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Abstract

Objective:

Methylphenidate (MPH) prescription rates for adults increase, but the extent of a parallel rise in toxic exposures and their causes and distribution between different MPH trade names are unexplored.

Method:

We retrospectively analyzed adult MPH exposures reported to the Danish Poison Information Centre from January 2006 to July 2012 and the association with MPH sales and the number of patients prescribed MPH.

Results:

Of the 394 exposures (57% males, median age 27 years) reported, MPH status was available in 249 of whom 65.5% were prescribed MPH. Exposure was in 54% motivated by suicidal attempt and in 40% by recreational use (based on 375 cases). Exposure was dominated by one trade name and exposure incidence correlated significantly with sales ( p = 0.001) and prevalence of MPH-treated patients ( p = 0.0008).

Conclusions:

The increase in MPH exposures parallels the prescription rates (particularly Ritalin^®/Ritalin^® Uno). Most exposures were intentional and motivated by suicide attempts or recreational use.

Keywords

Clinical toxicology poisoning epidemiology drug toxicology human toxicology regulatory toxicology

Introduction

In Denmark, the incidence rate of psychopharmacological treatment for adult attention-deficit hyperactivity disorder (ADHD) has risen substantially during the previous decade,¹ primarily in young adults in which the rate has risen from 0.1‰ in 2005 to 1.2‰ in 2010. In 2011, the prevalence of ADHD patients using therapeutic drugs was about 11‰ and 7‰ in young adult (18–24 years) males and females, respectively.²

In Denmark, methylphenidate (MPH) is registered for the treatment of ADHD in children and adolescents and for narcolepsy, but the use for adult ADHD is off-label. Still, MPH is considered first-line therapy for adult ADHD.³ MPH is an amphetamine-derived central nervous system (CNS) stimulant which is thought to inhibit the norepinephrine and dopamine reuptake transporters, thereby increasing the availability of both neurotransmitters in the synapses.⁴ Because MPH is widely misused, it is a controlled medication in many countries, including Denmark. Consequently, concern about MPH misuse and diversion to people who are not prescribed this drug has followed as a consequence of the steep increase in therapeutic MPH use among adults.

Numerous studies have shown that illicit MPH use is a relatively common phenomenon among students from the United States, for example, in a study of 2087 US college students, 5.3% reported a lifetime periodic use of nonprescribed MPH.⁵ Investigation of illicit use among therapeutic users is less thorough. Until now, the largest survey on MPH misuse among therapeutic users is from the United States and included 55 adolescent and adult subjects of whom 11% had diverted their medication to other people and 22% had misused it during the previous 4 years.⁶

To investigate further nonprescribed MPH exposures including both persons with prescriptions and persons without prescriptions, databases from poison control centers can be used as a source of knowledge. While pediatric MPH exposures have been thoroughly analyzed in large poison center database studies from the United States,^7,8 the largest sample of adult MPH exposures where adults were analyzed as a separate group not including other age-groups was a US study that included 22 cases.⁹ Considering the steep increase in off-label use of MPH prescriptions for adult ADHD, a thorough knowledge of this phenomenon and how it is influenced by therapeutic use seem warranted in connection with preventive strategies as well as treatment regimens. Furthermore, there is a need to investigate whether the findings from the small US studies can be replicated or supplemented in a European sample.

Aims of the study

The objectives of this study are to describe the demography of a population of adult patients exposed to MPH and to evaluate the number of exposures, treatment status (whether MPH was prescribed for a patient by a physician at the time of exposure), cause for exposure, and how these variables may change during the study period. Furthermore, trade name and toxicological aspects such as dose, route of administration, concurrent exposure defined as simultaneous exposure to other toxic substances, and exposure symptoms were evaluated, and finally, we looked at a possible association between exposure incidence and therapeutic MPH use and how this may differ among individual MPH products.

Methods

Data source and inclusion and exclusion criteria

In this study, we used a retrospective observational design to analyze data from the Danish Poison Information Centre (DPIC) on adult (≥18 years of age) MPH exposures between January 1, 2006 and June 30, 2012 (78 months). Exposure was defined as use of MPH not prescribed to the patient or deviation from a proper therapeutic regimen. Possible exposures that could not be confirmed by the patient or by observers were excluded as well as exposures where adult status could not be confirmed by age, date of birth, or from the case description.

Descriptive analysis of MPH-exposed subjects

The following data were extracted from the DPIC database: age, sex, whether or not MPH was prescribed for a patient by a physician at the time of exposure, trade name of MPH, reported cause for exposure, exposure dose, route of exposure, concurrent exposure, and exposure symptoms. The reported cause for exposure was classified as recreational use, suicide attempt, therapeutic error (defined as unintentional deviation from a proper therapeutic treatment schedule), wrong drug ingestion, other reason, or unknown reason. Symptoms included both subjective and objective symptoms. CNS symptoms and constitutional symptoms such as increased or decreased psychomotor activity, mood symptoms, and perceptual disorders were registered in the same category, as the data source was not sufficiently detailed to differentiate between the two. As the DPIC was not accessible to the general population until August 2006, this whole calendar year was excluded from the analysis of trends during the study period. For the same reason, and because the full statistics for 2012 are not yet available, the analysis of the exposure incidence/therapeutic use relationship was limited to the period 2007–2011 (60 months).

Enquiries to the DPIC, legal sale, and therapeutic users of MPH

Data on legal sale and treatment prevalence were extracted from the Danish State Serum Institute.¹⁰ Both legal sales in defined daily doses (DDD) and treatment prevalence were used as parameters for therapeutic use. The annual number of MPH exposures was corrected for increase in total calls to the DPIC in reference to 2007.

A similar analysis was conducted for each of the different MPH products (with different trade names). Legal sale in DDD was the only parameter used for therapeutic use, as data on treatment prevalence were not available for individual MPH products. Exposures without information about trade name were excluded, and exposure to more than one MPH product was counted as one exposure for each trade name used. Consequently, no correction for increase in the total number of calls to the DPIC was made.

Statistics

All variables were analyzed by means of descriptive statistics. Nominal variables were described with frequency and proportion. Only two variables, age and dose, were not nominal. As none of these were parametric, they were both described with median and interquartile range (IQR).

To explore the significance of correlations between exposure incidence and therapeutic use, an F test was performed using GraphPad Prism version 4 for Windows (GraphPad Software, San Diego, California, USA; www.graphpad.com). Analysis of covariance (ANCOVA) test was used for testing the significance of observed differences in enquiries/sale relationship between different MPH products. The significance level was defined as a two-tailed p value ≤ 0.05.

Results

Characterization of MPH-exposed subjects and reason for exposure

A total number of 394 MPH exposures were included in the study (225 males; 169 females; 1 unknown gender). Age was reported in 392 cases with a median age of 27 years (IQR = 20–35). Information about current MPH treatment was available in 249 (63%) cases, of which 163 (65%) had MPH prescribed by a physician at the time of exposure. The cause for exposure was reported in 375 cases (95%). Of these, suicide attempt was reported in 202 (54%) cases, recreational use in 149 (40%) cases, wrong drug ingestion in 11 (3%) cases, therapeutic error in 10 (3%) cases, and other reason in 3 (1%) cases. Table 1 shows the trends in these variables during the study period. Median age, gender predominance, and MPH treatment status fluctuate throughout the study period without any appreciable trends. The number of exposures increased during the study period. While exposures due to attempted suicide increased during the entire study period, the number of exposures due to recreational use initially increased but stabilized after 2010. Consequently, recreational use exposure rates increased from 18% in 2007 to 42% in 2009 ( p = 0.15). After 2009, the rate remained between 40% and 46%. In contrast, the proportion of suicide attempt decreased from 82% in 2007 to 51% in 2009 ( p = 0.05), then stabilized as well. When comparing subjects with prescriptions for MPH to subjects without prescriptions, suicide attempt was relatively more common among subjects with MPH prescriptions, while recreational use was relatively more common among subjects without prescriptions ( p = 0.07). Among subjects with prescriptions for MPH, exposures motivated by suicide attempt increased during the whole study period, whereas exposures motivated by recreational use have stabilized from 2009–2011. Accordingly, the proportion of exposures among subjects prescribed MPH motivated by recreational drug use increased from 2007 to 2009 ( p = 0.07) and decreased between 2009 and 2011 ( p = 0.16), and the proportion of exposures motivated by suicide attempts decreased from 2007 to 2008 ( p = 0.1164) and then stabilized on 54–65%. Among subjects without prescriptions for MPH, there were no exposures in 2007. However, exposures motivated by suicide attempt as well as exposures motivated by recreational use increased between 2008 and 2011 and 2009 and 2011, respectively. The proportion of exposures was stabile for both recreational use and suicide attempts between 2009 and 2011 (36–45%).

Table 1.

Summary of demographic data (age and sex), MPH treatment status, and cause for exposure for each calendar year between 2006 and 2012.^a

Calendar year	2007	2008	2009	2010	2011	2012 (Jan–Jun)
Number of MPH exposures	12	27	72	99	115	61
Demography
Age (median (IQR) years)	29 (20–41)	25 (21–33)	29 (22–34)	26 (20–34)/1^b	28 (20–39)	25 (20–33)/1^b
Sex: female/male	7/5	17/10	26/46	40/59	48/66/1^b	27/34
MPH treatment: yes/no/unknown	6/0/6	11/3/13	29/14/29	39/22/38	49/34/32	28/12/21
Cause for exposure^c
• Wrong drug (number; %)	0 (0)	0 (0)	4 (6)	3 (3)	1 (1)	3 (5)
• Recreational (number; %)	2 (18)	6 (23)	27 (42)	45 (46)	46 (41)	23 (40)
• Suicide attempt (number; %)	9 (82)	20 (77)	33 (51)	47 (48)	58 (52)	27 (47)
• Therapeutic error (number; %)	0 (0)	0 (0)	1 (2)	1 (1)	4 (4)	4 (7)
• Other (number; %)	0 (0)	0 (0)	0 (0)	1 (1)	2 (2)	0 (0)
• Unknown number	1	1	7	2	4	4
Intentional exposures and MPH status
+ Prescriptions^c
• Recreational (number; %)	0 (0)	4 (36)	12 (43)	15 (39)	13 (27)	8 (31)
• Suicide (number; %)	5 (100)	7 (64)	15 (54)	21 (55)	31 (65)	14 (54)
− Prescriptions^c
• Recreational (number; %)	0 (0)	0 (0)	5 (42)	10 (45)	15 (45)	4 (36)
• Suicide (number; %)	0 (0)	3 (100)	5 (42)	9 (41)	15 (45)	4 (36)

Note: + prescriptions means that patients had MPH prescribed by a physician at the time of exposure. − prescriptions means the patient did not have MPH prescribed by a physician at the time of exposure. MPH: methylphenidate; IQR: interquartile range.

^aFurthermore, data show the trends in recreational use and suicidal intent/emotinal strain for subjects with and without prescriptions, respectively.

^bUnknown.

^cPercentages of all exposures with known reason for exposure.

Exposures

Of the 316 cases (80%), whose exposure dose was known, the median dose was 300 mg (IQR = 135–600 mg). Information about the route of exposure was available in 393 (99.7%) cases. Of these, 353 (90%) were exposed orally, 20 (5%) by injection, 14 (4%) by nasal route, and 6 (2%) by a combination of oral and nasal route. In total, 166 (42%) were exposed only to MPH, while concurrent exposure was reported in 228 (58%) cases. Of these, 143 (63%) were exposed to other medications, 93 (41%) to alcohol, 70 (31%) to a wide range of recreational drugs, and 1 (0.4%) to other substances. The proprietary names of MPH (trade names) were reported in 389 cases (99%). As some patients were exposed to two or more trade names, the sum of MPH products reported in these exposures is 404.

Ritalin^® or Ritalin^® Uno was used in 259 exposures (64%), Motiron^® in 59 exposures (15%), Medikinet^® or Medikinet^® CR in 15 exposures (4%), Concerta^® in 69 exposures (17%), and Equasym^® or Equasym^® Depot in 2 exposures (0.5%).

Exposure symptoms

Information about exposure symptoms (subjective and objective) was available in 374 (95%) cases. Of these, 323 (86%) developed symptoms and 51 (14%) were asymptomatic. Of the symptomatic cases, CNS/constitutional symptoms were reported in 263 (81%) cases, cardiovascular symptoms in 227 (70%) cases, eye symptoms in 40 (12%) cases, gastrointestinal symptoms in 29 (9%) cases, respiratory symptoms in 29 (9%) cases, symptoms from mouth/pharynx in 6 (2%) cases, skin symptoms in 3 (1%) cases, and urinary retention in 1 (0.3%) case.

Enquiries to the DPIC, legal sale, and treatment prevalence

Figures 1 and 2 show the trends in MPH exposure incidence and therapeutic use presented as both legal sale (sale form pharmacies) and treatment prevalence. As seen on Figure 1, all three variables increased during the study period. Accordingly, Figure 2 shows that the number of exposures increased significantly with both legal sale (r ² = 0.982, p = 0.001) and treatment prevalence (r ² = 0.9845, p = 0.0008).

Figure 1.

Trends in adult MPH enquiries, sale to adults, and adult therapeutic users (patients) during 2007–2011. MPH enquiries were corrected for increase in the total number of calls to the DPIC in reference to 2007. MPH: methylphenidate; DPIC: Danish Poison Information Centre.

Figure 2.

MPH enquiries and (a) MPH sale and (b) MPH treatment prevalence from 2007 to 2011. MPH: methylphenidate.

Figure 3 shows the relationship between exposures and legal sale in DDD for each individual MPH product (different trade names). Exposure incidence increased with legal sale for Ritalin/Ritalin Uno, Medikinet/Medikinet CR, Concerta, and Motiron. For Equasym/Equasym Depot, the exposure incidence decreased with legal sale. Correlation between legal sale and the number of exposures was significant for Ritalin/Ritalin Uno (r ² = 0.798, p = 0.0412), Medikinet/Medikinet CR (r ² = 0.8831, p = 0.0176), and Concerta (r ² = 0.983, p = 0.0009) and nonsignificant for Motiron (r ² = 0.5228, p = 0.1675) and Equasym/Equasym Depot (r ² = 0.7234, p = 0.0678). For Ritalin/Ritalin Uno, the slope is markedly steep with 174 exposures per million DDD compared with 4.9 for Medikinet/Medikinet CR and 4.5 for Concerta. Furthermore, the figure shows a change in frequency of therapeutic use among the trade names. In 2007, Ritalin/Ritalin Uno accounted for 77% of legal sale compared to 26% in 2011. The legal sale in DDD increased by a factor of 1.09 for Ritalin/Ritalin Uno, 68.1 for Medikinet/Medikinet CR, and 347.5 for Concerta.

Figure 3.

Enquiries compared to sale for each trade name.

ANCOVA test for differences in the correlation between enquiries and therapeutic use (sale in DDD) between Concerta and Ritalin/Ritalin Uno showed an F value of 22.17 and a two-tailed p value of 0.003.

Discussion

This study analyzes 394 adult MPH exposures reported to DPIC between 2006 and 2012. To the best of our knowledge, this is the first study analyzing a large series of MPH exposures in an adult population. Furthermore, this is the first study analyzing the relation between prescriptions of MPH in adults and MPH exposures in general and in relation with different MPH products (different trade names). Thereby, it may be relevant not only to Denmark but to other countries with similar trends in MPH prescription and patterns of misuse as well.

Demography, reason for exposure, and MPH status

MPH exposures in adults were most common among young adult males who had MPH prescribed by a physician at the time of exposure. The high proportion of patients with MPH prescriptions among the exposed may be explained by the fact that MPH products are easily available in this population. Another contributing factor may be the heightened risk of illegal drug use in patients with ADHD.^11
–
14 For example, Huntley and Young found that the prevalence of “marked” or “severe” illegal drug use during the last 12 months was 24% for ADHD adults compared to 3% for healthy controls.¹¹

Regarding the cause for exposure, the number of therapeutic errors seems remarkably small, considering the extensive therapeutic use. This may be explained by selection bias in reference to MPH exposures in general. First of all, enquiry to the DPIC is voluntary. Second, as most enquiries are made by health-care professionals, referral bias may occur. In this context, it is noteworthy that hospitalization is always indicated after attempted suicide. As a consequence, more serious exposures and exposures due to attempted suicide are probably overrepresented in this sample.

Exposures and exposure symptoms

Of the 316 cases (80%) whose the exposure dose was known, the median dose was 300 mg (IQR = 135–600 mg) corresponding to a therapeutic index of at least 2. Despite concurrent exposure in 58% of cases, the most common adverse effects were CNS/constitutional symptoms and cardiovascular symptoms, as would be expected, considering MPH’s pharmacodynamics and common adverse effects.

Various studies on adverse effects of MPH have been conducted. However, the majority of these are limited by small sample size. As a consequence, the prevalence of different exposure symptoms in the current study is only compared to three larger studies on MPH exposures, the smallest of which includes 118 cases. These studies also show that CNS/constitutional symptoms followed by cardiovascular symptoms are the most commonly reported adverse effects to MPH treatment.^7,8,15 Considering the differences in age-groups as well as in inclusion and exclusion criteria among studies on MPH exposures, these symptoms seem strongly related to MPH exposure.

Relationship between MPH prescription rate and misuse

Although the number of exposures reported to the DPIC most certainly underestimates the full incidence of MPH misuse, it may still reflect the trends in MPH misuse and it draws a picture of the more serious exposures. Considering MPH’s abuse potential, the increased incidence in MPH exposures due to recreational use is of concern. However, as adult ADHD is probably strongly underdiagnosed, it is possible that some MPH misusers actually have undiagnosed ADHD and use MPH for the therapeutic effect. According to a recently published study on MPH prescriptions, consumption was fairly equally distributed among patients,² but this does not rule out the possibility of misuse and diversion of saved pills from skipped doses. Accordingly, a study of Canadian teenagers showed that MPH was most commonly misused sporadically among those who did not have an MPH prescription.¹⁶

It is uncertain whether the decrease in exposure incidence/therapeutic use ratio at the end of the study period represents a general tendency or whether it is merely a coincidental variation. A possible explanation for such a tendency may be that MPH is already easily available from therapeutic users or as a street drug. This theory is consistent with the stagnation in an absolute number of exposures due to recreational use between 2010 and 2011. Considering the extensive increase in MPH treatment prevalence, changes in the population of MPH users during the study period may be a contributing factor as well. Finally, increased awareness among the treating physicians may have an impact on MPH misuse. On the other hand, increased knowledge on MPH’s toxic effects in a population with misuse may decrease the likeliness that misusers seek advice from the DPIC in case of adverse effects seen in connection with MPH recreational use. As a consequence, the apparent stagnation in MPH recreational use may not reflect a true tendency.

In comparison, Klein-Schwartz and coworkers found that for both children and adolescents, the number of MPH exposures reported to poison control centers increased between 1993 and 1999 along with a similar increase in therapeutic use in these age-groups.^7,8 This trend parallels the steep increase in adult MPH exposures between 2006 and 2010 shown in the current study. According to a study conducted by Setlik et al., though, from 1998 to 2005, the incidence in MPH exposures among US teenagers reported to poison control centers decreased by 30%, although the number of MPH prescriptions in this age-group increased by 52%.¹⁷ This shows that exposure incidence cannot be fully accounted for by trends in the number of therapeutic users and sale.

Exposure/sale relationship for individual MPH products (trade names)

The nonsignificant results for Motiron and the reversed, nonsignificant enquiries/sale relationship for Equasym/Equasym Depot are probably due to small sample size for these trade names. Although the Motiron curve was nonsignificant, it is noteworthy that its slope was steeper than Concerta and Medikinet/Medikinet CR. Abuse potential has been shown to be higher for immediate-release formulations than extended-release formulations.^6,18 As Motiron includes only immediate-release formulations, this nonsignificant trend may reflect a true tendency. However, the apparantly high abuse potential for Ritalin/Ritalin Uno cannot be attributed to formulations as the Ritalin/Ritalin Uno group is a mix of immediate-release and extended-release formulations. In this context, it is noteworthy that in contrast to the other MPH products, the therapeutic use of Ritalin/Ritalin Uno fairly increased during the study period. Therefore, a possible explanation for the apparently high enquiries/sale relationship of Ritalin/Ritalin Uno may be changes in the population of MPH users during the study period. Furthermore, among the general public as well as in the media, MPH, regardless of the actual product, is often referred to as “Ritalin.” Therefore, Ritalin is a well-known recreational drug compared to the other trade names and as a consequence, trade names that include the word Ritalin may be more sought after for recreational use than the other trade names. On the other hand, this is a possible source of information bias. We suspect that the other trade names may sometimes be referred to as Ritalin when people call the DPIC for advice, thereby overestimating the number of Ritalin/Ritalin Uno exposures on account of the other trade names.

Limitations

Due to the descriptive design, the statistical significance of these results is limited. However, it is strengthened by the fact that all analyses were planned in advance and all relevant cases were systematically searched for and included in the study. As a consequence, the current study is a valuable source for generating future hypotheses. However, the applicability of this study to MPH exposures in general may be limited due to selection bias, as explained in connection with causes for exposure. Furthermore, the results from this study cannot be applied to a pediatric population, as only patients with a minimum age of 18 years were included in the study.

The results were encumbered with uncertainty due to insufficient information in some reports. The accuracy and adequacy of information depend on the enquirer as well as on the specialist who recieved the call, and information was interpreted by both parts. Also, as most calls were made by health-care professionals, this is merely a source of stray inaccuracy compared with systematic information bias. As information about ADHD status was unavailable in most exposures, this was not included in the study, although it is an important issue when discussing MPH misuse. Furthermore, suspected exposures (when there was doubt whether the patient had been exposed to MPH at all) were excluded as well as exposures where adult status could not be confirmed by age, date of birth, or from the case description. This constitutes a minor source of selection bias, as the sum of all these calls would still account for <10% of adult MPH exposures. Concerning therapeutic MPH use, the data source was not detailed enough to exclude patients with narcolepsia. However, as the prevalence of narcolepsia is about 0.05%,¹⁹ the prevalence in adult ADHD is about 2%, and this is unlikely to have major impact on the results.

Concluding remarks

The incidence of MPH exposure increased significantly parallel to a rise in therapeutic use. For Ritalin/Ritalin Uno, this relationship was particularly strong compared to other MPH products. Hence, this study suggests that the therapeutic use of different MPH products may have an impact on the risk pattern of MPH misuse. MPH exposure was most common among young adult males who at the time of exposure were treated with a prescribed dose of MPH and was most often motivated by suicide attempt (54%) or recreational use (40%).

Footnotes

Conflict of interest

The authors declared no conflicts of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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