Non-Opioid Analgesics

Non-Opioid Analgesics

June 5, 2024

By tracing the history of Analgesics, we can illustrate their use in the world today. From ancient remedies, to the rise of opioids and non-opioid options, tracking the history of pain relievers shows the progress of modern medical science, and how it is not always linear. This series will is a brief history of Analgesics, starting with pain relievers prior to the synthesis of morphine in the early 19th century, up to the present day. This article will focus on non-opioid analgesics.

The very term “non-opioid analgesic” is instrumental in understanding the presence opioids have in the current pain management landscape. For most of history, pain relief medications did not contain opioids. Yet from the synthesis of morphine in the early 19th century to the present day, opioids have had such a considerable stronghold in the medical world that ‘non-opioid analgesic’ must be used to describe the large selection of pain medications that do not have an opioid base. While opioids have their drawbacks (as discussed in this series’ previous article), their track record in alleviating pain is well documented and has earned them this prominence. However, this is not to say that non-opioid analgesics (NOAs) are ineffective or useful only for minor levels of pain. NOAs have been shown to be very effective in dealing with pain of varying causes and severity, and the promise new NOAs have shown in clinical trials brings optimism that opioids may not always need to be the last, best resort for pain. Here, we will discuss the recent history of NOAs, and how they are being developed in the present day.

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In this series we have briefly touched on the analgesic properties of the willow tree, and how from the salicin found in its bark, scientists were able to synthetize acetylsalicylic acid, better known as aspirin. What was not mentioned was how groundbreaking aspirin was as an analgesic. Since its introduction in the late 1890s, aspirin has been one of the most widely used drugs in the world.[1] Today, it is still a popular choice for common aches and pains, and inflammatory conditions like arthritis. In addition to this, aspirin has displayed efficacy in treating non-pain conditions. Its cardiovascular benefits are well documented in lessening the severity and occurrence of heart attacks and strokes. Simply put, aspirin is one of the most important medications – analgesic or otherwise – ever introduced, and its success paved the way for future NOAs.


Acetaminophen, also known as Paracetamol, was first synthesized in the 19th century, but was not sold commercially until the 1950s. An alternative not just to opioids but to other early-modern NOAs like aspirin, acetaminophen became a pivotal player in the realm of non-opioid analgesics. Seen as a safer alternative to aspirin (which was known to exacerbate ulcers and other gastrointestinal conditions),[2] acetaminophen quickly became one of the most popular over-the-counter medications ever sold, and is still an excellent option when dealing with mild to moderate pain.

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Following the worldwide popularity of aspirin and acetaminophen, the mid-20th century saw an explosion in the development of NOAs, with non-steroidal anti-inflammatory drugs (NSAIDs) being one of the innovate drug classes introduced during this time period. Ibuprofen, the most popular NSAID in terms of worldwide usage, was first discovered in 1961 by Stewart Adams.[3] With its potent anti-inflammatory and analgesic properties, ibuprofen proved very successful as a treatment for common aches and pains, and its prominence led to future NSAIDs such as naproxen and indomethacin.

Tetrodotoxin: the next step

Now, two decades into the 21st century, NOAs are potentially being revolutionized once more. For decades, a drawback of NOAs were that they were primarily used to treat mild to moderate pain. They were safer than opioids, but also less effective in managing severe pain, allowing for their over-the-counter sale but limiting their viability as genuine opioid alternatives. Today, there are clinical trials being conducted for newer, more potent NOAs that may be able to solve this problem, such as Tetrodotoxin (TTX). As we have covered before, TTX has shown genuine progress in treating a variety of serious pain conditions, and this viability gives hope to the idea that NOAs may not be relegated to minor pain treatment for much longer.

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The modern era of NOAs reflects the pressing need medical science has for opioid alternatives. As incidence of opioid dependence and overdoses grows, having medications that can treat pain without the inherent side effects of opioids is a top priority. On a larger scale, tracking the history of analgesics in general, from ancient remedies to cutting-edge NOAs, allows for an understanding of how imperfect pain treatments have been. Early treatments lacked the medical science needed to ensure they were administered in safe doses. Modern pain treatments have had to deal with the issue of trade-offs: choosing between the more effective but less safe route of opioids, or the reduced potency and better safety profile of NOAs. As of now, the ‘perfect’ analgesic has proven elusive, but improvements and innovations inspire hope that pain will be treated in increasingly more safe and efficient ways. Pain treatment has come very far since ancient times, and there are still new and promising avenues to explore.


[1] Montinari, M. R., Minelli, S., & De Caterina, R. (2019). The first 3500 years of aspirin history from its roots – a concise summary. Vascular Pharmacology, 113, 1–8.

[2] Ayoub, S. S. (2021). Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action. Temperature, 8(4), 351–371.

[3] Rainsford, K. D. (2012). Ibuprofen: From invention to an OTC therapeutic mainstay. International Journal of Clinical Practice, 67, 9–20.



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