Amantadine
Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended because of widespread drug resistance. It is also used for a variety of other conditions. The drug is taken by mouth.
Amantadine has a mild side-effect profile. Common neurological side effects include drowsiness, lightheadedness, dizziness, and confusion. Because of its effects on the central nervous system, it should be combined cautiously with additional CNS stimulants or anticholinergic drugs. Given that it is cleared by the kidneys, amantadine is contraindicated in persons with end-stage kidney disease. Due to its anticholinergic effects, it should be taken with caution by those with enlarged prostates or glaucoma.
The pharmacology of amantadine is complex. It acts as a sigma σ1 receptor agonist, nicotinic acetylcholine receptor negative allosteric modulator, dopaminergic agent, and weak NMDA receptor antagonist, among other actions. The precise mechanism of action of its therapeutic effects in the treatment of CNS disorders is unclear. The antiviral mechanism of action is inhibition of the influenza virus A M2 proton channel, which prevents endosomal escape. Amantadine is an adamantane derivative and is related to memantine and rimantadine.
Amantadine was first used for the treatment of influenza A. After its antiviral properties were initially reported in 1963, amantadine received approval for prophylaxis against the influenza virus A in 1966. In 1968, its antiparkinsonian effects were serendipitously discovered. In 1973, the Food and Drug Administration approved amantadine for use in the treatment of Parkinson's disease. In 2020, the extended-release formulation was approved for use in the treatment of levodopa-induced dyskinesia.
Medical uses
Amantadine was initially developed to prevent replication of the influenza A virus. Its main clinical use today is treatment of Parkinson's disease. Other uses include treatment of drug-induced extrapyramidal side effects, motor fluctuations during levodopa therapy in Parkinson's disease, traumatic brain injury, and autistic spectrum disorders.Parkinson's disease
Amantadine is used to treat Parkinson's disease-related dyskinesia and drug-induced parkinsonism syndromes. Amantadine may be used alone or in combination with another anti-Parkinson's or anticholinergic drug. The specific symptoms targeted by amantadine therapy are dyskinesia and rigidity. The extended release amantadine formulation is commonly used to treat dyskinesias in people receiving levodopa therapy for Parkinson's disease. A 2003 Cochrane review had concluded evidence was insufficient to prove the safety or efficacy of amantadine to treat dyskinesia.In 2008, the World Health Organization reported amantadine is not effective as a stand-alone parkinsonian therapy, but recommended it could be used in combination therapy with levodopa.
Influenza A
Amantadine is not recommended for treatment or prophylaxis of influenza A in the United States. Amantadine has no effect preventing or treating influenza B infections. The US Centers for Disease Control and Prevention found 100% of seasonal H3N2 and 2009 pandemic flu samples were resistant to adamantanes during the 2008–2009 flu season.The U.S. CDC guidelines recommend only neuraminidase inhibitors for influenza treatment and prophylaxis. The CDC recommends against amantadine and rimantadine to treat influenza A infections.
Similarly, the 2011 WHO virology report showed all tested H1N1 influenza A viruses were resistant to amantadine. WHO guidelines recommend against use of M2 inhibitors for influenza A. The continued high rate of resistance observed in laboratory testing of influenza A has reduced the priority of M2 resistance testing.
A 2014 Cochrane review did not find evidence for efficacy or safety of amantadine used for the prevention or treatment of influenza A.
Extrapyramidal symptoms
An extended-release formulation of amantadine is used to treat levodopa-induced dyskinesia in patients with Parkinson's disease. The WHO recommends the use of amantadine as a combination therapy to reduce levodopa side effects.Off-label uses
Fatigue in multiple sclerosis
A 2007 Cochrane literature review concluded that no overall evidence supports the use of amantadine in treating fatigue in patients with multiple sclerosis. A follow-up 2012 Cochrane review stated that some amantadine-induced improvement in fatigue may occur in some people with MS. Despite multiple control trials that have also demonstrated improvements in subjective and objective ratings of fatigue, no final conclusion has been drawn regarding its effectiveness.Consensus guidelines from the German Multiple Sclerosis Society in 2006 state that amantadine produces moderate improvement in subjective fatigue, problem solving, memory, and concentration. Thus, in 2006, GMSS guidelines recommended the use of amantadine in MS-related fatigue.
In the UK, NICE recommends considering amantadine for MS fatigue.
Disorders of consciousness
include coma, vegetative state, and minimally conscious state. Amantadine has been shown to increase the rate of emergence from a MCS, defined by consistent demonstration of interactive communication and functional objective use. In traumatic brain injury patients in the intensive care unit, amantadine has also been shown in various randomized control trials to increase the rate of functional recovery and arousal, particularly in the time period immediately following an injury. Also, significantly improved consciousness has been reported in patients treated for nontraumatic cases of DoC, such as in the case of a subarachnoid hemorrhage, cerebral hemorrhage, and hypoxic encephalopathy. In 2018, the American Academy of Neurology updated treatment guidelines on the use of amantadine for patients with prolonged DoC, recommending the use of amantadine for adults with DoC 4 to 16 weeks after injury to support early functional recovery and reduce disability.Brain injury recovery
In various studies, amantadine and memantine have been shown to accelerate the rate of recovery from a brain injury. The time-limited window following a brain injury is characterized by neuroplasticity, or the capacity of neurons in the brain to adapt and compensate after injury. Thus, physiatrists often start patients on amantadine as soon as impairments are recognized. Some case reports also show improved functional recovery with amantadine treatment occurring years after the initial brain injury. Evidence is insufficient to determine if the functional gains are a result of effects through the dopamine or norepinephrine pathways. Some patients may benefit from direct dopamine stimulation with amantadine, while others may benefit more from other stimulants that act more on the norepinephrine pathway, such as methylphenidate. If treatment with amantadine improves long-term outcomes or simply accelerates recovery is unclear. Nonetheless, amantadine-induced acceleration of recovery reduces the burden of disability, lessens health-care costs, and minimizes psychosocial stressors in patients.Contraindications
Amantadine is contraindicated in persons with end-stage kidney disease, as the drug is renally cleared.Amantadine may have anticholinergic side effects. Thus, patients with an enlarged prostate or glaucoma should use with caution.
Live attenuated vaccines are contraindicated while taking amantadine. Amantadine might inhibit viral replication and reduce the efficacy of administered vaccines. The U.S. Food and Drug Administration recommends avoiding amantadine for two weeks prior to vaccine administration and 48 hours afterward.
Side effects
Amantadine is generally well tolerated and has a mild side effect profile.Neurological
Side effects include drowsiness, lightheadedness, falls, and dizziness. Patients on amantadine should avoid combination with other CNS-depressing agents, such as alcohol. Excessive alcohol usage may increase the potential for CNS effects such as dizziness, confusion, and light-headedness.Rare severe adverse effects include neuroleptic malignant syndrome, depression, convulsions, psychosis, and suicidal ideation. It has also been associated with disinhibited actions and diminished control over compulsions.
Amantadine may cause anxiety, feeling overexcited, hallucinations, and nightmares.