Accepted

Chronic pain is considered a public health priority by the World Health Organization and European health institutions. It has reached alarming proportions in terms of disability, consumption of health and social resources, and impact on primary and specialist care services. Primary care physicians are often called on to manage this condition. Chronic pain management can be challenging due to its complexity. It has traditionally been considered to include nociceptive pain that that persists longer than the normal healing time, neuropathic pain lasting more than 3 months, or a combination of these. More recently, a third descriptor, nociplastic (primary) pain, was added to classify patients with chronic pain conditions such as fibromyalgia, nonspecific back pain, or mixed pain that persists or other conditions in which altered central pain modulation results in central sensitization and chronic pain in the absence of actual or threatened damage to tissues, including in the somatosensory nervous system. This document provides an overview of pain types and their underlying mechanisms. Successful pain management is facilitated by identification of the pain type. A set of diagnostic tools and a pain algorithm are presented to guide the clinician toward the correct diagnosis. The algorithm identifies cases that may require referral to a pain specialist. Once the site of origin of the pain (the "pain generator") is identified, or a primary pain syndrome is suspected, the accompanying article provides information and rationale to support treatment decisions based on patient characteristics.

The opioid crisis is more severe in the United States than in any other country. This may be due, in part, to a cultural problem related to pain: Americans have come to expect quick, easy, physician-provided pain relief. Pharmaceuticals can neither cure injuries nor correct the underlying cause of any chronic musculoskeletal condition. Fortunately, people who regularly exercise have less pain, and guidelines for the management of painful chronic conditions already recommend exercise therapies over passive care. This suggests that self-care approaches emphasizing exercise are the logical, lowest-cost, first-line treatment. For patients who require guidance with exercise, the stepped-care approach to pain management commonly taught in medical school curricula should include guided physical rehabilitation early, if not first. This has been shown to be associated with fewer high-cost services and less opioid medication. Keeping people opioid naïve, when appropriate, could save tens of thousands of American lives annually and many more globally. Attitudes, behaviors, and policies must evolve to shed the culture of first-line pharmaceutical pain management. .

Electrical signaling was a dramatic development in evolution, allowing complex single-cell organisms like Paramecium to coordinate movement and early metazoans like worms and jellyfish to send regulatory signals rapidly over increasing distances. But how are electrical signals generated in biology? In fact, voltage-gated sodium channels conduct sodium currents that initiate electrical signals in all kingdoms of life, from bacteria to man. They are responsible for generating the action potential in vertebrate nerve and muscle, neuroendocrine cells, and other cell types. Because of the high level of conservation of their core structure, it is likely that their fundamental mechanisms of action are conserved as well. Here we describe the complete cycle of conformational changes that a bacterial sodium channel undergoes as it transitions from resting to activated/open and inactivated/closed states, based on high-resolution structural studies of a single sodium channel. We further relate this conformational cycle of the ancestral sodium channel to the function of its vertebrate orthologs. The strong conservation of amino acid sequence and three-dimensional structure suggests that this model, at a fundamental level, is relevant for both prokaryotic and eukaryotic sodium channels, as well as voltage-gated calcium and potassium channels.