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Summary: What is known and objective: Although pain is one of the most common afflictions, it is often inadequately managed because the available analgesic options are relatively limited due to insufficient efficacy, unacceptable adverse effects or the potential for misuse or abuse. However, recent publications suggest that an alternative approach—indirect enhancement of endogenous pain‐relieving pathways—might be desirable. We review this approach, in particular the dual enkephalinase inhibitors (DENKIs). Methods: Published literature and Internet sources were searched for information related to the basic science and clinical data on inhibition of metabolic pathways of endogenous analgesic agents. The identified sources were reviewed, assessed and synthesized. Emphasis was placed on the benefits of the approach, as well as on the individual agents. Results: Inhibition of the enzymes that degrade the endogenous opioid ligands Met‐ and Leu‐enkephalin results in an increased synaptic concentration of the enkephalins and an analgesic effect in a variety of animal models of pain and in preliminary trials in humans. The design of compounds that inhibit both of the two major enkephalin‐degrading enzymes (neprilysin and aminopeptidase N) has been found to be better than those that inhibit only one of the enzymes. These dual‐acting enkephalinase inhibitors yield analgesia with less adverse effects than current opioid drugs. What is new and conclusion: Unlike currently available analgesics, inhibitors of the metabolic degradation of endogenous analgesic substances attempt to elicit a more “natural” and targeted analgesic effect. This indirect approach offers an opportunity for novel additions to the otherwise relatively limited choice of analgesic classes. [ABSTRACT FROM AUTHOR]

Summary: What is known and objective: Current analgesic pharmacotherapy—opioids, non‐steroidal anti‐inflammatory drugs (NSAIDs), acetaminophen (paracetamol) and related drugs—is effective for acute pain, but their use is limited by adverse effects on the renal, hepatic, cardiovascular or gastrointestinal systems, or they have potential for abuse. Therefore, alternative options are desired. Compounds used in traditional medicine might offer such alternatives, but the evidence must be based on pharmacologic properties and on clinical trial data. This review summarizes the evidence for one of these: the analgesic properties of turmeric and other curcumins. Methods: The PubMed database and other sources were searched using keywords related to turmeric, curcumin, antinociception and analgesia. Primary sources and reviews of preclinical and clinical studies were identified, assessed and summarized. Bibliographies within these sources provided additional information. Results: Turmeric has consistently been demonstrated to produce analgesic and anti‐inflammatory effects in animal models and in clinical trials, and appears to have less serious adverse effects than many current analgesics. What is new and conclusions: Turmeric (curcumin) appears to be a possible candidate for consideration for use as a stand‐alone analgesic, or in analgesic combinations as part of opioid‐, NSAID‐ or paracetamol (acetaminophen)‐sparing strategies. [ABSTRACT FROM AUTHOR]

Summary: What is known and objective: Advances in pain research have led to an understanding that many pains are driven by more than one underlying (patho)physiologic cause (ie, they are “multimechanistic”) and that better pain relief is obtained with fewer adverse effects when an analgesic is correspondingly multimechanistic. At least two of the more‐modern analgesics combine opioid and non‐opioid mechanisms, and have become known as “atypical opioids.” Less well known is that just as Nature evolved opioids, it also evolved atypical opioids, presaging modern drug discovery efforts. Comment: Traditional (typical) opioids are extracts or analogs of substances derived from the poppy plant. They produce their analgesic and adverse effects primarily through a single, opioid mechanism (albeit with individual differences). Two most recent analgesics were developed to have both an opioid mechanism and, a second, non‐opioid mechanism of action (inhibition of monoamine neurotransmitter reuptake). Little known is that Nature had already evolved a plant source of compounds with the same properties. What is new and conclusion: As debate about the use and abuse potential of kratom swirls, conflicting, often contradicting, opinions are expressed. A review of the basic pharmacology of kratom reveals the explanation for the bifurcation in viewpoints: kratom has both opioid and non‐opioid properties. Fascinatingly, just as the poppy plant (Papaver) evolved the typical opioids, Mitragyna evolved the mitragynines—Nature's “atypical opioids.” [ABSTRACT FROM AUTHOR]

Summary: What is known and objective: Menthol has been used as a non‐opioid pain reliever since ancient times. A modern understanding of its molecular mechanism of action could form the basis for generating targets for discovery of novel non‐opioid analgesic drugs. Methods: The PubMed database was queried using search words related to menthol, pain and analgesia. The results were limited to relevant preclinical studies and clinical trials and reviews published in English during the past 5 years, which yielded 31 reports. The bibliographies of these articles were sources of additional supporting articles. Results: Menthol is a selective activator of transient receptor potential melastatin‐8 (TRPM8) channels and is also a vasoactive compound. As a topical agent, it acts as a counter‐irritant by imparting a cooling effect and by initially stimulating nociceptors and then desensitizing them. Topically applied menthol may also activate central analgesic pathways. At high concentrations, menthol may generate cold allodynia. What is new and conclusions: Recent elucidation of TRPM8 channels has provided a molecular basis for understanding the molecular action of menthol and its ability to produce both a cooling sensation and reduction in pain associated with a wide variety of pain(ful) conditions. The more modern mechanistic understanding of menthol and its pharmacologic mechanism of action may lead to an expanded role for this substance in the search for replacements for opioid analgesics, particularly those that can be applied topically. [ABSTRACT FROM AUTHOR]

What is known and objective Abundant clinical data now confirm that ketamine produces a remarkable rapid-onset antidepressant effect - hours or days - in contrast to the delayed onset (typically weeks) of current antidepressant drugs. This surprising and revolutionary finding may lead to the development of life-saving pharmacotherapy for depressive illness by reducing the high suicide risk associated with the delayed onset of effect of current drugs. As ketamine has serious self-limiting drawbacks that restrict its widespread use for this purpose, a safer alternative is needed. Our objective is to review the proposed mechanism(s) of ketamine's rapid-onset antidepressant action for new insights into the physiological basis of depressive illness that may lead to new and novel targets for antidepressant drug discovery. Methods A search was conducted on published literature (e.g. PubMed) and Internet sources to identify information relevant to ketamine's rapid-acting antidepressant action and, specifically, to the possible mechanism(s) of this action. Key search words included 'ketamine', 'antidepressant', 'mechanism of action', 'depression' and 'rapid acting', either individually or in combination. Information was sought that would include less well-known, as well as well-known, basic pharmacologic properties of ketamine and that identified and evaluated the several hypotheses about ketamine's mechanism of antidepressant action. Results Whether the mechanistic explanation for ketamine's rapid-onset antidepressant action is related to its well-known antagonism of the NMDA ( N-Methyl- d-aspartate) subtype of glutamate receptor or to something else has not yet been fully elucidated. The evidence from pharmacologic, medicinal chemistry, animal model and drug-discovery sources reveals a wide variety of postulated mechanisms. What is new and conclusion The surprising discovery of ketamine's rapid-onset antidepressant effect is a game-changer for the understanding and treatment of depressive illness. There is some convergence on NMDA receptor antagonism as a likely, but to date unproven, common mechanism. The surprising number of other mechanisms, and the several novel biochemical aetiologies of depression proposed, suggests exciting new drug-discovery targets. [ABSTRACT FROM AUTHOR]

What is known and objective Chronic pain presents a difficult clinical challenge because of the limited efficacy, the limiting adverse-effect profile or the abuse potential of current analgesic options. Cebranopadol is a novel new agent in clinical trials that combines dual agonist action at opioid and nociceptin/orphanin FQ peptide ( NOP) receptors. It is the first truly unique, centrally acting analgesic in several years. We here review the basic and clinical pharmacology of cebranopadol. Methods Published literature and Internet sources were searched to identify information related to the basic science (pharmacology and medicinal chemistry) and development (clinical trial) information on the mechanism of dual opioid and NOP receptor pharmacologic action in general, and for cebranopadol in particular. The identified sources were reviewed and the information synthesized. Results The preclinical testing of cebranopadol has characterized it as a dual opioid and NOP receptor agonist that displays antinociceptive and antihyperalgesic action in a variety of acute and chronic pain models in animals. Unlike most current traditional opioids, it is generally more potent against neuropathic than nociceptive pain. Several phase 2 clinical trials have been completed. What is new and conclusion Despite the medical need, a truly novel centrally acting analgesic has not been developed in many years. Cebranopadol represents a truly novel mechanistic approach. Its actual place in pain pharmacotherapy awaits the results of phase 3 clinical trials. [ABSTRACT FROM AUTHOR]

What is known and objective Optimal utilization of opioid analgesics is significantly limited by the central nervous system adverse effects and misuse/abuse potential of currently available drugs. It has been postulated that opioid-associated adverse effects and abuse potential would be greatly reduced if opioids could be excluded from reaching the brain. We review the basic science and clinical evidence of one such approach - peripherally restricted kappa-opioid receptor ( KOR) agonists ( pKORAs). Methods Published and unpublished literature, websites and other sources were searched for basic science and clinical information related to the potential benefits and development of peripherally restricted kappa-opioid receptor agonists. Each source was summarized, reviewed and assessed. Results The historical development of pKORAs can be traced from the design of increasingly KOR-selective agonists, elucidation of the pharmacologic attributes of such compounds and strategies to restrict passage across the blood-brain barrier. Novel compounds are under development and have progressed to clinical trials. What is new and conclusions The results from recent clinical trials suggest that peripherally restricted opioids can be successfully designed and that they can retain analgesic efficacy with a more favourable adverse effect profile. [ABSTRACT FROM AUTHOR]

What is known and objective Pain is a prevalent, and due to the ageing population, increasing medical problem. Opioids are frequently prescribed to meet the unmet medical need. Unfortunately, with the increase in the legitimate use of opioids, there has been a corresponding increase in abuse. A practical way to retain the pain relief afforded by opioids while decreasing opportunities for abuse is to make it more difficult to extract the opioid from the product or to make it less desirable to do so by designing an abuse-deterrent formulation ( ADF). We provide a brief overview of the strategies and early evidence related to opioid ADFs. Methods Published and unpublished literature, websites, and other sources were searched for current opioid formulation options, including immediate-release and extended-release products. Each was summarized, reviewed and assessed. Results The strategies that have been used to design the current opioid ADFs involve one or more of four approaches: a physical barrier; incorporation of an opioid receptor antagonist (e.g. naloxone) that self-limits opioid action when taken in excess amount; inclusion of a noxious agent that is released during inappropriate use; or a pro-drug. What is new and conclusions Legitimate use of opioid analgesics carries with it certain risks, including the risk of abuse. The new ADFs utilize four major strategies and provide innovative additions to the armamentarium. They likely will become an important part of a comprehensive approach to limiting, although not eliminating, opioid misuse and abuse. [ABSTRACT FROM AUTHOR]

What is known and objective Opioid-induced constipation ( OIC) is one of the most common opioid-induced adverse effects. Pregnancy also predisposes to bowel dysfunctions due to the associated endocrine changes. Pregnant women are thus at greater risk of OIC. We review the non-pharmacologic and pharmacologic treatment options as a guide for achieving a clinically optimal strategy for the management of OIC during pregnancy. Methods The published literature was searched for current therapeutic options, including non-pharmacologic dietary modifications, laxatives, and the peripherally acting mu-opioid receptor antagonists ( PAMORAs). Each was assessed for efficacy and safety, particularly as they relate to pregnancy. Results and discussion Non-pharmacologic approaches such as dietary change are generally safe, but generally insufficient when used alone to control OIC in pregnancy. Laxatives (bulking, osmotic, stimulant) can be effective, but have potential adverse effects that might be particularly troublesome during pregnancy (e.g. electrolyte disturbances, dehydration, abdominal pain, and pulmonary oedema or hypermagnesaemia in the extreme). PAMORAs, which attenuate OIC without affecting opioid-induced analgesia, have been associated with only minimal side effects during the clinical studies to date. What is new and conclusions Conventional non-pharmacologic and pharmacologic options for the management of OIC in pregnancy are often suboptimal due to insufficient efficacy or adverse effects particularly troublesome during pregnancy. The PAMORA strategy appears to provide a safe and effective new option superior to conventional therapies for the management of OIC during pregnancy. [ABSTRACT FROM AUTHOR]

What is known and objective The endogenous opioid system co-evolved with chemical defences, or at times symbiotic relationships, between plants and other autotrophs and heterotrophic predators - thus, it is not surprising that endogenous opioid ligands and exogenous mimetic ligands produce diverse physiological effects. Among the endogenous opioid peptides (endomorphins, enkephalins, dynorphins and nociception/orphanin FQ) derived from the precursors encoded by four genes ( PNOC, PENK, PDYN and POMC) are the pentapeptides Met-enkephalin (Tyr-Gly-Gly-Phe-Met) and Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu). The physiological effects of the enkephalins are mediated via 7-transmembrane G protein-coupled receptors, including delta opioid receptor ( DOR). We present a concise update on the status of progress and opportunities of this approach. Methods A literature search of the PUBMED database and a combination of keywords including delta opioid receptor, analgesia, mood and individual compounds identified therein, from industry and other source, and from . Results and discussion DOR agonist and antagonist ligands have been developed with ever increasing affinity and selectivity for DOR over other opioid receptor subtypes and studied for therapeutic utility, primarily for pain relief, but also for other clinical endpoints. What is new and conclusion Selective DOR agonists have been designed with a large increase in therapeutic window for a variety of potential CNS applications including pain, depression, and learning and memory among others. [ABSTRACT FROM AUTHOR]

What is known and objective The current pharmacotherapeutic treatment of major depressive disorder ( MDD) generally takes weeks to be effective. As the molecular action of these drugs is immediate, the mechanistic basis for this lag is unclear. A drug that has a more rapid onset of action would be a major therapeutic advance and also be a useful comparator to provide valuable mechanistic insight into the disorder and its treatment. Comment Recent evidence suggests that ketamine produces rapid-onset antidepressant action. Important questions are as follows: is it specific or coincidental to other effects; is there a dose-response relationship; and is the mechanism related to that of current antidepressants. NMDA receptor antagonism is unlikely the explanation for ketamine's antidepressant action. What is new and conclusion It is not an exaggeration to state that the new findings, if validated, might produce a revolution in understanding and treating depressive disorders. [ABSTRACT FROM AUTHOR]

What is known and objective Based on in vitro assays and select animal models, buprenorphine is commonly called a 'partial agonist'. An implication is that it should produce less analgesic effect in humans than so-called 'full agonists' such as morphine or fentanyl. However, buprenorphine has a multimechanistic pharmacology, and thus partial agonism at a specific receptor is not particularly relevant to its overall analgesic action. We review published clinical trials that directly compared the magnitude of buprenorphine's analgesic effect to analgesics commonly considered full agonists. Comment Due to different signal transduction pathways, a drug can be a full agonist on one endpoint and a partial agonist on another. Therefore, we limited the present review to buprenorphine's analgesic effect. What is new and conclusion Twenty-four controlled clinical trials were identified, plus a case report and dose-response curve. Based on complete or comparable pain relief, in buprenorphine had full clinical analgesic efficacy in 25 of the 26 studies. [ABSTRACT FROM AUTHOR]

What is known and objective The prevailing theory regarding Alzheimer disease ( AD) is that insoluble amyloid β-peptide ( Aβ) plays a critical role in the cortical plaques characteristic of the disease. Because Aβ is formed from the sequential splicing of amyloid precursor protein ( APP) catalysed by 'secretase' enzymes (α, β and γ), clinical trials of secretase inhibitors will either result in beneficial pharmacotherapy or, if negative, cast doubt on the role of Aβ in AD. With recent clinical trial failures, is the Aβ theory wrong? Methods Literature searches were conducted on the topics of secretases and clinical trials, including Pub Med searches, United States clinical trials directory, pharmaceutical company websites and news reports. The information was collected and evaluated for relevance and quality. Results and discussion Several direct-acting (e.g. CTS-21166, LY2811376) and indirect-acting (e.g. ACI-91) β-secretase inhibitors and several γ-secretase inhibitors ( e.g. avagacestat, JNJ-40418677 and semagacestat) have not fared well in early clinical trials due to the lack of efficacy or concerns over possible serious side effects. What is new and conclusion The failures of secretase inhibitors in clinical trials appear to bring into question the long-hypothesized association between AD and Aβ production. However, the disease might have been too advanced in these patients to benefit from this type of therapy (mainly preventive). Secretase inhibitors are still being studied, along with new diagnostic tools, with the hope of testing patients earlier, that is, with less advanced disease. If these trials also fail, the prevailing view of the role of Aβ in AD will truly be in doubt. [ABSTRACT FROM AUTHOR]

What is known and objective A novel class of antidiabetic drugs - SGLT2 (Na+/glucose cotransporter type 2) inhibitors - target renal reabsorption of glucose and promote normal glucose levels, independent of insulin production or its action at receptors. We review this new mechanistic approach and the reported efficacy and safety of clinical testing of lead compounds. Methods Information was obtained from various bibliographic sources, including PubMed and others, on the basic science and the clinical trials of SGLT2 inhibitors. The information was then summarized and evaluated from the perspective of contribution to a fuller understanding of the potential and current status of the lead clinical candidates. Results and discussion Diabetes mellitus is a spectrum of disorders that involves inadequate insulin function resulting in adverse health sequelae due to acute and chronic hyperglycaemia. Current antidiabetic pharmacotherapy primarily addresses either insulin production at the pancreatic β-cells or insulin action at insulin receptors. These drugs have less than full clinical effectiveness and sometimes therapy-limiting adverse effects. The third major component of glucose balance, namely elimination, has not been a significant therapeutic target to date. SGLT2 inhibitors are a novel approach. What is new and conclusion A sufficient number of clinical trials have been conducted on sufficiently chemically diverse SGLT2 inhibitors to reasonably conclude that they have efficacy (HbA1c reductions of 0·4-1%), and thus far, the majority of adverse effects have been mild and transitory or treatable, with the caveat of possible association with increased risk of breast cancer in women and bladder cancer in men. [ABSTRACT FROM AUTHOR]

What is known and Objective Cancer chemotherapy-associated cognitive impairments (termed 'chemo-fog' or 'chemo-brain'), particularly in memory, have been self-reported or identified in cancer survivors previously treated with chemotherapy. Although a variety of deficits have been detected, a consistent theme is a detriment in visuospatial working memory. The parietal cortex, a major site of storage of such memory, is implicated in chemotherapy-induced damage. However, if the findings of two recent publications are combined, the (pre)frontal cortex might be an equally viable target. Two recent studies, one postulating a mechanism for 'top-down control' of working memory capacity and another visualizing chemotherapy-induced alterations in brain activation during working memory processing, are reviewed and integrated. Comment A computational model and the proposal that the prefrontal cortex plays a role in working memory via top-down control of parietal working memory capacity is consistent with a recent demonstration of decreased frontal hyperactivation following chemotherapy. What is new and Conclusion Chemotherapy-associated impairment of visuospatial working memory might include the (pre)frontal cortex in addition to the parietal cortex. This provides new opportunity for basic science and clinical investigation. [ABSTRACT FROM AUTHOR]

What is known and Objective The deleterious effect of vitamin D deficiency on bone health has long been known. More recent studies suggest a deleterious effect of low vitamin D (hypovitaminosis D) on general health. And specific studies propose an association between hypovitaminosis D and the aetiology and progression of type 2 diabetes ( T2 DM). Given a commonly assumed lack of toxicity of vitamin D, routine measurement of plasma vitamin D and supplementation is rapidly becoming accepted general practice. Comment Authoritative practice guidelines have raised the level of vitamin D that is to be considered minimal for optimum health. This recommendation was based on a wealth of information and definitive evidence for skeletal benefits of vitamin D, but there was a lack of compelling evidence that hypovitaminosis D is causally related to extra-skeletal health outcomes such as diabetes. Hence, vitamin D supplementation for the purpose of achieving a level consistent with good health is evidence based, but measurement and supplementation for the purpose of preventing or treating T2 DM is not. What is new and Conclusion Although the maintenance of adequate vitamin D levels is desirable for all patients, we conclude that routine measurement of vitamin D level in every patient or initiating high-dose supplementation for the purpose of preventing or treating T2 DM is not evidence based. [ABSTRACT FROM AUTHOR]

What is known and Objective: The potential beneficial therapeutic effects of cannabinoid CB1 receptor antagonists or partial agonists have driven drug discovery and development efforts and have led to clinical candidates. It is generally assumed that these compounds are CB1'selective' and produce their effects exclusively via CB1 receptors. Methods: A literature search was conducted of preclinical publications containing information about non-CB1 receptor pharmacology of these agents. The information was summarized and evaluated from the perspective of contribution to a fuller understanding of this aspect of these compounds. Results and Discussion: A number of recent studies have revealed that these compounds have CB1-independent pharmacological actions. We highlight the evidence regarding effects produced in cells lacking CB1 receptors, effects on neuronal membranes from CB1 receptor-deficient mutant KO 'knockout' mice and affinity for μ-opioid receptors. What is new and Conclusion: CB1'selective' antagonists and partial agonists have been studied for their anorexigenic and other potential therapeutic uses. An awareness of CB1-independent mechanism(s) of these agents might contribute to a better understanding of the pharmacologic and toxicologic profiles of these agents. [ABSTRACT FROM AUTHOR]