- Email: [email protected]
Negative myoclonus induced by gabapentin and pregabalin: A case series and systematic literature review
Journal of the Neurological Sciences 382 (2017) 36–39
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Negative myoclonus induced by gabapentin and pregabalin: A case series and systematic literature review
MARK
Jung Bin Kima, Jin-Man Jungb, Moon-Ho Parkb, Eun Ju Leec, Do-Young Kwonb,⁎ a b c
Department of Neurology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea Department of Neurology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, South Korea Medical Library, Korea University, Seoul, South Korea
A R T I C L E I N F O
A B S T R A C T
Keywords: Negative myoclonus Pregabalin Gabapentin Renal function T-type calcium channel
Introduction: Negative myoclonus is a jerky, brief, and sudden interruption of voluntary muscle contraction. Although gabapentin and pregabalin have been reported to induce positive myoclonus in some patients with impaired renal function, there are only a few studies describing pregabalin- or gabapentin-induced negative myoclonus. This study reviewed patients who had developed pregabalin- or gabapentin-induced negative myoclonus. Methods: We collected the patients with negative myoclonus who were referred to the department of neurology at a university-affiliated hospital and selected pregabalin- or gabapentin-induced negative myoclonus. Then reviewed the literature with respect to pregabalin- or gabapentin-induced negative myoclonus. Results: A total of 77 patients with negative myoclonus were reviewed. Among them, 21 neuropathic pain patients who were prescribed and developed negative myoclonus induced by pregabalin (9 cases) or gabapentin (12 cases). To prove causality of the drug, probable and certain level of category according to the WHO-UMC criteria were recruited. Of the 21 patients, 3 had impaired renal function, while 18 had normal renal function. Review of the literature identified 7 further cases (6 had normal renal function) with pregabalin- or gabapentininduced negative myoclonus. Conclusion: Pregabalin- and gabapentin-induced negative myoclonus can develop even in patients with normal renal function. Physicians should keep in mind the possibility of patients developing negative myoclonus under treatment of pregabalin or gabapentin even in short period of time and with low dosage, and in the normal range of renal function. Further prospective study investigating incidence and risk factors is warranted.
1. Introduction Negative myoclonus (NM) refers to a jerky, shock-like involuntary movement, due to a sudden interruption of voluntary muscle contraction. The concept was first introduced by Shahani and Young in an effort to characterize post-hypoxic intention myoclonus and asterixis [1]. At present, the term NM encompasses all involuntary movements of brief and spasmodic interruption of tonic muscle activities that can lead to a sudden postural lapse [2]. It has been suggested that NM may develop from the dysfunction of neural circuits responsible for the maintenance of sustained muscle contractions, such as lesions in the ventrolateral thalamus, or by a generalized neurochemical imbalance in metabolic encephalopathies [3]. Various drugs and toxic metabolic encephalopathies are known to cause acute-onset positive myoclonus. Among the drugs linked to the development of myoclonus, there have been several reports that
⁎
demonstrated pregabalin- or gabapentin-induced positive myoclonus [4–10]. Indeed, an observational study showed that myoclonus had developed in 13 of 104 (12.5%) patients, with the occurrence of epilepsy among those taking gabapentin [10]. Moreover, it has been found that the possibility of developing pregabalin- or gabapentin-induced myoclonus in patients with impaired renal function is relatively high compared to patients with normal renal function [4,6,8,9]. Given that positive and negative myoclonus share common precipitating factors, it is plausible that pregabalin and gabapentin may be implicated in the development of NM. However, to the best of our current knowledge, there is a paucity of reports describing NM induced by pregabalin or gabapentin [11–14]. In addition, NM patients easily considered as having a tremor or weakness in clinic, which lead to underdiagnosis of those conditions and the incidence could be underestimated. We therefore aimed to identify the clinical characteristics of patients with pregabalin- or
Corresponding author at: Department of Neurology, Korea University Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan 15355, South Korea. E-mail address: [email protected] (D.-Y. Kwon).
http://dx.doi.org/10.1016/j.jns.2017.09.019 Received 27 June 2017; Received in revised form 11 September 2017; Accepted 14 September 2017 Available online 18 September 2017 0022-510X/ © 2017 Published by Elsevier B.V.
Journal of the Neurological Sciences 382 (2017) 36–39
J.B. Kim et al.
gabapentin-induced NM. To this end, we reviewed medical records of NM patients using registry data from the department of neurology at a university-affiliated medical center. We then reviewed the literature with respect to pregabalin- or gabapentin-induced negative myoclonus.
Table 1 Classification of patients with negative myoclonus. Classification
Symptomatic Infectious or post-infectious Herpes simplex encephalitis Metabolic Hepatic failure Renal failurea Hypocalcemia Toxic and drug-induced Pregabalina Gabapentina Alcohol Other drugs (NSAIDs, antibiotics, codeine, tramadol etc.) Focal nervous system lesion Post-stroke Psychogenic Epileptic Undetermined
2. Materials and methods This study is a retrospective review of prospectively-collected registry data. Using the hospital registry database, we reviewed the medical records of all patients who were referred to the department of neurology at university-affiliated hospital for NM (defined as a shocklike, involuntary jerky movement, due to a sudden and brief interruption of muscle activity) [2]. The NM registry data were collected for 4 years. Diagnosis of the NM was based on clinical features, such as sudden falls or dropping of objects due to interruption of muscle activity. Patients with NM were finally included in the registry after a confirmation through neurologic examination by a movement disorder specialist. According to the etiology of NM, all patients with NM were classified into physiologic, essential, epileptic, symptomatic, and psychogenic myoclonus [15,16]. Based on medical records, we further investigated the demographic and clinical data of patients with pregabalin- or gabapentin-induced NM. Cases of probable and certain level of World Health Organization-Uppsala Monitoring Centre (WHO-UMC) causality categories were enrolled, considering temporal relationship to drug intake and response to withdrawal. Response to rechallenge was proved, in some cases [17]. That is, all of the pregabalin- or gabapentininduced NM was defined as the occurrence of NM after administration and the recovery of symptoms after withdrawal of the drugs. All patients with pregabalin- or gabapentin-induced NM had no evidence of acute lesions on brain MRI and epileptogenic conditions on electroencephalography. We collected data such as age at NM onset, duration of NM symptoms, comorbidities, and findings of serologic laboratory tests (i.e. blood urea nitrogen [BUN], creatinine, aspartate transaminase [AST], and alanine transaminase [ALT]). A literature search of PubMed was performed on March 29, 2017 using the search terms “Myoclonus OR Asterixis OR Flapping tremor AND Pregabalin OR Gabapentin OR Voltage dependent calcium channel”. The search was limited to articles in English. PubMed yielded 47 articles. A manual review of all 47 abstracts was then performed to exclude duplicate and irrelevant articles. In total, 6 articles were deemed relevant and accessible for our systematic review of pregabalin- or gabapentin-induced NM.
Number of cases (n = 77)
1 1 14 1 9 12 7 18
2 2 1 12
NSAIDs non-steroidal anti-inflammatory drugs. a Two patients with gabapentin-induced and one patient with pregabalin-induced negative myoclonus also had renal failure.
neuropathic pain in 6 cases and for controlling simple partial seizures in 1 case. Of the 7 cases, 2 had impaired renal function, while 5 had normal renal function.
4. Discussion Our review demonstrated that pregabalin- or gabapentin-induced NM was the leading cause of NM in our study population. Almost all patients (18 of 21 cases, 85.7%) with NM induced by pregabalin or gabapentin were found to have normal renal function on serologic test. Moreover, the dose of the pregabalin or gabapentin was not considerably high, and the time lapse until development of NM after administration of those drugs was not very long. On the literature review, we found that only 7 patients with pregabalin- or gabapentin-induced NM were reported. Most of the previously reported pregabalin- or gabapentin-induced NM patients (5 out of 7) had normal renal function. In addition, NM was developed within 4 days after administration of pregabalin or gabapentin. These findings were very similar to those of our study population. NM can be observed in a variety of clinical situations, such as encephalopathies associated with toxic and metabolic dysfunctions, as well as epileptogenic conditions. It has been relatively well-known that positive myoclonus could be induced by pregabalin or gabapentin, whereas there have been only a few reports describing pregabalin- or gabapentin-induced NM [11–14,18,19]. Therefore, the pathophysiological mechanisms that underlie the development of NM induced by pregabalin or gabapentin remain unknown. In addition, unlike positive myoclonus, NM may easily misdiagnose as having a tremor or weakness in clinic which lead to underestimation of their incidence. With regard to positive myoclonus, the involvement of the serotonin neurotransmitter system has been suggested as the mechanism responsible for the development of myoclonus [10]. In addition, most cases of pregabalin- or gabapentin-induced myoclonus were observed in patients with impaired renal function; therefore, drug intoxication due to impaired renal excretion was proposed as a possible underlying mechanism in the development of myoclonus [4,6]. However, a different study suggested that pregabalin-induced myoclonus seemed to depend on a threshold effect rather than a linear dose dependency [20], suggesting an effect of the pregabalin per se in the development of myoclonus. Our findings also suggest that effects of pregabalin or gabapentin per se may play an important role in development of NM for the following reasons: 1)
3. Results A total of 77 patients with NM (mean age = 65.8; 7 females) were initially included in this study. The etiological classification of included NM patients is summarized in Table 1. The most common etiology of NM was found as symptomatic (62 cases; 80.5%), followed by undetermined (12 cases; 15.6%), psychogenic (2 cases; 2.6%), and epileptic (1 case; 1.3%). Among the 62 symptomatic NM patients, the NM of 21 patients was found to be induced by pregabalin (9 cases) or gabapentin (12 cases). All of the 21 patients were prescribed pregabalin or gabapentin for the controlling of neuropathic pain. Of the 21 patients, 3 showed impairment of renal function (mean BUN = 58.1 mg/dl; mean creatinine = 7.0 mg/dl), while 18 had normal renal function (mean BUN = 16.3 mg/dl; mean creatinine = 1.0 mg/dl). Mean administration dosage of pregabalin and gabapentin was 217 mg/day and 400 mg/day, respectively. The mean time lapse until development of NM after administration of pregabalin or gabapentin was 3.5 days. Clinical data for patients with NM induced by pregabalin or gabapentin is described in Table 2. Our literature search on pregabalin- or gabapentin-induced NM identified 5 reports of single cases and 1 report of 2 cases. Table 3 summarizes the reported cases of pregabalin- and gabapentin-induced NM. Pregabalin or gabapentin was administrated for controlling 37
Journal of the Neurological Sciences 382 (2017) 36–39
J.B. Kim et al.
Table 2 Clinical data of cases with pregabalin- or gabapentin-induced negative myoclonus. No
Age (years)
Sex
Comorbidity
BUN (mg/dl)
Cr (mg/dl)
AST (mg/dl)
ALT (mg/dl)
Offending drug
Dosage (mg/day)
Time lapse (days)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
57 64 76 63 50 63 51 65 59 78 91 70 66 23 59 80 72 70 73 67 84
M F F M M M F M M M F M F F F M M M M M M
– – – DM, HTN DM, HTN – DM, HTN, CKD – HTN DM, HTN, CKD DM HTN – – DM DM, HTN DM – HTN, prostatic hyperplasia DM, HTN, CKD DM, HTN, Parkinson's disease
23 17.7 25 17.8 15.4 16.1 54 14.5 10.8 72.5 17.3 19.4 16.5 8 12 13 9.4 18.3 17.1 47.8 21.9
1.11 0.87 1.44 1.29 1.14 0.93 10.2 0.78 1.49 2.82 1.01 1.1 0.81 0.5 0.9 0.8 1.13 0.66 1.16 8.11 0.85
21 19 26 21 19 22 16 26 22 16 17 29 32 22 23 13 16 27 22 14 31
36 27 17 32 12 20 16 32 18 4 10 46 22 15 19 16 12 36 53 11 25
GBP PGB GBP GBP PGB GBP GBP GBP GBP GBP PGB PGB GBP GBP PGB GBP PGB GBP PGB PGB PGB
600 150 300 300 150 300 300 300 600 600 150 300 300 600 300 300 150 300 300 150 300
7 1 2 2 1 5 1 1 5 4 3 3 2 7 1 3 3 1 1 7 13
M male, F female, DM diabetes mellitus, HTN hypertension, CKD chronic kidney disease, BUN blood urea nitrogen, AST aspartate transaminase, ALT alanine transaminase, GBP gabapentin, PGB pregabalin. The time lapse represents the time elapsed from first use of the offending drug to the development of the negative myoclonus.
Our study has some limitations that should be addressed. First, because this was a retrospectively review, causal relationships between drugs and NM would be inherently limited, though the cases collected prospectively and temporal relationship between drug use and occurrence/recovery of NM symptom was clear. We adopt only probable and certain category of the standardized case causality assessment to ensure. Second, this study only reviewed medical records of patients who were referred to the department of neurology; therefore, the selection bias should be considered. Third, we only checked serological study to assess renal function and did not measure 24-hour urine collection study, which did not completely exclude the possibilities of underlying renal impairment and/or combined etiologies. Despite these limitations, and to the best of our knowledge, this study is the first case series and systematic review of pregabalin- or gabapentin-induced NM. Finally, NM was diagnosed based on clinical features and electrophysiologic studies for differential diagnosis have been performed in a small number of NM patients; therefore, the possibilities of coexistence of NM and positive myoclonus and intrapersonal bias to diagnose NM during the registration period cannot be excluded. Interpreting our results as the findings confined to NM may be limited. Further prospective studies incorporating a longitudinal design
pregabalin- or gabapentin-induced NM were observed in those with normal renal function; 2) the doses of these medications were not significantly high; and 3) the temporal relationship between the use of drugs and the development of NM was clear. The similar trends observed in previously reported cases through literature review may further support our speculation. Pregabalin and gabapentin bind to the alpha 2 delta (α2δ) ligands of low voltage-dependent T-type calcium channels. The T-type calcium channel has a relatively low threshold; therefore, the channel requires lesser membrane depolarization to open. In addition, the channel is tonically inactivated quickly after opening. The highly sensitive properties of the voltage in T-type calcium channels enable them to regulate cellular excitability and oscillatory behavior near the resting membrane potential [21]. Because these channels are highly distributed in the thalamocortical circuit, T-type calcium channels have been implicated in the synchronization of a circuit which is important in the generation of generalized spike-wave-discharges [21,22]. Given the aforementioned properties of T-type calcium channels, we speculate that pregabalin and gabapentin might disturb the physiological action of the channels, resulting in the development of NM as well as positive myoclonus.
Table 3 Summary of reviewed case reports of pregabalin- or gabapentin-induced negative myoclonus. References
Age (years)
Sex
Comorbidity
BUN (mg/ dl)
Cr (mg/dl)
AST (mg/ dl)
ALT (mg/ dl)
Offending drug
Dosage (mg/ day)
Time lapse (days)
Jacob et al. [11] Sechi et al. [12]
60 76
F F
Normal Normal
Normal Normal
Normal Normal
Normal Normal
GBP GBP
900 900
Sechi et al. [12] Babiy et al. [13] Heckmann et al. [18] Hellwig et al. [14]
77 74 89
F F F
– HTN, post-stroke epilepsy DM HTN, breast cancer HTN
Normal Normal Normal
Normal Normal Normal
Normal NA Normal
Normal NA Normal
GBP GBP PGB
3600 600 300
4 3 (confirmed by rechallenge) 3 months NA NA
71
M
114
3.4
NA
NA
PGB
100
8 h (initial single dose)
Wahba et al. [19]
68
M
CKD, sick sinus syndrome HTN, CKD, lung cancer
26
2.3
Normal
Normal
GBP
300
2
M male, F female, DM diabetes mellitus, HTN hypertension, CKD chronic kidney disease, BUN blood urea nitrogen, AST aspartate transaminase, ALT alanine transaminase, GBP gabapentin, PGB pregabalin, NA not available. Time lapse represents the time elapsed from the use of offending drug to the occurrence of the negative myoclonus.
38
Journal of the Neurological Sciences 382 (2017) 36–39
J.B. Kim et al.
end-stage renal disease, Epilepsia 46 (1) (2005) 156–158. [5] F. Ege, Y. Kocak, A.P. Titiz, S.M. Ozturk, S. Ozturk, S. Ozbakir, Gabapentin-induced myoclonus: case report, Mov. Disord. 23 (13) (2008) 1947–1948. [6] M. Holtkamp, A. Halle, H. Meierkord, F. Masuhr, Gabapentin-induced severe myoclonus in a patient with impaired renal function, J. Neurol. 253 (3) (2006) 382–383. [7] K.T. Cho, S.K. Hong, Myoclonus induced by the use of gabapentin, J. Korean Neurosurg. Soc. 43 (5) (2008) 237–238. [8] D.G. Healy, G.T. Ingle, P. Brown, Pregabalin- and gabapentin-associated myoclonus in a patient with chronic renal failure, Mov. Disord. 24 (13) (2009) 2028–2029. [9] S. Knake, K.M. Klein, K. Hattemer, A. Wellek, W.H. Oertel, H.M. Hamer, F. Rosenow, Pregabalin-induced generalized myoclonic status epilepticus in patients with chronic pain, Epilepsy Behav. 11 (3) (2007) 471–473. [10] J. Asconape, A. Diedrich, J. DellaBadia, Myoclonus associated with the use of gabapentin, Epilepsia 41 (4) (2000) 479–481. [11] P.C. Jacob, R.P. Chand, S. Omeima el, Asterixis induced by gabapentin, Clin. Neuropharmacol. 23 (1) (2000) 53. [12] G. Sechi, B. Murgia, G. Sau, L. Peddone, A. Tirotto, M. Barrocu, G. Rosati, Asterixis and toxic encephalopathy induced by gabapentin, Prog. Neuro-Psychopharmacol. Biol. Psychiatry 28 (1) (2004) 195–199. [13] M. Babiy, M.D. Stubblefield, M. Herklotz, M. Hand, Asterixis related to gabapentin as a cause of falls, Am. J. Phys. Med. Rehabil. 84 (2) (2005) 136–140. [14] S. Hellwig, F. Amtage, Pregabalin-induced cortical negative myoclonus in a patient with neuropathic pain, Epilepsy Behav. 13 (2) (2008) 418–420. [15] M. Kojovic, C. Cordivari, K. Bhatia, Myoclonic disorders: a practical approach for diagnosis and treatment, Ther. Adv. Neurol. Disord. 4 (1) (2011) 47–62. [16] C.D. Marsden, M. Hallett, Stanley Fahn, The nosology and pathophysiology of myoclonus, Mov. Disord. (2013) 1. [17] I.R. Edwards, J.K. Aronson, Adverse drug reactions: definitions, diagnosis, and management, Lancet 356 (9237) (2000) 1255–1259. [18] J.G. Heckmann, K. Ulrich, M. Dutsch, B. Neundorfer, Pregabalin associated asterixis, Am. J. Phys. Med. Rehabil. 84 (9) (2005) 724. [19] M. Wahba, O. Waln, Asterixis related to gabapentin intake: a case report and review, Postgrad. Med. 125 (5) (2013) 139–141. [20] H.J. Huppertz, T.J. Feuerstein, A. Schulze-Bonhage, Myoclonus in epilepsy patients with anticonvulsive add-on therapy with pregabalin, Epilepsia 42 (6) (2001) 790–792. [21] H.S. Shin, E.J. Cheong, S. Choi, J. Lee, H.S. Na, T-type Ca2 + channels as therapeutic targets in the nervous system, Curr. Opin. Pharmacol. 8 (1) (2008) 33–41. [22] E. Cheong, H.S. Shin, T-type Ca(2)(+) channels in absence epilepsy, Biochim. Biophys. Acta 1828 (7) (2013) 1560–1571. [23] S.M. van der Salm, R.J. de Haan, D.C. Cath, A.F. van Rootselaar, M.A. Tijssen, The eye of the beholder: inter-rater agreement among experts on psychogenic jerky movement disorders, J. Neurol. Neurosurg. Psychiatry 84 (7) (2013) 742–747. [24] R. Zutt, M.E. van Egmond, J.W. Elting, P.J. van Laar, O.F. Brouwer, D.A. Sival, H.P. Kremer, T.J. de Koning, M.A. Tijssen, A novel diagnostic approach to patients with myoclonus, Nat. Rev. Neurol. 11 (12) (2015) 687–697.
could provide clues about the causal relationship between the aforementioned drugs and NM. In addition, further experimental studies are needed to elucidate the pathophysiological mechanisms that underlie pregabalin- and gabapentin-induced NM, and their association with the modulation of T-type calcium channels. In conclusion, pregabalin- or gabapentin-induced NM could be developed even in patients with normal renal function. Clinically, pregabalin- or gabapentin-induced NM could be underrecognized and misdiagnosed other movement disorders such as tremor. Given the reversibility, accurate diagnosis of pregabalin- or gabapentin-induced NM would be essential though differential diagnosis among the hyperkinetic movement disorders is difficult even for movement disorder specialists [23,24]. Physicians have to keep in mind the possibility of developing NM in patients under treatment of pregabalin or gabapentin even in the normal range of renal function and use low dose of the offending drug. Competing interests None. Funding source Nothing. Acknowledgments Nothing to declare. References [1] B.T. Shahani, R.R. Young, Physiological and pharmacological aids in the differential diagnosis of tremor, J. Neurol. Neurosurg. Psychiatry 39 (8) (1976) 772–783. [2] G. Rubboli, C.A. Tassinari, Negative myoclonus. An overview of its clinical features, pathophysiological mechanisms, and management, Neurophysiol. Clin. 36 (5–6) (2006) 337–343. [3] R.R. Young, B.T. Shahani, Asterixis: one type of negative myoclonus, Adv. Neurol. 43 (1986) 137–156. [4] C. Zhang, D.G. Glenn, W.L. Bell, C.A. O'Donovan, Gabapentin-induced myoclonus in
39
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Negative myoclonus induced by gabapentin and pregabalin: A case series and systematic literature review
MARK
Jung Bin Kima, Jin-Man Jungb, Moon-Ho Parkb, Eun Ju Leec, Do-Young Kwonb,⁎ a b c
Department of Neurology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea Department of Neurology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, South Korea Medical Library, Korea University, Seoul, South Korea
A R T I C L E I N F O
A B S T R A C T
Keywords: Negative myoclonus Pregabalin Gabapentin Renal function T-type calcium channel
Introduction: Negative myoclonus is a jerky, brief, and sudden interruption of voluntary muscle contraction. Although gabapentin and pregabalin have been reported to induce positive myoclonus in some patients with impaired renal function, there are only a few studies describing pregabalin- or gabapentin-induced negative myoclonus. This study reviewed patients who had developed pregabalin- or gabapentin-induced negative myoclonus. Methods: We collected the patients with negative myoclonus who were referred to the department of neurology at a university-affiliated hospital and selected pregabalin- or gabapentin-induced negative myoclonus. Then reviewed the literature with respect to pregabalin- or gabapentin-induced negative myoclonus. Results: A total of 77 patients with negative myoclonus were reviewed. Among them, 21 neuropathic pain patients who were prescribed and developed negative myoclonus induced by pregabalin (9 cases) or gabapentin (12 cases). To prove causality of the drug, probable and certain level of category according to the WHO-UMC criteria were recruited. Of the 21 patients, 3 had impaired renal function, while 18 had normal renal function. Review of the literature identified 7 further cases (6 had normal renal function) with pregabalin- or gabapentininduced negative myoclonus. Conclusion: Pregabalin- and gabapentin-induced negative myoclonus can develop even in patients with normal renal function. Physicians should keep in mind the possibility of patients developing negative myoclonus under treatment of pregabalin or gabapentin even in short period of time and with low dosage, and in the normal range of renal function. Further prospective study investigating incidence and risk factors is warranted.
1. Introduction Negative myoclonus (NM) refers to a jerky, shock-like involuntary movement, due to a sudden interruption of voluntary muscle contraction. The concept was first introduced by Shahani and Young in an effort to characterize post-hypoxic intention myoclonus and asterixis [1]. At present, the term NM encompasses all involuntary movements of brief and spasmodic interruption of tonic muscle activities that can lead to a sudden postural lapse [2]. It has been suggested that NM may develop from the dysfunction of neural circuits responsible for the maintenance of sustained muscle contractions, such as lesions in the ventrolateral thalamus, or by a generalized neurochemical imbalance in metabolic encephalopathies [3]. Various drugs and toxic metabolic encephalopathies are known to cause acute-onset positive myoclonus. Among the drugs linked to the development of myoclonus, there have been several reports that
⁎
demonstrated pregabalin- or gabapentin-induced positive myoclonus [4–10]. Indeed, an observational study showed that myoclonus had developed in 13 of 104 (12.5%) patients, with the occurrence of epilepsy among those taking gabapentin [10]. Moreover, it has been found that the possibility of developing pregabalin- or gabapentin-induced myoclonus in patients with impaired renal function is relatively high compared to patients with normal renal function [4,6,8,9]. Given that positive and negative myoclonus share common precipitating factors, it is plausible that pregabalin and gabapentin may be implicated in the development of NM. However, to the best of our current knowledge, there is a paucity of reports describing NM induced by pregabalin or gabapentin [11–14]. In addition, NM patients easily considered as having a tremor or weakness in clinic, which lead to underdiagnosis of those conditions and the incidence could be underestimated. We therefore aimed to identify the clinical characteristics of patients with pregabalin- or
Corresponding author at: Department of Neurology, Korea University Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan 15355, South Korea. E-mail address: [email protected] (D.-Y. Kwon).
http://dx.doi.org/10.1016/j.jns.2017.09.019 Received 27 June 2017; Received in revised form 11 September 2017; Accepted 14 September 2017 Available online 18 September 2017 0022-510X/ © 2017 Published by Elsevier B.V.
Journal of the Neurological Sciences 382 (2017) 36–39
J.B. Kim et al.
gabapentin-induced NM. To this end, we reviewed medical records of NM patients using registry data from the department of neurology at a university-affiliated medical center. We then reviewed the literature with respect to pregabalin- or gabapentin-induced negative myoclonus.
Table 1 Classification of patients with negative myoclonus. Classification
Symptomatic Infectious or post-infectious Herpes simplex encephalitis Metabolic Hepatic failure Renal failurea Hypocalcemia Toxic and drug-induced Pregabalina Gabapentina Alcohol Other drugs (NSAIDs, antibiotics, codeine, tramadol etc.) Focal nervous system lesion Post-stroke Psychogenic Epileptic Undetermined
2. Materials and methods This study is a retrospective review of prospectively-collected registry data. Using the hospital registry database, we reviewed the medical records of all patients who were referred to the department of neurology at university-affiliated hospital for NM (defined as a shocklike, involuntary jerky movement, due to a sudden and brief interruption of muscle activity) [2]. The NM registry data were collected for 4 years. Diagnosis of the NM was based on clinical features, such as sudden falls or dropping of objects due to interruption of muscle activity. Patients with NM were finally included in the registry after a confirmation through neurologic examination by a movement disorder specialist. According to the etiology of NM, all patients with NM were classified into physiologic, essential, epileptic, symptomatic, and psychogenic myoclonus [15,16]. Based on medical records, we further investigated the demographic and clinical data of patients with pregabalin- or gabapentin-induced NM. Cases of probable and certain level of World Health Organization-Uppsala Monitoring Centre (WHO-UMC) causality categories were enrolled, considering temporal relationship to drug intake and response to withdrawal. Response to rechallenge was proved, in some cases [17]. That is, all of the pregabalin- or gabapentininduced NM was defined as the occurrence of NM after administration and the recovery of symptoms after withdrawal of the drugs. All patients with pregabalin- or gabapentin-induced NM had no evidence of acute lesions on brain MRI and epileptogenic conditions on electroencephalography. We collected data such as age at NM onset, duration of NM symptoms, comorbidities, and findings of serologic laboratory tests (i.e. blood urea nitrogen [BUN], creatinine, aspartate transaminase [AST], and alanine transaminase [ALT]). A literature search of PubMed was performed on March 29, 2017 using the search terms “Myoclonus OR Asterixis OR Flapping tremor AND Pregabalin OR Gabapentin OR Voltage dependent calcium channel”. The search was limited to articles in English. PubMed yielded 47 articles. A manual review of all 47 abstracts was then performed to exclude duplicate and irrelevant articles. In total, 6 articles were deemed relevant and accessible for our systematic review of pregabalin- or gabapentin-induced NM.
Number of cases (n = 77)
1 1 14 1 9 12 7 18
2 2 1 12
NSAIDs non-steroidal anti-inflammatory drugs. a Two patients with gabapentin-induced and one patient with pregabalin-induced negative myoclonus also had renal failure.
neuropathic pain in 6 cases and for controlling simple partial seizures in 1 case. Of the 7 cases, 2 had impaired renal function, while 5 had normal renal function.
4. Discussion Our review demonstrated that pregabalin- or gabapentin-induced NM was the leading cause of NM in our study population. Almost all patients (18 of 21 cases, 85.7%) with NM induced by pregabalin or gabapentin were found to have normal renal function on serologic test. Moreover, the dose of the pregabalin or gabapentin was not considerably high, and the time lapse until development of NM after administration of those drugs was not very long. On the literature review, we found that only 7 patients with pregabalin- or gabapentin-induced NM were reported. Most of the previously reported pregabalin- or gabapentin-induced NM patients (5 out of 7) had normal renal function. In addition, NM was developed within 4 days after administration of pregabalin or gabapentin. These findings were very similar to those of our study population. NM can be observed in a variety of clinical situations, such as encephalopathies associated with toxic and metabolic dysfunctions, as well as epileptogenic conditions. It has been relatively well-known that positive myoclonus could be induced by pregabalin or gabapentin, whereas there have been only a few reports describing pregabalin- or gabapentin-induced NM [11–14,18,19]. Therefore, the pathophysiological mechanisms that underlie the development of NM induced by pregabalin or gabapentin remain unknown. In addition, unlike positive myoclonus, NM may easily misdiagnose as having a tremor or weakness in clinic which lead to underestimation of their incidence. With regard to positive myoclonus, the involvement of the serotonin neurotransmitter system has been suggested as the mechanism responsible for the development of myoclonus [10]. In addition, most cases of pregabalin- or gabapentin-induced myoclonus were observed in patients with impaired renal function; therefore, drug intoxication due to impaired renal excretion was proposed as a possible underlying mechanism in the development of myoclonus [4,6]. However, a different study suggested that pregabalin-induced myoclonus seemed to depend on a threshold effect rather than a linear dose dependency [20], suggesting an effect of the pregabalin per se in the development of myoclonus. Our findings also suggest that effects of pregabalin or gabapentin per se may play an important role in development of NM for the following reasons: 1)
3. Results A total of 77 patients with NM (mean age = 65.8; 7 females) were initially included in this study. The etiological classification of included NM patients is summarized in Table 1. The most common etiology of NM was found as symptomatic (62 cases; 80.5%), followed by undetermined (12 cases; 15.6%), psychogenic (2 cases; 2.6%), and epileptic (1 case; 1.3%). Among the 62 symptomatic NM patients, the NM of 21 patients was found to be induced by pregabalin (9 cases) or gabapentin (12 cases). All of the 21 patients were prescribed pregabalin or gabapentin for the controlling of neuropathic pain. Of the 21 patients, 3 showed impairment of renal function (mean BUN = 58.1 mg/dl; mean creatinine = 7.0 mg/dl), while 18 had normal renal function (mean BUN = 16.3 mg/dl; mean creatinine = 1.0 mg/dl). Mean administration dosage of pregabalin and gabapentin was 217 mg/day and 400 mg/day, respectively. The mean time lapse until development of NM after administration of pregabalin or gabapentin was 3.5 days. Clinical data for patients with NM induced by pregabalin or gabapentin is described in Table 2. Our literature search on pregabalin- or gabapentin-induced NM identified 5 reports of single cases and 1 report of 2 cases. Table 3 summarizes the reported cases of pregabalin- and gabapentin-induced NM. Pregabalin or gabapentin was administrated for controlling 37
Journal of the Neurological Sciences 382 (2017) 36–39
J.B. Kim et al.
Table 2 Clinical data of cases with pregabalin- or gabapentin-induced negative myoclonus. No
Age (years)
Sex
Comorbidity
BUN (mg/dl)
Cr (mg/dl)
AST (mg/dl)
ALT (mg/dl)
Offending drug
Dosage (mg/day)
Time lapse (days)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
57 64 76 63 50 63 51 65 59 78 91 70 66 23 59 80 72 70 73 67 84
M F F M M M F M M M F M F F F M M M M M M
– – – DM, HTN DM, HTN – DM, HTN, CKD – HTN DM, HTN, CKD DM HTN – – DM DM, HTN DM – HTN, prostatic hyperplasia DM, HTN, CKD DM, HTN, Parkinson's disease
23 17.7 25 17.8 15.4 16.1 54 14.5 10.8 72.5 17.3 19.4 16.5 8 12 13 9.4 18.3 17.1 47.8 21.9
1.11 0.87 1.44 1.29 1.14 0.93 10.2 0.78 1.49 2.82 1.01 1.1 0.81 0.5 0.9 0.8 1.13 0.66 1.16 8.11 0.85
21 19 26 21 19 22 16 26 22 16 17 29 32 22 23 13 16 27 22 14 31
36 27 17 32 12 20 16 32 18 4 10 46 22 15 19 16 12 36 53 11 25
GBP PGB GBP GBP PGB GBP GBP GBP GBP GBP PGB PGB GBP GBP PGB GBP PGB GBP PGB PGB PGB
600 150 300 300 150 300 300 300 600 600 150 300 300 600 300 300 150 300 300 150 300
7 1 2 2 1 5 1 1 5 4 3 3 2 7 1 3 3 1 1 7 13
M male, F female, DM diabetes mellitus, HTN hypertension, CKD chronic kidney disease, BUN blood urea nitrogen, AST aspartate transaminase, ALT alanine transaminase, GBP gabapentin, PGB pregabalin. The time lapse represents the time elapsed from first use of the offending drug to the development of the negative myoclonus.
Our study has some limitations that should be addressed. First, because this was a retrospectively review, causal relationships between drugs and NM would be inherently limited, though the cases collected prospectively and temporal relationship between drug use and occurrence/recovery of NM symptom was clear. We adopt only probable and certain category of the standardized case causality assessment to ensure. Second, this study only reviewed medical records of patients who were referred to the department of neurology; therefore, the selection bias should be considered. Third, we only checked serological study to assess renal function and did not measure 24-hour urine collection study, which did not completely exclude the possibilities of underlying renal impairment and/or combined etiologies. Despite these limitations, and to the best of our knowledge, this study is the first case series and systematic review of pregabalin- or gabapentin-induced NM. Finally, NM was diagnosed based on clinical features and electrophysiologic studies for differential diagnosis have been performed in a small number of NM patients; therefore, the possibilities of coexistence of NM and positive myoclonus and intrapersonal bias to diagnose NM during the registration period cannot be excluded. Interpreting our results as the findings confined to NM may be limited. Further prospective studies incorporating a longitudinal design
pregabalin- or gabapentin-induced NM were observed in those with normal renal function; 2) the doses of these medications were not significantly high; and 3) the temporal relationship between the use of drugs and the development of NM was clear. The similar trends observed in previously reported cases through literature review may further support our speculation. Pregabalin and gabapentin bind to the alpha 2 delta (α2δ) ligands of low voltage-dependent T-type calcium channels. The T-type calcium channel has a relatively low threshold; therefore, the channel requires lesser membrane depolarization to open. In addition, the channel is tonically inactivated quickly after opening. The highly sensitive properties of the voltage in T-type calcium channels enable them to regulate cellular excitability and oscillatory behavior near the resting membrane potential [21]. Because these channels are highly distributed in the thalamocortical circuit, T-type calcium channels have been implicated in the synchronization of a circuit which is important in the generation of generalized spike-wave-discharges [21,22]. Given the aforementioned properties of T-type calcium channels, we speculate that pregabalin and gabapentin might disturb the physiological action of the channels, resulting in the development of NM as well as positive myoclonus.
Table 3 Summary of reviewed case reports of pregabalin- or gabapentin-induced negative myoclonus. References
Age (years)
Sex
Comorbidity
BUN (mg/ dl)
Cr (mg/dl)
AST (mg/ dl)
ALT (mg/ dl)
Offending drug
Dosage (mg/ day)
Time lapse (days)
Jacob et al. [11] Sechi et al. [12]
60 76
F F
Normal Normal
Normal Normal
Normal Normal
Normal Normal
GBP GBP
900 900
Sechi et al. [12] Babiy et al. [13] Heckmann et al. [18] Hellwig et al. [14]
77 74 89
F F F
– HTN, post-stroke epilepsy DM HTN, breast cancer HTN
Normal Normal Normal
Normal Normal Normal
Normal NA Normal
Normal NA Normal
GBP GBP PGB
3600 600 300
4 3 (confirmed by rechallenge) 3 months NA NA
71
M
114
3.4
NA
NA
PGB
100
8 h (initial single dose)
Wahba et al. [19]
68
M
CKD, sick sinus syndrome HTN, CKD, lung cancer
26
2.3
Normal
Normal
GBP
300
2
M male, F female, DM diabetes mellitus, HTN hypertension, CKD chronic kidney disease, BUN blood urea nitrogen, AST aspartate transaminase, ALT alanine transaminase, GBP gabapentin, PGB pregabalin, NA not available. Time lapse represents the time elapsed from the use of offending drug to the occurrence of the negative myoclonus.
38
Journal of the Neurological Sciences 382 (2017) 36–39
J.B. Kim et al.
end-stage renal disease, Epilepsia 46 (1) (2005) 156–158. [5] F. Ege, Y. Kocak, A.P. Titiz, S.M. Ozturk, S. Ozturk, S. Ozbakir, Gabapentin-induced myoclonus: case report, Mov. Disord. 23 (13) (2008) 1947–1948. [6] M. Holtkamp, A. Halle, H. Meierkord, F. Masuhr, Gabapentin-induced severe myoclonus in a patient with impaired renal function, J. Neurol. 253 (3) (2006) 382–383. [7] K.T. Cho, S.K. Hong, Myoclonus induced by the use of gabapentin, J. Korean Neurosurg. Soc. 43 (5) (2008) 237–238. [8] D.G. Healy, G.T. Ingle, P. Brown, Pregabalin- and gabapentin-associated myoclonus in a patient with chronic renal failure, Mov. Disord. 24 (13) (2009) 2028–2029. [9] S. Knake, K.M. Klein, K. Hattemer, A. Wellek, W.H. Oertel, H.M. Hamer, F. Rosenow, Pregabalin-induced generalized myoclonic status epilepticus in patients with chronic pain, Epilepsy Behav. 11 (3) (2007) 471–473. [10] J. Asconape, A. Diedrich, J. DellaBadia, Myoclonus associated with the use of gabapentin, Epilepsia 41 (4) (2000) 479–481. [11] P.C. Jacob, R.P. Chand, S. Omeima el, Asterixis induced by gabapentin, Clin. Neuropharmacol. 23 (1) (2000) 53. [12] G. Sechi, B. Murgia, G. Sau, L. Peddone, A. Tirotto, M. Barrocu, G. Rosati, Asterixis and toxic encephalopathy induced by gabapentin, Prog. Neuro-Psychopharmacol. Biol. Psychiatry 28 (1) (2004) 195–199. [13] M. Babiy, M.D. Stubblefield, M. Herklotz, M. Hand, Asterixis related to gabapentin as a cause of falls, Am. J. Phys. Med. Rehabil. 84 (2) (2005) 136–140. [14] S. Hellwig, F. Amtage, Pregabalin-induced cortical negative myoclonus in a patient with neuropathic pain, Epilepsy Behav. 13 (2) (2008) 418–420. [15] M. Kojovic, C. Cordivari, K. Bhatia, Myoclonic disorders: a practical approach for diagnosis and treatment, Ther. Adv. Neurol. Disord. 4 (1) (2011) 47–62. [16] C.D. Marsden, M. Hallett, Stanley Fahn, The nosology and pathophysiology of myoclonus, Mov. Disord. (2013) 1. [17] I.R. Edwards, J.K. Aronson, Adverse drug reactions: definitions, diagnosis, and management, Lancet 356 (9237) (2000) 1255–1259. [18] J.G. Heckmann, K. Ulrich, M. Dutsch, B. Neundorfer, Pregabalin associated asterixis, Am. J. Phys. Med. Rehabil. 84 (9) (2005) 724. [19] M. Wahba, O. Waln, Asterixis related to gabapentin intake: a case report and review, Postgrad. Med. 125 (5) (2013) 139–141. [20] H.J. Huppertz, T.J. Feuerstein, A. Schulze-Bonhage, Myoclonus in epilepsy patients with anticonvulsive add-on therapy with pregabalin, Epilepsia 42 (6) (2001) 790–792. [21] H.S. Shin, E.J. Cheong, S. Choi, J. Lee, H.S. Na, T-type Ca2 + channels as therapeutic targets in the nervous system, Curr. Opin. Pharmacol. 8 (1) (2008) 33–41. [22] E. Cheong, H.S. Shin, T-type Ca(2)(+) channels in absence epilepsy, Biochim. Biophys. Acta 1828 (7) (2013) 1560–1571. [23] S.M. van der Salm, R.J. de Haan, D.C. Cath, A.F. van Rootselaar, M.A. Tijssen, The eye of the beholder: inter-rater agreement among experts on psychogenic jerky movement disorders, J. Neurol. Neurosurg. Psychiatry 84 (7) (2013) 742–747. [24] R. Zutt, M.E. van Egmond, J.W. Elting, P.J. van Laar, O.F. Brouwer, D.A. Sival, H.P. Kremer, T.J. de Koning, M.A. Tijssen, A novel diagnostic approach to patients with myoclonus, Nat. Rev. Neurol. 11 (12) (2015) 687–697.
could provide clues about the causal relationship between the aforementioned drugs and NM. In addition, further experimental studies are needed to elucidate the pathophysiological mechanisms that underlie pregabalin- and gabapentin-induced NM, and their association with the modulation of T-type calcium channels. In conclusion, pregabalin- or gabapentin-induced NM could be developed even in patients with normal renal function. Clinically, pregabalin- or gabapentin-induced NM could be underrecognized and misdiagnosed other movement disorders such as tremor. Given the reversibility, accurate diagnosis of pregabalin- or gabapentin-induced NM would be essential though differential diagnosis among the hyperkinetic movement disorders is difficult even for movement disorder specialists [23,24]. Physicians have to keep in mind the possibility of developing NM in patients under treatment of pregabalin or gabapentin even in the normal range of renal function and use low dose of the offending drug. Competing interests None. Funding source Nothing. Acknowledgments Nothing to declare. References [1] B.T. Shahani, R.R. Young, Physiological and pharmacological aids in the differential diagnosis of tremor, J. Neurol. Neurosurg. Psychiatry 39 (8) (1976) 772–783. [2] G. Rubboli, C.A. Tassinari, Negative myoclonus. An overview of its clinical features, pathophysiological mechanisms, and management, Neurophysiol. Clin. 36 (5–6) (2006) 337–343. [3] R.R. Young, B.T. Shahani, Asterixis: one type of negative myoclonus, Adv. Neurol. 43 (1986) 137–156. [4] C. Zhang, D.G. Glenn, W.L. Bell, C.A. O'Donovan, Gabapentin-induced myoclonus in
39