Download Inconspicuous and Miscalculated Opioid Risks

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.
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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.
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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.
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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.
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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.
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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.
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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
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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
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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
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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