Recent Trends in Opioid Prescription in Cancer Patients in Korea

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INTRODUCTION

Painisdefinedasanunpleasantsensoryandemotionalexperience associatedwithactualorpotentialtissuedamageordescribedintermsof suchdamage^.¹⁾Itiscommonlyexperiencedbypatientswithcancer^, whichhasnegativeimpactontheirqualityoflife.²⁾Theprevalenceof pain amongpatientswith cancer rangesfrom20^%to 50^%,³⁾and approximately80^%ofpatientswithadvancedcancerexperiencemoderate toseverecancerpain^.⁴⁾InKorea^,morethan50^%to60^%ofpatients

withcancersufferfromundertreatedcancerpain^.⁵⁾Accordingtothe WorldHealth Organization⁽WHO^)’sthree-stepanalgesicladderfor cancerpainrelief^,opioidsplayanimportantrolein treatingcancer pain^.⁶⁾Recently^,thesepainmanagementguidelineshavebeenrevisedto allowforthemoreliberalprescriptionofopioidsatallstagesofpain^.^7,8)

Theuseofopioidsisknowntobeanimportantindicatorofnational progressinrelievingcancerpain^.^9,10)Sincethe1990s^,theconsumptionof opioidstotreatnon-cancerchronicpainandcancerpainhasincreased^,¹¹⁾ resultinginaparallelincreaseinsafetyconcerns^,suchasopioid-related

Received August 18, 2020 Revised November 13, 2020 Accepted March 23, 2021

Corresponding author Hee-Taik Kang Tel: +82-43-269-6301, Fax: +82-43-269-6675 E-mail: [email protected]

ORCID: https://orcid.org/0000-0001-8048-6247

This is an open-access article distributed under the terms of the Creative Commons At- tribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Original Article

https://doi.org/10.21215/kjfp.2021.11.2.142 eISSN 2233-9116

Korean J Fam Pract. 2021;11(2):142-146

Korean Journal of Family Practice

KJFP

한국의 암환자에서의 마약성 진통제 최신 처방 경향 분석

윤지현¹, 김형섭², 이재우¹, 김정연², 강희택^1,3,*

1충북대학교병원 가정의학과, ²충북대학교 정보통계학과, ³충북대학교 의과대학 가정의학교실

Recent Trends in Opioid Prescription in Cancer Patients in Korea

Jihyun Yoon¹, Hyeong-Seop Kim², Jae-Woo Lee¹, Joungyoun Kim², Hee-Taik Kang^1,3,*

1Department of Family Medicine, Chungbuk National University Hospital; ²Department of Information & Statistics, Chungbuk National University;

3Department of Family Medicine, Chungbuk National University College of Medicine, Cheongju, Korea

Background: This study aimed to estimate the trends in opioid prescriptions for pain control in patients with and without cancer between 2002 and 2015.

Methods: This retrospective study was based on data from the 2002 and 2015 Korean National Health Insurance Service-National Health Screening Cohort Study. Prescriptions of commonly used opioids, including morphine, oxycodone, fentanyl, and hydromorphone, were included in this study.

A joinpoint regression analysis was adopted to analyze significant changes in the trends of annual opioid prescriptions, specifically considering the annual percentage change (APC) and average APC (AAPC).

Results: The proportion of cancer patients to the total number of opioid prescriptions increased significantly, from 0.18/10,000 registrants in 2002 to 62.27/10,000 registrants, increasing with an AAPC of 62.3% (95% confidence interval [CI], 44.7–82.1, P<0.05) during this study. The annual prescription rate also increased by 49.9% (95% CI, 22.6–83.2, P<0.05) in the non-cancer groups over the study period. In particular, there was a dramatic increase in prescriptions from 2006 to 2009, with an APC of 230.2% (95% CI, 27.0–758.6; P<0.05).

Conclusion: Opioid prescriptions substantially increased, regardless of the cancer diagnosis, over the study period. This may imply that awareness of active pain control has improved in Korea.

Keywords: Analgesics, opioid; Epidemiology; Pain; Neoplasms

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disordersandmortalities^.¹²⁾Althoughtheconsumptionofopioidshas increasedglobally^,theaveragerateofconsumptioninKoreawaslower thanthatofotherdevelopedcountries^.^13,14)Somereasonsforinadequate painmanagementincludeineffective assessmentofpain^,opioidaccess andregulations, andthesocialandmoralenvironmentassociatedwith usingopioids.⁵⁾Thus, itisnecessarytouseopioidssafelyandproperlyto avoid0pain^.

Therefore^,thisstudyaimedtoprovideanupdateonthetrendsofthe mostcommonlyprescribedstrongopioidsinKoreafrom2002to2015 usingdatafromtheKoreanNationalHealthInsuranceService⁽NHIS⁾- NationalHealthScreeningCohort⁽NHIS-HEALS^),stratifiedbycancer andnon-cancergroups.

METHODS

1. Study population and total prescription

Dataonopioidconsumptionfrom2002to2015wereextractedfrom the NHIS-HEALScohort. Thedatacomprised514,866individuals, takenasarandomsamplefrom5.15millionhealthinsuranceholdersat theendofDecember2002^.Allstudyparticipantsunderwentatleastone healthscreeningbetweenJanuary2002andDecember2003^.Theclaims data includethepatients^’medicalhistoryrecords^,suchasdiagnosis codes^,prescriptiondetails^,andhealthscreeningresultsfromJanuary 2002toDecember2015^.Inaddition^,thedataincludedsociodemographic information, suchasage, sex, death, pastmedicalhistory (malignant neoplasm, hypertension, anddiabetes), health behaviors (physical activity^,cigarettesmoking^,andalcoholintake^),householdincomelevel^, andhealthcareunitinformationthatthesubjectsvisited^.Becausethis cohortwasaclosedsystemandnonewindividualswereregisteredafter theinitialregistration^,thenumberofregistrantsdecreasedeachyeardue todeathorcensoring^.

Thisstudywas approved by theInstitutional Review Boardof Chungbuk NationalUniversityHospital⁽CBNUH-2019-12-034⁾and followedtheguidelinesoftheDeclarationofHelsinki⁽1975^).TheEthics CommitteeofNHISwaivedtheneedforinformedconsentbecausethe datafromtheNHIS-HEALSwereanonymizedatallstages^,including during datacleaningand statisticalanalysis^.Allexperiments were conductedinaccordancewiththerelevantguidelinesandregulations.

2. Definition and variables

Fourcommonlyprescribedopioidswerechosenforanalysis^,namely morphine^,oxycodone^,fentanyl^,andhydromorphone^.Weexaminedthe numberofopioidprescriptionsper10^,000registrantsamongpatients withand withoutcancer, whichwerecalculatedannually. Dataare presentedasthenumberper10,000registrants, includingindividuals receivingmorethanoneopioidprescriptioninagivenyear^.Tocompare thetrendsofopioidprescriptionsinpatientsaccordingtothepresenceof cancerdiagnosis^,individualsweredividedintocancerandnon-cancer groups^,basedon themain sickcodeof thetenth edition of the InternationalClassificationofDisease⁽C00–C97^).Thedefinitionofthe cancergroupincludedpatientswhosemaindiagnosiscodewascancerat leastonceduringthestudyperiod^.

3. Statistical analysis

ThestatisticalpackageSASenterpriseguideversion7^.1⁽SASInc^., Cary^,NC^,USA⁾andRstudioversion3^.3^.3⁽RFoundationforStatistical Computing, Vienna, Austria) wereusedtoperformtheanalysesinthis study. Totestwhethertherewasachangein opioidprescriptions, a simplelinearregressionwasfittedafterthelogarithmictransformation^, consideringthenon-zeroslopesoftheyears^.Furthermore^,ajoinpoint regressionanalysis⁽version4^.7^.0^.0^;NationalCancerInstitute^,Bethesda^, MD^,USA⁾wasperformedtodetectanysignificanttrendchanges^.¹⁵⁾The overalltrendfrom2002to2015wascalculatedastheaverageannual percentagechange (AAPC). Whenthetrendchangedsignificantly, the trendsofshortertimesegmentswerecalculatedastheannualpercentage change⁽APC^).APC and AAPCaremarkedwith 95^%confidence intervals⁽CIs^).AllP-valuesweretwo-sided^,andstatisticalsignificance wassetatP<0^.05^.Alltheresultswerecalculatedasweightper10^,000 registrants^,consideringthenumberofregistrantseach year^.Allzero valueswerereplacedwith0^.00001toensureanaccuratecalculation^. RESULTS

Table1presentsthebaselinecharacteristicsofthestudypopulation^. Between2002and2015^,there were18^,150prescriptionsofthefour aforementionedopioidtypes^.Duringthestudyperiod^,thenumberof newlyprescribedopioidsincreasedfrom5to990 (β coefficient=1.514, P fortrend<0.001).

Theannualopioidprescriptionsper10^,000registrants^,dependingon

Original Article

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whethertheyhadacancerdiagnosis^,areshowninSupplement1^.Inthe cancergroup^,opioidprescriptionsincreasedfrom0^.18in2002to62^.27 in2015 (β coefficient=1^.623^,Pfortrend<0^.001^).Ontheotherhand^,in thenon-cancergroup^,theseincreasedfrom0^.25in2002to45^.30in 2015 (β coefficient=1.648, Pfortrend<0.001).

Table2showsthetrendsintherateofannualopioidprescriptionsper 10^,000registrantsusingjoinpointregressionanalysis^.Theproportionof thecancergrouptothetotalnumberofopioidprescriptionsincreased significantly^,withanAAPCof62^.3^{% (}95^%CI^,44^.7–82^.1^;P<0^.05^).The rateofannual opioidprescriptionsalsoincreasedby49^.9^{% (}95^%CI^, 22^.6–83^.2^;P<0^.05⁾inthenon-cancergroupbetween2002and2015^.In particular, therewasadramaticincreaseintheprescriptionsfrom2006 to 2009^,with anAPCof 230^.2^{% (}95^%CI^,27^.0–758^.6^;P<0^.05^).

Additionally^,wefoundthatthenumberofeachopioidprescriptionper 10^,000registrantsincreasedover14yearsbetween2002and2015^.Ofthe four typesofopioids^,oxycodone wasthemostprescribedin2015^, followed byfentanyl^,hydromorphone^,andmorphine^.The greatest increasesinthenumbersofprescriptionswereseeninfentanyl (0.18to 11.62) andoxycodone (0.34to5.83) between2007and2009, respectively. In2010^,thenumberofprescriptionsofoxycodonesurpassedthat of fentanyl⁽11^.00vs10^.44per10^,000registrants^,respectively^).Thenumber of hydromorphone prescriptions hassteadily increasedsince its introductioninKoreain2006^,surpassingthatofmorphinein2009⁽data notshown^).

DISCUSSION

Inthisstudy^,weobservedthattheproportionofpatientswithcancer whowereprescribedopioidsincreasedinKorea^.Furthermore^,therewas anincreaseinthenumberofprescriptionsregardlessofthepresenceof cancerdiagnosis^,implyingashifttomoreaggressive paincontrolin recentyears.

Basedonourfindings^,theremightbesomepossiblefactorsrelatedto the increasingnumberof opioidprescriptionsinKorea^.First^,the prevalence of cancer andcancer-relatedgovernment support has increased^.Everyyear^,10^,000–20^,000patientsarediagnosedwithcancer^, andthenumberofcancersurvivorsandtheir5-yearrelativesurvivalrate havebothincreaseddue toadvances incancerdiagnostictoolsand pharmaceutical developments.^16,17) Inaddition, thereis improved awarenessofcancerpainmanagementandincreasedgovernmentsupport Table 1. Baseline characteristics of study population Year20022003200420052006200720082009201020112012201320142015Exp (β)P-value Total number of prescription514,866514,531512,802509,900506,189503,007498,566494,192490,255487,835483,421478,740472,214467,132 Newly prescribed51423251616602952373134486738349901.514<0.001

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throughhospicesandpalliative careservices^.¹⁸⁾Forexample^,patients with cancerpayonly5^%oftheirtotalhospitalbillsduetoinsurance coveragebeingrecordedwithaspecialcode, leadingtoimprovementsin activepainmanagement^.Second^,thenumberofelderly peoplehas increasedasKoreaisoneofthefastestagingcountries^.Currently^,13^% ofthepopulationisagedover65years^.¹⁶⁾Accordingtopreviousstudies^, age was associated withopioid consumption^.^9,19,20) Third^,various formulations anddosagesofvariousopioidshavebeenintroducedin Korea. OxycodoneandhydromorphonewereintroducedinKoreain 2001 and2005, respectively. Inaddition, theeasy administrationof transdermalandtransmucosalfentanylandthevariousformulationsof opioids^,suchassustained-releaseoralandparenteraltypes^,mighthave promotedtheincreaseinopioidprescriptionsforpaincontrol^,including fentanyl^,oxycodone^,and hydromorphone⁽datanotshown^).These results wereconsistent withpreviousstudies that reportedhigher consumptionratesfor fentanyl, oxycodone, andhydromorphone.^21-23) Theseresultsalsosupportourfindingsofincreasedopioidprescriptions inthenon-cancergroup^,whichmaymeanthataggressivetreatmentis alsoprescribedfornon-cancerchronicpain^.Opioidsareknowntobe effective againstchronicnon-cancerdiseases^,suchasosteoarthritis^, herpeszoster^,andrheumatoidarthritis^.However^,nationalguidelinesfor theuseofopioidsfornon-cancerpainhaveyettobeestablished^.^17,24) Therefore, furtherstudiesmaybeneededtopreventmisuse, addiction, anddeathcausedbyexcessiveuseofopioidsinnon-cancerpatients^.

Thisstudyhad severallimitations^.First^,we assumedthatthe prescriptionofopioidsincreasedinproportiontotheintensityofpain^. Thatis^,itwasnotpossibletodirectlyexplainwhethertherewasan adequateprescriptionofopioidsforindividualsbecauseindividualpain wasnotevaluated. However, arecentstudyreportedthattheuseof strongopioidsincreasedproportionallywithincreasingpainseverity,²⁵⁾ whichmayvalidateourstudy^.Second^,thedatadidnotincludeclinical

informationonthereasonforprescriptionorcompliancewithtreatment using opioids^.Thus^,wemight haveoverestimated the numberof prescriptionsforcancerpainbecauseapatientwithcancermayhave beenprescribedopioidsforthereliefofnon-cancerpain^,whichwecould notruleout^.Additionally^,itwasdifficulttodiscernthenumber of opioidsconsumed^.Third^,becausetheKoreanNHIS-HEALScohort datadidnotenrollnewregistrantsduringthestudyperiodafterbaseline enrollment^,theaccumulationofdouble-countedregistrantsineachyear mayhaveinfluencedtheobservedtrendsofopioidprescriptions. Asfor thisstudy’sstrengths, itwasabletoinvestigatelong-termtrendsinthe prescriptionofopioidsforcancerpainusinganationallyrepresentative cohort^.

Insummary^,theprescriptionofopioidsincreasedbetween2002and 2015^,indicatinganadvancementincancerandnon-cancerpaincontrol inKorea^.Furtherstudiesontheprescriptionsandmisuseofopioidsat theindividualandpopulationlevelareneeded.

ACKNOWLEDGEMENTS

This researchwassupported by agrantfromthe KoreaHealth Technology R^&D Project through the Korea Health Industry DevelopmentInstitute⁽KHIDI^),fundedbytheMinistryofHealth^&

Welfare, RepublicofKorea (grantnumber: HI19C0526). Hee-TaikKang hasreceivedresearchgrantsfromMinistryofHealthandWelfarein Korea^.

CONFLICT OF INTEREST

Nopotentialconflictofinterestrelevanttothisarticlewasreported. Table 2. Trends in rate of opioid prescriptions per 10,000 registrants during 2002–2015

Overall trend (2002–2015)

Joinpoint analysis

Trend 1 Trend 2 Trend 3

AAPC, %

(95% CIs) Year APC, %

(95% CIs)

Cancer 62.3^a

(44.7–82.1)

N.A. N.A. N.A. N.A. N.A. N.A.

Non-cancer 49.9^a

(22.6–83.2) 2002–2006 -3.9

(-28.9–30.0) 2006–2009 230.2^a

(27.0–758.6) 2009–2015 35.8^a

(15.5–59.6) AAPC, average annual percentage change; APC, annual percentage change; CIs, confidence intervals; N.A., not available.

aThe APC or AAPC is significantly different from zero (P<0.05).

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ORCID

JihyunYoon^,https^://orcid^.org^/0000-0002-1057-2235 Hyeong-SeopKim^,https^://orcid^.org^/0000-0001-5284-1731 Jae-WooLee, https://orcid.org/0000-0003-1784-6494 JoungyounKim, https://orcid.org/0000-0002-9092-5423 Hee-TaikKang^,https^://orcid^.org^/0000-0001-8048-6247

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