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 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.