PREFACE

The VA Evidence-based Synthesis Program (ESP) was established in 2007 to provide timely and accurate syntheses of targeted healthcare topics of particular importance to clinicians, managers, and policymakers as they work to improve the health and healthcare of Veterans. QUERI provides funding for four ESP Centers, and each Center has an active University affiliation. Center Directors are recognized leaders in the field of evidence synthesis with close ties to the AHRQ Evidence-based Practice Centers. The ESP is governed by a Steering Committee comprised of participants from VHA Policy, Program, and Operations Offices, VISN leadership, field-based investigators, and others as designated appropriate by QUERI/HSR&D.

The ESP Centers generate evidence syntheses on important clinical practice topics. These reports help:

• Develop clinical policies informed by evidence;
• Implement effective services to improve patient outcomes and to support VA clinical practice guidelines and performance measures; and
• Set the direction for future research to address gaps in clinical knowledge.

The ESP disseminates these reports throughout VA and in the published literature; some evidence syntheses have informed the clinical guidelines of large professional organizations.

The ESP Coordinating Center (ESP CC), located in Portland, Oregon, was created in 2009 to expand the capacity of QUERI/HSR&D and is charged with oversight of national ESP program operations, program development and evaluation, and dissemination efforts. The ESP CC establishes standard operating procedures for the production of evidence synthesis reports; facilitates a national topic nomination, prioritization, and selection process; manages the research portfolio of each Center; facilitates editorial review processes; ensures methodological consistency and quality of products; produces “rapid response evidence briefs” at the request of VHA senior leadership; collaborates with HSR&D Center for Information Dissemination and Education Resources (CIDER) to develop a national dissemination strategy for all ESP products; and interfaces with stakeholders to effectively engage the program.

Comments on this evidence report are welcome and can be sent to Nicole Floyd, ESP CC Program Manager, at vog.av@dyolF.elociN.

EXECUTIVE SUMMARY

Posttraumatic stress disorder (PTSD) is the third most common psychiatric diagnosis among Veterans seen in the Veterans Health Administration (VHA). PTSD can be debilitating, leading to a decline in quality of life (QoL) and causing significant medical, mental health, interpersonal, and social impairment. First-line treatments for PTSD include psychotherapy, pharmacotherapy, or their combination; however, several challenges have been identified in their effectiveness and reach. Stellate ganglion block (SGB), also called cervical sympathetic block, has been promoted as an adjuvant in individuals with PTSD who have not fully responded to conventional therapies. One proposed mechanism of action is that SGB might inhibit connections between the peripheral sympathetic nerve system and regions of the cerebral cortex thought to be abnormally activated in PTSD. Some proposed benefits of SGB for PTSD include (1) it may destigmatize treatment by offering a biologic approach to PTSD management, (2) it may offer a fast-acting treatment alternative with improvements reported within minutes to days of the procedure, and (3) it may increase compliance as it does not require continuous daily or weekly administration.

Our objectives were (1) to determine to what extent SGB provides clinically relevant benefits for patients with PTSD, (2) to determine SGB’s potential harms, and (3) to identify Veterans who are most likely to benefit from SGB.

In uncontrolled, unblinded, retrospective case series, SGB for PTSD had high rates of rapid clinical improvement in PTSD symptoms (70% to 75%). However, findings from the first randomized trial (RCT) of SGB for PTSD were inconclusive, neither confirming nor refuting findings from case series. In the RCT, the range of mean percent PTSD improvement after one round of SGB was 5.4% to 14.7%, and was 12.1% to 21.2% after the second round, which was no better than an injection of saline. However, certain population characteristics and intervention and comparator techniques used in the RCT were suboptimal for determining efficacy and it was too small to estimate rates of serious complications. The majority of study participants were active-duty military personnel with unknown psychological and medical comorbidities and previous conventional therapy trials.

The pattern of very encouraging results in a few case series, followed by a negative RCT, is quite common. The pattern suggests that, while it is possible that some patients benefit, the response rates seen in case series will not hold up in actual practice. Substantial uncertainty remains about the potential harms of SGB as well. The RCT, as well as RCTs of SGB for complex regional pain syndrome (CRPS), were inadequately powered to support or refute findings from the frequently cited, but methodologically weak, 1992 German questionnaire survey of 45,000 SGBs that found 1.7 instances of severe complications per every 1000 individuals.

Evidence was also insufficient to determine which Veterans are most likely to benefit from SGB for PTSD. Clinical factors that could be used to select patients include failure to respond to, or high risk of noncompliance with, conventional therapies, low risk of bleeding and other complications, patient preference, and availability of SGB.

To determine whether some patients benefit, and which Veterans are most likely to benefit, new RCTs designed to correct the deficiencies of the first trial should be conducted. These trials, as well as a registry that adheres to methodological standards, should also be designed to ascertain the frequency and severity of side effects. If further investigation of SGB for PTSD is prioritized in VA, it should include a clear plan to address the following identified important limitations that are also characteristic of research on conventional treatments for PTSD as a whole: (1) adequately powering studies to measure clinically relevant benefits and harms; (2) improved documentation of predominant PTSD symptom types, index trauma types, and comorbidities; (3) improved documentation of prior and concomitant PTSD treatments; and (4) use of longer follow-up periods to determine sustainability. We did not investigate whether SGB should be a higher priority than other innovative treatments for PTSD, such as ketamine, MDMA (±3,4-Methylenedioxymethamphetamine)-assisted psychotherapy, and cranial electrical stimulation, or comparative costs.

INTRODUCTION

METHODS

The ESP included studies that met the following criteria:

• Population: Adults with posttraumatic stress disorder (PTSD)
• Intervention: Stellate ganglion block (SGB)
• Comparator: Any
• Outcomes:
  • Clinical health outcomes: Remission and % of patients achieving minimally important difference in PTSD symptom scores (% responding). Although no definitive guidance has been established for prioritization of instruments and thresholds to use to best measure clinically significant improvement in PTSD symptoms, we used these as our general guideposts: ≥ 15-point reduction on the Clinically-Administered PTSD Scale (CAPS),⁵⁶ a ≥ 10-point reduction on the PTSD Checklist (PCL)⁵⁷ and a ≥ 30% reduction in general ⁵⁸
  • Intermediate benefits: Change in symptom scale scores for PTSD, depression, functional status, quality of life
• Harms: Complications including arrhythmia; hypotension; hematoma due to injury to adjacent vascular structures; thoracic duct injury; injection of local anesthetic into the intravascular, intrathecal, epidural space, or brachial plexus; direct spread of local anesthetic to the recurrent laryngeal or phrenic nerves; soft tissue infection; osteitis; and meningitis
• Timing: Any study follow-up durations
• Setting: Any
• Study design: Systematic reviews, randomized controlled trials, or concurrently controlled cohort studies. Case series will be briefly discussed to provide frequently cited context, but will not be formally evaluated due to their inherent weaknesses^59,60

To identify articles relevant to the key questions, we searched MEDLINE®, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, CINAHL, PsychINFO, and PILOTS on 12/30/2016 and updated on 2/7/2017, using terms for stellate ganglion block and PTSD. (See Appendix A in the supplemental materials for complete search strategies.) We limited the search to articles involving human subjects available in the English language. We sought additional citations through hand-searching reference lists, relevant journals, and consultation with content experts. Study selection was based on the eligibility criteria described above. We searched numerous other sources to identify unpublished and less-accessible forms of data (Appendix A in supplemental materials). Titles, abstracts, and full-text articles were reviewed by one investigator and checked by another. All disagreements were resolved by consensus.

Four reviewers (KP, DB, JA, KM) independently assessed the internal validity of the randomized controlled trial using criteria established by the Drug Effectiveness Review Project.⁶¹ This approach involves assigning ratings of good, fair, or poor quality to reflect the adequacy of methods for randomization, allocation concealment, blinding, outcome measurement and analysis, and acceptability of levels of adherence and attrition. One reviewer abstracted data from the randomized controlled trial on its design, patient characteristics, and results for each included outcome and these were then checked by another. All disagreements were resolved by consensus.

We graded the strength of the evidence based on the AHRQ Methods Guide for Comparative Effectiveness Reviews.⁶² This approach incorporates 4 key domains: risk of bias (includes study design and aggregate quality), consistency, directness, and precision of the evidence. It also considers other optional domains that may be relevant for some scenarios, such as a dose-response association, plausible confounding that would decrease the observed effect, strength of association (magnitude of effect), and publication bias. Strength of evidence is graded for each key outcome measure and ratings range from high to insufficient, reflecting our confidence that the evidence reflects the true effect. Strength of evidence grades were first completed by one reviewer and checked by another and all disagreements were resolved using consensus.

A draft version of this report was reviewed by 3 technical experts and clinical leadership. Their comments and our responses are presented in the supplemental materials.

The complete description of our full methods can be found on the PROSPERO international prospective register of systematic reviews (http://www.crd.york.ac.uk/PROSPERO/; registration number CRD42016053908).

RESULTS

LITERATURE FLOW

Searches resulted in 174 potentially relevant articles after removal of duplicates (Figure 1). Of these, we identified one study with a concurrent comparison group, which was an RCT.⁶³ Detailed reasons for exclusion are provided in Appendix B of the supplemental materials.

Figure 1

Literature Flowchart.

TO WHAT EXTENT DOES SGB PROVIDE CLINICALLY RELEVANT BENEFITS FOR PTSD?

Case Series

Uncontrolled case series of predominantly males in their early forties who were active-duty military with combat-related PTSD (N=202) have found high rates of clinically meaningful improvement with SGB (70% to 75%),^39,64,65 including in those with extreme PTSD.⁶⁵ Case series can be valuable in providing an initial indication of promise. However, their lack of a control group is a major drawback that prevents drawing conclusions regarding treatment effect.⁶⁰ For example, it is quite common to see very encouraging results in a few case series, followed by smaller benefits or contradictory findings in subsequent RCTs.⁶⁶

Randomized Trials

To date there is only one published randomized trial on SGB for PTSD.⁶³ This study compared ultrasound-guided SGB with 5 cc of 0.5% ropivacaine to an inactive sham procedure with normal saline, in 42 primarily limited-duty male military participants with both combat and noncombat PTSD.⁶³ SGB was administered on the right side of the neck, generally at the C6 level. The main finding of this RCT was that at one week and one month after the first round of treatment, the magnitude of mean reduction in PTSD symptoms for SGB and sham neither met the proposed criteria for clinical relevance nor were different between groups, regardless of whether they were measured based on the Clinically-Administered PTSD Scale (CAPS) or the PTSD Checklist (PCL) (Table 1). In the subset of patients who received a second round of SGB or sham, the SBG group reached a clinically significant reduction after one week based on the CAPS, but not the PCL, but again there were no significant differences between SGB and sham.

Table 1

Mean Change from Baseline for SGB versus Sham in the RCT.

Because these findings come from a single study with imprecise findings, moderate methodological limitations, and did not directly focus on clinically relevant outcomes or use the most common administration techniques, they provide an insufficient basis upon which to draw conclusions about SGB for treatment of PTSD in Veterans. Although this study did well in using blinded outcome assessors, we rated the methodological quality of this trial as fair because there were more active-duty participants in the SGB group (96% vs 73%), attrition was high overall (57%) – primarily due to “lost to follow-up at 3 month post treatment or completed outside of 3 month post treatment window” – and was higher in the SGB group (67% vs 40%), and the study did not report on or account for potential between-group differences in concurrent PTSD treatments. Although no definitive guidance has been established for prioritization of instruments and thresholds to use to best measure clinically significant improvement in PTSD symptoms, this trial did not report on the key outcomes that have been suggested as general guideposts: ≥ 10- to 15-point reduction on the CAPS,⁵⁶ a ≥ 10-point reduction on the PCL,⁵⁷ and/or a ≥ 30% reduction in general.⁵⁸ Although in previous case series the most commonly used anesthetic type and dosage used have been 7 cc of ropivacaine, or bupivacaine 0.5% solution, this trial used 5 cc ropivacaine, a 28%-lower dose, and provided no rationale for doing so. Also, it is unclear whether the ropivacaine injection actually reached the stellate ganglion in all patients. Although the stellate ganglion is typically located at C6 to C7, the level of target needle placement was C5 to C6 in this study. Although the study author confirmed that the injection was “typically” at C6, some could have been at C5 and missed the stellate ganglion. Other commonly criticized limitations of this trial that may have altered SGB effects include that (1) it used an inappropriate population who were in the process of disability evaluation and may have had secondary financial incentives to resist treatment,^63,67 and (2) the use of saline instead of an active control that mimicked the side effects of SGB was potentially inadequate and may have reduced the effectiveness of the blinding, as patients may have been able to easily tell if they received SGB or sham based on the occurrence of the Horner’s syndrome eye droop. Effectiveness of the blinding was not formally assessed.

SUMMARY AND DISCUSSION

Emergence of an intervention’s first randomized trial is always a highly anticipated event. For SGB, however, findings from its first randomized trial for PTSD proved to be disappointing. In uncontrolled, unblinded, retrospective case series, SGB for PTSD had high rates of rapid clinical improvement in PTSD symptoms (70% to 75%). In the RCT, the range of mean percent PTSD improvement after one round of SGB was 5.4% to 14.7%, and was 12.1% to 21.2% after the second round, which was no better than an injection of saline. The RCT was too small to estimate complication rates and did not report the number of patients in each group, if any, who responded to treatment. Instead it reported group averages. What do we make of this? It is not surprising that SGB’s benefits were less impressive in the RCT than in the case series, as empirical evaluation has shown that, on average, benefits are generally larger in observational studies.⁶⁶ However, what was surprising is that by using a somewhat lower than usual dose of ropivacaine (5 cc versus 7 cc) and a population that may have been motivated to resist treatment, design features may have limited the RCT’s chances of generating meaningful data on efficacy.⁷¹ Substantial uncertainty remains about the potential harms of SGB as well, as the RCT and previous case series in PTSD, as well as RCTs for CRPS,⁶⁸ were inadequately powered to support or refute findings from the 1992 German questionnaire survey of 45,000 SGBs. We agree with the conclusions of previous reviews that further research is needed to more precisely determine the balance of benefits and harms of SGB for PTSD.^39,52,72

CONCLUSIONS

Findings from the first RCT of SGB for PTSD were inconclusive, neither confirming nor refuting findings of rapid and high rates of clinically relevant improvement and low risk of serious adverse events from unblinded, uncontrolled case series. It is appropriate to listen to criticism of the RCT, envision a better study of SGB for PTSD, and investigate whether SGB should be a higher priority than other innovative treatments for PTSD.

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Supplemental Materials

Prepared for: Department of Veterans Affairs, Veterans Health Administration, Quality Enhancement Research Initiative, Health Services Research & Development Service, Washington, DC 20420.

Prepared by: Evidence-based Synthesis Program (ESP), Coordinating Center, Portland VA Health Care System, Portland, OR, Mark Helfand, MD, MPH, MS, Director.

Recommended citation: Peterson K, Bourne D, Anderson J, Mackey K, Helfand M. Evidence Brief: Effectiveness of Stellate Ganglion Block for Treatment of Posttraumatic Stress Disorder. VA ESP Project #09-199; 2017. [PubMed: 28742302]

This report is based on research conducted by the Evidence-based Synthesis Program (ESP) Coordinating Center located at the Portland VA Health Care System, Portland, OR, funded by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative. The findings and conclusions in this document are those of the author(s) who are responsible for its contents; the findings and conclusions do not necessarily represent the views of the Department of Veterans Affairs or the United States government. Therefore, no statement in this article should be construed as an official position of the Department of Veterans Affairs. No investigators have any affiliations or financial involvement (eg, employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties) that conflict with material presented in the report.