Philip Davis Prize Essay Pregabalin: A Future Treatment in the Management of Behavioural and Psychological Symptoms of Dementia?

Transcription

1 Philip Davis Prize Essay 2012 : A Future Treatment in the Management of Behavioural and Psychological Symptoms of Dementia? Dr George Crowther, ST5 in Old Age Psychiatry, Yorkshire Deanery. Correspondence: georgecrowther@nhs.net Abstract Behavioural and Psychological Symptoms of Dementia (BPSD) occur in up to 90% of people with dementia. This collection of psychiatric symptoms is associated with increased rates of carer stress, and admission to residential care. Anxiety is a commonly recognised symptom of BPSD and can cause considerable agitation for the sufferer. Current non-pharmacological and pharmacological treatments for BPSD and anxiety within BPSD exist, but assessment is marred by communication difficulties, and treatment strategies have moderate efficacies at best. In the UK, pregabalin is indicated for peripheral and central neuropathic pain, adjunctive therapy for focal seizures and generalised anxiety disorder. It is not recommended for use in dementia, however, anecdotal evidence is emerging that in small doses it may be a useful agent to treat anxiety symptoms in BPSD. A literature review was undertaken to ascertain what had been published in this area to support clinical practice. No randomised controlled studies (RCTs), open-label studies or systematic reviews on the use of pregabalin to treat agitation, BPSD, or anxiety in dementia were identified. However, there is evidence to support its use to treat generalised anxiety disorder and neuropathic pain in elderly people. If the neuropathology of anxiety in a patient with dementia and without dementia is similar then it might give benefit for treating anxiety in dementia. Unfortunately there is currently a lack of good quality data in this patient group and further research is needed to enable clinical decisions to be evidence based. Introduction The prevalence of dementia increases from approximately 0.7% in people aged years, doubling every 5 years or so to nearly 40% in those aged years. The symptoms and signs of dementia consist both of features attributable directly to cognitive deficits and also to non-cognitive features, some of which include disturbed behaviours (e.g. aggression, wandering, sexually inappropriate behaviour) and psychiatric symptoms (e.g. hallucinations, delusions and affective disturbances). These are sometimes referred to as Behavioural and Psychological Symptoms of

2 Dementia (BPSD), a term introduced by the International Psychogeriatric Association in the early 1990s to facilitate clinical trials in this area [1]. BPSD are experienced in up to 90% of patients with dementia [2] and cause considerable distress for patients and their families [1]. The most common symptoms are apathy, depression, anxiety and agitation [3]. It is estimated that significant anxiety occurs in between 39% and 46% of patients with BPSD [4,5], and age matched prevalence rates of anxiety are 40% higher in patients with dementia than the general population [6]. Anxiety is also a significant contributor to secondary agitation and aggression. Agitation in patients with dementia causes significant patient and carer stress [7] and often results in admission to 24-hour care settings with consequent emotional and financial implications [8]. The prevalence of dementia is predicted to increase; it stands to reason therefore that the prevalence of agitation will increase in parallel [9]. The aetiology of BPSD can be varied and difficult to assess. Physical illness, pain, drug side effects, communication difficulties and environmental factors are all recognised causes [10, 11, 12, 13]. Assessment of either the root cause of BPSD or the symptoms being suffered is notoriously difficult, and although rating scales exist these are often impractical and imprecise. Drug prescribing in patients with BPSD has evolved over the years in a haphazard and anecdotal way. As a result, patients have been exposed to a wide range of drugs, some of which have significant side-effects [14]. Current recommended pharmacological and non-pharmacological strategies for treating BPSD are limited [15, 16, 17], however a number of drug groups have been tried for the management of BPSD including benzodiazepines, antipsychotics, antidepressants, antidementia drugs and anticonvulsants. Several of these have a good evidence base. A detailed review of the various drug treatments is beyond the scope of this essay but useful reviews have been published [18, 19, 20, 21, 22, 23]. potential use in patients with dementia is indicated for peripheral and central neuropathic pain, adjunctive therapy for focal seizures and generalised anxiety disorder (GAD). Its use in patients with dementia is not licensed or recommended but increasing anecdotal evidence is emerging about its efficacy for reducing agitation in BPSD. has been shown to be efficacious in 2

3 treating GAD in the general adult population [24, 25] and is recommended for patients who have not tolerated SSRIs (eg paroxetine) or SNRIs (eg venlafaxine or duloxetine) as first line treatments [26]. s mechanism of action is via Voltage Sensitive Calcium Channels (VSCCs). VSCC s are composed of several subunits which together create a pore in the cell membrane which allows calcium to enter the cell when open. Four transmembrane units join together to form the pore (α-1 unit). In all cases the direction of ion flow is into the cell when the pore is open. Several other proteins are associated with the pore including a γ-unit that spans the membrane and a cytoplasmic β-unit. In addition, there is also an α2δ unit the δ part is transmembrane and the α2 part is extracellular. There are a number of different VSCCs but they are all associated with nerve cell bodies and dendrites and regulate synaptic integration and neurotransmitter release. is an α2δ ligand. It binds to the α2δ unit and has an inhibitory effect which subsequently reduces the release of several neurotransmitters [25]. The memory service in Wakefield, UK receives at least 1,500 new referrals each year from a population of older people of approximately 50,000. A considerable number of those require follow up and subsequent treatment for BPSD. Pharmacological treatment options are often limited due to potentially serious side-effects. is occasionally used in very low doses (eg 25 mg twice daily) for dementia patients who have significant anxiety causing agitation and in whom previous pharmacological interventions have failed or have been stopped due to side-effects. Anecdotal evidence from this use has been positive and few adverse events have been reported. In order to support clinical practice I undertook a review of the literature to ascertain what had been published in this area to support clinical practice. Specifically, I wanted to identify published articles that reviewed pregabalin as a pharmacological treatment for BPSD. Literature search The literature review aimed to identify all randomised controlled trials (RCTs), open-label studies and reviews on the use pregabalin in dementia to target BPSD. Papers for this review were obtained using OVID with the following electronic databases: PsychINFO, PsychArticles, EMBASE and 3

4 MEDLINE. In search one, search terms included: dementia, Alzheimer disease, Lewy Body Dementia, Parkinson disease dementia and vascular dementia. These search terms were combined using the Boolean term or. In search two terms included: pregabalin, pregabaline, Lyrica. These search terms were combined using the Boolean term or. The results of the two aforementioned searches were then combined using the Boolean term and. The search was limited to English language articles, and duplicates were removed. Seventy-three articles were identified and abstracts were searched by hand for relevance. The OVID search was deliberately broad as it was known that little published information existed in this area. Many cited dementia or pregabalin, however these were subtext rather than the focus of the paper. There were no open label studies or systematic reviews directly relating to the use of pregabalin in dementia to target BPSD. One randomised control trial was identified demonstrating the efficacy of treating pain to reduce behavioral disturbances in residents of nursing homes with dementia [12]; pregabalin was one of the analgesic medications used. However, those treated with pregabalin were not considered separately in any published results therefore the effect of pregabalin could not be reviewed. Ongoing trials were also searched using the clinical trials database. One study looking at pain in patients with dementia with behavioral disturbance was identified [27]. This study is completed but as yet unpublished; it lists pregabalin as one of the interventions. No results were available at the time of writing. Pfizer (UK) was also contacted to identify any other unpublished literature but none was identified. A further literature search was performed to review RCTs on the use of pregabalin in GAD in people over 65 years using the same method as above. Search terms included: anxiety, generalised anxiety disorder, generalized anxiety disorder and panic disorder and pregabalin, pregabaline, and Lyrica. Two hundred and four articles were identified and searched by hand for relevance. There was one relevant article. 4

5 Montgomery et al. conducted a randomised, double-blind, placebocontrolled trial of pregabalin in 366 patients over the age of 65 years with GAD. Strict exclusion criteria applied and patients with dementia and amnestic disorder were excluded. 177 people were randomised to receive treatment with pregabalin at a dose titrated up from 50mg/24hrs to a maximum of 600mg/24 hours. 96 were randomised to the placebo arm of the trial. The primary outcome measure was the Hamilton Rating Scale for Anxiety (HRSA) psychic and somatic. Other efficacy measures included the Hamilton Rating Scale for depression (HRSD-17), Global Clinical Impression - Improvement Scale (CGI-I), Symptom Check List 90 Revised (SCL-90-R), Mini-Mental Stated Examination (MMSE) and the SCL-90-R subscale for anxiety. A summary of results is shown in table 1. Significant p values indicate improvement[28]. Table 1: Placebo-controlled study of pregabalin for the treatment of generalised anxiety disorder in older people: summary of outcomes [48] Outcome Measure Change in score at end point* with Change in score at end point* with placebo P - Value HRSA psychic * HRSA somatic HRAS total * HRSD * CGI-I 58.4% 48.4% SCL-90-R anxiety subscale * SCL-90-R *last observation carried forward. An important area highlighted by Montgomery et al was adverse events. Of the 177 people in the treatment arm of the study 10% dropped out because of adverse events. This compared with 9.3% in the placebo arm. The most commonly reported adverse events in the treatment arm, in 5

6 decreasing order of incidence were; dizziness, somnolence, headaches, nausea and infection. Dizziness and somnolence could cause further injury through falls. This trial highlights the potential use of pregabalin for treating GAD in elderly people. The trial was of short duration, had relatively low power and its many exclusion criteria severely restrict its generalisability. This limits its usefulness when considering the management of patients with dementia, who are likely to have considerable co-morbidities. However, age and tolerability data are likely to be similar to the trial group, suggesting that targeting specific anxiety symptoms in patients with BPSD using pregabalin may be a useful and well tolerated intervention. Discussion Although difficult to identify, anxiety is a common source of agitation in patients with dementia. Pain is also a potential source of agitation either through a direct causal pathway or secondary to depression caused by chronic pain. is licensed to treat GAD and neuropathic pain in adults, but is not licensed in dementia. is being increasingly prescribed off licence in low doses in elderly people with dementia to treat agitation thought to be caused by anxiety. It is hypothesised that if pregabalin is used to target either anxiety and/or neuropathic pain in patients with dementia that secondary agitation can be reduced. This review has demonstrated that no randomised, placebo-controlled trials exist to support this practice. However there is some evidence in similar groups [12, 28]. If the neuropathology of anxiety in a patient with dementia and without dementia is similar then one can link this to the potential benefit of using pregabalin for treating anxiety and secondary agitation in dementia. Chronic nociceptive pain (such as arthritis) is known to be common in elderly people. Those with dementia will experience similar rates of pain and have a greater difficulty communicating the experience [11]. A Cochrane review undertaken in 2009 reviewed the use of pregabalin in pain control in adults aged years. Pooled results from 19 studies demonstrated effective pain control for neuropathic pain. No significant analgesic effects were demonstrated in acute nociceptive pain. As neuropathic pain is relatively rare it is unlikely that pregabalin exerts its 6

7 therapeutic effect in those with BPSD via its analgesic effects alone. [24, 25] When considering the tolerability of pregabalin in patients with dementia one has to be vigilant. In a recent meta-analysis of the adverse event profile of pregabalin, Zaccara et al demonstrated that, of the 20 significant adverse events associated with pregabalin, 16 affected cognition and coordination. Of particular note, pregabalin 450mg/day compared with placebo has been shown to increase the incidence of dizziness, incoordination, balance, and ataxia, all of which will predispose to falls and the associated morbidity this brings [29]. These relative risk figures, however, compare favourably with other anxiolytic treatment options, for instance benzodiazepines [30]. Conclusion There is some anecdotal evidence from clinical practice and a good theoretical basis for using pregabalin in the management of anxiety and secondary agitation in patients with BPSD. Treatment of BPSD remains an under researched area and many of the pharmacological strategies rely on the utilisation of medications that were trialled in younger populations with specific target symptoms, (not BPSD), and fewer co morbidities. Old age psychiatrists regularly utilise existing medications outside their specific licence agreements in attempts to relieve distress in this oft neglected patient group. If successful the benefits to the patient (reduced suffering), their families (reduced stress and worry) and society in general (economic burden), are great. Unfortunately there is a lack of good quality evidence to support much of this practice rendering psychiatrists more reluctant to prescribe as they are unable to support decisions with efficacy and safety data. I would argue that a placebo controlled RCT, or at a minimum an open label study into whether pregabalin is effective at reducing anxiety symptoms and secondary agitation would be a worthy research avenue. References 1. Finkel SI, Costa e Silva J, Cohen G, et al. (1996) Behavioral and psychological signs and symptoms of dementia: a consensus statement on current knowledge and implications for research and treatment. International Journal of Psychogeriatrics, 3 (8 Suppl), Dorey JM, Beauchet O, Thomas Anterion C, et al. (2008) Behavioral and psychological symptoms of dementia and bipolar spectrum disorders: review of the evidence of a relationship and treatment implications. CNS Spectrums, 13,

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