Clinical Review

Evaluation of Clonidine and Prazosin for the Treatment of Nighttime Posttraumatic Stress Disorder Symptoms

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Part of the discrepancy between these results and previously reported successes with clonidine and prazosin may be attributable to the classic issue of efficacy vs effectiveness. Many of the studies that have informed us on the efficacy and tolerability of prazosin for nighttime PTSD symptoms described outcomes of prospective clinical research. Furthermore, these prospective trials were limited to < 6 months in duration. To date, neither clonidine nor prazosin has been evaluated for long-term efficacy and effectiveness in well-designed, prospective trials. This retrospective analysis may help provide a realistic estimate of the long-term effectiveness of these therapies, especially within the veteran population.

Limitations

This was a single-center, retrospective study conducted primarily in white male patients. Although likely applicable to the U.S. veteran population at large, these data may be poorly generalizable to patient populations outside the VA health care system.

Aside from external validity, this study has several significant limitations. The primary limitation of this project is that it was not designed to allow for statistical comparison of clonidine and prazosin. Such an analysis would have better defined the role of clonidine in PTSD treatment, either by establishing similar effectiveness of clonidine and prazosin for nighttime symptoms or by providing evidence of the superiority of one over the other. In designing the project, investigators suspected based on experience that the majority of patients prescribed clonidine would receive the drug after having already failed first-line therapy with prazosin. Had this been the case, a direct comparison may have been biased in favor of prazosin. In retrospect, however, only 24% of the clonidine group had previously been prescribed prazosin, and only 7% of the prazosin group had been prescribed clonidine. This suggests that clonidine may be used first line more often than the investigators anticipated and that a future direct comparison would be worthwhile.

Second, the subjective data collected for this project required investigators to read and interpret chart notes, although the review of all records by a single investigator helped limit variability in interpretation. At times, information in the CPRS was incomplete in terms of determining continuation of therapy or cause for discontinuation.

Third, although it is implied that a significant number of veterans have combat-related PTSD, the nature of the traumatic event(s) leading to PTSD was not recorded in this study, and no subgroup analysis was done to compare the effect of α2-adrenergic agents between combat- and noncombat-related PTSD. Owing to their exclusion by design, it is also difficult to apply these results to veterans who have lasting cognitive impairment as a result of TBI, who are presumably among those most likely to have experienced traumas that could provoke PTSD.

The design of this project also did not include a subgroup analysis based on antidepressant type, and it is unclear whether the potential pharmacodynamic interaction 
between noradrenergic antidepressants (ie, SNRIs) and anti–
α2-adrenergic agents had any impact on clinical outcomes. The use of complementary nonpharmacologic treatment modalities (ie, psychotherapy, eye movement desensitization and reprocessing) was also not evaluated.

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Finally, the primary outcome of patient-reported improvement in symptoms does not provide information on the magnitude or specific nature of benefits derived. Given the retrospective nature, data used in prospectively designed studies (eg, rating scales pertinent to PTSD), which might have helped to quantify the benefit of treatment, was not consistently available. Even a baseline PCL-C score, collected in order to describe the patient population, was available only in 37% of the patients assessed. Furthermore, nighttime PTSD symptoms vary among individuals, but the primary outcome of this study pools any benefits seen in areas such as nightmares, awakenings, night sweats, or sleep quality into a single outcome of symptom improvement.

Conclusions

This study indicates that both clonidine and prazosin may be effective for the treatment of nighttime PTSD symptoms in the veteran population but that their long-term utility may be limited by waning effectiveness, tolerability, and adherence issues. At this time, it is unclear whether either agent has an advantage over the other in terms of effectiveness or tolerability; further studies are needed to address that question.

Despite its limitations, the authors anticipate that this study will provide information regarding the effectiveness and tolerability of clonidine and prazosin to treat nighttime PTSD symptoms. Findings from this study may help clinicians to anticipate the needs and challenges of patients using β2-adrenergic agents for nighttime symptoms of PTSD.

Acknowledgements
The authors wish to acknowledge Brian Wilcox, PharmD, for his assistance in generating patient data reports, and Ronald Brown, RPh, MS, for his guidance regarding data analysis.

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