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American College of Physicians Internal Medicine Meeting 2016 Washington, DC SAFE Opioid Prescribing: Strategies. Assessment. Fundamentals. Education. Wednesday, May 4, 2016 CME ACCREDITATION The American College of Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The ACP designates this live activity for a maximum of 3.5 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. MAINTENANCE OF CERTIFICATION POINTS Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 3.5 MOC points and patient safety credit in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC points. DISCLOSURE It is the policy of the American College of Physicians (ACP) to ensure balance, independence, objectivity, and scientific rigor in all its educational activities. To this end, and consistent with the policies of the ACP and the Accreditation Council of Continuing Medical Education (ACCME), faculty for all ACP continuing medical education activities are required to disclose all financial relationships they have with any entity producing, marketing, re‐ selling, or distributing health care goods or services consumed by, or used on, patients. Faculty are asked to use generic names only in the discussion of therapeutic options. If trade‐name products manufactured by companies with whom they have relationships are to be discussed, faculty are asked to provide evidence‐based citation in support of the discussion. The information is reviewed by the course director and, if necessary, adjustments to the topic or faculty are made to balance the discussion. Further, all participants are asked to evaluate each session for commercial bias so that future decisions about content and faculty are made in light of this information. Faculty disclosure information can be found at the beginning of this book. Faculty are required to inform the audience if they will be discussing unapproved or investigative use of a commercial product or device. This educational activity is supported by an independent educational grant from the ER/LA Opioid Analgesic REMS Program Companies. Please see http://ce.er‐la‐opioidrems.com/IwgCEUI/rems/pdf/List_of_RPC_Companies.pdf for a listing of the member companies. This activity is intended to be fully compliant with the ER/LA Opioid Analgesic REMS education requirements issued by the US Food & Drug Administration. EDUCATIONAL DISCLAIMER The primary purpose of this meeting is educational. Information presented, as well as publications, technologies, products, and/or services discussed, are intended to inform participants about the knowledge, techniques, and experiences of the faculty who are willing to share such information with colleagues. A diversity of professional opinion exists, and the views of the faculty are their own and not those of the ACP. The ACP disclaims any and liability for damages and claims, which may result from the use of information, publications, technologies, products, and/or services presented at this meeting or distributed in association with this meeting. NOTICE ©2016 American College of Physicians. All rights reserved. Reproduction of presentations, or print or electronic material associated with presentations, is prohibited without written permission from the ACP. Any use of program content, the name of a speaker and/or program title, or the name of ACP without the written consent of ACP is prohibited. For purposes of the preceding sentence, “program content” includes, but is not limited to, oral presentations, audiovisual materials used by speakers, program handouts, and/or summaries of the same. This rule applies before, after, and during the activity. American College of Physicians Internal Medicine Meeting 2016 SAFE Opioid Prescribing: Strategies. Assessment. Fundamentals. Education. May 4, 2016 Disclosure Information Course Director: Charles E. Argoff, MD, FABMP2 Professor of Neurology, Director, Comprehensive Pain Management Center, Department of Neurology, Albany Medical College, Albany, NY Faculty: Michael J. Brennan, MD2 Medical Director, The Pain Center of Fairfield, Fairfield, CT Steven Stanos, DO2 Medical Director, Swedish Pain Services, Swedish Health System, Seattle, WA The following individuals were involved in curriculum development: Daniel Chandler, MD1 Lyerka Miller, PhD1 Marc L. Mosier, MD1 NOTES: 1 Has no relationships with any proprietary entity producing health care goods or services consumed by or used on patients. 2 Has disclosed a relationship with a proprietary entity(s) producing health care goods or services as noted below: Charles E. Argoff, MD, FABMP Research Grants/Contracts: Grunenthal, Forest, Endo, Lilly Royalties: Elsevier Honoraria: Endo, Teva, Allergan, Purdue, Depomed Speakers Bureau: AstraZeneca, Allergan, Teva Michael J. Brennan, MD Stock Options/Holdings: Cara Consultantship: Purdue, Teva, Depomed, Insys, Endo, Cara, Kaleo Speakers Bureau: Purdue, Teva, Depomed, Pernix, Insys, AstraZeneca, Endo, Cara, Kaleo Steven Stanos, DO Consultantship: Daiichi Sankyo, Endo, MyMatrixx, Pfizer, Purdue, Scilex, Teva The ER/LA Opioid Analgesics REMS Program covers the following products produced by companies with which faculty have disclosed relationships: Brand Name Products Depomed Nucynta® ER (Tapentadol extended-release oral tablets) Endo Pharmaceuticals Opana® ER (Oxymorphone hydrochloride extended-release tablets) Purdue Pharma Butrans® (Buprenorphine transdermal system) Hysingla™ ER (Hydrocodone bitartrate extended-release tablets) MS Contin® (Morphine sulfate extended-release tablets) OxyContin® (Oxycodone hydrochloride extended-release tablets) ® Targiniq ER (Oxycodone hydrochloride and naloxone hydrochloride extended-release tablets) Pfizer Avinza® Embeda® (Morphine sulfate extended-release capsules) (Morphine sulfate and naltrexone extended-release capsules) Pernix Therapeutics Zohydro® ER (Hydrocodone bitartrate extended-release capsules) Generic Products Endo Pharmaceuticals Oxymorphone Hydrochloride (Oxymorphone hydrochloride extended-release tablets) Vintage Pharmaceuticals LLC, d/b/a Qualitest Pharmaceuticals and a subsidiary of Endo Pharmaceuticals Inc. Morphine Sulfate (Morphine sulfate extended-release tablets) American College of Physicians ACP Internal Medicine Meeting 2016 Washington, DC SAFE Opioid Prescribing: Strategies. Assessment. Fundamentals. Education. 1:30-2:15 p.m. Module 1: Evaluation is Essential for Safe and Effective Pain Management Using ER/LA Opioids------------------------------------------------------- 9 2:15-2:45 p.m. Module 2: Best Practices for How to Start Therapy with ER/LA Opioids, How to Stop, and What to Do in Between ------------------------------- 23 2:45-3:15 p.m. Module 3: Evidence-Based Tools for Screening for Patients at Risk and Monitoring for Adherence to Prescribed ER/LA Opioids ------------- 37 3:15-3:30 p.m. Break 3:30-4:00 p.m. Module 4: Talk to Me: Proven Methods to Counsel Your Patients on ER/LA Opioids and Achieve Positive Outcomes ----------------------- 49 4:00-4:30 p.m. Module 5: Everything You Always Wanted to Know About ER/LA Opioids as a Drug Class --------------------------------------------------------------- 61 4:30-5:00 p.m. Module 6: Getting the Most Clinical Insights from Specific ER/LA Product Information Sources --------------------------------------------------------- 75 5:00-5:15 p.m. Q&A SAFE Opioid Prescribing Strategies. Assessment. Fundamentals. Education Extended-Release and Long-Acting Opioid Analgesics Risk Evaluation and Mitigation Strategy (REMS) American College of Physicians Internal Medicine Meeting 2016 Washington, DC Wednesday, May 4, 2016 1 Faculty Information Charles E. Argoff, MD, FABMP Professor of Neurology, Director, Comprehensive Pain Management Center, Department of Neurology, Albany Medical College, Albany, NY Michael J. Brennan, MD Medical Director, The Pain Center of Fairfield, Fairfield, CT Steven Stanos, DO Medical Director, Swedish Pain Services, Swedish Health System, Seattle, WA 2 1 Faculty Disclosure Information Faculty are required to inform the audience if they will be discussing unapproved or investigative use of a commercial product or device. Also, in accordance with ACP policy, faculty must disclose financial relationships that they have with any entity that produces, markets, resells, or distributes health care goods or services consumed by, or used on, patients. The following relationships exist related to this presentation. 3 Disclosure of Financial Relationships Charles E. Argoff , MD, FABMP Has disclosed relationships with an entity producing, marketing, reselling, or distributing health care goods or services consumed by, or used on, patients. Research Grants/Contracts: Grunenthal, Forest, Endo, Lilly Royalties: Elsevier Honoraria: Endo*, Teva, Allergan, Purdue*, Depomed* Speakers Bureau: AstraZeneca, Allergan, Teva * The ER/LA Opioid Analgesics REMS Program covers products produced by these companies. See the following list of products. 4 2 The ER/LA Opioid Analgesics REMS Program covers the following products produced by companies with which I have disclosed a relationship: Brand Name Products Purdue Pharma Butrans® Hysingla™ Buprenorphine transdermal system ER Hydrocodone bitartrate extended‐release tablets MS Contin® Morphine sulfate extended‐release tablets OxyContin® Oxycodone hydrochloride extended‐release tablets Targiniq® ER Oxycodone hydrochloride and naloxone hydrochloride extended‐release tablets Depomed Nucynta® ER Tapentadol extended‐release oral tablets Endo Pharmaceuticals Opana® ER Oxymorphone hydrochloride extended‐release tablets 5 The ER/LA Opioid Analgesics REMS Program covers the following products produced by companies with which I have disclosed a relationship: Generic Products Vintage Pharmaceuticals LLC, d/b/a Qualitest Pharmaceuticals and a subsidiary of Endo Pharmaceuticals Inc. Morphine Sulfate Morphine sulfate extended‐release tablets Endo Pharmaceuticals Oxymorphone Hydrochloride Oxymorphone hydrochloride extended‐release tablets 6 3 Disclosure of Financial Relationships Michael J. Brennan, MD Has disclosed relationships with an entity producing, marketing, reselling, or distributing health care goods or services consumed by, or used on, patients. Consultant: Speaker’s Bureau: Stock Holder: Purdue, Teva, Depomed, Insys, Endo, Cara, Kaleo Purdue, Teva, Depomed, Pernix, Insys, AstraZeneca, Endo, Cara, Kaleo Cara * The ER/LA Opioid Analgesics REMS Program covers products produced by these companies. See the following list of products. 7 The ER/LA Opioid Analgesics REMS Program covers the following products produced companies with which I have disclosed a relationship: Brand Name Products Purdue Pharma Butrans® Hysingla™ (Buprenorphine transdermal system) ER (Hydrocodone bitartrate extended‐release tablets) MS Contin® (Morphine sulfate extended‐release tablets) OxyContin® (Oxycodone hydrochloride extended‐release tablets) Targiniq® ER (Oxycodone hydrochloride and naloxone hydrochloride extended‐release tablets) Depomed Nucynta® (Tapentadol extended‐release oral tablets) Pernix Therapeutics Zohydro® ER (Hydrocodone bitartrate extended‐release capsules) 8 4 The ER/LA Opioid Analgesics REMS Program covers the following products produced by companies with which I have disclosed a relationship: Brand Name Products (continued) Endo Pharmaceuticals Opana® ER (Oxymorphone hydrochloride extended‐release tablets) Generic Products Vintage Pharmaceuticals LLC, d/b/a Qualitest Pharmaceuticals and a subsidiary of Endo Pharmaceuticals Inc. Morphine Sulfate (Morphine sulfate extended‐release tablets) Endo Pharmaceuticals Oxymorphone Hydrochloride (Oxymorphone hydrochloride extended‐release tablets) 9 Disclosure of Financial Relationships Steven Stanos, DO Has disclosed relationships with an entity producing, marketing, reselling, or distributing health care goods or services consumed by, or used on, patients. Consultantship: Daiichi Sankyo, Endo, MyMatrixx, Pfizer, Purdue, Scilex, Teva * The ER/LA Opioid Analgesics REMS Program covers products produced by these companies. See the following list of products. 10 5 The ER/LA Opioid Analgesics REMS Program covers the following products produced by companies with which I have disclosed a relationship: Brand Name Products Purdue Pharma Butrans® (Buprenorphine transdermal system) Hysingla™ ER (Hydrocodone bitartrate extended‐release tablets) MS Contin® (Morphine sulfate extended‐release tablets) OxyContin® (Oxycodone hydrochloride extended‐release tablets) Targiniq® (Oxycodone hydrochloride and naloxone hydrochloride extended‐release tablets) ER Pfizer Avinza® (Morphine sulfate extended‐release capsules) Embeda® (Morphine sulfate and naltrexone extended‐release capsules) Pernix Therapeutics Zohydro® ER (Hydrocodone bitartrate extended‐release capsules) 11 The ER/LA Opioid Analgesics REMS Program covers the following products produced by companies with which I have disclosed a relationship: Brand Name Products (continued) Endo Pharmaceuticals Opana® ER (Oxymorphone hydrochloride extended‐release tablets) Generic Products Vintage Pharmaceuticals LLC, d/b/a Qualitest Pharmaceuticals and a subsidiary of Endo Pharmaceuticals Inc. Morphine Sulfate (Morphine sulfate extended‐release tablets) Endo Pharmaceuticals Oxymorphone Hydrochloride (Oxymorphone hydrochloride extended‐release tablets) 12 6 Educational Grants in Support of this CME Activity This educational activity is supported by an independent educational grant from the ER/LA Opioid Analgesic REMS Program Companies (RPC). Please see http://ce.er-laopioidrems.com/IwgCEUI/rems/pdf/List_of_RPC_Companie s.pdf for a listing of the member companies. This activity is fully-compliant with the ER/LA Opioid Analgesics REMS education requirements issued by the U.S. Food & Drug Administration (FDA). 13 Overall Program Learning Objectives Sessions I–VI Upon completion of this initiative, the participants will be better able to: Implement patient assessment strategies, including tools to assess risk of abuse, misuse, or addiction when prescribing extended-release (ER/LA) opioids Employ approaches to safely initiate therapy, modify dose, and discontinue ER/LA opioids Monitor patients by evaluating treatment goals and implementing periodic urine drug testing (UDT) Employ patient education strategies about the safe use of ER/LA opioids Identify similarities and differences among ER/LA opioids 14 7 Background: Painkiller Overdoses = Public Health Epidemic In 2014, 4.3 million people ≥12 years old reported current (past month) nonmedical opioid use Overdose deaths from opioid analgesics • • • • • • 18,893 in 2014; >4x # in 2000 Of opioid-analgesic deaths: Benzodiazepines involved in 31%; alcohol in 19% Highest prescription painkiller overdose rates in middle-aged adults Highest rates in rural counties Highest rates in Whites and American Indians or Alaska Natives Many more Rx opioid overdose deaths in men than women In 2011, nearly 420,000 ED/ER visits involving nonmedical use of opioids Direct health care costs of nonmedical prescription painkiller use: $72.5 billion annually In 2016, the CDC issued an Opioid Prescribing Guideline for primary care While improper use of any opioid can result in serious side effects, including overdose and death, risks may be greater with Rx ER/LA Opioids SAMHSA 2015; Rudd RA et al. MMWR Morb Mortal Wkly Rep. 2016 Jan 1;64(50-51):1378-82. Chen LH, et al. NCHS Data Brief, No. 166, September 2014; Opioids drive continued increase in drug overdose deaths. The DAWN Report 2013. 15 Drug Overdose Rates by State – 2014 www.cdc.gov. 16 8 Amount of All Prescription Opioids Sold by State – 2012 www.cdc.gov. 17 The Prevalence of Chronic Pain in the United States Is High Approximately 100 million US adults experience chronic pain (33%) Numerous studies indicate undertreated pain: eg, cancer, older adults, children, minorities Goal: define most appropriate analgesic regimen for each person in pain, which may include the use of ER/LA opioids Ensure availability of opioids for patients with pain AND Establish systems of control to prevent abuse IOM (Institute of Medicine). Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. 2011; www.painpolicy.wisc.edu. 18 9 Goals of Risk Evaluation and Mitigation Strategy (REMS) CME on ER/LA Opioid Analgesics In 2012, the US Food and Drug Administration (FDA) directed all ER/LA opioid companies to provide independent CME grants to educate prescribers and to provide information for patients to: • Ensure that the benefits of ER/LA opioids outweigh the risks • Help to reduce risk for ER/LA opioid analgesics misuse, abuse, and overdose while ensuring access to pain medication • Follow FDA “Blueprint” on ER/LA opioids CME to engage and educate prescribers and be in compliance with standards for continuing education for physicians and other health care professionals, including Accreditation Council for Continuing Medical Education (ACCME) This 6-Session Activity Is FDA REMS-Compliant CME CME, continuing medical education. FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed Jan 4, 2016. 19 Goals of This REMS-Compliant Education for ER/LA Opioid Analgesics As clinicians, WE are best positioned to balance treatment of pain against risks of serious adverse outcomes, including addiction, unintentional overdose, and death In this 6-session curriculum, we will review many best-practice aspects of managing ER/LA opioid analgesic therapy • • • • • • Patient assessment Therapy initiation, dose modification, and discontinuation Therapy management Counseling of patients and caregivers General drug information Product-specific drug information FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed Jan 4, 2016 20 10 Session I Evaluation is Essential for Safe and Effective Pain Management Using ER/LA Opioids 21 Learning Objectives for Session I Upon completion of this module, the participants will be better able to: Identify risk factors for opioid-related aberrant behavior Differentiate among tolerance, physical dependence, and addiction 22 11 Demographic Question 1 ? Do you have a DEA license for Schedule II and/or Schedule III drugs? 1. Yes 2. No 23 Demographic Question 2 ? In the last 12 months, have you prescribed any ER/LA opioid analgesics? 1. Yes 2. No 24 12 Pre-test Q1 ? Addiction is: 1. A neurobiological disease characterized by compulsive drug use despite harm 2. Any use of an illegal drug 3. A neuroadaptation in which an increasing dose is required to maintain the same pharmacological effect 4. Offering opioids to another person who is in pain 25 Pre-test Q2 ? You are assessing whether to prescribe an ER/LA-opioid to a new patient and are assessing her for increased risk of opioid-related aberrant behavior. If she is at risk, she will present with which of the following: 1. Personal history of treated substance abuse 2. Significant family history of substance abuse 3. Past/Comorbid psychological disorder 4. Age > 45 5. Answers 1 and 3 6. Answers 1, 2, and 3 7. All of the above 26 13 Opioid Therapy in Chronic Pain Management Opioids ARE commonly prescribed for chronic pain • Efficacious for many types of pain, though not necessarily for all people who experience a certain type of pain • Appropriate use is KEY to safety and success Goals of chronic opioid therapy: • Improve and/or stabilize pain intensity • Improve function • Improve quality of life (QOL) However, significant gaps exist between guideline recommendations for safe prescribing practices of ER/LA opioids and how they are being used in practice • Highlights need for further education McCarberg BH. Postgrad Med. 2011;123(2):119-130. 27 Opioid Therapy – Good Pain Management Principles Evidence-based Multidimensional Based on appropriate assessment A dynamic process 28 14 But There Are Also Risks Opioid analgesics are among the most commonly misused or abused pharmaceuticals • Over- or under-concern by physicians, patients, and/or caregivers is disruptive to physician-patient relationship as well as to effective care • Other drugs also commonly abused, eg, stimulants, benzodiazepines Misuse: • Using a medication other than as directed or indicated, whether intentional or not, and whether harm results or not - eg, taking more than recommended dose of an opioid analgesic because pain is poorly controlled - eg, offering opioid analgesics to another person who is in pain Abuse: • Intentionally taking a medication for a nonmedical purpose - eg, taking an opioid to get high Both misuse and abuse are of concern • Can lead to an overdose • Common misconception that because opioid is a prescription drug it is safe Chou R, et al. J Pain. 2009;10(2):113-130. 29 Risk Factors Associated With ER/LA Opioids Overdose with ER/LA formulations Life-threatening respiratory depression Abuse by patient or household contacts Misuse and addiction Physical dependence and tolerance Interactions with other medications and substances Risk of neonatal opioid withdrawal syndrome with prolonged use during pregnancy Inadvertent exposure by household contacts, especially children FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed Jan 4, 2016 30 15 Who Misuses/Abuses Opioids and Why? Nonmedical Use Medical Use • Recreational abusers • Pain patients seeking more pain relief • Patients with disease of addiction • Pain patients escaping emotional pain 31 Key Concepts Term Definition Tolerance State of adaptation. Exposure to a drug induces changes that result in a diminution of 1 or more of the drug’s effects over time. Indicated by a need for increasing doses to achieve the same effect. Commonly occurs with opioids. Tolerance is not indicative of addiction. Physical Dependence State of adaptation manifested by drug class-specific withdrawal syndrome that can occur with abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. Physical dependence occurs in all patients using opioids for a period of time. Physical dependence is not indicative of addiction. Addiction A primary, chronic, neurobiologic disease with genetic, psychosocial, and environmental components. Characteristic behaviors include 1 or more of the following: impaired control over drug use, compulsive use, continued use despite harm, craving. Savage SR, et al. J Pain Symptom Manage. 2003;26(1):655-667; Jamison RN, et al. Clin Neuropsychol. 2013;27(1):60-80. 32 16 Tolerance, Dependence, and Addiction — Critical Differences What a patient who has developed tolerance to the analgesic effect of the prescribed opioid would say to you: “The fentanyl patch that you prescribed used to work really well, and now it doesn’t seem to be easing as much of the pain as before. I am worried.” What a patient who has become opioid-dependent will typically say to you: “I went up to the lake this weekend and forgot to take along my long-acting morphine. I was without it for 2 days. I got so sick that I went to the ER.” 33 Tolerance, Dependence and Addiction — Critical Differences Behavior that the addicted patient may display: “ My husband used his entire month’s supply of that extended-release opioid you gave him in 1 week. He seems like a totally different person. I am very concerned.” 34 17 The FDA Definition of Opioid Tolerance Opioid naïve vs opioid tolerant Patients are considered opioid tolerant if they are taking, for 1 week or longer, at least: • • • • • • Oral morphine – 60 mg daily Transdermal fentanyl – 25 mcg/h Oral oxycodone – 30 mg daily Oral hydromorphone – 8 mg daily Oral oxymorphone – 25 mg daily Equianalgesic daily dose of another opioid www.fda.gov. 35 Key Concepts Term Definition Abuse Any use of an illegal drug, or the intentional self-administration of a medication for a nonmedical purpose, such as altering one’s state of consciousness—for example, getting high Misuse Use of a medication (for a medical purpose) other than as directed or as indicated, whether willful or unintentional, and whether harm results or not Aberrant Drug-Related Behavior A behavior outside the boundaries of the agreed-on treatment plan Chou R, et al. J Pain. 2009;10(2):113-130. 36 18 Examples of Misuse and Abuse What patients will typically say to you: “Sometimes in the morning I need to take extra pills just to get going…” “My friend was visiting this weekend and had terrible back pain. I gave her one of my oxycodone pills. It really helped her. That’s OK, right?” “That hydrocodone you gave my wife—well, it seems to make her feel a little too good sometimes. I think she’s taking more than you’ve prescribed and I’m worried about it…” 37 Prescribers Can Play an Active Role in Reducing the Risks Associated With Opioids Establish diagnosis • History and physical • Relevant diagnostic tests When opioids are being considered as part of acute or chronic pain treatment plan, complete an appropriate risk assessment • This is an active and ongoing process McCarberg BH. Postgrad Med. 2011;123(2):119-130; Brennan MJ, et al. PM R. 2010;2(6):544-558. 38 19 Risk Factors for Opioid-Related Aberrant Behaviors Family history of substance abuse • Alcohol, illegal drugs, prescription drugs - Prescription drug abuse history carries greater risk Personal history of substance abuse • Alcohol, illegal drugs, prescription drugs - Prescription drug abuse history carries greater risk Age 16 to 45 years History of preadolescent sexual abuse Psychological disease • Increases risk for women • Attention deficit disorder (ADD) or depression - ADD carries higher risk Use of Risk Stratification Tools and Ongoing Monitoring KEY to Safe and Effective Opioid Use Webster LR, et al. Pain Med. 2005;6(6):432-442. 39 Risk Stratification and Monitoring Tools Risk Stratification Tool (used before opioids are prescribed) Screener and Opioid Assessment for Patients with Pain (SOAPP) Opioid Risk Tool (ORT) Available www.painEDU.org www.partnersagainstpain.com 40 20 Opioid Risk Tool (ORT) Category Risk Factor Score if Female Score if Male Family History of Substance Abuse Alcohol Illegal Drugs Prescription Drugs 1 2 4 3 3 4 Personal History of Substance Abuse Alcohol Illegal Drugs Prescription Drugs 3 4 5 3 4 5 Age Age 16-45 years 1 1 3 0 2 2 1 1 History of Preadolescent Sexual Abuse Psychological Disease ADD, OCD, Bipolar Disorder, Schizophrenia Depression Total Risk Score Total Score Risk Category Low Risk 0–3 Moderate Risk 4–7 High Risk ≥8 OCD, obsessive compulsive disorder. Webster LR, et al. Pain Med. 2005;6(6):432-442. Opioid Risk Tool. www.partnersagainstpain.com/printouts/Opioid_Risk_Tool.pdf. Accessed January 8, 2013. Reprinted with permission: Lynn Webster, MD. 41 SOAPP — Sample Questions Please answer the questions below, using the following scale: 0 = Never, 1 = Seldom, 2 = Sometimes, 3 = Often, 4 = Very Often 1. How often do you have mood swings? 01234 2. How often do you smoke a cigarette within an hour after you wake up? 01234 3. How often have you taken medication other than the way that it was prescribed? 01234 4. How often have you used illegal drugs (for example, marijuana, cocaine, etc) in the past five years? 01234 5. How often, in your lifetime, have you had legal problems or been arrested? 01234 42 21 Stratify Risk Moderate Risk • History of treated substance abuse • Significant family history of substance abuse • Past/Comorbid psychological disorder Consider referring high-risk patients or any patient you have concerns about to a pain specialist Webster LR, et al. Pain Med. 2005;6(6):432-442. 43 Meet Peter 45-year-old white male, railroad worker for line maintenance and reconstruction S/p lumbar fusion with chronic back and leg pain Hx of back pain prior to injury that led to surgery, otherwise healthy Still experiencing pain despite multiple treatments described below History Injured at work; pain on lower right side, radiating down right leg to outside of foot • Pain described as aching and throbbing • Pain severity 6/10 at rest and 7-9/10 when bending, coughing, or straining with a bowel movement NSAIDs, muscle relaxant, and light work duty attempted Patient struggled on job; complaints of severe pain NSAID, nonsteroidal anti-inflammatory drug. 44 22 Peter History (cont) • Physical therapy (PT), Xray, MRI (L5-S1 disc w impingement of S1 nerve root) • Failed steroid taper, hydrocodone, epidural steroid, more PT • Sleep deprived, anxious, withdrawn, financially stressed • Surgery and rehabilitation – no improvement • Pain specialist prescribed: Oxycodone CR tablets 40 mg every 12 hours Hydrocodone/acetaminophen 5/300 8/day for breakthrough pain Gabapentin 300 mg/ 2 tablets TID Zolpidem 10 mg/HS Returns to your office for ongoing pain management CR, controlled-release; MRI, magnetic resonance imaging. 45 Next Steps: Make No Assumptions Even though the prescriber of the CR oxycodone and hydrocodone/acetaminophen has evaluated Peter’s risk for opioid misuse before initiating these drugs, should you re-assess his level of risk now that the patient is back in your care? Yes, because the risk level can change and you want to document you have performed a risk assessment CR, controlled-release 46 23 Peter’s Score on ORT Category Risk Factor Score if Female Score if Male Family History of Substance Abuse Alcohol Illegal Drugs Prescription Drugs 1 2 4 3 3 4 Personal History of Substance Abuse Alcohol Illegal Drugs Prescription Drugs 3 4 5 3 4 5 Age Age 16-45 years 1 1 3 0 2 2 1 1 History of Preadolescent Sexual Abuse Psychological Disease ADD, OCD, Bipolar Disorder, Schizophrenia Depression Total Risk Score 4 Total Score Risk Category Low Risk 0–3 Moderate Risk 4–7 High Risk ≥8 Webster LR, et al. Pain Med. 2005;6(6):432-442. Opioid Risk Tool. www.partnersagainstpain.com/printouts/Opioid_Risk_Tool.pdf. Accessed January 8, 2013. Reprinted with permission: Lynn Webster, MD. 47 Peter – Next Steps: Make No Assumptions Complete history and physical Ask Peter about his goals for treatment: • Explain that complete pain relief is rarely achieved • Focus on functional goals, eg, return to work, work part-time, able to play golf on weekends, able to walk the dog daily Risk for aberrant drug behavior – Moderate (4 on ORT) Evaluate mental health status Peter’s Rx: oxycodone CR, hydrocodone/APAP, gabapentin, zolpidem – any other Rx? OTC? Drug-drug interactions? Re-establish care with new treatment agreement and UDT Peter’s household – What is the possibility of inadvertent exposure to the opioids you are prescribing by household contacts, especially children? Have you discussed safe storage? 48 24 Opioid Therapy – Ongoing Monitoring ANALGESIA ADVERSE EFFECTS The 4 A’s ACTIVITIES OF ABERRANT DRUG-TAKING DAILY LIVING BEHAVIORS Important to remember two other “A’s”: Assessment and Action (treatment plan) Passik SD, et al. Adv Ther. 2000;17(2):70-83. 49 Additional Tools for Ongoing Monitoring Current Opioid Misuse Measure (COMM) – Sample Questions In the past 30 days, how often have you taken your medications differently than how they are prescribed? In the past 30 days, how much of your time was spent thinking about opioid medications (having enough, taking them, dosing schedule, etc)? In the past 30 days, how often have you had to visit the Emergency Room? Available at www.painEDU.org Pain Assessment and Documentation Tool (PADT) – Sample Questions Is the patient’s functioning with the current pain reliever(s) better, the same, or worse since last assessment? Is patient experiencing any side effects from current pain reliever(s)? Check-list of potential aberrant drug-related behavior Available at www.ucdenver.edu 50 25 Post-test Q1 ? Addiction is: 1. A neurobiological disease characterized by compulsive drug use despite harm 2. Any use of an illegal drug 3. A neuroadaptation in which an increasing dose is required to maintain the same pharmacological effect 4. Offering opioids to another person who is in pain 51 Post-test Q2 ? You are assessing whether to prescribe an ER/LA-opioid to a new patient and are assessing her for increased risk of opioid-related aberrant behavior. If she is at risk, she will present with which of the following: 1. Personal history of treated substance abuse 2. Significant family history of substance abuse 3. Past/Comorbid psychological disorder 4. Age > 45 5. Answers 1 and 3 6. Answers 1, 2, and 3 7. All of the above 52 26 Session II Best Practices for How to Start Therapy with ER/LA Opioids, How to Stop, and What to Do in Between 53 Learning Objectives for Session II Upon completion of this module, the participants will be better able to: Convert patients from immediate-release to ER/LA opioids as well as from one ER/LA opioid to another Identify predisposing risk factors for significant respiratory depression 54 27 Pre-test Q1 ? Patients are considered opioid tolerant if they are taking: 1. Oral morphine 60 mg daily for 3 days or more 2. Oral oxycodone 30 mg daily for 1 week or more 3. Oral hydromorphone 4 mg daily for 1 week or more 4. Oral morphine 30 mg daily for 1 week or more 55 Pre-test Q2 ? Which of the following ER/LA opioid agents should be prescribed only to opioid tolerant patients regardless of dose? 1. Avinza (morphine sulfate ER) and MS Contin (morphine sulfate CR) 2. Duragesic (fentanyl transdermal system) and Exalgo (hydromorphone HCl ER) 3. Oxycontin (oxycodone CR) and Opana ER (oxymorphone ER) 4. Nucynta ER (tapentadol ER) and Butrans (buprenorphine) 56 28 Key Principles of Safe Prescribing Know how to: • Identify the ER/LA opioid and dosage to use in the appropriate patient • Supplement pain management with immediate-release opioids and non-opioids • Convert patients from immediate-release to ER/LA opioids and from one ER/LA opioid to another • Identify the warning signs and symptoms AND PREDISPOSING RISK FACTORS for significant respiratory depression • Safely taper an opioid dose when therapy is no longer needed Keep current with regulations for opioid prescribing, both federal and those in your own state FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 23, 2013. 57 Benefits and Limitations of ER/LA Opioids Potential Benefits Provide more consistent plasma concentrations of drug compared with short-acting agents This minimizes serum level fluctuations that could contribute to end-of-dose breakthrough pain More consistent nighttime pain control Less clock-watching by patients Possible improved compliance/ adherence due to a lower pill volume Not for Not for as needed or “prn” use Not for mild pain Not for pain that is not expected to persist for an extended duration Not for acute pain Not for routine use in headache disorders or post-operative pain ER/LA opioids are indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Nicholson B. Pain Pract. 2009;9(1):71-81; www.fda.gov. 58 29 ER/LA Opioids – Contraindications Significant respiratory depression Acute or severe asthma in an unmonitored setting or in absence of resuscitative equipment Known or suspected paralytic ileus Hypersensitivity See individual product information for additional contraindications FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016. 59 Opioid-Naïve vs. Opioid-Tolerant Tolerance is a function of both time and dose • Patients who have not taken an opioid recently are considered opioid naïve • THESE patients are at greater risk for respiratory depression and sedation 60 30 Know The Risk Factors for Respiratory Depression Generally preceded by sedation and decreased respiratory rate Risk factors for respiratory depression include: Sleep apnea or a sleep disorder diagnosis Morbid obesity with a high risk of sleep apnea Snoring Risk increases with age No recent opioid use Post-surgery (particularly upper abdominal or thoracic) Preexisting pulmonary or cardiac disease or dysfunction or major organ failure Smoking (>60) Use of other sedating drugs (CNS depressants) The Joint Commission. Sentinel Event Alert. August 8, 2012;49. www.jointcommission.org. Accessed February 22, 2013. 61 The FDA Definition of Opioid Tolerance Opioid naïve vs opioid tolerant Patients are considered opioid tolerant if they are taking, for 1 week or longer, at least: • • • • • • Oral morphine – 60 mg daily Transdermal fentanyl – 25 mcg/h Oral oxycodone – 30 mg daily Oral hydromorphone – 8 mg daily Oral oxymorphone – 25 mg daily Equianalgesic daily dose of another opioid www.fda.gov. 62 31 Be Aware Certain ER/LA-opioid medications should ONLY be initiated in patients who have become opioid tolerant as a result of ongoing therapy www.fda.gov. 63 Be Aware Some agents should never be prescribed unless a patient is opioid tolerant • Duragesic (fentanyl transdermal system) • Exalgo (hydromorphone hydrochloride ER) Some agents can be prescribed to opioid-naïve patients, but not at higher doses -- some ER/LA opioid doses can ONLY be used in opioid-tolerant patients ER/LA Opioid Doses that can be used in opioidtolerant patients ONLY Avinza (morphine sulfate ER) 90 mg and 120 mg Belbuca (buprenorphine buccal film) 600 mcg, 750 mcg, and 900 mcg Butrans (buprenorphine transdermal system 10 mcg/h, 15 mcg/h and 20 mcg/h Embeda (morphine sulfate ER-naltrexone) 100 mg/4 mg Kadian (morphine sulfate ER) 100 mg and 200 mg Morphabond (morphine sulfate ER) 100 mg MS Contin (morphine sulfate controlled-release [CR]) 100 mg and 200 mg Oxycontin (oxycodone hydrochloride CR) >40 mg single dose or >80 mg daily Dolophine (methadone hydrochloride) >2.5 mg to 10 mg every 8 to 12 hrs Targiniq ER (oxycodone HCl / naloxone HCl) >40 mg/20 mg single dose or >80 mg/40 mg daily Zohydro (hydrocodone bitartrate ER) >40 mg single dose or >80 mg daily www.fda.gov. 64 32 Opioid Tolerance—Agents and Dosing (Refer to full prescribing information) Agent (Oral) Selected Doses for Use in Opioid-Tolerant Patients Only Avinza (morphine sulfate ER capsules) 90 mg and 120 mg capsules for use in opioid-tolerant patients only Embeda (morphine sulfate ER-Naltrexone capsules) 100 mg/4 mg capsule for use in opioid-tolerant patients only Hysingla (hydrocodone bitartrate ER tablets) Daily dose greater than or equal to 80 mg is for use in opioit-tolerant patients only Kadian (morphine sulfate ER capsules) 100 mg and 200 mg capsules for use in opioid-tolerant patients only MorphaBond (morphine sulfate ER tablets) 100 mg tablets or a total daily dose >120 mg for use in opioid-tolerant patients only MS Contin (morphine sulfate CR tablets) 100 mg and 200 mg tablets for use in opioid-tolerant patients only OxyContin (oxycodone hydrochloride CR tablets) Single dose greater than 40 mg or total daily dose greater than 80 mg for use in opioid-tolerant patients only Targiniq ER (oxycodone HCl/ naloxone HCl) Single dose greater than 40 mg/20 mg or total daily dose of 80 mg/40 mg for use in opioid-tolerant patients only Dolophine (methadone hydrochloride tablets) When used as first opioid analgesic, initiate therapy with small doses, no more than 2.5 mg to 10 mg every 8 to 12 hours. www.fda.gov. 65 Opioid Tolerance—Agents and Dosing (Refer to full prescribing information) Agent (transdermal) Butrans (buprenorphine transdermal system) Agent Selected Doses for Use in Opioid-Tolerant Patients Only 10 mcg/hr, 15 mcg/hr, and 20 mcg/hr transdermal systems are for use in opioidtolerant patients only Use in Opioid-Tolerant Patients Only – All Doses Duragesic (fentanyl transdermal system) All doses indicated for use in opioid-tolerant patients only Exalgo (hydromorphone hydrochloride ER tablets) All doses indicated for use in opioid-tolerant patients only Agent Use in Opioid-Naive Patients Belbuca (buprenorphine buccal film) In opioid-naïve patients or patients taking less than 30 mg oral morphine sulfate equivalents, initiate treatment with 75 mcg buccal film daily or every 12 hrs Hysingla ER (hydrocodone bitartrate ER tablets) In opioid-naïve patients, initiate treatment with 20 mg tablets every 24 hrs Nucynta ER (tapentadol ER tablets) In opioid-naïve patients, the initial dose is 50 mg twice a day Opana ER (oxymorphone hydrochloride ER tablets) In opioid-naïve patients, initiate treatment with 5 mg every 12 hours Zohydro ER (hydrocodone bitartrate ER capsules) In opioid-naïve patients, initiate treatment with 10 mg every 12 hours www.fda.gov. 66 33 Initiating Therapy: Dose Selection and Titration Individually titrate all opioids to a dosage that provides adequate analgesia and minimizes adverse reactions Drug Initial Dosing Avinza (morphine sulfate ER capsules) • Once daily • Initial dose as first analgesic (opioid-naive patients) is 30 mg once daily • Titrate using a minimum of 3-day intervals (4-day intervals for opioid-naïve patients) • Maximum daily dose 1600 mg (due to risk of renal toxicity) Butrans (buprenorphine transdermal system) • One transdermal system applied every 7 days • Initial dose as first analgesic (opioid-naïve patients) is 5 mcg/hour • Initial dose if prior total daily dose <30 mg oral morphine equivalents/day – 5 mcg/hour • When converting from 30-mg to 80-mg morphine equivalents – first taper to 30-mg morphine equivalent, then initiate with 10 mcg/hour dose • The minimum Butrans titration interval is 72 hours • Maximum daily dose: 20 mcg/hour (due to risk of QTc interval prolongation) www.fda.gov. 67 Initiating Therapy: Dose Selection and Titration Drug Initial Dosing Dolophine (methadone HCl tablets) • Every 8 to 12 hours • Initial dose as first opioid analgesic (opioid-naïve patients) is 2.5 mg to 10 mg • Conversion of opioid-tolerant patients using equianalgesic tables can result in overdose and death. Use low doses according to the table in the full prescribing information • Special considerations: Methadone is characterized by complicated and variable pharmacokinetics and pharmacodynamics and should be initiated and titrated cautiously by clinicians familiar with its use and risks (Refer to Module VI) Duragesic (fentanyl transdermal system) • • • • • Embeda (morphine sulfate and naltrexone HCl) ER • Once a day or every 12 hours • Initial dose as first opioid is 20 mg/0.8mg • Dosage adjustments may be done every 1 to 2 days www.fda.gov. Every 72 hours (3 days) Duragesic is contraindicated in opioid non-tolerant patients Use product-specific information for dose conversion from prior opioid Use 50% usual dosage in mild or moderate hepatic or renal impairment Titrate using no less than 72-hour intervals 68 34 Initiating Therapy: Dose Selection and Titration Drug Initial Dosing Exalgo (hydromorphone HCl ER tablets) • Once a day • Not for use in opioid non-tolerant patients. Do not begin any patient on Exalgo as the first opioid • Use the conversion tables in the full prescribing information • Start patients with moderate hepatic impairment on 25% usual dosage • Start patients with moderate renal impairment on 50%, and patients with severe renal impairment on 25% usual dosage • Titrate using a minimum of 3- to 4-day intervals Belbuca (buprenorphine buccal film) • Every 12 hours • For opioid-naïve patients and those taking less than 30 mg oral morphine sulfate equivalents, initiate treatment with a 75 mcg buccal film once daily, or if tolerated, every 12 hours • Titrate to 150 mcg every 12 hrs no earlier than 4 days after initiation • Titrate using a minimum of 4 day intervals and increments of 150 mcg • Start patients with severe hepatic impairment on 50% initial dose Hysingla ER (hydrocodone bitartrate ER tablets) • • • • • Once a day For opioid-naïve patients, initiate with 20 mg tablets Dose titration may occur every 3 to 5 days in increments of 10 mg to 20 mg Daily doses greater than or equal to 80 mg are for opioid tolerant patients only Start patients with severe hepatic or renal impairment on 50% initial dose www.fda.gov. 69 Initiating Therapy: Dose Selection and Titration Drug Initial Dosing Nucynta ER (tapentadol HCl ER tablets) • • • • Kadian (morphine sulfate ER capsules) • Once a day or every 12 hours • Not recommended as a first opioid • Titrate using a minimum of 2-day intervals MorphaBond (morphine sulfate ER tablets) • Every 8 hours or every 12 hours • Not recommended as first opioid • Titrate using a minimum of 1 to 2-day intervals MS Contin (morphine sulfate CR tablets) • Every 8 hours or every 12 hours • Not recommended as a first opioid • Titrate using a minimum of 2-day intervals Opana ER (oxymorphone HCl ER tablets) • • • • www.fda.gov. Every 12 hours Use 50 mg every 12 hours as initial dose in opioid non-tolerant patients Titrate by 50 mg increments using a minimum of 3-day intervals Maximum total daily dose is 500 mg Every 12 hrs; some may benefit from asymmetric dosing (higher in the AM than PM) Use 5 mg every 12 hours as initial dose in opioid non-tolerant patients Titrate dose at increments of 5-10 mg every 12 hours, at 3-7 day intervals Start with lowest dose in patients with mild hepatic impairment and renal impairment (creatinine clearance <50 mL/min) and in patients older than 65 years of age 70 35 Initiating Therapy: Dose Selection and Titration Drug Initial Dosing OxyContin (oxycodone HCl CR tablets) • • • • • Every 12 hours Initiate treatment with 10 mg every 12 hours in opioid non-tolerant patients Titrate using a minimum of 1- to 2-day intervals Hepatic impairment: start with one-third to one-half usual dosage Renal impairment (creatinine clearance <60 mL/min): start with one-half usual dosage Targiniq ER (oxycodone hydrocloride / naloxone hydrochloride tablets) • • • • Every 12 hours For opioid-naïve patients, initiate with 10 mg/5 mg tablet every 12 hours Titrate using a minimum of 1 to 2 day intervals Contraindicated in moderate and severe hepatic impairment. Start with onethird to one-half dose in mild hepatic impairment. Start with one-half dose in renal impairment Zohydro ER (hydrocodone bitartrate ER capsules) • • • • Every 12 hours For opioid-naïve patients, initiate with 10 mg capsule every 12 hours Titrate dose at increments of 10 mg every 12 hours, at 3-7 day intervals Start with low initial dose in patients with renal impairment and severe hepatic impairment www.fda.gov. 71 Supplementing ER/LA Opioids Patients who are on ER/LA opioids for chronic pain may need supplemental analgesia Increase dose of ER/LA opioid No treatmentlimiting effects— continue with higher dose Treatment-limiting adverse effects occur—reduce dose Treat with non-opioid analgesics Acetaminophen or NSAIDs Antidepressants and anticonvulsants Treat with short-acting opioids Initial and ongoing analysis of therapeutic benefit vs risk Zeppetella G. Curr Opin Support Palliat Care. 2009;3:1-6; Prommer E, et al. Patient Prefer Adherence. 2012;6:465-475; Chou R, et al. J Pain. 2009;10(2):113-130; Burton AW. Medscape. June 15, 2005. www.medscape.org/viewarticle/506124. Accessed September 7, 2012; Rhiner MI, et al. J Support Oncol. 2010;8:232-238. 72 36 Peter S/p lumbar fusion with chronic back and leg pain Returns to your primary care office for ongoing pain management Current medications: Goals of therapy: Opioid rotation may be considered if goals of therapy are not met, adverse effects are intolerable, or to lower opioid dose • • • • Oxycodone CR tablets 40 mg every 12 hours Hydrocodone/acetaminophen 5/300; 8/day for breakthrough pain Gabapentin 300 mg/2 tabs TID Zolpidem 10 mg/HS • Work a full day • Sleep through the night • Improve daytime somnolence 73 Rationale for Opioid Rotation Opioid rotation is switching from one opioid to another Rationale for opioid rotation • Adverse effects or toxicity of initial opioid • Lack of efficacy of initial opioid • Lowering the dose Rotation may work because of: • Incomplete cross-tolerance among opioids • Inter-patient variability of response based on opioid receptor genetic polymorphisms Note: Conservative dose-conversion ratios are advised Fine PG, et al. J Pain Symptom Manage. 2009 Se;38(3):418-25; Chou R, et al. J Pain. 2009;10(2):113-130. 74 37 Equianalgesic Dose Table – An Example Equianalgesic (mg) Dose Oral Opioid Equianalgesic (mg) Dose Other Morphine 60 PO 10 IM/IV/SQ Hydromorphone 7.5 PO 1.5 IM/IV/SQ 20-30 PO No information available Oxymorphone 15 PO 1 IM/IV/SQ; 10 PR Levorphanol 4 PO 2 IM/IV/SQ Methadone 20 PO Oxycodone 10 IM/IV/SQ 50-100 mcg IV/SQ Fentanyl Hydrocodone potency ranges 1:1 to 1:2 with morphine, but safest approach is 1:1 Be aware that individual responses may vary Refer to individual full prescribing information (PI) for complete information Knotkova H, et al. J Pain Symptom Manage. 2009;38(3):426-439. 75 Another Example: Duragesic (fentanyl transdermal system) Recommended Initial Duragesic Dose Based Upon Daily Oral Morphine Dose Oral 24-hour Morphine (mg/day) DURAGESIC Dose (mcg/hour) 60-134 25 135-224 50 225-314 75 315-404 100 405-494 125 495-584 150 585-674 175 675-764 200 765-854 225 855-944 250 945-1034 275 1035-1124 300 Duragesic Full Prescribing Information. Available at www.fda.gov. 76 38 Incomplete Cross-Tolerance Pharmacologic phenomenon whereby tolerance developed to the effects of one drug translates into tolerance to other drugs from the same class • Incomplete cross-tolerance: Failure to develop complete cross-tolerance, increasing the likelihood of therapeutic effects as well as adverse effects It is known to occur among opioids • Mechanism behind opioid rotation • Also reason for caution in converting from one opioid to another 2 1 3 Chou R, et al. J Pain. 2009;10(2):113-130. 77 Converting Patients From Immediate-Release to ER/LA Opioids or to Another ER/LA Agent Guidelines for select agents • Belbuca (buprenorphine buccal film) - Equipotency to oral morphine not established • Butrans (buprenorphine transdermal system) - Converting from 30‐mg to 80‐mg morphine equivalents: First taper to 30‐mg morphine equivalent per day Then initiate with 10‐mcg/hr dose • Dolophine (methadone HCl tablets) - Converting opioid‐tolerant patients using equianalgesic tables can result in overdose and death. - To minimize risk, use low doses according to table in full PI - Note: Relative potency to oral morphine varies, depending on patient’s prior opioid experience • Duragesic (fentanyl transdermal system) - For relative potency to oral morphine, see individual product‐specific PI for conversion recommendations from prior opioid www.fda.gov. Always refer to full prescribing information (PI) 78 39 Converting Patients From Immediate-Release to ER/LA Opioids or to Another ER/LA Agent • Exalgo (hydromorphone HCl ER tablets) - Use conversion ratios in individual product‐specific PI - Relative potency to oral morphine approximately 5:1 oral morphine to hydromorphone oral dose ratio • Hysingla ER (hydrocodone bitartrate) - See individual product‐specific PI for conversion recommendations from prior opioid • Nucynta ER (tapentadol HCl ER tablets) - Equipotency to oral morphine not established • Opana ER (oxymorphone HCl ER tablets) - Relative potency to oral morphine approximately 3:1 oral morphine to oxymorphone oral dose ratio • OxyContin (oxycodone HCl CR tablets) - Relative potency to oral morphine approximately 2:1 oral morphine to oxycodone oral dose ratio • Targiniq ER (oxycodone HCl/naloxone HCl tablets) - See individual product‐specific PI for conversion recommendations from prior opioid • Zohydro ER (hydrocodone bitartrate) - For relative potency to oral morphine, see individual product‐specific PI for conversion recommendations from prior opioid Always refer to full prescribing information (PI) www.fda.gov. 79 Tapering and Discontinuing ER/LA Opioid Analgesics When ER/LA opioid analgesic is no longer required, gradually titrate downward to prevent signs and symptoms of withdrawal in the physically dependent patient Do not abruptly discontinue these products • Decrease original dose by 10% per week Abrupt discontinuation of chronic opioids may cause withdrawal characterized by: • Stomach cramps, diarrhea, rhinorrhea, sweating, elevated heart rate, increased blood pressure, irritability, dysphoria, hyperalgesia, and insomnia FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016; Manchikanti L et al. Pain Phys. 2012;15(3 suppl):S67-S116; Morgan MM, et al. Br J Pharmacol. 2011;164(4):1322-1334. 80 40 Federal DEA Controlled Substance Schedules: ER/LA-Opioids are Schedule II Sch Description Examples I No currently accepted medical use in the U.S.; high potential for abuse Heroin, LSD, marijuana, peyote, methaqualone, Ecstasy II High potential for abuse, which Hydromorphone, methadone, meperidine, may lead to severe psychological or oxycodone, fentanyl, morphine, opium, and codeine, physical dependence amphetamine, methamphetamine, methylphenidate, hydrocodone combination products III Potential for abuse, which may lead Products containing ≤ 90 mg codeine per dose, to moderate or low physical buprenorphine, benzphetamine, phendimetrazine, dependence or high psychological ketamine, anabolic steroids dependence IV Low potential for abuse Alprazolam, carisoprodol, clonazepm, clorazepate, diazepam, lorazepam, midazolam, temazepam, tramadol (as of 2014), triazolam V Low potential for abuse Cough preparations containing ≤ 200 mg codeine per 100 ml or per 100 g, ezogabine State Laws/Regulations Vary. KNOW YOUR OWN STATE Rx REQUIREMENTS DEA Diversion Control. Available at www.deadiversion.usdoj.gov/schedules/index.htm. Accessed Jan, 2016 Post-test Q1 81 ? Patients are considered opioid tolerant if they are taking: 1. Oral morphine 60 mg daily for 3 days or more 2. Oral oxycodone 30 mg daily for 1 week or more 3. Oral hydromorphone 4 mg daily for 1 week or more 4. Oral morphine 30 mg daily for 1 week or more 82 41 Post-test Q2 ? Which of the following ER/LA opioid agents should be prescribed only to opioid tolerant patients regardless of dose? 1. Avinza (morphine sulfate ER) and MS Contin (morphine sulfate CR) 2. Duragesic (fentanyl transdermal system) and Exalgo (hydromorphone HCl ER) 3. Oxycontin (oxycodone CR) and Opana ER (oxymorphone ER) 4. Nucynta ER (tapentadol ER) and Butrans (buprenorphine) 83 Session III Evidence-Based Tools for Screening for Patients at Risk and Monitoring for Adherence to Prescribed ER/LA Opioids 84 42 Learning Objectives for Session III Upon completion of this module, the participants will be better able to: Evaluate and manage adverse effects of ER/LA opioids Differentiate strategies for monitoring patient adherence 85 Pre-test Q1 ? Oxymorphone is a metabolite of: 1. Hydrocodone 2. Codeine 3. Oxycodone 4. Morphine 86 43 Pre-test Q2 ? Your patient reports no relief on codeine and UDT is negative for morphine. Possible explanations include: 1. Laboratory error 2. Patient is not taking the codeine because she is hoarding it 3. Patient is not able to metabolize codeine 4. Answers 1 and 2 are correct 5. All of the above 87 Key Principles of Managing Therapy With ER/LA Opioids Use clinical evidence-based guidelines to: Screen for risk, including assessment of psychiatric comorbidities Establish analgesic and functional goals Use Patient Prescriber Agreements (PPAs) and monitor patient adherence Anticipate/manage adverse effects and periodically assess benefits and side effects Reevaluate patient’s underlying medical condition if clinical presentation changes over time Use referral sources for the treatment of abuse and addiction FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016. 88 44 Realistic Individualized Goal-Setting Reach agreement with patient on treatment goals Patient-specific goals may include 1 or more of the following • Pain reduction: 30% considered clinically significant - Explain to patient that complete pain relief rarely achieved • Improvement in select functional areas: - eg, ability to work full time at previous or modified job; play golf once a week, walk the dog daily • Improved mood 89 Patient Prescriber Agreement (PPA) Clinical evidence and guidelines support use of agreements Any of following can be used as a PPA: • Informed consent documents • Treatment agreement documents • PPA available for download at no cost* Benefits • Informed decision making with patient • Enables clear and mutual understanding of goals and expectations and respective responsibilities of patient and clinician • Can be jointly signed during patient visit *eg, www.caresalliance.org. Chou R, et al. J Pain. 2009;10(2):113-130. 90 45 What Is Typically in a Patient Prescriber Agreement (PPA) Understanding of risks and benefits of opioid therapy Taking the opioid exactly as prescribed One prescribing doctor and one designated pharmacy and whether or not refills will be called into pharmacy without an office visit Urine/serum drug testing when requested Pill counts at each office visit No early refills How to safeguard their opioids medication List of behaviors that may lead to discontinuation of opioids Places for signature and dating Chou R, et al. J Pain. 2009;10(2):113-130. 91 Monitoring Patient Adherence Level of monitoring depends on risk stratification level determined during initial screening (using ORT or other tool) • • • • State PDMPs (Prescription Drug Monitoring Programs) Urine drug testing (UDT) Pill counts Behavioral assessment at each visit - If indicated, refer for substance abuse treatment Chou R, et al. J Pain. 2009;10(2):113-130. 92 46 Monitoring Patient Adherence Prescription Drug Monitoring Programs (PDMPs) State-run electronic databases that track dispensing of controlled substances Can provide clinicians with critical information about patient prescription history and identify “doctor shoppers” Currently available in almost all states No national standards for guidance; implementation of programs is variable Real-time data access not yet available in all states • Each state has its own rules and laws • Follow state guidelines Dahl J. J Pain. April 2012;13:Abstract 245; Dahl J, et al. J Pain. April 2012;13:Abstract 246. 93 PDMPs: 2015 Operational or Legislated in 49 States, 1 Territory www.namsdl.org 94 47 A Sample PDMP Report: West Virginia = Board Of Pharmacy – Patient Profile Date 4/15/2012 Date of Birth 12-10-1966 Beginning Date: 04-01-11 =nbsp Ending Date: 04-15-12 First Name: MIKE Last Name: =OWEN First Name Address Zip Fill date Rx no. Product Name Strength Qty Doctor Name Doctor DEA Pharm Name Pharm DEA Ph Zip MIKE 319 LOWER 25526 4/2/2011 11222 APAP/HYDRO 500MG10MG 180 SMITH JOE DH0267890 TOM’S PHARM GF1234567 25526 MIKE 319 LOWER 25526 5/3/2011 19976 APAP/HYDRO 500MG10MG 180 SMITH JOE DH0267890 TOM’S PHARM GF1234567 25526 MIKE 319 LOWER 25526 5/27/2011 23466 APAP/HYDRO 500MG10MG 180 SMITH JOE DH0267890 TOM’S PHARM GF1234567 25526 MIKE 319 LOWER 25526 6/4/2011 31111 APAP/HYDRO 500MG10MG 180 JOHN JOHN DH0267890 BILL’S PHARM AF1245687 25526 95 Monitoring Patient Adherence: Urine Drug Testing (UDT) Recommended for all patients for reasons of safety and to remove the stigma associated with UDTs Testing does not imply a lack of trust; it is a conversation starter Self reports of drug use and behavioral monitoring often fail to detect abuse problems UDTs can identify use of prescribed opioids as well as illicit drug use Know limitations of UDT or laboratory that you use Katz NP, et al. Anesth Analg. 2003;97(4):1097-1102; Heit HA, et al. J Pain Symptom Manage. 2004;27(3):260-267. 96 48 Urine Drug Testing – KEY POINTS Know what to expect and how to interpret results Parent compound and or metabolite should show up in the urine • Oxycodone → oxymorphone • Hydrocodone → hydromorphone • Codeine → morphine Is the substance present that you expect? Are there substances present that you do not expect? Know what your laboratory does 97 Common UDT Scenarios Peter undergoes UDT in office and the test is negative for opioids • UDTs do differ • Certain drugs, including oxycodone, may not be detected by certain laboratory techniques • UDT is a conversation starter: “Why do you think your UDT is negative?” - Is diversion a possibility? - Is he bingeing and then running out of opioids? - Is he failing to take the prescribed drug because symptoms have abated? - Do you give him a 30-day Rx supply? Heit HA, et al. J Pain Symptom Manage. 2004;27(3):260-267. 98 49 Common UDT Scenarios Patient on LA morphine undergoes UDT. Test results positive for morphine and hydromorphone Possible explanations include: • Patient using another opioid obtained from another physician • Hydromorphone is a trace metabolite of morphine found only when very high morphine concentrations are present 99 Common UDT Scenarios Patient being treated with hydrocodone has UDT positive for hydrocodone and hydromorphone After hydrocodone use, urine may be positive for: • Hydrocodone only • Hydrocodone and hydromorphone (metabolite) • Hydromorphone only 100 50 Common UDT Scenarios Patient reports no relief on codeine and UDT is negative Possible explanations include • Laboratory error • Diversion • Patient is a slow metabolizer of codeine Heit HA, et al. J Pain Symptom Manage. 2004;27(3):260-267. 101 Screening vs Confirmatory UDTs ANALYSIS TECHNIQUE SENSITIVITY (POWER TO DETECT A CLASS OF DRUGS) SPECIFICITY (POWER TO DETECT AN INDIVIDUAL DRUG) TURNAROUND OTHER SCREENING CONFIRMATORY Immunoassay GC-MS or HPLC Low or none when testing for semi-synthetic or synthetic opioids High Varies (can result in false-positives or false-negatives) High Rapid Slow Intended for a drug-free population. May not be useful in pain medicine. Legally defensible results GC-MS, gas chromatograph mass spectrometer; HPLC, high performance liquid chromatography. www.opioidrisk.com. 102 51 Anticipating and Managing Adverse Effects Adverse Effect Treatment Nausea and vomiting Anti-emetics; Switch opioids* Sedation Lower dose (if possible); Add nonsedating co-analgesic; Add stimulant or attention enhancer Constipation Treat prophylactically with stool softeners, bowel stimulants; Nonpharmacologic and pharmacologic treatment *Opioid switching is an option for any adverse effect. Swegle JM, et al. Am Fam Physician. 2006;74(8):1347-1354. Chou R, et al. J Pain. 2009;10(2):113-130. 103 Anticipating and Managing Adverse Effects Adverse Effect Treatment Itching Antipruritic therapy (eg, antihistamines) Endocrine dysfunction/Reduced libido/Loss of menstrual period Endocrine monitoring; Testosterone replacement; Endocrine consultation Edema and sweating Switch opioids* Dizziness Antivertigo agents Confusion Titrate dose *Opioid switching is an option for any adverse effect. Swegle JM, et al. Am Fam Physician. 2006;74(8):1347-1354; Chou R, et al. J Pain. 2009;10(2):113-130. 104 52 Anticipating and Managing Adverse Events Emerging issues • Hyperalgesia - An increased response to a normally painful stimulus - May occur at higher doses • Sleep - Central and obstructive sleep apnea - Sleep architecture Brush DE. J Med Toxicol. 2012 Dec;8(4):387-92; Dimsdale JE et al. J Clin Sleep Med. 2007 Feb 15;3(1):33-6 105 Respiratory Depression – The Most Serious Adverse Effect Most serious adverse effect associated with opioids is RESPIRATORY DEPRESSION Occurs when • • • • Initial doses are too high Therapy is titrated too rapidly Drug-drug interactions Opioids combined with other drugs that may potentiate opioid-induced respiratory depression - Benzodiazepines - Herbals - OTC preparations that contain diphenhydramine More common in patients with sleep apnea Respiratory depression may be fatal OTC, over-the-counter. Manchikanti L, et al. Pain Physician. 2012;15(3 suppl):S67-S116. 106 53 ER/LA Opioid Analgesics in Pregnancy Be aware of the pregnancy status of your patient There re no adequate and well-controlled studies of ER/LA opioids in pregnant women ER/LA opioids should be used in pregnancy only if the potential benefit justifies the risk to the fetus If opioid use is required, advise the patient of risk of neonatal opioid withdrawal syndrome 107 Reevaluating the Patient’s Condition Reevaluate if the presentation changes to determine if opioid therapy continues to be effective or necessary Reevaluate or refer if there is new pain Continue opioid therapy if appropriate analgesia and functional status improvements are maintained Chou R, et al. J Pain. 2009;10(2):113-130. 108 54 What to Do if Your Patient Needs Treatment for Abuse and Addiction Know treatment centers in your area Work out a plan with the center you are referring to With a clear indication of abuse or addiction, discontinue prescribing of opioids 109 Referral Sources for Abuse and Addiction Treatment Balancing Pain Management and Prescription Opioid Abuse Available at www.cdc.gov/primarycare/materials/opoidabuse/index.html Find Substance Abuse and Mental Health Treatment Available at www.samhsa.gov/treatment National Institute on Drug Abuse Available at www.nida.nih.gov American Council for Drug Education Available at www.acde.org American Academy of Addiction Psychiatry • Providers’ Clinical Support System for Opioid Therapies: www.pcss‐o.org • Providers’ Clinical Support System for Medication Assisted Treatment: www.pcssmat.org 110 55 Post-test Q1 ? Oxymorphone is a metabolite of: 1. Hydrocodone 2. Codeine 3. Oxycodone 4. Morphine 111 Post-test Q2 ? Your patient reports no relief on codeine and UDT is negative for morphine. Possible explanations include: 1. Laboratory error 2. Patient is not taking the codeine because she is hoarding it 3. Patient is not able to metabolize codeine 4. Answers 1 and 2 are correct 5. All of the above 112 56 Questions? 11 3 Session IV Talk to Me: Proven Methods to Counsel Your Patients on ER/LA Opioids and Achieve Positive Outcomes 11 4 57 Learning Objectives for Session IV Upon completion of this module, the participants will be better able to: Implement counseling strategies to ensure patients know to take ER/LA opioids exactly as prescribed Use counseling strategies to explain signs of ER/LA opioid overdose to patients and caregivers ER/LA, extended-release and long-acting. 115 Pre-test Q1 ? Patients and caregivers need to be counseled about the signs of an opioid overdose, including: 1. Shallow rapid breathing 2. Stomach cramps 3. Elevated heart beat 4. Miosis 116 58 Pre-test Q2 ? Which of the following statements are TRUE: 1. Sharing prescription opioids is legal in some states, but should be avoided because opioid overdose can occur 2. Opioids prescribed for one person should never be shared with anyone else 3. It is sometimes ok to open an ER/LA opioid capsule and sprinkle contents on applesauce 4. Unused opioids should never be flushed down the toilet 5. 1 and 2 6. 2 and 3 7. All of the above 117 Patient Counseling Document ER/LA Analgesics REMS. http://www.er-la-opioidrems.com/IwgUI/rems/pcd.action. Accessed February 1, 2016. 118 59 Counseling Patients and Caregivers About ER/LA Opioids Use Patient Counseling Document for ER/LA opioids to: • Explain product-specific information • Explain how to take and importance of adherence • Tell patient and/or caregiver they will receive a Medication Guide from the dispensing pharmacy - Stress importance of reading the Guide and getting answers to any questions they may have from the pharmacist or you • Warn patients not to tamper with ER/LA formulation • Caution patients about use of other CNS depressants, including alcohol CNS, central nervous system. FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016. 119 Counseling Patients and Caregivers (cont’d) • Instruct patients to tell you about all medications they are taking • Warn patients to never abruptly discontinue their ER/LA opioid • Caution patients about all adverse effects - Specifically about signs and symptoms of respiratory depression, gastrointestinal obstruction, and allergic reactions - Instruct them on when and how to call you about side effects they experience so that you can work with them to manage Side effects can be reported to FDA at 1-800-FDA-1088 • Caution patients to never share their ER/LA opioid with ANYONE • Counsel patients about the risk of falls, working with heavy machinery and driving • Advise patients to store their medication carefully and dispose of safely when no longer needed - Medication Guides typically include specific disposal information 120 60 Why is patient and caregiver education so important? 121 Patient Education and Counseling Works! Utah Department of Health statewide program demonstrated effectiveness of patient education to reduce unintentional deaths from prescription opioids • Media campaign “Use Only As Directed” from May 2008 to May 2009, including: - Television and radio spots - Distribution of opioid prescribing guidelines and copies of print materials (bookmarks, patient information cards, educational posters) Results: • In 2008-2009, 14% decrease in unintentional overdose deaths from prescription opioids compared with 2007 Johnson EM, et al. Pain Med. 2011;12 suppl 2:S66-S72. 122 61 How to Counsel Patients to “Use Exactly as Prescribed” THE “DOs” Tell your patients: • • • • • Read Medication Guide from dispensing pharmacy Take your medicine exactly as prescribed Store your medicine away from children and in a safe place Flush unused medicine down the toilet Call your health care provider for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088 FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016. 123 How to Counsel Patients to “Use Exactly as Prescribed” THE “DON’Ts” Tell your patients: • Do not give your medicine to others • Do not take medicine unless it was prescribed for you • Do not stop taking your medicine without talking to your health care provider • Do not break, chew, crush, dissolve, or inject your medicine. If you cannot swallow your medicine whole, talk to your health care provider • Do not drink alcohol while taking this medicine FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016. 124 62 Patient Counseling Document Patient Counseling Document (PCD) on ER/LA opioid analgesics is a tool designed to facilitate important discussions with patients and: • Clearly describes “Do’s” and “Don’ts” related to safe use • Gives clinician area to write patient-specific issues and instructions that can be taken by patient from the visit • Helps to consolidate informed consent discussion PCD should be provided to and reviewed with patient and/or the caregiver at time of prescribing PCD is available at no charge at www.er-la-opioidrems.com/IwgUI/rems/pcd.action ER/LA Analgesics REMS. http://www.er-la-opioidrems.com/IwgUI/rems/pcd.action. Accessed February 1, 2016. 125 Case — Joan 62-year-old female with severe right hip osteoarthritis Has significant medical issues that prevent her from undergoing total hip replacement Started physical therapy, but stopped because of increase in pain Her pain is significantly affecting her quality of life • Unable to take NSAIDs because of previous GI bleed • Her PCP initiated a trial of Ultram (tramadol), 50 mg, 1-2 TID, with no reported analgesia • This was followed by a 2-week course of Nucynta (tapentadol), 50 mg, 1 PO Q 6 hrs - Reported pain relief for only 3-4 hours, with VRS decreasing from 8 to 5/10 • Because of less than optimal duration of effect, PCP decides to initiate a trial of Nucynta ER (tapentadol ER), 100 mg PO Q 12 hrs GI, gastrointestinal; PCP, primary care physician; VRS, verbal rating scale 126 63 Ensure Patients Know to Take Opioids ONLY As Prescribed Instructions need to be product-specific: • For instance, since Joan is taking Nucynta ER (tapentadol ER); she should be advised to: - Not crush or chew her medication - Place tablet in mouth and take it with enough water to ensure complete swallowing immediately afterward - Take a dose every 12 hours at same time every day • But, if you had prescribed Kadian to Joan, you would advise her to - Swallow capsule intact (whole); never to crush, dissolve or chew the pellets - If she cannot swallow the capsule whole, contents of the Kadian capsule (pellets) can be sprinkled on applesauce and then swallowed without chewing www.fda.gov. 127 Patients Need to Know About Adherence to Prescribed Opioid Regimen Counsel patients and caregivers • ER/LA opioid medication and dosage is based on their individual needs. • Doubling up on a dose or taking it sooner than prescribed risks overdose with possible life-threatening consequences • Taking more than prescribed constitutes misuse or abuse • Missing a dose may result in inadequate pain relief • What to do if a dose is missed FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016. 128 64 Explain the Dangers of Combining Opioids With Other Substances Caution patients and caregivers that overdose or death can occur if ER/LA opioids are used with other CNS depressants, including: • Sedative-hypnotics: eg, zolpidem (Ambien); triazolam (Halcion); temazepam (Restoril) • Anxiolytics: eg, diazepam, clonazepam • Illegal drugs: eg, heroin Fatal opioid poisonings have been associated more often with concomitant use of benzodiazepines or alcohol Advise patients to use other CNS depressants, including other opioids, only under instruction of their prescriber Advise patients to tell all their health care providers about all medications they are taking FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016. 129 Discuss the Dangers of Abruptly Discontinuing Medication Warn patients to not abruptly discontinue or reduce their ER/LA opioid analgesic and to discuss with you, the opioid prescriber, how to safely taper the dose if they wish to discontinue Abruptly discontinuing an opioid may lead to withdrawal syndrome • Stomach cramps, diarrhea, rhinorrhea, sweating, elevated heart rate, increased blood pressure, irritability, dysphoria, hyperalgesia, insomnia FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016; Morgan MM, et al. Br J Pharmacol. 2011;164(4):1322-1334. 130 65 Inform Patients of Seriousness of Adverse Events Associated With Opioids Caution patients and caregivers that opioids can cause serious side effects that may lead to death Discuss: • Signs and symptoms of an overdose, such as: lethargy and somnolence, cognitive impairment • Opioid-induced respiratory depression • Risk for severe constipation and gastrointestinal obstruction - Emphasize the importance of healthy bowel habits: keeping hydrated, less sedentary • Possibility of allergic reactions FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016. 131 Opioid Overdose Fatal overdose is not instantaneous—there is usually time for remedial action • Naloxone can quickly reverse the effects Both patients and caregivers need to know how to identify opioid overdose, as signs of an overdose are often missed Opioid overdose signs include: • • • • Mental depression Hypoventilation (decreased respiration) Reduced bowel motility Miosis (contracted pupils) Green TR, et al. Addiction. 2008;103(6):979-989; Williams RH, et al. Laboratory Med. 2000;31:334-342. 132 66 Update on Joan Joan returns to office after 1 month Reports better pain relief and improved quality of life Tolerating Nucynta ER (tapentadol ER) 100 mg BID and oxycodone 5 mg, 1-2 per day for breakthrough pain Urine drug toxicology testing (UDT) is completed She reports running out 2 days early and is requesting early refill • She states: “My daughter hurt her back, so I gave her a couple of my pills. It helped her pain, too.” What should you do? 133 Dangers of Sharing Medication: Legal Responsibilities of the Patient In our society, a commonly held belief among patients and caregivers is that sharing prescription medications is not dangerous or a problem because “prescription medications are safe”. Here’s what you should do: • Counsel Joan about importance of not giving her medication to or sharing it with others, even her daughter • Advise her that drugs prescribed for one patient can have serious or even fatal consequences for another • Tell her that sharing prescription medications is illegal Manchikanti L, et al. Pain Physician. 2012;15(3 suppl):S67-S116; SAMHSA (2010). 2009 National Survey on Drug Use and Health. www.samhsa.gov/data/2k9/2k9Resultsweb/web/2k9results.htm. Accessed February 22, 2013. 134 67 Storing ER/LA Opioids Safely Patients and caregivers must understand importance of storing opioids carefully and protecting them from theft • A secure place away from children, family members, household visitors, and pets - eg, a medication safe, which not only deters theft, but also inadvertent use in children, which could be fatal Manchikanti L, et al. Pain Physician. 2012;15(3 suppl):S67-S116; SAMHSA (2010). 2009 National Survey on Drug Use and Health. www.samhsa.gov/data/2k9/2k9Resultsweb/web/2k9results.htm. Accessed February 22, 2013. 135 Disposing of ER/LA Opioids Counsel patients to dispose of any ER/LA opioid analgesics that are no longer needed Encourage them to read product-specific disposal information, including the Medication Guide Safe disposal methods include: • Dropping off medication at a DEA-designated drop box or take-back program • Removing medication from original bottles, mixing with used coffee grounds or kitty litter, and throwing it in the garbage • Flushing it down the toilet - Many patients believe that medications should NOT be flushed into the toilet or put into septic or sewer systems. Education can help them understand this is an appropriate disposal DEA, Drug Enforcement Administration. FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016; Practical Pain Management. Opioid Disposal: Dos and Don’ts. www.practicalpainmanagement.com/opioid-disposal-dos-don-ts. Accessed January 8, 2013. 136 68 Post-test Q1 ? Patients and caregivers need to be counseled about the signs of an opioid overdose, including: 1. Shallow rapid breathing 2. Stomach cramps 3. Elevated heart beat 4. Miosis 137 Post-test Q2 ? Which of the following statements are TRUE: 1. Sharing prescription opioids is legal in some states, but should be avoided because opioid overdose can occur 2. Opioids prescribed for one person should never be shared with anyone else 3. It is sometimes ok to open an ER/LA opioid capsule and sprinkle contents on applesauce 4. Unused opioids should never be flushed down the toilet 5. 1 and 2 6. 2 and 3 7. All of the above 138 69 Session V Everything You Always Wanted to Know About ER/LA-Opioids as a Drug Class 13 9 Learning Objectives for Session V Upon completion of this module, the participants will be better able to: Assess the differences in opioid metabolism and how these impact appropriate ER/LA prescribing Identify how opioid-drug interactions influence ER/LA opioid prescribing 140 70 Pre-test Q1 ? The opioid with the greatest risk of prolongation of the QTc interval is: 1. Tapentadol 2. Oxycodone 3. Oxymorphone 4. Methadone 141 Pre-test Q2 ? Of the following cytochrome P450 enzymes, which one is particularly important in opioid metabolism? 1. CYP2E1 2. CYP2C19 3. CYP3A4 4. CYP1A2 142 71 Opioids As A Drug Class – General Information ER/LA Opioid Analgesic Products Key Points 1. ER/LA opioid analgesic products are scheduled under Federal Controlled Substances Act • Can be misused and abused • Risk for diversion 2. Most serious adverse effect: respiratory depression 3. Most common long-term side effect: constipation 4. Drug-drug interaction profiles: Vary among products • Important to recognize and avoid clinically significant interactions 5. Tolerance to sedating and respiratory-depressant effects • Clinician and patient understanding of tolerance is fundamental for safe use 6. Adherence to ER/LA opioid dosing instructions is critical • Oral formulations must be taken as directed and patients instructed to not tamper with the formulation • For transdermal products, external heat, fever, or exertion can increase absorption 143 Neurobiology of Opioids Opioid receptors are ubiquitous • Found throughout CNS and within GI tract • Accounts for their numerous effects, including potent analgesia, sedation, and reduced GI motility • Are G-coupled receptors • Both endogenous and exogenous opioids exert their effect by acting as ligands on these receptors . Schäfer M. Opioids in Pain Medicine. In: Kopf A, et al, eds. Guide to Pain Management in Low-Resource Settings. Washington, DC: International Association for the Study of Pain; 2010. http://www.iasppain.org/AM/Template.cfm?Section=Home&Template=/CM/ContentDisplay.cfm&ContentID=12166. Accessed March 2, 2013. 144 72 Opioid Receptors and Analgesia Analgesic effects likely mediated through mu opioid receptors • Highly concentrated in the outer laminae of spine dorsal horn • Two areas of brainstem—rostral ventromedial medulla (RVM) and periaqueductal gray (PAG) area 145 Respiratory Depression Most common serious adverse effect • Can be immediately life-threatening Factors that may increase risk for respiratory depression include: • • • • • • Sleep apnea or snoring Morbid obesity Older age Opioid naïve Concomitant use of other sedating drugs Smoking Schäfer M. Opioids in Pain Medicine. In: Kopf A, et al, eds. Guide to Pain Management in Low-Resource Settings. Washington, DC: International Association for the Study of Pain; 2010. http://www.iasppain.org/AM/Template.cfm?Section=Home&Template=/CM/ContentDisplay.cfm&ContentID=12166. Accessed March 2, 2013. 146 73 Constipation Most common long-term side effect • Activation of GI peripheral opioid receptors decreases GI motility and increases fluid absorption Nausea and vomiting may develop as primary AE or over time as a sign of chronic constipation Constipation should be anticipated and managed prophylactically • eg, increase fiber and water intake • OTC agents include bulking, lubricants, stimulants • Prescription agents include stimulants, chloride ion (CIC-2) activators (eg, lubiprostone) and opiate antagonists (eg, methylnaltrexone, naloxegol) • Opioid rotation may be warranted AE, adverse event. Schäfer M. Opioids in Pain Medicine. In: Kopf A, et al, eds. Guide to Pain Management in Low-Resource Settings. Washington, DC: International Association for the Study of Pain; 2010. http://www.iasp pain.org/AM/Template.cfm?Section=Home&Template=/CM/ContentDisplay.cfm&ContentID=12166. Accessed March 2, 2013; National Comprehensive Cancer Network Guidelines Version 1.2012. Adult Cancer Pain. http://www.nccn.org/professionals/physician_gls/pdf/pain.pdf. Accessed February 27, 2013; Chou R, et al. J Pain. 2009;10(2):113130. 147 Drug-Drug Interactions (DDI) Are Common and Vary Among Opioids Underlying mechanisms • Pharmacodynamics (pD) - Pharmacological effects • Pharmacokinetics (pK) - Drug absorption, metabolism and clearance • DDI may enhance or inhibit either pK or pD, thus altering intended and/or precipitating unintended effects FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 23, 2013. 148 74 CNS Depressants May Potentiate Opioid Effects Pharmacodynamic (PD) interaction Concomitant use increases risk of: • Respiratory depression • Hypotension • Profound sedation, coma Management includes reducing the initial dose of both opioid and CNS depressant Examples of CNS depressants Sedatives Hypnotics Tricyclic Antidepressants general anesthetics antiemetics phenothiazines alcohol marijuana other tranquilizers FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016. 149 Alcohol and ER/LA Opioids Pharmacodynamic (PD) Interactions With some ER/LA opioid formulations, rapid release of opioid may occur when exposed to alcohol • Known as “dose dump” • Can result in fatal toxicity Alcohol may increase opioid drug levels and predispose to adverse effects, including overdose How to manage: • Counsel patients to not consume alcohol when taking opioids • See product-specific warnings U.S. Food and Drug Administration. FDA Alert [7/2005]: Alcohol-Palladone Interaction. www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ ucm129288.htm. Accessed March 3, 2013. 150 75 MAOIs and ER/LA Opioids PD Interactions Concomitant use of monoamine oxidase inhibitors (MAOIs) and opioids may increase risk of respiratory depression May also cause serotonin syndrome Serotonin Syndrome Symptoms • • • • • • • • • • • Agitation or restlessness Diarrhea Fast heart beat and high blood pressure Hallucinations Increased body temperature Loss of coordination Nausea Overactive reflexes Rapid changes in blood pressure Vomiting Spontaneous or induced clonus How to Manage • Maintain hemodynamics • Reduce/Discontinue offending agent FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016; Gillman PK. Br J Anaesth. 2005;95(4):434-441. 151 Opioids and Other Drug Interactions Opioids can induce release of antidiuretic hormone (ADH) • Can reduce efficacy of diuretics Avoid co-administration of opioids with partial agonists or mixed agonist/antagonist analgesics • May reduce the analgesic effect and can precipitate withdrawal symptoms - Buprenorphine (Butrans) - Nalbuphine (Nubain) - Butorphanol (Stadol) Reisine T, et al. In: Goodman & Gilman’s: The Pharmacological Basis of Therapeutics (9th ed). McGraw-Hill; 1996. 521-555; FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016. 152 76 Opioids and Other Drug Interactions (cont’d) Skeletal Muscle Relaxants • Opioids may enhance neuromuscular blocking action and increase risk of respiratory depression Anticholinergics • Increased risk of urinary retention • Increased risk of severe constipation, which may lead to paralytic ileus FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016. 153 Summary of Opioid-Drug Interactions Concomitant Use of ER/LA Opioids With: Potential Effects Other CNS depressants (alcohol, sedatives, hypnotics, tranquilizers, tricyclic antidepressants) Increased risk of respiratory depression, hypotension, profound sedation, or coma; reduce the initial dose of 1 or both agents Partial agonists, mixed agonist/antagonist analgesics (buprenorphine, pentazocine, nalbuphine, butorphanol) May reduce analgesic effect or precipitate withdrawal symptoms; avoid concurrent use Skeletal muscle relaxants Increased respiratory depression Anticholinergic agents Increased risk of urinary retention and severe constipation, which may lead to paralytic ileus Drugs that act as inhibitors or inducers of various cytochrome P450 enzymes Higher or lower than expected blood levels of some opioids FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed August 2014. 154 77 Opioids and QTc Prolongation Methadone and buprenorphine can prolong QTc interval in some patients Dose-related incidence in patients on long-term methadone maintenance • 9% at a dose >300 mg/d • 83% at a dose >600 mg/d Management: • Monitor EKG • Consider alternative drugs should any abnormality develop www.fda.gov; Reddy S, et al. J Palliat Med. 2010;13(1):33-38. 155 Cytochrome P450 Enzymes Account for almost 50% of overall elimination of commonly used drugs, including: • • • • • • • Statins SSRIs Calcium channel blockers Benzodiazepines Beta Blockers Opioids Warfarin CYP450 drug-drug interactions often clinically relevant SSRI, selective serotonin reuptake inhibitor. Indiana University School of Medicine. Drug Interactions. http://medicine.iupui.edu/flockhart/table.htm. Accessed November 6, 2012; Wilkinson GR. N Engl J Med. 2005;352(21):2211–2221. 156 78 Opioids and CYP450 Interactions Pharmacokinetic drug-drug interactions can cause higher or lower blood levels of opioid than expected and result in: • Excess opioid effects (including fatal toxicity) • Loss of analgesia • Misinterpretation of drug tests Overholser BR, et al. Am J Manag Care. 2011;17 suppl 1:S276-S287. 157 ER/LA Opioids and CYP450 Enzyme Interactions Metabolism of several commonly used opioids occurs through enzyme CYP3A4, but CYP2D6 is also important • 3A4 is a potent inactivation enzyme • 2D6 is an activating enzyme Inhibition Stimulation However, if an agent is a pro-drug, an inhibitor can decrease drug effects, while an inducer increases the rapidity with which the active compound enters the bloodstream Refer to product-specific information for specific opioid-DDIs before prescribing • Can increase drug plasma levels, resulting in greater drug-related effects • Can decrease drug plasma levels and decrease drug-related effects Overholser BR, et al. Am J Manag Care. 2011;17 suppl 1:S276-S287. 158 79 Peter’s Current Medication Regimen Returns to your office complaining of serious foot fungus. Current medications: • • • • Oxycodone CR tablets 40 mg every 12 hours Hydrocodone/acetaminophen 5/300 8/day for breakthrough pain Gabapentin 300 mg/2 tablets TID Zolpidem 10 mg/HS When considering a medication to treat the fungus, should you be concerned about possible drug-drug interactions? YES – many commonly used antifungals have known CYP450 interactions 159 Overview of Opioid Metabolism Active Components Metabolism (CYP450) Morphine Not significantly metabolized by CYP450 Oxymorphone Not significantly metabolized by CYP450 Tapentadol Not significantly metabolized by CYP450 Hydromorphone Not significantly metabolized by CYP450 Oxycodone 2D6, 3A4 Hydrocodone 3A4 Hydrocodone + Acetaminophen 2D6, 3A4 Tramadol 2D6, 3A4 Codeine 2D6 Fentanyl 3A4 Methadone 3A4, 2B6, 2D6, 2C9, 2C19 Oxycodone + Acetaminophen 2D6, 3A4 www.accessdata.fda.gov. 160 80 Interactions With Other Agents and Substances Agent Concomitant Use With: Potential Effect on Opioid Levels and Other Effects Avinza (morphine sulfate ER capsule) • Alcohol • PGP Inhibitors (quinidine) (potentially fatal dose) Belbuca (buprenorphine buccal film) • • • • CNS depressants and benzodiazepines CYP3A4 inhibitors CYP3A4 inducers Class IA and III antiarrythmics, other potentially arrhythmogenic agent Respiratory depression QTc prolongation and torsade de pointe risk Butrans (buprenorphine transdermal system) • • • • CYP3A4 inhibitors CYP3A4 inducers Benzodiazepines Class IA and III antiarrythmics, other potentially arrhythmogenic agent Respiratory depression QTc prolongation and torsade de pointe risk Dolophine* (methadone HCl tablets) • • • • • CYP450 inhibitors CYP450 inducers Anti-retroviral agents Benzodiazepines Potentially arrhythmogenic agents Mixed effects on levels Respiratory depression QTc prolongation and torsade de pointe risk * Pharmacokinetic drug-drug interactions with methadone are complex. Refer to package insert for additional information. FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed January 1, 2016. 161 Interactions With Other Agents and Substances Agent Concomitant Use With: Potential Effects on Opioid Levels and Other Effects Duragesic (fentanyl transdermal system) • CYP3A4 inhibitors • CYP3A4 inducers Embeda (morphine sulfate ER-naltrexone capsules) • Alcohol • PGP Inhibitors (quinidine) (potentially fatal dose) Exalgo (hydromorphone HCl ER tablets) None Hysingla ER (hydrocodone bitartrate ER tablets) • CYP3A4 inhibitors • CYP3A4 inducers Kadian (morphine sulfate ER capsules) • Alcohol • PGP Inhibitors (quinidine) (potentially fatal dose) MorphaBond (morphine sulfate ER tablets) • PBP inhibitors (quinidine) MS Contin (morphine sulfate CR tablets) • PGP Inhibitors (quinidine) FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016. 162 81 Interactions With Other Agents and Substances Agent Concomitant Use With: Potential Effects on Opioid Levels and Other Effects Nucynta ER (tapentadol HCl ER tablets) • Alcohol • MAOIs (potentially fatal dose) Contraindicated in patients taking MAOIs Opana ER (oxymorphone HCl ER tablets) • Alcohol (potentially fatal dose) OxyContin (oxycodone HCl CR tablets) • • • • CYP3A4 inhibitors CYP3A4 inducers 2D6 inhibitors 2D6 inducer Targiniq ER (oxycodone HCl / naloxone HCl) • CYP3A4 inhibitors • CYP3A4 inducers Zohydro ER (hydrocodone bitartrate ER capsules) • CYP3A4 inhibitors • CYP3A4 inducers Increased effect FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016. 163 Drug Interactions Between Methadone or Buprenorphine and Select Medications Medication Methadone Buprenorphine AZT Increase in AZT concentrations; possible AZT toxicity No clinical significant interaction Lopinavir/Ritonavir Opiate withdrawal may occur No clinically significant interaction Rifampin Opiate withdrawal may occur Opiate withdrawal may occur Fluconazole Increased methadone plasma concentrations Ciprofloxacin Increased methadone plasma concentrations Sertraline No associated adverse drug interactions Duloxetine Potentially increases duloxetine exposure Dextromethorphan Associated with delirium No clinically significant interaction Aripiprazole No clinically significant interaciton No clinically significant interaction Carbamazepine Associated with opiate withdrawal Not studied Methylphenidate No clinically significant interaction No clinically significant interaction Diphenhydramine May have synergistic depressant effect Adapted from McCance-Katz EF, et al. Am J Addict. 2010;19(1):4-16. 164 82 Tolerance to Sedating and Respiratory Depressant Side Effects Opioid-naïve patients – no prior opioid exposure • Especially prone to most serious adverse effects of opioids Tolerance to sedating and respiratory-depressant effects critical to safe use of certain opioid products, dosages, and strengths • Opioid-tolerant patient: at least 1 wk of tx = 60 mg morphine or equivalent/day • Patients must be opioid tolerant before using any strength of transdermal fentanyl or ER hydromorphone • With other ER/LA products, patients must be opioid tolerant before using certain strengths or certain daily doses FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/ucm277916.pdf. Accessed February 1, 2016. 165 Other Important Opioid Safety Issues Oral formulations of ER/LA opioids must be taken as directed. Instruct patients to not tamper with the formulation: - Swallow tablets whole Swallow capsules whole/intact If necessary, pellets from some capsules can be sprinkled on applesauce and swallowed without chewing For transdermal products, instruct patients on proper and safe use • External heat, fever, and exertion can increase absorption of the opioid, leading to fatal overdose • Transdermal products with metal foil backings are not safe for use in MRIs www.fda.gov 166 83 Post-test Q1 ? The opioid with the greatest risk of prolongation of the QTc interval is: 1. Tapentadol 2. Oxycodone 3. Oxymorphone 4. Methadone 167 Post-test Q2 ? Of the following cytochrome P450 enzymes, which one is particularly important in opioid metabolism? 1. CYP2E1 2. CYP2C19 3. CYP3A4 4. CYP1A2 168 84 Session VI Getting the Most Clinical Insights from Specific ER/LA Product Information Sources 16 9 Learning Objectives for Session VI Upon completion of this module, the participants will be better able to: Differentiate the prescribing information among available ER/LA opioids Identify ER/LA opioids and dosages indicated for opioid-tolerant patients only 170 85 Pre-test Q1 ? Which of the following is TRUE about Exalgo (hydromorphone HCl) Extended Release? 1. If the patient is unable to swallow Exalgo, capsule can be opened and pellets sprinkled on applesauce 2. All doses are indicated for use in opioid-tolerant patients only 3. Its relative potency to oral morphine has not been established 4. Patients should rotate site of application 171 Pre-test Q2 ? Which of the following is TRUE about Opana ER (oxymorphone HCl) Extended Release? 1. If the patient is unable to swallow Opana ER, capsule can be opened and pellets sprinkled on applesauce 2. All doses are indicated for use in opioid-tolerant patients only 3. Its relative potency to oral morphine has not been established 4. Some patients may benefit from asymmetric dosing (different dose given in AM than in PM) 172 86 Prescribers Must Be Knowledgeable Before prescribing an opioid, each clinician needs to be knowledgeable about specific characteristics of each available ER/LA opioid, including: • • • • • Drug substance Formulation Strength Dosing interval Key instructions – reserve for use in patients for whom alternative treatment options (eg, non-opioid analgesics or immediaterelease opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain 173 Prescribing Information For detailed information, prescribers can refer to the prescribing information available online: • DailyMed at www.dailymed.nlm.nih.gov • www.fda.gov/drugsatfda 174 87 Avinza—Morphine Sulfate ER Morphine Sulfate ER Capsules, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, and 120 mg Avinza Dosing Interval Once a day Initial dose in opioid non-tolerant patients: 30 mg Maximum daily dose: 1600 mg Key Instructions • Initial dose in opioid non-tolerant patients: 30 mg • Titrate using minimum of 3-day intervals (4-day intervals in opioid nontolerant patients) Instruct patient: - Swallow capsule whole (do not chew, crush, or dissolve) - If unable to swallow, capsule can be opened and pellets sprinkled on applesauce for patients Specific Drug Interactions • Avoid alcoholic beverages or medications containing alcohol; may result in “dose dump” and absorption of potentially fatal dose of morphine • PGP inhibitors (eg, quinidine) may increase absorption/exposure of morphine sulfate by approximately 2x Use in Opioid-Tolerant Patients Use 90 mg and 120 mg capsules in opioid-tolerant patients ONLY PGP, P-glycoprotein www.fda.gov 175 Belbuca—Buprenorphine Buccal Film Belbuca Dosing Interval Buprenorphine Buccal Film, 75 mcg, 150 mcg, 300 mcg, 450 mcg, 600 mcg, 750 mcg, 900 mcg Every 12 hours (or once every 24 hrs for initiation in opioid-naïve pts and those taking <30 mg oral morphine equivalents) • Maximum dose: 900 mcg every 12 hrs due to risk of QTc prolongation Key Instructions • Initiate treatment with a 75 mcg buccal film in opioid-naïve or if prior total daily dose of opioid < 30 mg oral morphine equivalents/day • Titrate in increments of 150 mcg q 12 hrs • The minimum titration interval is 4 days • In severe hepatic impairment and in oral mucositis, reduce dose by 50% • Do not use if package seal is broken or film damaged in any way Specific Drug Interactions • • • • Use in Opioid-Tolerant Patients • 600 mcg, 750 mcg and 900 mcg are for use following titration from lower doses Product-Specific Safety Concerns • QTc prolongation ad torsade de pointes • Hepatotoxicity Relative Potency to Oral Morphine • Equipotency to oral morphine has not been established. www.fda.gov CYP3A4 inhibitors may increase buprenorphine levels CYP3A4 inducers may decrease buprenorphine levels Benzodiazepines may increase respirator depression Class IA and III antiarrhythmics and other potentially arrhythmogenic agents may increase risk for QTc prolongation and torsade de pointes 176 88 Butrans—Buprenorphine Butrans Dosing Interval Buprenorphine Transdermal System, 5 mcg/hr, 7.5 mcg/hr, 10 mcg/hr, 15 mcg/hr, and 20 mcg/hr One transdermal system every 7 days • Initial dose: 5 mcg/hr. • Maximum dose: 20 mcg/hr due to risk of QTc prolongation Key Instructions • When used as first opioid analgesic initiate treatment with 5 mcg/hr • If prior total daily dose of opioid < 30 mg oral morphine equivalents per day, initiate treatment with 5 mcg/hr dose • If prior total daily dose of opioid between 30 mg to 80 mg of oral morphine equivalents, taper patient’s opioid for up to 7 days to no more than 30 mg of morphine equivalents, then initiate with 10 mcg/hr dose • The minimum titration interval is 72 hours Instruct patient • • • • • • • Apply only to sites indicated in full prescribing information Apply to intact/non-irritated skin Skin may be prepped by clipping hair, washing site with water only Rotate site of application; allow a minimum of 3 weeks before reapplying to same site Do not cut Avoid exposure to heat Dispose of used/unused patches by folding the adhesive side together and flushing down toilet www.fda.gov 177 Butrans—Buprenorphine (cont’d) Butrans Buprenorphine Transdermal System, 5 mcg/hr, 7.5 mcg/hr, 10 mcg/hr, 15 mcg/hr and 20 mcg/hr Specific Drug Interactions • • • • CYP3A4 inhibitors may increase buprenorphine levels CYP3A4 inducers may decrease buprenorphine levels Benzodiazepines may increase respiratory depression Class IA and III antiarrythmics, other potentially arrhythmogenic agents, may increase risk for QTc prolongation and torsade de pointe Use in Opioid-Tolerant Patients Use 7.5 mcg/hr, 10 mcg/hr, 15 mcg/hr and 20 mcg/hr transdermal systems in opioid-tolerant patients ONLY Drug-Specific Safety Concerns • QTc prolongation and torsade de pointe • Hepatotoxicity • Application site skin reactions Torsade de pointe (TdP) –a form of polymorphic ventricular tachycardia that may result in syncope or cardiac arrest. www.fda.gov 178 89 Dolophine—Methadone Hydrochloride Dolophine Methadone Hydrochloride Tablets, 5 mg and 10 mg Dosing Interval Every 8 to 12 hours Initial dose in opioid non-tolerant patients: 2.5 mg to 10 mg slowly titrated to effect Key Instructions • Conversion of opioid-tolerant patients using equianalgesic tables can result in overdose and death; use low doses according to table in full prescribing information (PI) • High interpatient variability in absorption, metabolism, and relative analgesic potency • Opioid detoxification or maintenance treatment shall only be provided in a federally certified opioid (addiction) treatment program Specific Drug Interactions • • • • • Complex pharmacokinetic drug-drug interactions with methadone CYP450 inducers may increase methadone levels CYP450 inhibitors may decrease methadone levels Antiretroviral agents have mixed effects on methadone levels Potentially arrhythmogenic agents may increase risk for QTc prolongation and torsade de pointe • Benzodiazepines may increase respiratory depression www.fda.gov 179 Dolophine—Methadone Hydrochloride (cont’d) Dolophine Methadone Hydrochloride Tablets, 5 mg and 10 mg Use in Opioid-Tolerant Patients Refer to full prescribing information Product-Specific Safety Concerns • QTc prolongation and torsade de pointe • Peak respiratory depression occurs later and persists longer than analgesic effect • Clearance may increase during pregnancy • False-positive urine drug screens possible Relative Potency to Oral Morphine Varies depending on patient’s prior opioid experience www.fda.gov 180 90 Duragesic—Fentanyl Transdermal System Duragesic Fentanyl Transdermal System, 12, 25, 37.5*, 50, 62.5*, 75, 87.5*, and 100 mcg/hr (*these strengths available only in generic form) Dosing Interval Every 72 hours (3 days) Key Instructions • Use product-specific information in the full prescribing information for dose conversion from prior opioid • Use 50% of the dose in mild or moderate hepatic or renal impairment; avoid use in severe hepatic or renal impairment • Titrate generally using no less than 72-hour intervals; some patients may require 48 hour titration if adequate analgesia not achieved at 72 hour dose Instruct patient: - Apply to intact/non-irritated/non-irradiated skin on a flat surface Skin may be prepped by clipping hair, washing site with water only Rotate site of application Do not cut Avoid exposure to heat Avoid accidental contact when holding or caring for children Dispose used/unused patches by folding the adhesive side together and flushing down the toilet Specific contraindications: • Patients who are not opioid-tolerant • Management of acute or intermittent pain, or in patients who require opioid analgesia for a short period of time • Management of postoperative pain, including use after outpatient or day surgery • Management of mild pain www.fda.gov 181 Duragesic—Fentanyl Transdermal System (cont’d) Duragesic Fentanyl Transdermal System, 12, 25, 37.5*, 50, 62.5*, 75, 87.5*, and 100 mcg/hr (*these strengths available only in generic form) Specific Drug Interactions • CYP3A4 inhibitors may increase fentanyl drug levels and exposure • CYP3A4 inducers may decrease fentanyl drug levels and exposure • Discontinuation of a concomitantly used CYP3A4 inducer may result in an increase in fentanyl plasma concentration Use in Opioid-Tolerant Patients Indicated for use in opioid-tolerant patients ONLY Product-Specific Safety Concerns • Accidental exposure due to secondary exposure to unwashed/unclothed application site • Increased drug exposure with increased core body temperature or fever • Bradycardia • Application site skin reactions Relative Potency to Oral Morphine See full prescribing information for conversion recommendations from prior opioid www.fda.gov 182 91 Embeda—Morphine Sulfate ER-Naltrexone Embeda Morphine Sulfate ER-Naltrexone Capsules, 20 mg/0.8 mg, 30 mg/1.2 mg, 50 mg/2 mg, 60 mg/2.4 mg, 80 mg/3.2 mg, and 100 mg/4 mg Dosing Interval Once a day or every 12 hours Initial dose as first opioid: 20 mg/0.8 mg Titrate using 1-2 day intervals Key Instructions • Swallow capsules whole (do not chew, crush, or dissolve) • Instruct patient: - Crushing or chewing will release morphine, possibly resulting in fatal overdose, and naltrexone, possibly resulting in withdrawal symptoms - If unable to swallow capsule whole, can open capsule and sprinkle pellets on applesauce; use immediately Specific Drug Interactions • Alcoholic beverages or medications containing alcohol may result in the rapid release and absorption of a potentially fatal dose of morphine • GP inhibitors (eg, quinidine) may increase the absorption/exposure of morphine sulfate by approximately 2-fold Use in Opioid-Tolerant Patients Use 100 mg/4mg capsule in opioid-tolerant patients ONLY www.fda.gov 183 Exalgo—Hydromorphone Hydrochloride Exalgo Hydromorphone Hydrochloride Extended-Release Tablets, 8 mg, 12 mg, 16 mg, and 32 mg Dosing Interval Once a day Titrate using a minimum of 3- to 4-day intervals Key Instructions • Use conversion ratios in the full prescribing information • Start patients with moderate hepatic impairment on 25% of the dose that would be prescribed for a patient with normal hepatic function • Start patients with moderate renal impairment on 50%, and patients with severe renal impairment on 25% of the dose that would be prescribed for a patient with normal renal function • Do not use in patients with sulfa allergy • Instruct patient to swallow tablets whole - DO NOT chew, crush, or dissolve Specific Drug Interactions None Use in Opioid-Tolerant Patients Use in opioid-tolerant patients ONLY Drug-Specific Adverse Reactions Allergic manifestations to sulfa component Relative Potency to Oral Morphine Approximately 5:1 oral morphine to hydromorphone oral dose ratio, use conversion recommendations in the full prescribing information www.fda.gov 184 92 Hysingla ER—Hydrocodone Bitartrate Hysingla ER Hydrocodone Bitartrate Extended-Release Tablets, 20, 30, 40, 60, 80, 100 mg Dosing Interval Once a day (every 24 hours) Titrate in increments of 10 mg to 20 mg every 3-5 days Key Instructions • • • • • • In patients who are not opioid tolerant, initiate therapy with 20 mg QTc prolongation has been observed with daily doses of 160 mg Hepatic impairment: use half the initial dose Renal impairment: use half the initial dose Instruct patients to swallow tablets whole Consider alternative analgesic in patients who have difficulty swallowing or have underlying GI disorders that may predispose them to obstruction Specific Drug Interactions • • • • CYP3A4 inhibitors may increase hydrocodone exposure CYP3A4 inducers may decrease hydrocodone exposure Concomitant use with strong laxatives may decrease hydrocodone absorption Concomitant use of MAOIs or TCAs may increase the effect of either drug Use in Opioid-Tolerant Patients Doses equal to or greater than 80 mg are for use in opioid tolerant patients only Abuse Deterrence This product is formulated with physicochemical properties intended to make the tablet more difficult to manipulate for misuse and abuse. www.fda.gov 185 Hysingla ER—Hydrocodone Bitartrate (cont’d) Hysingla ER Product-Specific Safety Concerns Hydrocodone Bitartrate Extended-Release Tablets, 20, 30, 40, 60, 80, 100 mg • • • • Relative Potency to Oral Morphine Use with caution in patients with difficulty swallowing or with underlying GI disorders that may predispose them to obstruction Esophageal obstruction, dysphagia, and choking have been reported with Hysingla ER In nursing mothers, discontinue nursing or discontinue drug QTc prolongation has been observed with Hysingla ER following daily doses of 160 mg. Avoid use in patients with congenital long QTc syndrome. This observation should be considered in making clinical decisions regarding patient monitoring when prescribing Hysingla ER in patients with CHF, bradyarrhythmias, electrolyte abnormalities, or if taking medications known to prolong QTc interval. In patients who develop QTc prolongation, consider reducing the dose. See individual product information for conversion recommendations from prior opioid. www.fda.gov 186 93 Kadian—Morphine Sulfate Kadian Morphine Sulfate Extended-Release Capsules, 10 mg, 20 mg, 30 mg, 50 mg, 60 mg, 70 mg, 80 mg, 100 mg, 130 mg, 150 mg, and 200 mg Dosing Interval Once a day or every 12 hours Titrate using a minimum of 2-day intervals Key Instructions • Do not use as first/initial opioid (see PI) • Instruct patient: - Swallow capsules whole • DO NOT chew, crush, or dissolve - If unable to swallow capsule whole, can open capsule and sprinkle pellets on applesauce; use immediately Specific Drug Interactions • Do not use with alcoholic beverages or medications containing alcohol as may result in the rapid release and absorption of a potentially fatal dose of morphine • PGP inhibitors (eg, quinidine) may increase the absorption/exposure of morphine sulfate by approximately 2-fold Use in Opioid-Tolerant Patients Kadian 100-mg, 130 mg, 150 mg and 200-mg capsules are for use in opioidtolerant patients ONLY www.fda.gov 187 MorphaBond—Morphine Sulfate MorphaBond Morphine Sulfate Extended-Release Tablets, 15 mg, 30 mg, 60 mg, 100 mg Dosing Interval Every 8 hours or every 12 hours Titrate using a minimum of 1 to 2-day intervals Key Instructions • Do not use as first/initial opioid (see PI) • Instruct patient to swallow tablets whole - Do NOT chew, crush, or dissolve Specific Drug Interactions PGP inhibitors (eg, quinidine) may increase the absorption/exposure of morphine sulfate by approximately 2-fold Use in Opioid-Tolerant Patients Use MorphaBond 100 mg tablet strengts in opioid-tolerant patients ONLY www.fda.gov 188 94 MS Contin—Morphine Sulfate MS Contin Morphine Sulfate Controlled-Release Tablets, 15 mg, 30 mg, 60 mg, 100 mg, and 200 mg Dosing Interval Every 8 hours or every 12 hours Titrate using a minimum of 2-day intervals Key Instructions • Do not use as first/initial opioid (see PI) • Instruct patient to swallow tablets whole - Do NOT chew, crush, or dissolve Specific Drug Interactions PGP inhibitors (eg, quinidine) may increase the absorption/exposure of morphine sulfate by approximately 2-fold Use in Opioid-Tolerant Patients Use MS Contin 100-mg and 200-mg tablet strengths in opioid-tolerant patients ONLY www.fda.gov 189 Nucynta ER—Tapentadol Nucynta ER Tapentadol Extended-Release Tablets, 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg Dosing Interval Every 12 hours • Use 50 mg every 12 hours as initial dose in opioid non-tolerant patients • Titrate by 50 mg increments using a minimum of 3-day intervals • Maximum total daily dose is 500 mg Key Instructions • Dose once daily in moderate hepatic impairment with 100 mg per day maximum • Avoid use in severe hepatic and renal impairment • Instruct patient : - Swallow tablets whole • Do not chew, crush, or dissolve - Take 1 tablet at a time and with enough water to ensure complete swallowing immediately after placing in the mouth Specific Drug Interactions • Do not use with alcoholic beverages or medications containing alcohol as may result in the rapid release and absorption of a potentially fatal dose of tapentadol • Contraindicated in patients taking MAOIs www.fda.gov 190 95 Nucynta ER—Tapentadol (cont’d) Tapentadol Extended-Release Tablets, 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg Nucynta ER Use in Opioid-Tolerant Patients No product-specific considerations Product-Specific Safety Concerns • Risk of serotonin syndrome • Angioedema Relative Potency to Other Oral Opioids • • Equipotency to oral morphine not established Studies leading to its FDA approval use a dose ratio of 5:1 of Tapentadol ER to Oxycodone CR www.fda.gov 191 Opana ER—Oxymorphone Hydrochloride Opana ER Oxymorphone Hydrochloride Extended-Release Tablets, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, and 40 mg Dosing Interval Every-12-hours dosing; some benefit from asymmetric (different dose given in AM than PM) dosing Key Instructions • Use 5 mg every 12 hours as initial dose in opioid non-tolerant patients and patients with mild hepatic impairment and renal impairment (creatinine clearance <50 mL/min) and in patients over 65 years of age • Titrate using 3-7-day intervals • Contraindicated in moderate and severe hepatic impairment Instruct patient: • Swallow tablets whole (do not chew, crush, or dissolve) • Take 1 tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth • Use with caution in patients who have difficulty swallowing or have underlying GI disorders that may predispose them to obstruction Specific Drug Interactions Do not use with alcoholic beverages or medications containing alcohol as may result in absorption of a potentially fatal dose of oxymorphone Use in OpioidTolerant Patients No product specific considerations Relative Potency to Oral Morphine Approximately 3:1 oral morphine to oxymorphone oral dose ratio www.fda.gov 192 96 OxyContin—Oxycodone Hydrochloride OxyContin Oxycodone Hydrochloride Controlled-Release Tablets, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg Dosing Interval Every 12 hours Key Instructions • • • • Specific Drug Interactions • CYP3A4 inhibitors may increase oxycodone exposure • CYP3A4 inducers may decrease oxycodone exposure Opioid-naïve patients: initiate treatment with 10 mg every 12 hours Titrate using a minimum of 1- to 2-day intervals Hepatic impairment: start with one-third to one-half usual dosage Renal impairment (creatinine clearance <60 mL/min): start with one-half usual dosage • Consider use of other analgesics in patients who have difficulty swallowing or have underlying GI disorders that may predispose them to obstruction • Instruct patient: - Swallow tablets whole • DO NOT chew, crush, or dissolve - Take 1 tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth www.fda.gov 193 OxyContin—Oxycodone Hydrochloride (cont’d) OxyContin Oxycodone Hydrochloride Controlled-Release Tablets, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg Use in Opioid-Tolerant Patients Single dose greater than 40 mg or total daily dose greater than 80 mg is for use in opioid-tolerant patients ONLY Product-Specific Safety Concerns • Choking, gagging, regurgitation, tablets stuck in the throat, difficulty swallowing the tablet • Contraindicated in patients with GI obstruction Relative Potency to Oral Morphine Approximately 2:1 oral morphine to oxycodone oral dose ratio New as of 4/16/2013 This product has abuse-deterrent properties. The tablet is more difficult to crush, break, or dissolve. It forms a viscous hydrogel and cannot be easily prepared for injection. New as of 8/13/2015 Indicated for opioid-tolerant pediatric patients 11 years and older who are already receiving and tolerate a minimum daily opioid dose of at least 20 mg oxycodone orally or its equivalent www.fda.gov 194 97 Targiniq ER—Oxycodone HCl / Naloxone HCl Targiniq ER Oxycodone Hydrochloride / Naloxone Hydrochloride Extended-Release Tablets, 10 mg/5 mg, 20 mg/10 mg, and 40 mg/20 mg Dosing Interval Every 12 hours Key Instructions • • • • Specific Drug Interactions • CYP3A4 inhibitors may increase oxycodone exposure • CYP3A4 inducers may decrease oxycodone exposure Opioid-naïve patients: initiate treatment with 10 mg/5 mg every 12 hours Titrate using a minimum of 1- to 2-day intervals Do not exceed 80 mg/40 mg total daily dose Hepatic impairment: contraindicated in moderate and severe hepatic impairment. In mild hepatic impairment, start with one-third to one-half usual dosage • Renal impairment (creatinine clearance <60 mL/min): start with one-half usual dosage • Instruct patient: - Swallow tablets whole • DO NOT chew, crush, split or dissolve as this will release oxycodone possibly resulting in fatal overdose, and naloxone, possibly resulting in withdrawal symptoms - Take 1 tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth www.fda.gov 195 Targiniq ER—Oxycodone HCl / Naloxone HCl Targiniq ER Oxycodone Hydrochloride / Naloxone Hydrochloride Extended-Release Tablets, 10 mg/5 mg, 20 mg/10 mg, and 40 mg/20 mg Use in opioid-tolerant patients Singe dose greater than 40 mg/20 mg or total daily dose of 80 mg/40 mg are for use in opioid-tolerant patients only Product-specific safety concerns • Contraindicated in moderate and severe hepatic impairment. Relative potency to oral morphine • See individual product information for conversion recommendations from prior opioid www.fda.gov 196 98 Zohydro ER—Hydrocodone Bitartrate Zohydro ER Hydrocodone Bitartrate Extended-release capsules 10 mg, 15 mg, 20 mg, 30 mg, 40 mg and 50 mg Dosing Interval Every 12 hours Key Instructions • • • • Specific Drug Interactions • CYP3A4 inhibitors may increase hydrocodone exposure • CYP3A4 inducers may decrease hydrocodone exposure Use in Opioid-Tolerant patients • Single dose greater than 40 mg or total daily dose greater than 80 mg are for use in opioid-tolerant patients only Relative Potency to Oral Morphine • Approximately 1.5:1 oral morphine to hydrocodone oral dose ratio Opioid-naïve patients: initiate treatment with 10 mg every 12 hours Titrate using 3- to 7-day intervals Renal impairment (creatinine clearance <60 mL/min): start with a low dose Instruct patient: - Swallow capsules whole • DO NOT chew, crush, or dissolve www.fda.gov 197 Post-test Q1 ? Which of the following is TRUE about Exalgo (hydromorphone HCl) Extended Release? 1. If the patient is unable to swallow Exalgo, capsule can be opened and pellets sprinkled on applesauce 2. All doses are indicated for use in opioid-tolerant patients only 3. Its relative potency to oral morphine has not been established 4. Patients should rotate site of application 198 99 ? Post-test Q2 Which of the following is TRUE about Opana ER (oxymorphone HCl) Extended Release? 1. If the patient is unable to swallow Opana ER, capsule can be opened and pellets sprinkled on applesauce 2. All doses are indicated for use in opioid-tolerant patients only 3. Its relative potency to oral morphine has not been established 4. Some patients may benefit from asymmetric dosing (different dose given in AM than in PM) 199 Questions? 20 0 100