Opioid-Induced Constipation

OPIOID-INDUCED CONSTIPATION Proactive 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.

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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

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

Scientific Insights Into OIC Key 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)

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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.

Rising Rates of Chronic Pain

Arthritis Prevalence (1000x)a

• 100 million US adults are currently affected by chronic pain • Prevalence is predicted to increase with aging population 80,000 70,000 60,000 50,000 40,000 30,000 20,000 10,000

aProjected

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65+ years old 45-64 years old 18-44 years old

0 2005

2010

2015

Year

2020

2025

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.

2030

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

No. of Prescriptions (millions)

250

Total Hydrocodone Oxycodone

200 150 100

85 87 76 79 82

94 97

105

116

126

138 142

149 155

163

174

184

196 202

210

219 217

207

124

53

50

Year

6

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

2013

2012

2011

2010

2009

2008

2007

2006

2005

2004

2003

2002

2001

2000

1999

1998

1997

1996

1995

1994

1993

1992

1991

0

Opioid-Induced Constipation • Constipation is the most common AE of prescription opioid analgesics1,2 Up to 1 of every 2 patients on opioid therapy will experience constipation symptoms3

Constipated

Not Constipated

1 of every 3 patients on opioid therapy does not discuss his or her constipation symptoms with his/her healthcare provider4

Silently Suffering

Discusses Constipation

Discusses Constipation

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

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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.

OIC Multidisciplinary Working Group Definition A change when initiating opioid therapy from baseline bowel habits that is characterized by any of the following: • Reduced bowel movement frequency • Development or worsening of straining to pass bowel movements • A sense of incomplete rectal evacuation • Harder stool consistency

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

Constipation What Does It Mean to Your Patient?1,2

Hard stools Straining

Constipation

Incomplete evacuation

Bloating

Pain Infrequent stools

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1. 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 Stanley 61-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 10

ER = extended release.

Stanley Additional 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”

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Development of OIC Risk Factors

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Patient characteristics

Dietary considerations

• Female gender • Advanced age

• Dehydration • Nutritional deficits

Drug regimen

Medical issues

• Opioid type/ strength

• 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.

Approaching Stanley Potential Dialogue CLINICIAN

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

PATIENT

“1 or 2” CLINICIAN

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

PATIENT

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

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

www.ExchangeCME.com/OICPCP2015 14

Rentz 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.

Bristol Stool Form Scale

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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

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

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

Patient Assessment of Constipation (PAC-SYM) • 12-item questionnaire of patient-reported symptoms 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)

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

Patient Resources

Patient educational tool

Patient conversation guide

www.ExchangeCME.com/OICPCP2015 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.

Patient-Provider Partnership

Educate • On the risks of developing OIC – ~50% of patients on chronic opioid therapy – Increased likelihood if patients have risk factors

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Discuss • 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

Coordinate • With other members of the healthcare team

Stanley Assessment 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

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• 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

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

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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

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Type of Laxative

Specific Example

Stool softener

Docusate sodium, docusate calcium

Stimulant

Senna, bisacodyl, castor oil

Osmotic

Polyethylene glycol, lactulose

Lubricant

Mineral oil

Bulking agent

Psyllium, bran, methylcellulose

Ford 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 • Calculate new opioid dose based on equianalgesic table

STEP 1

• 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

STEP 2

– Larger reductions for patients on high current opioid doses, non-Caucasians, and older or medically frail individuals

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• 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

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

Stanley OIC 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

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Additional Treatment Options for OIC

Currently Approved Therapies Agent

Methylnaltrexone

Naloxegol

Mechanism of action

Chloride channel activator

Mode of administration

Oral

Subcutaneous

Oral

Recommended dose

24 µg

12 mg/0.6 mL

25 mg/12.5 mg

Twice daily

Once daily

Once daily

Dosing frequency

Clinical considerations

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Lubiprostone

• Take with food and water • May be used concomitantly for length of opioid treatment • May be less effective in patients taking methadone

Peripherally acting μ-opioid receptor antagonist (PAMORA)

• 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

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.

• 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

Lubiprostone Chloride Channel Activator Mean Change From Baseline in SBM Frequency

5

Lubiprostone 24 µg twice daily (n = 210) P = .091

P = .005

4

Placebo (n = 208)

3.4

3.3 3

P = .004

2.6

2.4

2.2

2

1.6

1 0 Week 8

Week 12

Overall

14‐week, double‐blind, randomized, placebo‐controlled, phase 3 clinical trial Primary end point: Change at week 8 from the baseline weekly frequency of SBMs SBMs = spontaneous bowel movements, defined as bowel movements where no laxatives were used within the last 24 hours.

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Cryer B, et al. Pain Med. 2014;15:1825-1834.

Lubiprostone 14-Week Safety Data

AE, No. (%) of Patients

Placebo Twice Daily (n = 206) 112 (54.4)

≥1 AEb AEs in ≥5% of either treatment arm Nausea 12 (5.8) Diarrhea 6 (2.9) Abdominal distention 5 (2.4) ≥1 treatment-related AE 48 (23.3) Treatment-related AEs in ≥2% of either treatment arm Nausea 11 (5.3) Abdominal distention 5 (2.4) Diarrhea 3 (1.5) Flatulence 5 (2.4) Vomiting 4 (1.9) Upper abdominal pain 7 (3.4) Abdominal pain 1 (0.5) aP

Lubiprostone 24 µg Twice Daily (n = 208) 132 (63.5)

Cryer B, et al. Pain Med. 2014;15:1825-1834.

.072

35 (16.8) 20 (9.6) 17 (8.2) 76 (36.5)

<.001 .007 .014 .004

32 (15.4) 16 (7.7) 15 (7.2) 8 (3.8) 5 (2.4) 1 (0.5) 8 (3.8)

.001 .023 .006 .575 1.000 .037 .037

values are from Fisher’s exact test; bAEs in patients who received ≥1 dose of study medication.

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P Valuea

Methylnaltrexone Peripherally Acting Îź-Opioid Receptor Antagonist

Patients With >3 SBMs During 4-Week Period (%)

Response Rates in the Modified Intent-to-Treat Populationa 70 60

b

59

50

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40 30 20 10 0 Methylnaltrexone 12 mg Once Daily (n = 150)

Placebo (n = 162)

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 aIncluded

all randomized patients who received â&#x2030;Ľ1 dose of double-blind study medication; bP <.001 vs placebo; N = 312 patients with chronic noncancer pain.

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

Methylnaltrexone 4-Week Safety Data Methylnaltrexone 12 mg Placebo AE Once Daily (n = 162), % (n = 150), % AEs occurring in â&#x2030;Ľ1% of patients receiving methylnaltrexone and at an incidence greater than placebo Abdominal pain Nausea Diarrhea Hyperhidrosis Hot flush Tremor Chills AEs leading to treatment discontinuation Any AE

21 9 6 6 3 1 1

6 6 4 1 2 <1 0

7

3

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

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

Naloxegol Peripherally Acting μ-Opioid Receptor Antagonist

Patients (%)

Response Rates in the Intent-to-Treat Population

n = 214

n = 213

n = 214

n = 232

n = 232

n = 232

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

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) aP

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<.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

Naloxegol 25 mg (n = 214) 131 (62.2)

Any AEa AE leading to 22 (10.3) discontinuation Serious AE 7 (3.3) AEs in â&#x2030;Ľ5% of any treatment armb Abdominal pain 27 (12.6) Diarrhea 20 (9.3) Nausea 16 (7.5) Flatulence 12 (5.6) Upper abdominal pain 11 (5.1) Vomiting 6 (2.8)

Study 04 Naloxegol 12.5 mg (n = 211) 104 (49.3)

100 (46.9)

Naloxegol 25 mg (n = 232) 160 (69.0)

9 (4.3)

12 (5.6)

24 (10.3)

12 (5.2)

12 (5.2)

11 (5.2)

11 (5.2)

8 (3.4)

14 (6.1)

12 (5.2)

18 (8.5) 7 (3.3) 15 (7.1) 9 (4.3) 3 (1.4) 3 (1.4)

7 (3.3) 9 (4.2) 10 (4.7) 4 (1.9) 4 (1.9) 7 (3.3)

44 (19.0) 21 (9.1) 20 (8.6) 14 (6.0) 6 (2.6) 14 (6.0)

25 (10.9) 18 (7.8) 14 (6.1) 4 (1.7) 5 (2.2) 7 (3.0)

18 (7.8) 10 (4.3) 10 (4.3) 7 (3.0) 3 (1.3) 6 (2.6)

Placebo (n = 213)

Study 05 Naloxegol 12.5 mg (n = 230) 137 (59.6)

Placebo (n = 231) 136 (58.9)

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 aOccurring

during either the treatment or posttreatment follow-up period; bOccurring during the treatment period.

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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 Mechanism of Administration Action Peripherally selective μ-opioid receptor antagonist

Phase 3

Oral

Peripherally acting μ-opioid receptor antagonist

Phase 3

Oral

Peripherally selective μ-opioid receptor antagonist

Phase 2, completed

Naldemedine1 Oral

Bevenopran2

Axelopran3

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Current Developmental Stage

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/AnestheticAnd AnalgesicDrugProductsAdvisoryCommittee/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 PCE Promotes Practice Change 37

Stanley Assessment 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

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• 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