Tuesday, 18.05.2021

Peter R. Martin: Historical Vocabulary of Addiction

 

Sedative

 

       The title of this entry was selected because according to the Oxford English Dictionary (OED), the word sedative was the first one used in the English language (c. 1425) of the many others that have very closely related meanings.  Almost all of these are relevant to addiction as they are often used for self-medication of various distressing symptoms and are prescribed by physicians for their patients with recalcitrant medical and psychiatric conditions.  Each will be discussed in the sequence and context they appeared in the English language.  These closely related words are all nouns and some are also adjectives: hypnotic (1625), soporific (1690) sedative-hypnotic (mentioned in OED in relation to pentobarbital, 1931), hypnosedative (not mentioned in OED), ataractic/ataraxic (1941), minor tranquillizer (1960) – although tranquillizer alone appeared much earlier (1800) – and anxiolytic (1962).    

       According to the current electronic version of OED, the noun sedative is derived from the French sédatif and from the medieval Latin sēdātīvus and Latin sēdāre.  The noun sedative is defined as: “That has the property of allaying, assuaging, or soothing. A sedative medicine.”  An example of its first use in the English language appears in Treatises of Fistula in Ano by John of Arderne (1307 - 1392), an English surgeon considered one of the fathers of surgery, who in his writings set out not only his operative procedures but also his code of conduct for the ideal medical practitioner (1400): “Oile roset complete is resolutiue, confortatyue, and conueniently cedatyue of akyng.”  He also recommended opium, so that the patient “shal sleep so that he shal feel no cutting” (Anonymous 1965).  In A System of Medicine edited by Sir Thomas Clifford Allbutt (1836–1925), an English physician who was commissioner for lunacy in England and Wales 1889-1892, also states that sedation is not a unique consequence of only one medicine but many can have this pharmacological action (1899): “Sedatives such as bromides and valerian… must be administered.”

       The noun hypnotic is derived from the French hypnotique and from the Latin hypnōticus and the Greek ὑπνωτικός meaning “inclined to sleep, sleepy; also, putting to sleep, narcotic” and ὑπνοῦν meaning “to put to sleep.”  The noun hypnotic is defined in OED as: “An agent that produces sleep; a sedative or soporific drug.”  An example of the first appearance of this word in the English language was in the book The Anatomie of Vrines (Hart 1625): “Not neglecting hypnoticke, cordiall, and deoppilatiue medicines.”  Thomas Willis (1621–1675), an English physician, a founding member of the Royal Society and a pioneer in research into the anatomy of the brain, nervous system and muscles, provides an example of the noun (1681): “Hypnoticks are oft necessary in this Disease.”  Willis thus recognized that sedation can be a helpful component of treatment of certain conditions, not only to cause sleep and allow surgery in healthy individuals.

       The noun soporific is derived from the Latin sopōrificus which is a combination of sopor, meaning “sleep” and the suffix -fic, forming adjectives from nouns, with the sense “making, causing, producing.”  The noun soporific is defined in OED as: “A substance, especially a medicament, which induces sleep.”  An example of its first use in the English language is in An Essay Concerning Humane Understanding by John Locke (1632–1704), the British philosopher who contributed to modern empiricism (1690): “The Colour and Taste of Opium… as well as its soporifick or anodyn Virtues.”  The philosopher and historian David Hume (1711–1776) raised the notion that medicines may not work in an identical manner in every patient, much before personalized (precision) medicine emerged as pivotal concept in modern medicine (1777): “Nor has rhubarb always proved a purge, or opium a soporific.”  Although the word soporific is not commonly used today, it was widely employed in the 19th century, as suggested by Sir Thomas Clifford Allbutt (1899): “The use of soporifics is limited by the extent of their other pharmacological effects.”  This phrase alludes to the fundamental concept that sedation can be produced by various, pharmacologically distinct agents and that understanding the characteristic action mechanisms is essential for rational pharmacotherapy.

       As noted above, the word hypnosedative is not mentioned in OED and sedative-hypnotic is only mentioned in relation to pentobarbital, which is defined as: “A synthetic sedative-hypnotic and anticonvulsant barbituric drug.”  It is clear that neither the word sedative-hypnotic nor hypnosedative significantly refine the meaning of either word by their combination as each element means much the same thing — that the agent is a sedative drug. 

       The adjectiveataractic/ataraxic is derived from Greek ἀτάρακτος, meaning “not disturbed, calm,” combined with the suffix -ic which is used to form adjectives, many of which can also be nouns.  The adjective is closely related to the noun ataraxy (“Freedom from disturbance of mind or passion; stoical indifference”).  The OED definition of ataractic/ataraxic is: “Calm, serene.” An example of the word’s first use in the English language is in the novel Colossus of Maroussi, by the American writer Henry Miller (1891–1980) describing his time in Greece (1941): “Mycenae… reared in anthropophagous luxury, reptilian, ataraxic, stunning and stunned.”  This word does seem reasonably closely related to sedative.  However, as the word evolved, it acquired another meaning.  The medical definition of ataractic/ataraxic is: “Of drugs: inducing calmness, tranquillizing.” 

       The first use of ataractic was by Howard Fabing (1907-1970), an American neurologist who was “a pioneer in the field of psychotherapeutic drugs, being the first to use LSD to produce a mock psychosis as a means of searching for a preventative for true psychosis (Mayfield, Schwemlein and Hawkins 1971).”  Fabing stated (1955): “The Epicureans were especially fond of the term ‘ataraxia’ which meant freedom from confusion, peace of mind... It is proposed, therefore, that drugs of this type be designated ataraxics, and that the adjectival form, ataractic, be used to describe this therapeutic property in drugs.”  He then applied this term to an entire class of drugs with seemingly little similarity to the psychopharmacologic actions of sedatives: “Proposal is made to adopt the generic term, ataraxics, for pharmacological agents such as chlorpromazine, rauwolfia compounds, Frenquel, and others, which bring about ataraxy, or freedom from confusion.”  

       The nountranquillizer is related to the verb tranquillize which is a combination of the adjective tranquil and the suffix -ize (“with the transitive sense of ‘make or conform to, or treat in the way of, the thing expressed by the derivation’”).  Tranquil is defined: “Free from agitation or disturbance; calm, serene, placid, quiet, peaceful” and is derived from the Latin tranquillus, meaning “quiet” and related to the French tranquille. The definition of tranquillizer in OED is: “that which tranquillizes; specifically any of a large class of drugs in widespread use since the 1950s for the reduction of tension or anxiety and the treatment of psychotic states.”  The word tranquillizer was used in 1800 by Frances Burney (1752–1840), an English satirical novelist, diarist and playwright in The journals and letters of Fanny Burney (Madame D'Arblay): “I find, however, useful employment the best tranquiliser, &… I have less of the violent emotions which have hitherto torn me.”  In this quotation, the word is not used to refer to effect of a medicine, but rather, to a circumstance that can lessen the intensity of emotions, easing tension and anxiety.  Such is a very important observation as comparable beneficial effects have been demonstrated for psychotherapeutic and psychopharmacologic treatments in management of mild to moderate anxiety/depressive symptoms (Holland, Morrow, Schmale et al. 1991).  An example of the contemporary meaning of the word appears in a quotation of Thomas De Quincey (1785–1859), an English essayist best known for his Confessions of an English Opium-Eater (1856): “A tranquilliser of nervous and anomalous sensations.”  A tranquillizer is intended to allow a person to carry on in a seemingly normal state without objective signs of the effects of the medication, lessening tension, anxiety or related distressing symptoms; this differs from sedation and calming so as to facilitate sleep; of note, however, as the dose of a tranquillizer is increased, objective evidence of sedation can occur.  This is explained by Hollister (1958): “The distinguishing features of tranquilizing drugs in contrast to conventional sedatives is that they calm without producing sleep and that their site of action in the central nervous system [CNS] is predominantly subcortical. The principal sites of action are important regulating centers of the brain: thalamus, hypothalamus, reticular activating system and portions of the limbic system.” Of note, the nouns tranquillizer and ataractic/ataraxic seem interchangeable, but the later is not now commonly used

       It makes little sense to modify the word tranquillizer with the adjective minor, borrowed from French and Latin, meaning “smaller, lesser, younger” because the differences are not simply of degree.  A minor tranquillizer was intended to be distinctly different from the tranquillizers.  Instead, they were considered to be among the least sedating members of the sedative group of drugs, the anxiolytics (see below).  Accordingly, the noun minor tranquillizer is defined in OED as:  “any of a group of sedative drugs, including especially the benzodiazepines, used to treat anxiety states (as opposed to psychoses).”  An example of its first use in the English language (Hinsie and Campbell 1960) is: “Four classes of tranquilizing drugs are generally recognised: ... Classes (3) and (4) [sc. substituted propanediols and diphenylmethane derivatives] are sometimes called minor tranquilizers...; their principal effect is on the psyche to reduce anxiety.”  This latter classification (Hollister 1958) may seem confusing today because it was conceived prior to the introduction of the benzodiazepine anxiolytics, which have become synonymous with minor tranquillizers.  It should be noted, however, that medications primarily intended as anxiolytic sedatives had been introduced a decade before the benzodiazepines (Berger 1954).  A quotation from William Styron (1925–2006), an American novelist who wrote about depression in his novel Darkness Visible: a Memoir of Madness, exemplifies the lack of precision in the vernacular concerning the word tranquillizer  (1991): “Aided by the minor tranquilizer Halcion [triazolam], I had managed to defeat my insomnia and get a few hours’ sleep.”  A particularly appropriate quote to explain the connection between tranquillizers, minor tranquillizers and the anxiolytics is found in the British National Formulary (1996): “Anxiolytics, particularly the benzodiazepines, have been termed ‘minor tranquillisers’. This term is misleading because not only do they differ markedly from the antipsychotic drugs (‘major tranquillisers’) but their use is by no means minor.”

       The noun anxiolytic was formed within English, after the French anxiolytique by compounding the noun anxiety (“Worry over the future or about something with an uncertain outcome; uneasy concern about a person, situation, etc.; a troubled state of mind arising from such worry or concern”), the connective term -o- and lytic (“ending of adjectives corresponding to nouns that end in -lysis).  The definition in OED is: “A drug or substance that reduces anxiety; specifically any of a class of drugs that reduce anxiety without producing significant sedation.”  An example of the first use of the word anxiolytic is in the proceedings of a scientific meeting on electroencphalography and clinical neurophysiology in Paris (1962): “Librium, or Ro 5-0690, is essentially an anxiolytic drug without hypnotic effect which has been recently introduced into psychiatry.”  This quotation depicts a sedative as having greater specificity, namely able to reduce the distress of tension/anxiety while allowing wakefulness and (near) normal performance of daily activities. 

       While anxiolytics seem an ideal solution to the familiar concerns faced in the modern world, a wise word of caution is raised in the British National Formulary (1986): “Anxiolytic treatment should be limited to short periods.”  This is a prescient warning of the serious risk of addiction to these presumably “very safe” drugs, initially publicized as being without abuse liability (Martin, Weinberg and Bealer 2007).  If treatment continues beyond “short periods,” increasing doses of the medication tend to be self-administered due to neuroadaptation, brain functioning can become subtly compromised over time and if use is precipitiously discontinued, a withdrawal syndrome ensues (Martin, Bhushan, Kapur et al. 1979; Busto, Sellers, Naranjo et al. 1986).  Insightful comparisons of anxiolytics to other drugs of abuse are plentiful in the lay press, for example, “Liquor is western man's oldest anxiolytic (Anonymous 1975)”; “Benzodiazepines have replaced barbiturates as the most common type of ‘anxiolytics’ or ‘anxiety dissolving’ drugs” (Anonymous 1988); and “Valium is simply alcohol in tablet form” (Martin, Weinberg and Bealer 2007).

       It is instructive to review how Robert Kinglake (1765–1842), an English physician and medical writer, understood the role of sedatives in the medicine of his day (1802):

       “No question in Physiology has been less satisfactorily agitated than that which divides the medical world on the operation of sedative substances… It is familiarly imagined, that certain substances act on the animal economy as direct sedatives, that is, that they repress the action of motive power; but those who entertain this opinion do not feel equal facility, in assigning a reason for this extraordinary effect.

       “Sedative influence may obtain in two different ways, either by universally exciting and invigorating the system, or by withholding or prohibiting excessive stimulation; in the former order of efficiency may be ranked whatever may be capable of subduing, by congenial excitement, morbid debility and its consequent quickened action; in the latter may be included a suitably reduced temperature, abstinence, increased evacuations, shaded light, and mental depression.

       “The mode in which these positive and negative powers operate, is formally opposite but efficiently familar; the one retards hurried action by the superceding influence of accessorial vigour, while the other obviates undue exhaustion by withholding noxious excitement. These different species of sedative power are applicable to opposite states of disease; the positive influence is adapted to restrain and controul the quickened action of debility, while the negative is suitable to diminishing immoderate excitement.

       “How such opposite effects can arise from the same power, on different parts of the animal body, does not appear, nor does any principle of philosophising, applicable to the animal economy, warrant such a contradictory inference; it has therefore been unscientifically assumed to subserve the delusion of a pre-conceived erroneous opinion.”

       That a sedative can cause both psychic inhibition and disinhibition and can heal and cause pathological states, especially addiction, remains an enigma to this day (Stein and Berger 1969; Vashchinkina, Panhelainen, Aitta-aho and Korpi 2014). 

       The word sedative refers to shared pharmacologic action(s) of all CNS depressants, rather than that of a single agent.  Therefore, despite the different names for sedatives throughout history, all these medications are characterized by the fact that they very effectively calm and soothe and allow rest and sleep.  Stressful circumstances can cause tension and anxiety; relief from these distressing symptoms can rapidly be obtained through self-medication with sedatives.  All sedatives depress the CNS by activating inhibitory GABAergic neurotransmission (Tallman, Thomad and Gallager 1978; Paul, Marangos and Skolnick 1981), and inhibiting excitatory glutamatergic neurotransmission (Moreau, Pieri and Prud’hon 1989). 

       The basis of the activation/inhibition enigma, mentioned above, resides in the complexity of neural circuits within the brain on which sedatives act, such that intoxication is typically biphasic, stimulation followed by inhibition; stimulation likely results from inhibition of inhibitory neurons, leading to disinhibition, resembling relative stimulation (Martin and Patel 2017).  Recent hypotheses have proposed that predisposition to addiction to CNS depressants (alcohol and sedatives) are related to their stimulatory properties (Quinn and Fromme 2016), rather than the inhibitory effects, which have been the primary focus of ongoing research on the risk for developing alcoholism (Paulus, Schuckit, Tapert et al. 2012).

       With repeated use of any sedative, neuroadaptive changes occur, including the need for increasing doses and the emergence of a characteristic withdrawal syndrome on discontinuing use.  Each of the drugs discussed above, including tranquillizers/ataractics, have, at one time or other, been deployed to treat severe CNS depressant withdrawal, however tranquillizers/ataractics are not as effective and may even precipitate withdrawal seizures (Martin 2019).  

       An important characteristic that sets the tranquillizers/ataractics apart from the CNS depressant sedatives is their limited abuse liability.  Deneau,Yanagita and Seevers (1969) demonstrated that non-human primates self-administer all CNS depressants but not tranquillizers/ataractics.  For this reason, treatment of anxiety symptoms can be accomplished with low doses of  tranquillizers/ataractics (Denber 1982) and are actually preferred in individuals who are addicted to CNS depressants and are struggling to remain abstinent (Martin, Weinberg and Bealer 2007).  Ultimately, the major question that remains is the origin of anxiety.  There are those who would consider anxiety as a psychiatric disorder, whereas others recognize its promiscuous occurrence throughout medicine — from hyperthyroidism, myocardial infarctions, pneumonia, schizophrenia and depression among many other conditions.  The parsimonious explanation is that anxiety is a signal to the organism that all is not well, whether or not that contention is based in reality — addressing the cause seems to make more sense than suppressing the symptom or calling it a disorder in its own right.     

 

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February 4, 2021