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Inconspicuous and Miscalculated Opioid Risks Plus Updates on Rescheduling Hydrocodone Jeffrey Fudin, B.S., Pharm.D., FCCP Diplomate, American Academy of Pain Management Adjunct Associate Professor of Pharmacy Practice, Albany College of Pharmacy & Health Sciences Adjunct Assistant Professor of Pharmacy Practice, UCONN College of Pharmacy Clinical Pharmacy Specialist in Pain Mgmt & PGY2 Residency Director, Stratton VA Albany NY Website: www.paindr.com Presented: May 2, 2014 at the New York State Council of Health-system Pharmacists Annual Assembly Saratoga NY Learning Objectives 1. Describe recent changes to NYS Regulation regarding rescheduling hydrocodone, including expectations, potential pitfalls, and current outcomes. 2. Differentiate among the various chemical classes of opioids. 3. Identify the various Cytochrome P450 iso-enzymes that affect metabolism of commonly prescribed opioid analgesic therapy. 4. Understand the usefulness and pitfalls of serum and UDS analysis with respect to opioids. 5. Recognize important drug interactions resulting from P450 metabolic and p-gylcoprotein absorption pharmacokinetics. Suggested Readings 1. Crana S, Fudin J. Drug Interactions Among HIV Patients Receiving Concurrent Antiretroviral and Pain Therapy. Practical Pain Management 2011 October:105-118,120-124. 2. Fudin J, Fontenelle DV, Payne A. Rifampin Reduces Oral Morphine Absorption; A Case of Transdermal Buprenorphine Selection Based on Morphine Pharmacokinetics. Journal of Pain & Palliative Care Pharmacotherapy. 2012;26:362–367. 3. Debboli A. ISTOP: Progress in NYS, Opioid Abuse & Diversion. (Available on paindr.com at http://paindr.com/istop-progress-in-nys-opioid-abuse-diversion/) 4. Fudin J, Atkinson TJ. Opioid Prescribing Level Off, but is Less Really More? Pain Medicine. January 2014. 2014; 15: 184–187. 5. Fudin J, Marcoux MD, Fudin JA. Mathematical Model For Methadone Conversion Examined. Practical Pain Management. Sept. 2012. 46-51. 6. Hammett-Stabler CA, Webster LR. A Clinical Guide to Urine Drug Testing. An educational activity designed for primary care physicians, family physicians, and pain physicians. 7. Leavitt SB, Reisfield GM. Introducing “Understanding UDT in Pain Care”. Blog post on Paintopics.org. August 27, 2012. 3/22/2014 Disclosures Inconspicuous and Miscalculated Risks of Opioid Therapy Jeffrey Fudin, B.S., Pharm.D., FCCP Diplomate, American Academy of Pain Management Clinical Pharmacy Specialist & PGY2 Pain Residency Director Stratton VA Medical Center Adjunct Affiliations: UCONN School of Pharmacy, SUNY/University at Buffalo, Western New England University Speakers Bureau for Millennium Laboratories, Inc. Author, Opioid Conversion Calculator in collaboration with Practical Pain Management paindr.com Practice Pearls to Mitigate Opioid Risks Underappreciated drug interactions risks Dose conversion disasters Equivalent dose of morphine • Is it possible to determine? • How do drug interactions affect equivalency? Multiple Barriers Exist to Opioid Utilization Communication between HCP and patient3 HCP Factors Patient Factors Fear of addiction4 and side effects3 Fear of disciplinary action or prosecution1,2 Opioid Barriers Concern about potential for abuse2 Socioeconomic and psychological factors3 What can I do to mitigate risks? • Education and Slow Titration • Understanding the UDS versus Serum Analysis Poor patient knowledge3 Inadequate training3 Reimbursement issues3 HCP=healthcare professional. 1. Richard J, Reidenberg MM. J Pain Symptom Manag. 2005;29(2):206‐212. 2. Gilson AM, et al. J Pain. 2007;8(9):682‐691. 3. Glachen M. J Am Board Fam Pract. 2001;14(3):211‐218. 4. McCracken LM, et al. J Pain. 2006;7(10):726‐734. Highly Prescribed Products Compared With Opioid Products Commonly Prescribed in the US The Opioid Pendulum Atorvastatin Highly Prescribed Products in US Amoxicillin Hydrocodone/Combo Oxycodone/Combo Avoidance Even dying people at risk of addiction Balance Risk stratification and principles of addiction medicine applied to opioid prescribing regardless of the pain problem at hand Widespread Use Opiophobia must go Tramadol/Combo Codeine/Combo Oxycodone Fentanyl Morphine Hydromorphone With permission from Dr. Steven Passik 0 20 40 60 80 100 Number of Prescriptions (in Millions) 120 IMS NPA+, 2006. 1 3/22/2014 Pain Relievers Obtained for Nonmedical Use: Sources Reported by Users* 70 60 59.8 Percent 50 40 30 16.8 20 10 0 4.3 Friend/Relative One Doctor Dealer/Stranger 0.8 Internet *Source of drugs for the most recent nonmedical use of pain relievers reported by persons aged 12 or older in the United States 2005. Current Events January 25, 2013 • FDA advisory panel voted 19/10 recommending to the FDA commissioner to reschedule hydrocodone combinations to C‐II status 1 February 23, 2013 • NYS officially rescheduled hydrocodone to CII February 7‐8, 2013 • FDA held a public hearing on the “Impact of Approved Drug Labeling on Chronic Opioid Therapy.”2 • The purpose? (Next Slide) 1. American Academy of Pain Medicine. FDA Panel Votes to Up‐Schedule Vicodin: Tighter Controls. http://www.magnetmail.net/actions/email_web_version.cfm?recipient_id=579797123&message_ i d =2474 4 5 6 & u s e r_ i d = A A PM& g r o u p _id=864439&jobid=12800979. Accessed February 21, 2013. 2. FDA. U.S. Food and Drug Administration. FDA: Impact of Approved Drug Labeling on Chronic Opioid Therapy. Part 15 Public Hearing. February 7‐8, 2013. http://www.tvworldwide.com/events/fda/130207/default. cfm. Accessed February 21, 2013. SAMHSA. Results From the 2005 National Survey on Drug Use and Health. DHHS Publication No. SMA 06-4194, 2006. Citizen’s Petition (from PROP) The petition requested 3 labeling changes by the FDA 1) Strike the term “moderate” from the indication of opioids for noncancer pain • Leaving “severe pain” as the only indication 2) MDD daily opioid dose, equivalent to 100mg of morphine for noncancer pain 3) Add a maximum duration of 90 days for continuous (daily) opioid use for noncancer pain. 2 3/22/2014 Metabolic Pathway for RX Elimination Pharmacokinetic and Therapeutic Considerations Volles DF, McGory R. Pharmacokinetc considerations, 15:5:Jan 1999. Select Opioid Analgesic Choices Opioid Analgesic P‐Kinetics • Extended Release Products: Agent Time to Peak (hr) Half-life (hr) Analgesic Onset (min) Analgesic Duration (hr) Morphine (IM) 0.5-1 2 10-20 3-5 Hydromorphone (IM) 0.5-1 2-3 10-20 3-5 Levorphanol (PO) 0.5-1 12-16 10-20 5-8 Hydrocodone (PO) 1 4 30-60 4-6 Codeine (IM) 0.5-1 3 10-20 4-6 Oxycodone (PO) 0.5-1 2-3 30-60 4-6 Meperidine (IM) 0.5-1 3-4 10-20 2-5 Fentanyl (IM) 10-20 3-4 7-15 1-2 Methadone (IM) 0.5-1 15-30 10-20 <8 (chronic) Rx EXAMPLES > MORPHINE PENTAZOCINE morphine pentazocine codeine diphenoxylate hydrocodone* loperamide hydromorphone* levorphanol* oxycodone* oxymorphone* buprenorphine* nalbuphine butorphanol* naloxone* heroin (diacetyl-morphine) PROBABLE POSSIBLE PHENYLPIPERIDINES DIPHENYLHEPTANES MEPERIDINE meperidine fentanyl sufentanil alfentanil remifentanil METHADONE methadone propoxyphene See handout for tapentadol & tramadol X-SENSITIVITY > LOW RISK • Long Biological T1/2 & intermediate analgesic T1/2 • Levorphanol • Methadone Opioid Rotation Chemical Classes of Opioids BENZOMORPHANS Buprenorphine Transdermal Patch Transdermal Fentanyl Patch Hydromorphone‐ER Morphine‐ER (several products available) Oxycodone‐ER Oxymorphone‐ER Hydrocodone‐ER (Zohydro,® HydroContin®) • Synthetic Atypical: Combined data from: Reisine T, Paternak G 1995 and Pasero C, Portenoy RK, McCaffery M. 1999 PHENANTHRENES • • • • • • • LOW RISK *These agents lack the 6-OH group of morphine, possibly decreasing cross-sensitivity within the phenanthrene group. Reisine T, Pasternak G. Opioid analgesics and antagonists. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill Companies; 1996:521-555. Willette RE. Analgesic Agents. In: Delgado JN, Remers WA, eds. Wilson and Grisvold’s Textbook of Organic Medicinal Chemistry. 9th ed. JB Lippincott Company, Philadelphia, Pa. 1991:629-654. Courtesy of Dr. J. Fudin 2003 • Switching a chronic pain patient from one opioid to another • Reported to provide more effective analgesia • Interpatient variability of response • Incomplete cross‐tolerance • Indications for opioid rotation • Poorly controlled pain with inability to increase dose due to side effects • Adverse event or toxicity with current opioid • Rapid development of tolerance • Development of opioid hyperalgesia Mercadante S. Cancer. 1999;86:1856-1866. 3 3/22/2014 Available Online Opioid Conversion Calculators Morphine 100mg equivalent? • “Recent evidence suggests that the use of dose conversion ratios published in equianalgesic tables may lead to fatal or near‐fatal opioid overdoses.”1 • What source(s) do you reply upon to convert doses? A. B. C. D. E. Package inserts Primary Literature Textbooks Websites Online Opioid Calculators • • • • • • • • WA State Agency Med Calc Pain Research Pain Physicians Hopkins Palliative Care Global RPh Practical Pain Management (PPM) 1. Webster L, Fine P. Review and Critique of Opioid Rotation. Pain Medicine 2012; 13: 562‐570. Shaw/Fudin 2012 (+/‐) % Variation (Compared to Manual Calculation) FENTANYL METHADONE New Opioid Calculator RISKS: Overdose & Death +242% +100% 0% http://opioidcalculator. practicalpainmanagem ent.com/ RISKS: ‐33% Underdose & Withdrawal ‐55% Kathryn Shaw, Pharm.D. Presented at Eastern States Residency Conference, May 2012. VARIOUS OPIOIDS Variability in Opioid Equivalence Survey Sept 13 thru Nov 4, 2013, 362 Respondents RPhs, MD/DOs, NPs, PAs Convert to Daily MEQ: • Hydrocodone 80mg; Fentanyl 75mcg/hr; Methadone 40mg; Oxycodone 120mg; Hydromorphone 48mg Rennick A, Atkinson T, Cimino N, McPherson ML, Fudin J. Variability in Opioid Equivalence. (Poster: 9‐236). American Society of Health‐System Pharmacists (ASHP) 2013 Midyear Clinical Meeting and Exhibition in Orlando FL. What do you think were the most outrageous conversions? Rennick A, Atkinson T, Cimino N, McPherson ML, Fudin J. Variability in Opioid Equivalence. (Poster: 9‐236). American Society of Health‐System Pharmacists (ASHP) 2013 Midyear Clinical Meeting and Exhibition in Orlando FL. 4 3/22/2014 Methadone Statistics, CDC 2012 • 2% of prescriptions for opioid analgesics are for methadone • Methadone accounts for nearly 1 in 3 prescription opioid overdose deaths in the U.S., 6X times the number in 2009 http://www.cdc.gov/features/vitalsigns/methadoneoverdoses/ Serum Fentanyl Concentrations Following Multiple Applications of DURAGESIC® 100mcg/h (n=10) Transdermal Fentanyl Conversion • Conversion suggested in • Donner & Colleagues, manufacturer’s package Breibart & Colleagues, insert: American Academy of Hospice & Palliative Medicine suggested conversion: Duragesic (Fentanyl Transdermal System) Prescribing Information. Available at http://www.duragesic.com/duragesic/shared/pi/duragesic.pdf#zoom=100. Accessed July 27, 2008. Donner B, et al. Direct conversion from oral morphine to transdermal fentanyl: a multicenter study in patients with cancer pain. Pain. 1996;64:527–534.28 Breitbart W, Chandler S, Eagel B, et al. An alternative algorithm for dosing transdermal fentanyl for cancer-related pain. Oncology. 2000;14:695–705. Methadone Conversion Study • Ripamonti, et al 1998 • Cross‐sectional • Morphine to methadone • 38 patients • Dose Ranges Morphine (mg) Morphine to Methadone Ratio 30‐90 3.70 to 1 91‐300 7.75 to 1 301 and higher 12.25 to 1 J Clin Oncol 1998;16:3216-3221 Fudin J, Marcoux MD, Fudin JA. Mathematical Model For Methadone Conversion Examined. Practical Pain Management. Sept. 2012. 46-51. 5 3/22/2014 Fudin J, Marcoux MD, Fudin JA. Mathematical Model For Methadone Conversion Examined. Practical Pain Management. Sept. 2012. 46-51. Sample Urine Drug Screen Cutoff Levels Methadone (mg) Equianalgesic Dose of Morphine to Methadone Screen Cutoff (ng/mL) Amphetamine 1000 Barbiturate 200 Benzodiazepine 200 Cocaine 300 300mg Morphine = 60mg Methadone Opiates 2000 / 300 (Lab Dependent) 302.5mg Morphine = 30mg Methadone Cannabinoids 50 Methadone 300 PCP (phencyclidine) 25 Morphine (mg) 33 Case 1 (Monitoring!) Case #1 Questions • A 42 year old man with documented chronic back pain post‐surgery for back x 2 is receiving • MSContin® 100mg PO TID MDD= • MSContin® 60mg PO BID 600mg • Morphine sulfate 30mg IR PO Q4H PRN • For 10 years, the patient fills the prescriptions regularly. • AWP vs. ASP? } A. Morphine 600mg PO per day is too high B. There is never maximum dose of morphine C. MDD is based on monitoring by prescriber and ability to tolerate RX D. If 600mg per day is required, it would be best to switch to a different opioid 6 3/22/2014 UDS vs. Serum Chemical Adulterants HOUSEHOLD PRODUCTS A.What will a UDS tell us? B. What will a serum tell us? C. When should a serum be ordered? D.When is the cost justified? Adulterant Drug Test Affected Chlorine Bleach Marijuana, Morphine, Amphetamine Liquid Drain Cleaner Morphine, Amphetamine Vinegar Amphetamine PROMOTIONAL PRODUCTS Adulterant Drug Test Affected Pyridinium Chlorochromate Amphetamine, Cocaine, Morphine (PCC) Marijuana, Phencyclidine UR’n Kleen All of the above except Amphetamine American Clinical Laboratory, 21(1):37‐39, 2002. Instant Clean and Stealth Marijuana, Phencyclidine, Cocaine Slide adopted from Virginia L. Ghafoor, Pharm.D. as presented at 2004 Annual ACCP Meeting. Dallas TX. Case Study: Jack o 34‐year‐old man, history of chronic trigeminal neuralgia, multiple interventional procedures and multiple medication trials with no sustained benefit o Past Medical History (PMH): otherwise negative o Current pharmacologic regimen includes: • Gabapentin (Neurontin®) • Hydromorphone ER (Exalgo®) • Hydrocodone + APAP (Vicodin®) • Venlafaxine (Effexor®) The Clean Whiz Kit (http://www.youtube.com/watch?v=91knqnsu_hU) Case Study: Jack Per published guidelines, Jack’s physician utilizes urine drug testing to monitor prescribed drug therapy, as well as monitor for illicit and non‐prescribed drug use. In‐Office Test Result Test Result LC‐MS/MS Laboratory Test Results Test Result Opiate Negative Hydromorphone Negative PCP (phencyclidine) Positive Hydrocodone Negative Gabapentin Positive Venlafaxine Positive PCP (phencyclidine) Negative www.paindr.com 7 3/22/2014 Street Value Perspective • 120 Percocet 5/325 (brand name) • $600.00 • 120 Lortab 10/500 (any brand) • $600.00 • 60 Oxycontin 80mg • $1500.00 • 120 Actiq Lollipop 200mcg • $3240.00 • Knowing when your patient is diverting drug… • PRICELESS! Case #2: Rifampin & Morphine • 51 YOWM with hx of heroin abuse • Admitted to hospital with endocarditis • RX on admission: • Oxacillin 2 g, infuse over 30 min q4h IV • Hydromorphone 2 mg/1 mL q4h PRN IV • Nystatin 500,000 units/5 mL PO TID • Gentamicin 100 mg, infuse over 30 min q8h • Warfarin 7.5 mg PO daily • Lactobaccilus 1 tab PO BID Reference: Fudin J, Fontenelle DV, Payne A. Rifampin Reduces Oral • Omeprazole 40 mg PO BID Morphine Absorption; A Case of Transdermal Buprenorphine Selection • Enoxaparin 80 mg/0.8 mL BID SQ Based on Morphine Pharmacokinetics. Journal of Pain & • Rifampin 600 mg PO daily Palliative Care Pharmacotherapy. 2012;26:362–367. http://streetrx.com/ Case #2: Rifampin & Morphine DATE PLAN PATIENT RESPONSE 7/19 Discontinue hydromorphone Initiate morphine SA 75 mg PO q8h No IV opioids under any circumstances, Clonidine 0.2 mg PO QAM and 0.1 mg PO QPM 36.9 (±15.1) ng/mL of serum free morphine for every 100 mg of morphine SR 3/10 SERUM LEVEL ORDERED Morphine SA 60 mg PO q8h Morphine sulfate 15 mg IR PO q8h PRN Morphine SA 45 mg 6 AM and 2 PM Morphine SA 60 mg q 10 PM IR coverage provided 3/10, No BT RX requested 7/24 7/30 EXPECTED = 83ng/mL ACTUAL= 19ng/mL Why is the serum morphine so low? A. Rifamipin is a potent CYP450 inducer that will lower serum morphine levels B. Rifamipin is a potent CYP450 inhibitor that will lower serum morphine levels C. Rifampin doesn’t affect CYP450 D. Morphine levels are diminished for another reason 3/10, No BT RX requested Case #2: Rifampin & Morphine A. Buprenorphine transdermal is okay based on the prescribed dose B. Based on FDA labeling, buprenorphine transdermal is contraindicated C. Based on Serum morphine of 19ng/mL, buprenorphine transdermal is plausible D. B and C above The Answer Rifampin induces the gastric p‐glycoprotein efflux pump 8 3/22/2014 Resolution Strategies Encourage the use of risk stratification tools • See painedu.org Education for all prescribers & pharmacists Slow escalation of opioid doses upon conversion Know the advantages & pitfalls of conversion schematics Pharmacists must act as ambassadors for the healthcare team and work with regulatory agencies to achieve a balance 9 Chemical Classes of Opioids PHENANTHRENES MORPHINE BENZOMORPHANS PENTAZOCINE morphine pentazocine codeine diphenoxylate hydrocodone* loperamide hydromorphone* levorphanol* oxycodone* oxymorphone* buprenorphine* nalbuphine butorphanol* naloxone* heroin (diacetyl-morphine) Rx EXAMPLES > CROSSSENSATIVITY > RISK PROBABLE POSSIBLE PHENYLPIPERIDINES DIPHENYLHEPTANES MEPERIDINE meperidine fentanyl sufentanil alfentanil remifentanil LOW RISK METHADONE methadone propoxyphene** LOW RISK *These agents lack the 6-OH group of morphine, possibly decreasing cross- sensitivity within the phenanthrene group. *No longer available on the U.S. market, propoxyphene is included because previous use history is often a predictor of a patient’s ability to tolerate methadone. ________________________________________________________________________ Tapentadol is a 3-[(1R,2R)-3-(dimethylamino)1-ethyl-2-methylpropyl]phenol monohydrochloride. Tramadol is a (±)cis-2-[(dimethylamino)methyl]-1(3-methoxyphenyl cyclohexanol hydrochloride. REFERENCES: 1. Fudin J, Levasseur DJ, Passik SD, Kirsh KL, Coleman J. Chronic pain management with opioids in patients with past or current substance abuse problems. Journal of Pharmacy Practice. 2003, 16;4:291-308. 2. Reisine T , Pasternak G. Opioid analgesics and antagonists. In Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG,eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill Companies; 1996:521-555. 3. Willette RE. Analgesic Agents. In: Wilson and Grisvold’s Textbook of Organic Medicinal Chemistry. Ninth Edition, Editors: Delgado JN, Remers WA. JB Lippincott Company, Philadelphia, PA. 1991:629-654. Courtesy of Dr. Jeffrey Fudin (http://www.paindr.com) Copyright Certificate # TXu 1-771-217 Updated January 6, 2012