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Unintentional misuse of prescription medicines bpacnz, October 2018
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- Methadone may be suitable for people whose pain is uncontrolled with, or who are unable to tolerate, morphine
- Methadone has complex pharmacokinetics and pharmacodynamics and requires careful dosing and monitoring
- The general rule for dosing methadone in opioid naïve patients is “start low, go slow”
- Methadone interacts with other drugs, be especially aware of a change in therapeutic effect that may indicate an
interacting drug is being used concurrently
- Monitor for adverse effects, especially respiratory depression
- Educate patients about the safe and effective use of methadone
Methadone is a strong opioid
In BPJ 16 (September 2008), we provided guidance about the
of chronic pain. The three step pain ladder was recommended for managing pain; start with a non-opioid analgesic,
add a weak opioid if pain is uncontrolled, and finally change to a strong opioid if pain continues to be uncontrolled.
Methadone is a strong opioid and may be suitable for people whose pain is uncontrolled with morphine (e.g. neuropathic
pain) or who are unable to tolerate morphine (e.g. idiosyncratic reactions, or in renal failure).
Methadone has complex pharmacokinetics and pharmacodynamics
Methadone has a long half-life (30 hours) and displays wide variations between individuals. The duration of analgesic
effect is much shorter. Methadone takes five to seven days to reach steady state and so is a difficult analgesic to titrate.
If the dose is titrated too rapidly, accumulation and toxicity can occur. In the community, there is a high risk of unobserved
respiratory depression and death if doses are escalated too quickly.
Because of the potential for fatal respiratory depression, it is recommended to never use methadone for breakthrough
Despite these issues, methadone is an excellent analgesic for complex pain and is increasingly being used as a first,
rather than second or third-line opioid. With precautions methadone can be safely introduced in the community.
Methadone is a NMDA antagonist
Aside from its agonist activity at the mu opioid receptor, methadone has other actions that are believed to contribute
to its unique analgesic activity.
Compared to morphine it is an agonist to a broader spectrum of opioid receptors and is also an antagonist at the
N-methyl-D-aspartate (NMDA) receptor and inhibits the re-uptake of both noradrenaline and serotonin. These actions
are believed to contribute to its increased analgesic efficacy for patients with chronic pain syndromes, hyperalgesia
and neuropathic pain.
Safe methadone dosing in the community
|Example of methadone titration
Many patients gain good analgesic control with once daily or twice daily regimens especially once a steady
state is achieved. In situations where patients develop pain prior to their next dose, methadone given three or four
times daily may be more effective.
||2.5 mg twice daily
||5 mg twice daily
||7.5 mg twice daily
||10 mg twice daily
||10 mg three times daily or 15mg twice daily
||20 mg twice daily or 10 mg four times daily
Quicker titration regimens are available but because of the risk of respiratory depression are not recommended
in the community and inpatient admission is required. There are conversion regimens that can fully titrate methadone
doses in about a week. Specialist advice/input is recommended.
|Other opioids for breakthrough pain may be required
Patients who require extra analgesia outside of their methadone regimen can be initially prescribed
either, codeine 30–60 mg as required, maximum four times per day, or morphine 2.5–5 mg as required (doses depend on
clinical factors such as age, renal function and previous response to codeine).
Methadone for opioid naïve patients – start low, go slow
When therapy with methadone is started, patients need to be carefully monitored for signs of toxicity, especially
respiratory depression. This will require daily monitoring in the first days of treatment. Home visits may not be necessary
and telephone calls may be adequate if the health professional can talk to a reliable adult. Ask about confusion, excessive
drowsiness and control of pain. The patient should not be left home alone for the first five to seven days.
|Table 1: Morphine equivalent doses
||Equivalent to 10 mg morphine (oral)
||5 – 7.5 mg
||1.5 – 2
For patients who have not been taking regular opioids, a safe starting dose is 2.5 mg every 12 hours or 5 mg once daily.
If pain is not controlled, and methadone is tolerated, doses can be increased slowly every five to seven days (see box
for an example).1
Methadone for opioid tolerant patients – ratios change based on current opioid dose
Because the analgesic effect of methadone is a result of more than its opioid effects, the conversion ratios
with morphine are not linear but change with increasing doses. Various conversion ratios for morphine to methadone have
been developed (see Table 2 for an example).
If the previous dose of morphine is much higher than 300 mg/day the ratio increases even further. When converting at
these doses it may be more suitable to do this in an inpatient setting where the patient can be monitored more closely.
|Table 2: Suggested safe and effective starting doses when changing patients from oral
morphine to oral methadone3
|Morphine dose (mg/day)
||Morphine to methadone equianalgesic dose ratio
||Methadone starting dose
||e.g. 90 mg morphine per day = 22.5 mg methadone per day
||e.g. 200 mg morphine per day = 25 mg methadone per day
||maximum = 30 mg methadone per day as outpatient
It is recommended to not start higher than 30 mg of methadone per day unless the patient is in hospital.
|Methadone dosing in special populations
|Liver disease and renal dysfunction
The dose of methadone does not need to be adjusted in stable liver disease and does not accumulate in people with
renal dysfunction, although dosage adjustment may be required in end-stage renal disease.
Elderly people are more susceptible to the side effects of confusion, drowsiness and respiratory depression. It is
recommended to start with once daily dosing in this population e.g. 2.5 mg once daily. For frail elderly people an
even smaller starting dose can be used e.g. 1 mg once daily (0.5 mL of methadone oral liquid 2 mg/mL).2 Dose
changes should not occur faster than once weekly in this group.
To convert a patient from another opioid to methadone:1
||Assess current daily opioid dose – add up all long-acting and short-acting doses.
||If the current opioid is not morphine, convert this to a daily morphine equivalent dose.
||Based on this estimated daily equivalent morphine dose, work out the recommended methadone dose using the ratio.
Clinical scenario 1. Patient currently taking morphine for musculoskeletal pain associated
with hemiplegia. Appears to be suffering thalamic pain. Plan change of opioid to methadone.
||Current opioid use: morphine 90 mg per day
||Methadone dose: Divide the total daily morphine dose by the appropriate equianalgesic dose ratio (Table 2). In this
case the equianalgesic dose ratio is 4:1.
90 mg morphine divided by 4 = 22.5 mg methadone per day given as 7.5 mg three times daily or rounded down to 10 mg twice
Breakthrough analgesia is usually 1/6th of the total daily opioid dose. For this example, continue with previous breakthrough
analgesia – morphine 90 mg/6 = 15 mg (morphine syrup) as required.
Clinical scenario 2. Patient currently taking oxycodone for pain from spinal stenosis.
On increasing dose has developed severe itch. Plan change of opioid to methadone.
||Current opioid use: oxycodone 150 mg per day
||Morphine equivalent dose: Convert to a daily morphine equivalent dose (see Table 1 for morphine equivalent ratios).
Equivalent morphine dose 150 mg x 2 = 300 mg morphine per day. Practitioners may be surprised at this equivalency.
||Methadone dose: Divide the total daily morphine dose by the appropriate equianalgesic dose ratio (Table 2). In this
case the equianalgesic dose ratio is 8:1.
300 mg morphine equivalent divided by 8 = 37.5 mg methadone per day. As the maximum starting dose recommended is 30
mg methadone per day, start at 15 mg twice a day or 10 mg three times a day.
Breakthrough – continue with previous breakthrough analgesia e.g oxycodone 150 mg/6 = 25 mg as required.
In all cases review daily to check the effects until a stable dose is reached. Doses may be adjusted depending on the
effect e.g. with signs of toxicity (drowsiness/respiratory depression) reduce dose. If pain is poorly controlled, increase
the dose by 30-50% with extreme caution. Monitor for drowsiness and confusion.
Methadone has a number of interactions that are not seen with morphine. It is mainly metabolised by CYP3A4 along with
other CYP enzymes. Drugs that inhibit or induce these enzymes will affect the plasma concentration and therapeutic effect
of methadone. Azole antifungals (e.g. fluconazole) inhibit CYP3A4 and may increase the concentration of methadone and
increase the likelihood of adverse effects and overdose. Drugs that induce these enzymes, e.g. St John’s Wort and some
anticonvulsants (e.g. phenytoin, carbamazepine), may reduce the plasma concentration of methadone decreasing its therapeutic
Concomitant use of drugs that affect the CNS, for example, alcohol, benzodiazepines, or other opioids, may increase
the likelihood of adverse effects such as sedation and respiratory depression.4
Methadone can cause QT prolongation which may lead to the development of potentially fatal arrhythmias. This is particularly
associated with higher doses (e.g. >150 mg/day). Other risk factors include concomitant use of drugs that also prolong
the QT interval, and use in patients with cardiac disease. ECG monitoring is recommended for these patients.5, 6
Large dose changes of methadone are not often required after initial titration unless the clinical picture changes.
If therapeutic effect changes during treatment, consider whether the potential addition of another drug has altered the
plasma concentration of methadone and therefore its therapeutic effect.1
Adverse effects – monitoring for respiratory depression is especially
Constipation, drowsiness and respiratory depression are potential adverse effects. Respiratory depression is a particular
concern and patients should be monitored on a daily basis during the initial titration period. Consider hospital admission
for a patient with a respiratory rate of less than 12 breaths per minute.
Methadone causes significant constipation as do other opioids. A stimulant/softener laxative should always be prescribed
Educate patients about the safe and effective use of methadone:
- Effective pain relief can take several days.1 Advise that the initial dose may not provide adequate pain
relief but reduces the chance of adverse effects, and the dose will be titrated to an effective level.2
- Use of methadone in combination with other opioids, other drugs or alcohol can be fatal.
- Frequent monitoring is required during initiation and maintenance of treatment. Patients should be instructed to immediately
report any increasing or intolerable adverse effects.
- Constipation is a common adverse effect so advise patients to take laxatives as prescribed, eat a well-balanced diet
containing plenty of fibre and drink adequate fluids.
- Patients may be aware that methadone is used to treat opioid addiction and may be concerned about the social stigma.
Reassure them that this is an accepted pain medication and explain the difference between dependence and addiction.
- Toombs JD. Oral methadone dosing for chronic pain. A practitioner’s guide. Pain treatment topics 2008. Available
from: http://pain-topics.org/ (Accessed November 2008).
- Veterans Administration/Department of Defence (VA/DoD). Clinical practice guideline for the management of opioid
therapy for chronic pain 2003. Available from: http://pain-topics.org/ (Accessed
- Manfredi PL, Houde RW, Prescribing methadone, a unique analgesic. J Support Oncol 2003;1:216-20.
- Baxter K (ed). Stockley’s Drug Interactions. [online] London: Pharmaceutical Press.
- Medsafe. Cardiac vigilance recommended for methadone. Prescriber Update 2005; 26(2):23-5.
- M Sweetman SC (ed), Martindale: The Complete Drug Reference 35. [online] London: Pharmaceutical Press. Available
from: http://www.medicinescomplete.com (Accessed November 2008).