Can Nicotine be Used Medicinally in Parkinson's Disease?

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

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

Abstract and Introduction

Abstract

The risk of Parkinson's disease is reduced by cigarette smoking, which raises some unanswered questions. Nicotine, a major component of tobacco smoke, could exert either nonreceptor-mediated biological effects or, more importantly, act on the different subtypes of nicotinic brain receptors, in particular those associated with the nigrostriatal dopaminergic pathway. There is now robust experimental evidence for a neuroprotective effect of nicotine upon dopaminergic neurons. By contrast, in animal models of Parkinson's disease, nicotine alone has slight or no motor effects. However, nicotine may modulate dopamine transmission and has clear motor effects when associated with L-DOPA, reducing L-DOPA-induced dyskinesias. Clinical trials have yielded inconclusive results thus far and are hampered by different designs and small cohorts. Ongoing studies address either symptomatic motor or nonmotor symptoms, or neuroprotection. There is still no agreement on the daily dosage of nicotine or the method of administration. Together, these data suggest that nicotine or nicotinic receptor drugs have therapeutic potential for Parkinson's disease, although the specific treatment regimens remain to be determined.

Introduction

Although many symptoms of Parkinson's disease (PD) are related to the neurodegeneration of the nigrostriatal dopaminergic pathway, other neurotransmitter systems are involved in PD, such as the nicotinic cholinergic system. The exact role of the latter system in the pathophysiology of PD is not fully understood; however, some major results should be highlighted. First, numerous studies converge to support a role of smoking in protection against PD.^[1] Nicotine might be responsible for such an effect and experimental data suggest that it has a neuroprotective action.^[2] Second, there is an interaction between the stimulation of nicotinic receptors and the release of dopamine in the striatum.^[3,4] Interestingly, post-mortem and recent imaging studies show that the density of nicotinic receptors is reduced in the brain and especially in the nigrostriatal dopaminergic system of PD patients^[5] and experimental models of PD.^[4] Finally, despite controversial results, the question has been raised of a possible clinical benefit of nicotine in PD patients. The goal of the present article is to answer, to the best of our current knowledge, the actual question: 'What is the evidence that medicinal use of nicotine in PD is clinically useful?', using epidemiological, preclinical and clinical data. We searched the literature (PubMed) with several keywords: 'nicotine and Parkinson' yielded 154 results, and 'smoking and Parkinson' yielded 655. The Cochrane database reported no review, but nine clinical trials. We added papers from our personal files and older papers quoted among the reviews. Among search results, we mainly selected reviews for experimental data and original papers for all clinical trials. Ongoing trials were searched on the NIH website; more data were collected on the websites of Neuraltus Inc. and the Michael J Fox foundation website.^[101,102]

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Table 1. Open-label clinical trials of the clinical efficacy of nicotine on motor symptoms^†.
Patients (n)	Product (dose)	Duration (total/max dose)^‡	Efficacy's evaluation	Results (efficacy)	Tolerance (AE)	Ref.
Post-encephalitic parkinsonism^§ (13)	Hypodermic injections (1/5–1/10 grain × 3/day)	2–3 weeks	Tone of the muscles, 'shortening and lengthening reactions'	+ Improvement in 9	Change in pulse rate, vomiting	[47]
Tremor > 1 year Parkinsonian tremor (7) (15) (ET, rubral, cerebellar tremor associated with anxiety)	Nicotine hydrogen tartrate 3–6 mg iv. (1–2 mg nicotine)	2 min	Recording of tremor	+ Reduction in 6 at 6 mg, increasing in 1 at 3 mg	'Often' Tingling, numbness, pallor, sick-feeling, perspiration	[51]
Smokers Early-onset IPD (6)	Smoking, gum	Acute	Tremor, rigidity, bradykinesia, gait	+ Smoking > gum; first > second	Good tolerance	[48]
IPD: clinical criteria for preliminary PD H&Y = 1–3; MMS >27, Mattis >123 (15)	Nicotine iv. (1.25 μg/kg/min x 30 min) Transdermal (14 mg/day)	15 days, 30 min (iv.)	Cognitive +++ Arms' bradykinesia and stand– walk–sit test	+ (improvement persists 1 month later)	Good tolerance (no precision)	[59]
Early-onset parkinsonism (4/8 smokers) (8)	Gum (2 mg)	Acute	UPDRS, auditory event-related potentials	+ in smokers, 0 in nonsmokers		[49]
Nondemented IPD; H&Y = 1–3 (22 + 10 controls)	Transdermal (21 mg/day)	39/3 days	Bradykinesia, UPDRS-III; cognitive tests	0 (9 completed)	10 withdrawal due to AE	[42]
Nondemented IPD H&Y = 3 (6)	Transdermal nicotine (105 mg/day)	29/4 weeks	UPDRS total and III, l-DOPA dose	+	Vomiting: 4/6; insomnia: 3; orthostatic hypotension: 6	[52]

^†Among these studies, doses given to patients have been highly variable from 1 to 105 mg/day and duration of treatment before evaluation vary from 1 min to 29 weeks, which may account at least partially for the differences of results.
^‡Duration (total/max dose) means: total duration of administration of nicotine/duration of administration at maximal dose.
^§Parkinsonism: parkinsonism not related to PD as postencephalitic parkinsonism [46] or when there is not enough precision in the article to know if patients included have IPD or other parkinsonism.
+: Efficacy found; 0: No efficacy found.
AE: Adverse event; ET: Essential tremor; H&Y: Hoehn and Yahr; IPD: Idiopatic Parkinson's disease; iv.: Intravenous; UPDRS: Unified Parkinson's Disease Rating Scale.

Table 2. Controlled studies of the clinical efficacy of nicotine on motor symptoms^†.
Type of study	Patients (n treated/n placebo)	Product (dose)	Study's duration/duration of treatment^‡	Primary efficacy criteria	Results (efficacy)	Tolerance (AE)	Ref.
Two independent, placebo-controlled, dose-reversal, double-blind	1 dystonic parkinsonism (little DOPA sensitivity), 1 akinetic former smoker PD(2/2)	Polacrilex gum (4 mg/patch 15/35 mg)	26/19 days (P1) 27/25 weeks (P2)	Self-rating of tremor, rigidity, sleep, thinking	+	Good tolerance, transient increasing of awakenings at night in half	[46]
Placebo-controlled, double-blind	48 mild-to-moderate IPD; no on–off, no dementia (25/23)	Polacrilex gum (2 mg × 3)	4 h 30/2 × 30 min	UPDRS-III Tolerance	0	2 (T) withdrawal < vomiting, 1 (P) < dyskinesia	[43]
Placebo-controlled, double-blind, crossover	16 H&Y = 1–3 Not demented (16/16)	Transdermal (35 mg nicotine, = 14 mg/day)	12 h/12 h	UPDRS-III	p < 0.05	Good; Sleep disturbance (4), nausea (1), sweating (1)	[44]
Randomized, placebo, double-blind	32 No fluctuations, no Dk (16/16)	Transdermal (14 mg/day)	12/3 weeks	Subscore D (bradykinesia, gait) +1/6 subscore E (finger, foot tapping, dexterity) of the CURS	0	Good AE treatment = AE placebo	[45]

^†The one 'positive' trial included only two patients; the report of worsening of motor performance with nicotine was measured in 'acute' treatment conditions and in defined off status, that is, after 12 h without dopaminergic drugs. In the last trial, the treatment was given 3 weeks before double-blind assessment. None of the global or fine motor testing, nor cognitive or psychiatric symptoms, differed between nicotine and placebo.
^‡Study's duration: total duration of the study for each patient; duration of treatment: time during which each patient received nicotine.
+: Efficacy found; 0: No efficacy found.
AE: Adverse events; CURS: Columbia University Rating Scale; Dk: Dyskinesia; H&Y: Hoehn and Yahr; IPD: Idiopathic Parkinson's disease; P: Placebo group; T: Treated group; UPDRS: Unified Parkinson's Disease Rating Scale.

Table 3. Ongoing studies of nicotine in Parkinson's disease patients^†.
Sponsor	Type of study	Product (dose)	Duration	Major end point	Patients (n)	Disease stage
AP-HP (France)	Open-label, randomized, blind examiners	Transdermal (up to 90 mg/day)	30 weeks	UPDRS 'off' motor score	40	Advanced fluctuating PD
Neuraltus Pharmaceuticals, Inc. (USA)	Double blind parallel	Oral nicotine (6 mg/day)	10 weeks	Adverse events, measure of ICD dyskinesias	60	Advanced fluctuating PD
University of Vermont (USA)	Double-blind, crossover	Transdermal (up to 24 mg)	Acute	Impulsivity, stop signal task	60	PD patients with ICD, without motor complications
Michael J Fox Foundation (USA/Germany)	Double-blind, parallel	Transdermal (NA)	NA	NA	150	Naive PD patients

^†All these trials have larger cohorts than published trials. However, there are major differences in the duration of treatment, the dose and the main end points of each trial.
ICD: Impulse control disorder; NA: Not available; PD: Parkinson's disease; UPDRS: Unified Parkinson's Disease Rating Scale. Data from [101,103].

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