Download The Price of Pain Relief: Opioid Induced Constipation

The Price of Pain Relief:
Opioid Induced Constipation
Maria Foy, PharmD, BCPS, CPE
Patient Care Coordinator, Palliative Care
Abington-Jefferson Health
Chris Herndon, PharmD, BCPS, CPE
Associate Professor
Southern Illinois University Edwardsville
2
Disclosures
• Dr. Foy is on the speakers bureau for AstraZeneca
• Dr. Herndon declares no conflicts of interest, real or
• Target Audience: Pharmacists
apparent, and no financial interests in any company,
product, or service mentioned in this program, including
grants, employment, gifts, stock holdings, and honoraria.
• ACPE#: 0202-0000-16-056-L01-P
• Activity Type: Application-based
The American Pharmacists Association is accredited by the Accreditation
Council for Pharmacy Education as a provider of continuing pharmacy
education.
3
4
Which of the following is the most commonly
reported, troublesome side effect of opioids?
Learning Objectives
• Answer questions from patients and health care providers about
a)
b)
c)
d)
the potential for constipation during opioid use.
• Discuss lifestyle modifications that may help prevent and
manage constipation associated with opioid therapy.
• Compare current treatment options for the management of
opioid-induced constipation.
Constipation
Drowsiness
Nausea
Indigestion
• Evaluate patient cases and make clinical recommendations for
patients with opioid-induced constipation.
• Describe patient education strategies that promote adherence to
therapy to prevent and manage opioid-induced constipation
5
© 2016 by the American Pharmacists Association. All rights reserved.
6
The inhibition of the _____________ plexus
is the most likely cause of opioid induced
constipation.
a)
b)
c)
d)
Submucosal
Myenteric
Celiac
Brachial
Which lifestyle change can help
prevent constipation?
a)
b)
c)
d)
Eat primarily high fat foods
Exercise
Increase in intake of coffee
Waiting until there is enough time to have a complete
bowel movement
7
Which of the following options should NOT
be a part of an opioid induced constipation
(OIC) bowel regimen?
Which of the following is a peripherally
acting mu opioid antagonist?
a)
b)
c)
d)
8
Lubiprostone
Senna
Polyethylene glycol
Methylnaltrexone
a)
b)
c)
d)
e)
Bisacodyl Suppository
Docusate sodium
Psyllium
Sennasides
Polyethylene glycol
9
Which opioid side effect is not associated
with the development of tolerance?
a)
b)
c)
d)
e)
Nausea
Respiratory depression
Constipation
Sedation
Confusion
10
What is Opioid Induced Constipation (OIC)?
• Cause of constipation differs from functional constipation
• Suggested definition
– Change in bowel habits after opioid therapy initiated
• Decrease in bowel movement (BM) frequency from baseline
• Increased straining during defecation
• Feeling of incomplete evacuation of stool
• Harder stools
• Opioids may worsen constipation in patients with a
predisposition
11
© 2016 by the American Pharmacists Association. All rights reserved.
12
Meet Caroline
Etiologies of Constipation
52 year old female with persistent non-cancer pain due to osteogenesis
imperfecta Type 1
PMHx: Osteogenesis Imperfecta, HTN, Depression
Meds: Fentanyl TTS 75mcg/hr Q72 hours, hydromorphone IR Q8H as
needed, lisinopril 40mg QD, citalopram 40mg QD, senna plus docusate 2
tablets Q12, PEG 17gms QD, lubiprostone 24mcg Q12 hours
All: NKDA
SHx: Denies tobacco use, EtOH, recreational drug use
ROS: Unremarkable other than significant constipation. Last BM 5 days
ago.
Vitals: 130/74 mmHg, HR 90, RR 16, Temp 98.6
Labs: All within normal limits, specifically Ca and Mg
Tests: Abdominal CT negative for diverticulitis
Medications
Pain
Metabolic
Bowel
Dysfunction
Mobility
Diet
Structural
Autonomic
13
Incidence versus Bothersomeness of
Common Opioid Adverse Effects
Prevalence of OIC, Opioid Regimen
90
80
70
60
50
40
30
20
10
0
14
No Opioid
PRN Opioid
ATC Opioid
PRN + ATC
Villars P, et al. Differences in the prevalence and severity of side effects based on the type of
analgesic prescription in patients with chronic cancer pain. J Pain Symptom Manage
2007;33:67-77.
15
Symptom
% patients reporting
Constipation
81
Bothersomeness Rank
1
Straining
58
2
Fatigue
50
3
Small / hard bowel
movement
50
4
5
Insomnia
40
Incomplete evacuation
45
6
Passing gas
34
7
Bloating
33
8
Lower abdominal
discomfort
31
8
Nausea
26
10
Bell TJ, et al. The prevalence, severity, and impact of opioid induced bowel dysfunction:
Results of a US and European patient survey (Probe 1). Pain Medicine 2009;10:35-42.
Opioid Induced Bowel Dysfunction
The “Poop or No Poop” Game
•
•
•
•
•
•
•
•
•
•
•
Xerostoma
Gastroesophageal reflux
Retroperistalsis
Bloating
Abdominal pain
Incomplete evacuation
Opioid-induced constipation
•
16
Each table will be one team
One captain per table will control the buzzer
Please turn your button on now
The first team to press the button and answer
the question correctly will get one point
The team with the most points will get a
nominally significant prize
Brock C, et al. Opioid induced bowel dysfunction: Pathophysiology and management. Drugs
2012;72(14):1847-1865.
17
© 2016 by the American Pharmacists Association. All rights reserved.
18
Poop or No Poop Sample Question
Poop or No Poop
Which MLB team won the World Series in 2015?
Which of the following opioid dosing strategies has the
highest risk of constipation?
a)
b)
c)
d)
e)
St. Louis Cardinals
Baltimore Orioles
Cincinnati Reds
Kansas City Royals
Oakland Athletics
a)
b)
c)
d)
around the clock dosing of opioid
as need dosing of opioid
around the clock and as needed dosing of opioid
transdermal dosing of opioid
19
Pathophysiology of OIC
20
Opioid Receptors and the Intestine
•
•
•
•
•
•
Reproduced with permission under Creative Commons via OpenStax CNX via Rice University
Attribution: Download for free at http://cnx.org/contents/14fb4ad7-39a1-4eee-ab6e-3ef2482e3e22
21
Inhibition of distension-dependent peristaltic contractions
Gastric emptying inhibition
Gastrointestinal ion and fluid transport inhibition
Increased pyloric resting muscle tone
Elevation in resting anal sphincter pressure
Decreased defecation response
1. Holzer P. Opioid receptors in the gastrointestinal tract. Regul Pept 2009;155:11-17.
2. Rosti G, et al. Opioid-related bowel dysfunction: Prevalence and identification of predictive
factors in a large sample of Italian patients on chronic treatment. Eur Rev Med Pharmacol Sci
2010;14:1045-50.
Poop or No Poop
Risk Factors for OIC
Which cooked vegetable has the highest dietary fiber
content?
• Female gender
• Age > 70 years
• Concurrent aluminum antacids, antidepressants, and
a)
b)
c)
d)
e)
asparagus
cabbage
peas*
spinach
squash
antihistamines
• Opioid dose
• Magnesium and calcium status
• Opioid type and route of administration
23
© 2016 by the American Pharmacists Association. All rights reserved.
22
1. Rosti G, et al. Opioid-related bowel dysfunction: Prevalence and identification of predictive
factors in a large sample of Italian patients on chronic treatment. Eur Rev Med Pharmacol
Sci 2010;14:1045-50.
2. Talley NJ, et al. Risk factors for chronic constipation based on a general practice sample.
Am J Gastroenterology 2003;98:1107-1111.
3. Herndon CM, et al. Management of opioid-induced gastrointestinal effects in patients
receiving palliative care. Pharmacotherapy 2002;22:240-250.
24
Assessment Tools
Caroline’s Bowel History
•
•
•
•
•
•
•
•
•
Bristol Scale
Constipation Assessment Scale
Bowel Function Index
Patient Assessment of Constipation Symptoms
Hard, ball-like stool (Bristol Scale Type 1)
Last BM 5 days ago
Trialed sodium phosphate (Fleets) enema without laxation
Normal BM frequency every other day in the morning
Describing cramping and abdominal pain
25
Bristol-type Stool Assessment Scale
Type
Bowel Function Index (BFI)
Description
1
Separate hard lumps, similar to nuts
2
Lumpy, sausage-like pieces
3
Like sausage, but with cracks
4
Like a sausage or snake, but smooth and soft
5
Soft blobs with definable edges
6
Fluffy, mushy pieces with ragged edges
7
Watery, no solid pieces
Adapted from:
http://www.bowelcontrol.nih.gov/Bristol_Stool_Form_Scale_508.pdf.
Accessed Jan 7, 2016.
ITEM
27
Constipation Assessment Scale
Symptom
Patient Rating
Abdominal distension or bloating
None / Some / Severe
Change in amount of gas passed
rectally
None / Some / Severe
Less frequent bowel movements
None / Some / Severe
Oozing liquid stool
None / Some / Severe
Rectal fullness or pressure
None / Some / Severe
Rectal pain with bowel movement
None / Some / Severe
Small volume of stool
None / Some / Severe
Unable to pass stool
None / Some / Severe
McMillan SC, et al. Validity and reliability of the Constipation Assessment Scale. Cancer Nurs
1989;12:183-8.
© 2016 by the American Pharmacists Association. All rights reserved.
26
INTENSITIY
Ease of defecation in the
prior 7 days
1
2
3
4
5
6
7
8
9
10
Feeling of incomplete bowel
evacuation
1
2
3
4
5
6
7
8
9
10
Patient’s personal
assessment of constipation
1
2
3
4
5
6
7
8
9
10
Adapted from Validation of Drug Function Index to detect clinically meaningful changes in opioid
induced constipation. Rentz AM, et. al. Journal of Medical Economics. (2009)
28
Assessment
• Patient medical and medication history
• Physical exam
• Laboratory
– Electrolyte abnormalities
– Fluid status
• Testing
– Abdominal CT
• Adherence
29
30
Current Therapeutic Approaches
Poop or No Poop
•
•
•
•
•
•
•
•
Which common drug is most likely to exhibit a side effect of
constipation?
Behavioral health changes
Medication Rotation
Oral stool softeners and laxatives
Enemas or suppositories
Manual disimpaction/evacuation
Propulsion agents
Ion channel modulators
Peripherally acting mu opioid receptor antagonists
a)
b)
c)
d)
e)
metoprolol
amlodipine
sertraline
aripiprazole
metformin
31
Pharmacologic Treatment Options
32
Poop or No Poop
Which laxative / stool softener has the quickest onset of
action?
• Bulk laxatives
• Osmotic laxatives
• Stimulant laxatives
• Chloride channel activators
• Peripherally acting mu opioid receptor
a)
b)
c)
d)
e)
senna
polyethylene glycol
lactulose
magnesium citrate
bisacodyl
antagonists (PAMORA)
33
Bulk Forming Laxatives
Poop or No Poop
• Mechanism
– Increases stool bulk
– Colonic distension
– Stimulates peristalsis
• Commercially available
– psyllium (Metamucil)
– methylcellulose (Citrucel)
– polycarbophil (FiberCon)
– wheat dextrin (Benefiber)
• Inconsistent clinical evidence of utility
• Avoid in OIC due to risk of obstruction and lack of benefit
1. Bharucha AE, et al. American Gastroenterological Association technical review on
constipation. Gastroenterol 2013;144(1):218-238.
2. Ramkumar D, et al. Efficacy and safety of traditional medical therapies for chronic
constipation: Systematic review. Am J Gasterenterol 2005;100(4):936-971.
© 2016 by the American Pharmacists Association. All rights reserved.
34
The recommended daily intake of dietary fiber for a healthy
adult is:
Psyllium
35
a)
b)
c)
d)
e)
5-10 g/day
10-15 g/day
15-20 g/day
20-25 g/day
25-30 g/day
36
Osmotic Laxatives
Stimulant Laxatives
• Pulls water into the colon, hydrating and softening stools
• Types of osmotic laxatives
• Mechanism
– Increasing colonic muscle contractions facilitates
peristalsis
– Reduces intraluminal water and electrolyte
absorption
• Types of stimulant laxatives
– Senna, bisacodyl most commonly used
– Other options: cascara, aloe, castor oil
• Dosing
– Senna: 2 tablets at bedtime or twice daily
– Can titrate as tolerated to 8 tablets/day
– Scheduled bisacodyl suppositories every 2-3 days in
NPO patients
Senna
37
– Polyethylene glycol (PEG)
– carbohydrate laxatives (lactulose, sorbitol)
– phosphate, magnesium, or saline
• PEG studied for OIC use
– Increase of softened stools seen in study of methadone induced
constipation
– As effective as other laxatives in chronic constipation
– Initial dose: 17 g daily
• Lactulose studied for functional constipation
– May be beneficial in concomitant liver disease
– Initial dose: 30 ml daily
Freedman MD, et al. J Clin Pharmacol 1997;37(10):904–907.
Ramkumar D, et al. Am J Gastroenterol 2005;100(4):936–971.
Ford AC, et al. Gut 2011;60(2):209–218.
Adverse Effects of Laxatives
Poop or No Poop
• Generally well tolerated
• Gastrointestinal side effects
Which of the following therapies is not FDA indicated for
opioid-induced constipation?
a)
b)
c)
d)
– Nausea/vomiting
– Diarrhea
– Abdominal pain
38
naloxegol
methylnaltrexone
alvimopan
lubiprostone
• Tolerance to laxatives with long term use
• Dysfunctional bowel syndrome may occur
39
Chloride Channel Activators
40
Opioid Antagonists
• Mechanism
• Naloxone primarily studied
– Works by increasing fluid secretion and gut motility
• Available agents
•
•
•
•
– Low dose oral naloxone
– Equivocal data in palliative care
– Lubiprostone
– Linaclotide
Lubiprostone FDA approved for OIC in non-cancer pain
– Efficacy lessened in trials including methadone
– Linaclotide currently being studied, not yet approved
Dosing: 24 mcg twice daily
Generally well tolerated
– N/V, diarrhea, abdominal pain reported in studies
Cost: Approximately $6/dose
Cryer B., et.al.. Pain Med 2014; 15: 1825–1834.
Jamal MM, et al.. Am J Gastroenterology 2015; 110:725.
© 2016 by the American Pharmacists Association. All rights reserved.
•
•
•
•
•
Oral bioavailability low
Dose studied: 2-4 mcg three times a day
Small number of patients enrolled
Efficacy seen but reversal of analgesia occurred in up to 1/3 of patients
Naloxone prolonged release (PR) added to oxycodone SR studied
– Efficacious, but tolerability similar to placebo
– Fixed dose studied, higher doses may cause withdrawal symptoms
• Naloxone monotherapy not recommended for OIC
41
42
Peripherally Acting Mu Opioid
Receptor Antagonists (PAMORA)
Methylnaltrexone (Relistor)
• Methyl group added to naltrexone allows blocking of opioid receptors in
the gut without crossing the blood brain barrier
– Analgesia not affected
• Designed to antagonize peripheral mu opioid receptors in
• Approved for OIC in both cancer and non-cancer opioid when other
the gut without reversing analgesia
therapies have failed
• Dosing:
– Does not cross the blood brain barrier
– Will not produce withdrawal symptoms
– 8-12 mg subcutaneously (SC) every other day for advanced illness
• In patients >114 kg, weight based dosing is recommended
– 12 mg SC daily recommended for non-cancer pain
• Available agents
– Methylnaltrexone (Relistor)
– Naloxegol (Movantik)
– Alvimopan (Entereg)
• Generally well tolerated
– GI side effects most common adverse reaction seen in studies
• Cost: Approximately $55 per 12 mg dose
43
Naloxegol (Movantik)
44
Alvimopan (Entereg)
• Polyethylene glycol group added to naloxone to prevent the naloxone
• Potent peripheral mu receptor antagonist that blocks opioid receptors
from crossing the blood brain barrier
• First oral agent for treatment of OIC in non-cancer pain
• Dosing
in the gut without crossing the blood brain barrier
• Indicated for prevention of post op ileus in colorectal and abdominal
surgeries
• Initial studies showed inconsistent results for OIC treatment
• Recent meta-analysis of clinical trials (4) demonstrated potential
– 25 mg po daily in the am on empty stomach
– Reduce to 12.5 mg if 25 mg dose not tolerated
– Reduce dose in renal impairment recommended (<60 ml/min)
efficacy of alvimopan for OIC
• Substrate of CYP3A4 metabolism and P-glycoprotein
• Cardiovascular adverse events in early trials
– Contraindicated in moderate/strong CYP3A4 inhibitors and strong CYP3A4
inducers
• GI side effects most common
• Cost: Approximately $10/dose
– Seen in patients with previous CV events or were high risk for CV adverse
reactions
• Cost: Approximately $130 for 12 mg tablet
– Lower doses studied for OIC
45
Ford AC, et al. Am J Gastroenterol 2013;108:1566–74
The Bottom Line on Docusate
Other Anecdotal Options
• Facilitates the incorporation of water and fats into the stool
• Prucalopride
•
allowing for softening
Not recommended as monotherapy for OIC
– “You just get the mush, not the push”
• Usually given in combination with a stimulant laxative
– May be beneficial in patients who report hard stools
• Efficacy not demonstrated in OIC studies when compared
•
•
46
– Selective 5HT4 receptor agonist
– Stimulates gut motility
– Usual dose: 2-4 mg/day
Misoprostol
Colchicine
to placebo
– NOT NEEDED in every patient who is on opioids
– NOT NEEDED in patients receiving PEG therapy for OIC
Tarumi Y, et al. J Pain Sympt Manage 2013; 45(1): 2–13.
© 2016 by the American Pharmacists Association. All rights reserved.
47
Taqhavi SA, et al. Int J Colorectal Dis 2010;25(3):389-394.
Roarty TP TP, et al. Aliment Pharmacol Ther 1997;11(6):1059-1066.
48
Additional Management Strategies
How to Rotate to Another Opioids
• Healthy bowel habits
• Assess your patients for comorbidities that affect choices
• Determine the correct dosing formulation
• Individualize dosage based on pain control on current opioid and/or
–
–
–
–
–
Eat consistent meals at consistent times daily
Smaller meals
Eat breakfast!
Increase non-caffeinated fluid intake
Try to “schedule” bowel movements
adverse reactions
• Calculate current 24 hour opioid usage
• Decrease for incomplete cross tolerance
•
•
•
•
• Opioid dose decrease
• Opioid rotation
• Diary of bowel movements
No correlation of tolerance between opioids
Dose is typically reduced by 25-75%
Decrease dose if pain controlled and switching to an alternative opioid
No dose reduction needed when switching to the SAME opioid
• Reassess, reassess, reassess
49
Treatment Algorithm
50
Tips for OIC Prevention
•
•
•
•
Drink plenty of water
Avoid high fat foods
Avoid foods high in sugar
Exercise
AND….
IF YOU GET THAT FEELING, JUST GO!!!!
Holding it in can make it worse. Don’t wait until you get
home.
51
Fiber Content of Common Foods
FOOD
FIBER CONTENTS
Various beans
5-16 g per 1 cup
All bran cereal
10 g per ½ cup
Corn
4 g per 1 cup
Oatmeal
4 g per 1 cup
Banana
3 g for medium size
Whole wheat bread
2g
Quinoa
8 g per 1 cup
Various nuts
12-16 g per 1 cup
Patient Education
•
•
•
•
•
53
© 2016 by the American Pharmacists Association. All rights reserved.
52
Adequate fluid intake
Maintain activity
Dietary fiber intake
Avoidance of bulk forming laxatives
Avoidance of straining
54
Patient Education Strategies
Patient Resources
• Areas of focus for education
• Patient Guide to Constipation Management
– How to avoid OIC
– Information on appropriate prevention strategies utilizing medications
• Stool softener not enough!
– Titration information based on response
– Re-evaluation of bowel regimen with opioid dose changes
– https://www.cmecorner.com/constipation/eimpacct_patient_guide.pdf
• Pharmacist letter
– Lets get going: what helps for constipation
• Provide written education on the importance of constipation prevention
• Develop a mechanism to ensure that EVERY patient on opioids
• Harvard Patient Education Center
– http://www.patienteducationcenter.org/articles/constipation-andimpaction/
receive information on constipation prevention
• Individual PAMORA web sites
55
56
Return to Caroline
Take Home
• Patient is requesting rotation to different analgesics despite
• OIC is a significant barrier to effective pain control
• Aggressive anticipation, monitoring, and treatment greatly
•
•
•
favorable pain control
She has trialed numerous commercially available treatment
modalities
Discussed with patient the pros and cons of either orally
administered naloxone or misoprostol
What wound up happening?
improves patient-related outcomes
• Discussing the bowel habits of a patient in pain is NOT
taboo
57
Which of the following is the most commonly
reported, troublesome side effect of opioids?
a)
b)
c)
d)
Constipation
Drowsiness
Nausea
Indigestion
The inhibition of the _____________ plexus is
the most likely cause of opioid induced
constipation.
a)
b)
c)
d)
59
© 2016 by the American Pharmacists Association. All rights reserved.
58
Submucosal
Myenteric
Celiac
Brachial
60
Which lifestyle change can help
prevent constipation?
a)
b)
c)
d)
Which of the following is a peripherally
acting mu opioid antagonist?
a)
b)
c)
d)
Eat primarily high fat foods
Exercise
Increase in intake of coffee
Waiting until there is enough time to have a complete
bowel movement
Lubiprostone
Senna
Polyethylene glycol
Methylnaltrexone
61
Which of the following options should NOT
be a part of an OIC bowel regimen?
a)
b)
c)
d)
e)
Which opioid side effect is not associated
with the development of tolerance?
a)
b)
c)
d)
e)
Bisacodyl Suppository
Docusate sodium
Psyllium
Sennasides
Polyethylene glycol
63
© 2016 by the American Pharmacists Association. All rights reserved.
62
Nausea
Respiratory depression
Constipation
Sedation
Confusion
64