Managing Opioid Induced Constipation

The Big Slow-Down: Managing Opioid Induced Constipation

Letitia Warunek, Pharm.D., BCPS Assistant Professor of Pharmacy Practice Wilkes University Nesbitt School of Pharmacy Clinical Pharmacist Geisinger Community Medical Center, Scranton, PA Disclosures

The presenter for this activity had been required to disclose all relationships with any proprietary entity producing healthcare goods or services, with the exemption of non-profit or government organizations and non-health care related companies.

No significant financial relationships with commercial entities were disclosed by the speaker. Learning Objectives

1. Explain the pathophysiology of opioid induced constipation (OIC).

2. Describe the mechanism of action, efficacy, adverse effects, and contraindications for medications used to treat opioid induced constipation (OIC).

3. Determine an appropriate treatment plan for opioid induced constipation (OIC) through a patient case example. Patient JC

 JC is a 68 year old female  Hospital Course:

 Admitted to the general medicine  Chest X-ray showed right lower lobe service for pneumonia infiltrate  Pneumonia managed with Ceftriaxone/  PMH: hypertension, diabetes, heart Cefdinir for 7 days failure (EF 35%), COPD, chronic low back pain, anemia  Elevated blood pressure  Added amlodipine 10 mg

 Pain management issues for chronic  Current Vitals and Labs lower back pain

BP 136/72, HR 68, Temp 98.4˚F  Was receiving oxycodone-acetaminophen 5-325 mg every 6 hours prior to admission

139 102 12 11.1  Dose increased to 7.5-325 mg every 6 hours 145 6.9 260 3.2 30 1.0 32 Current Hospital Medication List Scheduled

Amlodipine 10 mg daily Cefdinir 300 mg twice a day Lisinopril 40 mg daily Metoprolol succinate 25 mg twice a day Furosemide 40 mg daily Spironolactone 25 mg daily Fluticasone/ umeclidinium/ vilanterol 100 mcg/ 62.5 mcg/ 25 mcg 1 puff daily Oxycodone-acetaminophen 7.5-325 mg 1 tablet every 6 hours for pain Ferrous sulfate 325 mg daily Metformin 1,000 mg twice a day

As Needed

Albuterol-ipratropium 3 mg/ 0.5 mg inhale 1 vial every 4 hours as needed Polyethylene glycol 1 packet daily as needed for constipation  Today is hospital day 7

 Pneumonia is resolved – completed 7 days of antibiotics

 Pain is better controlled with higher dose of oxycodone-acetaminophen

 Blood pressure is improved after adding amlodipine

 Medical team plans to discharge JC today

 New medication orders for discharge

 Oxycodone-acetaminophen 7.5-325 mg every 6 hours

 Amlodipine 10 mg daily During Patient Rounds…

Patient reporting No bowel movement Discharge delayed constipation, since day 1 of until constipation is abdominal admission addressed discomfort, bloating

How should we manage this patient now?

How can we prevent this from happening again? Epidemiology of Opioid Use

 United States

 9-12 million suffering with chronic pain annually

 4-5% of the population uses prescription opioids

 Pennsylvania (2017)

 57.7 opioid prescriptions for Figure 2. The U.S. and Pennsylvania opioid prescribing rate every 100 persons per 100 persons. Source: CDC and IQVIA Xponent 2006–2017.

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. National Institute on Drug Abuse. “Pennsylvania Opioid Summary.” NIDA, 22 May 2019, Accessed 17 Dec 2019, www.drugabuse.gov/opioid-summaries-by-state/pennsylvania-opioid-summary. “U.S. Opioid Prescribing Rate Maps.” Centers for Disease Control and Prevention, 3 Oct. 2018, Accessed 17 Dec 2019, www.cdc.gov/drugoverdose/maps/rxrate-maps.html. OIC Pathophysiology

 Three receptor types

 Mu (μ), Kappa (κ), Delta (δ)

 Central vs peripheral location

 Opioid activation of receptors in the periphery

 Reduced gut motility

 Altered fluid secretion and absorption

 Gut sphincter dysfunction

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. Drugs. 72, 1847-1865 (2012). doi: 10.2165/11634970-000000000-00000. Prevalence of Constipation Among Opioids

 2007 survey

 n = 1113 patients

 Chronic non-cancer pain

 Receiving opioid therapy for greater than one month

Aliment Pharmacol Ther. 2008 Jun;27(12):1224-32. doi: 10.1111/j.1365-2036.2008.03689.x. Clin J Pain. 2019;35(2):174–188. doi:10.1097/AJP.0000000000000662 Clinical Presentation of OIC

Abdominal Bloating, Incomplete Constipation, cramps, abdominal bowel straining spasms distension evacuation

Hard dry Bowel noise Chronic Nausea and stools and flatus visceral pain vomiting

Gastro- Gut sphincter Dry mouth esophageal dysfunction reflux

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. Drugs. 72, 1847-1865 (2012). doi: 10.2165/11634970-000000000-00000. Rome IV Diagnostic Criteria for OIC

 New or worsening symptoms of constipation when initiating, changing, or increasing opioid therapy  Must include two or more of the following in ≥ 25% of defecations:

 Straining

 Lumpy or hard stools

 Sensation of incomplete evacuation

 Sensation of stool obstruction or blockage

 Requiring manual maneuvers to facilitate evacuation of stool

 Fewer than three spontaneous bowel movements per week

Curr Gastroenterol Rep. 2017;19(4):15. doi:10.1007/s11894-017-0554-0 Consequences of OIC

 Serious complications

 Fecal impaction, bowel perforation, anal fissures, rectal bleeding

 Reduced quality of life

 45% reported experiencing fewer than three bowel movements per week

 50% reported a resulting moderate-to-great or great impact on quality of life

 Increased resource utilization

 Evaluation of 2430 patients receiving opioids; 359 experiencing OIC

 Over a six month period:

 More physician visits (mean difference 3.84 visits; p < 0.05)

 More alternative care provider visits (mean difference 1.73 visits; p < 0.05)

Gastroenterol Res Pract. 2014;2014:141737. doi:10.1155/2014/141737 J Opioid Manag. 2009 May-Jun;5(3):137-44. doi: 10.5055/jom.2009.0014 Pain Med. 2009 Jan;10(1):35-42. doi: 10.1111/j.1526-4637.2008.00495.x. Tolerance to Opioid Side Effects Interactive

True or False?

Patients receiving chronic opioid therapy will eventually develop tolerance to constipation.

False

 Patients will not develop a tolerance to constipation  Constipation will likely require treatment over time Assessment of OIC

Patient Assessment Patient Bowel Function of Constipation History and Index Symptoms Survey Physical (BFI) (PAC-SYM)

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. Patient History and Physical

Patient History

• Complete history and physical • Defecation patterns (consistency, frequency) • Dietary patterns • Presence of alarm symptoms Medical History

• Comorbid illnesses • Medication use: • Recent opioid therapy • Chronic medication use • Medications used to relieve constipation

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. Bowel Function Index

 Three item questionnaire

 Questions rated on a scale of 0 to 100

 Mean of the three scores

 Score < 28.8

 Indicates absence of constipation

 Score ≥ 30

 Escalate therapy from conventional laxatives to prescription medications for OIC

 Score change by > 12 points

 Indicates a clinically meaningful difference

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. Clin Gastroenterol Hepatol. 2017;15(9):1338–1349. doi:10.1016/j.cgh.2017.05.014 Patient Assessment of Constipation Symptoms Survey Abdominal • Discomfort in your stomach • Pain in your stomach  12 item questionnaire • Bloating in your stomach • Stomach cramps  Each item is scored on a 5-point Likert scale Rectal

 0 = symptom absent • Painful bowel movements  1 = mild • Rectal burning during or after a bowel movement • Rectal bleeding or tearing during or after a bowel  2 = moderate movement

 3 = severe Stool

 4 = very severe • Incomplete bowel movement, felt like you didn’t finish • Bowel movements were too hard  Mean total score is calculated in • Bowel movements were too small the range of 0-4 • Straining or squeezing to try and pass bowel movements • Feeling like you had to pass a bowel movement but could not

Aliment Pharmacol Ther. 2017;46(11-12):1103–1111. doi:10.1111/apt.14349 Management of OIC Proposed Clinical Decision Support Tool

American Gastroenterological Association Institute Guideline on the Medical Management of Opioid-Induced Constipation

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. Other Causes of Constipation

Comorbid illnesses • Parkinson’s disease, multiple sclerosis, cerebrovascular accidents • Diabetes, hypothyroidism Bowel Dysfunction • Pelvic outlet dysfunction • Mechanical obstruction or rectal prolapse

Electrolyte Abnormalities • Hypokalemia, hypocalcemia, hypomagnesemia Lifestyle Habits • Poor diet • Low physical activity

Am Fam Physician. 2011 Aug 1;84(3):299-306. Medications that Cause Constipation

 Pain Medications  Antidepressants

 Opioids  Tricyclic antidepressants

 Tramadol  Aripiprazole

 Anticholinergic agents  Supplements

 Antihistamines  Iron

 Antispasmodics  Aluminum antacids

 Urge incontinence  Non-DHP Calcium Channel Blockers

 Verapamil

Am Fam Physician. 2011 Aug 1;84(3):299-306. Let’s Evaluate JC Interactive

What are other factors that could be causing JC’s constipation?

 JC is a 68 year old female  Current Vitals and Labs

 Admitted to the general BP 136/72, HR 68, Temp 98.4˚F medicine service for pneumonia 139 102 12  PMH: hypertension, diabetes, 145 heart failure (EF 35%), COPD, 3.2 30 1.0 chronic low back pain, anemia 11.1 6.9 260 32

Endocrine Disorder Hypokalemia Let’s Evaluate JC Only associated with Scheduled non-DHP calcium channel blockers Amlodipine 10 mg daily Cefdinir 300 mg twice a day Lisinopril 40 mg daily Metoprolol succinate 25 mg twice a day Furosemide 40 mg daily Spironolactone 25 mg daily Fluticasone/ umeclidinium/ vilanterol 100 mcg/ 62.5 mcg/ 25 mcg 1 puff daily Oxycodone-acetaminophen 7.5-325 mg 1 tablet every 6 hours for pain Ferrous sulfate 325 mg daily Metformin 1,000 mg twice a day

As Needed Need to evaluate how often JC is using Albuterol-ipratropium 3 mg/ 0.5 mg inhale 1 vial every 4 hours as needed polyethylene glycol Polyethylene glycol 1 packet daily as needed for constipation Management of OIC per AGA Guidelines

Non-pharmacologic therapies

Conventional laxatives

Peripherally acting mu-opioid receptor antagonists (PAMORAs)

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. Non-Pharmacologic Therapies

Rotate opioid Use minimum Evaluate for Evaluate therapy or use dose abuse and alternative narcotic use necessary misuse agents

Lifestyle Increase fluid Adequate Regular intake fiber intake physical modifications (1.5-2 L/day) (25-30 g/day) activity

Raise feet Proper Implement a with a step Do not resist toilet toileting stool during the urge to go schedule habits defecation

Gastroenterology. 2016;150(6):1393-1407 doi: 10.1053/j.gastro.2016.02.031. Conventional Laxatives – First Line Therapy

Stimulant • Directly stimulate the intestinal mucosa to increase peristalsis and soften stool by altering fluid and (senna, bisacodyl) electrolyte secretion

Osmotic • Increase fecal water content and stimulate (polyethylene glycol) peristalsis via distention of the bowel

Stool Softener • Facilitates the incorporation of water and fat into (docusate sodium) the stool

Soluble Fiber (psyllium, • Bulking agents that draw water into the colon methylcellulose)

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. Conventional Laxatives – Evidence

Moderate evidence for laxative use in Availability chronic (OTC, cost) idiopathic constipation

Limited adverse effects

AGA recommendation for laxatives as first-line agents for OIC Laxative Refractory OIC

Moderate or severe symptoms of constipation, despite the use of laxatives from one or more laxative classes for a minimum of four days within a two-week period

 Coyne KS, LoCasale RJ, Datto CJ, et al. 2014

 Evaluated patients receiving daily opioid therapy ≥ 30 mg for ≥ 4 weeks and self- reported opioid-induced constipation

 Patient Assessment of Constipation-Symptoms Survey Tool (PAC-SYM)

 Straining/squeezing to pass bowel movements (83%)

 Bowel movements too hard (75%)

 Flatulence (69%)

 Bloating (69%)

 Prevalence of inadequate response to one laxative agent was 94%

 Inadequate response to two or more agents from different laxative classes was 27%

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. Clinicoecon Outcomes Res. 2014;6:269–281. Published 2014 May 23. doi:10.2147/CEOR.S61602 Conventional Laxatives

 AGA recommendations

 First line agents for OIC

 Combination of at least two types of laxatives before escalating therapy

 Scheduled use of laxatives (vs “as needed”) is required before determining whether alternative OIC therapy is necessary

 Limited evidence to support a specific combination of agents

 Stimulant agents are preferred

 Can add a stool softener if needed (not as monotherapy)

 Limited role for soluble fibers

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. Proposed Clinical Decision Support Tool

American Gastroenterological Association Institute Guideline on the Medical Management of Opioid-Induced Constipation

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. Peripherally Acting Mu-opioid Receptor Antagonists (PAMORAs)

Naldemedine Naloxegol Methylnaltrexone (Symproic®️) (Movantik®️) (Relistor®️)

 Mechanism of action  Block μ opioid receptors in the gastrointestinal tract  Restore function of the enteric nervous system  No affect on analgesia  Avoid in disease states with compromised blood brain barrier  Risk of opioid reversal → withdrawal

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. Considerations when Initiating PAMORAs Interactive

 What should you do with maintenance laxative therapies the patient is Continue Discontinue receiving prior to initiation of PAMORAs? laxatives laxatives

 If there is a suboptimal response with PAMORAs, when should you consider After 3 days After 7 days adding on additional laxative therapy?

 What should you do with the PAMORA if Continue Discontinue opioid therapy is discontinued? PAMORA PAMORA

Naldemedine, Naloxegol, Methylnaltrexone Bromide. In: DRUGDEX [database on the internet]. Ann Arbor (MI): Truven Health Analytics; 2019 [accessed 5 Jan 2020]. Available from: www.micromedexsolutions.com. Naldemedine

 Formulation:  Derivative of naltrexone plus a side chain

 Indications:  OIC in chronic non-cancer pain  Dosing: 0.2 mg orally once daily  OIC in patients with cancer (off label use)  Dosing: 0.2 mg orally once daily

 Dose Adjustments:  Severe hepatic impairment: avoid use

Naldemedine. In: DRUGDEX [database on the internet]. Ann Arbor (MI): Truven Health Analytics; 2019 [accessed 28 Dec 2019]. Available from: www.micromedexsolutions.com. Naldemedine Evidence

 Four randomized double blind trials of naldemedine vs placebo

 Study period: 52 weeks

 Primary Endpoint

 Ability to achieve at least three spontaneous bowel movements per week

 Results

 52% patients receiving naldemedine vs 35% patient receiving placebo

 RR 1.51 (95% CI, 1.32 – 1.72)

 Adverse Events

 More common with naldemedine

 RR 1.44 (95% CI, 1.03 – 2.03)

 Infection, abdominal pain, diarrhea, flatulence, nausea, back pain

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. Naldemedine Clinical Pearls

Contraindications

• GI obstruction

Warnings

• Risk of GI perforation and opioid withdrawal

Side Effects

• Abdominal pain, diarrhea, nausea, gastroenteritis

Administration Pearls

• Take with or without food

Naldemedine. In: DRUGDEX [database on the internet]. Ann Arbor (MI): Truven Health Analytics; 2019 [accessed 28 Dec 2019]. Available from: www.micromedexsolutions.com. Naldemedine Drug Interactions

Avoid Concomitant Use Monitor for Adverse Reactions

 Strong CYP3A inducers  Moderate/strong CYP3A4 inhibitors

 Decreased naldemedine  Increased naldemedine concentrations concentrations

 Other opioid antagonists  P-gp inhibitors

 Potential for additive effect and  Increased naldemedine increased risk of opioid withdrawal concentrations

Naldemedine. In: DRUGDEX [database on the internet]. Ann Arbor (MI): Truven Health Analytics; 2019 [accessed 28 Dec 2019]. Available from: www.micromedexsolutions.com. Naloxegol

 Formulation:

 An oral pegylated derivative of naloxone

 Indication:

 OIC in chronic non-cancer pain

 Dosing: 25 mg orally once daily in the morning on an empty stomach

 Can reduce to 12.5 mg once daily if not tolerated

 Dose Adjustments:

 Renal impairment (CrCl less than 60 mL/min): 12.5 mg once daily

 If tolerated, may increase to 25 mg once daily

 Hepatic impairment (severe): Avoid use

Naloxegol. In: DRUGDEX [database on the internet]. Ann Arbor (MI): Truven Health Analytics; 2019 [accessed 28 Dec 2019]. Available from: www.micromedexsolutions.com. Naloxegol Evidence

 Two phase-three double blind randomized controlled trials

 Compared naloxegol 25 mg, naloxegol 12.5 mg, and placebo  Primary Endpoint

 Three or more weekly spontaneous bowel movements and at least one more spontaneous bowel movement per week compared to baseline  Results

 Better response with naloxegol 25 mg vs placebo in both studies

 (44.4% versus 29.4%, p < 0.05; and 39.7% versus 29.3%, p < 0.05)

 Incidence of adverse effects leading to discontinuation of therapy

 10% receiving naloxegol 25 mg and 5% receiving naloxegol 12.5 mg

 Adverse effects included diarrhea, abdominal pain, nausea, and vomiting

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. Naloxegol Clinical Pearls

Contraindications • GI obstruction • Concomitant use of strong CYP 3A4 inhibitors

Warnings • Risk of GI perforation and opioid withdrawal • Severe abdominal pain and diarrhea • Discontinue in severe symptoms – consider restarting at 12.5 mg dose

Side Effects • Abdominal pain, diarrhea, nausea, vomiting, flatulence, headache

Naloxegol. In: DRUGDEX [database on the internet]. Ann Arbor (MI): Truven Health Analytics; 2019 [accessed 28 Dec 2019]. Available from: www.micromedexsolutions.com. Naloxegol Drug Interactions

Avoid Concomitant Use

 Moderate CYP 3A4 inhibitors  Increased naloxegol concentrations Strong CYP 3A4  Reduce dose to 12.5 mg and monitor for ADE inhibitors are  Strong CYP 3A4 inducers contraindicated

 Decreased naloxegol concentrations  Other opioid antagonists

 Potential for additive effect and increased risk of opioid withdrawal

Naloxegol. In: DRUGDEX [database on the internet]. Ann Arbor (MI): Truven Health Analytics; 2019 [accessed 28 Dec 2019]. Available from: www.micromedexsolutions.com. Naloxegol Administration Pearls

• At least 1 hour prior to the first meal of the day or 2 Take on an hours after the meal • Avoid consumption of grapefruit or grapefruit juice empty stomach during treatment

• Mix with 120 mL of water and drink immediately Crushed tablet • Refill the glass with 120 mL of water, stir, and drink the contents

Administration • Mix crushed tablet with 60 mL of water via nasogastric • Flush the tube with additional 60 mL water tube

Naloxegol. In: DRUGDEX [database on the internet]. Ann Arbor (MI): Truven Health Analytics; 2019 [accessed 28 Dec 2019]. Available from: www.micromedexsolutions.com. Methylnaltrexone

 Formulation:

 Quaternary ammonium cation derivative of naltrexone

 Indications:  OIC in advanced illness for cancer related pain or palliative care  (less than 38 kg) 0.15 mg/kg subQ every other day as needed

 (38 kg to less than 62 kg) 8 mg subQ every other day as needed

 (62 kg to 114 kg) 12 mg subQ every other day as needed

 (greater than 114 kg) 0.15 mg/kg subQ every other day as needed

 OIC in chronic non-cancer pain

 12 mg subQ once daily OR 450 mg orally once daily

Methylnaltrexone Bromide. In: DRUGDEX [database on the internet]. Ann Arbor (MI): Truven Health Analytics; 2019 [accessed 1 Dec 2019]. Available from: www.micromedexsolutions.com. Methylnaltrexone

 Same dose adjustment for:  Renal impairment (CrCl < 60 mL/min)  Severe hepatic impairment

 OIC in advanced illness for cancer related pain or palliative care  (less than 38 kg) 0.075 mg/kg subQ every other day as needed  (38 kg to less than 62 kg) 4 mg subQ every other day as needed  (62 kg to 114 kg) 6 mg subQ every other day as needed  (greater than 114 kg) 0.075 mg/kg subQ every other day as needed

 OIC in chronic non-cancer pain  6 mg subQ once daily OR 150 mg orally once daily

Methylnaltrexone Bromide. In: DRUGDEX [database on the internet]. Ann Arbor (MI): Truven Health Analytics; 2019 [accessed 1 Dec 2019]. Available from: www.micromedexsolutions.com. Methylnaltrexone Evidence

 Five randomized controlled trials

 Three studies evaluated endpoint of three bowel movements per week

 Two studies evaluated non-cancer pain  Pooled study results

 43% improvement in rescue free bowel movements

 RR 1.43 (95% CI, 1.21 - 1.68)

 Improvement in “laxation response” (within 4 hours)

 RR 3.16 (95% CI, 2.18 - 4.58)

 No statistically significant increase in adverse events

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. Methylnaltrexone Clinical Pearls

Contraindications

• GI obstruction

Warnings

• Risk of GI perforation and opioid withdrawal • Severe or persistent diarrhea

Side Effects

• Tablet: • Abdominal pain, diarrhea, flatulence, nausea, hyperhidrosis, anxiety • Injection: • Abdominal pain, nausea, diarrhea, hyperhidrosis, hot flash, tremor, chills

Methylnaltrexone Bromide. In: DRUGDEX [database on the internet]. Ann Arbor (MI): Truven Health Analytics; 2019 [accessed 1 Dec 2019]. Available from: www.micromedexsolutions.com. Methylnaltrexone

 Administration Pearls

 Be within close proximity to toilet facilities once administered

 Inject in upper arm, abdomen, or thigh

 Take tablets with water on an empty stomach at least 30 minutes before the first meal of the day

 Drug Interactions

 Other opioid antagonists

 Potential for additive effect and increased risk of opioid withdrawal

 Patients receiving opioids for less than four weeks may be less responsive

 Inclusion criteria in phase three clinical trials

 Patients receiving a stable opioid morphine equivalent daily dose of at least 30 mg or more

 Receiving opioid therapy for at least four weeks before enrollment

 Patient self-reported symptoms of OIC

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. PAMORAs in Acute vs Chronic Management

 Studied for chronic management of OIC  No evidence to support use in acute management of OIC

 Time to onset of effects

 Naldemedine unknown

 Time to Tmax 0.75hr, delayed with food

 Naloxegol 6-12 hours

 Methylnaltrexone 30-60 minutes

Naldemedine Naloxegol Methylnaltrexone

Indicated in non-cancer pain X X X

Indicated in cancer pain X (off label) X Can take with or without food X Available as an injection X Safe to crush tablets X Safe in renal impairment (CrCl <60 mL/min) X Reduce dose Reduce dose

Safe in severe hepatic impairment Avoid use Reduce dose Reduce dose

Safe with CYP 3A4 inducers and inhibitors X

 Naldemedine Oral tablet 0.2 mg 30 tablets $452.53  Naloxegol Oral tablet 25 mg 30 tablets $426.46 Oral tablet 12.5 mg 30 tablets $426.46  Methylnaltrexone Oral tablet 150 mg 90 tablets $2,079 Subcutaneous Solution 1 dose $138.65 12 mg/0.6 mL

Naldemedine, Naloxegol, Methylnaltrexone Bromide. In: REDBOOK [database on the internet]. Ann Arbor (MI): Truven Health Analytics; 2019 [accessed 5 Jan 2020]. Available from: www.micromedexsolutions.com. PAMORAs

Naldemedine Naloxegol (Symproic®️) (Movantik®️)

Methylnaltrexone Alvimopan (Relistor®️) (Entereg®️) Alvimopan

 PAMORA indicated for the prevention and treatment of post- operative ileus following bowel surgery

 Safety concerns with prolonged use and risk of myocardial infarction

 Contraindication

 Use of opioids at therapeutic doses for more than 7 consecutive days immediately prior to taking alvimopan

 Only available through the E.A.S.E. REMS Program

 Maximum of 15 doses

 Limited to inpatient use only

“E.A.S.E.®️ ENTEREG®️ REMS Program.” ENTEREG REMS Program, 2015, www.enteregrems.com/ Other Medications Indicated for OIC

Lubiprostone Prucalopride (AmitizaTM) (MotegrityTM)

 Per the AGA

 No specific recommendations for the use of these agents

 Quality of evidence was low

 Concerns for selective reporting bias and study imprecision

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. Lubiprostone

 Formulation: bicyclic fatty acid  Mechanism of action: chloride channel activator

 Stimulates intestinal and colonic secretion of chloride-rich fluid into the intestine

Lubiprostone. In: DRUGDEX [database on the internet]. Ann Arbor (MI): Truven Health Analytics; 2019 [accessed 1 Dec 2019]. Available from: www.micromedexsolutions.com. Clin Interv Aging. 2013;8:191–200. doi:10.2147/CIA.S30729 Lubiprostone

 Indications:  Chronic idiopathic constipation  24 mcg orally twice daily  Irritable bowel syndrome with constipation  8 mcg orally twice daily  OIC in chronic non-cancer pain  24 mcg orally twice daily  Dose Adjustments:  Hepatic impairment  Moderate: 16 mcg twice a day  Severe: 8 mcg twice a day

Lubiprostone. In: DRUGDEX [database on the internet]. Ann Arbor (MI): Truven Health Analytics; 2019 [accessed 1 Dec 2019]. Available from: www.micromedexsolutions.com. Lubiprostone Evidence

 Three phase three randomized controlled trials

 Lubiprostone 24 mcg twice daily with meals and 8 ounces of fluid vs placebo

 Study period: 12 weeks  Spontaneous bowel movement

 38% receiving lubiprostone vs 32.7% receiving placebo

 RR 1.15 (95% CI, 0.97-1.37)  Adverse effects

 6.4% receiving lubiprostone vs 3.0% receiving placebo

 Diarrhea, nausea, abdominal pain, headache, vomiting

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. Lubiprostone Clinical Pearls

Contraindications

• GI obstruction

Warnings

• Severe diarrhea, dyspnea, avoid in severe hepatic impairment, hypotension, syncope

Side Effects

• Abdominal pain, diarrhea, flatulence, nausea, headache

Administration Pearls

• Take with food and water

Lubiprostone. In: DRUGDEX [database on the internet]. Ann Arbor (MI): Truven Health Analytics; 2019 [accessed 1 Dec 2019]. Available from: www.micromedexsolutions.com. Prucalopride

 Role of 5-HT receptor agonists

 Regulating gastric motility, enteric neuronal signaling, and visceral pain  Mechanism of Action

 Selective agonist of 5-HT4 receptors

 5-HT4 stimulation promotes acetylcholine release from enteric nerves resulting in colonic motility via high-amplitude propagating contractions  Indication

 Chronic idiopathic constipation

 Dosing: 2 mg orally once daily

Prucalopride. In: DRUGDEX [database on the internet]. Ann Arbor (MI): Truven Health Analytics; 2019 [accessed 1 Dec 2019]. Available from: www.micromedexsolutions.com. Prucalopride Evidence

 Phase two, four week double blind trial

 Prucalopride 2 mg (n=66), prucalopride 4 mg (n=64), and placebo (n=66)

 Study period: 4 weeks  Primary endpoint

 Proportion of patients with increase from baseline of ≥ 1 spontaneous complete bowel movement per week  Results

 60.7% (prucalopride 2 mg) and 69.0% (prucalopride 2 mg) vs 43.3% (placebo)  Study limitations

 Terminated early

Dig Dis Sci. 2010 Oct;55(10):2912-21. doi: 10.1007/s10620-010-1229-y Prucalopride Clinical Pearls

Contraindications

• Intestinal perforation or obstruction due to structural or functional disorder of gut wall, obstructive ileus, or severe inflammatory conditions of intestinal tract

Warnings

• Suicidal ideation

Side Effects

• Abdominal pain, diarrhea, flatulence, nausea, headache, fatigue

Prucalopride. In: DRUGDEX [database on the internet]. Ann Arbor (MI): Truven Health Analytics; 2019 [accessed 1 Dec 2019]. Available from: www.micromedexsolutions.com. Evidence Gaps

 Comparing laxatives to PAMORAs and other therapies  Effectiveness of laxatives in combination with prescription therapies  Lack of clinical evidence supporting lubiprostone and prucalopride in OIC  Limited data on long term use of prescription therapies

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. Emerging Therapies

 PAMORA  Axelopran  Analog of human uroguanylin  Dolcanatide

 Assessment of other constipation medications for efficacy in OIC

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. Back to Our Patient JC Interactive

What can we do now to manage JC’s constipation?

Senna 17.2mg daily and polyethylene glycol 1 packet daily

What can we do to manage JC’s constipation long term?

Lifestyle changes Increase fiber and fluid intake, engage in regular exercise Continue scheduled laxative therapy Can consider initiating a PAMORA if laxative therapy is inadequate Role of the Pharmacist

 Evaluate patients

 Patients at risk of OIC

 Presenting with alarm symptoms  Ensure patients receiving opioids have a bowel regimen

 Recommend for patients with a new opioid prescription or chronic therapy  Discuss the risks vs benefits of available therapies

 Chart review to identify other medication causes of constipation  Patient education

 Review lifestyle modifications and non-pharmacologic therapies

Gastroenterology. 2019 Jan;156(1):218-226. doi: 10.1053/j.gastro.2018.07.016. Key Points

Patients will not develop tolerance to OIC and will eventually require treatment.

Laxatives are the first line medication therapy for management of OIC.

Naldemedine, naloxegol, and methylnaltrexone are indicated for OIC after failure with laxative therapy.

Ensure patients receive education about OIC upon initiation and throughout opioid therapy.

Evaluate patients for OIC and ensure appropriate management. The Big Slow-Down: Managing Opioid Induced Constipation

Letitia Warunek, Pharm.D., BCPS Assistant Professor of Pharmacy Practice Wilkes University Nesbitt School of Pharmacy Clinical Pharmacist Geisinger Community Medical Center, Scranton, PA [email protected] References

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