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Initiating Therapy, Modifying
Dosing, and Discontinuing
Use of ER/LA Opioid Analgesics
Unit 2
Eric Widera, M.D.
Objectives
• Access federal and state regulations.
• Select correct dose when initiating therapy.
• Convert from IR to ER/LA opioids and from
one ER/LA to another.
• Define warning signs of respiratory
depression.
• Discuss need for tapering doses before
discontinuing and ER/LA opioid.
• Describe when and how to supplement ER/LA
opioids with IR analgesics, opioids, and nonopioids
Comply w/ current federal & state laws & regulations
that govern the use of opioid therapy for pain
- Federal
• Code of Federal Regulations, Title 21 Section 1306: rules governing the
issuance & filling prescriptions pursuant to section 309 of the Act (21
USC 829)
- www.deadiversion.usdoj.gov/21cfr/cfr/2106cfrt.htm
• United States Code (USC) - Controlled Substances Act, Title 21,
Section 829: prescriptions
- www.deadiversion.usdoj.gov/21cfr/21usc/829.htm
- State
• Database of state statutes, regulations, & policies for pain management
- www.medscape.com/resource/pain/opioid-policies
- www.painpolicy.wisc.edu/database-statutes-regulations-otherpolicies-pain-management
www.medscape.com/resource/pain/opioid-policies#CA
Case:
Wilma
73 Year Old Female
Case: Wilma
• Advanced colon cancer
− w/ peritoneal & liver metastases
• Presents w/ increasing abdominal pain
−Wakes frequently at night in severe pain
• Regimen: oxycodone IR 5 mg q6h + 1 at
bedtime
−She has some resistance to opioids
• Morphine means she’s about to “die” & methadone is for
“addicts”
• Does not like to take a lot of pills
Short Acting vs Long Acting?
Modified-release or long half-life drugs
(extended release ER/ long-acting LA)
• Chronic pain
• Improved treatment adherence
• Possibility of
- less pain fluctuation
- better sleep
• Poor evidence that long term opioid therapy
improves pain or function
Von Korff M, Kolodny A, Deyo RA, Chou R. Long-term opioid therapy reconsidered.
Ann Intern Med. 2011;155(5):325.
Benefits of Short-acting immediaterelease (IR) opioids
• Acute pain
• Breakthrough pain
• Dose finding
• Ability to crush or give as a liquid
• Those who are not yet “tolerant” to opioids
Case: Wilma
• Regimen:
−Oxycodone IR 5 mg q6h
−Oxycodone IR 5mg at bedtime
• She has some resistance to opioids
• Morphine means she’s about to “die” & methadone is for
“addicts”
• Does not like to take a lot of pills
• Consider rotating to a ER/LA opioid: fewer pills
& may allow her to sleep through the night
−Her total current oxycodone dose is 25 mg/d
• She is NOT opioid tolerant
Initiating a ER/LA Opioid in an OpioidTolerant Patient
• Patients considered opioid tolerant are
those who are taking at least
- 60 mg oral morphine/day
For 1 week
- 25 mcg transdermal fentanyl/hour
or longer
- 30 mg oral oxycodone/day
- 8 mg oral hydromorphone/day
- 25 mg oral oxymorphone/day
- An equianalgesic dose of another opioid
Picking A Pain Medication and Dosage
• Clinician experience
• Patient experience
• Patient’s health status
• Formulation availability, cost and third-party
coverage
• Know when and how to supplement ER/LA
opioids with immediate release analgesics (opioid
and non-opioid)
Extended Release Oral Opioids
• Common Oral Preparations available:
- Morphine (MS Contin), Oxycodone
(Oxycontin), Methadone
• Steady-state
• Titration
Extended Release Oral Opioids
• Common Oral Preparations available:
- Morphine (MS Contin), Oxycodone
(Oxycontin), Methadone
• Steady-state
• Titration
• A Word on Crushing
A Word On Methadone
Deaths reported to poison centers per 10,000
single substance exposures
A Word on Transdermal Fentanyl
• No analgesic effect for 12-24 hrs
• Steady state only after 72 hr
• Do not use for initial dose titration
• Fentanyl levels decay with half-life of 17 hrs
after removal of a patch
• Need “Breakthrough” medication
How Much Pain Medication to Rotate
to for Wilma?
The Good and Bad of Conversion Tables
Drug
PO
IV
Morphine
Hydrocodone
Oxycodone
Hydromorphone
Fentanyl*
Methadone
* 2:1 rule for patch (50 mg PO morphine approx 25 mcg/hr TD fentanyl)
The Good and Bad of Conversion Tables
Drug
PO
IV
Morphine
30 mg
10 mg
Hydrocodone
30 mg
--
Oxycodone
20 mg
--
Hydromorphone
7.5 mg
1.5 mg
Fentanyl*
Dosing Chart*
0.1 mg (100 mcg)
Methadone
see dosing guide
* 2:1 rule for patch (50 mg PO morphine approx 25 mcg/hr TD fentanyl)
Oral to Parenteral Conversion Ratios
J Pain Symptom Manage 2009;38:409e 417
Equianalgesic Dose Ratio Ranges for
Opioid Rotation to Morphine
J Pain Symptom Manage 2009;38:409e 417
Mu-Opioid Receptors & Incomplete
Cross-Tolerance
• Mu opioids bind to mu receptors
Drug 2
MOR-1D
MOR-1C
MOR-1B1
MOR-1A
Drug 1
MOR-1
- Mu opioids produce subtly
different pharmacologic response
based on distinct activation
profiles of mu receptor subtypes
• May help explain
- Inter-patient variability in response
to mu opioids
- Incomplete cross-tolerance among
mu opioids
Potency
• Many mu-receptor subtypes
Mu-opioid receptor
subtype
Limitations of Conversion Tables
• Single-dose potency studies using a specific
route, conducted in patients w/ limited opioid
exposure
• Did not consider
− Chronic dosing
− High opioid doses
− Other routes
− Different pain types
− Comorbidities or organ dysfunction
− Gender, ethnicity, advanced age, or concomitant
medications
− Direction of switch from 1 opioid to another
− Interpatient variability in pharmacologic response to
opioids
− Incomplete cross-tolerance among mu opioids
Fine PG, et al. J Pain Symptom Manage. 2009;38:418-25. Knotkova H, et al. J Pain Symptom Manage. 2009;38:426 -39. Shaheen PE, et al. J Pain
Symptom Manage. 2009;38:409-17. Webster LR, et al. Pain Med. 2012;13:562-70.
Reasons for Opioid Rotation
• Poor opioid responsiveness
− Dose titration yields intolerable/unmanageable AEs
− Poor analgesic efficacy despite dose titration
• Other potential reasons
− Patient desire or need to try a new formulation
− Cost or insurance issues
− Adherence issues
− Concern about abuse or diversion
− Change in clinical status requires an opioid w/
different PK
− Problematic drug-drug interactions
Fine PG, et al. J Pain Symptom Manage. 2009;38:418-25. Knotkova H, et al. J Pain Symptom Manage. 2009;38:426-39. Cruciani
R, et al. Oncology. 2005;19:1-4.
Guidelines for Opioid Rotation
• Calculate equianalgesic dose of new opioid from
EDT
• Reduce calculated equianalgesic dose by 25%-50%*
−Select % reduction based on clinical judgment
• Closer to 50% reduction if patient is
− Receiving a relatively high dose of current opioid regimen
− Not Caucasian
− Elderly or medically frail
• Closer to 25% reduction if patient
− Does not have these characteristics
− Is switching to a different administration route of same drug
Fine PG, et al. J Pain Symptom Manage. 2009;38:418-25.
Opioid Rotation for Wilma
Convert Wilma’s Oxycodone to MS Contin
Opioid Rotation for Wilma
Convert Wilma’s Oxycodone to MS Contin
#1 Add up total opioids used in 24 hours:
5 mg oxycodone x 5 = 25mg/24hrs
#2 Convert to New Opioid
25 mg PO Oxycodone x
30 mg PO Morphine
20 mg PO Oxycodone
37.5 mg PO Morphine/24hrs
#3 Divide new 24 hour drug dose by number of times to be
given per day
MS Contin: 37.5 mg/2 for q12h dose ~> 19 mg MsContin PO q12h
#4 Account for residual drug in system, cross-tolerance,
patient factors by taking 25-50% off
=
Opiate Side Effects: Sedation
• Distinguish sedation from exhaustion
• Resolves over 2-5 days after achieving
steady state
• Obtain patient and family goals
• If drowsiness continues
− Alternate opiate or route may help
− May need to reduce dose
ER/LA Opioid-Induced Respiratory Depression
• Respiratory depression more likely to occur
−In elderly, cachectic, or debilitated patients—may
have altered pharmacokinetics or altered
clearance
• ER/LA opioids contraindicated in patients w/
respiratory depression or conditions that
increase risk of life-threatening respiratory
depression
−If given concomitantly w/ other drugs that depress
respiration
ER/LA Opioid-Induced Respiratory Depression
• Reduce the risk of respiratory depression
−Proper dosing & titration are essential
−Do not overestimate the dose when converting
patients from another opioid product
• Can result in fatal O/D w/ first dose
−Instruct patients to swallow tablets/capsules
whole
• Dose from cut, crushed, dissolved, or chewed
tablets/capsules may be fatal, particularly in opioidnaïve individuals
Continuing or Increasing Dosing
• Therapy should be goal-directed
• Monitor:
• pain intensity
• functional status
• progress toward therapy goals
• adverse effects
• adherence with prescribed pharmacologic and
ancillary treatment
Titrating dosages
• Titration should be based on efficacy and
tolerability.
• If uncontrolled after 24 hrs and using at
least 3 breakthrough medications increase:
− Mild to moderate pain: 25-50% of total dose
− Moderate to severe pain: 50-100% of total dose
− Or increase by total dose of rescue medication over
the last 24hrs
Implement appropriate exit strategies to
safely discontinue ER/LA opioids
• Patient is not improving and may have opioid-
resistant pain
• Some patients experience improvement in function
and pain control when chronic opioids are stopped
• Patient may have a new problem and may need
substance abuse treatment
• Be clear that you will continue to work on pain
management using non-opioid therapy
• Taper patient slowly to prevent opioid withdrawal
Case 2: Mrs F
• Mrs F has been taking methadone for back
pain but has required escalating doses
during the last 3 months without any noted
pain relief.
• Since her pain is not opioid-responsive, you
would like to taper her off methadone and
try another approach. She is currently
taking methadone 40 mg TID and there is
no acute need to taper her rapidly, so a
slow taper as follows is reasonable.
Suggested Tapering Regimens for
Long-Acting Agents
• Methadone
− Decrease dose by 20%-50% per day to 30 mg/day, then…
− Decrease by 5 mg/day every 3-5 days to 10 mg/day,
then...
− Decrease by 2.5 mg/day every 3-5 days.
• Morphine CR (controlled-release)
− Decrease dose by 20%-50% per day to 45 mg/day, then…
− Decrease by 15 mg/day every 2-5 days.
• Oxycodone CR (controlled-release)
− Decrease by 20%-50% per day to 30 mg/day, then
− Decrease by 10 mg/day every 2-5 days
USVA (U.S. Veterans Affairs Administration). Clinical Practice Guideline for the
Management of Opioid Therapy for Chronic Pain. 2003; Appendix Y: 52-53.
Mrs F’s Taper
• Start with 10 mg methadone tablets:
− Week 1: 30 mg TID
− Week 2: 20 mg TID
− Week 3: 15 mg TID
− Week 4: 10 mg TID
− Week 5: 10 mg qam, 5 mg qnoon, 10 mg qpm
− Week 6: 5 mg qam, 5 mg qnoon, 5 mg qpm
− Week 7: 5 mg qam, 5 mg qnoon, 5 mg qpm
• Switch to 5mg methadone tablets…
− Week 8: 5 mg qam, 2.5 mg qnoon, 5 mg qpm
− Week 9: 2.5 mg qpm, 2.5 mg qnoon, 5 mg qpm
− Week 10: 2.5 mg TID
− Week 11: 2.5 mg BID
− Week 12: 2.5 mg Daily
• Then discontinue