Methadone

Question 1

What are some beneficial properties of methadone

Answer 1

1) NMDA receptor antagonist
2) Opioid agonist
Inactive metabolites
3) Eliminated by the bowel
4) No clearance by kidneys
5) methadone is not dialysed

Question 2

What are common reasons to initiate methadone?

Answer 2

1) Opioid tolerance
2) Neuropathic pain
3) Pain in renal failure
4) Inadequate analgesia from other opioids
5) Opioid induced hyperalgesia
6) Opioid toxicity

Question 3

When can you expect steady state to be achieved?

Answer 3

3 days

Question 4

What makes methadone particularly unique when compared to other opioids?

Answer 4

NMDA receptor antagonists

Question 5

Methadone has effects on serotonin and norepinephrine similar to what class of antidepressants?

Answer 5

SNRIs

Question 6

What organ transforms the metabolites to become inactive?

Answer 6

The liver

Question 7

Where are the metabolites eliminated from?

Answer 7

Bowel

Question 8

TRUE or FALSE?

Loss of renal function has little to no impact on clearance and methadone is not dialysed.

Answer 8

TRUE

Question 9

List 6 common indications for methadone treatment

Answer 9

1) opioid tolerance
2) neuropathic pain
3) pain in renal failure
4) inadequate analgesia from other opioids
5) opioid induced hyperalgesia
6) opioid toxicity

Question 10

When it comes to methadone’s pharmokinetic profile, what historically made physicians weary to prescribe it?

Answer 10

1) Methadone’s potency can vary widely btwn individuals so it can be difficult to predict an equianalgesic dose of methadone when switching from another opioid.
2) Methadone’s long half- life leads to a higher risk of accumulation.

Question 11

Why is there little correlation between prior opioid and eventual methadone dose?

Answer 11

2) 1) Patients on high-dose opioids have developed a degree of tolerance
2) Methadone’s opioid receptor agonist profile may differ substantially from other opioids (non-cross-tolerance).
3) Patients on high dose opioids often have a degree of opioid induced hyperalgesia. When the offending opioid and its metabolites are allowed to clear, hyperalgesia will usually resolve and pain will improve- thus lowering analgesic requirements.

Question 12

With the start low and go slow approach what dose would you start in someone on high dose of opioid?
What dose would you start in elderly and frail?

Answer 12

1) 2 or 2.5mg q8 hours
2) 0.5mg q8 hours

Question 13

What is an example of a stepped substitution method for methadone?

Answer 13

Modified Edmonton method: a 3 x 3 stepped substitution

Question 14

What is the best known stop and go method?

Answer 14

Morley and Makin Method

Question 15

What are the potential side effects of methadone?

Answer 15

1) somnolence/sedation
2) respiratory depression
3) constipation
4) nausea

The propensity of methadone to cause constipation is similar to that of TD fentanyl which is less than that of other opioids

Question 16

Methadone can prolong the QT interval and therefore can increase the risk of what?

Answer 16

Ventricular cardiac arrhythmia torsades de pointes

Question 17

Why is the risk of torsades de pointes so low in patients taking methadone for pain?

Answer 17

Lower doses required

Question 18

What dose of methadone is a good threshold to check the QT interval?

Answer 18

120mg/day of methadone

Question 19

How is the QTc calculated?

Answer 19

QTc= QT/square root of R-R interval

Question 20

What is the normal QTc interval for men ?

Answer 20

QTc= 350-430ms

Question 21

What is the normal QTc interval for women?

Answer 21

QTc= 350-450ms

Question 22

A patient is at increased risk for torsades de point when QTc is > than what?

Answer 22

500ms

Begin to be concerned if 450-500

Question 23

What 3 electrolyte disturbances place a patient at higher risk for torsades de pointes?

Answer 23

1) hypomagnesaemia
2) hypokalaemia
3) hypocalcaemia

Question 24

Drugs which interact with methadone generally involve inducers or inhibitors of the cytochrome ________

Answer 24

P450 (CYP) system
-CYP3A4

Question 25

Inhibitors of **P450 CYP3A4** are most clinically significant bc they decrease the clearance and thereby increase the blood levels of methadone. What are some common examples of P450 CYP34A inhibitors?

Answer 25

ketoconazole fluconazole ciprofloxacin erythromycin fluvoxamine (Luvox) fluoxetine (Prozac) Cimetidine

Question 26

Inducers of P450 CYP3A4 will increase or decrease the amount of methadone in the blood?

Answer 26

Decrease methadone blood levels

Question 27

What are some common drug examples of P450 CYP3A4 drug inducers?

Answer 27

Rifampin phenytoin phenobarbital carbamazepine

Question 28

What are 6 classes of medications that are QT prolonging?

Answer 28

1) Antidepressants 2) Antipsychotics 3) Antibiotics 4) Antimalarials 5) Antihistamines 6) Antiarrhythmics

Question 29

List 4 properties of methadone which make it a good analgesic agent

Answer 29

1. **NMDA antagonism** reducing central sensitization ane causing opioid sparing effect 2. No active metabolites, so generally less toxic 3. **Mu receptor agonism** for combined nociceptive and neuropathic pain management

Question 30

Name 4 clinical conditions where you would use methadone

Answer 30

1. Opioid induced neurotoxicity 2. opioid use disorder 3. chronic pain 4. malignant neuropathic pain 5. Renal failure/dialysis 6. Allergy to other opioids

Question 31

What is the main methadone cytochrome enzyme?

Answer 31

Main enzyme is: CYP 3A4

Question 32

List the two opioid receptors that methadone works on, and 2 non opioid receptors it works on.

Answer 32

Mu opioid receptor agonist Kappa opioid receptor agonist NMDA- N methyl D aspartate receptor antagonist Serotonin-norepinephrine (noradrenaline) inhibitor

Question 33

Methadone can lead to hypo or hyper glycemia?

Answer 33

Hypoglycaemia