SummaryWhat is known and objective: Serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used for various psychiatric conditions and neuropathic pain syndromes.SNRIs inhibit the reuptake of serotonin (5-HT) and norepinephrine (NE); however, NE reuptake inhibition is thought to be the primary mediator for their analgesic effect. Comment: Key differences in pharmacodynamics and receptor affinities exist betweenSNRIs. The selectivity for each monoamine differs among SNRIs based on the agent's affinity and activity at the monoamine reuptake transporter. We review differences in receptor affinities and monoamine selectivity among SNRIs and the corresponding clinical impact. What is new and conclusion:The varying selectivity for 5-HT and NE among the SNRIs may help explain the therapeutic dosing required for neuropathic pain as well as dose-related adverse effects. It is important to understand the pharmacologic differences among SNRIs, in addition to the data from clinical trials, to guide their safe and effective use. K E Y W O R D Santidepressants, binding affinity, neuropathic pain, pain, serotonin-norepinephrine reuptake inhibitors

Purpose: Opioids are highly addictive potent analgesics and anti-allodynics whose use has dramatically increased in recent decades. The precipitous rise in opioid dependency and opioid use disorder is an important public health challenge given the risks for severely adverse health outcomes. The long-term opioid impact on hypothalamicpituitary axes is particularly underappreciated among both endocrinologists and primary care physicians. We review the effects of opioids on hypothalamic-pituitary-target gland function and their implications for clinical practice.Methods: Experts in hypothalamic-pituitary disorders and opioid pharmacology reviewed recently published literature and considered strategies for diagnosing and managing these opioid-induced endocrine effects.Results: Opioid suppression of hypothalamic-pituitary axes can lead to hypogonadotropic hypogonadism, central adrenal insufficiency, and hyperprolactinemia. These important clinical manifestations are often under-estimated, poorly evaluated, and typically either untreated or not optimally managed. Data on biochemical testing for diagnosis and on the effect of hormone replacement in these patients is limited and prospective randomized controlled studies for guiding clinical practice are lacking. Conclusions:Patients should be informed about risks for hypogonadism, adrenal insufficiency, and hyperprolactinemia, and encouraged to report associated symptoms. Based on currently available evidence, we recommend clinical and biochemical evaluation for potential central adrenal insufficiency, central hypogonadism, and/or hyperprolactinemia in patients chronically treated with opioids as well as the use of current expert guidelines for the diagnosis and treatment of these conditions.

Background: Chronic noncancer pain is pervasive throughout the general patient population, transcending all chronic disease states. Patients with end-stage renal disease (ESRD) present a complicated population for which medication management requires careful consideration of the pathogenesis of ESRD and intimate knowledge of pharmacology. The origin of pain must also guide treatment options. As such, the presentation of neuropathic pain in ESRD can present a challenging case. The authors aim to provide a review of available classes of medications and considerations for the treatment of neuropathic pain in ESRD. Summary: In this narrative review, the authors discuss important strategies and considerations for the treatment of neuropathic pain in ESRD, including the pathogenesis of neuropathic pain, physiological changes for consideration in ESRD patients, and disease-specific consideration for medication selection. Pharmacotherapeutic classes discussed include: anticonvulsants, antiarrhythmics, antidepressants, topicals, and opioids. Key Message: Pain management in ESRD patients re-quires careful assessment of drug-specific properties, accumulation, metabolism (presence of active/toxic metabolites), extraction by dialysis, and presence of drug -drug interactions. In the absence of pharmacokinetic data in ESRD patients, therapeutic window and potential risks should be factored in the decision making along with continued monitoring throughout therapy.

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