Intermittent Subcutaneous Methadone Administration in the Management of Cancer Pain

ARTICLES

Intermittent Subcutaneous Methadone Administrationin the Management of Cancer Pain

Carlos CentenoFrancisco Vara

ABSTRACT. Methadone is a strong opioid analgesic that has been used successfully in cancerpain management. The oral route of administration is generally preferred for opioid analgesics.However that route sometimes cannot be used. Experience with continuous subcutaneous metha-done infusions has produced local intolerance. The aim of this study was to analyze the use of in-termittent subcutaneous methadone injections. Ten patients whose pain was well-controlled withoral methadone (average dose 30 mg, range 10 to 120 mg) participated in the study. A subcutane-ous small vein needle (butterfly) was used exclusively for administration of methadone. Over a pe-riod of seven days the local discomfort of each injection was evaluated by means of a VerbalNumerical Rating Scale (NRS) and the site of infusion was observed. When any degree of ery-thema or inflammation was seen, the infusion site was changed. The initial subcutaneous dose wasthe same as the previously administered oral dose. A daily record was kept of the dose used, levelof pain, and toxicity symptoms. This close vigilance was aimed at avoiding dosage errors due tovariations among individuals in acceptance to previous oral medication. Changes in dosage wereallowed according to standard medical criteria. Two patients were withdrawn from the study due tonon-painful irritation at the infusion point. Another eight patients tolerated repeated administrationof subcutaneous methadone over seven days. Any local irritation from subcutaneous methadonethat occurred was managed satisfactorily by changing the infusion site and limiting doses to 30 mg.In seven of 182 repeat administration, injection site changes were necessitated by local irritation.The NRS for local discomfort was 2/10. The two patients who were intolerant of the subcutaneousinjections were receiving injected doses which were significantly higher than the others (42 mg ascompared to 25 mg). Dose adjustments needed when changing from the oral to the subcutaneousmethadone route were minimal. Subcutaneous intermittent administration of methadone appearsto be a useful alternative to oral administration in selected clinical situations when oral administra-tion is not feasible. [Article copies available for a fee from The Haworth Document Delivery Service:1-800-HAWORTH. E-mail address: <docdelivery@haworthpress.com> Website: <http://www.HaworthPress.com> 2005 by The Haworth Press, Inc. All rights reserved.]

Carlos Centeno, MD, PhD, is Consultant in Palliative Medicine at Clínica Universitaria, Universidad de Navarra,Spain.

Francisco Vara, MD, PhD, is Consultant in Pain and Palliative Care at Hospital Los Montalvos, Salamanca,Spain.

Address correspondence to: Carlos Centeno, MD, PhD, Equipo de Medicina Paliativa, Clínica Universitaria,Universidad de Navarra, Avenida Pío XII, 36. 31008-Pamplona (Navarra) (E-mail: ccenteno@unav.es).

This paper is based on an oral communication presented in the 8th International Congress of the European Asso-ciation of Palliative Care (EAPC), The Hague, The Netherlands, April, 2003.

Journal of Pain & Palliative Care Pharmacotherapy, Vol. 19(2) 2005Available online at http://www.haworthpress.com/web/JPPCP

2005 by The Haworth Press, Inc. All rights reserved.Digital Object Identifier: 10.1300/J354v19n02_03 7

J Pa

in P

allia

t Car

e Ph

arm

acot

her

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itat d

e G

iron

a on

11/

26/1

4Fo

r pe

rson

al u

se o

nly.

KEYWORDS. Methadone, subcutaneous, intermittent, cancer, pain

INTRODUCTION

Most pain in cancer patients can be con-trolled with orally administered analgesics.However, it is sometimes necessary to use al-ternativeroutes forpatientswhohavedifficultytaking medication orally. The recommenda-tions of the European Association of PalliativeCare (EAPC) Expert Group, in cases of opioidtoxicity, are to use an alternative route, de-crease thedoseandchange the typeofopioid.1

The subcutaneous (SC) route for morphineis widely used in hospitalized patients. For pa-tients withadvancedcancer inwhomaparenteralrouteof administration is required, the subcuta-neous route is preferred to the intramuscularroute. That is because the latter is painful, couldbe associated with wide fluctuations in absorp-tion, and many advanced disease patients havepoor muscle mass. The intravenous route canbe very effective when access is readily avail-able. However, that route may be difficult to es-tablish in patients who have previously receivedchemotherapyandcanbeuncomfortableordif-ficult to maintain due to agitation, phlebitis, orthe home care environment in which care is in-creasingly being provided. In home care, theSC route is used with a varietyof continuous in-fusion systems. Recently, other studies haveaddressed use of the subcutaneous route to ad-minister other drugs that are used in palliativecare including clodronate,2 loxapine,3 and anti-biotics such as ceftriaxone.4

Methadone is a strong opioid with good oralbioavailability. However, in patients with dys-phagia or vomiting for whom methadone is in-dicated, and in patients with delirium or in finalstages of diseasewhen those patientshad previ-ously been treated effectively with methadoneand subsequently cannot takeoral medications,anextra-oral route for theanalgesic isneeded.

In 1991, Bruera et al. reported experiencefrom two centers in Edmonton, Alberta, Can-ada, andMilan, Italy,whereSCmethadonewasused for patients with dysphagia.5 In seven pa-tients, continuous SC infusion was used and forone, it was intermittent. The doses used variedfrom 30 mg to 816 mg per day. Unfortunately,seven patients experienced symptoms of ery-

thema or induration at the infusion point andtreatment was therefore suspended. Böhrer andSchmidt commenting on that report added theirexperience in intensive care where for patientsexperiencing opioid withdrawal symptoms theyused repeated 5 mg of levo-methadone as abolus injection resulting in no local reactions.6These authors hypothesized that the infusionsite reaction reported by Bruera et al. mighthavebeendue to theuseof racemicmethadone.

In 2000, Mathew and Storey reported theirexperience with six patients to whom they ad-ministered continuous SC methadone infusedat doses of 100 to 280 mg.7 Localized infusionsite reactions were noted. The severity of the ir-ritation depended on a number of variables andimproved through rotating the infusion pointand the simultaneous administration of dexa-methasone. Other authors have described po-tentialproblems with this combinationof drugsand have suggested adding hyaluronidase tomethadone infusions. That method has been re-ported to improved tolerability of the infusionsin 12 patients.8

In our experience, for those cases in whichwe have found it necessary to use SC metha-done, reactions such as those described werenot noted. We have also received communica-tions about similar experiences from other col-leagues working in home care. Based on thesepreliminary observations, we suggest that thelocal infusion site reactions with SC metha-done may have been overestimated and we hy-pothesize that local toxicity to SC methadonemay be linked to the continuous subcutaneousinfusion. If this is the case, we believe thatmethadone could be administered intermittentlyasaSCbolusand that treatmentwith thisopioidmight be continued by changing the infusionsite as often as is necessary and tolerable.

MATERIALS AND METHODS

The inclusion criteria for this study were pa-tients who (1) had advanced cancer, (2) werehospitalized in a Palliative Care Unit, (3) whosepain was controlled (using an 11 point [0-10]verbal numerical pain intensity rating scale

8 JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY

J Pa

in P

allia

t Car

e Ph

arm

acot

her

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itat d

e G

iron

a on

11/

26/1

4Fo

r pe

rson

al u

se o

nly.

with which pain intensity was less than 5 out of10), (4) who had stable oral methadone doses,at less, in the seven days prior and (5) who con-sented to participate in the study. The protocoland procedures were approved by the Univer-sity Hospital Ethical Clinical Research Com-mittee.

When designing the study the lack of a gen-erally accepted analgesic equivalence for SCmethadone and methadone administered byother routes was considered. The majority ofexperimental studies show oralmethadonebio-availabilityof around 85%,9 but there have alsobeencases describedof patients in whom meth-adone bioavailability under 50%. For this rea-son some pharmacology guides recommend aconversion factor of 3:1 or 2:1 when changingfrom oral to parenteral routes in order to avoidthe risk of overdose for patients with poor oralmethadone absorption. We felt that the greaterrisk would be providing insufficient medica-tion to the majority of patients by only adminis-tering a third or a half of their previous dose.For this reason we decided to use same doseorally and subcutaneously and to admit into thestudyonlyhospitalizedpatientswhowerecloselymonitored.

Parenteral methadone was used over a pe-riod of seven days during which they receivedthe same dose subcutaneously that they hadpreviously received orally. Rescue doses forbreakthrough pain were provided for use asnecessary and daily adjustments to the medica-tion dose were permitted by the attending phy-sician. Methadone was administered as a bolusthrough a small vein needle (butterfly-type, 23gauge,30 mm),which had been insertedsubcu-taneously at the beginning of the study and wasused exclusively for methadone administra-tion. The needle was inserted using soft pres-sure on the skin at an angle of 30 degrees andheld in place with transparent adhesive tape al-lowing us to see the infusion point. After eachmethadone administration we added 2 mL ofsaline solution to avoid flush any traces of themedication remaining in the infusion set intothe SC tissue.

How well each SC injection could be toler-ated was determined by asking the patient aboutlocal discomfort (pain, stinging, discomfort,itching) which the patient then rated using thenumerical intensity rating scale, and by observ-

ing the infusion site each time a dose was ad-ministered for any anomalies.When symptomsor signs of irritation, i.e., reddening, inflamma-tion, induration, or local discomfort were ob-served, a new SC needlewas placed in a new lo-cation and a record was kept in each suchsituation. Criteria for withdrawing a patientfrom the study were: observation of importantor repeated local irritation, moderate local dis-comfort (numerical rating scale report of morethan 5), at the patient’s request, or when paincontrol was poor.

A daily record was kept of the total dose ofmethadone used and of the pain intensity as de-termined with the numerical pain intensity scale.Each day, the attending physician interviewedthe patient to evaluate for symptoms of opioidoverdose or toxicity (changes in level of con-sciousness, hallucinations, myoclonus, and cog-nitive impairment). On the final day of thestudy, the physician evaluated the overall toler-ability using a five item verbal scale (from verybad to very good). At the end of the study thepatients were asked for their preference as towhich route to continue treatment.

RESULTS

Ten inpatients were included from the CentroRegional de Medicina Paliativa y TratamientodelDolor,HospitalLosMontalvos inSalamanca,Spain. The results obtained are shown in Ta-ble1.Eightpatientsparticipated in thestudy forseven days of evaluations. Two patients werewithdrawn from the study due to local intoler-ance of the intermittent injections, one on thesecond day and the other on the fourth.

In total, 182 intermittent subcutaneous bolusdoses wereevaluated.Followingsevenof thesedoses, the infusion site was changed due to red-dening and/or induration. The SC methadonedid not cause local discomfort. The average nu-merical rating for discomfort caused by the in-jection was 2.1 out of 10. One patient had pain-ful erythema (rating of 4.25 out of 10) from theinitiation of intermittent SC methadone dosingand for this reason was withdrawn from thestudy on the second day. The patients who didnot tolerate the SC methadone boluses werethose who received the higher doses, i.e., 40and 45 mg.

Carlos Centeno and Francisco Vara 9

J Pa

in P

allia

t Car

e Ph

arm

acot

her

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itat d

e G

iron

a on

11/

26/1

4Fo

r pe

rson

al u

se o

nly.

The average pain intensity reported by thepatients prior to SC methadone administrationwas 3.3 out of 10. At the end of the study thisvalue had barely changed, i.e., it was 3.5 out of10. The initial average dose of oral methadonewas 30 mg per day (range 10 to 120 mg). Thedose of subcutaneous methadone at the end ofthe study averaged 33 mg per day (range 10-90).During the study only minor adjustments wereneeded due to slight signs of local irritation orpain, except in the patient with the highest dose(120 mg per day) for whom a 30% reductionwas needed. The relationship between the ini-tial dose of oral methadone and the final SCdose of methadone was 1:1 (minimum 1:0.7,maximum 1:1.3). The doses and dosing inter-vals were 5 to 45 mg per bolus administered ev-ery 8 or 12 hours.

The physician evaluation of overall tolera-tion of the treatment was “good” or “verygood” for the eight patients who completed theseven-day study. One patient chose the oralroute at the end of the treatment. Seven patientsindicated their preference for SC administra-tion. Some of the reasons for justifying thischoice were the rapidity of effect, the bitter

taste of the oral preparation, and the reliabilityand convenience of the administration by nurs-ing staff. No other reasons were reported.

DISCUSSION

In this study, bolus SC methadone doses of25 mg or less were repeatedly well tolerated inover 160 administrations of the drug. Subcuta-neous injection caused very little local pain andwith repeat administrations thepatients reportedless local irritation discomfort (Figure 1). Twopatients who received higher doses in eachbolus (40 and 45 mg) were withdrawn from thestudy because they repeatedly developed red-dening and/or induration at the injection sites.

When comparing these results with those ofother studies (Table 2), the greater tolerabilitycannot be explained by the methadone formu-lation used since this is almost identical in allthe studies. Nor does the dose or concentrationseem to be decisive factors in the developmentof local injection site reactions because lowdose methadone administered as a continuousinfusion also caused intolerable irritation. In

10 JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY

TABLE 1. Intermittent subcutaneous methadone administration

Patient1

Patient2

Patient3

Patient4

Patient5

Patient6

Patient7

Patient8

Patient9

Patient10

Total/averages

Cancer type Myeloma Colon Gastric Lung Esophagus Rectum Lung Pancreas Lung Breast

Patient gender and agein years

M 51 M 60 M 66 M 75 M 75 F 67 M 81 M 63 M 46 F 64

Pain intensity day 0 4 5 4 3 1 2 3 3.5 4.5 1 3.3

Average pain days 1-7 4.3 4.7 2.5 0.5 2.9 1 1.5 3.5 3.6 0.9 3.5

Methadone dose day 0(PO) and day 1 (SC)

20 30 15 75 17,5 120 10 90 45 30 30.0

Methadone dose finalday of study

20 36 12 87.5 12 80 10 90 45 30 33.0

Equivalence SC/POfinal day of study

1.0 1.3 0.9 1.1 0.7 0.8 1.0 1.0 1.0 1.0 1.0

Regular doses (mg/h) 10 mgq12h

10 mgq12h

5 mgq8h

25 mgq8h

5 mgq8h

40 mgq8h

5 mgq12h

45 mgq12h

15 mgq8h

10 mgq8h

Total bolus studied 14 23 27 27 21 9 14 4 21 21 182

Average localdiscomfort

3.1 1.5 0.6 0 3.8 2.6 0.8 4.25 2.6 0.7 2.1

Change of site forindurations orreddening

1 1 1 2 1 1 7

Days of administration 7 7 7 7 7 4 7 2 7 7 6.2

Overall toleration ofadministration

Verygood

Good Verygood

Verygood

Verygood

Withdrawn Good Withdrawn Normal Verygood

Patients’ routepreference

SC SC SC SC SC - PO - PO SC

J Pa

in P

allia

t Car

e Ph

arm

acot

her

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itat d

e G

iron

a on

11/

26/1

4Fo

r pe

rson

al u

se o

nly.

another study tolerability was improved byadding dexamethasone to the infusion. It ap-pears that methadone routinely causes a certaindegree of SC irritation. On seven occasions wehad to change the infusion site due to reddeningof the area and in two others we had to suspendtreatment.

Changing the infusion site due to slight dis-comfort is acustomaryprocedure inour unit forSC administration of any drug, not only formethadone. However, this study demonstratesthat SC methadone can be used without majorproblems by intermittent administration andthat limiting the dose infused as a SC boluspoint minimizes patient discomfort. Other au-thors have reported a lack of local injection siteirritation with SC L-methadone. It has beensuggested that this may be due to the racemicformula employed. Reported clinical adminis-tration of the levorotatory isomer was with sub-cutaneous intermittent boluses at low doses.Results with L-methadone were similar to ourresults suggesting that the lack of local irrita-tion with that form may have been due to thelow drug doses and administration method ratherthan the levorotatory isomer, per se.

This small study suggests that intermittentSC administrationof low dose boluses of meth-adone may be a useful clinical alternative whenthe oral route cannot be used. In a recent pro-spective study,10 the majority of patients treatedwith methadone for cancer pain received aver-age doses of 25 mg, administered twice or threetimes. Such SC methadone doses should nor-mally be well tolerated locally. Other strategies

may be necessary when higher doses are re-quired: for example, dividing the dosage andusing multiple injections at different sites oradministering smaller doses at shorter dosingintervals. Rectal administration also may be anoption given its excellent acceptance at 80% ofthe oral dose. However, compared to the SCroute, rectal administration may be uncomfort-able, esthetically less acceptable to some pa-tients and families, and would provide no ad-vantage for the patient except in some cases ofhome-based care and when specially preparedsuppositories were available for each case.

The possibility of administering methadonesubcutaneously in selected cases provides newpossibilities for wider use of this opioid in can-cer pain, for patients in their final days, thosewith head and neck tumors, and others havingdifficulty with oral administration. Subcutane-ous administration allows rapid titration in in-cident pain. Pharmacodynamic studies of thisroutewouldprovidemorevaluable information.

This small study has highlighted the need forclarificationof the analgesicequivalence to usewhen changing from the oral to the subcutane-ous route. We found no difficulty using anequivalenceof1:1accompaniedbyactivemoni-toring of the patient during the first few days.For the patient who received the highest dailydoses, we did find it necessary to significantlyreduce the dose. Considering that there may bepatients with low acceptance of oral metha-done, the change in route should be undertakenunder supervision in order to avoid overdosing,especially when the previous doses were high.In our opinion the routine dosage reduction of50% to 66% when changing from the oral to theparenteral route that has been recommended bysome authors is not justified. Conclusive stud-ies on methadoneacceptanceare needed to pro-vide clearer guidelines. In the case of higherdoses (for example, more than 80 to 100 mg perday), it might be reasonable to reduce the dosageby a third.

In conclusion, SC methadone administra-tion may be a valid alternative to oral adminis-tration and the risk of local intolerance can beavoided by using an intermittent regimen andby limiting the maximum dose.

Carlos Centeno and Francisco Vara 11

5

4

3

2

1

01 2 3 4 5 6 7

Average

Day

Dai

lyav

erag

elo

cal d

isco

mfo

rt(V

NE

0-10

)FIGURE 1. Local discomfort caused by discontin-ues subcutaneous methadone injection

J Pa

in P

allia

t Car

e Ph

arm

acot

her

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itat d

e G

iron

a on

11/

26/1

4Fo

r pe

rson

al u

se o

nly.

REFERENCES

1. Hanks GW, Conno F, Cherny N, Hanna M, KalsoE, McQuay HJ, Mercadante S, Meynadier J, Poulain P,Ripamonti C, Radbruch L, Casas JR, Sawe J, TwycrossRG,Ventafridda V. Morphine and alternative opioids incancer pain: the EAPC recommendations. Br J Cancer2001;84:587-93.

2. Walker P, Watanabe S, Lawlor P, Hanson J,Pereira J, Bruera E. Subcutaneous clodronate: a studyevaluating efficacy in hypercalcemia of malignancy andlocal toxicity. Ann Oncol 1997;8:915-6.

3. Sauder C, Porterfield P, Shalansky KF, Tong KL.Subcutaneous administration of loxapine. Am J HealthSyst Pharm 1999;56:1259-61.

4. Borner K, Lode H, Hampel B, Pfeuffer M,Koeppe P. Comparative pharmacokinetics of ceftriaxoneafter subcutaneous and intravenous administration. Che-motherapy 1985; 31: 237-45.

5. Bruera E, Fainsinger R, Moore M, Thibault R,Spoldi E, Ventafridda V. Local toxicity with subcutane-ous methadone. Experience of two centers. Pain 1991;45:141-3.

6. Bohrer: Comment on Bruera et al. Local toxicitywith subcutaneous methadone. Experience of two cen-ters. Pain 1991; 45:141-143

7. Mathew P, Storey P. Subcutaneous methadone interminally ill patients: manageable local toxicity. J PainSymptom Manage. 1999 Jul;18(1):49-52.

8. Makin, MK, Subcutaneous methadone in termi-nally-ill patients. J Pain Symptom Manage. 2000;19:237-8.

9. Gourlay GK, Cherry DA, Cousins MJ. A com-parative study of the efficacy and pharmacokinetics oforal methadone and morphine in the treatment of severepain in patients with cancer. Pain 1986; 25:297-312.

10. Mercadante S, Casuccio A, Fulfaro F, et al.Switching from morphine to methadone to improve an-algesia and tolerability in cancer patients: a prospectivestudy. J Clin Oncol 2001; 19: 2898-904.

11. Ripamonti C, Zecca E, Brunelli, et al. Rectalmethadone in cancer patients with pain. A preliminaryclinical and pharmacokinetic study. Ann Oncol 1995;6:841-3.

SUBMITTED: 08/20/04REVISED: 11/15/04

ACCEPTED: 11/30/04

12 JOURNAL OF PAIN & PALLIATIVE CARE PHARMACOTHERAPY

TABLE 2. Comparison between published experiences with methadone by subcutaneous injection

Group ofPatients

ActivePrinciple

Presentation(composition) Supplied by SC

Administration PatientsDaily

Doses(mg)

Order Reactions

Edmonton5 Methadone HCl 10-50 mg/mLsolution(methadone HClpowder in sterilewater forinjection)

EdmontonGeneral HospitalPharmacyDepartment

Continuousinfusion

3 30-816 2.5-34 mg/h Skin erythemaand induration

Bolus 1 160 40 mg/mL q6h Skin erythemaand induration

Milan5 Methadonechlorhydrate

10 mg/mL vials(composition notreported)

ShimesPharmaceuticalMilan, Italy

Continuousinfusion

3 28-38 1.2-1.6 mg/h Skin erythemaand induration

1 28 1.2 mg/h None

Heidelberg6 L-Methadonehydrochloride

5 mg/mL(composition notreported)

Hoechst,Frankfurt

Bolus > 200 20-40 5mg q 3h-q6h None

Houston7 Methadonehydrochloride

10 mg/mLsolution forinjection(composition notreported)

Dolphine: RoxaneLabs/ Eli LillyUSA

Continuousinfusion

6 75-280 3.1-11.6 mg/h Manageablelocal toxicity:in 7 patientsdexamethasonewas added

Salamanca Methadonechlorhydrate

10 mg/mL vials(methadonechlorhydrate 10mg, ClNA 8mg/mL sterile waterfor injection 1 mL)

LaboratoriosEsteve,Barcelona, Spain

Bolus 8 30-75 5-25 mg/8-12h None

2 90-120 40-45 mg/8h Skin erythemaand induration

J Pa

in P

allia

t Car

e Ph

arm

acot

her

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

itat d

e G

iron

a on

11/

26/1

4Fo

r pe

rson

al u

se o

nly.