ARTICLE OPEN ACCESS

Characterizing opioid use in a US population

with migraine
Results from the CaMEO study
Richard B. Lipton, MD, Dawn C. Buse, PhD, Benjamin W. Friedman, MD, Lisa Feder, PhD, Correspondence
Aubrey Manack Adams, PhD, Kristina M. Fanning, PhD, Michael L. Reed, PhD, and Todd J. Schwedt, MD Dr. Lipton
Richard.Lipton@
®
Neurology 2020;95:e457-e468. doi:10.1212/WNL.0000000000009324 einsteinmed.org

Abstract MORE ONLINE

Objective CME Course

To determine the prevalence of and risk factors associated with opioid use in the treatment of NPub.org/cmelist
migraine, we examined demographics and clinical characteristics of 867 individuals who
reported using opioids for the treatment of migraine.

Methods
We analyzed data from the CaMEO study (Chronic Migraine Epidemiology and Outcomes),
a cross-sectional, longitudinal, Internet study, to compare sociodemographics, clinical char-
acteristics, and migraine burden/disability of opioid users vs nonusers. Covariates were entered
as categorical or continuous variables. Factors associated with opioid use were identified using
nested, multivariable binary logistic regression models.

Results
Of 2,388 respondents with migraine using prescription medications for acute treatment, 36.3%
reported that they currently used or kept on hand opioid medications to treat headaches.
Current opioid users had significantly more comorbidities, greater headache-related burden,
and poorer quality of life than nonusers. Regression models revealed factors significantly
associated with opioid use, including male sex, body mass index, allodynia, increasing monthly
headache frequency, Total Pain Index score (excluding head, face, neck/shoulder), anxiety,
depression, ≥1 cardiovascular comorbidity, and emergency department/urgent care use for
headache in the past 6 months. Self-reported physician-diagnosed migraine/chronic migraine
was associated with significantly decreased likelihood of opioid use.

Conclusions
Of respondents who were using acute prescription medications for migraine, more than one-
third used or kept opioids on hand, contrary to guidance. This analysis could not distinguish
risk factors from consequences of opioid use; thus further research is needed to guide the
development of strategies for reducing the inappropriate use of opioids in migraine.

From the Department of Neurology (R.B.L., D.C.B., B.W.F.), Albert Einstein College of Medicine, Bronx, NY; Peloton Advantage, LLC, an OPEN Health Company (L.F.), Parsippany, NJ;
Global Medical Affairs (A.M.A.), Allergan plc, Irvine, CA; Vedanta Research (K.M.F., M.L.R.), Chapel Hill, NC; and Neurology Research (T.J.S.), Mayo Clinic, Phoenix, AZ.

Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

The Article Processing Charge was funded by Allergen plc.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading
and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. e457
 Glossary
AMPP = American Migraine Prevalence and Prevention; BMI = body mass index; CaMEO = Chronic Migraine Epidemiology
and Outcomes; CI = confidence interval; CV = cardiovascular; ED = emergency department; GAD-7 = 7-item Generalized
Anxiety Disorder scale; HCP = health care professional; ICHD-3 = International Classification of Headache Disorders, 3rd
edition; MIDAS = Migraine Disability Assessment; MOH = medication overuse headache; MSQ = Migraine-Specific Quality of
Life Questionnaire; MSSS = Migraine Symptom Severity Score; NSAID = nonsteroidal anti-inflammatory drug; OR = odds
ratio; PHQ-9 = 9-item depression module of the Patient Health Questionnaire scale; TPI = Total Pain Index; UC = urgent care.

Migraine, a highly prevalent, chronic neurologic disease, typi- features and conditions, including migraine characteristics, al-
cally manifests with episodic attacks of pain associated with lergies and respiratory disorders, cardiovascular disease, chronic
other incapacitating symptoms, such as nausea, photophobia, pain, chronic fatigue, sleep disorders, autonomic disorders,
phonophobia, and allodynia.1,2 The second-highest specific psychiatric disorders, gastrointestinal disorders, and overactive
cause of disability worldwide,3 migraine produces substantial bladder.
individual, familial, economic, and societal burdens.4–6 Man-
agement of migraine includes acute and preventive medication, From September to October 2012, screening and recruitment
as well as nonpharmacologic approaches. The goals of acute of study respondents occurred from an Internet research panel
treatment include rapid resolution of pain and associated (Research Now, Plano, TX) with 2.4 million active US mem-
symptoms without recurrence, side effects, and the need for bers, with cross-sectional and longitudinal CaMEO study
backup or rescue medications.7 Practice guidelines do not modules administered from September 2012 to November
recommend opioids for treating migraine except under limited 2013 and longitudinal assessments occurring at 3-month
circumstances. However, a substantial proportion of individuals intervals (3, 6, 9, and 12 months after the baseline assessment).
use opioids for acute treatment of migraine.7–12 In the Amer- The CaMEO study was approved by the Albert Einstein Col-
ican Migraine Prevalence and Prevention (AMPP) study, ap- lege of Medicine Institutional Review Board (12-04-177E). All
proximately 30% of community-residing respondents reported study authors had full access to all data.
opioid use for migraine.9 In the emergency department (ED),
59% of visits for migraine involved opioid administration or Standard protocol approvals, registrations,
prescription.10 Despite the potential for short-term benefits, and patient consents
opioids are associated with only modest initial efficacy, in- Data included in this analysis were from the CaMEO study
creased risk for migraine chronification,13–17 and potential for (ClinicalTrials.gov identifier: NCT01648530). The in-
misuse, abuse, and dependence.9,18 stitutional review board of the Albert Einstein College of
Medicine approved the CaMEO study and waived written
Factors associated with opioid use for migraine require ad- informed consent for study volunteers, who had the right to
ditional exploration as a step toward preventing the negative accept or refuse participation in the survey.
consequences of this common pattern of treatment. This
analysis of the Chronic Migraine Epidemiology and Out- Study respondents
comes (CaMEO) study explored demographic and clinical This study used quota sampling with the aim of recruiting
characteristics associated with opioid use for migraine. a demographically representative sample of the United States
based on age, sex, and income.19 Eligible respondents were at
least 18 years of age, agreed to participate, completed initial
Methods surveys in a reasonable time (at least 10 minutes), provided
data on headache frequency, reported consistent age and sex
Study design throughout the survey, and met modified International Classi-
The CaMEO study characterized the course of migraine over 1 fication of Headache Disorders, 3rd edition (ICHD-3) symptom
year in a broad cohort of respondents with migraine represen- criteria for migraine using the validated American Migraine
tative of the US population. Details of the study design Study/AMPP study migraine screener.1,20 Classification into
have been published previously.19 Briefly, CaMEO is a cross- chronic or episodic migraine was determined by using modified
sectional and longitudinal Internet study with screening, re- Silberstein-Lipton criteria (headache frequency of at least 15
cruitment, and assessment phases. CaMEO was designed to days [chronic migraine] or fewer than 15 days [episodic mi-
characterize the clinical course of migraine, family burden, graine] per month over the preceding 3 months).1
barriers to care, endophenotypes, and comorbidities among
respondents with chronic and episodic migraine using both Variables: sociodemographics, clinical
cross-sectional and longitudinal study modules. This analysis characteristics, and other factors associated
evaluated data from the comorbidities and core modules. The with opioid use
modules collected data from respondents who passed the This analysis compared sociodemographics, clinical char-
screener and were assessed every 3 months on a broad set of acteristics, and migraine-related disability of self-reported

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opioid users and nonusers who met criteria for migraine. scored from 0 to 3.24 Scores of at least 10 were categorized as
Sociodemographic characteristics included age, sex, em- positive for anxiety. Respondents reporting current use of
ployment, education, income, and body mass index (BMI). medications for the acute treatment of migraine attacks in-
Headache characteristics included monthly headache days, dicated which medications they were taking, or had available
Migraine Disability Assessment (MIDAS; score based on 5 to use, by referring to a precoded list and answering the
disability questions in 3 areas, assessed over the preceding 3 question “Which of these medications (if any) are you cur-
months),21 and Migraine Symptom Severity Score (MSSS), rently using (or typically keep on hand) to treat your
a composite index based on the frequency of 7 primary mi- headaches when you have them?” The precoded list included
graine features (unilateral pain, pulsatile pain, moderate or both generic and brand names of triptans, opioids, barbitu-
severe pain intensity, routine activities worsening pain, nau- rates, ergotamines, and nonsteroidal anti-inflammatory drugs
sea, photophobia, and phonophobia). Responses ranged from (NSAIDs).
1 to 4, with the overall sum score ranging from 7 to 28. The
presence of cutaneous allodynia was determined using the The present analysis defined current opioid users as individuals
12-item Allodynia Symptom Checklist, in which scores of at who self-reported current use of an opioid or had opioid medi-
least 3 indicate the presence of allodynia.22 Noncephalic pain cine on hand to treat headache. Opioid use indicating risk for
data were collected using the validated Total Pain Index medication overuse headache (MOH) was defined as opioid use
(TPI). The TPI assesses pain frequency and intensity over on at least 10 days each month to best align to the ICHD-3
the preceding 3 months in 8 specified body regions (head, criteria.1 Opioid users confirmed use of at least 1 of the follow-
face, neck or shoulders, back, arms or hands, legs or feet, ing prescription opioid medications: acetaminophen/codeine,
chest, and abdomen or pelvis). Pain noted at “any other acetaminophen/hydrocodone, acetaminophen/oxycodone,
location” was recorded and attributed to its specific re- acetaminophen/oxycodone hydrochloride, hydrocodone,
spective body part. It replaced the pain value for a given lo- meperidine, morphine, oxycodone, oxycodone hydrochlo-
cation only if worse than the original score. For each location, ride, propoxyphene, propoxyphene/acetaminophen, trama-
respondents rated their pain from 0 (no pain) to 10 (worst dol, tramadol/acetaminophen, and hydrocodone/ibuprofen.
pain imaginable). Respondents also rated pain frequency on
a scale from 0 (none of the time) to 4 (all of the time). These Statistical analysis
ratings were recoded to 0 = 0% of the time, 1 = 35%, 3 = 75%, A cross-sectional analysis compared the sociodemographics,
and 4 = 100% of the time to provide an estimate of the clinical characteristics, and migraine-related disability of self-
approximate amount of time represented by each response. reported opioid users and nonusers who met criteria for mi-
The TPI was derived by multiplying the pain frequency graine. With the exception of age and BMI, sociodemographic
percentage for each body location by its pain rating. The covariates were coded as categorical variables. For clinical
score for each location can range from 0 to 10, with total characteristics and migraine-related disability, mean monthly
scores ranging from 0 to 80. This analysis considered head, headache frequency, MSSS, and MSQ scores were coded as
face, and neck or shoulder pain to be cephalic pain, removing continuous variables. Factors classed as other clinical charac-
them from TPI scoring, leaving 5 body locations and a pos- teristics were coded as categorical variables. Between-group
sible score range of 0–50. (opioid users vs nonusers) differences in continuous variables
were assessed using a 2-tailed t test. The χ 2 test was used for
Health care variables included physician diagnosis of mi- testing between-group differences in categorical variables. For
graine or chronic migraine and use of an ED or urgent care all tests, α was set at 0.05.
(UC) facility in the preceding 6 months for headache. Other
respondent characteristics included psychiatric comorbid- A series of nested multivariable binary logistic regression
ities, including anxiety and depression, presence of at least 1 models, in which opioid use vs nonuse was the dependent
cardiovascular (CV) comorbidity (heart disease or angina, variable, assessed factors associated with opioid use. Cova-
heart attack, irregular heart rhythms, any heart valve disease riates were entered in sequential blocks, starting with socio-
or abnormality, hypertension, stroke, and TIA), and demographic variables, followed by headache and respondent
Migraine-Specific Quality of Life Questionnaire (MSQ) characteristics, and health care variables. The final model was
consisting of 3 domains, which included role function: pre- adjusted for the presence of at least 1 cardiovascular
ventive, role function: restrictive, and emotional, scored on comorbidity. Odds ratios (ORs) (95% confidence interval
a scale ranging from 0 to 100, with higher scores indicating [CIs]) were calculated for each variable. After each block was
better quality of life. Depression was assessed using the entered, nonsignificant variables were trimmed from the
9-item depression module of the Patient Health Question- model.
naire scale (PHQ-9), with scores ranging from 0 to 27, as
each of the 9 items can be scored from 0 (not at all) to 3 Data availability
(nearly every day).23 Scores greater than 10 were catego- Data reported in this manuscript are available within the ar-
rized as moderate to severe depression. Anxiety was assessed ticle. Additional data from the CaMEO study (ClinicalTrials.
using the 7-item Generalized Anxiety Disorder scale (GAD- gov Identifier: NCT01648530) may be requested at aller-
7), with scores ranging from 0 to 21, as each of the 7 items is ganclinicaltrials.com/en/patient-data.

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 Results a health care professional (HCP). Opioid users were less
likely to have received a migraine diagnosis by an HCP and
Analysis population and sociodemographics had more visits to an ED or UC facility. A similar percentage
During the screening phase, the CaMEO study invited a total of opioid users (14.4%) and nonusers (14.9%) reported that
of 489,537 respondents from the 2.4 million active US a specialist was treating or managing their headaches. The
members listed in the Research Now database (figure 1).19 A respondents who reported opioid use were more likely to
total of 16,789 respondents qualified for inclusion in the have their headaches managed by pain specialists, whereas
CaMEO study during the recruitment phase. From this group, those not reporting opioid use were more likely to have their
12,810 respondents completed the comorbidities module.19 headaches managed by neurologists or headache specialists
Of these, 10,431 reliably reported the use of 1 or more acute (figure 2A). Among the 867 respondents categorized as cur-
medications for migraine and 2,388 (22.9%) were current rent opioid users, 213 (24.5%) reported using an opioid on 10
users of prescription medication for the acute treatment of or more days per month. In addition, current opioid users
migraine. Among people with migraine treated with acute were less likely than opioid nonusers to take triptan or bar-
prescription medications, 867 (36.3%) reported opioid use, biturate medications (figure 2B).
and 1,521 (63.7%) did not.
Additional characteristics
The 2,388 respondents categorized as current users of pre- Compared with opioid nonusers, current opioid users had
scription medication for acute treatment of migraine attacks a higher prevalence of allodynia (65.6% vs 57.1%), diabetes
had a mean age of approximately 46 years. Most respondents diagnosed by an HCP (14.9% vs 8.1%), moderate to severe
were women, white, and insured (table 1). Nearly two-thirds depression based on a PHQ-9 score of at least 10 (49.9% vs
of the respondents were employed, and 99% had a source of 29.2%), anxiety based on a GAD-7 score of at least 10 (42.3%
household income (based on the total income from all people vs 25.6%), higher mean TPI scores (18.7 vs 13.7), and higher
living in a particular household); among these, more than 60% mean TPI scores excluding head, face, and neck (8.3 vs 6.7)
had an annual income of $50,000 or more. More than half (p < 0.001 for all). The mean MSSS was lower among opioid
were married, and nearly half of the respondents had a college users (16.6 vs 17.3; p < 0.001). However, a higher pro-
degree. Respondents who reported opioid use were more portion of current opioid users than nonusers (p < 0.05)
likely than opioid nonusers to be male, have a higher BMI, and reported all CV comorbidities, including heart disease or
have lower income. They were less likely to be employed and angina, heart attack or myocardial infarction, irregular heart
have a 4-year college degree. rhythms, any heart valve issues, hypertension, stroke, and
TIA (table 3).
Headache characteristics and health
care variables Migraine-related disability and health-related
Opioid users had significantly more monthly headache days quality of life scores
than nonusers (table 2). They also reported significantly more Current opioid users and nonusers differed with respect to
medication use. Nearly 80% of all current users of prescription patient-reported outcomes. Current opioid users had greater
medication for migraine had received a migraine diagnosis by headache-related disability based on their MIDAS scores than
opioid nonusers. A greater proportion of current opioid users
had MIDAS grade IV (figure 3A). Mean MSQ scores were
Figure 1 Analysis population also significantly lower among current opioid users than in
opioid nonusers across all 3 of the MSQ domains (figure 3B),
indicating that opioid users had reduced migraine-specific
quality of life.

Factors associated with opioid use based on

multivariable binary logistic regression models
We ran a series of 5 nested models. Factors significantly asso-
ciated with opioid use in the fully adjusted model (model 5)
included male sex (p < 0.001), increasing BMI (p = 0.011),
presence of allodynia (p = 0.001), increasing monthly headache
frequency (10–14 days vs 0–4 days: p = 0.034; ≥15 days vs 0–4
days: p = 0.001), TPI excluding head, face, and neck (p <
0.001), anxiety (p = 0.008), depression (p = 0.001), at least 1
CV comorbidity (p < 0.001), and ED/UC facility use for
headache in the past 6 months (p < 0.001) (table 4). Physician-
CaMEO = Chronic Migraine Epidemiology and Outcomes; CV = cardiovas-
diagnosed migraine or chronic migraine (p < 0.001) and ele-
cular; Rx = prescription; TPI = Total Pain Index. vated MSSS (p < 0.001) were associated with a significantly
decreased likelihood of opioid use.

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Table 1 Demographics of study sample by opioid users and nonusers among persons with migraine using a prescription
treatment for migraine
Characteristic Opioid users (n = 867) Opioid nonusers (n = 1,521) Total (n = 2,388)a χ2 p Value

Age, y 46.1 ± 13.7 46.4 ± 13.3 46.3 ± 13.5 0.51b 0.609

Sex — — — 40.36 <0.001

Men 230 (26.5) 240 (15.8) 470 (19.7) — —

Women 637 (73.5) 1,281 (84.2) 1,918 (80.3) — —

White 737 (85.2) 1,328 (87.4) 2,065 (86.6) 2.35 0.125

Married 459 (52.9) 855 (56.3) 1,314 (55.0) 2.44 0.118

Employed 476 (54.9) 966 (63.5) 1,442 (60.4) 17.11 <0.001

Health insurance 792 (91.8) 1,409 (93.4) 2,201 (92.8) 2.10 0.147

Education, ≥4-year degree 367 (42.3) 780 (51.3) 1,147 (48.0) 17.73 <0.001

2 b
BMI, kg/m 30.9 ± 8.4 28.8 ± 7.4 29.6 ± 7.8 6.14 <0.001

Incomec — — — 36.22 <0.001

<$30,000 213 (24.7) 239 (15.8) 452 (19.1) — —

$30,000–$49,999 138 (16.0) 268 (17.7) 406 (17.1) — —

$50,000–$74,999 207 (24.0) 332 (22.0) 539 (22.7) — —

≥$75,000 303 (35.2) 671 (44.4) 974 (41.1) — —

Abbreviation: BMI = body mass index.

Values are mean ± SD or n (%).
a
Unless otherwise shown or indicated.
b
Independent samples t test.
c
n for this category = 2,371.

In initial models (table 4), full- or part-time employment respondents’ headache characteristics eliminated these asso-
status and income greater than $75,000/year were associated ciations. Moderate to severe MIDAS-based disability was as-
with higher odds of opioid use, but adjustment for sociated with opioid use when the model was adjusted for

Table 2 Headache characteristics and use of specialists by opioid users and nonusers
Characteristic Opioid users (n = 867) Opioid nonusers (n = 1,521) Total (n = 2,388) χ2 p Value

a
Monthly headache days 8.3 ± 7.7 6.5 ± 6.5 7.2 ± 7.0 6.04 <0.001

Monthly headache days — — — 36.14 <0.001

0–4 377 (43.5) 815 (53.6) 1,192 (49.9) — —

5–9 197 (22.7) 352 (23.1) 549 (23.0) — —

10–14 124 (14.3) 170 (11.2) 294 (12.3) — —

≥15 169 (19.5) 184 (12.1) 353 (14.8) — —

Use of NSAIDs ≥15 days/mo; others ≥10 days/mo 336 (38.8) 350 (23.0) 686 (28.7) 66.85 <0.001

Opioid use ≥10 days/mo 213 (24.5) — — — —

Headaches managed by neurology, pain, or 125 (14.4) 226 (14.9) 351 (14.7) 0.086 0.770
headache specialist, past 6 months

Migraine or CM diagnosed by HCP 584 (67.4) 1,311 (86.2) 1,895 (79.4) 119.58 <0.001

ED/UC, past 6 months 143 (16.5) 124 (8.2) 267 (11.2) 38.69 <0.001

Abbreviations: CM = chronic migraine; ED = emergency department; HCP = health care professional; NSAID = nonsteroidal anti-inflammatory drug;
UC = urgent care.
Values are mean ± SD or n (%).
a
Independent samples t test.

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 Figure 2 Opioid use and nonuse by specialist type and medication overuse by medication class

(A) Opioid use and nonuse distribution across

specialties differed significantly (χ2 = 29.18; p <
0.001); more opioid users than nonusers repor-
ted having their headaches managed by pain
specialists. Neurologists and headache special-
ists managed more opioid nonusers. (B) Medi-
cation use among opioid users vs nonusers. This
analysis presents medication use meeting crite-
ria of ≥15 days/month for respondents using
nonsteroidal anti-inflammatory drugs and ≥10
days/month for all other classes/agents. *p <
0.001; other differences not statistically signifi-
cant. NSAID = nonsteroidal anti-inflammatory
drug.

headache characteristics and remained associated when the important for a global audience, especially in countries where
model was adjusted for psychiatric comorbidities. This asso- prescriptions for opioids are increasing.
ciation did not persist when past 6-month ED/UC use was
added to the model, suggesting that disability is associated The association between male sex and greater opioid use in
with ED/UC use. this analysis is consistent with previous findings from the
AMPP study showing that the use of opioids was associated with
a greater risk of migraine chronification in men (adjusted
Discussion OR [95% CI] 2.76 [1.20–6.38]) than in women (1.28
Consensus statements and guidelines do not recommend [0.81–1.97]).27 The nature of the relationships among male sex,
opioids to manage migraine because of limited efficacy, lack of opioid use, and migraine chronification remains to be unraveled.
migraine specificity, increased disability, risks of overuse and A recent analysis of acute medication overuse from the Migraine
migraine chronification over the longer term, as well as the in America Symptoms and Treatment study showed that, in
potential for dependence, abuse, and misuse, a serious public respondents with migraine, men had higher rates of acute med-
health concern.7,15,17,25,26 Nevertheless, these medications are ication overuse than did women.26 It is unknown whether these
commonly prescribed to individuals with migraine.9 The findings are a consequence of prescribing patterns, migraine
current analysis confirmed that opioid use among individuals characteristics such as severity or frequency, differing genetic
with migraine is not uncommon. Results of this study are vulnerabilities, or interactions among these or other variables.

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Table 3 Cardiovascular comorbidities of study sample by opioid users and nonusers
Self-report of HCP-diagnosed comorbidity Opioid users (n = 867) Opioid nonusers (n = 1,521) Total (n = 2,388) χ2 p Value

Heart disease/angina 39 (4.5) 26 (1.7) 65 (2.7) 16.22 <0.001

Heart attack (MI) 20 (2.3) 16 (1.1) 36 (1.5) 5.86 0.016

Irregular heart rhythms 140 (16.1) 157 (10.3) 297 (12.4) 17.21 <0.001

Any heart valve disease or abnormality 54 (6.2) 65 (4.3) 119 (5.0) 4.46 0.035

Hypertension 310 (35.8) 354 (23.3) 664 (27.8) 42.86 <0.001

Stroke 22 (2.5) 16 (1.1) 38 (1.6) 7.78 0.005

TIA 25 (2.9) 22 (1.4) 47 (2.0) 5.91 0.015

Abbreviations: HCP = health care professional; MI = myocardial infarction.

Values are n (%).

Higher prevalence of depression and anxiety was also noted multiple pain presentations with a single agent. It is also
among opioid users compared with nonusers in the AMPP possible that opioid-induced hyperalgesia28 could contribute
study.9 Further research is needed to help determine the to the development of extracephalic pain and allodynia via
nature and directionality of the association between de- central sensitization,29 thereby contributing to the associa-
pression and anxiety and opioid use. It is possible that opioids tions among TPI, allodynia, and increased opioid use.
contribute to a worsening of depression and anxiety. In ad-
dition, these psychiatric comorbidities could contribute to In this analysis, a substantial proportion of current opioid
worsening of headache, with a resulting increase in opioid users reported using an opioid on at least 10 days per month,
prescribing. These possibilities are not necessarily mutually which puts them at risk for MOH.30 These findings highlight
exclusive. the risk of MOH with opioid use and the need for more
effective acute treatments for migraine.
In the present analysis, seeking treatment for headache in ED/
UC facilities was associated with opioid use and with mod- In the current study, there was no association between in-
erate to severe disability as measured by MIDAS, an un- come, current employment, or education among opioid users
surprising finding. Although the reasons for high prescribing or nonusers. In the AMPP study, opioid use was associated
rates of opioids in this setting have not been investigated with lower rates of marriage and current employment, as well
systematically, it may be that HCPs in the ED prefer to use as lower annual household income.9 As in the AMPP study,
opioids as rescue treatment because of perceived rapidity of our analysis revealed a higher incidence of CV comorbidities
their efficacy or perceived short-term safety. It is also possible in opioid users than nonusers. The design of the current
that a proportion of patients presenting to the ED for mi- analysis did not permit us to determine if CV comorbidities
graine treatment have already used and not adequately were related to opioid use or if HCPs were prescribing opioids
responded to guideline-recommended medications, such as rather than triptans to patients with CV comorbidities owing
NSAIDs and triptans. Additional education of the ED/UC to the absolute and relative contraindications to triptans be-
and pain specialist physician populations about appropriate cause of potential CV risks. However, among 29,025 partic-
acute treatments for migraine attacks may be needed to de- ipants of the prospective Reasons for Geographic and Racial
crease the prescribing rates of opioids in these settings. Differences in Stroke (REGARDS) study, adult women, but
not men, using prescription opioids were at higher risk for
Other associations between opioid use and variables evaluated coronary heart disease and CV death.31
in this analysis may reflect the diagnostic and treatment
challenges with migraine. For example, we noted that a phy- Overall, our results confirm that opioid use for the treatment of
sician diagnosis of migraine and an elevated symptom severity migraine is common and are consistent with the results from
score (MSSS) showed a decreased association with opioid the AMPP study, which showed that 15.9% of people with
use. The association of physician-diagnosed migraine and migraine were current opioid users for migraine and 13.8%
decreased opioid use in this analysis may reflect greater un- were former opioid users for migraine.9 However, it is impor-
derstanding of the benefit-risk profile and limitations of tant to note that the samples of the 2 studies differed in that the
opioids among clinicians who are able to make a migraine CaMEO population was younger and had a slightly higher
diagnosis. Higher MSSS scores may result in an increased income than the AMPP population32; therefore, direct com-
likelihood of a migraine diagnosis and initiation of more parisons of percentages cannot be made. In addition, the nature
specific medications. The increased use of opioids associated of this current analysis does not allow us to determine causation
with TPI scores and allodynia may indicate attempts to treat or directionality, as our data are derived from a cross-sectional

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 Figure 3 Migraine-related disability and quality of life among opioid users and nonusers

(A) For migraine-related disability among opioid

users and nonusers, current opioid users had
a greater headache-related burden overall than
did opioid nonusers (χ2 = 47.55; p < 0.001). (B)
Migraine-related quality of life scores among
opioid users and nonusers. *p < 0.001 for all
between-group comparisons. MIDAS = Migraine
Disability Assessment; MSQ = Migraine-Specific
Quality of Life Questionnaire.

analysis. Nevertheless, the results provide descriptive in- genetic factors) in migraine and its management may help to
formation about the characteristics of opioid users and non- close the gaps to optimal management.
users. Further examination of our data may help to characterize
the types of patients who are not well-served by currently The limitations of the CaMEO study have been discussed
available acute treatments for migraine attacks and spur re- previously.19 The CaMEO study design used probability
search into causative factors and potential solutions, such as sampling from a nationally distributed online panel to provide
new treatments. Continuing this line of inquiry also may lead to a broad, representative US population; nevertheless, partici-
a better understanding of the patterns of care accessed by those pation rates were low, and this subanalysis comprised a small
with migraine and thereby reveal potential gaps in HCP un- group of those individuals using prescription medication to
derstanding of optimal migraine treatment. Finally, it is hoped treat headache, which may have introduced participation bias.
that better definition of these issues will lead to a reduction in However, the analysis sample was limited to respondents who
the use of opioids for the acute treatment of migraine attacks. were consistent in their reporting of medication use, sup-
Within this context, identifying modifiable variables (such as porting the reliability of study findings. Our assessment did
obesity, some comorbidities, medication overuse, and lifestyle not include information on the number of doses per day and,
factors) and unmodifiable variables (such as age, sex, race, and therefore, cannot be used to evaluate any dose–response

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Neurology.org/N

Table 4 Factors associated with opioid use based on nested multivariable binary logistic regression models
Demographic Headache characteristics ED/UC past 6 months
Variable model of respondents Psychiatric comorbidities for headache ≥1 CV comorbidity

a a a a
Male 2.11 (1.71–2.62) 1.92 (1.53–2.41) 1.80 (1.43–2.27) 1.77 (1.40–2.22) 1.74 (1.38–2.19)a

Age, y

25–34 (ref: 18–24) 0.98 (0.65–1.46) 0.99 (0.65–1.50) 0.91 (0.60–1.38) 0.91 (0.59–1.38) 0.88 (0.58–1.35)

35–44 0.81 (0.55–1.20) 0.83 (0.55–1.26) 0.81 (0.54–1.22) 0.84 (0.56–1.26) 0.78 (0.52–1.18)

45–54 0.87 (0.59–1.29) 0.84 (0.56–1.26) 0.89 (0.60–1.33) 0.90 (0.60–1.35) 0.80 (0.53–1.20)

55–64 0.88 (0.58–1.33) 0.92 (0.60–1.42) 0.98 (0.65–1.50) 0.99 (0.65–1.51) 0.83 (0.54–1.27)

≥65 0.73 (0.46–1.16) 0.86 (0.53–1.39) 1.11 (0.69–1.77) 1.08 (0.68–1.73) 0.88 (0.54–1.42)

Employed (FT/PT) 0.76 (0.62–0.92)a 0.83 (0.67–1.01) Trimmedb — —

Education: ≥4-y degree 0.83 (0.69–1.00)a 0.89 (0.73–1.08) — — —

Income

$30,000–$49,000 (ref: <30,000) 0.66 (0.50–0.88)a 0.75 (0.55–1.01) Trimmed — —

$50,000–$74,000 0.85 (0.65–1.12) 0.98 (0.74–1.31) Trimmed — —

≥$75,000 0.63 (0.49–0.82)a 0.77 (0.59–1.02) Trimmed — —

2 a a a
BMI, kg/m 1.03 (1.02–1.04) 1.02 (1.00–1.03) 1.02 (1.01–1.03) 1.02 (1.01–1.03) 1.02 (1.00–1.03)a
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MIDAS (moderate to severe) — 1.41 (1.14–1.76)a 1.18 (0.94–1.48) — —

MHDs

5–9 (ref: 0–4 MHDs) — 1.14 (0.89–1.44) 1.17 (0.92–1.49) 1.21 (0.96–1.53) 1.19 (0.95–1.51)

a
10–14 — 1.30 (0.97–1.75) 1.29 (0.96–1.74) 1.39 (1.04–1.85) 1.37 (1.02–1.82)a

≥15 — 1.64 (1.24–2.18)a 1.51 (1.13–2.02)a 1.67 (1.27–2.19)a 1.62 (1.24–2.13)a

Diagnosed migraine/chronic migraine — 0.38 (0.31–0.48)a 0.38 (0.30–0.49)a 0.39 (0.31–0.49)a 0.38 (0.30–0.48)a

Allodynia — 1.43 (1.17–1.75)a 1.36 (1.11–1.66)a 1.39 (1.14–1.70)a 1.39 (1.14–1.70)a

MSSS — 0.94 (0.91–0.97)a 0.93 (0.90–0.96)a 0.94 (0.91–0.97)a 0.94 (0.91–0.97)a

Continued
e465
 relationship with outcome variables. It is likely that opioid

Abbreviations: BMI = body mass index; CV = cardiovascular; ED = emergency department; FT/PT = full-time/part-time; GAD-7 = Generalized Anxiety Disorder, 7-item scale; MHD = monthly headache days; MIDAS = Migraine
≥1 CV comorbidity

1.32 (1.15–1.52)a

1.49 (1.18–1.89)a

1.37 (1.08–1.73)a

1.73 (1.30–2.31)a

1.56 (1.28–1.90)a
users represent a diverse population with potentially varied
outcomes. Currently, available data cannot distinguish be-
tween those who are receiving opioids in the ED/UC setting
for migraine and those visiting these facilities more frequently
for other comorbidities. Data are self-reported and were not
confirmed by HCPs or medical records. Strengths of the
CaMEO study include that it is a large nationwide sample (n =
16,789) that provides a substantial volume of data to assist in
ED/UC past 6 months

characterizing people with migraine in terms of comorbidities,

treatment consultation, diagnosis, and patterns of care. Fur-
1.35 (1.18–1.55)a

1.51 (1.20–1.91)a

1.36 (1.07–1.71)a

1.76 (1.33–2.34)a
for headache

thermore, descriptive data such as those provided are limited

in the literature, as many published studies have been limited
to the assessment of sociodemographic factors associated with
—

opioid misuse, abuse, and overdose.33–35

The current analysis of population (as opposed to clinical)

data extends our knowledge about the associations among
Psychiatric comorbidities

sociodemographic, headache, and other characteristics asso-

Table 4 Factors associated with opioid use based on nested multivariable binary logistic regression models (continued)

ciated with opioid use in those with migraine. Opioid use is

Disability Assessment; MSSS = Migraine Symptom Severity Score; PHQ = Patient Health Questionnaire; TPI = Total Pain Index; UC = urgent care.

generally associated with greater headache-related burden;

1.34 (1.17–1.54)a

1.44 (1.14–1.82)a

1.30 (1.03–1.65)a

markers of worse health, including elevated BMI and CV, and

psychiatric comorbidities; elevated TPI and ED/UC facility
use; and poorer quality of life. Variables associated with
a higher likelihood of opioid use include absence of a physi-
—

cian diagnosis of migraine and more monthly headache days.

The results reported here may help HCPs to identify indi-
viduals at risk for opioid use, and future research may help to
elucidate the nature of associations between identified varia-
Headache characteristics

bles and opioid use, including their directionality.

1.42 (1.24–1.63)a

Acknowledgment
of respondents

Writing and editorial assistance was provided to the authors

by Peloton Advantage, LLC, an OPEN Health company,
Trimmed indicates nonsignificant variables were subsequently excluded from the model.

Parsippany, NJ, and was funded by Allergan plc. The opinions

—

expressed in this article are those of the authors. The authors

received no honorarium/fee or other form of financial
support related to the development of this article. Valerie
Marske of Vedanta Research worked with authors to develop
the assessment tools and to manage respondent recruiting
Demographic

and data collection.

model

Study funding
—

This study was sponsored by Allergan plc, Dublin, Ireland.

Values are odds ratio (95% confidence interval).

Disclosure
R.B. Lipton is the Edwin S. Lowe Professor of Neurology at the
Past 6 months ED/UC for headache

Albert Einstein College of Medicine in New York. He receives

Statistically significant associations.

research support from the NIH: 2PO1 AG003949 (mPI),

5U10 NS077308 (PI), RO1 NS082432 (investigator), 1RF1
TPI (no head, face, or neck)

Anxiety present (GAD-7)

AG057531 (site PI), RF1 AG054548 (investigator), 1RO1

AG048642 (investigator), R56 AG057548 (investigator), K23
≥1 CV comorbidity
Depression (PHQ)

NS09610 (mentor), K23AG049466 (mentor), and K23

NS107643 (mentor). He also receives support from the Mi-
graine Research Foundation and the National Headache
Variable

Foundation. He serves on the editorial board of Neurology® and

is senior advisor to Headache and associate editor for
b
a

e466 Neurology | Volume 95, Number 5 | August 4, 2020 Neurology.org/N

Cephalalgia. He has reviewed for the NIA and NINDS; holds
stock options in eNeura Therapeutics and Biohaven Holdings; Appendix (continued)
serves as consultant, advisory board member, or has received Name Location Contribution
honoraria from American Academy of Neurology, Alder,
Allergan, American Headache Society, Amgen, Autonomic Benjamin W. Albert Einstein Interpreted the data, drafted the
Friedman, College of Medicine, manuscript for intellectual
Technologies, Avanir, Biohaven, Biovision, Boston Scientific, MD Bronx, NY content, revised the manuscript
Dr. Reddy’s, Electrocore, Eli Lilly, eNeura Therapeutics, for intellectual content

GlaxoSmithKline, Merck, Pernix, Pfizer, Teva, Trigemina, Lisa Feder, Peloton Advantage, Drafted the manuscriptand
Vector, and Vedanta. He receives royalties from Wolff’s Head- PhD LLC, Parsippany, NJ revised the manuscript under the
guidance of the authors and
ache, 7th and 8th edition (Oxford Press University, 2009), approved the final manuscript for
Wiley, and Informa. D.C. Buse has received grant support and submission
honoraria from Allergan, Avanir, Amgen, Biohaven, Eli Lilly Aubrey Allergan plc, Irvine, Designed and conceptualized
and Company, and Promius and for work on the editorial Manack CA study, major role in the
Adams, PhD acquisition of data, interpreted
board of Current Pain and Headache Reports. She was not the data, drafted the manuscript
compensated for writing or presenting any abstracts, posters, for intellectual content, revised
platforms, manuscripts, editorials, or other scientific commu- the manuscript for intellectual
content
nications. B.W. Friedman reports no disclosures relevant to the
manuscript. L. Feder is an employee of Peloton Advantage, Kristina M. Vedanta Research, Interpreted the data, drafted the
Fanning, Chapel Hill, NC manuscript for intellectual
LLC, an OPEN Health company. A. Manack Adams is an PhD content, revised the manuscript
employee of Allergan plc. K.M. Fanning is an employee of for intellectual content

Vedanta Research, which has received research funding Michael L. Vedanta Research, Designed and conceptualized
from Allergan, Amgen, Dr. Reddy’s Laboratories, Eli Lilly, Reed, PhD Chapel Hill, NC study, major role in the
enrollment of patients and the
GlaxoSmithKline, Merck & Co., Inc., and Novartis, via grants acquisition of data, interpreted
to the National Headache Foundation. Vedanta has received the data, drafted the manuscript
for intellectual content, revised
funding directly from Allergan for work on the CaMEO study. the manuscript for intellectual
M.L. Reed is Managing Director of Vedanta Research, which content
has received research funding from Allergan, Amgen, Eli Lilly, Todd J. Mayo Clinic, Interpreted the data, drafted the
GlaxoSmithKline, Merck & Co., Inc., and Promius, and grants Schwedt, Phoenix, AZ manuscript for intellectual
MD content, revised the manuscript
from the National Headache Foundation. Vedanta Research for intellectual content
has received funding directly from Allergan for work on the
CaMEO study. T.J. Schwedt has served as a consultant for
Alder, Allergan, Amgen, ATI, Aural Analytics, Avanir, Cipla,
References
Dr. Reddy’s Laboratories, Eli Lilly, Ipsen Bioscience, Nocira, 1. Headache Classification Committee of the International Headache Society. The In-
Novartis, Promius Pharma, Second Opinion, Teva, and Xoc. ternational Classification of Headache Disorders, 3rd edition. Cephalalgia 2018;38:1–211.
2. Pietrobon D, Moskowitz MA. Pathophysiology of migraine. Annu Rev Physiol 2013;
He holds stock options in Aural Analytics, Nocira, and Second 75:365–391.
Opinion and has received research funding from Amgen. Go to 3. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, re-
gional, and national incidence, prevalence, and years lived with disability for 328
Neurology.org/N for full disclosures. diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global
Burden of Disease Study 2016. Lancet 2017;390:1211–1259.
4. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine
Publication history prevalence, disease burden, and the need for preventive therapy. Neurology 2007;68:
Received by Neurology May 20, 2019. Accepted in final form 343–349.
November 7, 2019. 5. Lipton RB, Bigal ME, Scher AI, Stewart WF. The global burden of migraine.
J Headache Pain 2003;4:S3–S11.
6. Buse DC, Murray S, Dumas PK, et al. Life with migraine, effect on relationships, career
and finances, and overall health and well-being results of the Chronic Migraine
Epidemiology and Outcomes (CAMEO) study [abstract MTIS2008-009]. Cepha-
Appendix Authors lalgia 2018;38(1 suppl):9–10.
7. Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache
Name Location Contribution (an evidence-based review): report of the Quality Standards Subcommittee of the
American Academy of Neurology. Neurology 2000;55:754–762.
Richard B. Albert Einstein Designed and conceptualized 8. Bonafede M, Wilson K, Xue F. Long-term treatment patterns of prophylactic and
Lipton, MD College of Medicine, study, major role in the acquisition acute migraine medications and incidence of opioid-related adverse events in patients
Bronx, NY of data, interpreted the data, with migraine. Cephalalgia 2019;39:1086–1098.
contributed to data analysis, 9. Buse DC, Pearlman SH, Reed ML, Serrano D, Ng-Mak DS, Lipton RB. Opioid use
drafted the manuscript for and dependence among persons with migraine: results of the AMPP study. Headache
intellectual content, revised the 2012;52:18–36.
manuscript for intellectual content 10. Friedman BW, West J, Vinson DR, Minen MT, Restivo A, Gallagher EJ. Current
management of migraine in US emergency departments: an analysis of the National
Dawn C. Albert Einstein Designed and conceptualized Hospital Ambulatory Medical Care Survey. Cephalalgia 2015;35:301–309.
Buse, PhD College of Medicine, study, major role in the 11. Franklin GM. Opioids for chronic noncancer pain: a position paper of the American
Bronx, NY acquisition of data, interpreted Academy of Neurology. Neurology 2014;83:1277–1284.
the data, drafted the manuscript 12. Langer-Gould AM, Anderson WE, Armstrong MJ, et al. The American Academy of
for intellectual content, revised Neurology’s top five choosing wisely recommendations. Neurology 2013;81:1004–1011.
the manuscript for intellectual 13. Lipton RB, Fanning KM, Serrano D, Reed ML, Cady R, Buse DC. Ineffective acute
content treatment of episodic migraine is associated with new-onset chronic migraine. Neu-
rology 2015;84:688–695.

Neurology.org/N Neurology | Volume 95, Number 5 | August 4, 2020 e467

 14. Mathew NT, Reuveni U, Perez F. Transformed or evolutive migraine. Headache 26. Schwedt TJ, Alam A, Reed ML, et al. Factors associated with acute medication overuse
1987;27:102–106. in people with migraine: results from the 2017 Migraine in America Symptoms and
15. Bigal ME, Lipton RB. Excessive acute migraine medication use and migraine pro- Treatment (MAST) study. J Headache Pain 2018;19:38.
gression. Neurology 2008;71:1821–1828. 27. Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine
16. Bigal ME, Lipton RB. Clinical course in migraine: conceptualizing migraine trans- medications and evolution from episodic to chronic migraine: a longitudinal
formation. Neurology 2008;71:848–855. population-based study. Headache 2008;48:1157–1168.
17. Bigal ME, Lipton RB. Overuse of acute migraine medications and migraine chron- 28. Roeckel LA, Le Coz GM, Gaveriaux-Ruff C, Simonin F. Opioid-induced hyperalgesia:
ification. Curr Pain Headache Rep 2009;13:301–307. cellular and molecular mechanisms. Neuroscience 2016;338:160–182.
18. Finocchi C, Viani E. Opioids can be useful in the treatment of headache. Neurol Sci 29. Burstein R, Noseda R, Borsook D. Migraine: multiple processes, complex patho-
2013;34(suppl 1):S119–S124. physiology. J Neurosci 2015;35:6619–6629.
19. Manack Adams A, Serrano D, Buse DC, et al. The impact of chronic migraine: the 30. Thorlund K, Sun-Edelstein C, Druyts E, et al. Risk of medication overuse headache
Chronic Migraine Epidemiology and Outcomes (CaMEO) study methods and across classes of treatments for acute migraine. J Headache Pain 2016;17:107.
baseline results. Cephalalgia 2015;35:563–578. 31. Khodneva Y, Muntner P, Kertesz S, Kissela B, Safford MM. Prescription opioid use
20. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden and risk of coronary heart disease, stroke, and cardiovascular death among adults from
of migraine in the United States: data from the American Migraine Study II. Headache a prospective cohort (REGARDS study). Pain Med 2016;17:444–455.
2001;41:646–657. 32. Lipton RB, Manack Adams A, Buse DC, Fanning KM, Reed ML. A comparison of the
21. Stewart WF, Lipton RB, Dowson AJ, Sawyer J. Development and testing of the Chronic Migraine Epidemiology and Outcomes (CaMEO) study and American
Migraine Disability Assessment (MIDAS) Questionnaire to assess headache-related Migraine Prevalence and Prevention (AMPP) study: demographics and headache-
disability. Neurology 2001;56:S20–S28. related disability. Headache 2016;56:1280–1289.
22. Lipton RB, Bigal ME, Ashina S, et al. Cutaneous allodynia in the migraine population. 33. Chang YP. Factors associated with prescription opioid misuse in adults aged 50 or
Ann Neurol 2008;63:148–158. older. Nurs Outlook 2018;66:112–120.
23. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity 34. Zocca J, Sharifzadeh Y, Mackey S, Hah J. Factors associated with prescription opioid
measure. J Gen Intern Med 2001;16:606–613. abuse in a cross-sectional cohort of new pain clinic patients [abstract 149]. J Pain
24. Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing generalized 2015;16:S13.
anxiety disorder: the GAD-7. Arch Intern Med 2006;166:1092–1097. 35. Nechuta SJ, Tyndall BD, Mukhopadhyay S, McPheeters ML. Sociodemographic
25. Matchar DB, Young WB, Rosenberg JH, et al. Evidence-Based Guidelines for Mi- factors, prescription history and opioid overdose deaths: a statewide analy-
graine Headache in the Primary Care Setting: Pharmacological Management of Acute sis using linked PDMP and mortality data. Drug Alcohol Depend 2018;190:
Attacks. Minneapolis: American Academy of Neurology; 2000. 62–71.

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