Epidural methadone results in dose-dependent analgesia in cancer pain, further enhanced by epidural dexamethasone.

0.18 MB·English

by  Lauretti, G R

FULL PAPER
British Journal of Cancer (2013) 108, 259–264 | doi: 10.1038/bjc.2012.593
Keywords: cancer pain; epidural methadone; epidural dexamethasone
Epidural methadone results in dose-
dependent analgesia in cancer pain, further
enhanced by epidural dexamethasone
G R Lauretti*,1, C C Rizzo1, A L Mattos1 and S W Rodrigues1
1TeachingHospital,DepartmentofBiomechanics,MedicineandRehabilitationofMembersoftheFacultyofMedicineofRibeira˜o
Preto,UniversityofSa˜oPaulo,AvBandeirantes3900,Ribeira˜oPreto-Sa˜oPaulo14039900,Brazil
Background:Thisstudywasdesignedtoevaluatetheroleofepiduralmethadone-lidocaineincancerpaincombinedornotto
epidural dexamethasone.
Methods: In all, 72 cancer patients, 32- to 67-year-old were randomized to six groups (n¼12) and prospectively studied to
examineanalgesiaandadverseeffectsfor3weeks.Patientsreceivedsingle-doseprotocolepiduraltestdrugs:Controlgroup(CG)
receivedepidural40-mglidocainedilutedto10-mlvolumewithsaline.Dexamethasonegroup(DG)40-mglidocaineplus10-mg
dexamethasone. The 2.5MetG 2.5-mg epidural methadone with 40-mg lidocaine; the 5MetG, 5-mg epidural methadone plus
40-mglidocaine,the7.5MetG,7.5-mgepiduralmethadoneplus40-mglidocaineandfinallythe7.5Met-DexG,7.5-mgmethadone
with40-mglidocaine and10-mg dexamethasone.
Results:GroupsCG,DGand2.5MetGweresimilarregardinganalgesiaandsideeffects.Patientsfrom5MetGand7.5MetGtook
3±1and5±1days,respectively,torestartoralmorphine.Patientsfrom7.5MetDGtook14±2torestartoralmorphine(Po0.001).
Dailysomnolenceandappetite improved inthe7.5MetDG during2-weekevaluation (Po0.005).Fatigueimproved forbothDG
and7.5MetDG during2-weekevaluation (Po0.005).Bythethird weekof evaluation, allpatientswere similar.
Conclusions: Epidural methadone plus lidocaine resulted in dose-dependent analgesia, further improved by epidural
dexamethasone, whichalso improved fatigue.
Spinal analgesics have been suggested as the fourth step in the effects from high doses. The opioid methadone has a broad-
World Health Organisation guidelines in the management of spectrumofsuggestedspinalactions:mreceptoragonist,N-methyl-
cancer pain for those patients who suffer from severe and D-aspartate receptor (NMDA) receptor antagonist (Sotgiu et al,
refractory pain, or are incapable to bear the adverse effects from 2009), glial activator (Hutchinson et al, 2010), and has been
oral opioids (Christo and Mazloomdoost, 2008; Hattori et al, increasingly used as a second-line opioid in recent years in the
2009). Although there are not sufficient clinical trials to evaluate management of cancer-related pain (Leppert, 2009; Anghelescu
spinal opioids in adult cancer patients (Kurita et al, 2011), et al, 2011; Mercadante, 2012). In addition, corticosteroids were
morphinehasbeenoneofthecornerstonesforthemanagementof described to be commonly used in cancer pain, in spite of its
chronic intractable cancer pain. Due to the proximity to the limited scientific evidence (Leppert and Buss, 2012). The purpose
receptor sites, the therapeutic efficacy of spinal opioid application of the present study was to examine thepotential role of epidural
lastslongerandalsoreduces systemicside effects.However,some methadone in cancer pain therapy. Its efficacy was further
patients unable to tolerate spinal morphine may suffer with side- evaluated by the association of epidural dexamethasone.
*Correspondence:DrGRLauretti;E-mail:[email protected]
Received28May2012;revised20November2012;accepted10December2012;publishedonline15January2013
&2013CancerResearchUK.Allrightsreserved0007–0920/13
www.bjcancer.com|DOI:10.1038/bjc.2012.593 259
BRITISHJOURNAL OF CANCER Epidural methadone|dexamethasone forcancer pain
dailyconsumptionoforalmorphineandthelistedadverseeffects.
MATERIALS AND METHODS
Patients assigned as ‘yes’ or ‘no’ the final impression of the side
effects listed at the final of each week evaluation: (1) daily
The Ethics Committee at the University of Sa˜o Paulo’s Teaching somnolence,(2)nocturnalinsomnia,(3)nausea,(4)occurrenceof
Hospital,Ribeira˜oPreto,approvedthestudyprotocol.Afterwritten vomiting, (5) constipation, (6) diminished appetite, (7) fatigue,
informed consent, 72 from the total of112 patients suffering from (8) sadness. Complain of nausea 43cm in a 10cm VAS and
cancerpainwereselectedatthePainClinic(B64%inclusion).The occurrence of vomiting was treated with 8mg sublingual
72 patients were randomized to one of six groups (n¼12) and ondansetron two-three times daily, if necessary. Constipation was
prospectively studied usinga placebo-controlled designto examine treated with improved ingest of fibres and/or oral laxative if
analgesia and adverse effects and assigned to treatments using a necessary.Patientshadfreeaccesstothepersonalcellphoneofone
randomizednumbergeneratorinacomputer programme. of the authors that was unaware of the study groups.
The study was designed to have a power of 80% to detect a
treatment difference of 1-day analgesia on a two-sided level of Statistical analysis. The normality of the distributions was
significance of a¼0.05 assuming a standard deviation of 2 days, assessed using the Shapiro–Wilk’s test. Groups were compared
and a minimum number of eight patients per group. Eligible for demographic data (age, weight, and height) by one-way
patients were aged 32–67 year-old, with a diagnosis of cancer, ANOVA. Incidence of adverse events, gender and site of primary
documented history of moderate/severe, chronic cancer pain, disease werecomparedamonggroupsbyw2analysiscorrectedfor
classified as Tumour-Node-Metastasis stage III or IV, requiring multiplecomparisons.Pwasconsideredsignificantifo0.008.VAS
round-the-clock opioid, and capacity to understand the study scores;andthedailymorphineconsumptionfromday-zerotoday-
protocol. Patients were excluded from the study for the following 21 were compared among groups by two-way ANOVA for
reasons:evidenceofclinicallyunstabledisease,clinicallysignificant repeated measures (Dexter and Chestnut, 1995). The statistical
gastro-intestinal disease, cyclic chemotherapy within 3 weeks analysis compared among the six different groups on each day of
beforescreening visit orplanned duringthecore study(shownin the study. Tukey Honest analysis was applied to correct P values
the past to influence bowel function); radiotherapy that would for multiple group comparisons. Po0.05 was considered sig-
influence bowel function or pain, refusal, allergy to any of the nificant. Data are expressed as mean±s.d., otherwise stated.
drugsusedorinabilitytoingesttheoralrescueanalgesicmorphine.
Theconceptofavisualanaloguescale(VAS),whichconsistedofa
10-cm line with 0 equalling ‘no pain at all’ and 10 equalling ‘the RESULTS
worstpossiblepain’wasintroduced.ThepatientbroughttheVAS
scores and daily morphine consumption recorded each day at the Four patients from the CG, 3 from the DG, 2 from the 2.5MetG,
weekly appointments (21-day study). However, patients were free 5Met and 7.5Met G; and finally one from the 7.5MetDG were
tocontactoneoftheauthorsanytimebyapersonalphonenumber, excluded from the final analysis due to incomplete data collection.
through a collect call, whenever necessary. However,theminimumofeightpatientspergroupwasmaintained
All patients were regularly taking oral amitriptyline 25mg at for statistical purposes. The exclusion reasons are detailed: three
bedtime as part of our institutional protocol, and oral morphine patientsfromtheCGtooktheirowndecisiontotakeoralcodeineor
regimenindividuallyadjustedtoamaximaloraldoseof80–90mg diclofenac during the study period combined with oral morphine,
per day, in order to keep the VAS score o4/10. When patients while the remaining patient did not come to the last appointment.
complainedofpain(VASZ4/10),despitethe80–90mgdailyoral Related to the DG group, two patients forgotten to make notes
morphine, they were submitted to the epidural test drugs and all related to VAS pain scores or oral morphine consumption, and
patientswereblindtothetreatments.Thedaybeforetheepidural other patient included by its own oral diclofenac during the study
test block was considered day-zero, and the day of the epidural period. Two patients from 2.5MetG and 7.5MetG and 1 from the
block was performed was considered day-1 of the study. The 5MetG were also excluded due to incomplete data collection
groups were computer divided into six as follow: The Control regarding oral morphine consumption and pain VAS. One patient
group(CG)receivedepidural40mglidocaine(1%,20mlampoule from 5MetG did not come to the last week appointment. Finally,
withnoadrenaline,Cristalia)dilutedto10-mlvolumewithsaline. 1patientfromthe7.5MetDGwasexcludedduetoingestionoforal
The Dexamethasone group (DG) received 40mg lidocaine plus metamizolfor pain control duringthe study period.
10mg dexamethasone (8mg dexamethasone acetate þ2mg Thegroupsshowednodifferencesregardinggender,weight,age
dexamethasone phosphate, Ache). The 2.5MetG received 2.5mg andheight(Table1),distributionoftheprimarysiteofthecancer
epidural methadone (Methadone, 1ml ampoule, dl-racemic pathology(Table2)andincidenceofmetastasis,whichvariedfrom
mixture, 10mg|ml, conservative-free, Cristalia) combined with
40mglidocaine;the5MetGreceived5mgepiduralmethadoneplus
40mglidocaine,the7.5MetGreceived7.5mgepiduralmethadone Table1.Demographicanalysis
plus 40mg lidocaine and finally the 7.5Met-DG received 7.5mg
epidural methadone combined with 40mg lidocaine and 10mg Gender(male/ Weight Age Height
dexamethasone.Allpatientsreceivedsacralblockonly,whichwas female)a (kg)a (age)a (cm)a
doneunderasepticconditionsalwaysbythesameanaesthetistthat CG 3/5 58±11 53±14 165±9
wasunaware ofthestudy drugprepared byasecondanaesthetist. DG 4/5 55±8 56±9 162±7
Thedrugsweredilutedina10-mlcoveredsyringeinordertokeep
2.5MetG 4/6 57±7 53±11 167±9
the blindness of the study. The correct position of the needle as
assessed by fluoroscopy and by injection of 1ml contrast 5MetG 4/6 66±16 50±8 167±8
(Omnipaque, 300mg|ml iohexol, Sanofi). All sacral blocks were 7.5MetG 5/5 56±13 52±13 164±6
performed in the morning. Patients were free to manipulate their 7.5MetDG 5/6 54±12 47±13 162±6
daily oral morphine consumption, in order to keep daily pain
VASo4/10 and were followed on a weekly basis during 3 Abbreviations:CG¼controlgroup;DG¼dexamethasonegroup;2.5MetG¼2.5mgmetha-
consecutive weeks. The 10mg morphine tablets were given by done group; 5MetG¼5mg methadone group; 7.5MetG¼7.5mg methadone group;
thegovernment.Allpatientsregisteredonceadaybeforebed-time 7.5MetDG¼7.5mgmethadone-dexamethasonegroup.P40.05.
aDataareexpressedasmean±s.d.
(at23-h)theVASresemblingthepainaverageoftheday,thefinal
260 www.bjcancer.com|DOI:10.1038/bjc.2012.593
Epidural methadone|dexamethasone forcancerpain BRITISH JOURNALOF CANCER
Table2.Distributionoftheprimarysiteofthecancerpathologyandincidenceofmetastasisamongthegroups
CG(n¼8) DG(n¼9) 2.5MetG(n¼10) 5MetG(n¼10) 7.5MetG(n¼10) 7.5MetDG(n¼11)
Oropharynx 1 1 1 2 1 1
Breast 3 4 4 3 3 4
Lung 1 0 1 0 1 0
Uterus 2 1 2 1 1 2
Prostate 1 2 1 2 2 2
Digestivetract 0 0 0 1 1 1
Kidney 0 0 1 0 1 0
Liver 7 1 0 1 0 1
Incidenceofmetastasis(%) 63% 66% 60% 70% 60% 73%
Abbreviations:CG¼controlgroup;DG¼dexamethasonegroup;2.5MetG¼2.5mgmethadonegroup;5MetG¼5mgmethadonegroup;7.5MetG¼7.5mgmethadonegroup;7.5MetDG¼7.5
mgmethadone-dexamethasonegroup.P40.05.Incidenceofmetastasisatthetimeofinclusionatthestudyprotocol.
60% to 73% (P40.05; Table 2). In addition, all overall daily VAS 180
scoreswereo4cmtoallgroupsduringthestudyperiod(P40.05, g) 160
datanotshown).Onday-zero(daybeforetheepiduraltestdrugs) m
all patients were taking 80–90mg oral morphine, as part of the n ( 140
o
stotutdaykeproortaolc1o0lm(Pg4m0o.0r5p)h.iOnenatshmefuoclhloawsinngecdeasysas,rypaintieonrtdsewretorekfereepe mpti 120
u
pain VAS o4|10cm. Final VAS scores. ns 100
o
On day-1 (the day patients were submitted to epidural test c
e 80
drugs), only the CG, DG and 2.5MetG kept the daily oral n
consumptionof80–90mgmorphine.Thesethreegroupsgradually phi 60
increased daily oral morphine consumption until day-21 (150– mor 40
170mg morphine) (P40.05). CG¼DG¼2.5MetG during all the y
21-day evaluation regarding oral daily morphine consumption Dail 20
(P40.05; Figure 1). 0
Related to the 5MetG, from day-1 to day-3, the daily intake 1 3 5 7 9 11 13 15 17 19 21
of oral morphine was: 5MetG¼7.5MetG¼7.5MetDG d
(P40.05)oCG¼DG¼2.5MetG(Po0.001).Fromday-4,patients CG DG 2.5MetG
started getting daily increasing oral morphine intake, which was
similar to the CG, DG and to the 2.5MetG from day-7 forwards 5MetG 7.5MetG 7.5MetDG
(daily evaluation-P40.05; Figure 1). The evaluation of the
7.5MetG revealed that from day-1 to day-5, the daily intake of Figure1.Dailyconsumptionoforalmorphineinthegroups.
oral morphine was: 7.5MetG¼7.5MetDG (P40.05)oCG¼ CG¼controlgroup;2.5MetG¼2.5mgmethadonegroup;
DG¼2.5MetG (Po0.001). From day-6, patients started getting 5MetG¼5mgmethadonegroup;7.5MetG¼7.5mgmethadone
daily increasing oral morphine intake, which was similar to the group;7.5MetDG¼7.5mgmethadone-dexamethasonegroup.Day-
CG, DG and to the 2.5MetG from day-10 forwards (daily 1¼theCG,DGand2.5MetGkeptthedailyoralconsumptionof80–
evaluation-P40.05; Figure 1). Related to the 7.5MetDG, from 90mgmorphine(P40.05).CG¼DG¼2.5MetGduringallthe21-day
day-1today-15,thedailyintakeoforalmorphinewaslesserwhen evaluationregardingoraldailymorphineconsumption(P40.05).
compared with the CG¼DG¼2.5MetG (Po0.001). On day-4, Patientsstartedtheevaluationonday-1taking80–90mgoral
7.5MetDGo5MetG (Po0.05). On day-6, 7.5MetDGo7.5MetG morphine,whichwasgraduallyincreasingforCG,DGand2.5MetG
(Po0.05). From day-15, the oral intake of daily morphine was untilday-21(150–170mgmorphine)(dailyevaluation-P40.05)
similar to all groups (P40.05). 5MetG¼fromday-1today-3,thedailyintakeoforalmorphinewas:
The incidence of adverse effects is described in Table 3. The 5MetG¼7.5MetG¼7.5MetDG(P40.05)oCG¼DG¼2.5MetG
complaints of gastric upsetting, constipation, sadness and noctur- (Po0.001).Fromday-4,patientsstartedgettingdailyincreasingoral
nal insomnia were similar among groups at day-7, -14 and -21 morphineintake,whichwassimilartotheCG,DGandtothe2.5MetG
evaluations (P40.05). Related to all adverse effects questioned, fromday-7forwards(dailyevaluation-P40.05).7.5MetG¼fromday-1
daily somnolence and appetite improved in the 7.5MetDG during today-5,thedailyintakeoforalmorphinewas:7.5MetG¼7.5MetDG
atday-7and-14evaluations(Po0.005).Fatigueimprovedforboth (P40.05)oCG¼DG¼2.5MetG(Po0.001).Fromday-6,patients
DGand7.5MetDGduringatday-7and-14(Po0.005).However, startedgettingdailyincreasingoralmorphineintake,whichwassimilar
allsideeffectsweresimilaratthethirdweekevaluation(P40.05). totheCG,DGandtothe2.5MetGfromday-10forwards(daily
No other adverse effects rather than the questioned were evaluation-P40.05).7.5MetDG¼fromday-1today-15,thedailyintake
spontaneously described by the patients. oforalmorphinewaslesserwhencomparedwiththe
CG¼DG¼2.5MetG(Po0.001).Onday-4,7.5MetDGo5MetG
(Po0.05).Onday-6,7.5MetDGo7.5MetG(Po0.05).Fromday-15,the
oralintakeofdailymorphinewassimilartoallgroups(P40.05).
DISCUSSION
before bedtime showed a dose-dependent analgesia after a single
In the present study, patients suffering from cancer pain treated dose of 2.5, 5 and 7.5mg epidural methadone, which was further
chronically with oral morphine at round clock and amitriptyline increased by the addition of epidural dexamethasone. Previously,
www.bjcancer.com|DOI:10.1038/bjc.2012.593 261
BRITISHJOURNAL OF CANCER Epidural methadone|dexamethasone forcancer pain
Table3.Numberofpatientswhocomplainedatday-7andday-14evaluation(totalnumberofpatientscomplainingpergroup)
CG DG 2.5MetG 5MetG 7.5MetG 7.5MetDG
Dailysomnolenceþ 8 9 10 9 5 1
Nocturnalinsomnia 6 7 7 7 6 5
Nausea 6 5 7 6 5 2
Vomiting 2 0 2 2 2 1
Constipation 8 8 8 7 8 7
Diminishedappetite 8 6 9 10 9 1
Fadigue 8 3þ 10 10 10 2
Sadness 8 7 10 9 10 6
Abbreviations: CG¼control group; 2.5MetG¼2.5mg methadone group; 5MetG¼5mg methadone group; 7.5MetG¼7.5mg methadone group; 7.5MetDG¼7.5mg methadone-
dexamethasonegroup.Dailysomnolenceandappetiteimprovedinthe7.5MetDGatday-7and-14evaluations(Po0.005).FatigueimprovedforDGand7.5MetDGatday-7and-14(Po0.005).
doses varying from daily epidural 12–32mg methadone were A different combination of drugs was the DG, which patients
formerly described to result in pain control in 80% of cancer received both epidural dexamethasone and lidocaine. Dexametha-
patientssufferingfromvisceralorsomaticpain,withanaverageof sone profits may be secondary to glucocorticoid receptor
27-dailyinfusionandnoseriousside-effects(Shiretal,1991).We activation, in turn rapidly suppressing basal and stress-induced
used a single bolus of epidural racemic methadone for treating hypothalamus–pituitary–adrenal activity partly through a central
cancer pain, as the purpose of the study. Methadone was mechanism of action (Andrews et al, 2012). At the level of the
demonstrated to act primarily as agonist of m-opioid receptor, paraventricular nucleous, dexamethasone rapidly reduced
and its d isomer has also NMDA receptor antagonist activity hypothalamus–pituitary–adrenalaxisactivationinanon-genomic,
(Inturrisi,2005).Ithashighlipidsolubilitythatcouldfacilitateits membrane-associated manner, involving cannabinoid receptor
entrance from the epidural space into the spine, although a type 1 signalling (Evanson et al, 2010). Apart, corticosteroid was
peripheral action has also been described (He et al, 2010). demonstrated to effectively reduce myelin changes accompanying
Nevertheless, epidural methadone has an intrinsic spinal effect brain oedema (Kozler et al, 2011) that would benefit patients
regardless of whether or not there is extra-spinal action arising suffering from oedema secondary to spinal metastasis or to
from systemic absorption (Parramon et al, 2003). hidroeletrolytic disturbances. In addition, high levels of glucocor-
Epiduralmethadonecombined(Prieto-Alvarezetal,2002;Pe´rez ticoid receptor and mineralocorticoid receptor are colocalized in
et al, 2010) or not (Parramon et al, 2003) to local anaesthetic has thesubstantiagelatinosawherepainpathwaysappeartobeundera
been described before as analgesic for acute pain in patients and strong regulation of these receptors, and nociception was
horses (Olbrich and Mosing, 2003). Different combinations have attenuated by spinal dexamethasone (Gu et al, 2011). Other
been used in the actual multimodal cancer pain study. Clinically possible speculated mechanism of action for the epidural
used Naþ channel blockers such as lidocaine, at doses which do dexamethasone could be the attenuation of the ciclooxigenase-2-
notblockconductioncanrelievespinalsensitizationandfacilitator dependent production of prostanoids, mainly vasoactive prosta-
processes in dorsal horn neurons via blockade of Naþ and Kþ glandin-E(2) (Font-Nieves et al, 2012) from the astrocytes that
channels (Olschewski et al, 2009), can directly modulate NMDA- surround thesynapse between thefirst- and second-order neuron
receptorinthesuperficialdorsalhorn,caninhibitpersistentNaþ in the spinal cord. Apart from spinal mechanism of action,
currentininjureddorsalrootganglionneurons(Dongetal,2008), dexamethasone could also decrease astrocyte-to-neuron commu-
andadditionallymayhaveageneralglycine-likeactionoflidocaine nication in the hypothalamus through inhibition of production of
or some of its metabolites on inhibitory strychnine-sensitive the gliotransmitter prostaglandin-E(2) (Clasadonte et al, 2011).
receptors and on strychnine-insensitive glycine receptors (Muth- Dexamethasone also prevented lidocaine-induced neurotoxicity in
Selbachetal,2009;Furutanietal,2010).Otherinherentactionof tumourcellsthroughpreventionofmitochondrialpotentialdecline
lidocaine would be the phosphorylation attenuation of p38 and also increased levels of threonine-serine protein kinase B
mitogen-activated protein kinase in the activated microglia of phosphorylation (Ma et al, 2010). Finally, the final combination
spinal cord, reversing established tactile allodynia in chronic evaluated in this clinical setting was epidural lidocaine plus
constrictioninjurymodelofrats(Guetal,2008).Inourstudy,the methadone plus the glucocorticoid dexamethasone. Co-adminis-
association of low-dose lidocaine and escalating doses of epidural trationofdexamethasoneandglutamatereceptorantagonists(such
methadone was evaluated. The results demonstrated that neither as spinal methadone and lidocaine) for treating nociception have
the epidural dose of 40mg lidocaine alone nor combined with been previously described in rats in the periphery (Lam and Ng,
2.5mg methadone were effective for improving cancer pain. 2012) and centrally (Bertorelli et al, 1998). In accordance, our
Lidocaine has been previously demonstrated to produce analgesia results revealed around 14 days of pain relief from a single bolus
for somatic and visceral pain at the spinal level, which was dose of the combination of the three drugs.
synergistic with a non-NMDA glutamate receptor antagonist in Additional benefits in patients who received epidural dexa-
rats (Imamashi et al, 1999). Isobolographic analysis also revealed methasone included decreased incidence of daily somnolence,
that the epidural opioid morphine and lidocaine interacted decrease fatigue and appetite improvement after both dexametha-
synergistically in both somatic and visceral nociception tests, and sone and 7.5mg methadone during the first 14 days evaluation,
naloxone antagonised the antinociceptive effects produced by the while only fatigue improved for DG at day-7 and -14. Probably
combination (Kaneko et al, 1994). Whether local anaesthetics somnolence and appetite improvement were not enriched in this
wouldactasanti-inflammatoryandinmicro-molarconcentrations groupduetothehigheroraldailydoseofmorphineconsumption
would inhibit extracellular oxygen release in spinal microglia; as theydisplayed.Thegradualincreaseinmorphineconsumptionto
describedelsewhereforneutrophilprimingandactivation(Ploppa allgroupsafterday-15wasprobablyreflectionoftheparticularity
et al, 2010), is unknown. of the study population (high incidence of metastasis) and of the
262 www.bjcancer.com|DOI:10.1038/bjc.2012.593
Epidural methadone|dexamethasone forcancerpain BRITISH JOURNALOF CANCER
study drug protocol, where only morphine was allowed as rescue hormone(GnRH)neuronfiringviaEP2receptoractivation.ProcNatl
analgesic. Another point to be considered is that cancer patients AcadSciUSA108:16104–16109.
suffer from stress of the disease knowledge, anxiety and pain that DexterF,ChestnutDH(1995)Analysisofstatisticalteststocomparevisual
may result in dysfunction of glutamatergic neurotransmission, analogscalemeasurementsamonggroups.Anesthesiology82:896–902.
including effects on glutamate release, glutamate receptors and DongH,FanYH,WangYY,WangWT,HuSJ(2008)Lidocainesuppresses
subthresholdoscillationsbyinhibitingpersistentNa(þ)currentin
glutamateclearanceandmetabolism(Popolietal,2011).Apositive
injureddorsalrootganglionneurons.PhysiolRes57:639–645.
effectofthecombinationoflidocaine,methadoneanddexametha-
EvansonNK,TaskerJG,HillMN,HillardCJ,HermanJP(2010)Fastfeedback
sone in this population could be at least partly due to their
inhibitionoftheHPAaxisbyglucocorticoidsIsmediatedby
neuroprotective effect on the dorsal root ganglion and Schawnn
endocannabinoidsignaling.Endocrinology151:4811–4819.
cells (Zhu and Glaser, 2008; Ma et al, 2010), as antagonists of Font-NievesM,Sans-FonsMG,GorinaR,Bonfill-TeixidorE,Salas-Pe´rdomo
NMDA receptor combined with dexamethasone have been A,Ma´rquez-KisinouskyL,SantaluciaT,PlanasAM(2012)Inductionof
describedtoreducetheproductionoftumournecrosisfactorlevel COX-2enzymeanddown-regulationofCOX-1expressionby
in the brain. lipopolysaccharide(LPS)controlprostaglandinE2productionin
In summary, dexamethasone would enhance methadone astrocytes.JBiolChem287:6454–6468.
analgesia partly through: (1) overwhelming the hypothalamus– FurutaniK,IkomaM,IshiiH,BabaH,KohnoT(2010)Bupivacaineinhibits
pituitary–adrenal activity (Andrews et al, 2012), that would be glutamatergictransmissioninspinaldorsalhornneurons.Anesthesiology
112:138–143.
further enhanced by ciclooxigenase-2 attenuation at astrocytes in
GedneyJA,LiuEH(1998)Side-effectsofepiduralinfusionsofopioid
the hypothalamus (Clasadonte et al, 2011); (2) inhibition of
bupivacainemixtures.Anaesthesia53:1148–1155.
glutamate release at the dorsal raphe serotonergic 5-HT neurons
GuX,PengL,YangD,MaQ,ZhengY,LiuC,ZhuB,SongL,SunX,MaZ
(Evanson et al, 2010; Wang et al, 2012); and (3) ciclooxigenase-2
(2011)TherespectiveandinteractioneffectsofspinalGRsandMRson
attenuation (Font-Nievis et al, 2012) from the astrocytes at the radicularpaininducedbychroniccompressionofthedorsalrootganglion
spine(Clasadonteetal,2011).Inaddition,becausementalfatigue intherat.BrainRes1396:88–95.
isrelatedtoactivationofNMDAreceptors(Morimotoetal,2012), GuYW,SuDS,TianJ,WangXR(2008)Attenuatingphosphorylationofp38
it would be improved by NMDA antagonist such as methadone. MAPKintheactivatedmicroglia:anewmechanismforintrathecal
Another detail that deserves attention is that cannabinoids have lidocainereversingtactileallodyniafollowingchronicconstrictioninjury
beendescribedtoimprovefatigueincancerpatients(Johnsonetal, inrats.NeurosciLett431:129–134.
2012) and dexamethasone is known to bind at glucocorticoid HattoriS,SanoH,TanakaK,YokotaM(2009)Intrathecalmorphine
treatmentinadvancedcancerpainpatients.Masui58:1384–1392.
receptors,activateG-proteincoupledreceptorsandbesignalledby
HeL,KimJ,OuC,McFaddenW,vanRijnRM,WhistlerJL(2010)
endocannabinoid messengers (Morimoto et al, 2012) and could
Methadoneantinociceptionisdependentonperipheralopioidreceptors.
therefore diminish fatigue by acting indirectly as adjuvant
JPain10:369–379.
cannabinoid.
HutchinsonMR,LewisSS,CoatsBD,RezvaniN,ZhangY,WieselerJL,
Other adverse effects described in the literature, however, not SomogyiAA,YinH,MaierSF,RiceKC,WatkinsLR(2010)Possible
mentioned by our population was pruritus and urinary retention. involvementoftoll-likereceptor4/myeloiddifferentiationfactor-2activity
The incidence of pruritus after epidural methadone was signifi- ofopioidinactiveisomerscausesspinalproinflammationandrelated
cantly slighter compared with morphine. Epidural morphine was behavioralconsequences.Neuroscience167:880–893.
also associated with a significantly greater incidence of urinary ImamachiN,SaitoY,HaraK,SakuraS,KosakaY(1999)Thenon-NMDA
retention than methadone (Gedney and Liu, 1998). glutamatereceptorantagonistCNQXaugmentslidocaineantinociception
In conclusion, epidural 2.5–7.5mg methadone combined to throughaspinalactioninrats.AnesthAnalg89:416–421.
InturrisiCE(2005)Pharmacologyofmethadoneanditsisomers.Minerva
low-doselidocaine(40mg)resultedindose-dependentanalgesiain
Anestesiol71:435–437.
cancerpainpatients.Thisanalgesiceffectwasfurtherenhancedby
JohnsonJR,LossignolD,Burnell-NugentM,FallonMT(2012)Anopen-label
10mg epidural dexamethasone, associated with improvement of
extensionstudytoinvestigatethelong-termsafetyandtolerabilityof
fatigue, daily somnolence and appetite.
THC/CBDoromucosalsprayandoromucosalTHCsprayinpatientswith
terminalcancer-relatedpainrefractorytostrongopioidanalgesics.JPain
SymptomManageS0885-3924(12):00439–3.
ACKNOWLEDGEMENTS KanekoM,SaitoY,KiriharaY,CollinsJG,KosakaY(1994)Synergistic
antinociceptiveinteractionafterepiduralcoadministrationofmorphine
andlidocaineinrats.Anesthesiology80:137–150.
We thank Cristalia for the donation of conservative-free racemic KozlerP,RiljakV,Pokorny´J(2011)Methylprednisolonereducesaxonal
Methadoneampoules.Thecostofthestudywassupportedbythe impairmentintheexperimentalmodelofbrainoedema.NeuroEndocrinol
Center for Pain management-HC-FMRP-USP. Lett32:831–835.
KuritaGP,KaasaS,SjøgrenP.EuropeanPalliativeCareResearch
Collaborative(EPCRC)(2011)Spinalopioidsinadultpatientswithcancer
pain:asystematicreview:aEuropeanPalliativeCareResearch
REFERENCES
Collaborative(EPCRC)opioidguidelinesproject.PalliatMed25:560–577.
LamFF,NgES(2012)SubstancePandglutamatereceptorantagonists
AndrewsMH,WoodSA,WindleRJ,LightmanSL,IngramCD(2012)Acute improvetheanti-arthriticactionsofdexamethasoneinrats.BrJ
glucocorticoidadministrationrapidlysuppressesbasalandstress-induced Pharmacol159:958–969.
hypothalamus-pituitary-adrenalaxisactivity.Endocrinology153:200–211. LeppertW(2009)Theroleofmethadoneincancerpaintreatment–areview.
AnghelescuDL,FaughnanLG,HankinsGM,WardDA,OakesLL(2011) IntJClinPract63:1095–1109.
Methadoneuseinchildrenandyoungadultsatacancercenter:a LeppertW,BussT(2012)Theroleofcorticosteroidsinthetreatmentofpain
retrospectivestudy.JOpioidManag7:353–361. incancerpatients.CurrPainHeadacheRep16:307–313.
BertorelliR,AdamiM,DiSantoE,GhezziP(1998)MK801and MaR,WangX,LuC,LiC,ChengY,DingG,LiuL,DingZ(2010)
dexamethasonereducebothtumornecrosisfactorlevelsandinfarct Dexamethasoneattenuatedbupivacaine-inducedneuroninjuryinvitro
volumeafterfocalcerebralischemiaintheratbrain.NeurosciLett246: throughathreonine-serineproteinkinaseB-dependentmechanism.
41–44. Neuroscience167:329–342.
ChristoPJ,MazloomdoostD(2008)Interventionalpaintreatmentsforcancer MercadanteS(2012)Switchingmethadone:a10-yearexperienceof345
pain.AnnNYAcadSci1138:299–328. patientsinanacutepalliativecareunit.PainMed13:399–404.
ClasadonteJ,PoulainP,HanchateNK,CorfasG,OjedaSR,PrevotV(2011) MorimotoY,ZhangQ,AdachiK(2012)Effectsofmemantine,anN-methyl-
ProstaglandinE2releasefromastrocytestriggersgonadotropin-releasing D-aspartatereceptorantagonist,onfatigueandneuronalbraindamagein
www.bjcancer.com|DOI:10.1038/bjc.2012.593 263
BRITISHJOURNAL OF CANCER Epidural methadone|dexamethasone forcancer pain
aratmodelofcombined(physicalandmental)fatigue.BiolPharmBull resultsineffectivepostoperativeanalgesiaandlowplasmaconcentrations.
35:481–486. CanJAnaesth49:25–31.
Muth-SelbachU,HermannsH,StegmannJU,KolloscheK,FreynhagenR, Pe´rezJ,deSantosP,PlazaA,MercadalJ(2010)Adjuvantmethadoneor
BauerI,LipfertP(2009)Antinociceptiveeffectsofsystemiclidocaine: fentanylinspinalanesthesiawithbupivacaine:arandomized,double-
involvementofthespinalglycinergicsystem.EurJPharmacol613: blind,placebo-controlledtrial.RevEspAnestesiolReanim57:546–552.
68–73. ShirY,ShapiraSS,ShenkmanZ,KaufmanB,MagoraF(1991)Continuous
OlbrichVH,MosingM(2003)Acomparisonoftheanalgesiceffectsofcaudal epiduralmethadonetreatmentforcancerpain.ClinJPain7:339–341.
epiduralmethadoneandlidocaineinthehorse.VetAnaesthAnalg30: SotgiuML,ValenteM,StorchiR,CaramentiG,BiellaGE.Cooperative(2009)
156–164. N-methyl-D-aspartate(NMDA)receptorantagonismandmu-opioid
OlschewskiA,Schnoebel-EhehaltR,LiY,TangB,Bra¨uME,WolffM(2009) receptoragonismmediatethemethadoneinhibitionofthespinalneuron
Mexiletineandlidocainesuppresstheexcitabilityofdorsalhornneurons. pain-relatedhyperactivityinaratmodelofneuropathicpain.Pharmacol
AnesthAnalg109:258–264. Res60:284–290.
ParramonF,Garc´ıaCh,Gambu´sP,VilaplanaJ,Aragone´sN,VillalongaA WangJ,ShenRY,Haj-DahmaneS(2012)Endocannabinoidsmediatethe
(2003)Postoperativepatient-controlledanalgesiaismoreeffectivewith glucocorticoid-inducedinhibitionofexcitatorysynaptictransmissionto
epiduralmethadonethanwithintravenousmethadoneinthoracicsurgery. dorsalrapheserotoninneurons.JPhysiol590(Pt22):5795–808.
RevEspAnestesiolReanim50:326–331. ZhuTS,GlaserM(2008)Neuroprotectionandenhancementofremyelination
PloppaA,KieferRT,HaverstickDM,GrovesDS,UnertlKE,DurieuxME byestradiolanddexamethasoneincoculturesofratDRGneuronsand
(2010)Localanestheticeffectsonhumanneutrophilprimingand Schwanncells.BrainRes1206:20–32.
activation.RegAnesthPainMed35:45–50.
PopoliM,YanZ,McEwenBS,SanacoraG(2011)Thestressedsynapse:the
Thisworkispublishedunderthestandardlicensetopublishagree-
impactofstressandglucocorticoidsonglutamatetransmission.NatRev
Neurosci13:22–37. ment. After 12 months the work will become freely available and
Prieto-AlvarezP,Tello-GalindoI,Cuenca-Pen˜aJ,Rull-BartomeuM,Gomar- the license terms will switch to a Creative Commons Attribution-
SanchoC(2002)Continuousepiduralinfusionofracemicmethadone NonCommercial-Share Alike 3.0 Unported License.
264 www.bjcancer.com|DOI:10.1038/bjc.2012.593