opioid-induced constipation
Post on 22-Jul-2016
229 Views
Preview:
DESCRIPTION
TRANSCRIPT
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
19
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
25
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
30
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
top related