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 non-opioids

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) 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-other- 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 (http://www.painpolicy.wisc.edu/united-states-resources).

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. 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.

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

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

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

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.

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 48-72 hour. Some need to changed Q 48 instead of 72.

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 48-72 hour. Some need to changed Q 48 instead of 72.

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

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 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)

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)

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 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

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 Possibly: morphine & methadone but need to talk about her resistance

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 Possibly: morphine & methadone but need to talk about her resistance

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??

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 opioid-naïve 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 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

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 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 30-45 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: 52-53. Daniel Alford, MD, MPH

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