Understanding Methadone: Uses, Abuses, and Innovations

Opioid Epidemic: Uses, Abuses, and Innovation: Methadone Jin Bai & Stephen Bogert

1. Introduction to Methadone Identity, Structure, and Uses & Abuses

Identity Belongs in the opioid family Belongs in the opioid family Synthetic opioid Synthetic opioid High oral bio High oral bio- -availability Opioid receptor agonist Opioid receptor agonist2 2 Long half Long half- -life life2 2 availability2 2 1Hasan, P.; Williams, J. Basic Opioid Pharmacology: An Update. British Journal of Pain, 2012 2Grissinger, M. Keeping Patients Safe From Methadone Overdoses. Pharmacy and Therapeutics, 2011 462-466 2012, 6.1, 11-16. 2011, 36-8,

Structure

Uses & Abuses Treatment of opioid addiction Treatment of opioid addiction3,4 Maintenance therapy Maintenance therapy3 3 Administered via clinics Administered via clinics3 3 Highly regulated Highly regulated4 4 Addiction occurs through negligence Addiction occurs through negligence3 3 Abuse occurs by accident Abuse occurs by accident3,4 No true dosage guidelines No true dosage guidelines5 5 3,4 3,4 3American Addiction Center. What to Know about Methadone Clinics. AAC, <www.americanaddictioncenters.org/methadone-addiction/clinic-facts> (accessed 11 March, 2018) 4CDC. Methadone Overdose. CDC, < www.cdc.gov/vitalsigns/MethadoneOverdoses> (accessed 6 March, 2018) 5Trafton, J.; Minkel, J.; Humphreys, K. Determineing Effective Methadone Dose for Individual Opioid-Dependent Patient. PLoS Medicine, 2006 2006, 3-3, e80.

2. Making Methadone Preparation, Synthesis, and Analytical Data

Na 6Schultz, E. Reaction of Aminoaklylhalides and Diphenylacetonitrile. J. Am. Chem. Soc, 1947, 69, 188. 7Brode, W. Rearrangement of the 1,2-dimethylaminochloropropanes. J. Am. Chem. Soc, 1947 8Schultz, E. The Structures of Amidone. J. Am. Chem. Soc, 1947 9Easton, N. Synthesis and Confirmation of the Amidone Structure. J. Am. Chem. Soc, 1947 10Barnett, C. Modification of Methadone Synthesis Process Step. US PAT, 1947 1947, 69, 724. 1947, 69, 2454-2459. 1947, 69, 2941-2942. 1947, 4-084, 211.

6Schultz, E. Reaction of Aminoaklylhalides and Diphenylacetonitrile. J. Am. Chem. Soc, 1947, 69, 188. 7Brode, W. Rearrangement of the 1,2-dimethylaminochloropropanes. J. Am. Chem. Soc, 1947 8Schultz, E. The Structures of Amidone. J. Am. Chem. Soc, 1947 9Easton, N. Synthesis and Confirmation of the Amidone Structure. J. Am. Chem. Soc, 1947 10Barnett, C. Modification of Methadone Synthesis Process Step. US PAT, 1947 1947, 69, 724. 1947, 69, 2454-2459. 1947, 69, 2941-2942. 1947, 4-084, 211.

C:::N aromatic C::C sp2C:H aromatic C::C sp2C:H C:N C::O 6Schultz, E. Reaction of Aminoaklylhalides and Diphenylacetonitrile. J. Am. Chem. Soc, 1947, 69, 188. 7Brode, W. Rearrangement of the 1,2-dimethylaminochloropropanes. J. Am. Chem. Soc, 1947 8Schultz, E. The Structures of Amidone. J. Am. Chem. Soc, 1947 9Easton, N. Synthesis and Confirmation of the Amidone Structure. J. Am. Chem. Soc, 1947 10Barnett, C. Modification of Methadone Synthesis Process Step. US PAT, 1947 1947, 69, 724. 1947, 69, 2454-2459. 1947, 69, 2941-2942. 1947, 4-084, 211.

3. Mechanism of Methadone Function and Performance

Functionality Competitive inhibition Competitive inhibition11 Maintenance Maintenance Eliminates highs and lows Eliminates highs and lows11 Absence of euphoria Absence of euphoria11 11 11 11 11Anderson, I.; Kearney, T. Use of Methadone. West J Med., 2000 2000, 172.1, 43-46

Performance High oral High oral- -bioavailability bioavailability Long duration Long duration High efficacy High efficacy12 12 12Marsch, L. The Efficacy of Methadone Maintenance Interventions in Reducing Illicit Opiate Use, HIV Risk Behavior and Criminality: a Meta-Analysis. SSA, 1998 1998, 93-4, 515-532.

Oral Bio-availability Onset Effect Avg. Half-life Typical Duration Codeine 70-90% 45-60m Prodrug 4-6h Pethidine 40-60% 20-40m 4h 2-4h Morphine 30-40% 30-45m 3h 3-4h Oxycodone 60-80% 45-60m 3.5h 4-6h Hydrocodone 60-80% 45-60m 3.5h 4-6h Hydromorphone 24% 30m 2.6h 2-3h Oxymorphone 10% 20-40m 1.3h 3-4h Levorphanol 50% 20-40m 11-16h 4-8h Methadone 80% 60-90m 22h 6-12h Fentanyl 10-15% 10-20m 3.5h 1-2h Buprenorphine 10-15% 60m 36h 4-12h Tramadol 70% 60-90m 6.5h 4-6h Tapentadol 30-40% 30-45m 4.5h 2-4h

4. The Good & Bad of Methadone Merits and Deficiencies of Methadone

Prevent[ing] opiate withdrawal symptoms and minimizing the craving 11 Prevent any appearance of euphoria 11 There was a gradual onset of action of orally administered methadone 13 11Anderson, I.; Kearney, T. Use of Methadone. West J Med., 2000, 172.1, 43-46 13Institute of Medicine. Federal Regulation of Methadone Treatment. NAP, 1995 1995, 1, 1-112.

High addiction rate3 Negligence leads to addiction3 Lack of euphoria11 3American Addiction Center. What to Know about Methadone Clinics. AAC, <www.americanaddictioncenters.org/methadone- addiction/clinic-facts> (accessed 11 March, 2018) 11Anderson, I.; Kearney, T. Use of Methadone. West J Med., 2000 172.1, 43-46 2000,

Buprenorphine: An alternative? Better half-life and duration14 Poorer performance14 Clear-headed feeling14 Higher cost14 Not orally available14 14Whelan, P.; Remski, K. Buprenorphine vs Methadone Treatment: A Review of Evidence in Both Developed and Developing Worlds. J Neurosci Rural Pract, 2012 2012, 3-1, 45-50.

Summary Used in treatment of opioid Used in treatment of opioid addiction addiction Effective receptor agonist and Effective receptor agonist and competitive inhibitor competitive inhibitor High duration and efficacy High duration and efficacy Produces no euphoria Produces no euphoria High addiction rate High addiction rate

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