Morphine Use after Combat Injury in Iraq and Post-Traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) is a disease faced by civilian and military survivors who have experienced trauma.  The disease can greatly effect a person’s quality of life so a lot research is being done regarding pharmacotherapy after serious physical injury and other traumatic events to prevent PTSD from occurring.  Some drugs, including opioids, may decrease memory formation, and therefore the fear associated with the memory, if administered as part of trauma care.

This study involved 696 injured U.S. military personnel who did not have a traumatic brain injury.  The participants’ records were collected including their medication records from the combat trauma registry and their diagnosis of PTSD from the personnel system, which was then verified through medical records.  The results of the study showed that the use of morphine was significantly associated with a lower risk of PTSD.  61% of patients that were diagnosed with PTSD received morphine while 76% of the patients who were not diagnosed with PTSD received morphine.  This difference was statistically significant.

PTSD is a serious issue for returning military members.  I believe that more steps should be taken to prevent PTSD as the disease can reduce quality of life and lead to other problems including depression, anxiety, etc.  Since this is an acute usage of the medication, there should be little worry of abuse.  However, more research should be done since opioids are a common allergenic so other options, including those listed in the article, should be explored.

Holbrook TL, Galarneau MR, Dye JL, et al. Morphine Use after Combat Injury in Iraq and Post-Traumatic Stress Disorder. N Engl J Med. 2010;362(2):110-17.

http://www.nejm.org/doi/full/10.1056/NEJMoa0903326#t=article

The effect of dexamethasone on symptoms of posttraumatic stress disorder and depression after cardiac surgery and intensive care admission

Following cardiac surgery, patients are typically admitted to the intensive care unit (ICU) for a short period of time. Studies suggest that 14 to 25 percent of these patients develop posttraumatic stress disorder (PTSD) and 23 to 32 percent develop depression. Corticosteroids produced via the hypothalamus-pituitary-adrenal (HPA) axis bind to glucocorticoid and mineralocorticoid receptors and help patients adapt to changing environments. Therefore, it is thought that patients with reduced HPA axis activity may be less able to adapt to such changes.

Kok, Hillegers, Veldhuijzen, et al. studied the effect of dexamethasone on the prevention of PTSD and depression among 1,125 patients admitted to the ICU following cardiac surgery between April 2006 and November 2011. Dexamethasone is a synthetic glucocorticoid, which acts on glucocorticoid receptors (GR) to produce anti-inflammatory effects. Of the 1,125 patients enrolled in this study, 561 patients received 1 mg/kg dexamethasone intravenously. This dose was administered following the start of anesthesia and prior to cardiopulmonary bypass. The remaining 564 patients received placebo.

In their 1.5-year follow-up, the authors report similar numbers of patients with PTSD or depression between the treatment and control groups. Among patients who received dexamethasone, 52 patients and 69 patients developed PTSD or depression, respectively. In comparison, 66 patients who received placebo had PTSD and 78 had depression at the time of follow-up. Overall, these results suggest that intraoperative administration of 1 mg/kg dexamethasone has no effect on patients’ likelihood of developing PTSD or depression following ICU discharge. However, dexamethasone was found to have a positive effect on female patients, reducing the prevalence of these psychiatric conditions in this subgroup.

Although this article specifically discusses the development of PTSD and depression following cardiac surgery, it is also applicable to other surgical procedures that require patients be admitted to the ICU. Therefore, this problem effects many patients we will see in the future as pharmacists. By suggesting that dexamethasone is not effective for the prevention of psychiatric conditions in patients following ICU discharge, the authors also demonstrate the need for further research for a solution.

Crit Care Med. 2016;44(3):512-20.

From non-pharmacological treatments for post-traumatic stress disorder to novel therapeutic targets

This paper touches on the complexity of post-traumatic stress disorder and the challenges associated with finding new treatment for patients with the condition. Like other anxiety disorder, PTSD is often treated with selective serotonin reuptake-inhibiting medications, and has been for decades. Psychological therapies are time-consuming and laborious, while pharmacological treatment with SSRIs suffers from lack of effect, relapse, and side effects. On top of that, both type of treatments seem to work only in a subset of patients. More effective treatment with fewer side effects is needed.

One large obstacle to pharmacological and non-pharmacological treatment of this disease is the establishment of an animal model. The large number of PTSD symptoms and the strong cognitive component in this anxiety disorder make it difficult to find a valid animal model for PTSD that meets all the criteria. There exists three animal models for PTSD currently: early life stress, inescapable foot shock (IFS), and social defeat. No model is perfect though the IFS model does provide a reproducible traumatic event, allowing researchers to manipulate the severity of the trauma for experimental reasons. While the early life stress and social defeat models may provide a benefit for the research on sensitivity to trauma, the IFS model is generally regarded as the best. However, symptoms that are not likely to be modeled in animals, such as flashbacks, intrusive memories, and nightmares, will still remain.

In an effort to reduce anxiety from PTSD via non-pharmacological means, two therapies have been identified: environmental enrichment combined with voluntary exercise and methods for re-exposure to the fear-eliciting stimulus in order to initiate extinction. Environmental enrichment enhances neurogenesis in the dentate gyrus and stimulates dendritic branching and spine forming in the hippocampus, effects also often seen after treatment with anti-depressants. By understanding the mechanisms underlying the beneficial behavioral changes of environmental enrichment, we may be able to elucidate future pharmacological treatment possibilities.

Re-exposure treatment is also an effective non-pharmacological psychological therapy option because exposure to a fearful stimulus in a safe environment can decrease the emotional reaction that this stimulus elicits in future exposures. This treatment involves an associative learning process known as ‘extinction’. MRI scans have shown that the areas involved in extinction, amygdala, hippocampus, and prefrontal cortex, are affected in PTSD patients. It is likely that re-exposure induces many other changes in gene expression. The challenge is how to identify those molecular changes that are causally related to the beneficial effects of this non-pharmacological treatment.

From the animal models discussed in the paper, the IFS model shows the most potential for patients with PTSD though it still is not perfect. Animal models help to acquire knowledge of the mechanisms underlying non-pharmacological interventions that can point out neurobiologically relevant processes leading to behavioral recovery. If we understand why the behavioral therapies are good for the brain, we may be able to identify new therapeutic targets.

Hendrikus Hendriksen, Berend Olivier, Ronald S. Oosting, From non-pharmacological treatments for post-traumatic stress disorder to novel therapeutic targets, Eur J Pharmacol. 2014;732:139-158