Establishment of an Individualized Chronotherapy, Autonomic Nervous System, and Variability-Based Dynamic Platform for Overcoming the Loss of Response to Analgesics

Abstract

Background: Control of chronic pain and mainly the partial or complete loss of response to analgesics is a major unmet need. Multiple mechanisms underline the development of tolerance to analgesics in general and specifically to opioids. The autonomic nervous system (ANS) plays a role in the development of analgesic tolerance and chronobiology. Objectives: To review the mechanisms associated with the development of nonresponsiveness to analgesics. Study Design: Literature review. Setting: The review is followed by a description of a new method for overcoming resistance and improving the response to analgesics. Methods: Conducted a detailed review of the relevant studies describing the mechanisms that underlie tolerance to pain medications, and the potential roles of the ANS and chronobiology in the development of drug resistance. Results: The autonomic balance is reflected by heart rate variability, an example of a fundamental variability that characterizes biological systems. Chronotherapy, which is based on the circadian rhythm, can improve the efficacy and reduce the toxicity of chronic medications. In this article, we present the establishment of an individualized variability- and chronobiology-based therapy for overcoming the compensatory mechanisms associated with a loss of response to analgesics. We describe the premise of implementing personalized signatures associated with the ANS, and chronobiology, as well as with the pathophysiology of pain for establishing an adaptive model that could improve the efficacy of opioids, in a highly dynamic system. Limitations: The studies presented were selected based on their relevance to the subject. Conclusions: The described variability-based system may ensure prolonged effects of analgesics while reducing the toxicity associated with increasing dosages. Key words: Painkillers, opioids, drug resistance, compensatory mechanisms

Department of Medicine 2040: Implementing a Constrained Disorder Principle-Based Second-Generation Artificial Intelligence System for Improved Patient Outcomes in the Department of Internal Medicine

“… 1 , 2 , 70 , 71 Dosing and medication administration times are altered in these systems to ensure sustainable responses to treatments. 62, 70 - 92 CDP-based systems can also improve digital twin accuracy by accounting for biological noise in a personalized manner. An illustration of how second-generation AI systems can be implemented into therapies is shown in Figure 1D .…”

The Constrained-Disorder Principle Assists in Overcoming Significant Challenges in Digital Health: Moving from “Nice to Have” to Mandatory Systems

“…In addition, there is marked inter and intra-subject variability in response to chronic therapies [ 239 , 240 , 241 , 242 ]. The CDP-based second-generation AI systems provide a platform for overcoming drug resistance and improving adherence by implementing variability-based therapeutic regimens for patients with chronic diseases [ 76 , 108 , 242 , 243 , 244 , 245 , 246 , 247 , 248 , 249 , 250 , 251 , 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 , 260 ]. The system enables personalized therapies based on individual variability signatures [ 146 , 239 , 257 , 261 ].…”

Enhancing the plasticity, proper function and efficient use of energy of the Sun, genes and microtubules using variability

“…Methods for increasing variability were proposed for biological systems, such as introducing patterns of variability based on quantifying inherent variabilities. 12,64,[116][117][118][119][120][121][122][123][124][125][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141][142] The response to disease-inducing triggers and therapies varies between subjects and within the same subject over time. 118,[143][144][145] Patterns of variability can be disease-, subject-or intervention-dependent.…”

“…The development of methods for enhancing the functions of systems, whether they are malfunctions due to loss of variability or other designing functioning systems, requires increasing their levels of variability. Methods for increasing variability were proposed for biological systems, such as introducing patterns of variability based on quantifying inherent variabilities 12,64,116–125,127–142 …”