NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

VA Evidence Synthesis Program Evidence Briefs [Internet]. Washington (DC): Department of Veterans Affairs (US); 2011-.

Cover of VA Evidence Synthesis Program Evidence Briefs

VA Evidence Synthesis Program Evidence Briefs [Internet].

Show details

Evidence Brief: Effectiveness of Stellate Ganglion Block for Treatment of Posttraumatic Stress Disorder (PTSD)

, MS, , BS, , MPH, , MD, and , MD, MS, MPH.

Created: .

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

Background

The ESP Coordinating Center (ESP CC) is responding to a request from Office of Community Engagement’s (OCE) Center for Compassionate Innovation (CCI) for an evidence brief on the effectiveness of stellate ganglion block (SGB) for treatment of posttraumatic stress disorder (PTSD). Findings from this evidence brief will be used to inform Subject Matter Experts’ consideration of clinical use and research and program prioritization of SGB for PTSD in the VA.

Methods

To identify studies, we searched MEDLINE®, CINAHL, and more, through December 2016. We used prespecified criteria for study selection, data abstraction, and rating internal validity, and strength of the evidence. See our PROSPERO protocol for our full methods.

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

PURPOSE

The ESP Coordinating Center (ESP CC) is responding to a request from Office of Community Engagement’s (OCE) Center for Compassionate Innovation (CCI) for an evidence brief on the effectiveness of stellate ganglion block (SGB) for treatment of posttraumatic stress disorder (PTSD). Findings from this evidence brief will be used to inform Subject Matter Experts’ consideration of clinical use and research and program prioritization for SGB for PTSD in VA.

BACKGROUND

Posttraumatic Stress Disorder (PTSD) and Its Impact

Posttraumatic stress disorder (PTSD) is a trauma- and stress-related disorder than can develop following exposure to a traumatic event. PTSD can affect survivors not only of combat experience, but any life-threatening event or traumatic emotional experience. According to the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5), PTSD is defined by 4 clusters of symptoms: (1) intrusive re-experiencing of a traumatic event, (2) avoidance of trauma-related stimuli, (3) negative changes in mood and cognition, and (4) persistent physiological arousal and reactivity. Diagnosis of PTSD requires that the symptoms significantly impair functioning and last for at least one month.1

PTSD is the third most common psychiatric diagnosis among Veterans seen in the Veterans Health Administration (VHA).2 The latest reports on VHA healthcare utilization by Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) Veterans shows that 378,993 Veterans have been diagnosed with PTSD at some point between FY 2002 and FY 2015.3 The lifetime prevalence of PTSD in Veterans (12–30%)49 has consistently been found to be greater than that observed in the general population (7%).10,11 According to research summarized by the Department of Veterans Affairs National Center for PTSD (NCPTSD), experts estimate that up to 20% of Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) Veterans,46 up to 12% of Gulf War Veterans,7 and up to 30% of Vietnam War Veterans8,9 have experienced PTSD. Consequently, the need for PTSD treatment may increase within the Veteran population in the coming years.12

PTSD can be debilitating and lead to a decline in quality of life (QoL).13 Mental health impairments can include increased risk of suicide, depression, other mood/anxiety disorders, eating disorders, and substance use disorders.1419 PTSD has also been linked to increased rate of aging and early mortality.20 Interpersonal and social impairments can include strained marital and family relations, parenting difficulties, and difficulty finding and maintaining employment.2126 As a result, overall healthcare service needs are high among people with PTSD.27 Congressional Budget Office data from fiscal years 2004 through 2009 indicate that, compared to Veterans without PTSD, those with PTSD were more likely to use VHA healthcare services in general – regardless of their relationship to a PTSD diagnosis.27 In 2015, the RAND Center for Military Health Policy Research reported that for OEF/OIF Veterans with PTSD, the estimated 2-year costs to society – from healthcare needs and lost productivity – were substantial.6

Challenges of Conventional Treatments

Commonly recommended first-line treatments for PTSD include psychotherapy, pharmacotherapy, or their combination.2833 Examples of psychotherapy modalities used for PTSD include: Exposure-based therapies (ET), Cognitive-based therapies (CPT), Stress Inoculation Training (SIT), and Eye Movement Desensitization and Reprocessing (EMDR).28 These psychotherapies include 5 core components: (1) narration, (2) cognitive restructuring, (3) in vivo exposure, (4) stress inoculation skills (eg, relaxation), and (5) psychoeducation.34 Pharmacotherapy for PTSD typically consists of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). If unsuccessful, treatment may expand to mood stabilizers, anticonvulsants, antipsychotics, or other agents.

However, several challenges have been identified in the effectiveness and reach of common psychological and pharmacological treatments for PTSD.34 The overall success of current PTSD treatments is low and variable, with rates of remission generally ranging from 30% to 40%.35,36 Whether treatment success differs based on particular clinical characteristics is largely unknown.35 According to surveys of Veterans with PTSD, barriers to seeking and accessing treatment include concerns about treatment, emotional readiness for treatment, stigma, and logistical difficulties.37,38 Contributors to poor compliance with common psychological and pharmacological treatments may include the many weeks to months required, potential side effects, and co-morbidities.39 Due to these limitations, there is a great need for innovative approaches to further improving the health and well-being of people with PTSD.

What is Stellate Ganglion Block (SGB)?

The stellate ganglion, part of the sympathetic nervous system, is a cluster of nerve cell bodies located between the C6 and C7 vertebrae. Injection of local anesthetic to the stellate ganglion, a procedure known as stellate ganglion block (SGB), inhibits sympathetic nerve impulses to the head, neck, and upper extremities. SGB is an outpatient procedure, performed by anesthesiologists or interventional pain management physicians, that has been used to treat various disorders including complex regional pain syndrome, hot flashes, migraines, facial pain, and upper extremity pain.

Because the stellate ganglion is connected to brain regions thought to be abnormally activated in PTSD, such as the amygdala, SGB has been explored as a potential alternative treatment option for PTSD.40 Studies that have examined brain imaging before and after PTSD treatment provide potential evidence of this biological rationale for the effect of SGB on PTSD. A 2015 study comparing fluorodeoxyglucose (FDG) PET brain scans of 5 Veterans with combat-related PTSD one week before and after undergoing right-sided SGB found that the right amygdala and hippocampal areas were relatively overactive when PSTD symptoms were more prominent.41 A 2016 longitudinal study comparing functional MRIs and symptom scores of 72 Veterans with and without PTSD during which PTSD patients received trauma-focused therapy suggested that higher baseline dorsal anterior cingulate cortex (dACC), insula, and amygdala activation may predict poor response to PTSD treatment.42

SGB has also been associated with biologic markers of sedation. A 2014 study on the effects of SGB in rats found that SGB was associated with decreased EEG activity, suggesting a sedative effect.43 Similarly, a 2015 study of healthy adult volunteers found that SGB was associated with a sedative effect compared to sham as measured by the bispectral index system (based on EEG) and Observer’s Assessment of Alertness/Sedation scores.44

The specific mechanism of action by which SGB may mitigate PTSD symptoms remains incompletely understood. SGB results in peripheral vasodilation, but the mechanism by which SGB impacts symptoms of PTSD is likely more complex. A proposed explanation for the prolonged effectiveness of SGB on PTSD, as well as symptoms of hot flashes and complex regional pain syndrome, is that application of local anesthetic to the stellate ganglion leads to a reduction in nerve growth factor and a resulting decrease in sympathetic nerve sprouting and brain norepinephrine levels.45

Ropivacaine or bupivacaine, 7 cc of 0.5% solution, are the most common anesthetic types and dosages used in SGB.39 To avoid potential serious adverse effects of inaccurate needle placement to the anatomy surrounding the stellate ganglion, use of image-guidance techniques such as ultrasound, fluoroscopy, or computed tomography are recommended to help visualize the injection area. SGB performance also requires the availability of continuous vital sign monitoring technology and resuscitative equipment and personnel to monitor and respond to changes in respiration and circulation that may occur as a result of unintentional intravascular injections. Identification of a successful SGB is made by diagnosing temporary Horner’s syndrome occurring within 15 minutes of the procedure – a constricted pupil, weak and droopy eyelid, decreased sweating, and potential inset eyeball – which is recommended to be quantitatively graded by a third-party medical professional.46

Regulation, Guidance, and Advocacy for SGB

Ropivacaine and bupivacaine are FDA-approved for production of local or regional anesthesia for surgery and acute pain management, including in the head and neck area. Injection of these drugs into the stellate ganglion for PTSD is considered an “off-label” use for a different disease than described in the drug label, which is legal and unregulated. PTSD treatment guidelines from the VA/DoD and other professional societies do not reference SGB,28,29,33 but in 2015, Lieutenant Colonel Sean W. Mulvaney, MD and colleagues published clinical guidelines in the Journal of Special Operations Medicine.46 The main source of public advocacy for SGB for PTSD comes from pain management anesthesiologist, Eugene Lipov, MD, who founded the Global Post-Traumatic Stress Injury Foundation (GPTSIF) to facilitate access to innovative biological treatment for PTSD,47 and who has made numerous network television appearances and authored numerous articles about SGB for PTSD.4852 Advocates such as Drs. Lipov and Mulvaney have promoted SGB for PTSD primarily based on the notably high rates of clinically meaningful improvement (70% to 75%) in uncontrolled case series of predominantly males in their early forties who were active-duty military with combat-related PTSD.39,53,54 Advocates commonly describe SGB as safe, with the most frequently cited supporting evidence coming from a questionnaire survey with a 51% response rate that included responses from 39 West German departments of anesthesiology, representing approximately 45,000 SGBs, that reported low rates (1.7 per 1000) of severe complications such as convulsions.55

What Are Possible Roles for SGB for PTSD?

SGB for PTSD has typically been promoted as an adjuvant in individuals who have not fully responded to conventional therapies.53 Some proposed benefits of SGB for PTSD include (1) it may destigmatize treatment by offering a biologic approach to PTSD management,39 (2) it may offer a faster-acting treatment alternative with improvements reported within 30 minutes to days of the procedure,39 and (3) it increases compliance as it does not require continuous daily or weekly administration.53

Objectives of this Evidence Review

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

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 weaknesses59,60

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.

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.

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.

WHAT ARE SGB’S POTENTIAL HARMS?

Substantial uncertainty remains about the potential serious harms of SGB due to a lack of adequately powered studies using clearly reliable and valid assessment methods. Although the frequently cited 1992 West German questionnaire survey of approximately 45,000 SGBs from 39 anesthesiology departments appears to provide the most precise estimates of serious complications, it has important methodological weaknesses that seriously limit our confidence in its findings. At 1.7 per 1000, rates of severe complications, such as convulsions, were reportedly low in this questionnaire survey.55 However, we have no information about what methods were used to collect and analyze these data, such as the rating criteria used, how they were implemented, what the time period was between the procedure and outcome assessment, what data monitoring standards were used to reduce error, the level of which and how missing data were handled, and how consistent these factors were across departments. Without this information, we cannot be sure of the reliability and validity of these data. Compared to the “blind” technique used in the West German SGBs from the survey, we agree that the modern standard of using image-guidance techniques has the potential to increase needle placement accuracy and result in lower severe complications than reported in this survey. However, we have no way of knowing how much or in what direction the potential limitations in the outcome assessment methods may affect the reported rates.

Although RCTs of SGB for PTSD,63 and CPRS,68 and case series of SGB for PTSD,39,54,69 may have used stronger assessment methods, their findings are limited by imprecision and do not importantly improve our knowledge about the risk of serious complications. In the RCT and case series of SGB for PTSD,63 there were no instances of serious complication such as arrhythmia, hypotension, hematoma due to injury to adjacent vascular structures, thoracic duct injury, injection of local anesthetic into the intravascular, intrathecal, or epidural space or brachial plexus, direct spread of local anesthetic to the recurrent laryngeal or phrenic nerves, soft tissue infection, osteitis, or meningitis. In the RCT,63 after one month post-injection, 28 mild adverse events were recorded, resulting in a potential complication rate of 33%. An IRB-designated scientific reviewer categorized the adverse events as “Unrelated,” “Remote,” “Possible,” or “Related.” Ten of the events were classified as “Related” or “Possible,” for a complication rate of 12%. There was no significant difference in the rate of complications between the SGB and sham injection groups. Complications included increased injection site pain, which could potentially have been reduced by using a smaller needle such as in prior studies (20 gauge in RCT vs 22–25 gauge in case series). The most notable event was prolonged eye drooping, which was observed in one patient and resolved after 4 days.

Because of the limited data on harms for SGB in PTSD, we looked to the larger literature on its use for CRPS. A 2016 Cochrane review on sympathetic blockades for CRPS identified 3 studies that provided specific data regarding adverse effects of SGB for CRPS (N=115).68 Adverse event rates ranged from 0% to 14.3% and included significant nausea and emesis, paresthesia during needle positioning, pain at the injection site, varying rates of drowsiness, dizziness, or hoarseness based on the anesthetic used, increased pain, headache, dysphagia, hematoma, dyspnea, shivering, cold feeling, face swelling, mouth numbness, and blurred vision. The most prevalent complaint was pain at the injection site. Due to the small size of the included studies, Cochrane review authors could not draw conclusions regarding the safety of sympathetic blockades.

WHO IS MOST LIKELY TO BENEFIT?

There is insufficient information to determine which Veterans, if any, are most likely to benefit from SGB for PTSD. We found no studies that compared outcomes between subgroups of patients with different demographics, predominant PTSD symptom clusters, or comorbidities. Findings from a case series of 30 active-duty military service members with combat-related PTSD suggest that people with predominantly hyperarousal and avoidance types of symptoms may be more likely to benefit from SGB.70 Evidence for this effect is very weak as it is based on inference from evaluation of which symptoms are most impacted after SGB, rather than from direct comparison of response rates between people with different levels of these symptoms at baseline.

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

LIMITATIONS

Overall, a key limitation of the evidence on SGB is that it is based primarily on uncontrolled, unblinded studies. Also key is that evidence on SGB for PTSD has unclear applicability to Veterans. Although most studies have been conducted in military populations, the majority were active-duty military members. In the largest case series (N = 166), a majority of participants continued exposure to combat after treatment.54 The majority of study participants were male, as in VA, but mean age was late thirties to early forties and prevalence of depression, anxiety, pain, and other medical comorbidities was unclear.

The limitations of the evidence base for SGB for PTSD are similar to those for other PTSD treatments.35 First, SGB studies have generally been underpowered to adequately measure the most clinically important outcomes of remission, response, and serious adverse events. Second, although SGB has been recommended for use as an adjuvant for other therapies,53 evidence is insufficient to support recommendations about specifically when to initiate SGB in the order of recommended conventional pharmacotherapies and psychotherapies. How much failed conventional therapy is “enough” before trying SGB? Although likely many study participants had already failed “gold standard” therapy and their lack of success suggests the need for an innovative approach, the studies’ lack of specific criteria for establishing “failure” of conventional therapy, and/or dose and duration and order of conventional therapies makes it difficult for readers to compare their patient with those in the studies. For example, in the largest case series of N = 166, only 3% of patients were taking psychotropic medication before SGB and there was no information about dose and duration and no information about any psychotherapy.54 In the RCT, the only information about other mental health treatments was that 9.5% participated since deployment, 26% during deployment, and 69% after deployment, but no details were provided about type or duration.63 Third, there was insufficient information to determine applicability to and which Veterans, if any, are most likely to benefit from SGB for PTSD, due to inadequate documentation of predominant PTSD symptom types, index trauma types, comorbidities, optimization of prior dose, and duration of prior treatments. Fourth, evidence is insufficient to fully assess the clinical relevance of the benefits of SGB for PTSD. Although the studies consistently used the recommended tools – the CAPS and the PCL – none assessed remission (loss of PTSD diagnosis). Although the largest case series measured proportion of patients who were “responders” using the recommended PCL criteria of a ≥ 10-point reduction, the RCT did not measure the proportion of patients meeting any clinically relevant threshold. Finally, we could not assess long-term sustainability of response as follow-up was generally limited to 3 months post-SGB.

Publication bias is the primary potential limitation of our review process. We attempted to minimize the risk of publication bias by specifically searching for unpublished studies, and we did not find any negative case series or previously unreported outcomes. Nonetheless, we may have missed such data.

CLINICAL AND RESEARCH IMPLICATIONS

SGB for PTSD has been recommended for use as an adjuvant in individuals who have not fully responded to conventional therapies.53 Other practical considerations that may guide treatment decisions include access to, contraindications for, and patient preference for SGB. Access to SGB may require efforts to increase psychiatrists’ education about SGB and promote development of partnerships between psychiatry and anesthesiology and pain management specialists.39 Contraindications for SGB may include a history of an anesthetic allergy, and because of the potential risks of ocular, cardiac, and circulatory adverse events, SGB should be avoided in individuals with coagulopathy, a recent cardiac infarction, a severe conduction block, or glaucoma.73 Finally, although those who have undergone SGB have found it highly acceptable,69 the invasive nature of SGB may be a barrier for some candidates to try it in the first place.

SGB for PTSD is currently supported only by evidence from uncontrolled, unblinded case series which was neither confirmed nor refuted by a single RCT with imprecise findings, moderate methodological limitations, and which did not directly focus on clinically relevant outcomes. In currently used evidence grading systems,62 such evidence is considered “insufficient” for estimating an effect. More rigorous studies are needed to more precisely determine the balance of benefits and harms of SGB for the treatment of PTSD. Both randomized trials and observational studies can contribute to our knowledge of SGB for PTSD. RTI International is conducting a U.S. Army-funded randomized trial that will compare SGB to placebo in a planned enrollment of 204 active-duty military personnel with PTSD (US Army Medical Research Acquisition Activity, grant number W81XWH-15-2-0015).74 This trial will help answer the overarching question of whether SGB is effective, but follow-up is only 8 weeks and it is not expected to address all of the gaps in the existing evidence.

We agree with Dr. Lipov53 that the VA could be an ideal setting to perform further practice-based research on SGB for PTSD to evaluate remission, response, and serious complication rates, with follow-up longer than 8 weeks. An observational design could be appropriate, but it should be incorporate precautions against bias that were lacking in prior studies. In particular,

  1. Rigorous standards for registry studies should be followed (see below);
  2. Assessment of preferences as part of the research protocol;
  3. Inclusion of Veterans with PTSD who are offered (and either do or do not undergo) conventional treatments, followed prior to and after consideration of SGB; and
  4. Outcome assessment and data analysis should be conducted by research or quality improvement personnel who do not have strong prior views of the effectiveness of SGB.

In addition, future VA research on SBG should include a clear plan to address shortcomings of previous research through use of the following rigorous standards for registry studies: (1) sufficient sample size to assess the 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) longer follow-up periods.

A controlled observational study designed in this way could provide better justification for conducting another RCT to strengthen our certainty about the benefits. If a future RCT is undertaken, we also suggest considering adding functional magnetic resonance imaging (fMRI) assessment both to improve our understanding of SGB’s neural mechanisms and to help clarify the impact of inadequate blinding. Differences in fMRI results between SGB and control group participants could help refute an argument that clinical differences were due to knowing whether or not they got SGB.

We did not investigate whether SGB should be a higher priority than other innovative treatments for PTSD. Examples of other potentially rapid and innovative treatments include ketamine, MDMA (±3,4-Methylenedioxymethamphetamine)-assisted psychotherapy, and cranial electrical stimulation. Each has their own unique set of potential harms, such as addiction and neurotoxicity, which would have to be considered in relation to SGB’s net benefits. Cost of these innovative treatments compared to conventional psychotherapy and pharmacotherapies should also be assessed in the prioritization process. SGB costs have been estimated to be lower than conventional PTSD therapies ($2,000 for two SGB injections vs a range of $6,000 to $30,000).75 However, we have not formally evaluated comparative costs or how these estimates apply to the current VA environment.

For additional related evidence review work, we recommend that a review of the state of the science of PTSD outcome assessment methods, such as has been done in the field of chronic pain outcome assessment,76 could be useful in informing the direction of future research for PTSD as a whole.

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.

REFERENCES

1.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5®). American Psychiatric Pub; 2013.
2.
Stecker T, Fortney J, Owen R, McGovern MP, Williams S. Co-occurring medical, psychiatric, and alcohol-related disorders among veterans returning from Iraq and Afghanistan. Psychosomatics. Nov–Dec 2010;51(6):503–507. [PubMed: 21051682]
3.
Group EPP-DH. Analysis of VA Health Care Utilization among Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) Veterans, from 1st Qtr FY 2002 through 2nd Qtr FY 2015. In: Affairs V, ed. Washington, DC2015.
4.
Hoge CW, Castro CA, Messer SC, McGurk D, Cotting DI, Koffman RL. Combat duty in Iraq and Afghanistan, mental health problems and barriers to care. U.S. Army Medical Department journal. Jul–Sep 2008:7–17. [PubMed: 20088060]
5.
Terhakopian A, Sinaii N, Engel CC, Schnurr PP, Hoge CW. Estimating population prevalence of posttraumatic stress disorder: an example using the PTSD checklist. Journal of traumatic stress. Jun 2008;21(3):290–300. [PubMed: 18553416]
6.
Holdeman TC. Invisible wounds of war: psychological and cognitive injuries, their consequences, and services to assist recovery. Am Psychiatric Assoc; 2015.
7.
Kang HK, Natelson BH, Mahan CM, Lee KY, Murphy FM. Post-traumatic stress disorder and chronic fatigue syndrome-like illness among Gulf War veterans: a population-based survey of 30,000 veterans. American journal of epidemiology. Jan 15 2003;157(2):141–148. [PubMed: 12522021]
8.
Dohrenwend BP, Turner JB, Turse NA, Adams BG, Koenen KC, Marshall R. The psychological risks of Vietnam for U.S. veterans: a revisit with new data and methods. Science (New York, N.Y.). Aug 18 2006;313(5789):979–982. [PMC free article: PMC1584215] [PubMed: 16917066]
9.
Kulka RA, Schlenger WE, Fairbank JA, et al. Trauma and the Vietnam war generation: Report of findings from the National Vietnam Veterans Readjustment Study. Brunner/Mazel; 1990.
10.
Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Archives of general psychiatry. Jun 2005;62(6):593–602. [PubMed: 15939837]
11.
Pietrzak RH, Goldstein RB, Southwick SM, Grant BF. Prevalence and Axis I comorbidity of full and partial posttraumatic stress disorder in the United States: results from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions. Journal of anxiety disorders. Apr 2011;25(3):456–465. [PMC free article: PMC3051041] [PubMed: 21168991]
12.
Vasterling JJ, Aslan M, Proctor SP, et al. Longitudinal Examination of Posttraumatic Stress Disorder as a Long-Term Outcome of Iraq War Deployment. American journal of epidemiology. Dec 01 2016;184(11):796–805. [PubMed: 27852604]
13.
Pagotto LF, Mendlowicz MV, Coutinho ES, et al. The impact of posttraumatic symptoms and comorbid mental disorders on the health-related quality of life in treatment-seeking PTSD patients. Comprehensive psychiatry. Apr 2015;58:68–73. [PubMed: 25656798]
14.
Kessler RC. Posttraumatic stress disorder: the burden to the individual and to society. The Journal of clinical psychiatry. 2000;61 Suppl 5:4–12; discussion 13–14. [PubMed: 10761674]
15.
Panagioti M, Gooding P, Tarrier N. Post-traumatic stress disorder and suicidal behavior: A narrative review. Clinical psychology review. Aug 2009;29(6):471–482. [PubMed: 19539412]
16.
Nock MK, Hwang I, Sampson N, et al. Cross-national analysis of the associations among mental disorders and suicidal behavior: findings from the WHO World Mental Health Surveys. PLoS medicine. Aug 2009;6(8):e1000123. [PMC free article: PMC2717212] [PubMed: 19668361]
17.
Bernal M, Haro JM, Bernert S, et al. Risk factors for suicidality in Europe: results from the ESEMED study. Journal of affective disorders. Aug 2007;101(1–3):27–34. [PubMed: 17074395]
18.
Brewerton TD. Eating disorders, trauma, and comorbidity: focus on PTSD. Eating disorders. Jul–Sep 2007;15(4):285–304. [PubMed: 17710567]
19.
Harned MS, Najavits LM, Weiss RD. Self-harm and suicidal behavior in women with comorbid PTSD and substance dependence. The American journal on addictions. Sep–Oct 2006;15(5):392–395. [PubMed: 16966196]
20.
Lohr JB, Palmer BW, Eidt CA, et al. Is Post-Traumatic Stress Disorder Associated with Premature Senescence? A Review of the Literature. The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry. Jul 2015;23(7):709–725. [PMC free article: PMC4568841] [PubMed: 25959921]
21.
Taft CT, Watkins LE, Stafford J, Street AE, Monson CM. Posttraumatic stress disorder and intimate relationship problems: a meta-analysis. Journal of consulting and clinical psychology. Feb 2011;79(1):22–33. [PubMed: 21261431]
22.
Lambert JE, Engh R, Hasbun A, Holzer J. Impact of posttraumatic stress disorder on the relationship quality and psychological distress of intimate partners: a meta-analytic review. Journal of family psychology: JFP: journal of the Division of Family Psychology of the American Psychological Association (Division 43). Oct 2012;26(5):729–737. [PubMed: 22924422]
23.
Calhoun PS, Beckham JC, Bosworth HB. Caregiver burden and psychological distress in partners of veterans with chronic posttraumatic stress disorder. Journal of traumatic stress. 2002;15(3):205–212. [PubMed: 12092912]
24.
Hayes J, Wakefield B, Andresen EM, et al. Identification of domains and measures for assessment battery to examine well-being of spouses of OIF/OEF veterans with PTSD. Journal of rehabilitation research and development. 2010;47(9):825–840. [PubMed: 21174248]
25.
Resnick SG, Rosenheck RA. Posttraumatic stress disorder and employment in veterans participating in Veterans Health Administration Compensated Work Therapy. Journal of rehabilitation research and development. 2008;45(3):427–435. [PubMed: 18629751]
26.
Sherman MD, Gress Smith JL, Straits-Troster K, Larsen JL, Gewirtz A. Veterans’ perceptions of the impact of PTSD on their parenting and children. Psychological services. Nov 2016;13(4):401–410. [PubMed: 27441417]
27.
Bass E, Golding HL. The Veterans Health Administration’s treatment of PTSD and traumatic brain injury among recent combat veterans. 2012.
28.
Management of Post-Traumatic Stress Working Group. VA/DoD clinical practice guideline for management of post-traumatic stress. Washington (DC): Veterans Health Administration, Department of Defense. 2010.
29.
Association AP. Clinical Practice Guideline for the Treatment of Posttraumatic Stress Disorder (PTSD) in Adults [Draft] 2016.
30.
Forbes D, Creamer M, Phelps A, et al. Australian guidelines for the treatment of adults with acute stress disorder and post-traumatic stress disorder. The Australian and New Zealand journal of psychiatry. Aug 2007;41(8):637–648. [PubMed: 17620160]
31.
Health NCCfM. Post-traumatic stress disorder: management. 2005.
32.
Tol WA, Barbui C, Bisson J, et al. World Health organization guidelines for management of acute stress, PTSD, and bereavement: key challenges on the road ahead. PLoS medicine. Dec 2014;11(12):e1001769. [PMC free article: PMC4267806] [PubMed: 25514024]
33.
Benedek DM, Friedman MJ, Zatzick D, Ursano RJ. Guideline watch (March 2009): Practice guideline for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Focus. 2009;7(2):204–213.
34.
Hoge CW. Interventions for war-related posttraumatic stress disorder: meeting veterans where they are. Jama. Aug 03 2011;306(5):549–551. [PubMed: 21813436]
35.
Jonas DE, Cusack K, Forneris CA, et al. Psychological and Pharmacological Treatments for Adults With Posttraumatic Stress Disorder (PTSD). Rockville MD2013.
36.
Difede J, Olden M, Cukor J. Evidence-based treatment of post-traumatic stress disorder. Annual review of medicine. 2014;65:319–332. [PubMed: 24422573]
37.
Stecker T, Shiner B, Watts BV, Jones M, Conner KR. Treatment-seeking barriers for veterans of the Iraq and Afghanistan conflicts who screen positive for PTSD. Psychiatric services (Washington, D.C.). Mar 01 2013;64(3):280–283. [PubMed: 23450385]
38.
Hoge CW, Castro CA, Messer SC, McGurk D, Cotting DI, Koffman RL. Combat duty in Iraq and Afghanistan, mental health problems, and barriers to care. The New England journal of medicine. Jul 01 2004;351(1):13–22. [PubMed: 15229303]
39.
Navaie M, Keefe MS, Hickey AH, McLay RN, Ritchie EC, Abdi S. Use of stellate ganglion block for refractory post-traumatic stress disorder: a review of published cases. Journal of Anesthesia & Clinical Research. 2014;2014.
40.
Lipov EG, Joshi JR, Lipov S, Sanders SE, Siroko MK. Cervical sympathetic blockade in a patient with post-traumatic stress disorder: a case report. Annals of clinical psychiatry: official journal of the American Academy of Clinical Psychiatrists. Oct–Dec 2008;20(4):227–228. [PubMed: 19034755]
41.
Alkire MT, Hollifield M, Khoshsar R, Nguyen L, Alley SR, Reist C. Neuroimaging Suggests that Stellate Ganglion Block Improves Post-Traumatic Stress Disorder (PTSD) Through an Amygdala Mediated Mechanism. The Anesthesiology Meeting2015.
42.
van Rooij SJ, Kennis M, Vink M, Geuze E. Predicting Treatment Outcome in PTSD: A Longitudinal Functional MRI Study on Trauma-Unrelated Emotional Processing. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology. Mar 2016;41(4):1156–1165. [PMC free article: PMC4748440] [PubMed: 26289143]
43.
Jeong S, Jeon Y, Yeo J, Baek W. The effects of stellate ganglion block on the electroencephalogram in rats. J. 2014;28(4):601–605. [PubMed: 24408532]
44.
Yeo J, Jeon Y. Effects of stellate ganglion block on sedation as assessed by bispectral index in normal healthy volunteers. Pain physician. 2015;18:173–178. [PubMed: 25794203]
45.
Lipov EG, Joshi JR, Sanders S, Slavin KV. A unifying theory linking the prolonged efficacy of the stellate ganglion block for the treatment of chronic regional pain syndrome (CRPS), hot flashes, and posttraumatic stress disorder (PTSD). Medical Hypotheses. Jun 2009;72(6):657–661. [PubMed: 19237252]
46.
Mulvaney SW, Lynch JH, Kotwal RS. Clinical Guidelines for Stellate Ganglion Block to Treat Anxiety Associated With Posttraumatic Stress Disorder. J Spec Oper Med. 2015;15(2):79–85. [PubMed: 26125169]
47.
Adahan, HMA, J., Abdi, S., Ochberg, F., Hickey, A., Ritchie, E.C. Global Post-Traumatic Stress Injury Foundation. 2016. Accessed January 20, 2017.
48.
Lipov E. In search of an effective treatment for combat-related post-traumatic stress disorder (PTSD): can the stellate ganglion block be the answer? Pain Practice. Jul–Aug 2010;10(4):265–266. [PubMed: 20636577]
49.
Lipov E. Successful use of stellate ganglion block and pulsed radiofrequency in the treatment of posttraumatic stress disorder: a case report. Pain Res Treat. 2010;2010:963948. [PMC free article: PMC3196975] [PubMed: 22110919]
50.
Lipov E. The use of stellate ganglion block in the treatment of panic/anxiety symptoms (including suicidal ideation), with combat-related posttraumatic stress disorder. Posttraumatic stress disorder and related diseases in combat veterans. Cham, Switzerland: Springer International Publishing; Switzerland; 2015:179–196.
51.
Lipov E, Kelzenberg B. Sympathetic system modulation to treat post-traumatic stress disorder (PTSD): a review of clinical evidence and neurobiology. Journal of affective disorders. Dec 15 2012;142(1–3):1–5. [PubMed: 22840634]
52.
Lipov E, Ritchie EC. A review of the use of stellate ganglion block in the treatment of PTSD. Current Psychiatry Reports. 2015;17(8):599–599. [PubMed: 26073361]
53.
Lipov E, Ritchie EC. A review of the use of stellate ganglion block in the treatment of PTSD. Current Psychiatry Reports. Aug 2015;17(8):599. [PubMed: 26073361]
54.
Mulvaney SW, Lynch JH, Hickey MJ, et al. Stellate ganglion block used to treat symptoms associated with combat-related post-traumatic stress disorder: A case series of 166 patients. Military Medicine. Oct 2014;179(10):1133–1140. [PubMed: 25269132]
55.
Wulf H, Maier C. [Complications and side effects of stellate ganglion blockade. Results of a questionnaire survey]. Der Anaesthesist. Mar 1992;41(3):146–151. [PubMed: 1570888]
56.
Echeburua E, de Corral P, Zubizarreta I, Sarasua B. Psychological treatment of chronic posttraumatic stress disorder in victims of sexual aggression. Behavior modification. Oct 1997;21(4):433–456. [PubMed: 9337600]
57.
Monson CM, Gradus JL, Young-Xu Y, Schnurr PP, Price JL, Schumm JA. Change in posttraumatic stress disorder symptoms: do clinicians and patients agree? Psychological assessment. Jun 2008;20(2):131–138. [PubMed: 18557690]
58.
McLay RN, Wood DP, Webb-Murphy JA, et al. A randomized, controlled trial of virtual reality-graded exposure therapy for post-traumatic stress disorder in active duty service members with combat-related post-traumatic stress disorder. Cyberpsychology, behavior and social networking. Apr 2011;14(4):223–229. [PubMed: 21332375]
59.
Effective Practice and Organization of Care. What study designs should be included in an EPOC review and what should they be called. http://epoc​.cochrane​.org/sites/epoc.cochrane​.org/files/public​/uploads/EPOC%20Study​%20Designs%20About.pdf. Accessed February, 2017.
60.
Carey TS, Boden SD. A critical guide to case series reports. Spine. 2003;28(15):1631–1634. [PubMed: 12897483]
61.
McDonagh MS, Jonas DE, Gartlehner G, et al. Methods for the drug effectiveness review project. BMC Med. Res. Methodol. 2012;12:140. [PMC free article: PMC3532217] [PubMed: 22970848]
62.
Berkman ND, Lohr KN, Ansari M, et al. Grading the Strength of a Body of Evidence When Assessing Health Care Interventions for the Effective Health Care Program of the Agency for Healthcare Research and Quality: An Update Methods Guide for Effectiveness and Comparative Effectiveness Reviews. 2013.
63.
Hanling SR, Hickey A, Lesnik I, et al. Stellate Ganglion Block for the Treatment of Posttraumatic Stress Disorder: A Randomized, Double-Blind, Controlled Trial. Regional Anesthesia & Pain Medicine. Jul–Aug 2016;41(4):494–500. [PubMed: 27187898]
64.
Mulvaney SW, Lynch JH, Hickey MJ, et al. Stellate ganglion block used to treat symptoms associated with combat-related post-traumatic stress disorder: a case series of 166 patients. Military Medicine. Oct 2014;179(10):1133–1140. [PubMed: 25269132]
65.
Alkire MT, Hollifield M, Khoshsar R, et al. Prolonged Relief of Chronic Extreme PTSD and Depression Symptoms in Veterans Following a Stellate Ganglion Block The Anesthesiology annual Meeting: Long Beach VA Healthcare System, Long Beach, California; 2014.
66.
Brignardello-Petersen R, Ioannidis J, Tomlinson G, Guyatt G. Surprising results of randomized trials. Users’ guide to the medical literature. A manual for evidence-based clinical practice, 3rd ed. New York: McGraw-Hill. 2015.
67.
Lipov E. A Randomized, Double-Blind, Placebo-Controlled Trial of Stellate Ganglion Block in the Treatment of Post-Traumatic Stress Disorder: Scientific Poster. J Trauma Treat S. 2015;4:2167–1222.
68.
O’Connell NE, Wand BM, Gibson W, Carr DB, Birklein F, Stanton TR. Local anaesthetic sympathetic blockade for complex regional pain syndrome. Cochrane Database of Systematic Reviews. 2016(7). [PubMed: 27467116]
69.
McLean B. Safety and Patient Acceptability of Stellate Ganglion Blockade as a Treatment Adjunct for Combat-Related Post-Traumatic Stress Disorder: A Quality Assurance Initiative. Cureus. 2015;7(9):e320. [PMC free article: PMC4601906] [PubMed: 26487996]
70.
Lynch JH, Mulvaney SW, Kim EH, de Leeuw JB, Schroeder MJ, Kane SF. Effect of Stellate Ganglion Block on Specific Symptom Clusters for Treatment of Post-Traumatic Stress Disorder. Military Medicine. Sep 2016;181(9):1135–1141. [PubMed: 27612365]
71.
Kessler DA, Rose JL, Temple RJ, Schapiro R, Griffin JP. Therapeutic-class wars--drug promotion in a competitive marketplace. The New England journal of medicine. Nov 17 1994;331(20):1350–1353. [PubMed: 7935706]
72.
Summers MR, Nevin RL. Stellate Ganglion Block in the Treatment of Post-traumatic Stress Disorder: A Review of Historical and Recent Literature. Pain practice: the official journal of World Institute of Pain. Oct 14 2016. [PubMed: 27739175]
73.
Abdi S, Zhou Y, Saini B, Nelson J. A new and easy technique to block the stellate ganglion. Pain Physician. 2004;7(3):327–332. [PubMed: 16858470]
74.
Olmstead K, Walters B, Morgan J, Vandermaas-Peeler R. Stellate Ganglion Block for Treatment of Posttraumatic Stress Disorder Symptoms: A Multi-Mode Study. RTI International; 2016.
75.
Lipov EG, Navaie M, Stedje-Larsen ET, et al. A novel application of stellate ganglion block: preliminary observations for the treatment of post-traumatic stress disorder. Military Medicine. Feb 2012;177(2):125–127. [PubMed: 22360054]
76.
Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain. 2005;113(1–2):9–19. [PubMed: 15621359]

Supplemental Materials

APPENDIX A. SEARCH STRATEGIES

Database: Ovid MEDLINE

(December 30, 2016)

Database: Ovid MEDLINE(R) <1946 to December Week 1 2016>, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations <December 29, 2016>
Search Strategy:
  1. stellate ganglion block.mp. (632)
  2. (PTSD or post-traumatic stress disorder).mp. (22757)
  3. Stress Disorders, Post-Traumatic/(29126)
  4. 2 or 3 (35367)
  5. 1 and 4 (18)
  6. remove duplicates from 5 (18)

Expanded Search

(February 7, 2017)

Database: Ovid MEDLINE(R) without Revisions <1996 to January Week 4 2017>
Search Strategy:
  1. (stellate adj5 block*).mp. (390)
  2. nerve block.mp. or exp Nerve Block/(12206)
  3. exp Anesthetics, Local/or anesthetics.mp. (73303)
  4. bupivacaine.mp. (8470)
  5. lidocaine.mp. (13981)
  6. (nerve* adj5 block*).mp. (14395)
  7. (sympathetic* adj5 block*).mp. (1491)
  8. sympatholytic*.mp. (1941)
  9. (local adj5 (anaesthetic* or anesthetic*)).mp. (26245)
  10. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 (90120)
  11. post traumatic stress disorder.mp. or exp Stress Disorders, Post-Traumatic/(23908)
  12. 10 and 11 (81)
  13. limit 12 to (english language and humans) (64)

Database: CINAHL

(December 30, 2016)

Database: CINAHL Plus with Full Text
Search Strategy:
  1. “stellate ganglion block” (126)
  2. PTSD OR post-traumatic stress disorder (7,224)
  3. S1 AND S2 (12)

Expanded Search

(February 7, 2017)

Database: CINAHL Plus with Full Text
Search Strategy:
  1. nerve block (6,642)
  2. local anesthetic* (1,861)
  3. bupivacaine (3,328)
  4. lidocaine (4,736)
  5. nerve* N5 block* (6,968)
  6. stellate adj5 block* (0)
  7. sympathetic* N5 block* (297)
  8. sympatholytic* (389)
  9. local N5 (anaesthetic* or anesthetic*) (7,966)
  10. S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 (17,227)
  11. PTSD (5,955)
  12. post-traumatic stress disorder (2,813)
  13. post traumatic stress disorder (2,813)
  14. S11 OR S12 OR S13 (7,298)
  15. S10 AND S14 (15)

Database: PsycINFO

(December 30, 2016)

Database: PsycINFO <1806 to December Week 4 2016>
Search Strategy:
  1. stellate ganglion block.mp. (29)
  2. (PTSD or post-traumatic stress disorder).mp. (30258)
  3. exp Posttraumatic Stress Disorder/(26439)
  4. 2 or 3 (34382)
  5. 1 and 4 (10)

Expanded Search

(February 7, 2017)

Database: PsycINFO <1806 to January Week 5 2017>
Search Strategy:
  1. (stellate adj5 block*).mp. (47)
  2. nerve block.mp. or exp Nerve Block/(245)
  3. exp Anesthetics, Local/or anesthetics.mp. (1491)
  4. bupivacaine.mp. (219)
  5. lidocaine.mp. (1020)
  6. (nerve* adj5 block*).mp. (807)
  7. (sympathetic* adj5 block*).mp. (198)
  8. sympatholytic*.mp. (108)
  9. (local adj5 (anaesthetic* or anesthetic*)).mp. (824)
  10. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 (3800)
  11. post traumatic stress disorder.mp. or exp Stress Disorders, Post-Traumatic/(8323)
  12. 10 and 11 (12)
  13. limit 12 to (human and english language) (12)

Database: Cochrane

(December 30, 2016)

Database: EBM Reviews - Cochrane Central Register of Controlled Trials <November 2016>, EBM Reviews - Cochrane Database of Systematic Reviews <2005 to December 21, 2016>, EBM Reviews -Cochrane Methodology Register <3rd Quarter 2012>
Search Strategy:
  1. stellate ganglion block.mp. (124)
  2. (PTSD or post-traumatic stress disorder).mp. (1960)
  3. Stress Disorders, Post-Traumatic/(1125)
  4. 2 or 3 (2245)
  5. 1 and 4 (1)

Expanded Search

(February 7, 2017)

Database: EBM Reviews - Cochrane Central Register of Controlled Trials <November 2016>
Search Strategy:
  1. (stellate adj5 block*).mp. (135)
  2. nerve block.mp. or exp Nerve Block/(4639)
  3. exp Anesthetics, Local/or anesthetics.mp. (16210)
  4. bupivacaine.mp. (8082)
  5. lidocaine.mp. (7734)
  6. (nerve* adj5 block*).mp. (5110)
  7. (sympathetic* adj5 block*).mp. (467)
  8. sympatholytic*.mp. (403)
  9. (local adj5 (anaesthetic* or anesthetic*)).mp. (10088)
  10. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 (26152)
  11. post traumatic stress disorder.mp. or exp Stress Disorders, Post-Traumatic/(1425)
  12. 10 and 11 (6)
  13. limit 12 to english language (5)

Database: PILOTS

(December 30, 2016)

Search Strategy:
  1. stellate ganglion block (16)

Expanded Search

(February 8, 2017)

Search Strategy:
  1. (stellate ganglion block) OR (stellate block OR nerve block) OR (anesthetics OR bupivacaine) OR (lidocaine OR sympathetic block) OR sympatholytic AND (post traumatic stress disorder OR PTSD) (98)

Systematic Review Searching

(December 5, 2016)

Database: Ovid MEDLINE(R) <1946 to November Week 4 2016>, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations <December 02, 2016>, EBM Reviews - Health Technology Assessment <4th Quarter 2016>
Search Strategy:
  1. meta-analysis.pt. (81216)
  2. meta-analysis/or systematic review/or meta-analysis as topic/or “meta analysis (topic)”/or “systematic review (topic)”/or exp technology assessment, biomedical/(107793)
  3. ((systematic* adj3 (review* or overview*)) or (methodologic* adj3 (review* or overview*))).ti,ab. (111055)
  4. ((quantitative adj3 (review* or overview* or synthes*)) or (research adj3 (integrati* or overview*))).ti,ab. (8042)
  5. ((integrative adj3 (review* or overview*)) or (collaborative adj3 (review* or overview*)) or (pool* adj3 analy*)).ti,ab. (18235)
  6. (data synthes* or data extraction* or data abstraction*).ti,ab. (20009)
  7. (handsearch* or hand search*).ti,ab. (8026)
  8. meta-analysis.pt. (81216)
  9. meta-analysis/or systematic review/or meta-analysis as topic/or “meta analysis (topic)”/or “systematic review (topic)”/or exp technology assessment, biomedical/(107793)
  10. ((systematic* adj3 (review* or overview*)) or (methodologic* adj3 (review* or overview*))).ti,ab. (111055)
  11. ((quantitative adj3 (review* or overview* or synthes*)) or (research adj3 (integrati* or overview*))).ti,ab. (8042)
  12. ((integrative adj3 (review* or overview*)) or (collaborative adj3 (review* or overview*)) or (pool* adj3 analy*)).ti,ab. (18235)
  13. (data synthes* or data extraction* or data abstraction*).ti,ab. (20009)
  14. (handsearch* or hand search*).ti,ab. (8026)
  15. (mantel haenszel or peto or der simonian or dersimonian or fixed effect* or latin square*).ti,ab. (20022)
  16. (meta-analy* or metaanaly* or systematic review* or biomedical technology assessment* or biomedical technology assessment*).mp,hw. (197889)
  17. (meta regression* or metaregression*).ti,ab. (5108)
  18. (meta-analy* or metaanaly* or systematic review* or biomedical technology assessment* or biomedical technology assessment*).mp,hw. (197889)
  19. (medline or cochrane or pubmed or medlars or embase or cinahl).ti,ab,hw. (145258)
  20. (cochrane or (health adj2 technology assessment) or evidence report).jw. (21091)
  21. (meta-analysis or systematic review).ti,ab. (151446)
  22. (comparative adj3 (efficacy or effectiveness)).ti,ab. (10226)
  23. (outcomes research or relative effectiveness).ti,ab. (6709)
  24. ((indirect or indirect treatment or mixed-treatment) adj comparison*).ti,ab. (1498)
  25. 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 (327917)
  26. stellate ganglion block.mp. (632)
  27. 25 and 26 (7)
  28. remove duplicates from 27 (7)

Grey Literature Searching

(December 22, 2016)

General Databases
Date Searched: 12/22/2016
Sources:Evidence:
CADTH Grey Mattershttps://www​.cadth.ca​/resources/finding-evidence/grey-matters
Search: Stellate Ganglion Block
Relevant results:
None
Conference Papers Indexhttp://library​.pdx.edu/dofd/subjects
Search: Stellate Ganglion Block
Relevant results:
None
Grey Literature Reporthttp://www​.greylit.org/home
Search: Stellate Ganglion Block
Relevant results:
None
Clinical Trialshttps://www​.clinicaltrials.gov/
Search: Stellate Ganglion Block
Relevant results:
A Randomized, Placebo-Controlled Trial of Stellate Ganglion Block in the Treatment of Post Traumatic Stress Disorder NCT01629537
Status: Published, DOI: 10.1097/AAP.0000000000000402
The Efficacy of Stellate Ganglion Block as Post-traumatic Stress Disorder (PTSD) Therapy: A Pilot Study NCT01533610
Status: Unknown, the completion date has passed and the status has not been verified in more than two years
Clinical Trial Resultswww​.clinicaltrialresults.org/
Search: Stellate Ganglion Block
Relevant results:
None
WHO International Clinical Trials Registry Platformhttp://apps​.who.int/trialsearch/default​.aspx
Search: Stellate Ganglion Block
Relevant results:
No new results
RePORT
Research Portfolio Online Reporting Tool
https:​//projectreporter​.nih.gov/reporter.cfm
Search: Stellate Ganglion Block
Relevant results:
None
OpenGrey
Repository System for Information on Grey Literature in Europe
http://www​.opengrey.eu/
Search: Stellate Ganglion Block
Relevant results:
None
Trip
Turning Research Into Practice. Trip is a clinical search engine
https://www​.tripdatabase.com/
Search: Stellate Ganglion Block AND PTSD
Relevant results:
No new results
UKCTG
UK Clinical Trials Gateway
http://www​.ukctg.nihr.ac.uk/default.aspx
Search: Stellate Ganglion Block
Relevant results:
None
NICE
National Institute for Health and Care Excellence
https://www​.nice.org​.uk/guidance?action=find
Search: Stellate Ganglion Block
Relevant results:
None
Health Quality Ontario Publications and OHTAC
Recommendations
http://www​.hqontario​.ca/Evidence-to-Improve-Care​/Health-Technology-Assessments
Search: Stellate Ganglion Block
Relevant results:
None
Scopus
(limit to conference papers)
http://libguides​.ohsu.edu/az.php?a=s
Search: Stellate Ganglion Block
Relevant results:
None
DoPHER
Database of promoting health effectiveness reviews
http://eppi​.ioe.ac.uk/cms/Default​.aspx?tabid=53
http://eppi​.ioe.ac.uk​/webdatabases4/Intro.aspx?ID=9
Search: Stellate Ganglion Block
Relevant results:
None

APPENDIX B. LIST OF EXCLUDED STUDIES

Exclude reasons: 1=Ineligible population, 2=Ineligible intervention, 3=Ineligible comparator, 4=Ineligible outcome, 5=Ineligible timing, 6=Ineligible study design, 7=Ineligible publication type, 8=Outdated or ineligible systematic review, 9=Protocol for eligible study

#CitationExclude reason
1Alino J, Kosatka D, McLean B, Hirsch K. Efficacy of stellate ganglion block in the treatment of anxiety symptoms from combat-related post-traumatic stress disorder: a case series. Military Medicine. Apr 2013;178(4):e473–476.E(6)
2Alkire MT, Hollifield M, Khoshsar R, et al. Prolonged Relief of Chronic Extreme PTSD and Depression Symptoms in Veterans Following a Stellate Ganglion Block The Anesthesiology annual Meeting: Long Beach VA Healthcare System, Long Beach, California; 2014.E(6)
3Hickey AH, Navaie M, Stedje-Larsen ET, Lipov EG, McLay RN. Stellate ganglion block for the treatment of posttraumatic stress disorder. Psychiatric Annals. Feb 2013;43(2):87–92.E(7)
4Hicky A, Hanling S, Pevney E, Allen R, McLay RN. Stellate ganglion block for PTSD. The American Journal of Psychiatry. Jul 2012;169(7):760.E(6)
5Lipov E. The use of stellate ganglion block in the treatment of panic/anxiety symptoms (including suicidal ideation), with combat-related posttraumatic stress disorder. Posttraumatic stress disorder and related diseases in combat veterans. Cham, Switzerland: Springer International Publishing; Switzerland; 2015:179–196.E(6)
6Lipov E, Ritchie EC. A review of the use of stellate ganglion block in the treatment of PTSD. Current Psychiatry Reports. Aug 2015;17(8):599.E(7)
7Lipov EG, Joshi JR, Sanders S, Slavin KV. A unifying theory linking the prolonged efficacy of the stellate ganglion block for the treatment of chronic regional pain syndrome (CRPS), hot flashes, and posttraumatic stress disorder (PTSD). Medical Hypotheses. Jun 2009;72(6):657–661.E(6)
8Lipov EG, Navaie M, Brown PR, Hickey AH, Stedje-Larsen ET, McLay RN. Stellate ganglion block improves refractory post-traumatic stress disorder and associated memory dysfunction: A case report and systematic literature review. Military Medicine. Feb 2013;178(2):e260–e264.E(6)
9Lipov EG, Navaie M, Stedje-Larsen ET, et al. Local Anesthetics Offer First Biologic Treatment for PTSD. Canadian Journal of Anesthesia/Journal canadien d’anesthésie. 2012;59(1):1–190.E(6)
10Lipov EG, Navaie M, Stedje-Larsen ET, et al. A novel application of stellate ganglion block: Preliminary observations for the treatment of post-traumatic stress disorder. Military Medicine. Feb 2012;177(2):125–127.E(6)
11Lynch JH, Mulvaney SW, Kim EH, de Leeuw JB, Schroeder MJ, Kane SF. Effect of Stellate Ganglion Block on Specific Symptom Clusters for Treatment of Post- Traumatic Stress Disorder. Military Medicine. Sep 2016;181(9):1135–1141.E(6)
12McLean B. Safety and Patient Acceptability of Stellate Ganglion Blockade as a Treatment Adjunct for Combat-Related Post-Traumatic Stress Disorder: A Quality Assurance Initiative. Cureus. 2015;7(9):e320.E(6)
13Mulvaney SW, Lynch JH, de Leeuw J, Schroeder M, Kane S. Neurocognitive Performance is Not Degraded After Stellate Ganglion Block Treatment for Post- Traumatic Stress Disorder: A Case Series. Military Medicine. May 2015;180(5):e601–604.E(6)
14Mulvaney SW, Lynch JH, Hickey MJ, et al. Stellate ganglion block used to treat symptoms associated with combat-related post-traumatic stress disorder: A case series of 166 patients. Military Medicine. Oct 2014;179(10):1133–1140.E(6)
15Mulvaney SW, Lynch JH, Kotwal RS. Clinical Guidelines for Stellate Ganglion Block to Treat Anxiety Associated With Posttraumatic Stress Disorder. J Spec Oper Med. 2015;15(2):79–85.E(7)
16Mulvaney SW, McLean B, de Leeuw J. The use of stellate ganglion block in the treatment of panic/anxiety symptoms with combat-related post-traumatic stress disorder; preliminary results of long-term follow-up: A case series. Pain Practice. Jul–Aug 2010;10(4):359–365.E(6)
17Navaie M, Keefe MS, Hickey AH, McLay RN, Ritchie EC, Abdi S. Use of stellate ganglion block for refractory post-traumatic stress disorder: a review of published cases. Journal of Anesthesia & Clinical Research. 2014;2014.E(8)
18Summers MR, Nevin RL. Stellate Ganglion Block in the Treatment of Post-traumatic Stress Disorder: A Review of Historical and Recent Literature. Pain practice: the official journal of World Institute of Pain. Oct 14 2016.E(8)

APPENDIX C. EVIDENCE TABLES

DATA ABSTRACTION OF INCLUDED STUDIES

Data Abstraction: Study Characteristics and Results

Author Year
Study Design
N
Age
Sex
Race
Military StatusMental Health Treatment SUDBaseline PTSD (CAPS, PCL)Mean Change PTSD (CAPS, PCL) Int. vs Ctrl.Baseline
Depression*
Anxiety**
Pain***
Mean Change
Depression*
Anxiety**
Pain***
Int. vs Ctrl.
Injection Site, Number of Injections
Hanling 20161
RCT
42
NR
81% Male
White 61.9%
Hispanic 19.0%
AA 11.9%
API 2.4%
Did not answer 4.8%
Active duty
88.1%
Retired
11.9%
Since deployment
9.5%
During deployment
26.2%
After deployment
69%
SUD: NR
CAPS
86.76
PCL
65.90
CAPS
6.55 vs 8.76
PCL
1.96 vs 2.43
PHQ-9
18.77
BAI
29.33
VAS
47.34
PHQ-9
1.07 vs 1.45
BAI
1.70 vs −1.68
VAS
−1.25 vs −1.78
C5 or C6
13 (31%) received one injection
29 (69%) received two injections

Abbreviations: NR = not reported; AA= African American; API= Asian/Pacific Islander; SUD = substance use disorder; Int. = intervention; Crtl. = control; CAPS = Clinician-Administered PTSD Scale; PCL = PTSD Checklist

*

PHQ-9 = Patient Health Questionare-9

**

BAI = Beck Anxiety Intervention

***

VAS = Visual Analog Scale

QUALITY ASSESSMENT OF INCLUDED STUDIES

Quality Assessment of RCTs

Author Year
Country
Randomization adequate?Allocation concealment adequate?Groups similar at baseline?Outcome assessors masked?Care provider/Patient masked?Intention-to-treat (ITT) analysis?Acceptable levels of crossovers, adherence, and contamination?Acceptable levels of overall attrition and between-group differences in attrition?Quality rating (Good, Fair, Poor)
Hanling, 20161
USA
Unclear
No description of sequence generation
Unclear
No information on allocation concealment
Unclear
More active duty in SGB group (96.3% vs. 73.3%, P=0.05), and most were undergoing medical disability evaluation board, introducing potential for secondary gain
YesNo
Yes
YesUnclear
No information about adherence
No
47% overall, and differential (67% SGB vs. 40% control)
Fair

Abbreviations: SGB = stellate ganglion block

STRENGTH OF EVIDENCE FOR INCLUDED STUDIES

Strength of Evidence per Intervention

SOE GradeStudy, Design (N)Study Limitations*DirectnessConsistencyPrecision**Findings
InsufficientHanling 20161
RCT (42)
MediumIndirectUnknownImpreciseResults indicate insignificant decreases in PTSD scores in both groups, and no statistical differences between groups.
*

High, medium, low based on study quality

**

Precision based on confidence intervals for PTSD score (CAPS)

Abbreviations: CAPS= Clinician-Administered PTSD Scale

APPENDIX D. ONGOING STUDIES

Ongoing Studies

Investigator
Title
Study design
N
Study SitesTreatment ComparatorOutcomeStatus Expected CompetitionSource Funding
Walters, Bradford
Effectiveness and Patient Acceptability of Stellate Ganglion Block (SGB) for Treatment of Posttraumatic Stress Disorder (PTSD) Symptoms among Active Duty Military Members
RCT
N= 240
Womack Army Medical Center, Fort Bragg, North Carolina
Tripler Army Medical Center, Honolulu, Hawaii
Landstuhl Regional Medical Center, Landstuhl, Germany
Stellate ganglion block (C6 or C7) at 0 and 2 weeks
Sham injection (C6 or C7) at 0 and 2 weeks
CAPS-5
PCL-5
PHQ-9
GAD-7
VAS
Active, recruiting
November, 2017
https://sgbstudy​.rti.org/
United States Army Medical Research Acquisition Activity (USAMRAA) W81XWH-15-2-0015

Abbreviations: CAPS-5= Clinician-Administered PTSD Scale-5; PCL-5= PTSD checklist-5; PHQ-9= Patient Health Questionnaire-9; GAD-7= Generalized Anxiety Disorder-7; SF-12= 12-item short form survey; VAS= visual analog pain scale

APPENDIX E. PEER REVIEW

Comment #Reviewer #CommentAuthor Response
Are the objectives, scope, and methods for this review clearly described?
11YesNone
22YesNone
33YesNone
44YesNone
55YesNone
Is there any indication of bias in our synthesis of the evidence?
61NoNone
72NoNone
83NoNone
94NoNone
105NoNone
Are there any published or unpublished studies that we may have overlooked?
111NoNone
122NoNone
133Alkire, Michael T., et al. “Neuroimaging suggests that stellate ganglion block improves post-traumatic stress disorder (PTSD) through an amygdala mediated mechanism.” American Society of Anesthesiology annual meeting. 2015., this is a VA study using PET scan in SGB Pts, 7 veterans treatedAdded to Background as reference for discussion of amygdala mechanism.
143Alkire, Michael T., et al. “Prolonged relief of chronic extreme PTSD and depression symptoms in veterans following a stellate ganglion block.” American Society of Anesthesiology, October 11 (2014). 12 veterans treated with extreme PTSDAdded to Benefits section to highlight effects in extreme PTSD.
153Summers, Mary R., and Remington L. Nevin. “Stellate Ganglion Block in the Treatment of Post-traumatic Stress Disorder: A Review of Historical and Recent Literature.” Pain Practice (2016). John HopkinsWe have already cited Dr. Summers’ review in the Discussion, along with other prior reviews, to confirm that 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.
163Lynch, James H., et al. “Effect of Stellate Ganglion Block on Specific Symptom Clusters for Treatment of Post-Traumatic Stress Disorder.” Military Medicine 181.9 (2016): 1135–1141. Specific symptoms affected by SGB in PTSDAdded to “Who is Most Likely to Benefit” section as supporting generation of the hypothesis that people with predominantly hyperarousal and avoidance types of symptoms may be more likely to benefit from SGB
173McLean, Brian. “Safety and patient acceptability of stellate ganglion blockade as a treatment adjunct for combat-related post-traumatic stress disorder: a quality assurance initiative.” Cureus 7.9 (2015). Safety and tolerance of SGB for PTSDAdded to Harms section
183Navaie, M., et al. “Use of stellate ganglion block for refractory post-traumatic stress disorder: a review of published cases.” J Anesth Clin Res 5.403 (2014): 2. review of literature to that date, 8 veterans with specific treatments summarizedThis study was captured in our search and discussed in our report in multiple places as a source for our summary of frequently cited case series findings(ref 39).
193Jeong, Seunghyun, et al. “The effects of stellate ganglion block on the electroencephalogram in rats.” Journal of anesthesia 28.4 (2014): 601–605.Added to Background as reference for potential sedative effects
203Mechanism paper Lipov, Eugene G., et al. “A unifying theory linking the prolonged efficacy of the stellate ganglion block for the treatment of chronic regional pain syndrome (CRPS), hot flashes, and posttraumatic stress disorder (PTSD).” Medical hypotheses 72.6 (2009): 657–661.Added to Background as reference for proposed prolonged effect
213Hoge, Charles W. “Interventions for war-related posttraumatic stress disorder: Meeting veterans where they are.” JAMA 306.5 (2011): 549–551.Already included in Introduction as source for information on challenges of conventional therapy.
224NoNone
235NoNone
Additional suggestions or comments can be provided below. If applicable, please indicate the page and line numbers from the draft report.
241With regards the search strategy, there are extensive search terms for identifying evidence from specific methodological sources but the search terms to capture the intervention, condition or outcomes are very limited indeed. While I think it is highly likely there is only the one trial identified here there may be a case for some sensitivity scoping using alternative terms.Per the 2016 O’Connell Cochrane review on local anaesthetic sympathetic blockade for complex regional pain syndrome, we added 9 new terms to capture the intervention. This resulted in 130 new citations, none of which met our inclusion criteria.
251With regards interpretation, while remission or “responder” analysis was not presented, there is very little hint in the between group difference that the inclusion of those outcomes would have altered the outcome of the trial. It seems unlikely that with such trivial differences between groups that there is an important subgroup of “responders”. Given that there is a case for clearly stating in the summary and conclusions that while it is possible that some patients benefit it is also possible that the technique is, in actuality, ineffective. This might also be better reflected in statements such as “evidence is insufficient to determine which veterans IF ANY are most likely to benefit….”From the Executive Summary, we removed our criticism that the RCT lacked response rate assessment as we agree that this is less relevant under the circumstances of low and similar mean changes between SGB and placebo. Also, changed conclusion from “Findings from the first RCT of SGB for PTSD failed to confirm..” to “…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
264In general I greatly enjoyed the ESP report. I though the writing style struck a nice balance between being academic and digestible. I liked the organization of the report for the post part, however, I did find myself wishing the description of the RCT was formatted in a similar style to a published original research article (ie subjects, method, design, results) rather than a narrative paragraph.For these Evidence Briefs, we have made a purposeful effort to assist readers with prioritizing information by front- loading our summaries with the main findings and most important details first, followed by other general information about subjects, methods and design.
274In retrospect, I wish we’d made sure that a summary of the case series research was included in the list of study designs the report included. Since the majoring of the clinical benefit information would be have published in this format, I would feel more confident that we are truly aware of the reported clinical benefit for SGB if we included these publications. I looked at the original SOW and see that ESP did not initially include case studies in the review design, so that is likely a shortcoming on our part. Thankfully, we do have the list of articles that were not included due to ineligible study design, so we can look at the publications on our own. I feel that one of the great features of the report is the concise summary of findings, limitations, and especially the recommendations for addressing the limitations in future research. This last feature will be very helpful for our advisory council and is extremely valuable feedback for the submitter.We added a brief summary of the case series studies to the results.
284The authors were clear in their search strategy and summarized their findings and limitation of the RCT; however, I agree that a short summary of the actual RCT, since there was only one, would have been helpful to the reader. Otherwise, I do think that the paper provides a good overview of the limitations of evidence for SGB.A summary of the RCT is located on page 9 under the heading “Randomized Trials”
292Page 3, line 23:
PTSD is no longer considered an anxiety disorder but is in a DSM-5 class of its own, trauma and stress-related disorders.
Changed to “…PTSD is a trauma and stress-related disorder…”
302Page 4, lines 45–48:
There is some skepticism about the proposed neuroanatomic connections and neurophysiological likelihood of important functional connections. Regarding input from the stellate ganglion to key brain regions such as dACC, amygdala, etc, there should be more discussion regarding the plausibility of this rationale for SGB’s proposed efficacy for PTSD (e.g. that SGB actually does reduce amygdala activation. As for dACC, one would expect that more (not less) activation would be therapeutic for PTSD.)
As the mechanisms are speculative and are covered elsewhere, we are minimizing our discussions of the plausibility of the rationale.
313Page 4, line 44: Biological rationale is not understood ( agree ), references 41 discusses over activation of the amygdala( this is consistent with Dr Alkire demonstrated amygdal deactivation in PTSD patients following SGB ), however this does not explain a prolonged effect of SGB, Dr Lipov believes it is due to reduction of neurotropic factor NGF leading to loss of trauma induced sympathetic sprouting ( lipov 2009)Added Lipov 2009 and the following to the Background to describe proposed explanation for prolonged effect: “The specific mechanism of action by which SGB may mitigate PTSD symptoms remains incompletely understood. SGB results in peripheral vasodilation, but the mechanism by which SGB impacts symptoms of PTSD is likely more complex. A proposed explanation for the prolonged effective of SGB on PTSD, as well as symptoms of hot flashes and complex regional pain syndrome, is that application of local anesthetic to the stellate ganglion leads to a reduction in nerve growth factor and a resulting decrease in sympathetic nerve sprouting and brain norepinephrine levels.{Lipov 2009}”
324The paper was definitely written for an audience with a clinical background. While I understand that it was aimed to be shared with SME’s (p. 3, line 15), it was written for individuals with a high working knowledge of neurophysiology (e.g. p. 4, lines 46–49), which I believe does the paper a disservice and limits dissemination. I believe that including introductory information about why the stellate ganglion would be blocked near p.4, line 35; e.g. what does the stellate ganglion do, why is it activated in PTSD, and/or why would someone hypothesize that blocking the stellate ganglion would alleviate PTSD sx’s would strengthen the rationale for the paper and intervention and allow for dissemination to a wider audience.We added more introductory information as requested.
334Additionally, while I’m not sure if it’s relevant to the request, I’d suggest that the authors review the paper for grammar and sentence structure before completing the final draft, as there may be other edits besides the ones I have identified below. There were also places where edits could be made to cut unnecessary information (p. 4, lines 13–15, core components of the first-line psychotherapies) or where sentences, when read aloud, were awkwardly stated (p.3, lines 56–58, “regardless of the relationship to a PTSD diagnosis”).We kept the core components of first-line psychotherapies, but improved the grammar of p.3, lines 56–58 and others this reviewer identified.
344p. 6, lines 3–12: There are too many semi-colons in this sentence and no period at the end of it. I would suggest creating a new sentence on line 4, at “Although no definitive…”Changed as suggested.
353Page 9, 34 to 37, Dr Hanling reported utilizing” Lidocaine 1% was injected to the skin overlying the right C5 or C6 vertebra (level chosen on safest needle path based on individual patient anatomy)”, the target for the SGB is C6 or C7, while all placebo injections were performed at C6, NOT C5, in fact no ganglion is described at C5 level. Thus with C5 placement and reduced amount of local anesthetic as discussed else where it is unclear as to the actual trial of the SGB ( ref 57 in current report )Added: 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.
363Page 9, 34 to 37. The concept of placebo with saline is problematic if not impossible with sympathetic injections, due to the inability to have an actual active placebo. I would suggest next study to have functional MRI as prior to and after the SGB for the end point plus CAPS.Added to Implications: If a future RCT is undertaken, we suggest considering adding functional magnetic resonance imaging (fMRI) assessment both to improve our understanding of SGB’s neural mechanisms and to help elucidate the impact of inadequate blinding. Differences in fMRI results between SGB and control group participants could help refute an argument that clinical differences were due to knowing whether or not they got SGB.
373Page 9 line 40 to 50, Dr Hanling reported the patients that received 2 SGB’s had a reduction of 19.8182, well with in >15 point reduction in CAPS for demonstrated efficacy, vs single SGB 8.1538, and Sham 10.3846, Dr Hanling reported that “ When looking at all participants (n = 29) who received 2 SGB treatments, paired t tests showed that the change in CAPS after the second treatment was greater than the change after the first treatment (P < 0.05).”No change. The data in our Table 1 (page 9, line 40 to 50) are from Table 2 in Hanling 2016 for results BEFORE the crossover. The larger mean changes this reviewer is citing are understandably larger as they are from AFTER the crossover (Table 3 in Hanling 2016) in the subset of patient who initially got placebo and then SGB. We agree that in general improvements are greater after the second treatment and had already made this point on page 9, lines 7–9.
382Page 9, lines 25–26
A 10 point reduction on the CAPS is generally considered the low end of clinical significance.
Changed to “≥ 10–15-point reduction on the CAPS”
392Page 10, lines 41–46
Please provide the complication rate as you have done in the preceding paragraph.
Added that adverse event rates ranged from 0% to 14.3%
402Pages 9–10
Some mention of relative costs should be inserted here.
Since we did not formally evaluate cost, we did not add them to our results section on pages 9–10. But we did add the following information about cost considerations to the
Discussion:
Cost of these innovative treatments compared to conventional psychotherapies and pharmacotherapies should also be assessed in the prioritization process. SGB costs have been estimated to be lower than conventional PTSD ($2,000 for two SGB injections vs a range of $6,000 to $30,000).[Lipov 2012] But, we have not formally evaluated comparative costs or how these estimates apply to the current VA environment.
413Page 9, 55 Safety of SGB for PTSD was assessed in over 100 patients by McLean ( McLean)At N=250, McLean 2015 is still too small to detect the types of significant complications that occurred in only 1.7 per 1000 patients in the 1992 German survey of 45.000 SGB’s. But, we did cite McLean 2015 as an additional case series that may have used stronger methods than the 1992 study, but still is likely too small to detect rare events.
423Page 10, line 28 to 36. potential complication rate of 33% should be addressed. #1 The needle used for the procedure is 18 Gauge, much larger than used by others 22 gauge and 25 gauge #2 Complications included were related to the procedure was 12% they included a increased pain after the placebo injection, a significant number of complications could potentially have been reduced with a smaller needle.Added: “Complications included increased injection site pain, which could potentially have been reduced by using a smaller needle such as in prior studies (20 gauge in RCT vs 22–25 gauge in case series).
433Page 10, line 50: Specific symptoms best responding to SGB have been studied by Dr Lynch:Specific symptoms affected by SGB in PTSD( Lynch)Under heading of “who is most likely to benefit”, starting on page 10, we added the findings from Lynch 2016: “Findings from a case series of 30 active duty military service members with combat-related PTSD suggest that people with predominantly hyperarousal and avoidance types of symptoms may be more likely to benefit from SGB.[cite Lynch 2016] But, this is very weak evidence as it is based on inference from evaluation of which symptoms are most impacted after SGB, rather than from direct comparison of response rates between people with different levels of these symptoms at baseline.
443Page 11, line 34: total of 27 veterans were treated via SGB (Navaie&Alkire 2014& Alkire 2015)No change. Agreed that the small number of Veterans represents the minority of SGB’s and is consistent with our statement that “Although most studies have been conducted in military populations, the majority were active-duty military members.”
453Page 11, lines 44 to 49: Inadequate reporting of previous treatments, it is my view that all the patients we have seen in my clinic had access to the “ gold standard “ therapy and did not respond to the same, the criteria used by most researchers have been PCL-M and or CAPS to make sure the patient have the diagnosis of PTSD. Further in the publication by Dr Hoge titled” Interventions for War-Related Posttraumatic Stress Disorder Meeting Veterans Where They Are” is exactly on point, his conclusions were the following “However, veterans remain reluctant to seek care, with half of those in need not utilizing mental health services.3,4 Among veterans who begin PTSD treatment with psychotherapy or medication, a high percentage drop out, commonly 20% to 40% in randomized clinical trials (RCTs)5,6 but considerably higher in routine practice.3 The rate of recovery of 60% to 80% among treatment completers declines to around 40% when noncompleters are accounted for (using intention- to-treat analyses).5–7”, basically the lack of current success due to what ever the reason does seem to require a new approachWe changed “Insufficient to support its use as adjuvant overall” to: “evidence is insufficient to support recommendations about specifically when to initiate SGB in the order of recommended conventional pharmacotherapies and psychotherapies. How much failed conventional therapy is “enough” before trying SGB? Although likely many study participants had already failed “gold standard” therapy and their lack of success suggested the need for an innovative approach, the studies’ lack of specific criteria for establishing “failure” of conventional therapy, and/or dose and duration and order of conventional therapies makes it difficult for readers to compare their patient with those in the studies.
463Page 12, line 6. Discussion of loss of PTSD diagnosis, this discussion is very complex due to implication for disability payment, a number of veterans treated did NOT wish to share their improvements with the VA hospitalsNo change. One page 12, line 6, in the Limitations section, we are noting that the overall lack of assessment of remission (loss of PTSD diagnosis) is a limitation of all the studies as a whole, regardless of whether the participants were involved in disability evaluation. The point we are making is that loss of PTSD diagnosis is a desired outcome of any PTSD treatment and the studies should assess it.
474p. 11, lines 31–32: “Overall, a key limitation the evidence on SGB is that it is based primarily on uncontrolled, unblinded studies.” reads awkwardly. There needs to be a preposition between “limitation” and “the”; e.g. “Overall, a key limitation of the evidence on SGB is that it is based primarily on uncontrolled, unblinded studies.”Changed as suggested.
484p. 11, lines 37–38: The majority of study participants were male, as in the VA, but mean age was late thirties to early forties and prevalence of depression, anxiety, pain, and other medical comorbidities were unclear.” Prevalence is singular and were is plural; since “unclear” refers to prevalence and not the listing of comorbidities that follows prevalence in the sentence, I believe that the singular, was, should be used instead.Changed as suggested.
494p. 12, line 24: “…considerations such access to, contraindications for, and patient preference may guide SGB,” a preposition between such and access is required, e.g. “such as access to…”Changed to: “Other practical considerations that may guide treatment decisions include access to, contraindications for, and patient preference for SGB.”
1I find myself in disagreement regarding the need for a large observational study. This would do little to reduce uncertainty regarding the benefits on the intervention though may be useful to outline possible harms. It is possible to conduct RCTs in this area and that should, in my view be the priority as it will afford the confidence to offer or withhold this intervention on the basis of effectiveness or lack thereof.Changed to: “Both randomized trials and observational studies can contribute to our knowledge of SGB for PTSD.”
502Regarding risks, I think there should be some mention of cost of this procedure compared to an office visit for psychotherapy or medication.Added to the Implications section: Cost of these innovative treatments compared to conventional psychotherapies and pharmacotherapies should also be assessed in the prioritization process. SGB costs have been estimated to be lower than conventional PTSD therapies ($2,000 for two SGB injections vs a range of $6,000 to $30,000).[Lipov 2012] But, we have not formally evaluated comparative costs or how these estimates apply to the current VA environment.
513satisfaction and acceptance of the procedure is over 90%(McLean)Added: Finally, although those who have undergone SGB have found it highly acceptable, [McLean 2015] the invasive nature of SGB may be a barrier for some candidates to try it in the first place.”
523Biological markers have been reported to have impacted in PTSD patients such as PET scan(Alkire) and EEG in normal volunteers (Yeo) following SGBAs noted above, added Akire and Yeo studies to Background as references for information on biological markers.
533No addiction or neurotoxicity of agents ( vs MDMA, or Ketamine )To our statement on pages 12–13 that “we did not investigate whether SGB should be a higher priority than other innovative treatments for PTSD, such as MDMA, ketamine or cranial electrical stimulation”, we added “But, each has their own unique set of potential harms, such as addiction and neurotoxicity, that would have to be considered in relation to SGB’s net benefits.”
543Speed of on set 30 minutes ( presented at PGA 2011)On page 5, changed “within minutes to days” to “within 30 minutes to days”
553Please read Dr Summers review form John Hopkins for a excellent up to date informationAgreed and we have already cited Dr. Summers’ review in the Discussion, along with other prior reviews, to confirm that 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.
565First report to review. Looks great.Thank you.

REFERENCES

1.
Hanling SR, Hickey A, Lesnik I, et al. Stellate Ganglion Block for the Treatment of Posttraumatic Stress Disorder: A Randomized, Double-Blind, Controlled Trial. Regional Anesthesia & Pain Medicine. Jul–Aug 2016;41(4):494–500. [PubMed: 27187898]

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.

Views

  • PubReader
  • Print View
  • Cite this Page
  • PDF version of this page (333K)

Other titles in this collection

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...