What's the evidence for using amantidine and/or methylphenidate for hepatic encephalopathy?

Comment by InpharmD Researcher

A comprehensive literature search found no literature on the neurological benefit of using amantadine in hepatic encephalopathy. One Cochrane review on dopamine agents showed no efficacy in managing symptoms or preventing mortality among these patients compared to placebo or no intervention; however, the paper did not include amantadine. Evidence on use of methylphenidate is limited to a case series in which cognitive impairment in transplant patients was presumed to be related to hepatic encephalopathy; improved mood and cognition and better rehabilitation was observed upon escalation to 20 mg/day doses (Table 1).

Background

A 2014 Cochrane review investigated the efficacy and safety of dopaminergic agents for treatment of hepatic encephalopathy. A total of 5 randomized trials were included, encompassing 144 participants with overt hepatic encephalopathy. The included trials were dated, having been published between 1979 to 1982. None of the included trials assessed amantadine; 3 trials assessed levodopa and 2 assessed bromocriptine. Overall results indicated that these dopamine agents demonstrated no efficacy for the management of symptoms or prevention of mortality related to hepatic encephalopathy compared to treatment with an inactive placebo or no intervention. Relevance of the provided data is limited due to the inclusion of differing medications, as the date of the included trials. [1]

References: [1] Junker AE, Als-Nielsen B, Gluud C, Gluud LL. Dopamine agents for hepatic encephalopathy. Cochrane Database Syst Rev. 2014;2014(2):CD003047. Published 2014 Feb 10. doi:10.1002/14651858.CD003047.pub3
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What's the evidence for using amantidine and/or methylphenidate for hepatic encephalopathy?

Please see Table 1 for your response.

 

Methylphenidate in Post Liver Transplant Patients

Design

 Case series

Case presentation #1

A 61-year-old man with a history of alcoholic cirrhosis exhibited cognitive deficits and psychomotor prior to a liver transplant in the setting of hepatic encephalopathy, which worsened after the transplant in addition to passive suicidal ideation. Despite renal function improvement, mental symptoms persisted.

Methylphenidate was started on day 27, which resulted in an increase in alertness within 24 hours; however, the cognitive impairment remained. After 5 days, the dosage was increased to 20 mg/day, after which mood and cognition slowly improved. By week 4, the patient had regained the ability to read and do crossword puzzles with visibly improved mood. Methylphenidate was discontinued after six weeks of treatment, with no worsening of mental state four days after discharge.

Case presentation #5

A 31-year-old man with a history of cirrhosis due to hepatitis C and prior alcohol use exhibited cognitive deficits prior to a liver transplant, thought to be secondary to hepatic encephalopathy. The patient's liver transplant was complicated by disseminated intravascular coagulation, renal failure, cachexia requiring feeding through a gastrostomy tube, and tracheostomy. Agitation, manifested as physical combativeness and disorientation, improved upon discharge from the surgical intensive care unit; however, the patient expressed passive suicidal ideation and irritability.

Occasional doses of haloperidol 0.5 mg orally did not improve his behaviors. Methylphenidate was started on day 98 at 5 mg/day and gradually increased to 15 mg/day, to which improved mood and motivation were noted. At 20 mg/day, the patient exhibited better rehabilitation effort and mood and continued the dosage after transferring to an inpatient physical rehabilitation center.

Case presentation #6

A 66-year-old man with a history of hypothyroidism and cryptogenic cirrhosis exhibited cognitive slowing pre-transplant thought to be due to hepatic encephalopathy. At the time of the procedure, he was treated with supplemental thyroxine. The patient's liver transplant was complicated by numerous infections, chronic rejection, and tracheostomy. By the fourth month post-transplant, the patient was visibly confused and agitated. He was chronically using a fentanyl drip, which was changed to haloperidol, which was eventually discontinued for the use of buspirone to treat ventilator anxiety.

Methylphenidate was started on day 122 at 5 mg/day, then increased to 10 mg BID over the next 5 days. The patient appeared more alert by day 7; at this point, buspirone was tapered and discontinued. The patient was more engaged by day 15, after which he remained on methylphenidate 20 mg/day with improved sleep and mood as well as response to supportive psychotherapy. The patient continued methylphenidate 20 mg/day after discharge.

Case presentation #7

A 60-year-old woman with a history of cryptogenic cirrhosis exhibited cognitive slowing pre-transplant thought to be due to hepatic encephalopathy. The patient's first liver transplant was met with acute rejection, to which a second transplant was done 13 days later. The patient appeared cognitively impaired and lethargic after her second transplant, with exhibition of passive suicidal ideation. Reduction of cyclosporine doses failed to improve her mental state.

Methylphenidate was started at 10 mg/day on day 30 after the second transplant, to which the patient appeared more alert but still cognitively impaired within 24 hours. A gradual increase to 20 mg/day saw improved rehabilitation effort and better mood, despite emotionally labile episodes, and the patient continued this dosage upon transfer to a nursing home.

Study Author Conclusions

Methylphenidate appears to be useful in the rehabilitation of post-liver transplant patients with cognitive and/or depressive symptoms. Additional clinical series may be expected to further define the role of stimulants in the treatment of postoperative liver transplant patients with neuropsychiatric morbidity.

Notably, the patients were a heterogeneous group with regard to psychiatric syndromes, and formal diagnostic classification was not attempted. Still, adverse events were manageable and did not require discontinuation of methylphenidate.

Careful monitoring of blood pressure may be warranted due to the potential compounded hypertensive effect with immunosuppressants and methylphenidate.

Patients without hepatic encephalopathy were not reported in this write-up.

 

References:
[1] Plutchik L, Snyder S, Drooker M, Chodoff L, Sheiner P. Methylphenidate in post liver transplant patients. Psychosomatics. 1998;39(2):118-123. doi:10.1016/S0033-3182(98)71358-1