MEDICALLY ASSISTED TREATMENT IN PROBLEMATIC OPIOID USE @joelbordman Punta Cana 2018
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CFPC CoI Templates: Slide 1 Faculty/Presenter Disclosure Faculty: JOEL BORDMAN Relationships with commercial interests: Grants/Research Support: N/A Speakers Bureau/Honoraria: Purdue, Indivior, OCFP, MedPlan, ECHO Consulting Fees: OCFP, CMPA, CNO, ONA, Purdue, Indivior, Other:
CFPC CoI Templates: Slide 2 Disclosure of Commercial Support This program has received financial support from SEA COURSES in the form of Honoraria. This program has received in-kind support from Sea Courses in the form of logistical support. Potential for conflict(s) of interest: Joel Bordman has received honoraria from Purdue, Indivior [Purdue, Indivior benefits from the sale of products that will be discussed in this program: Suboxone (Buprenorphine/Naloxone), OxNeo (Oxycodone LA-resistant to crushing), HydroMorphContin (Hydormorphone LA)
CFPC CoI Templates: Slide 3 Mitigating Potential Bias Every effort will be made to remind audience of potential bias throughout the presentation
OBJECTIVES To discuss treatment options in the difficult patient To review basic principles of Methadone and Buprenorphine/Naloxone. (what the non-prescriber needs to know)
Something to ponder A 30 year old male comes to your office asking to be your patient. He says wants to be honest with you and tells you that he is on Methadone. What is your reaction?
Addiction What is the easiest way to accept your patients condition? Remind yourself its a chronic disease
Stages of Recovery Pre-contemplative Contemplative Action Maintenance? Abstinence? Relapse
Treatment of Problematic Opioid Use Continue as before or increase the opioids? Immediate cessation of opioids? Rotate to another conventional opioid? Structured opioid therapy? Taper with goal of abstinence? Medically assisted treatment (MAT) with Methadone Buprenorphine/Naloxone
Opioid Agonist Treatment Does it work? NIH 1997 - the safety & efficacy or narcotic agonist maintenance treatment have been unequivocally established. 2008: WHO Bulletin: substitution therapies such as methadone remain the most promising method of reducing drug dependence.
What is Opioid Maintenance Treatment? Social work advocacy & case management Stabilization of opiate receptor requirements OPIOID Maintenance Therapy Treatment Protocol Harm Reduction Counselling Source: Health Canada Best Practices 2002 Slide 12
Methadone maintenance reduces illicit drug use improves health status decreases transmission of HIV and Hepatitis C decreases illegal activity and incarceration increases employment decreases cost to society (cost-effective) decreases mortality
Using methadone: Physician needs exemption from Health Canada to legally prescribe (Exemption for use for pain obtained from Health Canada directly) Exemption for use for addiction overseen by CSPO Conditions: CAMH course, preceptorship, adherence to Guidelines, practice assessments
Methadone: Historical Context Invented in Germany during WWII Commercially produced for the first time by Eli- Lilly in the U.S. in 1947 Became popular in the treatment of heroin addiction in the 1960s Lost favour in the 1970s Increased interest with better understanding of pharmacology in the 1980s
Methadone- 3 mechanisms of action 1. mu and delta opioid receptor agonist Analgesia and typical opioid SE profile; may have more diaphoresis and flushing Lynch ME. Pain Res Manag 2005; 10(3):133-44. Davis MP.Support Cancer Care 2001; 9;773-83. Fishman SM.Pain Med 2002; 3:339-48.
Methadone 3 mechanisms of action 2. NMDA receptor antagonist May help to prevent or reverse opioid tolerance and hyperalgesia Theoretical advantage for neuropathic pain Lynch ME. Pain Res Manag 2005; 10(3):133-44. Davis MP.Support Cancer Care 2001; 9;773-83. Fishman SM.Pain Med 2002; 3:339-48.
Methadone 3 mechanisms of action 3. Inhibits re-uptake of norepinephrine & serotonin Evolving evidence for this mechanism-based analgesia via descending modulation in neuropathic pain Lynch ME. Pain Res Manag 2005; 10(3):133-44. Davis MP.Support Cancer Care 2001; 9;773-83. Fishman SM.Pain Med 2002; 3:339-48.
Methadone: Pharmacokinetics Administration: once per day mixed with orange juice Onset of action: Oral: 30 to 60 minutes Time to peak concentration: Oral: 2.5-4 hours Steady state: 2-10 days (generally 3-4 days) Davis M. Support Care Cancer 2001; 9:73-83. Peng P. Can J Anesth 2005; 52:513-523. Toombs J. Amer Fam Phys 2005; 7(7):1353-1358.
Methadone Pharmacology During Initial Dosing Period (0 to 1 day) A Free fraction in plasma Drug elimination B Analgesia A B Majority of drug initially sequestered to tissue binding sites Small quantity of methadone available Gannon C. Eur J Palliative Care 1997; 4:152-8.
Methadone Pharmacology At Steady State (3 5 days +) C E D Analgesia C Once the reservoir is full, subsequent doses available to plasma (leading to reduced requirement) D E Increased dose fraction for analgesia In steady state equilibrium is maintained in effect a slow-release reservoir Gannon C. Eur J Palliative Care 1997; 4:152-8.
Methadone Drug Interactions There are 2 ways to cause an effect: 1. By starting a medication which will alter the metabolism, e.g.,: Starting fluconazole or paroxetine may reduce clearance resulting in increased serum levels and sedation/toxicity Starting retonavir or dilantin may increase clearance resulting in decreased levels and may reduce analgesia or ppt withdrawal
Methadone Drug Interactions 2. By stopping a medication which will alter the metabolism, e.g.,: Stopping fluconazole or paroxetine may increase clearance resulting in decreased serum levels and reduced analgesia or withdrawal symptoms Stopping retonavir or dilantin may decrease clearance resulting in increased levels and may increase analgesia or cause sedation/toxicity
Methadone Contraindications and Cautions (1) Caution during dose titration due to dose accumulation and variable half life Significant sleep apnea, 1 severe COPD, acute asthma or other clinically relevant states of respiratory depression Combining with alcohol or other sedating drugs, especially BZD 1. Wang D. Sleep Med Review 2007 Feb;11 (1) : 35-46.
Methadone Contraindications and Cautions (2) Concurrent administration of any other drugs that might result in drug-drug interactions (e.g., antiretrovirals) Patients unable to comply with use instructions Prolonged QT (> 440 msec in males or 460 msec in females) 1. Wang D. Sleep Med Review 2007 Feb;11 (1) : 35-46.
Primary care concerns for patients on Methadone Should you treat acute pain with opioids? Should you treat chronic pain with opioids? Consider screening for endocrine abnormalities (especially testosterone) Cardiac issues (QTc, endocarditis) Sleep Apnea (CENTRAL and peripheral) DRUG INTERACTIONS
Buprenorphine / Naloxone A more recently available long acting opioid (2008) An alternative to methadone Sublingual administration Note: you will also see buprenorphine in a transdermal preparation (lower dose, transdermal patch, approved for chronic pain)
Buprenorphine/Naloxone : A Confusing Combination Buprenorphine Partial mu agonist Kappa antagonist Naloxone Mu antagonist
HOW Buprenorphine/Naloxone WORKS Buprenorphine/Naloxone Recommended: Taken as Directed by Your Doctor Under the Tongue NOT Recommended: Misused by injecting Buprenorphine Naloxone Buprenorphine Naloxone Buprenorphine/Naloxone acts like buprenorphine alone. When Buprenorphine/Naloxone is taken under the tongue, as directed, the naloxone is silent it has no effect. Buprenorphine/Naloxone acts like naloxone. Naloxone will cause withdrawal symptoms for opioid-dependent people who have heroin or methadone (full agonists) in their bodies at the time of injection.
BUPRENORPHINE: A PARTIAL µ OPIOID RECEPTOR AGONIST Partial µ opioid agonist Kappa receptor antagonist Less dopamine release Heroin, oxycodone produce maximum dopamine release Buprenorphine produces less dopamine release Heroin, Oxycodone etc (Full agonist) Buprenorphine (Partial agonist) Red balls = µ opioid receptors Yellow balls = heroin Green shapes = buprenorphine Johnson RE, et al. Drug Alcohol Depend; 2003.
BUPRENORPHINE: A PARTIAL µ OPIOID RECEPTOR AGONIST High affinity for µ receptor Can displace full agonist opioids, such as heroin Heroin, Oxycodone etc (Full agonist) Dissociates slowly from the receptors Low intrinsic activity Ceiling on agonist effects Buprenorphine (Partial agonist) Red balls = µ opioid receptors Yellow balls = heroin Green shapes = buprenorphine Johnson RE, et al. Drug Alcohol Depend; 2003.
Opioid side effects Lets think of some serious side effects of opioids.. Is constipation (OIC) the most serious side effect? What about opioid induced apnea?
BUPRENORPHINE: A SAFE CEILING Unlike full agonists, agonist effects of buprenorphine reach a ceiling 1 Less likely to cause respiratory depression in overdose Ceiling can be compromised by concomitant alcohol or other central nervous system depressants, or when buprenorphine is misused 2 1 Johnson RE, et al. Drug Alcohol Depend; 2003. 2 Suboxone Product Monograph.
PHARMACOTHERAPY PHASES IN TREATMENT Therapy divided into 4 phases Induction Stabilization Maintenance Medically supervised withdrawal
Induction Dosing Day 1 target Buprenorphine/Naloxone dose: 4 to 8 mg (now up to 12mg) 1 Administer 4 mg; monitor efficacy and adverse effects 2 Have patient wait for dose to take effect 1 to 2 hours after first dose Reassess the patient s withdrawal symptoms Administer another 2-4 mg depending on the individual patient s requirement 1. SUBOXONE Product Monograph. Scarborough, ON: Reckitt Benckiser Pharmaceuticals Limited, April 2011. 2. Doran C et al. Heroin Addict Rel Clin Probl. 2005;7(1):7-18
Who to consider starting on a lower dose? Abstinent for a significant time Codeine users Past sensitivity to buprenorphine
ACTIVITY OF BUPRENORPHINE DEPENDS ON CONDITIONS AT THE MU RECEPTOR In absence of full agonist (heroin), buprenorphine binds to receptors and causes reinforcing effect Feeling normal If full agonist (heroin) is present, buprenorphine displaces agonist and causes withdrawal symptoms Wait until patient is experiencing withdrawal symptoms to avoid precipitating withdrawal Center for Substance Abuse Treatment; DHHS; 2004.
Buprenorphine/Naloxone Sublingual Tablets Dosing Summary >24 mg/day 16 mg/day to 24 mg/day 16 mg/day 1. SUBOXONE Product Monograph. Scarborough, ON: Reckitt Benckiser Pharmaceuticals Limited, April 2011.
MAINTENANCE Goals: Prevent opioid withdrawal symptoms Suppress opioid cravings Decrease the use of self-administered opioids Address the goals of rehabilitation with each patient Duration: Months to years, up to a lifetime Suboxone Product Monograph.
LESS THAN ONCE DAILY DOSING Buprenorphine can be dispensed every other day at twice the titrated daily dose Patient stabilized on 8 mg/day can be dispensed 16 mg every other day 1 Suboxone Product Monograph..
MEDICALLY SUPERVISED TAPER No scientific evidence that medical withdrawal is effective treatment Patients are at high risk for relapse during withdrawal 1,2 If the patient and physician decide to take this approach: Ensure that the patient has immediate access to maintenance treatment at all times Monitor patients on an ongoing basis for relapse 1 Kakko J, et al. Lancet; 2003. 2 Center for Substance Abuse; DHHS, 2004. 3 Suboxone Product Monograph
MAINTENANCE PROVEN MORE SUCCESSFUL THAN WITHDRAWAL No deaths 4 deaths Kakko J, et al. Lancet; 2003.
Buprenorphine for Maintenance vs. Methadone 1 Buprenorphine Methadone Blocks opioid effects At low doses At low doses Mechanism of action Partial opioid agonist Full opioid agonist Adverse events Precipitated withdrawal Less sedating Less risk of overdose Similar to other opioids More sedating More risk of overdose Withdrawal on cessation Less severe Severe, prolonged withdrawal Onset of action 30-60 minutes 7 30-60 minutes Peak effect 1-4 hours 7 1-7.5 hours Duration of action Up to 2-3 days at high doses 7 36-48 hours Titration More rapid titration to effect Lengthy process Mode of administration Sublingual Oral Metabolism Less clinical impact on liver function; metabolism through glucuronidation 7 All metabolism in cytochrome system; therefore more clinical impact on liver function 7 Drug interactions Fewer drug interactions 7 More drug interactions 7 46
Properties of a good MAT SAFETY EASE OF INITIATION EASE OF TAPER COST STIGMA
Safety comparison Diversion: Patients who use methadone non-medically have higher hospitalization rates, greater ICU utilization rates, and considerably worse medical outcomes when compared with patients who use buprenorphine nonmedically Benzodiazepines: non-medical use of benzodiazepines with methadone is associated with higher rates of hospitalization, greater ICU utilization rates and considerably worse medical outcomes when compared to nonmedical use of benzodiazepines with buprenorphine 1.Lee S, Medical outcomes associated with nonmedical use of methadone and buprenorphine, J Emerg Med 2013 2. Lee,SC et al, 2014
More primary care thoughts Your patient wants to taper off MAT, what would you discuss with him? Is there a role in primary care for Buprenorphine therapy? Is yes, what supports would you need? Other thoughts are welcome.
Thank you! @joelbordman