Wednesday, 28.10.2020

Peter R. Martin: Historical Vocabulary of Addiction

Withdrawal

 

            According to the current electronic edition of the Oxford English Dictionary (OED), the noun withdrawal originates from Latin and French roots and is formed by the joining of withdraw v. + -al suffix. The modern form of the word supersedes the earlier withdrawment n. , which, in turn, took the place of other earlier versions, i.e., withdraught n.and withdraw n. The current medical meaning of withdrawal corresponds to one of the definitions of the word found in the same edition: “cessation of use or provision of a drug; specifically, the interruption of doses of an addictive drug, with resulting craving and physical reactions.” However, specific reference to the discontinuation of self-administration of a neuropsychopharmacologic agent is not the primary meaning of withdrawal in the same electronic edition of the OED, nor is it the earliest use of the word in history. The earliest recorded written reference to the word withdraught in the English language, according to same electronic edition of the OED, occurred in Middle English in 1340 in a text in which the term was employed in its original meaning: “An act of voluntary abstinence from food, restraint in diet; also, a voluntary withdrawal (from evil thoughts and inclinations).” This very early reference to the origins of the word withdrawal combines restricting intake of an exogenous entity required for life (food) as well as limiting elements of one’s internal emotional life/experience (evil thoughts or inclinations). If one expands the medical construct of addiction to include out-of-control and self-destructive behaviors such as overeating (Martin 2018), the notion of restricting food intake can readily be related to discontinuation of a self-administered neuropsychopharmacologic agent.  However, the idea of removing oneself from “evil thoughts or inclinations” seems more compatible with the recently accepted nosological construct of addictive disorders in which substances do not factor, namely non-substance related addictive disorders according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, DSM-5 (American Psychiatric Association 2013).  Therefore, it seems that older constructs of the word withdrawal are recapitulated in our current broader nosological perspectives of addiction; stated otherwise, we have come full circle since the first very broad meaning of word in 1340, despite a minor detour in the last century, which restricted our focus to neuropsychopharmacological agents alone.

            According to the same electronic edition of the OED, the first reference in English literature to withdrawal as understood in medicine throughout most of the last century, came from an isolated entry in 1897 by Sir Thomas Clifford Allbutt (1836–1925) in his medical treatise, A system of medicine, the  first edition of which was published in London from 1896 to 1899 in eight volumes by Macmillan : “All authors agree that withdrawal [of morphine] is more distressing to the injector than to the eater of the drug.”  Fifty years after the advent of the hypodermic needle,  and well before we understood that the mechanism of action of opioids was through activation of opioid receptors in the nervous system, Albutt inferred, based on clinical observation alone, that the route of administration of an opioid may govern the difficulty the user experienced stopping self-administration of the drug (Pert and Snyder 1972; Rynd 1845)

            Albutt was not likely aware of the pharmacokinetic principles that would dictate greater bioavailability and pharmacological effect of morphine administered via injection.  (The relevant notion of bioavailability, currently defined as “the degree to which a drug or other substance is absorbed or reaches a target site in the body; especially the proportion of a dose of a drug taken orally which reaches the bloodstream” was first used in 1961 according to the same electronic edition of the OED. However, Albutt’s contention did require recognition of a characteristic withdrawal syndrome that emerges in individuals upon discontinuation of morphine use, the signs and symptoms (“distress”) of which were clinically identifiable and could be compared among individual users and under different conditions of use.  In addition, he was likely familiar with the pharmacological actions of morphine as suggested by a comment from 1850 attributed in the 2019 electronic edition of the OED to the great English female letter writer, Jane Welsh Carlyle, who wrote: “I took   morphine last night, and slept some.”  Therefore, Albutt may have noticed that the greater “distress” associated with stopping repeated morphine injections was accompanied by more intense or prolonged pharmacological effects compared to that observed with oral dosing.  The particular severity of opioid withdrawal associated with injection use is now well accepted as a general phenomenon for all drugs of abuse, a function of the “time of exposure” and “lifetime dose” (Kalant, LeBlanc and Gibbins 1971). 

            The emergence of the acute withdrawal syndrome results from the need for the drug of abuse (regardless of the route of administration) to be present in the brain to maintain “near-normal” functioning. If the drug is eliminated from the body so that it no longer occupies its site of action, homeostatic adaptations, termed neuroadaptation (Rounsaville, Spitzer and Williams 1986), are unmasked and manifested as a withdrawal syndrome that lasts until the system re-equilibrates to the absence of drug, typically days in duration. The manifestations of drug withdrawal depend on the class of drug abused and can range from mild dysphoria to life-threatening seizures.  Subsequently, a protracted withdrawal syndrome (Martin and Jasinski 1969), characterized by craving for the drug (i.e., an intense preoccupation with obtaining the drug), may emerge and continue indefinitely, typically for years, if not for a lifetime. Protracted withdrawal is also associated with subtle dysregulation of learning, drives/motivations, reward and the potential for relapse (Martin and Patel 2017). Distinguishing protracted withdrawal from premorbid risk factors for addiction that do not resolve with abstinence and from brain injury that is sustained as a result of drug use may not always be possible.

            Why an individual chooses to repeatedly be under the influence of a drug is likely the question underlying the choice of the route of administration of morphine.  The distress associated with attempting to discontinue use and the ensuing reluctance to stop using are probably consequences.  The repeated self-administration of morphine via injections might reflect a greater need to escape from one’s regular (painful) mental state or situation, a contemporary notion in addiction psychiatry (Khantzian, Mack and Schatzberg 1974).  It is not commonly appreciated that the term self-medication as defined in the February 20 issue of the British Medical Journal, in 1897 (“People are very partial to self-medication as it is, and rush to alcohol as a panacea for the ills to which flesh is heir” originated from the time of Albutt. This concept can readily be employed to explain why an individual chooses a more efficient injection route of administration, leading to greater or more continuous intoxication, thereby initiating a cycle of needing increasingly higher doses of morphine in order to obtain the same effect, termed tolerance (Martin 2018).

            A compelling reason not to discontinue morphine (or other drug) use and also to escalate doses is the fear of predictable disturbing consequences (“Tears were one of the symptoms of morphine withdrawal” [Hammett 1929]), the withdrawal symptoms experienced by most, if not all users, as noted in the OED. The suffering of withdrawal was deemed to require treatment in its own right: “Withdrawal of morphine by substitution and subsequent withdrawal of methadon” (Wilner and Kassebaum 1965).  Even now, the most commonly employed strategies for alleviating withdrawal from most drugs of abuse are to taper the dose of the drug slowly or to use a long-acting drug in the same class that demonstrates cross-tolerance (Kalant, LeBlanc and Gibbins 1971).

            For many years the severity of withdrawal was considered a primary driver of the disease of addiction, such that the vulnerable individual became imprisoned by fear of withdrawal to a state of almost continuous drug use (Bishop 1913).  Accordingly, treatment of the opioid withdrawal syndrome evolved into the ready focus for effective treatment of addiction per se by addressing “relief of narcotic hunger” (Dole and Nyswander 1965).  This approach has continued to evolve (Jasinski, Pevnick and Griffith 1978; Mello and Mendelson 1980) and remains effective (Johnson, Chutuape, Strain et al. 2000), despite awareness of the important roles of reward learning (Stephens 1933) and elucidation of underlying reward mechanisms in the brain (Olds 1958) that can shape behavior such as out-of-control self-administration of psychoactive agents.

 

References:

 

American Psychiatric Association. Diagnostic and Statistical Manual of Mental disorders, Fifth Edition. Arlington: American Psychiatric Publishing; 2013.

Bishop ES. Narcotic addiction — a systemic disease condition. JAMA 1913; 60: 431–?4.

Dole VP, Nyswander M. A medical treatment for diacetylmorphine (heroin) addiction: A clinical trial with methadone hydrochloride. JAMA, 1965; 193: 646–54.

Hammett D. The Dain Curse. New York: Alfred A. Knopf; 1929.

Jasinski DR, Pevnick JS, Griffith JD. Human pharmacology and abuse potential of the analgesic buprenorphine: a potential agent for treating narcotic addiction. Arch Gen Psychiatry 1978; 35:, 501–16.

Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, Bigelow GE. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med. 2000; 343::1290-7.

Kalant H, LeBlanc AE, Gibbins RJ. Tolerance to, and dependence on, some non-opiate psychotropic drugs. Pharmacol Rev. 1971; 239:135-9..

Khantzian, EJ, Mack JE, Schatzberg AF. Heroin use as an attempt to cope: clinical observations. Am J Psychiatry. 1974;131:160-4.

Martin PR. Tolerance. Historical Dictionary of Addiction. inhn.org.education. February 1, 2018.

Martin WR, Jasinski DR. Physiological parameters of morphine dependence in man—Tolerance, early abstinence, protracted abstinence. J Psychiatr Res. 1969; 7: 9-17.

Martin, PR, Patel S. Pharmacology of drugs of abuse.  In: DA Golan, EJ Armstrong, AW Armstrong, editors. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, Fourth Edition.  Philadelphia: Wolters Kluwer Health;2017, pp. 308-34.

Mello N, Mendelson J. Buprenorphine suppresses heroin use by heroin addicts. Science. 1980; 2076:657-9.

Olds J. Self-stimulation of the brain. Science  1958;123:6615-32

Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science. 1973;179:1011-4.

Rounsaville BJ, Spitzer RL, Williams JB.  Proposed changes in DSM-III substance use disorders: description and rationale. Am J Psychiatry. 1986; 143:463-8.

Rynd F.  Neuralgia - introduction of fluid to the nerve. Dublin Medical Press 1845; 13, 167–8.

Stephens JM. (1933). Punishment and reward in learning. Science. 1933;5560. :

Wilner DM, Kassebaum GC, editors) Narcotics. New York: McGraw‐Hill Book Company, Inc. (Blakiston):1965.

 

May 30, 2019