Abstract
Objective
The primary objective of this study was to evaluate opioid and barbiturate utilization before and after the first prescription of the calcitonin gene–related peptide receptor antagonist rimegepant in individuals with migraine.
Background
Although not recommended in migraine treatment guidelines, opioids and barbiturates are often prescribed for the acute treatment of migraine, despite the risks of dependence and harm. Initiating a migraine‐specific acute treatment might reduce the use of opioids and barbiturates.
Methods
This retrospective cohort study among adults in the United States with migraine and a first prescription for rimegepant (fill quantity of eight tablets, indicative of acute treatment) was based on administrative claims data from the IQVIA PharMetrics Plus longitudinal health plan database (September 1, 2019, through March 31, 2023). For opioids and butalbital (separately), number of prescription fills and average dispensed amounts (as morphine milligram equivalents [MME] and milligrams [mg], respectively) were assessed in the 180 days preceding (pre‐index) and the 180 days following (post‐index) rimegepant initiation. Subgroup analyses included individuals using ≥ 1 preventive treatment, and individuals with problematic opioid use (≥ 3 opioid prescriptions and/or MME in the fourth quartile).
Results
Among 1928 opioid users, rimegepant initiation was associated with a significant difference in opioid prescription fills (median [interquartile range (IQR)] 2 [1–5] pre‐index vs. 1 [0–5] post‐index, p < 0.001) and average dispensed MME (25 [17.5–37.5] pre‐index vs. 14 [0–30] post‐index, p < 0.001), and 740 users (38.4%) discontinued opioids. Among 873 butalbital users, rimegepant initiation was associated with a significant difference in butalbital prescription fills (median [IQR] 2 [1–4] pre‐index vs. 1 [0–3] post‐index, p < 0.001) and average dispensed mg (200 [100–300] pre‐index vs. 25 [0–187.5] post‐index, p < 0.001), and 422 users (48.3%) discontinued opioids. Rimegepant initiation was associated with reduction of opioid and butalbital utilization in the subgroups using preventive treatment, and reduction of opioid utilization in the subgroup with problematic opioid use.
Conclusions
Rimegepant initiation was associated with reductions in utilization of opioids and butalbital, including in individuals using preventive treatment for migraine, and with reduction of opioid utilization in individuals with problematic opioid use.
Keywords: barbiturate, butalbital, calcitonin gene–related peptide receptor antagonist, migraine, opioid, rimegepant
Plain Language Summary
Opioids and butalbital are often prescribed for the acute treatment of migraine but they are not recommended and can be addictive. We analyzed a claims database to find out if starting rimegepant treatment for migraine might decrease opioid and butalbital use. Our study showed opioid and butalbital use, for any reason, decreased in people with migraine after starting rimegepant, including those who were using the most opioids.
Abbreviations
- CGRP
calcitonin gene–related peptide
- ICD‐10‐CM
International Classification of Diseases, Tenth Revision, Clinical Modification
- IQR
interquartile range
- MME
morphine milligram equivalent
- MOH
medication overuse headache
- SD
standard deviation
INTRODUCTION
The harms associated with opioid use are a well‐established global problem. 1 , 2 The US Food and Drug Administration requires all opioid medications, including immediate release/short‐acting and extended release/long‐acting formulations, to carry a boxed warning on the label stating the risk for addiction, dependence, abuse, and misuse, which can lead to overdose and death. 3 , 4 Opioid use for migraine is associated with negative outcomes, 5 with frequent use (≥ 10 days/month for > 3 months 6 ) associated with medication‐overuse headache (MOH) and progression to chronic migraine; 7 , 8 , 9 , 10 MOH is associated with quality of life impairments, 11 greater disability, 12 and higher healthcare resource utilization. 13 , 14 Evidence suggests opioids are not as effective as acute migraine medications and their use may impair the effectiveness of acute treatments for migraine, such as triptans. 15 , 16 Clinical guidelines recommend against the use of opioids for migraine, except in limited circumstances. 3 , 17 , 18 , 19 , 20
However, patients with migraine are frequently prescribed opioids 9 , 21 , 22 , 23 , 24 or use opioids prescribed for other conditions. Opioid prescription is twice as common in people with migraine compared with non‐migraine controls. 21 , 25 In the American Migraine Prevalence and Prevention (AMPP) study, ~30% of respondents with migraine reported current or previous opioid use. 5 In a retrospective claims analysis of 147,832 people with migraine who initiated preventive treatment, 77.4% also received an opioid for acute treatment during the follow‐up period of up to 5 years. 26 Emergency department visits for migraine frequently result in administration of opioids or their prescription—20% in Australia 24 and 59% in the United States 27 —and this is associated with increased future health resource utilization. 28 Nearly 20% of patients presenting to a tertiary care headache center reported they first received opioids in the emergency department. 29
Barbiturates are frequently used for migraine, including butalbital, which is often found in combination products with analgesics such as aspirin, acetaminophen, or codeine. A survey of 9128 respondents with episodic migraine in the United States found 6% were using barbiturate‐containing products. 30 Analyses based on acute medication use by 3121 respondents in the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study found that 12.8% used barbiturates. 22 Similar to opioids, barbiturates are associated with risks of dependency, 31 MOH, and migraine progression, 16 , 32 and clinical guidelines discourage their use for migraine. 18 , 19
When patients with migraine are using an opioid or barbiturate, initiating a migraine‐specific acute medication recommended in treatment guidelines 17 , 18 could reduce their use of the respective opioid or barbiturate. Reducing utilization of opioids and barbiturates has the potential to benefit the individual in terms of safety, but also to reduce the societal burden associated with migraine.
The efficacy and safety of rimegepant, an orally administered small‐molecule calcitonin gene–related peptide (CGRP) receptor antagonist, have been established for the acute treatment 33 , 34 , 35 , 36 , 37 and preventive treatment 38 of migraine. Preliminary research suggested initiating rimegepant resulted in reduced utilization of opioids and barbiturates 39 , 40 but more data are needed. We hypothesized that the initiation of rimegepant would be associated with a reduction in the utilization of opioids and butalbital among individuals with migraine. Specifically, it was hypothesized that rimegepant initiation would result in a measurable reduction in the number of prescription fills, average dispensed amounts, and the overall duration of use of opioids and butalbital.
The primary objective of this study was to evaluate opioid and butalbital utilization before and after the first prescription of rimegepant in individuals with migraine, using healthcare claims data. Secondary objectives were to describe the characteristics, including demographics, comorbid conditions, and prior medication use of individuals initiating rimegepant, and to conduct subgroup analyses for individuals using ≥ 1 preventive treatment and those with problematic opioid use (≥ 3 opioid prescriptions and/or morphine milligram equivalents [MMEs] in the fourth quartile).
METHODS
Study design
This non‐interventional, retrospective cohort study was based on administrative claims data among US adults with migraine and a first prescription for rimegepant. The analyses used data from the IQVIA PharMetrics Plus longitudinal health plan database. The overall study period was from September 1, 2019, through March 31, 2023. These analyses used commercially available de‐identified data, so formal review and approval by an institutional review board/independent ethics committee was not sought. Similarly, informed consent from participants was not required.
Data source
IQVIA's PharMetrics Plus is a commercial claims database containing healthcare records of employees and their dependents sourced from employer‐sponsored healthcare plans in the United States. The database contains information on demographics, plan enrollment, inpatient and outpatient medical claims, and outpatient pharmacy claims. The data are a geographically representative sample of the commercially insured population < 65 years of age, with ~40 million people per year included.
Study population
The study analyzed individuals with a first prescription for rimegepant. The date of filling (dispensing) the first prescription of rimegepant was the index date. Individuals were followed during the 180 days preceding the index date (the pre‐index period) and the 180 days including and following the index date (the post‐index period). The 180‐day duration of both pre‐ and post‐index periods was selected to balance an adequate observation period with availability of data/sample size.
Eligibility criteria for inclusion in the study cohort were an index date between March 1, 2020, and October 1, 2022, a rimegepant index fill quantity of eight tablets (indicative of acute treatment), a period of rimegepant use ≥ 180 days (from the index date to the last fill date +30 days), and ≥ 1 prescription fill during the pre‐index period of one of the medications of interest: an opioid, butalbital (single ingredient or in a combination product), alprazolam, bronchodilating rescue inhaler, or hydroxymethylglutaryl‐CoA reductase inhibitor (statin). Also required for inclusion were ≥ 180 days of continuous enrollment in commercial medical and pharmacy benefits both prior to and following the index date. Individuals had to be ≥ 18 years of age on the index date, have a diagnosis of migraine (based on the presence of International Classification of Diseases, Tenth Revision, Clinical Modification [ICD‐10‐CM] code G43.xx at any time during the pre‐ or post‐index periods), have no diagnosis of cancer during the pre‐ or post‐index periods, and have no prior use of other novel acute migraine agents (gepants or ditans) in the pre‐index period.
Outcomes
Baseline was defined as the pre‐index period plus the index date. Baseline clinical characteristics were assessed based on medical and pharmacy claims, with demographic information sourced from the enrollment files, and comorbidities based on ≥ 1 inpatient or outpatient diagnosis unless otherwise specified. Prior medication use, at any time during the pre‐index period, was identified from pharmacy claims using National Drug Codes or from medical claims using Healthcare Common Procedure Coding System codes. Medication associated with migraine included acute treatments and preventive treatments; medications were categorized as such based on their common usage for migraine. The codes used in the analysis are available in the supporting information.
Individuals were grouped according to their pre‐index use of the five medications of interest into five separate groups (opioids, butalbital, alprazolam, rescue inhalers, or statins). Individuals using more than one of the medications of interest were included in each relevant group (the groups were not mutually exclusive). Of primary interest was the utilization (separately) of opioids and butalbital. The utilization of alprazolam, rescue inhalers, and statins was of secondary interest, as comparators of continuous use and episodic use prescription medications. For each medication of interest, outcome measures included the total number of prescription fills dispensed, total quantity dispensed (number of tablets or other medication units), average dispensed amount (calculated for opioids in MME and for butalbital and alprazolam in mg), total duration of use (days supplied), and the proportion of individuals with discontinuation (defined as the absence of any prescription fill in the post‐index period). Each outcome measure was calculated separately for the pre‐index period (study month 1 [corresponding to days 1–30] through study month 6 [days 151–180]) and post‐index period (study month 7 [days 181–210] through study month 12 [days 331–360]), based on pharmacy claims.
Statistical analysis
Baseline demographics, clinical characteristics, and migraine medication use were presented descriptively. The normality of continuous and discrete data was assessed via the Shapiro–Wilk test. For normally distributed data (age), mean with standard deviation (SD) were presented, while median (interquartile range [IQR], i.e., quartile 1–quartile 3) was presented for non‐normal data. Counts and percentages were presented for categorical variables.
Medication utilization outcomes from the pre‐index period to the post‐index period were based on aggregates for each outcome measure, calculated for the pre‐index period (study month 1–6) and post‐index period (study month 7–12), and presented as median (IQR). The differences between pre‐index and post‐index period were compared using the Wilcoxon signed rank test.
Two subgroups of interest were assessed separately. The first subgroup comprised all those individuals in the overall cohort using ≥ 1 preventive treatment for migraine during the pre‐index period; preventive medications were not predefined but were those commonly used for prevention of migraine. The second subgroup comprised all those individuals in the overall cohort with potentially problematic opioid use, defined as ≥ 3 opioid prescriptions during the pre‐index period, and/or MME in the fourth quartile during the pre‐index period.
Two sensitivity analyses were conducted on the overall study cohort for opioid users and butalbital users. The first sensitivity analysis investigated a longer duration of pre‐ and post‐index periods (360 days each), with April 1, 2022, as the end of cohort eligibility. The second sensitivity analysis excluded all individuals with a major surgical procedure or injury diagnosis at any point during the study period to exclude use of opioids for other non‐chronic conditions.
All data were used under license from the respective owner and analyzed in Pfizer's Global Real‐World Data infrastructure. Statistical analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC), and a two‐sided p < 0.05 was considered statistically significant.
No statistical power calculation was conducted prior to the study and the sample size was based on the available data after applying inclusion and exclusion criteria to the individuals in the database.
RESULTS
Study population
Of 52,591,063 commercially insured individuals in the database, 45,051 had an eligible first prescription for rimegepant, and 4049 met the other criteria for inclusion in the study cohort (Table S1 in supporting information). During the pre‐index period, there were 1928 opioid users, 873 butalbital users, 815 alprazolam users, 948 rescue inhaler users, and 1142 statin users. Of the 1928 opioid users, 1543 were taking preventive treatment for migraine and 1037 were in the subgroup with problematic opioid use (Table 1). Of the 873 butalbital users, 701 were taking preventive treatment for migraine (Table 1).
TABLE 1.
Baseline demographics and clinical characteristics among pre‐index opioid users, butalbital users, and the subgroups of interest.
| Opioid user | Butalbital user | ||||
|---|---|---|---|---|---|
| Overall (n = 1928) | Subgroup of preventive treatment users (n = 1543) | Subgroup with problematic opioid use (n = 1037) | Overall (n = 873) | Subgroup of preventive treatment users (n = 701) | |
| Age, years | |||||
| Mean (SD) | 46.64 (11.22) | 46.75 (11.20) | 47.62 (10.97) | 46.05 (11.26) | 46.11 (11.42) |
| Age category, years, n (%) | |||||
| 18–34 | 279 (14.5) | 216 (14.0) | 123 (11.9) | 144 (16.5) | 117 (16.7) |
| 35–54 | 1152 (59.8) | 927 (60.1) | 626 (60.4) | 522 (59.8) | 413 (58.9) |
| 55–64 | 430 (22.3) | 347 (22.5) | 243 (23.4) | 180 (20.6) | 147 (21.0) |
| ≥65 | 67 (3.5) | 53 (3.4) | 45 (4.3) | 27 (3.1) | 24 (3.4) |
| Sex, n (%) | |||||
| Female | 1699 (88.1) | 1365 (88.5) | 911 (87.8) | 791 (90.6) | 633 (90.3) |
| Male | 229 (11.9) | 178 (11.5) | 126 (12.2) | 82 (9.4) | 68 (9.7) |
| Region, n (%) | |||||
| East | 210 (10.9) | 160 (10.4) | 103 (9.9) | 131 (15.0) | 98 (14.0) |
| Midwest | 405 (21.0) | 339 (22.0) | 186 (17.9) | 182 (20.8) | 152 (21.7) |
| South | 1081 (56.1) | 871 (56.4) | 626 (60.4) | 489 (56.0) | 399 (56.9) |
| West | 230 (11.9) | 171 (11.1) | 121 (11.7) | 70 (8.0) | 52 (7.4) |
| Unknown | 2 (0.1) | 2 (0.1) | 1 (0.1) | 1 (0.1) | 0 (0.0) |
| Chronic pain and comorbidities, n (%) | |||||
| Any chronic migraine | 925 (48.0) | 818 (53.0) | 512 (49.4) | 442 (50.6) | 394 (56.2) |
| Any other (non‐migraine) chronic pain | 1132 (58.7) | 926 (60.0) | 701 (67.6) | 361 (41.4) | 301 (42.9) |
| Any chronic pain (migraine + other) | 1517 (78.7) | 1254 (81.3) | 876 (84.5) | 612 (70.1) | 521 (74.3) |
| Any injury diagnosis | 550 (28.5) | 448 (29.0) | 280 (27.0) | 166 (19.0) | 138 (19.7) |
| Any major surgical procedure | 709 (36.8) | 576 (37.3) | 344 (33.2) | 158 (18.1) | 134 (19.1) |
| Any Elixhauser comorbidity | 1442 (74.8) | 1182 (76.6) | 805 (77.6) | 590 (67.6) | 482 (68.8) |
Abbreviation: SD, standard deviation.
There were 267 individuals using both opioids and butalbital, comprising 13.8% of overall opioid users and 30.6% of overall butalbital users. There were 223 (14.5% of 1543) individuals in the subgroup taking preventive treatment for migraine and 149 (14.4% of 1037) were in the subgroup with problematic opioid use.
Baseline characteristics
Baseline demographics and clinical characteristics for opioid users and butalbital users and the subgroups of interest are provided in Table 1. Most individuals were female, and the mean (SD) age was 46.64 (11.22) years for opioid users and 46.05 (11.26) for butalbital users (Table 1). Opioid users and butalbital users were using a variety of treatments for migraine during the pre‐index period, with preventive treatments including beta‐blockers, tricyclic antidepressants, antidepressants, anticonvulsants, anti‐CGRP monoclonal antibodies, and onabotulinumtoxinA (Table 2). Elixhauser comorbidities were common at baseline, with 12.4% of opioid users and 8.6% of butalbital users having 4–5 comorbidities; 5.9% of opioid users and 2.6% of butalbital users had ≥ 6 comorbidities (Table S2 in supporting information).
TABLE 2.
Pre‐index medication use, among pre‐index opioid users, butalbital users, and the subgroups of interest.
| Opioid user | Butalbital user | ||||
|---|---|---|---|---|---|
| Overall (n = 1928) | Subgroup of preventive treatment users (n = 1543) | Subgroup with problematic opioid use (n = 1037) | Overall (n = 873) | Subgroup of preventive treatment users (n = 701) | |
| Medication associated with acute treatment for migraine, n (%) | |||||
| Triptan | 918 (47.6) | 747 (48.4) | 472 (45.5) | 393 (45.0) | 329 (46.9) |
| Ergot | 22 (1.1) | 19 (1.2) | 17 (1.6) | 7 (0.8) | 7 (1.0) |
| Nonsteroidal anti‐inflammatory drug | 698 (36.2) | 581 (37.7) | 389 (37.5) | 283 (32.4) | 240 (34.2) |
| Acetaminophen | 265 (13.7) | 221 (14.3) | 144 (13.9) | 826 (94.6) | 660 (94.2) |
| Isometheptene combination | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Antiemetic (migraine) | 435 (22.6) | 365 (23.7) | 269 (25.9) | 194 (22.2) | 174 (24.8) |
| Antiemetic (other) | 764 (39.6) | 642 (41.6) | 421 (40.6) | 300 (34.4) | 251 (35.8) |
| Medication associated with preventive treatment for migraine, n (%) | |||||
| Beta‐blocker | 441 (22.9) | 438 (28.4) | 255 (24.6) | 212 (24.3) | 209 (29.8) |
| Tricyclic antidepressant | 299 (15.5) | 299 (19.4) | 157 (15.1) | 176 (20.2) | 175 (25.0) |
| Antidepressant | 400 (20.7) | 398 (25.8) | 245 (23.6) | 166 (19.0) | 166 (23.7) |
| Anticonvulsant | 539 (28.0) | 538 (34.9) | 281 (27.1) | 260 (29.8) | 259 (36.9) |
| Anti‐CGRP monoclonal antibody | 658 (34.1) | 650 (42.1) | 372 (35.9) | 272 (31.2) | 271 (38.7) |
| OnabotulinumtoxinA | 399 (20.7) | 399 (25.9) | 230 (22.2) | 174 (19.9) | 174 (24.8) |
| Used ≥1 conventional oral prevention agent | 1227 (63.6) | 1223 (79.3) | 678 (65.4) | 565 (64.7) | 561 (80.0) |
| Used ≥1 of any prevention agent | 1555 (80.7) | 1543 (100.0) | 862 (83.1) | 706 (80.9) | 701 (100.0) |
Note: Medications associated with migraine were categorized as such based on their common usage for migraine.
Abbreviation: CGRP, calcitonin gene–related peptide.
Baseline demographics and clinical characteristics of alprazolam, rescue inhaler, and statin users are provided in Table S3 in supporting information.
Changes in utilization of opioids and butalbital and associations with rimegepant initiation
Rimegepant initiation was associated with reduction in utilization of opioids, including number of prescription fills, total quantity dispensed, average dispensed MME, and duration of use (Table 3). During the pre‐index period, overall opioid users (n = 1928) had a median (IQR) of 2 (1–5) opioid prescription fills, which was statistically significantly different (p < 0.001) from the median (IQR) of 1 (0–5) during the post‐index period. Similarly, the average dispensed MME in the pre‐index period was significantly different from that in the post‐index period (25 [17.5–37.5] pre‐index vs. 14 [0–30] post‐index, p < 0.001). A total of 740 (38.4%) opioid users overall discontinued opioids during the post‐index period (Table 3). The reductions in the proportion of the overall population using opioids encompassed a wide range of individual agents, including hydrocodone (43.1% to 25.6%), oxycodone (27.9% to 18.8%), tramadol (28.2% to 18.9%), and codeine (15.5% to 8.7%; Table 4).
TABLE 3.
Changes in utilization of opioids and butalbital after rimegepant initiation.
| Pre‐index | Post‐index | p value | Discontinuation a , n (%) | |
|---|---|---|---|---|
| Opioid utilization | ||||
| Opioid users overall (n = 1928) | 740 (38.4) | |||
| Number of prescription fills | 2 (1–5) | 1 (0–5) | <0.001 | |
| Total tablets/quantity dispensed | 53 (20–270) | 30 (0–300) | <0.001 | |
| Average dispensed MME | 25 (17.5–37.5) | 14 (0–30) | <0.001 | |
| Total duration of use (days) | 14 (5–107) | 7 (0–120) | <0.001 | |
| Opioid users, subgroup of preventive treatment users (n = 1543) | 555 (36.0) | |||
| Number of prescription fills | 2 (1–5) | 2 (0–5) | <0.001 | |
| Total tablets/quantity dispensed | 56 (20–280) | 35 (0–300) | <0.001 | |
| Average dispensed MME | 25 (17–37.5) | 15 (0–30) | <0.001 | |
| Total duration of use (days) | 14 (5–115) | 9 (0–120) | <0.001 | |
| Opioid users, subgroup with problematic opioid use (n = 1037) | 202 (19.5) | |||
| Number of prescription fills | 5 (3–7) | 5 (1–7) | <0.001 | |
| Total tablets/quantity dispensed | 230 (70–555) | 212 (28–560) | <0.001 | |
| Average dispensed MME | 30 (18.3–45) | 20 (9–37.5) | <0.001 | |
| Total duration of use (days) | 90 (18–180) | 90 (7–180) | <0.001 | |
| Butalbital utilization | ||||
| Butalbital users overall (n = 873) | 422 (48.3) | |||
| Number of prescription fills | 2 (1–4) | 1 (0–3) | <0.001 | |
| Total tablets/quantity dispensed | 60 (30–120) | 15 (0–90) | <0.001 | |
| Average dispensed mg | 200 (100–300) | 25 (0–187.5) | <0.001 | |
| Total duration of use (days) | 20 (7–60) | 4 (0–40) | <0.001 | |
| Butalbital users, subgroup of preventive treatment users (n = 701) | 329 (46.9) | |||
| Number of prescription fills | 2 (1–4) | 1 (0–4) | <0.001 | |
| Total tablets/quantity dispensed | 60 (30–135) | 20 (0–108) | <0.001 | |
| Average dispensed mg | 200 (100–300) | 33.3 (0–187.5) | <0.001 | |
| Total duration of use (days) | 21 (8–60) | 5 (0–45) | <0.001 |
Note: Duration of pre‐index period 180 days, duration of post‐index period 180 days. Data are median (interquartile range Q1–Q3) with Wilcoxon signed rank test p‐value.
Abbreviations: MME, morphine milligram equivalents; Q1, quartile 1; Q3, quartile 3.
Discontinuation of opioids.
TABLE 4.
Changes in use of individual opioids after rimegepant initiation, among pre‐index opioid users.
| Opioid users | ||||||
|---|---|---|---|---|---|---|
| Overall (n = 1928) | Subgroup of preventive treatment users (n = 1543) | Subgroup with problematic opioid use (n = 1037) | ||||
| Pre‐index | Post‐index | Pre‐index | Post‐index | Pre‐index | Post‐index | |
| Type of opioid used, n (%) | ||||||
| Buprenorphine | 52 (2.7) | 43 (2.2) | 45 (2.9) | 35 (2.3) | 49 (4.7) | 40 (3.9) |
| Codeine | 299 (15.5) | 168 (8.7) | 238 (15.4) | 146 (9.5) | 154 (14.9) | 108 (10.4) |
| Fentanyl | 23 (1.2) | 23 (1.2) | 18 (1.2) | 17 (1.1) | 23 (2.2) | 23 (2.2) |
| Hydrocodone | 831 (43.1) | 494 (25.6) | 658 (42.6) | 407 (26.4) | 442 (42.6) | 338 (32.6) |
| Hydromorphone | 68 (3.5) | 44 (2.3) | 56 (3.6) | 38 (2.5) | 55 (5.3) | 36 (3.5) |
| Meperidine | 1 (0.1) | 0 (0.0) | 1 (0.1) | 0 (0.0) | – | – |
| Methadone | 11 (0.6) | 14 (0.7) | 8 (0.5) | 11 (0.7) | 10 (1.0) | 13 (1.3) |
| Morphine | 41 (2.1) | 39 (2.0) | 37 (2.4) | 37 (2.4) | 41 (4.0) | 39 (3.8) |
| Oxycodone | 538 (27.9) | 363 (18.8) | 434 (28.1) | 302 (19.6) | 381 (36.7) | 283 (27.3) |
| Oxymorphone | 4 (0.2) | 4 (0.2) | 4 (0.3) | 4 (0.3) | 4 (0.4) | 4 (0.4) |
| Tapentadol | 18 (0.9) | 22 (1.1) | 16 (1.0) | 21 (1.4) | 17 (1.6) | 21 (2.0) |
| Tramadol | 543 (28.2) | 365 (18.9) | 447 (29.0) | 305 (19.8) | 292 (28.2) | 240 (23.1) |
| Other | 10 (0.5) | 4 (0.2) | 7 (0.5) | 3 (0.2) | 7 (0.7) | 3 (0.3) |
| Total number of prescription opioid agents used | ||||||
| Median (Q1–Q3) | 1 (1–1) | 1 (0–1) | 1 (1–1) | 1 (0–1) | 1 (1–2) | 1 (1–2) |
| 1 agent, n (%) | 1500 (77.8) | 855 (44.3) | 1189 (77.1) | 704 (45.6) | 682 (65.8) | 571 (55.1) |
| 2 agents, n (%) | 357 (18.5) | 277 (14.4) | 293 (19.0) | 236 (15.3) | 284 (27.4) | 221 (21.3) |
| ≥3 agents, n (%) | 71 (3.7) | 56 (2.9) | 61 (4.0) | 48 (3.1) | 71 (6.8) | 43 (4.1) |
Abbreviations: Q1, first quartile; Q3, third quartile.
Reductions in opioid utilization associated with rimegepant initiation were also seen in the subgroup of opioid users taking preventive treatment for migraine (n = 1543, Table 3), with reductions in the proportion of the subgroup using individual agents including hydrocodone (42.6% to 26.4%), oxycodone (28.1% to 19.6%), tramadol (29.0% to 19.8%), and codeine (15.4% to 9.5%; Table 4). In the subgroup with problematic opioid use (n = 1037), rimegepant initiation was associated with reductions in opioid utilization (Table 3), with reductions in the proportion of the subgroup using individual agents including hydrocodone (42.6% to 32.6%), oxycodone (36.7% to 27.3%), tramadol (28.2% to 23.1%), and codeine (14.9% to 10.4%; Table 4).
Rimegepant initiation was also associated with reduction in utilization of butalbital, including number of prescription fills, total quantity dispensed, average dispensed mg, and duration of use (Table 3). The overall butalbital users (n = 873) had a median (IQR) of 2 (1–4) butalbital prescription fills during the pre‐index period, which was significantly different from the post‐index period (1 [0–3], p < 0.001). Similarly, the average dispensed mg was also significantly different between the pre‐index period and the post‐index period (200 [100–300] vs. 25 [0–187.5], p < 0.001). A total of 422 (48.3%) butalbital users discontinued opioids during the post‐index period (Table 3). Reductions in butalbital utilization associated with rimegepant initiation were also seen for the subgroup of butalbital users taking preventive treatment for migraine (n = 701), in which a total of 329 (46.9%) discontinued opioids during the post‐index period (Table 3).
Changes in utilization of comparator medications (alprazolam, rescue inhalers, and statins)
Utilization of the comparator medications, alprazolam, rescue inhalers, and statins is shown in Table S4 in supporting information. There were statistically significant (p < 0.001) differences between post‐index and pre‐index period for the number of prescription fills, quantity dispensed, average dispensed mg, and duration of use. However, sizable differences in median were only seen in rescue inhaler utilization. For example, for rescue inhaler users, the median (IQR) of total quantity dispensed in the pre‐index period was 17 (8.5–36) compared with 0 (0–20.1) in the post‐index period. For alprazolam users, on the contrary, the median (IQR) of total quantity dispensed between pre‐index and post‐index period was 90 (30–210) and 90 (0–240), respectively.
Sensitivity analyses
The association between rimegepant initiation and reduction in opioid and butalbital utilization measures remained when the duration of pre‐index and post‐index periods were both increased to 360 days (Table S5 in supporting information) and when individuals with any injury or major surgical procedure during the study were excluded (Table S6 in supporting information).
DISCUSSION
This study found a reduction in measures of opioid and butalbital utilization among individuals with migraine in the United States following a first prescription for rimegepant. These are the first data evaluating changes in acute migraine treatment with opioids and barbiturates among patients who initiate rimegepant.
Rimegepant was associated with reductions in utilization of opioids and butalbital based on multiple measures: number of prescription fills, quantity dispensed, average dispensed amounts, and duration of use. This reflects an overall reduction in consumption of opioids and butalbital in the post‐index period by the study population. The utility of rimegepant for reducing opioid and butalbital utilization is underlined by the sizable proportion of users who discontinued opioids in the 6 months after their first prescription of rimegepant. The reduced utilization of opioids and butalbital was also seen in the subgroup taking preventive treatment for migraine; all patients with migraine require effective acute treatment and even those taking preventive treatment may need acute treatment optimization. Considerable reductions in utilization of opioids were seen in the subgroup with problematic opioid use. This subgroup had ≥ 3 opioid prescriptions and/or MME in the fourth quartile during the pre‐index period; the definition of problematic opioid use varies widely across different studies. 41
The reductions in utilization of opioids and butalbital associated with rimegepant initiation may be of benefit to patients with migraine who are reliant on opioids or butalbital. This is especially the case for those with problematic opioid use, by alleviating the potentially harmful consequences. Reductions in opioid‐related MOH could break the cycle of overuse of opioids causing more headaches. A reduction in opioid utilization associated with rimegepant initiation may also have societal benefits, considering the healthcare costs associated with opioid use in migraine. 21 , 28 , 42 Other groups with high opioid use may also benefit from rimegepant initiation; some, but not all, studies have identified racial/ethnic disparities in prescribing practices. 43 , 44
There are few comparable data evaluating the effect of individual treatments for migraine on opioids, barbiturates, or other acute medications. Initiation of ubrogepant was associated with reductions in opioid and barbiturate use. 45 , 46 Opioid use was reported to be high in new triptan users and remained high after triptan prescription. 47 Two studies have evaluated the impact of initiation of erenumab injections for the preventive treatment of migraine on opioid and barbiturate use. 48 , 49
In the current study, rimegepant initiation was associated with reductions in utilization of alprazolam, rescue inhalers, and statins. These medications were included in the study to provide comparators of continuous use and episodic use prescription medications and control for systematic bias, assuming that the utilization of the unrelated medications should be unchanged if rimegepant initiation was responsible for reductions of opioid or butalbital utilization. However, the observed reductions in utilization of the comparator medications were unexpected and difficult to explain. The reduction in alprazolam utilization on initiation of rimegepant is perhaps understandable in the context of migraine‐associated anxiety 50 , 51 because improvements in migraine symptoms might be expected to reduce anxiety and result in reduction of anti‐anxiety medication (alprazolam) use. The reduction in rescue inhaler use on initiation of rimegepant could potentially be a consequence of the role of CGRP in some types of asthma and the impact of rimegepant on the airway. 52 The reduction in statin use on initiation of rimegepant may perhaps be related to links between lipid metabolism and migraine, 53 and/or the impact of statins on the autonomic nervous system, 54 with some studies showing a beneficial effect of statin use on migraine symptoms. 55 These explanations are speculative and the cause of reductions in utilization of the comparator medications remains unclear, although it should be noted that variability (IQR) was high in some cases.
The association between rimegepant initiation and reductions in utilization of opioids and butalbital remained in both sensitivity analyses. This suggests the current findings are not driven by short‐term or post‐operative use of opioids or butalbital, and that the impact of rimegepant initiation on opioid and butalbital utilization is an enduring effect that is not just a consequence of prescribing a new medication.
This study had limitations. It is not known if the drugs investigated here (including opioids, butalbital, and the prior treatments) were being used to treat migraine, although in some cases migraine is the main use (e.g., butalbital) or only licensed indication (e.g., triptans). Although the data, based on a rimegepant index fill quantity of eight tablets, largely reflect an acute treatment pattern, it is not possible to establish if rimegepant was prescribed for acute or preventive treatment, or both. Information on the clinical outcome related to migraine management was not available so the implications of the observed reduction in opioid and butalbital utilization after rimegepant initiation are not known, and more research is needed to determine whether the changes translate into improved patient outcomes and reduced dependency risks. Further studies are also needed to investigate any role of prior treatment failures on the observed reductions in utilization of opioids and butalbital following rimegepant initiation to establish if the effects are specific to rimegepant or a response to the introduction of any effective treatment. The utilization measures were not independent of each other; for example, it is possible that the discontinuations from opioid use observed during the post‐index period contributed to the reductions in the other utilization measures analyzed in the current study. Further, establishing discontinuation can be difficult for medications taken as needed, although findings were consistent in the sensitivity analysis using a 360‐day duration for pre‐ and post‐index periods. The insurance claims database used for the study provided a large and robust sample but excluded some populations (such as people on public insurance policies such as Medicaid), limiting generalizability, and censoring effects are a possibility if health plan enrollment status changed. The database methodology necessitated the use of prescription dispensing as proxy for utilization of opioids and butalbital, and it is not possible to establish how much of each medication was actually taken as prescribed. The selection of appropriate control medications was challenging. Utilization of the current comparator medications was not expected to change, and the observed reductions are difficult to explain and may be confounded by the choice of medications. A challenge for future studies is the identification of a control drug prescribed as needed, and without a mechanistic link to rimegepant. It should also be noted that potential confounding factors for each individual patient could not be assessed; for example, whether a reduction of concomitant medications was discussed around the time of rimegepant initiation, if there were associated autonomic features of migraine that resolved with use of rimegepant rather than other medications, or if there was a holistic response to reduction of acute treatments for migraine other than opioids and barbiturates.
CONCLUSIONS
This study showed that starting patients with migraine on rimegepant can reduce their use of opioids and barbiturates. Rimegepant initiation was associated with reductions in utilization of opioids and butalbital, including in individuals using preventive treatment for migraine, and was associated with reduction of opioid utilization in individuals with problematic opioid use. Reduction in utilization of opioids and butalbital will benefit both the individual and society.
AUTHOR CONTRIBUTIONS
Noah Rosen: Conceptualization; visualization; writing – original draft; writing – review and editing. Aaron Jenkins: Visualization; writing – original draft; writing – review and editing. Karin Hygge Blakeman: Visualization; writing – original draft; writing – review and editing. Feng Dai: Formal analysis; visualization; writing – original draft; writing – review and editing. Lucy Abraham: Conceptualization; visualization; writing – original draft; writing – review and editing. Chelsea Leroue: Conceptualization; visualization; writing – original draft; writing – review and editing. Josh Brown: Conceptualization; data curation; visualization; writing – original draft; writing – review and editing.
FUNDING INFORMATION
This study was sponsored by Pfizer.
CONFLICT OF INTEREST STATEMENT
Noah Rosen reports speaker for AbbVie, American Headache Society, and Pfizer, and advisory boards for AbbVie, Eli Lilly, Lundbeck, and Pfizer. He has received research support from Amgen and Eli Lilly. He is a board member of AHS and section editor for Current Pain and Headache Reports. Aaron Jenkins, Karin Hygge Blakeman, Feng Dai, Lucy Abraham, and Chelsea Leroue are employees of Pfizer and own stock/stock options in Pfizer. Josh Brown was an employee of Pfizer at the time the study was conducted and owns stock/stock options in Pfizer.
Supporting information
Table S1.
Data S1.
ACKNOWLEDGMENTS
Medical writing support was provided by Kim Russell, PhD, of Engage Scientific Solutions and was funded by Pfizer. The authors would like to thank Gill L'Italien (Biohaven) and Linda Harris (Biohaven) for their contributions to the original study concept and design, and Ali Mohajer (QRAL) for analysis expertise in the original study.
DATA AVAILABILITY STATEMENT
The datasets analyzed in this study were used under license from IQVIA PharMetrics and cannot be shared.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1.
Data S1.
Data Availability Statement
The datasets analyzed in this study were used under license from IQVIA PharMetrics and cannot be shared.