American Journal of Kidney Diseases
Volume 54, Issue 6 , Pages 1127-1130, December 2009

Treatment of Pregabalin Toxicity by Hemodialysis in a Patient With Kidney Failure

  • Lawrence Yoo, MD

      Affiliations

    • Division of Nephrology, New York University Medical Center, New York, NY
    • ,
  • Daniel Matalon, MD

      Affiliations

    • Division of Nephrology, New York University Medical Center, New York, NY
    • New York University School of Medicine, New York, NY
    • ,
  • Robert S. Hoffman, MD

      Affiliations

    • New York University School of Medicine, New York, NY
    • New York City Poison Control Center and Department of Emergency Medicine, New York University Medical Center, New York, NY
    • ,
  • David S. Goldfarb, MD

      Affiliations

    • Division of Nephrology, New York University Medical Center, New York, NY
    • New York University School of Medicine, New York, NY
    • Nephrology Section, New York Harbor VAMC, New York, NY
    • Corresponding Author InformationAddress correspondence to David S. Goldfarb, MD, Nephrology Section/111G, New York DVAMC, 423 E 23 St, New York, NY 10010

Received 6 January 2009; accepted 1 April 2009. published online 04 June 2009.

Article Outline

Pregabalin is prescribed for neuropathic pain. We report the first case of pregabalin toxicity in a hemodialysis patient and her successful treatment with hemodialysis. The patient was a 30-year-old woman on long-term hemodialysis therapy who experienced significant myoclonus of the arms and legs when her dose of pregabalin was mistakenly increased. The drug has 3 properties that contribute to making it amenable to removal by hemodialysis: relatively low molecular weight (159.23 Da), relatively low volume of distribution (0.5 L/kg), and not bound to plasma proteins. We achieved hemodialysis clearance of 88.8 mL/min, which was associated with resolution of symptoms immediately after hemodialysis.

Index Words: 3-Isobutyl γ-aminobutyric acid (GABA), gabapentin, γ-aminobutyric acid, intoxication, Lyrica, poisoning, renal dialysis

 

Pregabalin (Lyrica; Pfizer, New York, NY) is an analogue of γ-aminobutyric acid (GABA). It is similar in structure to gabapentin, an antiepileptic drug.1, 2 The use of pregabalin is increasing because of its efficacy for neuropathic pain associated with diabetic neuropathy, postherpetic neuralgia, and fibromyalgia and as an adjunctive therapy for partial-onset seizures.3 Significant pregabalin toxicity at doses ranging from 50 to 600 mg/d has been reported.4, 5, 6 We describe a patient on long-term hemodialysis therapy who developed myoclonus after an increase in pregabalin dose. Hemodialysis led to rapid improvement in her symptoms during and immediately after treatment. This case illustrates the toxicity of pregabalin and its treatment in patients with chronic kidney disease.

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Case Report 

A 30-year-old woman was admitted for hypotension and fever. Her medical history was notable for seizure disorder, bladder cancer, and pelvic infections. She had been on hemodialysis therapy for several years because of obstructive uropathy. Her neurological evaluation results were unremarkable. She was given intravenous cefepime, 1,000 mg/d; linezolid, 600 mg, every 12 hours; and oral vancomycin, 125 mg, every 6 hours. Outpatient medications were continued: fentanyl patch, 50 μg every 3 days; midodrine, 10 mg/d; sevelamer hydrochloride, 600 mg every 8 hours; pantoprazole, 40 mg/d; sodium bicarbonate, 650 mg, orally every 8 hours; and levetiracetam, 250 mg, twice daily. She was using pregabalin, 50 mg/d, for neuropathic hand pain. On hospital day 2, the pregabalin dose was increased to 75 mg every 8 hours because of neuropathic back pain. Figure 1 shows a time line of subsequent events. On hospital day 5, she reported uncontrollable contractions of the face and arms. Her mental status was unaffected. A scheduled hemodialysis session was performed on the morning of hospital day 6, but her symptoms worsened that evening. Pregabalin had been administered at 6:00 am and then every 8 hours. She experienced continuous myoclonus of the legs, which left her unable to walk. Blood pressure was 106/61 mm Hg, heart rate was 64 beats/min, and temperature was 36.6°C. Physical examination findings were otherwise unremarkable.

On hospital day 7, pregabalin toxicity was considered. Laboratory results in the morning included the following values: sodium, 140 mEq/L; potassium, 4.8 mEq/L; chloride, 100 mEq/L; bicarbonate, 21 mEq/L; blood urea nitrogen, 31 mg/dL (11.1 mmol/L); creatinine, 8.6 mg/dL (760.2 μmol/L); glucose, 99 mg/dL (5.44 mmol/L); calcium, 10.0 mg/dL (2.5 mmol/L); and hemoglobin, 10.1 g/dL (100.1 g/L). A recurrence of the patient's seizure disorder was thought possible; sepsis was unlikely without fever or leukocytosis, and electrolyte levels were normal. The temporal relationship of the symptoms to the change in pregabalin dose was recognized as the likely cause of her symptoms. Pregabalin therapy was discontinued, and she received hemodialysis for 2 hours that evening with a blood flow rate of 340 mL/min and dialysate flow of 500 mL/min using an AM-BIO100 dialyzer (Asahi Kasei Medical America, Northbrook, IL). After dialysis, myoclonus resolved in her arms and legs, but fine residual tremors were noted around the mouth. On hospital day 8, she received a 4-hour hemodialysis treatment, after which no myoclonus was seen. Pregabalin concentrations were measured (National Medical Services, Willow Grove, PA) before and after hemodialysis for the 2-hour session on day 7 and for the 4-hour course on day 8 (Table 1). Given the hematocrit of 30.1% and dialysis blood flow rate of 340 mL/min, plasma flow rate was 340 × (1 − hematocrit) = 238 mL/min. The extraction ratio of pregabalin was calculated as the difference between the concentration of pregabalin entering the dialyzer and the concentration exiting the dialyzer as a proportion of the concentration that entered: (11 − 6.9)/11 = 37.3%. Dialysis clearance therefore was plasma flow × extraction ratio = (238)(0.373) = 88.8 mL/min.

Table 1. Pregabalin Concentrations
Pregabalin (μg/mL)
Day 7Day 8
Predialysis serum, time 0136.7
Predialyzer serum, 30 min11
Postdialyzer serum, 30 min6.9
Postdialysis serum6.52.0

Note: Pregabalin therapeutic range is up to 9.5 μg/mL; to convert μg/mL to μmol/L, multiply by 6.28.

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Discussion 

Pregabalin (CI-1008 or (S)-3-isobutyl GABA, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid) is an analogue of GABA, a major inhibitory central nervous system neurotransmitter. Its molecular weight is 159.23 Da, its apparent volume of distribution is 0.5 L/kg, and it is not bound to plasma proteins.7, 8 These properties contribute to it being amenable to removal by hemodialysis.

Pregabalin is absorbed rapidly and has oral bioavailability of 90%.9 It is not significantly metabolized, with 99% excreted unchanged in urine.10 Pregabalin has linear pharmacokinetics; plasma concentrations increase proportionally with single-dose increases up to 300 mg and multiple doses up to 900 mg/d.11 The maximum plasma concentration of 1.86 μg/mL after a single 50-mg pregabalin oral dose is achieved at 1 hour in patients with creatinine clearance greater than 60 mL/min (>1 mL/s).12 At a dose of 300 mg/d, maximum steady-state concentrations ranged from 2.5 to 6.0 μg/mL.13 In contrast, patients on hemodialysis therapy 3 times weekly achieve a steady-state concentration of 1.24 μg/mL with 50 mg/d.12 Our patient received 225 mg/d with a predialysis serum concentration of 13 μg/mL, at which point she experienced myoclonus. By comparison, a patient who ingested 11.5 g in a suicide attempt had a peak plasma pregabalin concentration of 60 μg/mL.5

In healthy volunteers, pregabalin was well tolerated up to 900 mg/d.10 Dizziness, somnolence, and ataxia were the most frequently reported adverse events during phase 3 trials; these were mild to moderate in intensity and increased with increasing doses.14 Only anecdotal data correlate pregabalin level with toxicity. Pregabalin was measured during its use in adults with partial seizures and normal kidney function. Levels with doses of 150 and 600 mg/d were 0.29 to 2.84 and 0.87 to 14.2 μg/mL, respectively.15 These values include some greater than the suggested maximum of our reference laboratory of 9.5 μg/mL.

Time to maximum concentration tends to increase with worsening kidney function.8 Pregabalin renal clearance decreased proportionately with decreases in kidney function and were approximately 58% of estimated creatinine clearance. Area under the curve and serum half-life values increased as kidney function decreased. In individuals with normal kidney function, the drug has a serum half-life of 9 hours, whereas during hemodialysis, half-life decreased to 3 hours. Approximately 50% to 60% of circulating pregabalin present at the start of hemodialysis was removed during each 4-hour session. Pregabalin clearance during hemodialysis was estimated by using either plasma or dialysate concentrations and averaged 200 to 250 mL/min. High pregabalin clearance with hemodialysis is consistent with the dialyzability of molecules with low molecular weight and relatively low volume of distribution. The molecular weight of 159.23 Da presumably accounts for less dialysance than that of urea. The efficacy of hemodialysis is entirely consistent with these pharmacokinetics.12 Our measured pregabalin clearance of 88.8 mL/min with hemodialysis was lower than experimentally achieved values, yet was associated with clear efficacy.

Doses of 150 to 600 mg/d of pregabalin have been associated with clinical efficacy in patients with creatinine clearances of 60 to 120 mL/min (1 to 2 mL/s).15, 16, 17 Pregabalin doses should be decreased by approximately 50% for each 50% decrease in creatinine clearance less than 60 mL/min (<1 mL/s). Reduced frequency of pregabalin administration may be considered. A supplemental dose should be given after each 4-hour hemodialysis treatment.12

Providing an extra hemodialysis session is clearly indicated in patients already being dialyzed. Performing the procedure in a patient with chronic kidney disease not on hemodialysis therapy should be reserved for patients with significant neurological or hemodynamic symptoms, such as shock, unresponsiveness, airway compromise, or arrhythmias. In our patient, although symptoms were not life threatening, the patient could not walk and would have warranted dialytic therapy in a patient with chronic kidney disease.

There was a temporal relationship between the high dose and rapid dose increase of pregabalin and the patient's subsequent development of myoclonus. Based on the adverse drug reaction probability scale, the drug was the “probable” cause of the reaction and was not graded as “definite” only because she was not rechallenged with it.18 Peak level on day 7 was 13.0 μg/mL, which is greater than the range of the reference laboratory, although it was in what was considered the therapeutic range (0.87 to 14.2 μg/mL) observed in patients with normal kidney function administered 600 mg/d.15 Hemodialysis produced lower postdialyzer levels (6.9 μg/mL) of pregabalin 30 minutes into the hemodialysis treatment on day 7 with an extraction ratio of 37%, which correlated with the intradialytic clinical improvement.

In summary, we report the first case of pregabalin toxicity in a long-term hemodialysis patient. An association of pregabalin level and myoclonus has not been reported previously in dialysis patients. As predicted from the drug's properties, it was removed by hemodialysis, leading to successful resolution of the drug overdose. More importantly, our case provides a treatment option for clinicians caring for patients with pregabalin toxicity.

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Acknowledgements 

Support: None.

Financial Disclosure: None.

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 Originally published online as doi:10.1053/j.ajkd.2009.04.014 on June 4, 2009.

 This is a US Government Work. There are no restrictions on its use.

PII: S0272-6386(09)00646-5

doi:10.1053/j.ajkd.2009.04.014

American Journal of Kidney Diseases
Volume 54, Issue 6 , Pages 1127-1130, December 2009

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