- Email: [email protected]
Safety of Low-Dose Oral Dantrolene Sodium on Hepatic Function
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ORIGINAL ARTICLE
Safety of Low-Dose Oral Dantrolene Sodium on Hepatic Function Jung Yoon Kim, MD, Sewoong Chun, MD, Moon Suk Bang, MD, PhD, Hyung-Ik Shin, MD, PhD, Shi-Uk Lee, MD, PhD ABSTRACT. Kim JY, Chun S, Bang MS, Shin H-I, Lee S-U. Safety of low-dose oral dantrolene sodium on hepatic function. Arch Phys Med Rehabil 2011;92:1359-63. Objective: To investigate the incidence of hepatobiliary dys-
function after administration of low-dose dantrolene sodium. Design: A retrospective survey of medical records. Setting: One secondary and 2 tertiary hospitals. Participants: Patients (N⫽243; 144 men, 27 children; mean age ⫾ SD, 47.8⫾19.7y) who were administered dantrolene at a daily dose of 12.5 to 400mg for more than 4 weeks. Interventions: Not applicable. Main Outcome Measures: Liver function test (LFT) results, including serum total bilirubin, aspartate transaminase, alanine transaminase, and alkaline phosphatase, were recorded before and at least 1 month after the initial dose of dantrolene. In cases of treatment cessation, the reason was investigated. Significantly elevated LFT levels were defined as ⱖ to 2 times the upper limit of the normal range. Results: Treatment duration was 268.0⫾428.5 days with a daily dose of 65.2⫾44.7mg. At the end of the investigation, 95 patients (39.1%) had been lost to follow-up, and 105 (43.2%) had stopped treatment. The reasons for cessation were improved spasticity (42.9%), no effect of the medication (27.6%), weakness (6.7%), and other medical problems (5.7%). Patients with weaknesses did not have elevated LFT values. A 32-yearold man with head injuries and multiple trauma developed hepatic dysfunction 82 days after the initial dose and 43 days after a dose increment to 400mg/d. Other patients did not experience significant LFT abnormalities. Conclusions: One case of hepatic dysfunction was recorded in 243 cases after at least 4 weeks of low-dose oral dantrolene administration. Low-dose dantrolene can be used safely with meticulous clinical and laboratory monitoring. Key Words: Dantrolene; Drug toxicity; Muscle spasticity; Rehabilitation. © 2011 by the American Congress of Rehabilitation Medicine
From the Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul (Kim, Chun, Bang, Shin, Lee); Department of Rehabilitation Medicine, Seoul National University Hospital, Seoul (Kim, Chun, Bang); Department of Rehabilitation Medicine, Seoul National University Bundang Hospital, Seoul (Shin); and Department of Rehabilitation Medicine, Seoul National University Boramae Hospital, Seoul (Lee), Korea. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated. Correspondence to Shi-Uk Lee, MD, PhD, Department of Rehabilitation Medicine, Seoul National University Boramae Medical Center, 39 Boramae-gil, Dong-jak gu, Seoul, Korea, e-mail: [email protected]. Reprints are not available from the authors. 0003-9993/11/9209-00246$36.00/0 doi:10.1016/j.apmr.2011.04.012
ANTROLENE SODIUM IS a muscle relaxant that acts D directly on muscles by decreasing calcium release from the sarcoplasmic reticulum. Dantrolene predominantly influ1
ences skeletal muscles instead of smooth muscles. As such, it successfully alleviates spasticity resulting from neuromuscular diseases including stroke, traumatic brain injury, spinal cord injury, cerebral palsy, and multiple sclerosis.2-4 In contrast to other muscle relaxants acting on the central nervous system, dantrolene has fewer adverse reactions related to the central nervous system.5 However, reported cases of fatal hepatic injuries induced by dantrolene have prevented its widespread use. Dantrolenerelated hepatic dysfunction varies from a slight elevation in liver enzyme levels to fatal hepatic injury. The incidence of hepatic dysfunction and fatal hepatic injury was reported to be 1.8% and .35%, respectively.6 More recently, researchers from the United States reported 122 cases of hepatic dysfunction related to dantrolene until 1987, of which 27 were fatal. The dantrolene dosage in the fatal cases was 582mg/d, and the administration period was 13.8⫾12.0 months. Most of the deceased patients were adults.7 The suggested mechanisms of dantrolene-induced hepatic dysfunction include direct hepatotoxicity, a drug-induced idiosyncratic reaction, and an autoimmune-mediated reaction,6-8 but the exact mechanism has not yet been established. Currently, dantrolene is used with much caution in adults, and the recommended daily dose is 12.5 to 400mg.1 Despite the recommendation of low-dose dantrolene use, there have never been any safety reports on the use of low-dose dantrolene in adults or in children. In this study, we aimed to investigate the incidence of dantrolene-related hepatic dysfunction with low-dose (25– 400mg daily) oral administration, and its safety in general. METHODS Participants Study subjects included patients who had been administered dantrolene sodium for 4 weeks or more, between January 2005 and February 2009, at the Department of Rehabilitation Medicine in 1 secondary and 2 tertiary hospitals. Institutional review board approvals were obtained before the survey. Data Collection Procedures Medical records of the subjects were reviewed to obtain the following information: age, sex, causal disease that
List of Abbreviations ALP ALT AST HBsAg LFT
alkaline phosphatase alanine transaminase aspartate transaminase hepatitis B surface antigen liver function test
Arch Phys Med Rehabil Vol 92, September 2011
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SAFETY OF LOW-DOSE DANTROLENE SODIUM, Kim
Fig 1. Flow chart illustrating subject breakdown at each step of the study.
resulted in spasticity, daily dose and administration duration of dantrolene, preadministration and postadministration liver function test (LFT) values, and reasons for dantrolene discontinuation. The levels of serum total bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) were recorded. LFT results before the first dose of dantrolene, usually within 4 weeks, were accepted as preadministration LFTs.9 Postadministration LFT values were accepted when those were obtained more than 4 weeks after the first dose during the administration of dantrolene. In cases of dantrolene discontinuation, the reasons were determined, and any adverse reactions related to dantrolene were recorded.
Main Outcome Measures The number and ratio of patients who showed elevated serum total bilirubin, AST, ALT, and ALP levels were recorded. A significant elevation in serum LFT levels was defined as any increase that was more than twice the upper reference limit.10 The ratio of the number of subjects with elevated LFT values to the total number of subjects was defined as the incidence of hepatic dysfunction. In cases of hepatic dysfunction after dantrolene administration, the causal relationship between medication and elevated LFT values was assessed by using a “scoring system for assessing causality for hepatocellular/cholestatic types of reactions,”11,12 which is a scoring system that encompasses the temporal relationship, time course, risk factors, concomitant drug and nondrug causes, previous information on hepatotoxicity of the drug, and rechallenge. Any occurrence of acute liver failure, defined as hepatic dysfunction with coagulation abnormalities and encephalopathy, was investigated.13 Hepatic dysfunction was classified into 4 categories6: (1) serum enzyme elevation only; (2) enzyme elevation with a serum bilirubin level of 2.5mg/dL or less; (3) jaundice or a serum bilirubin level greater than 2.5mg/dL; and (4) fatal hepatic dysfunction. Arch Phys Med Rehabil Vol 92, September 2011
Statistical Analysis Differences between preadministration and postadministration LFT values were investigated using the paired t test. All statistical analyses were conducted using SPSS for Windows version 17.0.a A P value less than .05 was considered statistically significant. All values were presented as mean ⫾ SD. Ranges were described as the lowest and the highest values from the observed data. RESULTS Participant Characteristics A total of 243 patients (144 men, 27 children) were prescribed dantrolene for 4 weeks or more during the study period. Their age was 47.8⫾19.7 years (children, 9.6⫾5.4y; adults, 52.6⫾15.0y). Administration of Dantrolene Sodium The duration of administration was 268.0⫾428.5 days (range, 28 –2517d), and the dosage was 65.2⫾44.7mg/d (range, 12.5– 400mg/d). Ninety-five patients (39.1%) were lost to follow-up, 43 (17.7%) were still taking dantrolene at the end of survey, and 105 (43.2%) had stopped the medication (fig 1). Table 1: Discontinuation No. of Subjects Reasons for Discontinuing
Children
Adults
Total
Improved spasticity No effect of medication Unknown causes General weakness Other medical problems Botulinum toxin injection Elevated liver enzymes Total
3 1 0 2 0 0 0 6
40 28 17 5 6 2 1 99
43 29 17 7 6 2 1 105
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SAFETY OF LOW-DOSE DANTROLENE SODIUM, Kim Table 2: Age Distribution and Daily Dose of Dantrolene Characteristic
Age (y) 1–10 11–20 21–30 31–40 41–50 51–60 61–70 71–80 81–89 Total Daily dose (mg/d) 12.5 25 50 75 100 125 150 200 225 300 400 Total
Frequency (n)
%
Subjects With Preadministration and Postadministration LFTs (n)
%
17 12 18 26 48 52 48 20 2 243
7.0 4.9 7.4 10.7 19.8 21.4 19.8 8.2 0.8 100.0
12 4 4 8 14 21 16 12 1 92
13.0 4.3 4.3 8.7 15.2 22.8 17.4 13.0 1.1 100.0
1 25 122 74 11 1 2 2 2 1 2 243
0.4 10.3 50.2 30.7 4.5 0.4 0.8 0.8 0.8 0.4 0.8 100.0
1 20 38 16 9 1 2 0 2 1 2 92
1.1 21.7 41.3 17.4 9.8 1.1 2.2 0.0 2.2 1.1 2.2 100.0
The reasons for discontinuation are listed in table 1. LFT Levels LFT values before and after dantrolene administration were available in 92 subjects (16 children, 76 adults), and their mean age ⫾ SD was 46.3⫾21.7 years (8.9⫾4.1y in children, 54.1⫾14.3y in adults). The age distribution of the subjects is listed in table 2. They had taken dantrolene for 393.1⫾497.6 days (range, 28 –2517d) with a daily dose of 70.5⫾66.5mg (range, 12.5– 400mg). The daily dose was 12.5 to 200mg in 87 subjects (94.6%) (see table 2). There were no significant differences between preadministration and postadministration LFT levels in children (P⫽.864, P⫽.151, P⫽.912, and P⫽.497 in total bilirubin, AST, ALT, and ALP levels, respectively, by paired t test) and in adults (P⫽.583, P⫽.569, P⫽.912, and P⫽.497 in total bilirubin, AST, ALT, and ALP levels, respectively, by paired t test) (table 3). Seven patients who developed weakness and stopped dantrolene did not have LFT abnormalities. In a 32-year-old man with head injuries and multiple traumas, elevated LFT values resulted in cessation of dantrolene. He was a hepatitis B surface antigen (HBsAg) carrier. His LFT values 20 days before the initial dose were as follows: total bilirubin, 0.5mg/dL; AST,
54IU/L; ALT, 123IU/L; and ALP, 167IU/L. Although AST, ALT, and ALP levels were above the reference limits, dantrolene was administrated to relieve spasticity. Silymarin and biphenyl dimethyl dicarboxylate were prescribed as hepatic protective agents, and LFTs were assessed every 3 to 7 days. He had taken dantrolene 75mg/d for 6 days, and 150mg/d for 33 days successively. The daily dose was then increased to 400mg (5.9mg/kg), and 4 days later, when he had been taking dantrolene for 47 days, his AST level was elevated to 121IU/L. However, it decreased to 57IU/L 3 days later without interrupting dosing. On the 82nd day after the initial dose and 43rd day after the dose increment, his ALP level rose to 245IU/L and AST level increased to 85IU/L, which were above the upper reference limits. Dantrolene administration was stopped at the 155th day. Because his serum bilirubin level was greater than 2.5mg/dL, this adverse reaction belongs to the third category of dantrolene-induced hepatic dysfunction. The patient’s ALP and AST levels remained elevated until dantrolene administration was ceased, leading clinicians to suspect that his chronic hepatitis B had become active. After cessation of dantrolene, his serum total bilirubin and ALP levels began to decrease, but the increased AST and ALT levels persisted. He was lost to follow-up, but when readmitted 2 years later owing
Table 3: Levels of Preadministration and Postadministration LFTs in Children and Adults Children
Total bilirubin (mg/dL) AST (IU/L) ALT (IU/L) ALP (IU/L)
Adults
Preadministration
Postadministration
Preadministration
Postadministration
0.49⫾0.21 25.19⫾7.00 16.88⫾10.20 198.21⫾136.17
0.49⫾0.19 23.00⫾4.75 16.69⫾8.91 169.36⫾54.193
0.62⫾0.28 22.57⫾10.21 21.95⫾13.19 101.03⫾92.34
0.64⫾0.28 21.92⫾8.94 22.46⫾14.65 94.34⫾69.02
NOTE. Values are mean ⫾ SD.
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SAFETY OF LOW-DOSE DANTROLENE SODIUM, Kim Table 4: Subjects Who Developed Generalized Weakness
Patient No.
1 2 3 4 5 6 7
Sex
Age (y)
Diagnosis
Daily Dose (mg)
Duration of Administration (d)
M M M M M M M
5 10 26 41 50 62 51
Cerebral palsy Cerebral palsy Cerebral palsy Cerebral palsy Stroke Stroke Spinal cord injury
50 100 300 100 25 50 25
79 622 203 69 1028 79 45
Abbreviation: M, male.
to chronic osteomyelitis, his LFT levels were within the reference limits. All the other patients did not show any significant elevations in postadministration LFT levels compared with those preadministration. Seven male subjects complained of general weakness (2 were children with cerebral palsy, 5 were adults) (table 4). When this symptom was considered as an adverse effect of dantrolene, 8 subjects (7 men with general weakness, 1 man with liver enzyme elevation) had developed adverse reactions. They were taking 25 to 300mg of dantrolene for 45 to 1028 days (see table 4). However, reported general weakness is a subjective and vague complaint, and can also be a manifestation of fatigue. DISCUSSION This survey investigated adverse effects detected in subjects taking dantrolene within a low-dose recommended range. Among the 92 subjects with preadministration and postadministration LFT values, 1 had developed hepatic dysfunction (incidence, 1.09%). There were no reports of adverse reactions related to dantrolene in 151 subjects who did not have preadministration and postadministration LFTs. Between 28 and 2517 days (mean ⫾ SD, 268.0⫾428.5d) of follow-up, no fatal hepatic injury had occurred in 243 patients. Regular LFT monitoring for a much longer follow-up period may be necessary in the subjects in this study, who had been taking dantrolene for 268.0⫾428.5 days (9.6⫾15.3mo). This is because in a previous report, subjects who had taken 201 to 400mg/d of dantrolene accounted for as many as 23% of patients with fatal hepatic injuries, which occurred after 13.8⫾12.0 months.7 However, the incidence of fatal hepatic injury in subjects of this study might be very low thereafter, because the daily dose was 100mg or less in 95.9% of all 243 subjects, and in 91.3% of 92 subjects with preadministration and postadministration LFT levels. Dantrolene-induced hepatic dysfunction has been shown to have a dose-response relationship,7 and there have been no reports of fatal hepatic injury induced by dantrolene at a daily dose of 200mg or less. A patient who had developed LFT abnormalities in this study tested positive for serum HBsAg and had liver enzyme levels that surpassed the upper reference limits. We could not apply the “scoring system for assessing causality for hepatocellular/cholestatic types of reactions” to this patient because of a lack of information after dantrolene cessation. Dantrolene is suspected of causing the aggravated hepatic dysfunction in this patient because his LFT values decreased after dantrolene was discontinued. We suggest that obtaining screening LFTs before administering dantrolene and avoiding dantrolene in patients with underlying liver disease may be helpful to minimize dantrolene-induced hepatic dysfunction. Moreover, monitoring LFT values more frequently than previously recommended7,14,15 may be necessary to detect danArch Phys Med Rehabil Vol 92, September 2011
trolene-induced hepatic dysfunction. We suggest monthly screening tests, as the above case presented hepatic dysfunction 43 days after a dose increase. There had been no significant elevation in LFT levels until a dose increment, and other patients were administered less than 200mg of dantrolene, consistent with previous reports.5,6 As such, a daily dose of less than 200mg may be safely used. Study Limitations A relatively small number of subjects compared with previous studies6,7 makes it difficult to confirm that no fatal hepatic dysfunction occurs with a dantrolene dosage of 200mg/d or less. A larger cohort might be more informative. Asymptomatic hepatic dysfunction had no chance to be discovered in the 107 patients who did not have LFT results. A detection bias of symptomatic dysfunction may be possible. CONCLUSIONS Only 1 of 243 subjects had significant hepatic dysfunction after at least 4 weeks of low-dose oral dantrolene sodium administration. Low-dose dantrolene sodium could be used safely with clinical and laboratory monitoring. References 1. Ward A, Chaffman MO, Sorkin EM. Dantrolene. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in malignant hyperthermia, the neuroleptic malignant syndrome and an update of its use in muscle spasticity. Drugs 1986; 32:130-68. 2. Chyatte SB, Basmajian JV. Dantrolene sodium: long-term effects in severe spasticity. Arch Phys Med Rehabil 1973;54:311-5. 3. Denhoff E, Feldman S, Smith MG, Litchman H, Holden W. Treatment of spastic cerebral-palsied children with sodium dantrolene. Dev Med Child Neurol 1975;17:736-42. 4. Dykes MH. Evaluation of a muscle relaxant: dantrolene sodium (Dantrium). JAMA 1975;231:862-4. 5. Gracies JM, Nance P, Elovic E, McGuire J, Simpson DM. Traditional pharmacological treatments for spasticity. Part II: general and regional treatments. Muscle Nerve Suppl 1997;6:S92-120. 6. Utili R, Boitnott JK, Zimmerman HJ. Dantrolene-associated hepatic injury. Incidence and character. Gastroenterology 1977;72: 610-6. 7. Chan CH. Dantrolene sodium and hepatic injury. Neurology 1990; 40:1427-32. 8. Durham JA, Gandolfi AJ, Bentley JB. Hepatotoxicological evaluation of dantrolene sodium. Drug Chem Toxicol 1984;7:23-40. 9. Graham DJ, Drinkard CR, Shatin D, Tsong Y, Burgess MJ. Liver enzyme monitoring in patients treated with troglitazone. JAMA 2001;286:831-3.
SAFETY OF LOW-DOSE DANTROLENE SODIUM, Kim
10. Bleibel W, Kim S, D’Silva K, Lemmer ER. Drug-induced liver injury: review article. Dig Dis Sci 2007;52:2463-71. 11. Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs—II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol 1993;46:1331-6. 12. Danan G, Benichou C. Causality assessment of adverse reactions to drugs—I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol 1993;46:1323-30.
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13. Polson J, Lee WM. AASLD position paper: the management of acute liver failure. Hepatology 2005;41:1179-97. 14. Kita M, Goodkin DE. Drugs used to treat spasticity. Drugs 2000; 59:487-95. 15. Wilkinson SP, Portmann B, Williams R. Hepatitis from dantrolene sodium. Gut 1979;20:33-6.
Supplier a. SPSS Inc, 233 S Wacker Dr, 11th Fl, Chicago, IL 60606.
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ORIGINAL ARTICLE
Safety of Low-Dose Oral Dantrolene Sodium on Hepatic Function Jung Yoon Kim, MD, Sewoong Chun, MD, Moon Suk Bang, MD, PhD, Hyung-Ik Shin, MD, PhD, Shi-Uk Lee, MD, PhD ABSTRACT. Kim JY, Chun S, Bang MS, Shin H-I, Lee S-U. Safety of low-dose oral dantrolene sodium on hepatic function. Arch Phys Med Rehabil 2011;92:1359-63. Objective: To investigate the incidence of hepatobiliary dys-
function after administration of low-dose dantrolene sodium. Design: A retrospective survey of medical records. Setting: One secondary and 2 tertiary hospitals. Participants: Patients (N⫽243; 144 men, 27 children; mean age ⫾ SD, 47.8⫾19.7y) who were administered dantrolene at a daily dose of 12.5 to 400mg for more than 4 weeks. Interventions: Not applicable. Main Outcome Measures: Liver function test (LFT) results, including serum total bilirubin, aspartate transaminase, alanine transaminase, and alkaline phosphatase, were recorded before and at least 1 month after the initial dose of dantrolene. In cases of treatment cessation, the reason was investigated. Significantly elevated LFT levels were defined as ⱖ to 2 times the upper limit of the normal range. Results: Treatment duration was 268.0⫾428.5 days with a daily dose of 65.2⫾44.7mg. At the end of the investigation, 95 patients (39.1%) had been lost to follow-up, and 105 (43.2%) had stopped treatment. The reasons for cessation were improved spasticity (42.9%), no effect of the medication (27.6%), weakness (6.7%), and other medical problems (5.7%). Patients with weaknesses did not have elevated LFT values. A 32-yearold man with head injuries and multiple trauma developed hepatic dysfunction 82 days after the initial dose and 43 days after a dose increment to 400mg/d. Other patients did not experience significant LFT abnormalities. Conclusions: One case of hepatic dysfunction was recorded in 243 cases after at least 4 weeks of low-dose oral dantrolene administration. Low-dose dantrolene can be used safely with meticulous clinical and laboratory monitoring. Key Words: Dantrolene; Drug toxicity; Muscle spasticity; Rehabilitation. © 2011 by the American Congress of Rehabilitation Medicine
From the Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul (Kim, Chun, Bang, Shin, Lee); Department of Rehabilitation Medicine, Seoul National University Hospital, Seoul (Kim, Chun, Bang); Department of Rehabilitation Medicine, Seoul National University Bundang Hospital, Seoul (Shin); and Department of Rehabilitation Medicine, Seoul National University Boramae Hospital, Seoul (Lee), Korea. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated. Correspondence to Shi-Uk Lee, MD, PhD, Department of Rehabilitation Medicine, Seoul National University Boramae Medical Center, 39 Boramae-gil, Dong-jak gu, Seoul, Korea, e-mail: [email protected]. Reprints are not available from the authors. 0003-9993/11/9209-00246$36.00/0 doi:10.1016/j.apmr.2011.04.012
ANTROLENE SODIUM IS a muscle relaxant that acts D directly on muscles by decreasing calcium release from the sarcoplasmic reticulum. Dantrolene predominantly influ1
ences skeletal muscles instead of smooth muscles. As such, it successfully alleviates spasticity resulting from neuromuscular diseases including stroke, traumatic brain injury, spinal cord injury, cerebral palsy, and multiple sclerosis.2-4 In contrast to other muscle relaxants acting on the central nervous system, dantrolene has fewer adverse reactions related to the central nervous system.5 However, reported cases of fatal hepatic injuries induced by dantrolene have prevented its widespread use. Dantrolenerelated hepatic dysfunction varies from a slight elevation in liver enzyme levels to fatal hepatic injury. The incidence of hepatic dysfunction and fatal hepatic injury was reported to be 1.8% and .35%, respectively.6 More recently, researchers from the United States reported 122 cases of hepatic dysfunction related to dantrolene until 1987, of which 27 were fatal. The dantrolene dosage in the fatal cases was 582mg/d, and the administration period was 13.8⫾12.0 months. Most of the deceased patients were adults.7 The suggested mechanisms of dantrolene-induced hepatic dysfunction include direct hepatotoxicity, a drug-induced idiosyncratic reaction, and an autoimmune-mediated reaction,6-8 but the exact mechanism has not yet been established. Currently, dantrolene is used with much caution in adults, and the recommended daily dose is 12.5 to 400mg.1 Despite the recommendation of low-dose dantrolene use, there have never been any safety reports on the use of low-dose dantrolene in adults or in children. In this study, we aimed to investigate the incidence of dantrolene-related hepatic dysfunction with low-dose (25– 400mg daily) oral administration, and its safety in general. METHODS Participants Study subjects included patients who had been administered dantrolene sodium for 4 weeks or more, between January 2005 and February 2009, at the Department of Rehabilitation Medicine in 1 secondary and 2 tertiary hospitals. Institutional review board approvals were obtained before the survey. Data Collection Procedures Medical records of the subjects were reviewed to obtain the following information: age, sex, causal disease that
List of Abbreviations ALP ALT AST HBsAg LFT
alkaline phosphatase alanine transaminase aspartate transaminase hepatitis B surface antigen liver function test
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SAFETY OF LOW-DOSE DANTROLENE SODIUM, Kim
Fig 1. Flow chart illustrating subject breakdown at each step of the study.
resulted in spasticity, daily dose and administration duration of dantrolene, preadministration and postadministration liver function test (LFT) values, and reasons for dantrolene discontinuation. The levels of serum total bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) were recorded. LFT results before the first dose of dantrolene, usually within 4 weeks, were accepted as preadministration LFTs.9 Postadministration LFT values were accepted when those were obtained more than 4 weeks after the first dose during the administration of dantrolene. In cases of dantrolene discontinuation, the reasons were determined, and any adverse reactions related to dantrolene were recorded.
Main Outcome Measures The number and ratio of patients who showed elevated serum total bilirubin, AST, ALT, and ALP levels were recorded. A significant elevation in serum LFT levels was defined as any increase that was more than twice the upper reference limit.10 The ratio of the number of subjects with elevated LFT values to the total number of subjects was defined as the incidence of hepatic dysfunction. In cases of hepatic dysfunction after dantrolene administration, the causal relationship between medication and elevated LFT values was assessed by using a “scoring system for assessing causality for hepatocellular/cholestatic types of reactions,”11,12 which is a scoring system that encompasses the temporal relationship, time course, risk factors, concomitant drug and nondrug causes, previous information on hepatotoxicity of the drug, and rechallenge. Any occurrence of acute liver failure, defined as hepatic dysfunction with coagulation abnormalities and encephalopathy, was investigated.13 Hepatic dysfunction was classified into 4 categories6: (1) serum enzyme elevation only; (2) enzyme elevation with a serum bilirubin level of 2.5mg/dL or less; (3) jaundice or a serum bilirubin level greater than 2.5mg/dL; and (4) fatal hepatic dysfunction. Arch Phys Med Rehabil Vol 92, September 2011
Statistical Analysis Differences between preadministration and postadministration LFT values were investigated using the paired t test. All statistical analyses were conducted using SPSS for Windows version 17.0.a A P value less than .05 was considered statistically significant. All values were presented as mean ⫾ SD. Ranges were described as the lowest and the highest values from the observed data. RESULTS Participant Characteristics A total of 243 patients (144 men, 27 children) were prescribed dantrolene for 4 weeks or more during the study period. Their age was 47.8⫾19.7 years (children, 9.6⫾5.4y; adults, 52.6⫾15.0y). Administration of Dantrolene Sodium The duration of administration was 268.0⫾428.5 days (range, 28 –2517d), and the dosage was 65.2⫾44.7mg/d (range, 12.5– 400mg/d). Ninety-five patients (39.1%) were lost to follow-up, 43 (17.7%) were still taking dantrolene at the end of survey, and 105 (43.2%) had stopped the medication (fig 1). Table 1: Discontinuation No. of Subjects Reasons for Discontinuing
Children
Adults
Total
Improved spasticity No effect of medication Unknown causes General weakness Other medical problems Botulinum toxin injection Elevated liver enzymes Total
3 1 0 2 0 0 0 6
40 28 17 5 6 2 1 99
43 29 17 7 6 2 1 105
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SAFETY OF LOW-DOSE DANTROLENE SODIUM, Kim Table 2: Age Distribution and Daily Dose of Dantrolene Characteristic
Age (y) 1–10 11–20 21–30 31–40 41–50 51–60 61–70 71–80 81–89 Total Daily dose (mg/d) 12.5 25 50 75 100 125 150 200 225 300 400 Total
Frequency (n)
%
Subjects With Preadministration and Postadministration LFTs (n)
%
17 12 18 26 48 52 48 20 2 243
7.0 4.9 7.4 10.7 19.8 21.4 19.8 8.2 0.8 100.0
12 4 4 8 14 21 16 12 1 92
13.0 4.3 4.3 8.7 15.2 22.8 17.4 13.0 1.1 100.0
1 25 122 74 11 1 2 2 2 1 2 243
0.4 10.3 50.2 30.7 4.5 0.4 0.8 0.8 0.8 0.4 0.8 100.0
1 20 38 16 9 1 2 0 2 1 2 92
1.1 21.7 41.3 17.4 9.8 1.1 2.2 0.0 2.2 1.1 2.2 100.0
The reasons for discontinuation are listed in table 1. LFT Levels LFT values before and after dantrolene administration were available in 92 subjects (16 children, 76 adults), and their mean age ⫾ SD was 46.3⫾21.7 years (8.9⫾4.1y in children, 54.1⫾14.3y in adults). The age distribution of the subjects is listed in table 2. They had taken dantrolene for 393.1⫾497.6 days (range, 28 –2517d) with a daily dose of 70.5⫾66.5mg (range, 12.5– 400mg). The daily dose was 12.5 to 200mg in 87 subjects (94.6%) (see table 2). There were no significant differences between preadministration and postadministration LFT levels in children (P⫽.864, P⫽.151, P⫽.912, and P⫽.497 in total bilirubin, AST, ALT, and ALP levels, respectively, by paired t test) and in adults (P⫽.583, P⫽.569, P⫽.912, and P⫽.497 in total bilirubin, AST, ALT, and ALP levels, respectively, by paired t test) (table 3). Seven patients who developed weakness and stopped dantrolene did not have LFT abnormalities. In a 32-year-old man with head injuries and multiple traumas, elevated LFT values resulted in cessation of dantrolene. He was a hepatitis B surface antigen (HBsAg) carrier. His LFT values 20 days before the initial dose were as follows: total bilirubin, 0.5mg/dL; AST,
54IU/L; ALT, 123IU/L; and ALP, 167IU/L. Although AST, ALT, and ALP levels were above the reference limits, dantrolene was administrated to relieve spasticity. Silymarin and biphenyl dimethyl dicarboxylate were prescribed as hepatic protective agents, and LFTs were assessed every 3 to 7 days. He had taken dantrolene 75mg/d for 6 days, and 150mg/d for 33 days successively. The daily dose was then increased to 400mg (5.9mg/kg), and 4 days later, when he had been taking dantrolene for 47 days, his AST level was elevated to 121IU/L. However, it decreased to 57IU/L 3 days later without interrupting dosing. On the 82nd day after the initial dose and 43rd day after the dose increment, his ALP level rose to 245IU/L and AST level increased to 85IU/L, which were above the upper reference limits. Dantrolene administration was stopped at the 155th day. Because his serum bilirubin level was greater than 2.5mg/dL, this adverse reaction belongs to the third category of dantrolene-induced hepatic dysfunction. The patient’s ALP and AST levels remained elevated until dantrolene administration was ceased, leading clinicians to suspect that his chronic hepatitis B had become active. After cessation of dantrolene, his serum total bilirubin and ALP levels began to decrease, but the increased AST and ALT levels persisted. He was lost to follow-up, but when readmitted 2 years later owing
Table 3: Levels of Preadministration and Postadministration LFTs in Children and Adults Children
Total bilirubin (mg/dL) AST (IU/L) ALT (IU/L) ALP (IU/L)
Adults
Preadministration
Postadministration
Preadministration
Postadministration
0.49⫾0.21 25.19⫾7.00 16.88⫾10.20 198.21⫾136.17
0.49⫾0.19 23.00⫾4.75 16.69⫾8.91 169.36⫾54.193
0.62⫾0.28 22.57⫾10.21 21.95⫾13.19 101.03⫾92.34
0.64⫾0.28 21.92⫾8.94 22.46⫾14.65 94.34⫾69.02
NOTE. Values are mean ⫾ SD.
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SAFETY OF LOW-DOSE DANTROLENE SODIUM, Kim Table 4: Subjects Who Developed Generalized Weakness
Patient No.
1 2 3 4 5 6 7
Sex
Age (y)
Diagnosis
Daily Dose (mg)
Duration of Administration (d)
M M M M M M M
5 10 26 41 50 62 51
Cerebral palsy Cerebral palsy Cerebral palsy Cerebral palsy Stroke Stroke Spinal cord injury
50 100 300 100 25 50 25
79 622 203 69 1028 79 45
Abbreviation: M, male.
to chronic osteomyelitis, his LFT levels were within the reference limits. All the other patients did not show any significant elevations in postadministration LFT levels compared with those preadministration. Seven male subjects complained of general weakness (2 were children with cerebral palsy, 5 were adults) (table 4). When this symptom was considered as an adverse effect of dantrolene, 8 subjects (7 men with general weakness, 1 man with liver enzyme elevation) had developed adverse reactions. They were taking 25 to 300mg of dantrolene for 45 to 1028 days (see table 4). However, reported general weakness is a subjective and vague complaint, and can also be a manifestation of fatigue. DISCUSSION This survey investigated adverse effects detected in subjects taking dantrolene within a low-dose recommended range. Among the 92 subjects with preadministration and postadministration LFT values, 1 had developed hepatic dysfunction (incidence, 1.09%). There were no reports of adverse reactions related to dantrolene in 151 subjects who did not have preadministration and postadministration LFTs. Between 28 and 2517 days (mean ⫾ SD, 268.0⫾428.5d) of follow-up, no fatal hepatic injury had occurred in 243 patients. Regular LFT monitoring for a much longer follow-up period may be necessary in the subjects in this study, who had been taking dantrolene for 268.0⫾428.5 days (9.6⫾15.3mo). This is because in a previous report, subjects who had taken 201 to 400mg/d of dantrolene accounted for as many as 23% of patients with fatal hepatic injuries, which occurred after 13.8⫾12.0 months.7 However, the incidence of fatal hepatic injury in subjects of this study might be very low thereafter, because the daily dose was 100mg or less in 95.9% of all 243 subjects, and in 91.3% of 92 subjects with preadministration and postadministration LFT levels. Dantrolene-induced hepatic dysfunction has been shown to have a dose-response relationship,7 and there have been no reports of fatal hepatic injury induced by dantrolene at a daily dose of 200mg or less. A patient who had developed LFT abnormalities in this study tested positive for serum HBsAg and had liver enzyme levels that surpassed the upper reference limits. We could not apply the “scoring system for assessing causality for hepatocellular/cholestatic types of reactions” to this patient because of a lack of information after dantrolene cessation. Dantrolene is suspected of causing the aggravated hepatic dysfunction in this patient because his LFT values decreased after dantrolene was discontinued. We suggest that obtaining screening LFTs before administering dantrolene and avoiding dantrolene in patients with underlying liver disease may be helpful to minimize dantrolene-induced hepatic dysfunction. Moreover, monitoring LFT values more frequently than previously recommended7,14,15 may be necessary to detect danArch Phys Med Rehabil Vol 92, September 2011
trolene-induced hepatic dysfunction. We suggest monthly screening tests, as the above case presented hepatic dysfunction 43 days after a dose increase. There had been no significant elevation in LFT levels until a dose increment, and other patients were administered less than 200mg of dantrolene, consistent with previous reports.5,6 As such, a daily dose of less than 200mg may be safely used. Study Limitations A relatively small number of subjects compared with previous studies6,7 makes it difficult to confirm that no fatal hepatic dysfunction occurs with a dantrolene dosage of 200mg/d or less. A larger cohort might be more informative. Asymptomatic hepatic dysfunction had no chance to be discovered in the 107 patients who did not have LFT results. A detection bias of symptomatic dysfunction may be possible. CONCLUSIONS Only 1 of 243 subjects had significant hepatic dysfunction after at least 4 weeks of low-dose oral dantrolene sodium administration. Low-dose dantrolene sodium could be used safely with clinical and laboratory monitoring. References 1. Ward A, Chaffman MO, Sorkin EM. Dantrolene. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in malignant hyperthermia, the neuroleptic malignant syndrome and an update of its use in muscle spasticity. Drugs 1986; 32:130-68. 2. Chyatte SB, Basmajian JV. Dantrolene sodium: long-term effects in severe spasticity. Arch Phys Med Rehabil 1973;54:311-5. 3. Denhoff E, Feldman S, Smith MG, Litchman H, Holden W. Treatment of spastic cerebral-palsied children with sodium dantrolene. Dev Med Child Neurol 1975;17:736-42. 4. Dykes MH. Evaluation of a muscle relaxant: dantrolene sodium (Dantrium). JAMA 1975;231:862-4. 5. Gracies JM, Nance P, Elovic E, McGuire J, Simpson DM. Traditional pharmacological treatments for spasticity. Part II: general and regional treatments. Muscle Nerve Suppl 1997;6:S92-120. 6. Utili R, Boitnott JK, Zimmerman HJ. Dantrolene-associated hepatic injury. Incidence and character. Gastroenterology 1977;72: 610-6. 7. Chan CH. Dantrolene sodium and hepatic injury. Neurology 1990; 40:1427-32. 8. Durham JA, Gandolfi AJ, Bentley JB. Hepatotoxicological evaluation of dantrolene sodium. Drug Chem Toxicol 1984;7:23-40. 9. Graham DJ, Drinkard CR, Shatin D, Tsong Y, Burgess MJ. Liver enzyme monitoring in patients treated with troglitazone. JAMA 2001;286:831-3.
SAFETY OF LOW-DOSE DANTROLENE SODIUM, Kim
10. Bleibel W, Kim S, D’Silva K, Lemmer ER. Drug-induced liver injury: review article. Dig Dis Sci 2007;52:2463-71. 11. Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs—II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol 1993;46:1331-6. 12. Danan G, Benichou C. Causality assessment of adverse reactions to drugs—I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol 1993;46:1323-30.
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13. Polson J, Lee WM. AASLD position paper: the management of acute liver failure. Hepatology 2005;41:1179-97. 14. Kita M, Goodkin DE. Drugs used to treat spasticity. Drugs 2000; 59:487-95. 15. Wilkinson SP, Portmann B, Williams R. Hepatitis from dantrolene sodium. Gut 1979;20:33-6.
Supplier a. SPSS Inc, 233 S Wacker Dr, 11th Fl, Chicago, IL 60606.
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