Baclofen-induced neurotoxicity in chronic renal failure patients with intractable hiccups.

To the Editor: Intractable hiccups (>48 h) are unsatisfactorily treated with most medications. Currently, baclofen--a [gamma]-aminobutyric acid (GABA) agonist which is eliminated predominantly by the kidneys--has been documented as one effective therapy for the treatment of intractable hiccups. (1) One of the disturbing side effects of baclofen, however, is neurotoxicity, which is often overlooked and rarely reported in patients with chronic renal failure (CRF). (2-5) We report two CRF patients who rapidly developed neurotoxicity after taking a low dose of baclofen for their intractable hiccups.

Patient 1

A 68-year-old male with CRF was admitted with altered consciousness, blurred vision and muscle weakness for 5 hours. Medication history included famotidine 20 mg daily q.d. for esophageal ulcers and baclofen 5 mg t.i.d. for the previous 4 days due to a 2-week history of intractable hiccups. He denied any head trauma, or recent alcohol, sedative, or hallucinogen abuse.

His body temperature was 36.4[degrees]C, blood pressure 130/85 mm Hg, heart rate 95 beats/min, and respiratory rate 15 breaths/min. Neurologic examination showed mental confusion, incoherent speech (Glasgow coma scale E2V4M5), and paresis with hyporeflexia of all limbs. Blood tests revealed a hemoglobin of 10.2 g/dL, urea of 45 mg/dL and a creatinine of 3.4 mg/dL. A computed tomography (CT) of the brain revealed senile atrophy. With supportive treatment, his neurologic symptoms gradually disappeared over 3 days following the cessation of baclofen, indicative of baclofen-induced encephalopathy, after exclusion of other identifiable causes.

Patient 2

A 73-year-old woman presented with confusion, disorientation, muscle paresis and vomiting for 4 hours. She had a diagnosis of diabetic nephropathy and took glimepiride with allopurinol regularly. Two days previously, she had been given oral baclofen 5 mg t.i.d. for a one-week history of intractable hiccups.

On presentation, she was in a confused state (Glasgow coma scale E3V3M5), and vitals revealed a blood pressure of 150/80 mm Hg, pulse rate 80 beats/min, respiratory rate of 22 breaths/ min and body temperature of 36.2[degrees]C. Neurologic examination showed disoriented consciousness with intact brainstem function, and generalized hypotonia and hyporeflexia. Pertinent laboratory data were unremarkable except for a hemoglobin of 9.8 g/dL, urea of 55 mg/dL, creatinine of 4.8 mg/dL and baclofen of 460 ng/mL. The brain CT showed old ischemic change. Under a working diagnosis of baclofen-induced encephalopathy, she received one course of hemodialysis and discontinued further baclofen use. Serum concentration of baclofen was reduced remarkably after the 8-hour hemodialysis (Fig.). Four hours after hemodialysis, she recovered completely without any neurologic sequelae.

[FIGURE OMITTED]

Oral baclofen can be absorbed almost completely and reaches its peak serum levels around two hours after ingestion. In a healthy patient, most of the ingested baclofen is excreted in an unchanged form in the urine with a half-life ranging from 2 to 6.8 hours. In patients with CRF, however, the recommended dose or even low doses could cause a rapid baclofen accumulation.

To date, there are only seven reported cases of baclofen-induced neurotoxicity in patients with renal failure, including ours (Table). (2-5) Serum levels of creatinine ranged from 1.8 mg/dL to 5.6 mg/dL (mean 3.75 mg/dL). The accumulated doses of baclofen ranged between 30 mg and 90 mg. The interval from the start of baclofen therapy to the onset of acute neurotoxicity ranged from 28 to 96 hours. Altered mentality was the major presenting feature of acute neurotoxicity. The neurotoxic effect of baclofen in CRF appeared to be associated with the degree of renal function impairment, the dose and duration of baclofen. There is no specific antidote for baclofen intoxication. Given these properties--small molecular weight (213 Da), moderately lipophilic with 30% protein binding, and a volume of distribution of 0.83 approximately 2.4 L/kg--hemodialysis is ideally recommended to remove serum baclofen more effectively than peritoneal dialysis or supportive treatment. This is supported by a rapid recovery from baclofen-induced neurotoxicity in our second patient.

Physicians should be aware of the possibility of baclofen-induced neurotoxicity in patients with CRF. Dosage adjustment of baclofen in CRF patients is crucial, and prompt hemodialysis is an effective means of reversing baclofen-induced neurotoxicity.

Chu-Lin Chou, MD

Chiou-An Chen, MD

Shih-Hua Lin, MD

Division of Nephrology, Department of Medicine

Tri-Service General Hospital, National Defense Medical Center

Taipei, Taiwan

Hsin-Hung Huang, MD

Division of Gastroenterology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center Taipei, Taiwan

References

1. Yaqoob M, Prabhu P, Ahmad R. Baclofen for intractable hiccups. Lancet 1989;2:562-563.

2. Dahlin PA, George J. Baclofen toxicity associated with declining renal clearance after ibuprofen. Drug Intell Clin Pharm 1984;18:805-808.

3. White WB. Aggravated CNS depression with urinary retention secondary to baclofen administration. Arch Intern Med 1985;145:1717-1718.

4. Mery JP, Kenouch S. Oral baclofen may be effective in patients with spasticity due to spinal cord injury or disease. Am J Kidney Dis 1987;10:326.

5. Chen KS, Bullard MJ, Chien YY, et al. Baclofen toxicity in patients with severely impaired renal function. Ann Pharmacother 1997;31:1315-1320.

Table. Clinical characteristics of baclofen-induced neurotoxicity in
patients with renal failure

                                                         Baclofen dose
                  Age          S. Cr                     (mg)
Reference         (y)  Gender  (mg/dL)  Purpose          Daily

Dahlin et al (2)  64   M       2.8      Spinal cord      20 mg tid for
                                          injury           2.5 m
White et al (3)   74   F       1.8      Spascitity       10 mg tid for
                                                           2 m and 15 mg
                                                           tid for 4 d
Mery et al (4)    85   M       4.5      Spasticity       10 mg tid for
                                                           3 d
Chen et al (5)    72   F       3.4      Gouty arthritis  10 mg bid for
                                                           2 d
Chen et al (5)    66   F       5.6      Low back pain    5 mg qid for
                                                           1.2 d
This case 1       68   M       3.4      Hiccups          5 mg tid for
                                                           4 d
This case 2       72   F       4.8      Hiccups          5 mg tid for
                                                           2 d

                  Baclofen dose
                  (mg)           Onset (a)  HD         Conscious
Reference         Total          (h)        (session)  disturbance (h)

Dahlin et al (2)  NA             55         -           96
White et al (3)   NA             96         -           36
Mery et al (4)    90             72         -           48
Chen et al (5)    40             48         Twice       24
Chen et al (5)    25             28         -          192
This case 1       60             96         -           72
This case 2       30             48         Once (b)    12

HD, hemodialysis; S. Cr, serum creatinine; h, hour; d, day w, week; m,
month; y, year; NA, not available; -, not done.
(a) The interval from the start of baclofen therapy to develop the onset
of clinical neurotoxicity.
(b) This hemodialysis was 8 hours.