ORIGINAL RESEARCH ARTICLE
CNS Drugs 2008; 22 (7): 603-611
1172-7047/08/0007-0603/$48.00/0
© 2008 Adis Data Information BV. All rights reserved.
Effect of Switching Drug
Formulations from Immediate-Release
to Extended-Release
OROS Methylphenidate
A Chart Review of Spanish Adults with Attention-Deficit
Hyperactivity Disorder
Josep Antoni Ramos-Quiroga,1,2 Rosa Bosch,1 Xavier Castells,1,3 Sergi Valero,1
Mariana Nogueira,1 Nuria Gómez,1 Silvia Yelmo,1 Marc Ferrer,1,2 Yolanda Martínez1
and Miguel Casas1,2
1
Adult ADHD Program, Department of Psychiatry, Hospital Universitari Vall d’Hebron,
Barcelona, Spain
2 Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona,
Barcelona, Spain
3 Clinical Pharmacology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain
Abstract
Background: The potential advantages of osmotic-release oral system (OROS)
methylphenidate (Concerta®) over immediate-release (IR) methylphenidate
(Rubifen®) in adults with attention-deficit hyperactivity disorder (ADHD), with
respect to medication adherence, effectiveness and tolerability, are yet to be
determined.
Objective: To compare the adherence, effectiveness and tolerability of OROS
methylphenidate versus IR methylphenidate in adults with ADHD. It was hypothesized (after data collection) that adherence and effectiveness would be higher
with OROS methylphenidate than with the IR formulation.
Study design: A chart review was carried out from April 2004 until April 2005.
Setting: Adult ADHD outpatient program in a general hospital in Spain.
Patients: Seventy adults with ADHD who met DSM-IV-TR criteria and who did
not have any other current major psychiatric disorder.
Intervention: Patients were treated with IR methylphenidate three times daily for
3 months and then switched to OROS methylphenidate once daily.
Main outcome measure: Effectiveness was assessed by means of the ADHD
rating scale-IV (ADHD-RS-IV) and the Clinical Global Impression-Improvement
(CGI-I) scale at 3 months (coinciding with treatment switch) and at 6 months. The
Simplified Medication Adherence Questionnaire (SMAQ) was used to assess
treatment adherence, and was administered at both 3 and 6 months.
Results: Seventy adult ADHD patients (mean age ± SD: 30 ± 9.6 years; n = 48
men [68.6%]) were included in this study. The mean baseline ADHD-RS-IV score
was 34.6 (SD = 10.9). The mean daily dose of IR methylphenidate was 52.1 mg
Ramos-Quiroga et al.
604
(SD = 13.8 mg) administered as three divided doses. After the treatment switch,
the mean OROS methylphenidate daily dose was 57.9 mg (SD = 16.5 mg)
administered once daily.
The switch from IR methylphenidate to OROS methylphenidate was associated
with a statistically significant improvement in all items of the SMAQ questionnaire. OROS methylphenidate was more effective than IR methylphenidate
(p = 0.0005) in reducing symptoms of ADHD. The percentage of responders was
28.6% with IR methylphenidate and 91.4% with the OROS formulation
(p = 0.0005). OROS methylphenidate was preferred by 97% of patients. The most
common adverse events for each formulation were dry mouth (30% IR methylphenidate) and mood instability (31% OROS methylphenidate). No patients
stopped treatment with methylphenidate because of adverse events.
Conclusions: The switch from IR to OROS methylphenidate was associated with
an improvement in both adherence and effectiveness. There were no differences
between IR and OROS methylphenidate in terms of tolerability.
Background
Attention-deficit hyperactivity disorder (ADHD)
is a chronic, disabling condition that is most commonly diagnosed in childhood but continues on into
adulthood for many patients affected in childhood.[1]
It has a worldwide prevalence rate of 8–12% in
children[2] and 1.2–7.3% in adults.[3] The average
prevalence rate in adults is 2–4%.[2,4,5] In adults,
ADHD impairs multiple aspects of functioning,
such as interpersonal relationships, academic performance and occupational status.[6] Furthermore, it
increases the risk of motor vehicle accidents,[7] comorbid substance abuse disorders[8] and legal problems.[6]
Stimulants are the gold-standard treatment of
ADHD in children[9-11] and have also proven effective for adults in controlled clinical trials.[12-15]
Methylphenidate is one of the most commonly prescribed and extensively researched pharmacological
treatments of ADHD.[16] However, methylphenidate
has a short half-life and requires administration up
to three times daily. This administration schedule
often leads to limited treatment adherence, resulting
in a reduction of stimulant effectiveness. The chronic nature of ADHD, together with the importance of
the drug administration schedule, makes adherence
a crucial issue for stimulant effectiveness in this
1
disorder. Non-adherence rates have been estimated
to be between 20% and 65% in children with
ADHD,[17] but are unknown in adults. Adherence is
inversely related to the number of tablets or capsules
ingested daily, and can therefore be improved by
reducing the frequency of dosage.[18,19]
During the past several years, different oncedaily drug formulations have become available.
Among these new formulations, only the osmoticrelease oral system (OROS) methylphenidate (Concerta®)1 formulation has been introduced in Spain.
In children and adolescents with ADHD, the OROS
formulation has proven effective,[20-22] has been
shown to improve treatment adherence,[22-24] and
patients can be effectively and safely switched to
this formulation from the immediate-release (IR)
formulation.[25]
Since the introduction of OROS methylphenidate
to the market, many adults treated with the IR formulation were switched to the OROS formulation
because it was expected to be at least as effective as
the IR formulation but to also have the additional
benefit of improving adherence because of its less
frequent administration. However, no study has yet
been conducted to assess whether this easier administration does improve adherence.
The use of trade names is for product identification purposes only and does not imply endorsement.
© 2008 Adis Data Information BV. All rights reserved.
CNS Drugs 2008; 22 (7)
Methylphenidate Formulation Switch in Adult ADHD
This study took advantage of the partially standardized clinical protocol (which was in force until
April 2005) at the Hospital Universitari Vall
d’Hebron, Barcelona, Spain, to investigate whether
the switch from IR to OROS methylphenidate increased drug adherence, resulting in improved effectiveness and tolerability. Patient preference was also
assessed.
Methods
Study Design
The Adult ADHD Program of the Psychiatry
Department of Hospital Universitari Vall d’Hebron,
Barcelona, Spain, follows a clinical protocol approved by the Institutional Review Board, and is
updated as significant new assessment tools or treatments become available. This specific and partially
standardized procedure made it possible to carry out
a chart review for those patients who decided to
change to OROS methylphenidate from the time it
was introduced to the Spanish market in April 2004
until April 2005, when OROS methylphenidate became the first-line treatment for adults with ADHD
in this program.
Patients
Charts were selected only if patients met the
following inclusion criteria: DSM-IV diagnosis of
ADHD; no other current major psychiatric disorders; no history of previous treatment for ADHD;
and having switched from IR methylphenidate to
OROS methylphenidate. Seventy patients fulfilled
the inclusion criteria and were included in the analysis.
The diagnostic and baseline assessment protocol
of the Adult ADHD Program is comprised of a
psychiatric evaluation, structured diagnostic interviews and a neuropsychological battery of tests. The
Conners Adult ADHD Diagnostic Interview for the
DSM-IV[26] and the Structured Clinical Interviews I
and II for DSM-IV (SCID-I and SCID-II)[27,28] were
used to confirm the diagnoses of ADHD in adulthood. All patients were evaluated by an experienced
psychiatrist (Drs Ramos-Quiroga, Gómez, Yelmo or
© 2008 Adis Data Information BV. All rights reserved.
605
Ferrer) and one of three clinical psychologists (Drs
Bosch, Nogueira or Martínez).
Treatment
The psychopharmacological treatment protocol
of the Adult ADHD Program adapted international
guidelines[11] to suit the Spanish pharmaceutical
market, and established methylphenidate as the drug
of choice unless contraindicated. When the OROS
methylphenidate formulation was introduced in
Spain in 2004, the Adult ADHD Program developed
the following two-step methylphenidate treatment.
During the first 3 months of treatment, patients were
treated with IR methylphenidate (Rubifen®) three
times daily. IR methylphenidate was titrated over
the first few days of treatment until a target dosage
of 1.0 mg/kg/day was reached.[29] In patients who
did not tolerate this target dosage, the dosage was
lowered to suit the patient. Once stabilized, patients
were maintained at a fixed dosage. After 3 months,
the patient could be switched to once-daily OROS
methylphenidate (Concerta®) in order to simplify
the administration schedule.
Because the IR methylphenidate formulation is
available in 5, 10 and 20 mg doses, and OROS
methylphenidate is only available in 18, 36 and
54 mg doses, the following conversion rule was
applied: a 15 mg dose of IR methylphenidate was
substituted with an 18 mg dose of OROS methylphenidate.[30] However, the dose could be decreased
if significant adverse effects were experienced after
the switch from the IR formulation to the OROS
formulation. These adjustments were based on clinical judgement. The commercially available methylphenidate formulations, manufactured by JanssenCilag (Concerta®) and Rubió Laboratories
(Rubifen®), were financed by the Spanish health
system.
Assessments
The follow-up assessment included an evaluation
at 3 months after the optimal dose of medication had
been established to ensure continuity of effectiveness and adherence. It included the ADHD Rating
Scale-IV (ADHD-RS-IV),[31] the Clinical Global
CNS Drugs 2008; 22 (7)
Ramos-Quiroga et al.
606
Impression-Improvement (CGI-I) scale[32] and the
Simplified Medication Adherence Questionnaire
(SMAQ).[33] The same follow-up assessment was
performed at 6 months. The diagnostic reliability
between raters was excellent; a κ of 1.0 was obtained for the ADHD-RS-IV and CGI-I, with a 95%
CI of 0.8, 1.0.
The SMAQ is a physician-rated questionnaire
comprising the following six items:
1. Do you ever forget to take your medicine?
2. Are you careless at times about taking your medicine?
3. Sometimes if you feel worse, do you stop taking
your medicine?
4. Thinking about the last week, how many times
have you not taken your medicine?
5. Did you not take any of your medicine over the
past weekend?
6. Over the past 3 months, how many days have you
not taken any medicine at all?
Item 6 was used to determine the proportion of
noncompliant patients. Those patients who reported
taking no methylphenidate tablets for ≥5 days, ≥10
days and ≥20 days over the past 3 months were
defined as mildly, moderately and highly noncompliant, respectively.
Medication preference was assessed at 6 months.
The study physician directly asked patients “In your
opinion, which methylphenidate would you prefer to
take from now on, IR methylphenidate or OROS
methylphenidate?”
Treatment responders were defined as patients
who showed a ≥30% improvement in their ADHDRS-IV score compared with baseline.
Statistical Analysis
Changes in both qualitative and quantitative variables from baseline were assessed at 3 and 6 months
by means of the McNemar and Wilcoxon tests,
respectively. A multiple regression analysis was
used to assess the effects of the independent variables on effectiveness. Results are reported with a
95% confidence interval, and p-values were twotailed. All statistical analyses were performed using
SPSS v.14 (SPSS Inc., Chicago, IL, USA).
© 2008 Adis Data Information BV. All rights reserved.
Results
Baseline data were collected on 48 male and 22
female patients. No patients withdrew from the
study. Mean age was 30 years (SD = 9.6 years) and
baseline weight was 71.4 kg (SD = 14.3 kg). The
most common disorder subtype was ADHD combined type (65%), followed by predominantly inattentive type (29%) and predominantly hyperactiveimpulsive type (6%). Mean baseline ADHD-RS-IV
score was 34.6 (SD = 10.9). The mean daily dose of
IR methylphenidate was 52.1 mg (SD = 13.8 mg)
administered as three divided doses. After the treatment switch, the mean OROS methylphenidate daily
dose was 57.9 mg (SD = 16.5 mg) administered
once daily. The administered dose of methylphenidate was higher for the OROS formulation than for
the IR formulation because the two formulations do
not have equivalent dosages.
Medication Adherence
As shown in table I, the switch from IR to OROS
methylphenidate was associated with an improvement in all items of the SMAQ questionnaire, indicating better adherence to the OROS formulation.
Adherence to OROS was superior during working
days as well as during the weekend. Moreover, the
number of days no medicine was taken at all was
7-fold higher with IR methylphenidate than OROS
methylphenidate. In addition, the proportion of
mildly, moderately and highly noncompliant patients was 37.1%, 11.4% and 4.7%, respectively,
while taking IR methylphenidate, and 2.9%, 0% and
0%, respectively, while receiving the OROS formulation. Thus, although the prescribed dose was only
slightly higher with the OROS formulation, because
patients were significantly more adherent to this
formulation, the adherence was likely to account for
more of the difference in the amount of drug taken
than the difference in prescribed dose.
Effectiveness
Not surprisingly, while both methylphenidate
formulations were found to be effective in the treatment of adults with ADHD, as assessed by either the
CNS Drugs 2008; 22 (7)
Methylphenidate Formulation Switch in Adult ADHD
607
Table I. Comparison of medication adherence, effectiveness and satisfaction between immediate-release (IR) methylphenidate and
osmotic-release oral system (OROS) methylphenidate in adult attention-deficit hyperactivity disorder (ADHD)
Outcome
IR methylphenidate (n = 70)
OROS methylphenidate (n = 70)
p-Value
Mean (SD) daily dose [mg]
52.1 (13.8)
57.9 (16.5)
0.0005
Patients reporting at least one missed dose (%)
[SMAQ item 1]
91.4
22.9
0.0005
Patients reporting not taking medication at the
scheduled time (%) [SMAQ item 2]
45.7
25.7
0.044
Patients reporting not taking medication when
feeling worse (%) [SMAQ item 3]
17.1
2.9
0.002
Patients reporting at least one missed dose
during the previous week (%) [SMAQ item 4]
88.6
20.0
0.0005
Patients reporting not taking any medicine over
the previous weekend (%) [SMAQ item 5]
74.3
20.0
0.0005
Mean (SD) days no medicine was taken over
the previous 3 months [SMAQ item 6]
4.66 (6.25)
0.66 (1.56)
0.0005
Mildly noncomplianta (%)
37.1
2.9
NA
Moderately noncompliantb (%)
11.4
0
Highly noncompliantc (%)
4.7
0
Adherence to treatment
Noncompliance
Effectiveness
ADHD-RS-IVd [mean (SD)]
25.1 (9.1)
15.1 (7.2)
0.0005
CGI-I (patient rating) [mean (SD)]
2.83 (0.82)
1.57 (0.55)
0.0005
CGI-I (physician rating) [mean (SD)]
2.80 (0.83)
1.57 (0.55)
0.0005
Treatment responders (%)e
28.6
91.4
0.0005
97
NA
Preference (%)f
a
3
Patients reported taking no methylphenidate for ≥5 days in the previous 3 months.
b
Patients reported taking no methylphenidate for ≥10 days in the previous 3 months.
c
Patients reported taking no methylphenidate for ≥20 days in the previous 3 months.
d
Baseline mean (SD) ADHD-RS-IV was 34.6 (10.9).
e
Responders were those patients showing a ≥30% improvement in their ADHD-RS-IV score compared with baseline.
f
Patients preferring each formulation.
ADHD-RS-IV = ADHD Rating Scale-IV;[31] CGI-I = Clinical Global Impression-Improvement scale;[32] NA = not applicable; SMAQ =
Simplified Medication Adherence Questionnaire.[33]
ADHD-RS-IV or the CGI-I, the OROS formulation
proved to be more effective than the IR formulation
irrespective of the assessment instrument (see table
I). Furthermore, nearly all patients (97%) preferred
OROS methylphenidate. When controlled for in the
multivariate analysis, the methylphenidate dose did
not affect the differences found between treatment
groups with regard to adherence, preference or effectiveness. Since patients receiving IR methylphenidate were primarily non-adherent (88.6% reported at least one missed dose during the previous
week) and patients receiving OROS methylphenidate were mostly adherent (80.0% reported no
© 2008 Adis Data Information BV. All rights reserved.
missed doses in the previous week), treatment effectiveness could not be adjusted for adherence.
Tolerability
Both formulations were well tolerated and no
patients stopped methylphenidate due to adverse
events. The most common adverse events with IR
and OROS methylphenidate were headache (21% vs
26%), decreased appetite (24% vs 20%), tachycardia (13% vs 27%), abdominal complaints (18% vs
23%), dry mouth (30% vs 28%), mood instability
(20% vs 31%) and insomnia (21% vs 18%). None of
these differences were statistically significant.
CNS Drugs 2008; 22 (7)
Ramos-Quiroga et al.
608
Discussion
The switch from IR methylphenidate three times
daily to OROS methylphenidate once daily in adults
with ADHD was associated with an improvement in
treatment adherence and was preferred by most patients. In addition, both methylphenidate formulations were effective for the treatment of adults with
ADHD, although the OROS formulation was superior to the IR formulation. These findings raise the
question of whether the superior adherence of
OROS methylphenidate is due to its greater effectiveness, or whether its superior effectiveness is due
to its better adherence.
The improved treatment adherence with OROS
methylphenidate was shown by an improvement on
all items of the SMAQ questionnaire. The mean
number of days no medicine was taken over the past
3 months (SMAQ item 6) was 7-fold higher with IR
methylphenidate (4.66) than with the OROS formulation (0.66). Frequency of dose and price are two
factors that could explain the difference in adherence rates between the two methylphenidate formulations.[19] Because of its once-daily dosage, the
OROS formulation is simpler to take, which may
partly explain its higher rate of adherence; however,
it is more expensive than the IR formulation, which
could also potentially affect adherence. Because the
Spanish National Health System pays 60% of all
pharmaceutical expenses, cost is a variable that likely has relatively limited impact on patient adherence
in Spain, relative to that in countries that have a
health system policy in which patients must pay for
a considerable amount of their medication expenses.
Our findings relating to higher adherence, effectiveness and satisfaction with the OROS formulation were similar to those previously reported in
children.[22] The greater effectiveness of the OROS
formulation compared with the IR formulation is
likely explained by its higher adherence (80% of
patients taking OROS methylphenidate and 11.4%
of patients taking IR methylphenidate reported no
missed doses in the previous week). It was not
possible to conduct an analysis of formulation effectiveness adjusted for adherence to determine whether the greater effectiveness of the OROS formula© 2008 Adis Data Information BV. All rights reserved.
tion was due to greater adherence or to a better
pharmacokinetic profile because these two factors
are interdependent. Another possible explanation for
the difference in effectiveness could have been the
difference in dosages between the two formulations;
however, this was not the case, as can be seen from
the multivariate analysis. Finally, the superior effectiveness of the OROS formulation could also be
explained by a time effect, because the IR formulation was always administered prior to the OROS
formulation; however, this seems unlikely because
of the relatively brief period of time required to
achieve a therapeutic effect with methylphenidate.
It is striking to note that, in our study, the percentage of responders was 28.6% for IR methylphenidate and 91.4% for the OROS formulation, in
contrast to the 75–80% of responders previously
reported in several controlled clinical trials for both
IR and OROS methylphenidate.[13,14,34] Moreover,
although no direct, head-to-head comparisons between IR and OROS methylphenidate exist, one
study combining data from two placebo-controlled
trials with OROS and IR methylphenidate found no
difference in efficacy between these two formulations.[35] However, Biederman et al.[35] found no
difference in adherence to treatment. In our study,
adherence was notably higher with OROS methylphenidate and, consequently, efficacy was also
higher. One explanation could be that, in controlled
clinical trials, adherence is a requirement and is
comprehensively monitored, and noncompliant patients are frequently withdrawn from the study. This
results in high adherence and efficacy, but low external validity because, in real clinical settings, as in
this naturalistic study, although patients are advised
to follow the recommendations of the physician,
they are not withdrawn from medical assistance if
they are noncompliant. As in the controlled clinical
trials, our study showed that OROS methylphenidate resulted in high adherence and effectiveness.
Conversely, unlike results from controlled clinical
trials, missed doses were common while taking IR
methylphenidate in our study, resulting in a low
response rate and low effectiveness. This suggests
that the controlled clinical trials have greater exterCNS Drugs 2008; 22 (7)
Methylphenidate Formulation Switch in Adult ADHD
nal validity with the OROS formulation than with
the IR formulation. The lower adherence rates that
we found for IR methylphenidate may explain its
lower effectiveness in this study compared with
those reported in the controlled clinical trials.[13,14,34]
It was not surprising that almost all patients preferred the OROS formulation as it was simpler to
take, resulting in better adherence, yielding higher
methylphenidate intake and thus resulting in higher
effectiveness, while having a similar tolerability
profile.
Finally, our study shows that both methylphenidate formulations were well tolerated, and only
dose-related adverse events were observed. Adverse
events were mild and no patient discontinued treatment. No patients abused methylphenidate, regardless of the formulation. Although no statistically
significant differences in the percentage of patients
experiencing adverse events were found between
the two methylphenidate formulations, it is notable
that reports of tachycardia and mood instability were
numerically more common in patients taking OROS
methylphenidate. This finding could be interpreted
as a consequence of higher adherence to the OROS
formulation, resulting in a higher methylphenidate
intake and thus more frequent adverse events, but a
controlled study should be carried out to confirm
this hypothesis.
This study had a naturalistic design, and the
foundation for reports of preference of medication
formulation, medication adherence and response to
treatment were obtained in a nonblinded fashion and
were thus potentially subject to reporter bias. Therefore, several limitations should be considered when
interpreting these results. Firstly, because this was a
single-centre study, the external validity is limited
and caution must be exercised in generalizing the
results. Secondly, the results on adherence must also
be considered with caution, since the adherence
assessment was based on self-report and not on
direct and objective measures such as methylphenidate blood concentrations. However, inaccuracy of
patient reports of adherence would be expected to
affect the results of both treatment groups in a
similar manner. Finally, the fact that drug adminis© 2008 Adis Data Information BV. All rights reserved.
609
tration and clinical assessments were not blinded
may have influenced our findings. However, it is
unlikely that bias explains the considerable adherence, efficacy and preference differences between
the IR and the OROS methylphenidate formulations
that were found in this study. Nevertheless, since the
main aim of this study was to compare adherence
between two methylphenidate formulations that
differed in their administration schedules, it was
essential to maintain a naturalistic design that kept a
three-times-daily and once-daily administration
schedule for the IR and OROS formulations, respectively. The use of a double-dummy design would not
allow for the assessment of differences in adherence
between the two formulations because all patients
would have received a three-times-daily administration to allow for blinding.
Conclusions
Methylphenidate can be effectively and safely
switched from an IR formulation to an OROS formulation in adults with ADHD within the clinical
setting. This switch is associated with greater medication adherence. Both OROS and IR methylphenidate formulations are effective and well tolerated for
the treatment of ADHD in adults, although the
OROS formulation appeared to be more effective in
this study. It should be noted that OROS and IR
methylphenidate are not approved in Spain or in any
other European nation for the treatment of ADHD in
adults. Additional studies are necessary to clarify if
OROS methylphenidate can be considered first-line
treatment for ADHD in adults.
Acknowledgements
This study was presented at the official symposium on
‘Adult ADHD’ at the World Psychiatry Association International Congress, which was held on 12–16 July 2006 in
Istanbul, Turkey.
This study was supported in part by a nonrestricted grant
from the Generalitat de Catalunya (Departament de Salut)
and the Fundació La Caixa (PAI-TLP 2006). It has also been
supported by a grant from the Spanish Ministry of Education
(Fondo de Investigaciones Sanitarias Instituto Carlos III FIS
PI04/0524) and a scholarship from the Spanish Ministry of
Health awarded to Xavier Castells, MD (ISCIII: 300056).
The authors are grateful to Yolanda Santaella, Ira
CNS Drugs 2008; 22 (7)
Ramos-Quiroga et al.
610
Potashner and Amy Larabel for their support in the preparation of this manuscript.
Dr Ramos-Quiroga and Dr Casas have received honoraria
for being speakers for and have been on the advisory boards
of Laboratorios Rubió and Janssen-Cilag. Dr Marc Ferrer has
received honoraria for being a speaker for and has been on the
advisory board of Janssen-Cilag. All other authors have no
conflicts of interest that are directly relevant to the content of
this study.
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Correspondence: Dr Josep Antoni Ramos-Quiroga, Servei de
Psiquiatria, Hospital Universitari Vall d’Hebron, Passeig
Vall d’Hebron no. 119-129, Barcelona 08035, Spain.
E-mail: jaramos@vhebron.net
CNS Drugs 2008; 22 (7)