In Greece the famous healer Asclepius was mentioned in Homers Iliad. He may have been an actual person who, over time, became deified. Asclepius had three sons, Machaon, the surgeon, Podalirious, the physician, and Telesporus, among his daughters; Hygeia guided preventive health measures, while Panacea influenced treatment. This mutimodal therapy group demonstrates the way in which the Greeks mingled the spiritual and the practical when approaching the mysteries of illness and suffering.

A further reference to pain relief is found in Homer's Odyssey, in which Helen of Troy provides Ulysses and his companions with a drug to "lull pain and anger, and bring forgetfulness to every sorrow". Archaeological evidence exists that strongly indicates the use of the opium poppy at the time of the Trojan Wars 1220 BC. It is safe to assume that Helen's soothing potion contained opium. Opium would have been part of an array of drugs, collectively know as Pharmaka. Temples of healing dedicated to Asclepius were built on many sites, with priests assuming the power of the god Asclepius. Despite this strong spiritual component in medicine, the Greeks recognized natural causes of disease, and rational methods of healing were important. The teachings of Hippocrates has long symbolized the rational yet compassionate approach to diagnosis and treatment. His injunction to study the patient rather than the disease is but one of many approaches still useful today and is an essential part of assessing the chronic pain patient. The frustrations of dealing with prolonged, incurable pain were recorded for posterity in the writings of  physician/philosopher Areteus 100 to 200 AD, who is also known for his description of migraine headaches. He instructed the physician to use compassion when caring for the hopelessly ill: "When he can render no  further aid, the physician alone can still mourn as a man  with his incurable patient. This is the physician's sad lot".

When Rome replaced Greece as the center of power in the Mediterranean, Roman physicians were strongly influenced by Greek medicine and philosophy, which thrived in the great center of learning at Alexandria from 331 BC to 290 AD. Perhaps the most influential figure in the practice of pain relief and medicine in the first century and beyond was Galen. He considered patients phlegmatic, sanguine, choleric, and melancholic terms, which are still in use today and which still frequently color our first impressions of patients suffering chronic pain. He increased the list of the Theriaca, an ancient antidote and panacea, to over 70 ingredients. This compound was used for 1800 years, well into the nineteenth century, by which time the ingredients numbered over 100. Along with snake venom, opium was among its ingredients..