Interprofessional Webinar Series

Opioids in the Medically Ill: Principles of Administration Russell K. Portenoy, MD Chief Medical Officer MJHS Hospice and Palliative Care Director MJHS Institute for Innovation in Palliative Care Professor of Neurology Albert Einstein College of Medicine

Financial Disclosures Russell K. Portenoy, MD, Planner/Speaker, has indicated a relationship with the following: Pfizer Inc. (grant to department). Any discussion of investigational or unlabeled uses of a product will be identified. No other Planning Committee Member has any disclosures.

Pain and the Palliative Plan of Care: Assessment Etiology Nociceptive mechanisms Pain Social support Coping Adaptation Suffering Pain consequences Neuropathic Psychiatric/ mechanisms psychosocial disorders/processes Physical/psychiatric and psychosocial/spiritual comorbidities and related concerns

Pain and the Palliative Plan of Care: Management History, Exam, Review of records, Family meeting, Objective data Pain diagnosis and consequences Physical, psychosocial, spiritual, and other comorbidities and concerns Primary treatment for the etiology of pain Primary treatment for the etiology of comorbidities Symptomatic therapies for pain Symptomatic therapies for consequences and comorbidities

Symptomatic Treatment of Pain Related to Serious Illness Pharmacotherapy Nonopioids Adjuvant analgesics Opioids Psychological Psycho-educational CBT Others Interventional Injection therapy Neural blockade Implant therapies Rehabilitative therapies Physical/Occupational therapy Modalities/orthotics Integrative therapies Acupuncture Chiropractic Music therapy Others Neuromodulation - - TENS and transcranial - - Invasive types Lifestyle changes - Weight loss

Best Practices in Analgesic Pharmacotherapy Opioid analgesics Nonopioid analgesics Adjuvant (nontraditional) analgesics

Opioid Therapy: 2012 EAPC Evidence-Based Guidelines 16 recommendations based on systematic reviews and expert consensus 10 focus on systemic opioid therapy Most are weak recommendations due to lack of evidence Caraceni A, et al, Lancet Oncol 2012 Feb;13(2):e58-68

EAPC Recommendations Reference the WHO Analgesic Ladder

WHO Analgesic Ladder: Perspective Appropriately promotes opioids as first-line for mod-severe chronic pain in some settings Is appropriate only for patients with active cancer or other serious illness Specific recommendations are no longer best practices

Opioid Therapy: EAPC Recommendations Recommendation for drugs conventionally considered step II opioids on the WHO Analgesic Ladder Start step II opioids for mild-moderate pain Low doses of a step III opioid may be used (weak) Short-acting drugs are simpler to titrate Caraceni A, et al, Lancet Oncol 2012 Feb;13(2):e58-68

Opioid Therapy: EAPC Recommendations Avoid codeine due to unpredictable responses caused by geneticallydetermined metabolic variation

Opioid Therapy: EAPC Recommendations Recommendation for drugs conventionally considered step III opioids on the WHO Analgesic Ladder Use morphine, oxycodone, or hydromorphone as first choice (weak) Use transdermal fentanyl or buprenorphine as alternatives (weak) Caraceni A, et al, Lancet Oncol 2012 Feb;13(2):e58-68

Opioid Therapy: EAPC Recommendations Recommendation for use of methadone Use methadone as a step III opioid, but it should be used only by experienced professionals (weak) Recommendation for use of opioids in renal failure Use fentanyl or buprenorphine as first-line at low starting doses (weak) Caraceni A, et al, Lancet Oncol 2012 Feb;13(2):e58-68

Expanding on the EAPC Recommendations More on drug selection For the patient with minimal prior opioid exposure Combination product containing hydrocodone or oxycodone, OR Single entity, short-acting pure mu-agonist at low dose, e.g., morphine, oxycodone, OR Mixed mechanism opioid: tramadol or tapentadol, OR Transdermal buprenorphine

Expanding on the EAPC Recommendations More on drug selection For the opioid-tolerant patient Usually a pure mu-agonist opioid Long-acting drug preferred (but not required) if pain is constant or frequently recurrent Short-acting drug for intermittent pain or breakthrough pain

Expanding on the EAPC Recommendations Long-acting formulations Morphine (MS Contin, Avinza, Kadian, Morphine ER) Oxycodone (Oxycontin) Fentanyl (Duragesic, transdermal fentanyl) Hydromorphone (Exalgo) Oxymorphone (Opana ER) Methadone Levorphanol Buprenorphine Short-acting formulations Combination products Single entity Codeine Morphine Oxycodone Hydromorphone Oxymorphone Fentanyl

Expanding on the EAPC Recommendations Which opioid is the best? Selection is by trial-and-error, informed by several considerations Favorable or unfavorable prior experience Cost and formulary issues Severe constipation or bowel disease suggests non-oral route History of drug abuse may suggest trial of methadone or buprenorphine

Methadone and Pain Management Methadone has potential advantages Low cost Anecdotal observations of greater-than-expected potency and efficacy Established benefit for the disease of addiction Methadone has potential disadvantages Higher risk: major factor in the rise of opioidrelated mortality during the past decade Requires understanding of pharmacology and guidelines for safe practice

Methadone Mentions Deaths with Mention of Methadone 1999-2003 3,500 3,000 2,500 2,000 1,500 1,000 500 All injury* Unintentional Suicide Undetermined 0 1999 2000 2001 2002 2003 Year *Includes intent categories homicide and legal intervention Minino AM, et al. Deaths: Injuries, 2002. NVSR 54:10. NCHS. 2006. Accessed April 19, 2007 at: http://www.cdc.gov/nchs/data/nvsr/nvsr54/nvsr54_10.pdf. Anderson RN, et al. Deaths: Injuries, 2001. NVSR 52:21. NCHS. 2004. Accessed April 19, 2007 at: http://www.cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_21acc.pdf. Accessed April 19, 2007.

Methadone Pharmacology Is Unique and Complex Half-life varies from 12 hours to >150 hours Time to steady state = 3 days to >37 days A mixture of 2 isomers (each 50%) l-isomer is the opioid; d-isomer is a NMDA receptor antagonist Interaction with d-isomer may explain unexpected potency Complicated hepatic metabolism CYP34A, CYP2B6 and CYP2D6 all involved May prolong the QTc interval and predispose to lifethreatening arrhythmia

Methadone: Safe Prescribing Dosing Starting dose in opioid-naïve patient: 2.5 mg two to four times per day Starting dose in opioid-treated patient Reduce calculated equianalgesic dose by 75-90% Do not exceed 40 mg/day Titrate doses no more frequently than every 5-7 days

Methadone: Safe Prescribing After starting or increasing the dose, monitor until clinically stable Check-in after several days Be very cautious in using methadone as a rescue dose for breakthrough pain Anticipate drug-drug interactions with numerous drugs Follow the guideline for QTc monitoring when clinically appropriate

Methadone and the QTc Interval: New Guideline from APS-CPDD Common risk factors for QTc prolongation Female sex Significant heart disease Use of other medications with QTc effects Low potassium Family history of long QT syndrome Baseline ECG should be reviewed in most cases

Methadone and the QTc Interval: New Guideline from APS-CPDD With rare exceptions, do not use methadone if QTc >500 ms Consider an alternative drug or manage factors that may prolong the QTc if the QTc >450 ms and <500 ms Repeat the ECG after 2 weeks or after increasing the dose, at least once or twice Consider repeat ECG if dose goes above 100 mg/day

Opioid Therapy: EAPC Recommendations Recommendation for alternative routes Use the SQ route if unable to use oral or transdermal Consider IV when SQ contraindicated or when rapid control is needed (strong) Caraceni A, et al, Lancet Oncol 2012 Feb;13(2):e58-68

Opioid Therapy: EAPC Recommendations Recommendation for opioid titration Use either immediate-release or slow-release formulations for dose titration (weak) Caraceni A, et al, Lancet Oncol 2012 Feb;13(2):e58-68

Expanding on the EAPC Recommendations Dose titration There is no maximal or correct dose Conventional recommendation Doses should be gradually increased until pain relief is adequate or intolerable and unmanageable side effects occur Controversial in the context of non-cancer pain

Expanding on the EAPC Recommendations Dose titration determines opioid responsiveness Responsiveness of an individual patient to a specific drug is not known unless dose has been increased to treatment-limiting toxicity If a patient is poorly responsive to a therapy, the therapy must be changed

Four Clinical Strategies for Poorly Responsive Pain Dose Escalation Adverse Effects Opioid rotation Better side effect management Systemic drug strategy to lower opioid requirement Other strategies to lower opioid requirement

Opioid Therapy: EAPC Recommendations Recommendation for opioid switching Consider switching drugs for inadequate analgesia or severe and/or unmanageable side effects (weak) Recommendation for relative opioid analgesic potencies When switching drugs, use a starting dose lower than the published equianalgesic ratios (varied levels of confidence) Caraceni A, et al, Lancet Oncol 2012 Feb;13(2):e58-68

Opioid Rotation: Evidence-Based Guideline Step 1 Calculate equianalgesic dose Reduce this by 25-50%, but Reduce less if pain severe Reduce more if medically frail Reduce less if same drug by different route Reduce fentanyl less Reduce methadone more: 75-90% Fine PG, Portenoy RK, et al., JPSM 2009;38:418-425

Opioid Rotation: Evidence-Based Guideline Step 2 Based on clinical assessment, consider another 15-30% increase or decrease Rescue is 5-15% of daily dose selected But if using a rapid onset fentanyl drug, always start with one of the lowest doses Titrate Fine PG, Portenoy RK, et al., JPSM 2009;38:418-425

Opioid Therapy: EAPC Recommendations Recommendation for breakthrough pain Titrate and optimize around-the-clock therapy Usual first-line: immediate-release oral opioid Buccal/intranasal fentanyl also can be used and may be preferable in some cases because of more-rapid onset and shorter duration (strong) Use immediate-release formulations with short half-lives to preemptively treat predictable episodes (weak) Caraceni A, et al, Lancet Oncol 2012 Feb;13(2):e58-68

More on Breakthrough Pain Breakthrough pain Highly prevalent: 33%-90% of cancer patients Associated with More severe pain Reduced responsiveness to opioid therapy Pain-related functional impairment Psychological distress Higher economic burden Svendsen et al. Eur J Pain. 2005; 9:195-206; Caraceni et al. Palliat Med. 2004;18:177-183; Portenoy et al. Pain 1999; 81:129-134; Fortner et al. Pain 2002;3:38-44. Bruera et al. JPSM 1995;10:348-355.

Breakthrough Pain: Treatment Issues Guidelines based on expert opinion Treat underlying etiology Optimize regularly scheduled opioid Non-pharmacologic therapies Rescue dose is the standard of care for the medically ill Conventional practice: 5%-15% of the daily baseline dose, or 1/24 of the daily infusion dose Portenoy and Hagen. Pain. 1990; Portenoy et al. Pain. 1999; 81:129-134. Mercadante et al. Cancer. 2002; 94:832-839.

New Therapy for Breakthrough Pain: Rapid-Onset Opioids Developed to address the mismatch between the time course of BTP and the time-action of oral rescue drugs Approved formulations in the US and Europe Oral transmucosal fentanyl citrate Fentanyl effervescent buccal tablet Bio-erodible mucoadhesive patch Sublingual fentanyl tablet Fentanyl solution nasal spray Fentanyl pectin nasal spray BTP Rescue dose Around-The-Clock Medication

Rapid-Onset Opioids for Breakthrough Pain Placebo-controlled RCTs Many studies show that rapid-onset formulations Are efficacious Are rapid in onset compared to expected time course of a typical oral drug Very few (3) comparative trials Suggest benefit over oral drugs Mercadante et al, Curr Med Res Opin. 2009;25(11):2805 Coluzzi et al. Pain 2001;91:123 Fallon et al, J Clin Oncol 28:15s, 2010 (suppl; abstr)

Rapid-Onset Opioids for Breakthrough Pain Concerns Comparative effectiveness not yet established May be attractive to those with addictive disease May be more prone to unintentional overdose Mandatory REMS may discourage appropriate use Conclusions Consider a rapid-onset opioid if oral rescue is ineffective Consider if BTP has a very rapid time course Consider if patient has responded well to fentanyl Best choice is unknown and cost issues must be considered

Managing Risk During Opioid Therapy Safe and effective prescribing requires Skills to optimize pharmacological outcomes Skills to minimize risk Risk of side effects and toxicities Risk of abuse-related outcomes Misuse or abuse Addiction Diversion Unintentional overdose

Opioids in the Medically Ill: Principles of Administration Q/A