On analgesic and narcotic plants: Pliny and his Greek sources, the history of a complex graft.

Grafting is an important concept in the study of Pliny the Elder, who is a compiler of written sources. We intend to examine how this grafting works in Pliny's discussion of analgesic and narcotic plants, especially the most famous: opium poppy, henbane, mandrake, and hound's berry. We will study Pliny's use of Greek sources and ask how he took up his predecessors' works while integrating the changes that took place during the centuries in the diagnosis and treatment of pain. This cultural graft remains elusive because we do not have access to all of Pliny's Greek sources. When Pliny speaks about these plants, he sometimes copies out information, adding or removing details, and occasionally makes significant mistakes. The graft was particularly difficult in this case because these analgesic plants were considered so special and poisonous that they were sometimes rejected or even condemned. Nevertheless, we can say that this cultural graft succeeded, despite some obstacles, because Pliny assimilated and adapted these old Greek materials to his own time, society, and project.

Early drug discovery and the rise of pharmaceutical chemistry.

Studies in the field of forensic pharmacology and toxicology would not be complete without some knowledge of the history of drug discovery, the various personalities involved, and the events leading to the development and introduction of new therapeutic agents. The first medicinal drugs came from natural sources and existed in the form of herbs, plants, roots, vines and fungi. Until the mid-nineteenth century nature's pharmaceuticals were all that were available to relieve man's pain and suffering. The first synthetic drug, chloral hydrate, was discovered in 1869 and introduced as a sedative-hypnotic; it is still available today in some countries. The first pharmaceutical companies were spin-offs from the textiles and synthetic dye industry and owe much to the rich source of organic chemicals derived from the distillation of coal (coal-tar). The first analgesics and antipyretics, exemplified by phenacetin and acetanilide, were simple chemical derivatives of aniline and p-nitrophenol, both of which were byproducts from coal-tar. An extract from the bark of the white willow tree had been used for centuries to treat various fevers and inflammation. The active principle in white willow, salicin or salicylic acid, had a bitter taste and irritated the gastric mucosa, but a simple chemical modification was much more palatable. This was acetylsalicylic acid, better known as Aspirin®, the first blockbuster drug. At the start of the twentieth century, the first of the barbiturate family of drugs entered the pharmacopoeia and the rest, as they say, is history.

[A short history of anti-rheumatic therapy--V. analgesics]. / Piccola storia della terapia antireumatica--V. Gli analgesici.

The pharmacological treatment of pain has very ancient origins, when plant-derived products were used, including mandrake extracts and opium, a dried latex obtained from Papaver somniferum. In the XVI and XVII centuries opium came into the preparation of two compounds widely used for pain relief: laudanum and Dover's powder. The analgesic properties of extracts of willow bark were then recognized and later, in the second half of the XIX century, experimental studies on chemically synthesized analgesics were planned, thus promoting the marketing of some derivatives of para-amino-phenol and pyrazole, the predecessors of paracetamol and metamizol. In the XX century, nonsteroidal anti-inflammatory drugs were synthesized, such as phenylbutazone, which was initially considered primarily a pain medication. The introduction on the market of centrally acting analgesics, such as tramadol, sometimes used in the treatment of rheumatic pain, is quite recent.

Transient receptor potential channels in pain and inflammation: therapeutic opportunities.

In ancient times, physicians had a limited number of therapies to provide pain relief. Not surprisingly, plant extracts applied topically often served as the primary analgesic plan. With the discovery of the capsaicin receptor (transient receptor potential cation channel, subfamily V, member 1 [TRPV1]), the search for "new" analgesics has returned to compounds used by physicians thousands of years ago. One such compound, capsaicin, couples the paradoxical action of nociceptor activation (burning pain) with subsequent analgesia following repeat or high-dose application. Investigating this "paradoxical" action of capsaicin has revealed several overlapping and complementary mechanisms to achieve analgesia including receptor desensitization, nociceptor dysfunction, neuropeptide depletion, and nerve terminal destruction. Moreover, the realization that TRPV1 is both sensitized and activated by endogenous products of inflammation, including bradykinin, H+, adenosine triphosphate, fatty acid derivatives, nerve growth factor, and trypsins, has renewed interest in TRPV1 as an important site of analgesia. Building on this foundation, a new series of preclinical and clinical studies targeting TRPV1 has been reported. These include trials using brief exposure to high-dose topical capsaicin in conjunction with prior application of a local anesthetic. Clinical use of resiniferatoxin, another ancient but potent TRPV1 agonist, is also being explored as a therapy for refractory pain. The development of orally administered high-affinity TRPV1 antagonists holds promise for pioneering a new generation of analgesics capable of blocking painful sensations at the site of inflammation and tissue injury. With the isolation of other members of the TRP channel family such as TRP cation channel, subfamily A, member 1, additional opportunities are emerging in the development of safe and effective analgesics.

[From willow bark to the coxibs. Development of antiphlogistic analgesics]. / Von der Weidenrinde zu den Coxiben. Entwicklung der antiphlogistischen Analgetika.

Antiphlogistic analgesics comprise the most widely used class of drugs worldwide. These compounds derive more or less directly from three prototypes which were discovered about 130 years ago in Central Europe: acetylsalicylic acid (aspirin), acetanilide (the forerunner of acetaminophen), and phenazone. All of them are still available. Attempts to improve their effect/side effect spectrum and enhance their analgesic activity led to the development of animal models of inflammatory pain which allowed for the screening and discovery of the so-called aspirin-like drugs, also termed nonsteroidal antiinflammatory drugs (NSAIDs) or cyclooxygenase inhibitors. This group presently dominates the market despite the fact that all these compounds imply the risk of unwanted drug effects, including gastrointestinal ulcers, renal dysfunction, inhibition of blood coagulation, pseudoallergic reactions, and possibly also accelerated development of atherosclerosis. Attempts to reduce these unwanted drug effects on the basis of molecular pharmacological insights resulted in the development of the so-called selective cyclooxygenase-2 inhibitors which are presently discussed ambiguously. These compounds appear to go along with less gastrointestinal toxicity, they do not inhibit blood coagulation, and have a reduced propensity for causing pseudoallergic asthmatic attacks. They may, on the other hand, cause more unwanted cardiovascular effects than the traditional NSAIDs. Hope for further reduction of unwanted drug effects comes from the recently discovered role of glycinergic spinal pain control. It is hoped that new classes of analgesic compounds may result from these new glycinergic mechanisms.

[Analgesic remedies in the Middle Ages]. / Schmerzmittel im Mittelalter.

The knowledge of analgesic remedies, sleeping drugs, and narcotics is well attested by numerous prescriptions in the medical literature since the early Middle Ages. The variety of analgesic remedies and the preferred use of particular plants (such as mandrake, henbane, and poppy) is just as remarkable as the many different forms of application: drug-soaked sponges, compresses and plasters, oils, ointments, smoke and smelling salts, drinks and waters, pills and troches, powders, electuaries, and confections. Various examples from different sources illustrate clearly that medieval physicians not only knew about analgesic remedies but really put their knowledge into practice.

An ancient Greek pain remedy for athletes.

While Hippocratic writings make no reference to the actual Olympics, there is frequent mention of diet, exercise, and the treatment of injuries sustained by the athletic participants. Indeed, Galen in his Composition of Medicines gives details of a remedy prescribed for the relief of pains and swellings, which was reserved for use by the winners of Olympic events, the so-called "Fuscum Olympionico inscriptum"--(ointment) entitled "dark Olympic victor's." In a time when the Olympic games have recently returned to their homeland, we examine the potential efficacy of this ancient remedy in terms of pain relief, the novelty of transdermal pain management, and the ability of ancient physicians to attend to the sports-related needs of highly tuned athletes.

Management of childhood diseases in the Byzantine period: I -- analgesia.

Evidence on the use of pain relievers for medical purposes in childhood was traced in medical treatises during Byzantine times (4th to 15th century ad). The texts of Aetius, Paulus Aeginitis, Orivasios and others strongly reveal influences from ancient Greek medicine. Greek physicians of the times, who helped the medical thinking of antiquity to stay alive, used opium with mandragoras, hyoscyamos and other sedative herbs to produce a kind of anesthetic state and to relieve pain. However, in children's cases they chose to selectively use substances in more standardized quantities, mainly in mixtures. Less aggressive methods such as warm baths, or appropriate food were highly respected by them and recommended for the treatment of sick children.

[Pain--life's dreaded companion. Cultural history of algology and the most important achievements]. / Smärta--livets fruktade följeslagare. Algologins kulturhistoria och de viktigaste landvinningarna.

Pain is a comprehensive phenomenon which concerns not only physiology, biochemistry and molecular biology but also music, art, religion, philosophy and everyday life. The early contributions to the development of the specificity theory is described, as are some of the important discoveries in the history of algology, such as Baillou's description of rheumatism, Heberden's description of angina pectoris and the development of the gate control theory. Despite a number of important discoveries and a much improved knowledge in basic science pain is still the dreaded companion of mankind.

Anesthetic and analgesic practices in Avicenna's Canon of Medicine.

Anesthetic and analgesic practices during the Middle Ages and the Renaissance are presented from a translation of the relevant sections of the Canon of Medicine by Avicenna (980-1037) one of the most widely read and authoritative textbooks of the period. Avicenna described tracheotomy, oropharyngeal intubation and a method for clearing upper airway secretions for the treatment of stridor and respiratory distress. He also identified certain plants with pharmacological action such as mandragora or nightshade, opium and henbane and gives various recipes for inducing both anesthesia and analgesia before surgery.

[Historical aspects of pain relief during normal parturition]. / Historische aspecten van het stillen van pijn tijdens de normale baring.

Traditional methods used for the relief of pain during normal delivery are few and the medical literature remained silent on this topic up to the middle of the 19th century. Indeed, the first effective method was etherization, and it was introduced by Simpson (Edinburgh) in 1847. Obstetric inhalation analgesia was followed by many other methods the development of which was based on new discoveries in chemistry, pharmacology, physiology, and psychosomatic medicine. This paper reviews the milestones in the historical development of obstetric analgesia.