Table Of Content(cid:2)RESEARCH ARTICLE
A review of common methods to
convert morphine to methadone
Eric Wong, Doctor of Pharmacy Candidate1 and
Kathryn A. Walker, PharmD, BCPS, CPE2,3*
1UniversityofMarylandSchoolofPharmacy,Baltimore,MD,USA;2DepartmentofPharmacyPractice
and Science, UniversityofMaryland SchoolofPharmacy, Baltimore,MD, USA; 3Department of
Medicine,Union MemorialHospital, Baltimore, MD,USA
Whendosedappropriatelyoncarefullychosenpatients,methadonecanbeaverysafeandeffectivechoicein
managing chronic pain. Many authors have discussed important issues surrounding patient selection, drug
interactions, screeningforQTcprolongationandmonitoring. Thisarticlewillfocusonthe dosingdilemma
thatexistsafterthepatientisdeemedanappropriatecandidateformethadoneandaconversionisnecessary
from anotheropioid. Despite many publications dedicated to addressing this challenging topic, there is no
consensusonthemostappropriatemethodforconvertinganopioidregimentomethadone.Giventhelackof
concreteguidance,cliniciansinacommunitysettingarelikelytobefacedwithanincreasedchallengeifthere
are no available pain specialists to provide clinical support. Common methods for converting morphine to
methadonewillbereviewedandtwoclinicalpatientscenariosusedtoillustratetheoutcomesofapplyingthe
methods.
Keywords: methadone;opioidrotation;conversion;painmanagement;equianalgesic
Received:14 August 2012; Revised:26 October 2012; Accepted:2 November 2012; Published: 7 January 2013
Theroleofmethadoneinpainmanagementisoften opioid to use in the conversion; and 2) unlike other
misunderstoodasitistraditionallyassociatedwith opioids,conversiontomethadoneisnotbasedonalinear
opioidagonisttherapyrelatedtosubstanceabuse. model (12). Methadone’s unique mechanism of mu
However, when dosed appropriately on carefully chosen receptor agonism paired with N-Methyl-D-Aspartate
patients, methadone can be a very safe and effective (NMDA) antagonism is thought to be responsible for
second-line option in managing chronic pain (1(cid:2)4). diminishing the tolerance developed as doses of other
Utilizing methadone as an analgesic can be compli- opioids are increased. Despite the evidence supporting
cated by the pharmacokinetic and pharmacodynamic thisnon-linearrelationship,thedecisionofwhichmethod
profile(5(cid:2)8).Thispresentsabarrierwhencomparedwith to use in clinical practice can be daunting (3, 10, 12, 14,
morepredicableopioidssuchasmorphine.Manyauthors 18(cid:2)21). We will illustrate the well-known methods for
have discussed important issues surrounding patient converting to methadone using community hospital case
selection, drug interactions, screening for QTc prolonga- examples (Table 1).
tion and monitoring (9(cid:2)12). This article will not discuss To begin the process of initiating methadone therapy,
making the decision of whether to use methadone in a onemustconsidermanyvariables.Theagentandpatient
specificpatientsituation,butinsteadfocusonthedosing variables must be carefully examined in light of the
clinical scenario to determine whether a patient is an
dilemma that exists after the patient is deemed an
appropriate candidate for methadone therapy. Both case
appropriate candidate. Despite many publications dedi-
example patients have been screened and determined
cated to addressing this challenging topic, there is no
to be appropriate for methadone therapy, however a
consensusonthemostappropriatemethodforconverting
conversion method must be chosen.
anopioidregimentomethadone(13(cid:2)17).Giventhelack
of concrete guidance, clinicians in a community setting
are likely to be facedwith an increased challenge if pain Methadone dosing methods
specialists are not available to provide clinical support. The manufacturer of methadone recommends that
Two things that are consistent among the different opioid-na¨ıve patients receive methadone 2.5(cid:2)5 mg PO
methodsare:1)theuseoforalmorphineasthestandard every8(cid:2)12hours(20).However,itiscommonforpatients
JournalofCommunityHospitalInternalMedicinePerspectives2012.#2012EricWongetal.ThisisanOpenAccessarticledistributedunderthetermsof 1
theCreativeCommonsAttribution-Noncommercial3.0UnportedLicense(http://creativecommons.org/licenses/by-nc/3.0/),permittingallnon-commercial
use,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
Citation:JournalofCommunityHospitalInternalMedicinePerspectives2012,2:19541-http://dx.doi.org/10.3402/jchimp.v2i4.19541
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EricWongetal.
Table1. Case examples algorithm(Fig.1).TheMorley(cid:2)Makinmodeldirectsthe
clinician to offer a methadone dose equal to 10% of the
Case1:A52-year-oldCaucasianmanwithahistoryof daily oral morphine dose (but not to exceed 30 mg) as
esophagealcancerstatusposttracheostomyandPEGtube neededevery3hours(21).After5daysofadministration,
placementisreceivingopioidsforthemanagementofchronic the total daily methadone doses required on days 4 and
pain.Hiscurrentcourseofpainmedicationismorphine 5areaveraged.Thisrepresentsthenewtotaldailydoseof
4mgIVevery3hoursscheduledtoavoidswallowingtablets methadone to be given in divided doses twice daily. In a
andithasbeeneffectivelyrelievinghispainwithminimaluseof community hospital setting, this approach can be very
breakthroughopioiddoses.Themedicalteamisconsidering resource intensive because of the frequent dose adminis-
methadoneliquidtoprovidelongactinganalgesia. tration required for the first 5 days. If the patient is
admitted during this time, it allows for verification of
Case2:A66-year-oldAfrican-Americanwomanwithahistoryof
administered doses and increased confidence in calculat-
severediabeticperipheralneuropathyandlowbackpain.She
hasbenefitedfromthelastincreaseinherlongactingopioids, ingasafedoseformaintenance.Thismethodisnotideal
howevershehaspresentedwithmyoclonusthoughttoberelated to use in a home setting where documentation of each
totheincreaseindose.Opioidrotationtomethadoneis dose and monitoring can be challenging.
considered,requiringaconversionfromhercurrentregimen, Ayonrinde and Bridge also performed a prospective
whichisequivalentto1,600mgoralmorphine. studyin2000thatledtoanothersetofconversionratios
(Table2)(3).Thisprotocolalsocallsforaloadingdoseof
25(cid:2)50%ofthetotaldailymethadonedosetobegivenon
in a community hospital setting who are candidates for
each of the first 2 days.
methadone therapy to be rotating from another opioid
Another approach published by Mercadante et al.
andnotopioid-na¨ıve.Commonlycitedmethodsandtheir
included a set of ratios using the same categories of
corresponding ratios are described below for use in
morphinedoserangesasRipamontietal.(Table2)(19).
performingmethadoneconversionsforpatientscurrently
However, the ratios are different for the categories and
receiving anotheropioid.
they range from 4:1 to 12:1 for doses over 300 mg daily
In1998,Ripamontietal.proposedasetofconversion
morphine. These ratios represent a more conservative
ratios that were stratified based on the initial oral
approach compared to Ripamonti et al. exceptfordoses
morphine dose (Table 2). Smaller proportionswere used between 30 and 90 mg oral morphine daily where the
for daily oral morphine equivalents over 300 mg. One ratio is the same.
criticism of this method and other methods that stratify The product information for methadone includes a
ratios based on ranges of total daily morphine useis the conversionmethodalso(Table2)(20).Themanufacturer
illogical nature of the cut-points (e.g., 88 mg of chosetopresenttheirconversionsintermsofpercentages
morphine(cid:3)22 mg oral methadone, whereas 93 mg of rather than ratios. This method is very similar to
morphine(cid:3)16 mg oral methadone). At doses near the Ayonrinde’s in terms of proportion and cut-points.
cut-pointbetweenratios,providersshouldbecautiousin Friedmanetal.proposedanotheralgorithmthattakes
not over-estimating the dose. into account the dose of morphine but is unique in also
Another proposed model for converting morphine to incorporating the patient’s age (Fig. 2) (10). This algo-
methadone was presented in 1990 in the form of an rithm may underestimate the methadone requirement at
Table2. Summaryof dosingratios
Ripamonti(18)
Morphinedose(mg/day) 30(cid:2)90 90(cid:2)300 (cid:2)300
Morphine:methadoneratio 4:1 6:1 8:1
Ayonrinde(3)
Morphinedose(mg/day) B100 101(cid:2)300 301(cid:2)600 601(cid:2)800 801(cid:2)1,000 (cid:2)1,001
Morphine:methadoneratio 3:1 5:1 10:1 12:1 15:1 20:1
Mercadante(4)
Morphinedose(mg/day) 30(cid:2)90 90(cid:2)300 (cid:2)300
Morphine:methadoneratio 4:1 8:1 12:1
Methadoneproductinformation(20)
Morphinedose(mg/day) B100 100(cid:2)300 300(cid:2)600 600(cid:2)1,000 (cid:2)1,000
Oralmethadoneaspercentoftotaldaily 20(cid:2)30% 10(cid:2)20% 8(cid:2)12% 5(cid:2)10% B5%
morphinedose
2
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Areviewofcommonmethods
Day 6: give average TDD methadone used
Initiate methadone
Discontinue previous on days 4 and 5 (administer as divided doses q12h)
as 10% of TDD
opioid and use 10–15% of new methadone
morphine q3h prn*
TDD as breakthrough offered q3h prn
TDD: total daily dose; q3h prn: every 3 hours as needed; BID: every 12 hours
*max dose of methadone is 30 mg/dose
Fig. 1. Summaryof the Morley(cid:2)Makin method.
lower doses because a very conservative percentage is of oral morphine equivalents increases. The X-axis
used for a wide range of possible dosing scenarios. represents increasing total daily doses of morphine and
Any calculated methadone dose below that of the the Y-axis represents the corresponding amount of
manufacturer’s stated dose for an opioid na¨ıve patient methadone required by each method to provide equia-
shouldberoundeduptoastartingdose.Manyclinicians nalgesia. The large difference in recommended doses at
prefer using this dosing method because the simplicity higher morphine doses reflects the lack of data. The
makes it easy to memorize and it represents a conserva- studies on which many of the conversion methods are
tive approach (12). basedrarelyincludeddatafordosesgreaterthan1,000mg
morphine/day,howeverthedosingschemesareleftopen-
endedtoincludehigherdoses.
Case review
Case2:Duetothehighmorphinerequirementsinthis
Case1:Asdiscussedinthisreview,wemustfirstcalculate
case, this patient developed signs of opioid-induced
histotaldailyoralmorphinerequirements.Athiscurrent
neurotoxicity and is planned to undergo opioid rotation
dose, heisreceiving32mgIVmorphinedailythatisthe
to methadone from her current dose of 1,600 mg oral
equivalentof96mgoralmorphinedaily.Thesummaryof
morphine equivalents. The summary of applying each
applying each method in converting his morphine to
methadonerevealsavarietyofpossiblecoursesofaction methodinconvertinghermorphinetomethadonereveals
for this patient (Table 3). a variety of possible courses of action for this patient
Based on the methods reviewed, the possible dosages (Table 4).
rangedfrom10to80mgperdayifthepatienttookevery In examining the existing options for Case 2, the
dose offered in the Morley(cid:2)Makin model. To determine divergence in doses becomes clearer and the decision-
the most appropriate dose, apractitioner must weigh up makingdifficultiesmoreapparent.ThepatientinCase2
the risks and benefits of aggressive versus conservative couldreceiveamethadonedoserangingfrom80mgdaily
methadone dosing. The Morley(cid:2)Makin method would usingtheFriedmanmethodto240mgdailyifeverydose
not be the most appropriate because this patient is weretakenusingthe Morley(cid:2)Makin model. Forpatients
approaching discharge from the hospital. Four of the on higher dosages of morphine, the lack of evidence
methods recommend doses between 10 and 20 mg daily, forces clinicians to dose very conservatively. Providers
soitwouldbeappropriatetostartwith5mgmethadone that are inexperienced in initiating methadone should
PO every 8 hours. seek guidance from someone experienced in dosing
The convenience of converging doses with different methadone before embarking on any conversion, but
methods is lost at higher doses. Figure 3 depicts the especially one involving high doses. The most conserva-
degreeofdivergenceinmethadonedosesasthedailydose tive dose produced from the various methods would be
Discontinue previous opioid
Patients receiving <1,000 mg TDD oral
morphine AND >65 years old
Patients receiving <1,000 mg TDD oral Patients receiving >2,000 mg TDD
OR
morphine AND <65 years old: oral morphine (any age):
Patients receiving <1,000–2,000 mg
10%* 3%*
TDD oral morphine (any age):
5%*
TDD: total daily dose; *represents the percentage of TDD oral morphine to be given as methadone in divided doses.
Fig. 2. Summaryof the Friedmanmethod.
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EricWongetal.
Table3. Case 1 example
Method Ripamonti Ayonrinde Mercadante Productinformation Morley(cid:2)Makin Friedman
Morphine:methadoneratio 6:1 3:1 8:1 20(cid:2)30% 10%q3hprn 10%
Methadonedailydose 16mg 32mg 12mg 19(cid:2)29mg 10mgq3hprn* 10mg
*Thisistheinitialdoseofferedfordays1(cid:2)5,notthefinalcalculateddoseforday6.
recommendedandstartingevenlowerwouldbeprudent. of morphine, most of the methods reviewed are reason-
Therefore, using the 20:1 conversion (i.e., 5%(cid:3)80 mg) able and result in comparable doses. The Friedman
would represent the highest dose recommended in this method does appear to produce the most conservative
situation. Starting with 20 mg methadone given every conversion across all dosage ranges. In contrast, the
8hourswouldbereasonable,alongwithprovidingliberal Ayonrinde method is the most aggressive at lower doses
breakthrough doses of short acting opioids to cover (i.e.,B300mgmorphine/day),inlinewithothermethods
uncontrolled pain. inmoderatedoses(i.e.,300(cid:2)1,000mgmorphine/day)and
equallyasconservativeastheFriedmanmethodatdoses
Discussion over 1,000 mg morphine/day. The Friedman method is
It is often difficult to determine the clearest path in the only method that encourages clinicians to adjust the
transitioningpatientstomethadonefromotheropioidsin ratio after the threshold of 2,000 mg morphine/day.
lightofthevarietyofmethodsavailable,whichsometimes Dosesabovethislevelshouldbeapproachedwithutmost
conflict. However, a clinician motivated to use metha- caution and much guidance from experienced pain
doneshouldrememberthatopioidrotationshouldnotbe specialists.
focused on the exact numerical dose of the method, but Inadditiontothesixmethodsreviewed,thereareother
on the importance of individualized titration, diligent methods published in the various resources. This article
assessment and careful monitoring (22). At lower doses was not meant to review every possibility of methadone
Fig. 3. Comparison of methadone dosing methods. Friedman A represents conversions for patient B65 years of age and
Friedman Brepresentsconversions forpatient (cid:2)65years of age.
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Table4. Case 2 example
Method Ripamonti Ayonrinde Mercadante Productinformation Morley(cid:2)Makin Friedman
Morphine:methadoneratio 8:1 20:1 12:1 5% 10%q3hprn 5%
Methadonedailydose 200mg 80mg 133mg 80mg 30mgq3hprn* 80mg
*Thisistheinitialdoseofferedfordays1(cid:2)5,notthefinalcalculateddoseforday6(maximumdoserecommendedinthismethod).
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