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

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

3. 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,
2Grissinger, M. Keeping Patients Safe From Methadone Overdoses. Pharmacy and Therapeutics, 2011, 36-8,

4. 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.

5. 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, < (accessed 11 March, 2018)
4CDC. Methadone Overdose. CDC, < (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

6. Preparation, Synthesis, and Analytical Data2.
Making Methadone
Preparation, Synthesis, and Analytical Data

7. 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,
9Easton, N. Synthesis and Confirmation of the Amidone Structure. J. Am. Chem. Soc, 1947, 69,
10Barnett, C. Modification of Methadone Synthesis Process Step. US PAT, 1947, 4-084, 211.

8. 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,
9Easton, N. Synthesis and Confirmation of the Amidone Structure. J. Am. Chem. Soc, 1947, 69,
10Barnett, C. Modification of Methadone Synthesis Process Step. US PAT, 1947, 4-084, 211.

9. 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,
9Easton, N. Synthesis and Confirmation of the Amidone Structure. J. Am. Chem. Soc, 1947, 69,
10Barnett, C. Modification of Methadone Synthesis Process Step. US PAT, 1947, 4-084, 211.

10. 3. Mechanism of Methadone
Function and Performance

11. 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.

12. 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

13. 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,

14. 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

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

16. “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,

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

18. 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,

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

20. QUESTIONS