Cortisol, a critical glucocorticoid hormone produced by the adrenal glands, plays a pivotal role in various physiological processes. Its release is finely orchestrated by the suprachiasmatic nucleus, governing the circadian rhythm and activating the intricate hypothalamic–pituitary–adrenal (HPA) axis, a vital neuroendocrine system responsible for stress response and maintaining homeostasis. Disruptions in cortisol regulation due to chronic stress, disease, and aging have profound implications for multiple bodily systems. Animal models have been instrumental in elucidating these complex cortisol dynamics during stress, shedding light on the interplay between physiological, neuroendocrine, and immune factors in the stress response. These models have also revealed the impact of various stressors, including social hierarchies, highlighting the role of social factors in cortisol regulation. Moreover, chronic stress is closely linked to the progression of neurodegenerative diseases, like Alzheimer’s and Parkinson’s, driven by excessive cortisol production and HPA axis dysregulation, along with neuroinflammation in the central nervous system. The relationship between cortisol dysregulation and major depressive disorder is complex, characterized by HPA axis hyperactivity and chronic inflammation. Lastly, chronic pain is associated with abnormal cortisol patterns that heighten pain sensitivity and susceptibility. Understanding these multifaceted mechanisms and their effects is essential, as they offer insights into potential interventions to mitigate the detrimental consequences of chronic stress and cortisol dysregulation in these conditions.

Background Extensive research into potential sources of neck pain and referred pain into the upper extremities and head has shown that the cervical facet joints can be a potential pain source confirmed by precision, diagnostic blocks. Study Design Systematic review and meta-analysis utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, quality assessment of the included studies, conventional and single-arm meta-analysis, and best evidence synthesis. Objective The objective of this systematic review and meta-analysis is to evaluate the effectiveness of radiofrequency neurotomy as a therapeutic cervical facet joint intervention in managing chronic neck pain. Methods Available literature was included. Methodologic quality assessment of studies was performed from 1996 to September 2021. The level of evidence of effectiveness was determined. Results Based on the qualitative and quantitative analysis with single-arm meta-analysis and Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system of appraisal, with inclusion of one randomized controlled trial (RCT) of 12 patients in the treatment group and eight positive observational studies with inclusion of 589 patients showing positive outcomes with moderate to high clinical applicability, the evidence is level II in managing neck pain with cervical radiofrequency neurotomy. The evidence for managing cervicogenic headache was level III to IV with qualitative analysis and single-arm meta-analysis and GRADE system of appraisal, with the inclusion of 15 patients in the treatment group in a positive RCT and 134 patients in observational studies. An overwhelming majority of the studies produced multiple lesions. Limitations There was a paucity of literature and heterogeneity among the available studies. Conclusion This systematic review and meta-analysis shows level II evidence with radiofrequency neurotomy on a long-term basis in managing chronic neck pain with level III to IV evidence in managing cervicogenic headaches.

The placebo effect has been widely documented across various medical conditions, demonstrating its ability to influence both subjective and objective outcomes. Placebo responses can significantly improve symptoms in these different conditions, such as pain, Parkinson’s disease, depression, anxiety, and addiction. Psychological mechanisms, particularly the power of patient expectations, appear to play a central role, with neurobiological evidence supporting the activation of dopamine, endogenous opioids, and endocannabinoids in response to placebo interventions. Studies have demonstrated that placebo injections and more complex procedures, including sham surgeries, can produce therapeutic effects comparable to real treatments, particularly in pain management and neurological disorders. Moreover, placebo responses could be amplified when patients are aware of receiving treatment, as shown by research on open-label placebos and open versus hidden medical treatments. The effectiveness of 0.9% sodium chloride solution as a placebo in clinical trials is debated, with some studies indicating its potential to induce clinical improvements, though it may not be an ideal control in inflammatory pain conditions. Advances in neuroimaging have revealed that placebo treatments trigger tangible biological processes in the brain and body and are supported by psychological and physiological mechanisms that interact, suggesting real biological processes are involved in the observed effects. Overall, the growing understanding of placebo mechanisms suggests that incorporating placebo-based strategies, with patient awareness and appropriate ethical considerations, may offer significant potential for improving patient outcomes, particularly in chronic pain, mental health, and neurological conditions.

Introduction Chronic refractory low back and lower extremity pain recalcitrant to conservative management and epidural injections secondary to postsurgery syndrome, spinal stenosis, and disc herniation are sometimes managed with percutaneous adhesiolysis. Consequently, this systematic review and meta-analysis was undertaken to assess the efficacy of percutaneous adhesiolysis in managing low back and lower extremity pain. Methods A systematic review and meta-analysis of randomized controlled trials (RCTs) utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was performed. A comprehensive literature search of multiple databases from 1966 to July 2022, including manual searches of the bibliography of known review articles was performed. Quality assessment of the included trials, meta-analysis, and best evidence synthesis was performed. The primary outcome measure was a significant reduction in pain (short term up to 6 months and long term more than 6 months). Results The search identified 26 publications, with 9 trials meeting the inclusion criteria. The results of dual-arm and single-arm analyses showed significant improvement in pain and function at 12 months. Opioid consumption was also significantly reduced at 6 months with dual-arm analysis, whereas single-arm analysis showed a significant decrease from baseline to treatment at the 3-, 6-, and 12-month analyses. At 1 year follow-up, seven of seven trials were positive for improvements in pain relief, function, and diminution of opioid use. Discussion Based on the present systematic review of nine RCTs, the evidence level is I to II, with moderate to strong recommendation for percutaneous adhesiolysis in managing low back and lower extremity pain. The limitations of the evidence include paucity of literature, lack of placebo-controlled trials, and the majority of the trials studying post lumbar surgery syndrome. Conclusion The evidence is level I to II or strong to moderate based on five high-quality and two moderate-quality RCTs, with 1 year follow-up that percutaneous adhesiolysis is efficacious in the treatment of chronic refractory low back and lower extremity pain.

Laxmaiah Manchikanti, Emilija Knezevic, Nebojsa Nick Knezevic, Mahendra R. Sanapati, Alan D. Kaye, Srinivasa Thota, and Joshua A. Hirsch. Korean J Pain 2021;34:346-68. https://doi.org/10.3344/kjp.2021.34.3.346