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Visceral hyperalgesia in chronic pelvic pain
N Aslam,
a
G Harrison,
a
K Khan,
a
S Patwardhan
b
a
Academic Department of Obstetrics and Gynaecology, Birmingham University Hospital, Birmingham, UK
b
Obstetrics and Gynaecology,
Walsgrave University Hospital, Coventry, UK
Correspondence: S Patwardhan, Consultant Obstetrics and Gynaecology, Walsgrave University Hospital, Clifford Bridge Road, Coventry CV2
2DX, UK. Email drsanjaypatwardhan@gmail.com
Accepted 26 May 2009. Published Online 14 August 2009.
Please cite this paper as: Aslam N, Harrison G, Khan K, Patwardhan S. Visceral hyperalgesia in chronic pelvic pain. BJOG 2009;116:1551–1555.
Introduction
Chronic pelvic pain (CPP), pain of at least 6 months’ dura-
tion involving the pelvis, lower abdomen and lower back, is a
common gynaecological problem with an estimated preva-
lence of 38 per 1000, a rate comparable to that of asthma (37
per 1000) and chronic back pain(41 per 1000).
1
It is also the
single most common indication for referral to gynaecology
clinics and for diagnostic laparoscopy.
2
A staggering amount
of money is spent on the management of this condition in
the UK
3
and other developed countries such as the USA.
4
Unfortunately, the pathogenesis of CPP is poorly under-
stood. Specific causes may include pelvic endometriosis,
interstitial cystitis, adhesions or pelvic inflammatory dis-
ease, but examination and testing are often nondiagnostic.
It has been postulated that an association may exist
between CPP and sexual/physical abuse. However, most of
the studies in which such an association was found were
retrospective and performed in the context of secondary
care.
5
Patterns of symptoms and diagnoses in population-
based studies suggest a broad pattern of pathophysiology.
Up to half of CPP cases have been found to be associated
with either genitourinary symptoms or symptoms of irrita-
ble bowel syndrome (IBS).
6
Increasing evidence suggests
that women with CPP often develop visceral and somatic
hyperalgesia as a result of visceral hypersensitivity arising
from the gastrointestinal and urinary tracts and the repro-
ductive organs. It is noteworthy that visceral and somatic
hyperalgesia have been considered as an important con-
founding factor associated with IBS and interstitial cystitis.
In addition, interstitial cystitis and IBS may be associated
with endometriosis, dysmenorrhoea, vulvodynia and adhe-
sions through the recruitment of additional neural path-
ways, thereby substantially complicating the diagnosis.
7
In this commentary, we describe the patho physiology and
presentation of visceral hyperalgesia and discuss approaches
that may be used in its management.
Pathophysiology of visceral
hyperalgesia
Recent studies employing animal models of visceral hyper-
sensitivity in the urinary bladder and gastrointestinal tract
have provided evidence that hyperalgesia at the site of an
irritated organ develops as a result of enhanced excitability
of respective neuronal soma within the dorsal root ganglia.
7
The signals that gastrointestinal sensory neurons convey to
the brain are rarely perceived as a conscious sensation
because they are processed only in autonomic and neuro-
endocrine circuits that control digestion in accordance with
the body’s need for energy, fluid and electrolytes.
Many gastrointestinal afferents, however, have the poten-
tial to encode noxious stimuli, a property that has a bear-
ing on the discomfort and pain associated with functional
bowel disorders.
It has been hypothesised that, in patients with functional
bowel disorders, digestive processes are represented in the
brain in a distorted fashion, possibly as a result of patho-
logical alterations in the environment of gut sensors, in the
sensory gain of afferent neurons or in the central process-
ing of afferent information from the gastrointestinal tract.
Diagnostically, it is obvious that many gut reactions to
physiological (e.g. food) and pathological (e.g. stress) stim-
uli are exaggerated and out of normal proportion to the
stimulus strength. There are also silent or mechanically
insensitive afferents that do not normally respond to ade-
quate stimuli that drive other afferents. However, after tis-
sue damage, inflammation or ischaemia, they become
spontaneously active or respond to previously ineffective
adequate stimuli, in many instances encoding the stimulus
intensity. In addition, the environment of nociceptive nerve
terminals in the guts of patients with functional bowel dis-
orders may be profoundly altered, given that the numbers
of enteroendocrine cells, mast cells and mucosal lympho-
cytes are increased in IBS.
ª2009 The Authors Journal compilation ªRCOG 2009 BJOG An International Journal of Obstetrics and Gynaecology 1551
DOI: 10.1111/j.1471-0528.2009.02305.x
www.bjog.org Commentary
Visceral afferent fibres are sensitised after inflammation.
In the gastrointestinal tract, following colonic or gastric
inflammation, there is an increase in the response rate of
afferent fibres, an increase in the spontaneous activity and
a decrease in the threshold for the stimulation.
Similarly, there is sensitisation of afferent fibres in the
genitourinary tract, reproductive organs, cardiac afferents
and probably most other organ systems.
8
Several neural
pathways underlie the propagation of nociceptive informa-
tion in the pelvis, including alterations in prespinal, spinal
and supraspinal processing. Noxious stimuli arising from
pelvic organs are detected by specific sensory neurons with
their cell bodies located in dorsal root ganglia. Afferent
information from pelvic viscera travels to the dorsal root
ganglia and then to the dorsal horn of the spinal cord,
mainly via hypogastric, splanchnic, pelvic and pudendal
nerves. These nerves convey sensory information from
major pelvic organs: the colon, rectum, urinary bladder
and uterus. Viscerovisceral pathological interactions and
reflexes among gastrointestinal, urinary and reproductive
systems are assumed to be mediated by a convergence of
sensory information via both peripheral and central mecha-
nisms of afferent stimulus processing.
7
Hyperalgesia has long been recognised clinically as a con-
sequence of tissue injury. Primary hyperalgesia (arising
from the site of injury) is generally considered to be caused
by sensitisation of sensory receptors (e.g. nociceptors) or
perhaps the activation of so-called ‘silent’ nociceptors by
mediators released or synthesised at, or attracted to, the
site of tissue injury.
Visceral hyperalgesia is a pain state caused by peripheral
and central sensitisation leading to abnormal perception of
both painful and nonpainful stimuli. Long-lasting pain
states, chronic inflammation, genetic factors and many
other factors are postulated to contribute to visceral hyper-
algesia or allodynia. Temporal and spatial summation of
pain stimuli is also thought to be important in the devel-
opment of hyperalgesia.
As hyperalgesia develops, several changes take place in
the central nervous system. These include increased activity
in the glutamate system, especially the activation of the
N-methyl-d-aspartate (NMDA) receptor complex and
increases in concentrations of nociceptive substances such
as dynorphins and nerve growth factor, causing increased
sensitivity and reduced endogenous inhibition of pain. Per-
sistent barraging of the spinal cord by noxious stimuli can
even result in excitotoxicity, which may cause cell death,
especially in the case of small inhibitory interneurons. The
net effect may be development of a pain memory as a
result of constant hyper excitability, leading to a persistent
pain although the primary cause has long disappeared.
9
Several potential mechanisms have been suggested for
visceral hypersensitivity.
10
Peripheral sensitisation
Peripheral sensitisation of primary afferent neuron termi-
nals within the gut results in a decrease in the intensity or
amplitude of the stimulus required to initiate their depo-
larisation and also in an increase in the number and/or
amplitude of neuronal discharges in response to such a
stimulus. This peripheral sensitisation is believed to result
from the release of proinflammatory substances at the site
of injury such as bradykinin, tachykinins, prostaglandins,
serotonin (5-HT), ATP and protons. Most of these media-
tors are known to be algogenic substances that act directly
on receptors located on sensory nerve terminals to depola-
rise these neurons and initiate nociceptive inputs to the
spinal cord. These mediators are likely to have at least
three different effects on primary afferent fibres: activation,
sensitisation and recruitment of ‘silent’ nociceptors, all of
which will result in an increased input to second-order
neurons in the dorsal horn. They can also lower the
threshold for activation by normally active stimuli and can
activate local immunocytes and/or mast cells. Nerve
growth factor released during mast cell degranulation may
also change the distribution of receptors of algogenic
mediators and enhance the expression of sodium channels,
which will further confound the peripheral sensitisat-
ion.
10,11
Central sensitisation
The term ‘central hyperexcitibility’ is used to describe the
circumstances associated with, if not responsible for, the
development of secondary hyperalgesia/allodynia. Central
sensitisation results from altered afferent input and the
release of neuroactive chemicals in the spinal cord dorsal
horn. These neuroactive chemicals increase the excitability
of spinal neurons and lead to expansion of peripheral
receptive fields. They can also lead to memory of the initi-
ating peripheral insult which can last under experimental
conditions for several hours. This nociceptive memory
manifests itself most prominently as post injury sensitisat-
ion; that is, after tissue damage, pain that results from sub-
sequent stimulation is exaggerated and prolonged and can
be initiated by low-intensity stimuli.
The increase in central excitability is associated with pro-
longed facilitation of reflexes and an increase in the recep-
tive field size of dorsal horn neurons. In addition to an
expansion of receptive fields, alterations at the level of the
dorsal horn neurons include a reduction in the threshold
and recruitment of novel inputs. A lowering of the thresh-
old of these cells will allow innocuous afferent stimuli to
excite previously unexcitable nociceptive pathways. By this
mechanism, normal afferent activity encoded by low-
threshold visceral afferents (such as physiological contrac-
tions or distension of the bowel wall) could trigger painful
sensations.
Aslam et al.
1552 ª2009 The Authors Journal compilation ªRCOG 2009 BJOG An International Journal of Obstetrics and Gynaecology
The molecular mechanisms involved in the development
of central sensitisation are incompletely understood. The
release of excitatory amino acids and the neuropeptides
substance P and calcitonin gene-related peptide (CGRP)
from the central terminals of primary afferent fibres appear
to play an important role in the observed central changes.
Roles for calcium fluxes through the NMDA receptor chan-
nel, nitric oxide and the expression of proto-oncogens such
as c-fos and c-jun in spinal dorsal horn neurons have been
demonstrated. It has been suggested that activation of the
NMDA receptors in the spinal cord dorsal horn is critical
to the development and maintenance of thermal hyperalge-
sia and chronic pain. It has been reported that the produc-
tion of nitric oxide in the spinal cord is required for the
short-term nocioceptive effects of NMDA.
12
In vitro and in vivo pharmacological studies suggest that
there is cooperation between substance P- and NMDA-
mediated events in the development and maintenance of
inflammation-induced central sensitisation. The increased
responsiveness of dorsal horn neurons in chronic inflam-
mation is largely mediated by activated NMDA receptors.
11
Descending facilitation from the brain
to the spinal cord and/or gut
Accumulating evidence indicates that descending pain facil-
itation from the rostral ventromedial medulla plays a cru-
cial role in hyperalgesia in many types of chronic pain
conditions.
13
Processing of incoming pain signals in the
spinal cord is subject to descending modulatory control
from the brain, which can be inhibitory or fascilitatory. A
series of electrophysiological and pharmacological studies
have shown that descending influences on spinal nocicep-
tive processing involve the peri-aqueductal grey and the
rostral ventromedial medulla, which seems to be the final
common output for descending influences from rostral
brain sites. It was later shown that the rostral ventromedial
medulla can also have facilitatory effects on spinal nocicep-
tive transmission. This bidirectional central control of noci-
ception may not only alleviate pain in situations where
antinociception is necessary for survival but could also
facilitate nociceptive processing and thereby contribute to
the maintenance of hyperalgesic states following peripheral
tissue damage. According to the findings of functional and
anatomical studies in animals and humans, the descending
pain-modulating pathway in the brain stem is connected to
a number of higher level brain areas including cingulofron-
tal regions, the amygdala and the hypothalamus, which
may represent the means by which cognitive and emotional
variables interact with nociceptive processing to influence
the resultant pain experienced. In particular, failure of inhi-
bition or increased facilitation of interceptive inputs has
been suggested to contribute to disorders such as CPP, IBS,
fibromyalgia and related conditions that are associated with
discomfort or pain but where tissue pathology is often
lacking.
14
Several in vivo and in vitro animal models have
been used to determine the role of this brainstem pain
facilitation in these pain conditions and to illustrate how it
was activated by various forms of pain.
13
Selective alterations of cerebral cortical processing
of ascending afferent input
The majority of published studies in control subjects and
patients with IBS have reported the activation of key com-
ponents of the so-called pain matrix (in particular, the
insular and dorsal anterior cingulated cortices) with less
consistent activation of the thalamus.
15
However, the degree to which each of these mechanisms
contributes to the overall perception of visceral pain and
therefore the generation of symptoms still remains unclear.
Clinical presentation prompting
visceral hyperalgesia in CPP
Symptoms of this diagnosis include the presence of extra-
genital symptoms in patients with CPP, including dyspha-
gia, intestinal symptoms, bladder symptoms (dysuria and
nocturia), muscle pain, migraine headaches and noncardiac
chest pain.
3
Similarly, in those patients with CPP where
established pathologies such as adhesions or endometriosis
do not correlate with the site or severity of pain, central
hyperalgesic dysfunction may explain the divergence of vis-
ceral afferent input to the spinal cord.
Diagnosis of visceral hyperalgesia may in the future be
established objectively as functional imaging modalities
develop. These approaches are being pursued in the context
of functional gastrointestinal disorders such as IBS.
16–18
The advent of techniques such as positron emission tomog-
raphy and functional magnetic resonance imaging now
allows neuroscientists and clinicians to observe the human
brain as it reacts to various stimuli including visceral sensa-
tions. Although positron emission tomography provides a
direct measurement of cerebral haemodynamics, its inher-
ent use of radio isotopes precludes its employment in serial
measurement studies. Functional magnetic resonance imag-
ing offers a noninvasive assessment of brain function that,
unlike positron emission tomography, has superior spatial/
temporal resolution, does not involve the use of nonionis-
ing radiation and allows the subject to be scanned on sev-
eral occasions. Currently, these modalities remain research
tools.
17
Management of visceral hyperalgesia
in CPP
An integrated approach that devotes attention to somatic,
psychological, emotional and physiotherapeutic factors is
Visceral hyperalgesia in chronic pelvic pain
ª2009 The Authors Journal compilation ªRCOG 2009 BJOG An International Journal of Obstetrics and Gynaecology 1553
likely to show improvements over simply surgical or medi-
cal interventions. Currently the main approaches to the
treatment of CPP include counselling or psychotherapy,
medical management with an analgesic regimen, use of
agents for neuropathic pain and modulation of hormonal
factors (using the oral contraceptive pill, progestogens
or gonadotrophin-releasing hormone agonists). Surgical
approaches include laparoscopy to exclude serious patho-
logy, excision of endometriosis, adhesiolysis, surgery to
interrupt nerve pathways and finally hysterectomy with
bilateral oophorectomy.
18,19
Currently, because of the lack of specific knowledge
about the site and cause of the defect in visceral hypersen-
sitivity and the frequent association with the presence of
major co-morbidities, research generating evidence regard-
ing the effects of treatment is rare. The lack of established
valid animal models makes successful development of vis-
ceral analgesic drugs difficult. Practically, if visceral hyper-
algesia is suspected in a case of CPP, potential treatment
options expand to include a range of drugs typically not
used in gynaecology such as opioid agonists, serotonin
receptor antagonists, mast cell inhibitors and immunomod-
ulators.
20
Opioid agonists (peripheral kappa agonists) have been
shown to inhibit somatic pain by acting directly on recep-
tors located on peripheral sensory endings. They can block
the nociceptive messages as well as the release of sensory
peptides. In volunteers, fedotozine is well tolerated and
produces none of the classical opioid central nervous sys-
tem adverse effects or the kappa diuretic effect in humans
after oral or intravenous administration.
20
Tricyclic antidepressants may be considered in patients
with CPP with neuropathic features. However, they have
not been evaluated formally in patients with CPP. Antide-
pressants are analgesic in patients with chronic pain with
no concomitant depression, indicating that the analgesic
and antidepressant effects occur independently. The analge-
sia induced by these drugs seems to be centrally mediated
but consistent evidence also indicates a peripheral site of
action. Several pharmacological mechanisms account for
their antinociceptive effect but the inhibition of mono-
amine transporters (and consequently the facilitation of
descending inhibition pain systems) is implicated on the
basis of mechanistic and knockout-mouse studies.
21
Selective serotonin reuptake inhibitors, both 5-HT3
antagonists (granisetron and cilansetron) and 5-HT4 agon-
ists, have been shown to be active in animal models of vis-
ceral pain linked to intestinal inflammation.
23
However, in
one study, no improvement was seen in women with CPP
taking sertraline compared with placebo. The Short Form-
36 Health Survey (SF-36) subscale ‘Health perception’
showed a small improvement in the sertraline arm, while
the ‘Role functioning-emotional’ subscale showed a large
fall in the sertraline arm.
24
Ion channels located either on
primary afferents or postsynaptically at the spinal cord level
are interesting targets for visceral antihyperalgesic drugs.
Drugs binding to calcium channels, such as gabapentin and
pregabalin, are able to modulate glutamate release at the
dorsal horn in rodents and have been found to be active in
visceral pain induced by septic shock, inflammation and
stress. Similarly, compounds that inactivate voltage-depen-
dent sodium channels may prevent in vivo glutamate
release at the spinal cord, impairing the transmission of the
nociceptive messages.
11
NMDA antagonists (ketamine and MK-80) have been well
studied in a variety of neuropathic pain models. NMDA
antagonists can both block and reverse central sensitisation.
However, the adverse effects observed with many of the com-
pounds limit their use. Continuing clinical trials of these
compounds in neuropathic pain will help further to establish
whether these compounds are useful in clinical practice.
25
Tachykinin receptor antagonists such as substance P,
neurokinin A (NKA) and neurokinin B (NKB) are particu-
larly expressed in small-diameter sensory fibres. The selec-
tive NK1 receptor antagonists, NK2 antagonists and NK3
antagonists have been shown to be effective in various ani-
mal models.
20
Similarly, bradykinin (B1 and B2 receptor)
antagonists have also been shown to be effective in reduc-
ing pain in several animal models.
11
CGRP released at the spinal cord from central endings of
primary afferents is thought to be important in the devel-
opment of visceral hyperalgesia. CGRP antagonists admin-
istered intravenously in rat models have been shown to be
useful in the prevention of both functional inhibitory
reflexes and pain.
11
Although cyclo-oxygenase 2 inhibitors have been
explored in pain management, their role is still uncertain
in these conditions.
Treatment must be tailored to the individual patient and
the goals of treatment must be realistic and involve input
from a pain specialist. Pain management must be focused
on restoration of normal function (minimising disability),
improvement of life quality and prevention of relapse of
chronic symptoms.
22
Conclusion
Visceral hyperalgesia may be an explanation for CPP in
many patients. There are no objective tests to prove or dis-
prove the existence of this condition in CPP, but after care-
ful history taking it may be strongly suspected. In such
patients, carefully chosen pain management approaches
directed at visceral hyperalgesia may provide substantial
symptom relief. It is to be hoped that the combination of
recent advances in the neuroimaging of pain, including
imaging of the brain stem and the spinal cord, molecular
Aslam et al.
1554 ª2009 The Authors Journal compilation ªRCOG 2009 BJOG An International Journal of Obstetrics and Gynaecology
imaging of neurotransmitter systems, pharmacological
modulation and/or genetic investigations in healthy sub-
jects and patients with distinct pathological states will
expand our understanding of the development of chronic
pain and finally lead to better treatment strategies. Future
research on functional imaging and interventional studies
targeting visceral hyperalgesia will improve the diagnosis
and management of CPP.
Glossary
Pain: An unpleasant sensory and emotional experience
associated with potential or actual tissue damage. It is
chronic if it persists for >3 months (International Associa-
tion for the Study of Pain [IASP]).
Pain threshold: The least experience of pain that a
subject can recognise (IASP taxonomy2008).
Nociceptors: ‘A receptor preferentially sensitive to a
noxious stimulus or to a stimulus which would become nox-
ious if prolonged’. Nociceptors are silent receptors and do
not sense normal stimuli. Only when activated by a threaten-
ing stimulus do they invoke a reflex. (IASP taxonomy—
[www.iasp-pain.org/AM/Template.cfm?Section=Home&
Template=/CM/ContentDisplay.cfm&ContentID=6633]).
Allodynia: Pain caused by a stimulus that does not nor-
mally provoke pain. This is not a reduction in the pain
threshold, as that would be hyperaesthesia. The important
difference is that allodynia is marked by a change in the
quality of the sensation, as the stimulus is not normally
painful, but the response is painful.
Hyperalgesia: Increased response to a stimulus that is
normally painful.
Visceral hyperalgesia: An increased sensitivity to visceral
stimulation following an injury or inflammation of an
internal organ.
Disclosure of interest
Not applicable.
Details of ethics approval
Not applicable.
Funding
Not applicable.
Acknowledgements
Not applicable. j
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