Accepted

P2X3 monomeric receptors (P2X3Rs) and P2X2/3 heteromeric receptors (P2X2/3Rs) in primary sensory neurons and microglial P2X4 monomeric receptors (P2X4Rs) in the spinal dorsal horn (SDH) play important roles in neuropathic pain. In particular, P2X4R in the spinal microglia during peripheral nerve injury (PNI), experimental autoimmune neuritis, and herpes models are useful to explore the potential strategies for developing new drugs to treat neuropathic pain. Recently, novel P2X4 antagonists, NP-1815-PX and NC-2600, were developed, which demonstrated potent and specific inhibition against rodent and human P2X4Rs. The phase I study of NC-2600 has been completed, and no serious side effects were reported. The roles played by purinergic receptors in evoking neuropathic pain provide crucial insights into the pathogenesis of neuropathic pain.

The term 'mixed pain' is increasingly applied for specific clinical scenarios, such as low back pain, cancer pain and postsurgical pain, in which there "is a complex overlap of the different known pain types (nociceptive, neuropathic, nociplastic) in any combination, acting simultaneously and/or concurrently to cause pain in the same body area." Whether mixed pain is the manifestation of neuropathic and nociceptive mechanisms operating simultaneously or concurrently, or the result of an entirely independent pathophysiological mechanism – distinct from nociceptive, nociplastic and neuropathic pain – is currently unknown. At present, the diagnosis of mixed pain is made based on clinical judgement following detailed history-taking and thorough physical examination, rather than by formal confirmation following explicit screening or diagnostic criteria; this lack of formalized screening or diagnostic tools for mixed pain is problematic for physicians in primary care, who encounter patients with probable mixed pain states in their daily practice. This article outlines a methodical approach to clinical evaluation of patients presenting with acute, subacute or chronic pain, and to possibly identifying those who have mixed pain. The authors propose the use of nine simple key questions, which will provide the practicing clinician a framework for identifying the predominant pain mechanisms operating within the patient. A methodical, fairly rapid, and comprehensive assessment of a patient in chronic pain – particularly one suffering from pain with both nociceptive and neuropathic components – allows validation of their experience of chronic pain as a specific disease and, importantly, allows the institution of targeted treatment.

The management of chronic non-cancer pain (CNCP) with Chronic Opioid Therapy (COT) is controversial. There is a lack of consensus on how COT is defined resulting in unclear clinical guidance. This scoping review identifies and evaluates evolving COT definitions throughout the published clinical and scientific literature. Databases searched included PubMed, Embase, and Web of Science. A total of 227 studies were identified from 8,866 studies published between January 2000 and July 2019. COT definitions were classified by pain population of application and specific dosage/duration definition parameters, with results reported according to PRISMA-ScR. Approximately half of studies defined COT as "days' supply duration >90 days" and 9.3% defined as ">120 days' supply," with other days' supply cut-off points (>30, >60, or >70) each appearing in <5% of total studies. COT was defined by number of prescriptions in 63 studies, with 16.3% and 11.0% using number of initiations or refills, respectively. Few studies explicitly distinguished acute treatment and COT. Episode duration/dosage criteria was used in 90 studies, with 7.5% by Morphine Milligram Equivalents (MME's)+days' supply and 32.2% by other "episode" combination definitions. COT definitions were applied in musculoskeletal CNCP (60.8%) most often, and typically in adults aged 18-64 (69.6%). The usage of ">90 days' supply" COT definitions increased from 3.2 publications /year before 2016 to 20.7 publications /year after 2016. An increasing proportion of studies define COT as ">90 days' supply". The most recent literature trends toward shorter duration criteria, suggesting that contemporary COT definitions are increasingly conservative. Perspective: This study summarized the most common, current definition criteria for chronic opioid therapy (COT) and recommends adoption of consistent definition criteria to be utilized in practice and research. The most recent literature trends toward shorter duration criteria overall, suggesting that COT definition criteria are increasingly stringent.