Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.55 no.1 Campinas Jan./Feb. 2005
Opium and opioids: a brief history*
Una historia breve del opio y de los opioides
Danilo Freire Duarte, TSA, M.D.
Livre Docente de Farmacologia - UFSC; Professor Titular de Anestesiologia - UFSC (inativo)
BACKGROUND AND OBJECTIVES: In addition
to their major influence on human behavior, opium and opioids have been used
for a long time as sedative and analgesic drugs. As from the 19th
century, with the isolation of opium alkaloids and easy parenteral administration
of these substances, there has been increased interest in the judicious medical
use of opioids and in the analysis of social consequences of their abuse, which
has justified a historical review of opium and opioids.
CONTENTS: Further understanding of opium, natural product extracted from Papaver somniferum, and of opioids, natural opium-extracted semi-synthetic and synthetic substances, as well as major references to these substances since ancient times are evaluated. Breakthroughs after Setürner's studies, which have resulted in morphine isolation, are emphasized. Reference is made to other authors' investigations in the search for synthetic substances with advantages over natural products. The importance the discovery of opioid receptors and their endogenous binders is highlighted.
CONCLUSIONS: In the dawning of the third millennium, regardless of studies with analgesic drugs of different pharmacological groups, opioids are still the most potent analgesics, although their efficacy has been questioned for some types of pain. Current Clinical Pharmacology knowledge allows for the selection of the opioid based on patient's disease and conditions, in the search for the best cost-benefit ratio.
Key words: ANALGESICS: opioids; ANESTHESIOLOGY, History
JUSTIFICATIVA Y OBJETIVOS: Desde tiempos
inmemoriales, el opio y sus derivados, junto con ejerceren ponderable influencia
sobre el comportamiento de los seres humanos, han sido empleados como sedante
y como analgésico. Desde el siglo XIX, con el aislamiento de los alcaloides
del opio y las facilidades para el empleo de esas substancias por vía parenteral,
hubo aumento del interés por el uso criterioso de los opioides en la área
médica y del análisis de las consecuencias sociales de su uso abusivo.
Se justifica, por lo expuesto, una revisión histórica del opio y de
CONTENIDO: La evolución de los conocimientos sobre el opio, producto natural extraído del Papaver somniferum, y sobre los opioides, substancias naturales, semi-sintéticas y sintéticas extraídas del opio, bien como las principales referencias a esas substancias desde la Antiguedad fueron evaluadas. Fue enfatizado el progreso logrado desde los trabajos de Setürner que resultaron en el aislamiento de la morfina. Las averiguaciones acarreadas por otros autores en la busca de substancias sintéticas que presentasen ventajas sobre los productos naturales fueron mencionadas. La importancia del hallazgo de los receptores opioides y de sus ligantes endógenos fue subrayada.
CONCLUSIONES: En el amanecer del tercer milenio, a despecho de las pesquisas realizadas con drogas analgésicas de otros grupos farmacológicos, los opioides continúan siendo los analgésicos más potentes, aunque su eficacia sea contestada en ciertos tipos de dolor. Los actuales conocimientos de Farmacología Clínica permiten seleccionar el opioide a ser administrado, considerando la enfermedad y las condiciones del paciente, en la busca de la mejor relación costo-beneficio.
Opioid names have been changed along the years. They have been called narcotics, hypnoanalgesics and narcoanalgesics, which are inadequate terms for including other sleep-inducing drugs 1,2. They have also been called opiates, initially a generic name and then restricted to natural opium products 1. The term opioid was proposed by Acheson to name drugs with actions similar to morphine, however with different chemical structure 3. Nevertheless, the concept of opioid has evolved to include all natural semi-synthetic or synthetic substances reacting with opioid receptors both as agonist or antagonist 3.
Opium, first substance of this pharmacological group, is extracted from poppies, popular name of Papaver somniferum, one of several species of the Papaveraceae family, characterized by solitary leaves and capsulated fruits. Papaver somniferum has probably evolved from a wild Asian species, or from a species called Papaver setegirum, which grew around the Mediterranean sea 4. From all known poppy species, only Papaver somniferum, and Papaver bracteatum produce opium in significant amounts. The latter however has no commercial significance 4.
Opium is known since pre-history or at least since very ancient historical eras. Poppy seeds and capsules were found in a Swiss Neolithic village 4. In any case, the oldest evidence of poppy cultures dates from 5 thousand years and was left by Sumerians. Poppy is described in an ideogram of this people as the "joy plant" 5.
Opium remnants were found in an Egyptian tomb from the 15th century b.C. Approximately in the same time, there were opium cultures around Thebes, therefore the fact that the Egyptian product was known as "Theban opium", and that one alkaloid discovered centuries later was called Thebain 4. The Ebers Papyrus(1552 b.C.) describes a blend of substances, among which opium, effectively used to sedate children 5. This was how the Goddess Isis would sedate her son Horus 6.
Opium, and possibly its hypnotic properties, was known in old Greece. In archeological excavations in Samos island, mud and ivory broches from the 7th century b.C. representing poppy capsules were found. A broche with the same representation was also found in the real tomb of the city of Mycenae 7.
It is reported that Demeter, a Greek divinity, knew the sedative and hypnotic properties of opium, so much so that, desperate with the rape of her daughter Persephone, she has taken this substance to sleep and forget her suffering 8. It is also said that this Goddess has given poppy to Triptolemus, King of Eleusis and her disciple in the art of tilling the ground, to make him sleep 8. It is very likely that opium was included in the worships of this Greek divinity 4. Nepenthe, mentioned in the Odyssey as the forgetfulness drug, is interpreted by many as being opium 4. However, Theophrastus, Greek philosopher who replaced Aristotle as Lyceum director, has questioned the existence of Nepenthe, attributing its description to Homer's poetic imagination trance. Dioscorides has admitted that it was a blend of poppy juice and Hog's bean. Kriticus and Papadaki have discussed different hypothesis on the nature of Nepenthe and have concluded that it is or contains opium in its composition 8.
Hippocrates did not attribute magic properties to opium, as it seems to have been true for Asclepiads priests 4. Considered the father of Medicine, he prescribed "meconium" (probably poppy juice) as purgative, narcotic and to cure leucorrhea 4,9. Prioreschi et al. have used a statistical method developed by the University of Omaha to determine whether ancient physicians would use some drugs as a function of their efficacy of for other reasons, and have concluded that in the days of Hippocrates opium analgesic properties were unknown 10.
Opium is a Greek name and means juice, therefore the Hebrew name ophion mentioned in the Talmud 9. According to some investigators, there is reference to opium in the Bible with the name of rôsh 9. At least in one Portuguese translation of the Bible there is mention to "water of gall" (Jer VIII - 14 and Jer IX - 15) 11. Buckland et al.'s Biblical dictionary 12 describes "water of gall" as the product of a plant known as "somniferum" which is poppy's Latin name. It is curious that this substance was not used for pleasant purposes. Conversely, it was given by the Lord as punishment for Israel's people apostasy. It is written in Jeremiah (Jer IX-15) "Therefore thus saith the LORD of hosts, the God of Israel; Behold, I will feed them, even this people, with wormwood, and give them water of gall to drink" 11.
Theophrastus in the 3rd century b.C., has referred to the latex obtained from poppy capsules as opium and has called meconium the juice obtained by crushing this plant 4. The Assyrian method of incising poppy capsules to obtain exudates was lost in time until it was rediscovered by Scribonius, physician of the Emperor Claudius, in the year 40 a.C., which has been described in his "Compositiones Medicamentorum" 4,9. Approximately 40 years later, Dioscorides has described a poppy syrup which he has called Dia-kodium, as has concluded that the plant extract was less active than the juice extracted from the capsule 9.
The process to obtain opium has not greatly changed along centuries. In general, the description by Cohen 5, Wryth 13 and Talmadge 14 is still followed. In summary, the process is started two weeks after leaves have fallen, when seed-containing capsules harden. At sunset, capsules are scarified with shallow incisions to allow latex to flow. It is then thickened due to evaporation in the capsule surface itself resulting in a brown gum which is removed next morning with an iron tool with the shape of a small mason's shovel. This gum is then made into powder.
Opium has been very important for the Roman civilization and represented sleep and death 4. Agripine, last Emperor Claudius' wife, has added this drug to the wine she offered to Britannicus, her stepson, to allow Nero, her own son, to inherit the throne 4. Plini, the Elder, has described poppy seed as hypnotic, and Virgil, the Roman poet, has attributed the same properties to opium both in the Ennead and the Georgics 4,13. Celsius, Roman physician born in the first century of the Christian era, would recommend opium for pain relief and has developed several opium-containing formulations14. By that time, opium was also known as lacrima papaveris 14.
Galen, in the 2nd century a.C., was an enthusiast of opium virtues, the use of which has become very popular in Rome. During the last years of the Empire, as it had already happened in Greece, poppy was mint in one head of a coin 8. Galen, who has been the greatest expression of Roman Medicine, realized the risks of the exaggerated use of opium after the case of Emperor Antoninus, his patient, who seems to have been victim of drug abuse 13. It is almost certain that opium analgesic properties started to be recognized from the Romans on.
After the fall or Rome in the 5th century a.C., Western Europe has dived in unquestionable intellectual stagnation, which has remained at least until the 12th Century. However, during this period, more precisely between the 9th and 16th centuries, the Muslim Civilization has flourished and has reactivated the study of several arts and sciences, among them Medicine 15.
The knowledge of drugs used by Greeks and Romans was recovered through Dioscorides works 6. Opium, called al-yun by the Arabs 9, was for Avicenna, a Muslim Medicine exponent, the most powerful of all analgesics, and was indicated to treat diarrhea and eye diseases 5,15. This substance was given both orally and rectally to treat ear and articular diseases, especially gout 15.
Opium toxicity was well known by Avicenna 16 who, according to some authors, abused of this substance and may have probably died from opium overdose 4. Spongia somnifera, a blend of opium, mandragora, cicuta and hyoscine to promote inhalational anesthesia for surgical procedures, is referred to by Arab physicians in the 9th century. Afterwards, spongia somnifera, has been used in Palermo with the same purpose 6. During the Golden Period of the Muslim Civilization, Arabs have mastered Indic Ocean trade and have introduced opium in India and then in China, where it was called o-fu-yung. For approximately 1000 years, Chinese people have used opium basically to control diarrhea.
It was Paracelsus, a Swiss physician who lived between 1493 and 1541, thus in the dawn of Renaissance, who reintroduced opium for medical use in Western Europe 6. Paracelsus was such an enthusiast of this drug that would always carry it with him calling it the "immortality stone" 9. The term laudanum is used in the medical literature of the 17th century to define a drug of proven efficacy and many laudanum were named after famous physicians. There are questions whether Paracelsus' laudanum would contain opium 17.
Sydenham's laudanum, on the other hand, was the major opium-containing formulation, used in England in the 17th century and in the Americas until early 20th century 18. Paracelsus has stated that "Among medicines offered by Almighty God to relieve human suffering none is so universal and effective as opium" 6. Sydehman's laudanum contained opium, wine, beer, saffron, clove and cinnamon 17. Still in the 17th century, other preparations have appeared between 1702 and 1718, including Dover's Powder, consisting of a blend of opium, salt, tartar, licorice and feveroot, and Paregoric, from Le Mort, professor of the University of Leyden.
A modified formulation called Paregoric Elixir with opium, honey, camphor, anis and wine was published in the London Pharmacopoeia in 1721 9. By the same time, another preparation known as Rousseau's laudanum was fashionable in Continental Europe 9. However, opium adverse effects were becoming increasingly known, worrying Sydenham himself, who was a notorious enthusiast of the drug.
In 1700, Londoner physician John Jones has published a book called Mysteries of Opium Reveal'd, possibly the first opium-specific book. The book called the attention to the risks of excessive use of this drug, admitting that adverse effects could be a consequence of residues not eliminated during preparation 4. Two other books were written in this Century about opium. George Young has published the Treatise on Opium, in 1750, and Samuel Crumpe has published the Inquiry into the Nature and Properties of Opium, in 1793 4. Both mentioned addiction and, more superficially, withdrawal symptoms. None of them, however, has suggested any restriction for opium, both as drug and as source of pleasure.
The 19th century was rich in events concerning the history of opioids. Already in its beginning there have been fierce discussions on opium modus operandi. The subject was reviewed by Haller Jr. 19 and, according to him, William Collen in 1808 in the Treatise on the Materia Medica admits that opium interrupts message flow from nerves to brain and vice-versa causing the "abolishment of all painful sensitivity and any of other irritation from any part of the system". He has also observed that although opium was sedative, it could have an initial exciting effect in some people. Conversely, other authors have proclaimed that opium would act as exciting drug in all cases, increasing physical vigor and clearing the mind. Although not knowing opium action mechanism, this drug has become major therapeutic support during the Victorian era 19.
One may say that the most important fact of early 19th century was the discovery of morphine, obtained by Friedrich Sertürner, a German pharmacist assistant, who has worked in isolating opium active principles. Sertürner has started his work in 1803 and published his first results in 1806 in the Journal of Pharmacie where he reported the discovery of an acid called meconic acid 4,9. Experiments with dogs, however, have revealed that this acid was pharmacologically inactive 18. Next, he has identified a crystalline water-insoluble substance called principium somniferum for being pharmacologically active when administered to animals.
It was an organic substance with alkaline properties, identified as an alkaloid. Sertürner himself has replaced this name by morphium after the Greek God of Dreams and, in 1816, he presented details of the chemical and pharmacological investigation of this drug 9. In an Editorial of a French journal which has translated Sertürner's studies, Gay Lussac has proposed the replacement of the name morphium by morphine, which became its permanent name 18. Some years after starting investigating the active principles of opium, Sertürner decided to self-test morphine. Based in his own symptoms he wrote: "I consider my duty to call the attention to the terrible effects of this new substance, so that a calamity may be prevented" 4. So morphine, first opium-extracted alkaloid, had its risks proclaimed by its own discoverer.
It is known today that one fourth of opium powder weight contains at least 25 alkaloids 5 which were classified in two separate groups for chemical and pharmacological reasons. Most important group is represented by phenanthrene-derived substances, which act primarily on the central nervous system (CNS). Morphine, prototype of this group, represents 10% of opium alkaloids. Codeine (methyl-morphine) was isolated by Robiquet in 1832, and tebaine (dimethyl-morphine) was isolated by Pelletier and Thibouméry, in 1835. Codeine and tebaine represent, respectively, 0.5% and 0.2% of opium alkaloids 2,9,20,21. Benzyl-isoquinoline derived substances, second opium alkaloid group, have primarily spasmolytic action and its major representative is papaverine, with 1% of opium alkaloids 20. Morphine has become commercially available in Europe and North America around 1820, and its popularity as analgesic agent has rapidly grown 4.
After natural opium-derived substances had their chemical structure determined, several semi-synthetic products were obtained with relatively simple changes in morphine and tebaine molecules, among them dihydromorphinone (Dilaudid®, acetyl-morphine (dionine), 6-metyl-dihydromor- phinone (Metopon®), l-14-hydroxymorphinone (oximorfam or numorfam) and diacetylmorphine (heroin) 2. Pantopom® has pure opium alkaloids in the relative ratio they are found in the natural product 21.
Subcutaneous drug administration was consolidated in the 19th century. In October 4, 1836, a communication by G. V. Lafargue, a St. Emilion physician, was submitted to the Academy of Medicine of Paris, in which he describes the inoculation of morphine paste under the skin using a vaccination lancet. He has observed a reddish aureole at inoculation site, which has increased in size, reaching it largest diameter in approximately one hour 22. This way, Lafargue has described a histaminoid reaction to morphine without knowing the cause.
In June 3, 1845, Irish physician Francis Rynd was the first to administer subcutaneous liquid morphine. Rynd has injected morphine acetate solution diluted in creosote through a tool developed by him. This was performed in the Meath Hospital, Dublin, in a 50-year old female patient with trigeminal neuralgia. Drug was injected in temporal, malar and buccal nerves pathway and, according to Rynd, pain relief was virtually instantaneous 22.
First subcutaneous morphine administration with hollow needle and a syringe was performed by Wood in 1853. His intention was to inject the substance in a nervous pathway to obtain local effect. However, according to his own words, "the effect of the narcotic applied this way is not confined to application site; the substance reaches the brain through venous circulation and produces distant effects" 22. Although the frequent use of subcutaneous morphine in Edinburgh, the method was poorly understood in London until Charles Hunter, young Londoner surgeon of the St. George Hospital, published in 1858 the "treatment by local narcotic injection in the affected region".
It was up to Hunter to conclude that morphine administration away from the painful region would promote a similar effect to injection around this area, and that the fact was due to systemic drug absorption 22. Thanks to Béhier's communication to the Academy of Medicine of Paris, in 1859, subcutaneous morphine administration was spread throughout Europe 22.
The belief that opium would not cause individual or collective damage started to tumble in 1830, and in 1860 this drug has become a medical and social problem as a function of mortality data. According to these data, one third of all lethal poisonings were due to opium overdose, taken both as a source of pleasure and with suicide intentions 4.
Three famous poets, Shelley, Baudelaire and Edgar Allan Poe were opium addicted and have attempted suicide with this drug. In the 19th century, more notorious people were included in this list of dependents, among poets George Grabbe and Francis Thompson, writer De Quincey and novelist Wilkie Collins 13. According to his own statement, Quincey, born in 1785, has taken opium for the first time in 1804 when studying in the Worcester College, Oxford, by recommendation of a colleague for tooth pain relief. This is how he described his first sensations:
"... within one hour, oh, Lord! What an extraordinary change! What a resurrection from the most unreachable depths of spirit! What a revelation of my inner world. The disappearance of my pains seemed insignificant. This negative effect was consumed in the abyss of a divine and suddenly revealed pleasure. Here was the panacea for each and any human suffering; here was the secret to happiness".
In 1821 he wrote his autobiography called Confessions of an English Opium Eater, which had great impact on public opinion 4.
The so-called opium war, in the early 19th century, has motivated the awareness, at least of more educated classes, of the problems generated by opium abuse 4. The habit of smoking opium was introduced in China in the 17th century 5. However, opium imports from China were expanded only in the second half of the 18th century, first by the Portuguese, then by the French and finally by the British, when the volume imported by this country was estimated in 10 thousand tons and 20 million pounds 9,13. Of course, those interested in such a profitable business have unscrupulously encouraged the habit of smoking opium.
It was natural, however, that the Chinese government would be concerned with the effects of this exaggerated import, and in 1800, an edit was published banning opium imports. As part of the proposed control, an opium warehouse belonging to the Western Indias Company was destroyed. This act has triggered the "opium war" between England and China being the latter defeated. With the signature of the Treaty of Nanking, Hong-Kong was assigned to England and some ports were opened to European and North American trade. In 1858, still as a consequence of the Treaty of Nanking, opium trade was legally admitted 9.
The incentive to opium use in China on part of the British government has brought about reactions in England itself, where the Society for the Suppression of Opium Trade was founded and chaired by Count Shaftesbury. This society has held several meetings aiming and protesting against the incentive to the hazardous habit of smoking opium 13.
In the second half of the 19th century, morphine availability and the possibility of subcutaneous administration have led to its increased use even because by that time it was admitted that when subcutaneously administered, the alkaloid would cause less inconvenient than when it was ingested 4.
The American Civil War has created major opportunity for the massive use both of oral opium and subcutaneous morphine in soldiers wounded in combat and, as a consequence, there were records of several cases of physical dependence generating a social problem for the US 6. British soldiers fighting the Crimea war have also used morphine injections to help them stand the terrible battlefield conditions. The same was true with Prussian soldiers during the 1870 war between France and Germany 4.
However, concepts of tolerance, psychic and physical dependence, as well as of addition, were only widely discussed in the 20th century. In theory the following definitions were accepted 23: tolerance is decreased responsiveness to the effect of a drug, requiring as a corollary the use of increased doses to maintain the same effect. Psychic dependence is a state in which the drug promotes satisfaction enough to promote the periodic or continuing use of this drug in search for the same pleasant feeling. Physical dependence is an adaptation state manifested by the presence of physical disorders, qualified as "withdrawal syndrome" when the drug is discontinued 23. Addiction was defined by a World Health Organization Committee as "a state of periodic or chronic intoxication, noxious to individuals and society, produced by the repeated use of a drug.
It characteristics are: absolute need to continue to use the drug (compulsion) and to obtain it at any means, and also tolerance, psychic dependence and sometimes physical dependence. This Committee does not consider the latter attribute mandatory, but the Committee of Drug Addiction, Ministry of Health, United Kingdom, emphasizes the mandatory presence of physical dependence, with the development of withdrawal syndrome when the drug is discontinued 24. It is interesting to note that Charles Towns, a New York physician, and probably the first to describe the addiction phenomenon had already pointed some of these characteristics 5.
The "heroin paradox" in the turn of the 20th century should be mentioned. It was claimed that this drug could replace morphine with advantages since it relieved morphine withdrawal symptoms, and so should not promote the inconvenients attributed to it. This blindness has remained for 12 years, when it was proven that heroin is one of the alkaloids most rapidly leading to dependence 5.
Notwithstanding the deception caused by heroin, the search for opioids better than morphine has continued and in 1939 meperidine, the first totally synthetic opioid, was introduced, starting a series of phenylpiperidine-derived drugs 25. Several other representatives of this series were synthesized and one of them, diphenoxilate, was developed to decrease intestinal hypermobility 25.
The structure of meperidine, standard drug of the series, is different from morphine's, being however possible to identify some common features. The same is true for methadone, synthesized in Germany during World War II, and prototype of the diphenyl-heptane series 25. The series of morphinanes and benzomorphanes, represented by levorfanol and petazocine, respectively, have chemical structures closer to morphine 25.
Dextromoramide was introduced in 1956 and phenoperidine in 1957, which were potent analgesics encouraging Janssen et al. investigations on new phenylpiperidine products 26. Fentanyl, the first of these new opioids, was available as from 1960. Between 1974 and 1976, the following fentanyl analogs were developed: carfentanil (1974), sufentanil (1974), lofentanil (1975), and alfentanil (1976) 26. In the early 90s, remifentanil was made available for clinical use. It is different from the others because it is an ester allowing biotransformation by enzymatic cleavage and generating inactive metabolites 27. All these new phenylpiperidine products are µ receptor agonists preferably aimed at anesthesia, analgesia and sedation of ICU patients.
All opioid effects, including adverse effects, are consequence of complex interactions of these drugs with specific receptors identified along ascending pain transmission system and descending inhibitory system 28.
The concept of opioid receptors was for a long time being discussed by investigators based on the stereospecificity, common to drugs of this pharmacological group, and on the possibility of obtaining specific antagonists by means of minor chemical changes in the agonist structure 29. However, only in 1971 Goldstein et al. from the Stanford University were the pioneers in the attempt to identify them 30. These authors have observed that levorfanol stereospecific binding in the brain of rats would represent only 2% of total drug used and was limited to certain fractions of membrane-containing substrate. As a consequence, they have admitted that stereospecific binding should correspond to that obtained with opioid receptors 30. In 1973, Snyder et al., Simon et al. and Terenius et al., the two formers from the USA and the latter from Sweden, have confirmed the existence of opioid receptors through independent studies 31.
Several receptor types and subtypes were suggested being mu (µ), delta (d) and kappa (k) receptors accepted by all investigators of the subject.
Opioid antagonists appeared in 1915 when the effect of N-alylcodeine on respiratory depression caused by its congener drugs was shown, and have gained clinical importance in mid 20th century, when an antidote was being searched for agonist drugs overdose and more specifically to revert respiratory depression caused by these drugs. Ideally, antagonists should not present any agonist activity.
However, the first clinically used substances of this group, N-alylmorphine (nalorphine) and levalorfam, are competitive µ receptor antagonists and k receptor agonists 20. Early clinical studies with nalorphine were conducted by Eckenhoff et al. between 1951 and 1953 32,33. Naloxone and naltrexone, oximorphine-derived alyl, are considered pure antagonists and interact with three types of opioid receptors 20. First naloxone studies were conducted in the early 60s, initially in animals and soon after in humans34. Nalmephene is a more recent pure µ receptors antagonist, and other substances selectively antagonizing other opioid receptors are being developed 20. One should also mention anti-opioids, substances that bind to receptors and have cellular and behavioral effects opposed to opioids. They are represented by neuropeptide FF, nociceptine and peptides derived from MIF (melanocites inhibitor factor) 35.
There is no question that opioid receptors understanding represented a major step forward and induced the discovery of endogenous binders, since it was already extremely unlikely the presence of receptors without the parallel existence of endogenous substances bound to them. These substances were developed as from Hughes' investigations published in 1975 36, where he has isolated a substance with properties similar to morphine from the brain of different animal species.
Afterward, it was confirmed that endogenous morphinemimetics are represented by three families of peptides, each one originated from a different gene: encephalins, endorphins and dinorphines 1,29. The physiologic role of endogenous binders is still not fully explained. They seem to have neuromediators, neurotransmitters and, in some cases, neuro-hormone functions 28.
Another 20th century breakthrough was the possibility of administering opioids by other approaches in addition to oral, subcutaneous and muscular, such as spinal, transdermal, submucosal (nasal and sublingual) and intra-articular approaches.
Spinal opioid administration, both in the subarachnoid and the epidural space was supported by experimental studies with rats, which have presented massive analgesia after subarachnoid injection through a resident catheter 37, and also by the identification of opioid receptors in the spinal cord dorsal horn, especially in Rexed laminae 1, 2 and 5 38. First studies reporting positive results in humans with chronic pain were published in 1979 by Wang et al. 39 and Behar et al. 40 using subarachnoid and epidural approaches, respectively, which were rapidly accepted not only to control chronic pain but also to relieve postoperative acute pain 38.
Transdermal administration is obtained with a special device by which the analgesic gets in contact with the skin through an adhesive with micropores. Major inconvenient is that when there is respiratory depression, it lasts for several hours after the removal of the device 41.
Submucosal administration, both nasally and orally, has been primarily used in Pediatrics 18. More recently, intra-articular opioid administration as single drug or associated to local anesthetics has also been successfully used 18,42, supported by the existence of opioid receptors, probably µ and d, in inflamed tissues, which may be activated by endogenous binders in experimental situations 43.
Patient-controlled analgesia, which was used for the first time with opioids in 1967, should also be mentioned. Since then, this method has been used with opioids and associations of opioids and local anesthetics by different approaches 18.
During these early years of the third millennium, opioids have maintained their position as the pharmacological group inducing most potent analgesia. There are, however, some questions: Are these drugs equally potent for any disease? In a recent review, Mc Quay observes that this is a controversial subject 44. There is consensus that nociceptive pain is sensitive to opioids. However, there is disagreement for neuropathic pain. Anyway, other drugs from other pharmacological groups are being successfully used for this type of pain, and others are being developed as from calcium channel blockers 45. Is it feasible to dissociate opioid analgesic effect from undesirable effects? It should be considered that most potent opioids are µ receptor agonists, the activation of which is also responsible for respiratory depression 1. k receptor agonists also respond for respiratory depression and a high percentage of dysphorias 44. Would it be possible to identify subtypes of one of these receptors which, when activated, could solely respond for analgesia? This is a perspective. Currently, the strategy to limit undesirable effects is "opioids rotation", that is the alternative use of two or more opioids 28,45. Is addiction a high risk for chronic pain patients receiving opioids for long periods? There are clues in the medical literature that adequate opioid doses are only very seldom responsible for addiction in chronic pain patients 28,45. However, if this happens to a cancer patient with limited survival, wouldn't it be a good price to pay?
Clinical pharmacologicy knowledge already acquired in the third millennium allows for opioid selection when this drug is indicated, to obtain maximum analgesia with minimum side effects. Cost/benefit ratio will become even more effective when investigations, which are certainly in progress. lead to better identification of receptor subtypes and to better understanding of opioid-receptor interaction, in addition to the synthesis of new opioids with more selective or even specific action.
01. Gozzani JL - Opióides e antagonistas. Rev Bras Anestesiol, 1994;44:65-73. [ Links ]
02. Corbett CE - Hipnoanalgésicos, em: Charles E Corbett, Elementos de Farmacodinâmica, 2ªEd, São Paulo, Livraria Editora Artes Médicas, 1966;217-234. [ Links ]
03. Martin WR - Pharmacology of opioids. Pharmacol Ver, 1983;35:283-303. [ Links ]
04. Booth M - Opium - a History, New York, St Martin's Griffin, 1998. [ Links ]
05. Cohen MM - The history of opium and opiates. Tex Med, 1969;65:76-85. [ Links ]
06. Baraka A - Historical aspects of opium. Middle East J Anesthesiol, 2000;15:423-436. [ Links ]
07. Kritikos PG - The history of opium in antiquity. J Am Pharm Assoc, 1968;8:446-447. [ Links ]
08. Kritikos PG, Papadaki SP - The history of poppy and opium and their expansion in antiquity in the Eastern Mediterranean Area. Bull. Narcotics, 1967;19:5-10. [ Links ]
09. Macht DI - The history of opium and some of its preparation and alkaloids. JAMA, 1915;64:477-461. [ Links ]
10. Prioreschi P, Heaney RP, Brehm F - A quantitative assessment of ancient therapeutics: poppy and pain in Hippocratic Corpus. Med Hypothese, 1998;51:325-331. [ Links ]
11. Bíblia Sagrada, São Paulo, Edições Paulinas, 1953. [ Links ]
12. Buckland AR, Williams L - Dicionário Bíblico Universal, 1ªEd, Lisboa, Livraria Evangélica, 1929;261. [ Links ]
13. Wright DA - The history of opium. Med Biol Illus, 1968;18:62-70. [ Links ]
14. Tallmadge CK - Some anesthetics of antiquity. J Hist Med Allied Sci, 1946;1:515-520. [ Links ]
15. Al-Mazroa AA, Abdel Halim RE - Anesthesia 1000 years ago, Royal Society of Medicine International Congress and Symposium Series, 1989;134:46-47. [ Links ]
16. Amaral JLG - Anestesiologia: a evolução de uma especialidade. Compacta, 1995;1:3-15. [ Links ]
17. Sigerist HE - Laudanum in the Works of Paracelsus. Bull Hist Med, 1941;9:530-544. [ Links ]
18. Hamilton GR, Baskett TF - In the arms of Morpheus the development of morphine for postoperative pain relief. Can J Anaesth, 2000;47:367-374. [ Links ]
19. Haller Jr JS - Opium usage in nineteenth century therapeutics. Bull N Y Acad Med, 1989;65:591-607. [ Links ]
20. Gutstein HB, Akil H - Opioid Analgesics, em: Hardman JG, Limbird LL - Goodman and Gilman's Pharmacological Basis of Therapeutics, 10th Ed, New York, Mc Graw-Hill. 2001;569-619. [ Links ]
21. Rocha e Silva M - Fundamentos da Farmacologia e suas Aplicações em Terapêutica 2ªEd, São Paulo, Edart, 1969;2:95-115. [ Links ]
22. Howard-Jones N - A critical study and the origins and early development of hypodermic medication. J Hist Med Allied Sci, 1947;2:201-249. [ Links ]
23. Basile AC, Sertie JAA, DeLucia R - Farmacodependência, em: DLucia R, Valle LBS, Oliveira Filho RM et al - Farmacologia Integrada, SP, Livraria Ateneu Editora, 1991;2:157-170. [ Links ]
24. Seevers MH - Medical perspectives on habituation and addiction. JAMA, 1962;181:92-98. [ Links ]
25. Murphree HB - Analgésicos Narcóticos: Analgésicos Sintéticos, em: DiPalma JR, Drill-Farmacologia Médica, México, La Prensa Médica Mexicana, 1969;291-299. [ Links ]
26. Janssen PA - Potent new analgesics tailor-made for different purposes. Acta Anaesthesiol Scand, 1982;26:262-268. [ Links ]
27. Nora FS, Fortis EAF - Remifentanil: porque precisamos de outros opióides? Rev Bras Anestesiol, 2001;51:146-159. [ Links ]
28. Inturrisi CE - Clinical pharmacology of opioids for pain. Clin J Pain, 2002;18:(Suppl4):S3-S13. [ Links ]
29. Simon EJ, Hiller JM, Edelman I - Stereospecific binding of the potent narcotic analgesic (3H)Etorphine to rat-brain homogenate. Proc Natl Acad Sci USA,1973;70:1947-1949. [ Links ]
30. Goldstein A, Lowney LI, Pal BK - Steriospecific and nonspecific interactions of the morphine congener levorphanol in subcellular fractions of mouse brain. Proc Natl Acad Sci USA, 1971;68:1742-1747. [ Links ]
31. Finck AD - Opioid receptor and endorphins: significance for Anesthesiology, Refresher Courses in Anesthesiology, 1979;7:103-114. [ Links ]
32. Eckenhoff JE, Elder JD, King BD - The effect of N-allyl normorphine in treatment of opiate overdose, Am J Med Sci, 1951;222:115. [ Links ]
33. Eckenhoff JE, Hoffman GL, Dripps RD - N-allylmorphine: an antagonist to the opiates. Anesthesiology, 1952;13:242-251. [ Links ]
34. Foldes FF, Lunn JN, Moore J et al - N-Allylnoroxy-morphone: a new potent narcotic antagonist, Am J Med Sci, 1963;245:23-30. [ Links ]
35. Muller A, Koch B, René F et al - Mécanismes de la tolérance et de la dépendance aux opiodes. Ann Fr Anesth Réanim, 1999;18:866-895. [ Links ]
36. Hughes J - Isolation of an endogenous compound from the brain with pharmacological properties similar to morphine. Brain Res, 1975;88:395-308. [ Links ]
37. Yaksh TL, Rudy TA - Analgesia mediated by a direct spinal action of narcotics. Science, 1976;192:1357-1358. [ Links ]
38. Bromage PR - Intraspinal narcotics: state of the art. Refresher Courses in Anesthesiology, 1982;10:27-36. [ Links ]
39. Wang JK, Nauss LA, Thomas JE - Pain relief by intrathecally applied morphine in man. Anesthesiology, 1979;50:149-151. [ Links ]
40. Behar M, Magora F, Olshwang D et al - Epidural morphine in treatment of pain. Lancet, 1979;1:527-529. [ Links ]
41. Nociti JR - Opiáceos: benefícios e riscos na Anestesiologia, na dor e nos cuidados intensivos. Rev Bras Anestesiol, 1993;43:277-282. [ Links ]
42. Lopes MB, Sousa LR, Porsani DF et al - Associação bupivacaína e morfina intra-articular para analgesia pós-operatória em cirurgia artroscópica de joelho. Rev Bras Anestesiol, 1999.49:165-168. [ Links ]
43. Stein C, Gramsch C, Herz A - Intrinsic mechanism of antinociception in inflammation: local opioid receptors and beta-endorphin. J Neurosci, 1990;10:1292-1298. [ Links ]
44. Mc Quay HJ - Opioid use in chronic pain, Acta Anaesthesiol Scand, 1977;17:(Suppl):175-183. [ Links ]
45. Holdcroft A, Power I - Recent developments: management of pain. BMJ, 2003;326:635-637. [ Links ]
Dr. Danilo Freire Duarte
Address: Rua Armínio Tavares, 67/802
ZIP: 88015-250 City: Florianópolis, Brazil
Submitted for publication May 4, 2004
Accepted for publication October 13, 2004
* Received from Universidade Federal de Santa Catarina, Florianópolis, SC