- Email: [email protected]
Adderall XR and peripheral arterial vasculopathy: A case report and a review of the literature
Reviews in Vascular Medicine 3 (2015) 1–4
Contents lists available at ScienceDirect
Reviews in Vascular Medicine journal homepage: www.elsevier.com/locate/rvm
Letter to the editor
Adderall XR and peripheral arterial vasculopathy: A case report and a review of the literature
a b s t r a c t Lower extremity peripheral arterial disease is a rare entity in the young population. When diagnosed, mostly it is non-atherosclerosis related [14]. Adderall XR is among the psychostimulant drugs and some case reports in the literature had linked it to arterial vasospasm. We thought to do a literature search investigating the rule of Adderall XR and peripheral arterial vasculopathy. & 2015 Published by Elsevier B.V.
Introduction Amphetamines (AMPHs) are among the vasoactive substances that may induce arterial vasospasm causing acute ischemic strokes, myocardial infarctions and Raynaud's phenomena [1,2]. Adderall Extended Release (XR) is a combination of amphetamine and dextroamphetamine, and is a commonly prescribed medication for patients with Attention Deficit Hyperactivity Disorder (ADHD).
The gold standard for diagnosing lower extremity peripheral arterial disease is angiography, however, CT angiography sensitivity and specificity of 95% and 96% respectively [13], our patient received the CTA (Figs. 1 and 2). On one month follow up after stopping the Adderall, the patient states that she still had moderate pain in the lower extremities but she was able to ambulate more freely and there was no ulceration or blue discoloration of the toes or feet.
Case report Discussion A 19-year-old Hispanic female with a past medical history of ADHD presented to our institution with lower extremity paresthesia and pain for one day. The patient was on Adderall XR for the past 3 years. The pain started in her feet and radiated to her thighs. She described the pain as cramping in nature and was associated with paresthesia and difficulty ambulating. The patient denied any history of drug abuse. Her physical examination was remarkable for diminished popliteal pulses, extremely diminished dorsalis pedis pulses and normal femoral pulses. She also had decreased strength in the lower extremities with grade 4/5 muscle power. The rest of her physical exam, family history and social history were unremarkable. A complete laboratory evaluation involving comprehensive metabolic panel, complete blood counts, were unremarkable except for positive AMPHs in the urine drug screen. Additionally, an evaluation for an underlying arteritis including antinuclear antibodies, rheumatoid factors, lupus panel, rapid plasma regain, HIV, erythrocytes sedimentation rate and C-reactive protein was negative. A computed tomography angiogram (CTA) of the lower extremities showed extremely diminutive lower extremity arterial flow extending from the superficial femoral artery, popliteal artery and involving trifurcation vessels without any evidence of arterial occlusion. Radiographically, these findings of long segment arterial narrowing were consistent with vasospasm. Interventional cardiology team was consulted and after reviewing the patient's CTA images it was agreed that the patient had no focal stenosis that required stenting or bypass. During the course of her admission, her symptoms and vascular exam improved with the use of Aspirin and calcium channel blockers. http://dx.doi.org/10.1016/j.rvm.2015.03.001 2212-0211/& 2015 Published by Elsevier B.V.
ADHD is psychiatric disorder that is usually diagnosed in childhood and is characterized by inattention, hyperactivity, impulsiveness or a combination of these problems. ADHD affects learning abilities and quality of life and can extend into adulthood [3–5]. Pharmacologic therapy is essential for the treatment of ADHD. Currently two classes of medications are employed, the first class of drugs are the stimulants such as amphetamines and methylphenidates and the second class of drugs comprises of nonstimulants such as guanfacine extended release and atomoxetin [6]. AMPHs role in ADHD is not fully understood yet. Amphetamines are sympathomimetic agent that blocks the reuptake of norepinephrine and dopamine from the presynaptic nerve terminals [7]. It has even been shown to antagonize of adrenergic neuron blockade in several preparations [8]. These sympathomimetic effects could cause elevated blood pressure and vasospasm [2]. Goldman et al. investigated the association of CNS stimulants (methylphenidate and dextroamphetamine) with Raynaud's phenomena and found that the use of these medications was significantly associated with Raynaud's. The paper suggested that inflammation in addition to vasospasm is responsible for this phenomenon, even though inflammatory biomarkers (ESR and CRP) were significantly lower in the population that was on CNS stimulants [17]. Yu et al. reported 4 patients that suffered Raynaud's syndrome while on CNS stimulants. All these patients were on methylphenidate – which works in a similar mechanism of action to Adderall – and two of these patients were on Adderall early during treatment [15].
2
Letter to the editor / Reviews in Vascular Medicine 3 (2015) 1–4
Fig. 1. Anterior CTA view showing sever vasospasm in the lower extremities and the lack of contrast flow.
Sayed et al. described 4 patients on CNS stimulants; patient A was on dextroamphetamine and experienced Raynaud's phenomenon that improved after the discontinuation of Dextreoamphetamin; of note ANA was positive along with IgG and IgM deposition in this case. Patient D was also on dextroamphetamine and experienced livedo reticularis with delayed capillary refill, and her anti-histones antibodies were at 1.7 (normalo1.00 IU). The investigators in this articles attributed Raynaud's phenomena to connective tissues disease rather than acute vasospasm even tough patient A improved after withdrawal of dextroamphetamine [16]. Aboud et al. presented a patient on Adderall who suffered blue toe syndrome; her symptoms resolved 4 weeks after discontinuation of the medication. This patient's inflammatory workup was unrevealing except for a mildly elevated ANA titer at 1:160 [2]. Leithauser et al. reported a case similar to ours in a 22-year-old patient who was abusing amphetamine and presented with lower extremity claudication and even ulceration, an angiogram was
Fig. 2. Lateral view showing the same findings.
performed and showed hemodynamically significant stenosis only in the lower leg region in the proximal posterior tibial and peroneal arteries on the left and right sides. The authors of this article attributed these toxic effects of methamphetamine mostly to inflammation in addition to vasospasm. They concluded that the inflammation mostly involved the vasa vasorum of the small and medium sized vessel of the lower extremities. In this case the patient's inflammatory workup including ESR, CRP, rheumatoid factor and ANA was unrevealing. AMPHs use has been associated with cerebral infarction, myocardial infarction, cardiomyopathy and cardiac arrhythmias [7,9–11].Two theories have been proposed to explain the association of amphetamine with acute myocardial infarction. Acute ingestion has been hypothesized to cause vasospasm with resultant ischemia. With chronic use, amphetamines can increase
Letter to the editor / Reviews in Vascular Medicine 3 (2015) 1–4
vasculopathy
thrombogenicity and cause accelerated atherosclerosis in addition to vasospasm [7,12]. Also, in the post-marketing period of Adderall XR, peripheral vasculopathy resulting in Raynaud's phenomena has been reported. In these reported cases, Raynaud's phenomenon resolved shortly after discontinuation of the drug. Conclusion In the case we presented, our patient was young, free of any cardiovascular risk factors and her inflammatory workup was unrevealing. She had been on Adderall XR for the past 3 years. Her acute presentation was mostly consistent with arterial vasospasm. This review demonstrates patients suffered Raynaud's phenomena, lower extremity vasospasm and blue toe syndrome. Most of these Patients' inflammatory workup was unrevealing or mildly positive towards inflammation. We postulate in our review that most of these finding are caused primarily by vasospasm in addition to a mild degree of inflammation. The articles that talked about Adderall and peripheral vasculopathy are summarized in table below. Author and Journal
Year
Title
Type
Findings
William Goldman et al. and Arthritis & Rheumatism
2008
Association between treatment with central nervous system stimulants and Raynaud's syndrome in children
A casecontrol design
Ahmad Al Aboud et al. and Journal of American Academy of Dermatology
2011
Case report
Reema H. Syed et al. and Journal of Clinical Rheumatology
2008
Blue toes after stimulant therapy for pediatric attention deficit hyperactivity disorder Methylphenidate and dextroamphetamineinduced peripheral
There was a significant association between between development of Raynaude's and therapy with CNS stimulants used for the treatment of ADHD (methylphenidate and dextroamphetamine) 9-year-old girl on Adderall XR presented with blue toe syndrome that resolved upon cessation of the medication.
3
Current case
2015
Lower extremity vasospasm caused by Adderall XR
Case report
dextroamphetamine and one of them improved after the withdrawal of the medication. We are describing a patient with isolated lower extremities vasospasm that was attributed to Adderall XR. Her inflammatory biomarkers were negative.
Conflict of interest
Case report
4 case reports —two of them about patient who experienced vasculopathy while on treatment doses of
None declared.
References [1] Sylves Angela L, et al. Acute myocardial infarction in a teenager due to adderall XR. Pediatr. Cardiol. 2012;33:155–157. [2] Ahmad Al Aboud, et al. Blue toes after stimulant therapy for pediatric attention deficit hyperactivity disorder. J. Am. Acad. Dermatol. 2011;64 (6):1218–1219. [3] Shaw Monica, et al. A systematic review and analysis of long-term outcomes in attention deficit hyperactivity disorder: effects of treatment and non. BMC Med. 2012;10:99. [4] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (Text Revision). 4th edition. Arlington, VA: American Psychiatric Association; 2000. [5] World Health Organization. International Classification of Diseases. 10th edition. Geneva, Switzerland: WHO; 1992. [6] Kavita Gajria, et al. Adherence, persistence, and medication discontinuation in patients with attention-deficit/hyperactivity disorder – a systematic literature review. Neuropsychiatr. Disease Treat. 2014;10 (Pages 1543 and 1544). [7] Jiao Xiangyang, et al. Myocardial infarction associated with Adderall XR and alcohol use in a young man. J. Am. Board Fam. Med. 2009;22:197–201. [8] Follenfant MJ, Robson RD. The antagonism of adrenergic neurone blockade by amphetamine and dexamphetamine in the rat and guinea-pig. Br. J. Pharmacol. 1970;38:792–801. [9] Bartel AG. Acute cardiomyopathy secondary to intravenous amphetamine abuse. Ann. Intern. Med. 1982;97:559–560. [10] Lucas PB, Gardner DL, Wolkowitz OM, Tucker EE, Cowdry RW. Methylphenidateinduced cardiac arrhythmias [letter]. N. Engl. J. Med. 1986;315:1485. [11] Ohta Keiko, et al. Delayed ischemic stroke associated with methamphetamine use. J. Emerg. Med. 2005;28(2):165–167. [12] Chen JP. Methamphetamine-associated acute myocardial infarction and cardiogenic shock with normal coronary arteries: refractory global coronary microvascular spasm. J. Invasive Cardiol. 2007;19:E89–E92. [13] Pollak Amy W, et al. Multimodality imaging of lower extremity peripheral arterial disease: current role and future directions. Circ. Cardiovasc. Imaging 2012. [14] Weinberg Ido, Jaff Michael R. Nonatherosclerotic arterial disorders of the lower extremities. Circulation 2012;126:213–222. [15] Yu Zheya Jenny, et al. Peripheral vasculopathy associated with psychostimulant treatment in children with attention-deficit/hyperactivity disorder. Curr. Psychiatry Rep. 2010;12:111–115. [16] Syed Reema H, et al. Methylphenidate and dextroamphetamine-induced peripheral vasculopathy. J. Clin. Rheumatol. 2008;14:30–33. [17] Goldman William, et al. Association between treatment with central nervous system stimulants and Raynaud's syndrome in children. Arthritis Rheumatism 2008;58(2):563–566.
4
Letter to the editor / Reviews in Vascular Medicine 3 (2015) 1–4
Abdulwahab Hritani, Vinay Minocha Internal Medicine Department, University of Florida, Jacksonville, FL, USA
Ambar Patel, Patrick Antoun n Cardiology Department, University of Florida, Jacksonville, FL, USA E-mail address: [email protected]fl.edu (P. Antoun) Received 8 December 2014; accepted 6 March 2015
n Corresponding author at: Coronary care unit, Director, University of Florida, Jacksonville, 655 west 8th street, Jacksonville, FL, 32209.
Contents lists available at ScienceDirect
Reviews in Vascular Medicine journal homepage: www.elsevier.com/locate/rvm
Letter to the editor
Adderall XR and peripheral arterial vasculopathy: A case report and a review of the literature
a b s t r a c t Lower extremity peripheral arterial disease is a rare entity in the young population. When diagnosed, mostly it is non-atherosclerosis related [14]. Adderall XR is among the psychostimulant drugs and some case reports in the literature had linked it to arterial vasospasm. We thought to do a literature search investigating the rule of Adderall XR and peripheral arterial vasculopathy. & 2015 Published by Elsevier B.V.
Introduction Amphetamines (AMPHs) are among the vasoactive substances that may induce arterial vasospasm causing acute ischemic strokes, myocardial infarctions and Raynaud's phenomena [1,2]. Adderall Extended Release (XR) is a combination of amphetamine and dextroamphetamine, and is a commonly prescribed medication for patients with Attention Deficit Hyperactivity Disorder (ADHD).
The gold standard for diagnosing lower extremity peripheral arterial disease is angiography, however, CT angiography sensitivity and specificity of 95% and 96% respectively [13], our patient received the CTA (Figs. 1 and 2). On one month follow up after stopping the Adderall, the patient states that she still had moderate pain in the lower extremities but she was able to ambulate more freely and there was no ulceration or blue discoloration of the toes or feet.
Case report Discussion A 19-year-old Hispanic female with a past medical history of ADHD presented to our institution with lower extremity paresthesia and pain for one day. The patient was on Adderall XR for the past 3 years. The pain started in her feet and radiated to her thighs. She described the pain as cramping in nature and was associated with paresthesia and difficulty ambulating. The patient denied any history of drug abuse. Her physical examination was remarkable for diminished popliteal pulses, extremely diminished dorsalis pedis pulses and normal femoral pulses. She also had decreased strength in the lower extremities with grade 4/5 muscle power. The rest of her physical exam, family history and social history were unremarkable. A complete laboratory evaluation involving comprehensive metabolic panel, complete blood counts, were unremarkable except for positive AMPHs in the urine drug screen. Additionally, an evaluation for an underlying arteritis including antinuclear antibodies, rheumatoid factors, lupus panel, rapid plasma regain, HIV, erythrocytes sedimentation rate and C-reactive protein was negative. A computed tomography angiogram (CTA) of the lower extremities showed extremely diminutive lower extremity arterial flow extending from the superficial femoral artery, popliteal artery and involving trifurcation vessels without any evidence of arterial occlusion. Radiographically, these findings of long segment arterial narrowing were consistent with vasospasm. Interventional cardiology team was consulted and after reviewing the patient's CTA images it was agreed that the patient had no focal stenosis that required stenting or bypass. During the course of her admission, her symptoms and vascular exam improved with the use of Aspirin and calcium channel blockers. http://dx.doi.org/10.1016/j.rvm.2015.03.001 2212-0211/& 2015 Published by Elsevier B.V.
ADHD is psychiatric disorder that is usually diagnosed in childhood and is characterized by inattention, hyperactivity, impulsiveness or a combination of these problems. ADHD affects learning abilities and quality of life and can extend into adulthood [3–5]. Pharmacologic therapy is essential for the treatment of ADHD. Currently two classes of medications are employed, the first class of drugs are the stimulants such as amphetamines and methylphenidates and the second class of drugs comprises of nonstimulants such as guanfacine extended release and atomoxetin [6]. AMPHs role in ADHD is not fully understood yet. Amphetamines are sympathomimetic agent that blocks the reuptake of norepinephrine and dopamine from the presynaptic nerve terminals [7]. It has even been shown to antagonize of adrenergic neuron blockade in several preparations [8]. These sympathomimetic effects could cause elevated blood pressure and vasospasm [2]. Goldman et al. investigated the association of CNS stimulants (methylphenidate and dextroamphetamine) with Raynaud's phenomena and found that the use of these medications was significantly associated with Raynaud's. The paper suggested that inflammation in addition to vasospasm is responsible for this phenomenon, even though inflammatory biomarkers (ESR and CRP) were significantly lower in the population that was on CNS stimulants [17]. Yu et al. reported 4 patients that suffered Raynaud's syndrome while on CNS stimulants. All these patients were on methylphenidate – which works in a similar mechanism of action to Adderall – and two of these patients were on Adderall early during treatment [15].
2
Letter to the editor / Reviews in Vascular Medicine 3 (2015) 1–4
Fig. 1. Anterior CTA view showing sever vasospasm in the lower extremities and the lack of contrast flow.
Sayed et al. described 4 patients on CNS stimulants; patient A was on dextroamphetamine and experienced Raynaud's phenomenon that improved after the discontinuation of Dextreoamphetamin; of note ANA was positive along with IgG and IgM deposition in this case. Patient D was also on dextroamphetamine and experienced livedo reticularis with delayed capillary refill, and her anti-histones antibodies were at 1.7 (normalo1.00 IU). The investigators in this articles attributed Raynaud's phenomena to connective tissues disease rather than acute vasospasm even tough patient A improved after withdrawal of dextroamphetamine [16]. Aboud et al. presented a patient on Adderall who suffered blue toe syndrome; her symptoms resolved 4 weeks after discontinuation of the medication. This patient's inflammatory workup was unrevealing except for a mildly elevated ANA titer at 1:160 [2]. Leithauser et al. reported a case similar to ours in a 22-year-old patient who was abusing amphetamine and presented with lower extremity claudication and even ulceration, an angiogram was
Fig. 2. Lateral view showing the same findings.
performed and showed hemodynamically significant stenosis only in the lower leg region in the proximal posterior tibial and peroneal arteries on the left and right sides. The authors of this article attributed these toxic effects of methamphetamine mostly to inflammation in addition to vasospasm. They concluded that the inflammation mostly involved the vasa vasorum of the small and medium sized vessel of the lower extremities. In this case the patient's inflammatory workup including ESR, CRP, rheumatoid factor and ANA was unrevealing. AMPHs use has been associated with cerebral infarction, myocardial infarction, cardiomyopathy and cardiac arrhythmias [7,9–11].Two theories have been proposed to explain the association of amphetamine with acute myocardial infarction. Acute ingestion has been hypothesized to cause vasospasm with resultant ischemia. With chronic use, amphetamines can increase
Letter to the editor / Reviews in Vascular Medicine 3 (2015) 1–4
vasculopathy
thrombogenicity and cause accelerated atherosclerosis in addition to vasospasm [7,12]. Also, in the post-marketing period of Adderall XR, peripheral vasculopathy resulting in Raynaud's phenomena has been reported. In these reported cases, Raynaud's phenomenon resolved shortly after discontinuation of the drug. Conclusion In the case we presented, our patient was young, free of any cardiovascular risk factors and her inflammatory workup was unrevealing. She had been on Adderall XR for the past 3 years. Her acute presentation was mostly consistent with arterial vasospasm. This review demonstrates patients suffered Raynaud's phenomena, lower extremity vasospasm and blue toe syndrome. Most of these Patients' inflammatory workup was unrevealing or mildly positive towards inflammation. We postulate in our review that most of these finding are caused primarily by vasospasm in addition to a mild degree of inflammation. The articles that talked about Adderall and peripheral vasculopathy are summarized in table below. Author and Journal
Year
Title
Type
Findings
William Goldman et al. and Arthritis & Rheumatism
2008
Association between treatment with central nervous system stimulants and Raynaud's syndrome in children
A casecontrol design
Ahmad Al Aboud et al. and Journal of American Academy of Dermatology
2011
Case report
Reema H. Syed et al. and Journal of Clinical Rheumatology
2008
Blue toes after stimulant therapy for pediatric attention deficit hyperactivity disorder Methylphenidate and dextroamphetamineinduced peripheral
There was a significant association between between development of Raynaude's and therapy with CNS stimulants used for the treatment of ADHD (methylphenidate and dextroamphetamine) 9-year-old girl on Adderall XR presented with blue toe syndrome that resolved upon cessation of the medication.
3
Current case
2015
Lower extremity vasospasm caused by Adderall XR
Case report
dextroamphetamine and one of them improved after the withdrawal of the medication. We are describing a patient with isolated lower extremities vasospasm that was attributed to Adderall XR. Her inflammatory biomarkers were negative.
Conflict of interest
Case report
4 case reports —two of them about patient who experienced vasculopathy while on treatment doses of
None declared.
References [1] Sylves Angela L, et al. Acute myocardial infarction in a teenager due to adderall XR. Pediatr. Cardiol. 2012;33:155–157. [2] Ahmad Al Aboud, et al. Blue toes after stimulant therapy for pediatric attention deficit hyperactivity disorder. J. Am. Acad. Dermatol. 2011;64 (6):1218–1219. [3] Shaw Monica, et al. A systematic review and analysis of long-term outcomes in attention deficit hyperactivity disorder: effects of treatment and non. BMC Med. 2012;10:99. [4] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (Text Revision). 4th edition. Arlington, VA: American Psychiatric Association; 2000. [5] World Health Organization. International Classification of Diseases. 10th edition. Geneva, Switzerland: WHO; 1992. [6] Kavita Gajria, et al. Adherence, persistence, and medication discontinuation in patients with attention-deficit/hyperactivity disorder – a systematic literature review. Neuropsychiatr. Disease Treat. 2014;10 (Pages 1543 and 1544). [7] Jiao Xiangyang, et al. Myocardial infarction associated with Adderall XR and alcohol use in a young man. J. Am. Board Fam. Med. 2009;22:197–201. [8] Follenfant MJ, Robson RD. The antagonism of adrenergic neurone blockade by amphetamine and dexamphetamine in the rat and guinea-pig. Br. J. Pharmacol. 1970;38:792–801. [9] Bartel AG. Acute cardiomyopathy secondary to intravenous amphetamine abuse. Ann. Intern. Med. 1982;97:559–560. [10] Lucas PB, Gardner DL, Wolkowitz OM, Tucker EE, Cowdry RW. Methylphenidateinduced cardiac arrhythmias [letter]. N. Engl. J. Med. 1986;315:1485. [11] Ohta Keiko, et al. Delayed ischemic stroke associated with methamphetamine use. J. Emerg. Med. 2005;28(2):165–167. [12] Chen JP. Methamphetamine-associated acute myocardial infarction and cardiogenic shock with normal coronary arteries: refractory global coronary microvascular spasm. J. Invasive Cardiol. 2007;19:E89–E92. [13] Pollak Amy W, et al. Multimodality imaging of lower extremity peripheral arterial disease: current role and future directions. Circ. Cardiovasc. Imaging 2012. [14] Weinberg Ido, Jaff Michael R. Nonatherosclerotic arterial disorders of the lower extremities. Circulation 2012;126:213–222. [15] Yu Zheya Jenny, et al. Peripheral vasculopathy associated with psychostimulant treatment in children with attention-deficit/hyperactivity disorder. Curr. Psychiatry Rep. 2010;12:111–115. [16] Syed Reema H, et al. Methylphenidate and dextroamphetamine-induced peripheral vasculopathy. J. Clin. Rheumatol. 2008;14:30–33. [17] Goldman William, et al. Association between treatment with central nervous system stimulants and Raynaud's syndrome in children. Arthritis Rheumatism 2008;58(2):563–566.
4
Letter to the editor / Reviews in Vascular Medicine 3 (2015) 1–4
Abdulwahab Hritani, Vinay Minocha Internal Medicine Department, University of Florida, Jacksonville, FL, USA
Ambar Patel, Patrick Antoun n Cardiology Department, University of Florida, Jacksonville, FL, USA E-mail address: [email protected]fl.edu (P. Antoun) Received 8 December 2014; accepted 6 March 2015
n Corresponding author at: Coronary care unit, Director, University of Florida, Jacksonville, 655 west 8th street, Jacksonville, FL, 32209.