ࡱ> _ Vbjbj ;bb6C22fffzzz8Lz)wv#(##$<>G?Lvvvvvvv$'y{vvfAW<W<^AAv2pP#6$vLLLA$R$vLAvLLRePD"2i$0@TDNFgvv0)wdgO|>FO|<2i2i*O|f\o8?>?,L?$!@???vvTI.???)wAAAAO|????????? : Q&A 302. 3 How should conversion from oral morphine to fentanyl patches be carried out? Prepared by UK Medicines Information ( HYPERLINK "http://www.ukmi.nhs.uk/ukmi/about/default.asp?pageRef=1" UKMi) pharmacists for NHS healthcare professionals Date prepared: 30th July 2012 (partial revision 17th December 2012) Background Fentanyl patches are an effective alternative to oral morphine and a common question is how to change a patient from oral morphine to a fentanyl patch (). Fentanyl patches are indicated in patients with stable pain who have difficulty swallowing, unacceptable side effects with oral morphine or other opiates e.g. oxycodone, hydromorphone; renal failure, persistent nausea and vomiting, gastrointestinal obstruction or poor compliance with oral medication (,). Each new patch is applied for 72 hours and provides continuous delivery of fentanyl ( NOTEREF _Ref254358012 \h 2). Fentanyl patches are not suitable for acute pain or for patients who have rapidly changing analgesic requirements because the long time to steady state prevents rapid titration of the dose (). The National Patient Safety Agency issued a rapid response report in July 2008 aimed at reducing dosing errors with opioid medicines (). This highlights dose conversion as one of the areas where prescribing errors can occur ( NOTEREF _Ref260314005 \h 5). It states: where a change in formulation or medicine is required, practitioners inexperienced in the use of opioids should use references for dose conversion to aid calculation of a safe dose ( NOTEREF _Ref260314005 \h 5). Answer Advice on equivalent potencies of oral morphine and transdermal fentanyl Manufacturers list a wide range of oral morphine doses corresponding to each fentanyl patch strength, with a resultant wide range in conversion ratios of oral morphine to transdermal fentanyl (approximately 75:1 to 223:1) ( NOTEREF _Ref254358012 \h 2,,,,,,,). Studies confirm the wide range in conversion ratios and note that ratios that are conservative in one direction may be excessive in the reverse ( NOTEREF _Ref254358012 \h 2,). Direct conversion from oral morphine to transdermal fentanyl with a ratio of oral morphine to transdermal fentanyl of 100:1 was examined in 98 patients with cancer pain (). Regression analysis at the end of the study revealed a mean oral morphine to transdermal fentanyl ratio of 70:1 ( NOTEREF _Ref254873702 \h 14). However, the authors concluded that a calculation table for the conversion of oral morphine to transdermal fentanyl with a ratio of 100:1 is safe and effective ( NOTEREF _Ref254873702 \h 14). Although this is lower than the true ratio determined in the study, it implies a sufficient margin for safety and may avoid overdoses caused by inter-individual differences in response to different opioids ( NOTEREF _Ref254873702 \h 14). A conversion ratio of 100:1 is also endorsed by the Palliative Care Formulary (PCF), a resource about the use of medicines in palliative care and the British National Formulary (BNF) ( NOTEREF _Ref254880543 \h 3, NOTEREF _Ref255379027 \h 4). However, manufacturers guidance and some local guidelines advocate a range of conversion ratios to avoid overdosing patients ( NOTEREF _Ref260315609 \h 6, NOTEREF _Ref260315611 \h 7, NOTEREF _Ref255380318 \h 8, NOTEREF _Ref255381896 \h 9, NOTEREF _Ref327888001 \h 10, NOTEREF _Ref260315616 \h 11, NOTEREF _Ref260315617 \h 12,). NICE advise to Use caution when calculating opioid equivalence for transdermal patches: A transdermal fentanyl 12 microgram patch equates to approximately 45 mg oral morphine daily (). Comparative doses of oral morphine to transdermal fentanyl are given in Table 1. The dose conversion used in this table of oral morphine: transdermal fentanyl demonstrates the ratio advocated in practice of 100:1 (recommended by the BNF and PCF). The Summary of Product Characteristics (SPC) for the specific fentanyl patch being used should also be consulted. The dose conversions advised vary between SPCs and may be up to 223:1. This is an approximate guide only as comprehensive data are lacking and there is inter-individual variation. Patients who are taking a daily dose of morphine that falls between fentanyl patch strengths will need to be changed to a patch which is either slightly less or slightly more potent than the morphine dose ( NOTEREF _Ref254880543 \h 3). This will be a clinical decision. In practice, many clinicians start at a lower dose and titrate with oral morphine ( NOTEREF _Ref260316879 \h 15). It is advisable to establish the exact analgesic requirement before initiating or changing the patch strength ( NOTEREF _Ref260316879 \h 15). If switching because of possible opioid-induced hyperalgesia, reduce the calculated equivalence by 25-50% ( NOTEREF _Ref254880543 \h 3). Patients will require frequent reassessment of efficacy and adverse effects and dose titration after patch initiation or dose change as well as a short acting opioid for breakthrough pain ( NOTEREF _Ref254358012 \h 2). Steady state concentrations of fentanyl are reported as being achieved after approximately 36 to 72 hours ( NOTEREF _Ref254880543 \h 3,). The patient should use breakthrough analgesia as needed for the first 3 days particularly the first 24 hours ( NOTEREF _Ref254880543 \h 3). Appropriate when required doses of morphine are given in Table 1. If the patient requires two or more rescue doses of morphine per day after 48 hours, the strength of the next patch to be applied (after 72 hours) should be increased by the equivalent patch strength (usually 12-25 micrograms/hour) ( NOTEREF _Ref254880543 \h 3, NOTEREF _Ref260316879 \h 15). Dose adjustment is not recommended more frequently than every 72 hours and dose titration should be limited to increments of 12 or 25 micrograms/hour as appropriate ( NOTEREF _Ref254880543 \h \* MERGEFORMAT 3, NOTEREF _Ref255220933 \h 13). Table 1: Conversion doses from oral morphine to transdermal fentanyl based on the dose ratios 100:1 (adapted from the PCF and the BNF) ( NOTEREF _Ref254880543 \h 3, NOTEREF _Ref255379027 \h \* MERGEFORMAT 4) Note: this table should be used in conjunction with Summary of Product Characteristics for the fentanyl patch being used Oral 24-hour morphine (milligrams/day)Transdermal fentanyl When required dose of morphine (milligrams) advised in PCFa(micrograms/hour)milligrams/24hours30120.3560 250.610120 501.220180 751.830240 1002.440using traditional 1/6 of total daily dose as when required dose More than one fentanyl patch may be used for dose adjustments and for doses greater than 100micrograms/hour ( NOTEREF _Ref255379027 \h \* MERGEFORMAT 4, NOTEREF _Ref260315616 \h 11). However, they should be applied at the same time to avoid confusion ( NOTEREF _Ref255379027 \h \* MERGEFORMAT 4). When should the regular oral morphine be stopped following the initiation of fentanyl patches? Effective systemic analgesic concentrations of fentanyl are usually reached less than 12 hours after applying the patch ( NOTEREF _Ref254880543 \h 3). When converting oral morphine to transdermal fentanyl: if taking 4 hourly oral morphine, continue giving regular doses for 12 hours after applying the fentanyl patch if taking 12 hourly modified release morphine, give the last dose and apply the first fentanyl patch at the same time if taking 24 hourly modified release morphine, apply the first fentanyl patch 12 hours after the final modified release dose ( NOTEREF _Ref254358012 \h 2, NOTEREF _Ref254880543 \h 3). Are there any other factors to consider when switching from oral morphine to fentanyl patches? Fentanyl is less constipating than morphine ( NOTEREF _Ref254880543 \h 3, NOTEREF _Ref254873702 \h 14). Therefore, when patients are converted from morphine to fentanyl, the dose of laxative(s) may need to be reduced and subsequently adjusted according to need ( NOTEREF _Ref254880543 \h 3, NOTEREF _Ref260316879 \h 15). Patients may suffer from withdrawal symptoms (e.g. restlessness, diarrhoea, colic, nausea, sweating) despite satisfactory pain relief ( NOTEREF _Ref254880543 \h 3, NOTEREF _Ref260315616 \h 11). These symptoms can be treated with rescue doses of morphine until they resolve after a few days ( NOTEREF _Ref254880543 \h 3). Since peak fentanyl levels occur after 12 to 24 hours of treatment, monitoring of the patient for adverse events, which may include hypoventilation is recommended for at least 48 hours after initiation of transdermal fentanyl or up-titration of the dose ( NOTEREF _Ref260315616 \h 11). Healthcare professionals should ensure patients and caregivers are aware of signs and symptoms of fentanyl overdose i.e. trouble breathing or shallow breathing; tiredness; extreme sleepiness or sedation; inability to think, walk or talk normally; and feeling faint, dizzy or confused. Patients and caregivers should be advised to seek medical attention immediately if overdose is suspected (). Fentanyl toxicity may be more subtle than morphine toxicity due to a lack of hallucinations, myoclonus etc. and can present as vagueness, drowsiness or not feeling well ( NOTEREF _Ref255220321 \h 17). When a fentanyl patch is removed a subcutaneous depot remains ( NOTEREF _Ref254358012 \h 2). Serum concentrations fall gradually, decreasing by 50% in 16 hours (range 13 to 22 hours) ( NOTEREF _Ref254358012 \h 2). Patients who experience serious adverse effects should have patches removed immediately and should be monitored for up to 24 hours after the patch is removed ( NOTEREF _Ref327974201 \h 18). Increased body temperature, exposure of patches to external heat sources, and concomitant use of CYP3A4 inhibitors may lead to potentially dangerous increases in serum fentanyl levels. Concomitant use of other CNS depressants might also potentiate fentanyl adverse effects ( NOTEREF _Ref327974201 \h 18) There are two different formulations of fentanyl patch reservoir and matrix which can be supplied against a direction for fentanyl patch. Where possible patients should be maintained on the same formulation ( NOTEREF _Ref260316879 \h 15). Abuse potential of reservoir patches should be a consideration in areas of high drug diversion ( NOTEREF _Ref260316879 \h 15). NICE Guidance states: Consider initiating transdermal patches with the lowest acquisition cost for patients in whom oral opioids are not suitable and analgesic requirements are stable, supported by specialist advice where needed ( NOTEREF _Ref331427612 \h 16). Summary Data from a small study has shown that conversion of oral morphine to transdermal fentanyl with a ratio of 100:1 is safe and effective. This ratio is also endorsed by the Palliative Care Formulary and the British National Formulary. This differs from ratios recommended in some UK Summary of Products Characteristics . The decision regarding which conversion ratio to use should be based on patient specific factors, the level of patient monitoring which can be offered and the clinical setting. Comparative doses of oral morphine and transdermal fentanyl are given in Table 1. This should be used in conjunction with the Summary of Product Characteristics for the fentanyl patch being used. Patients who are taking a daily dose of morphine that is not exactly equivalent to a particular fentanyl patch strength, will need to be changed to a patch which is either slightly less or slightly more potent than the morphine dose. This will be a clinical decision based on patient specific factors and patients should be monitored. Effective systemic analgesic concentrations of fentanyl are reached less than 12 hours after applying the patch. Guidance is given above regarding the discontinuation of the regular morphine dose. Patients will require frequent reassessment of efficacy and adverse effects and dose titration after patch initiation or dose change as well as a short acting opioid for breakthrough pain. Steady state concentrations of fentanyl are reported as being achieved after approximately 36 to 72 hours. The patient should use breakthrough analgesia as required for the first 3 days particularly the first 24 hours. The dose of laxative(s) may need to be reduced and subsequently adjusted according to need as fentanyl is less constipating than morphine. Limitations Caution is needed when converting patients between oral morphine and transdermal fentanyl. The conversion ratios given are an approximate guide only because of: wide inter-individual variation in opioid pharmacokinetics ( NOTEREF _Ref254880543 \h 3) variables such as concurrent medication and nutritional status ( NOTEREF _Ref254880543 \h 3) interproduct variability and generic prescribing of fentanyl products a lack of comprehensive trial data The data presented are derived from adults and may not be applicable to children. The information in this Q&A should be used in conjunction with the relevant Summary of Product Characteristics. Disclaimer Medicines Q&As are intended for healthcare professionals and reflect UK practice. Each Q&A relates only to the clinical scenario described. Q&As are believed to accurately reflect the medical literature at the time of writing. The authors of Medicines Q&As arenot responsible for the content of external websites and linksaremade available solely to indicate their potential usefulness to users of NeLM.You must use your judgement to determine the accuracy and relevance of the information they contain. This document is intended for use by NHS healthcare professionals and cannot be used for commercial or marketing purposes. See  HYPERLINK "http://www.ukmi.nhs.uk/activities/medicinesQAs/default.asp" www.ukmi.nhs.uk/activities/medicinesQAs/default.asp for full disclaimer. References      From the NHS Evidence website  HYPERLINK "http://www.evidence.nhs.uk" www.evidence.nhs.uk   From the NHS Evidence website  HYPERLINK "http://www.evidence.nhs.uk" www.evidence.nhs.uk National Prescribing Centre. The Use of Strong Opioids in Palliative Care. MeReC Briefing. 2003; Issue 22. Accessed online at http://www.npc.nhs.uk/merec/pain/otherback/resources/merec_briefing_no22.pdf on 25/6/2012 Scottish Intercollegiate Guidelines Network. Guideline 106: Control of Pain in Adults with Cancer. November 2008. Accessed online at  HYPERLINK "http://www.sign.ac.uk/guidelines/fulltext/106/index.html" http://www.sign.ac.uk/guidelines/fulltext/106/index.html on 25/6/2012 Twycross R, Wilcock A (eds). Palliative Care Formulary. 4th Edition. Nottingham:Palliativedrugs.com Ltd : 2011 pp391-399. Martin J (editor). British National Formulary December 2012 4. Accessed online via:  HYPERLINK "http://www.bnf.org" www.bnf.org on 17/12/2012 . National Patient Safety Agency. Rapid Response Report: NPSA/2008/RRR05. Reducing dosing errors with Opioid Medicines. July 2008. Accessed online via  HYPERLINK "http://www.nrls.npsa.nhs.uk/resources/?entryid45=59888&p=2&char=R" http://www.nrls.npsa.nhs.uk/resources/?entryid45=59888&p=2&char=R on 23/05/2012 Summary of Product Characteristics - Osmanil 100 micrograms/hr transdermal patch. Zentiva. Accessed online at http://www.medicines.org.uk/emc/medicine/25661/SPC/ on 23/05/12 [date of revision of the text 24/08/2011] Summary of Product Characteristics Mezolar Matrix Transdermal Patches. Accessed online at http://www.medicines.org.uk/emc/medicine/21734/SPC/on 11/06/12 [date of revision of the text 11/2010] Summary of Product Characteristics Durogesic DTrans 12/25/50/75/100mcg/hr Transdermal Patch. Accessed online at http://www.medicines.org.uk/emc/medicine/17086/SPC/ on 12/06/12 [date of revision of the text 20th January 2012] Summary of Product Characteristics Fencino 75 micrograms/hour Transdermal Patch. Accessed online at http://www.medicines.org.uk/emc/medicine/25010/SPC/ on 19/06/2012 [date of revision of the text August 2011] Summary of Product Characteristics - Fentalis Reservoir Transdermal patches. Accessed online at http://www.medicines.org.uk/emc/medicine/21735/SPC/ on 25/06/2012 [date of revision of the text September 2007]. Summary of Product Characteristics - Matrifen. Accessed online at http://www.medicines.org.uk/emc/medicine/19278/SPC/ on 19/6/2012 [date of revision of the text 03/01/2012] Summary of Product Characteristics Victanyl 100 micrograms/hour Transdermal Patch (Actavis UK Ltd). Accessed online at  HYPERLINK "http://www.medicines.org.uk/emc/medicine/21568/SPC%20on%2019/06/2012" http://www.medicines.org.uk/emc/medicine/21568/SPC on 19/06/2012 [date of revision of the text 21/11/2011] Patanwala A, Duby J, Waters D et al. Opioid Conversions in Acute Care. Ann Pharmacother 2007; 41: 255-267. Donner B, Zenz M, Tryba, M et al. Direct conversion from oral morphine to transdermal fentanyl: a multicenter study in patients with cancer pain. Pain 1996;64:527-534. Specialist palliative care pharmacist, The Royal Marsden NHS Foundation Trust formally working at St Peters Hospice. Personal communication19/3/2010 and 19/7/2012 National Institute for Health and Clinical Excellence. Opioids in palliative care: safe and effective prescribing of strong opioids for pain in palliative care of adults. NICE Clinical Guideline 140. Issue date: May 2012. Accessed online via  HYPERLINK "http://www.nice.org.uk" www.nice.org.uk on 23/7/ 2012 Bank, I. Fentanyl, Palliative Care Guidelines Plus. Accessed online at  HYPERLINK "http://book.pallcare.info" http://book.pallcare.info on 26/03/2012 MHRA.Drug Safety Update. Volume 2, Issue 2, September 2008. Accessed online at  HYPERLINK "http://www.mhra.gov.uk/Publications/Safetyguidance/%20DrugSafetyUpdate/CON025631on" http://www.mhra.gov.uk/Publications/Safetyguidance/%20DrugSafetyUpdate/CON025631on 20/6/2012 Quality Assurance Prepared by Emma Templeman, South West Medicines Information & Training, Bristol Date Prepared 30th July 2012 (partial revision 17th December 2012) Checked by Julia Kuczynska, South West Medicines Information & Training, Bristol Date of check 1st August 2012 (partial revision checked 20th December 2012) Search strategy BNF December 2012.  HYPERLINK "http://bnf.org/bnf/" http://bnf.org/bnf/ Electronic Medicines Compendium. Accessed via  HYPERLINK "http://www.medicines.org.uk/emc/" http://www.medicines.org.uk/emc/ Martindale, The Complete Drug Reference. Pharmaceutical Press. Accessed via  HYPERLINK "http://www.medicinescomplete.com" www.medicinescomplete.com, MICROMEDEX Accessed via  HYPERLINK "http://www.thomsonhc.com/home/dispatch" http://www.thomsonhc.com/home/dispatch National Electronic Library for Medicine. Accessed via  HYPERLINK "http://www.nelm.nhs.uk" www.nelm.nhs.uk National Institute for Health and Clinical Excellence. Accessed via  HYPERLINK "http://www.nice.org.uk" www.nice.org.uk Clinical Knowledge Summaries. Accessed via  HYPERLINK "http://www.cks.nhs.uk" www.cks.nhs.uk Cochrane Library. Accessed via  HYPERLINK "http://www.thecochranelibrary.com" www.thecochranelibrary.com National Prescribing Centre website. Accessed via  HYPERLINK "http://www.npc.co.uk" http://www.npc.co.uk SIGN Guidelines. Accessed via  HYPERLINK "http://www.sign.ac.uk" http://www.sign.ac.uk Specialist palliative care textbooks and websites Embase (exp fentanyl AND exp morphine AND exp transdermal drug administration) Medline (exp fentanyl AND exp morphine AND exp administration, cutaneous) Specialist palliative care pharmacist, The Royal Marsden, London. 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