Posttraumatic stress disorder influences the nociceptive and intrathecal cytokine response to a painful stimulus in combat veterans

ObjectiveAlthough posttraumatic stress disorder (PTSD) and chronic pain frequently occur in tandem, the pathophysiological mechanisms mediating this comorbidity are poorly understood. Because excessive inflammation occurs in both conditions, we examined the cerebrospinal fluid (CSF) concentrations of inflammatory response mediators interleukin 1-beta (IL-1β), interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-alpha (TNFα) and interleukin 10 (IL-10) after prolonged suprathreshold pain stimulus in 21 male combat veterans; 10 with PTSD and 11 combat controls (CC).MethodsAfter completing baseline quantitative sensory testing (QST) and psychological profiling, all patients received an injection of capsaicin into the quadriceps muscle. Spontaneously reported pain was measured for 30min after the capsaicin injection. The evoked pain measure of temporal summation was tested between 70 and 110min post capsaicin injection. Inflammatory (IL-1β, IL-6, IL-8 TNFα) and anti-inflammatory (IL-10) CSF cytokines were measured before (baseline) and after capsaicin injection over a time frame of 110min.ResultsFollowing intramuscular capsaicin injection, pro-inflammatory cytokines [TNFα, IL-6, IL-8] significantly increased (percent rise from baseline) in both groups, whereas IL-1β significantly increased in the PTSD group only. The anti-inflammatory cytokine IL-10 showed an immediate (within 10min) increase in the CC group; however, the IL-10 increase in the PTSD group was delayed and not consistently elevated until 70min post injection.ConclusionThese findings show significant central nervous system (CNS) differences in the inflammatory response to a deep pain stimulus in combat veterans with and without PTSD. They support the concept that abnormally elevated neuroinflammatory response to pain stimuli may be one CNS mechanism accounting for the high co-occurrence of PTSD and pain

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Unsupervised learning for prognostic validity in patients with chronic pain in transdisciplinary pain care.

Chronic pain is not a singular disorder and presents in various forms and phenotypes. Here we show data from a cohort of patients seeking treatment in a transdisciplinary pain clinic. Patients completed a multidimensional patient-reported battery as part of routine initial evaluation at baseline and at each of the four subsequent visits over 1-year follow-up (0, 1, 3, 6, 12 months). The goal of this work was to use unsupervised modeling approach to identify whether patients with chronic pain undergoing transdisciplinary intensive rehabilitation treatment: (1) can be derived based upon self-reported outcome measures at baseline (or before treatment initiation), (2) are clinically validated based on their clinical diagnosis and medication use, and (3) differ in treatment trajectories over 1 year of transdisciplinary treatment. We applied unsupervised clustering on baseline outcomes using nine patient-reported symptoms and examined treatment trajectories. The three-cluster solution was internally validated. Psychiatric diagnosis, chronic back pain-related disability and symptoms severity determined cluster assignment and treatment prognosis. Conversely, clinical pain severity had lesser effect. Furthermore, clusters showed stability over time despite symptoms improvement. The accurate and meaningful subgrouping of the underlying chronic pain phenotypes would greatly enhance treatment and provide personalized and effective pain management

Specific pain complaints in Iraq and Afghanistan veterans screening positive for post-traumatic stress disorder.

BackgroundPost-traumatic stress disorder (PTSD) and pain are highly comorbid.ObjectiveThe purpose of this study was to examine the association of PTSD with specific pain complaints in veterans of Operations Enduring and Iraqi Freedom (OEF/OIF).MethodA total of 381 primarily male (88.5%) veterans with a mean age of 30 years completed a battery of self-report questionnaires. A positive PTSD screen was defined as a score of ≥40 on the Davidson Trauma Scale. Logistic regression was used to examine the association of positive PTSD screen with specific pain complaints.ResultsThere were no significant demographic or physical and mental health differences between veterans who screened positive for PTSD only and those with PTSD and at least one pain complaint, although differences on rates of combat injury and depression approached significance. Veterans who screened positive for PTSD were 2 to 3 times more likely to report abdominal pain, muscle aches or cramps, and joint aches, even after controlling for age, gender, combat injury, and depression.ConclusionsSimilar to findings in other populations, there is a relationship between PTSD and pain complaints in OEF/OIF veterans. Future research should examine the mechanisms that link PTSD with specific pain complaints, especially abdominal pain

Specific pain complaints in Iraq and Afghanistan veterans screening positive for post-traumatic stress disorder.

BackgroundPost-traumatic stress disorder (PTSD) and pain are highly comorbid.ObjectiveThe purpose of this study was to examine the association of PTSD with specific pain complaints in veterans of Operations Enduring and Iraqi Freedom (OEF/OIF).MethodA total of 381 primarily male (88.5%) veterans with a mean age of 30 years completed a battery of self-report questionnaires. A positive PTSD screen was defined as a score of ≥40 on the Davidson Trauma Scale. Logistic regression was used to examine the association of positive PTSD screen with specific pain complaints.ResultsThere were no significant demographic or physical and mental health differences between veterans who screened positive for PTSD only and those with PTSD and at least one pain complaint, although differences on rates of combat injury and depression approached significance. Veterans who screened positive for PTSD were 2 to 3 times more likely to report abdominal pain, muscle aches or cramps, and joint aches, even after controlling for age, gender, combat injury, and depression.ConclusionsSimilar to findings in other populations, there is a relationship between PTSD and pain complaints in OEF/OIF veterans. Future research should examine the mechanisms that link PTSD with specific pain complaints, especially abdominal pain

Evidence for acute central sensitization to prolonged experimental pain in posttraumatic stress disorder.

BackgroundPost-traumatic stress disorder (PTSD) and pain have a well-documented high comorbidity; however, the underlying mechanisms of this comorbidity are currently poorly understood. The aim of this psychophysical study was to investigate the behavioral response to a prolonged suprathreshold pain stimulus in subjects with combat-related PTSD and combat controls (CC) for clinical evidence of central sensitization.MethodsTen male subjects with current PTSD related to combat and 11 CC male subjects underwent baseline quantitative sensory testing (QST), temporal pain summation, and psychological profiling followed by an intramuscular injection of capsaicin into the quadriceps muscle.ResultsThere was no significant between-group difference for the initial maximal pain response or an initial pain reduction for the first 15 minutes postinjection on QST or pain ratings. However, we observed significantly higher scores in the PTSD group for the second 15 minutes postinjection on both pain intensity and pain unpleasantness ratings. Assessment of temporal summation to repetitive pressure stimuli showed significantly higher subjective pain in the PTSD group.ConclusionThese findings are consistent with a significantly higher degree of acute central sensitization in individuals with PTSD. Increased acute central sensitization may underlie increased vulnerability for developing pain-related conditions following combat trauma

Evidence for acute central sensitization to prolonged experimental pain in posttraumatic stress disorder.

BackgroundPost-traumatic stress disorder (PTSD) and pain have a well-documented high comorbidity; however, the underlying mechanisms of this comorbidity are currently poorly understood. The aim of this psychophysical study was to investigate the behavioral response to a prolonged suprathreshold pain stimulus in subjects with combat-related PTSD and combat controls (CC) for clinical evidence of central sensitization.MethodsTen male subjects with current PTSD related to combat and 11 CC male subjects underwent baseline quantitative sensory testing (QST), temporal pain summation, and psychological profiling followed by an intramuscular injection of capsaicin into the quadriceps muscle.ResultsThere was no significant between-group difference for the initial maximal pain response or an initial pain reduction for the first 15 minutes postinjection on QST or pain ratings. However, we observed significantly higher scores in the PTSD group for the second 15 minutes postinjection on both pain intensity and pain unpleasantness ratings. Assessment of temporal summation to repetitive pressure stimuli showed significantly higher subjective pain in the PTSD group.ConclusionThese findings are consistent with a significantly higher degree of acute central sensitization in individuals with PTSD. Increased acute central sensitization may underlie increased vulnerability for developing pain-related conditions following combat trauma

Objective Epidural Space Identification Using Continuous Real-Time Pressure Sensing Technology: A Randomized Controlled Comparison With Fluoroscopy and Traditional Loss of Resistance

Performance of epidural anesthesia and analgesia depends on successful identification of the epidural space (ES). While multiple investigations have described objective and alternative methodologies to identify the ES, traditional loss of resistance (LOR) and fluoroscopy (FC) are currently standard of care in labor and delivery (L&D) and chronic pain (CP) management, respectively. While FC is associated with high success, it exposes patients to radiation and requires appropriate radiological equipment. LOR is simple but subjective and consequently associated with higher failure rates. The purpose of this investigation was to compare continuous, quantitative, real-time, needle-tip pressure sensing using a novel computer-controlled ES identification technology to FC and LOR for lumbar ES identification. A total of 400 patients were enrolled in this prospective randomized controlled noninferiority trial. In the CP management arm, 240 patients scheduled to receive a lumbar epidural steroid injection had their ES identified either with FC or with needle-tip pressure measurement. In the L&D arm, 160 female patients undergoing lumbar epidural catheter placements were randomized to either LOR or needle-tip pressure measurement. Blinded observers determined successful ES identification in both arms. A modified intention-to-treat protocol was implemented, with patients not having the procedure for reasons preceding the intervention excluded. Noninferiority of needle-tip pressure measurement regarding the incidence of successful ES identification was claimed when the lower limit of the 97.27% confidence interval (CI) for the odds ratio (OR) was above 0.50 (50% less likely to identify the ES) and P value for noninferioirty <.023. Demographics were similar between procedure groups, with a mild imbalance in relation to gender when evaluated through a standardized difference. Noninferiority of needle-tip pressure measurement was demonstrated in relation to FC where pain management patients presented a 100% success rate of ES identification with both methodologies (OR, 1.1; 97.27% CI, 0.52-8.74; P = .021 for noninferiority), and L&D patients experienced a noninferior success rate with the novel technology (97.1% vs 91%; OR, 3.3; 97.27% CI, 0.62-21.54; P = .019) using a a priori noninferiority delta of 0.50. Objective lumbar ES identification using continuous, quantitative, real-time, needle-tip pressure measurement with the CompuFlo Epidural Computer Controlled Anesthesia System resulted in noninferior success rates when compared to FC and LOR for CP management and L&D, respectively. Benefits of this novel technology may include nonexposure of patients to radiation and contrast medium and consequently reduced health care costs

Diminished vagal activity and blunted circadian heart rate dynamics in posttraumatic stress disorder assessed through 24-h linear and unifractal analysis

Background : Affected autonomic heart regulation is implicated in the pathophysiology of cardiovascular diseases and is also associated with posttraumatic stress disorder (PTSD). However, although sympathetic hyperactivation has been repeatedly shown in PTSD, research has neglected the parasympathetic branch. The objective of this study is the long-term assessment of heart rate (HR) dynamics and its circadian changes as an index of autonomic imbalance in PTSD. Since tonic parasympathetic activity underlies long-range correlation of heartbeat interval fluctuations in healthy state, we included nonlinear (unifractal) analysis as an important and sensitive readout to assess functional alterations. Methods : Electrocardiogram recordings over a 24-h period were conducted in 15 deployed male subjects with moderate to high levels of combat exposure (PTSD: n=7; combat controls: n=8). Analysis of HR dynamics included time domain, frequency domain and non-linear analysis based on detrended fluctuation analysis. Psychiatric symptoms were assessed using structured interviews, including the Clinician Administered PTSD Scale. Results : Subjects with PTSD showed significantly higher baseline HR, higher LF/HF ratio in frequency domain analysis, blunted differences between daytime and nighttime measures, as well as higher scaling coefficient &#x03B1;fast during the day, indicating diminished tonic parasympathetic activity. Conclusions : This study appears to be the first combining linear and non-linear methods to assess long-period autonomic and circadian differences in HR dynamics between combatants with and without PTSD. Diminished circadian differences and blunted tonic parasympathetic activity altering HR dynamics suggest central neuro-autonomic dysregulation that could represent a possible link to increased cardiovascular mortality in PTSD