Galcanezumab: a humanized monoclonal antibody for the prevention of migraine and cluster headache.

Migraine is a common, painful and highly disabling neurological condition that has plagued mankind for millennia, but its pathophysiology remained largely obscure until recently. The clinical success of triptans for treating migraine and the discovery that calcitonin gene-related peptide (CGRP) plays a prominent role in migraine led to increased research interest into this disease. An important improvement has been the development of monoclonal antibodies, including galcanezumab, that bind to CGRP or to its receptor, preventing its activation. Subsequent clinical trials have reported that galcanezumab is safe and well tolerated, and is effective in reducing the frequency of migraine attacks in patients with episodic or chronic migraine. At the same time, increased study of the pathophysiology of cluster headache, a relatively rare condition with excruciatingly painful headache attacks (i.e., "suicide headaches"), led to the discovery that, as in migraine, CGRP plays an important role in its pathology. Clinical trials suggest that galcanezumab is safe and effective for the prevention of episodic cluster headache, and it is under study for chronic cluster headache. Galcanezumab is approved for the prevention of migraine in the U.S., the European Union, Canada and Mexico, and was also approved for the treatment of episodic cluster headache in the U.S.

Indirect-acting strategy of opioid action instead of direct receptor activation: dual-acting enkephalinase inhibitors (DENKIs).

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.

Curcumin in turmeric: Basic and clinical evidence for a potential role in analgesia.

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.

Nature's first "atypical opioids": Kratom and mitragynines.

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."

The role and mechanism of action of menthol in topical analgesic products.

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.

The rapid-onset antidepressant effect of ketamine: More surprises?

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.

The fentanyl family: A distinguished medical history tainted by abuse.

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.

The "Darknet": The new street for street drugs.

WHAT IS KNOWN AND OBJECTIVE: The "Darknet" ("dark web") has emerged as a means by which illegal drug buys and deliveries can be arranged with apparent anonymity and impunity. Healthcare providers should be aware of this growing source of illicit drugs. COMMENT: The "Darknet" refers to networks isolated from the Internet that cannot be accessed via conventional search engines. They require special software that is protected by special encryption. The initial legitimate use of a "Darknet" to conceal personal information against misuse or political reprisal is being exploited to conceal the identity of buyers and sellers in illegal drug transactions. Instructions on how to obtain access to the "Darknet" are readily available on conventional Internet web pages. WHAT IS NEW AND CONCLUSION: The "Darknet" has changed the paradigm of illegal drug importation and distribution by providing a difficult-to-trace transaction, and delivery via legitimate couriers directly to the home.

What is the mechanism of Ketamine's rapid-onset antidepressant effect? A concise overview of the surprisingly large number of possibilities.

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.

Cebranopadol: novel dual opioid/NOP receptor agonist analgesic.

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.

The Centers for Disease Control and Prevention opioid guidelines: potential for unintended consequences and will they be abused?

WHAT IS KNOWN AND OBJECTIVE: The Centers for Disease Control and Prevention (CDC) have published guidelines for opioid prescribing, with the goal of helping guide clinicians to make safe prescribing choices. In the form of 12 statements, the CDC offers guidance that at times is not supported by the evidence or introduces new concepts (such as a requirement that opioids improve function). Our objective was to examine the new guidelines in terms of how well they could strike the balance between keeping opioids accessible to those who need them while appropriately restricting their use. WHAT IS NEW AND CONCLUSION: The CDC guidelines offer some reasonable and laudable guidance, but they also make some recommendations which are not supported by current scientific evidence. We also noted that the urgent need for greater education among opioid prescribers was not addressed in the new guidelines.

Will peripherally restricted kappa-opioid receptor agonists (pKORAs) relieve pain with less opioid adverse effects and abuse potential?

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.

Postoperative Pain Surveys in Italy from 2006 and 2012: (POPSI and POPSI-2).

OBJECTIVE: Despite established standards, effective treatments, and evidence-based guidelines, postoperative pain control in Italy and other parts of the world remains suboptimal. Pain control has been recognized as a fundamental human right. Effective treatments exist to control postsurgical pain. Inadequate postoperative analgesia may prolong the length of hospital stays and may adversely impact outcomes. MATERIALS AND METHODS: The same multiple-choice survey administered at the SIAARTI National Congress in Perugia in 2006 (n=588) was given at the SIAARTI National Congress in Naples, Italy in 2012 (n=635). The 2012 survey was analysed and compared to the 2006 results. RESULTS: Postoperative pain control in Italy was less than optimal in 2006 and showed no substantial improvements in 2012. Geographical distinctions were evident with certain parts of Italy offering better postoperative pain control than other. Fewer than half of hospitals represented had an active Acute Pain Service (APS) and only about 10% of postsurgical patients were managed according to evidence-based guidelines. For example, elastomeric pumps for continuous IV infusion are commonly used in Italy, although patient-controlled analgesia systems are recommended in the guidelines. The biggest obstacles to optimal postoperative pain control reported by respondents could be categorized as organizational, cultural, and economic. CONCLUSIONS: There is considerable room for improvement in postoperative pain control in Italy, specifically in the areas of clinical education, evidence-based treatments, better equipment, and implementation of active APS departments in more hospitals. Two surveys taken six years apart in Italy reveal, with striking similarity, that there are many unmet needs in postoperative pain control and that Italy still falls below European standards for postoperative pain control.

The role of abuse-deterrent formulations in countering opioid misuse and abuse.

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.

Management of opioid-induced constipation in pregnancy: a concise review with emphasis on the PAMORAs.

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.

Delta opioid agonists: a concise update on potential therapeutic applications.

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 www.clinicaltrials.com. 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.

Rapid-onset antidepressant action of ketamine: potential revolution in understanding and future pharmacologic treatment of depression.

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.

'Selective' COX-1 or COX-2 NSAIDs: time to change a misleading measure.

The ongoing important debate about the relative benefits/risks of COX-1 or COX-2 NSAIDs is hampered by the use of a measure of 'selectivity' that is inherently flawed. An alternative measure provides more meaningful and clinically relevant information.

The clinical analgesic efficacy of buprenorphine.

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.

Lack of synergistic interaction between the two mechanisms of action of tapentadol in gastrointestinal transit.

BACKGROUND: A multi-mechanistic approach offers potential enhancement of analgesic efficacy, but therapeutic gain could be offset by an increase in adverse events. The centrally acting analgesic tapentadol [(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines µ-opioid receptor (MOR) agonism and neuronal noradrenaline reuptake inhibition (NRI), both of which contribute to its analgesic effects. Previously, isobolographic analysis of occupation-effect data and a theoretically equivalent methodology determining interactions from the effect scale demonstrated pronounced synergistic interaction between the two mechanisms of action of tapentadol in two models of antinociception (low-intensity tail-flick and spinal nerve ligation). The present study investigated the nature of interaction of the two mechanisms on a surrogate measure for gastrointestinal adverse effect (inhibition of gastrointestinal transit). METHODS: Dose-response curves were generated in rats for tapentadol alone or in combination with the opioid receptor antagonist, naloxone, or the α2 -adrenoceptor antagonist, yohimbine, to reveal the effect of tapentadol based upon MOR agonism, NRI, and combined mechanisms. RESULTS: The dose-effect curve of tapentadol was shifted to the right by both antagonists, thereby providing data to distinguish between MOR agonism and NRI. Analysis revealed a simple additive interaction between the two mechanisms on this endpoint, in contrast to the synergistic interaction previously demonstrated for antinociception. CONCLUSIONS: We believe this is the first published evaluation of mechanistic interaction for a surrogate measure of adverse effect of a single compound with two mechanisms of action, and the results suggest that there is a greater separation between the analgesic and gastrointestinal effects of tapentadol than expected based upon its analgesic efficacy.