CLINICAL TRIAL

Serum concentrations of opioids when comparing twoswitching strategies to methadone for cancer pain

Kristin Moksnes & Stein Kaasa & Ørnulf Paulsen &

Jan Henrik Rosland & Olav Spigset & Ola Dale

Received: 7 September 2011 /Accepted: 15 January 2012 /Published online: 29 February 2012# Springer-Verlag 2012

AbstractPurpose Our aim was to compare pharmacological aspects oftwo switching strategies from morphine/oxycodone to metha-done; the stop and go (SAG) strategy in which methadone isstarted directly after the initial opioid has been stopped, and the3-days switch (3DS), in which morphine/oxycodone is gradu-ally changed to methadone by cross-tapering over 3 days.Methods Forty-two cancer patients with pain and/or opioidside effects were assessed in this randomised trial. Troughserum concentrations of methadone, morphine, morphine-6-glucuronide (M6G), and oxycodone were measured on days1, 2, 3, 4, 7, and 14. Primary outcome was number of patientswith methadone concentrations in apparent CSS on day 4.Secondary outcomes were exposure to opioids during the first3 days, interindividual variation of opioid concentrations,

and correlation between methadone concentrations andpain intensity (PI) day 3.Results Thirty-five patients received methadone (16 in theSAG group, 19 in the 3DS group). The median preswitchmorphine equivalent doses were 620 (range 350–2000)mg/day in the SAG group and 800 (range 90–3600) mg/day inthe 3DS group (p00.43);42% reached CSS for methadone inthe SAG group on day 4 compared with 22% in the 3DSgroup (p00.42). The SAG group was significantly lessexposed to morphine/M6G/oxycodone and significantly moreexposed to methadone in the first 3 days. Methadone showeda low correlation with PI. More patients dropped out afterintervention in the SAG group than in the 3DS group (38% vs.5%; p00.032). One SAG patient suffered from respiratorydepression on day 5.

ClinicalTrials.gov id: NCT0014496

K. Moksnes : S. Kaasa :Ø. Paulsen :O. DalePain and Palliation Research Group, Faculty of Medicine,Norwegian University of Science and Technology (NTNU),Trondheim, Norway

S. KaasaDepartment of Oncology, St. Olav’s University Hospital,Trondheim, Norway

Ø. PaulsenDepartment of Medicine, Palliative Care Unit, Telemark Hospital,Skien, Norway

J. H. RoslandSunniva Centre for Palliative Care,Haraldsplass Deaconess Hospital,Bergen, Norway

J. H. RoslandDepartment of Surgical Sciences, University of Bergen,Bergen, Norway

O. SpigsetDepartment of Clinical Pharmacology,St. Olav’s University Hospital,Trondheim, Norway

O. SpigsetDepartment of Laboratory Medicine, Children’s and Women’sHealth, Norwegian University of Science and Technology,Trondheim, Norway

O. DaleDepartment of Anaesthesiology and Emergency Medicine,St. Olav’s University Hospital,Trondheim, Norway

K. Moksnes (*)Department of Circulation and Medical Imaging, Pain andPalliation Research Group, St. Olav’s University Hospital,Bevegelsesbygget 3 etg,NO - 7006 Trondheim, Norwaye-mail: kristin.moksnes@ntnu.no

Eur J Clin Pharmacol (2012) 68:1147–1156DOI 10.1007/s00228-012-1228-3

Conclusion The SAG group was initially more exposed tomethadone and less to the replaced opioids but withoutobserved clinical benefit and with a higher dropout rate.Patients switched to methadone should be followed closelyfor the first 5 days, regardless of switching strategy.

Keywords Pharmacokinetics . Opioid switch .Methadone .

Cancer pain . Randomised

Introduction

Switching from one strong opioid to another is a recommendedprocedure in cancer patients with imbalance between painrelief and/or side effects [1]. Switching to methadone is ham-pered by a lack of commonly agreed upon conversion ratiosand switching strategies. Methadone has a higher oral bioavail-ability and longer elimination half-life than morphine and oxy-codone. The cytochrome P-450 (CYP) enzymes responsiblefor methadone metabolism remain controversial; CYP2B6 andCYP3A4 are suggested as main pathways, with less involve-ment of CYP1A2 and CYP2D6 [2–4]. Oxycodone is mainlymetabolized by CYP3A4 and CYP2D6 [4, 5]. Morphine ismetabolized to morphine-3-glucuronide (M3G) and the activemorphine-6-glucuronide (M6G) via UGT2B7 [6]. It is com-monly cited that the interindividual variability of the pharma-cokinetics of methadone is larger than for other opioids [7].

Two commonly used switching strategies to methadoneare the stop and go (SAG) strategy, in which the initialopioid is substituted with methadone the same day [8–10],and the 3-days switch (3DS), in which the initial opioid issubstituted stepwise with methadone over 3 days[11–14].Proponents of the 3DS strategy claim that it prevents meth-adone accumulation [12, 15], whereas SAG proponentsfavor the faster removal of morphine/metabolites and afaster achievement of steady state for methadone [9]. How-ever, conclusive evidence for these claims is lacking [16].Three studies have reported serum/plasma concentrations ofmethadone, morphine, and metabolites when switchingfrom morphine to methadone [9, 17, 18]. Mercadante et al.reported stable methadone concentrations in cancer patients1–2 days after SAG switching and almost complete removalof morphine and metabolites within 3 days [9]. Auret et al.reported that 11 of 13 cancer patients reached steady statefor the active methadone R-enantiomer 3.7–7.7 days afterSAG switching [18]. Fredheim et al. reported that morphineand metabolites were completely eliminated and steady statefor methadone reached within 1 week in 12 patients withnonmalignant pain after a 3DS [17]. Only one studydescribes plasma concentrations of methadone after a switchfrom oxycodone in cancer patients [19]. The switchingstrategy in that study was patient controlled, and methadoneconcentrations were at steady state after 2–3 days.

The study reported here was a part of a randomised phaseII trial examining whether SAG provided faster onset ofpain relief than 3DS when switching from morphine/oxy-codone to methadone[20]. The research questions for thispharmacokinetic part of the study were:

1. Are there more patients in apparent steady state formethadone in the SAG group than in the 3DS groupby day 4?

2. Is the SAG group more exposed to methadone and lessexposed to morphine, M6G, and oxycodone the first 3days after the switch?

3. Have patients with serious adverse events (SAEs)higher methadone serum concentrations than the restof the group?

4. Do the methadone serum concentrations show a higherinterindividual variation than the concentrations of mor-phine and oxycodone?

5. Is pain intensity and methadone concentration at day 3or day 14 associated?

Material and methods

Patients and setting

Cancer patients >18 years of age, treated with morphine oroxycodone for more than 1 week, and in whom an opioidswitch was indicated due to increasing pain considered to beuntreatable with further opioid escalation and/or opioid sideeffects, were eligible for inclusion in the study. Patients withcognitive impairment not caused by opioids, or who wereincapable of understanding Norwegian, were excluded. Fourhospitals in Norway recruited in- and outpatients to partic-ipate in this open, prospective, parallel group, multicenter,randomised controlled trial of 2 weeks’ duration (Fig. 1).

Switching and equianalgesic strategy

The opioid being taken was either substituted with an as-sumed equianalgesic dose of methadone from day 1 (SAGgroup) or reduced by one third and substituted with anequianalgesic dose of methadone every day for 3 days(3DS group) (Fig. 1). The equianalgesic methadone dosewas calculated dose-dependently [12, 21, 22] from the totaldose of orally administered morphine or oxycodone admin-istered the last 24 h before the switch (mean opioid rescuedose taken the previous 48 h was included), as follows: 30–90 mg morphine 4:1, 91–300 mg morphine 6:1, 301–600mg morphine 8:1, 601–1000 mg morphine 10:1, and >1000mg morphine 12:1. Parenterally administered morphine andoxycodone were converted to oral equivalents by factors ofthree and two, respectively. The rescue dose was one sixth

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of the baseline morphine dose. In order not to interfere withthe pharmacological assessments of morphine or oxyco-done, the patients received a different opioid as rescuemedication; those on morphine received oxycodone, andthose on oxycodone received morphine. Racemic metha-done was produced as capsules of 5, 10, 20, 50, and 100mg and mixture by St. Olav’s Hospital Pharmacy. Adjuvantnonopioid analgesics given regularly before inclusion andanticancer therapy were continued.

Recordings

Key background variables, concomitant diseases, cancertreatment, and opioid history were recorded at baseline bythe physician/investigator. Opioid doses and rescue episodeswere recorded daily. Patients reported their pain intensity(PI) at the time of assessment before noon at baseline, day 3,and day 14, on an 11-point numerical rating scale (NRS)from zero (no pain) to ten (worst imaginable pain) using thebrief pain inventory (BPI) [23, 24]. An electrocardiogram(ECG) was obtained at baseline. Patients with a preswitchrate-corrected QTc interval >480 ms (patients not at risk ofarrhythmia), or >460 ms (patients at risk of arrhythmia)were excluded. A SAE was defined as any medical occur-rence that resulted in death, was life threatening, requiredhospitalization or prolongation of existing hospitalization,or resulted in persistent or significant disability/incapacity.

Sampling and analysis

Venous blood taken before the first morning dose at about 8 amfor analysis of serum trough concentrations of methadone

(R-methadone+S-methadone), R-methadone, morphine,M6G, and oxycodone was drawn at days 1 (before the firstmethadone dose), 2, 3, 4, 7, and 14. Blood samples werestored at room temperature for 30 min before centrifugationat 2500g for 10 min. The serum was then transferred tocryotubes and stored at –20°C until analysis. Total metha-done and R-methadone were analyzed by a validated liquidchromatography mass spectrometry (LC-MS) method. Inbrief, 500 μl serum, 25 μl internal standard (d3-metadone,10 mg/ml), and 1000 μl 10 mM ammonium carbonate weremixed and applied onto a solid-phase extraction column(Varian Bond Elut C18; Varian, Palo Alto, CA, USA)previously equilibrated with methanol, water, and 10 mMammonium carbonate. The analytes were eluted with 0.5 Macetic acid in methanol. After evaporation and reconstitutionin 50 μl methanol, the samples were transferred to vials andinjected on an Agilent MSD 1100 LC-MS system (Agilent,Palo Alto, CA, USA). Separation was performed on aChiral-AGP 4 x 300-mm column (Sigma-Aldrich, St. Louis,MO, USA) with a mobile phase consisting of acetonitril:ammonium acetate (50:50). Methadone was monitored afterpositive electrospray ionisation at mass to charge ratio (m/z)310 (target ion) and 265 (qualifier), and the internal stan-dard d3-methadone was monitored at m/z 313. The limit ofquantification of the method was 15 nmol/l, and the methodwas linear at least up to 1500 nmol/l. Samples with higherconcentrations were diluted by a validated procedure. Qual-ity control samples covering the range from 50 to 1000nmol/l were analyzed with every batch of unknown sam-ples. Between-day coefficients of variation calculated fromquality control samples were<5.0% at 50 nmol/l and 6.1%at 1000 nmol/l.

Note that day 1 is the day of the switch to methadone

= Morphine/oxycodone dose = Methadone dose

Fig. 1 Study design and flowchart

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Serum concentrations of morphine and M6G were deter-mined essentially, as described by Dale et al. [25]. Quanti-fication of analytes were fully prerun, and in-run wasvalidated according to Dadgar et al. and Shah et al. usingindividual deuterated internal standards [26, 27]. The limitsof quantification were 3.5 nmol/l for morphine and 2.2nmol/l for M6G. The method for morphine and M6G waslinear up to at least 1500 nmol/l. Samples with higherconcentrations were diluted by a validated procedure. Qual-ity control samples of morphine and M6G covering therange from 10 nmol/l to 1400 nmol/l were analyzed withevery batch of unknown samples. Between-day coefficientsof variation calculated from quality control samples were8.9% at 10 nmol/l and 3.1% at 1400 nmol/l for morphine,and 11.1% at 7 nmol/l and 3.3% at 870 nmol/l for M6G.

Oxycodone concentrations were determined according toEdwards and Smith using an HP1100 API4000 liquidchromatography tandem mass spectrometry (LC-MS/MS)(Hewlett-Packard, Palo Alto, CA, USA) [28]. The limit ofquantification was 0.13 nmol/l, and the method was linear atleast up to 1500 nmol/l. Samples with higher concentrationswere diluted by a validated procedure. Quality control sam-ples covering the range from 0.3 to 1270 nmol/l were analyzedwith every batch of unknown samples. Between-day coeffi-cients of variation calculated from quality control sampleswere 9.9% at 0.3 nmol/l and 4.0% at 1270 nmol/l.

Statistics and analysis strategies

Sample-size estimation was performed for the primary clinicaloutcome [20]. Apparent steady state for methadone on day 4was defined as a concentration ≥90% [29] of the methadoneconcentration on day 7, when steady state should have beenreached. Means, medians, ranges and 95% confidence inter-vals (CI), percentages, and fractions are reported, as appropri-ate. Fisher’s exact test was used in significance testing of thenumber of patients with methadone concentrations in steadystate on day 4 and difference in dropout rate between groups.The Mann–Whitney test was used to compare preswitchdoses, opioid concentrations between groups (not normallydistributed), and dose-corrected areas under the curves(AUCcs). AUCs were calculated using the trapezoidal methodwith time-concentration areas from day 1 (before the firstmethadone dose) to day 4. As the preswitch morphine dosesapparently were unequal in the two groups, the AUCs weredose corrected [30] (adjusted as if every patient receivedthe same total dose of the drug from day 0 to day 3;methadone 100 mg, morphine and M6G 1000 mg, andoxycodone 500 mg). As an example, the AUCc of totalmethadone was calculated as follows: AUCc0measuredAUC x [100 mg/ total administered methadone dose (mg)from day 0 to 3]. Spearman’s rank correlation test was used forthe correlation between methadone concentrations and PIs,

whereas Pearson’s correlation test was used for correlationbetween total methadone and R-methadone concentrationsand between methadone concentrations at days 4 and 7 ineach group. The mean and variation (from day 2–14) of theslopes of the curves for the relation between total methadoneand R-methadone concentrations (not dose corrected) wascalculated. The degree of variability of dose-corrected opioidserum concentrations was estimated by calculating the coeffi-cient of variation (Cv0SD/mean). One-way ANOVAwith theGames Howell post hoc test and homogeneity of variance wasused for significance testing of the difference of variancebetween the respective opioids. The statistical software SPSS17.0 and 18.0 was used for all analyses.

Ethics and approvals

The study was conducted according to the principles of theDeclaration of Helsinki and was approved by the RegionalCommittee for Medical Research Ethics, Norwegian SocialScience and Data Services, and the Norwegian MedicinesAgency. Patients were included after they had given theirinformed, written consent.

Results

Patient characteristics

Forty-two cancer patients were randomised from June 2004to March 2008. Seven patients did not receive methadone:five in the SAG group (one protocol violation, one withdrewconsent, one converted to hydromorphone, and two hadprolonged QTc intervals), and two in the 3DS group (onewith prolonged QTc interval and one for whom no datacould be retrieved). Thirty-five patients (23 on morphineand 12 on oxycodone) were switched to methadone: 16 bythe SAG strategy and 19 by the 3DS strategy (Fig. 1). Sixpatients in the SAG group did not complete the study [twodied, the others were excluded because of: cognitive failure(n01), conversion back to morphine (n01), self-terminationof all medications (n01), and respiratory depression (n01)].In the 3DS group, one patient was excluded due to pro-longed QTc interval. The two groups were similar regardingkey background variables, such as sex (male:female ratio1:1), mean age (~60 years), Karnofsky performance status(≈ 60%), and ethnicity (98% Caucasian). Details on cancerdiagnoses, treatments, causes of opioid switches, concomi-tant diseases and drugs, pain relief, side effects, cognitivefunction, and QTc intervals from the switch, together with aConsolidated Standards of Reporting Trials (CONSORT)flowchart are reported elsewhere [20]. The median pre-switch equianalgesic oral morphine doses in the 35 patientsreceiving methadone were 620 (range 350–2000) mg/day in

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the SAG group (n016) and 800 (range 90–3600) mg/day inthe 3DS group (n019) (p00.43). All patients receivingmethadone (n035) were included in the opioid concentra-tion analysis, except one, who was excluded from the mor-phine analyses because of a technical error in the analysis ofmorphine. In total, 28 patients completed the study (ten inthe SAG group and 18 in the 3DS group), with a significantlyhigher dropout rate in the SAG group after randomisation(11/21; 52%) than in the 3DS group (3/21; 14%) (p00.006)(Fig. 1). The dropout rate after switching to methadone wasalso significantly higher in the SAG group (6/16; 38%)than in the 3DS group (1/19; 5%) (p00.032). The SAGgroup received a median methadone dose of 70 (range 30–160) mg/day the first day, whereas the 3DS group receiveda median dose of 35 (range 5–90) mg/day (p<0.001). The finalmedian methadone doses were 65 (range 30–190) mg/day inthe SAG group (n010),and 90 (range 30–240) mg/day in the3DS group (n018) (p00.24).

Steady state of methadone concentrations

At day 4 (i.e., 3 days after the switch), there was no signif-icant difference between the proportion of patients in steadystate for total methadone in the SAG (5/12; 42%) and 3DS(4/18; 22%) groups (p00.42). The median methadone con-centration was 937 (range (314–2164) nmol/l on day 4, and1129 (range 408–3053) nmol/l on day 7 in the SAG group(p00.87). In the 3DS group, the median concentration was1271 (range 190–3909) nmol/l on day 4, and 2196 (range204–4016) nmol/l on day 7 (p00.08). Concentrations werenot statistically significantly different between groups (day4, p00.70 and day 7, p00.24). The SAG group had signif-icantly higher concentrations of total methadone day 2 (i.e.,1 day after the switch) (661 nmol/l in the SAG group vs. 305nmol/l in the 3DS group; p00.002). No significant differ-ences were found between groups at days 3, 4, 7, or 14. The2-week time course of serum concentrations of total meth-adone and R-methadone in the two groups is displayed inFig. 2.

The total methadone concentrations were highly correlatedto the R-methadone concentrations on all sampling days (day14 r00.982, p00.01). Therefore, for simplicity results areonly presented for total methadone. The mean slope of thecurves from all days between total methadone and R-methadone concentrations was 0.49 (0.40–0.63, min–max),with the steepest slope found on day 14 (0.63). The decay ofmean morphine, M6G, and oxycodone concentrations (notdose corrected) from days 1 to 4 are shown in Fig. 3.

Exposure to opioids the first 3 days

Data on exposure to opioids expressed as dose-correctedAUC (AUCc) during the first 3 days are presented in Table 1.

The SAG group had a significantly higher exposure thanthe 3DS group to methadone (median AUCc 2601 nmol/l•day vs. 1670 nmol/l•day, p00.033). In contrast, therewas a significantly lower exposure to morphine in theSAG group than in the 3DS group (267 vs. 1160 nmol/l•day, p00.002), a significantly lower exposure to M6G(1069 vs. 3119 nmol/l•day, p00.029), and a significantlylower exposure to oxycodone (305 vs. 657 nmol/l•day,p00.007). The SAG group was significantly less exposedto morphine and M6G combined than was the 3DSgroup (median AUCc morphine+M6G 1454 (range 627–6517) nmol/l•day vs. 3946 (range 1179–16070) nmol/l•day,p00.030).

Methadone concentrations, adverse events, and dropouts

There were three SAEs in the SAG group (all switchedfrom morphine); two patients died from cardiac disease(one from pulmonary embolism and cardiac tamponadeday 13, and one from myocardial infarction day 7), andone patient experienced sedation and severe respiratorydepression on day 5. These three patients had similaropioid concentrations to the rest of the SAG group.However, the dose-corrected values for these twopatients were more than twofold higher than the medianmethadone value in the SAG group on day 4 ([38 and35 (nmol/l)/(mg/day), respectively, vs. a median of 13(nmol/l)/(mg/day)]. The patient with severe respiratorydepression was a 59-year-old man with larynx cancerand lung metastases. He had undergone surgery andradiotherapy the week before the switch. The preswitchmorphine dose was 1080 mg/day; equianalgesic metha-done dose was 90 mg/day (ratio 12:1). The patient whosuffered from myocardial infarction was a 72-year-oldman with maxillary cancer without metastases and withno cancer treatment the week before the switch. Thepreswitch morphine dose was 510 mg/day; equianalgesicmethadone dose was 60 mg/day (ratio 8:1). The dose-corrected morphine and M6G concentrations day 1 werenot higher in these patients than in the rest of the group.In the sedated patient with respiratory depression, the metha-done dose was reduced from 90 mg/day to 60 mg/day whenthe patient experienced drowsiness (day 3) and furtherreduced to 30 mg/day from day 4. The patient wasfound in his bed with respiratory arrest a few hoursafter the morning dose day 5. Respiration was normal-ized with a total of 1.2 mg of naloxone after 1.5 h.However, methadone was continued, and at day 14, heused a dose of 70 mg/day (final ratio 15.4:1). Thus theinitial switch dose of 90 mg/day was 30% higher thanthe final dose. The six patients who dropped out in theSAG group did not have significantly higher serumopioid concentrations than the completers in the SAG

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group at any day. This was also the case after concentrationswere dose corrected.

Pharmacokinetic variation

The interindividual variation of dose-corrected concentrationsat steady state of methadone, morphine, and oxycodone forthe patients completing the study (19 switched frommorphineand nine from oxycodone) were not significantly different(Fig. 4). The estimated coefficients of variation were 0.59for methadone, 0.75 for morphine, and 0.65 for oxycodone.

Correlation between methadone and pain intensity

Low correlations were found between methadone concen-trations and PI on days 3 and 14 in both groups (Table 2).There was no significant difference in PI scores between theSAG and 3DS groups on day 3 (p00.61) or day 14 (p00.40)(Table 2).

Discussion

The hypothesis that pain and side-effect scores are related toserum opioid concentrations when switching from high dosesof morphine or oxycodone to methadone in cancer patientswas not supported in this randomised trial. There was nosignificant difference between the number of patients in steadystate for total methadone concentrations on day 4 in the twogroups. Patients in the SAG group had a higher exposure(expressed as dose-corrected AUC) to methadone than patientsin the 3DS group and a lower exposure to morphine andoxycodone the first 3 days. However, this difference was notreflected in a lower mean pain score in the SAG group than inthe 3DS group, and no significant relationship was foundbetween serum concentrations and PI levels. For patients com-pleting the study, the variation of serum concentrations was notgreater for methadone than for morphine and oxycodone.Finally, a high correlation between concentrations of R-methadone and total methadone was found.

Fig. 2 Time course for total methadone and R-methadone concentrations (serum trough concentrations, nmol/l) from the individual patients in thestop and go group (n016) and the 3-daysswitch group (n019)

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Fig. 3 Decay of meanmorphine, morphine-6-glucuronide (M6G), andoxycodone trough concentra-tions (nmol/l) the first 3 daysafter the switch in both groupsa

Table 1 Exposure to total methadone, morphine, morphine-6-glucuronide (M6G), and oxycodone days 1–4 (i.e., the first 3 daysafter the switch), expressed as dose-corrected areas under the curves(AUCc) (nmol/l•day), n033 a

Group Number AUCc P value

Median Min-max SAG vs. 3DS

Totalmethadone

SAG 15 2601 924–6665 0.0333DS 18 1670 655–3869

Morphine SAG 10 267 114–610 0.0023DS 11 1160 199–3243

M6G SAG 10 1069 371–6306 0.0293DS 11 3119 667–14909

Oxycodone SAG 5 305 0.5–579 0.0073DS 7 657 548–1913

SAG stop-and-go, 3DS 3-day switcha Two patients were excluded from the analysis; one who dropped out day2 and one for whom there was a technical error in the analysis of morphine

Fig. 4 Relative deviation of individual dose-corrected concentrationsfrom the group mean of trough concentrations at steady state ofmorphine (day 1, n018), oxycodone (day 1, n09), and total methadone(day 14, n027) for the patients who completed the study. Concentrationmeans of the respective opioids were set to 100%

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Mercadante et al. reported that nine of ten cancer patientshad stable plasma concentrations of methadone 1–2 daysafter an SAG switch [9]. However, the patients wereobserved for 4 days only, blood samples were taken in theabsorption phase 1–2 h after methadone administration, andsteady state was defined as a higher methadone concentrationon day 2 than on day 3, which seems to too short a period oftime. In contrast, Auret et al., also using the SAG strategy butsampling at trough, reported that patients were in steady stateafter 4–8 days [18]. This finding seems to be in accordancewith the results of our study, in which 42% (SAG group) and22% (3DS group) reached stable methadone concentrationson day 4 (i.e., 3 days after switch). Our findings are also inagreement with the long elimination half-life of methadone,indicating steady state after about 5–6 days, corresponding tofive times the elimination half-life of methadone.

The only significant difference between groups for meth-adone concentrations was seen 1 day after the switch (day2). The lack of significant differences later in this phasemight be a type II error because of a small sample size, but itmight also be a factor that the 3DS group had a higherpreswitch morphine dose than the SAG group. Nevertheless,the results support previous findings that methadone dosealone cannot predict serum concentrations of methadone[17, 31].

As expected, exposure to methadone the first 3days washigher in the SAG group than in the 3DS group, whereasexposure to morphine, M6G, and oxycodone were lower.Regardless, the SAG group neither reported better paincontrol nor fewer side effects than the 3DS group on day 3[20]. Thus, the claim by Mercadante et al. [9] that a morerapid clearance of morphine and its metabolites with theSAG approach would result in fewer side effects and thata shorter time to stabilization of the methadone concentra-tion would give more rapid pain relief is not supported bythis study. The explanations may be that changes in serumconcentrations are less important than changes/exposure atthe site of action in the central nervous system (CNS).

Clearance of not only morphine, but its active metaboliteM6G in particular, from the CNS is probably much slowerthan the cerebral wash-in of methadone [32]. Consequently,one cannot rule out the possibility that the initial totalcerebral opioid burden of μ-opioid agonists after a switchmay be higher in the SAG group than in the 3DS group. Iftrue, this favors the 3DS approach, not least in frail patientsalready on very high opioid doses.

Auret et al. found no simple correlation between worstpain and methadone enantiomer plasma concentrations [18].However, in that study, as in our study, some patients mighthave developed a high degree of opioid tolerance prior tothe opioid switch. Consistent with such a phenomenon, nosimple relationships between plasma concentrations of mor-phine, metabolites, or metabolite ratios and clinical effectsin cancer patients have been identified in previous studies[33–35].

Although the R-enantiomer is considered responsible forthe mu-opioid-receptor-mediated analgesic effect of metha-done, the total methadone concentration (i.e. R- methadoneplus S-methadone) is most often studied [36]. In our study,the R-methadone concentrations were highly correlated tothe total methadone concentrations, implying that analyzingthe total concentration might be sufficient in most cases.

The concerns regarding variable pharmacokinetics of meth-adone and numerous drug interactions are often emphasizedwhen predicting equianalgesic doses and risk of accumulation.In this study, the concentration variation was not larger formethadone than for the other opioids in patients completing thestudy. In this respect, this study has a strong design: First, it ismost likely that the pre- and postswitch opioid concentrationswere pharmacokinetic steady-state values. Second, there was acrossover design for this outcome, as both pre- and postswitchvalues were available for the same patient. The dropouts didnot have higher opioid serum concentrations than those whocompleted. However, when dose correcting, two patients withSAEs had higher concentrations than the rest of the group,indicating different pharmacokinetics from that of the group asa whole, and that the ratios for dose conversion used mighthave been inappropriate. These two patients were excludedfrom the study because of myocardial infarction and respirato-ry depression and were thus not included in the analysis ofopioid concentration variation. Consecutive serum samples ofmorphine and methadone were available in the patient withrespiratory depression after a switch. It could therefore bedetermined that pharmacokinetic factors related to the switchwere probably the cause. Thus, the major cause of this incidentwas that the commonly used conversion ratio overestimatedhis methadone requirement by 30% as the patient later did wellon a lower dose of methadone. This indicates that the conver-sion dose in some patients may be difficult to predict, eventhough strict conversion protocols are followed. A conse-quence of the relatively long elimination half-life of methadone

Table 2 Pain-intensity scores (11-point numerical rating scale) andtrough serum concentrations of methadone (nmol/l) on days 3 (n034)and 14 (n028),;means [95% confidence intervals (CIs)[, with Spearman’srho (r) p-value correlations

Pain intensity Methadoneconcentration

Spearman’sRho

P value

Day 3

SAG 3.3 (1.6–5.0) 946 (663–1230) −0.31 0.13

3DS 2.8 (1.7–3.9) 829 (552–1105) −0.26 0.59

Day 14

SAG 3.3 (1.9–4.7) 1762 (852–2672) 0.22 0.72

3DS 2.6 (1.6–3.7) 2314 (1777–2851) −0.45 0.17

SAG stop-and-go, 3DS3-day switch

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is that the onset of overdose symptoms is delayed and insidi-ous, and the offset is similarly slow. The patient who experi-enced an overdose displayed sedation as early as day 3,followed by severe respiratory depression 2 days later. Retro-spectively, it is obvious that the methadone dose should havebeen temporarily stopped at day 3, not just reduced. Previousreports of sedation and/or respiratory depression duringmethadone treatment [14, 37, 38], together with thepatient with sedation in this study, strongly suggest thatpatients should be observed closely during the first 5 days onmethadone treatment, and if signs of overdose appears, dosingshould be stopped completely and a reduced dose given whensigns of toxicity disappear, regardless of which switchingstrategy is applied.

Accrual to this study took place from June 2004 to March2008. The slow attrition rate may be explained by healthcareprofessionals and relatives acting as gatekeepers for thesefrail patients [39]. Also, one of the hospitals withdrew fromthe study after including only one patient. However, thefindings should be valid, as no significant changes in clin-ical practice took place during this period.

Conclusion

The SAG group was initially more exposed to methadoneand less to the replaced opioids. Serum concentrations ofmethadone were not correlated to pain intensity. Interindi-vidual variability of methadone at steady state was similarto that of morphine and oxycodone. Moreover, there maybe a significant interindividual variability in conversiondoses for methadone; therefore, patients switched to meth-adone should be followed closely for the first 5 days.Signs of overdose should indicate a temporary cessationof the medication.

Acknowledgements We are grateful for the assistance from GunnhildJacobsen, Turid Nilsen, Trine Andreassen, and Kjell Aarstad for bloodanalyses, from Karin Tulluan for the randomisation process, and forvaluable advice from Olav M.S. Fredheim and Line Oldervoll. We alsothank the staff at the participating units and the patients for theirparticipation. This study was supported by grants from the NorwegianResearch Council and Norwegian Cancer Society.

Conflict of interest The authors declare that they have no conflict ofinterest

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