• Henny Azmanov, Edgar L Ross, and Yaron Ilan.
• Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
• Pain Physician. 2021 May 1; 24 (3): 243-252.

BackgroundControl 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.ObjectivesTo review the mechanisms associated with the development of nonresponsiveness to analgesics.Study DesignLiterature review.SettingThe review is followed by a description of a new method for overcoming resistance and improving the response to analgesics.MethodsConducted 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.ResultsThe 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.LimitationsThe studies presented were selected based on their relevance to the subject.ConclusionsThe described variability-based system may ensure prolonged effects of analgesics while reducing the toxicity associated with increasing dosages.

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