The Past, Present, and Future of Painkillers

Image Citation: [1]

Written by Lisa Yan ‘28

Edited by Matthew Lam ‘27

A headache, a sore back, a pulled muscle, whatever the reason, chances are you've reached for a painkiller this month. Maybe even this week. From bathroom cabinets to hospital shelves, these tiny pills are everywhere, offering fast relief with little thought. But behind each dose lies centuries of science and crisis. Painkillers have transformed medicine, reshaped our relationship with suffering, and continue to raise questions about how we treat pain.

Humans have sought ways to ease pain for thousands of years. Ancient civilizations used natural remedies like willow bark, an early form of aspirin, and opium from poppies, long before their active compounds were identified. These early treatments have created the foundation for modern pain medicine [2].

The first authentic records of opium, the dried latex or milk extracted from the opium poppy, date back to the 3rd century BCE Greece [3]. From there, opium followed trade across Persia, India, China, and Europe, incorporating itself in culture and commerce [4]. In the 1800s, the isolation of morphine, the active compound in opium that decreases pain, and the invention of the hypodermic syringe accelerated the unregulated use of opioids, but also in wartime and surgical medicine. Derived from morphine, heroin was created and marketed as a “safer” alternative, yet it still proves itself more addictive and potent [5].

As opiate addiction steadily spread, it has also sparked some of the most significant conflicts in history. While addiction thrived in China, the government's crackdown on British opium imports erupted into the First Opium War between Great Britain and China in 1839, followed by a second devastating loss, leaving lasting wounds on the Chinese territory and economy [6].

On the other hand, the United States has been fighting an internal opioid epidemic. Beginning in the 1990s, the overprescription of opioids triggered the start of the overwhelming number of overdose deaths in the U.S. The increased illegal use of heroin in 2010 set off another wave of deaths, and since 2013, synthetic opioids have been responsible for an overwhelming portion of overdoses. These drugs are manufactured domestically and smuggled in from abroad, and often contain potent fentanyl and its analogs. Although efforts are being made to combat the crisis, from law enforcement arrests to public health campaigns, the battle remains ongoing [7].

Although opiates have been dominant in their historical effects, non-habit-forming analgesics also appeared in ancient medicine. The folk remedy of willow bark inspired the extraction of salicin, which led to the synthesis of salicylic acid, and ultimately, the development of aspirin in 1897 [8]. This nonsteroidal anti-inflammatory drug (NSAID) quickly became one of the world’s most-used pain relievers. In contrast, the development of acetaminophen began in the late 19th century, but its effects were not fully appreciated until the 1950s. Soon, acetaminophen also rose to popularity as an over-the-counter pain reliever, especially as aspirin’s side effects became more apparent [9]. With their historical impact established, we can now explore the scientific mechanisms that make these drugs so powerful.

Opioids, such as morphine, oxycodone, and fentanyl, are used for severe or persistent pain. These drugs bind to opioid receptors, which are part of the G-protein-coupled receptor (GPCR) family. Located in the brain and spinal cord, these opioid receptors inhibit the transmission of pain signals when activated. They alter the flow of ions across neuron membranes and decrease nerve activity. This not only relieves pain but also produces feelings of relaxation and euphoria [10].

NSAIDS, including aspirin and ibuprofen, are commonly used for mild to moderate pain. They relieve pain by targeting cyclooxygenases (COX-1 and COX-2), which are enzymes that produce prostaglandins [11]. Prostaglandins are chemical messengers that play a role in inflammation and pain signaling. NSAIDs lower prostaglandin levels at the site of inflammation by inhibiting the COX enzymes, ultimately suppressing pain. However, prostaglandins also have functions in protecting the stomach lining and regulating kidney function. As a result, the overuse of NSAIDs can have gastrointestinal side effects, such as irritation, ulcers, and kidney complications [12].

Acetaminophen, also known as paracetamol, is also used to treat less severe pain. However, its precise molecular mechanisms are unknown. It is thought to inhibit a different version of the COX enzyme as well, but some evidence also suggests that it may affect other pathways instead of COX. AM404 is a metabolite of paracetamol and is believed to activate the cannabinoid receptors in brain regions involved in pain perception [13]. It also enhances the descending serotonergic pathways, which contribute to the suppression of pain. Despite its common use, the acetaminophen abuse can lead to severe liver damage [9].

While traditional painkillers remain essential, the search for safer alternatives has led to promising advancements. In early 2025, the FDA approved suzetrigine, or Journax, a novel non-opioid that can treat moderate to severe pain. Unlike opioids, which bind to pain receptors and trigger dopamine release in the brain’s reward system, suzetrigine acts in the peripheral nervous system. It interrupts pain signals before they reach the brain through Nav1.8 sodium channels. Since suzetrigine avoids the brain’s reward pathways, it does not trigger the euphoric effects that come with opioid use. Although it is currently only approved for short-term use in adults, suzetrigine represents a step towards safer and non-addictive pain relief [14].

Painkillers have come a long way, from ancient medicine to novel therapies. They have both relieved and caused suffering, shaping history and continuing to influence the world. As science continues to explore the biology of pain, the challenge is to not only develop effective treatments but also to prevent harmful consequences. The future of pain relief is balancing innovation with responsibility, ensuring that relief does not come at the cost of addiction and harm.

References

1. Stubler R. Mark Cuban is making medication costs an easier pill to swallow [Internet]. Musc.edu. 2024 [cited 2025 Apr 24]. Available from: https://gradstudies.musc.edu/about/blog/2024/09/easier-pill-to-swallow

2. Meldrum ML. A Capsule History of Pain Management. JAMA [Internet]. 2003 Nov 12 [cited 2025 Apr 24];290(18):2470. Available from: https://mcc-klik.nl/system/ckeditor_assets/attachments/455/Capsule_history_pain_management_JAMA_2003.pdf

3. Vadhel A, Bashir S, Mir AH, Girdhar M, Kumar D, Kumar A, et al. Opium alkaloids, biosynthesis, pharmacology and association with cancer occurrence. Open Biology [Internet]. 2023 May 3 [cited 2025 Apr 24];13(5):220355. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10154933/#:~:text=Opium%20alkaloids%20can%20be%20classified

4. Brownstein MJ. A brief history of opiates, opioid peptides, and opioid receptors. Proceedings of the National Academy of Sciences [Internet]. 1993 Jun 15 [cited 2025 Apr 24];90(12):5391–3. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC46725/pdf/pnas01469-0022.pdf

5. Paladini A, Jose Barrientos Penaloza, Ricardo Plancarte Sánchez, Tolga Ergönenç, Giustino Varrassi. Bridging Old and New in Pain Medicine: An Historical Review. Cureus. 2023 Aug 17;15(8).

6. Pletcher K. Opium Wars. In: Encyclopedia Britannica [Internet]. 2018 [cited 2025 Apr 24]. Available from: https://www.britannica.com/topic/Opium-Wars

7. CDC. Understanding the opioid overdose epidemic [Internet]. Overdose Prevention. 2024 [cited 2025 Apr 24]. Available from: https://www.cdc.gov/overdose-prevention/about/understanding-the-opioid-overdose-epidemic.html

8. Ayoub SS. Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action. Temperature. 2021 Mar 16;8(4):351–71.

9. Brune K, Renner B, Tiegs G. Acetaminophen/paracetamol: A history of errors, failures and false decisions. European Journal of Pain. 2014 Nov 27;19(7):953–65.

10. Al-Hasani R, Bruchas MR. Molecular Mechanisms of Opioid Receptor-dependent Signaling and Behavior. Anesthesiology. 2011 Oct;115(6):1.

11. Ozleyen A, Yilmaz YB, Donmez S, Atalay HN, Antika G, Tumer TB. Looking at NSAIDs from a historical perspective and their current status in drug repurposing for cancer treatment and prevention. Journal of Cancer Research and Clinical Oncology. 2022 Jul 25;149.

12. Montinari MR, Minelli S, De Caterina R. The first 3500 years of aspirin history from its roots – A concise summary. Vascular Pharmacology [Internet]. 2019 Feb [cited 2025 Apr 24];113(113):1–8. Available from: https://pubmed.ncbi.nlm.nih.gov/30391545/

13. Mallet C, Desmeules J, Pegahi R, Eschalier A. An updated review on the metabolite (AM404)-mediated central mechanism of action of paracetamol (acetaminophen): Experimental evidence and potential clinical impact. Journal of Pain Research [Internet]. 2023 Mar [cited 2025 Apr 24];Volume 16:1081–94. Available from: https://www.dovepress.com/an-updated-review-on-the-metabolite-am404-mediated-central-mechanism-o-peer-reviewed-fulltext-article-JPR

14. MacMillan C. FDA Approves  Non-Opioid Pain Medication Suzetrigine (JournavxTM) [Internet]. Yale Medicine. 2025 [cited 2025 Apr 24]. Available from: https://www.yalemedicine.org/news/new-non-opioid-pain-pill

15. Rao P, Knaus EE. Evolution of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Cyclooxygenase (COX) Inhibition and Beyond. Journal of Pharmacy & Pharmaceutical Sciences [Internet]. 2008 Sep 20 [cited 2025 Apr 24];11(2):81. Available from: https://pubmed.ncbi.nlm.nih.gov/19203472/