Methadone CBM Flashcards

1
Q

What is the pain diagnosis? Work up?

63 F with R sided breast cancer. 2 years after surgery, chemo and radiation, she presented with back and rib pain. Found to have multifocal bone metastases and lung mets.

Developed progressive severe R upper extremity pain below the elbow, accompanied by weakness and numbness of right hand.

Developed toxicity with increasing doses of morphine, therefore rotated to hydromorphone and also developed toxicity.

History: No neck pain. Dull, aching pain draped over right shoulder. Severe pain below the elbow in her right arm. Light touching of forearm, such a clothing, worsens her pain. There are brief stabs of electrical pain going down her right arm. Constant deep aching burning in right hand.

Physical: no cervical radiculopathy. Pattern of lower motor neuron dysfunction of right upper extremity, most consistent with a plexopathy.

MRI plexus : normal. EMG : active right brachial plexopathy. Radiation damange ruled out by EMG

A
  • Mixed pain syndrome (neuropathic, nociceptive, visceral)
  • Pleural pain - dull, aching pain draped over shoulder
  • Malignant brachial plexopathy
  • MR spine to rule out cervical radiculopathy, or epidural/intrathecal tumour
  • Follow up EMG or repeat MR in 2-3 months
  • Cancer does not have to be seen on imaging to cause tissue destruction and pain
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2
Q

How does methadone work as an analgesic?

A
  • Opioid agonist
  • racemic mixture of R and S methadone
  • mu, kappa, delta receptors (R methadone)
  • moderate antagonistic effect on NMDA receptors
  • Strong inhibitor of norepinephrine and serotonin reuptake (S methadone)
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3
Q

Methadone metabolism

A
  • entirely hepatic CYP 3A4 and 2B6 inhibitors
  • No renal
  • N-demthylation by
    • CYP 450
    • CYP 3A4
    • CYP 2B6
    • 2D6, 2C9, 2C19, 1A2
  • prefer to adjust in response to effect, not in anticipation as very unpredictable
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4
Q

What are the main indications for use of methadone?

A
  • pain in patients with tolerance, toxicity, allergy to other opioids
  • renal failure /dialysis
  • OIN
  • Neuropathic component to pain
  • Methadone maintenance therapy
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5
Q

What are the main challenges with use of methadone? Why is it dangerous at initiation?

A
  • long half life
  • neurotoxicity can last days
  • shorter interval, dosing tid-qid
  • poor correlation between metabolic half life and duration of analgesia
  • should be initiated in hospital
  • several days for accumulation to reach steady state
  • Fat soluble
  • Large volume of distribution
  • large doses initially, smaller doses a few days later
  • variable equianalgesic potency
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6
Q

German method of methadone rotation

A
  • 600 mg MEDD
  • stop original opioid
  • 5-10 mg methadone q4h x 72 hours
  • Day 4 (72 hours) : same numeric dose tid / q8h
  • Breakthrough methadone 5-10 mg po q2h prn
  • Increase dose every 1-2 days
  • Monitor carefully for respiratory depression, drowsiness, nausea during titration.
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7
Q

Cardiac complications of Methadone

A
  • Qtc prolongation
  • Torsades de pointe
  • Large doses (> 200 mg daily) - risk factor
  • At lower doses - hypokalemia, hypomagnesemia, other Qt prolonging agents
  • Rare Qtc prolongation with < 100 mg /day
  • ECG Day 1, Day 4
  • Replace Mg, K
  • Minimize medications that also prolong Qtc
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8
Q

QTc : definition

A
  • corrected for a rate of 60
  • start of Q wave to end of T
  • measures time for depolarization and repolarization of ventricles
  • SHORT Qtc with fast heart rate
  • LONG QTc with a slow heart rate

Torsades:

  • long Qtc causes R on T
  • R wave occurs during refractory period of repolarization
  • V fib

Qtc (lead II or V5-6):

  • > 440 men
  • > 460 women
  • > 500 risk of Torsades significantly high

Bazett’s formula:

Qtc= QT / square root RR

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9
Q

Other causes of Long Qtc

A
  • Hypo K
  • Hypo MG
  • Hypo Ca
  • Hypothermia
  • MI
  • Post Cardiac arrest
  • Raised ICP
  • Congenital
  • DRUGS
  • Congenital long QT
  • structural heart disease
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10
Q

Methadone conversion ratios:

A
  • MEDD morphine: methadone
  • <100mg. 3:1
  • 100-300 mg. 5:1
  • 300-600mg. 10:1
  • 600-800mg. 12:1
  • 800-1000mg. 15:1
  • >1000mg. 20:1
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11
Q

Common drugs that cause Qtc prolongation (CBM)

A
  • Amiodarone
  • Erythromycin
  • Fluconazole
    • Itraconazole
    • Ketoconazole
  • Fluoxetine (prozac)
  • Fluvoxamine
  • Paroxetine
  • Quinidine
  • Sertraline
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12
Q

Drugs that INCREASE methadone levels

A
  • Alcohol
  • Benzos (can use buspirone, lorazepam)
    • Alprazolam
    • Diazepam
  • Cannabis
  • Antibiotics (can use azithro)
    • Ciprofloxacin
    • Erthryomycin
    • Metronidazole
    • Alarithromycin
  • SSRIs (use mirtazapine instead)
    • Fluoxetine
    • Fluvoxamine
    • Sertraline
    • Paroxetine
  • Antifungals (use terbafafine, clotrimazole troche)
    • Fluconazole
    • Itraconazole
    • Ketoconazole
    • Voriconazole
  • Cardiac medications
    • Quinidine
    • Amiodarone
    • Verapimil
    • Diltiazem
  • Drugs
    • Alcohol
    • Cannabis
    • Heroin
    • Grapefruit
  • Other:
    • Cimetidine
    • Quetiapine
    • Topiramate
    • Na HC03
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13
Q

Drugs that DECREASE methadone levels

A
  • Alcohol (chronic ingestion)
  • Carbamazepine
  • Cocaine
  • Dexamethasone (> 16 mg / day)
  • Nicotine (CYP 1A2)
  • Phenobarbital
  • Phenytoin
  • Rifampin
  • Risperidone
  • Spironolactone
  • St John’s wort
  • Vit C
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14
Q

Drugs that can have an unpredictable interaction with methadone

A
  • Amitriptyline - Qtc prolongation
  • Desipramine Qtc prolongation, increased desipramine levels
  • Dextromethorphan - increased DM levels
  • Duloxetine - increased duloxetine and methadone levels
  • Nifedipine - increased nifedipine levels
  • Nortryptiline - Qtc prolongation, SS risk
  • Tamoxifen - decreased metabolites of tamoxifen
  • Tramadol - opioiate withdrawal
  • Venlafaxine - increased venlafaxine and methadone, qtc
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15
Q

Advantages to methadone

A
  • bone and neuropathic pain
  • NMDA antagonism may attenuate opioid tolerance
  • no active metabolites
  • titrated in small increments
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16
Q

Contraindications to methadone

A
  • hypersensitivity
  • mild, intermittent or short duration pain not well managed with methadone
  • initation in pain crisis not great idea
  • MAOI
  • severe liver disease
  • Acute resp depression
  • acute alcohol intoxication, withdrawal
  • CNS depression
  • paralytic ileus
17
Q

Condition for CAUTION with methadone

A
  • Severe COPD
  • severe OSA
  • long Qtc > 450
  • ETOH (inreased plasma levels of methadone)
18
Q

Is methadone associated with osteoporosis?

A

No

19
Q

Methadone and sexual function

A
  • suppress gonadotrophin levels
  • all opioids
  • testosterone replacement may be necessary
20
Q

Pharmacology of methadone

A
  • large volume of distribution
  • high plasma protein binding
  • lipophilic
  • long variable half life (15-60–> 120 hours)
  • slow elimination phase
  • steady state 5 days or more
  • racemic mixture R methadone (opioid receptor agonist, NMDA ant)
  • S methadone (NE, 5HT reuptake inhibhitor, NMDA)
21
Q

How is methadone released?

A
  • resevoir created in fat
  • free fraction in plasma maintained slowly
  • released slowly until tissue binding site resevoir exhausted
22
Q

Methadone absorption

A
  • oral, rectal 80-90%
  • sl 34% initially, then the rest absorped in proximal small bowel
23
Q

List common drugs classes that interact with methadone

A
  1. Antidepressants
  2. Antibiotics
  3. Antifungals
  4. Antipyschotics
24
Q

Methadone in renal failure :

A
  • 20% eliminated by kidneys
  • in RF –> liver will eliminate more
  • no need to dose adjust
25
Q

When would you choose methadone as a first line opioid?

A
  • severe intolerance to other opioids’
  • long term severe non cancer pain
  • renal failure
  • financial cost
26
Q

Start Low and Go Slow Approach

A
  • add as an adjuvant
  • low dose 1-2.5 mg po q8h
  • titrate q5-7 days
  • decreased original opioid by 20-30% at a time as tolerated once analgesia acheived with methadone
27
Q

How would you counsel a patient when rotating to methadone

A
  • Education around breakthroughs
  • risks of sedation, inadequate analgesia temporarily
  • more rapid rotation higher risk
  • Qtc prolongation
  • Drug interactions review all medications
  • Avoid alcohol, grapefruit juice
28
Q

When would you choose methadone as a breakthrough medication?

A
  • < 3 doses needed/ day
  • alternative opioids not desirable side effects
  • reliable observation
  • no other risk factors (Qtc, resp disease, OSA, etc)
29
Q

How to order methadone as a breakthrough

A
  • 10% total daily dose
  • < 3 BTA / day
  • increase baseline methadone based on 24 hour Total dose
  • titrate q5 days
30
Q

Common adverse side effects

A
  • Constipation
  • nausea
  • sedation
  • dizziness
31
Q

Infrequent by Serious Adverse Effects

A
  • Long Qtc
  • Serotonin Syndrome
  • Opioid Induced Neurotoxicity
  • Resp depression, apnea
  • Narcosis
32
Q

How to approach Qtc and methadone : practical guidelines

A
  • ECG Day 1 and 4
  • ECG when dose increases
  • Previous ECG within 3 months if risk factor
  • Qtc > 500, avoid methadone
  • Qtc 450-500 - consider altenative, correct risk factors
  • unusual to have long Qtc < 100 mg methadone/day
33
Q

Naloxone

A
  • 0.04 mg q2 min iv/im
  • short acting! likely will require infusion as methadone half life long
34
Q

How to store methadone safely at home

A
  • original labelled container
  • locked and inaccessible to pets and children
  • liquid methadone in locked box in fridge
  • shake bottle
  • measure accurately
  • check expiry
35
Q

Treating Thrush for a patient on methadone

A

Nystatin First

Avoid fluconazole if possible

36
Q

Principles of methadone dosing if starting a new medications that alters methadone levels:

A
  • observe first for effect
  • do not adjust prophylactically