Faculty Bibliography

INTRODUCTION: Chronic pain may have far-reaching effects on cognition. Several studies have used neuropsychological testing to assess cognition in subjects with chronic pain. These studies found impairments in memory, executive function, and psychomotor performance in subjects with pain compared to those without1,2. Patients with chronic pain often take analgesic medications which may also affect cognitive function. Most studies on the impact of chronic pain on cognitive function have been cross-sectional in nature and have excluded patients with pre-existing cognitive impairment. We used the longitudinal Alzheimer's Disease Neuroimaging Initiative (ADNI) database to examine the interaction of chronic pain, baseline cognitive status, and medication use on cognitive function. We hypothesized chronic pain would be associated with a decline in cognitive function. METHODS: Putative patients with chronic pain were selected by searching the "Concurrent Medications Log" for analgesic medications. Patients taking medications for a painful condition were considered to have chronic pain if the start date of medication use occurred prior to enrollment in ADNI and continued throughout the study. All subjects underwent neuropsychological assessment. Composite scores for executive function, (ADNI-EF), as well as memory, (ADNI-MEM), have been developed and validated in ADNI participants. Values were available for baseline, 6 month, 1 yr, and 2 yr time points. RESULTS: Our first result showed a dependence of ADNI-EF on age (p<0.001), baseline cognitive status (p<0.001), and presence of chronic pain (p=0.008). However, the dependence was such that the presence of pain led to increased ADNI-EF performance. We hypothesized this effect was due to the NSAID use which often accompanied pain symptoms. Repeated measures ANOVA revealed that over 4 time points (factor; p<0.001) the group pain/NSAID use versus control (no pain/no NSAID) had a positive impact (p= 0.027), with performance showing significant dependence also on baseline cognitive status (p<0.001) and age (p=0.019). For cognitively normal (NL) subjects, there was a slight increase in performance over time consistent with rehearsal effects. For subjects with mild cognitive impairment (MCI) and AD, there was a drop in performance over time, with marked deterioration for AD. Repeating this analysis with ADNI-MEM, we found that an effect of pain/NSAID group was only apparent in NL subjects where pain/ NSAID presence lead to increased ADNI-MEM at all 4 time points (p = 0.025). Examining pain in a repeated measures analysis for subjects without NSAIDs did not show a significant pain effect. CONCLUSION: Whereas it has been shown that chronic pain can lead to changes in cognitive performance, we show here this effect is complicated by the impact of medication use. Since there are numerous medications used to treat pain which may have differing impacts on the brain, it may become increasingly important in the future to consider the secondary effects when choosing a regimen of pain treatment

Acute pain induces depressed mood, and chronic pain is known to cause depression. Depression, meanwhile, can also adversely affect pain behaviors ranging from symptomology to treatment response. Pain and depression independently induce long-term plasticity in the central nervous system (CNS). Comorbid conditions, however, have distinct patterns of neural activation. We performed a review of the changes in neural circuitry and molecular signaling pathways that may underlie this complex relationship between pain and depression. We also discussed some of the current and future therapies that are based on this understanding of the CNS plasticity that occurs with pain and depression.

BACKGROUND:: Neuraxial local anesthetics may have neurological complications thought to be due to neurotoxicity. A primary site of action of local anesthetics is the dorsal root ganglia (DRG) neuron. Physiologic differences have been noted between young and adult DRG neurons; hence, the authors examined whether there were any differences in lidocaine-induced changes in calcium and lidocaine toxicity in neonatal and adult rat DRG neurons. METHODS:: DRG neurons were cultured from postnatal day 7 (P7) and adult rats. Lidocaine-induced changes in cytosolic calcium were examined with the calcium indicator Fluo-4. Cells were incubated with varying concentrations of lidocaine and examined for viability using calcein AM and ethidium homodimer-1 staining. Live imaging of caspase-3/7 activation was performed after incubation with lidocaine. RESULTS:: The mean KCl-induced calcium transient was greater in P7 neurons (P < 0.05), and lidocaine significantly inhibited KCl-induced calcium responses in both ages (P<0.05). Frequency distribution histograms of KCl-evoked calcium increases were more heterogeneous in P7 than in adult neurons. With lidocaine, KCl-induced calcium transients in both ages became more homogeneous but remained different between the groups. Interestingly, cell viability was decreased by lidocaine in a dose-dependent manner similarly in both ages. Lidocaine treatment also activated caspase-3/7 in a dose- and time-dependent manner similarly in both ages. CONCLUSIONS:: Despite physiological differences in P7 and adult DRG neurons, lidocaine cytotoxicity is similar in P7 and adult DRG neurons in vitro. Differences in lidocaine- and KCl-evoked calcium responses suggest the similarity in lidocaine cytotoxicity involves other actions in addition to lidocaine-evoked effects on cytosolic calcium responses.

BACKGROUND AND OBJECTIVE: Chlorhexidine is recommended by several anesthesiology societies for antisepsis before regional anesthesia, but there is concern it may be neurotoxic. We evaluated the cytotoxicity of chlorhexidine and povidone-iodine in human neuronal and rat Schwann cells. METHODS: Human SH-SY5Y neuroblastoma and rat RSC96 Schwann cells were incubated with serial dilutions of 2% chlorhexidine gluconate and 10% povidone-iodine for 10 minutes, and viability was assessed with the MTT colorimetry assay and a fluorescent assay using calcein and ethidium. Cell morphology during antiseptic incubation was observed under light microscopy. To estimate the amount of antiseptic a needle carries through tissues, tritium radioactivity was measured in an animal injection model. RESULTS: Chlorhexidine at all tested concentrations significantly decreased viability compared with controls in both SH-SY5Y and RSC96 cells (P < 0.001). Povidone-iodine significantly decreased viability for both cells at concentrations of 0.2% or higher (P < 0.001). At the same dilutions of 1:200, 1:150, and 1:100, chlorhexidine was more cytotoxic than povidone-iodine for both cells (P< 0.001). During chlorhexidine treatment, both cell types became rounded and shriveled. Less dramatic changes were observed with povidone-iodine. In the injection model, 1.75% +/- 1.29% of the maximum amount of radioactive contamination was carried through tissues. CONCLUSIONS: Chlorhexidine gluconate and povidone-iodine were cytotoxic to SH-SY5Y (neuronal) and RSC96 (Schwann) cells. Chlorhexidine was more potent than povidone-iodine at more dilute concentrations. However, the toxicity of the two was not different at concentrations used clinically. When using either of these agents for antisepsis before regional anesthesia, it is prudent to allow adequate drying time after application.