Transcript methadone - Canadian Hospice Palliative Care Conference

Methadone
Bernard J. Lapointe
Associate Professor, department of Oncology and
of Family Medicine
Eric M. Flanders Chair in Palliative Medicine
Potential conflict of interest
• I have not received any support from the
pharmaceutical industry in regard of the study
or the clinical use of methadone.
• I have received support from TEVA Canada for
participating to advisory boards.
• I have received support from Wex
Technologies for participating to an advisory
board.
Introduction
• Methadone is a synthetic opioid agonist
developed by a German scientist during the
second World War.
• Methadone is actually a mixture of 2
enantiomers:
– The R (Levro) methadone is the mu receptor
agonist
– The S (Dextro) methadone is stated to be the
NMDA receptor antagonist
Pharmacological properties
• Methadone has unique opioid receptor
interactions:
• It is a mu-opioid receptor agonist and it also
binds to the kappa and delta opioid receptors.
• Additional mechanisms of action include:
– inhibiting the re-uptake of serotonin and
norepinephrine
– works as an antagonist at the N-methyl-Daspartate (NMDA) receptor, thought to prevent
central sensitization and reduce/ reverse opioid
tolerance,
Methadone in Canada
• prescription of methadone for maintenance therapy
or analgesia in Canada is restricted under the
Controlled Substances and Regulations Act.
• Formulations available:
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Flavoured liquid preparation (refrigeration)
Tablets (1 mg, 5 mg, 10 mg and 25 mg)
Custom made capsules or suppositories
Injectable methadone (Synastone10 mg/ml) available
through Health Canada Special Access Program (very often
a lenghty process).
• Additional methadone delivery modes include:
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epidural,
intra-thecal,
rectal,
subcutaneous,
sublingual, rapid analgesic onset and avoidance of hepatic
first-pass metabolism and provides relief for breakthrough
cancer pain (Hagen et al., 2010)
– topical administration. The oral dose q8h and prn (often
reduced by 30%) may be compounded by an experienced
pharmacist with Lipoderm . Concentration range was 2
mg/0.2 ml to 25 mg/0.2 ml (Love and Bourgeois, 2014)
• Novel form of Methadone: Dextro-Methadone
– d-Methadone has been shown to possess NMDA
antagonist properties with virtually no opioid
activity at the expected therapeutic doses.
– Phase Two to start in 2016. clinical target:
neuropathic pain.
methadone has unique properties that
make it a little “trickier”
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Long and variable half-life
Potential drug interactions with multiple medications
Variability in equi-analgesic dose ratios
Association with prolongation of QTc (predisposes patients
to the ventricular arrhythmia torsades de pointes)
– “Proportion of methadone-associated deaths related to
arrhythmia is likely to be small relative to the proportion
related to accidental overdose, though reliable estimates
are not available” (Chou, APS)
South of the border…
• Methadone accounted for 1,7% of opioid prescriptions in
2009 and 9% in 2010.
• Since 2000, the rate of deaths from drug overdoses has
increased 137%, including a 200% increase in the rate of
overdose deaths involving opioids (opioid pain relievers and
heroin) MMWR 2016 Jan 1st
• Methadone was associated with 31% of opioid related deaths
and 40% of single drug deaths.
– MMWR 2012, 61-493-7
• In Ontario, Canada, methadone had the highest relative
percentage of deaths which were accidental (84%) when
compared with other opioids (Madadi et al., 2013)
Equi-analgesia conversion
Initiating methadone (Chou, APS)
• In opioid naïve patients or conversion from
low dose of other opioids (EDDM 40-60) do
not exceed methadone 2,5mg tid
– Dose increase no more than 5mg /day every 5-7
days.
Rotation to methadone
• Methods of Rotation From Another Strong
Opioid to Methadone for the Management of
Cancer Pain: A Systematic Review of the
Available Evidence
– Sarah McLean, MB, MAO, BCh, Feargal Twomey, MB, MRCPI.
Journal of Pain and Symptom Management, August 2015
– 3 days switch
– Rapid conversion: Stop and Go
– German model
– Outpatient titration
Recommendations AAHPM 2016
• EDDM
– 40-60mg / 24hrs 2-7,5 mg in 2-3 divided doses
– 60-200 mg /24hrs 10:1 (morphine: methadone)
– Over 200mg/24hrs 20:1
– Do not adjust dose for 5-7 days (or per clinical
judgement)
Who could benefit from methadone ?
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Patients with true morphine allergy
Patients with neuropathic pain
Opioids adverse effects with another opioid
Pain refractory to other opioids or
uncontrolled pain
• Significant renal impairment
Methadone may not be an option:
• Patients at the very end of their life (consider
as adjuvant)
• Needing drugs known to have an interaction
with methadone
• Drugs that prolong QTc interval
• Patient living alone, poor cognitive functioning
without a competent caregiver
• Prior history or suspicion of chemical coping
• Clinical instability/ liver failure
Monitoring of Methadone Initiation
and Titration:
• Check for:
– Excessive drowsiness/level of arousal
– Slowed respiration or periods of apnea, more rapid respiration,
shallow breathing
– Slurring of speech
– Loud snoring
– Pinpoint pupil size
• Since patients are not taking one large dose (as in an overdose
situation), it is important to monitor for these signs and
symptoms of toxicity over a 5–7 day period after initiation of
methadone therapy or a dosage change.
– McPHerson
• Monitor for sleep apnea.
Pharmaco-dynamic drug interactions
• Methadone and other opioids
• Increased analgesia
• Additive toxicities
• Methadone and cns depressants ( alcohol,
neuroleptics, benzos…)
• Methadone and other medications that prolong QT
interval. (antiarrhytmics, antidepressants)
– Proportion of death due to prolongation of QT in patients
receiving methadone is likely to be very low, but unknown.
Drug-drug Interactions with
Methadone
Enzyme Inducers
• The enzyme inducing medication will increase the metabolism
of methadone, resulting in a decreased methadone serum
level.
• The dose of methadone may be insufficient and the patient
can experience increased pain.
• Some of the Enzyme Inducers important to know when using
Methadone:
– Rifampicin/rifampin/rifabutin
– Phenytoin
– Spironolactone
– Nevirapine
– Amprenavir, Nelfinavir, Ritonavir
– Carbamazepine
– St. John’s Wort
Enzyme Inhibitors
• The enzyme inhibiting medication will slow the metabolism of
methadone, resulting in an increased methadone serum level.
The patient may become toxic from a methadone overdose.
• Some of the Inhibitors important to know when using
Methadone:
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Fluoxetine, Paroxetine
Sertraline
Ciprofloxacin
Fluvoxamine
Amitriptyline
Ketoconazole, Fluconazole
Erythromycin
Citalopram
Desipramine
Clarithromycin
Itraconazole
Methadone Safety Guidelines
• Methadone Safety: A Clinical Practice
Guideline From the American Pain Society and
College on Problems of Drug Dependence, in
Collaboration With the Heart Rhythm Society
– Roger Chou,* 2014, Pain
Should we monitor with ECG ?
• L-methadone blocks hERG potassium channel which results in
QTC prolongation, increasing risk of torsade de pointes.
• The American Pain Society recommends that clinicians obtain
an ECG prior to initiation of methadone in patients:
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with risk factors for QTc interval prolongation,
any prior ECG demonstrating a QTc > 450 ms,
or a history suggestive of prior ventricular arrhythmia;
An ECG within the past three months with a QTc < 450 ms in patients
without new risk factors for QTc interval prolongation can be used for
the baseline study
• An ECG higher than 500ms: no methadone
• 450-500 ms: are there other alternatives, can we change
some of the drugs contributing to QTC prolongation
Follow-up ECG recommendations
• In patients identified as a risk a follow-up ECG
should be obtained 2-4 weeks after initiation
or after significant dose increase
• Patients reaching 30-40 mg
• Patients reaching doses over 100 mg
• Signs or symptoms suggestive of arrythmia
Methadone Prescribing Rights:
• Authorized prescribers may write and sign prescriptions for
methadone.
• If a physician does not have the license to prescribe
methadone, he/she must apply for a temporary exemption to
prescribe methadone for a patient during hospital admission
• Only a staff physician is allowed to request for a temporary
exemption to prescribe methadone
• Methadone can be started for a patient while waiting for
Health Canada response
• Please note that a temporary exemption can be obtained
ONLY for a patient on methadone PRIOR to hospital
admission. A temporary exemption does not allow the
physician to initiate treatment but allows for dosage
modifications.
Co-administration of methadone
• Addition of a second opioid may improve opioid response in
cancer pain: preliminary data. Mercadante S et al. Support
Care Cancer 2004:12;762-6__ (14 cases, Palermo)
• Use of Methadone as Coanalgesic. McKenna M. J Pain
Symptom Manage 2011; 46(6)e5__(10 cases, UK)
• Addition of Methadone to Another Opioid in the
Management of Moderate to Severe Cancer Pain: A Case
Series. Wallace E. et al. J Pall Med 2013;16(3):305-9__(20
cases, Toronto)
• Use of Very low dose methadone for palliative pain control at
the prevention of opioid hyperalgesia. Salpeter S. et al. J Pall
2013; 16(6):616-622__ (96 cases, California)
• La methadone. Société québécoise des médecins en soins
palliatifs. Médecine Palliative. Elsevier, In press.
Co-administration of methadone
Conclusion:
The use of very-low-dose of methadone in conjunction with adjuvant
haloperidol Resulted in excellent pain control without dose escalation or
opioid-induced Hyperalgia, for both cancer and noncancer diseases. We
conclude that low-dose Methadone should be part of first-line treatment in
palliative pain management.
Take home messages:
• Assess risk for abuse or diversion
• Pay attention when attempting conversion
• Avoid benzodiazepines HS (potentiates sleep
disordered breathing)
• Use methadone as a 2nd or 3rd line agent or
use as adjuvant
• If respiratory tract infection monitor and
consider reducing daily dose by 30% (McPHerson
2016)
Methadone for Analgesia
KT Tools Project Litterature Search and
Review for Online Training Tool
Methadone for Analgesia
By: Jane Kondejewski PhD