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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: An effective rapid‐onset treatment for major depressive disorder could save lives. Extensive preclinical and clinical data demonstrate such an action of ketamine. However, the presumptive mechanism of action, inhibition of NMDA (N‐methyl‐D‐aspartate) receptors, has recently been challenged. Elucidation of the mechanism is important clinically for drug discovery and for understanding the (patho)physiology of depression. Comment: The best‐known pharmacologic property of ketamine is non‐competitive inhibition of the NMDA subtype of glutamate receptor. Although other mechanisms have been postulated, this action has been assumed the major one that accounts for ketamine's antidepressant effect. However, a ketamine metabolite and a different mechanism have now been claimed to be necessary and sufficient for the effect. What is new and conclusion: A metabolite has been proposed to be responsible for the antidepressant action of ketamine, via activation of non‐NMDA receptors. It will be important to determine which of the competing views is correct. [ABSTRACT FROM AUTHOR]

What is known and objective Beginning in the 1950s, a family of potent opioids was synthesized and developed (fentanyl and analogues). They continue to serve as valuable analgesic agents. But the recent spike and notoriety of their abuse has raised alarm, even calls for tighter control. We review the trajectory of these compounds. Comment To rectify shortcomings of the then available opioid analgesics, an analogue family of compounds was synthesized having a piperidine ring (presumptive principal active moiety in morphine and meperidine). The result was more potent and rapid-acting compounds, including alfentanil, carfentanil, fentanyl, sufentanil and others. These properties, plus availability in formulations for multiple routes of administration, impart broad therapeutic utility. They also unfortunately favour abuse. What is new and conclusion The abuse of fentanyl and its analogues (legal and illicit) serves as a case study for the dilemma and difficulties balancing a medical need against psychosocial realities. The fentanyl family provides relief for severe pain, but their very properties also engender abuse. [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 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: 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]

Reports on a second, a non-genomic, mechanism of action of steroids, and its possible opportunity for novel pharmacotherapy. Specific membrane-bound receptors coupled to second messenger transduction pathways; Consideration of the possibility that selective targeting of either the genomic or the non-genomic sites of steroid action could provide novel drugs possessing unique pharmacotherapeutic profiles; Traditional, or genomic, mechanism of action of steroids.

Summary What is known and Objective: Flupirtine is a widely known analgesic drug that is approved for the treatment of acute and chronic pain, particularly musculoskeletal pain. However, it is neither an NSAID nor an opioid. Given pending trials of flupirtine for the treatment of fibromyalgia pain, an understanding of flupirtine's (unique?) mechanism of analgesic action is of both clinical and basic science interest. Our objective was to trace the evolution of the understanding of flupirtine's mechanism of analgesic action to its current status. Methods: Information was gathered from various bibliographic sources, such as PubMed and others, and integrated for insight into postulated mechanism(s) of analgesic action of flupirtine. Results and Discussion: The major site of action of flupirtine appears to be the central nervous system (both spinal and supraspinal). Initial studies suggested involvement of descending adrenergic pathways, followed by a postulated (indirect) action at N-Methyl-D-aspartate (NMDA) receptors, to the present view of activation of a G-protein regulated inwardly rectifying K+ (GIRK) ion channel. The mechanism and relative contribution of metabolites (such as the active acetylated moiety) has not been fully defined. What is new and Conclusion: Flurpirtine might represent a novel class of analgesic agent. As such, it could be useful for the treatment of types of pains normally not amenable to conventional (NSAID or opioid) pharmacotherapy. It could also spawn new avenues of analgesic drug discovery efforts. [ABSTRACT FROM AUTHOR]

Chemotherapeutic drugs for cancer treatment are, of necessity, cytotoxic. Unintended damage to normal central nervous system neuronal structure or function might lead to deleterious adverse effects on cognitive function, a mild form of which is reported by some cancer survivors. Understanding the physiologic connection between cancer chemotherapy and the reported cognitive dysfunction, could help inform choice of drugs, treatment regimens and new drug development. Our objective is to comment on a proposed mechanism for 'chemo-fog'. An increasing number of patients are surviving cancer and are generating a new and rapidly growing category within the healthcare system. Some of these cancer survivors are reporting that they are experiencing residual and lingering effects from the cancer, or from its treatment, and that they now need care as survivors. This has given rise to the new field of 'survivor care'. Control of chemo-fog is an important aspect and understanding its mechanism, the basis for more rationale therapy. Such insight would also help direct drug-discovery efforts. New evidence suggests that 'chemo-fog' may be due to excessive cytokine release by the cytotoxic agents. Control of the elevated levels of the blood-brain-barrier-permeable pro-inflammatory cytokines, may help minimize this adverse effect. [ABSTRACT FROM AUTHOR]