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.

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.

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.

'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.

A modern analgesics pain 'pyramid'.

WHAT IS KNOWN AND OBJECTIVE: In an effort to provide guidance for the use of analgesics for pain management--while at the same time acknowledging the professional, patient and regulatory-legal concerns about the use of strong opioids--the World Health Organization (WHO) in 1986 suggested a conservative stepwise approach. In addition to the use of non-pharmacologic measures, the WHO recommended that pharmacotherapy be initiated using a non-opioid analgesic first and then progress through 'weak' opioids or analgesic combinations to 'strong' opioids if, and only if, needed. This approach gave a rationale, and a justification if necessary, for the use of opioids. This stepwise approach became widely known as the WHO analgesic 'ladder'. COMMENT: Since the initial WHO guidance, there have been significant changes in the understanding of pain. It is increasingly considered a physiological process that merits and deserves independent treatment. In addition, more analgesic options are available now than in 1986. WHAT IS NEW AND CONCLUSION: Because of the evolving understanding of the physiology of pain and better approaches to its management, we suggest that more modern best practice is an analgesic 'pyramid'.

Multi-mechanistic analgesia for opioid-induced hyperalgesia.

WHAT IS KNOWN AND OBJECTIVE: The phenomenon of opioid-induced hyperalgesia (OIH), an increased sensitivity to pain attributed to the very opioid drugs administered to manage the pain, is well established in animal models, and there is concern that it also occurs in patients. Our objective is to briefly summarize the basic science and clinical evidence about OIH as background to consider the possible benefit of using a multi-mechanistic analgesic approach. COMMENT: It is unclear how OIH occurs, or even why; presumably, it is part of an adaptive response. But development of OIH poses a serious treatment dilemma. OIH differs from tolerance, which also presents as reduced analgesic effect, in that tolerance is addressed by judicious and monitored increase in opioid dose, but OIH would be treated by a decrease in opioid dose. Therefore, it is important to avoid induction of OIH. Currently, it is not clear which patients are at greater risk of developing OIH, or which drugs are at greater risk of producing it. WHAT IS NEW AND CONCLUSION: We suggest that multi-mechanistic analgesia, accomplished within either a single drug or a combination of drugs, is a logical approach that might result in a reduced development of OIH.

The evolving understanding of the analgesic mechanism of action of flupirtine.

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.

Deciphering the mechanism(s) of action of natural products: analgesic peroxide oil as example.

BACKGROUND: There are multiple reports of natural products having therapeutic effect. In an era of evidence-based medicine, clinical trials inform clinical decisions regarding use of the product, but prevailing preference is to identify and use a single 'active ingredient'. Yet, the clinical benefit of a natural product might derive from the fortuitous combination of its multiple components. Therefore, the elucidation of the mechanism(s) of action of natural products is important, but presents significant challenges. This article examines this issue using peroxide oil (essential oxygen oil) as an illustrative example. OBJECTIVE: To review the published literature of a natural product in an effort to elucidate postulated mechanism(s) of action of a complex mixture. METHODS: The clinical and preclinical literature was reviewed from the perspective of its contribution to elucidating a mechanism of analgesic action of a natural product. RESULTS: Peroxide oil contains ingredients that are associated with analgesic mechanisms, such inhibition of lipid peroxidation and arachidonic acid metabolism and non-opioid, glibenclamide-sensitive receptor-mediated and K(ATP) -NO-cGMP channel pathways. CONCLUSION: Although its exact mechanism remains unknown, peroxide oil provides an example of how a natural product can be evaluated for plausible mechanistic explanation of its purported therapeutic efficacy. Such an approach seems valuable, since, as in this case, the constituents appear to contribute in an additive or synergistic manner, something not possible with a single substance.

Oxycodone combinations for pain relief.

No single analgesic drug provides the perfect therapeutic/adverse effect profile for every pain condition. In addition to convenience and possibly improved compliance, a combination of analgesic drugs offers the potential, requiring verification, of providing greater pain relief and/or reduced adverse effects than the constituent drugs when used individually. We review here analgesic combinations containing oxycodone. We found surprisingly little preclinical information about the analgesic or adverse effect profiles of the combinations (with acetaminophen, paracetamol, nonsteroidal anti-inflammatory drugs, morphine, gabapentin or pregabalin). Clinical experience and studies suggest that the combinations are safe and effective and may offer certain advantages. As with all combinations, the profile of adverse effects must also be determined in order to provide the clinician with the overall benefit/risk assessment.

Cryosurgery for unresectable primary hepatocellular carcinoma: a case report and review of literature.

Primary liver cancers are a significant cause of both morbidity and mortality. Although surgical resection remains the treatment of choice for these tumors, only 10 to 20 per cent of the primary liver tumors are found to be resectable. Presently, the options for these patients include liver transplantation, cryosurgery, or nonsurgical therapy, such as transarterial chemoembolization. Techniques such as alcohol injection, interstitial radiotherapy, laser hypothermia, and radiofrequency electrodissection have all been attempted with limited success. We present a case of a 68-year-old woman with a 10-year history of liver cirrhosis secondary to chronic active hepatitis C. A lateral segmentectomy was recommended but could not be done due to severe underlying cirrhosis. Cryosurgery aided by intraoperative ultrasonography was performed successfully. The patient developed recurrent disease at 58 months and died with disease at 62 months. Advances in instrumentation and intraoperative ultrasonography are making cryosurgery a viable surgical therapeutic alternative in the management of patients with unresectable hepatocellular carcinoma. The procedure can be performed safely with low morbidity.