JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Volume 25, Number x, 2015 ª Mary Ann Liebert, Inc. Pp. 1–2 DOI: 10.1089/cap.2014.0172
Letter to the Editor
Painful Muscle Cramps Possibly Associated with Withdrawal from Methylphenidate Murat Coskun, MD, and Ilyas Kaya MD
To The Editor:
the third cramp episode, her parents initially thought that this was a side effect of IR MPH. However, they later realized that it only occurred at next morning after a drug-free day. The patient continued her medication for 10 days and did not experience this condition at all. However she experienced the fourth cramp the next morning when her parents did not give her her medication. After several days of regular use of IR MPH, she experienced the final cramp episode when she had skipped a dose the previous morning. Afterward, her parents called the girl’s physician and it was suggested that they switch to OROS MPH 36 mg. They denied the use of any other medication, or of the girl having performed any unusual physical activity during this period. A general medical examination and laboratory workup while using OROS MPH 36 mg did not reveal significant problems other than mild iron-deficiency anemia. With regular use of OROS MPH 36 mg, the patient did not experience any cramps in her legs during the next 2 months.
A
s far as we know, there is no reported case of painful muscle cramps associated with withdrawal from immediate release (IR) or osmotic controlled release oral delivery system (OROS) methylphenidate (MPH) in children with attention-deficit/ hyperactivity disorder (ADHD). Here, we present a female subject with ADHD who developed painful muscle cramps in her legs associated with withdrawal from IR MPH. Case Report A 13-year-old girl with a normal developmental history and intellectual capacity had been followed-up with diagnoses of ADHD, anxiety disorders and obsessive compulsive disorders (OCD) since she was 6 years of age. She had been on several medications, including MPH, fluoxetine, fluvoxamine, risperidone and aripiprazole since she was 6 years of age. She had used these medications either as monotherapy or in different combinations. She had been taking only MPH for the previous 18 months, as her anxiety and OCD symptoms had remitted significantly. She had been taking OROS MPH during school days and IR MPH during weekends, because she had experienced some level of decreased appetite with OROS MPH. Besides decreased appetite without any significant weight loss, she had not experienced any significant side effects with MPH treatment. Her symptoms of ADHD showed moderate improvement with MPH treatment. It was suggested that she discontinue OROS MPH 36 mg and IR MPH 10 mg during the previous summer holiday, upon her parents’ request. Her parents restarted her medication as IR MPH 20 mg/day at morning at the beginning of school. The subject and her parents reported that she did not have any significant side effects with IR MPH other than some initial headache and nausea. However, sometimes they forgot or neglected to give her her medication, IR MPH 20 mg/day, because of her being in a hurry to leave for school. They reported that she started to experience severe and painful muscle cramps in her lower legs in the morning if she had not taken her IR MPH the previous morning. She did not experience this condition if she took IR MPH on regular basis. These muscle cramps were painful, and palpable by her parents. The subject was awakened by pain in her legs and crying and yelling in the mornings. These cramps continued for 20–30 minutes, and she experienced pain in her legs and difficulty in walking during the day. She did not take her IR MPH five times during 1 month, and she experienced this condition the next morning every time. Her parents stated that these cramps occurred in the morning before she took her medication. She took her medication on these days. After
Discussion MPH has been the first line psychopharmacological treatment in children and adolescents with ADHD, and results in significant improvement in 70–80% of affected children (Green 2007). Nausea, decreased appetite, weight loss, and sleep disturbances are among the most frequently reported side effects during MPH treatment (Green 2007). In addition to these common side effects, MPH has also been reported to cause some unusual side effects such as hallucinations (Coskun and Zoroglu 2008), hypersexuality or inappropriate sexual behaviors (Coskun and Zoroglu 2009), skin eruptions (Coskun et al. 2009), manic/psychotic reactions (Ross 2006), obsessive-compulsive symptoms (Coskun 2011) and gynecomastia (Coskun et al. 2014). These unusual side effects may cause treatment noncompliance, and may have important medical and/or mental health consequences. However, despite that the package insert of Ritalin includes ‘‘muscle cramps’’ among very rare side effects (Ritalin package insert 2006) a review of literature revealed no reported case of such a side effect associated with MPH treatment. Therefore, our case seems to be the first in the literature reporting painful muscle cramps associated with MPH treatment. It may be important to note that painful muscle cramps in this case emerged the next morning after a drug-free day and disappeared with regular use of IR or OROS MPH. Therefore they were considered to be associated with MPH withdrawal. It is not clear by which mechanisms MPH withdrawal can be associated with such painful cramps. One possible explanation may be the relative dopamine deficiency in the nigrostrial dopamine pathway. The nigrostrial dopamine pathway, which projects from
Child and Adolescent Psychiatry Department, Istanbul Medical Faculty, Istanbul, Turkey.
1
2
COSKUN AND KAYA
dopaminergic cell bodies in the substantia nigra of the brainstem via axons terminating in the basal ganglia or striatum, is one of the major dopamine pathways in the brain (Stahl 2002). The nigrostrial dopamine pathway is a part of the extrapyramidal nervous system and controls motor movements. Deficiencies in dopamine in this pathway cause movement disorders, including Parkinson’s disease, which is characterized by rigidity, akinesia or bradykinesia (i.e., lack of movement or slowing of movement), and tremor. Dopamine deficiency in the basal ganglia also can produce akathisia and dystonia (especially of the face and neck) (Stahl 2002). However, it may be difficult to designate these painful muscle cramps in the lower legs a dystonic reaction. Because a general medical examination and laboratory workup in our case did not reveal any problems that may have accounted for these painful cramps, this condition was considered to be associated with withdrawal from MPH. Naranjo causality scale revealed a score of 5, which shows a probable adverse drug reaction (Naranjo et al. 1981). Regardless of the underlying pathophysiological mechanisms, such an unusual side effect may pose significant distress to subjects and parents, and complicate treatment compliance. Clinicians treating children with ADHD should be familiar with rare side effects associated with MPH treatment. Disclosures No competing financial interests exist. References Coskun M: Methylphenidate induced obsessive-compulsive symptoms treated with sertraline. Bull Clin Psychopharmacol 21:275– 276, 2011. Coskun M, Adak I, Akaltun I: Bilateral gynecomastia in a preadolescent boy related with methylphenidate and paroxetine combination. J Clin Psychopharmacol 34:537–538, 2014.
Coskun M, Tutkunkardas MD, Zoroglu S: OROS methylphenidateinduced skin eruptions. J Child Adolesc Psychopharmacol 19:593– 594, 2009. Coskun M, Zoroglu S: A report of two cases of sexual side effects with OROS methylphenidate. J Child Adolesc Psychopharmacol 19:477–479, 2009. Coskun M, Zoroglu S: Tactile and visual hallucinations in a child with methylphenidate and fluoxetine combination. J Clin Psychopharmacol 28:723–725, 2008. Green WH: Sympathomimetic amines and central nervous system stimulants. In: Child and Adolescent Clinical Psychopharmacology, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2007; pp.55–90. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ: A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 30:239– 245, 1981. Ritalin 10 mg (immediate release methylphenidate), package insert. Novartis, Turkey, 2006. Ross R: Psychotic and manic-like symptoms during stimulant treatment of attention deficit hyperactivity disorder. Am J Psychiatry 163:1149–1152, 2006. Stahl MS: Essential Psychopharamacology: Neuroscientific Basis and Practical Applications, 2nd ed., New York: Cambridge University Press; 2002.
Address correspondence to: Murat Coskun, MD Istanbul Tıp Faku¨ltesi C¸ocuk ve Ergen Psikiyatrisi Anabilim Dalı _ Istanbul Tıp Faku¨ltesi Esnaf Hastanesi Klinikleri Su¨leymaniye Mah. _ 34116 Istanbul Turkiye E-mail: [email protected]
Letter to the Editor
Painful Muscle Cramps Possibly Associated with Withdrawal from Methylphenidate Murat Coskun, MD, and Ilyas Kaya MD
To The Editor:
the third cramp episode, her parents initially thought that this was a side effect of IR MPH. However, they later realized that it only occurred at next morning after a drug-free day. The patient continued her medication for 10 days and did not experience this condition at all. However she experienced the fourth cramp the next morning when her parents did not give her her medication. After several days of regular use of IR MPH, she experienced the final cramp episode when she had skipped a dose the previous morning. Afterward, her parents called the girl’s physician and it was suggested that they switch to OROS MPH 36 mg. They denied the use of any other medication, or of the girl having performed any unusual physical activity during this period. A general medical examination and laboratory workup while using OROS MPH 36 mg did not reveal significant problems other than mild iron-deficiency anemia. With regular use of OROS MPH 36 mg, the patient did not experience any cramps in her legs during the next 2 months.
A
s far as we know, there is no reported case of painful muscle cramps associated with withdrawal from immediate release (IR) or osmotic controlled release oral delivery system (OROS) methylphenidate (MPH) in children with attention-deficit/ hyperactivity disorder (ADHD). Here, we present a female subject with ADHD who developed painful muscle cramps in her legs associated with withdrawal from IR MPH. Case Report A 13-year-old girl with a normal developmental history and intellectual capacity had been followed-up with diagnoses of ADHD, anxiety disorders and obsessive compulsive disorders (OCD) since she was 6 years of age. She had been on several medications, including MPH, fluoxetine, fluvoxamine, risperidone and aripiprazole since she was 6 years of age. She had used these medications either as monotherapy or in different combinations. She had been taking only MPH for the previous 18 months, as her anxiety and OCD symptoms had remitted significantly. She had been taking OROS MPH during school days and IR MPH during weekends, because she had experienced some level of decreased appetite with OROS MPH. Besides decreased appetite without any significant weight loss, she had not experienced any significant side effects with MPH treatment. Her symptoms of ADHD showed moderate improvement with MPH treatment. It was suggested that she discontinue OROS MPH 36 mg and IR MPH 10 mg during the previous summer holiday, upon her parents’ request. Her parents restarted her medication as IR MPH 20 mg/day at morning at the beginning of school. The subject and her parents reported that she did not have any significant side effects with IR MPH other than some initial headache and nausea. However, sometimes they forgot or neglected to give her her medication, IR MPH 20 mg/day, because of her being in a hurry to leave for school. They reported that she started to experience severe and painful muscle cramps in her lower legs in the morning if she had not taken her IR MPH the previous morning. She did not experience this condition if she took IR MPH on regular basis. These muscle cramps were painful, and palpable by her parents. The subject was awakened by pain in her legs and crying and yelling in the mornings. These cramps continued for 20–30 minutes, and she experienced pain in her legs and difficulty in walking during the day. She did not take her IR MPH five times during 1 month, and she experienced this condition the next morning every time. Her parents stated that these cramps occurred in the morning before she took her medication. She took her medication on these days. After
Discussion MPH has been the first line psychopharmacological treatment in children and adolescents with ADHD, and results in significant improvement in 70–80% of affected children (Green 2007). Nausea, decreased appetite, weight loss, and sleep disturbances are among the most frequently reported side effects during MPH treatment (Green 2007). In addition to these common side effects, MPH has also been reported to cause some unusual side effects such as hallucinations (Coskun and Zoroglu 2008), hypersexuality or inappropriate sexual behaviors (Coskun and Zoroglu 2009), skin eruptions (Coskun et al. 2009), manic/psychotic reactions (Ross 2006), obsessive-compulsive symptoms (Coskun 2011) and gynecomastia (Coskun et al. 2014). These unusual side effects may cause treatment noncompliance, and may have important medical and/or mental health consequences. However, despite that the package insert of Ritalin includes ‘‘muscle cramps’’ among very rare side effects (Ritalin package insert 2006) a review of literature revealed no reported case of such a side effect associated with MPH treatment. Therefore, our case seems to be the first in the literature reporting painful muscle cramps associated with MPH treatment. It may be important to note that painful muscle cramps in this case emerged the next morning after a drug-free day and disappeared with regular use of IR or OROS MPH. Therefore they were considered to be associated with MPH withdrawal. It is not clear by which mechanisms MPH withdrawal can be associated with such painful cramps. One possible explanation may be the relative dopamine deficiency in the nigrostrial dopamine pathway. The nigrostrial dopamine pathway, which projects from
Child and Adolescent Psychiatry Department, Istanbul Medical Faculty, Istanbul, Turkey.
1
2
COSKUN AND KAYA
dopaminergic cell bodies in the substantia nigra of the brainstem via axons terminating in the basal ganglia or striatum, is one of the major dopamine pathways in the brain (Stahl 2002). The nigrostrial dopamine pathway is a part of the extrapyramidal nervous system and controls motor movements. Deficiencies in dopamine in this pathway cause movement disorders, including Parkinson’s disease, which is characterized by rigidity, akinesia or bradykinesia (i.e., lack of movement or slowing of movement), and tremor. Dopamine deficiency in the basal ganglia also can produce akathisia and dystonia (especially of the face and neck) (Stahl 2002). However, it may be difficult to designate these painful muscle cramps in the lower legs a dystonic reaction. Because a general medical examination and laboratory workup in our case did not reveal any problems that may have accounted for these painful cramps, this condition was considered to be associated with withdrawal from MPH. Naranjo causality scale revealed a score of 5, which shows a probable adverse drug reaction (Naranjo et al. 1981). Regardless of the underlying pathophysiological mechanisms, such an unusual side effect may pose significant distress to subjects and parents, and complicate treatment compliance. Clinicians treating children with ADHD should be familiar with rare side effects associated with MPH treatment. Disclosures No competing financial interests exist. References Coskun M: Methylphenidate induced obsessive-compulsive symptoms treated with sertraline. Bull Clin Psychopharmacol 21:275– 276, 2011. Coskun M, Adak I, Akaltun I: Bilateral gynecomastia in a preadolescent boy related with methylphenidate and paroxetine combination. J Clin Psychopharmacol 34:537–538, 2014.
Coskun M, Tutkunkardas MD, Zoroglu S: OROS methylphenidateinduced skin eruptions. J Child Adolesc Psychopharmacol 19:593– 594, 2009. Coskun M, Zoroglu S: A report of two cases of sexual side effects with OROS methylphenidate. J Child Adolesc Psychopharmacol 19:477–479, 2009. Coskun M, Zoroglu S: Tactile and visual hallucinations in a child with methylphenidate and fluoxetine combination. J Clin Psychopharmacol 28:723–725, 2008. Green WH: Sympathomimetic amines and central nervous system stimulants. In: Child and Adolescent Clinical Psychopharmacology, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2007; pp.55–90. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ: A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 30:239– 245, 1981. Ritalin 10 mg (immediate release methylphenidate), package insert. Novartis, Turkey, 2006. Ross R: Psychotic and manic-like symptoms during stimulant treatment of attention deficit hyperactivity disorder. Am J Psychiatry 163:1149–1152, 2006. Stahl MS: Essential Psychopharamacology: Neuroscientific Basis and Practical Applications, 2nd ed., New York: Cambridge University Press; 2002.
Address correspondence to: Murat Coskun, MD Istanbul Tıp Faku¨ltesi C¸ocuk ve Ergen Psikiyatrisi Anabilim Dalı _ Istanbul Tıp Faku¨ltesi Esnaf Hastanesi Klinikleri Su¨leymaniye Mah. _ 34116 Istanbul Turkiye E-mail: [email protected]
