Can Nicotine be Used Medicinally in Parkinson's Disease?

Claire Thiriez; Gabriel Villafane; Frédérique Grapin; Gilles Fenelon; Philippe Remy; Pierre Cesaro

Disclosures

Expert Rev Clin Pharmacol. 2011;4(4):429-436. 

In This Article

Studies in Humans

Preclinical studies mentioned above suggest that nicotine might have either a neuroprotective or a symptomatic effect in PD. In the following secttion, we will show that the nicotinic receptors are affected in PD and describe the first clinical studies of nicotine in humans.

Loss of Nicotinic Receptors in PD

Several convergent reports have shown that the density of nicotinic receptors is reduced in patients with PD and that this reduction mainly involves the nigrostriatal system. First, numerous post-mortem studies reported a reduction of such receptors in the striatum of deceased PD patients.[2,31–36] The amplitude of this reduction is marked, ranging between -30 and -50% of control values.[2,35,36] In addition, the substantia nigra was examined once[33] and a significant decrease of nicotinic receptors was also reported. This may result from a cell loss or a primary pathogenic disturbance in receptor number or subtype.

In line with these post-mortem data, recent in vivo studies using PET or SPECT radiotracers that bind to the nicotinic receptors have shown a reduction of these latter receptors, and especially the α4β2 subtype, in the brain of PD patients. For example, two SPECT studies reported a global reduction of the density of these receptors in the cortex of patients with PD.[37,38] More precisely, a PET study confirmed the more specific reduction of α4β2 nicotinic receptors in the striatum (-10%) and the substantia nigra (-14.9%) of nondemented PD patients.[5] Although significant, this mild reduction seems to be unrelated to the severity of PD measured either with clinical scores or with 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine (18F-DOPA) PET.[5]

Overall, post-mortem and in vivo studies confirm the reduction of nicotinic receptors in the brain of PD patients, especially in the nigrostriatal pathway. The main consequence on motor symptoms or disease progression might depend on the different subtypes involved in such processes.

Clinical Effect of Nicotine

With such epidemiological and fundamental data, studies in humans have logically been performed searching for a beneficial effect of nicotine in PD. Despite some benefit observed in case reports,[39,40] more systematic studies of the clinical efficacy of nicotine on motor symptoms yielded controversial results (Table 1 and Table 2. Such discrepancies may result from differences in the clinical stages of PD patients included in these trials, in smoking habits of patients, the method of nicotine administration, dosages and treatment duration (from acute to 29 weeks exposition). In one trial side effects limited the intake of active drug and therefore the evaluation of the efficacy of nicotine;[41,42] however, the overall tolerance was acceptable in most studies. Open-label studies obtain mostly positive results. One of the seven open-label studies[42] found no effect at all, and, more worryingly three out of four controlled studies found no benefit[43–45] (to our knowledge, only four placebo-controlled studies of nicotine on PD symptoms have been reported) (Table 2).[43–46] This mismatch could result from several bias, as for instance, placebo effect or believing in the efficacy of the raters. When analyzing all these studies, it is obvious that their methodologies have major differences that can explain such varied results.

The included patients were different, with atypical parkinsonism in some cases,[46,47] early-onset PD in two studies[48,49] and mild-to-moderate nondemented PD in most studies. According to the results, it is hard to find a link between these criteria and the effects of nicotine, even if it is possible that nicotine could act differently on the different symptoms, thus giving different results according to predominant symptoms. Furthermore, the smoker or nonsmoker state could be an important confounding factor: to our knowledge, every study in smokers has had positive results and, more strikingly, a study found positive results in four smokers and negative results in four nonsmokers.[49] This observation could have different explanations, from a nonspecific effect of well-being of nicotine on smokers, to a different genetic susceptibility or an increase of high-affinity nicotinic receptors in smokers.[50]

Some authors reported a worsening of PD symptoms with nicotine, which was ascribed to a subthreshold dopaminergic stimulation: an inhibitory effect of small striatal dopamine concentrations acting on a type of dopamine receptor.[44,51] The dose could thus be a fundamental factor; for instance, Villafane and colleagues observed an efficacy when transdermal nicotine was higher than 45 mg/day,[52] which could explain the negative results of several other studies.[42,44,45] The method of administration is also a variable, and probably important, factor, as it impacts on the two components of blood concentration of nicotine: the peak and the curve.[53] After a single inhalation, high levels of nicotine reach the brain in 10–20 s, faster than with intravenous administration,[54] which could explain the more potent effect of smoking (as in epidemiological studies) than other routes of administration. Some authors[50] hypothesized that keeping a basal concentration with a patch and adding some peak delivered by gum, intravenous or smoked nicotine, might be the best way to proceed.[46]

Even if some acute trials have found positive results, we can imagine that the duration of nicotine administration might be crucial to observe the benefit of the drug. Some epidemiological and preclinical data argue for a disease-modifying action of nicotine in PD,[55] which could explain the importance of the duration of treatment. Nevertheless, some trials reported positive effects of an acute exposition,[48,49,51] which could be due to a direct symptomatic effect.

Thus, there is not enough evidence to date to conclude about a potential symptomatic or neuroprotective effect of nicotine on PD. The lack of clear evidence can be due to the uncertainty of the optimal dosage, route of administration, duration of treatment or stage of disease. Furthermore, there could be different susceptibility to nicotine from PD patients according to their nicotinic receptors (or maybe other elements) which could also explain some of the results.

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