Methadone

Question 1

Indications for Methadone

Answer 1

1. Pain in patients with tolerance, toxicity or allergy to morphine or other opioids
2. Renal failure or on dialysis
3. Evolving opioid-induced hyperalgesia
4. Neuropathic component to pain
5. Methadone maintenance therapy

Question 2

Advantages of Methadone

Answer 2

• 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

Question 3

Contraindications to Methadone

Answer 3

• 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

Question 4

Conditions that merit caution in prescribing methadone

Answer 4

• Severe COPD
• Severe sleep apnea
• Long QTc (>450msec)
• Drug interactions
• Drinking alcohol (may result in increased plasma levels of methadone)

Question 5

Delivery of Methadone

Answer 5

• Liquids
• Tablets (preferred for PO delivery)
• Rectal
• SL/Buccal

Question 6

Is methadone associated with osteoporosis?

Answer 6

No - though those on methadone may have osteoporosis due to other risk factors

Question 7

Frequency of dosing methadone for pain

Answer 7

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

Question 8

Can methadone impair sexual function

Answer 8

Chronic use of all opioids can suppress gonadotropin levels. - as can underlying illness - testosterone replacement may be helpful

Question 9

Pharmacology of Methadone

Answer 9

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)

Question 10

How Methadone is released

Answer 10

1. Dose administered saturates tissue binding sites (creating reservoir) while a fraction is free in the plasma, providing analgesic effect
2. Free fraction in plasma is maintained slowly, even after methadone is discontinued, until the tissue binding site reservoir is exhausted (could take days)

Question 11

Absorption of methadone

Answer 11

• 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

Question 12

Common drug interactions:

Answer 12

1. Antidepressants
2. Antibiotics
3. Antifungals
4. Antipsychotics

Most drugs will increase plasma methadone levels (risking toxicity).

Grapefruit juice, anticonvulsants, and Rifampin can DECREASE plasma methadone levels

Question 13

Methadone in renal failure

Answer 13

20% eliminated by kidneys, but if in renal failure, liver will eliminate instead. No need for dose adjustment

Question 14

Initiation strategy: Start Low and go Slow

Answer 14

• 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

Question 15

When to use methadone as a first line opioid

Answer 15

• 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

Question 16

Indications to rotate to methadone

Answer 16

• improve analgesia (particularly with neuropathic pain)

- reduce opioid adverse effects (nausea, pruritis, cognitive changes)

Question 17

How to rotate to methadone when patient has ongoing uncontrolled pain at baseline (on opioid)

Answer 17

• 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

Question 18

How to rotate to methadone when patient has ongoing controlled pain at baseline (on opioid)

Answer 18

1. Reduce current opioid dose by 20%, ensure maintained BT dose
2. Add low dose methadone in the ‘Start low and go slow manner’ (1-2.5mg PO q8H)
3. Gradually titrate (reducing dose and increasing methadone) as tolerated

Question 19

Counselling to provide when rotating methadone

Answer 19

1. Education around effective breakthrough doses to understand need and ensure pain control
2. Discussion of risks of rotation and potential for overestimation of opioid needs (sedation, etc.)
3. More rapid conversion methods have higher risk
4. Note that there is no consensus around equivalence with other doses or the most effective approach to rotation
5. Ensure patient calls before starting any new meds given risk of interactions, and avoids alcohol, grapefruit juice and fruit

Question 20

Indications for methadone for breakthrough pain

Answer 20

• 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)

Question 21

Dosing methadone for breakthrough pain

Answer 21

• 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)

Question 22

Common adverse effects with methadone (10% or more)

Answer 22

• Constipation
• Nausea, mild sedation on initiation
• Dizziness and light headedness

Question 23

Less Common, but potentially severe effects with methadone (1%)

Answer 23

• Long QTc (unusual in patients on less than 100mg methadone/day)
• Serotonin Syndrome
• Opioid induced neurotoxicity (hyperalgesia, seizure, myoclonus)
• Respiratory depression, sleep apnea

Question 24

Risk factors for long QTc

Answer 24

• 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

Question 25

How to approach long QTc and methadone with patient

Answer 25

- 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

Question 26

Signs of excessive methadone dosing

Answer 26

- Somnolence - RR < 8/min - SBP <90mmHg or 20% less than baseline Note higher risk in those with OSA or COPD

Question 27

How to reverse a methadone overdose

Answer 27

- 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.

Question 28

Opioid induced neurotoxicity - presentation, management

Answer 28

- 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

Question 29

Safe storage of methadone at home

Answer 29

1. Store in original container, keep clearly labelled 2. Ensure inaccessible to children and pets 3. Keep liquid methadone in a locked box in the fridge or at room temp (as appropriate for formulation) 4. Shake bottle prior to use 5. Measure accurately for liquid methadone 6. Check the storage recommendations and expiry date before taking.

Question 30

Mechanism of action of methadone

Answer 30

- 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)

Question 31

Metabolism of methadone

Answer 31

- 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

Question 32

Why is initiation of methadone dangerous?

Answer 32

1. 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. 2. Variable equianalgesic potency compared with other opioids, depending in part on the total daily dose of previous opioid. Opioid conversions are challenging.

Question 33

Approach to methadone rotation: German method

Answer 33

- 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) 1. Stop old opioid 2. Give 5-10mg methadone PO q4h x 72 hours with 5-10mg PO q2H PRN 3. After 72 hours, give same dosage PO TID with 5-10mg PO q2H PRN 4. If ineffective, increase scheduled dose of methadone every 1-2 days

Question 34

Drugs that can increase methadone levels

Answer 34

1. Antibiotics - Alarithromycin - Cipro - Erythromycin - Metronidazole 2. Antifungals (risk of QTc prolongation) - Fluconazole - Itraconazole - Ketoconazole - Voriconazole 3. CNS depressants - Alcohol (competes for CYP 450) - Alprazolam - Cannabis (common metabolism pathway) - Diazepam - Heroin 4. 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 5. Cardiac meds - Amio (QTc) - Diltiazem - Verapamil 6. Other - Cimetidine - Grapefruit juice/fruit - Quinidine - Sodium bicarb (decreased renal elimination)

Question 35

Drugs that can decrease methadone levels

Answer 35

1. Recreational Drugs - Alcohol (chronic) - increased methadone metabolism - Cocaine (lowered methadone trough level) - Cigarettes (CYP1A2 inducer) 2. Antiepileptics - Carbamazepine (could cause opiate withdrawal) - Phenobarb (could cause opiate withdrawal) - Phenytoin (could cause opiate withdrawal) 3. Dexamethasone (>16mg/day) 4. Risperidone (could cause opiate withdrawal) 5. Spironolactone 6. Rifampin 7. St. John's Wort 8. Vit C (increased renal elimination)

Question 36

Drugs that have an unpredictable interaction with methadone

Answer 36

1. 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) 2. Other - Nifedipine (increased nifedeipine levels) - Tramoxifen (decreased formation of tamoxifen metabolites - Tramadol (opioid withdrawal) - Dextromethorphan (Increased DM levels)

Question 37

Treating thrush with patients on methadone

Answer 37

- Nystatin first | - Avoid fluconazole if possible

Question 38

How to manage methadone dosing if starting on an agent that can alter methadone levels

Answer 38

- Adjust dose only after observing patient response (do not adjust prophylactically)