한국임상약학회지 제31권 제1호 Korean Journal of Clinical Pharmacy

Korean J Clin Pharm, Vol. 31, No. 1, pp. 35−43, 2021 Official Journal of
Korean College of Clinical Pharmacy
Original Article pISSN 1226-6051 eISSN 2508-786X
https://doi.org/10.24304/kjcp.2021.31.1.35
Korean journal of clinical pharmacy (Online)
URL: http://www.ekjcp.org

Utilization of Preventive Therapy in Korean Migraine Patients

Yewon Kim, Susin Park, Eonjeong Kim, and Nam Kyung Je*
College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
(Received December 10, 2020 · Revised January 21, 2021 · Accepted February 10, 2021)

ABSTRACT
Background: Migraine is a common neurological disorder that affects the quality of life and causes several health problems.
Preventive migraine treatment can reduce migraine frequency, headache severity, and health care costs. This study aimed to estimate
the utilization of migraine preventive therapy and associated factors in eligible patients. Methods: We studied 534 patients with
migraine who were eligible for migraine preventive therapy using 2017 National Patient Sample (NPS) data from the Health
Insurance Review and Assessment Service (HIRA). We estimated the migraine days by calculating the monthly average number of
defined daily dose (DDD) of migraine-specific acute drug. Patients with a monthly average number of DDD of 4 or more were
considered as subjects for preventive treatment. Chi-square test and multiple logistic regression analysis were used to determine the
association between the preventive therapy and the influencing variables. Results: Less than half of the eligible patients for
prophylaxis (n=234, 43.8%) were prescribed preventive therapy. Multiple logistic regression results show that migraine preventive
therapy was influenced by age, the type of migraine, and some comorbidities. Patients over the age of 50 tend to receive less
prophylactic treatment than under the age of 40. On the other hand, migraine patients with epilepsy or depression were more likely to
receive preventive therapy. Sumatriptan was the most preferred medication for acute treatment, and propranolol was the most
commonly prescribed drug for prevention. Conclusions: More than half of the patients who were candidates for migraine
prophylaxis were not receiving suitable preventive treatment. Positive factors affecting the use of migraine prevention were the
presence of comorbidities such as epilepsy and depression.
KEYWORDS: Migraine, prophylaxis, migraine days, defined daily dose

Migraine is a common neurological disorder that occurs in migraine are migraine without aura (MWoA) and migraine
approximately 12% of adults in western countries and can with aura (MWA),5) and they are not completely distinct and
significantly impair the quality of life of the patients.1,2) In exclusive.5)
Korea, 6.1% of the population suffers from migraine headaches Appropriate acute therapy for migraine headaches can abort
at least once a year, and women roughly have three times migraine attacks and suitable preventive treatment can reduce
higher incidence of migraine than men. It is most frequent in migraine frequency, headache severity, and health care costs.6)
women aged 40-49 years and men aged 19-29 years.3) Acute treatments of migraines include serotonin receptor
This neurological disorder has a broad range of severity and agonists (triptans), ergot alkaloids, non-steroidal anti-inflammatory
symptoms; it is a unilateral, pulsatile pain, and aggravated by drugs (NSAIDs), acetaminophen, and opioids.7,8) The American
routine physical activity.4) In addition, migraine is accompanied Academy of Neurology (AAN) has published guidelines for
by one or more additional symptoms such as nausea, vomiting, preventing migraines in 2012.9) The AAN guidelines recommend
abdominal pain, dizziness, photophobia, and phonophobia.4) metoprolol, propranolol, timolol, valproic acid/valproate/
According to the International Classification of Headache divalproex, topiramate with strong evidence, and atenolol,
Disorders 3rd edition (ICHD-3), the two major subtypes of nadolol, amitriptyline, venlafaxine with moderate evidence.9)

*Correspondence to: Nam Kyung Je, Pusan National University, College of Pharmacy, 2 Busandeahark-ro 63 beon-gil, Geumjeong-Gu, Busan
46241, Republic of Korea
Tel: +82-51-510-2802, Fax: +82-51-513-6754
E-mail: [email protected]

35
36 / Korean J Clin Pharm, Vol. 31, No. 1, 2021

The purpose of this study was to (1) examine the utilization occurring in more than 5% of migraine patients according to a
of migraine preventive therapy in eligible patients, (2) previous study.11)
determine the factors influencing the use of preventive
therapy, and (3) assess the frequency of drugs prescribed for Candidates for migraine prophylaxis
migraine-specific acute therapy and preventive therapy among Based on the previous studies and clinical trials, we
Korean migraine patients. considered patients with more than four migraine days per
month as candidates for preventive treatment.4,12,13) To
Methods estimate each patient’s migraine days, the defined daily dose
(DDD) was used. DDD is an average maintenance dose of a
Data Source medication used by adults, which allows the drug used to be
We utilized the National Patient Sample data from the expressed in a standardized unit.14) We estimated how many
Health Insurance Review and Assessment Service in 2017 DDD of each migraine-specific medication was prescribed to
(HIRA-NPS-2017-0014). NPS data is health insurance claims a patient per month and summed them up. One DDD was
data of almost 1 million patients and includes patients’ regarded as one migraine day.
diagnosis, procedures, surgical history, medications, institutional
information, etc.10) Medication utilization of migraine-specific acute and
The patient’s diagnosis was identified using The Korean preventive treatment
Classification of Diseases, 7th edition (KCD-7) code. KCD Migraine-specific acute therapies include almotriptan,
code is the Korean version of the International Classification frovatriptan, naratriptan, sumatriptan, zolmitriptan, and a
of Diseases (ICD) code. There are three types of health combination of ergotamine and caffeine anhydrous (hereafter
insurance in Korea: The National Health Insurance (NHI), referred to as ergotamine). Medications that are approved for
Medical Aid (MedAid), and the Patriots & Veterans Insurance migraine prophylaxis in Korea include amitriptyline, flunarizine,
(PVI) plan. Approximately 97% of Koreans are covered by nadolol, propranolol, topiramate, and valproic acid/valproate/
NHI, about 3% of people are covered by MedAid, and 0.5% divalproex (Appendix A). Furthermore, we classified each
of people by the PVI plan. The drug codes (Appendix A) ingredient of the preventive therapy into the following drug
were used to extract information on migraine-specific acute classes: Amitriptyline was grouped under antidepressants,
and preventive therapy utilization. This study was approved by flunarizine under calcium channel blockers (CCB), nadolol
the Institutional Review Board of the Pusan National and propranolol as beta-blockers, and topiramate and valproic
University (PNU IRB/2019_126_HR). acid/valproate/divalproex as anticonvulsants. If any preventive
drug was prescribed at least once in 2017, then we considered
Study Population preventive medicine was utilized.
Migraine patients with a KCD-7 code of G43 were We evaluated the prescription pattern of migraine-specific
extracted. The patients were further classified into MWoA acute therapy and preventive therapy. In the case of usage of
(G430) and MWA (G431) using KCD-7 codes. In case a multiple medications by a patient, the drug that had the
patient received both diagnoses at different times, the patient highest number of DDD per month was regarded as the main
was labeled with the MWA type. The patients whose migraine acute therapy or main preventive therapy. Similarly, we
subtype were not specified, were categorized into “the other summed the number of DDD per month for drugs belonging
migraine type”. We grouped the patients by age into “<40 to a drug class, and the class with the highest number was
years”, “40-49 years” and “≥50 years”, and by insurance into considered the main drug class.
NHI and MedAid/PVI group.
The KCD-7 code was used to identify the following Statistical analysis
comorbidities: epilepsy, depressive disorders, insomnia, hypertension, Categorical variables of the patient's baseline characteristics
dyslipidemia, diabetes mellitus, osteoarthritis, rheumatoid were expressed in frequencies and percentages using frequency
arthritis, asthma, and Thyroid gland disorders (Appendix A). analysis. To determine the association between prophylactic
The comorbidities were referred to as common diseases prescription and explanatory factors in candidates for migraine
 Utilization of Preventive Therapy in Korean Migraine Patients / 37

preventive therapy, we performed a chi-square test and

multiple logistic regression analysis. Explanatory factors
include demographic factors such as age group, sex, and
insurance type; and health factors such as migraine type,
migraine frequency, and comorbidities. The Hosmer-Lemeshow
test was performed to check the fit of this model. We used the
R Statistical Software (version 4.0.0; R Foundation for
Statistical Computing, Vienna, Austria) to perform statistical
analysis, and considered p<0.05 as statistically significant.

Results

Characteristics of study subjects

The number of patients requiring migraine prophylaxis was
estimated as 534. The characteristics of study subjects and
migraine prophylactic drug utilization are summarized in
Table 1. Patients aged 50 years or older were the most among
Fig. 1. Case extraction diagram. HIRA-NPS, health insurance
the three age groups (41.6%). Female patients are almost 4
review and assessment service-national patient sample
times more than male patients (79.8% vs 20.2%). Most
patients (96.3%) were covered with NHI. Patients with
MWoA was almost 5 times more than patients with MWA. Patterns of acute and preventive therapy for migraine
For more than half of the patients, an appropriate migraine Table 3 presents the patterns of drugs prescribed for patients
type was not assigned due to the limited code information. who have an indication for migraine prophylaxis. Sumatriptan
The most frequent comorbidity was dyslipidemia (36.9%), was the most frequently prescribed medication as an acute
followed by osteoarthritis (30.0%), then depressive disorders treatment (29.0%), followed by ergotamine (27.3%), naratriptan
(24.0%). (19.1%), almotriptan (10.1%), zolmitriptan (8.8%), and frovatriptan
(5.6%).
Preventive therapy utilization rate The most commonly used preventive drugs were propranolol
Of the 534 patients, 234 (43.8%) were prescribed preventive (35.0%), followed by flunarizine (32.5%), topiramate (13.7%),
therapy at least once in 2017 (Table 1). Migraine preventive amitriptyline (12.8%), valproic acid/valproate/divalproex (3.8%),
drug use decreased with the advanced age (p=0.382), and was and nadolol (2.1%). When preventive therapies were classified
lower in men than in women (p=0.170). Further, migraine by the drug class, beta-blockers were the most prescribed
preventive therapy was higher in patients with epilepsy (p< (37.2%), followed by CCB (32.5%), anticonvulsants (17.5%),
0.001), depressive disorders (p<0.001), insomnia (p=0.016), and antidepressants (12.8%).
dyslipidemia (p=0.013), and osteoarthritis (p=0.038).
Discussion
Predictors of preventive therapy utilization
Table 2 presents the results of the multiple logistic This study investigated the utilization of migraine preventive
regression analysis. Patients aged 50 years or older were less therapy in eligible patients, determined the factors influencing
likely to use preventive drugs than those under 40 years of the use of preventive therapy, and analyzed the prescribing
age (odds ratio [OR]=0.513; confidence interval [CI]=0.302- patterns of migraine-specific medications and preventive
0.862). Among comorbidities, epilepsy was the most influencing medications.
factor (OR=7.326; CI=2.586-26.488). Patients with depressive Patients requiring migraine prophylaxis therapy was about
disorders are more than 2 times likely to utilize migraine 10% of the migraine patients who had been prescribed acute
preventive therapy (OR=2.439; CI=1.567-3.827). therapy at least once (n=5,390). This figure is low compared
38 / Korean J Clin Pharm, Vol. 31, No. 1, 2021

Table 1. Demographic characteristics and migraine prophylactic drug utilization.

N Prophylactic utilization (%) p-Value
Total 534 234(43.8)
<40 147(27.5) 71(48.3) 0.382
Age group 40-49 165(30.9) 72(43.6)
≥50 222(41.6) 91(41.0)
Male 108(20.2) 41(38.0) 0.170
Sex
Female 426(79.8) 193(45.3)
NHI 514(96.3) 225(43.8) 0.914
Insurance
MedAid/PVI 20(3.7) 9(45.0)
Migraine without aura 202(37.8) 113(55.9) <0.001
Migraine type Migraine with aura 40(7.5) 17(42.5)
Other migraine 292(54.7) 104(35.6)
No 508(95.1) 212(41.7) <0.001
Epilepsy
Yes 26(4.9) 22(84.6)
No 406(76.0) 152(37.4) <0.001
Depressive disorders
Yes 128(24.0) 82(64.1)
No 464(86.9) 194(41.8) 0.016
Insomnia
Yes 70(13.1) 40(57.1)
No 416(77.9) 178(42.8) 0.367
Hypertension
Yes 118(22.1) 56(47.5)
No 466(87.3) 198(42.5) 0.105
Diabetes mellitus
Yes 68(12.7) 36(52.9)
No 337(63.1) 134(39.8) 0.013
Dyslipidemia
Yes 197(36.9) 100(50.8)
No 374(70.0) 153(40.9) 0.038
Osteoarthritis
Yes 160(30.0) 81(50.6)
No 507(94.9) 222(43.8) 0.947
Rheumatoid arthritis
Yes 27(5.1) 12(44.4)
No 458(85.8) 194(42.4) 0.095
Asthma
Yes 76(14.2) 40(52.6)
No 434(81.3) 190(43.8) 0.968
Thyroid gland disorders
Yes 100(18.7) 44(44.0)
NHI, national health insurance; MedAid, medical aid; PVI, patriots & veterans insurance; COPD, chronic obstructive pulmonary disease

to 38.8% of migraine patients who are eligible for migraine underestimated in our study.
prophylaxis in the US.2) The claim data we used did not In this study, 43.8% of patients had been prescribed
identify the use of over-the-counter (OTC) drugs when preventive therapy at least once in 2017, and the proportion
estimating migraine days with the monthly average number of was similar or higher than in other countries. A study in the
DDD of acute therapy. Since a significant number of migraine US reported that about 39% of migraineurs had an indication
sufferers (49%) use OTC pain medications,15) those who are for migraine prophylaxis, but only 32% of them received
candidates for migraine preventive treatment might have been preventive therapy.2) Caetano et al. found that among 77
 Utilization of Preventive Therapy in Korean Migraine Patients / 39

Table 2. Multiple logistic regression analysis of migraine prophylactic drug utilization

Odds Ratio (OR) 95% CI p-Value
Total (N=534)
<40 Reference
Age group 40-49 0.695 0.425-1.133 0.146
≥50 0.513 0.302-0.862 0.012
Male Reference
Sex
Female 1.606 0.988-2.649 0.059
NHI Reference
Insurance type
MedAid/PVI 0.608 0.198-1.736 0.362
Migraine without aura Reference
Migraine type Migraine with aura 0.657 0.310-1.371 0.266
Other migraine 0.471 0.316-0.700 <0.001
Epilepsy 7.326 2.586-26.488 <0.001
Depressive disorders 2.439 1.567-3.827 <0.001
Insomnia 1.266 0.709-2.265 0.425
Hypertension 1.085 0.640-1.834 0.761
Diabetes mellitus 1.119 0.580-2.163 0.736
Comorbidities
Dyslipidemia 1.532 0.947-2.488 0.083
Osteoarthritis 1.467 0.951-2.268 0.083
Rheumatoid arthritis 1.359 0.553-3.282 0.496
Asthma 1.226 0.712-2.107 0.460
Thyroid gland disorders 0.687 0.406-1.149 0.157
c-statistic 0.713
p value of Hosmer-Lemeshow test 0.703
NHI, national health insurance; MedAid, medical aid; PVI, patriots & veterans insurance; COPD, chronic obstructive pulmonary disease

patients who were eligible for prophylactic treatment, only epilepsy, sleep disorders, stroke, and other pain disorders.19)
22% of them were on preventive treatment in Portugal.16) We Among various comorbidities, the most frequent comorbid
might have overestimated the preventive drug utilization rate conditions according to the results of our study are dyslipidemia
since we considered a patient as a preventive drug user if he/ (36.9%), osteoarthritis (30.0%), depressive disorders (24.0%),
she was prescribed the index drug at least once a year. and hypertension (22.1%).
Nevertheless, more than half of the patients had not received Diamond et al. reported that female and elderly patients
optimal preventive therapy in Korea. with migraine were more likely engaged with current or past
One previous study found that women experienced more utilization of preventive therapy.15) On the other hand, there
frequent migraine headaches, greater disability, and more was no significant relationship between sex and prescription
frequent consultation with their physicians about their of preventive agents according to a Netherlands study.20) We
headaches.17,18) The ratio of women to men in the population found that women received more preventive treatment, although
of candidates for migraine prophylaxis was 4:1, which differed it was not statistically significant, and preventive drug
in frequency by age groups. However, there was no significant prescriptions decreased in older people aged over 50 years.
relationship between sex and the use of preventive treatment This may be due to the high use of multiple medications by
in our study. Common comorbidities that occur with migraine older patients and physicians might be concerned about
and affect the treatment include depression, anxiety disorders, adverse drug reactions, drug-drug interactions, or drug-disease
40 / Korean J Clin Pharm, Vol. 31, No. 1, 2021

Table 3. Patterns of acute and preventive therapy in patients eligible prescribed drug was sumatriptan, followed by zolmitriptan,
for migraine prophylaxis and then rizatriptan.24) In comparison, at the time of this
N Drug utilization (%) research, rizatriptan was not available in Korea and thereby
Drug for acute therapy 534 100.0 excluded from the analysis. Since we analyzed the frequency
Sumatriptan 155 29.0 of prescriptions by considering the highest average number of
Ergotamine 146 27.3 DDD per month as the main acute therapy in each patient, the
Naratriptan 102 19.1 results may differ due to differences in the methodology
Almotriptan 54 10.1
between the studies.
According to the Canadian Headache Society guideline and
Zolmitriptan 47 8.8
the European Federation of Neurological Societies (EFNS)
Frovatriptan 30 5.6
guideline, ergotamine is not recommended for acute migraine
Drug for preventive therapy 234 100.0
attacks because it has lower efficacy and greater risk of side
Propranolol 82 35.0
effects than triptans.25,26) However, ergotamine was the second
Flunarizine 76 32.5
most frequently used medication after sumatriptan in Korea.
Topiramate 32 13.7 This is probably due to the cost advantage of ergotamine.
Amitriptyline 30 12.8 Triptans were about 50 to 80 times more expensive than
Valproic acid/valproate/divalproex 9 3.8 ergotamine at the time of this study.
Nadolol 5 2.1 The most commonly prescribed preventive medicine was
Drug class of preventive therapy 234 100.0 propranolol, followed by flunarizine, and topiramate. In terms
Beta-blockers 87 37.2 of drug classes, beta-blockers were the most commonly used
Calcium channel blockers 76 32.5 ones. The most frequently prescribed preventive drug in a US
Anticonvulsants 41 17.5 study was topiramate.11) Another study found that beta-
Antidepressants 30 12.8 blockers were the most frequently used preventive drug as
well as the first choice of physicians followed by TCA, CCB,
anticonvulsant (topiramate) in that order.27)
interactions.20,21) According to the international guidelines of the WHO/EHF,
Caetano et al. reported that patients with MWA had higher beta-blockers, topiramate, flunarizine, sodium valproate, amitriptyline
rates of migraine prophylaxis compared to the patients with are effective for migraine prevention and are recommended
MWoA.16) However, our results showed the opposite trend. for use as a first tier.28) The results of our study suggest that
We were not able to draw any meaningful hypothesis from the medications were used according to the guidelines.
this finding since more than half of the patients were not Hypertension is highly prevalent in Korea as well as
assigned to any specific migraine subtype. worldwide.29) The high prevalence of hypertension may be
More preventive agents were prescribed in the presence of related to the frequent prescription of beta-blockers and CCB
epilepsy and depressive disorder as comorbidities. This may as migraine prophylactic medication. The choice of migraine
be due to the fact that the approved migraine prophylaxis preventive therapy should take into account not only the
agents also have an indication of epilepsy or depression.22) In efficacy of the drug but also safety, tolerability, patient
particular, depression is associated with severe migraines, and preferences, and comorbidities.4,30)
frequent migraine headaches with high severity are linked to There are several limitations to our study. First, we used
increased use of migraine prevention treatments in these insurance claim data, originally generated for reimbursement
conditions.20,23) purposes. Considering that it is not collected for research
Sumatriptan was the most frequently prescribed drug for purposes, diagnostic information may be inaccurate. For
acute treatment, followed by ergotamine. According to a study example, it is difficult to compare patients with aura and
carried out in the US, sumatriptan was the most commonly without aura because migraine-type was not accurately
used drug for acute treatment, followed by rizatriptan.11) classified and many patients were assigned to “other migraines
Meanwhile, Sheftell et al. found that the most frequently group”. Second, the claim data did not provide detailed
 Utilization of Preventive Therapy in Korean Migraine Patients / 41

clinical information of the patient such as migraine severity, and years lived with disability for 328 diseases and injuries for 195
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 Utilization of Preventive Therapy in Korean Migraine Patients / 43

Appendix A. Disease and Drug Codes

Disease and Drug Codes (http://koicd.kr/)

Disease (KCD-7)
Migraine without aura G430
Migraine with aura G431
Other migraines G432, G433, G438, G439
Hypertension I10-13
Epilepsy G40-41
Schizophrenia F20
Depressive disorders F32-33
Anxiety disorders F064, F40, F410-413, F418, F419
Sleep disorders F51, G47
Insomnia F510, G470
Diabetes mellitus E10-14
Osteoarthritis M15-19
Rheumatoid arthritis M05, M06, M080, M120, M123
Asthma J45-46
Chronic obstructive pulmonary disease J44
Malaise and fatigue R53
Disorders of thyroid gland E00-07
Dyslipidemia E78
Obesity E66
Drug
Sumatriptan 233802ATB, 233803ATB
Naratriptan 415501ATB
Zolmitriptan 415601ATB
Almotriptan 499401ATB
Frovatriptan 509501ATB
Ergotamine/caffeine anhydrous 251800ATB
Amitriptyline 107501ATB, 107502ATB, 107504ATB
241801ACR, 241801ATB, 241802ACR, 241803ACH, 241803ATB,
Topiramate
241804ACH, 241804ATB
246901ATE, 246902ATE, 246903ATE, 247001ACS, 247002ACS,
Valproic acid/valproate/divalproex 229701ACR, 229701ATR, 229703ATB, 229705ATB, 229705ATR,
229706ATR, 229707ATR, 147701ATE, 147702ATR, 147801ACH
Propranolol 219901ATB, 219904ATB
Nadolol 198301ATB
Flunarizine 160501ACH
KCD; Korean Classification of Diseases