CNS effects of indomethacin: should patients be cautioned about decreased mental alertness and motor coordination?

AIMS: In many European countries as well as in the USA, the leaflet, or even the packaging of indomethacin, contains a specific warning to refrain from activities requiring mental alertness and motor coordination, such as driving a car. In this placebo-controlled randomized study with a crossover design we attempted to find evidence for that warning. METHODS: Indomethacin 75 mg slow release or a visually identical placebo with similar flavour was taken orally twice daily for 2.5 days. It was suggested that indomethacin affects the motor coordination required to avoid obstacles successfully during walking and that this effect will be even stronger when simultaneously performing a cognitive task that puts mental alertness to the test. Nineteen healthy middle-aged individuals (60 ± 4.7 years, eight female) performed an obstacle avoidance task on a treadmill), combined with a cognitive secondary task. Biceps femoris (BF) muscle response times, obstacle avoidance failure rates and composite scores ((100 × accuracy)/verbal response time) were used to evaluate the data. RESULTS: No differences between indomethacin and placebo were found on the outcome measures regarding motor coordination, avoidance failure rates (P = 0.81) and BF response times (P = 0.47), nor on the performance on the secondary cognitive task (P = 0.12). CONCLUSIONS: Even though surrogate methods were used, the current study provides evidence to suggest that there might be no need to caution patients who experience CNS side effects after indomethacin use to avoid activities requiring quick and adequate reactions, such as walking under challenging circumstances and maybe also driving a car.

Split-second decisions on a split belt: does simulated limping affect obstacle avoidance?

During normal gait a suddenly appearing obstacle is avoided either by making a large crossing step (long-step strategy, LSS) or by interrupting the swing phase (short-step strategy, SSS) depending on the time of appearance of the obstacle in the step cycle. Limping changes the proportion of time spent in the swing phase and the question arises whether this could affect the ability to avoid obstacles. This was investigated using a split-belt treadmill that induces behavior that is similar to limping even in normal adults. Subjects walked on a split-belt treadmill with speed ratios between left and right of 2:2 up to 2:8 km/h in combination with obstacle avoidance (OA) on the slow belt. The failure rate of obstacle avoidance increased markedly as speed differences between legs increased. This increment was paralleled by augmented use of the SSS, related to an increase in time pressure. In all split-belt walking conditions, the alternative strategy (LSS) yielded less OA failures but it required much longer preparation time than the SSS. In addition, the prolonged stance phases prior to crossing in the LSS required a concomitant prolongation of the contralateral swing phase. This was difficult to achieve at times and as a result the swing phase was sometimes interrupted, giving rise to a contralateral SSS (and a 2:1 coordination pattern). It is concluded that simulated limping greatly increases the risk of failing to avoid suddenly appearing obstacles.

Dual-tasking interferes with obstacle avoidance reactions in healthy seniors.

Dual-tasking can lead to falls, as does a deterioration of obstacle avoidance (OA) skills. Hence, it is expected that a combination of both would be even more detrimental, especially when OA is time-critical. Previous studies confirmed this expectation, however, due to several limitations in their design it is yet too early to draw any definitive conclusions on the allocation of attentional resources in OA under dual-task conditions. Therefore, attentionally demanding primary and secondary tasks were used with the instruction to perform as well as possible on both tasks. Nineteen healthy senior individuals (60±4.7 years, 8 females) performed an OA task on a treadmill while walking at 3 km/h as a single task and combined with an auditory Stroop task. Biceps femoris (BF) muscle response times, OA failure rates and composite scores were used to evaluate the data. Increased OA failure rates (3%, p=0.03) and delayed BF response times (21 ms, p<0.001) were found under dual-task conditions. Composite scores were reduced during (p<0.001) and just after obstacle crossing (p=0.003). In conclusion, dual-tasking during time-critical OA affects the motor as well as the cognitive task when subjects are instructed to keep up performance on both tasks. This adds to the evidence indicating an increased risk of tripping or falling when attention is divided during walking in the presence of unexpected obstacles.

Unraveling the association between SSRI use and falls: an experimental study of risk factors for accidental falls in long-term paroxetine users.

Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat depression and are also associated with an increased falls risk. However, the biological mechanism underlying accidental falls with SSRI intake has yet to be elucidated. The present experimental study was designed to investigate whether obstacle avoidance skills in long-term (>90 days), senior paroxetine users (61 ± 5.8 years) are affected during gait, simple and challenging postural balance tasks, as well as during manual reaction time tasks. The performance of the paroxetine users was compared with healthy group-matched controls (60 ± 4.8 years). The results demonstrated impaired postural balance in the paroxetine users, especially during one-legged stance or under various dual-task conditions. Although the deficit in one-legged stance could indicate vestibular involvement, this was deemed unlikely because performance of standing on compliant surface with closed eyes remained unaffected. Paroxetine use also failed to affect manual reaction times or obstacle avoidance performance. It is suggested that paroxetine affects attentional capacities particularly in conjunction with balance control. Compared with healthy seniors, long-term senior users of paroxetine seem to be at an increased risk of falling due to impairments in balance control, especially when attention has to be divided between 2 concurrent activities.

The effect of a non-steroidal anti-inflammatory drug on two important predictors for accidental falls: postural balance and manual reaction time. A randomized, controlled pilot study.

Accidental falls in older individuals are a major health and research topic. Increased reaction time and impaired postural balance have been determined as reliable predictors for those at risk of falling and are important functions of the central nervous system (CNS). An essential risk factor for falls is medication exposure. Amongst the medications related to accidental falls are the non-steroidal anti-inflammatory drugs (NSAIDs). About 1-10% of all users experience CNS side effects. These side effects, such as dizziness, headaches, drowsiness, mood alteration, and confusion, seem to be more common during treatment with indomethacin. Hence, it is possible that maintenance of (static) postural balance and swift reactions to stimuli are affected by exposure to NSAIDs, indomethacin in particular, consequently putting older individuals at a greater risk for accidental falls. The present study investigated the effect of a high indomethacin dose in healthy middle-aged individuals on two important predictors of falls: postural balance and reaction time. Twenty-two healthy middle-aged individuals (59.5 ± 4.7 years) participated in this double-blind, placebo-controlled, randomized crossover trial. Three measurements were conducted with a week interval each. A measurement consisted of postural balance as a single task and while concurrently performing a secondary cognitive task and reaction time tasks. For the first measurement indomethacin 75 mg (slow-release) or a visually identical placebo was randomly assigned. In total, five capsules were taken orally in the 2.5 days preceding assessment. The second measurement was without intervention, for the final one the first placebo group got indomethacin and vice versa. Repeated measures GLM revealed no significant differences between indomethacin, placebo, and baseline in any of the balance tasks. No differences in postural balance were found between the single and dual task conditions, or on the performance of the dual task itself. Similarly, no differences were found on the manual reaction time tasks. The present study showed that a high indomethacin dose does not negatively affect postural balance and manual reaction time in this healthy middle-aged population. Although the relatively small and young sample limits the direct ability to generalize the results to a population at risk of falling, the results indicate that indomethacin alone is not likely to increase fall risk, as far as this risk is related to above mentioned important functions of the CNS, and not affected by comorbidities.

Even low alcohol concentrations affect obstacle avoidance reactions in healthy senior individuals.

BACKGROUND: Alcohol is a commonly used social drug and driving under influence is a well-established risk factor for traffic accidents1. To improve road safety, legal limits are set for blood alcohol concentration (BAC) and driving, usually at 0.05% (most European countries) or 0.08% (most US states, Canada and UK). In contrast, for walking there are no legal limits, yet there are numerous accounts of people stumbling and falling after drinking. Alcohol, even at these low concentrations, affects brain function and increases fall risk. An increased fall risk has been associated with impaired obstacle avoidance skills. Low level BACs are likely to affect obstacle avoidance reactions during gait, since the brain areas that are presumably involved in these reactions have been shown to be influenced by alcohol. Therefore we investigated the effect of low to moderate alcohol consumption on such reactions.Thirteen healthy senior individuals (mean(SD) age: 61.5(4.4) years, 9 male) were subjected to an obstacle avoidance task on a treadmill after low alcohol consumption. Fast stepping adjustments were required to successfully avoid suddenly appearing obstacles. Response times and amplitudes of the m. biceps femoris, a prime mover, as well as avoidance failure rates were assessed. FINDINGS: After the first alcoholic drink, 12 of the 13 participants already had slower responses. Without exception, all participants' biceps femoris response times were delayed after the final alcoholic drink (avg ± sd:180 ± 20 ms; p < 0.001) compared to when participants were sober (156 ± 16 ms). Biceps femoris response times were significantly delayed from BACs of 0.035% onwards and were strongly associated with increasing levels of BAC (r = 0.6; p < 0.001). These delays had important behavioural consequences. Chances of hitting the obstacle were doubled with increased BACs. CONCLUSIONS: The present results clearly show that even with BACs considered to be safe for driving, obstacle avoidance reactions are inadequate, late, and too small. This is likely to contribute to an increased fall risk. Therefore we suggest that many of the alcohol-related falls are the result of the disruptive effects of alcohol on the online corrections of the ongoing gait pattern when walking under challenging conditions.

Dual task effects for asymmetric stepping on a split-belt treadmill.

Bilaterally asymmetric stepping during walking is common to a number of pathological gaits (e.g., hemiplegia, limping). In the present work, the attention level of asymmetric stepping was studied by having subjects walk on a split-belt treadmill with symmetric (2 km/h) and asymmetric (2 km/h vs 4 km/h and 2 km/h vs 6 km/h) belt speeds both with and without a dual auditory Stroop task. There was no significant change in response reaction times across walking conditions or between walking and standing. The proportion of stance phase was unchanged by the dual task during symmetric walking. Stance phase proportions, however, significantly increased during dual tasking for the limb on the faster belt for both asymmetric conditions, while they decreased for the limb on the slower belt for the most asymmetric condition. There were also small modifications to double support proportions and a main effect of dual tasking to double support proportion variability. Observed dual task changes showed interference by the cognitive task with asymmetric gait performance, suggesting that asymmetric stepping, such as seen in limping gaits, requires more attention than symmetric walking. Such attention may, in part, be due to the dynamic balance required in asymmetric limb loading and unloading.

NSAIDs and the risk of accidental falls in the elderly: a systematic review.

Accidental falls, especially those occurring in the elderly, are a major health and research topic nowadays. Besides environmental hazards and the physiological changes associated with aging, medication use (e.g. benzodiazepines, vasodilators and antidepressants) and polypharmacy are significant risk factors for falling as well. Exposure to NSAIDs has been associated with accidental falls too, although information on this area is less consistent. Therefore, the main goal of this review is to provide an updated overview of all the evidence published on the risk of falling due to NSAID use thus far. A systematic literature search for material published between 1966 and March 2008 in PubMed, EMBASE, the Cochrane Database of Systematic Reviews, Exerpta Medica, Current Contents and Science Citation Index was combined with a check of the reference lists of all the retrieved articles. Validity and data extraction of the eligible articles was assessed by adapted criteria, based on checklists that were originally developed to assess case-control or cohort studies. From the 16 selected articles, two studies were rejected because of clustering of data and one article was excluded because it contained the same data as that in one of the included articles. None of the articles retrieved included a randomized controlled trial. The remaining 13 studies all showed some lack in completeness of their statistical methods, and much variation in reporting of effects. The overall mean age was high in the study populations, leaving the results to be poorly generalizable to a larger population and other age categories. Despite these imperfections, all studies showed an increased risk of falling due to NSAID use (four significant, nine non-significant), and a tendency towards an increased fall risk with NSAID exposure could be noted. The results shown in the present review suggest that an increased risk for accidental falls is probable when elderly individuals are exposed to NSAIDs. The studies with the highest quality show that the community-dwelling elderly in particular appear to be at higher risk. This review can serve as a comprehensive overview of the published evidence on fall risk of elderly individuals attributable to the use of NSAIDs, and as an inducement for future research.

Online maintenance of sensory and motor representations: effects on corticospinal excitability.

Flexible behavior requires the ability to delay a response until it is appropriate. This can be achieved by holding either a sensory or a motor representation online. Here we assess whether maintenance of sensory or motor material drives the motor system to different functional states, as indexed by alterations of corticospinal excitability. We used single-pulse TMS to measure corticospinal excitability evoked during the delay period of a novel paradigm in which task contingencies, rather than explicit verbal instructions, induced participants to use either sensory or motor codes to solve a delay-nonmatch-to-sample (DNMS) task. This approach allowed us to probe the state of the motor system while the participants were retaining either sensory or motor codes to cross the delay period, rather than the control of short-term storage driven by verbal instructions. When participants could prepare the movement in advance (preparation trials), the excitability of the motor cortex contralateral to the moving hand increased, whereas the excitability of the ipsilateral motor cortex decreased. The increase in excitability was confined to the prime mover, whereas the decrease in excitability extended to cortical territories controlling muscles unrelated to the response. Crucially, these changes in excitability were evoked only during preparation trials and not during trials in which subjects needed to maintain sensory items online (memory trials). We infer that short-term storage of sensory information and preparation of motor responses have differential and specific access to the output stage of the motor system.

Effect of age and height on trunk sway during stance and gait.

The aim of the studies reported here was to quantify changes in balance control for stance and gait tasks with age and to pinpoint possible advantages and difficulties in using these tasks and measures derived from them to identify pathological balance control in patients. Some 470 normal subjects in the age range 6 to 82 were examined for a battery of 14 stance and gait tasks. During the tasks, angular velocity transducers mounted at lumbar 1-3 measured pitch and roll angular velocities of the body. A combination of outcome measures from several tasks was used to create an overall balance control index. Three types of sensory analyses on pitch angle and velocity amplitudes for stance trials were used to quantify possible changes in the contributions of visual, somatosensory and vestibular inputs to balance control with age for 2-legged stance tasks. Correlation analysis on task variables was used to determine the relationship of subjects' age and height on outcome measures. Outcome measures showed a characteristic "L" or "U" shaped profile with a rapid decrease in values between 7 and 25 years of age, a plateau until 55 then a gradual increase with age after 55 years of age for most stance and gait tasks. The sensory analysis technique using differences between stance tests indicated that visual contributions to balance control continuously increased with age between the ages of 15 and 80, and vestibular and lower leg somatosensory contributions remain relatively constant with age. Sensory analysis calculated as commonly-used quotients of outcome measures revealed large variance across all ages, asymmetric distributions, and no clear trends in sensory contributions to stance with age. A third technique based on a discriminant function analysis using measures from model patient populations indicated that proprioceptive but not vestibular contributions first increased with age and then decreased after 55 years of age. Correlations of outcome measures with age and height indicated that both contributed equally to changes in outcome measures between the ages of 7 and 25, otherwise height had no effect. We conclude that both stance and gait tasks should be selected for identifying changes in balance control from that of healthy persons with a preference for gait tasks as these show less variation with age. Because of the large increases in variance in the elderly and those younger than 20 years, appropriate age-matched reference values should be employed to ascertain if trunk sway is out of normal ranges.