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History of antipyretic analgesic therapy
History of Antipyretic Analgesic Therapy
HANS HAAS, M.D. Bad Herrenalb,
West Germany
The use of naturally occurring plant materials for the relief of pain dates back to 3,000 B.C., although rapid advances in aintipyretic analgesic therapy have been made more recently. Salicylic acid was synthesized in 1860, and the pyrazolone group, first represented by antipyrine, in 1883. Phenacetin was developed in 1886. Acetaminophen has been in use since the 1890s. For thousands of years, physicians and chemists obtained their products exclusively from nature, “the dispensary of God.” Pain-relieving remedies were among the first to be used therapeutically; the first historically documented attempt to relieve pain dates back to 3,000 B.C. The use of henbane and poppy as pain killers is contained in the Papyrus of Ebers, and a Babylonian clay slab from this period gives instructions for filling decaying teeth with a cement-like substance, mixed with henbane. From the classical era, it is known that Hippocrates, Dioscorides, Celsus, and Galen used poppy juice, henbane, and mandragora for pain relief. Galen and Alexander of Tralles had already warned about overdosing. Purging, sweat-inducing cures, bleeding, and the therapeutic benefits of the willow for combating pain were also known in the classical age. In the German literature, the use of willow bark was first mentioned in the works of Heilige Hildegard of Bingen and Konrad of Megenberg. It is also mentioned in the herbal remedies described by Hieronymus Bosch and Leonhard Fuchs. Because of their contracting effect, barks, sap, and ashes were recommended in the Middle Ages to prevent hematemesis and hemafecia. SALICYLATES In 1805, the chemist Sertiirner extracted morphine from poppies [ 1,2], and in 1806, during the time of the Napoleonic blockade of the continent, the bark of the silver willow, Salix alba, was first used as an antipyretic. Following this development, numerous plant alkaloids and glycosides were added, and in 1831 Leroux [3] isolated the crystalline, glycoside salicin, from willow bark. Eight years later, Piria [4,5] procured an acid from salicin, which he named salicylic acid. This was first used therapeutically when Kolbe [6,7] synthesized it in 1860. Kolbe then erected a factory at Heyden for this synthesizing process, and salicylic acid synthesis became the basis for a large pharmaceutical/chemical industry. The sodium salt of salicylic acid was introduced as an antipyretic by Buss [8,9] in 1875; in the following year, Stricker [lo] discovered
From the Department of Clinicum Mannheim of University Heiilbsrg, Mennheim, West Germany. Requests for reprints should be addressed to Dr. Hans Heas, Ett!ingerstr. 10, D-7506 Bad Herrenalb, West Germany.
that salicylic
acid in large doses was very effective
in the treatment
of rheumatic fever. In 1879 Campbell observed the dispersal of uric acid following the administration of salicylic acid, and he recommended its use for the treatment of gouty arthritis.
November 14, 1983
The American Journal of Medlclne
1
ANTIPYRETIC ANALGESICS SYMPOSIUM-HAAS
The first synthetically produced conversion product of salicylic acid was the acetic acid ester, which Gilm [ 1 I] synthesized in 1859. This gained therapeutic importance when Dreser [ 121 discovered its strong fever-reducing effect in 1899 and named it aspirin. Since then, this analgesic and anti-inflammatory agent has been used in large quantities. It has been the standard reference drug ever since. PYRAZOLONES Twenty-three years after Kolbe’s synthesis of salicylic acid, Knorr [ 131, while investigating quinine synthesis, discovered antipyrine. In 1884 Filehne [ 141 showed that this agent had an anti-inflammatory effect. The compound gained such therapeutic and scientific significance that mass production appeared very profitable to the Hoechst Chemical Company. Since that time, pyrazolones have played a large part in therapy of inflammatory disorders, especially as amidopyrine (Pyramidon), until its withdrawal from the market in Sweden, the United Kingdom, the United States (in 1978), and Germany because of its potential to induce agranulocytosis, first described clinically by Madison and Squier [ 151 in 1934. A number of analgesics and antipyretics are derived from pyrazole or dioxypyrazole. Most were developed for water-soluble preparations, which (unlike the insoluble amidopyrine) can be safely given by injection. All compounds of this group have analgesic, antipyretic, and anti-inflammatory properties. PHENACETIN A third group of mild analgesics was also discovered by chance. The inadvertent prescription of acetanilid, rather than naphthalene, by a Strasbourg pharmacy resulted in the discovery of its antipyretic properties.
Acetanilid was used therapeutically by Cahn and Hepp [ 161 in 1886. Because acetanilid reduces fever rapidly, it was named antifebrin. In vitro, it is oxidized to paminophenol, a finding that led to the synthesis of phenacetin (acetophenetidin). This was tested by Hinzberg and Kast [ 171 in 1887 and in 1888 by Mahnert [ 181. Its therapeutic success led to substitution of acetic acid with other acids, for example, lactophenin [ 191, In 1953, however, adverse effects of phenacetin were reported by Spuhler and Zollinger [20].
ACETAMINOPHEN Paracetamol (acetaminophen) was introduced into clinical practice by von Mering in 1893 [21]. However, it was not used extensively until 1943, when Brodie and Axelrod [22,23] recognized paracetamol as the main metabolite of phenacetin and the active analgesic form. Acetaminophen had already been synthesized by Morse in 1878 [24] and subsequently produced by numerous methods [ 25-271. Acetaminophen (Tylenol) was first marketed in the United States in 1955 by McNeil Laboratories. It is now the best-selling analgesic in this country.
COMMENTS Considering the amount of research devoted to developing new analgesics during the past century, it is surprising that relatively few have managed to find a permanent place in pain therapy. Equally surprising is that despite the use of these preparations for over 75 years, therapeutic discoveries are still being made, including the platelet aggregation blocking effect of salicylic acid [28] and the inhibition of prostaglandin synthetase by analgesic preparations [29-3 11.
REFERENCES 1. 2.
3. 4. 5. 6. 7.
8. 9.
2
Sertiirner FW: Auszuge aus briefen an den herausgeber. Tromsdorf J Pharm 1805; 13: 227-257. Serkirner FW: Darstellung der reinen mohn.s&re (opiumsaure) nebst einer them. Untersuchung des opiums. Tromsdorf J Pharm 1806; 14: 47-93. Leroux M: Discovery of salicine. J Chim M&d 1830; 6: 341. Piria R: Sur la composition de la salicine et quelques-unes de ses reactiones. CR Acad Sci 1838; 6: 620-624. Piria R: Recherches sur la salicine et les produits qui en devirent. Ann Chim Phys 1838; 69: 281-325. Kolbe H: Uber die synthese der salicyldure. Liebigs Ann 1860; 113: 125-127. Kolbe H: Uber eine neue darstellungsmethode und einige bemerkenswerte eigenschaften der salicylsaure. J Prakt Chem 1874; 10: 89-112. Buss CE: Uber die anwendung der salicylsaure als antipyretikum. Dtsch Arch Klin Med 1875; 15: 457-501. Buss CE: Zur antipyretischen bedeutung der salicylsaure und des neutralen salicylsauren natrons. Stuttgart: F. Enke 1876.
November 14, 1993
The American Journal of Medicine
10.
11. 12. 13. 14. 15. 16. 17. 18. 19.
Stricker F: Uber die resultate der behandlung der polyarthritis rheumatica mit salicylsaure. Berl Klin Wochenschr 1876; 13: 1-2, 15-16,99-103. Gilm von H: Acetylderivate der phloretin- und salicylsaure. Liebigs Ann 1859; 112: 180-182. Dreser H: Pharmacologisches uber aspirin (acetylsalicylsaure). Pflugers Arch Ges Phys 1899; 76: 306-318. Knorr L: Einwirkung von acetessigester auf phenylhydrazin. Ber Dtsch Chem Ges 1883; 16: 2597-2599. Filehne W: Uber das Pyramindon, ein antipyrindervato. Berliner Klin Wochenschr 1896; 33: 1061-1063. Madison FW, Squier HB: Etiology of primary granulocytopenia (agranulocytic angina). JAMA 1934; 102: 755. Cahn A, Hepp P: Das antifebrin, ein neues fiebermittel. Zentralbl Klin Med 1886; 33: 561-564. Hinzberg 0, Kast A: Uber die wirkung des acetophenetidin. Zentralbl Med Wissensch 1887; 25: 145-148. Mahnert F: Uber phenacetin vom klinischen u. physiologischen standpunkte. Dtsch Med Wschr 1888; 14: 1027-1030. Strauss H: Uber lactophenin. Ther Mh 1894; 8: 442-448,
ANTIPYRETIC
20.
21. 22.
23.
24.
25.
509-513. Splihler 0, Zollinger HU: Die chronische interstitielle nephritis. 2 Klin Med 1953; 151: l-10. Mehring von I: Beitrage zur Kenntniss der antipyretica. Therapeutische Monatsschrift 1893; 7: 577-579. Brodie 88, Axelrod AE: The fate of acetophenetidin (phenacetin) in man and methods for the estimation of acetophenetidin and its metabolites in biological material. J Pharmacol Exp Ther 1949; 97: 58-67. Brodie BB, Axelrod AE: The estimation of acetanilide and its metabolic products, aniline, n-acetyl-p-aminophenol and p-aminophenol (free and total conjugated) in biological fluids and tissues. J Pharmacol Exp Ther 1948; 94: 22-28. Morse HN: Uber eine neue darstellungsmethode des acetylaminophenols. Ber Dtsch Chem Ges 1878; 11: 232233. Bergmann M. Stern F: Verfahren zur gewinnung von acetylderivaten aus aminoverbindunoen. Chem Zentralbl 1928; I, 2663, DRP 453,577.
26.
27.
28.
29.
30.
3 1.
ANALGESICS
SYMPOSIUM-HAAS
Fierz-David HE, Kuster W: Zur kenntnis homologer reihen acylierter azofarbstoffe aus o- und pAcylamino-phenolen u. 1,7-Acylaminonaphtholen. Helv Chim Acta 1939; 22: 82-l 12. Pearson DE, Carter KN, Geer CM: The rearrangement of hydrazones and semicarbazones. J Am Chem Sot 1953; 75: 5905-5908. Breddin K, Scharrer J, Schepping M: Die hemmung der plattchenaggregation mit acetylsalicylsaure. Munch Med Wochenschr 1971; 113: 1285-1288. Ferreira SH, Moncada S, Vane JR: lndomethacin and aspirin abolish prostaglandin release from spleen. Nature (New Biol) 1971; 231: 237-239. Vane JR: Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs, Nature (New Biol) 1971; 231: 232-236. Vane JR: The release and fate of vaso-active hormones in the circulation. Br J Pharmacol 1969; 35: 209-242.
November
14, 1983
The American
Journal of Medicine
3
HANS HAAS, M.D. Bad Herrenalb,
West Germany
The use of naturally occurring plant materials for the relief of pain dates back to 3,000 B.C., although rapid advances in aintipyretic analgesic therapy have been made more recently. Salicylic acid was synthesized in 1860, and the pyrazolone group, first represented by antipyrine, in 1883. Phenacetin was developed in 1886. Acetaminophen has been in use since the 1890s. For thousands of years, physicians and chemists obtained their products exclusively from nature, “the dispensary of God.” Pain-relieving remedies were among the first to be used therapeutically; the first historically documented attempt to relieve pain dates back to 3,000 B.C. The use of henbane and poppy as pain killers is contained in the Papyrus of Ebers, and a Babylonian clay slab from this period gives instructions for filling decaying teeth with a cement-like substance, mixed with henbane. From the classical era, it is known that Hippocrates, Dioscorides, Celsus, and Galen used poppy juice, henbane, and mandragora for pain relief. Galen and Alexander of Tralles had already warned about overdosing. Purging, sweat-inducing cures, bleeding, and the therapeutic benefits of the willow for combating pain were also known in the classical age. In the German literature, the use of willow bark was first mentioned in the works of Heilige Hildegard of Bingen and Konrad of Megenberg. It is also mentioned in the herbal remedies described by Hieronymus Bosch and Leonhard Fuchs. Because of their contracting effect, barks, sap, and ashes were recommended in the Middle Ages to prevent hematemesis and hemafecia. SALICYLATES In 1805, the chemist Sertiirner extracted morphine from poppies [ 1,2], and in 1806, during the time of the Napoleonic blockade of the continent, the bark of the silver willow, Salix alba, was first used as an antipyretic. Following this development, numerous plant alkaloids and glycosides were added, and in 1831 Leroux [3] isolated the crystalline, glycoside salicin, from willow bark. Eight years later, Piria [4,5] procured an acid from salicin, which he named salicylic acid. This was first used therapeutically when Kolbe [6,7] synthesized it in 1860. Kolbe then erected a factory at Heyden for this synthesizing process, and salicylic acid synthesis became the basis for a large pharmaceutical/chemical industry. The sodium salt of salicylic acid was introduced as an antipyretic by Buss [8,9] in 1875; in the following year, Stricker [lo] discovered
From the Department of Clinicum Mannheim of University Heiilbsrg, Mennheim, West Germany. Requests for reprints should be addressed to Dr. Hans Heas, Ett!ingerstr. 10, D-7506 Bad Herrenalb, West Germany.
that salicylic
acid in large doses was very effective
in the treatment
of rheumatic fever. In 1879 Campbell observed the dispersal of uric acid following the administration of salicylic acid, and he recommended its use for the treatment of gouty arthritis.
November 14, 1983
The American Journal of Medlclne
1
ANTIPYRETIC ANALGESICS SYMPOSIUM-HAAS
The first synthetically produced conversion product of salicylic acid was the acetic acid ester, which Gilm [ 1 I] synthesized in 1859. This gained therapeutic importance when Dreser [ 121 discovered its strong fever-reducing effect in 1899 and named it aspirin. Since then, this analgesic and anti-inflammatory agent has been used in large quantities. It has been the standard reference drug ever since. PYRAZOLONES Twenty-three years after Kolbe’s synthesis of salicylic acid, Knorr [ 131, while investigating quinine synthesis, discovered antipyrine. In 1884 Filehne [ 141 showed that this agent had an anti-inflammatory effect. The compound gained such therapeutic and scientific significance that mass production appeared very profitable to the Hoechst Chemical Company. Since that time, pyrazolones have played a large part in therapy of inflammatory disorders, especially as amidopyrine (Pyramidon), until its withdrawal from the market in Sweden, the United Kingdom, the United States (in 1978), and Germany because of its potential to induce agranulocytosis, first described clinically by Madison and Squier [ 151 in 1934. A number of analgesics and antipyretics are derived from pyrazole or dioxypyrazole. Most were developed for water-soluble preparations, which (unlike the insoluble amidopyrine) can be safely given by injection. All compounds of this group have analgesic, antipyretic, and anti-inflammatory properties. PHENACETIN A third group of mild analgesics was also discovered by chance. The inadvertent prescription of acetanilid, rather than naphthalene, by a Strasbourg pharmacy resulted in the discovery of its antipyretic properties.
Acetanilid was used therapeutically by Cahn and Hepp [ 161 in 1886. Because acetanilid reduces fever rapidly, it was named antifebrin. In vitro, it is oxidized to paminophenol, a finding that led to the synthesis of phenacetin (acetophenetidin). This was tested by Hinzberg and Kast [ 171 in 1887 and in 1888 by Mahnert [ 181. Its therapeutic success led to substitution of acetic acid with other acids, for example, lactophenin [ 191, In 1953, however, adverse effects of phenacetin were reported by Spuhler and Zollinger [20].
ACETAMINOPHEN Paracetamol (acetaminophen) was introduced into clinical practice by von Mering in 1893 [21]. However, it was not used extensively until 1943, when Brodie and Axelrod [22,23] recognized paracetamol as the main metabolite of phenacetin and the active analgesic form. Acetaminophen had already been synthesized by Morse in 1878 [24] and subsequently produced by numerous methods [ 25-271. Acetaminophen (Tylenol) was first marketed in the United States in 1955 by McNeil Laboratories. It is now the best-selling analgesic in this country.
COMMENTS Considering the amount of research devoted to developing new analgesics during the past century, it is surprising that relatively few have managed to find a permanent place in pain therapy. Equally surprising is that despite the use of these preparations for over 75 years, therapeutic discoveries are still being made, including the platelet aggregation blocking effect of salicylic acid [28] and the inhibition of prostaglandin synthetase by analgesic preparations [29-3 11.
REFERENCES 1. 2.
3. 4. 5. 6. 7.
8. 9.
2
Sertiirner FW: Auszuge aus briefen an den herausgeber. Tromsdorf J Pharm 1805; 13: 227-257. Serkirner FW: Darstellung der reinen mohn.s&re (opiumsaure) nebst einer them. Untersuchung des opiums. Tromsdorf J Pharm 1806; 14: 47-93. Leroux M: Discovery of salicine. J Chim M&d 1830; 6: 341. Piria R: Sur la composition de la salicine et quelques-unes de ses reactiones. CR Acad Sci 1838; 6: 620-624. Piria R: Recherches sur la salicine et les produits qui en devirent. Ann Chim Phys 1838; 69: 281-325. Kolbe H: Uber die synthese der salicyldure. Liebigs Ann 1860; 113: 125-127. Kolbe H: Uber eine neue darstellungsmethode und einige bemerkenswerte eigenschaften der salicylsaure. J Prakt Chem 1874; 10: 89-112. Buss CE: Uber die anwendung der salicylsaure als antipyretikum. Dtsch Arch Klin Med 1875; 15: 457-501. Buss CE: Zur antipyretischen bedeutung der salicylsaure und des neutralen salicylsauren natrons. Stuttgart: F. Enke 1876.
November 14, 1993
The American Journal of Medicine
10.
11. 12. 13. 14. 15. 16. 17. 18. 19.
Stricker F: Uber die resultate der behandlung der polyarthritis rheumatica mit salicylsaure. Berl Klin Wochenschr 1876; 13: 1-2, 15-16,99-103. Gilm von H: Acetylderivate der phloretin- und salicylsaure. Liebigs Ann 1859; 112: 180-182. Dreser H: Pharmacologisches uber aspirin (acetylsalicylsaure). Pflugers Arch Ges Phys 1899; 76: 306-318. Knorr L: Einwirkung von acetessigester auf phenylhydrazin. Ber Dtsch Chem Ges 1883; 16: 2597-2599. Filehne W: Uber das Pyramindon, ein antipyrindervato. Berliner Klin Wochenschr 1896; 33: 1061-1063. Madison FW, Squier HB: Etiology of primary granulocytopenia (agranulocytic angina). JAMA 1934; 102: 755. Cahn A, Hepp P: Das antifebrin, ein neues fiebermittel. Zentralbl Klin Med 1886; 33: 561-564. Hinzberg 0, Kast A: Uber die wirkung des acetophenetidin. Zentralbl Med Wissensch 1887; 25: 145-148. Mahnert F: Uber phenacetin vom klinischen u. physiologischen standpunkte. Dtsch Med Wschr 1888; 14: 1027-1030. Strauss H: Uber lactophenin. Ther Mh 1894; 8: 442-448,
ANTIPYRETIC
20.
21. 22.
23.
24.
25.
509-513. Splihler 0, Zollinger HU: Die chronische interstitielle nephritis. 2 Klin Med 1953; 151: l-10. Mehring von I: Beitrage zur Kenntniss der antipyretica. Therapeutische Monatsschrift 1893; 7: 577-579. Brodie 88, Axelrod AE: The fate of acetophenetidin (phenacetin) in man and methods for the estimation of acetophenetidin and its metabolites in biological material. J Pharmacol Exp Ther 1949; 97: 58-67. Brodie BB, Axelrod AE: The estimation of acetanilide and its metabolic products, aniline, n-acetyl-p-aminophenol and p-aminophenol (free and total conjugated) in biological fluids and tissues. J Pharmacol Exp Ther 1948; 94: 22-28. Morse HN: Uber eine neue darstellungsmethode des acetylaminophenols. Ber Dtsch Chem Ges 1878; 11: 232233. Bergmann M. Stern F: Verfahren zur gewinnung von acetylderivaten aus aminoverbindunoen. Chem Zentralbl 1928; I, 2663, DRP 453,577.
26.
27.
28.
29.
30.
3 1.
ANALGESICS
SYMPOSIUM-HAAS
Fierz-David HE, Kuster W: Zur kenntnis homologer reihen acylierter azofarbstoffe aus o- und pAcylamino-phenolen u. 1,7-Acylaminonaphtholen. Helv Chim Acta 1939; 22: 82-l 12. Pearson DE, Carter KN, Geer CM: The rearrangement of hydrazones and semicarbazones. J Am Chem Sot 1953; 75: 5905-5908. Breddin K, Scharrer J, Schepping M: Die hemmung der plattchenaggregation mit acetylsalicylsaure. Munch Med Wochenschr 1971; 113: 1285-1288. Ferreira SH, Moncada S, Vane JR: lndomethacin and aspirin abolish prostaglandin release from spleen. Nature (New Biol) 1971; 231: 237-239. Vane JR: Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs, Nature (New Biol) 1971; 231: 232-236. Vane JR: The release and fate of vaso-active hormones in the circulation. Br J Pharmacol 1969; 35: 209-242.
November
14, 1983
The American
Journal of Medicine
3