Therapeutic interventions for sleep disorders in Parkinson's disease
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
Primary objective
To evaluate the efficacy and safety of pharmacological interventions for the management of nocturnal problems in PD.
Secondary objectives
To address the spectrum of pharmacological strategies proposed for the treatment of sleep problems in PD.
To address the methodological quality of trials investigating the treatment of sleep problems in PD.
Background
Parkinson's disease (PD) is a neurodegenerative disorder that affects 1% of people older than 65 years (Twelves 2003; Van Den Eeden 2003).
The effect of ageing in the global population and the consequent changes in demographic structure are expected significantly to increase this prevalence of PD.
Although the classical cardinal signs of this disease are bradykinesia (slowness), tremor (shakiness), rigidity (stiffness) and postural instability (unsteadiness), sleep problems associated with PD significantly compromise the quality of life of these patients (Karlsen 1999). Sleep disturbances do not constitute a new problem in the field of PD. In his original essay, James Parkinson described a clinical stage when, as a consequence of tremor, 'sleep became much disturbed' (Parkinson 1817).
It is estimated that 60% to 90% of patients with PD complain of difficulties related to sleep (Factor 1990; Lees 1988; Tandberg 1998; van Hilten 1993).
These sleep disturbances constitute two different problems: nocturnal sleep disorders and daytime somnolence.
Sleep disturbances may not be a major problem in the early stages of the disease (Carter 1990). However, with disease progression there are specific symptoms of PD that may interfere with global sleep quality. The most frequent sleep problems are sleep fragmentation and nocturia. Others include difficulty with turning over in bed, restless legs syndrome, vivid dreams, hallucinations, dyskinesias, pain, dystonia and others (Lees 1988). All these phenomena result in a worse quality of sleep when compared with a control group of similar age without PD (Ferreira 2006).
Present thinking attributes a multifactorial cause to disturbed sleep quality and/or induced sedation in patients with PD. Some factors are related to the disease itself (night‐time motor or psychiatric disorders) or to co‐morbidity (depression) or ageing, while others are linked to the direct or indirect effects of the numerous drugs prescribed to these patients for improving sleep and wakefulness mechanisms.
The classic factor correlated with disrupted sleep in PD is the duration of L‐dopa therapy (Lesser 1979; Nausieda 1982; Sweet 1975; Tandberg 1998). Conversely, L‐dopa is also frequently proposed as a therapeutic strategy to deal with sleep problems in PD patients.
Few clinical trials have been conducted in patients with PD to study specifically the effects of a given antiparkinsonian drug on sleep quality. These include open‐label non‐controlled clinical trials that have investigated the efficacy of a sustained‐release formulation of L‐dopa in the treatment of nocturnal disabilities in PD (Jansen 1988; Lees 1987; Van den Kerchove1993). Overall, the results suggested an improvement in night‐time symptoms. Other interventions have included: a bedtime immediate‐release dose of L‐dopa; continuous subcutaneous overnight apomorphine for nocturnal problems; and desmopressin for nocturia (Leeman 1987; Reuter 1999; Stocchi 1998; UK Madopar CR 1989).
The prevalence of these problems, their effect on the quality of life of patients with PD and the absence of a well defined strategy to approach these problems justify that this Cochrane systematic review of the literature be conducted.
Objectives
Primary objective
To evaluate the efficacy and safety of pharmacological interventions for the management of nocturnal problems in PD.
Secondary objectives
To address the spectrum of pharmacological strategies proposed for the treatment of sleep problems in PD.
To address the methodological quality of trials investigating the treatment of sleep problems in PD.
Methods
Criteria for considering studies for this review
Types of studies
We will include all randomised trials comparing any pharmacological therapy with placebo or no treatment using both random and quasi‐random methods of allocation.
Types of participants
We will include patients with a clinical diagnosis of PD and an abnormal sleep quality defined according to validated sleep rating scales. In the absence of a definition of a sleep disorder based on predefined rating scales we will include trials that state a clear and explicit definition of a nocturnal problem associated with PD. We will include patients of all ages, any duration of PD, all concomitant therapies and any duration of treatment. Included articles must have an adequate definition of sleep disturbance.
Types of interventions
We will include any pharmacological therapy or strategy (e.g. change in daily dosage, time of last dose, nocturnal administration, etc.) compared with placebo or with placebo or no treatment. All dosages and modes of administration will be accepted.
Types of outcome measures
Primary outcome measure
* Change in sleep quality scale values, generic or disease specific (e.g. Pittsburgh Sleep Quality Index (PSQI), SCOPA‐SLEEP night‐time sleep subscale, Parkinson's disease sleep scale, etc.)
Secondary outcome measures
* Subjective improvement in the frequency, duration or intensity of any sleep problem associated with PD
*
Changes in quality‐of‐sleep assessments
*
Subjective improvement in morning akinesia
*
Objective improvement in morning akinesia
*
Changes in the subjective evaluation of clinical status by clinicians
*
Changes in quality‐of‐life assessments
*
Number of dropouts after randomisation
*
Tolerability as measured by withdrawal from trials
*
Safety as measured by the incidence and type of adverse effects, serious adverse effects and adverse effects leading to withdrawal
Search methods for identification of studies
We will draw on the search strategy developed for the Movement Disorders Group as a whole and identify relevant trials by searching the following electronic databases:
1. Cochrane Movement Disorders Group Specialised Register (see Review Group details for more information);
2. Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2005, Issue 4);
3. MEDLINE (1966 to 2005);
4. EMBASE (1966 to 2005);
In addition, we will also:
5. search the reference lists of identified trials and review articles;
6. handsearch the journal Movement Disorders and the abstract books of international congresses of movement disorders and sleep;
7. attempt to make personal contact with other researchers in the field;
8. seek contact with drug manufactures in order to obtain additional information on trials published elsewhere and unpublished trials.
Our search terms will be a combination of thesaurus‐based and free‐text terms covering both the procedure of interest (pharmacological treatment or strategies) and PD. For MEDLINE and EMBASE we will use a modified version of the Cochrane controlled trials search strategy.
We will select trials irrespective of their publication status, language or blinding.
Data collection and analysis
Selection of trials
The authors will assess titles and abstracts identified from the literature search and obtain the full text of potentially relevant studies, resolving disagreements concerning inclusion by discussion. A second reviewer will subsequently extract and double check the data. We will attempt to contact study authors and/or the relevant drug manufacturers for further details of any missing data.
Quality assessment
Two reviewers will assess trials fulfilling the review inclusion criteria for methodological quality. We will extract information about randomisation and allocation concealment, blinding, sample size and dropouts after randomisation. This will be done using the criteria described in the Cochrane Handbook for Reviewers (Clarke 2003), which are based on the empirical evidence of a strong association between poor allocation concealment and overestimation of effect (Schulz 1995). This is defined as:
A. low risk of bias (adequate allocation concealment);
B. moderate risk of bias (unclear allocation concealment);
C. high risk of bias (inadequate allocation concealment, i.e. quasi‐randomised studies).
Data collection
Two reviewers will independently extract the data of included trials, with disagreement being resolved by extraction by a third reviewer.
Trials will be identified by the name of the first author and the year in which the trial was first published, and ordered chronologically. The following data will be extracted, checked, and recorded.
1. Characteristics of trials:
* year of publication, authors, country, language;
* publication status;
* sponsor of trial (specified, known or unknown);
* study design;
* control group;
* duration of follow up.
2. Characteristics of participants:
* number of participants in each group;
* age, sex;
* diagnostic criteria;
* disease severity measures.
3. Characteristics of interventions:
* class of pharmacological agent, dose, mode of administration, schedule.
4. Characteristics of outcome measures:
* whenever possible, the number of events previously listed under 'Types of outcome measures' will be recorded for each arm of randomised trials;
* primary outcome: clearly stated or unclear;
* further outcomes;
* access to single participant data.
Subgroup analysis
We will perform a subgroup analysis for each pharmacological agent or therapeutic strategy, and also an independent subgroup analysis for each sleep problem identified.
Data synthesis
We will analyse dichotomous data by calculating the relative risk for each trial, with the uncertainty in each result being expressed using 95% confidence intervals.
We propose to analyse continuous data by using the mean and standard deviation values for each trial and calculating the effect size (average mean difference) and the 95% confidence interval whenever comparisons made between the mean duration of symptoms in two groups are normally distributed.
If possible, we will perform formal meta‐analysis, although heterogeneity of the studies may prevent this.
Heterogeneity and publication bias
We will initially assess heterogeneity (degree of difference between the results of specific trials) by inspection of graphical presentations and by using a statistical test for heterogeneity (Chi‐squared). We anticipate that there will be between‐trial variation due to heterogeneity of definitions of the night‐time problems, and targeted patients and small sample sizes in the available trials. In order to assess the impact of these possible sources of heterogeneity on the main results we will perform subgroup analyses.
For the estimation of potential asymmetry and investigate potential publication bias, we will construct a funnel plot to demonstrate the precision of included trials (plots of logarithms of the relative risk for efficacy against the sample size). We will use a fixed‐effect model throughout the review, except in the event of significant heterogeneity between the trials (if a P value is less than 0.10), when we will use the random‐effects model.
In order to allow for an 'intention‐to‐treat analysis', we will seek data detailing the number of patients with data for each outcome event in each allocated treatment group, regardless of compliance and irrespective of whether or not these patients were subsequently deemed ineligible or otherwise excluded from treatment or follow up. If published data are not available, we will contact the principal investigators of the relevant trials for further information.
We will analyse the data using the Cochrane RevMan software.
Sensitivity analyses
For positive results we will also assess the effect of missing outcomes for patients excluded after randomisation by carrying out best and worse case sensitivity analyses. Other prespecified sensitivity analyses will be performed:
1. only trials in which the method of randomisation ensured adequate concealment of treatment allocation;
2. only trials in which all patients had a clinically diagnosed sleep disturbance based on validated sleep rating scales;
3. only trials that were placebo controlled;
4. only trials in which the follow up was 12 weeks or longer.
