Parkinsonism and Related Disorders 21 (2015) 823e824
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Letter to the Editor
Speech myoclonus due to probable pregabalin adverse drug-reaction
Keywords: Pregabalin Speech Myoclonus Peritoneal dialysis
Myoclonus, an involuntary muscle jerk is a brief, sudden, muscle contraction (positive myoclonus) or interruption of a muscle activity (negative myoclonus) [1]. Acute-onset myoclonus should prompt a search for medication adjustments or an adverse drug-event. Benzodiazepines, antidepressants, lithium, opioids, calcium channel blockers and anticonvulsants can all trigger myoclonus [1]. Pregabalin is an antiepileptic (AED) used in neuropathic pain, a derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which does not bind to GABA or benzodiazepine receptors. Pregabalin binds to a subunit of voltage-gated calcium channels (alpha2-delta site) [2] and probably modulates neurotransmitters release. Pregabalin-induced myoclonus is rare, in 1/ 100e1/1000 [3]. Pregabalin may accumulate in chronic kidney disease (CKD) as it is almost exclusively excreted by the kidneys [2]. A minimal amount of pregabalin is metabolised by liver, with little effect on the cytochrome P450 system and so drug interactions are less likely [2]. While patients on hemodialysis may need increased doses, there are no data regarding peritoneal dialysis [4]. A Pregabalin induced adverse drug-event has been reported in three patients on hemodialysis [6] and in one on peritoneal dialysis [5]. We report a probable adverse drug-reaction due to pregabalin in a patient on peritoneal dialysis manifesting as a prominent myoclonus affecting speech. A 66- year-old man with CKD on home peritoneal dialysis for 10 months was admitted with a five days history of gait ataxia and light-headedness. He had proliferative glomerulonephritis, hypertension, and gout. Urea was 31 mmol/L and creatinine 509 umol/L (creatinine clearance was unchanged at 13.4 ml/min). Full blood count, glucose, liver function tests, thyroid function tests, vitamin B12, folate, c-reactive protein and aluminium were normal. Magnetic resonance imaging (MRI) showed microvascular ischaemia in the brain and minor spondylotic changes in the cervical spine. Medications included pregabalin, allopurinol, aspirin, furosemide, doxazosin, alfacalcidiol, sevelamer carbonate, atorvastatin, esomeprazole, calcium acetate and amlodipine. Pregabalin 50 mg once a day had been prescribed for paraesthesiae six months previously and had been increased to 75 mg once a http://dx.doi.org/10.1016/j.parkreldis.2015.04.026 1353-8020/© 2015 Elsevier Ltd. All rights reserved.
day three months pre-admission. The last dose of pregabalin was 48-h prior to admission. He had no history of confusion, loss of consciousness or hallucinations. He was seen by a neurologist and examination revealed multifocal myoclonus affecting jaw, tongue and limbs with a dramatic effect on speech [video]. Positive, action myoclonus occurred when speaking or during any movement of the lower facial muscles involved in jaw opening and tongue movements. Negative myoclonus was present with posture-holding of arms and legs when outstretched but not at rest [video]. There was no palatal myoclonus. Myoclonus whilst swallowing was not assessed. Myoclonus was spontaneous and not stimulus-sensitive (startle, noise, touch). the gait was wide-based. Supplementary video related to this article can be found at http://dx.doi.org/10.1016/j.parkreldis.2015.04.026. The patient was diagnosed with a treatment-emergent probable adverse drug-reaction due to pregabalin as per Naranjo algorithm [7] and World Health Organisation case causality assessment [8]. This was a serious adverse-event requiring initial hospitalization and intervention (pregabalin was stopped and patient received peritoneal dialysis). Clinical examination of the patient when he was standing was not possible. The patient refers to the period of his hospitalisation as the time when “he was very sick”, was unable to walk and needed assistance with his activities of daily living (ADLS). Symptoms improved after 7 cycles of peritoneal dialysis with a full recovery by day 30. We hypothesized that the myoclonus was of cortical origin because it was positive, negative and action-induced. However it was not stimulus-sensitive, as is frequently found in cortical myoclonus [1]. Electroencephalography studies (EEG) or other neurophysiology tests were not performed. Higher doses of pregabalin have been associated with adverse drug-reactions affecting the nervous system and producing myoclonus (from 75 mg twice daily to 600 mg daily) [5,6], with two exceptions (50 mg once a day as an add-on anticonvulsant and 75 mg once a day in CKD IV) [6]. Our patient was also on a small dose of pregabalin (75 mg/day). The onset of myoclonus is usually between 8 h and 45 days following commencement of pregabalin. The long period between the introduction/change in dosage of pregabalin (6months/ 3months) and slow recovery (30 days) following cessation of pregabalin seen in our patient have not previously been described [5,6] and could lead to a delayed recognition of the adverse drugreaction. The patient's slow recovery after pregabalin was withdrawn might suggest an alternative cause, however only pregabalin was stopped as all other medications remained unchanged.
824
Letter to the Editor / Parkinsonism and Related Disorders 21 (2015) 823e824
Although myoclonus is a recognised adverse-event following administration of pregabalin, our patient's experience emphasizes that myoclonus can dramatically affect speech and lead to a delayed or incorrect diagnosis [video]. We are not aware of any reports of speech myoclonus due to an adverse reaction to pregabalin. There is a report of a patient with ataxia, dysarthria, and myoclonus with renal impairment on pregabalin [5]. Healy et al. [5] described the only case of myoclonus in a patient on peritoneal dialysis, but without speech involvement. We conclude that pregabalin can cause an adverse drugreaction in a form of myoclonus that disrupts speech. Caution is needed when adjusting medications in any patient with kidney failure on dialysis. This is particularly true of newer medications where experience of the adverse-events may be limited. Data on pregabalin clearance in peritoneal dialysis are not available and we are unable to state whether or not this contributed to the adverse drug-reaction in our patient. Consent: Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. Competing interests
SS: final correction of the manuscript, recorded first video of the patient. Disclosures No disclosures to report.
References [1] M. Kojovic, C. Cordivari, K. Bhatia, Myoclonic disorders: a practical approach for diagnosis and treatment, Ther. Adv. Neurol. Disord. 4 (2011) 47e62. [2] C. Toth, Pregabalin: latest safety evidence and clinical implications for the management of neuropathic pain, Ther. Adv. Drug Saf. 5 (2014) 38e56. [3] US Food and Drug Administration, www.accessdata.fda.gov/drugsatfda_docs/ label/2009/021446s013s014lbl.pdf. [4] G.H. Bailie, N.A. Mason, Dialysis of drugs, 2013. http:// renalpharmacyconsultants.com/assets/2013dodbooklet.pdf. [5] D. Healy, G. Ingle, P. Brown, Pregabalin- and gabapentin-associated myoclonus in a patient with chronic renal failure, Mov. Disord. 24 (2009) 2028. [6] D.W. Lee, H.J. Lee, H.J. Kim, S.H. Chang, D.J. Park, Two cases of pregabalin neurotoxicity in chronic kidney disease patients, NDT Plus 4 (2011) 138. [7] Essential Medicines and Health Products Information Portal, A World Health Organization resource http://apps.who.int/medicinedocs/en/d/Js4882e/7.7. html. [8] The use of the WHO-UMC system for standardised case causality assessment, http://who-umc.org/Graphics/24734.pdf.
Nothing to declare. Author's contribution DO: prepared first draft of manuscript, correction, recorded and edited second video. AC: correction of the first draft, recorded and edited second video. JW: consulted a patient for the first time, correction of manuscript. TL: critique and final correction of the manuscript.
Diana A. Olszewska, Albi J. Chalissery, Jennifer Williams, Tim Lynch, Shane Smyth* Department of Neurology at the Dublin Neurological Institute, Mater Misericordiae University Hospital, Dublin, Ireland *
Corresponding author. Dublin Neurological Institute, 57 Eccles Street, Dublin 7, Ireland. E-mail address: [email protected] (S. Smyth). 5 January 2015
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Letter to the Editor
Speech myoclonus due to probable pregabalin adverse drug-reaction
Keywords: Pregabalin Speech Myoclonus Peritoneal dialysis
Myoclonus, an involuntary muscle jerk is a brief, sudden, muscle contraction (positive myoclonus) or interruption of a muscle activity (negative myoclonus) [1]. Acute-onset myoclonus should prompt a search for medication adjustments or an adverse drug-event. Benzodiazepines, antidepressants, lithium, opioids, calcium channel blockers and anticonvulsants can all trigger myoclonus [1]. Pregabalin is an antiepileptic (AED) used in neuropathic pain, a derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which does not bind to GABA or benzodiazepine receptors. Pregabalin binds to a subunit of voltage-gated calcium channels (alpha2-delta site) [2] and probably modulates neurotransmitters release. Pregabalin-induced myoclonus is rare, in 1/ 100e1/1000 [3]. Pregabalin may accumulate in chronic kidney disease (CKD) as it is almost exclusively excreted by the kidneys [2]. A minimal amount of pregabalin is metabolised by liver, with little effect on the cytochrome P450 system and so drug interactions are less likely [2]. While patients on hemodialysis may need increased doses, there are no data regarding peritoneal dialysis [4]. A Pregabalin induced adverse drug-event has been reported in three patients on hemodialysis [6] and in one on peritoneal dialysis [5]. We report a probable adverse drug-reaction due to pregabalin in a patient on peritoneal dialysis manifesting as a prominent myoclonus affecting speech. A 66- year-old man with CKD on home peritoneal dialysis for 10 months was admitted with a five days history of gait ataxia and light-headedness. He had proliferative glomerulonephritis, hypertension, and gout. Urea was 31 mmol/L and creatinine 509 umol/L (creatinine clearance was unchanged at 13.4 ml/min). Full blood count, glucose, liver function tests, thyroid function tests, vitamin B12, folate, c-reactive protein and aluminium were normal. Magnetic resonance imaging (MRI) showed microvascular ischaemia in the brain and minor spondylotic changes in the cervical spine. Medications included pregabalin, allopurinol, aspirin, furosemide, doxazosin, alfacalcidiol, sevelamer carbonate, atorvastatin, esomeprazole, calcium acetate and amlodipine. Pregabalin 50 mg once a day had been prescribed for paraesthesiae six months previously and had been increased to 75 mg once a http://dx.doi.org/10.1016/j.parkreldis.2015.04.026 1353-8020/© 2015 Elsevier Ltd. All rights reserved.
day three months pre-admission. The last dose of pregabalin was 48-h prior to admission. He had no history of confusion, loss of consciousness or hallucinations. He was seen by a neurologist and examination revealed multifocal myoclonus affecting jaw, tongue and limbs with a dramatic effect on speech [video]. Positive, action myoclonus occurred when speaking or during any movement of the lower facial muscles involved in jaw opening and tongue movements. Negative myoclonus was present with posture-holding of arms and legs when outstretched but not at rest [video]. There was no palatal myoclonus. Myoclonus whilst swallowing was not assessed. Myoclonus was spontaneous and not stimulus-sensitive (startle, noise, touch). the gait was wide-based. Supplementary video related to this article can be found at http://dx.doi.org/10.1016/j.parkreldis.2015.04.026. The patient was diagnosed with a treatment-emergent probable adverse drug-reaction due to pregabalin as per Naranjo algorithm [7] and World Health Organisation case causality assessment [8]. This was a serious adverse-event requiring initial hospitalization and intervention (pregabalin was stopped and patient received peritoneal dialysis). Clinical examination of the patient when he was standing was not possible. The patient refers to the period of his hospitalisation as the time when “he was very sick”, was unable to walk and needed assistance with his activities of daily living (ADLS). Symptoms improved after 7 cycles of peritoneal dialysis with a full recovery by day 30. We hypothesized that the myoclonus was of cortical origin because it was positive, negative and action-induced. However it was not stimulus-sensitive, as is frequently found in cortical myoclonus [1]. Electroencephalography studies (EEG) or other neurophysiology tests were not performed. Higher doses of pregabalin have been associated with adverse drug-reactions affecting the nervous system and producing myoclonus (from 75 mg twice daily to 600 mg daily) [5,6], with two exceptions (50 mg once a day as an add-on anticonvulsant and 75 mg once a day in CKD IV) [6]. Our patient was also on a small dose of pregabalin (75 mg/day). The onset of myoclonus is usually between 8 h and 45 days following commencement of pregabalin. The long period between the introduction/change in dosage of pregabalin (6months/ 3months) and slow recovery (30 days) following cessation of pregabalin seen in our patient have not previously been described [5,6] and could lead to a delayed recognition of the adverse drugreaction. The patient's slow recovery after pregabalin was withdrawn might suggest an alternative cause, however only pregabalin was stopped as all other medications remained unchanged.
824
Letter to the Editor / Parkinsonism and Related Disorders 21 (2015) 823e824
Although myoclonus is a recognised adverse-event following administration of pregabalin, our patient's experience emphasizes that myoclonus can dramatically affect speech and lead to a delayed or incorrect diagnosis [video]. We are not aware of any reports of speech myoclonus due to an adverse reaction to pregabalin. There is a report of a patient with ataxia, dysarthria, and myoclonus with renal impairment on pregabalin [5]. Healy et al. [5] described the only case of myoclonus in a patient on peritoneal dialysis, but without speech involvement. We conclude that pregabalin can cause an adverse drugreaction in a form of myoclonus that disrupts speech. Caution is needed when adjusting medications in any patient with kidney failure on dialysis. This is particularly true of newer medications where experience of the adverse-events may be limited. Data on pregabalin clearance in peritoneal dialysis are not available and we are unable to state whether or not this contributed to the adverse drug-reaction in our patient. Consent: Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. Competing interests
SS: final correction of the manuscript, recorded first video of the patient. Disclosures No disclosures to report.
References [1] M. Kojovic, C. Cordivari, K. Bhatia, Myoclonic disorders: a practical approach for diagnosis and treatment, Ther. Adv. Neurol. Disord. 4 (2011) 47e62. [2] C. Toth, Pregabalin: latest safety evidence and clinical implications for the management of neuropathic pain, Ther. Adv. Drug Saf. 5 (2014) 38e56. [3] US Food and Drug Administration, www.accessdata.fda.gov/drugsatfda_docs/ label/2009/021446s013s014lbl.pdf. [4] G.H. Bailie, N.A. Mason, Dialysis of drugs, 2013. http:// renalpharmacyconsultants.com/assets/2013dodbooklet.pdf. [5] D. Healy, G. Ingle, P. Brown, Pregabalin- and gabapentin-associated myoclonus in a patient with chronic renal failure, Mov. Disord. 24 (2009) 2028. [6] D.W. Lee, H.J. Lee, H.J. Kim, S.H. Chang, D.J. Park, Two cases of pregabalin neurotoxicity in chronic kidney disease patients, NDT Plus 4 (2011) 138. [7] Essential Medicines and Health Products Information Portal, A World Health Organization resource http://apps.who.int/medicinedocs/en/d/Js4882e/7.7. html. [8] The use of the WHO-UMC system for standardised case causality assessment, http://who-umc.org/Graphics/24734.pdf.
Nothing to declare. Author's contribution DO: prepared first draft of manuscript, correction, recorded and edited second video. AC: correction of the first draft, recorded and edited second video. JW: consulted a patient for the first time, correction of manuscript. TL: critique and final correction of the manuscript.
Diana A. Olszewska, Albi J. Chalissery, Jennifer Williams, Tim Lynch, Shane Smyth* Department of Neurology at the Dublin Neurological Institute, Mater Misericordiae University Hospital, Dublin, Ireland *
Corresponding author. Dublin Neurological Institute, 57 Eccles Street, Dublin 7, Ireland. E-mail address: [email protected] (S. Smyth). 5 January 2015
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