The Oxford Neurological Society would like to welcome and encourage the change in pharmacological recommendations proposed by some members. Namely, we believe that the two group of drugs: the amantadine and anticholinergics are yet another example of basic science that fails to manifest any symptomatic improvement clinically.
A case against amantadine for PD treatment
Amantadine is a non-competitive NMDA glutamate receptor antagonist that both increases dopamine release and blocks dopamine reuptake, and some promising results have been published about its use. However, there is no evidence that amantadine is better than placebo in attenuating motor symptoms, neither has it been shown to alleviate hyperkinesia or dystonia symptoms.
There is also no evidence of usage of amantadine as a first-line treatment, and no evidence to justify the economic expense of its prescription.
Amantadine for compulsive and impulsive behaviour
We recognise that there are a number of case studies supporting the use of amantadine for compulsive and impulsive behaviour, inter alia.
Indeed, the Impulsive Behaviour has been linked to dopamine withdrawal, and an RCT of amantadine showed reduced impulsive behaviours in 12 patients. Thomas and colleagues also reported symptomatic relief in seven and reduced in the remaining five patients (Thomas et al., 2010). Furthermore, the symptoms returned after withdrawal of amantadine, suggesting that it must have alleviated those behaviours.
Poor quality of data and lack of long-term asessment
We would argue, however, that this low-power study did not investigate the effects of amantadine in patients in a period that is long enough to draw any substantial conclusion, or indeed to report on any significant side effects that could outweigh the proposed behavioural enhancements. The study finding also contradicts large observational studies that have found a significant association between compulsive behaviour and amantadine in PD patients (Lee et al., 2011; Weintraub et al., 2010). There are also reports of impulsive behaviours developing after starting amantadine and resolving on its discontinuation (Walsh and Lang, 2012).
In the light of this evidence, we strongly believe that amantadine should not be routinely offered for patients with PD diagnosis, even as a secondary or tertiary treatment for symptoms associated with PD.
Anticholinergics are used as an adjunct treatment to levodopa for people with inadequate symptomatic control in PD. They are, however, likely to cause significant cognitive decline and hallucinations, as well as, increase the risk of falls and urinary retention.
We, therefore, believe that they should not be offered to people with PD who have developed dyskinesia and/or motor fluctuations.
Issues with implementation of the recommendations
The recommendation limiting the use of anticholinergics and amantadine could prove particularly challenging due to the established role of these drugs in the scientific literature over the years. It is currently entrenched in the medical school curriculum and could be hard to overcome for clinicians who do not stay on top of current developments in PD treatment.
“Do not offer” recommendation
We understand why the committee decided against a categorical “do not offer” recommendation for all purposes of amantadine use. However, we believe that a stronger and clearer message is needed for these drugs; many textbooks or drug reviews still feature amantadine as a “promising drug” or as simply less effective for a first line treatment, as if it were equally proven to work.
We believe that it should be made clear that there is no clinical evidence to justify the use of amantadine or anticholinergics, and that there is substantive evidence of adverse effects associated with those drugs.
We trust that the committee reaches similar conclusions and the NICE recommendations for the pharmacotherapy of PD shall be amended accordingly.