Reversing chronic conditions remains an elusive goal of medicine. The modern medical paradigm based on blocking overactive pathways or augmenting deficient pathways offers symptomatic benefit, but tolerance to therapy can develop and treatment cessation can produce rebound symptoms due to compensatory mechanisms. We propose a paradoxical strategy for treating chronic conditions based on harnessing compensatory mechanisms for therapeutic benefit. Many current drugs may be repurposed for a paradoxical indication where the therapeutic effect is derived from compensatory response, rather than drug effect. For example, although exercise is associated with acute adrenergia, paradoxical downregulation of baseline sympathovagal ratio occurs as a remodeling response. For conditions that manifest chronic sympathetic bias such as cardiovascular diseases, judicious administration of adrenergic agonists may induce compensatory downregulation of baseline sympathovagal ratio. The concept may generalize to many other diseases, especially those involving pathways which exhibit strong homeostatic tendencies such as the neurologic, immune, and endocrine systems. Careful consideration of chronobiologic features is necessary to optimize dosing strategies for modulating compensatory responses, and eccentric dosing schedules, shorter-acting formulations, or pulsatile delivery may be desirable in some cases. To what extent the effect of desensitization to current therapy is mistaken for disease progression in conditions such as diabetes, myopia, depression, and hypertension warrants investigation. The merits of combining behavioral and drug therapies such as diet-insulin therapy for diabetes and exercise-β-blockade for cardiovascular disease should be revisited since there is a risk for exacerbating the underlying dysfunction. The reduced dynamic range of various environmental experiences and the tendency to revert to the mean through medical intervention, thermoregulation, and other modern lifestyle changes may play under-recognized roles in human diseases. Perhaps alternating agonists and antagonist may exercise the entire dynamic range of pathways and improve health.
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