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Evidence & Uncertainties
What the evidence may tell us
Research can help clinicians understand:
• Whether an intervention may reduce particular symptoms
• How quickly changes may occur
• How long improvements may last
• Which patients were included in clinical studies
• What adverse effects were recorded
• How an intervention compares with a placebo, sham procedure or another treatment
What research cannot guarantee
Even when a study reports a positive average result, it does not mean that every participant benefited. Research findings may also be affected by small samples, short follow-up periods, differences in treatment protocols and difficulty maintaining blinding.
Clinical evidence informs treatment decisions, but it does not replace an individual medical and psychiatric assessment.
Ketamine and mood disorders
Why is ketamine being studied?
Ketamine has been used in medicine as an anaesthetic for many years. Unlike conventional antidepressants, which commonly influence serotonin, noradrenaline or dopamine pathways, ketamine affects glutamate signalling, including activity involving the N-methyl-D-aspartate—or NMDA—receptor.
This different mechanism led researchers to investigate whether carefully administered, lower-dose ketamine could influence depressive symptoms, particularly in people whose symptoms had not improved sufficiently with established treatment.
What have studies found?
Early placebo-controlled studies reported reductions in depressive symptoms following a single intravenous administration. In some participants, changes were observed within hours or days (Berman et al., 2000; Zarate et al., 2006).
Later systematic reviews and meta-analyses have supported a rapid antidepressant effect in some adults with treatment-resistant depression. A 2024 meta-analysis of 21 randomized trials involving 2,042 participants found clinically meaningful short-term response estimates for racemic ketamine and esketamine, although the authors also identified limitations including possible functional unblinding and selective-reporting bias (Calder et al., 2024).
Racemic ketamine and esketamine are related but distinct medicines. They have different formulations, routes of administration, research bases and regulatory considerations and should not be presented as interchangeable (Bahji et al., 2021; McIntyre et al., 2021).
Suicidal thoughts
An individual-participant meta-analysis reported a short-term reduction in suicidal ideation following a single intravenous ketamine administration (Wilkinson et al., 2018).
This does not establish that ketamine prevents suicide or suicide attempts. Ketamine must not replace emergency assessment, crisis intervention or a comprehensive suicide-prevention plan.
What remains uncertain?
Important areas of uncertainty include:
• Which patients are most likely to respond
• The duration of benefit for an individual
• The most appropriate maintenance strategy
• Long-term safety with repeated exposure
• The comparative effectiveness of different formulations
• The contribution of expectations and functional unblinding
• How ketamine should best be combined with psychotherapy and continuing psychiatric care
A systematic review of maintenance treatment found encouraging results but concluded that knowledge about longer-term efficacy, safety and tolerability remained limited (Smith-Apeldoorn et al., 2022).
Safety and clinical oversight
Possible short-term effects include altered perception or dissociation, dizziness, nausea, sedation and increases in blood pressure or heart rate.
Potential concerns with repeated or longer-term exposure include cognitive, urinary, psychiatric and misuse-related risks. Expert guidance recommends careful patient selection, medical and psychiatric screening, appropriate monitoring and follow-up by suitably qualified clinicians (McIntyre et al., 2021; Sanacora et al., 2017).
Ketamine and pain management
Why is ketamine being studied?
Ketamine’s effects on NMDA-receptor activity have also led to research in pain medicine. NMDA-receptor signalling is involved in pain processing and may contribute to central sensitisation—the increased responsiveness of the nervous system that can occur in some persistent pain conditions.
Ketamine has therefore been investigated as a possible component of care for selected neuropathic and refractory pain presentations.
What does the pain research suggest?
A systematic review and meta-analysis of 18 randomized trials involving 706 participants found that adding ketamine to standard treatment was associated with lower neuropathic-pain intensity at certain follow-up points. The analysis also found increased discomfort and psychotomimetic or altered-perception effects (Guimarães Pereira et al., 2022).
Consensus guidance from the American Society of Regional Anesthesia and Pain Medicine, American Academy of Pain Medicine and American Society of Anesthesiologists concluded that the strength of evidence varies by pain condition. The guidance supports diagnosis-specific selection, appropriate clinician training, monitoring and careful consideration of risks and expected benefits (Cohen et al., 2018).
What remains uncertain?
The term “chronic pain” includes many different conditions. Evidence concerning one type of neuropathic pain cannot automatically be applied to another.
Outstanding questions include:
• Which pain conditions are most likely to respond
• The most appropriate dose and infusion duration
• The number and frequency of treatments
• The durability of any improvement
• The balance between symptom relief and adverse effects
• The role of ketamine within rehabilitation and multidisciplinary care
• The safety of repeated or extended treatment
A broader pain-management plan
Where clinically appropriate, an intervention should form part of a wider plan that may include:
• Medical investigation and diagnosis
• Medication review
• Physiotherapy or graded rehabilitation
• Psychological support
• Sleep and lifestyle interventions
• Functional goals
• Coordination with relevant specialists
Improvement in function, sleep and participation may be as important as a change in pain intensity.
Stellate ganglion block and trauma-related symptoms
What is the stellate ganglion?
The stellate ganglion is a collection of sympathetic nerves situated in the lower neck. A stellate ganglion block involves administering a local anaesthetic near this nerve structure, ordinarily using ultrasound or fluoroscopic image guidance.
The procedure has an established history in pain medicine. Researchers have more recently investigated whether temporarily altering sympathetic nervous-system activity may influence certain trauma-related symptoms.
Why is it being studied in trauma-related care?
Post-traumatic stress disorder can involve persistent hyperarousal, disturbed sleep, exaggerated startle, irritability and a heightened sense of threat.
Because the sympathetic nervous system is involved in the body’s threat response, researchers have investigated whether a stellate ganglion block might have a role as an adjunct—not a replacement—for comprehensive PTSD treatment.
What have studies found?
A multisite, sham-controlled randomized clinical trial involving 113 active-duty service members found a greater reduction in PTSD symptom-severity scores over eight weeks in participants receiving two stellate ganglion blocks than in participants receiving sham procedures (Rae Olmsted et al., 2020).
The researchers concluded that the intervention warranted further study as a PTSD treatment adjunct. They also noted that the participants generally had mild-to-moderate baseline symptoms, follow-up was short and the results might not generalise to a broader clinical population.
Is it proven for mood disorders?
No. The psychiatric research has focused mainly on PTSD and trauma-related symptoms—not mood disorders as a broad category.
A systematic review found that most published psychiatric studies concerned PTSD and that results from the randomized trials were mixed. One trial reported a significant difference, while another did not (Kerzner et al., 2021).
Some studies have reported changes in associated anxiety, depressive symptoms or distress. These secondary findings do not establish stellate ganglion block as a proven standalone treatment for major depressive disorder, anxiety disorders or bipolar disorder.
What remains uncertain?
Further research is needed to establish:
• Which patients may be most likely to benefit
• Whether findings apply beyond military populations
• The duration of any symptom change
• The most appropriate number and timing of procedures
• Whether laterality or technique affects outcomes
• How the procedure should be combined with psychotherapy
• Long-term safety and comparative effectiveness
Current guideline assessments have found insufficient evidence to recommend for or against stellate ganglion block as a PTSD treatment. This means that the evidence is still developing—not that benefit or lack of benefit has been conclusively established.
Stellate ganglion block and pain management
Why is it used in pain medicine?
The sympathetic nervous system can contribute to certain pain presentations. Stellate ganglion block has been used particularly in the assessment and management of sympathetically mediated pain affecting the head, neck or upper limb.
It has also been studied in complex regional pain syndrome, commonly abbreviated as CRPS.
What is complex regional pain syndrome?
CRPS is a persistent pain condition that often develops after an injury or medical event. Symptoms may include pain that is disproportionate to the original injury, changes in skin colour or temperature, swelling, altered sensation, sweating changes and reduced movement.
Diagnosis requires a comprehensive clinical assessment. Not all persistent limb pain is CRPS, and not all CRPS is maintained primarily by sympathetic activity.
What does the research suggest?
A 2023 systematic review and meta-analysis identified eight studies of stellate ganglion interventions for upper-limb CRPS. The pooled analysis reported improvements in pain and disability, but the studies differed considerably and the overall certainty of evidence was rated very low (Purohit et al., 2023).
A separate 2024 meta-analysis of 12 randomized trials also reported a reduction in CRPS-related pain. Its authors nevertheless emphasised the limited number of trials, differences between studies and the need for larger, high-quality research (Tian et al., 2024).
These findings are encouraging but do not demonstrate that stellate ganglion block is effective for every person with CRPS or for persistent pain generally.
What remains uncertain?
Research questions include:
• Which clinical features predict response
• How to identify sympathetically maintained pain reliably
• The best procedural technique
• The number and timing of blocks
• How long improvement may persist
• Whether the procedure improves function as well as pain
• How it compares with other multidisciplinary treatments
Rehabilitation, movement and functional restoration remain important components of CRPS care, whether or not a procedure is considered.
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General References
- Sarris, J., et al. (2022). Clinician's guide to integrative psychiatry: consensus recommendations and blueprints. Journal of Clinical Psychopharmacology, 42(3), 112-124.
- Berk, M., et al. (2019). The biological architecture of neuroinflammation and mitochondrial dysfunction in persistent depressive states. Nature Reviews Neuroscience, 20(8), 455-468.
- Lopresti, A. L. (2021). The role of nutritional psychiatry and botanical interventions in modern mental healthcare. Neuropsychopharmacology, 46(1), 201-213.
- Pariante, C. M. (2020). Hypothalamic-Pituitary-Adrenal axis dysregulation: a systematic review of psychobiological biomarkers. Molecular Psychiatry, 25(4), 780-795.
Clinical Abbreviations
- HPA Axis – Hypothalamic-Pituitary-Adrenal Axis (The central physiological system responsible for regulating the body's stress response).
- BDNF – Brain-Derived Neurotrophic Factor (A crucial biological protein that stimulates neuroplasticity, memory formation, and cellular survival).
- mPFC – Medial Prefrontal Cortex (The cortical hub primarily associated with emotional regulation, cognitive flexibility, and executive planning).
- rTMS – Repetitive Transcranial Magnetic Stimulation (A non-invasive clinical neuromodulation technique targeting localized cortical neurons).
- SNRI / SSRI – Serotonin-Norepinephrine Reuptake Inhibitor / Selective Serotonin Reuptake Inhibitor.