In 1803 Prussian pharmacist F.W.A. Serturner began work on isolating the active ingredients in opium, hoping to establish a dose scale. By 1817 he had narrowed his search down to morphine. The management of pain with morphine was somewhat limited, however, until the development of the hypodermic syringe and hollow needle. By 1853 these developments had been accomplished by Rynd in Ireland and Pravaz in France.

It is noteworthy that, even though chloroform, nitrous oxide and ether had all been discovered by 1831 and were used as intoxicants, at parties, they were not used as general anesthetics. It was not until March 30, 1842, that a Georgia physician Dr. Crawford W. Long of Jefferson, Georgia, administration the first ether anesthetic for surgery in an adult, removal of a tumor of the neck, followed in July, by the first pediatric ether anesthetic.  His history-making achievement and the continuous efforts by doctors to alleviate human suffering have become the basis for celebrating Doctors Day (March 30th) each year.  The Crawford W. Long Museum is located in Jefferson, Georgia, next to the site of Dr. Long's office where he performed the surgeries.

Then in 1846 a Boston dentist William T. G. Morton, made a dramatic public demonstration of ether inhalation's  effectiveness as a general anesthetic at Mass. General Hospital in Boston. At the conclusion of the surgery the surgeon said "Gentlemen this is no Humbug". In Germany, Differbach, a plastic surgeon, wrote of ether, "The wonderful dream that pain has been taken away from us has become a reality. Pain...must now bow before the power of the human mind, before the power of the ether vapor".

In 1874 James Simpson pioneered the  use of chloroform as a substitute for ether.  When announcing his successful use of chloroform in obstetrical procedures, Simpson declared it to be far more pleasant for the patient and more controllable than ether. Calvinist church leaders opposed the use of any general anesthetic during childbirth, clinging to the Biblical imperative that women should bring forth children in sorrow. Opposition vanished, however, after John Snow administered chloroform to Queen Victoria during childbirth. Chloroform later fell into disuse because of its association with long term liver damage and sudden death.

The fact that painless surgery became possible, due to anesthesia, allowed physicians to use surgery itself to deal with the cause of chronic pain. The outcome of all types of surgery dramatically improved after the acceptance of Joseph Lister's antiseptic technique, first introduced in 1867. Among those physicians who pioneered surgery for pain was Hersley of England, who originated  the operation for Trigeminal neuralgia. The American, Abbe, the originator of posterior rhizotomy; and Spiller and Frazier who introduced retrogasserian neurectomy and cordotomy, and Harvey Cushing made outstanding contributions to surgical treatment of pain, and the list goes on and on.