; OIC, opioid-induced constipation; PAMORA, peripheral acting mu tions of constipation exist.3,11,13,14 opioid receptor antagonists According to the American College of Gastroenterology definition, con- stipation is defined as unsatisfactory defecation with infrequent bowel evidence to support the use of these abnormalities.3,11,13,15 Unfortunately, movements, difficult stool passage, interventions for OIC, and they often patients may have inadequate symp- or both.11,15 Functional constipation, are ineffective, which necessitates use tom relief from OIC with these laxa- as outlined by the Rome III crite- of laxatives.3 Stimulant laxatives are tives alone or combined. ria, requires 2 or more of the follow- often used first-line due to their low ing symptoms to occur no less than cost and efficacy despite not correcting Pharmaceutical Therapy 25% of the time in the past 12 weeks: the underlying mechanism.3,13 Table 2 It is not often in medicine that a phar- straining with bowel movements, describes categories of anti-constipat- macological antidote exists to a drug passing lumpy or hard stools; feeling ing agents. treatment or adverse effect. Although of incomplete evacuation; feeling of Stimulant laxatives, including senna newer select agents (ie, ion channel anorectal obstruction; using manual and bisacodyl, work by increasing mus- activators) have been approved for maneuvers for facilitation of defecation; cle contractions. Patients, however, may OIC, there is only one class of drug and having less than 3 bowel move- develop tolerance and dependence to that targets the specific underlying ments per week.16 Even though this stimulant laxatives.3 Docusate, a sur- cause of OIC—binding of opioids to definition is not restricted to opioid- factant stool softener, does not assist the mu-receptors in the enteric ner- induced constipation, the Rome III with muscle contractility but is non- vous system. This new class, known criteria
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