Category:Barbiturates: Difference between revisions

The barbiturates are a class of medicines that depress the central nervous system, used for much of the twentieth century as sedatives, sleeping medicines, and anticonvulsants. For roughly the first half of that century they were among the most widely used medicines in the world. Their history is a particularly stark instance of a pattern that recurs across the history of medicine: introduced as the safe and modern answer to the dangers of an older remedy, they were used enormously, were found to carry grave dangers of their own, and were in turn displaced by a new class advertised as safer still.

The story begins in 1864, when the German chemist Adolf von Baeyer synthesized a new compound, barbituric acid, from urea and a derivative of malonic acid. The name's origin is uncertain and has attracted several colourful stories, most involving the name Barbara; what is not in doubt is that the compound itself had no obvious medical use, and von Baeyer set it aside.^[1]

Nearly four decades passed before barbituric acid yielded a medicine. In 1903 the chemist Emil Fischer, once von Baeyer's assistant, and the physician Joseph von Mering found that one derivative, diethylbarbituric acid, was a powerful sedative, far more effective at inducing sleep in dogs than the remedies then in use. It was brought to market by Bayer as Veronal, the first barbiturate medicine; the name is usually said to derive from the Italian city of Verona, though this too is disputed.^[1] A second early barbiturate of lasting importance, phenobarbital, followed from Bayer in 1912.

Veronal was the beginning of an era. Over the following decades dozens of barbiturates were developed and marketed, differing chiefly in how quickly they acted and how long their effects lasted. They were used as sedatives to calm anxiety, as hypnotics to induce sleep, in psychiatry for so-called "sleep cure" treatments, and, in the case of phenobarbital, as a genuine and lasting advance in the treatment of epilepsy, a use that continues today. Short-acting barbiturates such as thiopental became important in anaesthesia.^[1]

By the 1930s and 1940s the barbiturates had reached their greatest popularity, occupying a place in medicine comparable to the one the benzodiazepines would later hold.^[1] Production was vast: at the peak, billions of tablets were made each year in the United States alone. They became part of the texture of mid-century life, known colloquially as "goofballs" or "downers", widely prescribed, easily obtained, and used both medically and recreationally.

The drawbacks of the barbiturates were serious and, ultimately, could not be designed away. They carried a high risk of dependence, and a withdrawal syndrome that could be severe. Most dangerous of all was the narrow margin between an effective dose and a lethal one: barbiturates depress breathing, and an overdose, taken alone, or in combination with alcohol, could be fatal, with no antidote available.^[1]

Through the 1950s and 1960s, deaths from barbiturate overdose, both accidental and deliberate, rose into a recognized public-health problem; the death of the actress Marilyn Monroe in 1962 from barbiturate poisoning brought wide public attention to the danger.^[2] Public campaigns arose to restrict the drugs, and barbiturates were brought under tightened legal control. In the United States, they were scheduled under the Controlled Substances Act of 1970.^[1]

The decisive change, however, was the arrival of an alternative. The benzodiazepines, introduced from 1960, produced broadly similar sedative and anti-anxiety effects but were far less likely to cause death by overdose. They were marketed as the safer modern choice, and through the 1960s and 1970s they rapidly displaced the barbiturates for the treatment of anxiety and insomnia.^[2] The shift is credited with reducing overdose deaths at the population level.

Barbiturates have not vanished from medicine, but their role is now narrow and specific. phenobarbital and primidone remain in use as anticonvulsants; phenobarbital also has a role in managing withdrawal from sedatives. Short-acting agents such as thiopental have been used in anaesthesia, though here too newer medicines have displaced them. Barbiturates also have non-medical applications, including in euthanasia and, in some jurisdictions, in capital punishment. For the everyday treatment of anxiety and sleeplessness, the use that once made them ubiquitous, they have been almost entirely superseded.

Barbiturates are understood to act chiefly at the GABA-A receptor, the receptor for the brain's principal inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). Like the benzodiazepines, they enhance GABA's inhibitory effect, but they do so differently, and the difference matters: at higher concentrations barbiturates can activate the receptor directly, even without GABA present. This is understood to be a major reason barbiturates are more dangerous in overdose than benzodiazepines, whose action depends on GABA already being present and so has more of a ceiling. That barbiturates act at the GABA-A receptor is well established; the fuller relationship between that action and the range of their effects is more complex and remains a subject of research.

The barbiturates include phenobarbital and primidone (used as anticonvulsants), the intermediate- and short-acting sedative-hypnotics such as amobarbital, pentobarbital, secobarbital, and butalbital, and the very short-acting thiopental and methohexital used in anaesthesia. The list is not exhaustive.

The defining hazard of the barbiturates is the narrow margin between a therapeutic dose and a dangerous one. They depress breathing, and in overdose, particularly in combination with alcohol or other central nervous system depressants, this can be fatal; unlike for some other sedatives, there is no specific antidote. Regular use leads readily to tolerance and to physical dependence, and the withdrawal syndrome can be severe, in serious cases including seizures, so that barbiturates are not stopped abruptly after sustained use. It was this combination of properties, a high risk of dependence and a genuine risk of death in overdose, that led barbiturates to be displaced, for most purposes, by medicines with a wider margin of safety. Figures for these risks are population estimates that vary between studies, and individual response varies considerably between people.