Fundamental to modern neural blockade is the concept that pain is a sensory warning system conveyed by specific nerve fibres. This outlook may be traced back to developments in the study of physiology that superseded the view first expressed by Plato and Aristotle, that pain (like pleasure) is a passion of the soul. In the Seventeenth Century, Descartes introduced the mechanistic concept of neural connection from the periphery to the brain. Furthermore in 1803, Charles Bell and Magendie [1-3] defined important functions of the dorsal roots of the spinal nerves as distinct from those of the ventral roots, and initiated the search for a more complete understanding of sensory phenomena.
Attempts to influence neuralgic pain by applying a drug to the transmitting nerve appear to have been first published by Francis Rynd  of Ireland. In 1845, he described the idea of introducing a solution of morphine in the neighbourhood of a peripheral nerve with the intention of allaying neuralgic pain in the nerve. It seems that Rynd's idea foreshadowed both nerve block and, more remotely, opioid regional analgesia. An important step in developing the necessary equipment for regional blocks was the invention of the syringe and hypodermic hollow needle by Charles-Gabriel Pravaz  (Lyon, 1850s) and Alexander Wood  (Edinburgh, 1855), respectively. The discovery of the local analgesic effect of cocaine by Carl Koller [7,8] in 1884 made possible the vast array of peripheral local and regional analgesic therapy, whereas previously the only major site for pain control was thought to be the brain.
The use of many local anaesthetic drugs followed, including procaine, dibucaine, mepivacaine, tetracaine, lidocaine and bupivacaine. Procaine was introduced in 1905. Tetracaine, another ester-linked local anaesthetic introduced in 1931 - whose main advantage was its long duration of action - was one of the main agents used over five decades. But, like the other ester types, it is unstable, thus its effect is not as reliable as with the amide-type local anaesthetics. Lidocaine (lignocaine) - introduced by Nils Löfgren in 1943 - mepivacaine (1956) and bupivacaine (1966) were amides with a more reliable effect (Table 1).
The history of intrathecal analgesia
Hippocrates (470-400 BC), first spoke of 'water of the brain', when attempting to treat hydrocephalus by performing ventricular puncture. In 1692, Valsalva noted a watery fluid around the spinal cord of a dog, and in 1764 Domenico Cotugno  described the cerebrospinal fluid (CSF) in his paper De Ischiade Nervosa Commentarius. In 1825, Magendie described its circulation and coined the name, CSF .
Walter Wynter  in England (February 1889) and Heinrich Quincke  in Kiel, Germany (December 1890) independently introduced lumbar dural puncture. As Wynter did not report these cases until May 1891 in The Lancet, Quincke is usually credited with performing the first lumbar puncture.
August Bier  (1861-1949) is recognized as the father of intrathecal anaesthesia (Fig. 1). He theorized that his technique, which he called 'cocainization of the spinal cord', might provide the pain relief necessary for major surgery. Bier and his assistant Hildebrandt performed intrathecal anaesthesia on each other with cocaine on 16 August 1898 at the Royal Chirurgical Clinic in Kiel. Bier, who had the advantage of working at the same institution as Quincke, would have been familiar with Quincke's technique, and might even have borrowed his needles. With the first intrathecal anaesthesia came the first report of postdural puncture headache. Bier  described this complication after he performed experiments on himself and his assistant. Rudolph Matas  of New Orleans, USA, on 10 November 1899, was the first in the USA to apply intrathecal anaesthesia and might have been the first to inject morphine into the subarachnoid space.
In 1908, Thomas Jonnesco  and his assistant Amza Jianu of Bucharest, Romania, promoted intrathecal anaesthesia for a variety of suitable surgical procedures. Jonnesco used a cervical approach for thyroidectomy and thoracic procedures. Jonnesco and Jianu reported their experience with intrathecal analgesia at the Congress of International Surgery in Brussels (1901); however, the method was 'too novel and too innovative' to be accepted without opposition. In 1919 (Fig. 2), Jonnesco  published in Paris the first textbook of intrathecal anaesthesia La rachianesthésie générale.
The idea of making the intrathecal-injected solution hyperbaric with glucose, in order to obtain control over the intrathecal spread, was originated by Arthur E. Barker  in London, UK, in 1920. Barker was a professor of surgery at the University of London, and in his article (British Medical Journal, 1907) described experiments with a glass model of the spinal canal conforming to the shape seen in a cadaver. A refinement of Barker's theory and experiments was 'saddle-block' analgesia limited to the perineal region, described in detail by Adriani and Roman-Vega  of the USA in 1946.
It took 52 years after Corning's  discovery of epidural anaesthesia, and 39 years after Bier's intrathecal anaesthesia, until Soresi  first used a combination of epidural and intrathecal analgesia in 1937. However, it took another 42 years until Ion Curelaru and colleagues  of Romania in 1979 again used this combined intrathecal-epidural anaesthesia. James Corning devised one of the first lumbar puncture needles, which, being fashioned of gold or platinum alloy, was very expensive.
William T. Lemmon  first described a method for continuous intrathecal anaesthesia in 1940 by use of an indwelling malleable needle at the Mayo Clinic. In 1944, Edward Tuohy  of the Mayo Clinic introduced an important modification of continuous intrathecal techniques, by developing and performing continuous intrathecal anaesthesia by means of a ureteral catheter introduced into the subarachnoid space.
The history of epidural analgesia
Leonard J. Corning , a New York neurologist, in 1885 performed the first epidural analgesia inadvertently, by injecting cocaine between the spinous processes of the inferior dorsal vertebrae; with the intention of treating his patient's complaint of masturbation. From the description of his results and the manner of onset of anaesthesia, there is little doubt that epidural anaesthesia was produced, furthermore it was a 'walking' epidural: the man experienced some dizziness, but no inco-ordination or motor impairment was discernible in his gait. He left the clinic an hour or more after the injection. However, Corning introduced the term 'spinal anaesthesia' following this account.
In 1901, Fernand Cathelin  in Paris described the feasibility of injecting a local anaesthetic by the caudal route. His objective was to develop a method that would be less dangerous than intrathecal lumbar anaesthesia. Of further interest is Cathelin's promotion of epidural anaesthesia via the sacral route, which came only a week after Jean-Athanase Sicard had presented a paper on the same technique at the Society of Biology Meeting in Paris. It seems clear from Cathelin's remarks that competition for priority of publication was well established even at the turn of the century. However, Cathelin's work was more extensive than Sicard's and he presented results on dogs, cadavers and human beings.
In 1921, Fidel Pagés Mirave  of Madrid, a military surgeon, published the first report of lumbar epidural anaesthesia. He called this new type of anaesthesia 'metameric anaesthesia', but his practice was not disseminated to others or translated into other languages, and unfortunately he was killed in 1923 in an automobile accident. Many other historians consider the father of modern epidural anaesthesia to be A. M. Dogliotti  of Turin, an Italian surgeon. He described in detail the anatomy and physiology of the epidural space and developed the modern 'loss of resistance' technique for its clinical location. Dogliotti published his work in English in 1933 . Alberto Gutierrez  of Argentina in 1933 first described the 'hanging drop' method to identify the epidural space. In the two decades from the 1950s Philip Bromage  took the practice of epidural analgesia into the modern era with his book Epidural Anesthesia published in 1978, and he played a pivotal role in the widespread acceptance and utilization of epidural analgesia in surgery, obstetrics and pain management.
Intrathecal and epidural analgesia for obstetrics
Previous experience with intrathecal anaesthesia led Oscar Kreis  of Basel in 1900 to recognize advantages of a trial in childbirth. He injected 10 mg of cocaine at L4-L5, and claimed that this alleviated pain, with little impairment of somatic muscular power or uterine motility. In 1902, Hopkins  performed the first Caesarean section under intrathecal anaesthesia. The initiation of continuous regional anaesthesia in obstetrics came from Eugen Aburel [29,30] of Romania, who on 12 January 1931 presented his technique of continuous epidural (caudal) block for the relief of pain in childbirth at a meeting in Paris. Caudal block by catheter in obstetrics was introduced by Manalan  in 1942, and independently by Edwards and Hingson  in the same year.
The history of opioids
In the history of medicine, very few substances have enjoyed such prolonged and widespread use as the extract of Papaver somniferum. Its pharmacological effects were well known over 5000 years ago, when the Sumerians mentioned the poppy in their pharmacopeia, calling it 'Hu Gil', the plant of joy. According to Ebers Papyrus (c. 1534 BC), the Ancient Egyptians used the poppy to relieve insomnia and headache, deaden pain and provide anaesthesia.
The word 'opium' is derived from the Greek 'opus', which means vegetable juice. In ancient Hebrew medicine, opium was included in at least two different potions used to induce analgesia and sleep during surgical operation, and the use of opium during surgery is described in the records of the medical school of Salerno, in the Ninth Century AD. In the Thirteenth Century, Boccaccio mentions an opium potion in one of the novels of The Decameron. Paracelsus introduced laudanum, a mixture of opium 10% in a hydroalcoholic extract in the Sixteenth Century, which is still in use today for the treatment of pain. An alternative term for the state induced by opiates was 'narcosis', derived from the Greek word 'narco', meaning to numb or deaden . In 1803, Friedrich Serturner , a German pharmacist, isolated an alkaloid of opium and called it morphine, after Morpheus the Greek God of Sleep and Dreams (Fig. 3). This was the first extraction of a pure alkaloid from its natural source and initiated not only the use of opioid analgesics, but also their modern pharmacology. The synthesis of diamorphine by Beckett and Wright  in 1875 initiated the manufacture of effective opioid analgesics by chemical manipulation of the natural opioids.
Administration of intrathecal and epidural opioids
Opioids in the intrathecal and epidural space offer theoretical advantages over local anaesthetic agents given by the same route. Firstly, a dose of opioid lower than that used systemically may give analgesia without autonomic changes: loss of motor power, or impairment of sensation other than pain. Secondly, there exists a specific opioid antagonist with the capability of reversing unwanted side-effects namely, naloxone.
The first report of the use of opioids for the intrathecal route belongs to N. Racoviceanu-Pitesti of Romania in 1900. He injected morphine and cocaine for intrathecal anaesthesia, and was invited by Tuffier  to report his experience with intrathecal morphine analgesia at the Congress of International Surgery in Paris [29,36] (August, 1900). Shortly afterwards, in 1901, Katawata  of Japan reported the injection of morphine 10 mg and a local anaesthetic into the intrathecal space of two patients with uncontrollable back pain. The patients obtained excellent pain relief.
Opioid receptors were discovered in 1971 by A. Goldstein , and isolated in 1973 by Pert and Snyder . The identification of specific opioid receptors in the spinal cord has opened new concepts for the treatment of pain, furthermore it has contributed much to the understanding of pain mechanism and introduced the concept of opioid action at the spinal level. Stimulated by the above-reported findings, Yaksh and Rudy [41,42] in 1976 reported that opioids applied to the subarachnoid space of rats produced significant analgesia in a distribution identical with the segment of spinal cord exposed to the opioids. These studies of intrathecal morphine with local anaesthetic administration have shown augmentative effects on morphine-induced antinociception with postulat explanation being the respective cellular effects of both compounds. In 1978, LaMotte and colleagues investigated the regional distribution in the spinal cord of these opioid receptors [43,44]. Yaksh in 1983 reported that monkeys receiving epidural morphine for up to 16 months developed neither abnormal signs nor neuro-histological changes .
Meperidine (pethidine) was the first synthetic opioid used to provide analgesia in human beings. Eisleb and Schumann  discovered its analgesic properties in 1939. Nicolae Mircea  of Bucharest published the first report of meperidine as the sole agent for intrathecal anaesthesia in 1982 in a large series of 713 patients undergoing abdominal surgery.
Mechanism of action of intrathecal and epidural opioids
Drugs redistribute from the epidural space to the spinal cord by diffusion through the spinal meninges. Once drugs traverse the arachnoid mater to reach the CSF, their effective time in the CSF is dependent on their relative aqueous solubility. Hydrophilic drugs (e.g. morphine) spend relatively more time in the CSF than hydrophobic drugs (e.g. fentanyl). This fact explains the clinical observation that hydrophilic drugs undergo greater rostral spread than do hydrophobic drugs. In the CSF, opioids must penetrate the spinal cord to reach opioid receptors in the dorsal horn. Importantly, the spinal cord is not a homogenous tissue . Consequently, hydrophobic opioids can be expected to distribute preferentially into the white matter, and hydrophilic opioids into the grey matter. In vivo and in vitro animal studies demonstrated that increasing lipid solubility decreases the spinal cord bioavailability .
Morphine clearly produces analgesia by a spinal mechanism of action and is considered the 'gold-standard' for intrathecally-administered opioids. It is hydrophilic and highly ionized, has a slow onset of 30-60 min and a duration of action of 18-24 h. Morphine was the first opioid drug to receive the USA Food and Drug Administration approval for intrathecal and epidural use. Fentanyl, although widely used for epidural administration, does not confer any clinical benefit over the i.v. route, because the analgesic effect is mediated mainly by uptake into plasma and redistribution to brain. Fentanyl is hydrophobic and non-ionized; administered intrathecally it has a rapid onset of 5 min and a duration of 2-4 h.
Similarly, sufentanil and alfentanil have been shown to produce analgesia solely by systemic uptake from the epidural space and redistribution to the brain. However, intrathecal administration of fentanyl, sufentanil and alfentanil gained some popularity in clinical use.
The application of these techniques in human beings was first performed in Israel in 1979 by Behar and colleagues, who reported the injection of morphine into the epidural space in patients suffering from cancer pain and acute postoperative pain . Use of morphine and meperidine was variously reported for the treatment of cancer, ischaemic and traumatic pain by Wang and colleagues (1979)  and Cousins and Mather .
During 1980-1982, Bromage and colleagues , Pasqualucci and colleagues  and Scott and colleagues  reported the use of epidural or intrathecal opioids for postoperative, myocardial infarction and labour pain. Unlike local anaesthetics, the opioids did not cause motor blockade and, unsurprisingly, these techniques were enthusiastically adopted. Epidural patient-controlled analgesia with morphine was introduced by Sjostrom and colleagues  in 1988.
The first two prospective studies testing the analgesic potency of epidural morphine were reported from Scandinavia by Reiz and colleagues  in 1981 and by Hjortso and colleagues  in 1985. The understanding of the kinetics of opioid drugs has given rise to the suggestion that the actions of intrathecal and epidural opioids are due to a central rather than a spinal action.
Complications of intrathecal and epidural administration of opioids
After initial enthusiasm regarding the application of opioids neuraxially (epidurally or intrathecally) it became increasingly clear that not all types of pain could be controlled effectively by spinal opioids. Moreover, relatively high doses of intrathecal opioids had their own specific side-effects, such as hyperalgesia and myoclonia. High doses of epidurally administered opioids resulted in high systemic drug concentrations with side-effects similar to those following oral or parenteral administration.
In 1912, Gray and Parsons  of Birmingham, England, undertook the first extensive study of variations in BP associated with spinal anaesthesia. Gaston Labat  in 1915, emphasized that the danger was not the fall per se, but rather the associated 'cerebral anaemia' attributable to blood redistribution in the visceral vascular territory. He introduced two methods in order to avoid 'cerebral anaemia' by placing the patient in the Trendelenburg position and administrating ephedrine subcutaneously. Ephedrine is the sympathomimetic drug that is most widely used to sustain BP during intrathecal anaesthesia. The active principal was isolated from the chinese herb 'ma-huang' in 1885 by Yamanashi. Butterworth and colleagues  found that use of a mixed adrenergic agonist, such as ephedrine, more ideally corrected the non-cardiac circulatory sequelae of total intrathecal anaesthesia in dogs than did either a pure α-(phenylephrine) or a pure β-adrenergic agonist (isoproterenol (isoprenaline)).
Soon after the first report of Behar and colleagues , the reports of complications started to be published. In August 1979, Alexander Liolios  of Odense, Denmark, presented the first case of delayed respiratory depression 4 h after intrathecal morphine. Glynn and colleagues  in 1979 and Davies and colleagues  in 1980 reported other cases of respiratory depression after spinal morphine.
Sebastian Reiz and Mats Westberg  of Sweden published a report of epidural morphine in 1200 patients in July 1980. They found nausea and vomiting in 17%, urinary retention in 15% and respiratory depression in one patient. Two years later in 1982, Gustaffson and colleagues in Sweden published the first extensive survey of adverse effects of epidural-intrathecal opioids . The most worrisome side-effect of intrathecal opioids was respiratory depression, which may occur up to 12 h after administration. While this complication has been reported mostly with intrathecal narcotics, it also sporadically occurs with epidural application.
In 1981, at the Annual Meeting of the Association of Anaesthetists of Great Britain & Ireland in Nottingham, Maldwyn Morgan  presented an update on epidural and intrathecal opioids. He concluded that these methods were impracticable for the majority of the patients because of the close postoperative surveillance necessary if the dangers of respiratory depression and other complications were to be avoided. Furthermore in 1989, 10 years after the inception of epidural and intrathecal opioid analgesia, Morgan comprehensively reviewed the field, emphasizing that any patient undergoing these forms of analgesia should be accommodated in an intensive care, or high dependency, unit until the effect ceased . Myint and colleagues  published the first case report of cardiorespiratory arrest following opioid combined intrathecal-epidural anaesthesia in 1993. The patient recovered completely with no neurological deficit and did not develop a postspinal headache.
Pruritus is a known side-effect of opioid administration, and it seems to occur more commonly after epidural and intrathecal than after systemic administration. Reiz of Sweden in 1980, first described the association between epidural and intrathecal morphine and pruritus. Ballantyne and colleagues  reviewed this issue in 1988 in the journal Pain. Moreno and colleagues  described three patients treated by CSF exchange after total intrathecal block caused by mistaken overdose of local anaesthetic in the subarachnoid space (two after epidural and one after paravertebral block); CSF exchange was also used by Kaiser (for the treatment of subarachnoid morphine overdose ). In all the patients, clinical features of total spinal block appeared with severe hypotension, respiratory depression and loss of consciousness. After crystalloid infusion and epinephrine administration, CSF exchange was performed. A 22-G spinal needle was introduced in a cervical space in two patients and in a lumbar space in one patient. Repeated removal of 5 mL of CSF was followed by replacement of an equal volume of saline solution up to a volume of 50 mL. In less than 5 min all three patients recovered normal BP, spontaneous respiration and consciousness, while spontaneous movements of the four limbs were achieved within 20-30 min.
One hundred years ago, surgeons - who were also at the time pioneers in anaesthesia - discovered the advantages of regional conductive analgesia. The respiratory and cardiovascular stability of intrathecal-epidural techniques encouraged their use in suitable procedures. Adding opioids to the local anaesthetic solutions increased the analgesic effect and reduced the percentage of toxic reactions to local drugs. Today various opioids are used as single drugs for intrathecal and epidural postoperative analgesia, either by continuous infusion or patient controlled analgesia.
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