Major depressive disorder (MDD) is a significant psychiatric condition, with many affected individuals not gaining remission from conventional treatments, leading to classification as treatment-resistant depression (TRD). This study aimed to investigate the potential of intravenous (IV) ketamine, particularly the S-enantiomer esketamine in nasal spray form, for treating patients with TRD and associated comorbidities. We report three cases of patients with diverse psychiatric and medical backgrounds whom all reported significant symptomatic relief from depressive episodes and suicidal ideation (SI) following esketamine administration. Additionally, esketamine seemed to proffer benefits beyond the primary depressive symptoms, positively impacting other comorbid conditions, such as agitation, self-injurious behavior (SIB), and chronic pain. The goal of this paper is to highlight that while esketamine's primary utility is in addressing TRD, its therapeutic potential may extend to a variety of associated conditions. However, it is crucial to underscore the heterogeneity of MDD, emphasizing the necessity for individualized therapeutic approaches and further research into esketamine's broader applications.

The International Association for the Study of Pain has classified pain into nociceptive pain, neuropathic pain, and nociplastic pain based on the cause of the pain. At present, nociplastic pain is pain that is not nociceptive pain and has the following characteristics: no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain. If there is tissue damage, disease or lesion, it is neuropathic pain; if there is none, it is nociplastic pain. In other words, the difference in diagnosis is whether or not tissue damage, disease, or lesion can be found at the current medical level (testing equipment). The treatment of nociplastic pain is almost the same as the treatment of neuropathic pain. Fibromyalgia is included in nociplastic pain. To my knowledge, of the nociplastic pain and neuropathic pain, fibromyalgia is the disease with the highest number of pharmacological and non-pharmacological treatments with evidence of efficacy. Effective treatments for fibromyalgia are often given to neuropathic pain. This expands treatment options. I presume that tissue damage, disease or lesion will be found in fibromyalgia through advances in the medical science by the time humans emigrate to Mars. The distinction between nociplastic pain and neuropathic pain complicates the diagnosis of chronic pain. However, the distinction does not improve the treatment outcomes. Medical science is the discipline to find a treatment method that can produce better outcomes. In the event of a medical controversy, the medical theory with better treatment outcomes should be adopted. It is desirable to combine nociplastic pain and neuropathic pain into one pain. This will simplify diagnosis and increase treatment options (improve treatment outcomes) in nociplastic pain and neuropathic pain.

There is a growing body of evidence that the number of individuals suffering from chronic and acute pain is under-reported and the burden of the veteran, aging, athletic, and working populations is rising. Current pain management is limited by our capacity to collaborate with individuals continuing normal daily functions and self-administration of pain treatments outside of traditional healthcare appointments and hospital settings. In this review, the current gap in clinical care for real-time feedback and guidance with pain management decision-making for chronic and post-operative pain treatment is defined. We examine the recent and future applications for predictive analytics of opioid use after surgery and implementing real-time neural networks for personalized pain management goal setting for particular individuals on the path to discharge to normal function. Integration of personalized neural networks with longitudinal data may enable the development of future treatment personalizations paired with electrical simulations.