Visceral hyperalgesia in chronic pelvic pain

Commentary

DOI: 10.1111/j.1471-0528.2009.02305.x www.bjog.org

Visceral hyperalgesia in chronic pelvic pain N Aslam,a G Harrison,a K Khan,a S Patwardhanb 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 [email protected]

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’ duration involving the pelvis, lower abdomen and lower back, is a common gynaecological problem with an estimated prevalence 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 UK3 and other developed countries such as the USA.4 Unfortunately, the pathogenesis of CPP is poorly understood. Specific causes may include pelvic endometriosis, interstitial cystitis, adhesions or pelvic inflammatory disease, 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 populationbased 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 irritable 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 reproductive organs. It is noteworthy that visceral and somatic hyperalgesia have been considered as an important confounding factor associated with IBS and interstitial cystitis. In addition, interstitial cystitis and IBS may be associated with endometriosis, dysmenorrhoea, vulvodynia and adhesions through the recruitment of additional neural pathways, 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 hypersensitivity 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 neuroendocrine circuits that control digestion in accordance with the body’s need for energy, fluid and electrolytes. Many gastrointestinal afferents, however, have the potential to encode noxious stimuli, a property that has a bearing 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 pathological alterations in the environment of gut sensors, in the sensory gain of afferent neurons or in the central processing 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) stimuli 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 adequate stimuli that drive other afferents. However, after tissue 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 disorders may be profoundly altered, given that the numbers of enteroendocrine cells, mast cells and mucosal lymphocytes are increased in IBS.

ª 2009 The Authors Journal compilation ª RCOG 2009 BJOG An International Journal of Obstetrics and Gynaecology

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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 information 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 mechanisms of afferent stimulus processing.7 Hyperalgesia has long been recognised clinically as a consequence 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 hyperalgesia or allodynia. Temporal and spatial summation of pain stimuli is also thought to be important in the development 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. Persistent 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

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Peripheral sensitisation Peripheral sensitisation of primary afferent neuron terminals within the gut results in a decrease in the intensity or amplitude of the stimulus required to initiate their depolarisation 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 mediators are known to be algogenic substances that act directly on receptors located on sensory nerve terminals to depolarise 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 sensitisation.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 initiating peripheral insult which can last under experimental conditions for several hours. This nociceptive memory manifests itself most prominently as post injury sensitisation; that is, after tissue damage, pain that results from subsequent stimulation is exaggerated and prolonged and can be initiated by low-intensity stimuli. The increase in central excitability is associated with prolonged facilitation of reflexes and an increase in the receptive 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 threshold of these cells will allow innocuous afferent stimuli to excite previously unexcitable nociceptive pathways. By this mechanism, normal afferent activity encoded by lowthreshold visceral afferents (such as physiological contractions or distension of the bowel wall) could trigger painful sensations.


Visceral hyperalgesia in chronic pelvic pain

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 channel, 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 hyperalgesia and chronic pain. It has been reported that the production 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 NMDAmediated events in the development and maintenance of inflammation-induced central sensitisation. The increased responsiveness of dorsal horn neurons in chronic inflammation 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 facilitation from the rostral ventromedial medulla plays a crucial 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 nociceptive 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 nociceptive transmission. This bidirectional central control of nociception 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 cingulofrontal 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 inhibition 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 components 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 extragenital symptoms in patients with CPP, including dysphagia, 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 visceral 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 tomography and functional magnetic resonance imaging now allows neuroscientists and clinicians to observe the human brain as it reacts to various stimuli including visceral sensations. Although positron emission tomography provides a direct measurement of cerebral haemodynamics, its inherent use of radio isotopes precludes its employment in serial measurement studies. Functional magnetic resonance imaging offers a noninvasive assessment of brain function that, unlike positron emission tomography, has superior spatial/ temporal resolution, does not involve the use of nonionising radiation and allows the subject to be scanned on several 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


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likely to show improvements over simply surgical or medical 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 pathology, 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 hypersensitivity and the frequent association with the presence of major co-morbidities, research generating evidence regarding the effects of treatment is rare. The lack of established valid animal models makes successful development of visceral analgesic drugs difficult. Practically, if visceral hyperalgesia 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 immunomodulators.20 Opioid agonists (peripheral kappa agonists) have been shown to inhibit somatic pain by acting directly on receptors 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 system 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. Antidepressants are analgesic in patients with chronic pain with no concomitant depression, indicating that the analgesic and antidepressant effects occur independently. The analgesia 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 monoamine 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 agonists, have been shown to be active in animal models of visceral 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 Form36 Health Survey (SF-36) subscale ‘Health perception’ showed a small improvement in the sertraline arm, while the ‘Role functioning-emotional’ subscale showed a large

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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-dependent 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 compounds 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 particularly expressed in small-diameter sensory fibres. The selective NK1 receptor antagonists, NK2 antagonists and NK3 antagonists have been shown to be effective in various animal models.20 Similarly, bradykinin (B1 and B2 receptor) antagonists have also been shown to be effective in reducing 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 development of visceral hyperalgesia. CGRP antagonists administered 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 disprove the existence of this condition in CPP, but after careful 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


Visceral hyperalgesia in chronic pelvic pain

imaging of neurotransmitter systems, pharmacological modulation and/or genetic investigations in healthy subjects 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 Association 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 noxious if prolonged’. Nociceptors are silent receptors and do not sense normal stimuli. Only when activated by a threatening 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 normally 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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