Dul Oxe Tina Dolor

ORIGINAL CONTRIBUTION

Effect of Duloxetine on Pain, Function,and Quality of Life Among PatientsWith Chemotherapy-InducedPainful Peripheral NeuropathyA Randomized Clinical TrialEllen M. Lavoie Smith, PhDHerbert Pang, PhDConstance Cirrincione, MSStewart Fleishman, MDElectra D. Paskett, PhDTim Ahles, PhDLinda R. Bressler, PharmDCamilo E. Fadul, MDChetaye Knox, BSNguyet Le-Lindqwister, MDPaul B. Gilman, MDCharles L. Shapiro, MDfor the Alliance for Clinical Trials inOncology

APPROXIMATELY20%TO40%OFpatients with cancer who re-ceiveneurotoxicchemotherapy(eg, taxanes, platinums, vincaalkaloids,bortezomib)willdeveloppain-ful chemotherapy-induced peripheralneuropathy.1-3 Painful chemotherapy-induced neuropathy can persist frommonths to years beyond chemotherapycompletion,causingsignificantchallengesforcancersurvivorsduetoitsnegativein-fluence on function and quality of life(QOL).4-8 Chemotherapyinduced pe-ripheral neuropathy is difficult to man-age,andmostrandomizedcontrolledtrials testing a variety of drugs with diverse

mechanismsof action revealedno effec-tive treatment.9

There is mounting evidence thatserotonin and norepinephrine dualreuptake inhibitors are effective in treat-ing neuropathy-related pain.10 Both

serotonin and norepinephrine are keyneurotransmitters that suppress trans-mission of painful peripheral stimuli byCME available online at

www.jamanetworkcme.comand questions on p 1412.

Author Video Interview available atwww.jama.com.

Author Affiliations are listed at the end of this article.Corresponding Author: Ellen M. Lavoie Smith, PhD,University ofMichigan School of Nursing, Room2151,Ann Arbor, MI 48109 ([email protected]).

Importance There are no known effective treatments for painful chemotherapy-induced peripheral neuropathy.

Objective Todetermine theeffect of duloxetine, 60mgdaily, onaveragepain severity.

Design, Setting, and Patients Randomized, double-blind, placebo-controlled cross-over trial at 8 National Cancer Institute (NCI)funded cooperative research networksthat enrolled 231 patients who were 25 years or older being treated at communityand academic settings between April 2008 andMarch 2011. Study follow-upwas com-pleted July 2012. Stratified by chemotherapeutic drug and comorbid pain risk, pa-tients were randomized to receive either duloxetine followed by placebo or placebofollowed by duloxetine. Eligibility required that patients have grade 1 or higher sen-sory neuropathy according to the NCI Common Terminology Criteria for Adverse Eventsand at least 4 on a scale of 0 to 10, representing average chemotherapy-induced pain,after paclitaxel, other taxane, or oxaliplatin treatment.

Interventions The initial treatment consisted of taking 1 capsule daily of either 30mg of duloxetine or placebo for the first week and 2 capsules of either 30 mg of du-loxetine or placebo daily for 4 additional weeks.

MainOutcomeMeasures Theprimaryhypothesiswas thatduloxetinewouldbemoreeffective than placebo in decreasing chemotherapy-induced peripheral neuropathic pain.Pain severitywas assessedusing theBrief Pain Inventory-Short Formaveragepain itemwith 0 representing no pain and 10 representing as bad as can be imagined.

Results Individuals receivingduloxetine as their initial 5-week treatment reported ameandecrease in average pain of 1.06 (95%CI, 0.72-1.40) vs 0.34 (95%CI, 0.01-0.66) amongthose who received placebo (P=.003; effect size, 0.513). The observed mean differencein the average pain score between duloxetine and placebo was 0.73 (95% CI, 0.26-1.20). Fifty-nine percent of those initially receiving duloxetine vs 38% of those initiallyreceiving placebo reported decreased pain of any amount.

Conclusion and Relevance Among patients with painful chemotherapy-inducedperipheral neuropathy, the use of duloxetine compared with placebo for 5 weeks re-sulted in a greater reduction in pain.

Trial Registration clinicaltrials.gov Identifier: NCT00489411JAMA. 2013;309(13):1359-1367 www.jama.com

2013 American Medical Association. All rights reserved. JAMA, April 3, 2013Vol 309, No. 13 1359

inhibiting input to the spinal dorsalhorn neurons.11 Several phase 3 stud-ies show that duloxetine is an effec-tive treatment for painful diabetic neu-ropathy.12-15 Based on these trials, ourhypothesis was that duloxetine wouldameliorate chemotherapy-induced pe-ripheral neuropathic pain aswell. A ran-domized phase 3 trial was conductedto test this hypothesis.

METHODSSTUDY DESIGN

The Cancer and Leukemia Group B(CALGB/Alliance) conducted a ran-domizedphase 3double-blind, placebo-controlled crossover trial to assesswhether 60 mg of duloxetine takenorally once daily decreases the sever-ity of chemotherapy-induced periph-eral neuropathy (CALGB-170601,NCT00489411). The primary hypoth-esis was that duloxetinewould bemoreeffective than placebo in decreasing theaverage pain score after a 5-week treat-ment period. Secondary aims were toassess duloxetines effect on QOL andfunction and on adverse events. Thestudy was approved by each sites in-stitutional review board, and partici-pants provided signed informed con-sent. Enrollment occurred betweenApril 2008 andMarch 2011. Study fol-low-up was completed July 2012.

Patients

Using the National Cancer Institutes(NCIs) Clinical Trials Support Unitmechanism to facilitate accrual, par-ticipants were recruited from 8 multi-site NCI-funded cooperative researchnetworks, resulting in a geographi-cally diverse population of patients dis-tributed throughout the United States.The diagnosis of chemotherapy-induced peripheral neuropathywas de-termined based on symptom history,loss of deep tendon reflexes, or the pres-ence of symmetrical stocking-glovenumbness or paresthesias beginning af-ter neurotoxic chemotherapy. Eligiblepatients were 25 years or older, had atleast grade 1 sensory pain based on theNCICommonTerminologyCriteria forAdverse Events version 3.0 grading

scale, and reported 4 on a 10-pointscale, average neuropathic pain, for 3or more months after completing che-motherapy. Patientswith any cancer di-agnosis or stage were potentially eli-gible. To diminish the likelihood thatsymptoms would spontaneously re-solve over the course of the study,efficacy data were obtained over 5weeks.Initially, patients who had received

paclitaxel or oxaliplatin could partici-pate, but eligibility was later ex-panded to allow prior treatment withsingle-agent docetaxel, nanoparticle al-buminbound paclitaxel, or cisplatin.Prior or ongoing treatment with otherneurotoxic chemotherapeutic agentswas not allowed. Participants with adocumented medical history of neu-ropathy from any type of nerve com-pression (eg, carpal or tarsal tunnel syn-drome, radiculopathy, spinal stenosis,brachial plexopathy), leptomeningealcarcinomatosis, severe depression, sui-cidal ideation, bipolar disease, alcoholabuse, a major eating disorder, andmarkedly abnormal renal or liver func-tion tests were ineligible.Despite scant evidence supporting

the association between certain comor-bid illnesses and the risk of develop-ing severe pain,9,16 patients with diabe-tes mellitus and peripheral vasculardisease, whose pain was thought to befrom chemotherapy-induced periph-eral neuropathy, were eligible but weredefined as high risk. We controlled forcomorbid illness as a potential con-founder by assigning equal numbers ofhigh-risk patients to each treatmentgroup. Concurrent use of other drugsknown to influence serotonin levelswasnot allowed. Concomitant use of se-lected analgesics was allowed (eg, opi-oids, acetaminophen, aspirin, nonste-roidal anti-inflammatory drugs), butonly patients receiving stable doses inthe 2weeks before randomization couldparticipate: (1) no new analgesics wereadded, (2) no analgesics were discon-tinued, and (3) theweekly 24-hour totalanalgesic dose did not fluctuate up ordown bymore than 10% in the 2weeksbefore study registration.

InterventionEligible patients were randomizedusing a 1:1 allocation ratio to eithergroup A or group B. In this crossoverdesign, group A received 60 mg ofduloxetine daily during the initialtreatment period and placebo atcrossover period. Group B receivedplacebo as initial treatment andduloxetine as the crossover treat-ment. Randomization, provided bythe CALGB/Alliance Statistical Cen-ter, was stratified by neurotoxic drugclass (taxanes vs platinums) and bypain risk (high risk vs no risk). Acomputer-generated kit number wasused to order the blinded studydrug from a distribution center. Druglabels were applied to the capsulebottles at the distribution centerbefore being mailed to study sites;thus, all patients and personnel wereblinded to the treatment assignment.The initial (weeks 1-5) and cross-

over (weeks 8-12) treatment periodseach consisted of receiving 1 capsule ofeither placebo or 30 mg of duloxetinefor the first week and 2 capsules ofeither placebo or 30 mg of duloxetinefor 4 weeks. The initial 5-week periodwas followed by a 2-week washout pe-riod for a total study duration of 14weeks (FIGURE 1).

Data Collection and Instruments

Patient-reported pain severity and func-tional interferencewas assessedweeklyusing the well-validated Brief Pain In-ventory Short Form (BPI-SF).17-19 TheBPI-SF contains 4 items assessing av-erage, worst, least, and immediate painseverity in the last 24 hours. Pain se-verity items are scored using an 11-point numeric rating scale (0, no pain;10, pain as bad as you can imagine). TheBPI-SF worse pain severity item hasbeen shown to be reliable and valid foruse as a single item.20 However, wechose average pain severity as ourprimary outcome measure based onrecommendations from the Initiativeon Methods, Measurement, andPain Assessment in Clinical Trials(IMMPACT).21 In addition, average painhas been defined as the primary out-

DULOXETINE ON CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY PAIN

1360 JAMA, April 3, 2013Vol 309, No. 13 2013 American Medical Association. All rights reserved.

come measure in numerous dulox-etine phase 3 studies involving pa-tients with peripheral and centralneuropathic pain conditions due to dia-betic- and oxaliplatin-induced neu-ropathy, fibromyalgia, and osteoarthri-tis13-15,22-30 and thereby was chosen tofacilitate comparison of our findingsacross similar studies. Theminimal clini-cally important difference in pain sever-itywas defined for the current study asa 0.98 difference in mean average painseverity between the duloxetine andplacebo groups. Using an acceptedmethod for assessing the influence ofpain on function,13-15,26-29 7 BPI-SF itemswere used to quantify the degree towhich pain interfered with daily activi-ties or function (0, does not interfere;10, completely interferes). The 7 itemswere summed to obtain a total inter-ference score. Patient-reported QOLwas assessed using the Functional As-sessment of Cancer Treatment, Gyne-cologic Oncology Group Neurotoxic-ity (FACT/GOG-Ntx) subscale on day1 of weeks 1, 6, 8, and 13. The assess-ments strong psychometric proper-ties have been previously demon-strated.31-33 The instrument contains 11questions assessing numbness, tin-gling, and discomfort in the hands orfeet; difficulty hearing; tinnitus; jointpain or muscle cramps; weakness; ortrouble walking, buttoning buttons, orfeeling small shapeswhen placed in thehand. Items are scored from 0 to 4 (0,not at all; 4, very much) and summed(total score range, 0-44).33 Because thereare no published data defining a cutpoint for determining a clinically im-portant change in the score, we de-fined a 2- to 3-point change as a clini-callymeaningful improvement in QOLper published recommendations spe-cific to similar measures.34-37

Using the NCI CTCAE version 3.0,adverse events were reported weeklyand graded on a 0 to 4 scale (0, nor-mal; 4, life-threatening) 38 as was base-line sensory chemotherapy-induced pe-ripheral neuropathy (0, normal; 1,asymptomatic, weakness on physicalexamination, loss of reflexes, or pares-thesias not interferingwith function; 2,

weakness and sensory alterations in-terferingwith function; 3,weakness andsensory alterations interfering with ac-tivities of daily living or requiring brac-ing or assistive devices; and 4, lifethreatening, paralysis, or disabling).

Statistical Analyses

Statistical analyses were performed byCALGB/Alliance statisticians. The pri-mary study end point was the changefrom start to end of the initial treat-ment period (week 1 to week 5, mea-sured on day 1 of weeks 1 and 6) in av-erage pain based on the BPI-SF averagepain severity item. The comparison ofinterest was the difference between the2 treatment groups in pain change.With 232 patients (assuming 20% at-trition), the study had 90% power (2-sided of .05) to detect a 0.98-pointchange between the 2 groups assum-ing a standard error of 0.31. The tar-get difference of 0.98 is consistent with

diabetic research.30 We calculated theproportion of patients experiencing anydecrease in pain. Also, using another ac-cepted approach for assessing clinicalsignificance,13-15,22-24,26,39-41 we con-ducted an exploratory responder analy-sis based on the proportion of patientsin both groups who experienced a 30%(or 50%)decrease in pain severity. Rela-tive risk-benefit was the proportion ofpatients with 30% (or 50%) pain re-duction in the duloxetine group rela-tive to that in the placebo group. It wascalculated from contingency tables.Wealso conducted an exploratory sub-group analyses based on chemo-therapy class.Secondary end pointswere change in

chemotherapy-induced peripheral neu-ropathyrelatedQOL,measured by thetotal score of the FACT/GOG-Ntx, anddegree of pain-related functional inter-ference based on the BPI-SF interfer-ence score. Changes attributable to ini-

Figure 1. Patient Flow Chart of Initial and Crossover Periodsa

67 Included in crossover analysis7 Excluded (incomplete data)

74 Included in crossover analysis7 Excluded (incomplete data)

231 Patients enrolled

87 Included in primary analysis1 Excluded (incomplete data)

94 Included in primary analysis5 Excluded (incomplete data)

Group A115 Randomized to receive duloxetine followed by

crossover to placebo109 Received duloxetine as randomized

6 Withdrew consent prior to receiving theintervention

Group B116 Randomized to receive placebo followed by

crossover to duloxetine111 Received placebo as randomized

5 Withdrew consent prior to receiving theintervention

88 Completed initial intervention21 Discontinued duloxetine early

12 Toxic effects5 Withdrew consent1 Other3 Unknown

99 Completed initial intervention12 Discontinued placebo early

1 Toxic effects6 Withdrew consent2 Disease progression3 Unknown

85 Crossed over and received placebo 93 Crossed over and received duloxetine

74 Completed crossover intervention11 Discontinued intervention early

2 Toxic effects4 Withdrew consent1 Received alternate treatment4 Other

81 Completed crossover intervention12 Discontinued intervention early

5 Toxic effects2 Withdrew consent2 Disease progression3 Other

231 Randomized

aThe number screened and the number offered participation but declined was not captured, nor were thereasons captured for why patients did not participate in the crossover treatment period.



tial treatment were defined as thedifference between theweek1 andweek5 scores (measured on day 1 of weeks1 and 6). Changes for crossover treat-ment used week 8 and week 12 scores(measured on day 1 ofweeks 8 and 13).To test for a group effect during the

initial treatment period on the pri-maryandsecondaryendpoints,weused3 separate models of analysis of cova-riance, each stratified by neurotoxicagent and riskofpainful chemotherapy-induced peripheral neuropathy, andincluding the baseline measure of thecorresponding end point. Least squaremeans and their 95% confidence inter-vals were taken from analysis of cova-riancemodels. Additionally, for the pri-mary end point, generalized estimating

equations were used to determinewhether there was a treatment effectwhencombiningdata fromboth the ini-tial and crossover periods. Multipleimputation andpattern-mixturemodelwere used to evaluate the pattern andpotential influenceofmissing values forthe primary end point (eAppendixavailable at www.http://www.jama.com). To univariately compare treat-ment groups, the Wilcoxon rank testwas used for continuous variables andthe 2 test for proportions. The 95%confidence intervals for proportionsused exact binomial methods. Analy-ses included only patients who beganprotocol therapy. Statistical analyseswith 2-sided significance threshold ofP .05 were performed using SAS ver-

sion 9.2 (SAS Institute Inc). Data qual-ity was ensured by review of data by theCALGB/Alliance Statistical Center andby the study chairperson. The study un-derwent standard biannual monitor-ing by the CALGB/Alliance data andsafety monitoring board with 1 formalinterim efficacy analysis resulting instudy continuation.

RESULTSPatients

Patient disposition for the initial treat-ment period is illustrated in Figure 1.Of the 231 patients recruited to thestudy, 115 were allocated to group A(duloxetine first, placebo second), and116 to group B (placebo first, dulox-etine second). Eleven patients never re-ceived treatment, leaving 220 treatedpatients. The dropout rate due to ad-verse events in the duloxetine-firstgroup was 11% vs 1% in the placebo-first group (P.001). Despite using anintent-to-treat analysis approach, 6 pa-tients (1 in group A; 5 in group B) dur-ing the initial treatment periodwere ex-cluded from the primary analysisbecause they provided no data at all.This resulted in a 19% dropout rate.Patient characteristics are de-

scribed in theTABLE. Both groups weresimilar at baseline, except for themean(SD) pain score of 6.1 (1.7) in groupA, duloxetine first, and 5.6 (1.6) ingroup B, placebo first (P=.02).

Pain (Primary Outcome)

At the end of the initial treatment pe-riod, patients in the duloxetine-firstgroup reported a larger decrease in av-erage pain (mean change score, 1.06;95% CI, 0.72-1.40) than those in theplacebo-first group (mean change score,0.34; 95% CI, 0.01-0.66; P= .003;FIGURE 2). The effect size attributed toduloxetine was moderately large at0.513.42 The observed mean differ-ence in the average pain score betweenthe duloxetine-first and placebo-firstgroups was 0.73 (95% CI, 0.26-1.20).Results of the sensitivity analysis tak-ingmissing data into consideration areconsistent with the primary findings ofthe trial (eTables 1 and 2 available at

Table. Patient Demographics and Baseline Features

Characteristics

No. (%)of Participants

PValue

Group A(n = 109)

Group B(n = 111)

Total(n = 220)

DemographicsAge, y

30-39 2 (2) 1 (1) 3 (1)

.70a40-49 16 (15) 23 (21) 39 (18)

50-59 43 (39) 39 (35) 82 (37)

60-69 30 (28) 29 (26) 59 (27)

70 18 (17) 19 (17) 37 (17)

Mean (SD) 60 (10.4) 59 (10.6) 59 (10.5)

SexMen 38 (35) 44 (40) 82 (37)

.46Women 71 (65) 67 (60) 138 (63)

RaceWhite 91 (83) 87 (78) 178 (81)

.50Black 14 (13) 17 (15) 31 (14)

Other 4 (4) 5 (5) 9 (4)

Not reported 0 (0) 2 (2) 2 (1)

Stratification factorsNeurotoxic agent

Paclitaxel 44 (40) 43 (39) 87 (40)

N/AOxaliplatin 63 (58) 66 (59) 129 (59)

Other taxane 2 (2) 2 (2) 4 (2)

Other platinum 0 (0) 0 (0) 0 (0)

High risk of CIPNNo 46 (42) 51 (46) 97 (44)

N/AYes 63 (58) 60 (54) 123 (56)

Disease-related featuresPrimary disease

Breast 41 (38) 42 (38) 83 (38)

.99bGI 62 (57) 62 (56) 124 (56)

Both breast & GI tract 0 (0) 1 (1) 1 (0)

Genitourinary 4 (4) 4 (4) 8 (3)

Other 2 (2) 1 (1) 3 (1)

Missing 0 (0) 1 (1) 1 (0)

(continued)



http://www.jama.com): multiple im-putation (P = .002) and pattern-mixture model controlbased imputa-tion (P=.004). The primary analysis Pvalue lies between the slightlymore lib-eral multiple imputation approach andthe more conservative pattern-mixture model. A post hoc power cal-culation is provided in the eAppendix.Of the patients treated with dulox-

etine first, 59% reported any decreasein pain vs 38% of patients treated withplacebo first. Thirty percent of dulox-etine-treated patients reported nochange in pain and 10% reported in-creased pain. Based on the explor-atory responder analysis, the propor-tion of patients achieving various levelsof pain reduction is illustrated inFIGURE 3. Compared with placebo, therelative risk of experiencing a 30%painreduction with duloxetine was 1.96(95% CI, 1.15-3.35) and experiencinga 50%pain reductionwas 2.43 (95%CI,1.11-5.30; eTable 3).Although the study was powered to

detect differences between treatmentsas main effects only, in exploratoryanalyses, we examined the potential in-teraction between treatment group andchemotherapy class. Results sug-gested that patients who received plati-nums (oxaliplatin) experienced morebenefit fromduloxetine than thosewhoreceived taxanes (P= .13). The ob-

Figure 2. Duloxetine and Placebo Effects on Average Pain Severity During the Initial and Crossover Treatment Periods

6.5

5.0

5.5

6.0

4.5

4.0

3.5

3.0

No. patientsDuloxetine first (group A)Placebo first (group B)

1

8794

2

8692

3

8691

4

8791

5

8591

6(Washout)

8794

Week

Initial treatment period

Mea

n P

ain

Sco

re

6.5

5.0

5.5

6.0

4.5

4.0

3.5

3.0

No. patientsPlacebo second (group A)Duloxetine second (group B)

1

6774

2

6568

3

6571

4

6669

5

6366

6

6774

Week

Crossover treatment period

Mea

n P

ain

Sco

re

Duloxetine first (group A)Placebo first (group B) Duloxetine second (group B)

Placebo second (group A)

The mean average pain score was measured on the first day of each week in the initial and crossover treatments periods. Day 1 of the first week begins the initialtreatment period. Day 1 of week 6 begins the washout period when patients received 1 capsule of duloxetine or placebo. Patients took no drug during week 7. Errorbars represent 95% CIs.

Table. Patient Demographics and Baseline Features (continued)

Characteristics

No. (%)of Participants

PValue

Group A(n = 109)

Group B(n = 111)

Total(n = 220)

Disease-related featuresDisease stage

Early, I-II 38 (44) 38 (41) 76 (35)

.69III 34 (39) 42 (45) 76 (35)

Metastatic 14 (16) 12 (13) 26 (12)

Missing 1 (1) 2 (2) 3 (1)

Concurrent medications useNo 68 (62) 58 (52) 126 (57)

.10Yes 31 (28) 43 (39) 74 (34)

Missing 10 (9) 10 (9) 20 (9)

Performance status0 60 (55) 60 (54) 120 (55)

.781 44 (40) 47 (42) 91 (41)

2 4 (4) 2 (2) 6 (3)

3 1 (1) 1 (1) 2 (1)

Missing 0 (0) 1 (1) 1 (0)

Pretreatment sensory neuropathy grade1, Asymptomatic 1 (1) 2 (2) 3 (1)

.472, Moderate 77 (71) 84 (76) 161 (73)

3, Severe 31 (28) 24 (22) 55 (25)

4, Life-threatening 0 (0) 0 (0) 0 (0)

Missing 0 (0) 1 (1) 1 (0)

Pretreatment pain score4 2 (2) 2 (2) 4 (2)

.02a4-5 44 (40) 58 (52) 102 (46)

6-7 39 (36) 35 (32) 74 (34)

8-10 24 (22) 15 (14) 39 (18)

Missing 0 (0) 1 (1) 1 (0)

Mean (SD) 6.1 (1.7) 5.6 (1.6) 5.8 (1.7)

Abbreviations: CIPN, chemotherapy-induced peripheral neuropathy; GI, gastrointestinal; N/A, not applicable (comparativetesting is not applicable because these are stratification variables).

aTested as a continuous variable.bWhen testing for differences between groups based on primary disease, the groups were collapsed into 3 categories(breast, gastrointestinal, or other).



served mean difference in platinum-related average pain score between theduloxetine and placebo treatment was1.06 (95% CI, 0.48 to 1.63) vs 0.19(95% CI, 0.61 to 0.98) for patientstreated with taxane. Results of the ex-ploratory responder analysis revealedthat compared with placebo, the rela-tive risk of experiencing a reduction inpain by 30%with duloxetine among pa-tients treated with platinum was 3.05(95%CI, 1.49-6.27) and a reduction by50% was 3.78 (95% CI, 1.32-10.84;eTables 4-6 available at http://www.jama.com). However, compared withplacebo, the relative risk of experienc-ing a 30% pain reduction with dulox-etine among patients treated with tax-ane was 0.97 (95% CI, 0.41-2.32) anda 50%pain reductionwas 1.22 (95%CI,0.35-4.18), neither of which was sta-tistically significant. There was no dif-ference in duloxetine efficacy based onrisk of developing painful chemo-therapy-inducedperipheral neuropathy.We also concurrently evaluated

changes in pain severity during thecrossover treatment period. After ad-justing for the study stratifiers (che-motherapy class and pain risk), therewas a statistically significant treat-ment effect on change in pain score(P .001), but an order effect was notsignificant (P= .43). An additionalgeneralized estimating equationmodelwith carryover effect was performed.

The treatment remained significant(P=.002), whereas the period (P=.55)and carryover (P=.95) effects were not.The change in mean pain score duringthe crossover treatment period forgroup A (placebo second) was 0.41(95% CI, 0.06-0.89) and for group B(duloxetine second)was 1.42 (95%CI,0.97-1.87). The mean difference be-tween the 2 groups in mean changescore during the crossover period was1.01 (95% CI, 0.36-1.65).

Secondary Outcome

Pain InterferenceWithDaily Function.At the end of the initial treatment pe-riod, when comparedwith placebo, pa-tients treated with duloxetine first re-ported a greater decrease in the amountthat pain had interferedwith daily func-tioning (P=.01; eFigure 1). The changein mean interference score for patientstreated with duloxetine first was 7.9(95%CI, 5.4-10.5) vs 3.5 (95%CI, 1.1-5.9) for patients treated with placebofirst. The mean difference between the2 groups inmean change scorewas 4.40(95% CI, 0.93-7.88).Quality of Life.Pain-relatedQOL im-

proved to a greater degree for thosetreated with duloxetine during the ini-tial treatment than for those treatedwithplacebo. Themean change in the FACT/GOG-Ntx total scorewas 2.44 (95%CI,0.43-4.45) for patients treatedwith du-loxetine first vs 0.87 (95% CI, 1.09-

2.82) for patients treated with placebofirst (P=.03). The mean difference be-tween the 2 groups in mean changescore was 1.58 (95% CI, 0.15-3.00;P=.03).Adverse Effects.No hematologic or

grade 4 (moderately severe) or 5 (se-vere) adverse events were reported. Inthe initial treatment period, 16% treatedwith duloxetine and 27% treated withplacebo reported grade 2 (mild) and 7%treated with duloxetine and 3% treatedwith placebo reported grade 3 (mod-erate) nonhematologic adverse events.Fatigue (7%), insomnia (5%), and nau-sea (5%) were the most common ad-verse effects reported by patients treatedby duloxetine, whereas somnolence(8%), insomnia (7%), and fatigue (5%)were the most common adverse ef-fects reported by patients treated withplacebo (eTable 7 available at http://www.jama.com).

Other Findings

Nonpainful Symptoms. After the ini-tial treatment period, 41% of patientstreated with duloxetine reported a de-crease in numbness and tingling in thefeet (95% CI, 31%- 52%) vs 23% of pa-tients treatedwithplacebo(95%CI,15%-33%). The trendheld through the cross-over periodwith 41%of patients treatedwith duloxetine (95% CI, 31%-53%) vs21% of patients treated with placebo(95% CI, 13%-32%). The proportion ofpatients with improved hand numb-ness and tingling at the end of the ini-tial treatment periodwas similar amongthose treatedwith duloxetine (36%) andthose treated with placebo (34%).Ancillary Analgesics. Compared

with groupA (duloxetine first), a higherproportion of those in group B (pla-cebo first) were taking concomitantmedications at the start (43% of pa-tients in group B vs 31% in group A)and at the end of the initial treatmentperiod (36% in group B vs 29% in groupA).Twenty-seven percent of patientswho started out taking concomitantmedications in the group A discontin-ued all medications by the end of theinitial treatment period comparedwith19% of patients in group B.

Figure 3. Percent Decrease in Pain Score Due to Duloxetine vs Placebo

100

90

80

40

50

70

60

30

20

10

0

Pain Reduction From Baseline to End Pointof Initial Treatment Period, %

Per

cent

age

of P

atie

nts

0 10 20 30 40 50 60 70 80 90 100

Duloxetine (n = 87)Placebo (n = 94)

The plot shows the proportion of patients achieving various levels of pain reduction at the completion of theinitial treatment period.



COMMENTTreatment of painful chemotherapy-induced peripheral neuropathy contin-ues to be a challenge becausemost drugstested to date have fallen short of pro-viding adequate pain relief.43-47 To ourknowledge, the current study is the firstlarge phase 3 trial to elucidate an effec-tive intervention for painful chemo-therapy-induce peripheral neuropathycaused by platinum and taxane agents(mainly paclitaxel or oxaliplatin). Dur-ing initial treatment, the mean differ-ence between the 2 groups of the changein averagepain scorewas 0.73 (P=.003),which compares favorably to mean dif-ferences in average pain scores (range,0.60-0.98) observed in patients receiv-ing duloxetine for US Food and DrugAdministrationapproved indicationsfor painful diabetic neuropathy, fibro-myalgia, and osteoarthritis (eTable 8available at www.http://www.jama.com).13,26,30 The observed mean differ-ence in the average pain score betweentheduloxetine andplacebogroups inpa-tients treated with platinum was largerthan results reported by Goldstein andcolleagues13 (FIGURE 4). However, du-loxetine-related clinically meaningfulimprovement in other painful condi-tions may not be directly comparablewith painful chemotherapy-inducedpe-ripheral neuropathy.Inadditiontothemagnitudeof theim-

provement, several other factors shouldbeconsideredwhen judgingclinical sig-nificance, such as the treatment effectsize.39Our results revealedamoderatelylarge treatmenteffect size (0.513).Basedon the IMMPACT recommendations,clinicalmeaningfulness is also based onthe results of a responder analysis, spe-cifically theproportionofpatients expe-riencinga30%ora50%improvement inpainseverity.21,39,48A10%to20%decreaseinpainseverity isconsideredtorepresentaminimal clinically important change, a30%changerepresentsamoderately im-portant improvementanda50%changerepresents a substantially important im-provement.21,39,48Duringinitialtreatment,themeanchangeinaveragepainscorere-portedbypatientstreatedwithduloxetineinthecurrentstudywas1.06,animprove-

ment of approximately 10% that is con-sistentwith the IMMPACTdefinitionofaminimalclinically importantdifference.Inaddition, resultsof theexploratory re-sponderanalysis suggest that therelativerisk of experiencing a 30% and 50% im-provementinpainseveritystatisticallyfa-vored duloxetine.Other factors to consider when judg-

ing clinical significance include howquickly the drug takes effect, tolerabil-ity, and the drugs influence on other ef-ficacy end points such as function andQOL.39 In the current study, pain scoresdecreased in patients treated with du-loxetine relativelyquickly,within the firstweek of therapy (Figure 2). Consistentwith our results (eTable 7), several stud-ies show that duloxetine is safe andwell-tolerated.13,14,26,30,49-51 Furthermore, du-loxetine is associated with improvedfunction andQOL.Therefore, after con-sidering the many factors in addition tothe magnitude of improvement in painscores, study results strongly suggest thatduloxetine treatment is associated witha clinicallymeaningful improvement inchemotherapy-induced peripheral neu-ropathic pain.Resultsfromourexploratorysubgroup

analysis lendsupport to thepremise thatdifferences inpathophysiologicmecha-nismsmayhelp toexplainduloxetinere-sponseratevariationsacrossneuropathicpainconditions.Justasresponseratesmayvarywhenduloxetine isusedtotreatdia-betic vs chemotherapy-inducedperiph-eral neuropathy due to differences in

nerve injury mechanisms,16,52-55 themechanisms of taxane- vs platinum-inducedperipheralnerve injuryarequitedifferent,16 possibly explainingwhy pa-tients treatedwithplatinumreportedlesspain in the current study.The current trial has several strengths

and limitations.Thestrengths include theprospective, randomized, placebo-controlled trial designand thegeographi-cally diverse sample. Regarding limita-tions, first, therewas an imbalance in thedropout rate due to adverse effects in pa-tients treated with duloxetine vs pla-cebo (11% vs 1%, respectively), despitesimilar adverse effect rates in bothgroups. One reason for this differentialin the dropout rate may be the higherproportion of grade 3 adverse events re-ported by patients treated with dulox-etine. These patientsmayhave been ableto guess which drug they were taking,and those experiencing no or minimalpain relief may have dropped out.Anotherpotential study limitationhas

to dowith howbaseline painwas deter-mined. Oncology providers commonlyuse the NCI CTCAE, or other similargrading scales, to guide a history andphysical examination focused onchemotherapy-inducedperipheral neu-ropathy and to grade its severity.9,16

Therefore, we relied on standardCTCAE-guided practices for determin-ing severity at baseline.Wedid not spe-cifically train the examiners regardingCTCAEusebecause its grading isdeeplyembedded into oncology practice. Of

Figure 4. Comparison of the Mean Differences in Average Pain Scores Across DuloxetineChronic Pain Studies

FavorsPlacebo

FavorsDuloxetineSource

No. ofPatients

Mean Difference in MeanPain Scores (95% CI)

Goldstein et al,13 2005 176 0.98 (0.37 to 1.60)

Chappell et al,26 2011 225 0.79 (0.26 to 1.32)

Current study 181 0.73 (0.26 to 1.20)

Russell et al,30 2008 294 0.60 (0.05 to 1.16)

Neurotoxic agents, current studyPlatinums 106 1.06 (0.48 to 1.63)

Taxanes 75 0.19 (0.61 to 0.98)

2 1 0 1 2Mean Difference (95% CI)

Duloxetine was compared against placebo in studies involving patients with diabetic neuropathy, Goldstein etal; fibromyalgia, Russell et al; osteoarthritis, Chappell et al; and chemotherapy-induced peripheral neuropa-thy, the current study, including a breakdown by neurotoxic agent that patients in the current study took.



note, despite its everyday use in oncol-ogy clinical settings, the CTCAE isknown for its suboptimal interrater reli-ability and poor sensitivity to detectsubtle changes.32,56-60 As such, use of theCTCAE could have resulted in misdi-agnosis.Despite its limitations,CTCAEuse is consistent with community andacademic clinical practice,9 and thus thegeneralizability of our findings isenhanced. Other limitations are thatchanges in concurrent ancillary analge-sic dosagewerenot assessed, study find-ings may not be applicable to patientswith painful chemotherapy-inducedperipheral neuropathy caused by otherneurotoxic agents, and the studydidnotaddress long-term duloxetine treat-ment (beyond 5 weeks).Despiteduloxetinesacceptableadverse

effectprofile, theriskofduloxetine-druginteractions should not be overlooked.Duloxetineshouldnotbeusedwithotherdrugsthat inhibitserotoninreuptakedueto the associated increased risk of sero-tonin syndrome.61 Also, becausedulox-etine is a moderate cytochrome (CYP)P4502D6enzyme-inhibiter, coadminis-tration with CYP P450 2D6 substratescan lead to increased substrate drugserum concentrations and associatedtoxicities.62-65 Concurrent use of dulox-etine with warfarin, nonsteroidal anti-inflammatory drugs, or both may alsoincrease bleeding risk.61,66 Lastly, if du-loxetineandtamoxifenaretakentogether,duloxetine-induced CYP P450 2D6 en-zyme inhibitioncould inhibit tamoxifenconversion to its active metabolite, en-doxifen.61,63,67,68

In conclusion, 5 weeks of duloxetinetreatment was associated with a statisti-cally and clinically significant improve-ment inpaincomparedwithplacebo.Ex-ploratory analyses raise the possibilitythat duloxetine may work better foroxaliplatin-induced rather than taxane-inducedpainful chemotherapy-inducedperipheral neuropathy.Author Affiliations:University of Michigan School ofNursing, AnnArbor,Michigan (Dr Smith); Alliance Sta-tistics and Data Center (Dr Pang and Ms Cirrincione)andDepartment of Biostatistics and Bioinformatics (DrPang), DukeUniversity, Durham,North Carolina; Can-cer Supportive Services, Continuum Cancer Centersof New York, Beth Israel Hospital, and St LukesRoosevelt, New York, New York (Dr Fleishman); The

Ohio State University Comprehensive Cancer Center,College of Medicine, Department of Internal Medi-cine, Columbus (Dr Paskett); Department of Psychia-try and Behavioral Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York (DrAhles); Cancer and LeukemiaGroup B/Alliance CentralOffice, Chicago, Illinois (Dr Bressler); Department ofMedicine (Hematology/Oncology) and Neurology,Norris Cotton Cancer Center, Dartmouth-HitchcockMedical Center, Lebanon, NewHampshire (Dr Fadul);Illinois Oncology Research Association (Ms Knox andDr Le-Lindqwister); Main Line Hematology and On-cology Associates,Wynnewood, Pennsylvania (Dr Gil-man); and Division of Oncology, Department of In-ternal Medicine, The Ohio State University WexnerMedical Center and Comprehensive Cancer Center,and James Cancer Hospital, College of Medicine, De-partment of Internal Medicine Columbus (DrShapiro).Author Contributions: Drs Smith and Pang had fullaccess to all of the data in the study and take respon-sibility for the integrity of the data and the accuracyof the data analysis.Study concept and design: Smith, Pang, Fleishman,Paskett, Ahles, Bressler, Fadul, Shapiro.Acquisition of data: Cirrincione, Fleishman, Knox,Le-Lindqwister, Gilman.Analysis and interpretation of data: Smith, Pang,Cirrincione, Fleishman, Ahles, Fadul.Drafting of the manuscript: Smith, Pang, Cirrincione,Fleishman, Bressler, Knox.Critical revision of the manuscript for important in-tellectual content: Smith, Pang, Cirrincione, Fleish-man, Paskett, Ahles, Fadul, Le-Lindqwister, Gilman,Shapiro.Statistical analysis: Smith, Pang, Cirrincione.Obtained funding: Smith.Administrative, technical, or material support: Pang,F le ishman, Paskett , Ahles , Bress ler , Knox,Le-Lindqwister, Shapiro.Study supervision: Smith, Pang, Fleishman, Paskett,Fadul, Gilman.Conflict of Interest Disclosures:All authors have com-pleted and submitted the ICMJE Form for Disclosureof Potential Conflicts of Interest. Dr Smith reportedreceiving support from CALGB/Alliance for travel tomeetings.Dr Paskett reported institutional support fromCALGB/Alliance for travel to meetings. Dr Ahles re-ported receiving support from CALBG/Alliance fortravel to meetings. Dr Fadul reported pending insti-tutional grants from Genentech. Dr Gilman reportedinstitutional and direct grants pending from the NCI.No other financial disclosures were made.Funding/Support: This study was supported by grantCA31946 from the NCI Division of Cancer Preven-tion, the Alliance Statistics and Data Center, and theAlliance Chairman. Drug and placebo were suppliedby Eli Lilly. The NCI provided funding for data man-agement and statistical analysis.Role of the Sponsor: The NCI and Eli Lilly each re-viewed and approved the study concept via the usualpeer-review process. Minor suggestions were madeby each group regarding aspects of the study design.Neither the NCI Division of Cancer Prevention nor EliLilly had a role in data collection ormanagement, analy-sis, interpretation of the data, orwithmanuscript prepa-ration, review, or approval.Online-OnlyMaterial:The eAppendix, 8 eTables, eFig-ure, and Author Video Interview are available at http://www.jama.com.Additional Contributions:We thank the study partici-pants and the research staff at all participating sites. Spe-cial thanks are extended to the CALGBOncologyNurs-ingCommittee, Richard Schilsky,MD (American Societyof Clinical Oncology), Xiaofei Wang, PhD (Duke Uni-versity), John Taylor, MA (Alliance), Brandelyn Pitcher,MS (Duke University), Sara Jasinski, BA (Duke Univer-sity), Celia Bridges, BSN, RN (University of Michigan),

and Asa B. Smith, Student (University ofMichigan). DrWang,Mr Taylor, Ms Pitcher, andMs Jasinski receivedsalary support fromtheAllianceCooperativeGroupGrantfor their contributions to this work. All others providedassistance without receiving financial compensation.

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