GUIDELINES FOR CONVERSION FROM A STRONG OPIOID TO METHADONE GENERAL PRINCIPLES Methadone may be used as a strong opioid alternative when severe cancer-related pain responds poorly to other opioids, or when there are dose-limiting side effects with other opioids. 1,2,3 Methadone pharmacology is complex and the use of methadone is associated with a risk of drug accumulation. Conversion to methadone should take place in a specialist unit which is familiar with its use. 1,2,4,5 The dose of methadone should always be prescribed in milligrams (mg) and not millilitres (ml). 6 There are three different strengths of methadone solution used for pain control. These are 1mg/ml, 10mg/ml and 20mg/ml (unlicensed preparation). 1,6,7 Methadone Linctus is a solution of 2mg/5ml. It should only be prescribed for patients with intractable cough and should not be used for pain control. 7 There have been concerns raised about the cardiac toxicity of methadone, specifically related to effects on the QT interval with doses >100mg. 9,10 However, studies have not shown a link between oral methadone and cardiac toxicity in ambulatory cancer patients. 7,8,9,11 For patients with a history of cardiovascular disease the benefit should outweigh the risk and clinical judgment should be used. 6 Concomitant treatment of methadone with medication known to prolong the QT interval should be avoided where possible. For more information contact your local pharmacist (See Table 1) 12 Table 1 List of commonly prescribed medication that may increase QT interval prolongation. 12 Antidepressants Antibiotics Antiemetics Antifungals Antipsychotics Amitriptyline Citalopram Escitalopram Fluoxetine Paroxetine Sertraline Venlafaxine Domperidone Ondansetron Fluconazole Haloperidol Others Ciprofloxacin Clarithromycin Erythromycin Levofloxacin Alfuzosin Amiodarone Tolterodine Salmeterol Sotolol
These guidelines outline a five day dose titration phase using a 'loading dose' and fixed dose of methadone before converting to a 12-hourly dosage regimen for chronic treatment. 1,4 Methadone can potentially interact with drugs that inhibit CYP3A4 and CYP2B6. This includes erythromycin and azole anti-fungals. Although a 50mg dose of Fluconazole is unlikely to be significant, caution should still be used. 7,13 Prior to commencing methadone, patients should be warned that it may take 24-48 hours before there is any significant improvement in pain relief, or any reduction in side effects. There is no specific guidance available for use in hepatic or renal impairment, however doses should be titrated cautiously and dose reductions may be required. Plasma levels would be expected to be increased in hepatic impairment as methadone is metabolised by the liver. 14 GUIDELINES Calculating the loading dose of methadone 1 [Level 4] The loading dose of methadone should be 10% of the total oral morphine dose given over the preceding 24 hours. The dose should be taken orally. The upper limit of the loading dose of methadone should not exceed 30mg. For example, if a patient is taking MST Continus 90mg bd, the total 24-hour oral morphine dose is 180mg. The loading dose of methadone should be 180mg 10 = 18mg of methadone. When converting from diamorphine, oxycodone, hydromorphone or a fentanyl patch, firstly convert the dose to an equivalent 24-hour oral morphine dose. The loading dose of methadone will again be 10% of this dose with an upper limit of 30mg (see Guidelines on Strong Opioid Substitution). 17 Calculating the fixed dose of methadone 1, 14 [ Level 4] The fixed dose of methadone should be a third of the loading dose of methadone. This will be given orally as required but not more frequently than every three hours. This is due to the risk of toxicity from drug accumulation. If the patient requires analgesia within three hours of the previous dose of methadone, an alternative non-opioid analgesic or short acting opioid e.g. morphine sulphate solution, should be used. For example, if the loading dose of methadone was 18mg, the fixed PRN dose would be 18 3 = 6mg. Administration and titration phase 1, 14 [Level 4] See Figure 1 Stop the patient s previous opioids abruptly. Administer a loading dose as a once only prescription o If switching from 12 hourly modified release preparation If in pain give the loading dose of methadone 6 hours after the last dose If pain free give the loading dose of methadone 12 hours after the last dose
o If switching from 24 hourly modified release preparation or transdermal fentanyl If in pain - give the loading dose of methadone 12 hours after the last dose If pain free give the loading dose of methadone 24 hours after the last dose If pain relief is needed after discontinuation of the patients previous opioids and before administration of the loading dose, an alternative non-opioid analgesic or short acting opioid (patients previous dose) e.g. morphine sulphate solution, should be used. For the first 5 days, a 'fixed dose' equal to a third of the loading dose of methadone should be taken orally as required but not more frequently than every three hours. This should not be given until at least three hours after the loading dose. If the patient requires analgesia within three hours of the previous dose o r l o a d i n g d o s e o f methadone, an alternative non-opioid analgesic or short acting opioid (patients previous dose) e.g. morphine sulphate solution, should be used Consider reducing the fixed dose if use is infrequent e.g. twice daily; or if the patient shows signs of drowsiness or toxicity. During the dose titration phase, methadone requirements usually drop on day two and three before reaching a steady state on day four and five. On day six, the twice-daily dosage regimen is calculated by dividing the total dose of the previous 48 hours (i.e. day four and five) by four, and using this dose 12-hourly for chronic treatment. Other dosing schedules e.g. three or four times a day can be considered for patients who suffer from end of dose failure or increased drowsiness around the time of administration. If there is an unexpected escalation in pain during the titration phase, the conversion should be considered to have failed and the patient should return to the initial analgesic regimen. There is no recognised conversion from methadone back to another strong opioid. General advice is to base the dose on previous requirement but use lower doses (i.e. 30-50% lower) and re-titrate. Clinicians need to be prepared to increase the dose and ensure that appropriate rescue doses are available. 6,15 Administration of methadone via a C S C I i s not recommended during the titration phase due to the risk of drug accumulation. Chronic treatment following dose titration 1, 14 [Level 4] Methadone is given every 12 hours during chronic treatment or at intervals that optimise symptom control and avoid side effects. There is little consensus as to what should be used for rescue analgesia during chronic treatment with methadone. Success has been reported using oral methadone at a dose of either one sixth or one tenth of the 24-hour methadone dose. The rescue dose should not be given more frequently than every three hours. If more than two rescue doses are required over a 24-hour period, the twice-daily dose of methadone should be increased by 30-50% but the increase should not happen more frequently than every seven days. Routes of administration Methadone may be given by subcutaneous infusion if oral administration is not possible. The subcutaneous route is often complicated by site inflammation which may result in frequent site changes. It is possible to give intermittent subcutaneous injections. 1,6,16 [Level 4]
The dose of methadone given in the syringe pump over 24 hours should be half of the 24-hour oral dose. The methadone should be diluted with sodium chloride 0.9%. Syringe pump sites should be changed every 24 hours to avoid local irritation. Dexamethasone 1mg can be added to the syringe pump to avoid site reactions 1, 6. [Level 4] Methadone may be given rectally by suppository. Various strengths are available as unlicensed preparations from Martindale. The relative potency of rectal to oral methadone is 1:1. [Level 4] Monitoring Electrolytes (K +, Mg 2+ and Ca 2+ ) should be checked before initiating methadone treatment and periodically throughout, with corrections made as required [Level 4] Consider where available, ECG monitoring at baseline and after dose increases if other risk factors for QT interval prolongation present or using large doses [Level 4] Discharge of patients on methadone If a patient is discharged on oral methadone, the discharge letter should include a contact name and telephone number for advice on further management. 6 [Level 4] Prior to discharge, the designated community pharmacist should be contacted to discuss dose, concentration and the supply of methadone. 6 [Level 4] Copies of the discharge letter should be sent to all health care professionals involved in the patient s care. 6 [Level 4] STANDARDS 1. The decision to convert a patient to methadone should be clearly documented in the case notes. 6 [Grade D] 2. Methadone should always be prescribed in milligrams (mg). 6 [ Grade D] 3. Methadone should be administered orally during the dose titration phase. 4 [Grade D] 4. If administering methadone via a subcutaneous infusion, then sodium chloride 0.9% should be used for dilution. 1, 6 [Grade D] 5. Syringe pump sites should be changed every 24 hours. 6 [Grade D] 6. If a patient is discharged on methadone, the discharge letter should include a named contact and telephone number for further advice. 6 [Grade D] 7. Naloxone injection should be available in all units administering methadone to treat opioid toxicity 6 [Grade D] REFERENCES 1. Twycross R, Wilcock A. (editors) Palliative Care Formulary 4th edition.nottingham.palliative drugs.com Ltd. 2011.p.416-423. 2. Nicholson AB. Methadone for cancer pain. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD003971. DOI: 10.1002/14651858.CD003971.pub3.Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.cd003971.pub3/pdf [Last accessed January 2014]
3. Mercadante S, Casuccio A, Fulfaro F, Groff L, Botti R, Villari P et al. Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study. J Clin Oncol 2001; 19(11): 2898-2904. 4. Morley JS, Makin MK. The use of methadone in cancer pain poorly responsive to other opioids. Pain Reviews 1998; 5: 51-58. 5. Bruera E, Sweeney C. Methadone use in cancer patients with pain: a review. Palliat Med 2002; 5(1): 127-138. 6. and Cheshire Palliative Care Network Audit Group. Conversion to Methadone. Expert Consensus. 2012. 7. Joint Formulary Committee. British National Formulary 63. London: British Medical Association and Royal Pharmaceutical Society Great Britain, 2012. 8. FDA Public Health Advisory. Methadone Use for Pain Control May Result in Death and Life Threatening Changes in Breathing and Heart Rate. Available from: http://www.fda.gov/drugs/drug safety/public health advisories/ucml124346.htm. [Last accessed 27 June 2009] 9. Reddy S, Fisch M, Bruera E. Oral methadone for cancer pain. No evidence of QT interval prolongation or torsades de pointes. J Pain Symptom Manage 2004; 28(4): 301-303. 10. Cruciani RA. Methadone: To ECG or Not to ECG. That is Still the Question. J Pain Symptom Manage 2008; 36 (5): 545-552 11. Gray A. Systematic review of the safety of buprenorphine, methadone and naltrexone. WHO Guidelines for Psychosocially Assisted Pharmacotherapy of Opioid Dependency. Available from:www.who.int/substance_abuse/activities/buprenorhine_methadone_naltrexone.pdf. [Last accessed 29 June 2009] 12. QT interval REF: Arizona Cert. www.azcert.org/medical -pros/drug-lists/list- 03.cfm?sort=generic_name 13. Stockley s Drug Interactions. 9th Edition. London: Pharmaceutical Press. 2010 14. Dickman, A. Drugs in Palliative Care. 2 nd Edition. Oxford: Oxford University Press. 2012 15. Moryl N, Santiago-Palma J, Kornick C, Derby S, Fischberg D, Payne R et al. Pitfalls of opioid rotation, substituting another opioid for methadone in patients with cancer pain. Pain 2002; 96(3): 325-328. 16. Centeno C, Vara F. Intermittent subcutaneous methadone administration in the management of cancer pain. J Pain Pall Care Pharmacother 2005; 19(2): 7-12. 17. Cheshire and Palliative and end of Life Care Network Audit Group. Guidelines for Strong Opioid Substitution in Palliative Care. Standards and Guidelines 2010. 4 th edition 2010. Available from: http://www.nwcscnsenate.nhs.uk/files/7214/5944/0143/auditguidelines2010_updated_comm ents_march2016.pdf?pdfpathway=pdf
CONTRIBUTORS Lead Contributors Dr S Fradsham Speciality Registrar In Palliative Medicine Marie Curie Hospice Liverpool Dr A Thompson Assistant Medical Director Willowbrook Hospice External Reviewer Dr K Levshankov Consultant Anaesthetist St Helens and Knowsley Teaching Hospitals NHS Trust Dr A Coackley Consultant in Palliative Medicine Willowbrook Hospice and Clatterbridge Centre for Oncology NHS Foundation Trust Wirral Dr A Scott Specialty Registrar in Palliative Medicine Willowbrook Hospice Dr H Bonwick Associate Specialist in Palliative Medicine Marie Curie Hospice Liverpool and Liverpool Heart and Chest Hospital NHS Trust Liverpool Ms R Clark Palliative Care and Clinical Trials Pharmacist Marie Curie Hospice Liverpool Dr G Whyte Macmillan Consultant in Palliative Medicine Aintree University Hospitals NHS Foundation Trust Liverpool Mr A Dickman Consultant Pharmacist in Palliative Care Blackpool Teaching Hospitals NHS Foundation trust Blackpool