Parkinsonism and the place of Amantadine - Review Analysis

Parkinson's disease is a common neurological condition, especially in an aging population (1). Parkinson's disease is characterized by muscular stiffness, tremors, and other symptoms as it progresses.

The major cause of parkinsonian motor symptoms is striatal dopamine deficiency. So, to counteract this, most parkinsonian drug therapies are centered on 'correcting' the dopaminergic deficiency, hence easing the disease's primary motor symptoms. Levodopa has revolutionized the treatment of Parkinson's and has been the gold standard for many decades now. (2)

Studies now confirm that dyskinesias, described as involuntary, erratic, writhing movements of the face, arms, legs, or trunk, are one of the most common motor problems in Parkinson's disease patients, reducing their quality of life. (1) Dyskinesias occur due to the over-release of dopamine, in individuals who have been treated for a long time with levodopa. (1)

On chronic use, levodopa can have substantial physical and psychological side effects. (3) This has turned the focus on a lookout for new medications with better side-effect profiles to replace or supplement levodopa while lowering drug-associated dyskinesia.

Amantadine, a member of the adamantanamine class of drugs, administered alone or in combination with levodopa is considered another treatment option for Parkinson's. (4)Early research investigating the efficacy of Amantadine in Parkinson's disease patients suffering from dyskinesias has concluded that Amantadine(300 mg /day) exhibited significant benefits against dyskinesias when compared with placebo(1)in 60–70% of patients. (1)

Initially licensed in 1966 as preventive medicine against Asian influenza, Amantadine showed promise in Parkinson's disease after Schwab and colleagues co-incidentally found that one of their Parkinson's disease patients' cardinal symptoms improved after he was given Amantadine for flu prevention. These interesting findings prompted the first clinical study of Amantadine for Parkinson's disease, in 1968. (4)

The position of Amantadine in Parkinson's: A historical perspective- Amantadine became a well-known treatment option for Parkinson's in the 1970s, both as a stand-alone drug and as a supplement to levodopa or anticholinergic drugs. (4)

As experiments started revealing a major role of increased striatal glutamatergic signaling in the pathophysiology of levodopa-induced dyskinesias(4), the focus shifted to exploring the potential of this drug in controlling dyskinesia.

The discovery of Amantadine's glutamate receptor antagonistic properties propelled research in establishing its antidyskinetic efficacy in the 1990s. Today, Amantadine is the only medicine that is effective in treating levodopa-induced dyskinesias in Parkinson's disease patients. (4)

The drug pharmacology: How does Amantadine function in Parkinson's?

Amantadine is a synthetic tricyclic amine of the adamantanes class. It is available commercially as hydrochloride or sulfate salt. It is available as immediate-release or extended-release oral formulations and intravenous infusions. Even though this drug has been around for 5 decades, the exact mechanisms by which amantadine acts are yet to be fully explored. (4)

Amantadine exhibits a unique combination of antiparkinsonian and anti-dyskinetic properties, which makes it stand apart from other antiparkinsonian drugs. Research now highlights that its antiparkinsonian effectiveness is attributed to its effects on dopaminergic transmission, whilst anti-glutamatergic activities are recognized as the primary mechanism of its anti-dyskinetic activity. (4)

Amantadine increases dopamine transmission through both pre-and post-synaptic pathways. Owing to its low affinity, a non-competitive antagonist of N-methyl-D-aspartate receptor (NMDA) receptors, amantadine exhibits a strong anti-dyskinetic impact. (4)

Amantadine is now utilized as a reference medication in clinical studies to assess the efficacy of new medicines to treat dyskinesia. (4)

FDA approved uses of amantadine in clinical practice

• Symptomatic parkinsonism-Oral amantadine, as monotherapy or as an addition to levodopa, has remained a well-established treatment for motor symptoms in Parkinson's disease. It has been documented extensively as safe and effective drug therapy for early Parkinson's disease. (4)
• Research consistently highlights that Amantadine significantly improves all cardinal motor aspects of Parkinson's disease, while exhibiting a modest overall anti-parkinsonian effect. (4)
• Combination therapy - Combination therapy improves the efficacy by targeting multiple pathways; thus, the use of dopaminergic agonists in conjunction with Amantadine is a viable option. Because dopamine agonists, MAO-B inhibitors, and external-release Amantadine are all available in once-daily formulations, this approach is convenient for patients too. (4)

The effects of the extended-release formulation of Amantadine on motor fluctuations were investigated in the EASE-LID investigations in patients with Parkinson's disease and levodopa-induced dyskinesias. This study provided the first high-quality evidence that Amantadine can reduce motor fluctuations in Parkinson's disease patients. On this basis, the FDA authorized ADS-5102 for a second indication in February 2021 as adjunctive therapy to levodopa in Parkinson's disease patients. (4)

• Levodopa-induced motor complications- Amantadine is the only medicine with demonstrated effectiveness in lowering levodopa-induced dyskinesias in people with Parkinson's disease, without increasing parkinsonism. (4)
• A major study revealed that Immediate-release Amantadine reduced levodopa-induced dyskinesias by 60%, with clear effectiveness lasting up to a year. (4)
• Drug-induced parkinsonism-Antipsychotic-induced parkinsonism is one of the most prevalent kinds of drug-induced parkinsonism. (4)
• However, experts warn that before administration, the benefits of Amantadine in drug-induced parkinsonism must be carefully weighed against the adverse effects.

Other off-label clinical uses of amantadine-(4)

• Atypical parkinsonian illnesses including multiple system atrophy and progressive supranuclear palsy have a poor response to dopaminergic treatments in terms of parkinsonian motor characteristics. In such individuals, immediate-release Amantadine is frequently used to alleviate parkinsonism.
• Huntington's disease chorea and levodopa-Induced dyskinesias in Parkinson's disease often share overlapping pathophysiology. Considering such scenarios, the American Academy of Neurology's 2012 recommendations include Amantadine to be useful in reducing chorea, while the degree of impact is yet to be explored.

Analyzing the Safety of Amantadine- Amantadine has a low side effect profile, and most of the side effects are reversible with the withdrawal of medication. (5)

Patients with a history of drug-induced psychosis should avoid Amantadine. Caution with usage and dosage adjustments may be necessary for those with heart disease, seizure disorder, hepatic impairment, and renal impairment.

Sudden Amantadine withdrawal can result in an immediate exacerbation of parkinsonism or levodopa-induced dyskinesias, as well as mental status abnormalities such as agitation and delirium; thus a stepwise down-titration is recommended. (4)

Drug formulations and dosage recommendations-Oral immediate-release amantadine is a widely used formulation. (4)

An extended-release version of amantadine was authorized by the Food and Drug Administration (FDA) in 2018 for the treatment of Parkinson's disease. In February 2021, ADS-5102 was also approved by the FDA for the treatment of motor fluctuations in patients with Parkinson's disease. (4)

Amantadine is available as an intravenous solution in several countries. This unique feature makes this drug a primary choice during periods of severe swallowing problems, or during episodes of acute and severe worsening of Parkinson's.(4)

For the treatment of Parkinson's disease, amantadine is given orally at 100 mg twice daily and increased to 200 mg twice daily as needed. For patients taking other parkinsonian drugs, dosing should begin at 100 mg once daily. (5)

Take home message for clinicians-

• The efficacy of amantadine in the symptomatic treatment of Parkinson's disease has survived the test of time, and this medicine is widely used by neurologists today.
• Its unique pharmacological effects combine dopaminergic and glutamatergic features, which accounts for its dual impact on parkinsonian signs and symptoms as well as levodopa-induced dyskinesia.
• Growing evidence from clinical trials has validated amantadine's effectiveness in treating levodopa-induced dyskinesias in Parkinson's disease patients, and clinical investigations have also provided robust support for its ability to minimize motor fluctuations.

The way forward- FDA's approval of two innovative external-release formulations of amantadine in the last four years (4) has reignited interest in this medicine as a potent pharmacotherapy in Parkinson's.

Medical research is yet to decipher amantadine's unique pharmacological mechanisms in controlling dyskinesia. With accumulating research supporting the superior potency of this drug among other anti-parkinsonian drugs, the fullest potential of amantadine needs to be explored at the earliest.

References

1. Sawada H, Oeda T, Kuno S, et al. Amantadine for dyskinesias in Parkinson's disease: a randomized controlled trial. PLoS One. 2010;5(12):e15298.

2. Smith Y et al. Parkinson's disease therapeutics: new developments and challenges since the introduction of levodopa. Neuropsychopharamacology. 2012; 37(1):213-246

3. Crosby NJ et al. Amantadine in Parkinson's disease. Cochrane Database of Systematic Reviews. 2003(1):1-21.

4. Rascol, O et al. Amantadine in the treatment of Parkinson's disease and other movement disorders. The Lancet Neurology. 2021;20(12): 1048-1056

5. Adapted from https://www.ncbi.nlm.nih.gov/books/NBK499953/ accessed on 05.05..2022