JRENHEP_104.indd Journal of Renal and Hepatic Disorders 2021;6(1): 7–9 7 Journal of Renal and Hepatic Disorders CASE SERIES Gabapentin Toxicity and Role of Dialysis; Case Series and Literature Review Muzamil Latief1, Mohd Iqbal Bhat2, Mohd Latief Wani1, Obeid Shafi 3, L. Naresh Goud4, Farhat Abbas5, Mohsin Wani6 1Nephrology Division, Government Medical College, Srinagar, India; 2Nephrology Division, ASCOMS Hospital, Jammu, India; 3Flushing Hospital Medical Center, New York, NY, USA; 4Nova College of Pharmaceutical Education and Research, Hyderabad, India; 5Pathology Division, GMC, Srinagar, India; 6Government Medical College, Srinagar, India Abstract Gabapentin is frequently used as an analgesic in patients with chronic kidney disease (CKD). It is excreted exclusively through kidney, and therefore impairment in kidney function could lead to gabapentin accumulation and hence toxicity. We present our experience of 3 cases with Gabapentin toxicity who were managed according to the severity of symptoms. Case 1: A 32-year-old male was found lying unconscious after consuming around 12,000 mg of gabapentin and had respiratory depression, rhabdomyolysis, and acute kidney injury (AKI). Patient was man- aged with supportive care and hemodialysis (HD). Case 2: A 64-year-old male CKD Stage 5 (5D) patient with diabetic neuropathy was started on gabapentin 300 mg daily by his primary care physician 1 week back. Patient started to feel sleepy and developed altered sensorium and myoc- lonus. Discontinuation of gabapentin and a session of HD led to dramatic improvement in patient’s status. Case 3: A 70-year-old female diabetic patient with CKD Stage 3 and had diabetic neuropathy. Her neuropathic symptoms had improved with gabapentin 300 mg twice daily, but lately patient was feeling sleepy during the day and was confused. Discontinuation of the drug led to improvement in symptoms. Gabapentin is a rel- atively safe medication, but in certain clinical scenarios, particularly in impaired renal functions, can lead to severe complications. Moreover, it per se can rarely lead to rhabdomyolysis and AKI. Clinical suspicion and timely decontamination are needed, and sometimes dialytic therapy may be needed. Keywords: dialysis; gabapentin; myoclonus Received: 23 May 2021; Accepted after Revision: 1 September 2021; Published: 14 December 2021 Author for correspondence: Farhat Abbas, Pathology Division, Government Medical College, Srinagar, 190010 Kashmir, India. Email: farahabbas.m@gmail.com How to cite: Latief M et al. Gabapentin Toxicity and Role of Dialysis; Case Series and Literature Review. J Ren Hepat Disord. 2021 6(1):7–9. Doi: https://doi.org/10.15586/jrenhep.v6i1.104 Copyright: Latief M, et al. License: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/ licenses/by/4.0 P U B L I C A T I O N S CODON Introduction Gabapentin is frequently used as an analgesic in patients with chronic kidney disease (CKD). Gabapentin has a favor- able pharmacokinetic profi le (1). This drug has been often used in elderly patients who have multiple comorbidities, including CKD (2). Gabapentin is excreted exclusively via kidney, and therefore impairment in kidney function could lead to gabapentin accumulation and hence toxicity. Most of the published literature on gabapentin toxicity in CKD are case studies (3,4). Gabapentin is eliminated unmetabolized Latief M et al. Journal of Renal and Hepatic Disorders 2021;6(1): 7–9 8 through urine at a rate that is proportional to creatinine clearance. In patients with impaired renal function, gabapen- tin half-life can be prolonged up to 132 h. This prolonged half-life increases the risk of toxicity. In cases reported with gabapentin toxicity, patients had varying manifestations including tremors, altered mental status, and respiratory depression requiring intubation (5). Rhabdomyolysis is a very rare adverse effect of gabapentin and has been reported in a case study (6). We report three patients with gabapen- tin toxicity, which highlight the need of early suspicion and timely intervention. Case Series Case 1 A 32-year-old male, driver by occupation, was found in uncon- scious state with four empty strips of gabapentin (10 tablets in each strip of gabapentin 300 mg) lying bedside. The patient was rushed to hospital and on presentation had a BP of 110/70, was not responding to deep painful stimuli, and had passed urine and stools in bed. The patient had features of respiratory distress. The patient underwent endotracheal intu- bation and lavage. His labs revealed respiratory acidosis with normal counts and X-ray of the chest. After taking a sample for gabapentin levels, the patient underwent a hemodialysis (HD) session via femoral catheter, and post dialysis session he had dramatic improvement in sensorium and respiratory parameters and was extubated in next 12 h. Over next 3 days, creatinine peaked at 2.1 mg/DL. Serum creatine phosphoki- nase (CPK) was 1756 U/L, and lactate dehydrogenase (LDH) was 1140 U/L. Serum gabapentin level was 57 mcg/mL, and he received another session of HD next day. The patient was continued on supportive care and discharged on Day 5 after psychiatric consultation. On follow up at 2 weeks, he is doing well, and renal functions have normalized so have muscle enzymes, and he is continuing follow up with the psychiatrist. Case 2 A 64-year-old male CKD Stage 5 (5D) patient with diabetic neuropathy was started on gabapentin 300 mg daily by his primary care physician 1 week back. The patient started to feel sleepy and subsequently developed altered sensorium and myoclonic jerks. The patient reported to our hospital, and his hemodynamic parameters were normal including biochem- ical parameters (such as sodium 136 mEq/L, potassium 4.7 mEq/L, and calcium 9.9 mg/dL) and blood sugar (112 mg/ dL). Suspecting gabapentin toxicity, serum sample was sent for testing. The patient was given a session of HD for 4 h, and post dialysis he had dramatic improvement. Serum gab- apentin level was 27 mcg/mL. The patient and caregivers were counselled regarding the toxicity risk of this medication. Case 3 A 70-year-old female diabetic patient with CKD Stage 3 and diabetic neuropathy was our third patient. Her neuropathic symptoms had improved with gabapentin 300 mg twice daily, but lately the patient was feeling sleepy during the day and was confused. Her serum electrolytes and ECG were nor- mal, and blood sugars were reasonably controlled. Suspect- ing gabapentin toxicity, it was stopped, and the patient had marked improvement. She was put on nortriptyline for neu- ropathic pain and is doing well on follow up. Discussion In a study which included two cases of myoclonus associated with gabapentin toxicity in the setting of renal disease, the patients settled with HD and peritoneal dialysis (PD). The first patient after discontinuation of gabapentin and two ses- sions of HD had marked improvement and was discharged with normal renal function, a blood urea nitrogen (BUN) level of 20 mg/dL and creatinine (Cr) level of 1.1 mg/dL, and myoclonus had disappeared. In the same study, the second patient was a 55-year-old man with end-stage kidney disease on PD. The patient’s PD treatment was modified from four to six PD exchanges daily. The treatment modification along with discontinuation of gabapentin led to disappearance of myoclonus, and mental status improved within 4 days (7). In patients with renal impairment, the development of myoclo- nus and neurotoxicity may require withdrawal of gabapen- tin. Evidence suggests that serum gabapentin concentrations greater than 15 μg/mL are associated with symptomatic tox- icity. In patients who have normal kidney function, gabapen- tin is rapidly cleared based on its short half-life, therefore toxicity is rare. But in patients with kidney function impair- ment, the threshold for gabapentin toxicity is low. Patients with severe symptomatic toxicity should be considered for dialysis. Both intermittent and continuous forms of renal replacement therapy have been effectively utilized to treat gabapentin-induced neurotoxicity and myoclonus. Neurolog- ical sequelae following administration of the drug to patients with renal failure, varying from subtle changes in mental sta- tus to drowsiness and coma, have been reported in the lit- erature. However, serious cardiovascular and neurological sequelae seen with ingestion of other anticonvulsants such as carbamazepine and phenytoin are not seen with gabapentin, particularly in patients who have normal kidney functions (4). Gabapentin also finds its use in generalized uremic pru- ritus in patients on dialysis who fail to respond to antihista- mines and/or topical emollients (8). The molecular weight of gabapentin is 171.24, which is close to the molecular weight of glucose (MW: 180). The low molecular weight, low protein binding, and low volume of distribution make gabapentin amenable to removal using Gabapentin toxicity and role of dialysis Journal of Renal and Hepatic Disorders 2021;6(1): 7–9 9 3. Miller A, Price G. Gabapentin toxicity in renal failure: The importance of dose adjustment. Pain Med. 2009;10:190–2. http://dx.doi.org/10.1111/j.1526-4637.2008.00492.x 4. Hung T-Y, Seow V-K, Chong C-F, Wang T-L, Chen C-C. Gabapentin toxicity: An important cause of altered conscious- ness in patients with uraemia. Emerg Med J. 2008;25:178–9. http://dx.doi.org/10.1136/emj.2007.053470 5. Jones H, Aguila E, Farber HW. Gabapentin toxicity requir- ing intubation in a patient receiving long-term hemodi- alysis. Ann Intern Med. 2002;137(1):74. http://dx.doi. org/10.7326/0003-4819-137-1-200207020-00029 6. Qiu X, Tackett E, Khitan Z. A case of gabapentin overdose induced rhabdomyolysis requiring renal replacement ther- apy. Clin Case Rep. 2019;7:1596–9. http://dx.doi.org/10.1002/ ccr3.2302 7. Kaufman KR, Parikh A, Chan L, Bridgeman M, Shah M. Myoclonus in renal failure: Two cases of gabapentin tox- icity. Epilepsy Behav Case Rep. 2014;2:8–10. http://dx.doi. org/10.1016/j.ebcr.2013.12.002 8. Lau T, Leung S, Lau W. Gabapentin for uremic pruritus in hemodialysis patients: A qualitative systematic review. Can J Kidney Health Dis. 2016;3:14. http://dx.doi.org/10.1186/ s40697-016-0107-8 9. Goldfrank LR, Flomenbaum NF, Lewin NA, Weisman RS, Howland MA, Hoffman RS. Goldfrank’s toxicologic emergen- cies. 6th ed. Stamford (CT): Appleton & Lange; 1998. 694–5 p. 10. Fernandez MC, Walter FG, Petersen LR, Walkotte SM. Gabapentin, valproic acid, and ethanol intoxication: Elevated blood levels with mild clinical effects. J Toxicol Clin Toxicol. 1996;34(4):437–9. http://dx.doi.org/10.3109/15563659609013815 11. Verma A, St Clair EW, Radtke RA. A case of sustained massive gabapentin overdose without serious side effects. Therap Drug Monit. 1999;21:615–17. http://dx.doi. org/10.1097/00007691-199912000-00006 12. Fernandez MC, Walter FG, Kloster JC, Do SM, Brady LA, Villarin A, et al. Hemodialysis and hemoperfusion for treatment of valproic acid and gabapentin poisoning. Vet Human Toxicol. 1996;38:438–43. 13. Ibrahim H, Oman Z, Schuelke M, Edwards JC. Treatment of gabapentin toxicity with peritoneal dialysis: Assessment of gab- apentin clearance. Am J Kidney Dis. 2017;70(6):878–80. http:// dx.doi.org/10.1053/j.ajkd.2017.05.010 dialysis modalities (5). While the therapeutic and toxic ranges of plasma serum gabapentin levels have not been definitively established, it is suggested that serum level of 2–15 mcg/mL (2–15 mg/L) is therapeutic (9,10). Patients with toxicity symp- toms need monitoring until their symptoms resolve  (11). Early gastric lavage, if the ingestion occurred within 1 h of presentation to a health care facility, and activated charcoal help in decontamination. Further measures that have been used include extracorporeal membrane oxygenation, plas- mapheresis, and dialysis, in addition to the usual supportive care. There is no specific antidote for the drug. HD may be needed, particularly in patients with impaired renal function. In a series describing gabapentin overdose, symptomatic tox- icity effects resolve within 24 h (12). PD also helps in removal of gabapentin. Intensive PD can be used to treat gabapen- tin toxicity, provided the patient is stable; however, in case of emergency, HD will provide much more rapid removal of gabapentin. To avoid toxicity, it would be prudent to monitor gabapentin concentrations in dialysis patients, particularly after changes to dialysis prescription have been inducted (13). Conclusion Gabapentin is a relatively safe medication, but in certain clin- ical scenarios, particularly in impaired renal functions, can lead to severe complications. Moreover, it per se can rarely lead to rhabdomyolysis and acute kidney injury. References 1. Bassilios N, Launay-Vacher V, Khoury N, Rondeau E, Deray G, Sraer JD. Gabapentin neurotoxicity in a chronic haemodialysis patient. Nephrol Dial Transplant. 2001;16:2112–13. http://dx. doi.org/10.1093/ndt/16.10.2112 2. Dogukan A, Aygen B, Berilgen MS, Dag S, Bektas S, Gunal AI. Gabapentin-induced coma in a patient with renal failure. 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