History of Pain Relief and Aspirin

Opium poppies and opium preparations were known in the ancient Mediterranean and Near East, although the often-repeated claim that Sumerians called the poppy a “joy plant” is not securely supported by the surviving texts. Dioscorides’s De materia medica (c. 70 CE), a standard pharmacological text for centuries, described opium and willow remedies. Willow bark is also often attributed to Hippocrates (c. 400 BCE), but that attribution rests on later tradition rather than a surviving prescription. The wider context of these remedies is covered in ancient Egyptian medicine, the Ebers Papyrus timeline entry, and history of herbal medicine.

The limits of premodern analgesia were practical. Opiates worked powerfully but in unpredictable doses: too little did nothing, too much poisoned, and regular use bred dependence — a risk practitioners recognized even when they could not name it. Willow bark was safer but weaker, and its active principle was unknown. Pain was usually explained through humoral theory, and relief was often sought by restoring balance — bloodletting, purging, cooling — rather than by numbing the sensation itself.

Surgical pain was managed with speed, restraint, alcohol, and opiates until the anaesthetics of the 1840s changed the problem entirely. The history of anaesthesia covers that sequence; analgesics, by contrast, remained medicines people took at home, and their history is bound up with the pharmacy and apothecary trade that sold them.

In 1828 the German pharmacist Johann Andreas Buchner isolated a small quantity of salicin, the bitter principle of willow bark; the French pharmacist Henri Leroux obtained it in crystalline form the following year. In 1853 Charles Frédéric Gerhardt prepared acetylsalicylic acid, and in 1859 Hermann Kolbe developed a practical synthesis of salicylic acid. For the next forty years, salicylic acid and its sodium salt were used clinically, especially for rheumatic fever and arthritis. (Sneader, BMJ, 2000)

Sodium salicylate was effective but unpleasant: gastric irritation, nausea, and tinnitus were common at the doses that worked. The problem for the pharmaceutical laboratories of the 1890s was not to find a new molecule but to make a salicylate that kept the antirheumatic effect and dropped the side effects. That is the question Bayer’s Elberfeld laboratory was working on when acetylsalicylic acid re-entered the picture. (Sneader, BMJ, 2000)

The familiar account — that Hoffmann made the compound to help his rheumatic father — first appeared in 1934, as a footnote in a history of chemical engineering by Albrecht Schmidt, a recently retired Bayer chemist. In 1949, Hoffmann’s former colleague Arthur Eichengrün published a different version: he had directed the salicylate work, pressed for clinical testing, and tested the compound on himself before it reached physicians. Archival analysis published in 2000 supports Eichengrün’s account and throws doubt on the 1934 footnote: the derivative compounds the footnote says Hoffmann examined “long before” were in fact newly prepared for the salicylate programme, and the laboratory records show the work was already under way when Hoffmann wrote his synthesis report. (Sneader, BMJ, 2000)

The pharmacology was done by Heinrich Dreser, head of Bayer’s experimental pharmacology laboratory, who tested acetylsalicylic acid against propionyl, butyryl, valeryl, and benzoyl salicylic acids. The first published clinical report came from Kurt Witthauer of the Deaconess Hospital in Halle in April 1899, in the journal Die Heilkunde. Eichengrün’s account also preserves the anecdote that a dentist’s patient, given the drug for toothache and fever, exclaimed that his toothache was gone — a rapid onset of analgesia that distinguished the acetyl ester from salicylate. That story is retrospective testimony, not a controlled observation, but it matches the drug’s later reputation. (Sneader, BMJ, 2000)

Aspirin was launched for rheumatism and then for headache, toothache, and fever, sold in tablets with dosing instructions, and advertised across Europe and the United States. After the First World War, Bayer’s American assets were seized by the US government, and a US court ruled Aspirin a generic term in 1921. The dispute over who made aspirin is a case study in how corporate records, patents, antisemitism (Eichengrün, a Jewish chemist, was interned at Theresienstadt), and later commemoration shape inventor stories; see who gets credit for medical discovery. (Sneader, BMJ, 2000)

In 1804 the German pharmacist Friedrich Sertürner isolated morphine from opium, the first active principle separated from a plant. Morphine was a genuine therapeutic advance: a reliable, dose-able analgesic for the worst pains of surgery, trauma, and terminal illness. The hypodermic syringe, practical from the 1840s and 1850s, made injection routine, and the American Civil War (1861–1865) produced a generation of soldiers dependent on morphine — “laudism,” as it was then called.

The pharmaceutical industry kept pushing the boundaries. Bayer, the same company that launched aspirin, marketed diacetylmorphine (heroin) from 1898 as a cough remedy and an alternative to morphine; dependence proved a serious risk, and the product was withdrawn from general sale. Coca-Cola contained coca-leaf extract until 1903. Regulation followed: the US Harrison Narcotics Tax Act of 1914 taxed opium and cocaine prescriptions, pushing opiates out of the patent-medicine trade and into medical control — a pattern traced in the history of medical licensing and from materia medica to modern drugs.

The lesson of this period is that the same properties that make an analgesic valuable — potency, reliability, pleasure — make it dangerous in the wrong hands, at the wrong dose, or over the wrong number of days. Every later debate about pain treatment has replayed that tension.

In 1971 John Vane showed that aspirin and related drugs work by inhibiting the synthesis of prostaglandins, the lipid mediators of inflammation, fever, and pain. The finding explained the drug’s three classical effects — analgesia, antipyresis, and anti-inflammation — in one mechanism, and Vane shared the 1982 Nobel Prize in Physiology or Medicine for the work. (Vane, Nature New Biology, 1971)

The prostaglandin story had a platelet dimension. Aspirin irreversibly blocks the enzyme that makes thromboxane A2, a promoter of platelet aggregation, and the related work on prostacyclin clarified how blood vessels normally keep platelets in check. (Moncada & Vane, Philosophical Transactions of the Royal Society B, 1981) In 1975, the isolation of enkephalins — naturally occurring opioid peptides — showed that part of pain control was endogenous, and reframed opiates as tools that mimic a natural system. (Hughes et al., Nature, 1975)

Trials then converted the mechanism into practice. A 1988 meta-analysis by the Antiplatelet Trialists’ Collaboration, covering 25 completed trials and about 29,000 patients, found that antiplatelet treatment reduced vascular mortality by 15 percent and non-fatal vascular events by 30 percent. (Antiplatelet Trialists’ Collaboration, BMJ, 1988) The British Doctors’ Aspirin Trial (1988) and the Physicians’ Health Study (1989, 22,071 male physicians assigned 325 mg aspirin on alternate days) clarified both the potential reduction in myocardial infarction and the bleeding risk in primary prevention. Later evidence supported lower doses for most long-term antiplatelet uses. (Ridker et al., Annals of Internal Medicine, 1991)

The risks had a long history. Gastric irritation and bleeding were recognized complications. In 1963, Reye, Morgan, and Baral described a fatal combination of encephalopathy and fatty liver in children. US public-health warnings followed in the early 1980s, and warning labels were required in 1986 for aspirin use in children and teenagers with viral illnesses — the association now known as Reye’s syndrome. (Reye, Morgan & Baral, The Lancet, 1963) Current consensus is narrower than the 1990s: low-dose aspirin is standard for secondary prevention after a heart attack or stroke, while routine primary prevention is reserved for selected patients whose bleeding risk is low. (USPSTF, JAMA, 2022)