1. Initiating Therapy, Modifying Dosing, and Discontinuing Use of ER/LA Opioid Analgesics
Unit 2
Eric Widera, M.D.

2. 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 non-opioids

3. Comply w/ current federal & state laws & regulations that govern the use of opioid therapy for pain
Code of Federal Regulations, Title 21 Section 1306: rules governing the issuance & filling prescriptions pursuant to section 309 of the Act (21 USC 829)
United States Code (USC) - Controlled Substances Act, Title 21, Section 829: prescriptions -
- State
Database of state statutes, regulations, & policies for pain management -
policies-pain-management
Used CO*RE slide
Medications with the potential for abuse and addiction such as opioids are regulated, with restrictions on whether and how they can be prescribed. In the US, these drugs are designated "controlled substances" under a federal law known as the Controlled Substances Act (CSA), which places controlled prescription drugs in one of five ‘schedules’. Under the CSA, most opioids used for cancer pain management are schedule II, which indicates a high liability for abuse and diversion. Both federal and state laws are in force to regulate all scheduled drugs, particularly those in schedule II. Physicians are required to know and comply with these laws.
Ron: another potential resource is the database compiled by the Pain Policy Studies Group (

5. Case: Wilma 73 Year Old Female

6. 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

7. Short Acting vs Long Acting?

8. 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.
Ron: I know it is almost too basic to suggest, but in the category of never assume a participant knows anything, it may be useful to spell out “extended release / long-acting” as what ER/LA stands for. Some of us who have been working with the CO*RE group have advocated for consideration of a third category of pain besides acute and chronic. This would be the patient we not uncommonly see in HPM settings and has to do with chronic, non-ambulatory pain patients whose pain is not stable. The archetypical ‘chronic pain patient’ becomes a functional individual when the pain is managed. The HPM patient population more commonly has other medical conditions that prevent immediate (if ever) return to society once the pain is managed. For teaching purposes to our audience, at least some of whom do HPM part-time, making sure the distinction between these three categories of patients is important to emphasize in that it may significantly influence the choice of medications. Even within the strictly HPM patient population, there is a potentially big difference in prescribing based on whether the patient’s goals are predicated on clearly terminal versus potentially non-terminal prognosis.

9. Benefits of Short-acting immediate-release (IR) opioids
Acute pain
Breakthrough pain
Dose finding
Ability to crush or give as a liquid
Those who are not yet “tolerant” to opioids

10. Case: Wilma Regimen: She has some resistance to opioids
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
Not an option: hydromorphone ER or transdermal fentanyl
Only for opioid-tolerant patients

11. Initiating a ER/LA Opioid in an Opioid-Tolerant Patient
Patients considered opioid tolerant are those who are taking at least
- 60 mg oral morphine/day
- 25 mcg transdermal fentanyl/hour
- 30 mg oral oxycodone/day
- 8 mg oral hydromorphone/day
- 25 mg oral oxymorphone/day
- An equianalgesic dose of another opioid
For 1 week or longer
Discussion of who is an opioid-tolerant patient (there is no guidance on this, since the FDA has redefined opioid-tolerance on a product-by-product basis, ranging from 30mg/d to 100mg/d of morphine equivalent),
The ER/LA products are generally only indicated for demonstrated opioid-tolerant individuals.
Not an option: hydromorphone ER or transdermal fentanyl
Only for opioid-tolerant patients

12. 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)
Last bullet needed per FDA blueprint.

13. Extended Release Oral Opioids
Common Oral Preparations available:
- Morphine (MS Contin), Oxycodone
(Oxycontin), Methadone
Steady-state
Titration
ER: Extended release capsules with granules—need to be careful as bio-availability sometimes unpredictable
Died/untreated pain.
Steady state equilibrium between patch, subdermal pool, and circulation.
Even though taking patch off, there is a reserve in the skin—may still have med in system depending upon where are in hour. Some need to changed Q 48 instead of 72.

14. Extended Release Oral Opioids
Common Oral Preparations available:
- Morphine (MS Contin), Oxycodone
(Oxycontin), Methadone
Steady-state
Titration
A Word on Crushing
ER: Extended release capsules with granules—need to be careful as bio-availability sometimes unpredictable
Died/untreated pain.
Steady state equilibrium between patch, subdermal pool, and circulation.
Even though taking patch off, there is a reserve in the skin—may still have med in system depending upon where are in hour. Some need to changed Q 48 instead of 72.

15. A Word On Methadone Deaths reported to poison centers per 10,000 single substance exposures
Total prescriptions. Methadone represents less than 5% of total opioid prescriptions dispensed (Figure 2) [7], but a third of opioid-related deaths nationwide
(Figure 3)
Methadone was involved in about 30% of all overdoses treated in EDs (Figure 9) [7,9]. However, when adjusted for the number of dispensed outpatient prescriptions, the rate for methadone related visits was approximately 23 times greater than for hydrocodone and six times greater than for oxycodone (Figure 10)
Why? Initiating at too high of a dose, over-relying on published equianalgesic conversion tables when converting to methadone from another opioid, titrating doses too rapidly, lacking familiarity with the unique pharmacokinetics and pharmacodynamics of methadone, failing to identify and monitor patients at risk for substance misuse, and overestimating the tolerance to respiratory depression conferred by prior opioid use in patients with chronic pain.
Utah data showing death occurred within 7 days of beginning treatment for 70% of decedents who
held a methadone prescription

16. A Word on Transdermal Fentanyl
No analgesic effect for 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

17. How Much Pain Medication to Rotate to for Wilma?

18. The Good and Bad of Conversion Tables
Drug PO IV
Morphine
Hydrocodone
Oxycodone
Hydromorphone
Fentanyl*
Methadone
Pearl #3: Use an equianalegisic table to convert between opioids.
Once you have something that you know is a safe starting dose you can then convert that dose to the opioid you want to use.
Equianalgesic tables are derived largely from single-dose studies, expert opinion, and studies in noncancer patients.
* 2:1 rule for patch (50 mg PO morphine approx 25 mcg/hr TD fentanyl)

19. The Good and Bad of Conversion Tables
Drug PO IV
Morphine
30 mg
10 mg
Hydrocodone --
Oxycodone
20 mg
Hydromorphone
7.5 mg
1.5 mg
Fentanyl*
Dosing Chart*
0.1 mg (100 mcg)
Methadone
see dosing guide
Pearl #3: Use an equianalegisic table to convert between opioids.
Once you have something that you know is a safe starting dose you can then convert that dose to the opioid you want to use.
Equianalgesic tables are derived largely from single-dose studies, expert opinion, and studies in noncancer patients.
* 2:1 rule for patch (50 mg PO morphine approx 25 mcg/hr TD fentanyl)

20. Oral to Parenteral Conversion Ratios
J Pain Symptom Manage 2009;38:409e 417

21. Equianalgesic Dose Ratio Ranges for Opioid Rotation to Morphine
J Pain Symptom Manage 2009;38:409e 417

22. Mu-Opioid Receptors & Incomplete Cross-Tolerance
Mu opioids bind to mu receptors
Many mu-receptor subtypes
- 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
Drug 2
Drug 1
Potency
MOR-1
MOR-1A
MOR-1C
MOR-1B1
MOR-1D
Mu-opioid receptor subtype

23. 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: Knotkova H, et al. J Pain Symptom Manage. 2009;38: Shaheen PE, et al. J Pain Symptom Manage. 2009;38: Webster LR, et al. Pain Med. 2012;13:

24. 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: Knotkova H, et al. J Pain Symptom Manage. 2009;38: Cruciani R, et al. Oncology. 2005;19:1-4.

25. 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:

26. Opioid Rotation for Wilma
Convert Wilma’s Oxycodone to MS Contin
Possibly: morphine & methadone but need to talk about her resistance

27. 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 mg PO Morphine
20 mg PO Oxycodone = mg PO Morphine/24hrs
#3 Divide new 24 hour drug dose by number of times to be given per day
MS Contin: 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
Possibly: morphine & methadone but need to talk about her resistance

28. 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
Do you know what a bolus effect is and why it is important??

29. 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

30. 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 opioid-naïve individuals

31. 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

32. 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: % of total dose
Or increase by total dose of rescue medication over the last 24hrs .

33. 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
The benefit-to-harm evaluation of chronic opioid therapy should be considered and documented on an ongoing and periodic basis during treatment with chronic opioids
When you’ve decided to stop opioid analgesics – if the patient is not improving, they may have opioid resistant pain (some patients may actually experience improvement in function and pain when the opioids have stopped). The patient may have a new problem—“opioid dependence” or addiction. They may need substance abuse treatment and be clear that you will continue to work on pain management using non-opioid therapy. Taper the patient slowly to avoid opioid withdrawal, and refer them to addiction treatment if needed.
Ron: It might be worth pointing out that many in the HPM patient population would not have a goal that includes an appropriate exit strategy. THEY MIGHT ESPECIALLY FOR THE CANCER SURVIVORS THAT WE SEE
Daniel Alford, MD, MPH

34. 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.

35. 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
The last stage of tapering is the most difficult. The body adapts fairly well to the proportional dosage reduction to a point and then (less than mg of opioid/day) the body cannot adapt as well to the changes in concentration
USVA (U.S. Veterans Affairs Administration). Clinical Practice Guideline for the Management of Opioid Therapy for Chronic Pain. 2003; Appendix Y:
Daniel Alford, MD, MPH

36. 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