Safe and Appropriate Use of Opiates

NPA Annual Conference 2017 October 18, 2017 Safe and Appropriate Use of Opiates David Wensel, DO, FAAHPM Medical Director, Midland Care DWensel@midlandcc.org Kevin T. Bain, PharmD, MPH, BCPS, BCGP, CPH, FASCP Vice President of Medication Risk Mitigation, CareKinesis KBain@carekinesis.com Robert Alesiani, PharmD, BCGP Chief Pharmacotherapy Officer, CareKinesis RAlesiani@carekinesis.com

Objectives At the end of this webinar, participants should be able to: Understand the risks associated with opiate drug therapy in the elderly population Learn and understand safe and effective pain management practices with opiates Ascertain best practice for starting and ending opiate therapy using evidence-based tools Know which medications are available for older adults, which may have pharmacogenomic implications, and how to utilize pharmacogenomic information to assure medication safety and effectiveness Access resources to guide clinicians 2

Opioid-Related Drug Interactions Epidemic The crisis of opioid addiction is a public health tragedy of enormous proportions. We need to confront it like any explosive epidemic. - Remarks by Scott Gottlieb, MD, U.S. FDA Commissioner on July 10, 2017 during the FDA s Scientific Meeting on Opioids

Opioid Epidemic The rate of death from ODs of prescription opioids in the United States more than quadrupled between 1999 and 2010, far exceeding the combined death toll from cocaine & heroin ODs 2010 Prescription opioids: 16,651 OD deaths Heroin: 3,036 OD deaths 80-90% deemed UNINTENTIONAL Volkow ND, et al. N Engl J Med. 2014;370(22):2063-6. Jones CM, et al. JAMA. 2013;309(7):657-9. 4

Opioid Epidemic e.g., hydrocodone, oxycodone 5

Opioid Epidemic Why? It is estimated that almost 80% of opioid-related overdose deaths are considered accidental or unintentional Due, in part, to DRUG INTERACTIONS SAMHSA. Available at: https://www.samhsa.gov/data/sites/default/files/nsduh-frr1-2014/nsduh-frr1-2014.pdf Rudd RA. MMWR Morb Mortal Wkly Rep. 2016;64:1378-82. 6

Case Vignette Introduction

Opioid Pain Management Case Background J.D. is an 84-year old male with post-surgical repair of spinal stenosis (L1-L2). His PMH includes chronic, non-cancer pain with comorbid depression, HTN, COPD, and Diabetes Type II. He has NKDA. Following surgery, he was started on tramadol by the pain management specialist Tramadol 50mg: Take 1 to 2 tablets every 4 to 6 hours as needed for pain 8

Opioid Pain Management Case Background During his follow-up visit with PACE (PCP) approximately a week later, it was evident that he failed to achieve an adequate response and exhibited intolerable side effects with tramadol J.D. stated that he tried tramadol 50mg for 2 days but has been taking tramadol 100mg every 4 hours while awake for the past 5 days with only a small reduction in his pain (7/10 at best) He also expressed that he has been experiencing nausea, constipation, and dizziness 9

Opioid Pain Management Case Current Medication History His PCP changes tramadol to hydrocodone/apap His current medication profile is as follows: Hydrocodone/acetaminophen 5/325 mg every 4 hours PRN pain NEW Senna-S 2 tablets daily NEW Sertraline 50 mg/day Metoprolol succinate 50 mg/day Hydrochlorothiazide 25 mg/day Unchanged Beclomethasone 80 mcg/inhalation twice daily Albuterol MDI 2 puffs every 4 hours as needed 10 To Be Continued

Opioid Pain Management How potent is Hydrocodone compared to other opioids? Look for Equianalgesic table When switching from one opioid to another, reduce dose by 25% to account for cross tolerance Always start low and go slow 11

Opioid Pain Management 12

Opioid Pain Management Need to consider how the opioid will be metabolized and excreted Opioids are primarily metabolized by CYP2D6 2 exceptions are Fentanyl and Methadone Both are highly lipophilic Need to consider medications that compete for the same enzymes 13

Opioid Pain Management The number one side effect of all Opioids is CONSTIPATION not respiratory suppression Always write a prescription for Senna when you prescribe any opioid Must think of improving peristalsis to treat constipation 14

Opioid-Related Drug Interactions Pharmacodynamic Mechanisms

Respiratory Depression & Sedation Action-related (respiratory effects) Concomitant administration with drugs that cause respiratory depression Exemplar drugs that cause respiratory depression: Benzodiazepines (e.g. Diazepam [Valium ]) In 2010, Use among of opioids overdose in patients deaths with involving conditions opioids, accompanied the pharmaceuticals by hypoxia, most often hypercapnia, also involved or decreased in these deaths respiratory were reserve benzodiazepines (30.1%; 5,017), antidepressants COPD, cor pulmonale, (13.4%; 2,239), morbid and obesity antipsychotics or neuroleptics (4.7%; 783) Jones CM, et al. JAMA. 2013;309(7):657-9. Action-related (CNS effects) Concomitant administration with drugs that cause CNS depression Exemplar drugs that cause CNS depression: Benzodiazepine receptor agonists (e.g. diazepam ([Valium ]) Tricyclic antidepressants (e.g. amitriptyline [Elavil ]) Antipsychotics / Neuroleptics (e.g. quetiapine [Seroquel ]) 16

Respiratory Depression & Sedation Things to consider when respiratory depression occurs: How long has patient been in pain? Are they finally resting and their respirations have slowed? What is their SaO2? Do they need to be placed on oxygen? If they need naltrexone, how much should be given? 17

Opioid Pain Management When starting opioids or stopping them Taper them slowly to monitor effect Withdrawal is rare with low dose opioids, but can occur If raising dose of opioids and pain is getting worse, think about hyperalgesia due to active metabolites 18

Opioid-Related Drug Interactions Pharmacokinetic Mechanisms

Opioid Metabolic Pathways 20

Opioid Metabolism Strong Moderate Weak Opioid CYP2D6 CYP3A4 CYP2B6 Codeine 5* 10 Morphine NON P450 Tramadol 50* Oxycodone 15* 30 Oxymorphone NON P450 Hydrocodone 10* 55 Hydromorphone NON P450 Fentanyl 90 Methadone 10 50 Tapentadol 25 Dihydrocodeine 25 * = Pro-drug or drug that is converted to a more active metabolite https://www.intermedrx.com/ 21

Tramadol Metabolic Pathway CYP3A4 CYP2B6 Tramadol CYP2D6 50% Hepatocyte CYP3A4 CYP2B6 M3 M2 CYP2D6 M5 CYP3A4 CYP2B6 M1 Glucuronidation M4 = responsible for the analgesic effect Gong L. Pharmacogenet Genomics. 2014;24:374-80. 22

Oxycodone Metabolic Pathway Oxycodone CYP3A4 Noroxycodone Hepatocyte CYP2D6 15% CYP2D6 Oxymorphone CYP3A4 Noroxymorphone Glucuronidation = responsible for the analgesic effect Smith HS. Mayo Clinic Proceedings. 2009;84:613-24. 23

Drug-Drug Interaction Examples 24

Opioid Pharmacokinetic Interaction Competitive Inhibition Tramadol CYP2D6 Less ACTIVE Metabolite Expected (normal) analgesic response Metoprolol CYP2D6 Metabolite Reduced analgesic response 25

Opioid Pharmacokinetic Interaction Non-Competitive Inhibition Hydrocodone CYP2D6 Less ACTIVE Metabolite Expected (normal) analgesic response Paroxetine CYP2D6 Metabolite Reduced analgesic response 26

Opioid-Related Drug Interactions Pharmacogenomic (PGx) Mechanisms

How genetic variations affect drug disposition & response Impact of Genetic Variations Drug-Gene Interactions 28

Phenoconversion Competitive Inhibition Drug X CYP2D6 Metabolite Drug D CYP2D6 Metabolite 29

Phenoconversion Non-Competitive Inhibition Drug X CYP2D6 Less Active Metabolite Paroxetine Patients treated with both Paroxetine and Drug X may be phenoconverted into a poor metabolizer of Drug X. *1 *1 = Poor Normal Metabolizer (PM) (NM) 30

Phenoconversion Induction Drug X Rifampin CYP3A4 More Active Metabolite Remember: CYP2D6 is not inducible But the effect of CYP3A4 inducers Patients on treated opioid with metabolism both Rifampin is a different and Drug story. CYP3A4 inducers, such as rifampin, X may be can phenoconverted substantially increase into an ultra-rapid the proportion of opioid (e.g., codeine) that is converted metabolizer to inactive/less of Drug active X. metabolite (e.g., norcodeine) at the expense of conversion to active/more active metabolite (e.g., morphine), resulting in insufficient response (i.e., analgesia). *1 *1 = Ultra-rapid Normal Metabolizer (NM) (UM) Caraco Y. J Pharmacol Exp Ther. 1997;281:330-6. 31

Drug-Gene Interaction Examples Clinical Relevance Citations: Poulsen L. Eur J Clin Pharmacol. 1996;51:289-95. Gasche Y. N Engl J Med. 2004;351:2827-31. Ciszkowski C. N Engl J Med. 2009;361:827-8. Argoff CE. Clin J Pain. 2010;26:S16-S20. 32 Lurcott G. Anesth Prog. 1998;45:154-6.

Opioids Opioid CYP2D6 CYP3A4 CYP2B6 Codeine 5%* 10% Morphine NON P450 Tramadol 50% 10% 10% Oxycodone 15%* 30% Oxymorphone NON P450 Hydrocodone 10%* 55% Hydromorphone NON P450 Fentanyl 90% Methadone 10% 50% Tapentadol 25% Dihydrocodeine 25% * = Pro-drug or drug that is converted to a more active metabolite https://www.intermedrx.com/ 33

Oxycodone Response Normal Response Oxycodone CYP2D6 Oxymorphone CYP2D6 *1/*1 Normal Metabolizer (NM) 35

Oxycodone Response Reduced Response Oxycodone CYP2D6 Oxymorphone CYP2D6 *4/*4 Poor Metabolizer (PM) A CYP2D6 poor metabolizer clears CYP2D6 substrates (e.g., opioids) slowly and, therefore, has greater than expected exposure to the parent drug & lower than expected exposure to active metabolites Giving oxycodone to patients without CYP2D6 activity is like giving a placebo 36

Oxycodone Response Enhanced Response Oxycodone CYP2D6 CYP2D6 CYP2D6 CYP2D6 CYP2D6 CYP2D6 Oxymorphone CYP2D6 *1/*1x2 Ultra-rapid Metabolizer (UM) 37

Oxycodone Response Altered Response Phenoconversion CYP2D6 *1/*1 Normal Metabolizer (NM) Oxycodone CYP2D6 Oxymorphone Bupropion CYP2D6 behaves like an Intermediate Metabolizer (IM) or Poor Metabolizer (PM) This can be mitigated by giving Oxycodone 2-4 hours prior to Bupropion 38

Oxycodone Response Altered Response Phenoconversion CYP2D6 *1/*1 Normal Metabolizer (NM) Oxycodone CYP2D6 Oxymorphone Amiodarone CYP2D6 behaves like Poor Metabolizer (PM) This can NOT be mitigated by changing time of administration 39

Case Vignette Revisited

Opioid Pain Management Case Explained Tramadol 41

Opioid Pain Management Case Continued Following his PCP visit, J.D. begins taking the hydrocodone/acetaminophen as prescribed After several days, he calls his PCP to report that this pain medication does not seem to be helping much more than the tramadol His PCP writes a new prescription for hydrocodone/acetaminophen 10/325 mg every 4 to 6 hours PRN pain What should we expect? 42

Opioid Pain Management Case Explained Hydrocodone What happens next? 43

Opioid Pain Management Case Scenario 1 J.D. continues taking the hydrocodone/acetaminophen 10/325 mg as prescribed, with mild to modest analgesic response Takes 1 tablet 4-5 times per day Best 4-5/10 pain score on Likert scale Most improvement at night After several days, he calls his PCP to report that his analgesic response, and reports that his nausea & constipation is mitigated & his dizziness has improved Unsuspecting of a drug-drug interaction, his PCP orders a PGx test to determine his CYP2D6 genotype-phenotype status His result comes back as follows: CYP2D6*1/*1 normal metabolizer (NM) What should we expect? 44

Opioid Pain Management Case Explained Hydrocodone What happens next? 45

Opioid Pain Management Case Scenario 2 Unimpressed with the PGx test result, about a week later, the PCP decides to change J.D. from hydrocodone/acetaminophen to oxycodone Oxycodone extended-release 10 mg twice daily (every 12 hours) Oxycodone immediate-release 5 mg every 4 to 6 hours PRN breakthrough pain The PCP also adds pregabalin for potential nerve pain Pregabalin 50 mg at bedtime x 3 days then 50 mg twice daily J.D. begins taking his new prescriptions the following day What should we expect? 46

Opioid Pain Management Case Explained Oxycodone To Be Continued 47

Case Vignette Applied Mitigating Strategies

Opioid Pain Management Case Scenario 3 A week and a half later, J.D. calls his PCP to report that his pain control is relatively unchanged & that he tried taking the pregabalin twice daily but could not tolerate it because of fogginess & daytime sleepiness After consulting with the pharmacist that rotates in his practice, the PCP recognizes that J.D. is suffering from multiple drug interactions Oxycodone & pregabalin sedation Oxycodone & metoprolol competitive inhibition & phenoconversion He also realizes that J.D. has become physically & possibly psychologically addicted to opioids The PCP decides to stop the pregabalin and switch the metoprolol to atenolol Atenolol 50 mg/day What should we expect? 49

Opioid Pain Management Case Explained Oxycodone To Be Continued 50

Opioid Pain Management Case Scenario 4 Several days after changing from metoprolol to atenolol, J.D. s wife calls 9-11 She found J.D. slumped over in his chair and difficult to arouse J.D. is brought to the emergency department for urgent care What could have been done differently? 51

Opioid Pain Management Case Scenario 4 (cont.) What could have been done differently? When changing to atenolol, the PCP should have reduced the oxycodone dosage Why? J.D. was not fully metabolizing the previous opioids and, therefore, the concentrations were lower than expected However, when the competitive inhibition was mitigated, the opioid concentrations rose, and this occurred over several days (due to relatively high bioavailability of oxycodone) 52

Opioid Pain Management Case Scenario 4 (cont.) What could have been done differently? Instead of changing metoprolol to atenolol, the PCP could have changed the oxycodone to morphine or oxymorphone Why? These opioids do not undergo metabolism by the CYP2D6 isoenzyme In doing so, still, the estimated conversion should be significantly reduced (50-75%) to account for incomplete cross-tolerance (i.e., treat J.D. like he is opioid naïve) 53

Improving Opioid Prescribing Treatment of Opioid-Use Disorder (OUD) A psychiatric diagnosis that involves use despite negative consequences and/or loss of control over use, compulsion, and cravings

Schuckit MA. N Engl J Med. 2016;375(16):1596-97. Diagnostic and Statistical Manual of Mental Disorders, 5 th edition. Opioid-Use Disorder At a Glance Defined as the repeated occurrence within a 12-month period of 2 or more of 11 problems (see table) Diagnostic Criteria for an Opioid-Use Disorder * * If two or three items cluster together in the same 12 months, the disorder is mild; if four or five items cluster, the disorder is moderate; and if six or more items cluster, the disorder is severe. If the opioid is taken only as prescribed, this item does not count toward a diagnosis of an opioid-use disorder.

Tapering & Discontinuing Short-Term Risks What are the risks associated with tapering? Physical symptoms, psychological symptoms, and [generalized] pain Opioid Withdrawal Syndrome Characterized by signs & symptoms of sympathetic stimulation, due to decreased sympathetic antagonism by opioids, including: Anxiety, restlessness, diaphoresis, hot flashes, tremor, shivering Hypertension, tachycardia, dizziness Abdominal cramps, diarrhea, anorexia, nausea Mydriasis, lacrimation, rhinorrhea, sneezing, Insomnia, yawning Piloerection, myalgia or arthralgia 56 Berna C, et al. Mayo Clin Proc. 2015;90(6):828-42.

Tapering & Discontinuing Short-Term Risks Opioid Withdrawal Syndrome Symptoms start 2 to 3 half-lives after the last dose of opioid Most opioids (e.g., morphine, oxycodone) Half-life of 3-4 hours Symptoms start after 6-12 hours Symptoms peak at approximately 48-72 hours Symptoms resolve within 7-14 days Variability depends on specific dose, formulation, duration of use, and speed of taper Secondary abstinence syndrome can last up to 6 months (possibly longer) Craving for opioids, poor tolerance to stress, decreased well-being, general malaise, and fatigue 57 Berna C, et al. Mayo Clin Proc. 2015;90(6):828-42.

Tapering & Discontinuing Short-Term Risks Opioid Withdrawal Syndrome Tools allow clinicians to measure withdrawal symptoms Subjective Opiate Withdrawal Scale (SOWS) Subjective patient-rated assessment Clinical Opiate Withdrawal Scale (COWS) Objective clinician assessment Berna C, et al. Mayo Clin Proc. 2015;90(6):828-42. Handelsman L, et al. Am J Drug Alcohol Abuse. 1987;13(3):293-308. Wesson DR, et al. J Psychoactive Drugs. 2003;35(2):253-9. 58

Tapering & Discontinuing Short-Term Risks Opportunity to reduce patients fear Rebound (Increased) Pain According to studies of long-term opioid therapy tapers, overall, patients report improvements in function without associated worsening in pain or even decreased pain levels Rebound pain following opioid taper & discontinuation appears to be a brief, time-limited phenomenon Studies indicate that hyperalgesia may appear immediately after discontinuation of long-term opioid therapy Similarly, hyperalgesia has been described postoperatively, when the use of short-acting opioids is abruptly discontinued at the end of surgery 59 Berna C, et al. Mayo Clin Proc. 2015;90(6):828-42.

Tapering & Discontinuing Short-Term Risks Opportunity to reduce patients fear Dropout There is legitimate concern for the following: A patient will refuse to taper or discontinue opioids; or A patient will resume long-term opioid treatment, often with a different prescriber; and/or A patient will display aggressive behavior Dropout more commonly occurs when there is no plan In other words, patients without an opioid maintenance treatment option, in case of taper failure or following discontinuation, are more likely to quit Berna C, et al. Mayo Clin Proc. 2015;90(6):828-42. 60

Tapering & Discontinuing Long-Term Risks What are the risks associated with tapering? Relapse Ultimately, the goal is to maintain reduced opioid consumption or abstinence Relapse after a full opioid taper is influenced or predicted by: Higher pain scores at initiation & conclusion of taper Conversely, low pain scores at the end of an opioid taper is predictive of long-term abstinence from opioids Depressive symptoms at initiation of tapering It may also be influenced by the speed of opioid taper & coping strategies of the patient Berna C, et al. Mayo Clin Proc. 2015;90(6):828-42. Heiwe S, et al. Eur J Pain. 2011;15(9):966-70. 61

Tapering & Discontinuing Managing Risks How can the risks associated with tapering be managed? Preventing Taper Failure (Dropout & Relapse) Appropriate management of depression Non-pharmacologic (psychological) & pharmacologic therapies Psychological support Coping strategies SUD treatment Optimizing pain management Cognitive behavioral therapy (CBT) Physical therapy Other non-pharmacologic therapies (e.g., acupuncture, massage) Interdisciplinary approaches Non-opioid analgesics 62 Berna C, et al. Mayo Clin Proc. 2015;90(6):828-42.

Tapering & Discontinuing Managing Risks How can the risks associated with tapering be managed? Managing Withdrawal Symptoms Use of α 2 -adrenergic agonists Reduce sympathetic activity (e.g., anxiety, piloerection) Comparative studies have not found one to be superior Therefore, the choice is based on pharmacologic particularities of the different drugs Examples Clonidine 0.1-0.2 mg orally every 6 hours or transdermally once weekly Tizanidine 2 mg orally at bedtime, titrated by 2-4 mg every day up to 8 mg every 8 hours Side effects common to both include hypotension, dry mouth, & sedation Berna C, et al. Mayo Clin Proc. 2015;90(6):828-42. Gowing L, et al. Cochrane Database Syst Rev. 2014. 63

Tapering & Discontinuing Managing Risks Other Therapies Managing Withdrawal Symptoms Non-Opioid Therapies for Treatment of Opioid Withdrawal * How can the risks associated with tapering be managed? * A physical examination should be performed, and the patient should be screened for his or her willingness to participate in a rehabilitation program. Medications are administered according to symptoms; not all medications are administered to every patient. Doses are approximate. Clonidine is used on an off-label basis, and tizanidine is an alternative cited in the literature. Schuckit MA. N Engl J Med. 2016;375(16):1596-97. 64

Tapering & Discontinuing Medication-Assistance Treatment Volkow ND, et al. N Engl J Med. 2014;370(22):2063-6. SAMHSA: https://store.samhsa.gov/shin/content/sma09-4443/sma09-4443.pdf 65

Tapering & Discontinuing Medication-Assistance Treatment Treatment for Symptoms of Opioid Withdrawal * 66 Schuckit MA. N Engl J Med. 2016;375(16):1596-97.

Medication-Assistance Treatment Clinical Pearls Methadone A long-acting full µ-opioid receptor agonist that can be safely taken at the start of recovery It has a long & variable half-life (i.e., 15 to 40 hours) If initiated during withdrawal (i.e., added to opioid therapy during taper), need to be vigilant about dosing Risk for respiratory depression and/or sedation Pharmacodynamic drug interaction Risk of OD if the dose is increased too quickly A baseline ECG should be obtained before prescribing Risk of QT interval prolongation, especially at doses > 100 mg/day and/or Also keep in mind DRUG INTERACTIONS Berna C, et al. Mayo Clin Proc. 2015;90(6):828-42. 67 Volkow ND, et al. N Engl J Med. 2014;370(22):2063-6.

Medication-Assistance Treatment Clinical Pearls Buprenorphine +/- naloxone Pharmacokinetic drug interaction A µ-opioid receptor partial agonist Competitively antagonizes concomitantly administered full opioid agonists Introduced to patients in mild to moderate withdrawal because adding buprenorphine to a full opioid agonist can precipitate withdrawal Initiate 12-18 hours after last short-acting opioid; 48 hours after long-acting Naloxone becomes available only if the medication is dissolved & injected, blocking the effect of buprenorphine In which case, the withdrawal symptoms can be sudden & severe Berna C, et al. Mayo Clin Proc. 2015;90(6):828-42. 68 Volkow ND, et al. N Engl J Med. 2014;370(22):2063-6.

Medication-Assistance Treatment Clinical Pearls Naltrexone A µ-opioid receptor antagonist Blocks opioid effects helps maintain abstinence Cannot be taken until opioids are completely out of the body, usually 7 to 10 days after withdrawal begins / abstinence A good choice for preventing relapse because it takes away the high if the problem opioid(s) is used again Berna C, et al. Mayo Clin Proc. 2015;90(6):828-42. 69 Volkow ND, et al. N Engl J Med. 2014;370(22):2063-6.

Safe & Appropriate Use of Opiates Closing

Summary The CYP2D6 enzyme is responsible for metabolizing many commonly used opioids to more active metabolites These opioids are weak substrates and, therefore, can be competitively inhibited by moderate to strong substrates (e.g., antidepressants) This will result in reduced analgesic effect and potentially side effects Clinically, we tend to increase the opioid dosage to improve analgesic effect, which may result in opioid addiction, abuse, and/or misuse The CYP2D6 enzyme also is highly polymorphic Genetic variations and drug-gene interactions resulting in phenoconversion can significantly alter opioid response as well 71

Summary Inappropriate prescribing of opioids, entailing drug interactions, is a key upstream driver of the opioid epidemic Mitigating strategies are multifaceted and require careful consideration of the nature & extent of drug interactions involving the patient s complete drug regimen 72

Summary Efforts to address the opioid epidemic need to simultaneously reduce opioid abuse & safeguard legitimate & appropriate access to opioids Expanding access to addiction-treatment services & MATs is a crucial component of the effort to help patients recover 73