Thomas A. Ban
Neuropsychopharmacology in Historical Perspective
Education in the Field in the Post-Neuropsychopharmacology Era
The isolation of morphine
(Bulletin 9)

Preamble

 This “vignette” is based, in part, on information relevant to the story of morphine found on pages 165-166 of Thomas A. Ban’s “Psychopharmacology” (Baltimore: Williams & Wilkins; 1969).

The isolation of morphine

            Administration of “general anesthetics” (see Bulletin 8, Chapter 3) induces a state characterized by “loss of consciousness” with loss of “sensation” (“anesthesia”), whereas the administration of “narcotic analgesics” induces a state characterized by “impaired consciousness” and diminution of responsiveness to environmental stimuli with “analgesia.”  Analgesia is defined as insensibility to pain without loss of consciousness (Stedman 1990).

             The story of “narcotic analgesics” begins in the early years of the 19^th century with the isolation of “morphium” from opium and its timeline parallels the story of “general anesthetics.” The story of remedies which were to be referred to as “narcotic analgesia” parallels the story of “opium” and it is difficult to determine when and where it begins. The “psychological effects” of opium had been known to ancient Sumerians and its dependency-producing effect to the Greeks. The first undisputed reference to it can be traced to Theophrastus, who lived in the third century BC (Ban 1969).  

            In the early 16^th century Paracelsus (Theophrastus Hohenheim 1493-1541) referred to an opium based elixir, Laudanum, that was a potent “painkiller” (Hartmann 1918; Pichot 1983).             During the 17^th and 18^th centuries opium was extensively used in Britain and in the West “to quiet the mind” of the “insane” and to help those suffering from “insomnia” to sleep. Although opium usually induces a feeling of well-being, it was noted that in the treatment of “madness,” opium could cause “anger” and “sadness”; in the treatment of  “sadness,” opium could have, in the long run, a negative effect (Kramer 1979).           

            The active ingredient of opium, responsible for its somnolence producing and analgesic effects, was first isolated (extracted) from the opium poppy (Papaver Somniferum) between 1803 and 1805 by Friedrich Wilhelm Adam Sertürner (1783-1841), a German pharmacist.  It was the first substance ever isolated from a plant that was responsible for its particular effects, such as, in case of opium, “sleep-inducing analgesic.”  

     The first recorded note by Sertürner about his isolation of a “sleep-inducing” molecule from opium was in a letter to the editor of the Trommsdorff Journal de Pharmacie in 1805.  A year later, in 1806, he followed up his letter in the same journal with a report in which he determined that the substance was a weak base, soluble in acidic solution and described its chemical characteristics. He named the substance “morphium” after the Greek god of sleep and dreams (Sertürner 1806).

            Sertürner continued his research with the substance and, in 1817, published a comprehensive paper on its isolation, crystallization, crystal structure and chemical characterization. He also described some of its pharmacological properties and the effects of orally administered morphium to rats, dogs, himself and others. In these experiments he noted that in different doses the substance had different effects. In a relatively low dose morphium induced happy, light-headed sensations; in a higher dose it caused drowsiness and excessive fatigue; and subjects receiving an even higher dose became somnolent and confused. On the basis of his “findings” in these “experiments,” Sertürner determined the optimal dose (15 mg.) of orally administered morphium for “analgesia” (Sertürner 1817).                

            In 1818, one year after Sertürner published his comprehensive report, the term  “alkaloid” was introduced by Wilhelm Meissner (1792-1853) for nitrogen-containing organic compounds of plant origin with pharmacological action. Since his substance qualified for an “alkaloid,” Sertürner changed its name to “morphine,” to render it comparable to the names of other “alkaloids” by replacing the last three letters in morphium with the suffix, “ine”. By emphasising that morphine was an alkaloid, Sertürner challenged the prevailing notion of the time that all medicinal substances isolated from plants were acidic in nature. His success of developing morphine for clinical use stimulated interest in medicinal substances extracted from plants. By the end of the 19^th century, the “alkaloids” were an important class of drugs used in treatment (Halmai 1966; Huxtable and Schwarz 2001; Jacobsen 1882; Schmitz 1985).           

            Morphine became available for clinical use in 1817 when offered by Sertürner and Company as a pain medication (analgesic); in 1827, production of morphine began in Darmstadt, Germany, by the pharmacy that was to become the pharmaceutical company Merck. In 1833 another natural psychologically active opium alkaloid, “codeine,” was isolated by Pierre Jean Robiquet (1780-1844), and, in 1848, again another, “papaverine” by George Merck (1825-1873), but this one lacked psychological effects. With the growing number of opium alkaloids isolated and studied, it was recognized that they belong to one of two classes: the phenanthrenes, like morphine with, and the benzyl isoquinolines, like papaverine, without psychological effects (Merck 1848; Robiquet 1833).

            With the introduction of the “hypodermic needle” in the 1850s, the story of morphine entered a new phase. The possibility of parenteral administration of morphine broadened the scope of its use for analgesia. It also extended its indications from pain control to the control of hyperactivity, excitement and agitation of patients in mental hospitals (Shorter 1997). The first recorded use of morphine for analgesia by hypodermic needle took place in 1853, but it was reported only two years later (Wood 1855). Subcutaneous morphine for behavioral control was first introduced in 1863 in German mental hospitals (Grunau 1905).  

            In 1880, Albert Ladenburg, a German chemist, extracted “hyoscine” (scopolamine) from hyosciamine, a tropane alkaloid, isolated in 1833 from the henbane species of the Solanacea plant (Issekutz 1971). By the end of the 19^th century, the potent synergistic effect of morphine –hyoscine combinations were recognized and until the introduction of chlorpromazine in the 1950s, parenterally administered morphine-hyoscine combinations remained the primary choice of treatment of patients in need for rapid behavioral control.

             Since the isolation of morphine more than 200 years have passed. During these years numerous other “narcotic analgesics” were introduced. In spite of the availability of many drugs from this class, morphium is still extensively used for the relief of pain, and especially of pain after surgery (Hamilton and Baskett 2000). Irrespective of its clinical use, morphine provided the first means to show that one can affect selectively by drugs the sensory input to the brain that is experienced as pain.   

References:

Ban TA. Psychopharmacology. Baltimore: Williams & Wilkins; 1969.

Grunau H. Frequenz, Heilerforge und Sterblichkeit in den öffentlichen prussischen Irrenanstalten von 1875 bis 1900. Halle: Marhold; 1905. 

Halmai J. The inventor of morphine. (F. W. Sertürner). Orvosi hetilap (in Hungarian) 1966; 107: 895–7. 

Hamilton GR, Baskett TF. In the arms of Morpheus the development of morphine for postoperative pain relief. Can J Anaesth. 2000; 47:367–74. 

Hartmann F. Paracelsus. His Life and Doctrines. New York: Theosophical Publishing Co; 1918 

Huxtable RJ, Schwarz SK. The isolation of morphine - First principles in science and ethics. Mol Interv 2001; 1: 189–91.

Issekutz B. Die Geschichte der Arzneimittelforschung. Budapest: Akademia; 1971.

Jacobsen O. Alkaloide. In: Ladenburg A, ed. Handwörterbuch der Chemie. Breaslau: Edward Trewendt; 1882.

Kramer JC. Opium rampant medical use, misuse and abuse in Britain and in the West in the 17^th and 18^th century. British Journal of Addiction 1979; 74: 377-89.  

Ladenburg A. Lebenserinnerungen, Breslau: Trewendt & Granier; 1912.

Merck G. Vorläufige Notiz über eine neue organische Base im Opium. Annalen der Chemie und Pharmacie. 1848; 66: 125-8.                                                                                        "

Pichot P. A Century of Psychiatry. Paris: Roger Dacosta; 1983.

Robiquet PJ. Neue beobachtungen ueber die vorzürglichsten produkte aus den opium. Annalen der Chemie 1833; 5: 82-111.

Schmitz R. Friedrich Wilhelm Sertürner and the discovery of morphine. Pharm Hist. 1985; 27: 61–74.

Sertürner F. Darstellunng der reinen Mohnsäure nebst einer chemischen untersuchung des Opiums. Journal of Pharmacie 1806; 14: 47-93.

Sertürner F. Ueber das Morphium als Hauptbestandteil des Opiums. Annalen der Physik 1817: 25; 8-89.

Shorter E. A History of Psychiatry. New York: John Wiley and Sons; 1997. 265-81.

Stedman TL. Stedman’s Medical Dictionary. 25^th edition. Baltimore: Williams & Wilkins; 1982. 

Wood A. A new method for treating neuralgia by the direct application of opiates to the painful points. Edinburgh Medical and Surgical Journal 1855; 82: 265-81. 

March 15, 2018