Methadone Rotation for Cancer Patientswith Refractory Pain in a Palliative Care Unit:

An Observational Study

Wadih Rhondali, MD,1,2 Flora Tremellat, MD,1,3 Mathilde Ledoux, MD,1 Jean-Francois Ciais, MD,3

Eduardo Bruera, MD,2 and Marilene Filbet, MD1

Abstract

Background: Methadone has been reported to be as effective as morphine for cancer pain management. It iscommonly used as an alternative opioid in case of insufficient relief.Objective: Our aim was to assess efficacy and tolerance of opioid rotation to methadone for refractory cancerpain management in palliative care unit (PCU) inpatients.Methods: All the patients undergoing opioid rotation to methadone from 2008 to 2011 in two PCUs (Lyon andNice, France) were included. Pain assessments were undertaken on day 0 (D0), day 3 (D3), day 7 (D7), and day14 (D14) using a visual analogue scale (VAS; 0–10) and the Douleur Neuropathique 4 (DN4) scale for neuro-pathic pain. Patients reported pain relief using a 4-point Likert scale (1 = no relief; 4 = important relief ).Results: Nineteen patients (7 females) with a median age of 55 (Q1–Q3; 44–58) underwent methadone rotation.The most common type of cancer was gastrointestinal. Seventeen patients had a diagnosis of mixed painsyndromes. Morphine equivalent daily dose (MEDD) prior to switching was 480 mg (Q1–Q3; 100–1021), and atleast two nonmethadone opioid rotations had already been done for 13 patients. Between D0 and D7, the VASscore decreased by 4 points ( p < 0.001). The DN4 score became negative on D7 for 11 of 17 patients (65%). On D7,16 of 18 patients (89%) expressed moderate to greater than moderate pain relief. Methadone was discontinued inone patient on D7 because it was deemed ineffective and for 8 patients, who were unable to take oral drugs, itwas discontinued after D14.Conclusion: Our results suggest that methadone is effective and well tolerated for refractory cancer pain.

Introduction

Pain is one of the most common cancer-related symp-toms.1,2 This symptom can be very distressing for patients

and their families, affecting their activities, their interac-tions with other family members and friends, and theiroverall quality of life. Pain management is crucial for ade-quate palliation of other physical symptoms (e.g., anorexia,tiredness, and sleep disturbances), as well as psychologicalsymptoms (e.g., anxiety and depression) and to optimizecancer treatment.3–5

Deandrea et al.6 reported that more than 40% of cancerpatients have moderate or severe pain and do not get signif-icant relief, suggesting that cancer-related pain is still a sig-nificant public health issue.6,7

Oral morphine, oxycodone, and hydromorphone are re-commended as first-line strong opioids in the World HealthOrganization’s (WHO) ‘‘Cancer Pain Relief Guidelines’’8 andin the most recent European Association for Palliative Care(EAPC) recommendations.9 Recently, morphine and oxyco-done were reported to control approximately 80% (156/200)of cancer-related pain.10 The remaining 20% represents re-fractory pain, which causes severe distress among patientsand their families. In these situations, good clinical practice isto switch one opioid with an equianalgesic dose opioid and touse coanalgesics.11–13

Methadone, by its specific pharmacokinetic and pharma-codynamic properties, should be considered as an attractivealternative in these situations. Methadone is a synthetic opi-oid agonist on l opioid receptors and confers structural

1Department of Palliative Care, Centre Hospitalier de Lyon-Sud, Hospices Civils de Lyon, Lyon, France.2Department of Palliative Care and Rehabilitation Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.3Department of Palliative Care, Centre Hospitalier de Nice, Nice, France.Accepted June 12, 2013.

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properties similar to morphine. Methadone is also character-ized by an antagonistic effect on N-Methyl-D-aspartate(NMDA) receptors, which are involved in the phenomena ofcentral hypersensitivity and tolerance to opioids.14 Thisspecificity also suggests that methadone has a more potenteffect on neuropathic pain.15 Its excellent oral bioavailability,the absence of active metabolites, the possibility of use in caseof renal failure, and its low cost should sustain its use forcancer pain.16 However, high variability of individual me-tabolism and its long half-life make it more complex formedical teams with limited experience in the use of metha-done for cancer pain management.17,18

In the most recent EAPC recommendations for cancer painmanagement, there was no consensus regarding indications,titration, and monitoring for methadone.9 Very few reports onthe outcomes of methadone rotation for inpatients with re-fractory cancer pain have been published.

To our knowledge, few studies in the literature have ex-plored the impact of methadone on neuropathic pain in cancerpatients. The aim of this retrospective study was to assess ef-ficacy and tolerance of opioid rotation to methadone for themanagement of refractory cancer pain in palliative care unit(PCU) inpatients and especially on the neuropathic component.

Methods

We conducted a retrospective analysis of consecutive opi-oid rotation for cancer pain to methadone, which was per-formed from 2008 to 2012 in two PCUs (Lyon and Nice,France).

Patient eligibility

Patient charts were included if the patients had a diagnosisof advanced cancer (defined as locally advanced, recurrent, ormetastatic disease), and if they had been previously treatedwith opioids and had been rotated to methadone because ofrefractory pain during their stay in the PCU. Refractory painwas defined as pain that has persisted over time despite anadequate trial of analgesic therapies and nonpharmacologicalapproaches.19

Intervention

We used the ‘‘stop and go’’ strategy for starting methadonein the inpatient setting (i.e., the previous opioid is stoppedbefore the methadone is started).20,21 The starting dose ofmethadone is administered 12 hours after the last dose ofextended-release morphine or oxycodone, 12 hours after re-moving the transdermal fentanyl patch, or immediately afterstopping the continuous infusion of morphine or oxycodone.

The conversion ratio morphine/methadone strategy for theinitial dose was 5 to 1 for a baseline MEDD up to 90 mg, 8 to 1for a baseline MEDD ranging from 91 to 300 mg, and 12 ormore to 1 for a baseline MEDD higher than 301 mg.22,23 For aMEDD higher than 500 mg, physicians were allowed to use aconversion ratio of up to 30.

Methadone was initially prescribed every 8 hours. Whenthe pain relief was sufficient (improvement of ‡ 2 points ormore on the visual analogue scale [VAS]), methadone wascontinued every 12 hours. Patients are also allowed to takerescue doses every 4 hours (one-tenth of the daily dose) in caseof breakthrough pain.

In our PCU, all patients at risk of arrhythmia had an elec-trocardiogram (ECG) before the initiation of methadone.

Assessment

The research assistant documented from the medical re-cords patients’ age, sex, and type and stage (metastatic status)of cancer.

Pain assessment. In our PCU, the pain syndrome isassessed clinically and pain intensity is assessed using a VAS(0 = no pain to 10 = worst pain) in daily practice.24 When apatient is to be rotated to methadone, nurses systematicallyperform these assessments on day 1 (D0), day 3 (D3), day 7(D7), and day 14 (D14).

Neuropathic pain assessment is done routinely using theDouleur Neuropathique 4 (DN4) questionnaire. The DN4consists of a total of 10 items with 7 items relating to symp-toms (e.g., sensations of burning, electric shock, painful cold,tingling, pins and needles, numbness, and itching) and 3 itemsrelating to physical examination (touch hypoesthesia, pin-prick hypoesthesia, and tactile allodynia). The cutoff value forthe diagnosis of neuropathic pain is 4 out of 10.25

Patient pain drawings are also used to describe the painlocation on D0. This consists of pain drawings on paper fig-ures of the human body. Patients are asked to rate pain reliefusing a 4-point Likert scale on D7 (1 = no relief; 2 = mild relief;3 = moderate relief; 4 = important relief ).

Adverse effects. We documented any adverse effects(nausea, drowsiness, bradypnea) reported in the medicalchart during this period.

Medications. The research assistant collected the typeand dose of the previous opioid treatments used in the last 3months, and the associated side effects.

Methadone doses received on D1, D3, D7, and D14 werealso documented as well as any side effects reported in themedical chart during this period.

Statistical analyses

We report categorical variables as numbers and percent-ages and continuous variables by their median with the in-terquartile range. We defined clinical response as animprovement of at least 2 points or more on the VAS.26–28

Comparisons between VAS score between two time-pointswere made using the Wilcoxon signed rank test and com-parisons between the numbers of patients with a VAS score< 3 between two time-points were made using the Fisher’sexact test.

We used SPSS statistical package version 17.0.2 for Win-dows (SPSS, Chicago, IL) for all statistical analyses. For all ofour statistical analyses, a p value of < 0.05 was considered tobe statistically significant.

Results

Of the 756 patients who were admitted to the PCU dur-ing the study period, 19 (3%) were rotated to methadone.In all cases, rotation took place because of refractory pain.Seven patients were female and the median age was 55(Q1–Q3; 44–59).The most frequent type of cancers were

METHADONE ROTATION FOR CANCER PATIENTS 1383

gastrointestinal and head and neck cancer. Fourteen (74%)patients had metastatic disease. Patient demographics aresummarized in Table 1.

Pain assessment and medication on D0

Seventeen patients had a diagnosis of mixed pain syn-dromes (a combination of nociceptive and neuropathic pain)with a positive score for DN4. All the patients had experi-enced this pain for at least one month despite previous strongopioid treatment with adequate titration and neuropathicdrugs (e.g., tricyclic antidepressant and anticonvulsants).

Patients had a median baseline VAS score (D0) of 6 (Q1–Q3;5–8) and pain was mainly located in the back, the lower limbs,and the perineum. All of the patients had a VAS score > 3.

Thirteen patients had received two or more different opi-oids in the 3 months (not involving methadone) before therotation to methadone. Out of the 6 with only one type ofopioid in this time frame, 4 had changed the route of ad-ministration from oral to intravenous infusion.

All patients had received at least one treatment for neuro-pathic pain in the 3 months before rotation with 17 patientsstill receiving these treatments at the time of rotation. Forthese 17 patients, we did not stop the neuropathic treatment.

At the time of rotation, 11 patients received oral morphineor oxycodone, 6 received intravenous infusions of morphine,and 2 received fentanyl transdermal patches. The medianMEDD on D0 was 480 mg (Q1–Q3; 100–1021).

Nineteen patients had a complete evaluation on D0, 14 hadone on D3, 18 on D7, and 11 on D14. Two patients had onlytwo assessments (D0 and D3): methadone was stopped forone patient due to his death; however, it was not related tomethadone treatment. For the other one, methadone wasstopped on D7 because it was deemed ineffective by the pri-mary palliative care physician.

Pain relief intensity and methadone doses

Between D0 and D7, we found a median decrease of 4 (Q1–Q3; 2–5) points on the VAS ( p < 0.001). For 13 of 18 patients(72%), the differential between D0 and D7 was more than, orequal to, 3 points with 8 of 18 patients (44%) having a VASscore < 3. DN4 score was negative on D7 for 11 of 17 patients(65%; p = 0.001). On D7, 16 of 18 patients (89%) expressedmoderate to important pain relief using a 4-point Likert scale(1 = no relief; 2 = mild relief; 3 = moderate relief; 4 = importantrelief ).

Nine patients experienced some drowsiness in the first 4days of methadone treatment. One patient experienced bra-dypnea on D2 requiring the stopping of treatment for 24hours, which was then resumed at a lower dose (one third theinitial dose).

We had to discontinue methadone for 8 patients after D14because they were no longer able to take oral methadone(swallowing disorders).

The median dose of methadone on D1 was 60 mg (Q1–Q3;15–100) with a maximum of 200 mg per day per patient. Doseswere increased between D1 and D7 for 9 of 17 patients (2patients had only D0 and D3 assessments); doses remainedstable for 4 of 17 patients and were decreased for 4 of 17patients.

Conversion ratios on D1 showed large inter-individualvariability as reported in Table 2. The median ratio conversionto methadone was 9 (6–14) on D1. On D1, for MEDD doses< 100 mg the average ratio of conversion was 6, for MEDDdoses between 101 mg and 300 mg it was 7, and for doses> 300 mg it was 13. The average ratios remained relativelyconstant with a median ratio of 5 on D3, D7, and D14, as didthe methadone doses with median doses on D1, D3, D7, andD14 of 60 mg (Table 2).

Discussion

Caution is recommended in the literature for the use ofmethadone for pain relief because of the high variability ofindividual metabolism and its long half-life, requiring a lon-ger period to reach the steady state.29 We have presented herethe results of a retrospective study on 19 inpatients with ad-vanced cancer who had been rotated to methadone in a PCU.Before rotation to methadone, the median VAS was high (6/10), as was the median MEDD (480 mg) with a significantdecrease in VAS on D7 for 13 of 18 patients. The pain was < 3on the VAS for 9 patients, and 16 patients reported moderateor greater than moderate pain relief on D7. Our results sug-gest that pain was well controlled on D7 and that methadonehas good efficacy on refractory cancer pain, even in a vul-nerable population (i.e., palliative care inpatients).

In our sample, there was a higher prevalence of head andneck and colorectal cancer. These locations often result incomplex pain syndrome, associating nociceptive and neuro-pathic components by local invasion and compression (plexusinvolvement). These results are partially consistent withwhat has been reported by Breivik et al. regarding colorectalcancer.7 This type of pain is often refractory to the usualopioids such as morphine and oxycodone and requires oftenacting on the different pathways of pain. Methadone, inthis case, is a good alternative as it is known to act on noci-ceptive pathways, neuropathic pathways, and also centralsensitization.15,30

Table 1. Patient Characteristics (n = 19)

Patient characteristics N (%)

Female 7 (36)Age (years), median (Q1–Q3) 55 (44–59)Cancer diagnosis

Colorectal 6 (32)Head and neck 4 (21)Gynecologic 2 (11)Hematologic 2 (11)Other 5 (26)

Metastatic disease 14 (74)Baseline opioid MEDD median (Q1–Q3) 480 (100–1021)Opioid route

Oral 11 (58)IV infusion 6 (32)Transdermal 2 (10)

Pain locationa

Lower limb 6 (32)Perineum 4 (21)Back 4 (21)Face 6 (32)

aThe total is higher than 100% because some patients had multiplepain locations.

IV, intravenous; MEDD, morphine equivalent daily dose; Q1–Q3,first and third quartiles.

1384 RHONDALI ET AL.

Our results suggest that methadone was very efficient onthe neuropathic component with the improvement of the DN4score on D7 (positive score for 17/19 patients [89%] on D1versus 6/17 [35%] on D7). Our findings are consistent withresults reported in previous studies14–16,18,20,22,31,32; however,compared with previous studies that explored the efficacyand safety of methadone on cancer pain, our study is one ofthe first to evaluate the efficacy of methadone on neuropathicpain using a specific and validated tool among advancedcancer patients.

Furthermore, for 6 patients, methadone rotation allowedchanging from an intravenous infusion to an oral route, thusreducing the risk of iatrogenic complications and also im-proving the patients’ autonomy. These points are centralcomponents of the goal of care in palliative medicine andshould also be considered in the choice of the treatment.9

Regarding the conversion ratio, the analgesic potency tableproposed initially was not always perfectly respected. Thismight be partially explained by the methadone pharmacoki-netics and especially the patient’s tolerance resulting in theneed to individualize the ratio for each patient. Thus, in ourstudy we used very different ratios from 2 to 1 to 30 to 1according to the baseline MEDD. These variations weremainly related to the fact that our sample was a frail popu-lation with advanced cancer and that our first goal was to besure that there would not be side effects requiring discontin-uation of methadone. However, as shown in Table 2, themedian doses of methadone were not significantly differentamong D1, D3, and D7 after the rotation.

Our findings confirm that the dose (in mg) of methadonerequired to achieve pain relief was much lower than previousMEDD. Older studies promoted a ratio of almost 1 to 1, andnewer research has shown that methadone is much morepotent and the ratio varies according to the previous MEDD.17

Using the previously proposed dose ratio, our results suggestthat this is a very safe way to rotate from a previous opioid tomethadone in the inpatient setting.

Contrary to studies conducted in a one-day rotation (withinpatients and outpatients),33 in all cases our patients wereadmitted to the hospital and monitored by an experienced teamfor titration twice a day. Our results suggest that one-day ro-tation might be safe in the inpatient setting but research fromother groups suggests that the 3-day rotation strategy might bemore effective for outpatients or patients on very high doses.33

In our study, we did not have any serious adverse eventsand especially no cardiac arrhythmia. One patient died dur-

ing the study period, but the medical notes in the chart sug-gest that this was not linked to the methadone treatment butwas related to the disease progression. Prolongation of the QTinterval is associated with an increased risk of severe ar-rhythmia. We did not find significant prolongation of the QTinterval in our sample; however, patients’ ECG monitoringwas not systematic and it was reserved only for patients ‘‘atrisk’’ (cardiac arrhythmia). Several studies reported a linkbetween methadone and QTc prolongation,34,35 resulting intorsades de pointes, polymorphic ventricular tachycardia,and sudden death. The frequency of methadone-induced longQTc interval is reported to be correlated to methadone doses( > 300 mg/day),36,37 but most of these studies have been donein a methadone maintenance population. In our sample, thehigher dose was 200mg/day, which is lower than doses usedin methadone maintenance patients. A recent study fromReedy and coworkers38 report on a sample of 100 patientswith advanced cancer in whom significant QTc intervalhigher than 500 ms after methadone initiation rarely occurred,with no evidence of clinically significant arrhythmias.

Several patients experienced some side effects during thefirst days of methadone initiation, but they were acute sideeffects that were easily reversed by dose adjustment andprobably linked to the long half-life. This low rate of sideeffects and the delayed pattern have been previously reportedby other teams.32,39 In one patient, an episode of bradypneawas noted on D2. Methadone treatment was therefore dis-continued then later resumed at a lower dose. These side ef-fects reinforce the need to be cautious (e.g., using higherconversion ratios), especially during methadone initiation.

We had to discontinue methadone for 8 patients because ofdeglutition disorders, and the lack of an available parenteralroute seems to be a significant obstacle to the use of metha-done in this frail population. These results underline the needfor the development of parenteral administration in France.This will allow continuation of methadone administration inpalliative terminal-stage cancer patients and will prevent lateand uncertain opioid rotations. To date, we have very littledata regarding the rotation from methadone to anotheropioid.40,41

Methadone initiation occurred mostly in third-line therapy.Two thirds of patients had indeed received at least two dif-ferent opioids in the previous 3 months, and around 90% hadreceived at least one antidepressant and/or anticonvulsantfor pain management. It therefore appears that methadonewas used late in pain management history. These are

Table 2. Pain Assessment, Methadone Dose, and Conversion Ratio at D1, D3, D7

Variables D0 D1 D3 Pa D7 Pb

Median VAS (Q1–Q3) 6 (5–8) 6 (5–8) 4 (2–4) 0.002 c 3 (2–4) < 0.001c

Patients with VAS < 3 (n %) 0 (0) 0 (0) 4 (22) 0.103d 8 (44) 0.014d

Median DN4 (Q1–Q3) 5 (4–6) 5 (4–6) 3 (2–4) 0.002c 3 (2–4) 0.001c

Median methadone dose (Q1–Q3) mg/day — 60 (15–100) 60 (15–140) 0.247c 60 (12–160) 0.221c

Median conversion ratio (Q1–Q3) — 9 (6–14) 5 (5–8) 0.001c 5 (5–8) 0.011c

Median MEDD of previous opioid(Q1–Q3) mg/day

480 (100–1021) — — — — —

aP value between D1 and D3.bP value between D1 and D7.cWilcoxon signed rank test.dFisher’s exact test.DN4, Douleur Neuropathique 4; MEDD, morphine equivalent daily dose; Q1–Q3, first and third quartiles; VAS, visual analogue scale.

METHADONE ROTATION FOR CANCER PATIENTS 1385

refractory cases with complex situations and are probably notrepresentative of the general cancer patient population.15,30

Using methadone earlier in the trajectory of cancer painmanagement has been tested by Bruera and colleagues in arandomized, controlled trial and should be tested in a largersample using the limits underlined here (conversion ratio,close monitoring of the dose and schedule during the 2 firstweeks).31

At the present time, French regulations do not allow phy-sicians to use methadone for cancer pain management unlessall other alternatives have been exhausted. We need morerandomized, controlled trials to compare methadone efficacywith that of other opioids and also as an earlier option for painmanagement. Our findings suggest that this is an importantpractice that significantly decreases pain in patients with re-fractory pain. It is therefore important that changes are madeto French law to allow opioid rotation to methadone in theoutpatient setting.

However, our study had several limitations. First, we had avery small number of patients in our sample, with heteroge-neous primary cancer limiting the generalizability of our re-sults. We also encountered difficulties in completing theassessments at each time-point (D3, D7, and D14). Thisdrawback is probably related to the population’s vulnerabil-ity as patients experienced intense and frequent fatigue. Itmay also be partially due to the retrospective nature of ourstudy, which decreases the quality of the collected data.

Our findings support the conduction of larger studies in-cluding earlier use of methadone, especially in patients withneuropathic pain. More research is necessary with a largersample and prospective design (open-label study, random-ized, controlled trial) to confirm these preliminary results.

Acknowledgments

The authors would like to thank Murielle Ruer, RN, for herinvolvement and her support for this research, Avril Jacksonfor her thorough review of the final manuscript and her usefulcomments, and the patients and staff of the PCUs in Lyon andNice for their assistance with this study.

Drs. Rhondali and Tremellat contributed equally to themanuscript.

Author Disclosure Statement

No competing financial interests exist.

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Address correspondence to:Wadih Rhondali, MD

Department of Palliative and Supportive CareCentre Hospitalier de Lyon-Sud

Hospices Civils de Lyon165 Chemin du Grand Revoyet

69310 Pierre-BeniteFrance

E-mail: wadihrhondali@gmail.com

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