Pharmacotherapy with stimulant or nonstimulant medications is recommended as first-line treatment for attention-deficit/hyperactivity disorder (ADHD). Among patients prescribed stimulants, concomitant opioid use may increase the risk of drug dependence, exacerbate comorbid conditions, and compromise treatment adherence. However, limited evidence exists on the risk factors for initial opioid prescription in this population.
Objective:
To identify factors associated with incident opioid prescriptions among patients with ADHD prescribed stimulant therapy.
Methods:
We conducted a retrospective cohort study using the Merative® MarketScan® Commercial Claims and Encounters Database (2010-2020). We identified patients with ADHD who initiated stimulant therapy and followed them for 1 year to assess incident opioid prescription. Cox proportional hazards models were used to evaluate factors associated with opioid initiation.
Results:
Among 380 494 patients with ADHD initiating stimulants (mean age: 21.2 years; 56.5% male), 14.2% received an opioid prescription within 1 year. Factors significantly associated with incident opioid prescription included age ≥35 years (adjusted hazard ratio [aHR]: 10.84; 95% CI: 10.43-11.26), gender(aHR [female]:1.29; 95% CI: 1.27-1.31), geographic region (aHR [West]: 1.58; 95% CI: 1.52-1.64), multiple chronic conditions (aHR: 1.61; 95% CI: 1.54-1.67), anxiety (aHR: 1.19; 95% CI: 1.17-1.22), depression (aHR: 1.16; 95% CI: 1.14-1.19), severe mental illnesses (aHR: 1.18; 95% CI: 1.13-1.23), substance use disorders (SUDs) (aHR: 1.69; 95% CI: 1.63-1.75). Receipt of behavioral therapy before ADHD pharmacotherapy (aHR: 0.89; 95% CI: 0.87-0.92) was associated with a lower risk of receiving incident opioid prescriptions.
Conclusions and relevance:
Several demographic factors (e.g., age, gender, geographic region) and clinical factors (e.g., history of mental health conditions and SUDs) are associated with opioid initiation among stimulant-treated patients with ADHD. These findings may inform clinical strategies to mitigate unnecessary opioid exposure and associated harms.
BiedermanJSpencerT.Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder. Biol Psychiatry. 1999;46(9):1234-1242. doi:10.1016/S0006-3223(99)00192-4
2.
SharmaACoutureJ.A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). Ann Pharmacother. 2014;48(2):209-225. doi:10.1177/1060028013510699
SteinauS.Diagnostic criteria in attention deficit hyperactivity disorder—changes in DSM 5. Front Psychiatry. 2013;4:49. doi:10.3389/fpsyt.2013.00049
5.
BitskoRHClaussenAHLichsteinJ, et al. Mental health surveillance among children—United States, 2013–2019. MMWR Suppl. 2022;71(2):1-42. doi:10.15585/mmwr.su7102a1
6.
FaraoneSVWilensTE.Effect of stimulant medications for attention-deficit/hyperactivity disorder on later substance use and the potential for stimulant misuse, abuse, and diversion. J Clin Psychiatry. 2007;68(suppl1 1):15-22.
7.
ÖzgenHSpijkermanRNoackM, et al. Treatment of adolescents with concurrent substance use disorder and attention-deficit/hyperactivity disorder: a systematic review. J Clin Med. 2021;10(17):3908. doi:10.3390/jcm10173908
TargumSDAdlerLA.Our current understanding of adult ADHD. Innov Clin Neurosci. 2014;11(11-12):30-35.
10.
KesslerRCAdlerLBarkleyR, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry. 2006;163(4):716-723. doi:10.1176/ajp.2006.163.4.716
11.
MarkowitzJSYuG. Stimulants and other non-stimulants for attention-deficit/hyperactivity disorder (ADHD). In: JannMWPenzakSRCohenLJ, eds. Applied Clinical Pharmacokinetics and Pharmacodynamics of Psychopharmacological Agents. Springer International Publishing; 2016:303-327. doi:10.1007/978-3-319-27883-4_12
12.
CayeASwansonJMCoghillDRohdeLA.Treatment strategies for ADHD: an evidence-based guide to select optimal treatment. Mol Psychiatry. 2019;24(3):390-408. doi:10.1038/s41380-018-0116-3
13.
DaiwileAPCadetJL.Co-morbid use and misuse of opioids and stimulants: clinical neurobiology. Curr Addict Rep. 2025;12(1):37. doi:10.1007/s40429-025-00652-9
14.
PalisHXavierCDobrerS, et al. Concurrent use of opioids and stimulants and risk of fatal overdose: a cohort study. BMC Public Health. 2022;22(1):2084. doi:10.1186/s12889-022-14506-w
15.
StricklandJCGipsonCDDunnKE.Dopamine supersensitivity: a novel hypothesis of opioid-induced neurobiological mechanisms underlying opioid-stimulant co-use and opioid relapse. Front Psychiatry. 2022;13:835816. doi:10.3389/fpsyt.2022.835816
16.
IshøyPLJohannessenKBEHoumannTLevinEThomsenPH.Drug survival and risk factors for ADHD medication discontinuation in adults: a Danish Nationwide Registry-based cohort study. Acta Psychiatr Scand. 2024;150(3):160-173. doi:10.1111/acps.13724
17.
SikiricaVLuMGrevenP, et al. Adherence, persistence, and medication discontinuation in patients with attention-deficit/hyperactivity disorder—a systematic literature review. Neuropsychiatr Dis Treat. 2014;10:1543-1569. doi:10.2147/NDT.S65721
18.
Mohr-JensenCLangeAMThomsenPHDaleyD.Treatment of ADHD in adults—prevalence of discontinuation and associated factors—results from a cross-sectional analysis of Danish register data. Nord J Psychiatry. 2020;74(7):479-488. doi:10.1080/08039488.2020.1740781
19.
BrikellIWimberleyTAlbiñanaC, et al. Genetic, clinical, and sociodemographic factors associated with stimulant treatment outcomes in ADHD. Am J Psychiatry. 2021;178(9):854-864. doi:10.1176/appi.ajp.2020.20121686
20.
BrumbaughSTuanWJScottALatronicaJRBoneC.Trends in characteristics of the recipients of new prescription stimulants between years 2010 and 2020 in the United States: an observational cohort study. EClinicalMedicine. 2022;50:101524. doi:10.1016/j.eclinm.2022.101524
21.
PezallaERosenDErensenJHaddoxDMayneT.Secular trends in opioid prescribing in the USA. J Pain Res. 2017;10:383-387. doi:10.2147/JPR.S129553
22.
EllisMSKasperZACiceroTJ.Twin epidemics: the surging rise of methamphetamine use in chronic opioid users. Drug Alcohol Depend. 2018;193:14-20. doi:10.1016/j.drugalcdep.2018.08.029
23.
StricklandJCHavensJRStoopsWW.A nationally representative analysis of “twin epidemics”: rising rates of methamphetamine use among persons who use opioids. Drug Alcohol Depend. 2019;204:107592. doi:10.1016/j.drugalcdep.2019.107592
24.
JonesCMUnderwoodNComptonWM.Increases in methamphetamine use among heroin treatment admissions in the United States, 2008–17. Addiction. 2020;115(2):347-353. doi:10.1111/add.14812
25.
ScherrerJFSalasJGruczaR, et al. Prescription stimulant use during long-term opioid therapy and risk for opioid use disorder. Drug Alcohol Depend Rep. 2022;5:100122. doi:10.1016/j.dadr.2022.100122
26.
QuinnPDHurKChangZ, et al. Incident and long-term opioid therapy among patients with psychiatric conditions and medications: a national study of commercial health care claims. Pain. 2017;158(1):140-148. doi:10.1097/j.pain.0000000000000730
27.
WeiYJJZhuYLiuWBussingRWintersteinAG. Prevalence of and factors associated with long-term concurrent use of stimulants and opioids among adults with attention-deficit/hyperactivity disorder. JAMA Netw Open. 2018;1(4):e181152. doi:10.1001/jamanetworkopen.2018.1152
28.
TardelliVXuKYBisagaALevinFRFidalgoTMGruczaRA.Prescription amphetamines in people with opioid use disorder and co-occurring psychostimulant use disorder initiating buprenorphine: an analysis of treatment retention and overdose risk. BMJ Ment Health. 2023;26(1):e300728. doi:10.1136/bmjment-2023-300728
29.
ParkTWBaulTDMorganJRWilensTEYuleAM.Trends in attention-deficit hyperactivity disorder diagnosis and pharmacotherapy among adults with opioid use disorder. Psychiatr Serv. 2024;75(3):214-220. doi:10.1176/appi.ps.20220400
Von ElmEAltmanDGEggerM, et al. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med. 2007;147(8):573. doi:10.7326/0003-4819-147-8-200710160-00010
QuanHLiBCourisCM, et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol. 2011;173(6):676-682. doi:10.1093/aje/kwq433
34.
CiccaroneD.The rise of illicit fentanyls, stimulants and the fourth wave of the opioid overdose crisis. Curr Opin Psychiatry. 2021;34(4):344-350. doi:10.1097/YCO.0000000000000717
35.
FriedmanJShoverCL.Charting the fourth wave: geographic, temporal, race/ethnicity and demographic trends in polysubstance fentanyl overdose deaths in the United States, 2010–2021. Addiction. 2023;118(12):2477-2485. doi:10.1111/add.16318
36.
ChenCYGerhardTWintersteinAG.Determinants of initial pharmacological treatment for youths with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2009;19(2):187-195. doi:10.1089/cap.2008.096
37.
ChenCYYehHHChenKHChangISWuECHLinKM.Differential effects of predictors on methylphenidate initiation and discontinuation among young people with newly diagnosed attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2011;21(3):265-273. doi:10.1089/cap.2010.0107
38.
WintersteinAGGerhardTShusterJ, et al. Utilization of pharmacologic treatment in youths with attention deficit/hyperactivity disorder in Medicaid database. Ann Pharmacother. 2008;42(1):24-31. doi:10.1345/aph.1K143
39.
CoxERMotheralBRHendersonRRMagerD.Geographic variation in the prevalence of stimulant medication use among children 5 to 14 years old: results from a commercially insured US sample. Pediatrics. 2003;111(2):237-243. doi:10.1542/peds.111.2.237
40.
SteinhausenHCBisgaardC.Substance use disorders in association with attention-deficit/hyperactivity disorder, co-morbid mental disorders, and medication in a nationwide sample. Eur Neuropsychopharmacol. 2014;24(2):232-241. doi:10.1016/j.euroneuro.2013.11.003
41.
YoungJTCarruthersSKayeS, et al. Comorbid attention deficit hyperactivity disorder and substance use disorder complexity and chronicity in treatment-seeking adults. Drug Alcohol Rev. 2015;34(6):683-693. doi:10.1111/dar.12249
42.
LeeSSHumphreysKLFloryKLiuRGlassK.Prospective association of childhood attention-deficit/hyperactivity disorder (ADHD) and substance use and abuse/dependence: a meta-analytic review. Clin Psychol Rev. 2011;31(3):328-341. doi:10.1016/j.cpr.2011.01.006
43.
SepúlvedaDRThomasLMMcCabeSECranfordJABoydCJTeterCJ.Misuse of prescribed stimulant medication for ADHD and associated patterns of substance use: preliminary analysis among college students. J Pharm Pract. 2011;24(6):551-560. doi:10.1177/0897190011426558
OlatejuOAOkekeCShresthaMThorntonD.Association between buprenorphine adherence trajectories, health outcomes, and health care costs among Medicaid enrollees. J Addict Med. 2025;19(5):578-590. doi:10.1097/ADM.0000000000001458
SullivanMDEdlundMJZhangLUnützerJWellsKB.Association between mental health disorders, problem drug use, and regular prescription opioid use. Arch Intern Med. 2006;166(19):2087. doi:10.1001/archinte.166.19.2087
48.
ZulaufCASprichSESafrenSAWilensTE.The complicated relationship between attention deficit/hyperactivity disorder and substance use disorders. Curr Psychiatry Rep. 2014;16(3):436. doi:10.1007/s11920-013-0436-6
49.
LopezPLTorrenteFMCiapponiA, et al. Cognitive-behavioural interventions for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database Syst Rev. 2018;2018(3):CD010840. doi:10.1002/14651858.CD010840.pub2
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
