Abstract
Objective:
Little is known about trends in attention deficit hyperactivity disorder (ADHD) diagnosis and treatment amongst patients with opioid use disorder. This study aimed to assess the nationwide trends in ADHD diagnoses and treatment among patients with opioid use disorder and ADHD and examine predictors of stimulant medications in patients receiving medications for opioid use disorder (MOUD).
Methods:
This study used a claims-based database of commercially-insured patients aged 13–64 to conduct two analyses: 1) an annual cross-sectional study of 387,980 patients diagnosed with opioid use disorder between 2007–2017 to estimate the prevalence of ADHD diagnosis and treatment and 2) a retrospective cohort study of 158,591 MOUD patients to test the association between patient characteristics and stimulant medication receipt using multivariable regression.
Results:
From 2007–2017 among patients with opioid use disorder, ADHD diagnosis increased from 5 to 15% and ADHD treatment increased from 43 to 52%. Among all MOUD patients, 11% received ≥ 1 stimulant prescription during the study period. Female sex, geographic region, and presence of ADHD, mood, or anxiety disorders were associated with an increased likelihood of stimulant receipt. Stimulant use disorder and other substance use disorders were associated with a decreased likelihood of stimulant receipt.
Conclusions:
ADHD diagnosis and treatment in opioid use disorder patients has increased. Although stimulant treatment in MOUD patients tripled during the study period, a minority of ADHD patients on MOUD treatment received a stimulant prescription. Further study of the benefits and risks of ADHD treatment in patients with opioid use disorder is needed.
Attention-Deficit/Hyperactivity Disorder (ADHD) is commonly diagnosed in patients with substance use disorders. In one meta-analysis of primarily substance use disorder treatment-seeking patients, 23% of patients with substance use disorder had co-occurring ADHD (1). Co-occurring ADHD is associated with substance use disorder with earlier onset (2) and longer course (3), greater psychological impairment and worse quality of life (4), and lower substance use disorder treatment retention (5). Pharmacotherapy for ADHD when co-occurring with substance use disorder may reduce ADHD symptoms and improve substance use disorder outcomes and is associated with improved short- and long-term substance use disorder treatment retention (6).
Due to the ongoing opioid epidemic in the United States (U.S.), diagnosis and treatment of opioid use disorder has increased greatly (7,8). Studies of treatment samples in Europe indicate that 11–33% of adults receiving medication for opioid use disorder (MOUD) have current ADHD (9–11). Furthermore, national registry data from Norway indicate that among adults receiving MOUD treatment of ADHD with medication increased from 3.5 to 4.6% between 2015 to 2017 (12). However, little is known about the long-term nationwide trends in prevalence of ADHD diagnosis and treatment amongst patients with opioid use disorder in the U.S. ADHD pharmacotherapy, particularly stimulant medications, may have both risks and benefits in patients receiving opioid use disorder treatment. Deaths involving both synthetic opioids and stimulants with abuse liability have increased greatly (13,14), yet the prevalence of concurrent ADHD stimulant medications and MOUD prescription remains unclear.
In this study, we aimed to examine the trends in ADHD diagnosis and treatment among patients with opioid use disorder in the U.S. using a claims database of patients with employer-based health insurance. Furthermore, due to the potential benefits and risks of co-treatment with ADHD stimulant medications and MOUD, we conducted an exploratory analysis of demographic and diagnostic predictors of concurrent stimulant and MOUD treatment.
METHODS
Study design and data source
We used the MarketScan Commercial Claims and Encounters Data (15) to conduct two studies: 1) a retrospective, annual, cross-sectional study of 387,980 patients aged 13 to 64 years old with opioid use disorder and ≥ 6 months of continuous enrollment in a calendar year between January 2007 and December 2017 and 2) a retrospective cohort study of 158,591 patients with opioid use disorder aged 13 to 64 years who received MOUD between January 2006 and December 2017. MarketScan contains insurance claims data of patients with employer-sponsored insurance and their dependents and has been utilized in over 900 peer-reviewed publications since its launch in 1995 (16). Advantages of Marketscan include the large sample size – 273 million unique patients since 1995, longitudinal tracking with the ability to follow the majority of patients for at least 3 years, and detailed prescription drug information (15). Limitations of Marketscan include an overrepresentation from large employers, being a convenience sample rather than a random sample, and the lack of some demographic characteristics such as race and ethnicity. For this study, we used encounter-level diagnoses and procedures and outpatient pharmacy medication dispensing claims.
Cohort selection
For all analyses, we included only patients with opioid use disorder using a definition utilized elsewhere (17) and defined as one of the following: 1) ≥ 1 inpatient or ≥ 2 outpatient encounters with an International Classification of Diseases, Ninth Revision (ICD-9) or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis code for opioid dependence that occurred within 3 months of one another, 2) ≥ 1 encounter with a diagnosis code for opioid dependence, opioid use, or opioid abuse plus diagnosis codes for an encounter for opioid overdose or an injection-related infection, opioid-related inpatient detoxification or residential services, or 3) claims for MOUD or detoxification.
For the retrospective cohort study, we used National Drug Codes (NDC) extracted from Micromedex 2.0 (18) to identify patients who received sublingual buprenorphine, sublingual or oral mucosal buprenorphine/naloxone combinations, and oral and injectable naltrexone via national drug codes for these products. Additionally, we used the Q9991 and Q9992 procedure codes to identify patients who received injectable buprenorphine, the J2315 procedure code to identify patients who received injectable naltrexone, and the H0020 procedure code for methadone administration to identify patients who received methadone maintenance treatment.
Key variables
We defined ADHD as ≥ 2 inpatient or outpatient encounters with an ICD-9 or ICD-10 code for ADHD that occurred within a calendar year. To identify patients who received ADHD medications, we used NDCs for the following stimulant medications: methylphenidate, dexmethylphenidate, amphetamine, dextroamphetamine, lisdexamfetamine, methamphetamine; and the non-stimulant ADHD medication, atomoxetine. Using the medication dispensation date or the methadone procedure date, we defined concurrent stimulant medication receipt as receipt of stimulant medication ≤ 30 days either before or after receipt of MOUD. For both ADHD medications and MOUD, we only included patients that received ADHD medications after or at the same time as an ADHD diagnosis. We treated MOUD and opioid use disorder diagnoses similarly.
For the retrospective cohort study of patients who received MOUD, our outcome was concurrent stimulant medication receipt. We also extracted baseline characteristics to test their association with concurrent stimulant medication receipt. Data for independent variables was obtained during the calendar year prior to entering the cohort, which was when they first received MOUD. Demographic data included age, sex, geographical region, and psychiatric diagnoses. Diagnoses were categorized into mood disorders, anxiety, obsessive compulsive disorder (OCD), trauma-related disorders, psychotic disorders, ADHD, stimulant use disorders, and other substance use disorders.
Statistical analysis
For the annual, cross-sectional study, we calculated the prevalence of 1) ADHD diagnosis among patients with opioid use disorder, 2) receipt of any ADHD medication treatment among patients with ADHD and opioid use disorder, and 3) concurrent stimulant medication prediction among patients receiving MOUD in each calendar year between 2007 and 2017. Both opioid use disorder and ADHD were treated as chronic illnesses such that if counted in one year, they were counted in subsequent years as long as they remained an enrollee. ADHD treatment was also shown as stimulant medications and non-stimulant medications.
For the retrospective study of patients who received MOUD, we compared baseline characteristics in patients who received concurrent stimulant medication during the study period to those who did not receive a concurrent stimulant medication using χ2 tests. We then used a logistic regression model to test the association between baseline characteristics and receipt of concurrent stimulant medication.
Analyses were conducted with SAS version 9.4 (SAS Institute, Cary, NC). The data contain no identifying health information and the Boston University institutional review board deemed it exempt.
RESULTS
Trends in stimulant prescribing
Among a total of 387,980 people diagnosed with opioid use disorder with ≥ 6 months of continuous enrollment between 2007–2017, the number of people with opioid use disorder increased from 18,048 in 2007 to 90,597 in 2017. The proportion of patients with co-occurring ADHD grew annually from 5% in 2007 to 15% in 2017 (Figure 1a). Among those with co-occurring ADHD and opioid use disorder, ADHD treatment with medication increased overall from 43% in 2007 to 52% in 2017 with a slight but steady decrease between 2009 and 2014 before increasing again between 2014 and 2017. (Figure 1b). Among the ADHD medications studied, the majority of ADHD treatment consisted of stimulant medications (between 84% and 93%). The number of patients who received MOUD increased from 4,355 in 2007 to 31,392 in 2017. Among all patients who received MOUD with or without ADHD, the proportion of patients who received a concurrent stimulant medication increased annually from 2% in 2007 to 8% in 2017 (Figure 1c).
Figure 1.
(A) Prevalence of attention-deficit/hyperactivity disorder (ADHD) diagnosis among patients with opioid use disorder. (B) Prevalence of attention-deficit/hyperactivity disorder (ADHD) treatment among patients with ADHD and opioid` use disorder. (C) Prevalence of concurrent stimulant prescription in medications for opioid use disorder treatment.
Characteristics of patients who received concurrent stimulant medication and MOUD
Among the 158,591 patients who received MOUD between 2007 and 2017, 16,667 (11%) also received concurrent ADHD stimulant medication (Table 1). Higher proportions of patients who received concurrent stimulant medication were in younger age categories, male, and diagnosed with psychiatric diagnoses compared to patients who did not receive concurrent stimulant medication. Additionally, there were small differences in geographic distribution between patients who received concurrent stimulant medication and those who did not. The largest differences in psychiatric diagnosis in those who received concurrent stimulant medication and those who did not were ADHD (29% of patients who receive concurrent stimulants vs. 3% who did not receive concurrent stimulants), mood disorders (32% vs 22%), and anxiety, OCD, or trauma disorders (25% vs. 17%).
Table 1.
Characteristics of patients with medication for opioid use disorder, with vs. without prescription stimulant
| Total | Prescription Stimulant | No Prescription Stimulant | |||||
|---|---|---|---|---|---|---|---|
|
|
|||||||
| (N= 158,591) | (N= 16,667) | (N = 142,616) | |||||
|
|
|||||||
| Characteristic | N | % | N | % | N | % | p-value |
|
| |||||||
| Age – category | <0.001 | ||||||
| 13–17 | 1503 | 0.95% | 211 | 1.3% | 1292 | 0.91% | |
| 18–25 | 47043 | 29.7% | 5021 | 30.1% | 42022 | 29.6% | |
| 26–34 | 42880 | 27% | 5105 | 30.6% | 37775 | 26.6% | |
| 35–44 | 33230 | 20.9% | 3753 | 22.5% | 29477 | 20.8% | |
| 45–54 | 23460 | 14.8% | 1931 | 11.6% | 21529 | 15.2% | |
| 55–64 | 10475 | 6.6% | 646 | 3.9% | 9829 | 6.9% | |
| Sex | <0.001 | ||||||
| Male | 100182 | 63.2% | 10021 | 60.1% | 90161 | 63.6% | |
| Female | 58409 | 36.8% | 6646 | 39.9% | 51763 | 36.5% | |
| Region | <0.001 | ||||||
| Northeast | 35267 | 22.2% | 3620 | 21.7% | 31647 | 22.3% | |
| North Central | 31269 | 19.7% | 3221 | 19.3% | 28048 | 19.8% | |
| South | 65091 | 41.0% | 7509 | 45.1% | 57582 | 40.6% | |
| West | 24550 | 15.5% | 2063 | 12.4% | 22487 | 15.8% | |
| Unknown | 2414 | 1.5% | 254 | 1.5% | 2160 | 1.5% | |
| Psych Diagnosis * | |||||||
| ADHD | 8316 | 5.2% | 4837 | 29.0% | 3479 | 2.5% | <0.001 |
| Psychosis | 1976 | 1.3% | 301 | 1.8% | 1675 | 1.2% | <0.001 |
| Mood disorder | 36699 | 23.1% | 5293 | 31.8% | 31406 | 22.1% | <0.001 |
| Anxiety, OCD, trauma disorder | 28272 | 17.8% | 4051 | 25.3% | 24221 | 17.1% | <0.001 |
| Stimulant disorder | 4732 | 2.9% | 546 | 3.3% | 4186 | 2.9% | 0.019 |
| Other substance use disorder | 30487 | 19.2% | 3135 | 18.8% | 27352 | 19.3% | 0.152 |
ADHD = attention-deficit/hyperactivity disorder
OCD = obsessive compulsive disorder
psychiatric comorbidities can be overlapping, so each has an associated p-value
Predictors of concurrent stimulants and MOUD
In a multivariable logistic regression model, being aged 13–17 (adjusted odds ratio [aOR] = 1.24; 95% confidence interval [CI]: 1.05–1.47), 26–34 (aOR = 1:19; 95% CI: 1.14–1.25), or 3544 (aOR = 1:15; 95% CI: 1.09–1.21) compared to being aged 18–25, being from the Southern region of the U.S. (aOR = 1:10; 95% CI: 1.05–1.15) compared to being from the Northeast, and having ADHD (aOR = 15.50; 95% CI: 14.80–16.30), a mood disorder (aOR = 1:37; 95% CI: 1.32–1.43), or an anxiety, OCD, or trauma disorder (aOR = 1:08; 95% CI: 1.03–1.13) were associated with greater odds of receiving a concurrent ADHD stimulant medication (Table 2). Being aged 45–54 (aOR = 0.85; 95% CI: 0.80–0.90) or 55–64 (aOR = 0.65; 95% CI: 0.59–0.71) compared to being aged 18–25, being male (aOR = 0.86; 95% CI: 0.83–0.89), being from the Western region of the U.S. (aOR = 0.78; 95% CI: 0.74–0.84) compared to being from the Northeast, and having a stimulant use disorder (aOR = 0.88; 95% CI: 0.79–0.98) or a nonstimulant-related SUD (aOR = 0.74; 95% CI: 0.70–0.78) were associated with lower odds of receiving concurrent stimulant medication.
Table 2.
Factors associated with prescription stimulant among patients with medication for opioid use disorder following logistic regression
| Predictors | Wald X2 | p-value | aOR | 95% CI |
|---|---|---|---|---|
|
| ||||
| Age – category (reference: 18–25) | ||||
| 13–17 | 6.6 | 0.01 | 1.24 | 1.05–1.47 |
| 26–34 | 60.1 | <0.001 | 1.19 | 1.14–1.25 |
| 35–44 | 31.6 | <0.001 | 1.15 | 1.09–1.21 |
| 45–54 | 28.7 | <0.001 | 0.85 | 0.80–0.90 |
| 55–64 | 87.7 | <0.001 | 0.65 | 0.59–0.71 |
| Male (reference: female) | 67.7 | <0.001 | 0.86 | 0.83–0.89 |
| Region (reference: Northeast) | ||||
| North Central | 0.0027 | 0.958 | 0.99 | 0.95–1.05 |
| South | 16 | <0.001 | 1.10 | 1.05–1.15 |
| West | 58.9 | <0.001 | 0.78 | 0.74–0.84 |
| Unknown | 0.62 | 0.433 | 0.94 | 0.81–1.09 |
| Psychiatric Diagnosis | ||||
| ADHD | 11994.6 | <0.001 | 15.5 | 14.8–16.3 |
| Psychosis | 2.12 | 0.145 | 1.11 | 0.96–1.29 |
| Mood disorder | 218.9 | <0.001 | 1.37 | 1.32–1.43 |
| Anxiety, OCD, trauma disorder | 11.7 | <0.001 | 1.08 | 1.03–1.13 |
| Stimulant disorder | 5.5 | 0.019 | 0.88 | 0.79–0.98 |
| Other substance use disorder | 149.5 | <0.001 | 0.74 | 0.70–0.78 |
aOR = adjusted odds ratio
Ref = reference
ADHD = attention-deficit/hyperactivity disorder
OCD = obsessive compulsive disorder
DISCUSSION
ADHD is relatively frequently diagnosed and subsequently treated in adults with opioid use disorder. Between 2007 and 2017, ADHD diagnosis in patients with opioid use disorder tripled and ADHD treatment increased by 21% in patients with co-occurring ADHD and opioid use disorder in a claims-based database of commercially-insured patients aged 13–64 years in the U.S. Among patients receiving MOUD, 11% received at least one concurrent stimulant prescription. Female sex and being from the South region of the U.S. was associated with increased odds of receiving concurrent stimulant treatment. Among psychiatric diagnoses, documented ADHD, psychotic disorders, mood disorders, and anxiety, OCD, and trauma disorders were associated with increased odds of concurrent stimulant treatment. SUDs were associated with decreased odds of concurrent stimulant medication treatment.
Previous studies involving ADHD in patients receiving MOUD treatment found higher ADHD prevalence, ranging from 11–33% (9–11). The differences in prevalence may be related to those studies involving only patients receiving buprenorphine or methadone for opioid use disorder using the Adult ADHD Self-Report Scale (ASRS) – an ADHD screening and diagnostic instrument (19). Claims-based diagnoses may underestimate psychiatric diagnoses compared to more rigorous evaluations of mental health symptoms and behavior (20).
Interestingly, our data are similar to a Norwegian study that utilized national registry data that reported a similar percentage of patients treated with buprenorphine or methadone receiving ADHD medication treatment (3.5 to 4.6%) compared to our study (2 to 8%) (12). Though any differences between studies may be due to variation in the diagnosis and treatment of ADHD between countries, our definition for concurrent prescription (ADHD medication and MOUD dispensation dates ≤ 30 days), was more restrictive than their definition (within the calendar year). This suggests that concurrent stimulant medication prescribing in our study was most likely higher. Similar to our study, Vold et al. also found that females were more likely to receive concurrent ADHD medication treatment.
The increases in ADHD diagnosis and treatment observed in our study are not solely related to the opioid use disorder patient population. ADHD diagnosis and treatment have steadily grown worldwide, particularly in the adult population (21). But increases in ADHD diagnosis appear to have grown faster within the opioid use disorder patient population than the general population in a similar time frame. There is most likely increased recognition of the role of ADHD in opioid use disorder and other SUDs that may have resulted in this increase (22). Conversely, opioid use disorder may exacerbate ADHD symptoms over time and cause greater functional impairment, leading to an increased rate of ADHD diagnosis in the opioid use disorder population compared to the general population. We did find that ADHD treatment did not grow as rapidly as ADHD diagnosis in those with ADHD and opioid use disorder. We found a slight but steady decrease in the proportion of patients with ADHD and opioid use disorder who received ADHD medications between 2009 and 2014 before subsequently increasing again. This was driven by larger fluctuations in opioid use disorder diagnosis than ADHD treatment in our sample (data not shown), suggesting that clinicians only slightly changed their prescribing practices during the study period.
In our cross-sectional study, we found that a substantial proportion of patients with ADHD and opioid use disorder – 43% in 2007 to 52% in 2017 – were treated with ADHD medications, largely stimulant medications. This proportion is comparable to the 62% of children and adolescents with ADHD in the United States in 2016 who received ADHD medication given the potentially greater risks of prescribing stimulant medications to patients with opioid use disorder (23). Pharmacotherapy of ADHD in patients with SUD is associated with improved treatment retention (6). But randomized clinical trials indicate that ADHD pharmacotherapy is less effective in patients with co-occurring ADHD and SUD compared to patients with ADHD without SUD (24), though studies utilizing higher doses of longer-acting stimulant medication improved both ADHD symptoms and SUD outcomes (25,26).
Treatment with stimulant medication may improve ADHD and SUD outcomes in patients receiving MOUD, but there is growing concern that combined use of stimulants and opioids may have overdose risks. Among all patients in our sample who received MOUD with or without ADHD, the rate of stimulant co-prescribing quadrupled from 2% in 2007 to 8% in 2017. Overdose deaths attributed to opioids and psychostimulants have grown dramatically recently, though these deaths are likely due to illicit opioid and methamphetamine use (13,14). In a recent study, ADHD stimulant medication was associated with an increased risk of non-fatal overdose in patients receiving buprenorphine, though it was also associated with improved buprenorphine treatment retention (27). Given the potential for increased overdose risk in addition to potential diversion and misuse risks of stimulant medications (28), clinicians managing ADHD symptoms in patients receiving MOUD should carefully weigh the risks and benefits of stimulant treatment on an individual basis. We found that among patients receiving medications for opioid use disorder, any diagnoses of another substance use disorder decreased the likelihood of pharmacotherapy for ADHD. This suggests clinicians are considering the potential added risks of more severe or complicated substance use disorder when deciding whether to prescribe stimulants. Despite the challenges of managing patients with co-occurring ADHD and opioid use disorder, there is little clinical guidance on how best to prescribe stimulants in patients with opioid use disorder. Recent CDC guidelines on prescribing opioids for chronic pain may provide general guidance on prescribing potentially risky medications that can be utilized in stimulant prescribing such as 1) considering treatments with fewer risks (e.g. non-stimulant medications, cognitive behavioral therapy), 2) prescribing the lowest effective dose, 3) monitoring patients using toxicology testing and prescription drug monitoring programs, and 4) implementing treatment changes in patient-centered manner while avoiding patient abandonment (29).
Our analysis has several limitations. As with all administrative claims databases, the MarketScan database is limited to those procedures and diagnoses that were identified in the claims submitted. If there were systematic changes in the frequency of claims for ADHD or opioid use disorder by year or if there were systematic changes in the frequency of claims for other psychiatric diagnoses, then this could bias our results. We chose to define ADHD as ≥ 2 inpatient or outpatient encounters with an ADHD diagnosis. If this definition was too broad or restrictive, this could impact the accurate measurement of year-by-year prevalence of co-occurring ADHD but would not affect the ADHD trends found in this study. The Marketscan database used for this study did not contain race or ethnicity data and thus we were unable to study potential differences in ADHD diagnosis and treatment in patients with opioid use disorder by race/ethnicity. Finally, the MarketScan database only includes patients receiving employer-sponsored insurance and their families. Thus, our results may not be representative of the U.S. population and may limit the generalizability of our findings. Notably in one study, when the prevalence of stimulant prescribing for all adult patients with ADHD was compared in those with commercial versus public insurance, the prevalence of stimulant prescribing was consistently higher in adults commercially insured, though the trends over time were similar (21).
CONCLUSIONS
In this large, nationwide study of commercially-insured patients, ADHD diagnosis and treatment in patients with opioid use disorder has increased significantly. Many patients with ADHD and opioid use disorder are receiving medication treatment for ADHD. But although concurrent treatment with stimulants and MOUD quadrupled during the study period, only a minority of those with ADHD on MOUD treatment received a stimulant prescription. Further study of the benefits and risks of ADHD treatment in patients with opioid use disorder is needed.
HIGHLIGHTS.
Using a claims-based database of commercially insured patients, attention deficit hyperactivity disorder (ADHD) diagnosis in patients with opioid use disorder increased from 5 to 15% from 2007–2017.
Among patients receiving medications for opioid use disorder, 11% received at least 1 stimulant prescription for ADHD.
A substantial proportion of patients with ADHD and opioid use disorder – 43% in 2007 to 52% in 2017 – were treated with ADHD medications, largely stimulant medications, comparable to the 62% of children and adolescents with ADHD in the United States in 2016.
Female sex, mood, and anxiety disorders were associated with increased likelihood of stimulant receipt, and stimulant use disorder and other substance use disorders were associated with a decreased likelihood of stimulant receipt.
AUTHOR DISCLOSURES: Role of Funding Support
This work was supported by funding from the National Institute on Drug Abuse awards K23 DA044321 and P30DA040500. The sponsor had no role in the design and conduct of the study; in the collection, analysis and interpretation of the data; or in the preparation, review or approval of the manuscript of the decision to submit.
Conflict of Interest
TW reported receiving consulting fees to his institution from Ironshore outside the submitted work holding a patent for a diagnostic questionnaire with royalties paid from licensing agreement; receiving royalties from Guilford Press and Cambridge University Press; and serving as a clinical consultant to the Gavin Foundation, Bay Cove Human Services, US National Football League (ERM Associates), US Minor and Major League Baseball, and White Rhino/3D. AY currently has research funding from the National Institutes of Health (4UH3DA050252-02), the Doris Duke Charitable Foundation’s COVID-19 Fund to Retain Clinical Scientists collaborative grant program (2021261) through support from the John Templeton Foundation (62288), and the National Center for Advancing Translational Sciences, National Institute of Health, through the Boston University Clinical and Translational Science Institute (1UL1TR001430). She also has funding for clinical program development from the Jack Satter Foundation. She is a consultant to the Gavin House and BayCove Human Services (clinical services), as well as the American Psychiatric Association’s Providers Clinical Support System Sub-Award. No other disclosures were reported.
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