When Were Painkillers Invented? A Brief History

Painkillers were not invented at a single moment. The earliest recorded use of pain-relieving substances dates back more than 3,500 years, when ancient peoples chewed willow bark to ease aches and fevers, and cultivated the opium poppy for its sedating resin. What we think of as modern painkillers, though, are largely products of the 19th and 20th centuries, when chemists learned to isolate, purify, and eventually synthesize the active compounds hidden in those ancient plants. The story between those two endpoints is a surprisingly winding one, full of false starts and accidental discoveries.

Willow Bark, Opium, and the Ancient Roots of Pain Relief

The two oldest threads in the painkiller story both begin in the ancient world and run independently for thousands of years before converging in modern pharmacology. The first is willow bark. More than 3,500 years ago, people in parts of the ancient Near East and Mediterranean chewed or brewed willow bark to relieve pain and reduce fever. The bark contains salicin, a compound the body converts into salicylic acid, the chemical ancestor of aspirin.¹ Ancient Egyptian medical texts reference willow, and similar remedies appear in Greek and Roman writings. Nobody at the time understood why it worked. They just knew it did.

The second thread is the opium poppy. A Sumerian clay tablet dating to roughly 2100 BC is considered one of the oldest recorded lists of medical prescriptions, and some scholars believe it includes references to the opium poppy.² Juglets that appear to mimic the shape of poppy capsules have been found in both Cyprus and Egypt from the same era. Opium’s pain-dulling and sleep-inducing properties made it a fixture of medicine across civilizations for millennia. Ancient Greek physicians prescribed it freely, and it traveled the trade routes to become one of the most widely used drugs in the medieval Islamic world and eventually in Europe.

Medieval Remedies and Surgical Sponges

Between antiquity and the scientific revolution, pain management did not stand still, but it did not leap forward either. Medieval practitioners relied on a patchwork of herbal preparations, with one particularly creative approach standing out. Physicians from the Middle Ages through the late medieval period used sponges soaked in the juice of the mandrake root as a kind of primitive anesthetic before surgical procedures.³ Figures like Theodoric of Cervia and others documented their experiments with these “soporific sponges,” which were held under a patient’s nose to induce unconsciousness. Mandrake contains tropane alkaloids that genuinely do have sedative and deliriant properties, though at unpredictable and often dangerous doses. The sponges were the closest thing to general anesthesia that existed for centuries, but they were unreliable, and many surgeons simply relied on speed, restraint, and alcohol instead.

The 19th Century Changes Everything

The 1800s were the century when pain relief went from folk tradition to science, and two breakthroughs in particular deserve attention. The first was the isolation of morphine. In 1805, a young German pharmacist named Friedrich Sertürner reported that he had extracted a pure substance from opium that had powerful pain-relieving and sleep-inducing effects.⁴ He eventually named it “morphine” after the Greek god of dreams. This was the first time anyone had isolated a single active chemical from a plant drug, making it a landmark not just for pain medicine but for the entire field of pharmacology.⁵

Morphine was a revelation, but it had a practical bottleneck: it was hard to dose precisely when given by mouth. Its widespread clinical use had to wait nearly fifty years for the development of the hypodermic needle and syringe, which allowed doctors to inject measured amounts directly into patients.⁶ Once injectable morphine became available in the 1850s, it rapidly became the standard treatment for severe pain, especially on the battlefield. The American Civil War and the Franco-Prussian War saw it used in enormous quantities, which also revealed its major downside: addiction. Morphine dependence became so common among veterans that it was sometimes called “the soldier’s disease.”

The second great transformation of the century was the arrival of true anesthesia. On October 16, 1846, a dentist named William T.G. Morton publicly demonstrated ether anesthesia at Massachusetts General Hospital, an event now celebrated as “Ether Day.”⁷ Before that day, surgery without any effective pain control was the norm. Patients were held down, plied with whiskey, or simply expected to endure. Ether anesthesia turned surgery from an agonizing ordeal into something patients could survive without conscious suffering, and it opened the door to longer, more complex procedures that would have been unthinkable before.

Aspirin and the Dawn of Over-the-Counter Pain Relief

While morphine was transforming hospital medicine, chemists were independently working on the willow-bark problem. Salicylic acid had been identified and synthesized, but it was harsh on the stomach and unpleasant to take. In 1897, Bayer chemist Felix Hoffmann synthesized acetylsalicylic acid, a modified form that was gentler on the digestive tract while keeping the pain-relieving and fever-reducing properties.⁸ Bayer began marketing it under the brand name Aspirin in 1899, and it quickly became the world’s most popular painkiller, a status it held for decades.

Aspirin was revolutionary for a simple reason: it was the first effective painkiller that ordinary people could safely take at home for everyday aches, headaches, and fevers. It did not cause the sedation or addiction of opiates. It was cheap to produce and easy to distribute. For the first half of the 20th century, aspirin was essentially the only game in town for mild to moderate pain relief. Willow bark’s ancient promise, refined through centuries of chemistry, had finally become a mass-market product.

Cocaine, Local Anesthetics, and Numbing the Body Without Sedating the Mind

A parallel track in pain control focused not on dulling pain in the brain but on blocking it at the source, in the nerves themselves. The first local anesthetic was cocaine. Its nerve-numbing properties were discovered in the 1880s and quickly applied in dentistry and eye surgery. The problem was that cocaine is dangerously toxic and highly addictive, and deaths among both patients and medical staff mounted quickly.⁹

Chemists spent the next several decades trying to replicate cocaine’s numbing ability without its toxicity. Advances in organic chemistry led to the synthesis of pure cocaine in 1891 and then a cascade of synthetic alternatives. Between 1891 and 1930, a series of amino ester local anesthetics appeared, including benzocaine and tetracaine. From 1898 through the 1970s, a second chemical family, the amino amides, produced procaine, lidocaine, bupivacaine, and others. Each successive generation was meant to be less toxic than the last, though all carried some risk of side effects affecting the heart and nervous system. Lidocaine, introduced in the 1940s, eventually became the most widely used local anesthetic in the world and remains so today.

The Mid-Century Painkiller Boom

The mid-20th century brought a wave of new analgesics that filled specific gaps in the painkiller toolkit. Acetaminophen (sold as Tylenol in the United States and paracetamol elsewhere) had actually been synthesized in the late 19th century, but it took decades for it to gain widespread clinical use. It is now one of the most consumed drugs on the planet, yet its exact mechanism of action remains surprisingly unclear even after more than a century. The leading theory involves inhibiting certain enzyme activities in the central nervous system, but researchers still debate the details.¹⁰ A drug used by billions of people, and scientists still cannot fully explain how it works. That is a humbling fact about the state of pain medicine.

Ibuprofen emerged from a focused search for a better arthritis drug. In 1953, a pharmacologist named Stewart Adams at the Boots company in England set out to find a non-steroidal treatment for rheumatoid arthritis. He and chemist John Nicholson patented the compound that would become ibuprofen in 1961.¹¹ Adams was one of the first researchers working in what later became the field of non-steroidal anti-inflammatory drugs, or NSAIDs. Ibuprofen went on to become one of the most successful painkillers in history, available over the counter in most countries.

On the opioid side, chemists were not resting either. Fentanyl, a fully synthetic opioid far more potent than morphine, was introduced more than fifty years ago and became the most frequently used opioid for pain control during surgery.¹² Since the early 1990s, the fentanyl patch has been used for managing chronic pain in cancer and other severe conditions. The drug’s extreme potency, a feature that made it useful in controlled medical settings, is also what makes illicitly manufactured fentanyl so deadly on the street today.

Figuring Out Why the Old Drugs Worked

For most of painkiller history, people used drugs that worked without knowing why they worked. That began to change in the 1970s. In 1971, the British pharmacologist John Vane demonstrated that aspirin and similar drugs work by blocking the production of prostaglandins, chemical messengers that promote inflammation, pain, and fever.¹³ Specifically, aspirin inhibits the cyclooxygenase enzymes (COX) that cells use to make prostaglandins.¹⁴ Vane’s discovery earned him a Nobel Prize and gave scientists the conceptual framework to design better anti-inflammatory painkillers.

Two years later, in 1973, Candace Pert and Solomon Snyder published the clearest evidence that opioid receptors actually exist in the brain and nervous system, showing that drugs like morphine have a specific biological lock they fit into rather than just broadly suppressing the nervous system.¹⁵ Shortly after, researchers discovered the body’s own natural painkillers, the endorphins and enkephalins, which bind to those same receptors. This answered a long-standing puzzle: why would the brain have receptors perfectly shaped for a plant chemical? Because the brain makes its own version of it.

Together, these discoveries in the early 1970s reframed the entire field. Pain was no longer just a subjective experience to be drowned out; it was a biochemical process with identifiable steps that could, in theory, be interrupted with increasing precision.

COX-2 Inhibitors and the Limits of Targeted Design

Vane’s discovery of cyclooxygenase led, about two decades later, to the identification of a second version of the enzyme, called COX-2. Traditional NSAIDs like aspirin and ibuprofen block both COX-1 and COX-2, and the inhibition of COX-1 is what causes their most common side effect: stomach irritation and, in some cases, ulcers and bleeding. The thinking was straightforward: design a drug that blocks only COX-2, and you could relieve pain and inflammation while sparing the stomach.¹³

In 1999, the first selective COX-2 inhibitors, known as coxibs, reached the market. Arthritis patients were eager for a painkiller that eased joint pain with less risk of gastrointestinal problems.¹⁶ Sales were enormous. But within a few years, it became clear that at least some COX-2 inhibitors increased the risk of heart attacks and strokes, and the most prominent one, rofecoxib (Vioxx), was pulled from the market in 2004. The coxib saga was a cautionary tale: even when you understand the mechanism well enough to design a precise drug, the body’s biochemistry is interconnected in ways that produce unexpected consequences.¹⁷ Some COX-2 inhibitors remain available and useful for certain patients, but the dream of a perfectly safe NSAID has not been realized.

Migraine Gets Its Own Class of Painkillers

For most of painkiller history, migraine sufferers had to make do with general-purpose drugs that were not designed with their condition in mind. That changed with the development of therapies targeting a neuropeptide called calcitonin gene-related peptide, or CGRP, which plays a central role in migraine attacks. The first CGRP-receptor antagonist to show effectiveness against migraine in humans was olcegepant, reported in 2004.¹⁸

Since then, the field has expanded rapidly. There are now eight FDA-approved treatments targeting CGRP or its receptor, including both monoclonal antibodies given by injection for prevention and small-molecule drugs taken orally to stop attacks in progress.¹⁹ These drugs represent a genuinely new category: painkillers built from the ground up for a specific pain condition, based on molecular understanding of what goes wrong in that condition. For people with chronic migraine who had cycled through general painkillers without adequate relief, the CGRP drugs have been transformative.²⁰

The Quest for a Non-Addictive Painkiller

The opioid crisis has given renewed urgency to a question that has haunted pain medicine since the 1850s: can you get powerful pain relief without the risk of addiction? One of the most watched research targets in this space is a sodium channel called Nav1.7. In 2006, researchers discovered that people born with a rare genetic mutation that knocks out Nav1.7 are completely unable to feel pain, yet are otherwise healthy, with normal touch, temperature sensation, and cognition.²¹ The implication was tantalizing: block this one channel and you could potentially eliminate pain without any of the sedation, euphoria, or dependency that come with opioids.

In the fifteen-plus years since, pharmaceutical companies have poured resources into developing selective Nav1.7 blockers. The results have been humbling. Drugs that work beautifully in lab dishes have repeatedly failed to produce meaningful pain relief in clinical trials. The channel turns out to be harder to block selectively in a living human body than anyone expected, and pain signaling involves enough redundancy that shutting down one pathway does not always shut down the pain.²² Some researchers now believe that the most promising path forward involves combining Nav1.7 blockers with low-dose opioids or with drugs that boost the body’s own natural painkillers, potentially allowing effective analgesia at opioid doses low enough to avoid addiction.²³

Why Pain Is Still Hard to Treat

Looking at the full sweep of this history, a pattern emerges. Every era has produced a painkiller that seemed like the answer: opium for the ancients, morphine for the 19th century, aspirin for the early 20th, NSAIDs and acetaminophen for the postwar period, COX-2 inhibitors for the turn of the millennium. Each one turned out to have serious limitations, whether addiction, organ damage, cardiovascular risk, or simply not working well enough for certain kinds of pain. The reason is that pain is not one thing. It involves dozens of overlapping pathways, inflammatory signals, nerve fibers, receptors, and brain regions, and a drug that interrupts one pathway often leaves others untouched or creates problems elsewhere in the body.

Chronic pain conditions in particular have stubbornly resisted the one-drug-fixes-it model. Neuropathic pain, fibromyalgia, and complex regional pain syndrome respond poorly to the standard painkiller arsenal, which is why patients with these conditions often end up on combinations of drugs originally developed for completely different purposes, like antidepressants and anticonvulsants that happen to modulate pain-relevant nerve activity. The gap between acute pain, where modern medicine performs reasonably well, and chronic pain, where it often falls short, remains one of medicine’s most frustrating unsolved problems. The CGRP success in migraine offers a template for how condition-specific science might eventually close that gap: identify the molecular culprit in a specific pain syndrome, then build a drug that targets it precisely. Replicating that approach across other chronic pain conditions is the work of the next generation of painkiller research.