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Update in Intravenous Anaesthesia: Original Papers

Mechanisms of actions of opioids and non-steroidal anti-inflammatory drugs

Bovill, J. G.

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European Journal of Anaesthesiology: May 1997 - Volume 14 - Issue - p 9-15



Opioids and non-steroidal anti-inflammatory drugs (NSAIDs) are among the oldest drugs used to relieve human suffering. However, it is only recently that the mechanisms underlying their analgesic actions have been elucidated. In the past two decades enormous advances have been made in this field and the most important of these are discussed in this review.


Opioid drugs mimic the actions of the endogenous opioid peptides by interacting with specific receptors, the opioid receptors, to produce a variety of pharmacological effects. Currently three distinct opioid receptor types, μ, δ and κ, are recognized and all have recently been cloned. The μ receptor is important in sensory processing, including the modulation of nociceptive stimuli, extrapyramidal functioning and in limbic and neuroendrocine regulation. There are two subtypes of the μ receptor, a high-affinity μ, receptor and a low-affinity μ2 receptor. Two subtypes of the δ receptor and three subtypes of the κ receptor have also been described. The supraspinal mechanisms of analgesia produced by μ-opioid agonist drugs is thought to involve the μ1 receptor whereas spinal analgesia, respiratory depression and the effects of opioids on gastrointestinal function are associated with the μ2 receptor.

Recently a third μ subtype has been described that binds opioid alkaloids such as morphine, but has essentially no, or exceedingly low, affinity for the naturally occurring endogenous opioid peptides or non-alkaloid opioids such as fentanyl [1]. The μ3 receptor has a broad distribution in macrophage, astrocytes and endothelial cells. It may be involved in immune processes. The endogenous ligand for this receptor may be morphine or codeine. There is good evidence for endogenous morphine and codeine [2]. Morphine- and codeine-like substances have been isolated from the brain of several species, and biosynthetic pathways for morphine production have been demonstrated in mammals, similar to that used by the opium poppy [3].

Cellular mechanisms

The opioid receptors are G protein-coupled receptors that preferrentially couple to a pertussis toxin-sensitive G protein (Gi/G0) to influence one or more of three second messenger pathways; cytoplasmic free Ca2+ [Ca2+]i, the phosphatidylinositol-[Ca2+]i system and the cyclic nucleotide cAMP. Like other G protein-coupled receptors, the opioid receptors have seven trans-membrane spanning domains and three extra- and three intracellular loops. Charged residues in the trans-membrane domains are important for ligand binding and G protein coupling. The extracellular N-terminus does not appear to be essential for μ-opioid receptor function, but the deletion of 33 amino acids from the intracelllular C-terminus prevented the selective μ agonist DAMGO ([D-Ala2,MePhe4,GLy(ol)5] enkephalin), but not morphine from inhibiting adenylyl cyclase [4].

The actions of opioids are primarily inhibitory. Opioids close N-type voltage-operated calcium channels and open calcium-dependent inwardly-rectifying potassium channels. This results in hyperpolarization and a reduction in neuronal excitability [5]. Kappa receptors may act only on calcium channels [6]. There is recent evidence that P/Q type Ca2+ channels may be inhibited by μ, but not by δ-receptor opioids [7]. Opioids also inhibit adenylyl cyclase, which converts adenosine triphosphate to cyclic adenosine-3′,5′-monophosphate (cAMP), decreasing the concentration of cAMP. Changes in cAMP may be responsible for modulation of neurotransmitter release (e.g. substance P). Cyclic AMP also activates and regulates protein kinase C, which alters the expression of intermediate early genes such as c-fos. C-fos is a marker of activity in neurones that are associated with nociception and its expression is depressed by morphine [8].

Opioids also have excitatory effects that involve both disinhibition of interneurones and direct excitation of neurones themselves. Nanomolar concentrations, acting via Gs proteins, stimulate adenylyl cyclase activity in certain neurones [9]. This may be responsible for some responses to opioids, such as paradoxical hyperalgesia and pruritus. Another important stimulatory effect is a transient increase in cytoplasmic free Ca2+ [Ca2+]i, secondary to Ca2+ influx via L-type Ca2+ channel opening as well as mobilization of Ca2+ from inositol triphosphate-sensitive intracellular stores [10]. Mu agonists may also stimulate Ca2+ entry into neurones via G protein-coupled activation of phospholipase C to increase inositol(1,4,5)triphosphate formation, secondary to Ca2+ influx via L-type Ca2+ channel opening [10-12]. Changes in [Ca2+]i may contribute to opioid-induced inhibition of the release from central and peripheral endings of primary afferents of excitatory substances responsible for modulation of nociception, such as substance P and glutamate. Opioid-induced changes in [Ca2+]i are likely to be a component of the mechanism underlying opioid analgesia. Calcium channel blockers enhance morphine analgesia [13].


Endogenous opioids and opioid receptors are located at key points in the pathways involved in the transmission, modulation and sensation of pain (Fig. 1). The μ receptor is most commonly associated with analgesia, but specific δ- and κ-agonists also mediate antinociception at spinal and supraspinal sites. Opioids selectively modulate 'second pain' sensation carried by slowly conducting, unmyelinated C fibres but have little effect on 'first pain' carried by small, myelinated Aδ fibres. In the dorsal horn, transmission of peripheral nociceptive signals via C fibre neurones involves the presynaptic release of neuropeptides such as tachykinins (substance P and neurokinin A) and glutamate. The tachykinins bind to the postsynaptic neurokinin receptors, NK1 and NK2, glutamate to AMPA and NMDA receptors, leading to depolarization and changes in second messengers [14]. Release of these neurotransmitters from the afferent terminals of sensory fibres is inhibited by activation of presynaptic μ, δ and κ receptors. Opioids also directly hyperpolarize the postsynaptic membranes of dorsal horn neurones. They also interfere with the action of prostaglandins at peripheral sites, and μ-agonists particularly inhibit PGE2-induced hyperalgesia in a dose-dependent fashion [15].

Fig. 1
Fig. 1:
Connections between the various parts of the central nervous system involved in nociceptive processing and pain recognition. PAG: periaquaductal grey; NRM: nucleus raphe magnus of the reticular activating system.

Activation of supraspinal opioid receptors results in the transmission of descending impulses that block spinal nociceptive reflexes, inhibit spinal nociceptive neurones, and produce analgesia. Supraspinally, the μ, receptor is primarily involved in antinociception and analgesia is dramatically reduced by specific μ1 antagonists such as naloxazone or naloxonazine [16]. Delta ligands may have a modulatory rather than a primary analgesic role [17]. The periaquaductal grey (PAG) contains a very high density of μ receptors and is the major site of the supraspinal component of opioid analgesia. It receives inhibitory projections from the hypothalamus and the nucleus raphe magnus (NRM) in the reticular formation, and mediates descending inhibition of nociceptive transmission (Fig. 1). Descending inhibitory pathways use noradrenaline and 5-hydroxytryptamine as neurotransmitters in the spinal cord rather than opioid peptides.

Recently all three types of opioid receptors have been demonstrated on peripheral terminals of sensory nerves [18]. Activation of these receptors seems to require an inflammatory reaction since locally applied opioids do not produce analgesia in healthy tissue. This may be due to the disruption of the normally impermeable perineurium by inflammation, together with, in the later stages, an upregulation of the receptors by peripherally directed transport of opioid receptors from the dorsal horn. The inflammatory process also may render previously inactive receptors active.

Tolerance and physical dependence

Following prolonged or repeated exposure to opioids, there develops a diminished responsiveness to their actions, especially those causing analgesia, which can be seen at cellular level. While tolerance is often associated with chronic exposure for days or weeks, it can develop after minutes to hours. Physical dependence is a state, sometimes associated with drug tolerance, that comes about as a consequence of sustained exposure to a drug whereby adaptive changes occur leading to the required presence of the drug for normal function.

The exact mechanisms underlying the development of tolerance remain uncertain and it is likely that several are involved. Studies following chronic opioid exposure in animals have failed to find consistent changes in binding affinity or receptor number, or the changes that are observed do not correlate with the development of tolerance [19,20]. There is evidence that chronic exposure may involve an uncoupling of the receptor from a G protein with a resultant increase in adenylyl cyclase activity. Acute tolerance may also involve a change in the receptor itself such as receptor downregulation. However, if uncoupling of the receptor from the G protein-adenylyl cyclase cascade is the main mechanism of tolerance, this can only be partial since administration of naloxone to tolerant animals and humans causes an acute rebound exaggerated response, indicating that a connection between receptor occupation and subcellular responses remains intact.

It is more likely that as tolerance develops there is a cellular response to the continued presence of the opioid that compensates for its inhibitory effects. Chronic receptor stimulation may cause compensatory, slowly developing increases in adenylyl cyclase activity, and elevations in cellular cAMP. This in turn induces cAMP phosphodiesterase and an increase in the rate of degradation of cAMP resulting in a negative feedback mechanism maintaining homeostasis of cAMP concentrations [21]. The overshoot produced by naloxone in tolerant animals would then be a result of this compensatory response suddenly occurring in the absence of opioid inhibitory effects.

The biochemical events underlying the stimulatory, as opposed to the inhibitory, effects of opioids, such as increases in protein kinase C (PKC) are also involved in the development of tolerance [22]. Blocking the stimulatory effects of opioids prevents the development of tolerance [23]. Activation of PKC can desensitize the K+ channels normally opened by opioids [24]. The increase in PKC activity may be associated with upregulation of L-type calcium channels. Block of these channels with diltiazem prevents both the increase in PKC activity and the development of tolerance in rats.

Non-steroidal anti-Inflammatory drugs (NSAIDs)

NSAIDs are a heterogeneous group of compounds with analgesic, anti-inflammatory and antipyretic properties. Some, e.g. phenylbutazone, have a high toxicity that restricts their use to the treatment of chronic inflammatory conditions such as rheumatoid arthritis. Other, less toxic, compounds e.g. paracetamol, diclofenac and ketorolac, are commonly used for the treatment of postoperative pain. Paracetamol has analgesic and antipyretic effects similar to those of aspirin, but is has negligible anti-inflammatory activity. As such it is strictly not an NSAID. However, like aspirin it is a potent prostaglandin inhibitor but this activity is mainly restricted to within the CNS.

Analgesia and anti-inflammation

The mechanisms by which NSAIDs affect pain are different from those of opioids. Trauma and inflammation activate the release of mediators such as K+, H+, cytokines, bradykinin, histamine, 5-HT and substance P. In addition, noradrenaline and dopamine are released from damaged blood vessels and sympathetic nerves, increasing the production of prostaglandin E2 (PGE2) [25]. This 'sensitizing soup' activates phospholipase A2 that catalyses the production of arachidonic acid. Arachidonic acid, a major component of cell membrane phospholipids, is converted by cyclo-oxygenase (prostaglandin endoperoxide synthase) to the cyclic endoperoxides PGG2 and PGH2, which are in turn metabolized to various prostaglandins, prostacyclin (PGI2) and thromboxanes (Fig. 2).

Fig. 2
Fig. 2:
Metabolic pathways in the conversion of arachidonic acid to prostaglandins, thromboxanes and leukotrienes. The activity of phospholipase A2 is increased by angiotensin II, bradykinin and thrombin and inhibited by steroids. 5-HPETE: 5-hydroperoxyeicosatetraenoic acid; TXA: thromboxane A; TXB: thromboxane B.

The prostaglandins PGE2 and PGI2 and the leukotriene LTB4 are produced during inflammation and tissue damage and either excite nociceptors or, more usually, produce hyperalgesia by sensitizing them so that mechanical or chemical stimuli which would normally be painless produce pain [26]. Activation of high-threshold nociceptive afferent inputs increases Ca2+ influx into dorsal horn neurones, via activation of NMDA receptors and cellular depolarization, resulting in activation of phospholipase A2. This in turn leads to activation of the cyclo-oxygenase pathway followed by hypersensitization [26]. Inhibition of prostaglandin synthesis by cyclo-oxygenase is the principal mode of action of NSAIDs in the relief of pain secondary to tissue injury or chronic inflammation. Cyclo-oxygenase is inhibited irreversibly by aspirin and reversibly by other NSAIDs. In addition to inhibition of cyclo-oxygenase, an additional mode of anti-inflammatory activity of piroxicam and other oxicams is modulation of various cytokines, including interleukin 2, interleukin 6 and tumour necrosis factor alpha [27].

The effect on prostaglandin synthesis is not selective for inflamed tissue, and the widespread inhibition of cyclo-oxygenase is responsible for several of the adverse effects of these drugs. In addition, the lipoxygenase pathway, which converts arachidonic acid to leukotrienes, is inhibited by some NSAIDs (e.g. indomethacin and diclofenac), but not by salicylates. A component of the analgesic action of NSAIDs is also due to a central action by reduction of prostaglandin production within the CNS. This is the main action of paracetamol. NSAIDs interfere with a variety of membrane-associated processes, including the activity of NADPH oxidase in neutrophils and the activity of phospholipase C in macrophages. Some NSAIDs are thought to inhibit cellular processes by uncoupling protein-protein interactions within the lipid bilayer of the plasma membrane, including the processes regulated by G proteins [27]. The effects appear to be a direct interaction with the G protein, probably at the α site [28]. Because they act indirectly, NSAIDs have a latent period during which their effects are minimal and so have a slow onset of action, requiring up to 40 min for the onset of effective analgesia.

Cyclo-oxygenase exists in at least two isoforms. Type I, which is the constitutive form, is responsible for the production of prostaglandins involved in cellular 'house-keeping' functions such as the regulation of vascular homeostasis and coordinating the actions of circulating hormones [29]. Type II cyclo-oxygenase is induced in cells activated by exposure to mediators of inflammation such as cytokines and endotoxin, and may be responsible for the production of prostanoids that mediate inflammation, pain and fever. There are wide differences in the selectivity of NSAIDs for the isoforms. Some, such as aspirin, indomethacin and ibuprofen are more potent inhibitors of type I than type II. Diclofenac, paracetamol and naproxen are equipotent inhibitors of both types. The therapeutic effects of the NSAIDs may be due to their ability to inhibit the type II isoenzyme while the side-effects, such as gastric and renal damage, correlate with their ability to inhibit type I. Nabumetone is a more effective inhibitor of type 2 than type 1 cyclo-oxygenase and is less likely than other NSAIDs to cause gastric ulcers [30].

In addition to prostaglandin inhibition a central analgesic action has been demonstrated for diclofenac, mediated by β-endorphin [31]. Diclofenac and indomethacin also inhibit phosphodiesterase [32]. This results in an increase in cyclic AMP and may explain some of the effects of NSAIDs, such as those on smooth muscle [33]. A further mechanism for the analgesia produced by diclofenac may be a functional down-regulation of sensitized peripheral nociceptors. This seems to be the result of stimulation of the cyclic GMP system via the arginine-nitric oxide pathway [34].

Spinal actions of NSAIDs

It is now recognized that many of the features of acute and chronic pain are the result of functional changes in the dorsal hom of the spinal cord that develop consequent to continuing afferent nociceptive input. Acute post-surgical pain and the chronic pain caused by, for example, arthritis involves both central and peripheral sensitization [35]. There is evidence that NSAIDs have significant actions on the dorsal horn and that these contribute to their analgesic and anti-inflammatory actions [26,36,37]. Several NSAIDs, including ketoprofen, indomethacin and diclofenac appear in the cerebrospinal fluid (CSF) of humans at concentrations which equal or exceed the free fraction in plasma [38-40]. An exception is ketorolac. The CSF concentrations of ketorolac were of the order of 1000 times less than the total plasma concentrations following intramuscular injection, and the free concentrations of ketorolac in plasma were estimated to be about 10 times more than those in CSF [40]. Several receptors in the spinal cord, e.g. substance P receptors of the NK1 type and NMDA receptors are involved in spinal sensitization. These receptors exert their effects by activating several intracellular processes, including enhancing the formation of prostaglandins. Intrathecal NSAIDs reduce the hyperalgesia evoked by the spinal action of substance P, AMPA and NMDA in rats [42]. McCormack [36,37] reviewed the role of NSAIDs in spinal nociceptive processing and concluded that some of their central effects are independent of cyclo-oxygenase inhibition, but may be mediated by interactions with descending serotonergic pathways, together with modulation of neurotransmission at glycine or NMDA receptors. Thus, NSAIDs would seem to have a direct effect on spinal nociceptive processing, mediated by mechanisms that are independent of those involved in their peripheral analgesic and anti-inflammatory actions.

Antipyretic effect

The antipyretic effect of the NSAIDs is a consequence of central prostaglandin inhibition. Temperature regulation is controlled by the hypothalamus, which sets the point at which body temperature is maintained. In fever this is adjusted upwards, under the influence of pyrogens and prostaglandins released from the inflammatory process. Aspirin also prevents the release of endogenous pyrogens from white cells. NSAIDs in normal doses have no effect on temperature regulation in subjects with normal body temperature.

Platelet function

NSAIDs can interfere with platelet function by several mechanisms involving inhibition of cyclo-oxygenase. This blocks the formation not only of platelet-activating eicosanoids, such as PGG2, PGH2 and thromboxane A2, but also of the platelet inhibitors PGD2 and PGI2. PGI2 causes an increase in platelet cyclic AMP, which prevents them from aggregating but not from adhering to the endothelium, thus allowing minor endothelial injury healing. Aspirin is the only NSAID that is used therapeutically for its anti-platelet effects.

For most NSAIDs, except aspirin, the anti-platelet effect is present only while the drug is present in the body in sufficient concentration. In the case of aspirin the effect lasts for the 5-11 days of the life of the platelet because of the irreversible acetylation of platelet and megakaryocyte cyclo-oxygenase coupled with the inability of platelets to synthesize new enzyme.

Hypersensitivity reactions

In susceptible individuals NSAIDs may precipitate acute bronchospasm, a clinical syndrome referred to as aspirin-induced asthma. The mechanism is related to cyclo-oxygenase inhibition, with shunting of arachidonic acid metabolism from the prostaglandin pathway to the biosynthesis of leukotrienes with resulting bronchospasm, increased mucosal permeability and secretion and neutrophil influx to the tissues.


1 Lambert DG. Opioid receptors. Curr Opin Anaesthesiol 1995; 8: 317-322.
2 Hosztafi S, Furst Z. Endogenous morphine. Pharmacol Res 1995; 32: 15-20.
3 Kodaira H, Spector S. Transformation of thebaine to oripavine, codeine, and morphine by rat liver, kidney, and brain microsomes. Proc Natl Acad Sci USA 1988; 85: 1267-1271.
4 Surratt CK, Johnson PS, Moriwaki A et al. μ opiate receptor. Charged transmembrane domain amino acids are critical for agonist recognition and intrinsic activity. J Biol Chem 1994; 269: 20548-20553.
5 McFadzean DF. The ionic mechanisms underlying opioid actions. Neuropeptides 1988; 11: 173-180.
6 North RA. Opioid receptor types and membranes on ion channels. Trends Neurosci 1986; 9: 174-176.
7 Rhim H, Miller RJ. Opioid receptors modulate diverse types of calcium channels in the nucleus tractus solitarius of the rat. J Neurosci 1994; 14: 7608-7615.
8 Abbadie C, Besson J-M. Effects of morphine and naloxone on basal and evoked Fos-like immunoreactivity in lumbar spinal cord neurons of arthritic rats. Pain 1993; 52: 29-39.
9 Crain SM, Shen KF. Opioids can evoke direct receptor-mediated excitatory effects on sensory neurons. Trends Pharmacol Sci 1990; 11: 77-81.
10 Smart D, Smith G, Lambert DG. Mu-opioids activate phospholipase C in SH-SY5Y human neuroblastoma cells via calcium-channel opening. Biochem J 1995; 305: 577-581.
11 Smart D, Smith G, Lambert DG. Mu-Opioid receptor stimulation of inositol(1,4,5)trisphosphate formation via a pertussis toxin-sensitive G protein. J Neurochem 1994; 62: 1009-1014.
12 Wandless AL, Smart D, Lambert DG. Fentanyl increases intracellular Ca2+ concentrations in SH-SY5Y cells. Br J Anaesth 1996; 76: 461-463.
13 Santillan R, Maestre JM, Hurle MA, Florez J. Enhancement of opiate analgesia by nimodipine in cancer patients chronically treated with morphine: a preliminary report. Pain 1994; 58: 129-132.
14 De Leon-Cassola OA, Lema MJ. Postoperative epidural opioid analgesia: what are the choices? Anesth Analg 1996; 83: 867-875.
15 Ferreira SH, Nakamura M. II. Prostaglandin hyperalgesia: the peripheral analgesic activity of morphine, enkephalins and opioid antagonists. Prostaglandins 1979; 18: 191-200.
16 Callahan P, Pasternak GW. Opiates, opioid peptides, and their receptors. J Cardiothoracic Anesth 1987; 1: 569-576.
17 Heyman JS, Jiang Q, Rothman RB, Mosberg HI, Porreca F. Modulation of mu-mediated antinociception by delta agonists: characterization with antagonists. Eur J Pharmacol 1989; 169: 43-52.
18 Stein C. Peripheral mechanisms of opioid analgesia. Anesth Analg 1993; 76: 182-191.
19 Puttfarcken PS, Cox BM. Morphine induced desensitization and down regulation at mu-receptor in 7315c pituitary tumor cells. Life Sci 1989; 45: 1937-1942.
20 Yoburn BC, Sierra V, Lutfy K. Simultaneous development of opioid tolerance and opioid antagonist-induced receptor upregulation. Brain Res 1990; 529: 143-148.
21 Sibley DR, Benovic JC, Caron MG, Lefkowitz RJ. Regulation of transmembrane signalling by receptor phosphorylation. Cell 1987; 48: 913-922.
22 Smart D, Lambert DG. The stimulatory effects of opioids and their possible role in the development of tolerance. Trends Pharmacol Sci 1996; 17: 264-269.
23 Shen KF Crain SM. Antagonists at excitatory opioid receptors on sensory neurons in culture increase potency and specificity of opiate analgesics and attenuate development of tolerance/dependence. Brain Res 1994; 636: 286-297.
24 Mestek A, Hurley JH, Bye LS et al. The human mu opioid receptor: modulation of functional desensitization by calcium/calmodulin-dependent protein kinase and protein kinase C. J Neurosci 1995; 15: 2396-2406.
25 Alanko J, Riutta A, Vapaatalo H. Effects of catecholamines on eicosanoid synthesis with special reference to prostanoid/leukotriene ratio. Free Rad Biol Med 1992; 13: 677-688.
26 Malmberg AB, Yaksh TL. Antinociceptive actions of spinal nonsteroidal antiinflammatory agents on the formalin test in the rat. J Pharmacol Exp Ther 1992; 263: 136-146.
27 Brooks PM, Day RO. Nonsteroidal antiinflammatory drugs - differences and similarities. N Eng J Med 1991; 324: 1716-1725.
28 Abramson SB, Weissman G. The mechanisms of action of nonsteroidal antiinflammatory drugs. Arthritis Rheum 1989; 32: 1-9.
29 Simon, L.S. Actions and toxic effects of the nonsteroidal anti-inflammatory drugs. Curr Op Rheumatology 1994; 6: 238-251.
30 Helfgott SM. Nabumetone: A clinical appraisal. Semin Arthritis Rheum 1994; 23: 341-346.
31 Martini A, Bondiolotti GP, Sacerdote P et al. Diclofenac increases beta-endorphin plasma concentrations. J Int Med Res 1984; 12: 92-95.
32 Flower RJ, Vane JR. Inhibition of prostaglandin biosynthesis. Biochem Pharmacol 1974; 23: 1439-1450.
33 Gamaniel K, Wuorela H, Metsa-Ketela T, Vapaatalo H. Influence of piroxicam on the contractile action of prostaglandin E1 on the isolated rat uterus. Methods Find Exp Clin Pharmacol 1988; 10: 493-496.
34 Tonussi CR, Ferreira SH. Mechanism of diclofenac analgesia: direct blockade of inflammatory sensitization. Eur J Pharmacol 1994; 251: 173-179.
35 Woolf CJ. Recent advances in the pathophysiology of acute pain. Br J Anaesth 1989; 63: 139-146.
36 McCormack K. The spinal actions of nonsteroidal anti-inflammatory drugs and the dissociation between their anti-inflammatory and analgesic effects. Drugs 1994; 47 (Suppl 5): 28-45.
37 McCormack, K. Non-steroidal anti-inflammatory drugs and spinal nociceptive processing. Pain 1994; 59: 9-43.
38 Bannwarth B, Netter P, Lapicque F, Pere P, Thomas P, Gaucher A. Plasma and cerebrospinal fluid concentrations of indomethacin in humans. Relationship to analgesic activity. Eur J Clin Pharmacol 1990; 38: 343-346.
39 Netter P, Lapicque F, Bannwarth B, Tamisier JN, Thomas P, Royer RJ. Diffusion of intramuscular ketoprofen into the cerebrospinal fluid. Eur J Clin Pharmacol 1985; 29: 319-321.
40 Zecca L, Ferrario P, Costi P. Determination of diclofenac and its metabolites in plasma and cerebrospinal fluid by highperformance liquid chromatography with electrochemical detection. J Chromatogr 1991; 567: 425-432.
41 Rice ASC, LLoyd J, Bullingham RE, O'Sullivan G. Ketorolac penetration into the cerebrospinal fluid of humans. J Clin Anesth 1993; 5: 459-462.
42 Malmberg AB, Yaksh TL. Hyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal cyclo-oxygenase inhibition. Science 1992; 257: 1276-1279.

Section Description

Seventh International Symposium on Intravenous Anaesthesia, Lausanne, Switzerland, 2-3 May 1997

This publication is supported by grants from various pharmaceutical companies. The views in this publication are those of the authors and not necessarily those of supporting companies. Drugs and administration techniques referred to should only be used as recommended in the manufacturers' prescribing information.


Analgesics; Pharmacology, Nsaids, opioids; Receptors, adrenergic, transmembrane, calcium

© 1997 European Society of Anaesthesiology