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 Synthetic opioid High oral bio-availability2 Opioid receptor agonist2 Long half-life2 Methadone belongs in the opioid family Synthetic which mean it is produced entirely from man-made components Methadone’s high oral bioavailability means its if effective in pill form Methadone binds and activates opioid receptors when ingested and due to its long half-life, it stays bound to the receptor much longer than other opioids. 1Hasan, P.; Williams, J. Basic Opioid Pharmacology: An Update. British Journal of Pain, 2012, 6.1, 11-16. 2Grissinger, M. Keeping Patients Safe From Methadone Overdoses. Pharmacy and Therapeutics, 2011, 36-8, 462-466

Structure Methadone and other opioids function the same so its pharmacophore (core-structure) is very similar; however, due its modification methadone achieves a higher oral availability and longer activation duration.

Uses & Abuses Treatment of opioid addiction3,4 Maintenance therapy3 Administered via clinics3 Highly regulated4 Addiction occurs through negligence3 Abuse occurs by accident3,4 No true dosage guidelines5 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, 3-3, e80. Methadone is used in methadone clinics to help treat and/or maintain opioid levels in addicts This prevents withdrawal and cravings Methadone dosage must be monitored daily and must be adjusted as methadone resistance increases Because methadone has no feeling of euphoria, there is no physical feeling that the user can acknowledge when they use too much, leading to overdose Studies have shown that the effective and ineffective methadone dosage overlap each other: therefore, the dosage of Methadone should not be determined by a static guideline but by the titration of Methadone until the addict drug abstinence is attained

Preparation, Synthesis, and Analytical Data 2. Making Methadone Preparation, Synthesis, and Analytical Data

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

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

C:::N aromatic C::C sp2 C:H aromatic C::C sp2 C: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, 69, 724. 8Schultz, E. The Structures of Amidone. J. Am. Chem. Soc, 1947, 69, 2454-2459. 9Easton, N. Synthesis and Confirmation of the Amidone Structure. J. Am. Chem. Soc, 1947, 69, 2941-2942. 10Barnett, C. Modification of Methadone Synthesis Process Step. US PAT, 1947, 4-084, 211.

3. Mechanism of Methadone Function and Performance

Agonist attached to the receptor, triggering the release of a G-coupled protein. The two subunits will then bind to both the Potassium and Calcium channels, preventing depolarization and repolarization. This depresses nerve activity, eliminating the sensation of pain from the limbs to the brain.

Functionality Competitive inhibition11 Maintenance Eliminates highs and lows11 Absence of euphoria11 Methadone functions to block off the receptor from other opioids It is also used to achieve a static opioid receptor activity and because of its long half-life, it prevents the sudden rushes of a high or the sudden crashes of a low from other opioids. 11Anderson, I.; Kearney, T. Use of Methadone. West J Med., 2000, 172.1, 43-46

Performance High oral-bioavailability Long duration High efficacy12 The high oral availability of methadone means it is ingestible as a pill which is the preferred method instead of injections or suppositories. The long duration means it will function as competitive inhibitor for a long time with high efficacy. 12Marsch, L. The Efficacy of Methadone Maintenance Interventions in Reducing Illicit Opiate Use, HIV Risk Behavior and Criminality: a Meta-Analysis. SSA, 1998, 93-4, 515-532.

Oral Bio-availability   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% 3.5h Hydrocodone Hydromorphone 24% 30m 2.6h 2-3h Oxymorphone 10% 1.3h Levorphanol 50% 11-16h 4-8h Methadone 80% 60-90m 22h 6-12h Fentanyl 10-15% 10-20m 1-2h Buprenorphine 60m 36h 4-12h Tramadol 70% 6.5h Tapentadol 4.5h Methadone’s oral availability is much higher than other drugs with a much longer duration

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

“Prevent any appearance of euphoria” 11 “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, 1, 1-112.

Negligence leads to addiction3 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

Buprenorphine: An alternative? Better half-life and duration14 Poorer performance14 Clear-headed feeling14 Higher cost14 Not orally available14 Buprenorphine had a longer duration but also has a worst performance due to it’s weaker binding affinity for the mu-receptor. This does result in a feeling of clear-headedness as opposed to methadone users Buprenorphine also has a higher cost and is injection based 14Whelan, P.; Remski, K. Buprenorphine vs Methadone Treatment: A Review of Evidence in Both Developed and Developing Worlds. J Neurosci Rural Pract, 2012, 3-1, 45-50.

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

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