Methadone Flashcards
Indications for Methadone
- Pain in patients with tolerance, toxicity or allergy to morphine or other opioids
- Renal failure or on dialysis
- Evolving opioid-induced hyperalgesia
- Neuropathic component to pain
- Methadone maintenance therapy
Advantages of Methadone
- Effective for bone and neuropathic pain
- NMDA receptor antagonism may attenuate opioid tolerance (e.g. reduce activation of NMDA receptors, stimulation of which leads to CNS sensitization and hyperalgesia or allodynia)
- No known active metabolites
- titrated in small increments
Contraindications to Methadone
- Hypersensitivity
- Mild, intermittent, or short duration pain that can be managed with other pain medications
- Initiation in an acute, unstable pain scenario
- Patients taken monoamine oxidase inbitors (MAOIs)
- Patients with severe liver disease
Also consider:
- Acute respiratory depression, cor pulmonale, elevated pCO2
- Acute alcohol intoxication or withdrawal
- Severe CNS depression
- Paralytic ileus
Conditions that merit caution in prescribing methadone
- Severe COPD
- Severe sleep apnea
- Long QTc (>450msec)
- Drug interactions
- Drinking alcohol (may result in increased plasma levels of methadone)
Delivery of Methadone
- Liquids
- Tablets (preferred for PO delivery)
- Rectal
- SL/Buccal
Is methadone associated with osteoporosis?
No - though those on methadone may have osteoporosis due to other risk factors
Frequency of dosing methadone for pain
For treatment of addiction, methadone dosing is once per day. However, the in the treatment of pain, more constant plasma levels are required necessitating more frequent dosing
Can methadone impair sexual function
Chronic use of all opioids can suppress gonadotropin levels. - as can underlying illness - testosterone replacement may be helpful
Pharmacology of Methadone
High volume of distribution
High plasma protein binding
High lipophilicity (large reservoir of tissue binding sites)
Long, variable half life and slow elimination phase (half life usually 15-60 hours, but may be as high as 120 hours). Duration of half analgesia of approximately 8 hours, elimination half life averaging approximately one day.
Steady state may take five days or more - do not raise doses more frequently than every 3 days
Racemic mixture of R-methodone (opioid receptor agonist, NMDA antagonist) and S-methadone (norepi and serotonin re-uptake inhibitor, NMDA antagonist)
How Methadone is released
- Dose administered saturates tissue binding sites (creating reservoir) while a fraction is free in the plasma, providing analgesic effect
- Free fraction in plasma is maintained slowly, even after methadone is discontinued, until the tissue binding site reservoir is exhausted (could take days)
Absorption of methadone
- Oral dose - 80-90% absorbed
- Rectal is comprabale to oral
- SL is approximately 34% and most absorbed in the first 2.5 minutes, but note that much of the SL administered methadone may be subsequently absorbed in the proximal small bowel
Common drug interactions:
- Antidepressants
- Antibiotics
- Antifungals
- Antipsychotics
Most drugs will increase plasma methadone levels (risking toxicity).
Grapefruit juice, anticonvulsants, and Rifampin can DECREASE plasma methadone levels
Methadone in renal failure
20% eliminated by kidneys, but if in renal failure, liver will eliminate instead. No need for dose adjustment
Initiation strategy: Start Low and go Slow
- Start a dose approrpiate to dosing in an opioid naive person (usually 1-2.5 mg PO q8h)
- Slow titration, changing dose every 5 days
When to use methadone as a first line opioid
- History of severe intolerance to other opioids
- Likelihood of very long term opioid therapy (e.g. severe non-cancer pain)
- Renal failure
- Financial considerations precluding prescribing of SR med, and for whom q4h dosing is impractical
Indications to rotate to methadone
- improve analgesia (particularly with neuropathic pain)
- reduce opioid adverse effects (nausea, pruritis, cognitive changes)
How to rotate to methadone when patient has ongoing uncontrolled pain at baseline (on opioid)
- Add methadone to the existing analgesic as per the “start low and go slow approach” (e.g. 1-2.5mg PO Q8H)
- Titrate methadone at 5-7 days
- Once adequate analgesia is reached, decrease original opioid by 20-30% at a time, pace as tolerated
How to rotate to methadone when patient has ongoing controlled pain at baseline (on opioid)
- Reduce current opioid dose by 20%, ensure maintained BT dose
- Add low dose methadone in the ‘Start low and go slow manner’ (1-2.5mg PO q8H)
- Gradually titrate (reducing dose and increasing methadone) as tolerated
Counselling to provide when rotating methadone
- Education around effective breakthrough doses to understand need and ensure pain control
- Discussion of risks of rotation and potential for overestimation of opioid needs (sedation, etc.)
- More rapid conversion methods have higher risk
- Note that there is no consensus around equivalence with other doses or the most effective approach to rotation
- Ensure patient calls before starting any new meds given risk of interactions, and avoids alcohol, grapefruit juice and fruit
Indications for methadone for breakthrough pain
- Anticipated that at most, three doses per day might be needed
- Alternative opioids are not desirable due to adverse effects
- Reliable observation for adverse effects
- No other issues that may pose risk (e.g. borderline QTc, advanced respiratory disease, OSA)
Dosing methadone for breakthrough pain
- Conventionally, BT dose is 5-20% of total daily dose
- Limit methadone BT to 3 doses/24 h period
- May increase baseline methadone dosing based on 24 hour use (do not titrate more than q5 days)
Common adverse effects with methadone (10% or more)
- Constipation
- Nausea, mild sedation on initiation
- Dizziness and light headedness
Less Common, but potentially severe effects with methadone (1%)
- Long QTc (unusual in patients on less than 100mg methadone/day)
- Serotonin Syndrome
- Opioid induced neurotoxicity (hyperalgesia, seizure, myoclonus)
- Respiratory depression, sleep apnea
Risk factors for long QTc
- Lyte abnormalities (hypokalemia, hypomagnesemia) - consider with malnutrition or cisplatin
- Structural heart disease
- Hx of bradycardia or long QT
- Genetic predisposition or family history of long QT
- Use of other drugs associated with long QT
- Use of drugs that may increase serum methadone levels
- Impaired liver function
- High doses of methadone
How to approach long QTc and methadone with patient
- Consider obtaining an ECG on patients before initiating, particularly if there are risk factors or previous ECGs with QTc >450ms
- ECG within one year for no RF, and within 3 months if there are RF, can be considered appropriate
- If QTc >500msec, would avoid use
- If QTc 450-500mec, consider alternative rx strategies or correct risk factors
Unusual to have clinically significant long QTc with doses less than 100mg/day of methadone
Signs of excessive methadone dosing
- Somnolence
- RR < 8/min
- SBP <90mmHg or 20% less than baseline
Note higher risk in those with OSA or COPD
How to reverse a methadone overdose
- Naloxone (however use with caution, as it may cause a pain crisis)
If apnea or severe bradypnea, administer naloxone 0.04mg q2-4 mins until signs of overdose resolves. May require repeated naloxone dosing or an infusion due to the slow clearance of methadone.
Opioid induced neurotoxicity - presentation, management
- Presents with hallucinations, myoclonus, delirium, hyperalgesia, allodynia
- Typically treated by rotating to another opioid (with 30% dose reduction) and hydration
- If mild and with methadone, may simply reduce dose
- Rule out other causes of delirium and sedation
Safe storage of methadone at home
- Store in original container, keep clearly labelled
- Ensure inaccessible to children and pets
- Keep liquid methadone in a locked box in the fridge or at room temp (as appropriate for formulation)
- Shake bottle prior to use
- Measure accurately for liquid methadone
- Check the storage recommendations and expiry date before taking.
Mechanism of action of methadone
- Racemic mixture of R- and S-methadone
- Opioid agonist to mu, kappa, delta receptors (R-methadone)
- Moderate NMDA receptor antagonist (R and S-methadone
- Strong norepi and serotonin reuptake inhibitor (S-methadone)
Metabolism of methadone
- Hepatic metabolism (Mainly CYP3A4, also 2B6 and others to a lesser extent)
- Moderate inhibitor of CYP2D6 and CYP 3A4
- Not substantially influenced by severe renal failure, but could be impacted by liver disease
- Typically not dose adjusted for liver mets, but may require dose adjustment for liver failure
Why is initiation of methadone dangerous?
- Takes several days for the drug to accumulate in the body and reach steady state (slow metabolism, also fat soluble with large volume of distribution). As such, requires larger doses initially and smaller doses a few days later.
- Variable equianalgesic potency compared with other opioids, depending in part on the total daily dose of previous opioid. Opioid conversions are challenging.
Approach to methadone rotation: German method
- Used when a patient is on a very large dose of another opioid (e.g. 600mg OME)
- Monitor carefully for respiratory depression and drowsiness (many patients will develop these toxicities during initiation, but toxicity is usually mild and self-limiting)
- Stop old opioid
- Give 5-10mg methadone PO q4h x 72 hours with 5-10mg PO q2H PRN
- After 72 hours, give same dosage PO TID with 5-10mg PO q2H PRN
- If ineffective, increase scheduled dose of methadone every 1-2 days
Drugs that can increase methadone levels
- Antibiotics
- Alarithromycin
- Cipro
- Erythromycin
- Metronidazole - Antifungals (risk of QTc prolongation)
- Fluconazole
- Itraconazole
- Ketoconazole
- Voriconazole - CNS depressants
- Alcohol (competes for CYP 450)
- Alprazolam
- Cannabis (common metabolism pathway)
- Diazepam
- Heroin - Psych meds
- Fluoxetine (Serotonin syndrome risk, QTc prolongation)
- Fluvoxamine (Serotonin syndrome risk, QTc prolongation)
- Paroxetine (Serotonin syndrome risk, QTc prolongation)
- Sertraline (Serotonin syndrome risk, QTc prolongation)
- Quetiapine - Cardiac meds
- Amio (QTc)
- Diltiazem
- Verapamil - Other
- Cimetidine
- Grapefruit juice/fruit
- Quinidine
- Sodium bicarb (decreased renal elimination)
Drugs that can decrease methadone levels
- Recreational Drugs
- Alcohol (chronic) - increased methadone metabolism
- Cocaine (lowered methadone trough level)
- Cigarettes (CYP1A2 inducer) - Antiepileptics
- Carbamazepine (could cause opiate withdrawal)
- Phenobarb (could cause opiate withdrawal)
- Phenytoin (could cause opiate withdrawal) - Dexamethasone (>16mg/day)
- Risperidone (could cause opiate withdrawal)
- Spironolactone
- Rifampin
- St. John’s Wort
- Vit C (increased renal elimination)
Drugs that have an unpredictable interaction with methadone
- Antidepressants
- Amitriptyline (QTc)
- Desipramine (QTc, increased desipramine levels)
- Duloxetine (Increased duloxetine and methadone levels)
- Nortriptyline (QTc and serotonin syndrome)
- Venlafaxine (increased venlafaxine and methadone levels, QTc) - Other
- Nifedipine (increased nifedeipine levels)
- Tramoxifen (decreased formation of tamoxifen metabolites
- Tramadol (opioid withdrawal)
- Dextromethorphan (Increased DM levels)
Treating thrush with patients on methadone
- Nystatin first
- Avoid fluconazole if possible
How to manage methadone dosing if starting on an agent that can alter methadone levels
- Adjust dose only after observing patient response (do not adjust prophylactically)
