OPIOID-INDUCED CONSTIPATIONProactive Diagnosis and Targeted Management

Faculty Disclosures

• Dr Gudin: consultant: Zogenix, Inc.; consultant/research support/speakers bureau: Teva Pharmaceutical Industries Ltd.; consultant/speakers bureau: AstraZeneca, INSYS Therapeutics, Inc., Iroko Pharmaceuticals, LLC, Purdue Pharma L.P., Salix Pharmaceuticals, Inc.; speakers bureau: Depomed, Inc., Kaléo, Inc., XenoPort, Inc.

• Dr Lembo: consultant: AstraZeneca, Forest Laboratories, Inc., Ironwood Pharmaceuticals, Inc., Salix Pharmaceuticals, Inc.; consultant/research support: Prometheus Laboratories Inc.

2

Learning Objectives

• Evaluate bowel habits in patients on long-term opioid therapy

• Implement a prophylactic treatment plan to address OIC • Analyze current pharmacotherapies for OIC • Tailor treatment regimens for patients experiencing OIC • Discuss the essential elements of opioid pharmacology • Communicate with opioid-treated patients about

treatment-emergent AEs

AEs = adverse events; OIC = opioid-induced constipation.3

Scientific Insights Into OICKey Points

• Endogenous opioid analgesics modulate pain-related signaling along nociceptive neuraxis

• Opioid analgesics bind to opioid receptors throughout the central and peripheral nervous systems, including the GI tract

• Opioid receptor activation modulates physiologic processes from lower esophageal sphincter to rectum

• By antagonizing μ-opioid receptor activity, opioid antagonists reverse effects of opioid analgesics

• Peripherally acting μ-opioid receptor antagonists are intended to affect areas outside of the central nervous system (eg, the GI tract)

Brennan MJ, et al. J Multidiscip Healthc. 2013;6:265-280; De Schepper HU, et al. Neurogastroenterol Motil. 2004;16:383-394; Holzer P. Eur Rev Med Pharmacol Sci. 2008;12(suppl 1):119-127.4

Rising Rates of Chronic Pain

• 100 million US adults are currently affected by chronic pain• Prevalence is predicted to increase with aging population

Arth

ritis

Prev

alenc

e (10

00x)

a

2005 2010 2015 2020 2025 2030

80,000

Year

70,00060,00050,00040,00030,00020,00010,000

0

18-44 years old45-64 years old65+ years old

5

aProjected prevalence of doctor-diagnosed arthritis in the United States by age.Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: The National Academies Press; 2011; Hootman JM, Helmick CG. Arthritis Rheum. 2006;54:226-229.

IMS Health National Prescription Audit (NPA) & Vector One: National (VONA). Data extracted 2011 and 2014.

Rise in Therapeutic Opioid UseOpioid Prescriptions Dispensed by US Pharmacies, 1991-2013

No. o

f Pre

scrip

tions

(milli

ons)

Year

76 79 82 85 87 94 97 105116

126138 142 149 155 163

174184

196 202 210 219 217207

0

50

100

150

200

25019

9119

9219

9319

9419

9519

9619

9719

9819

9920

0020

0120

0220

0320

0420

0520

0620

0720

0820

0920

1020

1120

1220

13

OxycodoneHydrocodoneTotal

124

53

6

Up to 1 of every 2 patients on opioid therapy will experience

constipation symptoms3

1 of every 3 patients on opioid therapy does not discuss his or her constipation

symptoms with his/her healthcare provider4

Opioid-Induced Constipation

• Constipation is the most common AE of prescription opioid analgesics1,2

Constipated Not Constipated Silently Suffering

Discusses Constipation

Discusses Constipation

Clinicians need to evaluate patients on chronic opioid therapy for constipation symptoms.

1. Chou R, et al. J Pain. 2009;10:113-130; 2. Moore RA, McQuay HJ. Arthritis Res Ther. 2005;7:R1046-R1051; 3. Cook SF, et al. Aliment Pharmacol Ther. 2008;27:1224-1232; 4. Coyne KS, et al. Clinicoecon Outcomes Res. 2014;6:269-281. 7

OICMultidisciplinary Working Group Definition

• Reduced bowel movement frequency• Development or worsening of straining to pass bowel

movements• A sense of incomplete rectal evacuation• Harder stool consistency

A change when initiating opioid therapy from baseline bowel habits that is characterized by

any of the following:

8 Camillieri M, et al. Neurogastroenterol Motil. 2014;26:1386-1395.

ConstipationWhat Does It Mean to Your Patient?1,2

Constipation

Hard stools

Incomplete evacuationStraining

PainBloatingInfrequent

stools

91. Lacy BE, et al. Ther Adv Gastroenterol. 2012;5:233-247; 2. Coyne KS, et al. Clinicoecon Outcomes Res. 2014;6:269-281.

Let’s Meet Stanley61-Year-Old Man

• Recently moved to the area• Medical history

– Right knee osteoarthritis diagnosed 6 years ago • Pain restricted his mobility and forced him to retire early from

his job as a welder– No notable risk factors for aberrant drug use

• Current analgesic regimen (oxycodone ER 20 mg twice daily) has increased his mobility over the last 5 years

• Twice stopped taking oxycodone ER because he wanted a “break from all those pills”

– Dyslipidemia • Rosuvastatin 20 mg once daily

ER = extended release.10

StanleyAdditional Information

• When questioned, Stanley admits that his bowel movements have been less frequent since he started opioid therapy

• He did not discuss changes in his bowel habits with his previous primary care provider

• No record of prophylactic bowel regimen• Stanley’s wife notes that he “spends a long time in the

bathroom in the morning and evening”

11

Development of OICRisk Factors

Patient characteristics• Female gender• Advanced age

Drug regimen• Opioid type/

strength

Dietary considerations• Dehydration• Nutritional deficits

Medical issues• Relative immobility• Nausea/vomiting after

starting opioids• Mechanical obstruction• Recent hospitalizations

Ahmedzai SH, Boland J. BMJ Clin Evid. 2010;2010. pii: 2407; Clemens KE, Klaschik EK. Ther Clin Risk Manag. 2010;6:77-82; Wan Y, et al. Las Vegas, NV; 2013; Abstract 132.12

PATIENT

“1 or 2”

PATIENT

“I used to go to the bathroom more often before I started taking these pills.”

Approaching StanleyPotential Dialogue

CLINICIAN

“How many bowel movements are you having per week?”

CLINICIAN“Has the frequency of your bowel movements changed since beginning opioid therapy?”

CLINICIAN“Let’s use a bowel assessment tool to get a better idea about exactly how your bowel patterns have changed.”

Assessment of Bowel Habits

Bowel Function

Index

Bristol Stool Form Scale

Patient Assessment of Constipation

14Rentz AM, et al. J Med Econ. 2009;12:371-383; Frank L, et al. Scand J Gastroenterol. 1999;34:870-887; Lewis SJ, Heaton KW. Scand J Gastroenterol. 1997;32:920-924.

www.ExchangeCME.com/OICPCP2015

Bristol Stool Form Scale

Type 1 Separate hard lumps, like nuts

Type 2 Sausage-like but lumpy

Type 3 Like a sausage but with cracks in the surface

Type 4 Like a sausage or snake, smooth and soft

Type 5 Soft blobs with clear-cut edges

Type 6 Fluffy pieces with ragged edges, a mushy stool

Type 7 Watery, no solid pieces

15 Lewis SJ, Heaton KW. Scand J Gastroenterol. 1997;32:920-924.

Bowel Function Index (BFI)

• Scored by numerical assessment scale (0-100, free from symptom to most severe symptom experienced) for last 7 days– Ease of defecation– Feeling of incomplete evacuation– Personal judgment of constipation

• BFI score is the mean of the 3 component scores

16 Rentz AM, et al. J Med Econ. 2009;12:371-383.

Patient Assessment of Constipation (PAC-SYM)

• 12-item questionnaire of patient-reportedsymptoms over the last 2 weeks, using 3 subscales– Bowel movements– Rectal symptoms– Abdominal symptoms

• Scored from no problems (score 0) to very severe symptoms (score 4)

17 Frank L, et al. Scand J Gastroenterol. 1999;34:870-887.

Patient Resources

Patient educational tool Patient conversation guide

18

American College of Physicians. http://www.acponline.org/patients_families/products/health_tips/oic_en.pdf. Accessed May 26, 2015; The American Chronic Pain Association. http://www.theacpa.org/uploads/ACPA-Opioid_Constipation_Chart-V4.pdf. Accessed May 26, 2015.

www.ExchangeCME.com/OICPCP2015

Patient-Provider Partnership

Educate Discuss Coordinate• On the risks of

developing OIC– ~50% of patients on

chronic opioid therapy

– Increased likelihood if patients have risk factors

• Prophylactic treatment plan• Bowel habits at every follow-up

visit• Results of bowel function

evaluation • Importance of adherence to

opioid therapy and OIC management plan

• With other members of the healthcare team

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StanleyAssessment of Bowel Patterns

• BFI score, 71• Bristol Stool Form Scale, Type

1 and Type 2• Bowel movements are

infrequent– Hard and lumpy stool– Mild pain– Straining

• Previously advised by wife to increase dietary fiber and drink more water

• Uses psyllium (2 tbsp) in morning orange juice

• Takes 2-3 bisacodyl 5 mg tablets before bed when he is very uncomfortable or has not defecated in days

• When abdominal pain is severe, Stanley skips his oxycodone ER – Diarrhea develops after

1-2 days– Knee pain is unbearable

20

Prophylactic and Initial Management of OIC

Implementation of Prophylactic Treatment

• Guidelines on long-term opioid therapy recommend that all patients be advised on a prophylactic bowel regimen– Adequate dietary fiber– Adequate water intake– Regular exercise– Laxatives?

• Patients who receive prophylactic laxative therapy are less likely to experience constipation

22

Chou R, et al. Pain. 2009;10:113-130; Department of Veterans Affairs/Department of Defense. http://www.healthquality.va.gov/guidelines/Pain/cot/COT_312_Full-er.pdf. Accessed May 27, 2015.

Commonly Used Laxatives to Treat Constipation

Type of Laxative Specific Example

Stool softener Docusate sodium, docusate calcium

Stimulant Senna, bisacodyl, castor oilOsmotic Polyethylene glycol, lactuloseLubricant Mineral oilBulking agent Psyllium, bran, methylcellulose

23Ford AC, Suares NC. Gut. 2011;60:209-218; Lee YY. Front Med (Lausanne). 2014;1-5; Pare P, Fedorak RN. Can J Gastroenterol Hepatol. 2014;28:549-557.

Practical Issues Related to Laxative Treatment

• Bulking agents and medicinal fiber, such as psyllium, should be avoided1,2

– Efficacy data are lacking– May further harden the patient’s stool

• Laxatives may have side effects3,4

– Nausea, vomiting, diarrhea, abdominal pain—all of which usually dissipate after bowel movement

– May increase the chance of poor adherence• High dosages of laxatives may be needed to improve bowel

patterns4

– May increase the chance of poor adherence

24

1. Pare P, Fedorak RN. Can J Gastroenterol Hepatol. 2014;28:549-557; 2. Yang J, et al. World J Gastroenterol. 2012;18:7378-7383; 3. Mueller-Lissner SA, Wald A. BMJ Clin Evid. 2010;2010. pii: 0413; 4. Sykes NP. J Pain Symptom Manage. 1996;11:363-369.

Guidelines on Opioid Rotation

Fine PG, et al. J Pain Symptom Manage. 2009;38:418-425.

STEP

1

• Calculate new opioid dose based on equianalgesic table• Identify “dose reduction window” 25%-50% lower than equianalgesic dose (not for

methadone or fentanyl)– Switching to methadone: identify window 75%-90% lower than equianalgesic

dose– Switching to transdermal fentanyl: calculate dose conversions based on ratios

included in the product information• Choose smaller (25% of dose) or larger (50% of dose) reduction based on

characteristics of regimen or patient– Larger reductions for patients on high current opioid doses,

non-Caucasians, and older or medically frail individuals

STEP

2 • Reassess pain and other biopsychosocial characteristics to determine whether an additional 15%-30% dose increase or decrease is needed

• Repeatedly assess response and titrate new opioid to optimize outcomes

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StanleyOIC Management

• Prescribed laxative regimen – 3 docusate sodium 100 mg tablets after breakfast– 3 bisacodyl 5 mg tablets before bed

• 6-week follow-up – Some improvements in symptoms – BFI, 63 (previous score, 71)– Bristol Stool Form Scale, mostly Type 2– Bowel movements are more frequent – Some straining and mild pain

26

Additional Treatment Options for OIC

Agent Lubiprostone Methylnaltrexone NaloxegolMechanism of action

Chloride channelactivator Peripherally acting μ-opioid receptor antagonist (PAMORA)

Mode of administration Oral Subcutaneous Oral

Recommendeddose 24 µg 12 mg/0.6 mL 25 mg/12.5 mg

Dosing frequency Twice daily Once daily Once daily

Clinical considerations

• Take with food and water• May be used concomitantly

for length of opioid treatment• May be less effective in

patients taking methadone

• Discontinue laxative therapy prior to use• Need close proximity to toilet once administered• May be used concomitantly for length of opioid

treatment• Monitor for signs of opioid withdrawal

• Discontinue laxative therapy prior to use• Take on an empty stomach and avoid

grapefruit consumption• May be used concomitantly for length of

opioid treatment• Monitor for signs of opioid withdrawal

Currently Approved Therapies

Chey WD, et al. N Engl J Med. 2014;370:2387-2396; Cryer B, et al. Pain Med. 2014;15:1825-1834; Drugs@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed May 27, 2015.28

Lubiprostone Chloride Channel Activator

Mean

Cha

nge F

rom

Bas

eline

in S

BM F

requ

ency 3.3 3.4

2.22.4 2.6

1.6

0

1

2

3

4

5

Week 8 Week 12 Overall

Lubiprostone 24 µg twice daily (n = 210) Placebo (n = 208)

P = .005 P = .091

P = .004

Primary end point: Change at week 8 from the baseline weekly frequency of SBMs

14‐week, double‐blind, randomized, placebo‐controlled, phase 3 clinical trial

29

SBMs = spontaneous bowel movements, defined as bowel movements where no laxatives were used within the last 24 hours.Cryer B, et al. Pain Med. 2014;15:1825-1834.

Lubiprostone14-Week Safety Data

aP values are from Fisher’s exact test; bAEs in patients who received ≥1 dose of study medication. Cryer B, et al. Pain Med. 2014;15:1825-1834.

AE, No. (%) of PatientsPlacebo

Twice Daily(n = 206)

Lubiprostone 24 µg Twice Daily

(n = 208)P Valuea

≥1 AEb 112 (54.4) 132 (63.5) .072AEs in ≥5% of either treatment armNausea 12 (5.8) 35 (16.8) <.001Diarrhea 6 (2.9) 20 (9.6) .007Abdominal distention 5 (2.4) 17 (8.2) .014≥1 treatment-related AE 48 (23.3) 76 (36.5) .004Treatment-related AEs in ≥2% of either treatment armNausea 11 (5.3) 32 (15.4) .001Abdominal distention 5 (2.4) 16 (7.7) .023Diarrhea 3 (1.5) 15 (7.2) .006Flatulence 5 (2.4) 8 (3.8) .575Vomiting 4 (1.9) 5 (2.4) 1.000Upper abdominal pain 7 (3.4) 1 (0.5) .037Abdominal pain 1 (0.5) 8 (3.8) .037

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aIncluded all randomized patients who received ≥1 dose of double-blind study medication; bP <.001 vs placebo; N = 312 patients with chronic noncancer pain.Drugs@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed May 27, 2015.

4-week, double-blind, randomized, placebo-controlled, phase 3 clinical trial

Primary end point: Percentage of patients with >3 SBMs per week, during 4-week period

59

38

010203040506070

Methylnaltrexone 12 mg Once Daily(n = 150)

Placebo(n = 162)

Patie

nts

With

>3

SBM

sD

urin

g 4-

Wee

k Pe

riod

(%) b

Methylnaltrexone Peripherally Acting μ-Opioid Receptor Antagonist

Response Rates in the Modified Intent-to-Treat Populationa

31

Methylnaltrexone 4-Week Safety Data

AEMethylnaltrexone 12 mg

Once Daily(n = 150), %

Placebo(n = 162), %

AEs occurring in ≥1% of patients receiving methylnaltrexone and at an incidence greater than placeboAbdominal pain 21 6Nausea 9 6Diarrhea 6 4Hyperhidrosis 6 1Hot flush 3 2Tremor 1 <1Chills 1 0AEs leading to treatment discontinuationAny AE 7 3

Drugs@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed May 27, 2015.

Safety data from 48-week, open-label, uncontrolled study(N = 1034) were consistent with 4-week results

32

NaloxegolPeripherally Acting μ-Opioid Receptor Antagonist

Primary end point: 12-week response rate (≥3 SBMs/week and increase over baseline of ≥1 SBM for ≥9 of 12 weeks and ≥3 of the final 4 weeks)

Response Rates in the Intent-to-Treat Population

Two 12-week, double-blind, randomized, placebo-controlled, phase 3 clinical trials

Patie

nts (

%)

n = 214 n = 213 n = 214 n = 232 n = 232 n = 232

33aP <.05 vs placebo in each study; N = 652, Study 04; N = 700, Study 05.Chey WD, et al. N Engl J Med. 2014;370:2387-2396.

Naloxegol 12-Week Safety Data

AE n (%)1

Study 04 Study 05Naloxegol

25 mg (n = 214)

Naloxegol 12.5 mg (n = 211)

Placebo (n = 213)

Naloxegol 25 mg

(n = 232)

Naloxegol 12.5 mg (n = 230)

Placebo (n = 231)

Any AEa 131 (62.2) 104 (49.3) 100 (46.9) 160 (69.0) 137 (59.6) 136 (58.9)AE leading to discontinuation 22 (10.3) 9 (4.3) 12 (5.6) 24 (10.3) 12 (5.2) 12 (5.2)

Serious AE 7 (3.3) 11 (5.2) 11 (5.2) 8 (3.4) 14 (6.1) 12 (5.2)AEs in ≥5% of any treatment armb

Abdominal pain 27 (12.6) 18 (8.5) 7 (3.3) 44 (19.0) 25 (10.9) 18 (7.8)Diarrhea 20 (9.3) 7 (3.3) 9 (4.2) 21 (9.1) 18 (7.8) 10 (4.3)Nausea 16 (7.5) 15 (7.1) 10 (4.7) 20 (8.6) 14 (6.1) 10 (4.3)Flatulence 12 (5.6) 9 (4.3) 4 (1.9) 14 (6.0) 4 (1.7) 7 (3.0)Upper abdominal pain 11 (5.1) 3 (1.4) 4 (1.9) 6 (2.6) 5 (2.2) 3 (1.3)Vomiting 6 (2.8) 3 (1.4) 7 (3.3) 14 (6.0) 7 (3.0) 6 (2.6)

Safety data from 52-week, open-label, parallel-group phase 3 study (N = 804) with patients randomized 2:1 to either naloxegol 25 mg/day or usual care were similar to 12-week results2

34

aOccurring during either the treatment or posttreatment follow-up period; bOccurring during the treatment period. 1. Chey WD, et al. N Engl J Med. 2014;370:2387-2396; 2. Webster L, et al. Aliment Pharmacol Ther. 2014;40:771-779.

Emerging μ-Opioid Receptor Antagonists for Treatment of OIC

Agent Mode of Administration

Mechanism of Action

Current Developmental Stage

Naldemedine1 OralPeripherally selective μ-opioid receptor antagonist

Phase 3

Bevenopran2 OralPeripherally acting μ-opioid receptorantagonist

Phase 3

Axelopran3Oral

Peripherally selective μ-opioid receptor antagonist

Phase 2, completed

35

1. https://www.clinicaltrials.gov/ct2/show/NCT01965652. Accessed May 26, 2015; 2. https://clinicaltrials.gov/ct2/show/NCT01696643. Accessed May 26, 2015; 3. FDA. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/UCM400210.pdf. Accessed May 27, 2015.

PCE ACTION PLAN

PCE Action Plan

Educate patients on chronic opioid therapy about the risk for developing OIC

Routinely assess bowel habits in patients on chronic opioid therapy, especially if they have risk factors for developing OIC

Collaborate with patients and other members of the healthcare team to adequately control pain while managing treatment-emergent side effects

Implement a prophylactic bowel regimen in patients starting chronic opioid therapy

Consider an FDA-approved agent for the treatment of OIC in patients who have an inadequate response to laxative therapy

37

PCE Promotes Practice Change

StanleyAssessment of Bowel Patterns

• BFI score, 71• Bristol Stool Form Scale, Type

1 and Type 2• Bowel movements are

infrequent– Hard and lumpy stool– Mild pain– Straining

• Previously advised by wife to increase dietary fiber and drink more water

• Uses psyllium (2 tbsp) in morning orange juice

• Takes 2-3 bisacodyl 5 mg tablets before bed when he is very uncomfortable or has not defecated in days

• When abdominal pain is severe, Stanley skips his oxycodone ER – Diarrhea develops after

1-2 days– Knee pain is unbearable

38