Effects of upper respiratory tract illnesses, ibuprofen and caffeine on reaction time and alertness Andrew P. Smith & David J. Nutt
Psychopharmacology ISSN 0033-3158 Psychopharmacology DOI 10.1007/s00213-013-3339-7
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Author's personal copy Psychopharmacology DOI 10.1007/s00213-013-3339-7
ORIGINAL INVESTIGATION
Effects of upper respiratory tract illnesses, ibuprofen and caffeine on reaction time and alertness Andrew P. Smith & David J. Nutt
Received: 2 July 2013 / Accepted: 14 October 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Rationale Compared with healthy individuals, those with upper respiratory tract illnesses (URTIs) report reduced alertness and have slower reaction times. It is important to evaluate medication that can remove this behavioural malaise. Objectives The aim of this study was to compare the effects of a combination of ibuprofen plus caffeine with ibuprofen and caffeine alone, and placebo on malaise associated with URTIs, as measured by psychomotor performance and mood testing. Methods Volunteers were randomly assigned to one of four medication conditions as follows: 200 mg ibuprofen and 100 mg caffeine; 200 mg ibuprofen; 100 mg caffeine; placebo. A single oral dose was given and testing followed for 3 h. Efficacy variables were based on the volunteers' performance, measured by psychomotor performance and mood. Results The pre-drug results confirmed that those with an URTI had a more negative mood and impaired performance. Results from the simple reaction time task, at both 55- and 110-min post-dosing, showed that a single-dose of caffeinated products (I200/C100 and CAF100) led to significantly faster reaction times than IBU200 and placebo. These effects were generally confirmed with the other performance tasks. Subjective measures showed that the combination of ibuprofen and caffeine was superior to the other conditions. There were no serious adverse events reported, and study medication was well tolerated. Conclusions The results from the post-drug assessments suggest that a combination of ibuprofen and caffeine was the optimum treatment for malaise associated with URTIs in that
A. P. Smith (*) Centre for Occupational and Health Psychology, School of Psychology, Cardiff University, 63 Park Place, Cardiff CF10 3AS, UK e-mail:
[email protected] D. J. Nutt Neuropsychopharmacology Unit, Division of Brain Sciences, Imperial College, London, UK
it had significant effects on objective performance and subjective measures. Keywords Upper respiratory tract illness . Ibuprofen . Caffeine . Reaction time . Alertness
Introduction Upper respiratory tract illnesses (URTI), such as the common cold, not only induce local symptoms, such as a runny nose, but lead to a behavioural malaise (see Smith 1990, 2012a for reviews). This malaise can be measured by both subjective reports of mood and objective indicators of performance, such as reaction time (e.g. Bucks et al. 2008; Drake et al. 2000; Hall and Smith 1996; Matthews et al. 2001; Smith et al. 1998, 1999a; Smith 2012b, c, 2013). Impairments of reaction time and reductions in alertness have been observed with both experimentally induced and naturally occurring URTIs. This methodology can now be applied to determine whether medication not only produces symptomatic relief but also removes the malaise. This means that one can examine whether over-the-counter (OTC) medication improves quality of life, as indicated by subjective well-being and objective measures of function. Previous research aimed at removing malaise associated with URTIs has been based on the finding that caffeine can lead to increased alertness and performance in those with URTIs (Smith et al. 1997). Such an effect is consistent with the results showing that caffeine removes the impairments seen in other low alertness states (e.g. sleep deprivation— see Smith 2013, for a review). Other research (Smith et al. 1999b) has focused on the possible neurotransmitter basis of malaise and shown that a drug (Idazoxan) which increases the turnover of central noradrenaline also removes the impairments associated with URTIs. Caffeine is often added to OTC medication because it can have an adjuvant effect and increase the efficacy of other compounds. This can be seen by considering the literature on ibuprofen and caffeine.
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Ibuprofen, a 2-phenylpropionic acid derivative that chemically belongs to a class of 2-phenylalkanoic acids, is a nonsteroidal anti-inflammatory drug that has been recognised for its analgesic potential for many decades (Busson 1986). It has been used for an ever increasing range of clinical conditions for a long period of time (e.g. dental pain—Needle and Cooper 1976; Dionne and Cooper 1978; episiotomy pain—Bloomfield et al. 1974; and migraine—Pearce et al. 1983). Because ibuprofen has reliable analgesic activity and a good record of safety, it is now approved in many countries for OTC self-medication. Approved indications for OTC use are for the temporary relief of minor aches and pains associated with the common cold, headache, toothache, muscular aches, menstrual cramps, and other painful conditions. Winther and Mygind (2001) argued that ibuprofen may influence both systemic and nasal symptoms of URTIs. This was based on the view that the pathogenesis of the common cold is associated with inflammation of the nasal mucous membrane with polymorphonuclear cells and increased levels of inflammatory cytokines and mediators in nasal secretions. They investigated the effect of ibuprofen, 400 mg three times daily, in a placebo controlled trial of 80 adults with naturally occurring common colds. Ibuprofen caused a significant reduction of systemic symptoms (headache, earache, muscle/joint pain and body temperature) and also a 33 % reduction in the symptom score for sneezing. Other research has shown that treatment of URTIs with ibuprofen leads to few adverse events (Moore et al. 2002). Grebe et al. (2003) also examined the effects of ibuprofen on URTIs and found that 89 % of patients in the ibuprofen condition gave a global efficacy rating of “good” to “excellent” (compared with 32 % in the placebo group). Eccles (2006) reviewed the literature on the efficacy of OTC analgesics for the treatment of URTIs. He concluded that “despite the lack of clinical data on the safety and efficacy of analgesics for the treatment of colds and flu symptoms, a case can be made that these medicines are safe and effective for the treatment of these common illnesses”. Combinations of antiviral/anti-mediator treatment have also shown to be an effective treatment for URTIs (Gwaltney et al. 2002). Early clinical studies have demonstrated that caffeine enhances the analgesic efficacy of paracetamol, aspirin or their combinations in these products. Laska et al. (1994) combined data from 30 controlled clinical trials involving more than 10, 000 volunteers from a variety of pain models. A statistically significant effect was demonstrated for caffeine as an analgesic adjuvant with a pooled relative potency index of 1.4. Po and Zhang (1998) conducted a meta-analysis of the analgesic efficacy of ibuprofen alone and in combination with caffeine. They concluded that ibuprofen was an effective analgesic in post-operative pain but that any additive effect of caffeine requires validation. Derry et al. (2012) carried out a systematic review of the efficacy of caffeine as an analgesic adjuvant. They concluded that “the addition of caffeine (≥100 mg) to a standard dose of commonly used analgesics provides a small
but important increase in the proportion of participants who experience a good level of pain relief”. The objective of the present study was to compare the effects of a combination of ibuprofen plus caffeine with ibuprofen and caffeine alone and placebo on malaise associated with URTI, as measured by performance and mood testing. The methodology for studying the behavioural malaise associated with URTIs is well-established (see Smith 2012a). The two most robust effects are slowing of simple reaction time and a reduction of subjective alertness, and these were the primary outcomes examined here. These outcome measures reflect different aspects of the illness in that subjective alertness is associated with symptom severity, whereas changes in simple reaction time are independent of symptoms. Other performance and mood measures have often been shown to change when the person has an URTI (see Smith 2012a). Such measures include speed of serial response, cognitive vigilance, the speed of encoding of new information, choice reaction time, hedonic tone and anxiety (Smith 2012b). These effects are usually smaller than those seen with the primary efficacy variables, but they were examined here as secondary outcomes because they are also sensitive to changes in state produced by caffeine (Smith 2002; Smith et al. 2013). One feature of the effects of caffeine is that they are often most easily observed when arousal is low (e.g. in sleepdeprived individuals or when workload is high). A long battery of tests, including repetition of the same test at various time points throughout the battery, often demonstrates bigger effects of caffeine as the person becomes more fatigued. This methodological feature was incorporated here. Little is known about acute effects of ibuprofen on cognition and mood, although it has been suggested that regular use may be protective against Parkinson's disease (Gao et al. 2011) and Alzheimer's disease (Dokmeci 2004; Vlad et al. 2008). Animal studies show that systemic inflammation gives rise to metabolic and behavioural changes largely mediated by pro-inflammatory cytokines and prostaglandin production (Bluthe et al. 2000). Teeling et al. (2010) showed that LPSinduced systemic inflammation resulted in behavioural change and ibuprofen reversed these effects. The present study examined whether such effects are seen in healthy volunteers and those with URTIs. It also investigated whether a combination of caffeine and ibuprofen had greater effects that either individual compound.
Methods Ethical approval This study was approved by the United Bristol Healthcare National Health Service Trust Ethics Committee. It was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki.
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Study design
Screening visit and baseline procedures
This was a single-centre, single-dose, randomised, parallelgroup, double-blind study. Volunteers carried out a baseline session when all were healthy. Those who developed an URTI were randomly assigned to one of the medication conditions. The aim was to have at least 96 volunteers in the URTI condition. Once this was achieved, those who remained healthy were re-tested as healthy controls and were also randomly assigned to one of the four medication conditions. This method has been shown to produce identical results to studies which test ill and healthy participants concurrently (Smith 2012a).
Suitable volunteers (those who met the entry criteria) were invited to take part in the study when they attended for preliminary assessment, by one of the study site staff. At this time, all procedures were explained fully and the volunteer was provided with a copy of the volunteer information booklet, which included a study information sheet and an informed consent form. Volunteers were asked about their willingness to undergo a physical examination and to enter the study. The importance of refraining from caffeine-containing products from midnight on the evening prior to testing was emphasised. Decaffeinated tea and coffee were supplied to each volunteer to facilitate this. Volunteers were given suitable time to consider their entry to this study. After signing the informed consent form, volunteers were assigned a unique registration number and a medical examination was completed by a qualified doctor. Typical caffeine consumption data were collected. On completion of medical procedures, familiarisation of the testing equipment was conducted with a study assistant supervising. Once the volunteers had satisfied the assistant that they were fully competent at performing the performance and mood rating tasks, and the assistant was satisfied that they had refrained from caffeinecontaining products as requested, a series of healthy baseline measurements were then completed. Volunteers returned home but were requested to contact the researchers when they developed an URTI (volunteers recognised this by common cold symptoms). All volunteers who agreed to participate had a letter explaining the outline of the study sent to their general practitioner (GP). This informed the GP of the volunteer's inclusion into the study. Once the volunteers had cold symptoms, they then returned to complete the second procedure. Volunteers who did not contract an URTI acted as healthy controls and were recalled from this pool of recruits and when they were required. Volunteers were paid £50 for taking part in the study.
Participants Sample size considerations No formal sample size calculation was conducted because of the lack of information about possible effect sizes of ibuprofen and ibuprofen/caffeine. Smith (2013) has shown that the effects of URTIs on sensitive indicators such as alertness and variable fore-period reaction time are usually in the range of half a standard deviation, and this typically requires a sample size of 24 per group in a betweensubjects design with a pre-illness covariate. Similarly, Smith et al. (2013) recommend a similar sample size to detect effects of caffeine. These numbers were, therefore, used as a basis for the sample size of each group (cold status × medication condition). Recruitment A total of 242 volunteers (students from the University of Bristol) were screened, with 227 meeting the entry, post medical, pre-assessment and symptom screening inclusion/ exclusion criteria. Two hundred and twenty-one volunteers performed a series of healthy baseline measurements. Six volunteers did not return for their healthy baseline visit. Two hundred and seventeen volunteers became members of the pool of potential recruits. Four volunteers were excluded at healthy baseline, (according to the site's SOP, they had too many errors when performing the performance tasks). A total of 213 subjects were randomised to treatment. Six participants were excluded due to protocol deviations, giving a final sample of 207 participants (120 females, 87 males). The overall mean age of the sample was 21 years (range 18–34). Procedure Volunteers visited the laboratory at least twice and two main procedures were completed.
Screening visit where URTI sufferers were screened for their suitability for entry into the study Initially, volunteers were presented with a list of 11 common cold symptoms and were asked to indicate which symptoms they were experiencing using a five-point categorical scale. Following symptoms rating, volunteers first cleared their nose then collected all nasal secretions in tissues over a 15-min period. At least 0.2 g of nasal secretion had to be produced in order to be deemed suitable for inclusion. Those volunteers who did not rate a symptom score as defined in the inclusion criteria, and who did not produce at least 0.2 g of nasal secretion, were not eligible to enter the study and returned home. Volunteers who satisfied all the inclusion and exclusion criteria then completed pre-drug baseline tests. These volunteers were then supplied with study medication. All eligible
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volunteers remained at the study site for the duration of the study. During this time, volunteer performance and mood was assessed by means of psychomotor and visual analogue mood testing. Screening visit where healthy controls were screened for their suitability for entry into the study Once the required cohort of URTI sufferers had been tested (N =96), remaining healthy volunteers were recalled to act as controls for the URTI sufferers. If all inclusion and exclusion criteria were met, they were assigned a treatment number, provided with study medication and performed the tasks following the same procedure as the URTI volunteers. Inclusion/exclusion criteria The inclusion/exclusion criteria for entry into the study are shown in Table 1. Medication Study medication was provided as matching white round tablets. Study medications were designated for randomisation as follows: Medication A Ibuprofen 200 mg plus caffeine 100 mg (I200/ C100) Medication B Ibuprofen 200 mg (IBU200) Medication C Caffeine 100 mg (CAF100) Medication D Placebo (lactose) Two hundred milligrams of ibuprofen plus 100 mg of caffeine was the dose selected for this study as this has been shown to have a significant advantage over ibuprofen alone in analgesic studies. All study medication was provided as matching tablets in identical packaging. Efficacy measurements assessed Volunteers were given suitable time to practise all mood and performance psychomotor tasks and the study staff confirmed that the volunteer was totally familiar with all test procedures. All measurements were made under the direct supervision of a study assistant. Volunteers were asked to complete a battery of mood and performance tasks (approximate total duration of 45 min) at four assessment stages. Assessment stage 1 was completed during visit 1, collecting healthy baseline measurements. Visit 2 comprised the following three assessment stages: Measurements were made at: 1. 0 min (pre-drug baseline tests) 2. 55 min (post-drug, session 1) 3. 110 min (post-drug, session 2)
Table 1 Inclusion/exclusion criteria Inclusion criteria There were two stages of inclusion: Firstly, at the healthy baseline time point volunteers were included if they: (a) had given written informed consent prior to entering the study (b) were in good general health (scored a total of two or less for all cold symptoms) of either sex, any race and at least 18 years of age (c) were willing to abstain from any alcohol, smoking and caffeine from midnight prior to assessments and during the 3-h testing period (d) were willing to remain on-site for the duration of the study testing period Secondly, for inclusion into the URTI panel, volunteers also met the following criteria (in addition to the above): (e) must have had URTI symptoms for between 6 and 96 h (f) had to have scored a total of four or above in the first 3 cold symptoms (sneezing, runny nose and blocked nose) or scored 6 and above in all 11 cold symptoms (g) had to provide an objective indication of URTI, i.e. producing >0.2 g of nasal secretion over a 15-min period immediately prior to entering the study Exclusion criteria Any volunteers who met the following criteria were excluded from the study. Volunteers who: (a) (if female) were known to be pregnant, attempting to become pregnant, or lactating (Note: female volunteers of child-bearing potential were asked the question, “To the best of your knowledge, are you pregnant?” prior to participation) (b) had taken any analgesics or NSAIDs within 12 h prior to study entry, (Note: oral contraceptives were allowed) Long-acting NSAIDs (naproxen, etc.) within 48 h Steroids within 72 h Piroxicam within 7 days (c) smoked more than five cigarettes a day (d) had asthma, gastrointestinal disorders or stomach ulcers or had significant co-existing illness that, in the investigator's judgement, contraindicated administration of the study medication (e) had previously participated in this study and received any investigational drug or had participated in a device trial within 4 weeks of entering this study (f) had any known history of allergic, idiosyncratic or serious adverse reaction to ibuprofen, caffeine, aspirin and/or any other NSAIDs (g) had any concomitant medical condition present that would have compromised the ability of the volunteer to swallow, absorb, metabolise, excrete or tolerate the study medication (h) were an investigator or member of staff at the centre where the study was being performed (i) had used a decongestant and/or antihistamine-containing product within 12 h prior to study entry
Times were from the start of the pre-drug baseline measurements. The sequence of events for each volunteer is shown in Table 2.
Author's personal copy Psychopharmacology Table 2 Schedule of assessments The sequence of events for each volunteer was as follows: Baseline: 1 Familiarisation of testing equipment 2 Healthy baseline tests—assessment stage 1 1. Mood testing, (pre-performance tasks) 2. Performance tasks 3. Mood testing, (post-performance tasks) 3 Volunteers return home and become pool of potential recruits Visit 2: - 30 Inclusion and exclusion criteria checked - 15 Collect nasal secretion and weigh, subjects must provide >0.2 g 00 Pre-drug baseline tests—Assessment stage 2 1. Mood testing, (pre-performance tasks) 2. Performance tasks 3. Mood testing, (post-performance tasks) 45 Break and dose with medication 55 Post-drug session1 tests—assessment stage 3 1. Mood testing, (pre-performance tasks) 2. Performance tasks 3. Mood testing, (post-performance tasks) 100 Break 110 Post-drug session 2 tests—assessment stage 4 1. Mood testing, (pre-performance tasks) 2. Performance tasks 3. Mood testing, (post-performance tasks) 155 Volunteers return home when they are physically fit to do so
Primary efficacy variables The primary efficacy variables were the simple reaction time task and the subjective rating of alertness at the second post-drug test session (110 min after the start—about 60 min post-drug). Variable fore-period simple reaction time task—3 min duration (Smith et al. 1987a) In this task, a box was displayed on the screen, and at varying intervals (from 1–8 s), a square appeared in the box. Volunteers were required to press a response key as soon as they detected the square. Scores recorded were the mean reaction time for each minute. This task was repeated after each of the other performance psychomotor tasks, with a total of five SRT measurements being collected at each assessment stage. This was to allow analysis of the speed of onset of any effect and the sustainability of effects. Alertness (Smith et al. 1992a) Subjective alertness was assessed using eight computerised visual analogue scales (e.g. Drowsy-Alert). Volunteers moved a
cursor to the derived position on the scale and then pressed the space bar. The next scale was then displayed. Volunteer's mood was captured before and after the performance tasks (pre- and post-tasks). Secondary outcome measures Four other performance tasks were included in the test battery (focused attention choice reaction time task, categoric search choice reaction time task, five choice serial response task and repeated numbers detection task) because they have been shown to be sensitive to both the effects of URTIs and caffeine. Measures from these tasks were analysed as secondary efficacy variables. The tasks are described below. Focused attention choice RT task (Broadbent et al. 1986, approximately 5-min duration) Target letters appeared as upper case A's and B's. On each trial, three warning crosses were presented on the screen—the outside crosses were separated from the middle one by either 1.02 or 2.60°. Volunteers were told to respond to the letter presented in the centre of the screen and ignore any distracters presented in the periphery. The crosses were on the screen for 500 ms and were then replaced by the target letter. The central letter was either accompanied by (1) nothing, (2) asterisks, (3) letters which were the same as the target or (4) letters which differed—the two distracters were identical and the targets and accompanying letters were always A or B. The correct response to A was to press a key with the forefinger of the left hand, while the correct response to B was to press a different key with the forefinger of the right hand. Volunteers were given ten practise trials followed by three blocks of 64 trials. In each block, there were equal numbers of near/far conditions, A or B responses, and equal numbers of the four distracter conditions. The nature of the previous trial was controlled. The measures of interest from this task were the mean reaction time and speed of encoding of new information (the difference between alternations and repetitions). Categoric search choice RT task (Broadbent et al. 1986, approximately 5-min duration) Each trial started with the appearance of two crosses in the positions occupied by the non-targets in the focused attention task, i.e., 2.04 or 5.20° apart. Volunteers did not know in this task which of the crosses would be followed by the target. The letter A or B was presented alone on half the trials and was accompanied by a digit (1–7) on the other half. Again, the number of near/far stimuli, A versus B responses, and digit/ blank conditions were controlled. Half of the trials led to compatible responses (i.e. the letter A on the left side if the screen, or letter B on the right), whereas the others were
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incompatible. The nature of the preceding trial was also controlled. In other respects (practise, number of trials, etc.), the task was identical to the focused task. The main measure of interest in this task was the speed of encoding of new information.
Statistical analysis Analyses were carried out using a mixed model ANOVA programme from the BMDP statistical package. Initial analyses examined the primary efficacy variables using the relevant baseline measures as covariates.
Five choice serial response task (Smith et al. 1987b, 3-min duration) Results This psychomotor test measured the speed and accuracy of rapid movements in serial response. The task involved five light switches arranged in a pentagon. There was also a light switch in the centre of the pentagon. The task started with one of the lights coming on and the volunteer had to press that light with their dominant forefinger then press the central switch. Pressing the central switch lit the next light, and this process continued for 3 min. The main measure of interest was the number of trials completed. Repeated numbers vigilance task (Smith et al. 1992b, 3-min duration) This task measured the ability to detect targets occurring at irregular intervals. A sequence of three-digit numbers was presented in the centre of the computer screen, with only one three-digit number displayed at any one time. Each number differed from the one immediately preceding it by just one digit (e.g. 548, 578, 278). At intervals, a number was presented which was identical to the previous one. This was the target repeated number, to which volunteers were required to respond immediately by pressing the space key. The sequence consisted of 300 numbers, each visible on the screen for 500 ms, regardless of volunteer's responses. A 100 ms gap was left between presentations. The full sequence contained eight targets in every 100 signals (each minute of the task). The main measures of interest were the number of hits (targets correctly identified) and mean reaction time for these hits. Other aspects of mood (measured at the same time as alertness) The mood rating task measured alertness and two other mood dimensions: hedonic tone (e.g. happy-sad) and anxiety (e.g. tense-calm). These were also measured before and after the performance tasks. Each mood rating took about 3 min. Adverse events All adverse events were coded using the COSTART (1985) dictionary, documenting duration, severity, relationship to study medication, subject outcome, and if any therapy was required.
Ninety-six of the sample developed colds and 111 were healthy controls. Table 3 shows the demographic characteristics and regular caffeine intake for the different treatment groups for the colds and healthy conditions. Overall, the different groups were well balanced with regards to age, gender and usual caffeine intake. Effects of the cold (pre-drug) Analyses of covariance, with the healthy baseline measures as covariates, and the pre-drug measures as dependent variables were carried out on the primary and secondary efficacy variables. Table 4 shows that there were significant differences between the colds and healthy groups for all of the variables predicted to show differences. Effects of the medication: primary efficacy variables Analyses of covariance, with the healthy baseline measures as covariates, and the second post-drug measures as dependent variables were carried out on the primary efficacy variables. Figure 1 shows the simple reaction time data (averaged across the five occasions it was carried out) for the different drug groups with and without colds. The analysis showed that there was a significant main effects of having a cold (F 1,198=6.84, p
