History Of Analgesics
Analgesics, History Definition
Attempts to relieve pain are probably as old as mankind. Dioscourides, a Greek physician, prescribed extracts of willow bark against joint pain, whilst Hildegard von Bingen and the Reverend Stone, in his famous letter to the Royal Society of Medicine in London, suggested the same therapy (Brune 1997; Rainsford 1984). Local inflammation often goes along with "general inflammation" manifested by fever and malaise. The reasons for this were recently uncovered: the release of pyrogenic cytokines such as TNFa and IL-l. Fever along with malaise was treated on the basis of the Hippocratic concept by purgation, sweating and blood-letting (Brune 1984). Such practices were continued until the 19th century (Williams 1975) - probably without success.
It was only recently that the inhibition of the cytokine effect has become feasible (Smolen et al. 2000).
A scientific approach to pain therapy became possible in the 19th century, with substances isolated from plants including the willow tree (salic acid esters), and then the description of the complete synthesis by Kolbe (Marburg), (Brune 1997; Rainsford 1984). To provide sufficient amounts, the first "scale up" of a synthetic process was invented and the first drug factory built (Salicylic Acid Works founded by von Heyden, 1874; 6). Salicylic acid was found to be active against fever (Buss, Switzerland) and rheumatoid arthritis (Stricker, Berlin; Mac Lagan, Dundee) (Brune 1997; Rainsford 1984; Sneader 1985).
Earlier (1806), a pharmacist in Einbeck, Serturner, had isolated morphine, the main analgesic ingredient of the opium resin. He checked extracts from opium for sedative activity in his pack of dogs and ended up with a pure substance (morphine) (Serturner 1806; Sneader 1985). With morphine, for the first time, a pure (crystalline) drug was available. Death due to overdose or lack of effect could now be avoided by exact dosing (Bender 1966).
The next step was taken by chemists who tried to compensate for an impaired supply of opium, chinea bark (quinine) and others by chemical synthesis. It was made possible by E. Fischer's discovery of phenylhydrazine, which allowed the synthesis of nitrogen-containing ring systems. His scholar, L. Knorr, tried to synthesize quinine, but produced phenazone (Fig. l) (Brune 1997),
which proved to be active against fever. The patent for this compound (Antipyrine® was bought by a dye factory in Hoechst. This was the start of the pharmaceutical company Hoechst (Brune 1997). Another chemist (F. Hoffmann) esterified salicylic acid with acetate and (re-)discovered Aspirin. This synthesis was done in another dye factory, namely Bayer (Rinsema 1999). The new science of chemistry helped to transform the dye-industry by providing both synthetic dyes and new synthetic drugs.
Pain therapy was aided by another accidental discovery. In Strasbourg, two physicians, Cahn and Hepp, attempted to eradicate intestinal worms. The worms survived, but the fever resolved (Cahn and Hepp 1886). An analysis revealed that the pharmacy had provided acetanilide rather than naphthalene. This led to the discovery of acetanilide, which was marketed by another dye factory (Kalle) under the name Antifebrin® (Brune 1997; Sneader 1986). Bayer further investigated acetanilide and found that a by-product of aniline dye production, namely "acetophenitidine", was equally effective. It was marketed as Phenacetin® (Sneader 1986). These discoveries constituted, as Tainter phrased it (Tainter 1948), "[...] the beginning of the famous German drug industry and ushered in Germany's forty-year dominance of the synthetic drug and chemical field." Thus, by the end of the 19th century, 4 prototype substances were available for the treatment of pain: Morphine, salicylic acid, phenazone and phenacetin.
Chemical Modifications of Analgesics
Salicylic acid, phenazone and phenacetin were widely used, and physicians soon recognized the disadvantages of these drugs. They were of low potency, and had to
History of Analgesics,
acid in 1897.
be taken in gram quantities (spoon-wise). Sodium sal-icylate had an unpleasant taste. Taking several grams of phenacetin led to methaemoglobinaemia, while phenazone often caused allergic reactions. Consequently, the expanding drug industry set their chemists into action to produce improved derivatives. F. Hoffman, a young chemist at the Bayer Company, attempted to improve the taste of salicylic acid to please his father who suffered from rheumatoid arthritis (Brune 1997; Sneader 1986). On a suggestion of v. Eichengrun (Bayer), Hoffmann produced acetylsalicylic acid, which his father preferred (Brune 1997; Sneader 1986). Acetylsalicylic acid proved difficult to handle due to its instability. Bayer, therefore, took a patent on the water-free production process invented by Hoffmann and secured the name Aspirin® (derived from acetyl and the plant spirea ulmaria). H. Dreser, the first pharmacologist at Bayer, tried to demonstrate the reduced toxicity of aspirin as compared to salicylic acid. He employed a goldfish model, believing that the "mucosa" of their fins comprised an analogue of human intestinal mucosa. Dipping the fins of goldfish into solutions of either salicylic acid or aspirin, he observed that higher concentrations of aspirin were necessary to "cloudy" the fins (Fig. 2). He concluded that this was proof of better gastrointestinal tol-erability (Dreser 1899). Later, Heinrich Dreser himself recognised that he didn't measure a "gastrotoxic effect", but rather "acidity", and salicylic acid is more acidic than aspirin (Dreser 1907).
To further improve the tolerability of phenacetin, Bayer investigated a metabolite of phenacetin, acetaminophen
(paracetamol). It appeared that (their) acetaminophen (due to impurities?) also caused methaemoglobinaemia. In contrast, Sterling (UK) found acetaminophen free of methaemoglobinaemia and marketed it as Panadol® (Sneader 1985).
New Compounds: Pharmacology Comes into Play
In 1949, an unexpected observation once again paved the way for new analgesics. Hoping to reduce toxicity and increase effectiveness of aminophenazone, Geigy (Basel) produced an injection containing the salt of the basic aminophenazone with an acidic derivative - later named phenylbutazone (Fig. 3). This salt was found to be very active, particularly in rheumatoid pain (Brune
1997; Sneader 1985). Burns and Brodie related this effect to phenylbutazone, which was present for much longer periods of time than aminophenazone (Dome-joz I960). The conclusion was that the "salt forming" partner of aminophenazone was the dominant active ingredient. To further investigate this clinical observation, G. Wilhelmi (Geigy) developed novel models of inflammation (Wilhelmi 1949). Phenylbutazone turned out to be particularly active in reducing the UV erythema elicited in the skin of guinea pigs (Fig. 3) (Wilhelmi 1949). It was one of the first pharmacological models of inflammation, with which several phenylbutazone analogues were found.
In the USA, C. Winter, at Merck (MSD) and later at Parke Davis, developed his models of inflammatory pain. He introduced the cotton string granuloma and the carrageenin-induced rat paw model (Shen 1984). These assays turned out to be especially useful for measuring anti-inflammatory activity (Winter et al. 1962) (Fig. 4). A similar model was employed by Randall and Selitto for detecting analgesic activity (Randall and Selitto 1957). Using these models led to the discovery of several chemical classes of analgesics. Merck identified indols (including indomethacin and sulin-dac, T.Y. Shen) (Shen 1984), Boots found propionic acid derivatives (ibuprofen and flurbiprofen, S. Adams; (Adams 1992), Parke Davis developed fenamates (e.g. mefenamic acid) (Shen 1984), Geigy was successful with new aryl-acetic acids, e.g. diclofenac (Shen 1984) and Rhone Poulenc with Bayer introduced ketoprofen (Shen 1984), and finally, Lombardino at Pfizer rediscovered the ketoenolic acids (phenylbutazone). The advantage of these compounds is that all pharmacoki-netic parameters can be tailored by minor changes in
the molecular structure (Lombardino 1974). Pfizer's piroxicam (Otterness et al. 1982) was soon followed by tenoxicam (Roche) and meloxicam (Boehringer). All of these differ in their potency and in pharmacokinetic parameters including their metabolism and drug interactions, although their mode of action is basically the same. Most were identified using animal models before the mode of action of "aspirin-like" drugs - as these substances were formerly named - was determined. It was 70 years after the synthesis of aspirin when John
Carrageenan-induced rat paw edema
Vane's group could demonstrate that these compounds were inhibitors of prostaglandin synthesis (Vane 1971). This discovery, however, did not answer the question of why many of the old compounds (found by serendipity - such as phenazone, propyphenazone, phenacetin, paracetamol) were non-acidic chemicals that barely inhibited cyclooxygenases, whilst all the compounds developed in animal models of inflammation and pain were acidic and potent inhibitors (Brune 1974)? All pharmacological models inflict an acute inflammation elicited by local prostaglandin production. Consequently, drugs that work by blocking cyclooxy-genases in the inflamed tissue excel in these models. Acidic compounds (comprising pKa values of around 4, ~99% protein binding and amphiphilic structures) reach long lasting high concentrations in inflamed tissue, but also relatively high concentrations in liver, kidney and the stomach wall (Brune and Lanz 1985). This skewed distribution causes complete inhibition of prostaglandin synthesis in these locations resulting in superior anti-inflammatory activity, but also liver, kidney and stomach toxicity (Brune and Lanz 1985). This distributional selectivity may have reduced some of the side-effects including CNS toxicity and increased the anti-inflammatory effects. Non-acidic compounds such as phenazone or paracetamol distribute homogeneously throughout the body. Their inhibition of prostaglandin production in inflamed tissue is small. Consequently, they are used to curb mild pain, but not inflammation. The discovery of the existence of two cyclooxygenases, COX-l and COX-2 (Flower 2003), has changed the landscape again. It provided a new dimension of selectivity, not limited to differences of tissue distribution, but based on enzyme selectivity.
Analgesics in the Age of Molecular Pharmacology
selectivity to warrant Gl-tolerance (Tegeder et al. 1999). This situation changed with the discovery of the highly selective sulfonomides, celecoxib and valdecoxib, and methylsulfones, rofecoxib and etoricoxib. These compounds are relatives of old compounds like phenazone (Fig. l). They extend theparacetamol/phenazonegroup of non-acidic compounds which are devoid of gastrointestinal toxicity (Brune and Lanz 1985). However, these new analgesics are not free of other side effects. Inhibition of cyclooxygenase-2 affects kidney function, blood pressure and maybe more (for review, see e.g. Brune and Hinz 2004a; Hinz and Brune 2002). Another type of COX-2 selective inhibitor is Lumiracoxib. It is a relative of diclofenac and, like diclofenac, is sequestered into inflamed tissue. It combines COX-2 selectivity with selective tissue distribution (Feret 2003). The clinical success of this compound will tell us if this approach offers advantages.
After 120 years of development of pure analgesics, we have made some progress. Serendipity, as well as targeted research, has provided clinicians with many useful drugs that differ in many pharmacological and clinical aspects. Knowing a little of the history of their discovery and development may provide a perspective to better understand their effects and side-effects. A humble acknowledgment of the role of serendipity may change our attitude towards research and marketing claims. But then serendipity is not all, as E. Kastner, a German poet, phrased it:
Irrtumer sind ganz gut, Jedoch nur hier und da. Nicht jeder, der nach Indien fahrt, entdeckt AMERIKA. Errors are fine, but only sometime(s). Not everyone heading for India discovers AMERICA.
The helpful discussion with many scientists, in particular I. Otterness, A. Sallmann, T.Y. Shen (f) and G. Wil-helmi is gratefully acknowledged.
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