treier_oic

Treatment Options for

Opioid-Induced Constipation

Kimberly M. TreierPharmD Candidate 2016

February 4, 2016

Objectives• Describe the opioid use trends in the United

States• Describe the pathophysiology of opioid-induced

constipation• Identify current non-pharmacologic and OTC

treatment options for opioid-induced constipation• Compare and contrast methylnaltrexone and

naloxegol (indication, dose, cost and side effects)

OutlineI. Opioid Trends in the U.S.II. Opioid Effects in the Nervous SystemIII. Current Treatment Options for Constipation and

Opioid-Induced ConstipationIV. Knowledge QuestionsV. Journal Articles

I. Naloxegol Randomized Controlled TrialII. Methylnaltrexone Placebo Crossover Analysis

VI. Methylnaltrexone and Naloxegol ComparisonsVII.Current RecommendationsVIII.Knowledge QuestionsIX. Summary

Opioid Trends in the U.S.

Opioid Effects in the CNS

Opioid mu-receptor binding in the CNS:

respiration rate cough reflex euphoria sedation miosis (pupillary constriction) nausea and vomiting

ANALGESIA

Opioid Effects in the ENS

Opioid mu-receptor binding in the ENS:

propulsive contractions water and electrolyte secretion gastric emptying pyloric and rectal sphincter tone intestinal transit time net luminal fluid absorption

CONSTIPATION* Only side effect not diminished by tolerance

Current Non-Pharmacologic

Treatment Options

Lifestyle modifications• Dietary fiber: goal 20-25 g daily• Fluid intake: goal 1.5-2 L daily• Physical activity

Current Pharmacologic

Treatment OptionsOTCs

• Stool softeners/non-stimulant laxativeso Surfactants – fat and water incorporation

• Docusate: 100-400 mg once or twice dailyo Lubricants – decreased water extraction

• Mineral oil: 30-90 mL daily as neededo Osmotic – water incorporation

• Polyethylene glycol (PEG): 17 g daily

• Stimulant laxatives – increased propulsive muscle contractions via enteric reflexo Senna: 2 tablets daily, may titrate up to 4 tablets twice dailyo Bisacodyl: 10-15 mg daily, may titrate up to 3 times daily

Current Pharmacologic

Treatment OptionsPrescription Drugs

Selective chloride channel activator• Lubiprostone

Peripherally-Acting Mu-Opioid Receptor Antagonist (PAMORA)• Naloxegol• Methylnaltrexone

Methylnaltrexone• PAMORA

o Naltrexone derivativeo Mu-selectiveo Minimal blood-brain barrier penetration (polarity)

• FDA indications:o April 2008: OIC, advanced illness (including cancer) receiving palliative

careo September 2014: OIC in CNCP

Naloxegol• PAMORA

o Naloxone derivativeo Mu-selectiveo Minimal blood-brain barrier penetration (pegylation and P-gp substrate)

• FDA indications:o September 2014: OIC in CNCP

Knowledge Questions

1. From 1999 to 2012, the amount of opioid analgesics stronger than morphine used by adults in the U.S. increased from 17% to (27, 30, 37 or 40%)?

Opioid Trends in the U.S.

Knowledge Questions

2. Opioid binding in the gut can cause a decrease in all of the following except:

a. peristalsisb. water and electrolyte secretionc. gastric emptyingd. net luminal fluid absorption

Opioid Effects in the CNS

Opioid mu-receptor binding in the ENS:

propulsive contractions water and electrolyte secretion gastric emptying pyloric and rectal sphincter tone intestinal transit time net luminal fluid absorption

CONSTIPATION* Only side effect not diminished by tolerance

Naloxegol for Opioid-Induced Constipation in Patients with

Noncancer PainChey WD, et al. 2014

New England Journal of Medicine

Study Design• Two identical phase III trials• Randomized, double-blind, parallel-group,

placebo-controlled• Multi-center• U.S. and Europe

Chey WD, et al. 2014

Inclusion Criteria Exclusion Criteria• Uncontrolled pain despite

optimal opioid therapy• Cancer within 5 years prior to

enrollment• Predisposing factors to

diarrhea or constipation (excluding OIC)

• Evidence of GI obstruction• Increased risk of bowel

obstruction

• Outpatient• Age 18 – 84 years• Opioid therapy for non-cancer

pain• ≥ 4 weeks• Stable total daily opioid

dose of 30 – 1000 mg of morphine or equivalent

• Symptoms of active OIC: < 3 spontaneous BMs per week with one or more:

• Hard/lumpy stools• Straining• Sensation of incomplete

evacuation or anorectal obstruction in ≥ 25% of BMs during the 4 weeks prior to screening


Methods• 1:1:1 randomization of placebo, 12.5 mg or 25

mg naloxegol daily• Electronic patient diaries:

• BM occurrence• Stool consistency• Severity of straining• Completeness of evacuation

• 12-week treatment period• Rescue treatment permitted if no BM within 72

hours:• Bisacodyl 10-15 mg, max of 3 doses per episode• One-time use of an enema (if necessary)


• Pain level• Rescue laxative use• Opioid use for breakthrough pain

Primary Secondary• Response in inadequate

response to laxative (LIR) subpopulation

• Time to first post-dose SBM• Mean number of days per

week with ≥ 1 SBM• Mean number of SBMs per

week• Severity of straining (5-point

rating scale)• Stool consistency (Bristol stool

scale)• Rescue laxative use

• Response:• ≥ 3 SBMs per week • Increase of ≥ 1 SBMs per

week over baseline for at least 9 of the 12 treatment weeks

• At least 3 must be within final 4 weeks of treatment


Spontaneous BM (SBM): BM without use of rescue laxative within previous 24 hours

Endpoints

ResultsChey WD, et al. 2014

Primary Endpoint


(55.1%) (54.0%) (54.7%) (52.2%) (53.9%) (53.4%)

Secondary Endpoint

ResultsMean number of days per week with ≥ 1 SBM from

week 1 to week 12


Secondary Endpoint

ResultsAdverse Reactions

Adverse Reaction

Naloxegol 25 mg

(n = 446)

Naloxegol 12.5 mg (n = 441)

Placebo(n = 444)

Abdominal Pain 21% 12% 7%

Diarrhea 9% 6% 5%Nausea 8% 7% 5%

Flatulence 6% 3% 3%Vomiting 5% 3% 4%Headache 4% 4% 3%

Hyperhidrosis 3% <1% <1%

Results

Conclusions• Effective

o ~40-44% response with 25 mg dose o Effective in harder to treat patients (LIR subpopulation)o Clinical relevance?

• Better response with higher naloxegol doseo Versus 35-40% response with 12.5 mg dose

• Predominantly GI side effects, dose-dependento Abdominal pain 21% (25 mg dose) versus 7% (placebo)

• No increased risk of severe adverse effects

Considerations• Strengths:

o 2 simultaneous trialso Similar resultso Large sample sizes

• naloxegol 25mg (n = 446), naloxegol 12.5mg (n = 441), placebo (n = 444)

o Multiple institutions• Limitations:

o Only 12 weeks no long-term safety and efficacy datao Subjectivity in patient reportingo Female majorityo Large standard deviation with mean daily opioid doseo No quality of life evaluation

Efficacy and Safety of Methylnaltrexone for Opioid-Induced Constipation in Patients with

Chronic Noncancer Pain: A Placebo Crossover Analysis

Viscusi ER, et al. 2016Regional Anesthesia and Pain

Medicine

Purpose• Reproduce efficacy and safety findings of a RCT

via placebo crossover:

Viscusi ER, et al. 2016

Subcutaneous methylnaltrexone for treatment of opioid-induced constipation in patients with chronic, nonmalignant pain: a randomized controlled study.

Michna E, et al. 2011 Journal of Pain

Study Design• Phase III trial• Randomized, double-blind, placebo-controlled• Multi-center• U.S. and Canada• Placebo crossover analysis


Inclusion Criteria Exclusion Criteria• History of inflammatory bowel

disease, IBS or megacolon during the past 6 months

• Scheduled to undergo surgery during study period

• Has evidence of bowel obstruction or fecal incontinence

• History of rectal bleeding unrelated to hemorrhoids or fissures

• History of chronic constipation prior to opioid therapy


• Adult with CNCP for ≥ 2 months prior to screening

• Stable medical condition for ≥ 1 month

• Opioid use with average daily dose ≥ 50 mg oral morphine equivalent for ≥ 2 weeks

• Has OIC:• < 3 rescue-free BMs

(RFBMs) with ≥ 1 of the following for ≥ 25% of BMs:

• Hard or lumpy stools• Straining• Sensation of

incomplete evacuation

Rescue-free BM (RFBM): BM not occurring within 24 hours of rescue laxative use

Methods• 4-week RCT

o 1:1:1 randomization of placebo, 12 mg methylnaltrexone (MTNX) daily (QD) or 12 mg MTNX every other day (QOD)

• 8-week open-label extension (OLE)o MTNX- and placebo-treated participants who

completed RCT phaseo 12 mg MTNX as needed (no more often than

once daily)


MethodsViscusi ER, et al. 2016

Methods• Patient diaries:

o Number and time of BMo Stool consistency (Bristol Stool Form Scale)o Straining during BMo Sense of complete evacuation (yes/no)o Rescue laxative use

• Rescue laxative permitted if no BM for 3 consecutive days during study periodo Bisacodyl taken ≥ 4 hours after study drug administrationo Only 1 dose within 24-hour period


Demographics and Characteristics

EndpointsViscusi ER, et al. 2016

EfficacyPrimary Secondary

• % experiencing a RFBM within 4 hours of first dose

• % of injections resulting in a RFBM within 4 hours of dose

• % experiencing ≥ 3 RFBMs per week with and without ≥ 1-RFBM increase from baseline

• Weekly RFBM rate• % of weekly injections

resulting in a RFBM within 4 hours of dose

Safety• Adverse event monitoring• Clinical laboratory tests• Vital signs• Concomitant medications

ResultsViscusi ER, et al. 2016

Primary Efficacy Endpoints


Secondary Efficacy Endpoints

Endpoint Before crossover(placebo)

After crossover(12 mg MTNX)

% of patients experiencing ≥ 3 RFBMs per week with ≥ 1

RFBM increase from baseline

35-45% ~70%





Weekly RFBM rate ~2.5 ~4





% of weekly injections resulting in a RFBM within 4 hours of dose

~10% 35-45%

Conclusions• Effective

o ~70% experienced goal RFBM per week (placebo crossover group)o Participants on stronger opioids

• Fast-actingo ~46% experienced response within 4 hours (placebo crossover group)

• Adds validity to RCT results• Predominantly GI side effects

Considerations• Strengths:

o Crossover design• Patients served as their own controls

o Moderate sample size• Placebo crossover (n = 134), methylnaltrexone from RCT (n = 230)

• Limitations:o RCT only 4 weeks, OLE only 8 weekso Subjectivity in patient reportingo Male majorityo Strong opioids, large standard deviationo No quality of life evaluationo Non-standardized dose regimen during OLEo Primary efficacy endpoints only relate to the drug’s ability to act quickly

• Designed to make the drug look more favorableo Secondary endpoints more similar to the primary endpoint in the naloxegol

studyo Less elegant as naloxegol study

Key DifferencesNaloxegol Methylnaltrexone

Study Design RCT OLEGender (majority) Female MaleAverage daily morphine dose

~150 mg ~220 mg

Primary Endpoints • ≥ 3 SBMs per week

+ • ≥ 1 SBM increase

from baseline in 9/12 weeks (3 within last 4 weeks of treatment)

• % experiencing a RFBM within 4 hours of first dose

• % of injections resulting in a RFBM within 4 hours of dose

Place in Therapy

Cost and EfficacyComparison

Methylnaltrexone Naloxegol

Indication

- OIC in advanced illness (including cancer) receiving palliative care

- OIC in CNCP

- OIC in CNCP

Usual Adult Dosage 12 mg subcutaneously daily*

25 mg by mouth daily

Response Rate 59% vs. 38% 35-44% vs. 29%

NNT 4 (pooled MTNX groups in RCT)

12.5 mg: 8.825 mg: 6.7-9.7

Cost (NADAC) ~ $160 per unit $8.83 per unit

*For OIC in CNCPNADAC = National Average Drug Acquisition Cost

Methylnaltrexone Dosing for OIC

(Advanced Illness)

Dosage: 1 dose every other day as needed (max: 1 dose per 24 hours)

ADEs ComparisonAdverse Drug Effects

Methylnaltrexone NaloxegolAbdominal pain (21-29%)Nausea (9-12%)Flatulence (13%)

Abdominal pain (12-21%)Nausea (7-9.4%) Flatulence (3-6.9%)

Diarrhea (6-12.9%) Headache (4-9%)

Vomiting (3-5%) Arthralgia (6.2%)

Pharmacokinetic Comparison

Methylnaltrexone NaloxegolTMAX 0.25 hr < 2 hr

Protein Binding

11 - 15.3% 4.2%

VD 1.1 L/kg 968 - 2140 LMetabolism -- Hepatic

EliminationFecal: 17.3% unchanged

Renal: 53.6% unchanged

Fecal: 68%, 16% unchanged

Renal: 16%, < 6% unchanged

Elimination T1/2 8 hr 6-11 hrDose

AdjustmentsRenal Hepatic, renal

CurrentRecommendations

• American Gastroenterological Association (2013)*o 1st line: gradual increase in dietary fiber intakeo 2nd line: laxative (first osmotic then stimulant with suboptimal response)o 3rd line: newer pharmacologic agent, such as lubiprostone or linaclotideo Biofeedback therapy may augment these interventions

• Pharmacist’s/Physician’s Letter (2015)o 1st line: gradually increase dietary fiber intake to goal of 20-25 g/day, increase

fluid intake to goal of 1.5-2 L/day, increase physical activity as tolerated, bowel habit training

o 2nd line: osmotic laxative, stimulant laxative if suboptimal responseo 3rd line; lubiprostone or methylnaltrexone or naloxegol as indicated

*Constipation in Adults

Knowledge Questions

3. Surfactant laxatives increase fat and water incorporation into the bowel whereas lubricant laxatives decrease water extraction.

True or False?

Current Treatment Options for

Constipation• Lifestyle modifications

o Dietary fiber: goal 20-25 g dailyo Fluid intake: goal 1.5-2 L dailyo Physical activity

• OTCso Stimulant laxatives – increased propulsive muscle contractions via

enteric reflex• Senna: 2 tablets daily, may titrate up to 4 tablets twice daily• Bisacodyl: 10-15 mg daily, may titrate up to 3 times daily

o Stool softeners/non-stimulant laxatives• Surfactants – fat and water incorporation

o Docusate: 100-400 mg once or twice daily• Lubricants – decreased water extraction

o Mineral oil: 30-90 mL daily as needed• Osmotic – water incorporation

o Polyethylene glycol (PEG): 17 g daily

Knowledge Questions

4. Methylnaltrexone and naloxegol have the following in common (select all that apply):

a. parent compoundb. use in cancer patientsc. dosing scheduled. predominant side effect of abdominal paine. range of cost

Cost and EfficacyComparison

Methylnaltrexone Naloxegol

Indication

- OIC in advanced illness (including cancer) receiving palliative care

- OIC in CNCP

- OIC in CNCP

Usual Adult Dosage 12 mg subcutaneously daily*

25 mg by mouth daily

Response Rate 59% vs. 38% 35-44% vs. 29%

NNT 4 (pooled MTNX groups in RCT)

12.5 mg: 8.825 mg: 6.7-9.7

Cost (NADAC) ~ $160 per unit $8.83 per unit

*For OIC in CNCP onlyNADAC = National Average Drug Acquisition Cost

ADEs ComparisonAdverse Drug Effects

Methylnaltrexone NaloxegolAbdominal pain (21-29%)Nausea (9-12%)Flatulence (13%)

Abdominal pain (12-21%)Nausea (7-9.4%) Flatulence (3-6.9%)

Diarrhea (6-12.9%) Headache (4-9%)

Vomiting (3-5%) Arthralgia (6.2%)

SummaryMethylnaltrexone Naloxegol Both

PROs

• Approved for OIC in advanced illness (including cancer)

• Effective (NNT 4)• Fast-acting (within

4 hours)• Few side effects

• Effective (NNT 6.7-9.7)

• Easy administration (oral)

• Effective• Daily for OIC in

CNCP• Unique MOA (target

peripheral adverse effects while preserving centrally-acting analgesia)

CONs

• Injection only• More complicated

dosing for OIC in advanced illness (weight-based)

• COST!

• Only approved for OIC in CNCP

• Less effective than methylnaltrexone

• Abdominal pain common (~20%)

• Limited incorporation into guideline recommendations

• No head-to-head RCTs

References• Frenk SM, Porter KS, Paulozzi LJ. Prescription opioid analgesic use among adults: United States, 1999–2012. NCHS data brief, no 189.

Hyattsville, MD: National Center for Health Statistics. 2015.• Feng Y, He X, Yang Y, Chao D, Lazarus LH, Xia Y. Current Research on Opioid Receptor Function. Curr Drug Targets. 2012 Feb;13(2):230-

246.• Hi-Hasani R, Bruchas MR. Molecular Mechanisms of Opioid Receptor-Dependent Signaling and Behavior. Anesthesiology, 2011 Dec:

115(6):1363-1381. PMID:PMC3698859.• Kumar L, Barker C, Emmanuel A. Opioid-induced constipation: pathophysiology, clinical consequences, and management. Gastroenterol

Res Pract. 2014;1-6.• Chey WD, Webster L, Sostek M, Lappalainen J, Barker PN, Tack J. Naloxetol for Opioid-Induced Constipation in Patients with Noncancer

Pain. N Engl J Med 2014;370:2387-96. DOI: 10.1056/NEJMoa1310246 • Viscusi ER, Barrett AC, Paterson C, Forbes WP. Efficacy and Safety of Methylnaltrexone for Opioid-Induced Constipation in Patients With

Chronic Noncancer Pain: A Placebo Crossover Analysis. Regional Anesthesia and Pain Medicine. 2016;41(1):93-98. doi:10.1097/AAP.0000000000000341.

• Swegle JM, Logemann C. Management of Common Opioid-Induced Adverse Effects. Am Fam Physician. 2006 Oct 15;74(8):1347-1354.• American Gastroenterological Association, Bharucha AE, Dorn SD, Lembo A, Pressman A. American Gastroenterological Association

Medical Position Statement on Constipation. Gastroenterology. 2013; 144:211-217.• PL Detail-Document, Treatment of Constipation in Adults. Pharmacist’s Letter/Prescriber’s Letter. June 2015.• Lubiprostone. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at:

http://www.micromedexsolutions.com. Accessed 16 Jan 2016.• Methylnaltrexone. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at:

http://www.micromedexsolutions.com. Accessed 16 Jan 2016.• Naloxegol. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at: http://www.micromedexsolutions.com.

Accessed 16 Jan 2016.Gold Standard, Inc. Lubiprostone. Clinical Pharmacology [database online]. Available at: http://www.clinicalpharmacology.com. Accessed: 16 Jan 2016.

• Gold Standard, Inc. Methylnaltrexone. Clinical Pharmacology [database online]. Available at: http://www.clinicalpharmacology.com. Accessed: 16 Jan 2016.

• Gold Standard, Inc. Naloxegol. Clinical Pharmacology [database online]. Available at: http://www.clinicalpharmacology.com. Accessed: 16 Jan 2016.

• Movantik [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2015. • Abramowicz M, Zuccotti G, Pflomm JM. Naloxegol (Movantik) for Opioid-Induced Constipation. JAMA. January 12, 2016: 315(2):194-195.

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