Methadone medication

Methods of methadone titration

There are several methods of methadone titration based on the level of expertise of the clinician involved, the availability of the patient for review and assessment and the urgency of achieving optimal pain relief. They can be categorised according to:

  • the aim of the process which is either to reduce or complement the use of another opioid or to discontinue the other opioid and achieve a complete switch, and
  • the timeframe of titration which is to achieve it within two weeks or over a longer duration.

Stop and start

This is method that has been popularised by Makin-Morley in the 1990’s (12) It is based on a ‘de novo’ titration of methadone that takes partial account of the dose of the previous opioid used but is mainly determined by the ability of the patient to signal when the pain is returning to administer the next dose of methadone whilst observing the patient very closely throughout the process for signs of opioid toxicity. 

In the hands of experts, it can allow a rapid titration and control of the pain within a few days of starting methadone and can be completed in most cases within 10 days to two weeks. It requires clear safeguards including opioid side-effects monitoring, frequent reviews by nursing staff to ensure patients are not left in pain and side-effects are closely monitored and documented. It also requires a strong commitment of the medical team to daily reviews (sometimes several times per day) and availability out of hours to advice, including face to face reviews. 

It can only be done as an in-patient in a specialist unit. For teams that are not so experienced, it is possible to use this method but additional measures such a lower starting methadone dose and allowing the use of another opioid for pain breakthrough will reduce the risks but will inevitably delay the titration process.

This method of switching to methadone must be done in a specialist inpatient unit.

  • Perform baseline ECG to assess QTc interval
  • Patients must be given verbal explanations about the purpose of the switch and the potential potency of the drug necessitating frequent assessment especially during the first week of titration. This should be backed up by written information when appropriate. (Download PDF: Patient information – Methadone for pain relief).
  • Support of those close to the patient should be sought and assurance given that ongoing support will be available if discharge to the usual place of residence is likely.
  • Start monitoring the patient’s potential opioid side effects using a monitoring chart prior to the methadone titration and during the conversion period (Download PDF: Opioid Monitoring chart).
  • The choice of the first dose of methadone should be decided according to the following criteria:
    • It should never exceed 30mg but 20mg may be a safer maximum for less experienced teams. This dose applies to any previous opioid intake of more than 500mg morphine equivalent per day.
    • If the patient has been taking less than 500mg of oral morphine (or equivalent) per 24hours, consider giving 20mg if the previous opioid total daily dose was equivalent to 200-500mg of oral morphine per day, 10mg if 100-200mg or 5mg if less than 100mg. These doses can be reduced by up to 50% by less experienced clinicians or when individual patients had experienced intolerable opioid side-effects at low doses (Download PDF: Flowchart of conversion to methadone).
  • The first methadone dose should be given early in the morning to replace the twice daily opioid preparation. It can be given immediately after transdermal fentanyl patches are removed or an opioid drug syringe driver disconnected.
  • Prescribe the same dose of methadone to be given ad libitum (as often as necessary) up to every 3 hours. Some centres with less experience of monitoring methadone titration use only 50% of the initial dose. This may delay achieving satisfactory analgesia if the requirement ends up fairly high but preferable in some cases, as long as the patient is aware of this.
  • Prescribe PRN alternative analgesia for if the pain returns during the 3-hour window, paracetamol 1gr QDS. Some centres using lower starting doses of methadone may prefer to use the previous fast-acting opioid.
  • It is essential that the patient is frequently reviewed by the nursing or medical staff and given the next dose of methadone as soon after 3 hours as the pain returns or if it persists.
  • Patients should be reviewed at least daily by a senior doctor experienced in the use of methadone. The doctor should consider:
    • any evidence of opioid side-effects especially excessive drowsiness,
    • whether the patient still experiences pain during the 3-hour window especially after the second day of titration,
    • how frequently methadone has been required throughout the previous 24hrs and globally since the start of the titration
    • If 1 or 2 doses were only required in the previous 24 hour or on average since starting titration, the ad libitum dose needs reducing respectively by 50% or 30%. If 5 or more doses were required, the ad libitum dose can be increased by 30 to 50%
  • Once the patient’s pain is controlled and the average daily dose requirement has been stable (usually between day 5 and day 10) they can be converted to a regular daily dosing regimen in 3 to 4 divided doses eg, to convert to a three times daily dose: Calculate the total amount of oral methadone used in the previous 48 hours and divide this amount by 6 to prescribe a three times daily regular dose of methadone.
  • For breakthrough pain, once a regular regimen is in place, the next methadone dose can be given early allowing for a maximum frequency of 4 hours. During this 4-hour interval, the use of a non-opioid analgesic is recommended. In exceptional circumstances and under medical supervision, if the pain experienced by the patient is too severe to allow them to wait for the effect of the next oral dose of methadone and the above is ineffective, 1/3 of the next oral methadone dose can be given subcutaneously. The next oral dose does not need to be delayed beyond 30 minutes of the injection as absorption by the subcutaneous route is clinically significant within 15 minutes.

Start low, go slow

This method involves continuing with the previous opioid both in the form of background pain relief and management of breakthrough pain episodes. The aim may be simply to spare the use of the other opioid and stop the titration when both patient and clinician believe the current level of pain relief is satisfactory. However, in most cases, it should be possible to complete the switch in full over time.

This method is suitable for outpatient titration, or as an inpatient, when the patient’s ability to cooperate with the titration process is limited by anxiety and difficulties to report and verbalise pain levels.

Sometimes, the patient and the clinician agree that inpatient titration is not desirable, or the degree of urgency to improve pain control is considered low. If that method is adopted, patients must be warned that it can take several weeks until they start benefiting from clinically significant pain relief.

The basic principle of this method is the slow upwards titration of methadone and the down titration of the previous (or alternative) opioid(s). It is not possible to give detailed guidance on how frequently dose changes can be made as it depends on the frequency of clinical review. A minimum of 5 days is required to ascertain the tolerance of a given dose before a dose increase should be considered.  The first week is the critical time to evaluate tolerance to methadone and once the exposure exceeds 4 weeks, the risk of significant toxicity following dose increases becomes low, allowing for more substantial dose increases if required.

This method of switching to methadone is better suited to the outpatient set up but still requires close monitoring and availability of clinicians out of hours. It should only be started when this availability can be anticipated, and appropriate senior backup is available.

  • It can be done as an inpatient as an alternative to the first method in cases when a patient’s collaboration is limited by various factors, but this is not recommended in the last weeks of life. In those cases, adjuvant prescription can be sometimes considered, preferably as an inpatient.
  • On day one, a starting dose of 5mg methadone once daily or 2.5mg twice daily should be well tolerated in opioid tolerant patients. Anybody taking on less than 60mg of oral morphine per 24 hours should start at a lower dose of 2.5mg daily or less at least for the first 5 days.
  • Close monitoring during the first 5 days after introducing methadone is essential, observing for any signs of opioid toxicity. After day 6, if there has been no evidence of opioid side-effects and additional pain relief is required, the dose can be doubled safely (5 mg methadone twice daily if 5mg daily is the initial dose).
  • Clinicians with less experience should prescribe half the above doses (2.5mg once daily initially and 2.5mg twice daily in the second week). This is a prudent approach for patients who are fearful of side-effects or sensitive to opioids in general.
  • The dosage of the concomitant opioid should be reduced rapidly if side-effects such as excessive sedation occur in the context of fair or satisfactory pain control during methadone titration.
  • Further face-to-face assessment should be scheduled within 5 to 7 days to decide on the subsequent dose increase as necessary.
  • If there is any clinically evident improvement in analgesia, then the next dose increase should be no more than a 50% increase. The other opioid background analgesia can also be reduced especially if the breakthrough frequency requirements are low.
  • If there are no changes in analgesia and there is no occurrence or worsening of opioid side-effects, a larger dose increase (75% to maximum 100%) can be decided after a minimum of two weeks of methadone exposure but close monitoring should continue.
  • If pain relief is already noticeable and there is some evidence of drowsiness, then reduction of the other opioid being administered alongside methadone should be carried out. Dose reductions can and should be done very quickly especially when pain relief is maintained.
  • The rate of reduction of the original opioid for each patient should be discussed and agreed with a Specialist Palliative Medicine consultant, experienced in the titration of methadone.
  • The regular dosing regimen of methadone, as with the other titration method, should be decided with the patient to maximise convenience and minimise side-effects.

Using as an adjunct

The addition of a relatively small dose of methadone is reported to benefit patients with cancer-related pain who have failed to obtain adequate relief from an appropriately titrated dose of morphine or other strong opioid (17). It is most suited to complex nociceptive-neuropathic pain that is poorly controlled despite use of adjuvant analgesics.  In this method, existing opioids are continued as methadone is introduced or increased. 

This method is suitable for outpatient titration, or as an inpatient, when the patient’s ability to cooperate with the titration process is limited for example due to anxiety or difficulties to report and verbalise pain levels. When using methadone as an adjuvant, depending on the patient’s clinical circumstances (renal function, weight, opioid sensitivity, side effects), it is not necessary to reduce the original opioid on the first methadone dose. However, on subsequent titration of methadone, it would be worth considering reduction in opioid dosing depending on the benefits that the patient is getting from the methadone (16).

The use of methadone is well-suited to the outpatient setting but still requires close monitoring and availability of experienced clinicians out of hours. It should only be started when this availability can be anticipated, and appropriate senior support is available.

  • Methadone as an adjunct can be done as an inpatient as an alternative to the first method in cases when a patient’s collaboration is limited by various factors. It is not generally recommended in the last weeks of life.
  • It is recommended that a starting dose of 2mg oral methadone twice a day should be well tolerated in opioid tolerant patients (16).
  • Aim for regular reduction of the concomitant opioid alongside titration of Methadone. The dosage of the concomitant opioid should be reduced rapidly if side-effects such as excessive sedation occur in the context of fair or satisfactory pain control during methadone titration.
  • If there is any clinically evident improvement in analgesia, then the next dose increase should be no more than a 50% increase. The concomitant opioid background analgesia can also be reduced especially if the breakthrough frequency requirements are low.
  • If there are no changes in analgesia and there is no occurrence or worsening of opioid side-effects, a larger methadone dose increase (75% to maximum 100%) can be decided after a minimum of two weeks of methadone exposure but close monitoring should continue.
  • If pain relief is already noticeable and there is some evidence of drowsiness, then reduction of the concomitant opioid being administered alongside methadone should be carried out.
  • The rate of reduction of the concomitant opioid for each patient should be discussed and agreed with a specialist palliative medicine consultant, experienced in the titration of methadone.
  • All patients must be followed up by a consultant in outpatients on discharge if methadone is commenced as an inpatient.
  • If commenced as an outpatient, further face-to-face assessment should be scheduled within 5 to 7 days to decide on the subsequent dose adjustment as necessary.

Conversion of subcutaneous methadone from oral methadone

  • This should be done if there is inability to continue with the oral route because of nausea and vomiting or difficulties swallowing methadone in progressive disease.
  • The conversion ratio should be 50-66% of previous oral dose (2:1 or 3:2 conversion) based on oral bio-availability (5).
  • The continuous subcutaneous infusion should be started at the calculated dose between 8 and 24 hours after the last dose of oral methadone has been taken because blood levels take a long time to drop reflecting methadone long half-life.
  • Following switching of route of administration, all patients should be monitored for signs of pain or opioid side-effects using an opioid monitoring chart (Download PDF: Patient information – Methadone for pain relief). Should either of these occur the methadone dose should be modified accordingly.
  • Subcutaneous methadone is an irritant and can cause local site reactions.
  • These reactions can be reduced by:
    • Adding dexamethasone 0.66mg to the syringe containing methadone  (1, 5).
    • Maximising the dilution of the methadone by using a 30ml syringe.
    • Using sodium chloride 0.9% as the diluent (2).
    • Avoid mixing methadone with any drug other than dexamethasone in the same syringe whenever possible due to lack of compatibility data.
  • Breakthrough pain for patients receiving subcutaneous methadone should be managed with caution due to potential for accumulation. Up to two doses of 1/6 of the 24-hour dose is safe but beyond that an alternative short-acting opioid may be preferable. It should be noted that patients well pain controlled on regular methadone rarely face complex pain at the end of life.

Conversion of methadone to other opioids

  • It is not recommended and rarely required clinically but if this is required for other reasons, patients and health care professionals should be warned that it could result in the return of severe pain.
  • This should only be undertaken by specialist palliative care teams and is not covered in the remit of this guidance. Please refer to SPCT or specialist pain teams.

Opioid withdrawal symptoms

(See references 3,5,6,12)

Opioid withdrawal syndrome is important to recognise and manage due to its unpleasant symptoms and due to a small but significant risk of death.

  • Patients should be monitored for signs of opioid withdrawal. Opioid withdrawal syndrome may resemble a severe flu-like illness characterised by:
    Rhinorrhoea, Sneezing, Yawning, Lacrimation, Abdominal cramping, Leg cramping, Piloerection, Nausea, Vomiting, Diarrhoea, Dilated pupils
    Some patients may also experience anxiety, restlessness, irritability and insomnia
  • Disorientation, hallucinations and seizures which are characteristic of delirium tremens are not seen in opioid withdrawal.
  • If a patient should experience signs of opioid withdrawal, they should be promptly referred to the specialist palliative care or pain team. Management options include:

    • Use of methadone in the same way as for analgesia
    • Administration of breakthrough doses of the previous opioid
    • A benzodiazepine can be added to control insomnia and muscle cramps

Disclaimer (SPAGG - Rewrite)

This Guide is intended for use by healthcare professionals and the expectation is that they will use clinical judgement, medical, and nursing knowledge in applying the general principles and recommendations contained within. They are not meant to replace the many available texts on the subject of palliative care.

Some of the management strategies describe the use of drugs outside their licensed indications. They are, however, established and accepted good practice. Please refer to the current BNF for further guidance.

While WMPCPS takes every care to compile accurate information , we cannot guarantee its correctness and completeness and it is subject to change. We do not accept responsibility for any loss, damage or expense resulting from the use of this information.