Methadone CBM Flashcards
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
- 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
How does methadone work as an analgesic?
- 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)
Methadone metabolism
- 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
What are the main indications for use of methadone?
- pain in patients with tolerance, toxicity, allergy to other opioids
- renal failure /dialysis
- OIN
- Neuropathic component to pain
- Methadone maintenance therapy
What are the main challenges with use of methadone? Why is it dangerous at initiation?
- 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
German method of methadone rotation
- 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.
Cardiac complications of Methadone
- 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
QTc : definition
- 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
Other causes of Long Qtc
- Hypo K
- Hypo MG
- Hypo Ca
- Hypothermia
- MI
- Post Cardiac arrest
- Raised ICP
- Congenital
- DRUGS
- Congenital long QT
- structural heart disease
Methadone conversion ratios:
- 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
Common drugs that cause Qtc prolongation (CBM)
- Amiodarone
- Erythromycin
- Fluconazole
- Itraconazole
- Ketoconazole
- Fluoxetine (prozac)
- Fluvoxamine
- Paroxetine
- Quinidine
- Sertraline
Drugs that INCREASE methadone levels
- 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
Drugs that DECREASE methadone levels
- Alcohol (chronic ingestion)
- Carbamazepine
- Cocaine
- Dexamethasone (> 16 mg / day)
- Nicotine (CYP 1A2)
- Phenobarbital
- Phenytoin
- Rifampin
- Risperidone
- Spironolactone
- St John’s wort
- Vit C
Drugs that can have an unpredictable interaction with methadone
- 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
Advantages to methadone
- bone and neuropathic pain
- NMDA antagonism may attenuate opioid tolerance
- no active metabolites
- titrated in small increments
Contraindications to methadone
- 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
Condition for CAUTION with methadone
- Severe COPD
- severe OSA
- long Qtc > 450
- ETOH (inreased plasma levels of methadone)
Is methadone associated with osteoporosis?
No
Methadone and sexual function
- suppress gonadotrophin levels
- all opioids
- testosterone replacement may be necessary
Pharmacology of methadone
- 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)
How is methadone released?
- resevoir created in fat
- free fraction in plasma maintained slowly
- released slowly until tissue binding site resevoir exhausted
Methadone absorption
- oral, rectal 80-90%
- sl 34% initially, then the rest absorped in proximal small bowel
List common drugs classes that interact with methadone
- Antidepressants
- Antibiotics
- Antifungals
- Antipyschotics
Methadone in renal failure :
- 20% eliminated by kidneys
- in RF –> liver will eliminate more
- no need to dose adjust
When would you choose methadone as a first line opioid?
- severe intolerance to other opioids’
- long term severe non cancer pain
- renal failure
- financial cost
Start Low and Go Slow Approach
- 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
How would you counsel a patient when rotating to methadone
- 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
When would you choose methadone as a breakthrough medication?
- < 3 doses needed/ day
- alternative opioids not desirable side effects
- reliable observation
- no other risk factors (Qtc, resp disease, OSA, etc)
How to order methadone as a breakthrough
- 10% total daily dose
- < 3 BTA / day
- increase baseline methadone based on 24 hour Total dose
- titrate q5 days
Common adverse side effects
- Constipation
- nausea
- sedation
- dizziness
Infrequent by Serious Adverse Effects
- Long Qtc
- Serotonin Syndrome
- Opioid Induced Neurotoxicity
- Resp depression, apnea
- Narcosis
How to approach Qtc and methadone : practical guidelines
- 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
Naloxone
- 0.04 mg q2 min iv/im
- short acting! likely will require infusion as methadone half life long
How to store methadone safely at home
- original labelled container
- locked and inaccessible to pets and children
- liquid methadone in locked box in fridge
- shake bottle
- measure accurately
- check expiry
Treating Thrush for a patient on methadone
Nystatin First
Avoid fluconazole if possible
Principles of methadone dosing if starting a new medications that alters methadone levels:
- observe first for effect
- do not adjust prophylactically
