Dieuwke S. Veldhuijzen

Perspective on Diffuse Noxious Inhibitory Controls as a Model of Endogenous Pain Modulation in Clinical Pain Syndromes

UNLABELLED Altered function of endogenous pain modulation has been proposed as a mechanism that may underlie chronic pain conditions. Descending modulation of pain can be examined by diffuse noxious inhibitory controls (DNIC). DNIC comprises a spinal-medullary-spinal pathway that is activated when 2 concomitant painful stimuli are applied at the same time. This pain-inhibitory system can be easily triggered in an experimental setting. Therefore, studies on DNIC can help us to evaluate impairments in descending pain modulation, presumably primarily of inhibitory nature. This review summarizes recent findings on human DNIC trials with a specific focus on sex, age, and ethnic differences in DNIC effects and psychological mediators such as attention, expectation, and pain catastrophizing. Furthermore, the clinical relevance of DNIC studies will be discussed. Different methodological approaches used make it difficult to generalize results, but the research to date has shown good potential for DNIC to help in gaining insights in the underlying mechanisms of chronic pain conditions. PERSPECTIVE Recent literature on diffuse noxious inhibitory controls as a model of endogenous pain modulation in clinical pain syndromes was reviewed. DNIC may help to identify patients at risk for development of chronic pain and may open alternatives for treatment options.

Residual effects of middle-of-the-night administration of zaleplon and zolpidem on driving ability, memory functions, and psychomotor performance

Thirty healthy volunteers participated in this two-part study. Part 1 was a single-blind, two-period crossover design to determine the effects of a single dose of ethanol (0.03% < BAC < 0.05%) or ethanol-placebo on driving ability, memory, and psychomotor performance. Part 2 was a double-blind, five-period crossover design to measure the effects of a middle-of-the-night administration of zaleplon 10 or 20 mg, zolpidem 10 or 20 mg, or placebo on driving ability 4 hours after administration and memory and psychomotor performance 6 hours after administration. The on-the-road driving test consisted of operating an instrumented automobile over a 100-km highway circuit at a constant speed (95 km/h) while maintaining a steady lateral position between the right lane boundaries. The standard deviation of lateral position (SDLP) was the primary performance parameter of the driving test. The psychomotor and memory test battery consisted of the Word Learning Test, the Critical Tracking Test, the Divided Attention Test, and the Digit Symbol Substitution Test. Data for each part were analyzed separately using ANOVA for crossover designs. Zaleplon 10 and 20 mg did not significantly impair driving ability 4 hours after middle-of-the-night administration. Relative to placebo, after zolpidem 10 mg, SDLP was significantly elevated, but the magnitude of the difference was small and not likely to be of clinical importance. Memory and psychomotor test performance was unaffected after both doses of zaleplon and zolpidem 10 mg. In contrast, zolpidem 20 mg significantly increased SDLP and speed variability. Further, zolpidem 20 mg significantly impaired performance on all psychomotor and memory tests. Finally, driving performance, Digit Symbol Substitution Test, Divided Attention Test, and immediate and delayed free recall of the Word Learning Test were significantly impaired after ethanol. The results show that zaleplon (10 and 20 mg) is a safe hypnotic devoid of next-morning residual impairment when used in the middle of the night.

Hypnotics and driving safety: Meta-analyses of randomized controlled trials applying the on-the-road driving test

BACKGROUND Many people who use hypnotics are outpatients and are likely to drive a car the day after drug intake. The purpose of these meta-analyses was to determine whether or not this is safe. METHODS Placebo-controlled, randomized, double-blind trials were selected if using the on-the-road driving test to determine driving ability the day following one or two nights of treatment administration. Primary outcome measure of the driving test was the Standard Deviation of Lateral Position (SDLP); i.e., the weaving of the car. Fixed effects model meta-analyses were performed. Effect size (ES) was computed using mean standardized (weighted) difference scores between treatment and corresponding placebo SDLP values. RESULTS Ten studies, published from 1984 to 2002 (207 subjects), were included in the meta-analyses. The morning following bedtime administration, i.e. 10-11 hours after dosing, significant driving impairment was found for the recommended dose of various benzodiazepine hypnotics (ES=0.42; 95% Confidence Interval (CI)=0.14 to 0.71). Twice the recommended dose impaired driving both in the morning (ES=0.68; CI=0.39 to 0.97) and afternoon, i.e. 16-17 hours after dosing (ES=0.57; CI=0.26 to 0.88). Zopiclone 7.5 mg also impaired driving in the morning (ES=0.89; CI=0.54 to 1.23). Zaleplon (10 and 20 mg) and zolpidem (10 mg) did not affect driving performance the morning after dosing. Following middle-of-the-night administration, significantly impaired driving performance was found for zopiclone 7.5 mg (ES=1.51, CI=0.85 to 2.17), zolpidem 10 mg (ES=0.66, CI=0.13 to 1.19) and zolpidem 20 mg (ES=1.16, CI=0.60 to 1.72). Zaleplon (10 and 20 mg) did not affect driving performance. CONCLUSIONS The analyses show that driving a car the morning following nocturnal treatment with benzodiazepines and zopiclone is unsafe, whereas the recommended dose of zolpidem (10 mg) and zaleplon (10 mg) do not affect driving ability.

Memory functions in chronic pain: examining contributions of attention and age to test performance

ObjectivesPrevious studies have revealed that memory performance is diminished in chronic pain patients. Few studies, however, have assessed multiple components of memory in a single sample. It is currently also unknown whether attentional problems, which are commonly observed in chronic pain, mediate the decline in memory. Finally, previous studies have focused on middle-aged adults, and a possible detrimental effect of aging on memory performance in chronic pain patients has been commonly disregarded. This study, therefore, aimed at describing the pattern of semantic, working, and visual and verbal episodic memory performance in participants with chronic pain, while testing for possible contributions of attention and age to task performance. MethodsThirty-four participants with chronic pain and 32 pain-free participants completed tests of episodic, semantic, and working memory to assess memory performance and a test of attention. ResultsParticipants with chronic pain performed worse on tests of working memory and verbal episodic memory. A decline in attention explained some, but not all, group differences in memory performance. Finally, no additional effect of age on the diminished task performance in participants with chronic pain was observed. DiscussionTaken together, the results indicate that chronic pain significantly affects memory performance. Part of this effect may be caused by underlying attentional dysfunction, although this could not fully explain the observed memory decline. An increase in age in combination with the presence of chronic pain did not additionally affect memory performance.

Effect of chronic nonmalignant pain on highway driving performance

Abstract Most pain patients are treated in an outpatient setting and are engaged in daily activities including driving. Since several studies showed that cognitive functioning may be impaired in chronic nonmalignant pain, the question arises whether or not chronic nonmalignant pain affects driving performance. Therefore, the objective of the present study was to determine the effects of chronic nonmalignant pain on actual highway driving performance during normal traffic. Fourteen patients with chronic nonmalignant pain and 14 healthy controls, matched on age, educational level, and driving experience, participated in the study. Participants performed a standardized on‐the‐road driving test during normal traffic, on a primary highway. The primary parameter of the driving test is the Standard Deviation of Lateral Position (SDLP). In addition, driving‐related skills (tracking, divided attention, and memory) were examined in the laboratory. Subjective assessments, such as pain intensity, and subjective driving quality, were rated on visual analogue scales. The results demonstrated that a subset of chronic nonmalignant pain patients had SDLPs that were higher than the matched healthy controls, indicating worse highway driving performance. Overall, there was a statistically significant difference in highway driving performance between the groups. Further, chronic nonmalignant pain patients rated their subjective driving quality to be normal, although their ratings were significantly lower than those of the healthy controls. No significant effects were found on the laboratory tests.

Effects of an opioid (Oxycodone/Paracetamol) and an NSAID (Bromfenac) on driving ability, memory functioning, psychomotor performance, pupil size, and mood

ObjectiveIt has been suggested that driving a car is relatively safe when the driver is treated with nonsteroid anti-inflammatory drugs than when he or she is treated with opioid analgesics. However, the evidence for this statement is scarce. The objective of this study was to determine the effects of a nonsteroid anti-inflammatory drug (bromfenac 25 mg and 50 mg) and an opioid (oxycodone/paracetamol 5/325 mg and 10/650 mg), and placebo on driving ability, memory functioning, psychomotor performance, pupil size, and mood. MethodsOut of 30 healthy volunteers, 18 completed this randomized, double-blind, placebo-controlled crossover study, before the study had to be stopped due to bromfenac being pulled out from the market. One hour after administration of the drugs, the participants performed a standardized driving test during normal traffic. Thereafter, driving quality, mental effort and mental activation during driving were assessed. A laboratory test battery was performed 2.5 hours after administration of the drug. Visual analog scales assessing mood and pupil measurements were performed on several occasions during each test day. ResultsBoth analgesics did not significantly affect performance in any test. However, volunteers reported that significantly more effort was needed to perform the driving test when treated with oxycodone/paracetamol, and that they experienced increased sedation and reduced alertness. Also, the pupil size was significantly decreased. In contrast, subjective assessments after both doses of bromfenac matched that of placebo. DiscussionNo significant impairment in behavior was found in the volunteers for both bromfenac and oxycodone/paracetamol. The lack of impairment from oxycodone/paracetamol may have been related to the participants reporting increased effort during driving while under the influence of this drug.

Processing capacity in chronic pain patients: A visual event-related potentials study

Abstract Chronic pain may impair performance on attentional processing capacity tasks. In the present study, event‐related potentials were recorded to examine whether pain patients show performance decrements on attentional processing capacity tasks due to shared resources by pain and attention or, alternatively, due to deficits in allocating attentional resources during pain. Fourteen chronic pain patients and thirty age and education matched healthy controls were investigated. An attentional capacity probe task was used in which the difficulty level was manipulated, resulting in an easy and a difficult condition, while task‐irrelevant visual probes were presented. These probe‐elicited P3 amplitudes were assumed to provide the most pure estimate of processing capacity since they are relatively free from target‐related processes. Event‐related potentials were recorded from the midline electrodes Fz, Cz, Pz, and Oz. For the behavioral measures, it was found that pain patients maintained a different speed‐accuracy tradeoff. Pain patients showed faster reaction time responses and higher error rates compared to controls. No significant differences were found between pain patients and controls on the primary task. Pain patients differed from controls with respect to amplitudes elicited by task‐irrelevant probe stimuli. For healthy controls, the expected decreased amplitude was found for probe stimuli in the difficult compared to the easy task. In contrast, the pain patients did not show decreased probe amplitudes with increasing task load. The data may imply that allocation of attentional resources is deficient in pain patients, instead of attentional capacity.

Long-term outcome of delirium during intensive care unit stay in survivors of critical illness: a prospective cohort study

IntroductionDelirium is associated with impaired outcome, but it is unclear whether this relationship is limited to in-hospital outcomes and whether this relationship is independent of the severity of underlying conditions. The aim of this study was to investigate the association between delirium in the intensive care unit (ICU) and long-term mortality, self-reported health-related quality of life (HRQoL), and self-reported problems with cognitive functioning in survivors of critical illness, taking severity of illness at baseline and throughout ICU stay into account.MethodsA prospective cohort study was conducted. We included patients who survived an ICU stay of at least a day; exclusions were neurocritical care patients and patients who sustained deep sedation during the entire ICU stay. Delirium was assessed twice daily with the Confusion Assessment Method for the ICU (CAM-ICU) and additionally, patients who received haloperidol were considered delirious. Twelve months after ICU admission, data on mortality were obtained and HRQoL and cognitive functioning were measured with the European Quality of Life – Six dimensions self-classifier (EQ-6D). Regression analyses were used to assess the associations between delirium and the outcome measures adjusted for gender, type of admission, the Acute Physiology And Chronic Health Evaluation IV (APACHE IV) score, and the cumulative Sequential Organ Failure Assessment (SOFA) score throughout ICU stay.ResultsOf 1101 survivors of critical illness, 412 persons (37%) had been delirious during ICU stay, and 198 (18%) died within twelve months. When correcting for confounders, no significant association between delirium and long-term mortality was found (hazard ratio: 1.26; 95% confidence interval (CI) 0.93 to 1.71). In multivariable analysis, delirium was not associated with HRQoL either (regression coefficient: -0.04; 95% CI -0.10 to 0.01). Yet, delirium remained associated with mild and severe problems with cognitive functioning in multivariable analysis (odds ratios: 2.41; 95% CI 1.57 to 3.69 and 3.10; 95% CI 1.10 to 8.74, respectively).ConclusionsIn this group of survivors of critical illness, delirium during ICU stay was not associated with long-term mortality or HRQoL after adjusting for confounding, including severity of illness throughout ICU stay. In contrast, delirium appears to be an independent risk factor for long-term self-reported problems with cognitive functioning.

Intraoperative Dexamethasone and Delirium After Cardiac Surgery: A Randomized Clinical Trial

BACKGROUND:Delirium is common after cardiac surgery and may be partly related to the systemic inflammatory response triggered by the surgery and the use of cardiopulmonary bypass. We hypothesized that intraoperative administration of high-dose dexamethasone, a drug with potent anti-inflammatory effects, would reduce the incidence of delirium at any time point during the first 4 postoperative days after cardiac surgery. METHODS:This was a single-center substudy within a larger, multicenter placebo-controlled randomized clinical trial, the Dexamethasone for Cardiac Surgery (DECS) trial that randomized patients ≥18 years, undergoing cardiac surgery with cardiopulmonary bypass, to receive, in a double-blind fashion, either dexamethasone 1 mg/kg or placebo at the induction of anesthesia. Over the first 4 postoperative days, we compared between groups the incidence of delirium (based on the Confusion Assessment Method adapted for the intensive care unit, or after intensive care unit discharge, by the Confusion Assessment Method, accompanied by chart review), restraint use, and administered haloperidol, benzodiazepines, and opioids. Data were analyzed according to the intention-to-treat principle. The proportion of patients with delirium in the dexamethasone versus the placebo group was compared using the odds ratio (OR) with a 95% confidence interval (CI). The proportion also was compared using logistic regression to adjust for common baseline variables that might confound the presence of delirium between the 2 groups. RESULTS:Of 768 eligible patients, 737 subjects (96.0%) had complete data. The incidence of delirium was similar between the dexamethasone (14.2%) and placebo (14.9%) groups (crude OR = 0.95, 95% CI, 0.63–1.43; adjusted OR = 0.85, 95% CI, 0.55–1.31). Among patients who developed delirium, the median (interquartile range) duration of delirium was similar between the dexamethasone and placebo groups (2 [1–3] vs 2 [1–2] days, respectively, P = 0.45; WMWodds 0.98, 95% CI, 0.83–1.17). Restraint use and the administration of haloperidol, benzodiazepines, and opioids were also similar between the 2 groups. CONCLUSIONS:The intraoperative administration of dexamethasone did not reduce the incidence or duration of delirium in the first 4 days after cardiac surgery.

Executive and attentional functions in chronic pain: does performance decrease with increasing task load?

BACKGROUND Diminished executive function and attentional control has been reported in chronic pain patients. However, the precise pattern of impairment in these aspects of cognition in chronic pain remains unclear. Moreover, a decline in psychomotor speed could potentially influence executive and attentional control performance in pain patients. OBJECTIVE To examine different aspects of executive and attentional control in chronic pain together with the confounding role of psychomotor slowing. METHODS Neuropsychological tests of sustained attention, planning ability, inhibition and mental flexibility were administered to 34 participants with chronic pain and 32 control participants. RESULTS Compared with the controls, participants with chronic pain took longer to complete tests of sustained attention and mental flexibility, but did not perform worse on inhibition or planning tasks. The decreased performance on the mental flexibility task likely reflects a reduction in psychomotor speed. The pattern of performance on the sustained attention task reveals a specific decline in attention, indicated by a disproportionate decline in performance with an increase in task duration and by increased fluctuations in attention during task performance. No additional effect was noted of pain intensity, pain duration, pain catastrophizing, depressive symptoms, reduced sleep because of the pain or opioid use. CONCLUSIONS Executive and attention functions are not uniformly affected in chronic pain. At least part of the previously reported decline in executive function in this group may reflect psychomotor slowing. Overall, limited evidence was found that executive and attention performance is indeed lower in chronic pain. Therefore, it can be concluded that in chronic pain sustained attention performance is diminished while mental flexibility, planning and inhibition appear to be intact.