Multimodal Analgesia, Current Concepts, and Acute Pain Considerations.

PURPOSE OF REVIEW: Management of acute pain following surgery using a multimodal approach is recommended by the American Society of Anesthesiologists whenever possible. In addition to opioids, drugs with differing mechanisms of actions target pain pathways resulting in additive and/or synergistic effects. Some of these agents include alpha 2 agonists, NMDA receptor antagonists, gabapentinoids, dexamethasone, NSAIDs, acetaminophen, and duloxetine. RECENT FINDINGS: Alpha 2 agonists have been shown to have opioid-sparing effects, but can cause hypotension and bradycardia and must be taken into consideration when administered. Acetaminophen is commonly used in a multimodal approach, with recent evidence lacking for the use of IV over oral formulations in patients able to take medications by mouth. Studies involving gabapentinoids have been mixed with some showing benefit; however, future large randomized controlled trials are needed. Ketamine is known to have powerful analgesic effects and, when combined with magnesium and other agents, may have a synergistic effect. Dexamethasone reduces postoperative nausea and vomiting and has been demonstrated to be an effective adjunct in multimodal analgesia. The serotonin-norepinephrine reuptake inhibitor, duloxetine, is a novel agent, but studies are limited and further evidence is needed. Overall, a multimodal analgesic approach should be used when treating postoperative pain, as it can potentially reduce side effects and provide the benefit of treating pain through different cellular pathways.

The selective Rho-kinase inhibitor azaindole-1 has long-lasting erectile activity in the rat.

OBJECTIVE: To investigate the effects of the selective Rho-associated protein kinase (ROCK) inhibitor azaindole-1 on erectile function under physiologic and pathophysiologic conditions in the rat. METHODS: The effect of intracavernosal (i.c.) injections of azaindole-1 on change in intracavernous pressure (ICP), ICP/mean arterial pressure (MAP), area under the curve (AUC), and response duration were investigated in the anesthetized rat under control conditions and when nonadrenergic noncholinergic neurotransmission and cholinergic function or soluble guanylyl cyclase (sGC) were inhibited or after cavernosal nerve crush injury. RESULTS: The i.c. injections of azaindole-1 produced dose-related increases in ICP/MAP and AUC that were long-lasting at the highest doses studied compared with the prototypical ROCK inhibitor fasudil. Erectile responses were not altered by 7-nitroindazole and atropine in doses that reduced the response to cavernosal nerve stimulation by 86%, indicating that they were independent of NO release by cavernosal nerves or activation of muscarinic receptors in the corpora cavernosa. Erectile responses to azaindole-1 were not altered by the sGC inhibitor ODQ in a dose that attenuated responses to the NO donor sodium nitroprusside, indicating that they were independent of an action on sGC. The erectile response to i.c. injections of azaindole-1 or Y-27632, which was reported to be NO/cyclic guanosine monophosphate-dependent, was not attenuated after cavernosal nerve crush injury. CONCLUSION: The present studies indicate that azaindole-1 has long-lasting erectile activity that is independent of NO release, muscarinic receptor, or sGC activation or the integrity of the cavernosal nerves.

Analysis of erectile responses to BAY 41-8543 and muscarinic receptor stimulation in the rat.

INTRODUCTION: Soluble guanylate cyclase (sGC) is the receptor for nitric oxide (NO) and in pathophysiologic conditions where NO formation or bioavailability is impaired, erectile dysfunction (ED) occurs. AIM: The aim of this study was to investigate erectile responses to the sGC stimulator BAY 41-8543 in physiologic and pathophysiologic conditions. METHODS: Increases in intracavernosal pressure (ICP) in response to intracavernosal (ic) injections of BAY 41-8543 were investigated in the anesthetized rat. MAIN OUTCOME MEASURES: Increases in ICP/MAP in response to ic injections of BAY 41-8543 and the interaction of BAY 41-8543 with exogenous and endogenously released NO were investigated and the effect of the sGC stimulator on cavernosal nerve injury was assessed. The mechanism of the increase in ICP/MAP in response to ic injection of acetylcholine was investigated. RESULTS: The ic injections of BAY 41-8543 increased ICP/MAP and the duration of the response. BAY 41-8543 was less potent than sodium nitroprusside (SNP) and ic injections of BAY 41-8543 and SNP produced a larger response than the algebraic sum of responses to either agent alone. Simultaneous ic injection of BAY 41-8543 and cavernosal nerve stimulation produced a greater response than either intervention alone. Atropine and cavernosal nerve crush injury decreased the response to nerve stimulation and ic injection of BAY 41-8543 restored the response. CONCLUSION: These data show that BAY 41-8543 has significant erectile activity and can synergize with exogenous and endogenously released NO. This study shows that atropine and nerve crush attenuate the response to cavernosal nerve stimulation and that BAY 41-8543 can restore the response. The results with atropine, L-NAME and hexamethonium indicate that the response to ic injection of acetylcholine is mediated by muscarinic receptors and the release of NO with no significant role for nicotinic receptors. These results suggest that BAY 41-8543 would be useful in the treatment of ED.

Role of nitric oxide in developmental biology in plants, bacteria, and man.

Since its discovery, nitric oxide (NO) has been observed to play an important role in the physiology of single-celled organisms as well as high-order vertebrates. In this review, we will discuss the involvement of NO in bacterial, plant and human systems. NO originates from a variety of sources, namely bacterial, plant, and mammalian nitric oxide synthases which oxidize L-arginine. Bacterial NO is involved in toxin synthesis, signaling and biofilm formation. Organisms use NO to mediate oxidative stress incurred during the innate immune response. In plants, large amounts of NO hinder plant growth, while lower concentrations regulate normal development. NO and the associated reactive oxygen species (ROS) are effective antibacterial, anti-parasitic, and antifungal agents. Though NO has therapeutic effects in the immune system, the NO response is biphasic and concentration-dependent. NO promotes tumorigenesis within a concentration range, and induces apoptosis of cancerous cells at other concentrations. The biphasic response to NO is also evident in the regulation of chemokine, interleukins, and NF-κB, which can promote or inhibit inflammation. The physiologic response to NO is concentration dependent. NO, by way of non-adrenergic noncholinergic (NANC) nerve transmission, propagates a cascade of molecular signaling that facilitates smooth muscle cell relaxation and increased arterial inflow into the corpora, initiating an erectile response. Additional NO is released through NOS activity in the endothelium in response to cholinergic nerve activity and shear stress, which helps to maintain erection.