Ketamine hydrochloride is used as an adjuvant treatment for cancer-related neuropathic pain, but evidence of its effectiveness is limited.1 Findings of a large trial investigating the use of ketamine for general cancer pain were negative, but the population studied did not specifically have neuropathic pain. A randomized trial of oral ketamine for cancer-related neuropathic pain has been called for, and the present trial addresses that need

Fallon, Marie T.

Kelly, Caroline A.

Laird, Barry J. A.

Lewsley, Liz-Anne

Norrie, John

Paul, James

Wilcock, Andrew

Laird, Barry J.A.

Enlighten: Publications

Oral ketamine vs placebo in patients with cancer-related neuropathic pain: a randomized clinical trial

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Fallon, Marie T. and Wilcock, Andrew and Kelly, Caroline A. and Paul, James and Lewsley, Liz-Anne and Norrie, John and Laird, Barry J. A. (2018) Oral ketamine vs placebo in patients with cancer-related neuropathic pain. JAMA Oncology . ISSN 2374-2437 Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/51161/1/jamaoncology_Fallon_2018_ld_180004.pdfCopyright and reuse: The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions.This article is made available under the Creative Commons Attribution licence and may be reused according to the conditions of the licence.  For more details see: http://creativecommons.org/licenses/by/2.5/A note on versions: The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher’s version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.ukLettersRESEARCH LETTEROral Ketamine vs Placebo in PatientsWith Cancer-RelatedNeuropathic Pain:A Randomized Clinical TrialKetamine hydrochloride is used as an adjuvant treatmentfor cancer-related neuropathic pain, but evidence of itseffectiveness is limited.1 Findings of a large trial investigat-ing the use of ketamine for general cancer pain were nega-tive, but the populationstudied did not specificallyhave neuropathic pain.2 Arandomized trial of oral ketamine for cancer-related neuro-pathic pain has been called for,3 and the present trialaddresses that need.1Methods | A multicenter, double-blind randomized clinicaltrial of oral ketamine vs placebo was conducted in theUnited Kingdom cities of Edinburgh, Glasgow, Nottingham,and Lancashire in adults with cancer-related neuropathicpain, which was defined using set criteria (Leeds Assessmentof Neuropathic Symptoms and Signs). Patients had previ-ously been treated with adjuvant analgesics for neuropathicpain, which had been ineffective or suboptimal. Preexistinganalgesia was continued throughout the trial. Patients werecentrally randomized using minimization, then ketamine orplacebo was titrated across 2 weeks to an effective and toler-able dosage (Figure). The starting dosage was 40 mg/d, witha maximum dosage of 400 mg/d. Patients continued toreceive a stable dosage for 16 days. Patients who did notexperience an analgesic benefit were withdrawn from theFigure. CONSORT Study FlowDiagram513 Patients assessed for eligibility107 Randomized to receive ketamine hydrochloride 107 Randomized to receive placebo49 Entered pain-control maintenance phase 50 Entered pain-control maintenance phase24 Completed pain control maintenance phase with notreatment failure26 Completed pain control maintenance phase with notreatment failure296 Excluded115 Ineligible65 Investigator decision57 Declined to participate-other29 Too unwell21 Declined to participate-placebo9 Conflicting trial3 Did not participate beyond run-in phase2 Withdrew: achieved pain control during run-in1 Unable to comply57 Excluded for treatment failures duringtitration phase41 Investigator declared treatmentfailure16 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase0 >30% Increase in 24-h MEDD ofopioid24 Excluded for treatment failuresduring pain-control maintenance phase17 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase7 Investor declared treatment failure0 >30% Increase in 24-h MEDDof opioid58 Excluded for treatment failuresduring titration phase31 Investigator declared treatmentfailure26 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase1 >30% Increase in 24-h MEDD ofopioid25 Excluded for treatment failuresduring pain-control maintenance phase18 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase5 Investigator declared treatmentfailure2 >30% Increase in 24-h MEDDof opioid214 RandomizedAmong the 107 patients randomizedto ketamine, themedian(interquartile range [IQR]) time spentin the titration phase for the 58patients who experienced treatmentfailure and were excluded was 14(14-14) days; range, 7 to 28 days. Ofthe 49 patients who entered thepain-control maintenance phase, themedian (IQR) time spent in thetitration phase was 14 (14-15) days;range, 8 to 21 days. Among the 107patients randomized to placebo, themedian (IQR) time spent in thetitration phase for the 57 patientswho experienced treatment failureand were excluded was 14 (12.5-14.0)days; range, 0 to 22 days. Of the 50patients who entered thepain-control maintenance phase, themedian (IQR) time spent in thetitration phase was 14 (14-15) days;range, 5 to 20 days. MEDD indicatesmorphine-equivalent daily dose.Supplemental contentjamaoncology.com (Reprinted) JAMAOncology Published online April 5, 2018 E1Downloaded From:  by a University of Nottingham User  on 04/16/2018study. The study was approved by the West of Scotland Mul-ticentre Research Ethics Committee (the full trial protocol isavailable in the Supplement; isrctn.org Identifier:ISRCTN49116945 and clinicaltrialsregister.eu Identifier:2007-002080-27), and participants provided writteninformed consent.The primary end point was duration of analgesic benefit,defined as an improvement of 5 points or more in the indexpain score (using the Sensory Component of the Short FormMcGill PainQuestionnaire), comparedwith thebaseline scoreduring the 16 days of receiving a stable dosage of ketamine orplacebo. Patients inwhom titration failedwere considered tohaveadurationof0days.Maintenanceofanalgesicbenefitwasconsidered to have failed in patients whose opioid dosage in-creasedduring this time. Secondaryendpoints includedmeanandworstpain;mood (HospitalAnxietyandDepressionScore,a self-administered anxiety anddepression screening tool foruse in nonpsychiatric patients. The tool has 14 items, whichfocus on the emotional and cognitive aspects of each aspect.Each item is scored from 0 to 3 for a combined maximum of21 for eachaspect,withhigher scores reflectingahigher symp-tom load); mean change in global distress in the last 24 hours(NationalComprehensiveCancerNetworkDistressThermom-eter, which uses a scale of 0 to 10, where 0 is no distress and10 is extreme distress); quality of life (EuroQoL Thermom-eter, a patient-rated assessment of present quality of life com-prising5questions, eachassignedavalueof0 to2points,withhigher values representing better quality of life. The sum ofthese responses produces a score on a scale of 0 to 10, whichis then translated into a scale of 0 to 100); and serious ad-verse events (NationalCancer Institute, CommonToxicityCri-teria for Adverse Events version 3.0, which provides clini-cians with descriptive terminology for reporting adverseevents. Each adverse event is graded on a scale of 1 to 5, withhigher grades representing greater severity).An intention-to-treat approach was used, with a samplesize of 107 patients per arm providing 80% or greater powerto detect an improvement in the duration of analgesic ben-efit while receiving ketamine corresponding to a 20%increase in patients in whom analgesic benefit was main-tained at 16 days (maximum hazard ratio [HR], 0.58). Tocompare duration of analgesic benefit, we used Cox propor-tional hazards regression with a confirmatory log-rank test.Secondary end points were analyzed using parametric andnonparametric methods. Quality of life data were analyzedby calculating the mean of the area under the curve over thetime in the study after adjusting for the baseline value. All Pvalues are 2-tailed, and P < .05 was statistically significant.Statistical analyses were performed using SPSS version 22.0for Windows (IBM).Results |Twohundred fourteenpatients (median [IQR] age, 58[51-66]years; 141 [65.8%] female)were randomized,withcom-parable demographic features between arms (Figure). A vari-ety of cancer types were represented; however, in 160 pa-tients (74.7%) the cancer was in remission, andmost of thesepatients had chronic, chemotherapy-induced, neuropathicpain.Twohundredninepatients (97.6%)were following treat-ment regimens for neuropathic pain.Data ondurationof neu-ropathic pain were not collected. The median morphine-equivalent daily dose for both arms was 0 mg. There was nodifference in the duration of analgesic benefit between armsas assessed by the adjusted (minimization factors) Cox pro-portional hazardsmodel (ketamine to placebo HR, 0.95 (95%CI,0.70-1.29);P = .75), supportedby the log-rank test (P = .69).Themedian duration of analgesic benefit was 0 days (95%CI,0-1 day) for ketamine and 0 days (95% CI, 0-4 days) for pla-cebo. To illustrate, 34 of 107 patients (31.8%) receiving ket-amine vs 39 of 107 (36.4%) receiving placebo maintained an-algesic benefit at day 4 of the stable dosage (95% CI forTable. Secondary Outcomes and AUCAnalyses for Distress, Quality of Life, andMoodVariableKetamineHydrochloride PlaceboMedian Difference,Ketamine − Placebo (95% CI)aP ValueSecondaryOutcomesAUC AnalysesUnadjustedb AdjustedcSecondary OutcomesPatients with analgesic benefitat day 4, %34 (31.8) 39 (36.4) NA .47 NA NAPatients with an analgesic benefitat day 16, %24 (22.4) 27 (25.2) NA .63 NA NAAUC Analysesd,eNCCN Distress Thermometer −2.972 −3.053 0.081 (−0.500 to 0.833) NA .64 .92EuroQoL Thermometer −17.756 −20.279 2.523 (−5.667 to 9.250) NA .89 .92Hospital Anxietyand Depression ScoreAnxiety score −3.605 −3.625 0.020 (−1.417 to 1.250) NA .65 .92Depression score −3.481 −3.654 0.173 (−0.500 to 0.958) NA .66 .92Abbreviations: AUC, area under the curve; NA, not applicable; NCCN, NationalComprehensive Cancer Network.a Estimated using 100000 bootstrap samples.bDetermined using theMann-Whitney test.c Adjusted for multiple testing (false-discovery rate method).dMissing data were imputed (last observation carried forward) for the AUCanalyses only.e Descriptions, scales, and possible range of scores for the NCCN DistressThermometer, EuroQoL Thermometer, and Hospital Anxiety and DepressionScore can be found in theMethods section of this research letter.LettersE2 JAMAOncology Published online April 5, 2018 (Reprinted) jamaoncology.comDownloaded From:  by a University of Nottingham User  on 04/16/2018difference, −17% to8%). Corresponding figures at day 16were24 of 107 patients (22.4%) receiving ketamine and 27of 107(25.2%) receivingplacebo (95%CI fordifference, −14%to9%).There were no differences between arms among the second-ary outcomes (Table).Therewere 18 serious adverse events: 8 inpatients receiv-ing ketamine and 10 in patients receiving placebo. Commonadverse events were cognitive disturbance, dizziness, fa-tigue, nausea, and somnolence.Discussion | This trial reports that ketamine was equivalent toplacebo for cancer-related neuropathic pain. Findings en-hance previous work4 by examining ketamine in cancer-related neuropathic pain. There may be subgroups of pa-tients forwhomketamine ishelpful, suchas thosewith centralsensitization.A limitationof thepresent studywas thatwedidnot specifically select patients with clinical evidence of cen-tral sensitization, for whom it is reasonable to hypothesize amorespecific analgesic target forketamine.Future studies thatexamine ketamine in chronic neuropathic pain should focuson patients with central sensitization, which can be estab-lishedbyabedsidetest.Thisapproachwouldbecongruentwithpreclinical knowledge and would address an important re-maining unanswered question.5Marie T. Fallon, MDAndrewWilcock, MDCaroline A. Kelly, MScJames Paul, BScLiz-Anne Lewsley, CCRJohn Norrie, MScBarry J. A. Laird, MDAuthor Affiliations: Edinburgh Cancer Research Centre (IGMM), University ofEdinburgh, Edinburgh, United Kingdom. (Fallon, Laird); Faculty of Medicine andHealth Sciences, University of Nottingham, Nottingham, United Kingdom(Wilcock); Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences,University of Glasgow, Glasgow, United Kingdom (Kelly, Paul, Lewsley); UsherInstitute, University of Edinburgh, Edinburgh, United Kingdom (Norrie).Accepted for Publication: January 11, 2018.Published Online: April 5, 2018. doi:10.1001/jamaoncol.2018.0131OpenAccess: This is an open access article distributed under the terms of the CC-BY License. © 2018 Fallon MT et al. JAMA Oncology.Corresponding Author:Marie T. Fallon, MD, Institute of Genetics andMolecularMedicine, University of Edinburgh, Edinburgh EH4 2XR, UK(marie.fallon@ed.ac.uk).Author Contributions:Drs Fallon and Laird had full access to all the data in thestudy and take responsibility for the integrity of the data and the accuracy ofthe data analysis.Study concept and design: Fallon, Paul, Laird.Acquisition, analysis, or interpretation of data: All authors.Drafting of the manuscript: Fallon, Wilcock, Kelly, Paul, Lewsley, Laird.Critical revision of the manuscript for important intellectual content: Fallon,Wilcock, Kelly, Paul, Norrie, LairdStatistical analysis: Fallon, Wilcock, Kelly, Paul, Norrie, Laird.Obtained funding: Fallon, Paul, Lewsley, Laird.Administrative, technical, or material support: Fallon, Paul, Lewsley, Laird.Study supervision: Fallon, Paul.Conflict of Interest Disclosures:None reported.Funding/Support: This trial was funded by grant 07/031 from Cancer ResearchUK and grant A14197 fromMarie Curie Cancer Care. The University of Glasgowand NHS Greater Glasgow and Clyde acted as cosponsors. Themedicines usedin this trial (ketamine hydrochloride for the investigational medicinal product,and lactose [in powder form]) and placebo for the placebo were purchased andweremanufactured into a capsule formulation by the NHS Greater Glasgow andClyde Pharmacy Production Unit.Role of the Funder/Sponsor: The funders had no role beyond peer review forthe grants. Annual reports were submitted to the funders to enable continuedfunding. The funders had no role in the design and conduct of the study;collection, management, analysis, and interpretation of the data; preparation,review, or approval of themanuscript; and decision to submit themanuscriptfor publication.Additional Contributions:Wewish to thank the Ketamine Pain Study Group:S. M. Fleetwood-Walker, PhD, University of Edinburgh, basic sciencetranslational research collaborator; Diann Taggart, BSc, University of Glasgow,trial coordinator; and Dorothy Boyle, BSc, University of Edinburgh; Anne Todd,BA NHS Greater Glasgow and Clyde; and Alison Clarke, RGN, University ofSheffield, research nurses. Anne Todd; Dorothy Boyle; Catherine Johnston,MSc, NHS Greater Glasgow and Clyde; Debra Gordon, BSc, University ofEdinburgh; Kim Sladdin, MA Hons, RGN, University of Edinburgh; Lisa Ferguson,RGN, Oxford University Hospitals NHS Foundation Trust; and CathannManderson, RGN, NottinghamUniversity Hospitals NHS Trust, participated indata collection for this study. Miriam Johnson, MD, University of Hull; DenaCohen, PhD, University of Leeds; and Sara Booth, MD, University of Cambridge,served as the data monitoring committee; Anthony Byrne, MB ChB, Universityof Cardiff; TomHaswell; JohnWilson, MD, University of Edinburgh; BeeWee,PhD, University of Oxford; and Gareth Griffiths, PhD, University ofSouthampton, served as the trial steering committee; and Lesley Colvin, PhD,University of Edinburgh; Michael Bennett, MD, University of Leeds; Kay Pollock,BSc, Pharmacy Production Unit, NHS Greater Glasgow and Clyde; CatherineUrch, PhD, Imperial College, London; JohnWelsh, MB ChB, St Margaret ofScotland Hospice/University of Glasgow; Alison Parr, MB ChB, St Catherine’sHospice, Preston; and Patrick Stone, MD, University of London, served asresearch collaborators. They were not compensated for their contributions. Wealso wish to thank our colleagues at the sites where the trial was conducted fortheir support, particularly the Cancer Research UK Clinical Trials Unit, Glasgow.Finally, this trial would not have been possible without the support of thepatients who participated.1. Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancerpain. Cochrane Database Syst Rev. 2012;11:CD003351.2. Hardy J, Quinn S, Fazekas B, et al. Randomized, double-blind,placebo-controlled study to assess the efficacy and toxicity of subcutaneousketamine in themanagement of cancer pain. J Clin Oncol. 2012;30(29):3611-3617.3. Piano V, Verhagen S, Schalkwijk A, et al. Diagnosing neuropathic pain inpatients with cancer: comparative analysis of recommendations in nationalguidelines from European countries. Pain Pract. 2013;13(6):433-439.4. Leppert W. Ketamine in themanagement of cancer pain. J Clin Oncol. 2013;31(10):1374.5. SisignanoM, Baron R, Scholich K, Geisslinger G. Mechanism-based treatmentfor chemotherapy-induced peripheral neuropathic pain.Nat Rev Neurol. 2014;10(12):694-707.Lettersjamaoncology.com (Reprinted) JAMAOncology Published online April 5, 2018 E3Downloaded From:  by a University of Nottingham User  on 04/16/2018

Oral ketamine vs placebo in patients with cancer-related neuropathic pain

Kelly, Caroline

Edinburgh Research Explorer

     Edinburgh Research Explorer                                      Oral Ketamine vs placebo in patients with cancer-relatedneuropathic painCitation for published version:Fallon, M, Wilcock, A, Kelly, C, Paul, J, Lewsley, L-A, Norrie, J & Laird, B 2018, 'Oral Ketamine vs placeboin patients with cancer-related neuropathic pain: a randomized clinical trial' JAMA Oncology. DOI:10.1001/jamaoncol.2018.0131Digital Object Identifier (DOI):10.1001/jamaoncol.2018.0131Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Publisher's PDF, also known as Version of recordPublished In:JAMA OncologyPublisher Rights Statement:This is an open access article distributed under the terms of the CCBYLicense.©2018 Fallon MT et al. JAMA Oncology.General rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 30. Jun. 2018LettersRESEARCH LETTEROral Ketamine vs Placebo in PatientsWith Cancer-RelatedNeuropathic Pain:A Randomized Clinical TrialKetamine hydrochloride is used as an adjuvant treatmentfor cancer-related neuropathic pain, but evidence of itseffectiveness is limited.1 Findings of a large trial investigat-ing the use of ketamine for general cancer pain were nega-tive, but the populationstudied did not specificallyhave neuropathic pain.2 Arandomized trial of oral ketamine for cancer-related neuro-pathic pain has been called for,3 and the present trialaddresses that need.1Methods | A multicenter, double-blind randomized clinicaltrial of oral ketamine vs placebo was conducted in theUnited Kingdom cities of Edinburgh, Glasgow, Nottingham,and Lancashire in adults with cancer-related neuropathicpain, which was defined using set criteria (Leeds Assessmentof Neuropathic Symptoms and Signs). Patients had previ-ously been treated with adjuvant analgesics for neuropathicpain, which had been ineffective or suboptimal. Preexistinganalgesia was continued throughout the trial. Patients werecentrally randomized using minimization, then ketamine orplacebo was titrated across 2 weeks to an effective and toler-able dosage (Figure). The starting dosage was 40 mg/d, witha maximum dosage of 400 mg/d. Patients continued toreceive a stable dosage for 16 days. Patients who did notexperience an analgesic benefit were withdrawn from theFigure. CONSORT Study FlowDiagram513 Patients assessed for eligibility107 Randomized to receive ketamine hydrochloride 107 Randomized to receive placebo49 Entered pain-control maintenance phase 50 Entered pain-control maintenance phase24 Completed pain control maintenance phase with notreatment failure26 Completed pain control maintenance phase with notreatment failure296 Excluded115 Ineligible65 Investigator decision57 Declined to participate-other29 Too unwell21 Declined to participate-placebo9 Conflicting trial3 Did not participate beyond run-in phase2 Withdrew: achieved pain control during run-in1 Unable to comply57 Excluded for treatment failures duringtitration phase41 Investigator declared treatmentfailure16 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase0 >30% Increase in 24-h MEDD ofopioid24 Excluded for treatment failuresduring pain-control maintenance phase17 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase7 Investor declared treatment failure0 >30% Increase in 24-h MEDDof opioid58 Excluded for treatment failuresduring titration phase31 Investigator declared treatmentfailure26 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase1 >30% Increase in 24-h MEDD ofopioid25 Excluded for treatment failuresduring pain-control maintenance phase18 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase5 Investigator declared treatmentfailure2 >30% Increase in 24-h MEDDof opioid214 RandomizedAmong the 107 patients randomizedto ketamine, themedian(interquartile range [IQR]) time spentin the titration phase for the 58patients who experienced treatmentfailure and were excluded was 14(14-14) days; range, 7 to 28 days. Ofthe 49 patients who entered thepain-control maintenance phase, themedian (IQR) time spent in thetitration phase was 14 (14-15) days;range, 8 to 21 days. Among the 107patients randomized to placebo, themedian (IQR) time spent in thetitration phase for the 57 patientswho experienced treatment failureand were excluded was 14 (12.5-14.0)days; range, 0 to 22 days. Of the 50patients who entered thepain-control maintenance phase, themedian (IQR) time spent in thetitration phase was 14 (14-15) days;range, 5 to 20 days. MEDD indicatesmorphine-equivalent daily dose.Supplemental contentjamaoncology.com (Reprinted) JAMAOncology Published online April 5, 2018 E1Downloaded From:  by a University of Edinburgh Library User  on 04/12/2018study. The study was approved by the West of Scotland Mul-ticentre Research Ethics Committee (the full trial protocol isavailable in the Supplement; isrctn.org Identifier:ISRCTN49116945 and clinicaltrialsregister.eu Identifier:2007-002080-27), and participants provided writteninformed consent.The primary end point was duration of analgesic benefit,defined as an improvement of 5 points or more in the indexpain score (using the Sensory Component of the Short FormMcGill PainQuestionnaire), comparedwith thebaseline scoreduring the 16 days of receiving a stable dosage of ketamine orplacebo. Patients inwhom titration failedwere considered tohaveadurationof0days.Maintenanceofanalgesicbenefitwasconsidered to have failed in patients whose opioid dosage in-creasedduring this time. Secondaryendpoints includedmeanandworstpain;mood (HospitalAnxietyandDepressionScore,a self-administered anxiety anddepression screening tool foruse in nonpsychiatric patients. The tool has 14 items, whichfocus on the emotional and cognitive aspects of each aspect.Each item is scored from 0 to 3 for a combined maximum of21 for eachaspect,withhigher scores reflectingahigher symp-tom load); mean change in global distress in the last 24 hours(NationalComprehensiveCancerNetworkDistressThermom-eter, which uses a scale of 0 to 10, where 0 is no distress and10 is extreme distress); quality of life (EuroQoL Thermom-eter, a patient-rated assessment of present quality of life com-prising5questions, eachassignedavalueof0 to2points,withhigher values representing better quality of life. The sum ofthese responses produces a score on a scale of 0 to 10, whichis then translated into a scale of 0 to 100); and serious ad-verse events (NationalCancer Institute, CommonToxicityCri-teria for Adverse Events version 3.0, which provides clini-cians with descriptive terminology for reporting adverseevents. Each adverse event is graded on a scale of 1 to 5, withhigher grades representing greater severity).An intention-to-treat approach was used, with a samplesize of 107 patients per arm providing 80% or greater powerto detect an improvement in the duration of analgesic ben-efit while receiving ketamine corresponding to a 20%increase in patients in whom analgesic benefit was main-tained at 16 days (maximum hazard ratio [HR], 0.58). Tocompare duration of analgesic benefit, we used Cox propor-tional hazards regression with a confirmatory log-rank test.Secondary end points were analyzed using parametric andnonparametric methods. Quality of life data were analyzedby calculating the mean of the area under the curve over thetime in the study after adjusting for the baseline value. All Pvalues are 2-tailed, and P < .05 was statistically significant.Statistical analyses were performed using SPSS version 22.0for Windows (IBM).Results |Twohundred fourteenpatients (median [IQR] age, 58[51-66]years; 141 [65.8%] female)were randomized,withcom-parable demographic features between arms (Figure). A vari-ety of cancer types were represented; however, in 160 pa-tients (74.7%) the cancer was in remission, andmost of thesepatients had chronic, chemotherapy-induced, neuropathicpain.Twohundredninepatients (97.6%)were following treat-ment regimens for neuropathic pain.Data ondurationof neu-ropathic pain were not collected. The median morphine-equivalent daily dose for both arms was 0 mg. There was nodifference in the duration of analgesic benefit between armsas assessed by the adjusted (minimization factors) Cox pro-portional hazardsmodel (ketamine to placebo HR, 0.95 (95%CI,0.70-1.29);P = .75), supportedby the log-rank test (P = .69).Themedian duration of analgesic benefit was 0 days (95%CI,0-1 day) for ketamine and 0 days (95% CI, 0-4 days) for pla-cebo. To illustrate, 34 of 107 patients (31.8%) receiving ket-amine vs 39 of 107 (36.4%) receiving placebo maintained an-algesic benefit at day 4 of the stable dosage (95% CI forTable. Secondary Outcomes and AUCAnalyses for Distress, Quality of Life, andMoodVariableKetamineHydrochloride PlaceboMedian Difference,Ketamine − Placebo (95% CI)aP ValueSecondaryOutcomesAUC AnalysesUnadjustedb AdjustedcSecondary OutcomesPatients with analgesic benefitat day 4, %34 (31.8) 39 (36.4) NA .47 NA NAPatients with an analgesic benefitat day 16, %24 (22.4) 27 (25.2) NA .63 NA NAAUC Analysesd,eNCCN Distress Thermometer −2.972 −3.053 0.081 (−0.500 to 0.833) NA .64 .92EuroQoL Thermometer −17.756 −20.279 2.523 (−5.667 to 9.250) NA .89 .92Hospital Anxietyand Depression ScoreAnxiety score −3.605 −3.625 0.020 (−1.417 to 1.250) NA .65 .92Depression score −3.481 −3.654 0.173 (−0.500 to 0.958) NA .66 .92Abbreviations: AUC, area under the curve; NA, not applicable; NCCN, NationalComprehensive Cancer Network.a Estimated using 100000 bootstrap samples.bDetermined using theMann-Whitney test.c Adjusted for multiple testing (false-discovery rate method).dMissing data were imputed (last observation carried forward) for the AUCanalyses only.e Descriptions, scales, and possible range of scores for the NCCN DistressThermometer, EuroQoL Thermometer, and Hospital Anxiety and DepressionScore can be found in theMethods section of this research letter.LettersE2 JAMAOncology Published online April 5, 2018 (Reprinted) jamaoncology.comDownloaded From:  by a University of Edinburgh Library User  on 04/12/2018difference, −17% to8%). Corresponding figures at day 16were24 of 107 patients (22.4%) receiving ketamine and 27of 107(25.2%) receivingplacebo (95%CI fordifference, −14%to9%).There were no differences between arms among the second-ary outcomes (Table).Therewere 18 serious adverse events: 8 inpatients receiv-ing ketamine and 10 in patients receiving placebo. Commonadverse events were cognitive disturbance, dizziness, fa-tigue, nausea, and somnolence.Discussion | This trial reports that ketamine was equivalent toplacebo for cancer-related neuropathic pain. Findings en-hance previous work4 by examining ketamine in cancer-related neuropathic pain. There may be subgroups of pa-tients forwhomketamine ishelpful, suchas thosewith centralsensitization.A limitationof thepresent studywas thatwedidnot specifically select patients with clinical evidence of cen-tral sensitization, for whom it is reasonable to hypothesize amorespecific analgesic target forketamine.Future studies thatexamine ketamine in chronic neuropathic pain should focuson patients with central sensitization, which can be estab-lishedbyabedsidetest.Thisapproachwouldbecongruentwithpreclinical knowledge and would address an important re-maining unanswered question.5Marie T. Fallon, MDAndrewWilcock, MDCaroline A. Kelly, MScJames Paul, BScLiz-Anne Lewsley, CCRJohn Norrie, MScBarry J. A. Laird, MDAuthor Affiliations: Edinburgh Cancer Research Centre (IGMM), University ofEdinburgh, Edinburgh, United Kingdom. (Fallon, Laird); Faculty of Medicine andHealth Sciences, University of Nottingham, Nottingham, United Kingdom(Wilcock); Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences,University of Glasgow, Glasgow, United Kingdom (Kelly, Paul, Lewsley); UsherInstitute, University of Edinburgh, Edinburgh, United Kingdom (Norrie).Accepted for Publication: January 11, 2018.Published Online: April 5, 2018. doi:10.1001/jamaoncol.2018.0131OpenAccess: This is an open access article distributed under the terms of the CC-BY License. © 2018 Fallon MT et al. JAMA Oncology.Corresponding Author:Marie T. Fallon, MD, Institute of Genetics andMolecularMedicine, University of Edinburgh, Edinburgh EH4 2XR, UK(marie.fallon@ed.ac.uk).Author Contributions:Drs Fallon and Laird had full access to all the data in thestudy and take responsibility for the integrity of the data and the accuracy ofthe data analysis.Study concept and design: Fallon, Paul, Laird.Acquisition, analysis, or interpretation of data: All authors.Drafting of the manuscript: Fallon, Wilcock, Kelly, Paul, Lewsley, Laird.Critical revision of the manuscript for important intellectual content: Fallon,Wilcock, Kelly, Paul, Norrie, LairdStatistical analysis: Fallon, Wilcock, Kelly, Paul, Norrie, Laird.Obtained funding: Fallon, Paul, Lewsley, Laird.Administrative, technical, or material support: Fallon, Paul, Lewsley, Laird.Study supervision: Fallon, Paul.Conflict of Interest Disclosures:None reported.Funding/Support: This trial was funded by grant 07/031 from Cancer ResearchUK and grant A14197 fromMarie Curie Cancer Care. The University of Glasgowand NHS Greater Glasgow and Clyde acted as cosponsors. Themedicines usedin this trial (ketamine hydrochloride for the investigational medicinal product,and lactose [in powder form]) and placebo for the placebo were purchased andweremanufactured into a capsule formulation by the NHS Greater Glasgow andClyde Pharmacy Production Unit.Role of the Funder/Sponsor: The funders had no role beyond peer review forthe grants. Annual reports were submitted to the funders to enable continuedfunding. The funders had no role in the design and conduct of the study;collection, management, analysis, and interpretation of the data; preparation,review, or approval of themanuscript; and decision to submit themanuscriptfor publication.Additional Contributions:Wewish to thank the Ketamine Pain Study Group:S. M. Fleetwood-Walker, PhD, University of Edinburgh, basic sciencetranslational research collaborator; Diann Taggart, BSc, University of Glasgow,trial coordinator; and Dorothy Boyle, BSc, University of Edinburgh; Anne Todd,BA NHS Greater Glasgow and Clyde; and Alison Clarke, RGN, University ofSheffield, research nurses. Anne Todd; Dorothy Boyle; Catherine Johnston,MSc, NHS Greater Glasgow and Clyde; Debra Gordon, BSc, University ofEdinburgh; Kim Sladdin, MA Hons, RGN, University of Edinburgh; Lisa Ferguson,RGN, Oxford University Hospitals NHS Foundation Trust; and CathannManderson, RGN, NottinghamUniversity Hospitals NHS Trust, participated indata collection for this study. Miriam Johnson, MD, University of Hull; DenaCohen, PhD, University of Leeds; and Sara Booth, MD, University of Cambridge,served as the data monitoring committee; Anthony Byrne, MB ChB, Universityof Cardiff; TomHaswell; JohnWilson, MD, University of Edinburgh; BeeWee,PhD, University of Oxford; and Gareth Griffiths, PhD, University ofSouthampton, served as the trial steering committee; and Lesley Colvin, PhD,University of Edinburgh; Michael Bennett, MD, University of Leeds; Kay Pollock,BSc, Pharmacy Production Unit, NHS Greater Glasgow and Clyde; CatherineUrch, PhD, Imperial College, London; JohnWelsh, MB ChB, St Margaret ofScotland Hospice/University of Glasgow; Alison Parr, MB ChB, St Catherine’sHospice, Preston; and Patrick Stone, MD, University of London, served asresearch collaborators. They were not compensated for their contributions. Wealso wish to thank our colleagues at the sites where the trial was conducted fortheir support, particularly the Cancer Research UK Clinical Trials Unit, Glasgow.Finally, this trial would not have been possible without the support of thepatients who participated.1. Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancerpain. Cochrane Database Syst Rev. 2012;11:CD003351.2. Hardy J, Quinn S, Fazekas B, et al. Randomized, double-blind,placebo-controlled study to assess the efficacy and toxicity of subcutaneousketamine in themanagement of cancer pain. J Clin Oncol. 2012;30(29):3611-3617.3. Piano V, Verhagen S, Schalkwijk A, et al. Diagnosing neuropathic pain inpatients with cancer: comparative analysis of recommendations in nationalguidelines from European countries. Pain Pract. 2013;13(6):433-439.4. Leppert W. Ketamine in themanagement of cancer pain. J Clin Oncol. 2013;31(10):1374.5. SisignanoM, Baron R, Scholich K, Geisslinger G. Mechanism-based treatmentfor chemotherapy-induced peripheral neuropathic pain.Nat Rev Neurol. 2014;10(12):694-707.Lettersjamaoncology.com (Reprinted) JAMAOncology Published online April 5, 2018 E3Downloaded From:  by a University of Edinburgh Library User  on 04/12/2018

Oral Ketamine vs Placebo in Patients With Cancer-Related Neuropathic Pain: A Randomized Clinical Trial

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LettersRESEARCH LETTEROral Ketamine vs Placebo in PatientsWith Cancer-RelatedNeuropathic Pain:A Randomized Clinical TrialKetamine hydrochloride is used as an adjuvant treatmentfor cancer-related neuropathic pain, but evidence of itseffectiveness is limited.1 Findings of a large trial investigat-ing the use of ketamine for general cancer pain were nega-tive, but the populationstudied did not specificallyhave neuropathic pain.2 Arandomized trial of oral ketamine for cancer-related neuro-pathic pain has been called for,3 and the present trialaddresses that need.1Methods | A multicenter, double-blind randomized clinicaltrial of oral ketamine vs placebo was conducted in theUnited Kingdom cities of Edinburgh, Glasgow, Nottingham,and Lancashire in adults with cancer-related neuropathicpain, which was defined using set criteria (Leeds Assessmentof Neuropathic Symptoms and Signs). Patients had previ-ously been treated with adjuvant analgesics for neuropathicpain, which had been ineffective or suboptimal. Preexistinganalgesia was continued throughout the trial. Patients werecentrally randomized using minimization, then ketamine orplacebo was titrated across 2 weeks to an effective and toler-able dosage (Figure). The starting dosage was 40 mg/d, witha maximum dosage of 400 mg/d. Patients continued toreceive a stable dosage for 16 days. Patients who did notexperience an analgesic benefit were withdrawn from theFigure. CONSORT Study FlowDiagram513 Patients assessed for eligibility107 Randomized to receive ketamine hydrochloride 107 Randomized to receive placebo49 Entered pain-control maintenance phase 50 Entered pain-control maintenance phase24 Completed pain control maintenance phase with notreatment failure26 Completed pain control maintenance phase with notreatment failure296 Excluded115 Ineligible65 Investigator decision57 Declined to participate-other29 Too unwell21 Declined to participate-placebo9 Conflicting trial3 Did not participate beyond run-in phase2 Withdrew: achieved pain control during run-in1 Unable to comply57 Excluded for treatment failures duringtitration phase41 Investigator declared treatmentfailure16 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase0 >30% Increase in 24-h MEDD ofopioid24 Excluded for treatment failuresduring pain-control maintenance phase17 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase7 Investor declared treatment failure0 >30% Increase in 24-h MEDDof opioid58 Excluded for treatment failuresduring titration phase31 Investigator declared treatmentfailure26 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase1 >30% Increase in 24-h MEDD ofopioid25 Excluded for treatment failuresduring pain-control maintenance phase18 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase5 Investigator declared treatmentfailure2 >30% Increase in 24-h MEDDof opioid214 RandomizedAmong the 107 patients randomizedto ketamine, themedian(interquartile range [IQR]) time spentin the titration phase for the 58patients who experienced treatmentfailure and were excluded was 14(14-14) days; range, 7 to 28 days. Ofthe 49 patients who entered thepain-control maintenance phase, themedian (IQR) time spent in thetitration phase was 14 (14-15) days;range, 8 to 21 days. Among the 107patients randomized to placebo, themedian (IQR) time spent in thetitration phase for the 57 patientswho experienced treatment failureand were excluded was 14 (12.5-14.0)days; range, 0 to 22 days. Of the 50patients who entered thepain-control maintenance phase, themedian (IQR) time spent in thetitration phase was 14 (14-15) days;range, 5 to 20 days. MEDD indicatesmorphine-equivalent daily dose.Supplemental contentjamaoncology.com (Reprinted) JAMAOncology Published online April 5, 2018 E1Downloaded From:  by a Glasgow University Library User  on 04/13/2018study. The study was approved by the West of Scotland Mul-ticentre Research Ethics Committee (the full trial protocol isavailable in the Supplement; isrctn.org Identifier:ISRCTN49116945 and clinicaltrialsregister.eu Identifier:2007-002080-27), and participants provided writteninformed consent.The primary end point was duration of analgesic benefit,defined as an improvement of 5 points or more in the indexpain score (using the Sensory Component of the Short FormMcGill PainQuestionnaire), comparedwith thebaseline scoreduring the 16 days of receiving a stable dosage of ketamine orplacebo. Patients inwhom titration failedwere considered tohaveadurationof0days.Maintenanceofanalgesicbenefitwasconsidered to have failed in patients whose opioid dosage in-creasedduring this time. Secondaryendpoints includedmeanandworstpain;mood (HospitalAnxietyandDepressionScore,a self-administered anxiety anddepression screening tool foruse in nonpsychiatric patients. The tool has 14 items, whichfocus on the emotional and cognitive aspects of each aspect.Each item is scored from 0 to 3 for a combined maximum of21 for eachaspect,withhigher scores reflectingahigher symp-tom load); mean change in global distress in the last 24 hours(NationalComprehensiveCancerNetworkDistressThermom-eter, which uses a scale of 0 to 10, where 0 is no distress and10 is extreme distress); quality of life (EuroQoL Thermom-eter, a patient-rated assessment of present quality of life com-prising5questions, eachassignedavalueof0 to2points,withhigher values representing better quality of life. The sum ofthese responses produces a score on a scale of 0 to 10, whichis then translated into a scale of 0 to 100); and serious ad-verse events (NationalCancer Institute, CommonToxicityCri-teria for Adverse Events version 3.0, which provides clini-cians with descriptive terminology for reporting adverseevents. Each adverse event is graded on a scale of 1 to 5, withhigher grades representing greater severity).An intention-to-treat approach was used, with a samplesize of 107 patients per arm providing 80% or greater powerto detect an improvement in the duration of analgesic ben-efit while receiving ketamine corresponding to a 20%increase in patients in whom analgesic benefit was main-tained at 16 days (maximum hazard ratio [HR], 0.58). Tocompare duration of analgesic benefit, we used Cox propor-tional hazards regression with a confirmatory log-rank test.Secondary end points were analyzed using parametric andnonparametric methods. Quality of life data were analyzedby calculating the mean of the area under the curve over thetime in the study after adjusting for the baseline value. All Pvalues are 2-tailed, and P < .05 was statistically significant.Statistical analyses were performed using SPSS version 22.0for Windows (IBM).Results |Twohundred fourteenpatients (median [IQR] age, 58[51-66]years; 141 [65.8%] female)were randomized,withcom-parable demographic features between arms (Figure). A vari-ety of cancer types were represented; however, in 160 pa-tients (74.7%) the cancer was in remission, andmost of thesepatients had chronic, chemotherapy-induced, neuropathicpain.Twohundredninepatients (97.6%)were following treat-ment regimens for neuropathic pain.Data ondurationof neu-ropathic pain were not collected. The median morphine-equivalent daily dose for both arms was 0 mg. There was nodifference in the duration of analgesic benefit between armsas assessed by the adjusted (minimization factors) Cox pro-portional hazardsmodel (ketamine to placebo HR, 0.95 (95%CI,0.70-1.29);P = .75), supportedby the log-rank test (P = .69).Themedian duration of analgesic benefit was 0 days (95%CI,0-1 day) for ketamine and 0 days (95% CI, 0-4 days) for pla-cebo. To illustrate, 34 of 107 patients (31.8%) receiving ket-amine vs 39 of 107 (36.4%) receiving placebo maintained an-algesic benefit at day 4 of the stable dosage (95% CI forTable. Secondary Outcomes and AUCAnalyses for Distress, Quality of Life, andMoodVariableKetamineHydrochloride PlaceboMedian Difference,Ketamine − Placebo (95% CI)aP ValueSecondaryOutcomesAUC AnalysesUnadjustedb AdjustedcSecondary OutcomesPatients with analgesic benefitat day 4, %34 (31.8) 39 (36.4) NA .47 NA NAPatients with an analgesic benefitat day 16, %24 (22.4) 27 (25.2) NA .63 NA NAAUC Analysesd,eNCCN Distress Thermometer −2.972 −3.053 0.081 (−0.500 to 0.833) NA .64 .92EuroQoL Thermometer −17.756 −20.279 2.523 (−5.667 to 9.250) NA .89 .92Hospital Anxietyand Depression ScoreAnxiety score −3.605 −3.625 0.020 (−1.417 to 1.250) NA .65 .92Depression score −3.481 −3.654 0.173 (−0.500 to 0.958) NA .66 .92Abbreviations: AUC, area under the curve; NA, not applicable; NCCN, NationalComprehensive Cancer Network.a Estimated using 100000 bootstrap samples.bDetermined using theMann-Whitney test.c Adjusted for multiple testing (false-discovery rate method).dMissing data were imputed (last observation carried forward) for the AUCanalyses only.e Descriptions, scales, and possible range of scores for the NCCN DistressThermometer, EuroQoL Thermometer, and Hospital Anxiety and DepressionScore can be found in theMethods section of this research letter.LettersE2 JAMAOncology Published online April 5, 2018 (Reprinted) jamaoncology.comDownloaded From:  by a Glasgow University Library User  on 04/13/2018difference, −17% to8%). Corresponding figures at day 16were24 of 107 patients (22.4%) receiving ketamine and 27of 107(25.2%) receivingplacebo (95%CI fordifference, −14%to9%).There were no differences between arms among the second-ary outcomes (Table).Therewere 18 serious adverse events: 8 inpatients receiv-ing ketamine and 10 in patients receiving placebo. Commonadverse events were cognitive disturbance, dizziness, fa-tigue, nausea, and somnolence.Discussion | This trial reports that ketamine was equivalent toplacebo for cancer-related neuropathic pain. Findings en-hance previous work4 by examining ketamine in cancer-related neuropathic pain. There may be subgroups of pa-tients forwhomketamine ishelpful, suchas thosewith centralsensitization.A limitationof thepresent studywas thatwedidnot specifically select patients with clinical evidence of cen-tral sensitization, for whom it is reasonable to hypothesize amorespecific analgesic target forketamine.Future studies thatexamine ketamine in chronic neuropathic pain should focuson patients with central sensitization, which can be estab-lishedbyabedsidetest.Thisapproachwouldbecongruentwithpreclinical knowledge and would address an important re-maining unanswered question.5Marie T. Fallon, MDAndrewWilcock, MDCaroline A. Kelly, MScJames Paul, BScLiz-Anne Lewsley, CCRJohn Norrie, MScBarry J. A. Laird, MDAuthor Affiliations: Edinburgh Cancer Research Centre (IGMM), University ofEdinburgh, Edinburgh, United Kingdom. (Fallon, Laird); Faculty of Medicine andHealth Sciences, University of Nottingham, Nottingham, United Kingdom(Wilcock); Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences,University of Glasgow, Glasgow, United Kingdom (Kelly, Paul, Lewsley); UsherInstitute, University of Edinburgh, Edinburgh, United Kingdom (Norrie).Accepted for Publication: January 11, 2018.Published Online: April 5, 2018. doi:10.1001/jamaoncol.2018.0131OpenAccess: This is an open access article distributed under the terms of the CC-BY License. © 2018 Fallon MT et al. JAMA Oncology.Corresponding Author:Marie T. Fallon, MD, Institute of Genetics andMolecularMedicine, University of Edinburgh, Edinburgh EH4 2XR, UK(marie.fallon@ed.ac.uk).Author Contributions:Drs Fallon and Laird had full access to all the data in thestudy and take responsibility for the integrity of the data and the accuracy ofthe data analysis.Study concept and design: Fallon, Paul, Laird.Acquisition, analysis, or interpretation of data: All authors.Drafting of the manuscript: Fallon, Wilcock, Kelly, Paul, Lewsley, Laird.Critical revision of the manuscript for important intellectual content: Fallon,Wilcock, Kelly, Paul, Norrie, LairdStatistical analysis: Fallon, Wilcock, Kelly, Paul, Norrie, Laird.Obtained funding: Fallon, Paul, Lewsley, Laird.Administrative, technical, or material support: Fallon, Paul, Lewsley, Laird.Study supervision: Fallon, Paul.Conflict of Interest Disclosures:None reported.Funding/Support: This trial was funded by grant 07/031 from Cancer ResearchUK and grant A14197 fromMarie Curie Cancer Care. The University of Glasgowand NHS Greater Glasgow and Clyde acted as cosponsors. Themedicines usedin this trial (ketamine hydrochloride for the investigational medicinal product,and lactose [in powder form]) and placebo for the placebo were purchased andweremanufactured into a capsule formulation by the NHS Greater Glasgow andClyde Pharmacy Production Unit.Role of the Funder/Sponsor: The funders had no role beyond peer review forthe grants. Annual reports were submitted to the funders to enable continuedfunding. The funders had no role in the design and conduct of the study;collection, management, analysis, and interpretation of the data; preparation,review, or approval of themanuscript; and decision to submit themanuscriptfor publication.Additional Contributions:Wewish to thank the Ketamine Pain Study Group:S. M. Fleetwood-Walker, PhD, University of Edinburgh, basic sciencetranslational research collaborator; Diann Taggart, BSc, University of Glasgow,trial coordinator; and Dorothy Boyle, BSc, University of Edinburgh; Anne Todd,BA NHS Greater Glasgow and Clyde; and Alison Clarke, RGN, University ofSheffield, research nurses. Anne Todd; Dorothy Boyle; Catherine Johnston,MSc, NHS Greater Glasgow and Clyde; Debra Gordon, BSc, University ofEdinburgh; Kim Sladdin, MA Hons, RGN, University of Edinburgh; Lisa Ferguson,RGN, Oxford University Hospitals NHS Foundation Trust; and CathannManderson, RGN, NottinghamUniversity Hospitals NHS Trust, participated indata collection for this study. Miriam Johnson, MD, University of Hull; DenaCohen, PhD, University of Leeds; and Sara Booth, MD, University of Cambridge,served as the data monitoring committee; Anthony Byrne, MB ChB, Universityof Cardiff; TomHaswell; JohnWilson, MD, University of Edinburgh; BeeWee,PhD, University of Oxford; and Gareth Griffiths, PhD, University ofSouthampton, served as the trial steering committee; and Lesley Colvin, PhD,University of Edinburgh; Michael Bennett, MD, University of Leeds; Kay Pollock,BSc, Pharmacy Production Unit, NHS Greater Glasgow and Clyde; CatherineUrch, PhD, Imperial College, London; JohnWelsh, MB ChB, St Margaret ofScotland Hospice/University of Glasgow; Alison Parr, MB ChB, St Catherine’sHospice, Preston; and Patrick Stone, MD, University of London, served asresearch collaborators. They were not compensated for their contributions. Wealso wish to thank our colleagues at the sites where the trial was conducted fortheir support, particularly the Cancer Research UK Clinical Trials Unit, Glasgow.Finally, this trial would not have been possible without the support of thepatients who participated.1. Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancerpain. Cochrane Database Syst Rev. 2012;11:CD003351.2. Hardy J, Quinn S, Fazekas B, et al. Randomized, double-blind,placebo-controlled study to assess the efficacy and toxicity of subcutaneousketamine in themanagement of cancer pain. J Clin Oncol. 2012;30(29):3611-3617.3. Piano V, Verhagen S, Schalkwijk A, et al. Diagnosing neuropathic pain inpatients with cancer: comparative analysis of recommendations in nationalguidelines from European countries. Pain Pract. 2013;13(6):433-439.4. Leppert W. Ketamine in themanagement of cancer pain. J Clin Oncol. 2013;31(10):1374.5. SisignanoM, Baron R, Scholich K, Geisslinger G. Mechanism-based treatmentfor chemotherapy-induced peripheral neuropathic pain.Nat Rev Neurol. 2014;10(12):694-707.Lettersjamaoncology.com (Reprinted) JAMAOncology Published online April 5, 2018 E3Downloaded From:  by a Glasgow University Library User  on 04/13/2018

English

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     Edinburgh Research Explorer                                      Oral Ketamine vs Placebo in Patients With Cancer-RelatedNeuropathic Pain: A Randomized Clinical TrialCitation for published version:Fallon, MT, Wilcock, A, Kelly, C, Paul, J, Lewsley, L-A, Norrie, J & Laird, BJA 2018, 'Oral Ketamine vsPlacebo in Patients With Cancer-Related Neuropathic Pain: A Randomized Clinical Trial', JAMA Oncology,vol. 4, no. 6, pp. 870-872. https://doi.org/10.1001/jamaoncol.2018.0131Digital Object Identifier (DOI):10.1001/jamaoncol.2018.0131Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Publisher's PDF, also known as Version of recordPublished In:JAMA OncologyPublisher Rights Statement:This is an open access article distributed under the terms of the CCBYLicense.©2018 Fallon MT et al. JAMA Oncology.General rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 28. Nov. 2025LettersRESEARCH LETTEROral Ketamine vs Placebo in PatientsWith Cancer-Related Neuropathic Pain:A Randomized Clinical TrialKetamine hydrochloride is used as an adjuvant treatmentfor cancer-related neuropathic pain, but evidence of itseffectiveness is limited.1 Findings of a large trial investigat-ing the use of ketamine for general cancer pain were nega-tive, but the populationstudied did not specificallyhave neuropathic pain.2 Arandomized trial of oral ketamine for cancer-related neuro-pathic pain has been called for,3 and the present trialaddresses that need.1Methods | A multicenter, double-blind randomized clinicaltrial of oral ketamine vs placebo was conducted in theUnited Kingdom cities of Edinburgh, Glasgow, Nottingham,and Lancashire in adults with cancer-related neuropathicpain, which was defined using set criteria (Leeds Assessmentof Neuropathic Symptoms and Signs). Patients had previ-ously been treated with adjuvant analgesics for neuropathicpain, which had been ineffective or suboptimal. Preexistinganalgesia was continued throughout the trial. Patients werecentrally randomized using minimization, then ketamine orplacebo was titrated across 2 weeks to an effective and toler-able dosage (Figure). The starting dosage was 40 mg/d, witha maximum dosage of 400 mg/d. Patients continued toreceive a stable dosage for 16 days. Patients who did notexperience an analgesic benefit were withdrawn from theFigure. CONSORT Study Flow Diagram513 Patients assessed for eligibility107 Randomized to receive ketamine hydrochloride 107 Randomized to receive placebo49 Entered pain-control maintenance phase 50 Entered pain-control maintenance phase24 Completed pain control maintenance phase with notreatment failure26 Completed pain control maintenance phase with notreatment failure296 Excluded115 Ineligible65 Investigator decision57 Declined to participate-other29 Too unwell21 Declined to participate-placebo9 Conflicting trial3 Did not participate beyond run-in phase2 Withdrew: achieved pain control during run-in1 Unable to comply57 Excluded for treatment failures duringtitration phase41 Investigator declared treatmentfailure16 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase0 >30% Increase in 24-h MEDD ofopioid24 Excluded for treatment failuresduring pain-control maintenance phase17 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase7 Investor declared treatment failure0 >30% Increase in 24-h MEDDof opioid58 Excluded for treatment failuresduring titration phase31 Investigator declared treatmentfailure26 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase1 >30% Increase in 24-h MEDD ofopioid25 Excluded for treatment failuresduring pain-control maintenance phase18 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase5 Investigator declared treatmentfailure2 >30% Increase in 24-h MEDDof opioid214 RandomizedAmong the 107 patients randomizedto ketamine, the median(interquartile range [IQR]) time spentin the titration phase for the 58patients who experienced treatmentfailure and were excluded was 14(14-14) days; range, 7 to 28 days. Ofthe 49 patients who entered thepain-control maintenance phase, themedian (IQR) time spent in thetitration phase was 14 (14-15) days;range, 8 to 21 days. Among the 107patients randomized to placebo, themedian (IQR) time spent in thetitration phase for the 57 patientswho experienced treatment failureand were excluded was 14 (12.5-14.0)days; range, 0 to 22 days. Of the 50patients who entered thepain-control maintenance phase, themedian (IQR) time spent in thetitration phase was 14 (14-15) days;range, 5 to 20 days. MEDD indicatesmorphine-equivalent daily dose.Supplemental contentjamaoncology.com (Reprinted) JAMA Oncology Published online April 5, 2018 E1Downloaded From:  by a University of Edinburgh Library User  on 04/12/2018study. The study was approved by the West of Scotland Mul-ticentre Research Ethics Committee (the full trial protocol isavailable in the Supplement; isrctn.org Identifier:ISRCTN49116945 and clinicaltrialsregister.eu Identifier:2007-002080-27), and participants provided writteninformed consent.The primary end point was duration of analgesic benefit,defined as an improvement of 5 points or more in the indexpain score (using the Sensory Component of the Short FormMcGill Pain Questionnaire), compared with the baseline scoreduring the 16 days of receiving a stable dosage of ketamine orplacebo. Patients in whom titration failed were considered tohave a duration of 0 days. Maintenance of analgesic benefit wasconsidered to have failed in patients whose opioid dosage in-creased during this time. Secondary end points included meanand worst pain; mood (Hospital Anxiety and Depression Score,a self-administered anxiety and depression screening tool foruse in nonpsychiatric patients. The tool has 14 items, whichfocus on the emotional and cognitive aspects of each aspect.Each item is scored from 0 to 3 for a combined maximum of21 for each aspect, with higher scores reflecting a higher symp-tom load); mean change in global distress in the last 24 hours(National Comprehensive Cancer Network Distress Thermom-eter, which uses a scale of 0 to 10, where 0 is no distress and10 is extreme distress); quality of life (EuroQoL Thermom-eter, a patient-rated assessment of present quality of life com-prising 5 questions, each assigned a value of 0 to 2 points, withhigher values representing better quality of life. The sum ofthese responses produces a score on a scale of 0 to 10, whichis then translated into a scale of 0 to 100); and serious ad-verse events (National Cancer Institute, Common Toxicity Cri-teria for Adverse Events version 3.0, which provides clini-cians with descriptive terminology for reporting adverseevents. Each adverse event is graded on a scale of 1 to 5, withhigher grades representing greater severity).An intention-to-treat approach was used, with a samplesize of 107 patients per arm providing 80% or greater powerto detect an improvement in the duration of analgesic ben-efit while receiving ketamine corresponding to a 20%increase in patients in whom analgesic benefit was main-tained at 16 days (maximum hazard ratio [HR], 0.58). Tocompare duration of analgesic benefit, we used Cox propor-tional hazards regression with a confirmatory log-rank test.Secondary end points were analyzed using parametric andnonparametric methods. Quality of life data were analyzedby calculating the mean of the area under the curve over thetime in the study after adjusting for the baseline value. All Pvalues are 2-tailed, and P < .05 was statistically significant.Statistical analyses were performed using SPSS version 22.0for Windows (IBM).Results | Two hundred fourteen patients (median [IQR] age, 58[51-66] years; 141 [65.8%] female) were randomized, with com-parable demographic features between arms (Figure). A vari-ety of cancer types were represented; however, in 160 pa-tients (74.7%) the cancer was in remission, and most of thesepatients had chronic, chemotherapy-induced, neuropathicpain. Two hundred nine patients (97.6%) were following treat-ment regimens for neuropathic pain. Data on duration of neu-ropathic pain were not collected. The median morphine-equivalent daily dose for both arms was 0 mg. There was nodifference in the duration of analgesic benefit between armsas assessed by the adjusted (minimization factors) Cox pro-portional hazards model (ketamine to placebo HR, 0.95 (95%CI, 0.70-1.29); P = .75), supported by the log-rank test (P = .69).The median duration of analgesic benefit was 0 days (95% CI,0-1 day) for ketamine and 0 days (95% CI, 0-4 days) for pla-cebo. To illustrate, 34 of 107 patients (31.8%) receiving ket-amine vs 39 of 107 (36.4%) receiving placebo maintained an-algesic benefit at day 4 of the stable dosage (95% CI forTable. Secondary Outcomes and AUC Analyses for Distress, Quality of Life, and MoodVariableKetamineHydrochloride PlaceboMedian Difference,Ketamine − Placebo (95% CI)aP ValueSecondaryOutcomesAUC AnalysesUnadjustedb AdjustedcSecondary OutcomesPatients with analgesic benefitat day 4, %34 (31.8) 39 (36.4) NA .47 NA NAPatients with an analgesic benefitat day 16, %24 (22.4) 27 (25.2) NA .63 NA NAAUC Analysesd,eNCCN Distress Thermometer −2.972 −3.053 0.081 (−0.500 to 0.833) NA .64 .92EuroQoL Thermometer −17.756 −20.279 2.523 (−5.667 to 9.250) NA .89 .92Hospital Anxietyand Depression ScoreAnxiety score −3.605 −3.625 0.020 (−1.417 to 1.250) NA .65 .92Depression score −3.481 −3.654 0.173 (−0.500 to 0.958) NA .66 .92Abbreviations: AUC, area under the curve; NA, not applicable; NCCN, NationalComprehensive Cancer Network.a Estimated using 100 000 bootstrap samples.b Determined using the Mann-Whitney test.c Adjusted for multiple testing (false-discovery rate method).d Missing data were imputed (last observation carried forward) for the AUCanalyses only.e Descriptions, scales, and possible range of scores for the NCCN DistressThermometer, EuroQoL Thermometer, and Hospital Anxiety and DepressionScore can be found in the Methods section of this research letter.LettersE2 JAMA Oncology Published online April 5, 2018 (Reprinted) jamaoncology.comDownloaded From:  by a University of Edinburgh Library User  on 04/12/2018difference, −17% to 8%). Corresponding figures at day 16 were24 of 107 patients (22.4%) receiving ketamine and 27of 107(25.2%) receiving placebo (95% CI for difference, −14% to 9%).There were no differences between arms among the second-ary outcomes (Table).There were 18 serious adverse events: 8 in patients receiv-ing ketamine and 10 in patients receiving placebo. Commonadverse events were cognitive disturbance, dizziness, fa-tigue, nausea, and somnolence.Discussion | This trial reports that ketamine was equivalent toplacebo for cancer-related neuropathic pain. Findings en-hance previous work4 by examining ketamine in cancer-related neuropathic pain. There may be subgroups of pa-tients for whom ketamine is helpful, such as those with centralsensitization. A limitation of the present study was that we didnot specifically select patients with clinical evidence of cen-tral sensitization, for whom it is reasonable to hypothesize amore specific analgesic target for ketamine. Future studies thatexamine ketamine in chronic neuropathic pain should focuson patients with central sensitization, which can be estab-lished by a bedside test. This approach would be congruent withpreclinical knowledge and would address an important re-maining unanswered question.5Marie T. Fallon, MDAndrew Wilcock, MDCaroline A. Kelly, MScJames Paul, BScLiz-Anne Lewsley, CCRJohn Norrie, MScBarry J. A. Laird, MDAuthor Affiliations: Edinburgh Cancer Research Centre (IGMM), University ofEdinburgh, Edinburgh, United Kingdom. (Fallon, Laird); Faculty of Medicine andHealth Sciences, University of Nottingham, Nottingham, United Kingdom(Wilcock); Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences,University of Glasgow, Glasgow, United Kingdom (Kelly, Paul, Lewsley); UsherInstitute, University of Edinburgh, Edinburgh, United Kingdom (Norrie).Accepted for Publication: January 11, 2018.Published Online: April 5, 2018. doi:10.1001/jamaoncol.2018.0131Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2018 Fallon MT et al. JAMA Oncology.Corresponding Author: Marie T. Fallon, MD, Institute of Genetics and MolecularMedicine, University of Edinburgh, Edinburgh EH4 2XR, UK(marie.fallon@ed.ac.uk).Author Contributions: Drs Fallon and Laird had full access to all the data in thestudy and take responsibility for the integrity of the data and the accuracy ofthe data analysis.Study concept and design: Fallon, Paul, Laird.Acquisition, analysis, or interpretation of data: All authors.Drafting of the manuscript: Fallon, Wilcock, Kelly, Paul, Lewsley, Laird.Critical revision of the manuscript for important intellectual content: Fallon,Wilcock, Kelly, Paul, Norrie, LairdStatistical analysis: Fallon, Wilcock, Kelly, Paul, Norrie, Laird.Obtained funding: Fallon, Paul, Lewsley, Laird.Administrative, technical, or material support: Fallon, Paul, Lewsley, Laird.Study supervision: Fallon, Paul.Conflict of Interest Disclosures: None reported.Funding/Support: This trial was funded by grant 07/031 from Cancer ResearchUK and grant A14197 from Marie Curie Cancer Care. The University of Glasgowand NHS Greater Glasgow and Clyde acted as cosponsors. The medicines usedin this trial (ketamine hydrochloride for the investigational medicinal product,and lactose [in powder form]) and placebo for the placebo were purchased andwere manufactured into a capsule formulation by the NHS Greater Glasgow andClyde Pharmacy Production Unit.Role of the Funder/Sponsor: The funders had no role beyond peer review forthe grants. Annual reports were submitted to the funders to enable continuedfunding. The funders had no role in the design and conduct of the study;collection, management, analysis, and interpretation of the data; preparation,review, or approval of the manuscript; and decision to submit the manuscriptfor publication.Additional Contributions: We wish to thank the Ketamine Pain Study Group:S. M. Fleetwood-Walker, PhD, University of Edinburgh, basic sciencetranslational research collaborator; Diann Taggart, BSc, University of Glasgow,trial coordinator; and Dorothy Boyle, BSc, University of Edinburgh; Anne Todd,BA NHS Greater Glasgow and Clyde; and Alison Clarke, RGN, University ofSheffield, research nurses. Anne Todd; Dorothy Boyle; Catherine Johnston,MSc, NHS Greater Glasgow and Clyde; Debra Gordon, BSc, University ofEdinburgh; Kim Sladdin, MA Hons, RGN, University of Edinburgh; Lisa Ferguson,RGN, Oxford University Hospitals NHS Foundation Trust; and CathannManderson, RGN, Nottingham University Hospitals NHS Trust, participated indata collection for this study. Miriam Johnson, MD, University of Hull; DenaCohen, PhD, University of Leeds; and Sara Booth, MD, University of Cambridge,served as the data monitoring committee; Anthony Byrne, MB ChB, Universityof Cardiff; Tom Haswell; John Wilson, MD, University of Edinburgh; Bee Wee,PhD, University of Oxford; and Gareth Griffiths, PhD, University ofSouthampton, served as the trial steering committee; and Lesley Colvin, PhD,University of Edinburgh; Michael Bennett, MD, University of Leeds; Kay Pollock,BSc, Pharmacy Production Unit, NHS Greater Glasgow and Clyde; CatherineUrch, PhD, Imperial College, London; John Welsh, MB ChB, St Margaret ofScotland Hospice/University of Glasgow; Alison Parr, MB ChB, St Catherine’sHospice, Preston; and Patrick Stone, MD, University of London, served asresearch collaborators. They were not compensated for their contributions. Wealso wish to thank our colleagues at the sites where the trial was conducted fortheir support, particularly the Cancer Research UK Clinical Trials Unit, Glasgow.Finally, this trial would not have been possible without the support of thepatients who participated.1. Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancerpain. Cochrane Database Syst Rev. 2012;11:CD003351.2. Hardy J, Quinn S, Fazekas B, et al. Randomized, double-blind,placebo-controlled study to assess the efficacy and toxicity of subcutaneousketamine in the management of cancer pain. J Clin Oncol. 2012;30(29):3611-3617.3. Piano V, Verhagen S, Schalkwijk A, et al. Diagnosing neuropathic pain inpatients with cancer: comparative analysis of recommendations in nationalguidelines from European countries. Pain Pract. 2013;13(6):433-439.4. Leppert W. Ketamine in the management of cancer pain. J Clin Oncol. 2013;31(10):1374.5. Sisignano M, Baron R, Scholich K, Geisslinger G. Mechanism-based treatmentfor chemotherapy-induced peripheral neuropathic pain. Nat Rev Neurol. 2014;10(12):694-707.Lettersjamaoncology.com (Reprinted) JAMA Oncology Published online April 5, 2018 E3Downloaded From:  by a University of Edinburgh Library User  on 04/12/2018

Marie T. Fallon

Andrew Wilcock

Caroline A. Kelly

James Paul

Liz-Anne Lewsley

John Norrie

Barry J. A. Laird

Crossref

JAMA Oncology

Oral Ketamine vs Placebo in Patients With Cancer-Related Neuropathic Pain

Nottingham eTheses

LettersRESEARCH LETTEROral Ketamine vs Placebo in PatientsWith Cancer-Related Neuropathic Pain:A Randomized Clinical TrialKetamine hydrochloride is used as an adjuvant treatmentfor cancer-related neuropathic pain, but evidence of itseffectiveness is limited.1 Findings of a large trial investigat-ing the use of ketamine for general cancer pain were nega-tive, but the populationstudied did not specificallyhave neuropathic pain.2 Arandomized trial of oral ketamine for cancer-related neuro-pathic pain has been called for,3 and the present trialaddresses that need.1Methods | A multicenter, double-blind randomized clinicaltrial of oral ketamine vs placebo was conducted in theUnited Kingdom cities of Edinburgh, Glasgow, Nottingham,and Lancashire in adults with cancer-related neuropathicpain, which was defined using set criteria (Leeds Assessmentof Neuropathic Symptoms and Signs). Patients had previ-ously been treated with adjuvant analgesics for neuropathicpain, which had been ineffective or suboptimal. Preexistinganalgesia was continued throughout the trial. Patients werecentrally randomized using minimization, then ketamine orplacebo was titrated across 2 weeks to an effective and toler-able dosage (Figure). The starting dosage was 40 mg/d, witha maximum dosage of 400 mg/d. Patients continued toreceive a stable dosage for 16 days. Patients who did notexperience an analgesic benefit were withdrawn from theFigure. CONSORT Study Flow Diagram513 Patients assessed for eligibility107 Randomized to receive ketamine hydrochloride 107 Randomized to receive placebo49 Entered pain-control maintenance phase 50 Entered pain-control maintenance phase24 Completed pain control maintenance phase with notreatment failure26 Completed pain control maintenance phase with notreatment failure296 Excluded115 Ineligible65 Investigator decision57 Declined to participate-other29 Too unwell21 Declined to participate-placebo9 Conflicting trial3 Did not participate beyond run-in phase2 Withdrew: achieved pain control during run-in1 Unable to comply57 Excluded for treatment failures duringtitration phase41 Investigator declared treatmentfailure16 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase0 >30% Increase in 24-h MEDD ofopioid24 Excluded for treatment failuresduring pain-control maintenance phase17 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase7 Investor declared treatment failure0 >30% Increase in 24-h MEDDof opioid58 Excluded for treatment failuresduring titration phase31 Investigator declared treatmentfailure26 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase1 >30% Increase in 24-h MEDD ofopioid25 Excluded for treatment failuresduring pain-control maintenance phase18 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase5 Investigator declared treatmentfailure2 >30% Increase in 24-h MEDDof opioid214 RandomizedAmong the 107 patients randomizedto ketamine, the median(interquartile range [IQR]) time spentin the titration phase for the 58patients who experienced treatmentfailure and were excluded was 14(14-14) days; range, 7 to 28 days. Ofthe 49 patients who entered thepain-control maintenance phase, themedian (IQR) time spent in thetitration phase was 14 (14-15) days;range, 8 to 21 days. Among the 107patients randomized to placebo, themedian (IQR) time spent in thetitration phase for the 57 patientswho experienced treatment failureand were excluded was 14 (12.5-14.0)days; range, 0 to 22 days. Of the 50patients who entered thepain-control maintenance phase, themedian (IQR) time spent in thetitration phase was 14 (14-15) days;range, 5 to 20 days. MEDD indicatesmorphine-equivalent daily dose.Supplemental contentjamaoncology.com (Reprinted) JAMA Oncology Published online April 5, 2018 E1Downloaded From:  by a University of Nottingham User  on 04/16/2018study. The study was approved by the West of Scotland Mul-ticentre Research Ethics Committee (the full trial protocol isavailable in the Supplement; isrctn.org Identifier:ISRCTN49116945 and clinicaltrialsregister.eu Identifier:2007-002080-27), and participants provided writteninformed consent.The primary end point was duration of analgesic benefit,defined as an improvement of 5 points or more in the indexpain score (using the Sensory Component of the Short FormMcGill Pain Questionnaire), compared with the baseline scoreduring the 16 days of receiving a stable dosage of ketamine orplacebo. Patients in whom titration failed were considered tohave a duration of 0 days. Maintenance of analgesic benefit wasconsidered to have failed in patients whose opioid dosage in-creased during this time. Secondary end points included meanand worst pain; mood (Hospital Anxiety and Depression Score,a self-administered anxiety and depression screening tool foruse in nonpsychiatric patients. The tool has 14 items, whichfocus on the emotional and cognitive aspects of each aspect.Each item is scored from 0 to 3 for a combined maximum of21 for each aspect, with higher scores reflecting a higher symp-tom load); mean change in global distress in the last 24 hours(National Comprehensive Cancer Network Distress Thermom-eter, which uses a scale of 0 to 10, where 0 is no distress and10 is extreme distress); quality of life (EuroQoL Thermom-eter, a patient-rated assessment of present quality of life com-prising 5 questions, each assigned a value of 0 to 2 points, withhigher values representing better quality of life. The sum ofthese responses produces a score on a scale of 0 to 10, whichis then translated into a scale of 0 to 100); and serious ad-verse events (National Cancer Institute, Common Toxicity Cri-teria for Adverse Events version 3.0, which provides clini-cians with descriptive terminology for reporting adverseevents. Each adverse event is graded on a scale of 1 to 5, withhigher grades representing greater severity).An intention-to-treat approach was used, with a samplesize of 107 patients per arm providing 80% or greater powerto detect an improvement in the duration of analgesic ben-efit while receiving ketamine corresponding to a 20%increase in patients in whom analgesic benefit was main-tained at 16 days (maximum hazard ratio [HR], 0.58). Tocompare duration of analgesic benefit, we used Cox propor-tional hazards regression with a confirmatory log-rank test.Secondary end points were analyzed using parametric andnonparametric methods. Quality of life data were analyzedby calculating the mean of the area under the curve over thetime in the study after adjusting for the baseline value. All Pvalues are 2-tailed, and P < .05 was statistically significant.Statistical analyses were performed using SPSS version 22.0for Windows (IBM).Results | Two hundred fourteen patients (median [IQR] age, 58[51-66] years; 141 [65.8%] female) were randomized, with com-parable demographic features between arms (Figure). A vari-ety of cancer types were represented; however, in 160 pa-tients (74.7%) the cancer was in remission, and most of thesepatients had chronic, chemotherapy-induced, neuropathicpain. Two hundred nine patients (97.6%) were following treat-ment regimens for neuropathic pain. Data on duration of neu-ropathic pain were not collected. The median morphine-equivalent daily dose for both arms was 0 mg. There was nodifference in the duration of analgesic benefit between armsas assessed by the adjusted (minimization factors) Cox pro-portional hazards model (ketamine to placebo HR, 0.95 (95%CI, 0.70-1.29); P = .75), supported by the log-rank test (P = .69).The median duration of analgesic benefit was 0 days (95% CI,0-1 day) for ketamine and 0 days (95% CI, 0-4 days) for pla-cebo. To illustrate, 34 of 107 patients (31.8%) receiving ket-amine vs 39 of 107 (36.4%) receiving placebo maintained an-algesic benefit at day 4 of the stable dosage (95% CI forTable. Secondary Outcomes and AUC Analyses for Distress, Quality of Life, and MoodVariableKetamineHydrochloride PlaceboMedian Difference,Ketamine − Placebo (95% CI)aP ValueSecondaryOutcomesAUC AnalysesUnadjustedb AdjustedcSecondary OutcomesPatients with analgesic benefitat day 4, %34 (31.8) 39 (36.4) NA .47 NA NAPatients with an analgesic benefitat day 16, %24 (22.4) 27 (25.2) NA .63 NA NAAUC Analysesd,eNCCN Distress Thermometer −2.972 −3.053 0.081 (−0.500 to 0.833) NA .64 .92EuroQoL Thermometer −17.756 −20.279 2.523 (−5.667 to 9.250) NA .89 .92Hospital Anxietyand Depression ScoreAnxiety score −3.605 −3.625 0.020 (−1.417 to 1.250) NA .65 .92Depression score −3.481 −3.654 0.173 (−0.500 to 0.958) NA .66 .92Abbreviations: AUC, area under the curve; NA, not applicable; NCCN, NationalComprehensive Cancer Network.a Estimated using 100 000 bootstrap samples.b Determined using the Mann-Whitney test.c Adjusted for multiple testing (false-discovery rate method).d Missing data were imputed (last observation carried forward) for the AUCanalyses only.e Descriptions, scales, and possible range of scores for the NCCN DistressThermometer, EuroQoL Thermometer, and Hospital Anxiety and DepressionScore can be found in the Methods section of this research letter.LettersE2 JAMA Oncology Published online April 5, 2018 (Reprinted) jamaoncology.comDownloaded From:  by a University of Nottingham User  on 04/16/2018difference, −17% to 8%). Corresponding figures at day 16 were24 of 107 patients (22.4%) receiving ketamine and 27of 107(25.2%) receiving placebo (95% CI for difference, −14% to 9%).There were no differences between arms among the second-ary outcomes (Table).There were 18 serious adverse events: 8 in patients receiv-ing ketamine and 10 in patients receiving placebo. Commonadverse events were cognitive disturbance, dizziness, fa-tigue, nausea, and somnolence.Discussion | This trial reports that ketamine was equivalent toplacebo for cancer-related neuropathic pain. Findings en-hance previous work4 by examining ketamine in cancer-related neuropathic pain. There may be subgroups of pa-tients for whom ketamine is helpful, such as those with centralsensitization. A limitation of the present study was that we didnot specifically select patients with clinical evidence of cen-tral sensitization, for whom it is reasonable to hypothesize amore specific analgesic target for ketamine. Future studies thatexamine ketamine in chronic neuropathic pain should focuson patients with central sensitization, which can be estab-lished by a bedside test. This approach would be congruent withpreclinical knowledge and would address an important re-maining unanswered question.5Marie T. Fallon, MDAndrew Wilcock, MDCaroline A. Kelly, MScJames Paul, BScLiz-Anne Lewsley, CCRJohn Norrie, MScBarry J. A. Laird, MDAuthor Affiliations: Edinburgh Cancer Research Centre (IGMM), University ofEdinburgh, Edinburgh, United Kingdom. (Fallon, Laird); Faculty of Medicine andHealth Sciences, University of Nottingham, Nottingham, United Kingdom(Wilcock); Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences,University of Glasgow, Glasgow, United Kingdom (Kelly, Paul, Lewsley); UsherInstitute, University of Edinburgh, Edinburgh, United Kingdom (Norrie).Accepted for Publication: January 11, 2018.Published Online: April 5, 2018. doi:10.1001/jamaoncol.2018.0131Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2018 Fallon MT et al. JAMA Oncology.Corresponding Author: Marie T. Fallon, MD, Institute of Genetics and MolecularMedicine, University of Edinburgh, Edinburgh EH4 2XR, UK(marie.fallon@ed.ac.uk).Author Contributions: Drs Fallon and Laird had full access to all the data in thestudy and take responsibility for the integrity of the data and the accuracy ofthe data analysis.Study concept and design: Fallon, Paul, Laird.Acquisition, analysis, or interpretation of data: All authors.Drafting of the manuscript: Fallon, Wilcock, Kelly, Paul, Lewsley, Laird.Critical revision of the manuscript for important intellectual content: Fallon,Wilcock, Kelly, Paul, Norrie, LairdStatistical analysis: Fallon, Wilcock, Kelly, Paul, Norrie, Laird.Obtained funding: Fallon, Paul, Lewsley, Laird.Administrative, technical, or material support: Fallon, Paul, Lewsley, Laird.Study supervision: Fallon, Paul.Conflict of Interest Disclosures: None reported.Funding/Support: This trial was funded by grant 07/031 from Cancer ResearchUK and grant A14197 from Marie Curie Cancer Care. The University of Glasgowand NHS Greater Glasgow and Clyde acted as cosponsors. The medicines usedin this trial (ketamine hydrochloride for the investigational medicinal product,and lactose [in powder form]) and placebo for the placebo were purchased andwere manufactured into a capsule formulation by the NHS Greater Glasgow andClyde Pharmacy Production Unit.Role of the Funder/Sponsor: The funders had no role beyond peer review forthe grants. Annual reports were submitted to the funders to enable continuedfunding. The funders had no role in the design and conduct of the study;collection, management, analysis, and interpretation of the data; preparation,review, or approval of the manuscript; and decision to submit the manuscriptfor publication.Additional Contributions: We wish to thank the Ketamine Pain Study Group:S. M. Fleetwood-Walker, PhD, University of Edinburgh, basic sciencetranslational research collaborator; Diann Taggart, BSc, University of Glasgow,trial coordinator; and Dorothy Boyle, BSc, University of Edinburgh; Anne Todd,BA NHS Greater Glasgow and Clyde; and Alison Clarke, RGN, University ofSheffield, research nurses. Anne Todd; Dorothy Boyle; Catherine Johnston,MSc, NHS Greater Glasgow and Clyde; Debra Gordon, BSc, University ofEdinburgh; Kim Sladdin, MA Hons, RGN, University of Edinburgh; Lisa Ferguson,RGN, Oxford University Hospitals NHS Foundation Trust; and CathannManderson, RGN, Nottingham University Hospitals NHS Trust, participated indata collection for this study. Miriam Johnson, MD, University of Hull; DenaCohen, PhD, University of Leeds; and Sara Booth, MD, University of Cambridge,served as the data monitoring committee; Anthony Byrne, MB ChB, Universityof Cardiff; Tom Haswell; John Wilson, MD, University of Edinburgh; Bee Wee,PhD, University of Oxford; and Gareth Griffiths, PhD, University ofSouthampton, served as the trial steering committee; and Lesley Colvin, PhD,University of Edinburgh; Michael Bennett, MD, University of Leeds; Kay Pollock,BSc, Pharmacy Production Unit, NHS Greater Glasgow and Clyde; CatherineUrch, PhD, Imperial College, London; John Welsh, MB ChB, St Margaret ofScotland Hospice/University of Glasgow; Alison Parr, MB ChB, St Catherine’sHospice, Preston; and Patrick Stone, MD, University of London, served asresearch collaborators. They were not compensated for their contributions. Wealso wish to thank our colleagues at the sites where the trial was conducted fortheir support, particularly the Cancer Research UK Clinical Trials Unit, Glasgow.Finally, this trial would not have been possible without the support of thepatients who participated.1. Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancerpain. Cochrane Database Syst Rev. 2012;11:CD003351.2. Hardy J, Quinn S, Fazekas B, et al. Randomized, double-blind,placebo-controlled study to assess the efficacy and toxicity of subcutaneousketamine in the management of cancer pain. J Clin Oncol. 2012;30(29):3611-3617.3. Piano V, Verhagen S, Schalkwijk A, et al. Diagnosing neuropathic pain inpatients with cancer: comparative analysis of recommendations in nationalguidelines from European countries. Pain Pract. 2013;13(6):433-439.4. Leppert W. Ketamine in the management of cancer pain. J Clin Oncol. 2013;31(10):1374.5. Sisignano M, Baron R, Scholich K, Geisslinger G. Mechanism-based treatmentfor chemotherapy-induced peripheral neuropathic pain. Nat Rev Neurol. 2014;10(12):694-707.Lettersjamaoncology.com (Reprinted) JAMA Oncology Published online April 5, 2018 E3Downloaded From:  by a University of Nottingham User  on 04/16/2018

Repository@Nottingham

LettersRESEARCH LETTEROral Ketamine vs Placebo in PatientsWith Cancer-RelatedNeuropathic Pain:A Randomized Clinical TrialKetamine hydrochloride is used as an adjuvant treatmentfor cancer-related neuropathic pain, but evidence of itseffectiveness is limited.1 Findings of a large trial investigat-ing the use of ketamine for general cancer pain were nega-tive, but the populationstudied did not specificallyhave neuropathic pain.2 Arandomized trial of oral ketamine for cancer-related neuro-pathic pain has been called for,3 and the present trialaddresses that need.1Methods | A multicenter, double-blind randomized clinicaltrial of oral ketamine vs placebo was conducted in theUnited Kingdom cities of Edinburgh, Glasgow, Nottingham,and Lancashire in adults with cancer-related neuropathicpain, which was defined using set criteria (Leeds Assessmentof Neuropathic Symptoms and Signs). Patients had previ-ously been treated with adjuvant analgesics for neuropathicpain, which had been ineffective or suboptimal. Preexistinganalgesia was continued throughout the trial. Patients werecentrally randomized using minimization, then ketamine orplacebo was titrated across 2 weeks to an effective and toler-able dosage (Figure). The starting dosage was 40 mg/d, witha maximum dosage of 400 mg/d. Patients continued toreceive a stable dosage for 16 days. Patients who did notexperience an analgesic benefit were withdrawn from theFigure. CONSORT Study FlowDiagram513 Patients assessed for eligibility107 Randomized to receive ketamine hydrochloride 107 Randomized to receive placebo49 Entered pain-control maintenance phase 50 Entered pain-control maintenance phase24 Completed pain control maintenance phase with notreatment failure26 Completed pain control maintenance phase with notreatment failure296 Excluded115 Ineligible65 Investigator decision57 Declined to participate-other29 Too unwell21 Declined to participate-placebo9 Conflicting trial3 Did not participate beyond run-in phase2 Withdrew: achieved pain control during run-in1 Unable to comply57 Excluded for treatment failures duringtitration phase41 Investigator declared treatmentfailure16 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase0 >30% Increase in 24-h MEDD ofopioid24 Excluded for treatment failuresduring pain-control maintenance phase17 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase7 Investor declared treatment failure0 >30% Increase in 24-h MEDDof opioid58 Excluded for treatment failuresduring titration phase31 Investigator declared treatmentfailure26 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase1 >30% Increase in 24-h MEDD ofopioid25 Excluded for treatment failuresduring pain-control maintenance phase18 Failure to achieve ≥5-pointimprovement in index pain by endof titration phase5 Investigator declared treatmentfailure2 >30% Increase in 24-h MEDDof opioid214 RandomizedAmong the 107 patients randomizedto ketamine, themedian(interquartile range [IQR]) time spentin the titration phase for the 58patients who experienced treatmentfailure and were excluded was 14(14-14) days; range, 7 to 28 days. Ofthe 49 patients who entered thepain-control maintenance phase, themedian (IQR) time spent in thetitration phase was 14 (14-15) days;range, 8 to 21 days. Among the 107patients randomized to placebo, themedian (IQR) time spent in thetitration phase for the 57 patientswho experienced treatment failureand were excluded was 14 (12.5-14.0)days; range, 0 to 22 days. Of the 50patients who entered thepain-control maintenance phase, themedian (IQR) time spent in thetitration phase was 14 (14-15) days;range, 5 to 20 days. MEDD indicatesmorphine-equivalent daily dose.Supplemental contentjamaoncology.com (Reprinted) JAMAOncology Published online April 5, 2018 E1Downloaded From:  by a University of Nottingham User  on 04/16/2018study. The study was approved by the West of Scotland Mul-ticentre Research Ethics Committee (the full trial protocol isavailable in the Supplement; isrctn.org Identifier:ISRCTN49116945 and clinicaltrialsregister.eu Identifier:2007-002080-27), and participants provided writteninformed consent.The primary end point was duration of analgesic benefit,defined as an improvement of 5 points or more in the indexpain score (using the Sensory Component of the Short FormMcGill PainQuestionnaire), comparedwith thebaseline scoreduring the 16 days of receiving a stable dosage of ketamine orplacebo. Patients inwhom titration failedwere considered tohaveadurationof0days.Maintenanceofanalgesicbenefitwasconsidered to have failed in patients whose opioid dosage in-creasedduring this time. Secondaryendpoints includedmeanandworstpain;mood (HospitalAnxietyandDepressionScore,a self-administered anxiety anddepression screening tool foruse in nonpsychiatric patients. The tool has 14 items, whichfocus on the emotional and cognitive aspects of each aspect.Each item is scored from 0 to 3 for a combined maximum of21 for eachaspect,withhigher scores reflectingahigher symp-tom load); mean change in global distress in the last 24 hours(NationalComprehensiveCancerNetworkDistressThermom-eter, which uses a scale of 0 to 10, where 0 is no distress and10 is extreme distress); quality of life (EuroQoL Thermom-eter, a patient-rated assessment of present quality of life com-prising5questions, eachassignedavalueof0 to2points,withhigher values representing better quality of life. The sum ofthese responses produces a score on a scale of 0 to 10, whichis then translated into a scale of 0 to 100); and serious ad-verse events (NationalCancer Institute, CommonToxicityCri-teria for Adverse Events version 3.0, which provides clini-cians with descriptive terminology for reporting adverseevents. Each adverse event is graded on a scale of 1 to 5, withhigher grades representing greater severity).An intention-to-treat approach was used, with a samplesize of 107 patients per arm providing 80% or greater powerto detect an improvement in the duration of analgesic ben-efit while receiving ketamine corresponding to a 20%increase in patients in whom analgesic benefit was main-tained at 16 days (maximum hazard ratio [HR], 0.58). Tocompare duration of analgesic benefit, we used Cox propor-tional hazards regression with a confirmatory log-rank test.Secondary end points were analyzed using parametric andnonparametric methods. Quality of life data were analyzedby calculating the mean of the area under the curve over thetime in the study after adjusting for the baseline value. All Pvalues are 2-tailed, and P < .05 was statistically significant.Statistical analyses were performed using SPSS version 22.0for Windows (IBM).Results |Twohundred fourteenpatients (median [IQR] age, 58[51-66]years; 141 [65.8%] female)were randomized,withcom-parable demographic features between arms (Figure). A vari-ety of cancer types were represented; however, in 160 pa-tients (74.7%) the cancer was in remission, andmost of thesepatients had chronic, chemotherapy-induced, neuropathicpain.Twohundredninepatients (97.6%)were following treat-ment regimens for neuropathic pain.Data ondurationof neu-ropathic pain were not collected. The median morphine-equivalent daily dose for both arms was 0 mg. There was nodifference in the duration of analgesic benefit between armsas assessed by the adjusted (minimization factors) Cox pro-portional hazardsmodel (ketamine to placebo HR, 0.95 (95%CI,0.70-1.29);P = .75), supportedby the log-rank test (P = .69).Themedian duration of analgesic benefit was 0 days (95%CI,0-1 day) for ketamine and 0 days (95% CI, 0-4 days) for pla-cebo. To illustrate, 34 of 107 patients (31.8%) receiving ket-amine vs 39 of 107 (36.4%) receiving placebo maintained an-algesic benefit at day 4 of the stable dosage (95% CI forTable. Secondary Outcomes and AUCAnalyses for Distress, Quality of Life, andMoodVariableKetamineHydrochloride PlaceboMedian Difference,Ketamine − Placebo (95% CI)aP ValueSecondaryOutcomesAUC AnalysesUnadjustedb AdjustedcSecondary OutcomesPatients with analgesic benefitat day 4, %34 (31.8) 39 (36.4) NA .47 NA NAPatients with an analgesic benefitat day 16, %24 (22.4) 27 (25.2) NA .63 NA NAAUC Analysesd,eNCCN Distress Thermometer −2.972 −3.053 0.081 (−0.500 to 0.833) NA .64 .92EuroQoL Thermometer −17.756 −20.279 2.523 (−5.667 to 9.250) NA .89 .92Hospital Anxietyand Depression ScoreAnxiety score −3.605 −3.625 0.020 (−1.417 to 1.250) NA .65 .92Depression score −3.481 −3.654 0.173 (−0.500 to 0.958) NA .66 .92Abbreviations: AUC, area under the curve; NA, not applicable; NCCN, NationalComprehensive Cancer Network.a Estimated using 100000 bootstrap samples.bDetermined using theMann-Whitney test.c Adjusted for multiple testing (false-discovery rate method).dMissing data were imputed (last observation carried forward) for the AUCanalyses only.e Descriptions, scales, and possible range of scores for the NCCN DistressThermometer, EuroQoL Thermometer, and Hospital Anxiety and DepressionScore can be found in theMethods section of this research letter.LettersE2 JAMAOncology Published online April 5, 2018 (Reprinted) jamaoncology.comDownloaded From:  by a University of Nottingham User  on 04/16/2018difference, −17% to8%). Corresponding figures at day 16were24 of 107 patients (22.4%) receiving ketamine and 27of 107(25.2%) receivingplacebo (95%CI fordifference, −14%to9%).There were no differences between arms among the second-ary outcomes (Table).Therewere 18 serious adverse events: 8 inpatients receiv-ing ketamine and 10 in patients receiving placebo. Commonadverse events were cognitive disturbance, dizziness, fa-tigue, nausea, and somnolence.Discussion | This trial reports that ketamine was equivalent toplacebo for cancer-related neuropathic pain. Findings en-hance previous work4 by examining ketamine in cancer-related neuropathic pain. There may be subgroups of pa-tients forwhomketamine ishelpful, suchas thosewith centralsensitization.A limitationof thepresent studywas thatwedidnot specifically select patients with clinical evidence of cen-tral sensitization, for whom it is reasonable to hypothesize amorespecific analgesic target forketamine.Future studies thatexamine ketamine in chronic neuropathic pain should focuson patients with central sensitization, which can be estab-lishedbyabedsidetest.Thisapproachwouldbecongruentwithpreclinical knowledge and would address an important re-maining unanswered question.5Marie T. Fallon, MDAndrewWilcock, MDCaroline A. Kelly, MScJames Paul, BScLiz-Anne Lewsley, CCRJohn Norrie, MScBarry J. A. Laird, MDAuthor Affiliations: Edinburgh Cancer Research Centre (IGMM), University ofEdinburgh, Edinburgh, United Kingdom. (Fallon, Laird); Faculty of Medicine andHealth Sciences, University of Nottingham, Nottingham, United Kingdom(Wilcock); Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences,University of Glasgow, Glasgow, United Kingdom (Kelly, Paul, Lewsley); UsherInstitute, University of Edinburgh, Edinburgh, United Kingdom (Norrie).Accepted for Publication: January 11, 2018.Published Online: April 5, 2018. doi:10.1001/jamaoncol.2018.0131OpenAccess: This is an open access article distributed under the terms of the CC-BY License. © 2018 Fallon MT et al. JAMA Oncology.Corresponding Author:Marie T. Fallon, MD, Institute of Genetics andMolecularMedicine, University of Edinburgh, Edinburgh EH4 2XR, UK(marie.fallon@ed.ac.uk).Author Contributions:Drs Fallon and Laird had full access to all the data in thestudy and take responsibility for the integrity of the data and the accuracy ofthe data analysis.Study concept and design: Fallon, Paul, Laird.Acquisition, analysis, or interpretation of data: All authors.Drafting of the manuscript: Fallon, Wilcock, Kelly, Paul, Lewsley, Laird.Critical revision of the manuscript for important intellectual content: Fallon,Wilcock, Kelly, Paul, Norrie, LairdStatistical analysis: Fallon, Wilcock, Kelly, Paul, Norrie, Laird.Obtained funding: Fallon, Paul, Lewsley, Laird.Administrative, technical, or material support: Fallon, Paul, Lewsley, Laird.Study supervision: Fallon, Paul.Conflict of Interest Disclosures:None reported.Funding/Support: This trial was funded by grant 07/031 from Cancer ResearchUK and grant A14197 fromMarie Curie Cancer Care. The University of Glasgowand NHS Greater Glasgow and Clyde acted as cosponsors. Themedicines usedin this trial (ketamine hydrochloride for the investigational medicinal product,and lactose [in powder form]) and placebo for the placebo were purchased andweremanufactured into a capsule formulation by the NHS Greater Glasgow andClyde Pharmacy Production Unit.Role of the Funder/Sponsor: The funders had no role beyond peer review forthe grants. Annual reports were submitted to the funders to enable continuedfunding. The funders had no role in the design and conduct of the study;collection, management, analysis, and interpretation of the data; preparation,review, or approval of themanuscript; and decision to submit themanuscriptfor publication.Additional Contributions:Wewish to thank the Ketamine Pain Study Group:S. M. Fleetwood-Walker, PhD, University of Edinburgh, basic sciencetranslational research collaborator; Diann Taggart, BSc, University of Glasgow,trial coordinator; and Dorothy Boyle, BSc, University of Edinburgh; Anne Todd,BA NHS Greater Glasgow and Clyde; and Alison Clarke, RGN, University ofSheffield, research nurses. Anne Todd; Dorothy Boyle; Catherine Johnston,MSc, NHS Greater Glasgow and Clyde; Debra Gordon, BSc, University ofEdinburgh; Kim Sladdin, MA Hons, RGN, University of Edinburgh; Lisa Ferguson,RGN, Oxford University Hospitals NHS Foundation Trust; and CathannManderson, RGN, NottinghamUniversity Hospitals NHS Trust, participated indata collection for this study. Miriam Johnson, MD, University of Hull; DenaCohen, PhD, University of Leeds; and Sara Booth, MD, University of Cambridge,served as the data monitoring committee; Anthony Byrne, MB ChB, Universityof Cardiff; TomHaswell; JohnWilson, MD, University of Edinburgh; BeeWee,PhD, University of Oxford; and Gareth Griffiths, PhD, University ofSouthampton, served as the trial steering committee; and Lesley Colvin, PhD,University of Edinburgh; Michael Bennett, MD, University of Leeds; Kay Pollock,BSc, Pharmacy Production Unit, NHS Greater Glasgow and Clyde; CatherineUrch, PhD, Imperial College, London; JohnWelsh, MB ChB, St Margaret ofScotland Hospice/University of Glasgow; Alison Parr, MB ChB, St Catherine’sHospice, Preston; and Patrick Stone, MD, University of London, served asresearch collaborators. They were not compensated for their contributions. Wealso wish to thank our colleagues at the sites where the trial was conducted fortheir support, particularly the Cancer Research UK Clinical Trials Unit, Glasgow.Finally, this trial would not have been possible without the support of thepatients who participated.1. Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancerpain. Cochrane Database Syst Rev. 2012;11:CD003351.2. Hardy J, Quinn S, Fazekas B, et al. Randomized, double-blind,placebo-controlled study to assess the efficacy and toxicity of subcutaneousketamine in themanagement of cancer pain. J Clin Oncol. 2012;30(29):3611-3617.3. Piano V, Verhagen S, Schalkwijk A, et al. Diagnosing neuropathic pain inpatients with cancer: comparative analysis of recommendations in nationalguidelines from European countries. Pain Pract. 2013;13(6):433-439.4. Leppert W. Ketamine in themanagement of cancer pain. J Clin Oncol. 2013;31(10):1374.5. SisignanoM, Baron R, Scholich K, Geisslinger G. Mechanism-based treatmentfor chemotherapy-induced peripheral neuropathic pain.Nat Rev Neurol. 2014;10(12):694-707.Lettersjamaoncology.com (Reprinted) JAMAOncology Published online April 5, 2018 E3Downloaded From:  by a University of Nottingham User  on 04/16/2018

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Oral ketamine vs placebo in patients with cancer-related neuropathic pain

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