British Journal of Anaesthesia 1995; 75: 157–168
Capsaicin and pain mechanisms
J. WINTER, S. BEVAN AND E. A. CAMPBELL
Selective actions of capsaicin
Capsaicin, the active ingredient in hot chilli peppers,
has selective actions on unmyelinated C-fibres and
thinly myelinated A primary sensory neurones [37,
100] (Table 1). Most capsaicin-sensitive fibres are
polymodal nociceptors which respond to a range of
sensory stimuli including noxious pressure, heat and
chemical irritants [51, 100], and are the most abun-
dant class of nociceptive fibre. Nociceptive neurones
are likely to release glutamate as a rapid central
neurotransmitter, and also express neuropeptides
such as calcitonin gene-related peptide (CGRP),
substance P, neurokinin A and somatostatin which
can be released into the spinal cord during intense
stimulation [103]. The tachykinins (e.g. substance P
and neurokinin A) and excitatory amino acids
(EAAs) (e.g. glutamate) cooperate and are thought
to increase synaptic activation of dorsal horn neur-
ones via EAA receptors [103]. Noxious stimulation
in the peripheral nervous system results in long-term
increases in spinal excitability which may contribute
to central mechanisms of allodynia and hyperalgesia
[103]. Much of the neuropeptide synthesized in the
dorsal root ganglion (DRG) cell body is actually
exported peripherally rather than centrally. In
peripheral nerve peptide release can contribute to
neurogenic inflammation.
Although initial local application of capsaicin in
humans is algesic, repeated application leads to
desensitization, and high concentrations can block
C-fibre conduction and result in long-lasting sensory
deficits. These properties of capsaicin may explain
its efficacy in treating some painful conditions in
humans, for example cluster headache, reflex sym-
pathetic dystrophy, post-mastectomy pain, post-
herpetic neuralgia and diabetic neuropathy.
The capsaicin receptor/channel
Most mechanistic studies of capsaicin-induced ac-
tivation of nociceptive neurones have been made
using cultured sensory neurones and isolated nerves
in vitro. These studies have shown that capsaicin
induces a depolarization, during which there is an
(Br. J. Anaesth. 1995; 75: 157–168)
Key words
Pain, mechanism. Pain, threshold. Toxicity, neurotoxicity.
Analgesics non-opioid, capsaicin. Polypeptides, substance P.
lons, ion channels, pharmacology.
increase in membrane permeability to cations, par-
ticularly to calcium and sodium ions [9, 31, 115]. The
capsaicin-induced accumulation of calcium ions or
the flux of radiolabelled ions such as rubidium (in
place of potassium) and guanidinium (in place of
sodium) has been exploited to quantify the effects of
capsaicin-like molecules [115]. Cultured DRG from
avian species do not respond to capsaicin with such
ion fluxes, and birds are insensitive to capsaicin and
will eat chillies [115].
The membrane ion channel activated by capsaicin
is unique and is insensitive to conventional calcium
and sodium ion-channel blockers such as the di-
hydropyridines, -conotoxin and tetrodotoxin re-
spectively [5, 115]. It is blocked, however, by
ruthenium red [5, 115]. Ruthenium red appears to be
relatively selective in its actions at low concentrations
since it attenuates the effects (activation of
nociceptors and release of sensory neuropeptide)
induced by capsaicin but not other sensory nerve
stimulants such as bradykinin [2, 34, 69]. Capsaicin
activates a number of biochemical systems and
increases the concentration of cellular cGMP, diacyl
glycerol [33, 36, 115] and nitric oxide [4], and
stimulates inositol tris-phosphate turnover, and
arachidonic acid release [114]. However all these
biochemical events are secondary to calcium entry
and do not play a role in the initial activation of
sensory neurones by capsaicin.
CAPSAICIN ANALOGUES
The biological effects of capsaicin are dose de-
pendent. This fact, together with structure activity
data from a range of capsaicin analogues, points to a
specific membrane receptor for capsaicin. The best
evidence for the existence of a receptor comes from
capsazepine (fig. 1), a highly selective competitive
capsaicin antagonist which inhibits [6] the excitatory
effects of capsaicin in both in vivo and in vitro
experiments. Capsazepine itself does not appear to
be analgesic [82] which argues against the existence
of an endogenous activator of the capsaicin channel
that binds at the same site as capsaicin. In fact it
seems that capsaicin analogues must have some
agonistic activity to show efficacy as analgesics. Two
examples are olvanil (NE19550) and nuvanil
JANET WINTER, PHD, STUART BEVAN, PHD, ELIZABETH A.
CAMPBELL, PHD, Sandoz Institute for Medical Research, Gower
Place, London WC1E 6BN.
158 British Journal of Anaesthesia

Table 1 Subsets of cutaneous afferent units excited by capsaicin. Modified from Szolcsányi [100]. Data from
rabbit, rat, cat or human studies. Application of capsaicin is either by close arterial injection, intradermal or
topical

Excitation by Excitation by Excitation by

C-afferents capsaicin A afferents capsaicin A afferents capsaicin

Mechano heat Mechanoheat G-hair

High threshold High threshold Field
mechanoreceptor mechanoreceptor
Low threshold D-hair SA 1
mechanoreceptor
Mechanoheat Cold SA 11
insensitive
(chemonociceptor)
Warm
Cold

PROTONS

Low extracellular pH can stimulate some sensory

neurones by opening ion channels [5]. Recent
evidence suggests that one type of response to low
pH (elevation of the concentration of protons) is via
activation of the capsaicin channel itself, suggesting
that protons may be the endogenous activators of
these channels [7]. The pH of ischaemie or inflamed
tissue can fall into the range that directly activates
capsaicin-operated channels, and contribute to the
pain which can accompany these pathological con-
ditions [5]. Both capsazepine and ruthenium red
block some proton and capsaicin-evoked responses,
for example, smooth muscle contraction [66], CGRP
release from smooth and skeletal muscles (see e.g.
Santicioli and colleagues [88]) and nasal irritation,
consistent with the hypothesis that capsaicin and
protons operate via the same mechanism [5]. In
cultured DRG neurones, however, capsazepine
blocks capsaicin-induced but not proton-induced
ion fluxes [5]. It remains to be determined whether
the protons open capsaicin-operated channels di-
rectly or act indirectly via the release of another
mediator.
Figure 1 Structures of capsaicin and analogues.

REGULATION OF CHANNEL DENSITY

(NE21610) [14], each having some capsaicin-like
agonist actions, and both having analgesic properties
(fig. 1).
Another, ultrapotent capsaicin analogue, resini-
feratoxin (RTX, fig. 1) has become a useful tool in
studying capsaicin-sensitive neurones. Owing to
capsaicin’s low affinity and high lipophilicity,
identification of a capsaicin-binding site using radio-
labelled capsaicin, has not been successful. However
specific, saturable, capsaicin displaceable binding
has been shown using RTX as a binding ligand [97].
This naturally occurring irritant activates sensory
neurones and nociceptors in a manner identical to
that of capsaicin [10, 96, 110]. Further studies using
high energy radiation-inactivation analysis of the
[3H]-resiniferatoxin-binding protein have suggested
that the receptor complex has a molecular weight of
270 kD [95]. [3H]-resiniferatoxin has been used to
localize binding sites to the dorsal horn in rat spinal
cord sections, and to DRG but not superior cervical
ganglion (SCG) sections [112].
Capsaicin sensitivity itself is dependent on the
continued presence of nerve growth factor (NGF) in
adult DRG cultures [112]. As expected, the sustained
proton evoked current and RTX binding are also
NGF regulated in culture [7, 112]. In vivo, sciatic
nerve section or systemic treatment of animals with
capsaicin, which results in a chemical axotomy are
both treatments which are likely to deprive DRG
neurones of their normal supply of retrogradely
transported NGF from peripheral targets. In both
cases capsaicin sensitivity decreases. This phenom-
enon is probably not due to death of NGF-deprived
DRG neurones [111, 113 and Woolf, Hu-Tsai and
Winter, unpublished observations]. During develop-
ment, the majority of DRG sensory neurones require
NGF for survival, whereas in the adult animal NGF
has a more modulatory role and is not needed for
survival [58]. Recent studies have shown a key role
for NGF in inflammatory hyperalgesia [56, 116].
Concentrations of NGF increase in inflamed tissue
Capsaicin and pain mechanisms
[56]. Antibodies that neutralize NGF completely
inhibit development or reverse the established
hyperalgesia (both mechanical and thermal) that
follow an injection of complete Freund’s adjuvant
(CFA) into the rat paw [116]. In vivo and in vitro
studies have shown that NGF regulates several
characteristics of nociceptive neurones, including
the content of the neuropeptides substance P and
CGRP [57, 113] as well as capsaicin sensitivity. The
contribution of NGF-dependent upregulation of
capsaicin/proton sensitivity to inflammatory hyper-
sensitivity is presently unknown.
DESENSITIZATION
The ability of capsaicin to desensitize nociceptive
neurones has been well documented [45]. However,
two distinct phenomena have been reported under
the general heading of desensitization. The first
phenomenon is a classic pharmacological de-
sensitization where prolonged or repeated applic-
ations of capsaicin lead to a progressive decline in the
size of subsequent responses to capsaicin. We
propose that the term desensitization be reserved for
this specific effect. The second phenomenon is
“functional-desensitization”, where a challenge with
capsaicin leads to a reduction or loss of respon-
siveness of the neurone to other stimuli. The two
phenomena often occur together but can be separated
when low concentrations of capsaicin are employed.
Under these conditions, the responsiveness to
capsaicin is reduced or lost selectively and responses
to other types of noxious or innocuous stimuli are
unchanged [33]. The functional desensitization seen
with higher concentrations of capsaicin is believed to
be the basis for the analgesic and anti-inflammatory
effects of capsaicin.
The process of desensitization appears to be
calcium-dependent and little or no desensitization is
seen when calcium is removed from the extracellular
medium [21, 120]. It seems likely that the increase in
intracellular Ca2+ concentration evoked by capsaicin
promotes desensitization by stimulating a calcium-
and calmodulin-dependent cytosolic enzyme, pro-
tein phosphatase 2B (calcineurin). Calcineurin is
inhibited by a complex of cyclosporin A and its
cytoplasmic binding protein cyclophilin [59] and
capsaicin desensitization is almost abolished when
the cyclosporin-cyclophilin complex is introduced
into the cytoplasm of rat sensory neurones [119].
Conversely, treatments that raised the intracellular
concentrations of cyclic AMP increased capsaicin
responses in sensory neurones [85]. These findings
suggest that sensitivity to capsaicin is regulated by
phosphorylation of a key intracellular protein which
could be the receptor/ion channel itself or an
associated protein. Activation of calcineurin may
also be responsible for functional desensitization,
which could involve calcium-dependent dephos-
phorylation of other intracellular proteins such as
ion channels or enzymes. This hypothesis is con-
sistent with the observations that capsaicin-induced
functional desensitization requires the presence of
extracellular calcium [89] and is blocked by the
capsaicin antagonist, ruthenium red [2, 67].
159
Capsaicin stimulates the release of glutamate and
neuropeptides (GCRP, neurokinin A and substance
P) from the peripheral and central terminals of
sensory neurones [29, 39, 53, 60, 61, 62, 68]. This re-
lease is a direct consequence of the agonist action of
capsaicin and occurs by two distinct mechanisms.
The influx of calcium through capsaicin-activated
ion channels triggers release independent of action
potential generation and propagation. The
depolarization evoked by capsaicin also generates
action potentials that propagate and activate distant
regions of the nerve to release glutamate and
neuropeptides. Although capsaicin initially
stimulates neuropeptide release, it has a longer-term,
inhibitory effect which is one likely mechanism for
its analgesic and anti-inflammatory actions [14].
After capsaicin treatment, noxious stimuli no longer
release glutamate and neuropeptides despite the
presence of near normal levels of neuropeptides in
the nerves [3, 8, 76, 101]. This inhibitory effect of
capsaicin has been attributed to inhibition of the
voltage-gated calcium channels [9, 31, 83, 87], which
are responsible for the normal, nerve-evoked release
of transmitters from the central and peripheral
terminals. A block of transmitter release would
inhibit the transmission of noxious signals between
nociceptive sensory neurones and spinal cord
neurones and reduce or eliminate neurogenic inflam-
mation evoked by neuropeptide release from the
peripheral nerve terminals.
There have been several reports that capsaicin
inhibits voltage-activated calcium currents.
Capsaicin inhibits these currents in rat DRG
neurones by a mechanism that involves a capsaicin-
evoked influx of calcium with a resultant increase in
intracellular free calcium concentration [9, 31, 87].
The inhibitory mechanism has not been fully
elucidated but is likely to involve activation of an, as
yet, unidentified calcium-dependent process. Some
metabolic modification of a key molecule, perhaps
the ion channels themselves, is suggested by the
finding that the inhibition outlasts the period of
agonism by capsaicin. This mechanism means that
the analgesic and anti-inflammatory effects of
capsaicin are restricted to capsaicin-sensitive
neurones and occur at the low concentrations
required for agonism. Other mechanisms of func-
tional nerve block, such as depolarization block of
action potentials, may also contribute to the cell- and
agonism-specific effects of capsaicin.
DEGENERATION / NEUROTOXICITY
Capsaicin has a spectrum of effects on sensory
neurones ranging from excitation to cell death. Many
DRG neurones degenerate following neonatal
capsaicin treatment. The mechanisms of capsaicin-
induced neurotoxicity have been studied in vitro in
DRG neurones cultured from neonatal animals
[114]. The damage is partially osmotic and partially
through calcium entry, causing activation of calcium-
sensitive proteases among other mechanisms [114].
In vivo the severity of these effects depends on
factors such as the age of animal at the time of
treatment, and the route of administration, as well as
160
the dose of capsaicin used. Systemic injection of
neonatal rats kills many DRG neurones [47]. In
adult rats, many C-fibre terminals degenerate [22,
23] after large systemic doses of capsaicin, but most
cell bodies survive to respond vigorously to this
“chemical axotomy” by attempting to regenerate
[110, 112]. After perineural application of capsaicin,
C-fibres degenerate distally and extensive axonal
sprouting can be seen from the proximal nerve [63,
84, 112]. Levels of the growth-associated protein
(GAP-43) and its messenger RNA increase, and the
ability to form neurites in culture increases dra-
matically if the cells are taken from capsaicin-
pretreated animals [110, 112]. Although the neurones
with capsaicin-damaged axons attempt to regenerate,
they do not reinnervate their targets in vivo, and the
sensory deficit is essentially permanent. Following
systemic capsaicin treatments, neurodegeneration
can also be seen by a silver staining method in parts
of the brain [86]. Capsaicin treatment also causes
depletion of the neuropeptides substance P and
CGRP, and the enzyme fluoride-resistant acid phos-
phatase (FRAP) from the DRG neurones, and
appearance of vasoactive intestinal peptide (VIP),
similar to the effects of surgical axotomy [46, 112].
Summary of mechanism of action of
capsaicin (see fig. 2)
Desensitization is a capsaicin-induced loss of re-
sponsiveness to further capsaicin treatment. It is
reversible. Desensitization is calcium dependent and
probably involves activation of a phosphatase which
inactivates the capsaicin channel.
Functional desensitization is a loss of sensitivity to
a range of noxious stimuli and underlies the analgesic
effects of capsaicin. Functional desensitization is
reversible and may also depend on calcium-
dependent dephosphorylation of other intracellular
proteins such as enzymes or ion channels.
Neurotoxicity is induced by high doses of
capsaicin. Neuronal damage such as axon and
Figure 2 Scheme showing some mechanisms of action for capsaicin. Broken arrows indicate the more speculative
pathways.
British Journal of Anaesthesia
terminal degeneration and impaired nociception
tends to be irreversible, as regeneration does not take
place even if the cell bodies of capsaicin-sensitive
neurones survive. Both osmotic lysis and action of
calcium-dependent proteases may play a part.
In vivo studies—hyperalgesia and analgesia
ACUTE PAIN
Animal studies—systemic
As outlined above capsaicin mediates its actions
through a specific membrane receptor. This results
in an initial excitation of sensory neurones followed
by a period of insensitivity to noxious stimuli. The
time course of this effect ranges from a few hours to
several months in adult rats receiving either small
acute doses (1–10 mg kg1 s.c.) or larger doses which
deplete unmyelinated primary afferent neurones [47]
(single dose of 50 mg kg1 up to cumulative doses of
950 mg kg1 in total). In such high doses capsaicin is
neurotoxic when administered to neonatal animals
and hence the resultant effects on sensitivity to
noxious stimuli can be lifelong though the results
from analgesia tests are conflicting.
In adult rats that have been treated neonatally
with capsaicin, analgesia to noxious mechanical,
chemical stimuli, or both has been noted by several
groups [38, 42, 80]. In contrast, the responses to a
thermal challenge are not so consistent, with some
groups reporting an increase in thermal nociceptive
thresholds [40, 80] while others saw no change [19,
42]. In mice similar results were noted, with
significant analgesia to chemical [42] but not to
thermal stimuli [40, 42]. Nagy and yan der Kooy [80]
have suggested that the variability in results may
reflect either the different dosing regimens which
have been employed (number of applications/
concentrations used) or the considerable variability
in responsiveness which has been noted after ad-
ministration of single high doses of capsaicin to
neonatal animals.
Capsaicin and pain mechanisms
Similar results are obtained following systemic
treatment of adult animals with capsaicin
(35–950 mg kg1 s.c.). Although earlier studies sug-
gested that such doses produce mitochondrial dam-
age [50] and sensory neuropeptide depletion without
nerve fibre degeneration [49, 99] more recent studies
show C-fibre terminal loss [22, 23]. Animals showed
a clear reduction in chemical and mechanical
thresholds [44] and an increase [13, 40], no change or
a small reduction [44] in thermal thresholds.
When much lower doses are used
(1–10 mg kg1 s.c.) short-lasting (a few hours) an-
algesic and also anti-inflammatory activity have been
observed in a variety of animal models, both acute
and chronic [14, 15, 43]. However, the potential
therapeutic usefulness in humans of such a treatment
is limited by low oral availability and the narrow
window between the doses required to show an-
algesic activity and those which produce side effects
such as hypothermia.
Animal studies—local
The limited potential for the use of systemically
administered capsaicin has led clinicians to use
topical application of capsaicin in their clinical
studies. Studies in animals using local or topical
application yielded conflicting results. A reduction,
an increase or no effect on nociceptive thresholds
following topical skin application of capsaicin in
animals has been noted [18, 51, 64, 76].
Much of the variability may relate to the number
of application and different vehicles used to apply
the capsaicin to the skin and hence possible
differences in the rate and extent of skin penetration.
It is well known from human studies with topical
capsaicin that it often requires days to weeks of
treatment to see significant analgesic effects [93,
104]. Kenins [51] reported that local application of
capsaicin (1 %) to rat skin resulted in an initial
excitation followed by a period of desensitization to
noxious chemical, mechanical and thermal stimuli,
effects which were highly vehicle dependent. Carter
and Francis [18] saw no change in thermal threshold
following three times daily application of either 1 %
or 5 % capsaicin for 4 days. However, at the end of
this study an i.c. injection of 0.1 % capsaicin
(3.3 mmol litre1) produced a marked increase in
withdrawal latencies suggesting that the lack of effect
of topically administered capsaicin was the result of
poor bioavailability. In contrast three topical
applications of 1 % capsaicin over a 24-h period were
sufficient to cause a marked reduction in the plasma
extravasation evoked by either 5 % capsaicin or
antidromic nerve stimulation. Lynn and co-workers
[64] noted that a single application of 1 % capsaicin
to the skin was sufficient to reduce the vasodilatation
evoked by nerve stimulation. Surprisingly the skin
levels of substance P, a possible mediator of
vasodilatation, were still reduced several days later
when the vasodilatory response had returned to
normal. Similarly, 2 weeks after intradermal in-
jection of capsaicin, a normal vasodilatory response
to antidromic nerve stimulation occurred despite
depressed levels of substance P [64]. In contrast,
161
after 10 weeks’ application of either 0.075 % (Axsain,
Genderm) or 0.75 % capsaicin cream, McMahon
and co-workers [76] showed a significant reduction
in the extravasation response to mustard oil with no
change in the accumulation of either substance P or
CGRP in the ligated sural nerve. These observations
suggest that the reduction in vasodilatation response
cannot be correlated directly with changes in skin
peptide levels.
After topical application of capsaicin to the skin
and recording C-fibre activity directly in the sa-
phenous nerve Lynn and co-workers [64] noted a
loss of sensitivity to pressure while the sensitivity to
heat was lost or enhanced dependent on the vehicle
used. McMahon and co-workers [76] were unable to
see any thermal analgesia in rat paws even after 10
weeks’ application; in fact the 0.75 % capsaicin
cream produced hyperalgesia for the first few weeks
of treatment.
The available data suggest a separation between
the effects of topical capsaicin on the afferent and
efferent function of primary afferent neurones. From
the animal studies it seems that the efferent function
is more readily inhibited, which implies either a
possible involvement of different subpopulations of
fibres or suggests that the mechanisms involved in
local peptide release are more sensitive to capsaicin
than those involved in sensory signal transduction.
Human volunteer studies
Topical application or local injection of capsaicin in
normal human skin resulted in a concentration-
dependent burning sensation and a flare response
[17, 48, 94]. Within the area of flare, mechanical and
thermal hyperalgesia were apparent (primary hyper-
algesia) [17, 94]. Extending beyond the area of flare
there was an area of secondary (mechanical) hyper-
algesia [36, 54, 94]. Both the acute effects and the
hyperalgesia diminished with repeated capsaicin
administration.
Repeated application of a 1 % solution of capsaicin
over several days to the forearm resulted in a
reduction or complete abolition of the flare response
evoked by either noxious heat [17] or the chemical
irritant, mustard oil [48]. Pain thresholds to both
these noxious stimuli were increased in these same
subjects. The flare responses to injections of his-
tamine and vasoactive agents such as substance P,
VIP and somatostatin were also reduced in capsaicin-
pretreated skin [3, 8, 101]. Simone and Ochoa [93]
investigated the effect of 8 weeks’ topical treatment
with Axsain (0.075 %, Genderm) in normal subjects.
Heat-induced pain thresholds, which were initially
decreased after 1 day of capsaicin treatment, became
elevated by 3.5 C after 6 weeks. There was no
change in the thresholds for touch, cold, low
temperature or mechanical stimulation. The flare
response to histamine was, however, reduced.
Therefore, there is some evidence to support the
therapeutic use of topically applied capsaicin. There
also appears to be good potential for development of
compounds with an improved therapeutic profile
compared with capsaicin.
162
ARTHRITIS
Animal studies
There is a wealth of information implicating
capsaicin-sensitive primary afferent neurones in the
inflammation (neurogenic) and hyperalgesia
associated with animal models of peripheral inflam-
mation. From these animal studies it is well es-
tablished that the synovium in joints is richly
innervated by peptide (substance P)-containing
nerve fibres and following induction of arthritis in
rats there is an increase in the levels of substance P
in the joint [70]. Conversely, neonatal capsaicin
treatment or treatment of adult rats with a dose of
capsaicin which is known to deplete substance P will
reduce the inflammation and joint injury [24, 55].
Injection of substance P or capsaicin into non-
inflamed joints will induce a mechanical hyperalgesia
which persists for several hours [25, 26] and which
can be inhibited by a substance P antagonist while
substance P injection into inflamed joints is known to
enhance the inflammation [55].
After inflammation it has also been shown that
substance P levels are increased in the DRG and this
seems to be accompanied by increased axonal
transport [32, 116]. The elegant studies of Schaible
and co-workers [90] demonstrated that following
inflammation the high threshold sensory fibres
become sensitized to movement in the normal range
and initially insensitive sensory fibres become
mechanosensitive and may show spontaneous ac-
tivity. Thus, these sensory fibres will contribute to
the ongoing pain associated with the arthritis and
peripherally they will enhance inflammation by
release of neuropeptides. As discussed above when
capsaicin is used systemically in low doses short-
lasting analgesia is observed in acute tests. Perkins
and Campbell [82] demonstrated that this was also
the case in models of monoarticular arthritis in rats
induced by uric acid or Freund’s adjuvant injection
into the knee where capsaicin (6 mg kg91) reversed
the mechanical hyperalgesia for several hours, there-
fore this analgesic effect is not the result of
neurotoxicity.
Human studies
Rheumatoid arthritis. The normal human synovium
receives innervation from substance P-immuno-
reactive fibres which are associated with blood vessels
or as free fibres which extend into the intimal layer
of the synovial membrane. However, in chronic
rheumatoid arthritis the number of free fibres is
decreased and there is a reduction in the staining for
substance P-containing fibres in the intimal layer
[71, 81]. This reduced staining may to some extent
reflect increased release as synovial fluid levels of
substance P exceed plasma levels in most types of
arthritis suggesting direct release into the synovium
and synovial fluid [72].
To date the clinical studies using topically applied
capsaicin report conflicting results. Deal and co-
workers [28] reported significant reduction in pain
intensity and joint tenderness after 4 weeks of
British Journal of Anaesthesia
treatment (Zostrix, 0.025 %) in 31 patients with
rheumatoid arthritis of the knee. In contrast,
McCarthy and McCarty [73] using 0.075 % capsaicin
cream saw no significant improvement in seven
patients with rheumatoid arthritis of the hands. In
support of the findings of the former study Weisman
and co-workers [109] have recently reported that
application of topical capsaicin (0.075 %) for 6 weeks
produced a reduction in inflammatory mediators,
including substance P, in the synovial fluid of
patients with rheumatoid arthritis.
Osteoarthritis. As in the case of rheumatoid arthritis
substance P has also been implicated in the patho-
physiology of osteoarthritis. Substance P concen-
trations are increased in the plasma and synovial
tissue of patients with osteoarthritis [72, 78], Sub-
stance P has also been suggested to enhance cartilage
destruction [1].
Two earlier double-blind studies demonstrated a
significant improvement in pain relief following
treatment with capsaicin cream in patients with
osteoarthritis of the knee (0.025 % for weeks, 70
patients) [28] and hand (0.075 %, 14 patients) [73]. A
more recent multicentre double-blind trial involved
113 patients with osteoarthritis of the knee, ankle,
elbow, wrist or shoulder [1]. In patients given
0.025 % capsaicin cream four times daily for 12
weeks 81 % using capsaicin improved compared
with 54 % receiving vehicle based on the physician’s
evaluation with similar results obtained when com-
paring the data from the patients’ evaluation (visual
analogue scale).
NEUROPATHIC PAIN
Animal studies
The majority of clinical trials using capsaicin have
investigated its analgesic efficacy after topical ap-
plication in conditions of neuropathic pain. There is
little experimental evidence, however, on its effects
in animal models of neuropathic pain. Adult rats
which had been neonatally treated with capsaicin
(50 mg kg1 s.c.), did not develop the thermal hyper-
algesia which normally arises after either chronic
constriction injury or partial ligation of the sciatic
nerve [77, 91]. In contrast, in the same animals
which had received a partial ligation, mechanical
hyperaesthesia and allodynia developed as normal
[91]. Yamamoto and Yaksh [l17] administered
capsaicin intrathecally (15 g / 15 l) 2 days after
constriction injury and determined thermal paw
withdrawal thresholds to a thermal stimulus 5 days
later. Although the results were confusing it was
clear that the capsaicin-pretreated animals showed
no significant hyperalgesia on the ligated paw
compared with vehicle-treated animals. Kim and co-
workers [52] applied capsaicin (0.05–2.0 %) directly
around the nerve 1 week after ligation, and studied
thermal withdrawal latencies for up to 8 weeks.
Animals treated with doses of 0.1 % or higher
showed a significant, dose-dependent increase in
withdrawal latencies on the ligated paw compared
with the contralateral paw.
Capsaicin and pain mechanisms 163

Table 2 Clinical trials with topical or locally administered capsaicin where significant improvement in pain scores
was demonstrated compared with vehicle. The concentration of the capsaicin cream used is given together with
the duration of treatment in brackets (d, days ; wk, weeks ; mth, months ; yr, years)

Condition Dose of capsaicin Reference

Post-herpetic neuralgia 0.075 % (6 wk) Bernstein and colleagues [4a]

Diabetic neuropathy
Post-mastectomy pain
Stump pain
Reflex sympathetic
dystrophy
Trigeminal neuralgia
Oral neuropathic
pain
Osteoarthritis
Rheumatoid arthritis
Cluster headache
Fibromyalgia
0.025 % (4 wk) Watson and colleagues [107a]
0.1 mg/ml (5 wk) Bjerring and colleagues [8a]
0.025 % (8 wk) Peikert and colleagues [80a]
0.025 % (4 wk) Srebrnik and Brenner [94a]
0.075 % (6 wk) Watson and colleagues [108]
0.075 % (2 yr) Watson and colleagues [108]
0.075 % (8 wk) Scheffler and colleagues [90a]
0.075 % (8 wk) Capsaicin Study Group [16]
0.025 % (4 wk) Watson and colleagues [107c]
0.075 % (6 wk) Watson and Evans [107a]
0.025 % (8 wk) Dini and colleagues [30a]
0.025 % (1 wk) Rayner and colleagues [85a]
0.025 % (3 wk) Cheshire and Snyder [20a]
0.075 % (10–24 wk) Sinoff and Hart [94a]
0.05 % (15–20 d) Fusco and colleagues [38a]
0.025 % (5 mth) Epstein and Marcoe [37b]
0.025 % (4 wk) Deal and colleagues [38]
0.075 % (4 wk) McCarthy and McCarty [73]
0.025 % (12 wk) Altman and colleagues [1]
0.025 % (4 wk) Deal and colleagues [38]
100 l of 10 mmol litre91 (5 d) Sicuteri and colleagues [9la]
100 l of 10 mmol litre91 Fusco and colleagues [38a]
0.025 % (7 d) Marks and colleagues [71a]
0.025 % (4 wk) McCarty and colleagues [74]

These studies, therefore, implicate a role for
capsaicin-sensitive nerves in the thermal hyper-
algesia which develops in these animals. However,
the doses used are considerably higher than the
0.025–0.075 % topical capsaicin cream which is used
clinically.
Human studies
Despite the limited experimental evidence from
animal studies, the possible therapeutic usefulness of
topically applied capsaicin has been the subject of
many clinical trials in the area of neuropathic pain
(see table 2). In general, conditions involving
neuronal damage and subsequent development of
neuropathic pain respond poorly to conventional
analgesics. For this reason the possibility of a novel
approach to the treatment of such patients has
received considerable attention in the past few years.
Clinical trials (see table 2) demonstrating significant
improvement with topical capsaicin have been
carried out in patients with post-mastectomy pain,
stump pain, reflex sympathetic dystrophy, oral
neuropathic pain and trigeminal neuralgia. However,
the greatest numbers of patients studied have been in
the fields of diabetic neuropathy and post-herpetic
neuralgia where the efficacy reported in the early
trials has led to subsequent large multicentre studies.
In small numbers of patients the early reports
demonstrated a significant improvement in pain
scores after treatment with capsaicin. In general the
effects of capsaicin took several weeks to develop and
in most studies there was a significant number of
patients who dropped out in the early weeks owing to
the irritant properties of capsaicin which produced a
burning pain following application. Therefore,
although some of the trials claim to be double blind
this effect of capsaicin will clearly distinguish it from
placebo. With repeated application, however, this
unwanted side effect diminished.
The Capsaicin Study Group [16] studied a total of
277 patients (138 capsaicin 0.075 %, 139 placebo)
with diabetic neuropathy and reported significant
improvement in all measures (pain, walking, work-
ing, sleeping) after administration of capsaicin four
times daily for up to 8 weeks. Most studies have been
of a similar duration although Watson and co-
workers [108] followed 83 patients with post-
herpetic neuralgia for up to 2 years and found that in
86 % of the subjects the improvement in pain scores
was either maintained or further enhanced with no
serious adverse effects.
OTHER CLINICAL INDICATIONS
There have been several studies reporting the efficacy
of nasal application of capsaicin in the treatment of
cluster headache (see table 2). Patients applied the
capsaicin daily for up to 7 days with a resultant
significant improvement compared With placebo and
in some cases complete disappearance of symptoms.
The mechanism by which capsaicin provides relief in
such patients is unknown though substance P
containing neurones of the trigeminal nerve have
been implicated in the symptomatology of cluster
headache.
More recently the efficacy of topical capsaicin has
been assessed in the treatment of the pain associated
with fibromyalgia (table 2). After 4 weeks’ treatment
with 0.025 % capsaicin patients reported
significantly less tenderness; however, there was no
significant change in the visual analogue scale for
164
Table 3 Clinical trials with topical administered capsaicin where significant improvement in pruritic symptoms
was demonstrated compared with placebo. The concentration of the capsaicin cream used is given together with
the duration of treatment in brackets (wk, weeks)
Condition Dose of capsaicin
Psoriasis 0.025 % (8 wk)
0.025 % (6 wk)
Haemodialysis 0.025 % (6 wk)
Notalgia paraesthetica 0.025 % (6 wk)
Brachioradial pruritus 0.025 / 0.075 % (2 wk)
0.025 % (3 wk)
Aquagenic pruritus 0.025–1.0 % (4 wk)
pain. As mentioned above the beneficial effects of
capsaicin can take several weeks to develop, therefore
in this study perhaps a longer treatment period or
the use of 0.075 % capsaicin cream would have
shown better efficacy.
One further area which has also received attention
is the use of topical capsaicin in the treatment of
pruritus. Itch is believed to be mediated by a subset
of capsaicin-sensitive nociceptive neurones and
blocking C-fibre conduction suppresses itch [65, 75].
In human volunteer studies capsaicin treatment
inhibited the itch after histamine and allergen
challenge and has subsequently been shown to
reduce the itch associated with a variety of clinical
conditions (table 3).
The future
Capsaicin analogues
The potential therapeutic usefulness of an analogue
of capsaicin which retains its selective action on
primary afferent neurones and analgesic activity but
is devoid of unwanted side effects has prompted
several groups to try to develop novel therapeutic
drugs based on capsaicin.
Earlier structure-activity studies suggested that it
was not possible to produce an analogue with
significant antinociceptive activity but with reduced
excitatory effects [41, 98]. The latter group noted
that potent analgesic activity could not be separated
from a profound hypothermic effect evoked by all of
the analogues studied. However, more recent studies
have claimed analgesic activity with analogues of
capsaicin which lack pungency and have a reduced
side-effect profile [11, 12, 20, 92, 118]. Brand and co-
workers [11] reported significant thermal and mech-
anical analgesia and anti-inflammatory activity fol-
lowing administration of NE19550 (olvanil, N-(3-
methoxy-4-hydroxy-benzyl) oleamide, fig. 1), an
analogue which lacked the acute toxicity of capsaicin.
This compound also inhibited both the early and late
phases of the formalin response [35] and reduced
yeast-induced inflammation in mouse paws [15]. As
well as activity in these acute assays this compound
also showed dose-dependent analgesic activity in a
model of chronic pain, adjuvant-induced mono-
arthritis [14]. Further modification of this molecule
substituting an aminoethoxy group for the hydroxyl
group on the aromatic ring (NE21610, nuvanil, fig.
1) was claimed to improve solubility, and make the
compound more effective when administered orally
while being less irritant to the skin. Results from our
own laboratory demonstrated that while NE21610
British Journal of Anaesthesia
Reference
Kurkccuoglu and Alaybeyi [53a]
Ellis and colleagues [37a]
Breneman and colleagues [12a]
Leibsohn [54a]
Goodless and Eaglstein [40a]
Knight and Hayashi [52a]
Lotti and colleagues [59a]
Figure 3 Time course of load tolerated by hind limb on the
third day after Freund’s complete adjuvant (A) or 24 h after an
intra-articular injection of uric acid (B). (!) Capsaicin,
20 mol kg91 s.c. ; (") ; capsazapine 100 mol kg91 s.c. ; (!)
capsazepine 100 mol kg91. (Modified from Perkins arid.
Campbell [82].)
showed improved oral activity over capsaicin and
NE19550, significant analgesia was only seen, at
doses which produced profound hypothermia [14].
This compound, NE21610, has also been studied
in humans though only with local administration.
When given intradermally NE21610 was much less
excitatory than capsaicin but was still effective at
inhibiting burn-induced hyperalgesia and allodynia
[27, 79]. Genderm, the manufacturer that markets
the currently available capsaicin creams (Zostrix,
Axsain), is also reported to have an analogue in
development which is less irritant than capsaicin.
Chen and co-workers [20] described a series of
analogues based on substitutions at position 4 on the
aromatic ring, a region which Szolcsanyi and Jancsó-
Gábor [98] highlighted as being essential for pun-
gency. Several of these analogues were non-pungent
and showed reduced activation of vagally mediated
blood pressure reflexes yet retained marked antinoci-
ceptive activity. More recently, Walpole and co-
workers [105, 106, 107] reported a series of structure-
activity studies based on different parts of the
capsaicin molecule and described a rational basis for
the design of compounds with increased potency.
Capsaicin and pain mechanisms
The data therefore suggest that it may be feasible to
develop an analogue with the required profile of
antinociceptive activity and minimal unwanted side
effects.
Capsaicin antagonist
Recent data with the capsaicin antagonist
capsazepine support the hypothesis that some degree
of capsaicin-like agonism is essential for a capsaicin
analogue to show analgesic activity.
Capsazepine is a novel competitive antagonist of
capsaicin which selectively antagonizes capsaicin-
induced activation of nociceptors [6, 30, 102]. In
animal studies capsazepine showed none of the
known side effects of other capsaicin analogues;
however, it had no analgesic or anti-inflammatory
activity when administered on its own at doses up to
75 mg kg1, but it was able to inhibit capsaicin-
indueed, analgesia in both acute and chronic pain
models in a dose-dependent manner [82] (fig. 3).
This absence of analgesia with capsazepine alone in
inflammatory pain models argues against the pro-
duction of a structurally related capsaicin-like mol-
ecule that promotes pain and inflammation by
interacting with the capsaicin receptor.
Summary of efficacy of capsaicin and its
analogues in vivo
Capsaicin is a cell-specific peripheral analgesic.
Agonism, that is ability to open capsaicin-operated
channels, is required for efficacy.
There is growing evidence for efficacy of capsaicin
in a range of pain conditions.
A better window between analgesic doses and
doses which produce side effects is required for an
orally active therapeutic drug.
However, topical applications are effective and
without side effects.
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