Tharaka L. Dassanayake

Effects of benzodiazepines, antidepressants and opioids on driving: a systematic review and meta-analysis of epidemiological and experimental evidence

Background: Many individuals in the community are prescribed psychoactive drugs with sedative effects. These drugs may affect their daily functions, of which automobile driving is a major component.Objective: To examine the association of three classes of commonly used psychoactive drugs (viz. benzodiazepines and newer non-benzodiazepine hypnotics, antidepressants and opioids) with (i) the risk of traffic accidents (as indexed by epidemiological indicators of risk); and (ii) driving performance (as indexed by experimental measures of driving performance).Methods: A literature search for material published in the English language between January 1966 and January 2010 in PubMed and EMBASE databases was combined with a search for other relevant material referenced in the retrieved articles. Retrieved articles were systematically reviewed, carrying out meta-analyses where possible. Twenty-one epidemiological studies (13 case-control and 8 cohort studies) fulfilled the inclusion criteria by estimating the accident risk associated with drug exposure (ascertained by blood/urine analysis or prescription records). Sixty-nine experimental studies fulfilled the inclusion criteria by testing actual or simulated driving performance after administering a single dose or multiple doses.Results: Two meta-analyses showed that benzodiazepines are associated with a 60% (for case-control studies: pooled odds ratio [OR] 1.59; 95% CI 1.10, 2.31) to 80% (for cohort studies: pooled incidence rate ratio 1.81; 95% CI 1.35, 2.43) increase in the risk of traffic accidents and a 40% (pooled OR 1.41; 95% CI 1.03, 1.94) increase in ‘accident responsibility’. Co-ingestion of benzodiazepines and alcohol was associated with a 7.7-fold increase in the accident risk (pooled OR 7.69; 95% CI 4.33, 13.65). Subgroup analysis of case-control studies showed a lower benzodiazepine-associated accident risk in elderly (>65 years of age) drivers (pooled OR 1.13; 95% CI 0.97,1.31) than in drivers <65 years of age (pooled OR 2.21; 95% CI 1.31, 3.73), a result consistent with age-stratified risk differences reported in cohort studies. Anxiolytics, taken in single or multiple doses during the daytime, impaired driving performance independent of their half-lives. With hypnotics, converging evidence from experimental and epidemiological studies indicates that diazepam, flurazepam, flunitrazepam, nitrazepam and the short half-life non-benzodiazepine hypnotic zopiclone significantly impair driving, at least during the first 2–4 weeks of treatment. The accident risk was higher in the elderly (>65 years of age) who use tricyclic antidepressants (TCAs); however, the evidence for an association of antidepressants with accident risk in younger drivers was equivocal. Sedative but not non-sedative antidepressants were found to cause short-term impairment of several measures of driving performance. Limited epidemiological research reported that opioids may be associated with increased accident risk in the first few weeks of treatment.Conclusions: Benzodiazepine use was associated with a significant increase in the risk of traffic accidents and responsibility of drivers for accidents. The association was more pronounced in the younger drivers. The accident risk was markedly increased by co-ingestion of alcohol. Driving impairment was generally related to plasma half-lives of hypnotics, but with notable exceptions. Anxiolytics, with daytime dosing, impaired driving independent of their half-lives. TCAs appeared to be associated with increased accident risk, at least in the elderly, and caused short-term impairment in driving performance. Opioid users may be at a higher risk of traffic accidents; however, experimental evidence is limited on their effects on driving.

Long-term event-related potential changes following organophosphorus insecticide poisoning

OBJECTIVE To determine prolonged effects of organophosphorus (OP) insecticide poisoning on cognitive event-related potentials (ERPs). METHODS ERPs of a group of 32 patients recovered from cholinergic phase of OP insecticide poisoning were compared with those of two matched control groups: 32 healthy volunteers and nine patients hospitalised with paracetamol overdose. A follow-up assessment was done in 21 patients (66% of the initial sample) 6 months after OP intoxication and the findings were compared with their initial ERP data. RESULTS Patients showed highly significant prolongation of P300 latency, compared to healthy controls (p=0.003) and the controls with paracetamol overdose (p=0.016). Follow-up ERP findings of the patients revealed that this impairment remained unchanged even 6 months after OP poisoning (p=0.790). There was no significant difference in N100, P200 and N200 latencies or P300 amplitude either among the groups or between the two assessments of the patients with OP poisoning. CONCLUSIONS Our results suggest that acute OP poisoning causes a delay in cognitive processes involved in stimulus classification, lasting at least for 6 months. SIGNIFICANCE These findings highlight the possibility of development of long-lasting cognitive deficits following OP insecticide poisoning, and warrant longer-term prospective studies to determine whether this impairment is permanent.

Cognitive processing of visual stimuli in patients with organophosphate insecticide poisoning

Objective: To determine the effect of organophosphate (OP) insecticide poisoning on cognitive processing time of visual stimuli. Methods: We compared 33 patients who recovered from the cholinergic phase (on average, 15 days after poisoning) with an age- and sex-matched control group. The tests used were simple visual reaction time (SVRT), recognition visual reaction time (RVRT), visual evoked potentials (VEP), and motor evoked potentials (MEP). The term cognitive processing time (CPT) was used to denote the time taken from the initial cortical perception of a stimulus to initiation of the descending motor impulse. CPT of each type of visual reaction was calculated by subtracting the sum of the visual impulse duration and the motor impulse duration from reaction time (CPT = reaction time − [P100 latency + total motor conduction time]). Results: Both the SVRT and RVRT were significantly prolonged in patients. There was no significant difference in P100 latency or total motor conduction time (TMCT) between patients and the controls. However, CPT of simple visual reactions (CPTSVR) and the CPT of recognition visual reactions (CPTRVR) were significantly prolonged in patients. Conclusions: Acute organophosphate poisoning may slow higher-order cognitive processing involved in visual stimulus detection and visual stimulus discrimination, even after clinical recovery from the cholinergic phase.

Auditory event-related potential changes in chronic occupational exposure to organophosphate pesticides

OBJECTIVE To determine whether chronic occupational exposure to organophosphates (OP) pesticides leads to cognitive impairment using event-related potentials (ERPs). METHODS ERPs of 38 vegetable farmers applying OP pesticides and 35 controls were recorded using an auditory oddball paradigm. The N1, P2, N2 and P300 ERP components and the number of counting errors were compared between the groups. RESULTS The farmers made significantly more counting errors than controls in the oddball task. The mixed model ANOVA of component latencies revealed a significant componentxgroup interaction, suggesting farmers had a greater delay in later ERP components. Intergroup comparisons of individual components showed significant delays in N2 and P300 latencies. Subsequent ANCOVA showed significant P300 delay even after adjusting for the latency of the preceding component, N2. Intergroup differences of P300 amplitudes were not significant, although there was limited evidence of a difference in scalp topography. CONCLUSION Our findings indicate that chronic low-level occupational exposure to OP pesticides is associated with progressively increasing delay in successive ERP components, particularly P300. SIGNIFICANCE Chronic exposure to OP pesticides may delay the neurophysiological processes underlying early stages of selective attention and late stages of sensory information processing that include stimulus evaluation and updating of working memory.

Effect of temporal predictability on exogenous attentional modulation of feedforward processing in the striate cortex

Non-informative peripheral visual cues facilitate extrastriate processing of targets [as indexed by enhanced amplitude of contralateral P1 event-related potential (ERP) component] presented at the cued location as opposed to those presented at uncued locations, at short cue-target stimulus onset asynchrony (SOA). Recently, two lines of research are emerging to suggest that the locus of attentional modulation is flexible and depends on 1) perceptual load and 2) temporal predictability of visual stimuli. We aimed to examine the effect of temporal predictability on attentional modulation of feed-forward activation of the striate cortex (as indexed by the C1 ERP component) by high-perceptual-load (HPL) stimuli. We conducted two ERP experiments where exogenously-cued HPL targets were presented under two temporal predictability conditions. In Experiment 1 [high-temporal-predictability (HTP) condition], 17 healthy subjects (age 18-26years) performed a line-orientation discrimination task on HPL targets presented in the periphery of the left upper or diagonally opposite right lower visual field, validly or invalidly cued by peripheral cues. SOA was fixed at 160ms. In Experiment 2 [low-temporal-predictability (LTP) condition], (n=10, age 19-36years) we retained HPL stimuli but randomly intermixed short-SOA trials with long-SOA (1000ms) trials in the task-blocks. In Experiment 1 and the short-SOA condition of the Experiment 2, validly-cued targets elicited significantly faster reaction times and larger contralateral P1, consistent with previous literature. A significant attentional enhancement of C1 amplitude was also observed in the HTP, but not LTP condition. The findings suggest that exogenous visual attention can facilitate the earliest stage of cortical processing under HTP conditions.

Acute effects of theanine, caffeine and theanine–caffeine combination on attention

Objective: l-theanine is a constituent of tea which is claimed to enhance cognitive functions. We aimed to determine whether theanine and theanine–caffeine combination have acute positive effects on cognitive and neurophysiological measures of attention, compared to caffeine (a positive control) and a placebo in healthy individuals. Design: In a placebo-controlled, five-way crossover trial in 20 healthy male volunteers, we compared the effects of l-theanine (200 mg), caffeine (160 mg), their combination, black tea (one cup) and a placebo (distilled water) on cognitive (simple [SVRT] and recognition visual reaction time [RVRT]) and neurophysiological (event-related potentials [ERPs]) measures of attention. We also recorded visual (VEPs) and motor evoked potentials (MEPs) to examine any effects of treatments on peripheral visual and motor conduction, respectively. Results: Mean RVRT was significantly improved by theanine (P = 0.019), caffeine (P = 0.043), and theanine–caffeine combination (P = 0.001), but not by tea (P = 0.429) or placebo (P = 0.822). VEP or MEP latencies or SVRT did not show significant inter-treatment differences. Theanine (P = 0.001) and caffeine (P = 0.001) elicited significantly larger mean peak-to-peak N2-P300 ERP amplitudes than the placebo, whereas theanine–caffeine combination elicited a significantly larger mean N2-P300 amplitude than placebo (P < 0.001), theanine (P = 0.029) or caffeine (P = 0.005). No significant theanine × caffeine interaction was observed for RVRT or N2-P300 amplitude. Discussion: A dose of theanine equivalent of eight cups of back tea improves cognitive and neurophysiological measures of selective attention, to a degree that is comparable with that of caffeine. Theanine and caffeine seem to have additive effects on attention in high doses.

Cognitive impairment in patients clinically recovered from central nervous system depressant drug overdose

Abstract Central nervous system depressant drugs (CNS-Ds) are known to impair cognitive functions. Overdose of these drugs is common, and most of the hospital-treated patients are discharged within 24 to 48 hours. No previous studies have examined whether they have residual impairment at the time of discharge. Our aim was to evaluate whether patients with CNS-D overdose are impaired in cognitive domains important in daily activities at that time. We compared visuomotor skills (Trail-Making Test A and Choice Reaction Time), executive functions (viz attentional set-shifting: Trail-Making Test B; and planning: Stockings of Cambridge Task from the Cambridge Neuropsychological Test Automated Battery), working memory (Letter-Number Sequencing), and impulsivity and decision making (Cambridge Neuropsychological Test Automated Battery Information Sampling) in 107 patients with CNS-D overdose (benzodiazepines, opioids, or antipsychotics) with a control group of 68 with non–CNS-D overdose (acetaminophen, selective serotonin reuptake inhibitors, and serotonin noradrenaline reuptake inhibitors) on discharge from hospital. Outcome measures were adjusted for demographic and clinical covariates in multivariate regression models. Compared with the controls, patients in the CNS-D group were significantly impaired in all domains: they had prolonged Trail-Making completion times and reaction times, poorer working memory and planning and were more impulsive in decision making. Their Stockings of Cambridge Task performance was comparable to that of the control group for simple problems but worsened with increasing task complexity. The results show that patients with CNS-D overdose could be impaired in multiple cognitive domains underlying everyday functioning even at the time they are deemed medically fit to be discharged. Such impairments could adversely affect social and professional lives of this relatively young population during the immediate postdischarge period.

Cognitive Skills Underlying Driving in Patients Discharged Following Self-Poisoning With Central Nervous System Depressant Drugs

Background: Central nervous system–depressant (CNS-Ds) drugs can impair cognitive functions and driving. They are also the most common drugs taken in overdose in hospital-treated episodes of self-poisoning. In Australia most of these patients are discharged within 48 h, while they still have possible subclinical drug effects. We aimed to determine whether patients treated for self-poisoning with CNS-Ds are impaired in the Trail-Making Test (TMT, parts A and B), a neuropsychological test that is known to correlate with driving performance. Methods: This study was a conducted from November 2008 to April 2011 in a referral center for poisonings in New South Wales, Australia. One hundred seven patients discharged from the clinical toxicology unit following treatment for self-poisoning of CNS-Ds (benzodiazepines, atypical antipsychotics, or opioids) and a control group of 68 discharged following self-poisoning of non-CNS-depressant drugs (acetaminophen or nonsedating antidepressants) were tested with the TMT (parts A and B). Due to the known association of impaired TMT with driving impairment and increased risk of traffic accidents, performance less than the 10th percentile for age was defined as significant impairment in each part of the TMT. The odds ratio (OR) for impairment in each part was calculated in multivariate logistic regression (MLR) models adjusted for gender, education, IQ, and the presence of a major psychiatric illness. A secondary MLR analysis was conducted only for those patients (78 CNS-D and 54 control group participants) who were directly discharged home, after excluding those who were transferred for further psychiatric care. Results: The odds of impairment in the CNS-D group was 2.8 times that of the control group on the TMT-A (38 [35.5%] vs. 11 [16.2%]: adjusted OR = 2.76, 95% confidence interval [CI]: 1.28–5.97), and 4.6 times on the TMT-B (67 [62.6%] vs. 22 [32.4%]: adjusted OR = 4.63, 95% CI: 2.06–10.42). The results were similar in the subgroup of patients discharged home, and the odds of impairment in the CNS-D group was 3.3 times that of the control group on the TMT-A (25 [32.1%] vs. 7 [13.0%]: adjusted OR = 3.30, 95% CI: 1.28–8.52), and 3.6 times on the TMT-B (46 [59.0%] vs. 17 [31.5%]: adjusted OR = 3.64, 95% CI: 1.44–9.20). TMT-B impairment in the CNS-D group remained significant even after adjusting for TMT-A performance. Conclusions: Patients with CNS-D overdose may have significant impairment in cognitive skills underlying driving at the time of discharge from hospitals. Clinicians should warn these patients that their driving skills might still be impaired, even if they are considered clinically recovered and advise them not to drive during the first 1 to 2 days following discharge.

Risk of road traffic accidents in patients discharged following treatment for psychotropic drug overdose: a self-controlled case series study in Australia

AbstractBackground: Use of psychotropic drugs is known to impair driving and increase the risk of road traffic accidents. They are also the most common drugs taken in overdose in hospital-treated episodes of self-poisoning. Most patients who take psychotropic drug overdoses are discharged within 48 hours, while they still have possible subclinical drug effects. Objective: Using a self-controlled case series design, we aimed to determine whether patients with psychotropic drug overdose are at a higher risk of a traffic accident in the period following discharge compared with a control period not associated with hospital-treated drug overdose. Methodology: Using the New South Wales (NSW) Admitted Patient Data Collection (APDC) as the primary source, we retrieved 40 845 hospital separation records dated between 1 July 2000 and 30 June 2008 (8 years) in patients aged 18–80 years admitted to a hospital in NSW following an intentional self-poisoning with a psychotropic drug (coded X61 or X62 as the International Classification of Diseases, 10th Edition, [ICD-10] external causeof injury). Of these, 33 459 hospital separations (i.e. discharges, transfers and deaths) involving 24 284 patients were considered eligible as the patients were discharged directly into the community where they could have driven a motor vehicle. We selected three separate post-admission periods (3 days, 1 week and 4 weeks), subtracted the number of inpatient days from each and calculated three separate post-discharge periods (immediate, intermediate and extended, respectively) for each episode of overdose. The control period was the duration of the study period where the individual was aged 18 years or older, excluding the total person-days in the post-discharge period/s and the index inpatient period/s. The APDC dataset was linked to the NSW Roads and Traffic Authority CrashLink dataset to identify any accidents in which each patient was involved as a motor-vehicle driver during the follow-up period. Incidence rate ratio (IRR) for matched post-discharge and control periods was found using random effects Poisson regression. Results: Seventy-two percent of the subjects were discharged within 2 days following their admission with overdose. Compared with the corresponding control periods the risk of a traffic accident was 3.5 times higher (IRR =3.49; 95% CI 1.66, 7.33; p = 0.001) during the immediate, 1.9 times higher (IRR= 1.88; 95% CI 1.09, 3.25; p = 0.023) during the intermediate and 1.6 times higher (IRR= 1.65; 95% CI 1.27, 2.15; p = 0.0002) during the extended post-discharge period. Conclusions: Self-poisoning with psychotropic drugs is associated with a markedly increased risk of a traffic accident during the first few days following discharge. These findings raise clinical and medico-legal implications concerning fitness-to-drive during this period. The risk reduces with time but remains significantly elevated after 4 weeks post-overdose. Further research is necessary to find out the factors contributing to this ongoing risk.

P337: Stimulated single fibre electromyography using concentric needle electrode in organophosphate insecticide poisoning in Sri Lanka

form two conditions (standard, creature category). They were asked to immediately say a word starting with the last character of the written Japanese word shown in front of them, and this procedure was repeated 20 times. During control condition, they repeated the vowels “A, I, U, E, O”. Grand mean waveforms of the 20 responses were produced and changes in oxygenated hemoglobin (oxy-Hb changes) from the control state were converted to numeric values every 100 ms. The approximated value of area, peak amplitude and latency after performance were determined as data. Left channel 11 and right channel 12 in midfrontal area, left channel 19 and right channel 22 in frontopolar area were selected as the regions of interest (ROIs) and oxy-Hb changes in the ROIs was evaluated. This study was performed with the approval of the Ethical Committee, Kurume University and informed consent obtained from all subjects after a written explanation of the contents of the examination. Results: In ROIs, Patients showed decreased oxy-Hb changes compared with healthy subjects in both tasks. In addition, the peak amplitude was larger and latency was earlier in healthy subjects than those in patients during creature category shiritori task. There was significant correlation between the negative syndrome scales of the PANSS and oxy-Hb changes. Conclusion: These results suggest the usefulness of NIRS using shiritori tasks for evaluating psychophysiological indices.