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Baclofen Toxicity in a Patient with Hemodialysis-Dependent End-Stage Renal Disease
The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–2, 2016 Ó 2016 Elsevier Inc. All rights reserved. 0736-4679/$ - see front matter
http://dx.doi.org/10.1016/j.jemermed.2016.09.025
Selected Topics: Toxicology BACLOFEN TOXICITY IN A PATIENT WITH HEMODIALYSIS-DEPENDENT END-STAGE RENAL DISEASE Lauren M. Porter, DO, Stephanie S. Merrick, MD, and Kenneth D. Katz, MD Department of Emergency Medicine, Lehigh Valley Hospital and Health Network, Allentown, Pennsylvania Reprint Address: Kenneth D. Katz, MD, Department of Emergency Medicine, Lehigh Valley Hospital and Health Network/USF MCOM, Cedar Crest Boulevard and I-78, Allentown, PA 18103
, Abstract—Background: Oral baclofen toxicity is extremely rare, but can affect patients with renal disease due to the drug’s predominant renal clearance of approximately 69–85%. Patients with severely impaired renal function typically develop symptoms soon after initiating baclofen therapy, even at relatively low doses. Case Report: A 69-year-old woman with a history of hemodialysisdependent end-stage renal disease presented to the Emergency Department with encephalopathy, ataxia, and dystonia after the addition of a recent baclofen prescription for back pain (10 mg twice daily). She had been taking baclofen as prescribed for approximately 1 week when, the day prior to admission, she had increased her dose to a total of 40 mg. Diagnostic studies demonstrated the patient had chronic, end-stage renal disease and a supratherapeutic concentration of baclofen. Signs and symptoms resolved with hemodialysis. Why Should an Emergency Physician be Aware of This?: It is of critical importance for emergency physicians to appreciate impaired baclofen clearance in those with underlying renal disease to obviate the potential for significant drug toxicity. Ó 2016 Elsevier Inc. All rights reserved.
inhibition at the presynaptic motor neuron, leading to an antispastic response (1). It is primarily used in spinal cord disorders to limit spasticity; it has also been used to treat drug abuse by acting as an inhibitor in the dopamine reward pathways (2). Oral baclofen toxicity is extremely rare, but—even with therapeutic use—can affect patients with renal disease due to the drug’s predominant renal clearance of approximately 69–85%. Patients with severely impaired renal function typically develop symptoms soon after initiating baclofen therapy, even at relatively low doses (3). Additionally, the presenting symptoms can be quite profound in patients with endstage renal disease—including coma and respiratory depression—compared with the general population (4). Hemodialysis has been reported as a specific treatment modality to rapidly reverse baclofen toxicity in those with renal failure (5). Coincidentally, other authors at the same institution recently treated a comparable case of a patient with similar characteristics and presentation caused by oral baclofen toxicity (6).
, Keywords—baclofen; toxicity; hemodialysis; end-stage renal disease; impaired baclofen clearance
CASE REPORT A 69-year-old woman with a past medical history of endstage renal disease requiring hemodialysis was newly prescribed oral baclofen 10 mg twice daily for chronic back pain. Her routine medications included allopurinol, atorvastatin, Nephrocaps (Valeant Pharmaceuticals, Bridgewater, NJ), calcium acetate, cinacalcet, Colace (Purdue,
INTRODUCTION Baclofen is a lipophilic drug that acts as a gamma-butyric acid (GABA) B agonist with a half-life of 2–6 h. It induces
RECEIVED: 9 September 2016; ACCEPTED: 15 September 2016 1
2
L. M. Porter et al.
Stamford, CT), famotidine, gabapentin, hydroxychloroquine, levothyroxine, methocarbamol, pyridoxine, diltiazem hydrochloride, lidocaine-prilocaine, midodrine, MiraLAX (Bayer, Whippany, NJ), sodium phosphate, and a fentanyl patch. She had been taking baclofen as prescribed for approximately 1 week, when the day prior to admission she had increased her dose to a total of 40 mg. She experienced ataxia and dystonia that worsened throughout the evening, prompting evaluation in the Emergency Department the following day. Her physical examination demonstrated confusion, somnolence, muscle rigidity, and intermittent dystonia of her upper and lower extremities. Both radiographic and laboratory diagnostic testing were unremarkable, demonstrating only her baseline renal dysfunction with a glomerular filtration rate of 6 mL/min. Given her clinical presentation and absence of other obvious etiologies, baclofen toxicity was diagnosed, additional baclofen was withheld, and the patient was admitted to the hospital. The patient’s clinical condition readily improved during a routine 4-h dialysis session on hospital day (HD) 1, eventually returning to baseline neurologic function on HD 3. She was discharged uneventfully on HD 5. A serum baclofen concentration measured 0.51 mg/mL (0.08–0.40 mg/mL) on HD 1 just prior to initiation of hemodialysis, which then declined to 0.17 mg/mL after dialysis. With a dialysis flow rate of 400 mL/min, the calculated clearance of baclofen was 266.67 mg/min. DISCUSSION The mechanism of the patient’s baclofen-induced dyskinesia remains poorly understood. Rodent models have demonstrated that GABA B receptors are expressed on
both dopamine neurons, as well as GABA neurons. This would coincide with the previously reported druginduced dyskinesia reported with dopamine blocking agents. Also in rat models, exposure to baclofen activates the GABA B receptors leading to inhibition of GABAergic and dopaminergic neurons decreasing dopamine release (2). WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS? It is of critical importance for emergency physicians to appreciate impaired baclofen clearance in those with underlying renal disease to obviate the potential for significant drug toxicity. Furthermore, hemodialysis may be an effective treatment for such patients.
REFERENCES 1. El-Husseini A, Sabucedo A, Lamarche J, Courville C, Peguero A. Baclofen toxicity in patients with advanced nephropathy: proposal for new labeling. Am J Nephrol 2011;34:491–5. 2. Cruz HG, Ivanova T, Lunn ML, Stoffel M, Slesinger PA, Lu¨scher C. Bi-directional effects of GABA(B) receptor agonists on the mesolimbic dopamine system. Nat Neurosci 2004;7:153–9. 3. Wu VC, Lin SL, Lin SM, Fang CC. Treatment of baclofen overdose by haemodialysis: a pharmacokinetic study. Nephrol Dial Transplant 2005;20:441–3. 4. Beladi Mousavi SS, Beladi Mousavi M, Motemednia F. Baclofeninduced encephalopathy in patient with end stage renal disease: two case reports. Indian J Nephrol 2012;22:210–2. 5. Brvar M, Vrtovec M, Kovac D, Kozelj G, Pezdir T, Bunc M. Haemodialysis clearance of baclofen. Eur J Clin Pharmacol 2007;63: 1143–6. 6. Niehaus MT, Elliott NC, Katz KD. Baclofen toxicity causing acute, reversible dyskinesia. J Med Toxicol 2016. http:dx.doi.org/10.1007/ s13181-016-0556-6 [Epub ahead of print].
http://dx.doi.org/10.1016/j.jemermed.2016.09.025
Selected Topics: Toxicology BACLOFEN TOXICITY IN A PATIENT WITH HEMODIALYSIS-DEPENDENT END-STAGE RENAL DISEASE Lauren M. Porter, DO, Stephanie S. Merrick, MD, and Kenneth D. Katz, MD Department of Emergency Medicine, Lehigh Valley Hospital and Health Network, Allentown, Pennsylvania Reprint Address: Kenneth D. Katz, MD, Department of Emergency Medicine, Lehigh Valley Hospital and Health Network/USF MCOM, Cedar Crest Boulevard and I-78, Allentown, PA 18103
, Abstract—Background: Oral baclofen toxicity is extremely rare, but can affect patients with renal disease due to the drug’s predominant renal clearance of approximately 69–85%. Patients with severely impaired renal function typically develop symptoms soon after initiating baclofen therapy, even at relatively low doses. Case Report: A 69-year-old woman with a history of hemodialysisdependent end-stage renal disease presented to the Emergency Department with encephalopathy, ataxia, and dystonia after the addition of a recent baclofen prescription for back pain (10 mg twice daily). She had been taking baclofen as prescribed for approximately 1 week when, the day prior to admission, she had increased her dose to a total of 40 mg. Diagnostic studies demonstrated the patient had chronic, end-stage renal disease and a supratherapeutic concentration of baclofen. Signs and symptoms resolved with hemodialysis. Why Should an Emergency Physician be Aware of This?: It is of critical importance for emergency physicians to appreciate impaired baclofen clearance in those with underlying renal disease to obviate the potential for significant drug toxicity. Ó 2016 Elsevier Inc. All rights reserved.
inhibition at the presynaptic motor neuron, leading to an antispastic response (1). It is primarily used in spinal cord disorders to limit spasticity; it has also been used to treat drug abuse by acting as an inhibitor in the dopamine reward pathways (2). Oral baclofen toxicity is extremely rare, but—even with therapeutic use—can affect patients with renal disease due to the drug’s predominant renal clearance of approximately 69–85%. Patients with severely impaired renal function typically develop symptoms soon after initiating baclofen therapy, even at relatively low doses (3). Additionally, the presenting symptoms can be quite profound in patients with endstage renal disease—including coma and respiratory depression—compared with the general population (4). Hemodialysis has been reported as a specific treatment modality to rapidly reverse baclofen toxicity in those with renal failure (5). Coincidentally, other authors at the same institution recently treated a comparable case of a patient with similar characteristics and presentation caused by oral baclofen toxicity (6).
, Keywords—baclofen; toxicity; hemodialysis; end-stage renal disease; impaired baclofen clearance
CASE REPORT A 69-year-old woman with a past medical history of endstage renal disease requiring hemodialysis was newly prescribed oral baclofen 10 mg twice daily for chronic back pain. Her routine medications included allopurinol, atorvastatin, Nephrocaps (Valeant Pharmaceuticals, Bridgewater, NJ), calcium acetate, cinacalcet, Colace (Purdue,
INTRODUCTION Baclofen is a lipophilic drug that acts as a gamma-butyric acid (GABA) B agonist with a half-life of 2–6 h. It induces
RECEIVED: 9 September 2016; ACCEPTED: 15 September 2016 1
2
L. M. Porter et al.
Stamford, CT), famotidine, gabapentin, hydroxychloroquine, levothyroxine, methocarbamol, pyridoxine, diltiazem hydrochloride, lidocaine-prilocaine, midodrine, MiraLAX (Bayer, Whippany, NJ), sodium phosphate, and a fentanyl patch. She had been taking baclofen as prescribed for approximately 1 week, when the day prior to admission she had increased her dose to a total of 40 mg. She experienced ataxia and dystonia that worsened throughout the evening, prompting evaluation in the Emergency Department the following day. Her physical examination demonstrated confusion, somnolence, muscle rigidity, and intermittent dystonia of her upper and lower extremities. Both radiographic and laboratory diagnostic testing were unremarkable, demonstrating only her baseline renal dysfunction with a glomerular filtration rate of 6 mL/min. Given her clinical presentation and absence of other obvious etiologies, baclofen toxicity was diagnosed, additional baclofen was withheld, and the patient was admitted to the hospital. The patient’s clinical condition readily improved during a routine 4-h dialysis session on hospital day (HD) 1, eventually returning to baseline neurologic function on HD 3. She was discharged uneventfully on HD 5. A serum baclofen concentration measured 0.51 mg/mL (0.08–0.40 mg/mL) on HD 1 just prior to initiation of hemodialysis, which then declined to 0.17 mg/mL after dialysis. With a dialysis flow rate of 400 mL/min, the calculated clearance of baclofen was 266.67 mg/min. DISCUSSION The mechanism of the patient’s baclofen-induced dyskinesia remains poorly understood. Rodent models have demonstrated that GABA B receptors are expressed on
both dopamine neurons, as well as GABA neurons. This would coincide with the previously reported druginduced dyskinesia reported with dopamine blocking agents. Also in rat models, exposure to baclofen activates the GABA B receptors leading to inhibition of GABAergic and dopaminergic neurons decreasing dopamine release (2). WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS? It is of critical importance for emergency physicians to appreciate impaired baclofen clearance in those with underlying renal disease to obviate the potential for significant drug toxicity. Furthermore, hemodialysis may be an effective treatment for such patients.
REFERENCES 1. El-Husseini A, Sabucedo A, Lamarche J, Courville C, Peguero A. Baclofen toxicity in patients with advanced nephropathy: proposal for new labeling. Am J Nephrol 2011;34:491–5. 2. Cruz HG, Ivanova T, Lunn ML, Stoffel M, Slesinger PA, Lu¨scher C. Bi-directional effects of GABA(B) receptor agonists on the mesolimbic dopamine system. Nat Neurosci 2004;7:153–9. 3. Wu VC, Lin SL, Lin SM, Fang CC. Treatment of baclofen overdose by haemodialysis: a pharmacokinetic study. Nephrol Dial Transplant 2005;20:441–3. 4. Beladi Mousavi SS, Beladi Mousavi M, Motemednia F. Baclofeninduced encephalopathy in patient with end stage renal disease: two case reports. Indian J Nephrol 2012;22:210–2. 5. Brvar M, Vrtovec M, Kovac D, Kozelj G, Pezdir T, Bunc M. Haemodialysis clearance of baclofen. Eur J Clin Pharmacol 2007;63: 1143–6. 6. Niehaus MT, Elliott NC, Katz KD. Baclofen toxicity causing acute, reversible dyskinesia. J Med Toxicol 2016. http:dx.doi.org/10.1007/ s13181-016-0556-6 [Epub ahead of print].