Inconspicuous and Miscalculated Opioid Risks Plus Updates on Rescheduling Hydrocodone

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1 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: 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: , 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: Debboli A. ISTOP: Progress in NYS, Opioid Abuse & Diversion. (Available on paindr.com at 4. Fudin J, Atkinson TJ. Opioid Prescribing Level Off, but is Less Really More? Pain Medicine. January ; 15: Fudin J, Marcoux MD, Fudin JA. Mathematical Model For Methadone Conversion Examined. Practical Pain Management. Sept 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.

2 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 paindr.com Speakers Bureau for Millennium Laboratories, Inc. Author, Opioid Conversion Calculator in collaboration with Practical Pain Management Practice Pearls to Mitigate Opioid Risks Multiple Barriers Exist to Opioid Utilization Underappreciated drug interactions risks Dose conversion disasters Equivalent dose of morphine Is it possible to determine? How do drug interactions affect equivalency? What can I do to mitigate risks? Education and Slow Titration Understanding the UDS versus Serum Analysis HCP Factors Fear of disciplinary action or prosecution 1,2 Concern about potential for abuse 2 Inadequate training 3 HCP=healthcare professional. Communication between HCP and patient 3 Opioid Barriers Reimbursement issues 3 Patient Factors Fear of addiction 4 and side effects 3 Socioeconomic and psychological factors 3 Poor patient knowledge 3 1. Richard J, Reidenberg MM. J Pain Symptom Manag. 2005;29(2): Gilson AM, et al. J Pain. 2007;8(9): Glachen M. J Am Board Fam Pract. 2001;14(3): McCracken LM, et al. J Pain. 2006;7(10): The Opioid Pendulum Highly Prescribed Products Compared With Opioid Products Commonly Prescribed in the US Atorvastatin Amoxicillin Highly Prescribed Products in US Hydrocodone/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 With permission from Dr. Steven Passik Oxycodone/Combo Tramadol/Combo Codeine/Combo Oxycodone Fentanyl Morphine Hydromorphone Number of Prescriptions (in Millions) IMS NPA+,

3 Percent Pain Relievers Obtained for Nonmedical Use: Sources Reported by Users* Friend/Relative One Doctor Dealer/Stranger Internet *Source of drugs for the most recent nonmedical use of pain relievers reported by persons aged 12 or older in the United States SAMHSA. Results From the 2005 National Survey on Drug Use and Health. DHHS Publication No. SMA , 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. id = & u s e r_ id = A APM& g r o u p _id=864439&jobid= Accessed February 21, FDA. U.S. Food and Drug Administration. FDA: Impact of Approved Drug Labeling on Chronic Opioid Therapy. Part 15 Public Hearing. February 7 8, cfm. Accessed February 21, 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

4 Metabolic Pathway for RX Elimination Pharmacokinetic and Therapeutic Considerations Volles DF, McGory R. Pharmacokinetc considerations, 15:5:Jan Agent Opioid Analgesic P Kinetics Time to Peak (hr) Half-life (hr) Analgesic Onset (min) Analgesic Duration (hr) Morphine (IM) Hydromorphone (IM) Levorphanol (PO) Hydrocodone (PO) Codeine (IM) Oxycodone (PO) Meperidine (IM) Fentanyl (IM) Methadone (IM) <8 (chronic) Combined data from: Reisine T, Paternak G 1995 and Pasero C, Portenoy RK, McCaffery M Select Opioid Analgesic Choices Extended Release Products: Buprenorphine Transdermal Patch Transdermal Fentanyl Patch Hydromorphone ER Morphine ER (several products available) Oxycodone ER Oxymorphone ER Hydrocodone ER (Zohydro, HydroContin ) Synthetic Atypical: Long Biological T 1/2 & intermediate analgesic T 1/2 Levorphanol Methadone Chemical Classes of Opioids Opioid Rotation PHENANTHRENES BENZOMORPHANS PHENYLPIPERIDINES DIPHENYLHEPTANES MORPHINE PENTAZOCINE MEPERIDINE METHADONE Rx EXAMPLES > morphine pentazocine meperidine methadone codeine diphenoxylate fentanyl propoxyphene hydrocodone* loperamide sufentanil hydromorphone* alfentanil levorphanol* remifentanil oxycodone* oxymorphone* See handout for tapentadol & tramadol buprenorphine* nalbuphine butorphanol* naloxone* heroin (diacetyl-morphine) PROBABLE POSSIBLE X-SENSITIVITY > LOW RISK 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: 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: 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:

5 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. Package inserts B. Primary Literature C. Textbooks D. Websites E. Online Opioid Calculators Available Online Opioid Conversion 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: Shaw/Fudin 2012 (+/ ) % Variation (Compared to Manual Calculation) RISKS: Underdose & Withdrawal 55% 33% 0% FENTANYL +100% METHADONE +242% RISKS: Overdose & Death New Opioid Calculator practicalpainmanagem ent.com/ VARIOUS OPIOIDS Kathryn Shaw, Pharm.D. Presented at Eastern States Residency Conference, May 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 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. 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

6 Methadone Statistics, CDC % 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 Serum Fentanyl Concentrations Following Multiple Applications of DURAGESIC 100mcg/h (n=10) Transdermal Fentanyl Conversion Conversion suggested in manufacturer s package insert: Donner & Colleagues, Breibart & Colleagues, American Academy of Hospice & Palliative Medicine suggested conversion: Duragesic (Fentanyl Transdermal System) Prescribing Information. Available at Accessed July 27, Donner B, et al. Direct conversion from oral morphine to transdermal fentanyl: a multicenter study in patients with cancer pain. Pain. 1996;64: Breitbart W, Chandler S, Eagel B, et al. An alternative algorithm for dosing transdermal fentanyl for cancer-related pain. Oncology. 2000;14: Methadone Conversion Study Ripamonti, et al 1998 Cross sectional Morphine to methadone 38 patients Dose Ranges Morphine (mg) Morphine to Methadone Ratio to to and higher to 1 J Clin Oncol 1998;16: Fudin J, Marcoux MD, Fudin JA. Mathematical Model For Methadone Conversion Examined. Practical Pain Management. Sept

7 Fudin J, Marcoux MD, Fudin JA. Mathematical Model For Methadone Conversion Examined. Practical Pain Management. Sept Equianalgesic Dose of Morphine to Methadone Sample Urine Drug Screen Cutoff Levels Screen Cutoff (ng/ml) Methadone (mg) 300mg Morphine = 60mg Methadone 302.5mg Morphine = 30mg Methadone Amphetamine Barbiturate Benzodiazepine Cocaine Opiates Cannabinoids / 300 (Lab Dependent) 50 Methadone 300 PCP (phencyclidine) 25 Morphine (mg) 33 Case 1 (Monitoring!) A 42 year old man with documented chronic back pain post surgery for back x 2 is receiving MSContin 100mg PO TID MSContin 60mg PO BID Morphine sulfate 30mg IR PO Q4H PRN For 10 years, the patient fills the prescriptions regularly. AWP vs. ASP? } MDD= 600mg Case #1 Questions 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

8 UDS vs. Serum 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? Chemical Adulterants HOUSEHOLD PRODUCTS Adulterant Drug Test Affected Chlorine Bleach Marijuana, Morphine, Amphetamine Liquid Drain Cleaner Morphine, Amphetamine Vinegar Amphetamine PROMOTIONAL PRODUCTS Adulterant Drug Test Affected Pyridinium Chlorochromate (PCC) UR n Kleen Amphetamine, Cocaine, Morphine Marijuana, Phencyclidine All of the above except Amphetamine American Instant Clinical Clean Laboratory, and Stealth 21(1):37 39, Marijuana, Phencyclidine, Cocaine Slide adopted from Virginia L. Ghafoor, Pharm.D. as presented at 2004 Annual ACCP Meeting. Dallas TX. Case Study: Jack The Clean Whiz Kit ( o o o 34 year old man, history of chronic trigeminal neuralgia, multiple interventional procedures and multiple medication trials with no sustained benefit Past Medical History (PMH): otherwise negative Current pharmacologic regimen includes: Gabapentin (Neurontin ) Hydromorphone ER (Exalgo ) Hydrocodone + APAP (Vicodin ) Venlafaxine (Effexor ) 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 Opiate Negative PCP (phencyclidine) Positive LC MS/MS Laboratory Test Results Test Result Hydromorphone Negative Hydrocodone Negative Gabapentin Positive Venlafaxine Positive PCP (phencyclidine) Negative 7

9 Street Value Perspective 120 Percocet 5/325 (brand name) $ Lortab 10/500 (any brand) $ Oxycontin 80mg $ Actiq Lollipop 200mcg $ 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 Omeprazole 40 mg PO BID Enoxaparin 80 mg/0.8 ml BID SQ Rifampin 600 mg PO daily Reference: 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: 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 7/24 Morphine SA 60 mg PO q8h Morphine sulfate 15 mg IR PO q8h PRN 7/30 Morphine SA 45 mg 6 AM and 2 PM Morphine SA 60 mg q 10 PM IR coverage provided 3/10 SERUM LEVEL ORDERED EXPECTED = 83ng/mL ACTUAL= 19ng/mL 3/10, No BT RX requested 3/10, No BT RX requested 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 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

10 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

11 Chemical Classes of Opioids PHENANTHRENES BENZOMORPHANS PHENYLPIPERIDINES DIPHENYLHEPTANES MORPHINE PENTAZOCINE MEPERIDINE METHADONE Rx EXAMPLES > morphine pentazocine meperidine methadone codeine diphenoxylate fentanyl propoxyphene** hydrocodone* loperamide sufentanil hydromorphone* alfentanil levorphanol* remifentanil oxycodone* oxymorphone* buprenorphine* nalbuphine butorphanol* naloxone* heroin (diacetyl-morphine) CROSS- SENSATIVITY > RISK PROBABLE POSSIBLE LOW RISK 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: 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. 9 th ed. New York, NY: McGraw-Hill Companies; 1996: 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: Courtesy of Dr. Jeffrey Fudin ( Copyright Certificate # TXu Updated January 6, 2012