pharmacoepidemiology and drug safety 2014; 23: 534–538 Published online 7 March 2014 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/pds.3604
ORIGINAL REPORT
Trends in attention deficit hyperactivity disorder drugs consumption, Israel, 2005–2012 Alexander M. Ponizovsky1*, Eli Marom2 and Israel Fitoussi2 1 2
Mental Health Services, Ministry of Health, Jerusalem, Israel Pharmaceutical Administration, Ministry of Health, Jerusalem, Israel
ABSTRACT Purpose The aim of this study was to describe trends in attention deficit hyperactivity disorder (ADHD) drugs consumption in Israel (Ritalin, Concerta, Daytrana, Vyvanse, Focalin, and Adderall) over the 8 years, 2005–2012, and to explore explanations for changes in amounts and patterns of the utilization. Methods Data for the period from 2005 to 2012 were extracted from the database maintained by the Israel Ministry of Health’s Pharmaceutical Administration. The data were converted into a defined daily dose (DDD) per 1000 inhabitants per day. Results Consumption of all ADHD drugs covered by Israel’s national health care system doubled over the study period, from 4.02 DDD/ 1000 inhabitants/day in 2005 to 9.92 DDD/1000 inhabitants/day in 2012. This rise was largely due to a fivefold increase in Concerta consumption (from 0.46 DDD/1000 inhabitants/day in 2005 to 2.28 DDD/1000 inhabitants/day in 2012) and a threefold increase in Ritalin consumption (from 1.43 DDD/1000 inhabitants/day in 2005 to 4.84 DDD/1000 inhabitants/day in 2012). Adderall (amphetamine mixed salts) consumption rose by 30% for the same period. A substantial trend was noted for increased utilization of high-dose formulations together with proportional decline in low-dose consumption. In the same period, cost of the medications has been reduced an average by 20–25%. Conclusions There has been a drastic rise in ADHD drugs consumption in Israel over 2005–2012. This has been associated with substantial reduction in cost and changes in the pattern of prescribing that characterized by increased prescription of high-dose long-acting preparations of ADHD drugs and decreased prescription of their low-dose, short-acting formulations. Copyright © 2014 John Wiley & Sons, Ltd. key words—methylphenidate; Ritalin; Concerta; Daytrana; Focalin; Vyvanse; Adderall; ADHD; pharmacoepidemiology Received 17 October 2013; Revised 26 January 2014; Accepted 4 February 2014
INTRODUCTION Attention deficit hyperactivity disorder (ADHD)1 is a common neurobiological condition characterized by developmentally inappropriate levels of inattention, impulsivity, and hyperactivity, with a worldwide prevalence of 5% in children and 3–4% in adults.2,3 Despite continuing debates about the etiology of ADHD, evidence for a strong genetic contribution to the disorder has recently been reported.4 Psychostimulants are the well-established drugs of choice for ADHD treatment. The most popular of them, methylphenidate, inhibits the reuptake of dopamine and norepinephrine, and thus increases the levels of these neurotransmitters in the brain. Clinical *Correspondence to: A. M. Ponizovsky, Mental Health Services, Ministry of Health, 39 Yirmiyahu St., PO Box 1176, Jerusalem 9446724, Israel. E-mail:
[email protected];
[email protected]
Copyright © 2014 John Wiley & Sons, Ltd.
manifestations of the stimulant effects are improved attention, concentration, impulse control, learning, and memory. The side effects of psychostimulants are increased heart rate, blood pressure, and respiration, which with repeated use of high doses may impair cardiovascular functioning.5 Another potential dangerousness of the use of high-dose drugs is abuse, dependence, and sometimes psychosis.6 Because the pharmacological activity of methylphenidate is limited by 1–2 h of half-life, the medication requires increasing dosing frequency. In order to enhance compliance and overall effectiveness of methylphenidate, several long-acting formulations allowing once-a-day dosing have been developed in the past two decades: Concerta, Ritalin LA, Focalin XR (dexmethylphenidate), and Daytrana transdermal. In addition, long-acting formulations for the amphetamine salts (Adderall XR) and lisdexamphetamine (Vyvanse) have been introduced.
adhd drug consumption
Pharmacoepidemiological studies conducted over the world7–14 have shown continuous trends to substantial increase in licit consumption of ADHD medications over the last decades. An increasing global trend in the prescription of stimulant pharmaceuticals corresponds with almost threefold increase in the global manufacture and consumption of methylphenidate from 16 tons in 2000 to 43 tons in 2009.15 A trend toward greater use of expensive long-duration medications and subsiding for them from government agencies and insurance companies are noted in countries with more developed health care system, while the utilization of inexpensive immediate-release formulations is a rule in countries, where medication use is less common.16 In Israel, where health care system is based on health maintenance organizations (HMOs), two population-based prevalence studies of methylphenidate use among children17 and senior adolescents18 were conducted in 2004/2005. The former examined all children aged 0–18 years living in the central district of Clalit HMO who were prescribed methylphenidate in the 7-year period from 1998 to 2004 and found that the overall 1-year prevalence rate of methylphenidate use rose by a factor of 3.54, from 0.7% in 1998 to 2.5% in 2004. The latter study examined a community sample of 954 adolescents representing the Israeli adolescent population aged 14–17 years and found that methylphenidate was prescribed to 2.9% of adolescents, although those of Arab/Druse minority groups were underdiagnosed or untreated, whereas many of the Jewish majority were overdiagnosed and potentially overtreated. Both studies concluded that the continuous increasing rate of methylphenidate use in Israel represents a significant public health issue that requires further investigation. The present study describes the trends in ADHD medication consumption in Israel in the period from 2005 to 2012 to assess changing patterns of psychostimulants prescription practices and to explore explanations for changes in amounts and patterns of the utilization. METHODS Drug utilization data were derived from the national database maintained by the Ministry of Health’s Pharmaceutical Administration. This database contains, among others, data on the consumption of all methylphenidate formulations covered by Israel’s National Health Insurance system. Data on the total annual consumption of ADHD medications that require a special prescription form (Ritalin, Concerta, and Adderall) were evaluated over the 2005–2012 period. In addition, we analyzed consumption of Copyright © 2014 John Wiley & Sons, Ltd.
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two other ADHD drugs—Daytrana and Vyvanse that were marketed in Israel since 2008 and 2011, respectively. Aside from the trends in total consumption of ADHD drugs, we also analyzed changing patterns of the drugs’ prescription practices, dosages, and formulations. Dosages for all drugs were converted into a defined daily dose (DDD) per 1000 inhabitants per day, which is the average maintenance dosage as defined by the World Health Organization Collaborating Center for Drug Statistics.19 DDDs are based on the Anatomical Therapeutic Chemical classification index.20 For medications that do not have the official DDD (Adderall and Vyvanse), we proposed DDD = 30 mg per day on the basis of most frequent dosage used (except for Focalin, whose proposed DDD was 10 mg/day). To calculate consumption rates, we used the formula “number of DDD per 1000 inhabitants per day = number of packages dispensed × number of doses per package × number of mg per dose × 1000 inhabitants/DDD in mg × number of inhabitants in Israel for the year × 365 days”. The total population for each year studied was obtained from the Israeli Central Bureau of Statistics21 and used in the calculations. Total costs were estimated by multiplying the number of packages of each product by the price of each one—including taxes— regardless of the entity responsible for the payment. All costs are expressed in constant New Israel Shekels. RESULTS Over the study period, the total annual consumption of ADHD medications (Ritalin, Concerta, Daytrana, Vyvanse, Focalin, and Adderall) covered by Israel’s national health care system more than doubled, from 4.02 DDD/1000 inhabitants/day in 2005 to 9.92 DDD/1000 inhabitants/day in 2012. Table 1 and Figure 1 show that the consumption of Ritalin, as measured by DDD/1000 inhabitants per day, increased by a factor of 3.1, from 1.43 DDD/1000 inhabitants/ day in 2005 to 4.84 DDD/1000 inhabitants/day in 2012. The corresponding figures for Concerta demonstrated almost fivefold increase, from 0.46 DDD/1000 inhabitants/day in 2005 to 2.27 DDD/1000 inhabitants/day in 2012. In addition, there was a 30% rise in the consumption of Adderall (amphetamine mixed salts), from 2.13 DDD/1000 inhabitants/day in 2005 to 2.79 DDD/1000 inhabitants/day in 2012 (Figure 1). The utilization of other methylphenidate formulations (Daytrana transdermal, dexmethylphenidate—Focalin) and psychostimulants (lisdexamphetanine—Vyvanse) also rose substantially, however their proportion in the total ADHD drug consumption was negligible. Pharmacoepidemiology and Drug Safety, 2014; 23: 534–538 DOI: 10.1002/pds
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Table 1. Consumption in defined daily dose per 1000 inhabitants per day of attention deficit hyperactivity disorder drugs covered by Israel’s national health care system, 2005–2012
Ritalin Concerta Daytrana Adderall Vyvanse Focalin Total
2005
2006
2007
2008
2009
2010
2011
2012
1.43 0.46
1.75 0.72
1.70 0.67
2.13
1.04
1.17
2.01 0.86 0.0018 1.16
1.98 1.14 0.0072 1.87
3.43 1.58 0.0133 2.66
4.02
3.51
3.54
0.00036 4.03
0.00177 4.99
0.00147 7.68
4.46 2.28 0.0193 2.23 0.0011 0.00384 8.99
4.84 2.27 0.0108 2.79 0.0095 0.00708 9.92
DDD/1000 inhabitants/day
The blanks correspond to the periods in which the drugs were not marketed.
12 10 8 6 4 2 0 2005
2006
2007
2008
2009
2010
2011
2012
LA 20 mg rose from 3.5% to 11%, Ritalin LA 30 mg from 4% to 6%, and Ritalin LA 40 mg from 2.6% to 12%. The similar changes during the study period have occurred in proportions of Concerta 18 mg (a sixfold decline) and Concerta 54 mg (a threefold rise). Table 2 shows that in the period from 2008 to 2012, cost of each methylphenidate formulation decreased by an average of 20–25%, except for Ritalin SR 20 mg × 30 and 100 tablets, which kept their cost unchanged.
Year Concerta
Ritalin
Adderall
TOTAL
Figure 1. Consumption trends for attention deficit hyperactivity disorder drugs covered by Israel’s national health care system, 2005–2012
Figure 2 depicts change in proportions of low-dose and high-dose methylphenidate formulations consumed in Israel over the study period. As can be seen, there is a substantial trend towards increase in proportions of high-dose preparations alongside with diminution in the proportion of low-dose formulations. The most considerable decline was in the proportion of Ritalin 10 mg, from 50% in 2005 to 17% in 2012, and Ritalin SR 20 mg, from 37% in 2007 to 14% in 2012. Over the same period, the proportion of Ritalin
DISCUSSION During the 8-year period under study, the consumption of ADHD drugs rose drastically, with Concerta and Ritalin (methylphenidate) and, to lesser extent, Adderall (amphetamine) accounting for the increase. Within this trend, long-acting high-dosage ADHD drugs (e.g., Concerta 54 mg and Ritalin LA 40 mg) partially replaced short-acting low-dosage stimulants (e.g., Ritalin 10 mg). This trend has been occurred on the background of a substantial reduction in cost of the medication. The results suggest that there is a major public health problem with probable over-recognizing and overtreatment of ADHD, and with possible diversion and misuse of psychostimulants, as well.
Figure 2. Consumption trends for the high-dose/low-dose of methylphenidate formulations, Israel, 2005–2012. Note a substantial decline in low-dose drugs consumption with proportional increase in high-dose drugs utilization
Copyright © 2014 John Wiley & Sons, Ltd.
Pharmacoepidemiology and Drug Safety, 2014; 23: 534–538 DOI: 10.1002/pds
adhd drug consumption Table 2. Cost in New Israel Shekels of methylphenidate formulations in Israel, 2005–2012 Methylphenidate formulation Ritalin 10 mg 30 tab Ritalin LA 20 mg 30 cap Ritalin LA 30 mg 30 cap Ritalin LA 40 mg 30 cap Ritalin SR 20 mg 100 tab Ritalin SR 20 mg 30 tab Concerta 18 mg 30 tab Concerta 27 mg 30 tab Concerta 36 mg 30 tab Concerta 54 mg 30 tab
2008
2010
2012
50.19 n/a n/a n/a 265.05 133.27 339.96 392.21 434.96 550.25
47.82 173.41 231.79 280.77 265.05 132.69 301.42 346.49 390.59 507.09
39.54 148.05 198.94 279.56 n/a 132.12 263.71 293.74 342.21. 413.11
New Israel Shekels = USD 3.5 or EUR 4.7.
Changing patterns of pharmaceutical stimulant prescription in the treatment of ADHD by increased use of methylphenidate and amphetamine preparations have been reported in many countries. Thus, in the international comparison of licit consumption in 10 countries between 1994 and 2000,7 12% annual increase in the overall methylphenidate and dexamphetamine consumption has been found, with highest rates in the USA, followed by Canada and Australia. Data presented in the Report of the INCB for 200915 have shown that medical consumption of methylphenidate between 2004 and 2009 increased almost threefold, with the major consumers being the USA, Iceland, Canada, Israel, Norway, and the Netherlands. A recent Danish register-based study22 found that 61% of 11 553 children and adolescents (6–13 years old) diagnosed with ADHD were treated with one or more ADHD medications; prescription rates of the medications increased 6.3-fold between 2003 and 2010. Finally, the most recent survey of the utilization of psychotropic drugs in Australia23 reported that dispensing of ADHD drugs increased by 72.9% over the 12-year period, 2000–2011, and that is in agreement with data from a previous study covering 2002–2009.24 Diverse factors may have contributed to the observed increase in ADHD drugs consumption during the period under study. For instance, decreasing tolerance of teachers to behavioral manifestations of ADHD within schools may have promoted the increase in recognition and appropriate treatment of ADHD. Another explanation is increasing societal pressure on children requiring more prolonged attention with simultaneous awareness of efficacy of stimulant medications.23 Likewise, a growing public awareness of ADHD as a disorder that begin in early/middle childhood but continue through adolescence and into adulthood25,26 may have also played a role in the increase in ADHD treatment. Moreover, Copyright © 2014 John Wiley & Sons, Ltd.
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practical guides to recognition, diagnosis, and treatment of ADHD in adults in the primary care setting27 that have appeared during the last decade also may increasingly affect the ADHD drug consumption. Demographic factors could be responsible for the observed trends. The simplest assumption is that the trend may reflect changes in demographic structure of the Israeli population over the study period, i.e., increasing proportion of children and adolescent of schooling age (5–18 years) who are the main consumers of ADHD drugs. This assumption was not supported by statistical data,28 showing that this proportion decreased from 26.4% in 2005 to 25.6% in 2012. Although the relative size of the Arab/Druse youth population rose by nearly 2% over the same period, this fact cannot affect the study results, given that these minority groups are underdiagnosed or untreated.18 Economic factors also could account for the observed increase in ADHD drug consumption. The sharp increase in ADHD drugs consumption since 2008 (Figure 1) may be explained by a substantial decrease in their cost (approximately by 20–25% from 2008 to 2012). In Israeli health care system, ADHD drugs are not included in the pharmaceuticals basket and, hence, they do not reimburse, except for immediate-release methylphenidate (Ritalin 10 mg).29 However, in the USA30 and some other countries,13 ADHD drugs consumption has increased despite the increases in stimulant spending, mainly at the expense of the new methylphenidate preparations. These findings suggest that educational and possibly cultural factors, rather than economic factors, may explain the trends for ADHD drug consumption. Our study has several limitations. The data refer to the medications dispensed and we have no information whether they were actually consumed; hence, the term “consumption” is used conventionally. We have no data recording the indications for the prescriptions so we are unable to distinguish among prescriptions for ADHD or use for other indications such as for narcolepsy or obesity. Finally, we do not know how much the unsanctioned use of prescribed stimulants contributed to the general increasing trend. However, relying on data from the National Survey on Drug Use and Health conducted recently in the USA,14 we can assume that this contribution is relatively small. The National Survey on Drug Use and Health indicated that the overall general population prevalence of lifetime methylphenidate misuse has remained low and stable (1.8–2.1%) between 2003 and 2009. In order to affirm or reject the previous assumption, the analogical survey in Israel is Pharmacoepidemiology and Drug Safety, 2014; 23: 534–538 DOI: 10.1002/pds
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warranted. The strength of our study is that it is, to our knowledge, the first study to report total ADHD drugs consumption covered by Israel’s National Health Insurance system. CONFLICT OF INTEREST The authors declare no conflict of interest. KEY POINTS
• • •
A drastic rise in ADHD drugs consumption occurred in Israel over 2005–2012 that reflects the analogous world’s trends. Increased prescription of high-dose long-acting preparations of ADHD drugs and decreased prescription of their low-dose, short-acting formulations can be responsible for this rise. Substantial reduction in cost of ADHD drugs also could contribute to the increased consumption trends.
ETHICS STATEMENT This study did not require the Institutional Review Board’s approval due to impersonal nature of the data used. ACKNOWLEDGEMENT A. M. Ponizovsky was supported in part by the Ministry of Immigrant Absorption. REFERENCES 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th edn). text revision. American Psychiatric Association: Washington, DC, 2000. 2. Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA. The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry 2007; 164: 942–948. 3. Fayyad J, De Graaf R, Kessler R, et al. Cross-national prevalence and correlates of adult attention–deficit hyperactivity disorder. Br J Psychiatry 2007; 190: 402–409. 4. Posthuma D, Polderman TJ. What have we learned from recent twin studies about the etiology of neurodevelopmental disorders? Curr Opin Neurol 2013; 26: 111–121. 5. Vetter VL, Elia J, Erickson C, et al. Cardiovascular monitoring of children and adolescents with heart disease receiving medications for attention deficit/hyperactivity disorder [corrected]: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing. Circulation 2008; 117: 2407–2423.
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Pharmacoepidemiology and Drug Safety, 2014; 23: 534–538 DOI: 10.1002/pds
