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Each of the major types of analgesic drugs (eg opioids, NSAIDs, paracetamol and pentanoids) has mechanism-associated adverse effect or abuse potential limitations. Thus, there is interest in discovering new agents that produce pain relief by alternative mechanistic pathways. Natural substances have been a rich source of compounds that possess analgesic properties 1 and have spawned a variety of clinically useful synthetic analgesic drugs. Menthol has been used as a topical pain reliever since ancient times. 2 Perhaps because of that, it is tempting to dismiss either its efficacy or its mechanism of action as trivial. However, recent advances in the (patho)physiology of pain have uncovered new pathways-one of which is responsible for the analgesic action of menthol. It is thus timely and important to review the basic science, clinical efficacy data and safety profile related to the pain-relieving attributes of menthol. SummaryWhat 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. K E Y W O R D Sanalgesic, calcium channel, menthol, non-opioid analgesic, topical analgesic, TRPM8

Pain and inflammatory conditions are very often the main direct or underlying reasons why people seek medical care, and such conditions become even more common with ageing. 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 antiinflammatory 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. K E Y W O R D Sanalgesia, anti-inflammatory, curcumin, non-opioid, traditional medicine, turmeric

SummaryWhat 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 rapidacting 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. K E Y W O R D Sanalgesia, drug abuse, fentanyl, opioid, pharmacologic family

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."

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Among several opioid-associated endocrinopathies, opioid-associated adrenal insufficiency (OIAI) is both common and not well understood by most clinicians, particularly those outside of endocrine specialization. OIAI is secondary to long-term opioid use and differs from primary adrenal insufficiency. Beyond chronic opioid use, risk factors for OIAI are not well known. OIAI can be diagnosed by a variety of tests, such as the morning cortisol test, but cutoff values are not well established and it is estimated that only about 10% of patients with OIAI will ever be properly diagnosed. This may be dangerous, as OIAI can lead to a potentially life-threatening adrenal crisis. OIAI can be treated and for patients who must continue opioid therapy, it can be clinically managed. OIAI resolves with opioid cessation. Better guidance for diagnosis and treatment is urgently needed, particularly in light of the fact that 5% of the United States population has a prescription for chronic opioid therapy.

What is known and objective The sudden and extensive outbreak of coronavirus (SARS‐CoV‐2) has overshadowed another developing viral threat: the Zika flavivirus. Of particular concern is that pregnant women can pass Zika virus to the foetus, and there is a strong implication of an association between Zika virus infection and foetal microcephaly. Currently, there is no vaccine, and there is no cure. Methods Published literature and Internet sources were searched for information related to Zika virus, its transmission, its clinical presentation and sequalae, prevention and implications (practice and regulatory) for healthcare providers. The identified English sources were reviewed, assessed and synthesized. Emphasis was placed on providing an overview of the problem, and identification of unmet needs and future directions. Results and discussion Zika virus poses a major challenge for healthcare providers, particularly in areas unaccustomed to it, since it is transmitted to humans by the vector Aedes aegypti mosquito. The outbreak impacts every healthcare provider, because every provider is required to report cases of Zika infection to their state or local health agencies––whether the infection is confirmed or merely suspected. Since the virus has become a worldwide crisis, healthcare providers will need to work across national boundaries and medical disciplines in order to educate patients about Zika symptoms and the mosquito vector. Until further information is known, infected patients (male and female) are being advised to avoid conceiving a child. What is new and Conclusion Until a vaccine is developed or effective treatment for Zika virus is discovered, healthcare providers must be AVP (aware, vigilant and proactive) in order to lessen the spread and impact of the implicated devastating birth defects (microcephaly) and other neurological disorders (eg Guillain‐Barré Syndrome) of this infection. Unfortunately, many knowledge gaps exist. There is an urgent need for a reliable, inexpensive diagnostic test, an effective treatment and an approved and readily available vaccine.