(+)-Methadone - Faculty of pain medicine

METHADONE PHARMACOLOGY
Faculty of Pain Medicine: ANZCA
October 17, 2009 (Melbourne)
Andrew Somogyi
Discipline of Pharmacology (School of Medical Sciences)
Faculty of Health Sciences, Adelaide, Australia
andrew.somogyi@adelaide.edu.au

History of Methadone (1)
1920s: various opioids (eg. oxycodone) synthesised fi no
success
• too short acting-> multiple daily iv dosing; addiction
1938: Bockmuhl & Ehrhart (Physicians) - I.G. Farbenindustrie
in Hoechst-Am-Main (Germany)
- Hoechst 10820 (Amidon)
1947: methadone - clinical use as analgesic

History of Methadone (2)
• Used since mid 1960s as maintenance treatment for
opioid dependency
• Mid 1990s a revival in its use for chronic pain
management
– with limitations
• Knowledge of basic & clinical pharmacology
becomes important for its safe and effective use
• 2007: ~700 kg used in Australia

METHADONE: Chemistry
( )-6-dimethylamino-4,4-diphenylheptan-3-one
O
H N
CH 3
(R)-(-)methadone
• small molecular weight: 309 daltons
• pKa 9 (base)
• lipid soluble
CH 3
H 3
C
CH 3
N H
(S)-(+)methadone
– octanol/pH 7.4 = 126; [morphine 1; fentanyl 200]
H 3
C
* *
H 3
C
O

Methadone Receptor Binding Affinity
Opioid
Receptor
(R)-(-)-Methadone
(nM)
(S)-(+)-Methadone
(nM)
Mu 0.9 20(mor 1)
Delta 370 960 (mor 150)
Kappa 1860 1370 (mor 20)
NMDA Receptor 3000 5000 (ket 500)
NA Transporter 700 12700
5HT Transporter 149 90
I HERG 7000 2000
• 80 mg/day -> Cp ss 1000 nM-> C u p SS 200 nM
Codd et al JPET 274, 1263, 1995
Gorman et al NeuroSci Lett 223, 5, 1997
Eap et al Clin Pharmacol Ther 81,719,2007

Both Methadone Enantiomers equally
bind to TLR4
Glial activation
µ opioid
active
Hutchinson et al 2007

Methadone & Immune Effects:
Human Lymphocytes
0
Control Proliferative
response following infusion
% Baseline
proliferative response
-10
-20
-30
-40
-50
-60
* *
*
Saline Rac RM SM
*p

Methadone Therapeutic Index- Narrow :
Safety Corridor
• Dose too low
– Breakthrough pain dosage adjustment tricky
• Dose too high
– adverse effects respiratory depression
dose too high
dose too low
• Ratio: < 2
– Pharmacokinetics become important

METHADONE : Absorption &
Bioavailability
• intestine - passive diffusion- lipid soluble
• bioavailability > 80%
• time to maximum concentration 2 - 4 hours

METHADONE: Distribution
• distribution phase t 1/2 :1 - 6 hours
– tissues/organs not instantaneous equilibrium with blood
• volume of distribution: 3 - 5 L/kg (R 2 x >S)
– extensive tissue binding
– lung > liver, kidney, spleen > blood > brain
• plasma binding - 90%
– 20% unbound R, 10% unbound S
– a 1 -acid glycoprotein (ORM2A of S-AAG)
• NOT IMPORANT

Methadone: Brain Efflux by P-glycoprotein
• P-glycoprotein (P-gp): Transports drugs OUT of
tissues: gut, brain, kidney, ….
• Blood-brain barrier: P-gp effluxes
methadone- limiting CNS exposure
• Increased intensity & duration of
analgesia in P-gp knock out
mouse. 15-fold higher brain conc

METHADONE: Elimination
• Urine: < 10% as methadone
• major route of elimination is metabolism
– Major metabolite : EDDP – inactive; very low
concentrations in body
• Renal disease has minimal influence
– No dosage adjustment required
• An advantage compared to morphine
Somogyi et al Eur J Clin Pharmacol 2009

Methadone: Major Metabolism Pathway
O
H
*
N
CH 3
CH 3
CH 3
CYP3A4
CYP2B6
H
H 3
C
N C 2
H 4
CH 3
Methadone
EDDP
CYP3A4: > 200-fold intersubject variability in liver expression
CYP2B6: > 100-fold intersubject variability in liver expression
• Relative contribution 3A4/2B6: 0.9-12 (unpublished)
*

METHADONE: Pharmacokinetics (1)
• Clearance: steady-state concentration chronic dosing
– Low: 150 ml/min (large variability 30 - 2000); R=S
– determined by CYPs 3A4 and 2B6 enzymes
• Half-life: time to steady-state (5 half-lives)
– average 48 hours (large variability:10-150); R ~ 1.5x >S
• Steady state: 2 days - 30 days (average is 10 days)
– determined by Clearance and Volume of Distribution
• Why dose more frequently than once or twice daily

METHADONE: Pharmacokinetics (2)
Single vs Chronic Daily Dosing and Accumulation
• degree of accumulation is function of half-life
• t 1/2 = 15 hours
• t 1/2 = 60 hours
• t 1/2 = 90 hours
Long & unpredictable half life
1.3-fold accumulation
4.2-fold accumulation
8-fold accumulation
delayed toxicity
• Need to monitor regularly in 2 weeks following
initiation of therapy

METHADONE: Accumulation
Plasma Conc.
2.4
2.2
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
Half-life = 60 hours
Half-life = 15 hours
Respiratory Depression
Max Safe Conc
Pain Relief Conc
0
0 1 2 3 4 5 6 7 8 9 10 11
Days

Methadone Pharmacokinetics are
linear with dose
400
300
Cp SS (ng.ml -1 )
200
100
(S) - Methadone
(R) - Methadone
0
0 10 20 30 40 50 60 70
Dose (mg.day -1 )
Foster et al 2000

Methadone Pharmacokinetics:Sources
of Inter-individual Variability
• Clearance/metabolism
– CYP3A4: very large interindividual variability; R=S
• Environmental factors: age, sex, food, other drugs
– CYP2B6: large interindividual variability; S>R
• Genetic: 25% Caucasians variant nonfunctional alleles-> slow
metabolisers
• Environmental: other drugs
• Distribution
– Large tissue binding
• Factors are unknown

Drug-Methadone Interactions: Enzyme Induction
• Mainly metabolism (CYP3A4 & 2B6)
alters clearance
• Induction of metabolism:
– Carbamazepine, phenytoin
– Rifampicin, dexamethasone
– nevirapine (Heelon and Meade, 1999)
– efavirenz (Pinzami et al, 2000)
– ritonavir (Geletko and Erickson, 2000)
– St John’s Wort (Eich-Hochli et al, 2003)
i pain relief or withdrawal \ h DOSE

Drug-Methadone Interactions:
• Mainly CYP3A4
Enzyme Inhibition
• SSRIs: Fluvoxamine, fluoxetine, sertraline
• moclobemide (Hamilton et al, 2000)
• amitriptyline
• fluconazole (Cobb et al, 1998), voriconazole &
other antifungals
• ciprofloxacin (Herrlin et al, 2000)
• clarithromyicin & macrolides
sedation, confusion, respiratory depression
\ i DOSE

Methadone-Drug Interactions
• Inhibits CYP2D6 & UGT2B7
– CYP2D6: some SSRIs, TCAs, antipsychotics,
beta blockers,
– UGT2B7: mainly opioids so not an issue

Methadone and the Heart: Long QT & Torsades de
Pointes (1)[rapid polymorphic ventricular tachycardia-> syncope]
• I HERG – voltage-gated K + channel mediating the rapidly activating delayed
rectified current I Kr in heart
• S-Methadone more potent blocker of I HERG (Eap et al Clin Pharmacol
Ther 2007)
S-methadone: 2 µM R-methadone: 7 µM
• Krantz et al(2002): 17 cases QT prolongation & arrhythmias- Torsades &
sudden death; chronic pain/addiction patients on high doses (400 mg/day);
predisposing factors (hypokalaemia)

Very, Very Weak relationship between QTc and
Plasma Methadone Concentration
Pain
patients: 50
mg/day
• Prolonged QT
• Borderline
• Normal
Eap et al Clin Pharmacol Ther 81, 719, 2007

Methadone and the Heart: Long
QT & Torsades de Pointes (2)
• I HERG can be blocked by many drugs -> prolonged QT
– Amiodarone, haloperidol, clarithromycin, erythromycin,
fluconazole, voriconazole, quinine, dolasetron, TCAs, …
• Methadone-induced prolonged QT:
– doses > 80 mg/day
– predisposing factors: hypo-kalaemia, -magnesemia, CCF,
bradycardia, cirrhosis, other drugs, genetics of long QT
• Overemphasised

Role of Genetic Factors:
Metabolism & CYP2B6
• Slow 2B6 metabolisers have
higher plasma methadone
• Slow 2B6 metabolisers have
normal plasma methadone
Crettol et al CPT 78, 593, 2005
Somogyi Unpublished

Role of Genetic Factors: CNS
Distribution P-glycoprotein ABCB1
Methadone Dose (mg/day)
120
100
80
60
40
20
0
P=0.03
0 1 2
• Patients with
ABCB1 variant
alleles require lower
doses of methadone
for addiction
treatment
Number of AGCGC alleles

60
50
70%
Role of Genetic Factors: µ
Opioid Receptor OPRM1
HD MM
Control
Subject number
40
30
20
10
0
P = 0.002; c 2 = 12.43
28%
55%
31%
14% 2%
A/A A/G G/G
• Patients on high
methadone doses (> 200
mg/day) for addiction
have higher frequency of
OPRM1 allele (A118G)
A118G

Major Clinical Limitations of
Methadone Use
• Variable clearance half-life variable accumulation
• Not possible to a priori predict if patient has short or
long half life
– Population kinetics: 1-2 bloods first dose predict
individual patients PK
– Perhaps a genetic test in the future

Methadone: Opioid
Rotation/Substitution
• Increasing use of methadone for chronic pain and
cancer pain not responding to high dose opioid
(tolerance, disease progression)
• Methadone ~1/30th morphine dose (Ripamonti et al 1997)
– 100 mg morphine 3:1; 500 mg 10:1; >1000 mg 20:1
• acute pain : oral morphine & methadone equipotent
• Incomplete cross tolerance morphine methadone
• methadone: NMDA antagonist, 5-HT reuptake
inhibitor; less potent glial activator

Dose Conversion Ratios: other Opioids to Methadone
Confusion
Leppart et al Int J
Clin Pract 63, 1095,
2009

Methadone Use in Pain Treatment (1)
• Efficacy: methadone is a useful alternative to morphine for
treatment of cancer-related pain (2 nd line)
• Safety: use is complicated by long & unpredictable terminal
half-life which affects degree of accumulation on chronic
dosing
• Potency ratio to oral morphine 3-20:1
• “Pharmacokinetic studies are required in order to characterise
the sources of variation in elimination of methadone”
(Ripamonti et al., 1997)
• 1 blood at any time is all that is needed: any interest

Methadone for Cancer Pain Management
• Use limited by poor understanding of PK & dosage
regimen
• Dose interval: start with 4-6 hrly
once a day possible
8-12 hrly
• Start in the morning - easy to monitor
– Pain scores, respiratory rate, alertness/sedation
– Confused speech, disorientation, myoclonus early
signs of toxicity
Ayonrinde & Bridge Med J Aust 173: 536, 2002

Take Home Message
• Methadone a valuable & cheap addition to range of drugs
for chronic pain: IV, oral tablet & liquid
• Well tolerated by most patients
• Dose conversion from morphine tricky - guidelines
available
• Twice daily dosing
• Safe in renal/liver disease (titrate dose to effect)
• Risk of delayed toxicity (2 weeks) because of long and
unpredictable pharmacokinetics

ACKNOWLEDGEMENTS
• NHMRC
• Prof Jason White, Prof Felix Bochner, Dr
Richard Hallinan, Dr Paul Williamson
• Postdocs: David Foster, Mark Hutchinson,
Janet Coller
• PhD Student: Glynn Morrish