Methylphenidate

Methylphenidate-2D-skeletal.svg
Methylphenidate
Systematic (IUPAC) name
methyl 2-phenyl-2-(piperidin-2-yl)acetate
Identifiers
CAS number 113-45-1
ATC code N06BA04
PubChem 4158
DrugBank APRD00657
ChemSpider 4015
Chemical data
Formula C14H19NO2 
Mol. mass 233.31 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 11–52%
Protein binding 30%
Metabolism Liver
Half life 2–4 hours
Excretion Urine
Therapeutic considerations
Pregnancy cat.

C
Legal status

Controlled (S8)(AU) Schedule III(CA) Class B(UK) Schedule II(US)
Routes Oral, Transdermal, IV, Nasal
Indicated for:
  • ADD
  • ADHD
  • narcolepsy

Other uses:
Contraindications:
  • Use of tricyclic antidepressants (e.g. desipramine), as methylphenidate may dangerously increase their plasma concentrations, leading to potential toxic reactions (mainly, cardiovascular effects).
  • Use of MAO Inhibitors, such as phenelzine (Nardil) or tranylcypromine (Parnate), and certain other drugs.
  • methylphenidate should not be given to patients who suffer from the following conditions: Severe Arrhythmia, Hypertension or Liver damage.
  • Drug-seeking behaviour
  • Pronounced agitation or nervousness. Other side effects include drowsiness, and mood swings
Side effects:[1][2]

Atypical sensations:

Cardiovascular:

Ear, nose, and throat:

Endocrinal:

  • Appetite loss

Eye:

  • Blurred vision

Gastrointestinal:

  • Nausea/vomiting, abdominal pain

Hematological:

Musculoskeletal:

  • Muscle twitches

Neurological:

Psychological:

Respiratory:

  • Increased respiration rate

Skin:

Urogenital and reproductive:

Miscellaneous:

  • Fever

Methylphenidate[3] (MPH) is a prescription stimulant commonly used to treat Attention-deficit hyperactivity disorder, or ADHD. It is also one of the primary drugs used to treat the daytime drowsiness symptoms of narcolepsy and chronic fatigue syndrome. The drug is seeing early use to treat cancer-related fatigue.[4] Brand names of drugs that contain methylphenidate include Ritalin (Ritalina, Rilatine, Attenta, Methylin, Penid, Rubifen); and the sustained release tablets Concerta, Metadate CD, Methylin ER, Ritalin LA, and Ritalin-SR. Focalin is a preparation containing only dextro-methylphenidate, rather than the usual racemic dextro- and levo-methylphenidate mixture of other formulations. A newer way of taking methylphenidate is by using a transdermal patch (under the brand name Daytrana), similar to those used for hormone replacement therapy (HRT), nicotine release and pain relief (Fentanyl).

Contents

History

Methylphenidate was patented in 1954 by the CIBA pharmaceutical company (now Novartis) as a potential cure for Mohr's disease. Beginning in the 1960s, it was used to treat children with ADHD or ADD, known at the time as hyperactivity or minimal brain dysfunction (MBD). Today methylphenidate is the most commonly prescribed medication to treat ADHD around the world. Production and prescription of methylphenidate rose significantly in the 1990s, especially in the United States, as the ADHD diagnosis came to be better understood and more generally accepted within the medical and mental health communities.[5]

Most brand-name Ritalin is produced in the United States, and methylphenidate is produced in the United States, Mexico, Argentina and Pakistan. Other generic forms, such as "methylin", are produced by several U.S. pharmaceutical companies. Ritalin is also sold in the United Kingdom, Germany and other European countries (although in much lower volumes than in the United States). These generic versions of methylphenidate tend to outsell brand-name Ritalin four to one. In Belgium the product is sold under the name "Rilatine".

Another medicine is Concerta, a once-daily extended-release form of methylphenidate, which was approved in April 2000. Studies have demonstrated that long-acting methylphenidate preparations such as Concerta are just as effective, if not more effective, than IR (instant release) formulas.[6][7][8][9] Time-release medications are also less prone to misuse.

In April 2006, the FDA approved a transdermal patch for the treatment of ADHD called Daytrana.[10]

Indications

Methylphenidate 10 mg Tablet (Mallinckrodt)

Methylphenidate is a central nervous system (CNS) stimulant,[11][12][13]. Adults who have ADD often report that methylphenidate increases their ability to focus on tasks and organize their lives.

Methylphenidate has been found to have a lower incidence of side effects than dextroamphetamine, a less commonly prescribed medication.[14] When prescribed at the correct dosage, methylphenidate is usually well tolerated by patients.[6]

A 2006 review assessing the safety of methylphenidate on the developing brain found that in animals with psychomotor impairments, structural and functional parameters of the dopamine system were improved with treatment.[15] This indicates that in subjects with ADD, methylphenidate treatment may positively support brain development.

Pharmacology

Methylphenidate has binding affinity for both the dopamine transporter and norepinephrine transporter, with the Dextromethylphenidate enantiomers displaying a prominent affinity for the norepinephrine transporter. Both the dextro- and levorotary enantiomers displayed receptor affinity for the serotonergic 5HT1A and 5HT2B subtypes, though direct binding to the serotonin transporter was not observed.[16]

The enantiomers and the relative psychoactive effects and CNS stimulation of dextro- and levo-methylphenidate is analogous to what is found in amphetamine, where dextro-amphetamine is considered to have a greater psychoactive and CNS stimulatory effect than levo-amphetamine (levmetamfetamine is sold legally OTC in Vick's inhalers).

Mode of action

The means by which methylphenidate affects people diagnosed with ADHD are not well understood. Some researchers have theorized that ADHD is caused by a dopamine imbalance in the brains of those affected. Methylphenidate is a norepinephrine and dopamine reuptake inhibitor, which means that it increases the level of the dopamine neurotransmitter in the brain by partially blocking the dopamine transporter (DAT) that removes dopamine from the synapses.[17] This inhibition of DAT blocks the reuptake of dopamine and norepinephrine into the presynaptic neuron, increasing the amount of dopamine in the synapse. It also stimulates the release of dopamine and norepinephrine into the synapse. Finally, it increases the magnitude of dopamine release after a stimulus, increasing the salience of stimulus. An alternate explanation which has been explored is that the methylphenidate affects the action of serotonin in the brain.[18]

It has been established that Ritalin only works in ADHD when levels of an important neurotransmitter called Phenylethylamine is increased.

It is commonly asked why a stimulant should be used to treat hyperactivity, which seems paradoxical. However, CTs of ADHD brains show decreased activity in the brain centers critical to concentration and goal-directed activities. Treatment with methylphenidate (etc.) results in increased activity in those regions, in ADHD patients, and in healthy controls as well. Thus the model explanation is that hyperactive children (and adults) have underactive concentration centers, and stimulating them reduces hyperactivity. Thus the stimulants do not work paradoxically. They stimulate portions of the brain that are underactive by increasing dopamine and norepinephrine in the striatum and prefontal cortex.

One study finds that methylphenidate reduces the increases in brain glucose metabolism during performance of a cognitive task by about 50%. This suggests that, similar to increasing dopamine and norepinephrine in the striatum and prefontal cortex, methylphenidate may focus activation of certain regions and make the brain more efficient. This is consistent with the observation that stimulant drugs can enhance attention and performance in some individuals. If brain resources are not optimally distributed (for example, in individuals with ADHD or sleep deprivation), improved performance could be achieved by reducing task-induced regional activation. Stimulant delivery when brain resources are already optimally distributed may then adversely affect performance.[19]

Side effects

Reported methylphenidate side effects include psychosis (abnormal thinking or hallucinations), difficulty sleeping, mood swings, mood changes, nervousness, stomach aches, diarrhea, headaches, decreased sex drive, lack of hunger (leading to weight loss), gum and skin bleeding, dry mouth, and irritability.[20]

Less common side effects include palpitations, high blood pressure and tachycardia.

Known or suspected risks to health

Researchers have also looked into the role of methylphenidate in affecting stature, with some studies finding slight decreases in height acceleration.[21] Other studies indicate height may normalize by adolescence.[22][23] In a 2005 study, only "minimal effects on growth in height and weight were observed" after 2 years of treatment. "No clinically significant effects on vital signs or laboratory test parameters were observed."[24]

A 2003 study tested the effects of dextromethylphenidate (Focalin), levomethylphenidate, and (racemic) detro-, levomethylphenidate (Ritalin) on mice to search for any carcinogenic effects. The researchers found that all three preparations were non-genotoxic and non-clastogenic; d-MPH, d, l-MPH, and l-MPH did not cause mutations or chromosomal aberrations. They concluded that none of the compounds present a carcinogenic risk to humans.[25]

In February 2005, a team of researchers from The University of Texas M. D. Anderson Cancer Center led by R.A. El-Zein announced that a study of 12 children indicated that methylphenidate may be carcinogenic. In the study, 12 children were given standard therapeutic doses of methylphenidate. At the conclusion of the 3-month study, all 12 children displayed significant treatment-induced chromosomal aberrations. The researchers indicated that their study was relatively small and their results needed to be reproduced in a bigger population for a definitive conclusion about the genotoxicity of methylphenidate to be drawn.[26]

In response to the El-Zein study published in 2005, a team of six scientists from the Department of Child and Adolescent Psychiatry and Psychotherapy and the Department of Toxicology, University of Würzburg, Würzburg, Germany began a more in-depth study. They sought to respond to the challenge noted above to attempt to replicate the results of El-Zein et al. in a larger study. Their paper was completed in 2006 and published in 2007 in Environmental Health Perspectives (EHP), the peer-reviewed journal of the United States' National Institute of Environmental Health Sciences. This study used a larger cohort and a longer period of follow-up and included a small group of long-term users, but otherwise used what researchers believed to be an identical methodology to that used by El-Zein et al. (They note that El-Zein et al. published a short study report and did not publish detailed descriptions of methodology.) After follow-ups at six months, the researchers found no evidence that methylphenidate might cause cancer, stating "the concern regarding a potential increase in the risk of developing cancer later in life after long-term MPH treatment is not supported".[27]

The effects of long-term methylphenidate treatment on the developing brains of children with ADHD is the subject of study and debate.[28][29] Although the safety profile of short-term methylphenidate therapy in clinical trials has been well established, repeated use of psychostimulants such as methylphenidate is less clear.

The use of ADHD medication in children under the age of 6 has not been studied. Severe hallucinations may occur. ADHD symptoms include hyperactivity and difficulty holding still and following directions; these are also characteristics of a typical child under the age of 6. For this reason it may be more difficult to diagnose young children, and caution should be used with this age group.[30]

On March 22, 2006 the FDA Pediatric Advisory Committee decided that medications using methylphenidate ingredients do not need black box warnings about their risks, noting that "for normal children, these drugs do not appear to pose an obvious cardiovascular risk."[31] Previously, 19 possible cases had been reported of Cardiac arrest linked to children taking methylphenidate[32] and the Drug Safety and Risk Management Advisory Committee to the FDA recommend a "black-box" warning in 2006 for stimulant drugs used to treat attention deficit/hyperactivity disorder.[33]

According to a small study conducted by the Society of Nuclear Medicine, the use of methylphenidate in certain individuals for reasons outside of its intended clinical applications may adversely affect cognitive performance. Specifically, methylphenidate positively affected brain glucose metabolism in subjects who performed well at baseline on an accuracy-controlled cognitive task, but caused further deterioration of mental processing in subjects who performed poorly at baseline. In other words, certain individuals without ADHD who take the drug to enhance concentration and focus may inadvertently make things worse.[34]

However, in a paper published in Biological Psychiatry (June 24, 2008 online), researchers report that methylphenidate fine-tunes the functioning of neurons in the prefrontal cortex - a brain region involved in attention, decision-making and impulse control - while having few effects outside it. The team studied PFC neurons in rats under a variety of methylphenidate doses, including one that improved the animals' performance in a working memory task of the type that ADHD patients have trouble completing. Using microelectrodes, the scientists observed both the random, spontaneous firings of PFC neurons and their response to stimulation of the hippocampus. When they listened to individual PFC neurons, the scientists found that while cognition-enhancing doses of methylphenidate had little effect on spontaneous activity, the neurons' sensitivity to signals coming from the hippocampus increased dramatically. Under higher, stimulatory doses, on the other hand, PFC neurons stopped responding to incoming information.[35] Another study suggests that methylphenidate improves spatial orientation and working memory in rats on the radial arm maze.

Scheduling and abuse potential

It is generally accepted that methylphenidate is the closest pharmaceutical equivalent to cocaine, as studies have shown that cocaine addicts cannot distinguish between the two drugs when administered intravenously. However, cocaine has a much higher affinity for the serotonin receptor in comparison to methylphenidate, which is thought to be the mechanism of the euphoria associated with the cocaine high.[36]

In the United States, methylphenidate is classified as a Schedule II controlled substance, the designation used for substances that have a recognized medical value but present a high likelihood for abuse because of their addictive potential. Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances.[37]

Delivery formulations

Ritalin 10mg Pill (Ciba/Novartis)

All media are in milligrams.

Tablet

Capsules

Patches

Criticism

Main article: Attention-deficit hyperactivity disorder controversies
A Japanese Bottle Of Ritalin

Methylphenidate is frequently used in the treatment for ADHD, and as such criticism of the drug is typically related to the controversy about ADHD.

Generally criticism of methylphenidate revolves around the alleged or established side effects. There are also concerns about illicit use of the drug and the ethics of giving psychotropic drugs to children to reduce ADHD symptoms.[40] In 2002, a study showed that rats treated with methylphenidate are more receptive to the reinforcing effects of cocaine[36], which seeded doubts if the medication is a gateway drug to substance abuse. However, this contention has since been discredited by multiple sources.[41][42]

According to an article in the Los Angeles Times, "the uproar over Ritalin was triggered almost single-handedly by the Scientology movement."[43] The Citizens Commission on Human Rights, an antipsychiatry group associated with Scientology, conducted a major campaign against Ritalin in the 1980s and lobbied Congress for an investigation of Ritalin.[43] Though, some studies - namely by the U.S. government - concluded that side-effects often develop when starting this therapy at younger ages.

See also

References

  1. ↑ "Methylphenidate - Oral (Ritalin) side effects, medical uses and drug interactions". Retrieved on 2007-11-02.
  2. ↑ "Ritalin (methylphenidate) Side Effects and Abuse". Retrieved on 2007-11-02.
  3. ↑ Pronounciation
  4. ↑ "An Old Drug May Give Cancer Patients a Lift", ACS News Center, American Cancer Society (2002-01-24). Retrieved on 2008-02-24. 
  5. ↑ "News from DEA, Congressional Testimony, 05/16/00". Retrieved on 2007-11-02.
  6. ↑ 6.0 6.1 Steele, M., et al. (2006). "A randomized, controlled effectiveness trial of OROS-methylphenidate compared to usual care with immediate-release methylphenidate in Attention Deficit-Hyperactivity DisorderPDF (293 KB)". Can J Clin Pharmacol. 2006 Winter;13(1):e50-62.
  7. ↑ Pelham, W.E., et al. (2001). "Once-a-day Concerta methylphenidate versus three-times-daily methylphenidate in laboratory and natural settings". Pediatrics. 2001 Jun;107(6):E105.
  8. ↑ Keating, G.M., McClellan, K., Jarvis, B. (2001). "Methylphenidate (OROS formulation)". CNS Drugs. 2001;15(6):495-500; discussion 501-3.
  9. ↑ Hoare, P., et al. (2005). "12-month efficacy and safety of OROS methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder switched from MPHPDF". Eur Child Adolesc Psychiatry. 2005 Sep;14(6):305-9.
  10. ↑ Peck, P. (2006, 7 April). FDA Approves Daytrana Transdermal Patch for ADHD. MedPage today. Retrieved April 7, 2006, from http://www.medpagetoday.com/ProductAlert/Prescriptions/tb/3027.
  11. ↑ Fone KC; Nutt DJ. (February 2005). "Stimulants: use and abuse in the treatment of attention deficit disorder.". Current opinion in pharmacology. 5 (1): 87-93. doi:10.1016/j.coph.2004.10.001. PMID 15661631. 
  12. ↑ Sharma RP; Javaid JI, Pandey GN, Easton M, Davis JM. (April 1990). "Pharmacological effects of methylphenidate on plasma homovanillic acid and growth hormone.". Psychiatry research. 32 (1): 9-17. doi:10.1016/0165-1781(90)90130-W. PMID 2190251. 
  13. ↑ Shults T; Kownacki AA, Woods WE, Valentine R, Dougherty J, Tobin T. (May 1981). "Pharmacokinetics and behavioral effects of methylphenidate in Thoroughbred horses.". American journal of veterinary research. 42 (5): 722-6. PMID 7258793. 
  14. ↑ Barbaresi, W.J., et al. (2006). "Long-Term Stimulant Medication Treatment of Attention-Deficit/Hyperactivity Disorder: Results from a Population-Based Study". J Dev Behav Pediatr. 2006 Feb;27(1):1-10.
  15. ↑ Grund T., et al. "Influence of methylphenidate on brain development - an update of recent animal experiments", Behav Brain Funct. 2006 January 10;2:2.
  16. ↑ Markowitz JS "et al." (2006). "A Comprehensive In Vitro Screening of d-, l-, and dl-threo-Methylphenidate: An Exploratory Study". "J Child Adolesc Psychopharmacol". 2006 Dec;16(6):687-98.
  17. ↑ Volkow N., et al. (1998). "Dopamine Transporter Occupancies in the Human Brain Induced by Therapeutic Doses of Oral Methylphenidate". Am J Psychiatry 155:1325-1331, October 1998.
  18. ↑ Gainetdinov, Raul R.; Caron, Marc G. (March 2001). "Genetics of Childhood Disorders: XXIV. ADHD, Part 8: Hyperdopaminergic Mice as an Animal Model of ADHD". Journal of the American Academy of Child & Adolescent Psychiatry 40 (3): 380-382. http://www.med.yale.edu/chldstdy/plomdevelop/genetics/01margen.htm. Retrieved on 2006-11-11. 
  19. ↑ Volkow, ND; Fowler JS, Wang GJ, Telang F, Logan J, Wong C, Ma J, Pradhan K, Benveniste H, Swanson JM (April 2008). "Methylphenidate decreased the amount of glucose needed by the brain to perform a cognitive task". PLoS ONE 3 (4): e2017. PMID 18414677. http://scivee.tv/node/5977. Retrieved on 2008-11-26. 
  20. ↑ Concerta: Benefits and Side Effects
  21. ↑ Rao J.K., Julius J.R., Breen T.J., Blethen S.L. (1996). "Response to growth hormone in attention deficit hyperactivity disorder: effects of methylphenidate and pemoline therapy". Pediatrics. 1998 Aug;102 (2 Pt 3):497-500.
  22. ↑ Spencer, T.J., et al. (1996)."Growth deficits in ADHD children revisited: evidence for disorder-associated growth delays?". J Am Acad Child Adolesc Psychiatry. 1996 Nov;35(11):1460-9.
  23. ↑ Klein R.G. & Mannuzza S. (1988). "Hyperactive boys almost grown up. III. Methylphenidate effects on ultimate height". Arch Gen Psychiatry. 1988 Dec;45(12):1131-4.
  24. ↑ Wilens, T., et al. (2005). ADHD treatment with once-daily OROS methylphenidate: final results from a long-term open-label study". J Am Acad Child Adolesc Psychiatry. 2005 Oct;44(10):1015-23.
  25. ↑ Teo, S.K., et al. (2003). "D-Methylphenidate is non-genotoxic in vitro and in vivo assays". Mutat Res. 2003 May 9;537(1):67-79.
  26. ↑ El-Zein R.A., et al. (2005). "Cytogenetic effects in children treated with methylphenidate". Cancer Lett. 2005 December 18;230(2):284-91.
  27. ↑ Walitza, Susanne (June 2007). "Does Methylphenidate Cause a Cytogenetic Effect in Children with Attention Deficit Hyperactivity Disorder?". Environmental Health Perspectives 115 (6): 936–940. doi:10.1289/ehp.9866. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1892117. 
  28. ↑ ADHD & Women's Health - Attention-deficit hyperactivity disorder National Women's Health Report. February 2003. http://findarticles.com/p/articles/mi_m0NKT/is_1_25/ai_99698688/pg_4. Retrieved on 2007-11-03. "Although methylphenidate is perhaps one of the best-studied drugs available, with thousands of studies attesting to its longterm safety over the past 50 years, that hasn't stopped critics from raising alarms about the drug's long-term use on children's developing brains, particularly given research that finds the numbers of children taking the drug skyrocketing in recent years.". 
  29. ↑ Edmund J. S. Sonuga-Barke, Margaret Thompson, Howard Abikoff, Rachel Klein, Laurie Miller Brotman. "Nonpharmacological Interventions for Preschoolers With ADHD: The Case for Specialized Parent Training" (PDF). Infants & Young Children 19 (2): 142–153. http://depts.washington.edu/isei/iyc/sonuga_19.2.pdf. "While most recent studies suggest that methylphenidate is relatively well-tolerated by young children, some suggest that side effects might be more marked in preschoolers than in school-aged children (Firestone, Musten, Pisterman, Mercer, & Bennett, 1998). Furthermore, some researchers have argued that there is the potential for negative long-term effects on the developing brains of young children chronically medicated (Moll, Rothenberger, Ruther, & Huther, 2002).". 
  30. ↑ Attention Deficit Hyperactivity Disorder (ADHD)
  31. ↑ Minutes of the FDA Pediatric Advisory Committee. March 22, [2006].
  32. ↑ New Scientist 18 February 2006
  33. ↑ Minutes of the FDA Pediatric Advisory Committee, March 22, [2006]
  34. ↑ Popular Stimulant's Role In Brain Function Deterioration Is Cause For Concern, According To Researchers
  35. ↑ Study Uncovers How Ritalin Works in Brain to Boost Cognition, Focus Attention Newswise, Retrieved on June 24, 2008.
  36. ↑ 36.0 36.1 http://www.udel.edu/chemo/teaching/CHEM465/SitesF02/Prop26b/Rit%20Page4.html Pretreatment with methylphenidate sensitizes rats to the reinforcing effects of cocaine
  37. ↑ Green List: Annex to the annual statistical report on psychotropic substances (form P)PDF (1.63 MB) 23rd edition. August 2003. International Narcotics Board, Vienna International Centre. Accessed 2 March 2006
  38. ↑ Full Prescribing Information for Concerta. (215 KiB)
  39. ↑ Generic Concerta
  40. ↑ Lakhan SE; Hagger-Johnson G. The impact of prescribed psychotropics on youth. Clinical Practice and Epidemiology in Mental Health 2007;3(21).
  41. ↑ Wilens, T.E.., et al. (2003). "Does Stimulant Therapy of Attention-Deficit/Hyperactivity Disorder Beget Later Substance Abuse? A Meta-analytic Review of the Literature". PEDIATRICS. 2003 Vol. 111 No. 1:pp. 179-185
  42. ↑ Russell A. Barkley, PhD,et al. (2003). "Does the Treatment of Attention-Deficit/Hyperactivity Disorder With Stimulants Contribute to Drug Use/Abuse? A 13-Year Prospective Study". PEDIATRICS. 2003 Vol. 111 No. 1: pp. 97-109
  43. ↑ 43.0 43.1 Sappell, Joel; Welkos, Robert W. (1990-06-29). "Suits, Protests Fuel a Campaign Against Psychiatry", Los Angeles Times, p. A48:1. Retrieved on 2006-11-29.  Backup copy link here

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