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British Journal of Anaesthesia 1995; 75: 145–156
New molecules in analgesia
H. P. RANG AND L. URBAN
Analgesic therapy is currently dominated by the two
main classes of analgesic drug, namely opiates and
non-steroidal anti-inflammatory drugs (NSAID),
which have been used clinically from the earliest
phase of scientific therapeutics, which began around
the beginning of the 19th century. Many improved
synthetic variants have been developed, as well as
improved techniques of administration, but there
has been little conceptual innovation. In the field of
neuropathic pain, for which NSAID are ineffective,
and opiates relatively so, increasing use is now made
of the analgesic effect of tricyclic antidepressants,
agents that block sympathetic transmission, and
agents that reduce membrane excitability (local
anaesthetics and related drugs). Generally speaking,
these represent new uses for old molecules. Apart
from NSAID and opiate variants, new molecules
designed specifically as analgesic agents have not
been forthcoming, in spite of the obvious need. This
is probably because of the relatively slow advance,
until recently, in our understanding of the pathogenesis of chronic pain, which now distinguishes it
mechanistically from the acute response to a noxious
stimulus. These advances are reviewed by others in
this issue and elsewhere [see 24, 73, 131, 136, 145].
In this article we examine the prospects for new drug
therapies based on the mitigation of some of the
physiological and neurochemical changes that occur
in the nociceptive pathway after injury. Where
possible, we discuss actual molecules and their
properties, but there are many processes in which
the target can now be defined, but where the magic
bullet has yet to be invented, so the practical
realization will inevitably be some years off. Even
where molecules exist, it must be realized that many
conditions have to be satisfied—mainly related to its
specificity, pharmacokinetic and toxicological
characteristics—before a new compound with appropriate pharmacological effects can achieve the
status of a usable drug.
The main processes that are believed to contribute
to chronic pain (see fig. 1) can be divided into:
(1) peripheral mechanisms leading to abnormal
excitation of peripheral nociceptive afferent fibres;
(Br. J. Anaesth. 1995; 75: 145–156)
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(2) central mechanisms, resulting in facilitated
transmission in the dorsal horn and higher up the
nociceptive pathway.
The peripheral mechanisms that produce increased excitation of peripheral sensory neurones
include: (a) the action of inflammatory mediators
and cytokines on nociceptive nerve terminals; (b) the
effect of peripheral nerve damage (axotomy or
peripheral neuropathy). Pharmacological approaches
targeted on peripheral mechanisms are discussed
below.
Facilitation in the dorsal horn occurs as a direct
consequence of increased C-fibre input [73, 138].
This “wind-up” phenomenon (reviewed by Urban
and colleagues [128]) is due partly to the interaction
of two mediators released by the C-fibre terminals,
namely glutamate, which acts on AMPA (␣-amino3-hydroxy-5-methylisoxazole) and NMDA (Nmethyl-D-aspartate) receptors and substance P,
which acts on neurokinin (NK)-l receptors. Other
modulating influences, whose activity may be altered
in chronic pain states, include GABA-mediated
inhibition, and alterations in opioid peptidemediated synaptic inhibition, due partly to increased
cholecystokinin (CCK) release [111] acting in opposition to endogenous opioids. Many other peptide
and non-peptide mediators are believed to modulate
transmission in the nociceptive pathway. These
include peptides, such as calcitonin gene-related
peptide (CGRP), somatostatin, neuropeptide Y
(NPY); non-peptides such as adenosine, and various
amino transmitters; as well as modulators such
as eicosanoids and nitric oxide. Pharmacological
approaches based on these various chemical mediators acting at the spinal cord level are discussed
later.
Peripherally-acting agents
In this section we discuss first inflammatory mediators, kinins, prostanoids and cytokines, which
directly or indirectly influence peripheral nociceptors and effectively tune the spinal input to a
“crescendo” during inflammation. The receptor
sites and processing enzymes for such mediators are
the primary targets for drugs with analgesic activities. We also discuss drugs with direct neuronal
targets, designed to reduce the excitability and
H. P. RANG, MB, BS, DPHIL, FRS AND L. URBAN, MD, PHD, DSC,
Sandoz Institute for Medical Research, Gower Place, London
WC1E 6BN.
Correspondence to H. P. R.
146
British Journal of Anaesthesia
Figure 1
Sites of action of analgesic drugs.
activity of nociceptive primary afferents through
modulation of ion channels by direct influence or
through neuronal receptors.
INFLAMMATORY MEDIATORS AND INHIBITORS
Bradykinin
Bradykinin (BK) and kallidin are the products of the
blood clotting cascade and tissue injury, respectively.
They can also be formed by alternative routes
through activation of immune cells. Both molecules
contribute strongly to the events of inflammation
[23], and also (acting mainly on B2 receptors) cause
excitation and/or sensitization of primary afferent
nociceptors leading to pain and hyperalgesia. This
occurs partly through a direct action, and partly
through the production and release of other compounds which act on nociceptors. Accordingly,
bradykinin B2 receptor antagonists are analgesic in
New molecules in analgesia
147
Figure 2 Effects of NSAID on the constitutive and inducible forms of cyclo-oxygenase (COX-1 and COX-2).
acute inflammatory conditions [44, 49, 87, 115]. Recently it has been discovered that during prolonged
inflammation, B1 receptors play an important role,
and B1 receptor antagonists are also able to attenuate
the hyperalgesia [87]. The expression of the B1
receptor appears to be increased in inflamed tissue,
though so far there is no evidence of its existence on
neurones.
Because of bradykinin’s prominent function in the
pathogenesis of inflammatory pain, BK receptor
antagonists hold promise as novel analgesic agents.
Several B2 receptor antagonists have been described,
mainly peptide analogues such as NPC16731,
NPC567, HOE 140 and CP0127 which show antiinflammatory and analgesic activity in various animal
models [114, 115]. More recently a non-peptide B2
receptor antagonist (WIN 64338) has been designed
[95]. The only known B1 receptor antagonists so far
are peptides, the best characterized being
desArg9[Leu8]BK. This compound shows analgesic
activity in chronic hyperalgesia [87].
In conclusion, B1 and B2 receptor antagonists may
both prove to be useful as analgesic/antiinflammatory agents, though it will probably only be
when potent non-peptide compounds are discovered
that this approach will lead to drugs in the clinic.
Prostaglandin and other eicosanoid antagonists
Inflammatory mediators trigger arachidonic acid
(AA) production in a wide array of cells, resulting in
the formation of prostanoids through the cyclooxygenase (COX) pathway and leukotrienes through
the 5-lipoxygenase pathway.
In inflamed tissue PGE2 and PGI2 (prostacyclin)
are produced in excess. Recently two isoforms of the
COX enzyme were described [129, 139]. The constitutive form (COX-1) is present in different tissues
and its function is essential for the electrolyte balance
in the kidney [139] and for the cytoprotection of the
gastric mucosa [132]. The inducible isoform (COX2) plays the major role in inflammatory conditions
(fig. 2). Induction is stimulated by lipopolysaccharides (LPS) [63] and bacterial toxins [75], and
occurs in vivo in carrageenan-evoked inflammation
[9, 105].
Management of inflammatory pain conditions
relies heavily on NSAID which inhibit the formation
of prostaglandins and leukotrienes by a non-selective
inhibition of the COX isoforms. Some of their
unwanted effects, particularly those on the gastric
mucosa and the kidney, are believed to be associated
with inhibition of COX-1, so there is great interest in
the possibility of developing selective COX-2 inhibitors, which should show a better side-effect profile.
Prototype selective COX-2 inhibitors, such as
L-745,337 and SC-58125 block hyperalgesia and
plasma protein extravasation in carrageenan-induced
inflammation in the rat without any gastrointestinal
or renal side effects [9].
The alternative branch of the arachidonic acid
cascade (lipoxygenase) produces leukotrienes, some
of which, for example leukotriene B4 (LTB4) and
8R,15S-diHETE (8R,15S-dihydroeicosatetraenoic
acid), have been shown to sensitize mechano- and
thermoreceptors upon intradermal injection [70]. A
novel LTB4 receptor antagonist, CP-105,696 was
reported to attenuate the progression of collageninduced arthritis [45]. Although the general clinical
symptoms and histological changes were dramatically reduced by CP-105,696, at present there is no
evidence of its analgesic activity.
Cytokines
Cytokine release from immune cells is part of the
early host-defence reaction in inflammation [20].
Interleukin-1␤ (IL-1␤), IL-8 and tumour necrosis
factor ␣ (TNF-␣) are potent hyperalgesic agents in
animal models owing to their ability to stimulate
production and release of other pro-inflammatory
agents [35, 40]. The hyperalgesia induced by IL-1␤
depends partly on induction of bradykinin B1receptors [15]. Ferreira and colleagues [35] showed
that the peptide Lys-D-Pro-Thr, an IL-1 ␤ antagonist, was able to block inflammatory hyperalgesia. This is an interesting approach, though
it has not yet led to compounds for potential
clinical use.
Cytokine (IL-1 and TNF-␣) production is regulated at the transcriptional and translational level,
and compounds (known as cytokine-suppressive
anti-inflammatory drugs, or CSAID), are now being
discovered which inhibit their production. One of
these, SKF 86002, inhibits LPS-induced interleukin
production and shows analgesic activity in acute and
chronic pain models [61]. Recently the target of this
drug has been identified and cloned as a pair of novel
serine/threonine protein kinases [62]. CSAID, designed to block the activity of these kinases, may
provide new analgesic/anti-inflammatory drugs for
clinical use.
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British Journal of Anaesthesia
Table 1 Current uses of sodium channel blocking drugs as systemic analgesics
Drug
Local anaesthestics:
Lignocaine
Tocainide
Anticonvulsants
Carbamazepine
Phenytoin sodium
Antiarrhythmics: (see also Lignocaine)
Mexiletine
Indication
Reference
Chronic pain (rev.)
Neuropathic pain
Postoperative pain
Postherpetic neuralgia
Trigeminal neuralgia
Swerdlow [118]
Tanelian and Borse [122]
Tverskoy et al. [126]
Rowbotham et al. [93]
Lindstrom and Lindblom [66]
Neuropathic pain
Trigeminal neuralgia
Chronic pain
Tanelian and Brose [122]
Taylor et al. [123]
Swerdlow [117]
Neuropathic pain
Tanelian and Brose [122]
Chabal et al. [11]
Dejgard et al. [21]
Diabetic neuropathy
MODULATION OF ION CHANNELS
Drugs acting at sodium channels
In addition to their normal role in excitable membranes, which underlies the generation and propagation of action potentials in nerve and muscle cells,
there is evidence that abnormal sodium-channel
function may be important in neuropathic pain—a
clinical category that is often resistant to conventional analgesic drugs. Studies, mainly by Devor and
colleagues [17], have shown that spontaneous ectopic
activity develops in damaged sensory neurones,
originating both at the site of the neuroma (if
present) and in the cell body. It is suggested that this
results from abnormal accumulation of sodium
channels in the cell membrane.
The effectiveness of anticonvulsants, local anaesthetics and antiarrhythmic drugs in the treatment of
certain types of pain (particularly neuropathic [68,
122]) probably reflects the fact that they are all
sodium-channel blockers [10, 89, 104]. Lignocaine
selectively blocks ectopic discharges originating from
experimental neuromas, without affecting axonal
conduction [19], and this may be a general feature of
these drugs. There are various possible explanations
for this selectivity: (1) Ectopic discharges may
originate as the consequence of increase in the
number of sodium channels on DRG cells [18, 71],
and blockers may act at sites of ectopic discharge by
simply reducing the number of active sodium
channels below the threshold needed for spontaneous
activity. (2) The activity-dependent action of many
sodium channel-blocking drugs [92] may result in
inhibition of the tonic ongoing discharge at concentrations too low to interfere with action potential
condution under physiological conditions. (3) The
sodium channels expressed at the site of ectopic
discharge may be a different molecular species from
normal sodium channels, and more sensitive to
certain blocking drugs. It has been reported recently
that type III sodium channel mRNA (normally
expressed only during embryonic development) is
expressed in DRG cells after axotomy [130]. These
findings open the possibility of developing new types
of sodium channel-blocking drugs specifically for
use in neuropathic pain states, in addition to those
listed in Table 1.
Nociceptive sensory neurones under normal condi-
tions express at least two types of sodium channel, a
tetrodotoxin (TTX)-sensitive, fast-activating type
that is found in all sensory neurones, and a
tetrodotoxin-resistant, slow-activating type found
only in the class of small diameter slow-conducting
cells which includes polymodal nociceptors [56, 83,
91]. The slow TTX-resistant channel, because of its
selective expression by nociceptivie afferent neurones, offers an attractive drug target for novel
analgesic drugs, but nothing is yet known about its
sensitivity to known sodium channel-blocking drugs.
Modulation of potassium channels
In general, opening of potassium channels results in
membrane hyperpolarization, and inhibition of membrane excitability, an effect which might be exploited
in analgesia. Two of the many known types of
potassium channels have attracted most attention in
recent years, namely the large-conductance calciumdependent potassium channel (maxi-K channel), and
the ATP-sensitive potassium channel [27].
The maxi-K channel has partcularly interesting
features from the point of view of neuronal hyperexcitability. These channels are present in high
density in many neurones (as well as in smooth
muscle cells) though in sensory neruones they are
activated only at relatively high intracellular calcium
concentrations [82] and their functional significance
is not clear. The voltage and calcium sensitivity
of these channels means that they are activated
after the action potential, producing an afterhyperpolarization that limits the firing frequency of
the cells. Activators of these channels therefore
represent a possible approach to new analgesic drugs.
Dehydrosaponins, extracted from Desmodium adscendens [74] and more importantly substituted benzimidazolones (NS 004 and NS 1619) are potent maxiK-channel openers, but they lack selectivity as they
simultaneously block other membrane channels [26].
NS 1619 was found to inhibit presynaptic calcium
signals and transmitter release from peripheral
sensory nerves in the airways [106, 116].
Cromakalim, pinacidil and aprikalim, compounds
with diverse chemical structure, can activate type I
ATP-sensitive potassium channels in various tissues,
including neurones [27]. There have been no
reported studies of the analgesic effect of the maxi-K
or ATP-sensitive potassium channel openers, so
New molecules in analgesia
their potential usefulness in this indication remains
to be assessed. For practical purposes, it will be
necesary to identify drugs which lack the powerful
cardiovascular actions of the current generation of
compounds.
OTHER MECHANISMS
Peripherally-acting opiates
In addition to the well established central analgesic
effects of opiates, recent studies revealed that
immune cells could produce endogenous opiates
during inflammation [98]. This production of
opioids is matched by increased expression of
different opiate receptors on primary afferent nociceptors, where they can exert analgesic activity [14].
Experiments performed in several models of inflammatory and neuropathic pain suggest that the
antinociceptive effect of opiates is due, at least partly,
to their action on primary afferent nerve terminals
[1, 54] and sympathetic fibres [120]. Bradykinininduced mechanical hyperalgesia is attenuated by
agonists at ␮-, ␬-, or ␦-opioid receptors injected
locally, these effects being prevented by naloxone
[120]. In in vitro experiments, ongoing activity in Cfibres innervating inflamed tissue can be inhibited by
␮- or ␬-receptor agonists [1]. These data suggest that
both primary afferent nociceptors and sympathetic
fibres could be targets for opiates and raises the
possibility of developing peripherally acting opiates
as analgesics which would lack the sedative and
psychotropic effects of existing opiates, as well as
avoiding the dependence problem [108, 113].
Centrally-acting agents
In this section we focus first on neuropeptides that
have modulatory or transmitter functions in the
nociceptive pathway, whose receptors or processing
enzymes offer potential targets for new types of
analgesic drugs. We then discuss briefly other
mediators and targets, namely excitatory amino
acids, nitric oxide, eicosanoids and adenosine.
NEUROPEPTIDES AND NEUROPEPTIDE ANTAGONISTS
Tachykinins and CGRP in the nociceptive pathway
The tachykinins are a family of neuropeptides which
include the biologically important mammalian tachykinins, substance P (SP), neurokinin A (NKA) and
neurokinin B (NKB). There are three major types of
tachykinin receptors (NK-1, NK-2 and NK-3)
which recognize these peptides [81], SP being the
preferred agonist at NK-1 receptors [67]. In the
human CNS, NK-1 receptors predominate and are
believed to play a major role in pain transmission.
Tachykinins, particularly SP, the most intensively studied sensory neuropeptide, are known to
be important mediators in the nociceptive pathway
[65, 73, 85, 90]. SP is released, along with NKA, in
the spinal cord in vivo upon noxious peripheral
stimulation [25, 43, 124]. In acute nociception,
NKA, acting on NK-2 receptors, appears to play the
major role. NK-1 antagonists have only a small effect
149
on the slow exictatory synaptic potential in the spinal
cord elicited by C-fibre stimulation, whereas NK-2
antagonists are much more effective [38, 80], suggesting that, under normal physiological conditions,
SP is less important than other excitatory transmitters (particularly NKA), in this pathway. Accordingly NK-1 receptor antagonists produce only a
weak inhibition of acute nociceptive responses.
In models of pathological pain (particularly those
involving inflammatory hyperalgesia) NK-1 receptors become increasingly important [72, 125]. NK-1
receptors are upregulated during hyperalgesic conditions [72, 99] and the production and release of
tachykinins from primary afferent fibres also increase [22, 72, 100]. In the spinal cord the parallel
increase in the amount of SP released and in the
number of NK-1 receptors both contribute to the
enhancement of SP-mediated transmission. Substance P produces long-lasting depolarization of
dorsal horn neurones [79, 127]. This contributes to
the long-lasting facilitation of transmission (“windup”) in the nociceptive pathway that follows activity
in peripheral nociceptive neurones [128]. Facilitation
of nociceptive transmission is believed to be a major
factor in producing functional hyperalgesia; indeed
chronic pain and hyperalgesia are always associated
with an increased excitability of spinal neurones
[50].
Peptide antagonists specific for NK-1 and NK-2
receptors have been known for several years, and
used to study the functional role of these receptors,
but have not been developed for therapeutic use. An
important breakthrough came when Snider and
colleagues [109] reported the first non-peptide NK1 antagonist, CP 96345, which showed good oral
activity in a range of animal models. Several more
such compounds have subsequently been reported
[33, 34, 39, 42]. The first compound of this type, CP
96345, which has been the most widely studied, has
a significant blocking effect on calcium channels,
which resulted in cardiovascular side effects, and
partly accounted for its analgesic properties. This
side effect, which complicated the interpretation of
the analgesic effects in terms of NK-1 receptor
antagonism, has been eliminated in subsequent
compounds of this type.
Enhanced spinal excitability produced by SP or by
electrical or natural noxious stimulation is inhibited
by non-peptide NK-1-receptor antagonists [88,
141]. NK-1-receptor antagonists are also antinociceptive in various animal models in which hyperalgesia is allowed to develop, for example adjuvantinduced arthritis models [6, 32, 42, 77, 144]. In the
formalin model, the irritant response to an injection
of formalin into the paw of a rat shows two distinct
phases; the first phase (lasting for about 10 min) is
unaffected by NK-1 antagonists, whereas the second
phase (lasting for about 60 min, and representing the
phase of spinal hyperexcitability), is strongly inhibited. A recent study has shown that the hyperalgesia
which develops in rats with experimental diabetes, a
model for clinical neuropathic pain, is inhibited by
RP-67580, a selective NK-1 antagonist [13].
Substance P also has various functions in the
periphery, contributing to inflammation, immune
150
cell activation and the activity of secretory and
smooth muscle cells in different organs (for review,
see Maggi and colleagues [67]). Thus, the therapeutic indications for tachykinin antagonists may be
much broader than simply analgesia.
Migraine has been described as a neurogenic
inflammatory process in intracranial (meningeal)
blood vessels, primarily triggered by trigeminal
nerve activation [69]. Neuropeptides (SP and
CGRP) released from these afferents cause vasodilatation and plasma protein extravasation and, in
addition, amplify these inflammatory processes by
stimulating the release of bradykinin and other
inflammatory mediators from non-neuronal cells.
NK-1-receptor antagonists strongly inhibit the leakage of plasma protein from dural blood vessels in
response to trigeminal nerve stimulation [64, 78,
107], a model for the acute migraine attack.
Though tachykinins and tachykinin receptors are
widely distributed in the central nervous system,
NK-1 antagonists have not so far been reported to
have marked effects on CNS function, apart from
their analgesic action and an anti-emetic effect [41],
so there is hope that such drugs will be relatively free
of unwanted effects compared with the currently
available analgesic drugs. Clinical trials of several
non-peptide NK-1 antagonists are currently in
progress, and such drugs should soon become
available for more general clinical use as analgesics.
Other neuropeptides
In addition to the neurokinins, many other peptides
are released by primary afferent nociceptive neurones
[60], though little is known so far about their
functional role. The expression of several of these
peptides changes under pathological conditions, such
as axotomy or peripheral inflammation, which are
associated with clinical pain states. It is therefore
reasonable to expect in the future that new drugs
able to influence the synthesis, release or degradation
of some of these peptides, or to act as mimetics or
antagonists at their receptors, will have a role in pain
therapy. At present, there are only a few clues as to
which peptides are likely to offer promising drug
targets.
Calcitonin gene-related peptide. CGRP is released by
nociceptive afferent fibres in the dorsal horn in
response to noxious stimuli [76]. It produces slow
depolarizing responses in dorsal horn neurones, and
also potentiates the depolarizing effect of SP.
Intrathecal administration of a neutralizing antibody
to CGRP produces an antinociceptive effect [59],
suggesting that an effective receptor antagonist might
have useful analgesic properties. Unfortunately, in
contrast with the situation with SP, the only CGRP
antagonist known is a large peptide, CGRP8–37, which
has not yet been assessed by the intrathecal route.
Non-peptide antagonists at CGRP receptors have
not yet been reported.
In contrast with SP and CGRP, which are
excitatory neuropeptides, where a receptor antagonist is likely to have analgesic properties, other
British Journal of Anaesthesia
sensory neuropeptides have mainly inhibitory
actions in the dorsal horn. Three in particular,
somatostatin, cholecystokinin and galanin, have
recently been the subject of considerable investigation.
Somatostatin. Somatostatin along with its stable
peptide analogues, octreotide and vapreotide, produce analgesia in various animal models, and are also
effective in humans after intravenous, epidural or
intrathecal administration [5]. Somatostatin analogues generally show affinity for opioid receptors,
and in some studies their analgesic effects are
reported to be reversible by naloxone, so it is not
clear whether they cause analgesia by acting specifically on somatostatin receptors, or as surrogate
opioids. Studies in rats have shown significant
neurotoxicity after spinal administration of somatostatin, leading to motor dysfunction, but this has
not been reported with the synthetic analogues.
Currently only peptide analogues of somatostatin,
which do not reach spinal sites unless given intrathecally or epidurally, have been described. None
the less there are several reports showing that
octreotide produces analgesia in humans when given
systemically [86, 101, 134]; the mechanism of its
action remains unclear.
Cholecystokinin. CCK differs from most of the other
neuropeptides that modulate nociceptive transmission in that it appears to act, not directly, but by
interaction with the opioid system; it can be regarded
as an endogenous inhibitor of opioid-mediated
analgesia [2, 111]. CCK given intrathecally antagonizes the analgesic effect of opiates acting on the ␮receptor, but does not by itself produce hyperalgesia
under normal conditions. Under conditions of stress,
however, when the endogenous antinociceptive
opioid systems are activated, CCK produces hyperalgesia, similar to that produced by naloxone.
Conversely, CCK antagonists, such as L365260 and
CI988, enhance the analgesic effect of opiates [2,
112]. This accentuation is clearly evident in normal
animals, but under conditions of chronic inflammation, in which the antinociceptive potency of
morphine is enhanced compared with the normal
situation, CCK antagonists have no effect. It is
postulated that the release of endogenous CCK is
inhibited under these conditions, so that the “CCKbrake” on opioid action is removed, and antagonism
of CCK at the receptor level is without effect. Many
neuropathic pain states are associated with hyperalgesia and allodynia that is relatively resistant to
opiates. It is suggested [111, 140] that this results
from increased release of CCK, since CCK antagonists enhance the effect of morphine in animal
models of neuropathic hyperalgesia. The antagonists
L365260 and CI988 are selective for the CCKB
receptor, which is found in the central nervous
system of rodents. In the primate spinal cord, the
CCKA receptor predominates, so for use in primates
CCKA antagonists, such as devazepide or nonselective antagonists, such as lorglumide [135] are
theoretically preferable. Such drugs are being developed for clinical use. Though they are unlikely to
New molecules in analgesia
be useful as analgesics on their own, they may
usefully enhance the analgesic potency of opiates
without increasing the respiratory depressant and
other unwanted effects.
Galanin. Galanin [4] is another neuropeptide
released by nociceptive afferent neurones. Unlike SP
and CGRP, the synthesis of galanin is upregulated
by peripheral nerve damage, and it is postulated
[133] that it exerts a tonic inhibitory effect on transmission in the dorsal horn. Galanin-like agonists
would therefore be a possible strategy for developing
new analgesic drugs.
OTHER APPROACHES
Excitatory amino acid antagonists
Antagonists at NMDA receptors, such as AP-5 and
dizocilpine (MK801), prevent the phenomenon of
“wind-up” in the spinal cord [46, 137], which is
believed to play an important role in inflammatory
hyperalgesia [143], and show analgesic activity in
various animal models when administered intrathecally. New NMDA-receptor antagonists are being developed for various indications, including
ischaemic brain damage, head trauma and epilepsy,
but their use as analgesics may be limited by
unwanted side effects, particularly psychotomimetic
effects and motor disturbances. A recent clinical
study [58] showed that an NMDA-receptor antagonist, CPP, given intrathecally to a patient with
severe neuropathic pain, reduced the tendency for
mechanical stimulation to produce progressively
worsening pain (presumed to reflect the “wind-up”
phenomenon) though it did not affect the resting
pain level. The patient, however, developed marked
anxiety and hyperacusis, and studies in rats [57]
showed that there was little margin between doses
needed for antinocieptive effects and those causing
motor paralysis, so this approach does not appear to
be very promising at present. Ketamine, a dissociative anaesthetic which (like MK801) blocks the
ion channel associated with the NMDA receptor is
effective as an analgesic agent, given on its own or as
an adjunct to morphine [28, 48]. Another clinically
available drug, the antiviral agent memantine, also
possesses NMDA-blocking activity, and has been
shown to be antinociceptive in the formalin test in
rats, with a reasonable margin between this action
and disturbance of motor function [31]. The analgesic activity of this drug in humans has not yet
been reported. Though blocking NMDA-receptor
function appears, in principle, to be an attractive
approach to new analgesic agents, experience so far
has been disappointing because the selectivity of
existing drugs for the nociceptive pathway is insufficient for analgesia to be produced without major
unwanted effects.
Adenosine analogues
There is considerable evidence suggesting that
adenosine exerts a modulatory effect on nociceptive
151
transmission both in the periphery and in the central
nervous system [96]. Adenosine receptors fall into
two main classes, A1 and A2. A1 receptors mediate
predominantly inhibitory effects on synaptic transmission, whereas A2 receptors are mainly excitatory.
Both receptor types are expressed in the central
nervous system, and both types occur in the
superficial region of the dorsal horn, where they are
believed to be present on small interneurones.
Intrathecal administration of adenosine analogues
produces a powerful antinociceptive effect [52, 53,
96], though this is often accompanied by motor
impairment. Systemic administration of adenosine
agonists is also effective [51], but is accompanied by
cardiovascular effects (hypotension and cardiac depression). Studies with receptor-selective agonists
suggest that the antinociceptive action results from
activation of A1 receptors, which are known to exert
pre- and post-synaptic inhibitory effects in the dorsal
horn. The physiological role of adenosine modulation of nociceptive transmission is not well understood, though there is some evidence that opioid
actions may be mediated in part through the release
of adenosine. Thus, adenosine receptor antagonists
inhibit the antinociceptive effects of morphine, and
morphine has been shown to elicit adenosine release
[97]. Furthermore, A1-receptor agonists act synergistically with opiates when both drugs are given
intrathecally.
Adenosine analogues also affect nociceptive transmission through an action in the periphery.
Adenosine produces pain after administration to the
blister base in human subjects [7] and causes
mechanical hyperalgesia in the rat when injected
locally. This results from A2-receptor activation,
which can be blocked by the selective A2 blocker, PD
081360-0002 [119]. On the other hand peripheral
application of the A1-receptor agonist analogue Rphenylisopropyl-adenosine (R-PIA [102, 103]) prevents paw licking in mice after formalin injection
[51]. At both central and peripheral sites, therefore,
A1 receptors mediate antinociceptive effects, whereas
A2 receptor agonists have the opposite effect.
These findings suggest the possibility that selective A1-receptor agonists might prove to be useful
analgesic agents, either as systemic agents, provided
that the problems of cardiovascular side effects and
effective penetration into the central nervous system
can be overcome, or for use as intrathecal or epidural
agents, possibly in combination with opiates. An
alternative approach is suggested by the work of Keil
and DeLander [55], who showed that spinal administration of the adenosine kinase inhibitor, 5⬘amino5⬘deoxyadenosine, which inhibits the degradation of
endogenous adenosine, produces an antinociceptive
effect.
Adrenoceptor agonists
The analgesic action of clonidine, an alpha2adrenoceptor agonist, has been known for many
years [142], and it is sometimes used by systemic or
intrathecal administration for this purpose [8, 29,
30], usually in combination with other agents. The
main disadvantages are sedation and hypotension.
152
British Journal of Anaesthesia
Table 2 Summary of potential new drugs in analgesia (COX, cyclo-oxygenase; CSAID, cytokine-suppressive anti-inflammatory
drugs; CGRP, calcitonin gene-related peptide; CCK, cholecystokinin; NMDA, N-methyl-D-aspartate)
Short/medium term
Long term
Target
Notes
Target
Notes
Selective COX-2 inhibitors
Prototype compounds
Leukotriene antagonists
Prototype compounds
Bradykinin B2/B1-receptor
antagonists
CSAID
NK-1 receptor antagonists
Several compounds in
development
Non-peptide compounds needed for
therapeutic use
Prototype compounds known—IL-1
antagonists and agents that inhibit
cytokine production
Specificity for nociceptive neurones
not yet achieved
No non-peptides known
Peptide analogues available. No nonpeptides known
No non-peptides known
Peripherally-acting opiates
CCK-A and/or B receptor
antagonists
Adenosine A1 receptor
agonists
Novel alpha2-adrenoceptor
agonists
Several compounds in
development
Compounds in development
Novel Na-channel blockers
and K-channel openers
CGRP-receptor antagonists
Somatostatin-receptor
agonists
Galanin-receptor agonists
Prototype compounds
NMDA-receptor antagonists
Nicotinic-receptor agonists
Used topically, as a transdermal patch, clonidine has
also been reported to relieve hyperalgesia in patients
with sympathetically-mediated pain, possibly by
acting presynaptically on sympathetic nerve terminals in the skin [16].
Dexmedetomidine, an alpha2-receptor agonist
used in veterinary anaesthesia, is more potent in
antinociceptive assays than clonidine when given
intrathecally, but produces similar motor disturbances, and appears to offer little advantage [36].
The mechanism of action of alpha1-receptor agonists
is thought to involve inhibition of SP release from
primary afferent neurones [84, 121], though they
also appear to exert a postsynaptic inhibitory effect
on dorsal horn neurones [47]. Recently, a novel
alpha2-receptor agonist, S 12813-4, was shown to
produce analgesic effects in animal models [54], and
to inhibit the release of SP from the spinal cord [12].
There is some reason to believe that the antinociceptive effects of alpha2-receptor agonists may be
mediated by a specific subtype of the receptor, so
there is a possibility of finding a new agent which
will act more selectively, and thus avoid the unwanted hypotension and sedation that occurs with
clonidine.
Future trends
Epibatidine
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Several compounds known. Side effect
problem may not be surmountable
Several compounds known. Side effect
problem may not be surmountable
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