Journal of Anesthesia History xxx (2017) xxxxxx

Contents lists available at ScienceDirect

Journal of Anesthesia History

journal homepage: www.anesthesiahistoryjournal.org

The Chemical History of Morphine: An 8000-year Journey, from Resin

to de-novo Synthesis
physical property
Karolina Brook , Jessica Bennett , Sukumar P. Desai
a b c,
application
a
Department of Anaesthesia, Harvard Medical School Massachusetts General Hospital, Boston, MA
b
Independent Scholar, Richmond, Virginia chemical property
c
Department of Anaesthesia, Harvard Medical School Brigham and Women's Hospital, Boston, MA

a r t i c l e i n f o a b s t r a c t

Article history: Evidence of human use of opium dates back as far as the sixth millennium BCE. Ancient societies through
Received 19 December 2016 the Renaissance period created a variety of opium products, proliferating its common use and subsequent
Received in revised form 6 February 2017 addiction. Because the active moiety was not known at this time, the potency of these opium concoctions
Accepted 8 February 2017
could neither be predicted nor controlled. The rst step in identifying opium's active ingredient, morphine,
Available online xxxx
was its chemical isolation in the early 1800s by Wilhelm Sertrner. The subsequent elucidation of
morphine's chemical formula and Sir Robert Robinson's derivation of morphine's structural formula,
which won him the 1947 Nobel Prize in Chemistry, round out 150 years of the incremental advances in
our chemical understanding of morphine. Nevertheless, our attempts to synthesize morphine, despite
our advanced knowledge in synthetic chemistry, are still no match for the plant-based extraction of
morphine from the poppy plant. The status quo remains problematic socially, economically, and politically;
the relationships between the countries laboriously growing poppy plants to extract morphine and those
countries importing these painkillers are unstable at best. In this study, we contrast the cumulative
scientic discoveries that have led to our current chemical knowledge of morphine with the centuries-
old natural method of morphine production that still dominates the opioid market today.
2017 Anesthesia History Association. Published by Elsevier Inc. All rights reserved.

Introduction allowing us to come closer to achieving a viable synthetic alternative

Plants were the rst source for medications and continue to play
an important role in modern medicine. For instance, D-Tubocurarine,
used for muscle relaxation, is derived from a climbing vine in South
America; the alkaloid scopolamine, which helps with the nausea
associated with motion sickness, comes from the belladonna plant;
and atropine, used to treat a slow heartbeat, naturally occurs in the
nightshade family of plants. Morphine, an alkaloid derived from the
poppy, is one of the best known examples of a plant-derived medi-
cine. The poppy plant has a long history of medicinal use, with mor-
phine being a more recent variant. In this article, we explore each of
the incremental steps in our knowledge of the chemistry of morphine
starting from primitive man and concluding with modern medicine.
We will examine the signicant contributions made by individuals
who improved our understanding of morphine's chemical nature,
for mass commercial use.
From Opium to Morphine
The word for opium comes from ancient Greek , meaning
vegetable juice, and refers to the dried latex derived from the
Opium Poppy (Papaver somniferum, Latin papver poppy; somni
sleep + ferre to bring) (Fig. 1). It is not known how early man deter-
mined that the poppy possessed medicinal properties or how these
properties were discovered. 1 References to the use of the poppy are
found in ancient Greek, 210 Egyptian, 79 Indian, 7,8 Chinese, 68 and
in early Roman texts (Fig. 2).1,2,10,11 Opium use became widespread
in the Middle Ages through the Renaissance period for medicinal pur-
poses as well as for pleasure, leading to addiction in many famous
historical gures.1,4,5,8,1215

This work was supported by intramural funds.

Corresponding author at: Department of Anesthesiology, Perioperative and Pain
Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.
Tel.: +1 617 732 8510; fax: +1 617 277 2192.
E-mail address: sdesai@partners.org (S.P. Desai).
The Identication and Extraction of Morphine
In the mid-1800s, a typical English chemist stocked opium soap,
lead and opium pills, opiate lozenges, opiate plasters, opium enema,

http://dx.doi.org/10.1016/j.janh.2017.02.001
2352-4529/ 2017 Anesthesia History Association. Published by Elsevier Inc. All rights reserved.

Please cite this article as: Brook K, et al. The Chemical History of Morphine: An 8000-year Journey, from Resin to de-novo Synthesis. J Anesth
Hist (2017), http://dx.doi.org/10.1016/j.janh.2017.02.001
2 K. Brook et al. / Journal of Anesthesia History xxx (2017) xxxxxx
Fig. 1. The lanced pod of Papaver somniferum showing extrusion of the opium contain-
ing resin. By KGM007 [Public domain], via Wikimedia Commons.
opium liniment, and other products such as vinegar of opium. 1 At
this point in history, opium tablets and tinctures had retained the
properties of opium resin, the dried latex juice obtained from the
poppy pod which is dehydrated in the sun to obtain the consistency
of beeswax. The potency of these materials that were sold to the
population could not be predicted or controlled until the active
ingredient (which we now know is the alkaloid morphine) was
identied and isolated in the opium resin. 1 This meant that the
same dose of even the same brand of opium product could have
varying levels of potency.
Most of the advances in the nineteenth century took advantage of
the differential solubility of morphine in water, alcohol, and organic
solvents, a process known as extraction, which was rst introduced
by Nicolas Lmery (16451715), a French chemist.14 It is possible mor-
phine was extracted as early as the mid-1600s by Daniel Ludwig
(16251680), the court physician of the Duke of Saxe-Gotha who,
after dissolving opium in an acid and then saturating it with an alkali,
obtained a substance he called Magisterium Opii. 1 Using similar
methods, Robert Boyle (16271691) mixed opium in tartar (potassium
carbonate) and alcohol in an attempt to isolate the active compound
from opium, although he was unsuccessful.14 Jean-Franois Derosne
(17741855), a French apothecary, prepared opium salts which were
likely a mixture of morphine and narcotine, and later in 1803 isolated
narcotine. 10,14,1618 It is believed that Armand Squin (17671835)
presented his experimental ndings in isolating opium's active ingre-
dient to the Institute of France in 18034, although his report to the
Academy of Sciences was not published until 1814. 10,19 Despite all
this, the credit for the isolation of morphine goes to the German
apothecary Friedrich Wilhelm Adam Sertrner (17831841) who
published his isolation of opium's active ingredient in 1805 (Fig. 3).20
Sertrner was born near Paderborn in 1783, and was working as a
pharmacist's assistant when he reported the discovery of the chemical
substance meconic (or poppy) acid in opium in 1805 and successfully
isolated it at the age of only twenty-one.18,20,21 Within the following
year, he reported isolating the active narcotic substance in
opium.18,20,21 He noted that this substance was soluble in acid water
and was precipitated by ammonia, thereby giving it the characteristic
of a weak base.20 He described it as a vegetable alkali. 10,14,18,20 He
named the white crystalline powder morphium, after Morpheus, the
Please cite this article as: Brook K, et al. The Chemical History of Morphine: An 8000-year Journey, from Resin to de-novo Synthesis. J Anesth
Hist (2017), http://dx.doi.org/10.1016/j.janh.2017.02.001
Greek god of dreams.1,2,4,8,10,18,20 He masked the bitter-tasting crystals
with sugar syrup and trialed doses in rats, mice, cats and dogs. 2,8,9
Despite the fact that at least one of the dogs died during these trials,
Sertrner used 100 mg of morphine in himself to relieve pain and
tried it in three other young men as human experimental subjects.2
Sertrner's work was originally largely ignored, and it took over a
decade1 along with the help of French Chemist J.L. Gay-Lussac
(17781850)18 (who changed the name from morphium/morphia
to morphine) before Sertrner's ndings were published in 1817.1
Despite the increased precision and relative increased potency of
Sertrner's isolate, other opium products remained the easiest and
least expensive method to obtain morphine's benecial effects.1 The
commercial production of morphine began as early as the 1820s in
Europe, and the 1830s in the United States,2 but it was not listed in
the London Pharmacopeia until 1836. 7,14 In the 1850s the work of
Charles-Gabriel Pravaz (17911853) and Alexander Wood (1817
1884) led to the creation of the hypodermic needle, and it was this
advance that fueled morphine's meteoric rise in popularity.2 The
combination of the increased potency of morphine over opium and
the ability to inject the solution directly into the bloodstream provided
swifter pain relief.2 These properties propelled the use of morphine in
treating soldiers during the Crimean War (18531856), the American
Civil War (18611865), and the Franco-Prussian war (18701871).2
During the nal years of popular opium-use in the United States
and the patent-medicine craze of the 1880s and 1890s, over 300 patent
medicines containing opium were offered by American companies. 2
Recognition of the science of addiction had nally caught up with
opium and morphine, however, and by the late 1800s the United
States had restricted the importation of opium for smoking, although
it still allowed medicinal opium. 2 In 1912 the United States and
many other countries signed the International Opium Convention
which controlled the import, manufacture and sale of morphine. 22
Soon after, anti-narcotic laws began to appear in many countries.
Morphine's medicinal uses were still numerous however, with oral
morphine being introduced in the 1950s and with dosage regimens
improved in the 1970s and 1980s.22 Although the global commentary
is now changing given the opioid epidemic, as recently as 2013,
morphine was still hailed as the gold standard opioid analgesic
for cancer-related pain. Firmly established as the World Health
Organization's rst choice of strong opioid, morphine is the most
commonly used opioid for moderate to severe pain in people with
cancer in the UK and other European countries and in the United
States for non-malignant pain.22
Discovering the Chemical and Structural Formulae of Morphine
In 1819, just 2 years after Sertrner's publication of his extraction
of morphine, German apothecary C.F. Wilhelm Meissner (1792
1853) identied the type of substance Sertrner had isolated and
called the class of compounds alkaloids (originally Arabic al-qali
soda ash or potash + ancient Greek having the likeness of),
which were originally dened to include all basic molecules derived
from plants. 23 Morphine was the rst successfully identied alkaloid.
The discovery of the chemical formula for morphine was another
step that built upon a lengthy history of invention. Antoine Lavoisier
(17431794), the father of modern chemistry, studied both organic
and inorganic compounds. Lavoisier recognized and named oxygen
and hydrogen, but he also asserted that organic substances were
largely comprised of carbon, hydrogen and oxygen, occasionally
nitrogen, but rarely sulfur and phosphorus.14 It was these analytical
methods that propelled chemistry as a quantitative science. 14
Between 1810 and 1815, J.L. Gay Lussac and Louis Jacques Thnard
(17771857) established methods for the quantitative estimation
of these elements found in organic compounds. 14 Without these
 This page contains the application of morphine
K. Brook et al. / Journal of Anesthesia History xxx (2017) xxxxxx 3

Fig. 2. A timeline highlighting important periods in the history of opium and morphine.

innovations, the formula for morphine and other compounds could
not have been elucidated. 14
In the 1820s and 1830s, Justus von Liebig (18031873) and Henri
Victor Regnault (18101878) determined the chemical formula for
morphine to be C34H36N 2O6 and C35H40N2O6, respectively. 10,24
Although these were very close, especially given the technology and
knowledge of the time, both these formulas were incorrect. In 1847,
August Lauren (18091853), formed salts of morphine by
excluding all humidity and by careful calculation was able to produce
the correct chemical formula for morphine, C34H38N2O6 (which cor-
responds to the now-accepted empirical formula of C17H19NO3).24
The next step was to take the chemical formula and derive the
structural formula for this organic compound from it. This was
achieved by Sir Robert Robinson (18861975). Robinson published
his rst paper on alkaloids in 1907 at the age of 21 on the synthesis
of hydrastic acid (Fig. 4). 25 In 1917, he synthesized the alkaloid
tropinone from acetone and carbinolamine, demonstrating that com-
plex products could be derived from simple starting substances. 25
This became an essential contribution to the chemist's understanding
of the biogenesis of natural products. He went on to the challenging
syntheses of physostigmine and strychnine, before moving onto
morphine. Undertaking this work with John M. Gulland (1898
1947), Robinson began by proposing the hypothetical structure of
dihydrocodeine, and then, based on his own extensive experiments,
he proposed a structure for codeine based on the chemical principle
of aromatization, a chemical property in which some arrangements

Please cite this article as: Brook K, et al. The Chemical History of Morphine: An 8000-year Journey, from Resin to de-novo Synthesis. J Anesth
Hist (2017), http://dx.doi.org/10.1016/j.janh.2017.02.001
4 K. Brook et al. / Journal of Anesthesia History xxx (2017) xxxxxx
Fig. 3. The German apothecary Friedrich Wilhelm Adam Sertrner (17831841) isolated
a crystalline powder from opium and named it morphium. Julius Giere [Public domain],
via Wikimedia Commons.
of the same set of atoms have more stability than other arrangements.
Robinson used this proposed structure to rationalize the rearrange-
ments of morphine, codeine and thebaine. He showed that the
molecular structure of morphine contained a four-ring system, which
he called morphinan; and alkaloids with this ring system are referred
to as morphinan alkaloids (Figs. 5 and 6). 26 Amazingly, he accom-
plished this at a time when spectroscopic, crystallographic and compu-
tational methods were unavailable, and theories of organic reaction
mechanisms still remained to be established. 25,27 Knowledge of the
molecular structure of morphine allowed Robinson and others to de-
termine the structure of papaverine and narcotine, as well as develop
many effective antimalarial drugs.28 Robert Robinson received knight-
hood in 1939 and was awarded the Nobel Prize in Chemistry in 1947.28
The Means of Production of Morphine
There is archeological evidence that opium poppies were being
grown as far back as during the Neolithic and Bronze ages, and likely
Fig. 4. British organic chemist Sir Robert Robinson (18861975) discovered the molecular
structure of morphine. He was awarded the Nobel Prize in Chemistry in 1947. Photograph
copyright The Nobel Foundation.
Please cite this article as: Brook K, et al. The Chemical History of Morphine: An 8000-year Journey, from Resin to de-novo Synthesis. J Anesth
Hist (2017), http://dx.doi.org/10.1016/j.janh.2017.02.001
Fig. 5. The chemical structure of morphine. Reproduced with permission from
Dreamstime.com.
originated in the northeastern part of the Mediterranean in Asia
Minor and Turkey.8,11 Opium was introduced to India, speculatively
by Alexander the Great in the fourth century, or by invading armies
in the eighth century, although the fteenth century marks the rst
recorded cultivation in India.11,18 Also, in the fourth century, opium
from Egypt begins to appear in China. 29 It was reintroduced in
Europe in the 1500s after Portuguese explorers discovered its usage
in China.29 Colonization and globalization provided Europeans with
knowledge from countries that had continued to make scientic dis-
coveries during the Dark Ages, but also led to exploitation, trade and
diplomatic disagreements, and the systemic smuggling of opium.29
The Opium Wars erupted between China and the British Empire,
WHO controlled the export of Indian opium to China.1,2,8,9,29 The sins
committed by the Western World in the opium trade alone are legion
and beyond the scope of this article but must be acknowledged. The
process to obtain opium from the poppy plant and then to extract the
alkaloid morphine is a laborious problem one that the Western estab-
lishment has long left to underpaid workers in Middle Eastern coun-
tries. In the 1990s, Afghanistan was still the largest producer of
opium. 30 The unstable relationships between many of the countries
reliant on the poppy plant for the foundations of its painkillers and
the countries where the plant is most popularly grown may be one of
the driving forces in the efforts to produce a synthetically created alter-
native. Although total success has not yet been achieved, a lengthy
history of progress has propelled the scientic and medical community
ever closer to realizing its goal.
The Natural Method of Morphine Production
P. somniferum is an annual herb that grows up to 1.5 m in height,
possesses elongated ovate leaves, and has white, pink or purple
owers. 6,7,11,26 The poppy blossoms in AprilMay, maturing in
MayJuly. 11,18 Each plant bears 58 capsules. 11,18 As the capsules
ripen, they change from blue-black to yellow-white in color.11
The opium latex is present throughout the poppy plant but is
concentrated in the developing fruit, likely serving an evolutionary
purpose to protect the seeds for the next generation. 8 The owers
of the poppy mature into capsules, which contain the latex.26 Around
15 days after petal fall, while the capsule is still unripe, a milky/pink
opium latex is exuded by cutting the capsule cross-wise, taking care
to avoid cutting through the capsule wall, which would lead to
leakage of latex within the interior of the capsule. 4,6,8,11,18,19,26
Opium is only present in the wall of the maturing capsule for up to
10 days of its entire life cycle and will contain up to four times
more morphine if the latex is collected in the early morning. 8
Although liquid at rst, the white droplets quickly turn into a brown
semi-solid.11,26 The same capsule can be lanced up to 45 times over
the week to yield more opium latex with the third lancing purportedly
 K. Brook et al. / Journal of Anesthesia History xxx (2017) xxxxxx
Fig. 6. A 3-dimensional ball and stick model representing morphine (C17H19NO3). Black (carbon), white (hydrogen), red (oxygen), blue (nitrogen). Reproduced with permission
from Dreamstime.com.
producing the best yield.6,11 By the morning following each lancing,
this latex turns black and can be scraped off the capsule with an iron
scoop and then collected.6,11,26 However, rainy weather between the
incision and collection can ruin the harvest. 26 The raw opium is
kneaded into balls wrapped in poppy leaves, and is dehydrated
through baking in the sun, creating a black resinous gum. 4,6,11,19
Methods to obtain natural supplies have not drastically changed
since antiquity, and even today opium is harvested manually using
the methods described by Dioscorides, a Greek botanist-physician
(c. 4090), although today no truly wild opium poppies exist.4,8,12
Since the process described above is extremely laborious, mor-
phine is now increasingly obtained from poppy straw; a by-product
of poppy cultivation for use of the poppy seeds. The poppy straw is
obtained from cutting and drying the dried capsule and stem of
P. somniferum and then crushing and dissolving the dry poppy capsules
to form a dark liquid. The liquid is then mixed with acids, dried in
centrifuges and ovens, to form a poppy straw concentrate.6,11,16,26
The Synthetic Means of Morphine Production
The structure of morphine proposed by Robert Robinson could
only be conrmed 27 years later by Marshall D. Gates, Jr. (1915
2003) and his co-worker Gilg Tschudi who performed the rst total
synthesis of morphine in 1952. 4,31 Total synthesis (the construction
of a compound from simple compounds that are available commer-
cially) of morphine would allow scientists, in very simplied terms,
to create morphine from scratch, rather than extract it from the
poppy plant. Although the structure of the morphine molecule was
known, the long period between structure identication and the
achievement of synthesis was a result of the numerous difculties
encountered in the challenging synthesis, as well as technological
barriers. Gates, Jr. and Tschudi's technique did not employ tools
commonplace today such as NMR spectroscopy that can be used to
determine the chemical and physical properties of a molecule.
Instead, they had to break apart each component. By creating
chemical derivatives of morphine that had a similar structure (called
derivatization studies), and studying how natural morphine degraded,
they were able to determine the identities of synthetic intermediates.
In other words, they were able to determine its composition by
identifying its breakdown products. They then used melting points
and infrared spectra to conrm the identities of these compounds.3234
One of the reasons it took until 1952 for this synthesis to be com-
pleted was that it was only in 1950 that Otto Diels (18761954)
and Kurt Alder (19021958) discovered the eponymous chemical
reaction that was critical in the synthesis of morphine. 35 For this
Please cite this article as: Brook K, et al. The Chemical History of Morphine: An 8000-year Journey, from Resin to de-novo Synthesis. J Anesth
Hist (2017), http://dx.doi.org/10.1016/j.janh.2017.02.001
5
accomplishment they were awarded the 1950 Nobel Prize in Chemis-
try. The Diels-Alder reaction, along with several oxidations, reduc-
tions and isomerizations (the transfer of one molecule into another
molecule that has the same atoms but in a different arrangement),
brought about the synthesis of codeine. 32,33 Once the production
of codeine was achieved, the nal step was its conversion into a par-
ticular mixture of morphine called racemic morphine by removing
carbon and hydrogen atoms. This process had been previously
described by Rapoport, Lovell and Tolbert, 3 chemists at Berkley in
1951, and is still used frequently as an illicit means of turning
codeine-based pharmaceuticals into morphine and heroin. 36 The
total synthesis of morphine required 28 steps.31
By using chemical synthesis and X-ray crystallography, the rela-
tive spatial arrangements of the molecules in morphine were found
to be arranged in ve chiral centers, notated as 5R, 6S, 9R, 13S,
14R. 3741 A chiral center is a carbon atom in a molecule that is
surrounded by four atoms; each of a different element. 42 When a
plant (in this case, the poppy) creates morphine, it replicates an
exact arrangement of molecules that follow the chiral center cong-
uration cited above. When done synthetically in a laboratory howev-
er, chemical reactions generally produce a 50:50 mix (racemic
mixture) of the natural compound as well as its mirror image (its
enantiomer).42 The pharmacologically active ()-morphine isomer
occurs naturally while the articially synthesized (+)-morphine
enantiomer has been found to have no analgesic properties. 37,43 If
synthetic morphine is to be used in the future, this information is
imperative in order to produce the most potent medication.
Since Gates's publication of his synthesis, almost every decade has
brought about new attempts to synthesize morphine, all trying to
compete with the natural harvesting process. 44 A truly practical
synthetic route to morphine, which ideally would be produced in
68 steps from inexpensive materials and would compete with
natural supplies, is still elusive, partly because of the low-wage
investment in the areas harvesting opium today. 4,34,45 It is still
cheaper to grow and harvest the poppy plant than to produce
morphine in a laboratory since those doing the physical work are
not being paid substantial wages. To date, the only process that has
the possibility of competitive large scale production was described
by Kenner C. Rice (1940) and his co-workers in 1980.34
Conclusion
Morphine, the world's rst true drug, and the active ingredient in
one of man's oldest medical remedies, is currently obtained using
techniques largely unchanged over eight millennia. It is a drug that
6 K. Brook et al. / Journal of Anesthesia History xxx (2017) xxxxxx
has stood the test of time, and it remains one of the most commonly
used drugs for the control of severe pain. This story highlights the
challenges that were overcome in identifying the structure of
morphine, and it parallels the advances made in structural chemistry,
culminating in the 1947 Nobel Prize in Chemistry being awarded to
Robinson for elucidating morphine's chemical structure. In spite of
these successes, human ingenuity in mass production and advanced
synthetic chemistry are still no match for the far more economical
and efcient plant-based extraction. Our persistent inability to
synthesize an alternative that would overcome morphine's greatest
drawbacks of respiratory depression and drug dependence is another
glaring failure. The contrast of our successes and failures in
morphine's story is truly humbling.
References
1. Davenport-Hines RPT. The Pursuit of Oblivion: A Global History of Narcotics.
New York: Norton; 2002.
2. Hodgson B. In the Arms of Morpheus: The Tragic History of Laudanum, Morphine,
and Patent Medicines. Buffalo, New York: Firey Books; 2001.
3. Cumston CG. An Introduction to the History of Medicine from the Time of the
Pharaohs to the end of the XVIIIth Century. New York: Dorset Press; 1987.
4. Blakemore PR, White JD. Morphine, the Proteus of organic molecules. Chem
Commun. 2002;38:59-68.
5. Nicolaou KC, Montagnon T. Morphine. In: Nicolaou KCMT, ed. Molecules that
Changed the World. New York: Wiley-VCH; 2008.
6. White PT, Raymer S. The poppy. Natl Geogr. 1985;167:142-188.
7. Wink M, van Wyk BE. Mind-Altering and Poisonous Plants of the World. Portland,
Oregon: Timber Press, Inc.; 2008.
8. Sumner J. The Natural History of Medicinal Plants. Portland, Oregon: Timber Press, Inc.;
2000.
9. Mann J. Murder, Magic, and Medicine. 2nd ed. Oxford, UK: Oxford University Press;
2000.
10. University of the Sciences in Philadelphia. Remington: The Science and Practice of
Pharmacy. 21st ed. Philadelphia: Lippincott Williams & Wilkins; 2006.
11. Tyler VE, Brady LR, Robbers JE. Alkaloids. In: Tyler VE, Brady LR, Robbers JE, eds.
Pharmacognosy. 9th ed. Philadelphia: Lee & Febiger; 1988.
12. Friedman M, Friedland GW. Crawford Long and surgical anesthesia. In: Friedman
M, Friedland GW, eds. Medicine's 10 Greatest Discoveries. New Haven, Connecticut:
Yale University Press; 1988.
13. Schwarcz J. The Right Chemistry: A History of Morphine. Montreal: Gazette; 2016.
[http://montrealgazette.com/opinion/columnists/the-right-chemistry-a-history-
of-morphine].
14. Trease GE. Pharmacy in History. London: Baillire, Tindall and Cox; 1964.
15. Singer K. Stoned Shelley: revolutionary tactics and women under the inuence.
Stud Romant. 2009;48:687-707.
16. Cordell GA. Introduction to Alkaloids: A Biogenic Approach. New York: John Wiley &
Sons Inc.; 1981.
17. Derosne JF. Mmoires sur l'opium. Ann Chim. 1803;45:257-285.
18. Ebadi M. Pharmacodynamic Basis of Herbal Medicine. Boca Raton, Florida: CRC
Press; 2002.
Please cite this article as: Brook K, et al. The Chemical History of Morphine: An 8000-year Journey, from Resin to de-novo Synthesis. J Anesth
Hist (2017), http://dx.doi.org/10.1016/j.janh.2017.02.001
19. Bentley KW. The Chemistry of the Morphine Alkaloids (Monographs on the Chemistry
of Natural Products). Oxford, UK: Clarendon Press; 1954.
20. Sertrner FWA. Darstellung der reinen Mohnsure (Opiumsure) nebst einer
Chemischen Untersuchung des Opiums mit vorzglicher Hinsicht auf einendarin
neu entdeckten Stoff und die dahin gehrigen Bemerkungen. J Pharme rzte,
Apoth Chem. 1806;14:47-93.
21. Jurna I. Sertrner and morphium a historical vignette. Schmerz. 2003;17:
280-283.
22. Bryan J. Even today, morphine remains a popular opioid analgesic for cancer-related
pain. Pharm J. 2013. [http://wwwpharmaceutical-journalcom/news-and-analysis/
news/even-today-morphine-remains-a-popular-opioid-analgesic-for-cancer-related-
pain/11120070article].
23. Meissner W. Uber Panzenalkalien: II. Uber ein neues panzenalkali (alkaloid).
J Chem Phys. 1819;25:379-381.
24. Laurent A. Sur la composition des alcalis organiques et de quelques combinaisons
azoles. Ann Chim Phys. 1847;19:359-361.
25. Bentley KW. Sir Robert Robinson. Nat Prod Rep. 1987;4:13-23.
26. Samuelsson G. Drugs of Natural Origin: A Textbook of Pharmacognosy. 4th ed.
Stockholm, Sweden: Apotekarsocieteten (Swedish Pharmaceutical Press); 1999.
27. Gulland JM, Robinson R. The constitution of codeine and thebaine. Mem Lit Philos
Soc Manch. 1925;69:79-86.
28. NobelMedia AB. Sir Robert Robinson - biographical. http://www.nobelprize.org/
nobel_prizes/chemistry/laureates/1947/robinson-bio.html 2013.
29. Booth M. Opium: A History. London: Simon & Schuster, Ltd.; 1996.
30. Berridge V. Opium: Pleasure and pain. In: Bynum W, Bynum H, eds. Great
Discoveries in Medicine. New York: Thames & Hudson; 2011.
31. Maier M. Synthesis of morphine. In: Waldmann H, ed. Organic Synthesis Highlights
II. New York: VCH Publishers; 1995:357-370.
32. Gates M, Tschudi G. The synthesis of morphine. J Am Chem Soc. 1952;74:1109-1110.
33. Gates M, Tschudi G. The synthesis of morphine. J Am Chem Soc. 1956;78:1380-1393.
34. Rinner U, Hudlicky T. Synthesis of morphine alkaloids and derivatives. Top Curr
Chem. 2012;309:33-66.
35. NobelMedia AB. The Nobel Prize in chemistry 1950. http://www.nobelprize.org/
nobel_prizes/chemistry/laureates/1950/ 2013.
36. Rapoport H, Lovell CH, Tolbert BM. The preparation of morphine-N-methyl-C14.
J Am Chem Soc. 1951;73:5900.
37. Abraham DJ. Burger's Medicinal Chemistry and Drug Discovery. 6 vol. setHoboken,
New Jersey: Wiley-Interscience; 2003.
38. Bentley KW, Cardwell H. The morphinethebaine group of alkaloids. Part IV. The
absolute stereochemistry of the morphine, benzylisoquinoline, aporphine, and
tetrahydroberberine alkaloids. J Chem Soc. 1955:3245-3252.
39. Kalvoda J, Buchschacher P, Jeger O. ber die absolute Konguration des Morphins
und verwandter Alkaloide. Helv Chim Acta. 1955;38:1847-1856.
40. Mackay M, Hodgkin DC. A crystallographic examination of the structure of
morphine. J Chem Soc. 1955:3261-3267.
41. Rapoport H, Lavigne JB. Stereochemical studies in the morphine series. The
relative conguration at carbons thirteen and fourteen. J Am Chem Soc. 1953;75:
5329-5334.
42. Unknown. Chirality. A Primer (Updated). Opiophilia; 2012. [http://opiophilia.
blogspot.com/2012/12/chirality-primer.html].
43. Casy AF, Dewar GH. The Steric Factor in Medicinal Chemistry. Dissymetric Probes of
Pharmacological Receptors. New York: Plenum Press; 1993.
44. Bentley KW. Beta-phenylethylamines and the isoquinoline alkaloids. Nat Prod Rep.
2000;17:247-268.
45. Novak BH, Hudlicky T, Reed J, Mulzer J, Trauner D. Morphine synthesis and
biosynthesis - an update. Curr Org Chem. 2000;4:343-362.