Author: Flavio Guzman, MD

Dr. Guzman has no conflicts of interest to disclose

Methylphenidate is a CNS stimulant approved for the treatment of narcolepsy and attention deficit
hyperactivity disorder (ADHD).

Methylphenidate inhibits the reuptake of dopamine and norepinephrine, increased

dopaminergic and noradrenergic activity in the prefrontal cortex may explain its efficacy in ADHD.

There are many formulations available, these can be grouped into short-acting, intermediate-
acting, and long-acting methylphenidate.

When deciding which formulation is the most suitable for a given patient, it is important to
consider two parameters: time to initial effect and duration of action.

Under normal circumstances the prefrontal cortex regulates attention, behavior and emotion.
Deficits in prefrontal cortex functioning have been linked to ADHD symptoms such as: poor
impulse control, weak sustained attention and heightened distractibility [1]. Norepinephrine (NE)
and dopamine (DA) are key neurotransmitters for prefrontal functioning, there is an inverted-U
dose-response relationship for catecholamines and prefrontal abilities.

The images below show the relationship between levels of catecholamine release and prefrontal
abilitites in fatigued, alert and stressed states.

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 Fatigued state: Too little dopamine and norepinephrine, prefrontal abilities are impaired

Fig. 1. Fatigued state

Alert state: Moderate release of norepinephrine and dopamine, optimal prefrontal
functioning

Fig. 2. Alert state

Stressed state: Excessive catecholamine release, prefrontal abilities impaired

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 Fig. 3. Stressed state

Methylphenidate modulates the activity of DAT and NET

The dopamine transporter (DAT) influences synaptic concentrations of dopamine.

The norepinephrine transporter (NET) is in charge of norepinephrine reuptake from the
synaptic space to presynaptic neurons.

Fig. 4. Methylphenidate inhibits DAT and NET

Methylphenidate blocks the norepinephrine and dopamine transporters, leading to increased
availability of norepinephrine and dopamine at the synaptic space [2]. The difference with
amphetamine is that methylphenidate does not promote dopamine release from synaptic vesicles.

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 Short-acting methylphenidate is available as tablet, chewable tablets and a liquid
formulation. Dexmethylphenidate is available as tablets. The duration of action of
short action formulations is between 3 to 5 hours.

Table: Advantages and disadvantages of short-acting formulations

Advantages Disadvantages

May be useful when a top-up of the once-daily Shorter duration than long-acting versions
dosing is required

May offer more flexibility Prone to having peak/trough effects that may
be uncomfortable

Time to initial effect and duration of action

o Time to initial effect: 20 to 60 minutes
o Duration of action: 3 to 5 hours

Dexmethylphenidate
Methylphenidate
o Tablet
o Tablet
Focalin
Ritalin
Methylin
o Chewable tablet
Methylin CT
QuilliChew ER
o Liquid
Methylin Oral Solution

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 Time to initial effect and duration of action
Onset of action: 2060 minutes
Duration of action: Up to 8 hours

Wax matrix tablets

Brand names: Metadate ER, Ritalin SR

Wax matrix at times can result in inconsistent release of medication and thus inconsistent
effects

Extended release methylcellulose base

Brand name: Methylin ER

The following are long-acting methylphenidate formulations: Osmotic Release Oral

System (OROS), sustained release capsules, controlled delivery methylphenidate,
Spheroidal Oral Drug Absorption System (SODAS), dexmethylphenidate sustained
release capsules, a transdermal patch and an oral suspension.

Brand name:
o Concerta
Delivery technology:
o Osmotic Release Oral System (OROS)
IR/ER ratio (%):
o 22 % IR / 78% ER
Duration of action:
o Up to 12 hours

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 Fig.5. Osmotic release technology
Fig. 5 shows methylphenidate osmotic release technology. The yellow outer layer contains an
immediate release methylphenidate overcoat. The extended release portion has two drug
compartments, there is also a push compartment.

Fig. 6. Osmotic release technology

Osmotic pressure activates the push compartment so that the system can release
methylphenidate from the drug compartments through the orifice [3].

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 Fig. 7. Diffucaps system

Diffucaps system. Each capsule contains 30% of immediate release beads and 70% of extended release beads.

Brand names:
o Metadate CD
o Equasym XL
Delivery technology:
o Diffucaps
IR/ER ratio (%):
o 30 % IR / 70% ER
Duration of action:
o Up to 8 hours
Approximates a twice per day dosing schedule [4]

Brand name:
o Ritalin LA
Delivery technology:
o SODAS ( Spheroidal Oral Drug Absorption System)
o Similar to a twice per day dosing schedule
IR/ER ratio (%):
o 50 % IR / 50 % ER

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 Duration of action:
o 812 hours
o Two distinct peaks approximately 4 hours apart

Brand name:
o Focalin XR
Mechanical sustained release preparation
o Contains only the d-MPH isomer
IR/ER ratio (%):
o 50 % IR / 50% ER
o Similar efficacy at lower dose than methylphenidate
Duration of action:
o 812 hours [5]

Brand name
o Daytrana
Delivery technology:
o Transdermal delivery
Duration of action:
o 8 12 hours

Table: Advantages and disadvantages of the methylphenidate patch

Advantages Disadvantages

May have lower abuse potential than oral formulations Slower onset than oral formulations

May enhance adherence

Brand name:
o Quillivant XR
Delivery technology:
o Powder that needs to be reconstituted with water
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 Duration of action:
o 8 12 hours [6]

1. Arnsten, A. F., & Berridge, C. W. (2014). Catecholamine influences on prefrontal cortex

circuits and function. Attention-Deficit Hyperactivity Disorder in Adults and Children, 161.
2. Wilens, T. E. (2006). Mechanism of action of agents used in attention-deficit/hyperactivity
disorder. Journal of Clinical Psychiatry, 67, 32.
3. Katzman, M. A., & Sternat, T. (2014). A Review of OROS Methylphenidate (Concerta) in the
Treatment of Attention-Deficit/Hyperactivity Disorder. CNS drugs, 28(11), 10051033.
4. Prince, J. B., Wilens, T. E., Spencer, T. J., & Biederman, J. (2015). 10 Stimulants and Other
Medications for ADHD. Massachusetts General Hospital Psychopharmacology and
Neurotherapeutics, 99.
5. Focalin XR (Dexmethylphenidate sustained release) [Prescribing Information] East Hanover,
NJ: Novartis Pharmaceuticals CorporationAccessed May 2015
6. Methylphenidate (Quillivant XR) [Prescribing Information] New York, NY : Pfizer Inc..
Accessed May 2015