- Email: [email protected]
Hyperactivity Disorder and comorbid substance use disorders
European Neuropsychopharmacology (]]]]) ], ]]]–]]]
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Methylphenidate doses in Attention Deficit/ Hyperactivity Disorder and comorbid substance use disorders Charlotte Skoglunda,n, Lena Brandtb, Brian D’Onofriod, Henrik Larssonc, Johan Francka a
Department of Clinical Neuroscience, Division of Psychiatry, Karolinska Institutet, Norra Stationsgatan 69, SE-113 64 Stockholm, Sweden b Center for Pharmacoepidemiology, Department of Medicine, Karolinska Institutet, Department of Medicine, Solna, Karolinska University Hospital, SE-171 76 Stockholm, Sweden c Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, SE-171 77 Stockholm, Sweden d Department of Psychological and Brain Sciences Indiana University, 1101 East 10th Street, Bloomington, IN 47405, USA Received 26 July 2016; received in revised form 15 July 2017; accepted 30 August 2017
KEYWORDS
Abstract
Methylphenidate; Drug prescription; Substance use disorder
Patients with Attention Deficit/Hyperactivity Disorder (ADHD) and comorbid Substance Use Disorders (SUD) are increasingly being treated with central stimulant medication despite limited evidence for its effectiveness. Lack of longitudinal follow-up studies of dosing and adverse effects has resulted in conflicting treatment guidelines. This study aims to explore whether individuals with ADHD and comorbid SUD are treated with higher stimulant doses than individuals with ADHD only, and whether doses increase over time as a sign of tolerance, a core symptom of addiction. Information on methylphenidate doses for 14 314 Swedish adults, including 4870 individuals with comorbid SUD was obtained through linkages of Swedish national registers between 2006 and 2009. Differences in doses between patients with and without SUD were estimated using logistic regression while a linear regression model calculated time trends in mean doses. Individuals with SUD were prescribed higher methylphenidate doses than those without (ORday365; 2.12, 95% CI 1.81–2.47: ORday730 2.65, 95% CI 2.13–3.30). Patients with SUD were, two years after initiating stimulant treatment, prescribed approximately 40% higher doses compared to individuals with ADHD only. The results may suggest a need for increased doses in this population to achieve optimal ADHD symptom control. A tendency towards increasing doses during the first years of treatment, more pronounced in individuals with comorbid SUD, may reflect a reluctance to prescribe adequate
n
Corresponding author. Fax: +46 8 346563. E-mail address: [email protected] (C. Skoglund).
http://dx.doi.org/10.1016/j.euroneuro.2017.08.435 0924-977X/& 2017 Published by Elsevier B.V.
Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
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C. Skoglund et al. doses due to lack of clinical guidelines. Mean doses stabilized after about two years in both groups, which does not lend support to continuously increasing tolerance over time. & 2017 Published by Elsevier B.V.
1.
Introduction
Attention Deficit/Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental disorder (Wilens and Spencer, 2010), and individuals with ADHD are at increased risk for Substance Use Disorders (SUD) (van Emmerik-van Oortmerssen et al., 2012). Despite a substantial overlap and signs of common pathophysiological mechanisms (Frodl, 2010) little is known about how patients with ADHD and comorbid SUD can be safely and effectively treated (Cunill et al., 2015). It is well established that pharmacological treatment of ADHD using stimulant medication improves ADHD core symptoms (Faraone and Buitelaar, 2010, Faraone and Glatt, 2010). Methylphenidate is the most commonly used stimulant medication (NICE guidelines 2008, Kooij et al., 2010) with an expected treatment response observed in about 80% of the patients (Pliszka, 2007). Serious adverse effects are rarely associated with stimulant medication use (Santosh et al., 2011). However, stimulant medications are controlled substances (Controlled Substance Act, FDA, 2016) that increase dopamine levels in brain areas involved in development of addiction and thus can be recreationally abused (Wilens et al., 2008). Whereas stimulant treatment among patients with ADHD has increased in recent years (McCarthy et al., 2012), few studies have addressed treatment efficacy in individuals with comorbid SUD (Cunill et al., 2015). Consistent with clinical observations that individuals with SUD may need substantially higher stimulant doses than those with ADHD only, two recent randomized controlled trials showed significant improvements in ADHD symptoms and SUD outcomes using higher stimulant doses than earlier studies (Konstenius et al., 2014, Levin et al., 2015). Although tolerance is a core symptom of addiction and may underlie a need for higher initial stimulant doses in patients with SUD, continuously increasing doses during maintenance pharmacotherapy should raise concerns as that may reflect a worsening of the SUD. Societal and clinical concerns or inappropriate beliefs about the safety of stimulant treatment in individuals with coexisting SUD (Cassidy et al., 2015, Faraone and Glatt, 2010, Kaye and Darke, 2012), lack of longitudinal follow-up studies of dosing and adverse effects, such as harmful use and dependence, and a fear that stimulant treatment might put susceptible individuals at risk for future SUD, relapse or worsening of ongoing SUD is mirrored in conflicting treatment guidelines (Bolea-Alamanac et al., 2014, Cunill et al., 2015, NICE 2008). Observational studies allow for large sample sizes to relatively small economical costs and can provide longitudinal information on changes in prescribed
methylphenidate doses over time. In this population-based cohort study of all 14 314 adults with one or more prescriptions of methylphenidate between 2006 and 2009 in Sweden, we aimed to explore potential differences in prescribed stimulant doses between individuals with and without comorbid SUD, and whether doses increase over time as a proxy for medication tolerance.
2. 2.1.
Experimental procedures Sample
The study was approved by the Research Ethics committee at Karolinska Institutet, Stockholm, Sweden, protocol no. 2009/5:10, 2009/939-31/5. We obtained data from a record linkage of four population-based registries in Sweden; personal identification numbers enabled accurate linkage. The Swedish Prescribed Drug Register includes information on drug identity using Anatomical Therapeutic Chemical (ATC) codes and dates of all prescribed drugs filled at Swedish pharmacies since July 2005. Each unique prescription has a specific dose text describing the quantity and dosage filled out by the prescribing physician. The National Patient Register provides data on in-patient psychiatric care since 1973 and outpatient care since 2001, categorized according to diagnostic coding in the eighth, ninth and tenth revision of the International Classification of Diseases (ICD-8, ICD-9 and ICD-10). To account for death and migration all data was linked to the Cause of Death Register and the Migration Register.
2.2.
Measures
2.2.1. Diagnostic categories A total of 14 314 individuals, aged 18–59, with an initial prescription of methylphenidate (ATC code for methylphenidate N06BA04 in the Prescribed Drug register), including 4870 with a diagnosis of SUD, were included in the main analysis. The National Patient Register and the Prescribed Drug Register were used to identify patients diagnosed with alcohol and/or drug use disorders in accordance with the ICD diagnostic guidelines and/or a prescription including an ATC code for drugs used exclusively in the treatment of SUD. Alcohol use disorder was defined using ICD codes from the National Patient Register (ICD-8: 291 and 303, ICD-9: 291, 303 and 305A and ICD-10: F10.0-F10.9) and ATC codes for prescriptions of medications used in the treatment of alcoholism (N07BB03 (acamprosate), N07BB04 (naltrexone) and N07BB01 (disulfiram)) from the Prescribed Drug Register. Psychoactive drug abuse was measured by ICD codes from the National Patient Register (ICD-8: 304, ICD-9: 292, 304 and 305X and ICD-10: F11.0–F16.9 and F18.0–F19.9) and ATC codes from the Prescribed Drug Register for prescriptions of medications used in the treatment of drug abuse (N02AE01 (buprenorphine), N07BC51 (buprenorphine+naltrexone) and N07BC02 (methadone)). An individual was classified as having SUD or not when included in the study (at the time of the initial prescription of methylphenidate). In addition, the National Patient Register
Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders provided data on coexisting psychiatric ICD-8, ICD-9 and ICD-10 diagnoses other than alcohol and/or drug use disorders. 2.2.2. Operationalization of doses and treatment periods Individual daily methylphenidate doses were estimated by means of the text variable in the Prescribed Drug Register. Each prescription contains a text variable containing the quantity of medication prescribed and individualized instructions on how the drug is to be consumed. If a prescription of equal dosage was filled before the last prescription was due to run out, we assumed the first filled prescription to have been consumed. If prescriptions of different dosage were filled on the same occasion, we assumed them to have been consumed simultaneously according to the text variable on each prescription. The prescribed dose was calculated every 100 days and annual point estimates. We defined a treatment period as the number of days the prescription would last according to the text variable on the prescription, plus 25% to avoid individual minor irregularities in dispensing patterns. During subsequent periods or those without any new prescription, the patient was assumed to be off treatment. To ensure that participants had not been receiving methylphenidate treatment prior to follow up, we used information about prescription dates six months before start of follow-up at January 1, 2006. Differences in mean methylphenidate doses between patients with and without SUD were stratified into 0–72 mg and 472 mg based on recommendations issued by the British Association for Psychopharmacology (recommended maximum dose 100 mg) (Bolea-Alamanac et al., 2014), the US Food and Drug Administration (recommended maximum dose 72 mg) (Controlled Substance Act, FDA), the National Institute for Health and Care Excellence (recommended maximum dose 60 mg) (NICE) and clinical expertise. Also, Osmotic Release Oral System (OROS) is the most commonly prescribed methylphenidate formulation in Sweden, and only commercially available in multiples of 18 mg. To validate the semi-manual method of extracting doses from the text variable, an independent clinician proofread 4000 randomly selected records in the material. A total of 0.3% of the prescriptions were not coded correctly or were interpreted differently by the proof-reader.
2.3.
Statistical analyses
Descriptive measures and distribution of daily doses in categories were tabulated for individuals with and without SUD with point estimates at day 100, day 365, day 730 and day 1095 after the date of the first filled prescription. Logistic regression models were calculated for the dependent variable (e.g. methylphenidate dose) at day 365 and 730. Given the potential confounding effects of several explanatory variables (e.g. SUD subtype, gender, age, calendar year of the initial prescription and comorbid psychiatric diagnoses) these covariates were simultaneously fitted into the adjusted model. Odds ratios (ORs) with Wald 95% confidence intervals were presented using the LOGISTICS PROCEDURE, SAS version 9.4. The development of doses over time in patients with and without SUD was described in a graph depicting a point estimate of the mean dosage every 100 days. Time trends in mean doses were tested with linear regression and described in a graph depicting a point estimate of the mean dosage every 100 days. The means were weighted with the inverse of the number of subjects in treatment at the time. Time was arbitrarily divided into two periods: 100–600 and 700–1200 days after the initial prescription. 2.3.1. Sensitivity analysis We performed a sensitivity analysis to test whether individuals with methylphenidate doses over 72 mg/day actually picked up doses
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corresponding to the one prescribed by the physician. A subsample of the population with doses over 72 mg/day (N=659) was selected, and the doses in the Prescribed Drug Register on days 300 and 400 were compared to the total accumulated dose filled by the pharmacy between days 200 and 400.
3.
Results
A sample of 14 314 adults (including 4870 individuals with a diagnosis of SUD) with a prescription of methylphenidate between January 1, 2006, and December 31, 2009 was included in the main analysis (Figure 1). Out of the targeted population, 93% was monitored during the entire follow-up period (Table 1). The mean period was approximately 550 days in both populations and allowed for times during which medication was discontinued or resumed. Psychiatric comorbidity including personality disorders and conduct disorder was more prevalent among individuals with comorbid SUD than among individuals with ADHD only (Table 1). Table 2 shows that, at day 365, 37.1% of individuals with comorbid SUD were prescribed methylphenidate doses over 72 mg compared to 20.6% of those with ADHD only (chi-square po0.0001). At day 730, 44.4% of individuals with comorbid SUD were prescribed methylphenidate doses over 72 mg, compared to 22.8% of individuals with ADHD only (chi-square po0.0001). Among individuals with SUD, 7.3% had doses exceeding 180 mg/day at day 730, compared to 1.2% of those with ADHD only (chi-square po0.0001). Retention to treatment at day 730 was 48% in the SUD population and 42% in individuals with ADHD only (chi-square po0.0001). The proportion of patients who had been prescribed extended release preparations at day 730 was high both in patients with SUD (86%) and in patients with ADHD only (82%)(chi-square p=0.01). ORs for methylphenidate doses exceeding 72 mg/day in individuals with comorbid SUD and ADHD only are shown in Table 3. Individuals with SUD were at increased risk for exceeding a daily dose of 72 mg (ORSUDday365 2.12 and ORSUDday730 2.65). A diagnosis of drug abuse (DA), a combined diagnosis of both DA and alcohol use disorder (AUD) and a diagnosis of psychoactive stimulant use (SU) significantly increased the risk for exceeding a dose of 72 mg/day (ORDAday365 2.53, ORDAday730 3.09, ORDA + AUDday365 2.53 and ORDA + AUDday730 2.97, ORSUday365 3.08, ORSUday730 3.63). The corresponding risk associated with a diagnosis of AUD only was lower (ORAUDday365 1.49 and ORAUDday730 2.01), indicating that SUD subtype and/or severity is correlated to methylphenidate dose. Figure 2 shows a small but significant increase in mean doses (1.1 mg/100 days) between days 100 and 600 in individuals with ADHD only. The increase of mean doses in individuals with comorbid SUD was greater (3.2/100 days) (p-value for interaction 0.001). In contrast no statistically significant trend in mean doses was observed between days 700 and 1200 (p=0.30 in the entire population; p=0.21 in individuals with comorbid SUD and p=0.15 in individuals with ADHD only).
3.1.
Sensitivity analysis
Our sensitivity analysis showed that 90% (95% CI 87.5 to 92.1) of individuals who were prescribed a daily dose of over 72 mg on days 300 and 400 picked up corresponding daily doses of over 72 mg at the pharmacy between days 200 and 400.
4.
Discussion
This nationwide, register-based cohort study of adult ADHD patients treated with methylphenidate, shows that patients with comorbid SUD, two years into stimulant treatment,
Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
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C. Skoglund et al.
Fig. 1 Flowchart.
were prescribed approximately 40% higher methylphenidate doses than individuals with ADHD only. Doses in both groups stabilized during the first two years of treatment. The findings of higher doses in the ADHD plus SUD group may indicate that patients with SUD need higher methylphenidate doses to achieve optimal ADHD symptom control. One interpretation of these findings, supported by the finding that individuals with a diagnosis of psychoactive stimulant use were prescribed higher methylphenidate doses compared to other SUD subtypes, is that individuals with comorbid SUD might have developed a tolerance to central stimulants. An increase in tolerance is likely to result in a need for higher doses and prolonged titration periods. This would be consistent with two recent randomized controlled trials (Konstenius et al., 2014, Levin et al., 2015) showing significant improvements in both ADHD symptoms and SUD outcomes using higher stimulant doses than earlier studies. If true, this may explain why previous research have found little evidence for any beneficial effects of methylphenidate on SUD-related outcomes (Cunill et al., 2015, Perez-Mana et al., 2013) using doses recommended by current guidelines (mean doses 62.2 mg/
day) (Bolea-Alamanac et al., 2014, NICE 2008. Kooij et al., 2010). An alternative explanation for the different doses could be ADHD subtype, with differences in symptom severity, or psychiatric comorbidity. Whereas ADHD and personality disorders frequently co-occur in adult non-SUD populations (Matthies and Philipsen, 2016), a recent crosssectional study also showed that 75% of SUD patients with ADHD had at least one additional comorbid disorder compared with 37% patients without ADHD (van Emmerik-van Oortmerssen et al., 2014). As the present dataset cannot be linked to individual clinical data, this needs to be further explored in future studies. Mean doses stabilized over time in both populations at the end of follow-up even though, among individuals with comorbid SUD, a continuous increase in mean dose was observed up to approximately two years of treatment. Assuming that the initial dosing may have been inadequate, the tendency towards increasing doses during the first two years of treatment, more pronounced in individuals with comorbid SUD, may reflect a reluctance to prescribe adequate doses due to lack of clinical guidelines, and/or prescribers’ inappropriate beliefs. The dose-response
Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders
Table 1 Distribution of study variables across individuals with and without comorbid SUD. SUD
No SUD
(n = 4870)
(n = 9444)
%
%
Follow-up Until December 31, 2009 Censoreda
93.1 6.9
93.8 6.2
Observation Mean days (sd)
550.6 (388.6)
549.8 (400.4)
Age Mean years (sd) Female
34.6 (10.3) 36.1
31.7 (10.5) 47.9
Psychiatric diagnosis Schizophreniab Schizoaffective disorderb Mood disordersb Bipolar disordersb Anxiety disordersb Eating disordersb Personality disordersb Conduct disorderb
3.2 1.1 38.4 10.0 50.3 3.7 26.9 2.4
0.7 0.4 30.6 7.28 34.4 3.4 11.2 1.3
SUD=Substance Use Disorders. b ATC code: N05BA, N05CF, N05C. a Censored due to; Emigration n=89, Deceased n=138, Participation in clinical trial n=5, Prescriptions of dexamphetamine or amphetamine n=691 b ICD8-10 diagnoses: Schizophrenia (ICD-8: 295.0–295.4, 295.6, 295.8–295.9; ICD-9: 295A-295E, 295G, 295W, 295X; ICD-10: F20), Schizoaffective disorder (ICD-8 295.7; ICD-9 295H; ICD-10 F25), Mood disorders (ICD8: 296.2, 298.0, 300.4; ICD9: 296B, 300E; ICD10: F32–F39), Bipolar disorders (ICD-8: 296.1, 296.3, 296.8; ICD-9: 296A/C/D/E/W; ICD-10: F30–F31), Anxiety disorders (ICD8, ICD9: 300; ICD10:F40-48), Eating disorders (ICD8: 306.5; ICD9: 307B/F; ICD10: F50), Personality disorders (ICD8, ICD9: 301; ICD10:F60, Conduct disorder (ICD9: 312; ICD-10: F91).
relationship of methylphenidate on ADHD symptoms is well established in children (Greenhill et al., 2001). Less is known about dose-response in adults and inter-individual serum concentration variability in relation to ADHD symptom control (Ermer et al., 2010), and clinicians are left to arbitrarily titrate the medication based on the patient's subjective response. Given the lack of objective assessment procedures, biomarkers or clear treatment guidelines, clinicians might be reluctant to increase doses to optimal levels for individuals with ADHD and SUD due to fear of misuse, abuse or diversion (Wilens et al., 2008, Kaye and Darke 2012). An important question that deserves further investigation is whether methylphenidate primarily targets ADHD
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symptoms, modulates the pathophysiology of SUD directly, or both. Adequate treatment, more specifically adequate dosage, may increase the motivation to stay in treatment and prevent relapses to illegal drug use. While the efficacy of agonist maintenance therapy available for opioid addiction has been extensively studied (Mattick et al., 2014), substitution treatment for psychoactive stimulant use has been less investigated (Galloway et al., 2011, Longo et al., 2010, Mariani et al., 2014, Miles et al., 2013, Tiihonen et al., 2007). Research targeting the direct effect of central stimulant medication on SUD pathophysiology is as yet inconclusive (Galloway et al., 2011, Longo et al., 2010, Miles et al., 2013, Tiihonen et al., 2007). In the present study, a diagnosis of drug abuse (DA), a combined diagnosis of both DA and alcohol use disorder (AUD) and a diagnosis of psychoactive stimulant use (SU) significantly increased the risk for exceeding a dose of 72 mg/day indicating that SUD severity and/or subtype may be correlated to methylphenidate dose. Also, at any given time point during the followup, individuals with comorbid SUD had higher adherence to treatment than those with ADHD only. Three years following the initial prescription of methylphenidate, 45% of patients with ADHD and SUD, compared to 37% of individuals with ADHD only, were still actively picking up their prescriptions. Population-based register data have several strengths compared with clinical trials including substantial sample sizes representative for the population. Research based on nationwide registers can avoid problems arising from referral bias, selective participation, and other threats to validity and generalizability. Information on SUD was acquired using both ICD-codes from the National Patient Register and ATC-codes in the Prescribes Drug Register, thus minimizing the risk of informant and recall bias. Medication for ADHD is recorded in the Prescribed Drug Register when a prescription is filled, and therefore free from recall bias. The present results need to be interpreted in the light of some important limitations regarding the diagnostic procedure of ADHD and SUD, assumptions of individual doses and duration of active medication. The ascertainment of ADHD was predominantly based on prescribed medication unique for the treatment of ADHD. Since the National guidelines for medication of ADHD, issued by the Swedish National Board of health and Welfare in 2002, stated that medication should be reserved for cases where other supportive interventions have failed, this strategy could probably not avoid producing false negatives, but we consider bias due to false positive ADHD diagnosis more unlikely, not least due to the strict enforcement of malpractice regulations in Sweden and the limitation to only psychiatrists and pediatricians specializing in pediatric neurology to prescribe central stimulants. Due to methodological limitations inherent in the study design such as lack of clinical information on ADHD subtype, symptom severity, dose-response data, and other psychosocial interventions targeting ADHD and/or SUD there is limited adjustment for these potential confounders and the results should be interpreted with caution. Also, the possibilities of long-term follow up due to collect data from three different diagnostic systems (ICD-8, ICD-9 and ICD-10) must be weighted against potential problems arising from differences in definition of the ADHD and SUD diagnoses across these three generations of coding systems. Given the
Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
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C. Skoglund et al.
Table 2 Methylphenidate (MPH); mean daily doses and distribution of doses and formulations over time in individuals with substance use disorder compared to individuals with ADHD only. 100 daysa
365 daysa
730 daysa
1095 daysa
SUD
No SUD
SUD
No SUD
SUD
No SUD
SUD
No SUD
n =4280
n = 8194
n =2930
n = 5565
n =1527
n = 2940
n =558
n = 1197
On MPH, n (%) Prescribed dose known n (%) Mean daily dose in mg (sd) Median (quartiles) Min-max
3146 (74%) 2659 (85%) 67.3 (44.6) 54 (36;90) 5–440
5888 (72%) 5400 (92%) 53.9 (30.9) 54 (36;72) 4–324
1587 (54%) 1400 (88%) 76.6 (51.9) 64 (40;92) 4–420
2762 (50%) 2610 (94%) 59.4 (36.8) 54 (36;72) 4–620
739 (48%) 657 (89%) 87.0 (64.1) 72 (46;108) 9–590
1 231 (42%) 1169 (95%) 60.7 (38.3) 54 (36;72) 10–452
249 (45%) 211 (85%) 84.8 (59.2) 72 (40;108) 9–360
445 (37%) 4196 (94%) 60.7 (38.4) 54 (36;72) 10–320
Dose distribution, % r 54 mg 55–72 mg 73–180 181–360 4360
54.2 16.8 26.7 2.2 0.1
69.1 14.1 16.2 0.6 0.0
45.1 17.8 33.1 3.8 0.2
61.4 18.0 19.5 1.0 0.1
40.3 15.2 37.1 6.7 0.6
59.8 17.5 21.6 1.0 0.2
42.2 15.2 34.1 8.5 0.0
58.5 18.9 21.5 1.2 0.0
Formulations, % ER/OROS IR ER/OROS + IR
89.3 3.9 6.8
85.5 6.9 7.6
87.0 4.2 8.8
83.4 6.7 9.8
86.5 4.9 8.7
82.0 7.8 10.2
87.1 5.2 7.6
81.1 7.0 11.9
MPH=Methylphenidate, SUD=Substance Use Disorder, OROS=Osmotic Controlled Release Oral Delivery, ER=Extended Release Formulation, IR=Immediate Release Formulation. a After initial prescription of methylphenidate.
Table 3
Logistic regression model of methylphenidate doses exceeding 72 mg/day. Day 365
Day 730 Dose 472 mg/day
Dose 472 mg/day
Unadjusted
Adjusteda
OR (95% C.I.)
OR (95% C.I.)
n
%
Total
4010
26
SUD No Yes
2610 1400
21 37
ref =1 2.28 (1.98–2.64)
SUD Subtypeb AUD DA AUD + DA SU
473 453 474 500
29 41 42 47
1.56 2.69 2.77 3.48
(1.25–1.94) (2.18–3.32) (2.25–3.40) (2.85–4.25)
Unadjusted
Adjusteda
OR (95% C.I.)
OR (95% C.I.)
n
%
1826
31
ref =1 2.12 (1.81–2.47)
1169 657
23 44
ref =1 2.72 (2.21–3.34)
ref =1 2.65 (2.13–3.30)
1.49 2.53 2.53 3.08
208 227 222 256
37 48 48 53
2.00 3.14 3.10 3.79
2.01 3.09 2.97 3.63
(1.19–1.87) (2.03–3.15) (2.03–3.16) (2.49–3.81)
(1.46–2.73) (2.34–4.21) (2.31–4.17) (2.86–5.02)
(1.46–2.78) (2.28–4.20) (2.16–4.09) (2.69–4.91)
MPH=Methylphenidate, SUD =Substance Use Disorder, AUD=Alcohol Use Disorder, DA=Drug Abuse, SU=Stimulant Use Disorder (Ever diagnose of F15 304E, 304,60 = Mental and behavioural disorders due to psychoactive stimulant use). a Adjusted for sex, age, year of initial prescription, and psychiatric comorbidity. b Diagnosis of /Medication for.
Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders
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course of stimulant medication and development of methylphenidate doses over time should increase the evidence base for stimulant pharmacotherapy among individuals with combined ADHD/SUD.
Declaration of interest The authors state no conflicts of interest.
Role of the funding source
Fig. 2 Mean methylphenidate doses over time in individuals with SUD compared to individuals with ADHD only. SUD =Substance use disorder, SUD =Individuals with comorbid Substance use disorder who have been prescribed methylphenidate, No SUD=Individuals with ADHD only who have been prescribed methylphenidate.
observational nature of the study the investigators lacked control over how unknown potentially confounding factors were distributed across the two groups. Future studies should explore the need for higher doses due to liver enzyme induction following cigarette smoking, coexisting psychopharmacological treatment or somatic disorders. The study design does not allow for differentiating between the quantity of medication prescribed and received, and the amount of medication actually consumed. Thus the observed finding of higher methylphenidate doses in individuals with ADHD and comorbid SUD might also to some extent be explained by diversion, a phenomenon that may be more prevalent in certain populations (Cassidy et al., 2015). Studies targeting the extent of non-medical use of stimulants (Kaye and Darke, 2012), in “high-risk” populations such as individuals with ADHD and comorbid SUD is limited (Wilens et al., 2008) and this should be an important focus for future research. Also, given that treatment with methylphenidate, a schedule II classed medication (Controlled Substance Act, FDA) is controlled (Heal et al., 2009, Khan, 1979) and treatment guidelines often recommend abstinence from abused substances prior to and during such pharmacological treatment (NICE 2008, CADDRA) individuals with ADHD and comorbid SUD might therefore be more closely monitored (Heal et al., 2009). The proportionally higher adherence to treatment among patients with SUD might reflect the fact that these individuals, in order to prevent abuse and medication diversion, receive more intense psychosocial interventions and/or monitoring. In conclusion, individuals with ADHD and comorbid SUD were prescribed significantly higher methylphenidate doses than those with ADHD only. Across the longitudinal followup, mean prescribed doses stabilized over time in both groups and the results do not lend support to continuously increasing tolerance. Putative factors contributing to such dosing differences need to be tested using prospective designs. A clearer understanding of the natural long-term
C Skoglund had financial support from the Regional Agreement on Medical Training and Clinical Research (K14262011; 20120334) between the Stockholm County Council and Karolinska Institutet, the Swedish Research Council (20132280; 2012-2607), Swedish Initiative for Research on Microdata in the Social and Medical Sciences (SIMSAM) framework (Grant no. 340-2013-5867), and National Institute of Mental Health (NIMH) (Grant no. 1R01MH102221). H Larsson has served as a speaker for Eli-Lilly and has received a research grant from Shire; both outside the submitted work.
Contributors C Skoglund is the lead author of the manuscript and affirms that the manuscript is an honest, accurate, and transparent account of the study being reported and that no important aspects of the study have been omitted. C Skoglund and J Franck conceived and designed the study. L Brandt performed the analyses and, with H Larsson, assisted in the study design. C Skoglund performed the search and drafted the report, which was revised by B D’Onofrio. All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Conflicts of interests The funders of the study had no role in the design or conduct of the study, data collection, management, analysis or interpretation, or in the preparation, review or approval of the report. C Skoglund and L Brandt had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. There were no financial or other conflicts of interest among the other authors. The lead author assumes responsibility for the integrity of the data and the accuracy of the data analysis.
Acknowledgements C Skoglund had financial support from the Regional Agreement on Medical Training and Clinical Research (K1426-2011; 20120334) between the Stockholm County Council and Karolinska Institutet, the Swedish Research Council (2013-2280; 2012-2607), Swedish Initiative for Research on Microdata in the Social and Medical Sciences (SIMSAM) framework (Grant no. 340-2013-5867), and National Institute of Mental Health (NIMH) (Grant no. 1R01MH102221).
Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
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Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
www.elsevier.com/locate/euroneuro
Methylphenidate doses in Attention Deficit/ Hyperactivity Disorder and comorbid substance use disorders Charlotte Skoglunda,n, Lena Brandtb, Brian D’Onofriod, Henrik Larssonc, Johan Francka a
Department of Clinical Neuroscience, Division of Psychiatry, Karolinska Institutet, Norra Stationsgatan 69, SE-113 64 Stockholm, Sweden b Center for Pharmacoepidemiology, Department of Medicine, Karolinska Institutet, Department of Medicine, Solna, Karolinska University Hospital, SE-171 76 Stockholm, Sweden c Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, SE-171 77 Stockholm, Sweden d Department of Psychological and Brain Sciences Indiana University, 1101 East 10th Street, Bloomington, IN 47405, USA Received 26 July 2016; received in revised form 15 July 2017; accepted 30 August 2017
KEYWORDS
Abstract
Methylphenidate; Drug prescription; Substance use disorder
Patients with Attention Deficit/Hyperactivity Disorder (ADHD) and comorbid Substance Use Disorders (SUD) are increasingly being treated with central stimulant medication despite limited evidence for its effectiveness. Lack of longitudinal follow-up studies of dosing and adverse effects has resulted in conflicting treatment guidelines. This study aims to explore whether individuals with ADHD and comorbid SUD are treated with higher stimulant doses than individuals with ADHD only, and whether doses increase over time as a sign of tolerance, a core symptom of addiction. Information on methylphenidate doses for 14 314 Swedish adults, including 4870 individuals with comorbid SUD was obtained through linkages of Swedish national registers between 2006 and 2009. Differences in doses between patients with and without SUD were estimated using logistic regression while a linear regression model calculated time trends in mean doses. Individuals with SUD were prescribed higher methylphenidate doses than those without (ORday365; 2.12, 95% CI 1.81–2.47: ORday730 2.65, 95% CI 2.13–3.30). Patients with SUD were, two years after initiating stimulant treatment, prescribed approximately 40% higher doses compared to individuals with ADHD only. The results may suggest a need for increased doses in this population to achieve optimal ADHD symptom control. A tendency towards increasing doses during the first years of treatment, more pronounced in individuals with comorbid SUD, may reflect a reluctance to prescribe adequate
n
Corresponding author. Fax: +46 8 346563. E-mail address: [email protected] (C. Skoglund).
http://dx.doi.org/10.1016/j.euroneuro.2017.08.435 0924-977X/& 2017 Published by Elsevier B.V.
Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
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C. Skoglund et al. doses due to lack of clinical guidelines. Mean doses stabilized after about two years in both groups, which does not lend support to continuously increasing tolerance over time. & 2017 Published by Elsevier B.V.
1.
Introduction
Attention Deficit/Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental disorder (Wilens and Spencer, 2010), and individuals with ADHD are at increased risk for Substance Use Disorders (SUD) (van Emmerik-van Oortmerssen et al., 2012). Despite a substantial overlap and signs of common pathophysiological mechanisms (Frodl, 2010) little is known about how patients with ADHD and comorbid SUD can be safely and effectively treated (Cunill et al., 2015). It is well established that pharmacological treatment of ADHD using stimulant medication improves ADHD core symptoms (Faraone and Buitelaar, 2010, Faraone and Glatt, 2010). Methylphenidate is the most commonly used stimulant medication (NICE guidelines 2008, Kooij et al., 2010) with an expected treatment response observed in about 80% of the patients (Pliszka, 2007). Serious adverse effects are rarely associated with stimulant medication use (Santosh et al., 2011). However, stimulant medications are controlled substances (Controlled Substance Act, FDA, 2016) that increase dopamine levels in brain areas involved in development of addiction and thus can be recreationally abused (Wilens et al., 2008). Whereas stimulant treatment among patients with ADHD has increased in recent years (McCarthy et al., 2012), few studies have addressed treatment efficacy in individuals with comorbid SUD (Cunill et al., 2015). Consistent with clinical observations that individuals with SUD may need substantially higher stimulant doses than those with ADHD only, two recent randomized controlled trials showed significant improvements in ADHD symptoms and SUD outcomes using higher stimulant doses than earlier studies (Konstenius et al., 2014, Levin et al., 2015). Although tolerance is a core symptom of addiction and may underlie a need for higher initial stimulant doses in patients with SUD, continuously increasing doses during maintenance pharmacotherapy should raise concerns as that may reflect a worsening of the SUD. Societal and clinical concerns or inappropriate beliefs about the safety of stimulant treatment in individuals with coexisting SUD (Cassidy et al., 2015, Faraone and Glatt, 2010, Kaye and Darke, 2012), lack of longitudinal follow-up studies of dosing and adverse effects, such as harmful use and dependence, and a fear that stimulant treatment might put susceptible individuals at risk for future SUD, relapse or worsening of ongoing SUD is mirrored in conflicting treatment guidelines (Bolea-Alamanac et al., 2014, Cunill et al., 2015, NICE 2008). Observational studies allow for large sample sizes to relatively small economical costs and can provide longitudinal information on changes in prescribed
methylphenidate doses over time. In this population-based cohort study of all 14 314 adults with one or more prescriptions of methylphenidate between 2006 and 2009 in Sweden, we aimed to explore potential differences in prescribed stimulant doses between individuals with and without comorbid SUD, and whether doses increase over time as a proxy for medication tolerance.
2. 2.1.
Experimental procedures Sample
The study was approved by the Research Ethics committee at Karolinska Institutet, Stockholm, Sweden, protocol no. 2009/5:10, 2009/939-31/5. We obtained data from a record linkage of four population-based registries in Sweden; personal identification numbers enabled accurate linkage. The Swedish Prescribed Drug Register includes information on drug identity using Anatomical Therapeutic Chemical (ATC) codes and dates of all prescribed drugs filled at Swedish pharmacies since July 2005. Each unique prescription has a specific dose text describing the quantity and dosage filled out by the prescribing physician. The National Patient Register provides data on in-patient psychiatric care since 1973 and outpatient care since 2001, categorized according to diagnostic coding in the eighth, ninth and tenth revision of the International Classification of Diseases (ICD-8, ICD-9 and ICD-10). To account for death and migration all data was linked to the Cause of Death Register and the Migration Register.
2.2.
Measures
2.2.1. Diagnostic categories A total of 14 314 individuals, aged 18–59, with an initial prescription of methylphenidate (ATC code for methylphenidate N06BA04 in the Prescribed Drug register), including 4870 with a diagnosis of SUD, were included in the main analysis. The National Patient Register and the Prescribed Drug Register were used to identify patients diagnosed with alcohol and/or drug use disorders in accordance with the ICD diagnostic guidelines and/or a prescription including an ATC code for drugs used exclusively in the treatment of SUD. Alcohol use disorder was defined using ICD codes from the National Patient Register (ICD-8: 291 and 303, ICD-9: 291, 303 and 305A and ICD-10: F10.0-F10.9) and ATC codes for prescriptions of medications used in the treatment of alcoholism (N07BB03 (acamprosate), N07BB04 (naltrexone) and N07BB01 (disulfiram)) from the Prescribed Drug Register. Psychoactive drug abuse was measured by ICD codes from the National Patient Register (ICD-8: 304, ICD-9: 292, 304 and 305X and ICD-10: F11.0–F16.9 and F18.0–F19.9) and ATC codes from the Prescribed Drug Register for prescriptions of medications used in the treatment of drug abuse (N02AE01 (buprenorphine), N07BC51 (buprenorphine+naltrexone) and N07BC02 (methadone)). An individual was classified as having SUD or not when included in the study (at the time of the initial prescription of methylphenidate). In addition, the National Patient Register
Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders provided data on coexisting psychiatric ICD-8, ICD-9 and ICD-10 diagnoses other than alcohol and/or drug use disorders. 2.2.2. Operationalization of doses and treatment periods Individual daily methylphenidate doses were estimated by means of the text variable in the Prescribed Drug Register. Each prescription contains a text variable containing the quantity of medication prescribed and individualized instructions on how the drug is to be consumed. If a prescription of equal dosage was filled before the last prescription was due to run out, we assumed the first filled prescription to have been consumed. If prescriptions of different dosage were filled on the same occasion, we assumed them to have been consumed simultaneously according to the text variable on each prescription. The prescribed dose was calculated every 100 days and annual point estimates. We defined a treatment period as the number of days the prescription would last according to the text variable on the prescription, plus 25% to avoid individual minor irregularities in dispensing patterns. During subsequent periods or those without any new prescription, the patient was assumed to be off treatment. To ensure that participants had not been receiving methylphenidate treatment prior to follow up, we used information about prescription dates six months before start of follow-up at January 1, 2006. Differences in mean methylphenidate doses between patients with and without SUD were stratified into 0–72 mg and 472 mg based on recommendations issued by the British Association for Psychopharmacology (recommended maximum dose 100 mg) (Bolea-Alamanac et al., 2014), the US Food and Drug Administration (recommended maximum dose 72 mg) (Controlled Substance Act, FDA), the National Institute for Health and Care Excellence (recommended maximum dose 60 mg) (NICE) and clinical expertise. Also, Osmotic Release Oral System (OROS) is the most commonly prescribed methylphenidate formulation in Sweden, and only commercially available in multiples of 18 mg. To validate the semi-manual method of extracting doses from the text variable, an independent clinician proofread 4000 randomly selected records in the material. A total of 0.3% of the prescriptions were not coded correctly or were interpreted differently by the proof-reader.
2.3.
Statistical analyses
Descriptive measures and distribution of daily doses in categories were tabulated for individuals with and without SUD with point estimates at day 100, day 365, day 730 and day 1095 after the date of the first filled prescription. Logistic regression models were calculated for the dependent variable (e.g. methylphenidate dose) at day 365 and 730. Given the potential confounding effects of several explanatory variables (e.g. SUD subtype, gender, age, calendar year of the initial prescription and comorbid psychiatric diagnoses) these covariates were simultaneously fitted into the adjusted model. Odds ratios (ORs) with Wald 95% confidence intervals were presented using the LOGISTICS PROCEDURE, SAS version 9.4. The development of doses over time in patients with and without SUD was described in a graph depicting a point estimate of the mean dosage every 100 days. Time trends in mean doses were tested with linear regression and described in a graph depicting a point estimate of the mean dosage every 100 days. The means were weighted with the inverse of the number of subjects in treatment at the time. Time was arbitrarily divided into two periods: 100–600 and 700–1200 days after the initial prescription. 2.3.1. Sensitivity analysis We performed a sensitivity analysis to test whether individuals with methylphenidate doses over 72 mg/day actually picked up doses
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corresponding to the one prescribed by the physician. A subsample of the population with doses over 72 mg/day (N=659) was selected, and the doses in the Prescribed Drug Register on days 300 and 400 were compared to the total accumulated dose filled by the pharmacy between days 200 and 400.
3.
Results
A sample of 14 314 adults (including 4870 individuals with a diagnosis of SUD) with a prescription of methylphenidate between January 1, 2006, and December 31, 2009 was included in the main analysis (Figure 1). Out of the targeted population, 93% was monitored during the entire follow-up period (Table 1). The mean period was approximately 550 days in both populations and allowed for times during which medication was discontinued or resumed. Psychiatric comorbidity including personality disorders and conduct disorder was more prevalent among individuals with comorbid SUD than among individuals with ADHD only (Table 1). Table 2 shows that, at day 365, 37.1% of individuals with comorbid SUD were prescribed methylphenidate doses over 72 mg compared to 20.6% of those with ADHD only (chi-square po0.0001). At day 730, 44.4% of individuals with comorbid SUD were prescribed methylphenidate doses over 72 mg, compared to 22.8% of individuals with ADHD only (chi-square po0.0001). Among individuals with SUD, 7.3% had doses exceeding 180 mg/day at day 730, compared to 1.2% of those with ADHD only (chi-square po0.0001). Retention to treatment at day 730 was 48% in the SUD population and 42% in individuals with ADHD only (chi-square po0.0001). The proportion of patients who had been prescribed extended release preparations at day 730 was high both in patients with SUD (86%) and in patients with ADHD only (82%)(chi-square p=0.01). ORs for methylphenidate doses exceeding 72 mg/day in individuals with comorbid SUD and ADHD only are shown in Table 3. Individuals with SUD were at increased risk for exceeding a daily dose of 72 mg (ORSUDday365 2.12 and ORSUDday730 2.65). A diagnosis of drug abuse (DA), a combined diagnosis of both DA and alcohol use disorder (AUD) and a diagnosis of psychoactive stimulant use (SU) significantly increased the risk for exceeding a dose of 72 mg/day (ORDAday365 2.53, ORDAday730 3.09, ORDA + AUDday365 2.53 and ORDA + AUDday730 2.97, ORSUday365 3.08, ORSUday730 3.63). The corresponding risk associated with a diagnosis of AUD only was lower (ORAUDday365 1.49 and ORAUDday730 2.01), indicating that SUD subtype and/or severity is correlated to methylphenidate dose. Figure 2 shows a small but significant increase in mean doses (1.1 mg/100 days) between days 100 and 600 in individuals with ADHD only. The increase of mean doses in individuals with comorbid SUD was greater (3.2/100 days) (p-value for interaction 0.001). In contrast no statistically significant trend in mean doses was observed between days 700 and 1200 (p=0.30 in the entire population; p=0.21 in individuals with comorbid SUD and p=0.15 in individuals with ADHD only).
3.1.
Sensitivity analysis
Our sensitivity analysis showed that 90% (95% CI 87.5 to 92.1) of individuals who were prescribed a daily dose of over 72 mg on days 300 and 400 picked up corresponding daily doses of over 72 mg at the pharmacy between days 200 and 400.
4.
Discussion
This nationwide, register-based cohort study of adult ADHD patients treated with methylphenidate, shows that patients with comorbid SUD, two years into stimulant treatment,
Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
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C. Skoglund et al.
Fig. 1 Flowchart.
were prescribed approximately 40% higher methylphenidate doses than individuals with ADHD only. Doses in both groups stabilized during the first two years of treatment. The findings of higher doses in the ADHD plus SUD group may indicate that patients with SUD need higher methylphenidate doses to achieve optimal ADHD symptom control. One interpretation of these findings, supported by the finding that individuals with a diagnosis of psychoactive stimulant use were prescribed higher methylphenidate doses compared to other SUD subtypes, is that individuals with comorbid SUD might have developed a tolerance to central stimulants. An increase in tolerance is likely to result in a need for higher doses and prolonged titration periods. This would be consistent with two recent randomized controlled trials (Konstenius et al., 2014, Levin et al., 2015) showing significant improvements in both ADHD symptoms and SUD outcomes using higher stimulant doses than earlier studies. If true, this may explain why previous research have found little evidence for any beneficial effects of methylphenidate on SUD-related outcomes (Cunill et al., 2015, Perez-Mana et al., 2013) using doses recommended by current guidelines (mean doses 62.2 mg/
day) (Bolea-Alamanac et al., 2014, NICE 2008. Kooij et al., 2010). An alternative explanation for the different doses could be ADHD subtype, with differences in symptom severity, or psychiatric comorbidity. Whereas ADHD and personality disorders frequently co-occur in adult non-SUD populations (Matthies and Philipsen, 2016), a recent crosssectional study also showed that 75% of SUD patients with ADHD had at least one additional comorbid disorder compared with 37% patients without ADHD (van Emmerik-van Oortmerssen et al., 2014). As the present dataset cannot be linked to individual clinical data, this needs to be further explored in future studies. Mean doses stabilized over time in both populations at the end of follow-up even though, among individuals with comorbid SUD, a continuous increase in mean dose was observed up to approximately two years of treatment. Assuming that the initial dosing may have been inadequate, the tendency towards increasing doses during the first two years of treatment, more pronounced in individuals with comorbid SUD, may reflect a reluctance to prescribe adequate doses due to lack of clinical guidelines, and/or prescribers’ inappropriate beliefs. The dose-response
Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders
Table 1 Distribution of study variables across individuals with and without comorbid SUD. SUD
No SUD
(n = 4870)
(n = 9444)
%
%
Follow-up Until December 31, 2009 Censoreda
93.1 6.9
93.8 6.2
Observation Mean days (sd)
550.6 (388.6)
549.8 (400.4)
Age Mean years (sd) Female
34.6 (10.3) 36.1
31.7 (10.5) 47.9
Psychiatric diagnosis Schizophreniab Schizoaffective disorderb Mood disordersb Bipolar disordersb Anxiety disordersb Eating disordersb Personality disordersb Conduct disorderb
3.2 1.1 38.4 10.0 50.3 3.7 26.9 2.4
0.7 0.4 30.6 7.28 34.4 3.4 11.2 1.3
SUD=Substance Use Disorders. b ATC code: N05BA, N05CF, N05C. a Censored due to; Emigration n=89, Deceased n=138, Participation in clinical trial n=5, Prescriptions of dexamphetamine or amphetamine n=691 b ICD8-10 diagnoses: Schizophrenia (ICD-8: 295.0–295.4, 295.6, 295.8–295.9; ICD-9: 295A-295E, 295G, 295W, 295X; ICD-10: F20), Schizoaffective disorder (ICD-8 295.7; ICD-9 295H; ICD-10 F25), Mood disorders (ICD8: 296.2, 298.0, 300.4; ICD9: 296B, 300E; ICD10: F32–F39), Bipolar disorders (ICD-8: 296.1, 296.3, 296.8; ICD-9: 296A/C/D/E/W; ICD-10: F30–F31), Anxiety disorders (ICD8, ICD9: 300; ICD10:F40-48), Eating disorders (ICD8: 306.5; ICD9: 307B/F; ICD10: F50), Personality disorders (ICD8, ICD9: 301; ICD10:F60, Conduct disorder (ICD9: 312; ICD-10: F91).
relationship of methylphenidate on ADHD symptoms is well established in children (Greenhill et al., 2001). Less is known about dose-response in adults and inter-individual serum concentration variability in relation to ADHD symptom control (Ermer et al., 2010), and clinicians are left to arbitrarily titrate the medication based on the patient's subjective response. Given the lack of objective assessment procedures, biomarkers or clear treatment guidelines, clinicians might be reluctant to increase doses to optimal levels for individuals with ADHD and SUD due to fear of misuse, abuse or diversion (Wilens et al., 2008, Kaye and Darke 2012). An important question that deserves further investigation is whether methylphenidate primarily targets ADHD
5
symptoms, modulates the pathophysiology of SUD directly, or both. Adequate treatment, more specifically adequate dosage, may increase the motivation to stay in treatment and prevent relapses to illegal drug use. While the efficacy of agonist maintenance therapy available for opioid addiction has been extensively studied (Mattick et al., 2014), substitution treatment for psychoactive stimulant use has been less investigated (Galloway et al., 2011, Longo et al., 2010, Mariani et al., 2014, Miles et al., 2013, Tiihonen et al., 2007). Research targeting the direct effect of central stimulant medication on SUD pathophysiology is as yet inconclusive (Galloway et al., 2011, Longo et al., 2010, Miles et al., 2013, Tiihonen et al., 2007). In the present study, a diagnosis of drug abuse (DA), a combined diagnosis of both DA and alcohol use disorder (AUD) and a diagnosis of psychoactive stimulant use (SU) significantly increased the risk for exceeding a dose of 72 mg/day indicating that SUD severity and/or subtype may be correlated to methylphenidate dose. Also, at any given time point during the followup, individuals with comorbid SUD had higher adherence to treatment than those with ADHD only. Three years following the initial prescription of methylphenidate, 45% of patients with ADHD and SUD, compared to 37% of individuals with ADHD only, were still actively picking up their prescriptions. Population-based register data have several strengths compared with clinical trials including substantial sample sizes representative for the population. Research based on nationwide registers can avoid problems arising from referral bias, selective participation, and other threats to validity and generalizability. Information on SUD was acquired using both ICD-codes from the National Patient Register and ATC-codes in the Prescribes Drug Register, thus minimizing the risk of informant and recall bias. Medication for ADHD is recorded in the Prescribed Drug Register when a prescription is filled, and therefore free from recall bias. The present results need to be interpreted in the light of some important limitations regarding the diagnostic procedure of ADHD and SUD, assumptions of individual doses and duration of active medication. The ascertainment of ADHD was predominantly based on prescribed medication unique for the treatment of ADHD. Since the National guidelines for medication of ADHD, issued by the Swedish National Board of health and Welfare in 2002, stated that medication should be reserved for cases where other supportive interventions have failed, this strategy could probably not avoid producing false negatives, but we consider bias due to false positive ADHD diagnosis more unlikely, not least due to the strict enforcement of malpractice regulations in Sweden and the limitation to only psychiatrists and pediatricians specializing in pediatric neurology to prescribe central stimulants. Due to methodological limitations inherent in the study design such as lack of clinical information on ADHD subtype, symptom severity, dose-response data, and other psychosocial interventions targeting ADHD and/or SUD there is limited adjustment for these potential confounders and the results should be interpreted with caution. Also, the possibilities of long-term follow up due to collect data from three different diagnostic systems (ICD-8, ICD-9 and ICD-10) must be weighted against potential problems arising from differences in definition of the ADHD and SUD diagnoses across these three generations of coding systems. Given the
Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
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Table 2 Methylphenidate (MPH); mean daily doses and distribution of doses and formulations over time in individuals with substance use disorder compared to individuals with ADHD only. 100 daysa
365 daysa
730 daysa
1095 daysa
SUD
No SUD
SUD
No SUD
SUD
No SUD
SUD
No SUD
n =4280
n = 8194
n =2930
n = 5565
n =1527
n = 2940
n =558
n = 1197
On MPH, n (%) Prescribed dose known n (%) Mean daily dose in mg (sd) Median (quartiles) Min-max
3146 (74%) 2659 (85%) 67.3 (44.6) 54 (36;90) 5–440
5888 (72%) 5400 (92%) 53.9 (30.9) 54 (36;72) 4–324
1587 (54%) 1400 (88%) 76.6 (51.9) 64 (40;92) 4–420
2762 (50%) 2610 (94%) 59.4 (36.8) 54 (36;72) 4–620
739 (48%) 657 (89%) 87.0 (64.1) 72 (46;108) 9–590
1 231 (42%) 1169 (95%) 60.7 (38.3) 54 (36;72) 10–452
249 (45%) 211 (85%) 84.8 (59.2) 72 (40;108) 9–360
445 (37%) 4196 (94%) 60.7 (38.4) 54 (36;72) 10–320
Dose distribution, % r 54 mg 55–72 mg 73–180 181–360 4360
54.2 16.8 26.7 2.2 0.1
69.1 14.1 16.2 0.6 0.0
45.1 17.8 33.1 3.8 0.2
61.4 18.0 19.5 1.0 0.1
40.3 15.2 37.1 6.7 0.6
59.8 17.5 21.6 1.0 0.2
42.2 15.2 34.1 8.5 0.0
58.5 18.9 21.5 1.2 0.0
Formulations, % ER/OROS IR ER/OROS + IR
89.3 3.9 6.8
85.5 6.9 7.6
87.0 4.2 8.8
83.4 6.7 9.8
86.5 4.9 8.7
82.0 7.8 10.2
87.1 5.2 7.6
81.1 7.0 11.9
MPH=Methylphenidate, SUD=Substance Use Disorder, OROS=Osmotic Controlled Release Oral Delivery, ER=Extended Release Formulation, IR=Immediate Release Formulation. a After initial prescription of methylphenidate.
Table 3
Logistic regression model of methylphenidate doses exceeding 72 mg/day. Day 365
Day 730 Dose 472 mg/day
Dose 472 mg/day
Unadjusted
Adjusteda
OR (95% C.I.)
OR (95% C.I.)
n
%
Total
4010
26
SUD No Yes
2610 1400
21 37
ref =1 2.28 (1.98–2.64)
SUD Subtypeb AUD DA AUD + DA SU
473 453 474 500
29 41 42 47
1.56 2.69 2.77 3.48
(1.25–1.94) (2.18–3.32) (2.25–3.40) (2.85–4.25)
Unadjusted
Adjusteda
OR (95% C.I.)
OR (95% C.I.)
n
%
1826
31
ref =1 2.12 (1.81–2.47)
1169 657
23 44
ref =1 2.72 (2.21–3.34)
ref =1 2.65 (2.13–3.30)
1.49 2.53 2.53 3.08
208 227 222 256
37 48 48 53
2.00 3.14 3.10 3.79
2.01 3.09 2.97 3.63
(1.19–1.87) (2.03–3.15) (2.03–3.16) (2.49–3.81)
(1.46–2.73) (2.34–4.21) (2.31–4.17) (2.86–5.02)
(1.46–2.78) (2.28–4.20) (2.16–4.09) (2.69–4.91)
MPH=Methylphenidate, SUD =Substance Use Disorder, AUD=Alcohol Use Disorder, DA=Drug Abuse, SU=Stimulant Use Disorder (Ever diagnose of F15 304E, 304,60 = Mental and behavioural disorders due to psychoactive stimulant use). a Adjusted for sex, age, year of initial prescription, and psychiatric comorbidity. b Diagnosis of /Medication for.
Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders
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course of stimulant medication and development of methylphenidate doses over time should increase the evidence base for stimulant pharmacotherapy among individuals with combined ADHD/SUD.
Declaration of interest The authors state no conflicts of interest.
Role of the funding source
Fig. 2 Mean methylphenidate doses over time in individuals with SUD compared to individuals with ADHD only. SUD =Substance use disorder, SUD =Individuals with comorbid Substance use disorder who have been prescribed methylphenidate, No SUD=Individuals with ADHD only who have been prescribed methylphenidate.
observational nature of the study the investigators lacked control over how unknown potentially confounding factors were distributed across the two groups. Future studies should explore the need for higher doses due to liver enzyme induction following cigarette smoking, coexisting psychopharmacological treatment or somatic disorders. The study design does not allow for differentiating between the quantity of medication prescribed and received, and the amount of medication actually consumed. Thus the observed finding of higher methylphenidate doses in individuals with ADHD and comorbid SUD might also to some extent be explained by diversion, a phenomenon that may be more prevalent in certain populations (Cassidy et al., 2015). Studies targeting the extent of non-medical use of stimulants (Kaye and Darke, 2012), in “high-risk” populations such as individuals with ADHD and comorbid SUD is limited (Wilens et al., 2008) and this should be an important focus for future research. Also, given that treatment with methylphenidate, a schedule II classed medication (Controlled Substance Act, FDA) is controlled (Heal et al., 2009, Khan, 1979) and treatment guidelines often recommend abstinence from abused substances prior to and during such pharmacological treatment (NICE 2008, CADDRA) individuals with ADHD and comorbid SUD might therefore be more closely monitored (Heal et al., 2009). The proportionally higher adherence to treatment among patients with SUD might reflect the fact that these individuals, in order to prevent abuse and medication diversion, receive more intense psychosocial interventions and/or monitoring. In conclusion, individuals with ADHD and comorbid SUD were prescribed significantly higher methylphenidate doses than those with ADHD only. Across the longitudinal followup, mean prescribed doses stabilized over time in both groups and the results do not lend support to continuously increasing tolerance. Putative factors contributing to such dosing differences need to be tested using prospective designs. A clearer understanding of the natural long-term
C Skoglund had financial support from the Regional Agreement on Medical Training and Clinical Research (K14262011; 20120334) between the Stockholm County Council and Karolinska Institutet, the Swedish Research Council (20132280; 2012-2607), Swedish Initiative for Research on Microdata in the Social and Medical Sciences (SIMSAM) framework (Grant no. 340-2013-5867), and National Institute of Mental Health (NIMH) (Grant no. 1R01MH102221). H Larsson has served as a speaker for Eli-Lilly and has received a research grant from Shire; both outside the submitted work.
Contributors C Skoglund is the lead author of the manuscript and affirms that the manuscript is an honest, accurate, and transparent account of the study being reported and that no important aspects of the study have been omitted. C Skoglund and J Franck conceived and designed the study. L Brandt performed the analyses and, with H Larsson, assisted in the study design. C Skoglund performed the search and drafted the report, which was revised by B D’Onofrio. All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Conflicts of interests The funders of the study had no role in the design or conduct of the study, data collection, management, analysis or interpretation, or in the preparation, review or approval of the report. C Skoglund and L Brandt had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. There were no financial or other conflicts of interest among the other authors. The lead author assumes responsibility for the integrity of the data and the accuracy of the data analysis.
Acknowledgements C Skoglund had financial support from the Regional Agreement on Medical Training and Clinical Research (K1426-2011; 20120334) between the Stockholm County Council and Karolinska Institutet, the Swedish Research Council (2013-2280; 2012-2607), Swedish Initiative for Research on Microdata in the Social and Medical Sciences (SIMSAM) framework (Grant no. 340-2013-5867), and National Institute of Mental Health (NIMH) (Grant no. 1R01MH102221).
Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435
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Please cite this article as: Skoglund, C., et al., Methylphenidate doses in Attention Deficit/Hyperactivity Disorder and comorbid substance use disorders. European Neuropsychopharmacology (2017), http://dx.doi.org/10.1016/j.euroneuro.2017.08.435