The balancing act: endogenousmodulation of pain in functionalgastrointestinal disordersClive H Wilder-Smith1,2

ABSTRACTFunctional gastrointestinal disorders (FGIDs) arecharacterised by visceral pain or discomfort with anunknown cause. There is increasing evidence forabnormal processing of sensory input in FGIDs.Modulation of sensory input occurs at all levels of thenervous system, with a dynamic balance betweenfacilitation and inhibition and close integration with thebody’s wider homoeostatic control. Cognitive, emotional,autonomic and spinal reflex pathways effectivelyorchestrate supraspinal and spinal pain modulation, asdemonstrated in neurophysiological and brain imagingstudies. Endogenous pain modulation has been studied invisceral pain conditions and abnormal regulation hasbeen shown in irritable bowel syndrome (IBS) andfunctional dyspepsia, as well as other chronic painsyndromes. A majority of patients with IBS havediminished pain inhibition or even pain facilitationcompared with healthy controls. Brain imaging duringspecific activation of endogenous pain modulationdemonstrates a fairly consistent functional hub of mainlyfrontal, limbic and brainstem modulatory regions inhealthy humans. Patients with IBS have a differentpattern of activation and a correlation between theimaging and sensory changes. Because the modulatorybalance of inhibition and facilitation appears to bedistributed within the same functional network, futureimaging studies of modulation mechanisms shouldinclude conditions allowing quantification of inhibitoryand facilitatory components. An altered modulatorybalance may well be a unifying pathophysiologicalmechanism in FGID as it can be driven by bothtop-down (ie, CNS pathology) and bottom-up (ie,peripheral immune activation) influences, but furthervalidation in diverse FGID groups over time is required.Therapeutic manipulation of the modulatory system ispossible by both pharmacological and non-pharmacological means.

INTRODUCTIONVisceral pain is one of the most frequent reasons formedical consultation and is an integral part of themost common gastrointestinal syndromesdthefunctional gastrointestinal disorders (FGIDs) suchas irritable bowel syndrome (IBS) and functionaldyspepsia (FD). Recent evidence is transformingour concepts regarding the pathogenesis of visceralpain in FGIDs as a prominent number of affectedindividuals can now been shown to have eithercognitive, behavioural or sensory dysfunction, or

subclinical signs of immune activation, all withvery similar clinical symptoms.1 Pain represents anintegrated response of multiple body systemswhich affect homoeostatic control functions, suchas autonomic nervous and immune regulation.2

Chronic pain is often accompanied by a loweredpain threshold (allodynia) and increased pain toa stimulus (hyperalgesia).3 This sensitisation maybe driven by peripheral, spinal or central nervoussystem changes. Recent data suggest that an indi-vidual’s pain response is dependent on the uniquedynamic balance between pain inhibition andfacilitation, providing at least a partial explanationfor the widely differing pain responses.4 5 Thebalance between pain inhibition and facilitation isgoverned by a modulatory network of brain andbrainstem regions closely linked to spinalpathways.6e8 Pain modulation has been shown tobe abnormal in several chronic pain disorders (seebox 1). The ability to favourably influence endog-enous pain modulation (EPM), pharmacologicallyas well as cognitively, emphasises the clinicalimportance of these mechanisms. This paperdiscusses the role of the body ’s pain regulatorymechanisms in FGID. These mechanisms willcollectively be referred to as EPM (see box 2).

BACKGROUNDPhysiology of EPMEndogenous modulation of pain can be defined asthe body ’s adaptation of incoming nociceptiveinformation to momentary as well as long-termcircumstances and needs. This definition closelyparallels the definition of homoeostasis proposed byWilliam Cannon in the early 1900s: the property ofa living system to regulate its internal environmentto maintain a stable constant condition.9 Painmodulation is a dynamic process balancing inhibi-tion and facilitation and is intricately connected toother homoeostatic systems (figure 1).2 3 6 7 19

Modulation can occur at all levels of the sensorynervous systemdthat is, the peripheral, spinal andsupraspinal levelsdas well as via the autonomicnervous system and is dependent on the context ofthe injury as well as endogenous factors such as thepsychological and genetic background (figure 1).This review will concentrate on the central so-called descending modulation of pain, but a briefsummary of modulation at the more peripherallevels is included for better understanding of theintegration between all levels of pain processing(figure 2).

1Brain-Gut Research Group,Gastroenterology GroupPractice, Bern, Switzerland2Department of Medicine,National University ofSingapore, Singapore

Correspondence toDr Clive H Wilder-Smith,Gastroenterology GroupPractice, Bubenbergplatz 11,CH-3011 Bern, Switzerland;cws@braingut.com

Published Online First18 July 2011

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Peripheral pain modulationInjury or inflammation can lead to persistentperipheral input and sensitisation. In IBS thereis mounting evidence of sensitisation and ofchronic low-grade intestinal immune activationprobably associated with increased intestinalpermeability.20 21 Upon tissue insult, pro-algesicand pro-inflammatory mediators are released byimmune, neuronal, endothelial and epithelial cells.This algesic process is balanced by endogenousanalgesic mechanisms including the release ofanalgesic and anti-inflammatory cytokines andendocannabinoids.22 Immunocyte- and leucocyte-derived opioid peptides released in the immediatevicinity of sensory neurons and acting on mu-(MOR), delta- (DOR) and kappa- (KOR) opioidreceptors have a distinct local analgesic and anti-inflammatory effect.22e24 The analgesic effect isdependent on the presence of inflammatory cellsand hence inflammation.

Spinal pain modulationExtensive adaptation of peripheral afferent sensoryinput occurs at the spinal level, with a dynamicbalance of inhibition and facilitation conferred bylocal interneurons and by multiple pathways orig-inating supraspinally.6 25e29 Pro-inflammatorycytokines, chemokines, biogenic amines, bradyki-nins, prostaglandins, substance P, calcitoninG-related peptide and several neurotrophins areamong the facilitatory mediators. Endo-opioids,anti-inflammatory cytokines and endocannabinoidstip the balance in favour of inhibition. Dependingon the subtype of receptor activated, serotonin,dopamine and norepinephrine can have eitherexcitatory or inhibitory function.6 30 Feedforwardand feedback control of input is effected via spinal-supraspinal-spinal loops. Nociceptive input isconveyed from the dorsal horn to subcortical nucleiand then onwards to a hub of brain processingregions (figure 3).3 19

Supraspinal (descending) modulation of painThe function of the supraspinal pain controlpathways is to either amplify or to subordinatenoxious or potentially noxious stimuli in coordi-nation with the individual’s homoeostatic needs.2

Control of the brain over spinal input is bothinhibitory and facilitatory and, importantly, thesame brain centres can exert both inhibitory andfacilitatory influences.3 7 19 The majority ofresearch on descending pain modulation hasconcentrated on inhibition, which has led to anambiguous interpretation of brain imaging data invisceral pain. Regulation of the dynamic balancebetween inhibition and facilitation occurs withinthe brainstem rostroventral medulla (RVM) - peri-aqueductal grey (PAG) axis and in connectedbrainstem and higher cortical centres.19 32e35 Thebrainstem modulation may not be restricted to painbut appears to extend to a wide range of homoeo-static mechanisms.2 The balance of modulationdepends on the type of activated afferent nervefibres, the duration, the type and the backgroundstate or context of the injury.30 Chronic and intensenoxious stimulation involving C-nerve fibres morecommonly leads to sensitisation and activatesmodulatory mechanisms more extensively thanshort-lasting input.19 36 This distinction mayexplain some of the divergent results in sensorystudies of IBS and other chronic pain states.Supraspinal modulation of pain is triggered by

cognitive, emotional and autonomic influences viaa hub of cortical and limbic regions bidirectionallyconnected to the modulatory brainstem nuclei, aswell as efferent motor and autonomic centres(figure 3).4 6 8 10 11 37e43 The considerable func-tional overlap of so-called cognitive and limbicareas in recent connectivity functional MRI (fMRI)studies questions a clear identification of regionswithin the dynamic coalitions of networks aspurely affective or cognitive.11 Cortical processesprominent in FGIDsdsuch as expectation, vigi-lance, memory and distractiondexert profounddescending modulation via brainstem-spinal

Box 1 Conditions in which endogenous pain modulation has been shownto be dysfunctional

< Irritable bowel syndrome< Fibromyalgia< Functional dyspepsia< Chronic pancreatitis< Temporomandibular joint dysfunction< Increased postoperative pain/requirements for analgesia< Migraine< Tension-type headache< Osteoarthritis< Rheumatoid arthritis< Chronic trapezius myalgia< Neuropathic pain< Chronic widespread pain< Pain catastrophising

Box 2 What is endogenous pain modulation and what is its relevance ingastroenterology?

< All painful input is modulated at the levels of the peripheral nerve, the spinaland supraspinal (brainstem and brain) nervous system. These levels areintricately connected and modulate other homoeostatic mechanisms as wellas pain.

< Modulation is a dynamic balance between inhibition and facilitation, which isinfluenced by bottom-up (ie, spinal and peripheral) as well as top-down (ie,central nervous system) factors. This balance is highly individual and appearsto correlate with different clinical measures of pain sensitivity.

< Pain modulation is abnormal in irritable bowel syndrome as well as in otherchronic pain conditions, with a decrease in the inhibition seen in health ora facilitation. This may be driven by peripheral inflammation as well as bypsychological changes.

< Endogenous pain modulation is strongly influenced by cognitive, analgesicand anti-inflammatory measures and may explain some of their therapeuticeffectiveness.

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pathways including the so-called diffuse noxiousinhibitory controls (DNIC).12 44 45 Isolatedperceptional modulation of pain at a cortical levelor by brainstem-spinal loops is unlikely.41e43

Descending control over spinal dorsal hornneuronal activity is through noradrenergic, opioi-dergic, serotoninergic, dopaminergic and cannabi-noid pathways which themselves can be eitherinhibitory or facilitatory depending on the receptorsubtype activation (figure 4).6 13 30 37 46e58

Modulation by the autonomic nervous systemSensory processing from the viscera differs from thesuperficial organs in the extensive primaryinvolvement of the autonomic nervous system (seerecent reviews59e61). Parasympathetic vagal affer-ents contain large numbers of sensory fibresrelaying information to brainstem regions and thenonwards to forebrain centres.62 63 The overlap ofthese areas with those responsible for bodilyhomoeostasis and pain-related responses, such asillness behaviour, autonomic, emotional, motor andimmune reactions, emphasises extensive visceralinput convergence and integration.62 64 Vagalstimulation may attenuate pain both centrally andperipherally and has an anti-inflammatory effect.65

The sympathetic nervous system appears to exertlittle influence on pain in physiological conditions,but possibly plays a role in neuropathic painstates.48 An important efferent function of thesympathetic nervous system is the control ofimmune activation via the locus coeruleus, influ-encing inflammatory activity and the immuneresponses central to most forms of chronic pain.

ENDOGENOUS PAIN MODULATION (EPM) INFGIDSThe dynamic balance between pro- and anti-noci-ception and the integration with other bodilycontrol mechanisms is clearly established in health.Changes in this equilibrium may well play animportant role in chronic visceral pain syndromes,with a shift towards sensitisation and pain facilita-tion. In the following sections, evidence of changesin painmodulation in IBS aswell as early data for FDis summarised. FGIDs are associated with severalfactors which potentially shift the balance of painmodulation such as stress, anxiety, chronic inflam-mation and hypervigilance as well as other paincomorbidities.1 66e69 Because of the extensive inte-gration of the modulatory pathways, both bottom-up (eg, chronic mucosal immune activation) as wellas top-down (eg, cognitive-limbic dysfunction)influences could drive the disequilibrium.

Sensory testing shows abnormal EPM in FGIDsEvidence for altered endogenous sensory modula-tion in FGIDs exists at several levels. Quantitativesensory testing has confirmed visceral andddepending on the stimulation proceduredsomatic hypersensitivity in a majority of patientswith IBS.70e75 This suggests sensitisation, but isnot proof of abnormal modulation. Several testprocedures have been developed specifically to

Figure 1 Factors known to affect the balance between pain inhibition andfacilitation.10e18

Figure 2 Interaction between levels of pain modulation. Inhibition and facilitation aredetermined interactively at every level of pain processing.

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assess EPM (see box 3). The best characterisedmodel is termed DNIC, heterotopic stimulation orheterotopic noxious conditioning stimulation,where a primary painful stimulation is appliedalone and then simultaneously with a seconddistant conditioning stimulation which normallyreduces the pain intensity of the primary stimula-tion (figure 5). DNIC mechanisms have beenextensively validated both in health and in diseasein animals and in humans with a flexion reflex (RIIIreflex) or the closely correlated changes in painratings.76e84 They are classically postulated toengage spino-bulbo-spinal pain modulatory loops,but recent brain imaging studies have shownconsiderable involvement also of supraspinal andcortical regions.44 45 85 It should be pointed out thatheterotopic stimulation does not separately iden-tify the magnitude of inhibition and facilitation,but quantifies the summation of both effects. Afurther stepwise water immersion paradigm hasalso been developed.86 Using these techniques,either a decreased pain inhibition or a facilitationcompared to controls has been demonstrated ina majority of patients with IBS from a variety ofethnicities (figure 6), and there was a goodcorrelation between the magnitudes of abnormalpain modulation and of changes in painsensitivity.44 45 75 87e90 The presence of bothabnormal visceral and somatic pain modulation aswell as sensitisation in IBS indicates a generalisedrather than a specifically visceral sensory disorder.This pain modulation is not sufficiently explainedby distraction or attentional effects, althoughemotional and cognitive effects feed into the samegeneral modulatory network.44 91 92 In healthycontrols, heterotopic stimulation generally achievesa pain inhibition of 15e35%, with some racialdifferences between Asians, Black Africans andCaucasians.76 90 93 Over the past few years work byour group has demonstrated abnormal modulationby heterotopic stimulation in 70e85% of patientswith IBS, with facilitation rather than inhibitionoccurring in approximately 50% and weaker thannormal inhibition in the majority of the remainingpatients.44 45 75 More recently, abnormal EPM hasalso been demonstrated in patients with FD usinga novel and reproducible heterotopic stimulationmodel with capsaicin-induced gastric pain andsimultaneous thermal foot pain.94 In healthycontrols the gastric pain was reduced by a highlysignificant 65% by heterotopic foot stimulationcompared with an insignificant reduction inpatients with FD.94 Furthermore, the magnitude ofabnormal modulation in patients with FD corre-lated with their clinical symptom intensity.94 Thedata in FD needs confirmation in larger trials and insubsets of patients with FD. These simplepsychophysical techniques demonstrate abnormalmodulation in most but not all patients with IBSand FD, and further validation in large diversegroups of patients with FGIDs in longitudinalstudies is advised. Integration of the assessment ofEPM with studies of other potential disease mech-anisms such as immune activation, autonomic

Figure 3 Brain areas consistently shown in imaging studies to be active in theprocessing and modulation of pain. Adapted from Tracey and Mantyh.31

Figure 4 Descending pain modulation pathways identifying the main transmittersystems. Adapted from Benarroch.6

Anteriorcingulategyrus

Periaqueductalgray

DopamineNorepinephrineSerotoninOpioid

Dorsolateralprefrontalcortex

A11(periventricularposteriorhypothalamus)

A6A5’

Dorsalhorn

Rostralventromedialmedulla

Frontal

Limbic

Brainstem

Spinal

(locus coeruleus)

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dysregulation or hypervigilance is likely to lead toa more complete understanding of the underlyingand heterogenous-appearing pathologies in FGID.Abnormal pain modulation has also been shownwith these tests in fibromyalgia, which oftenoverlaps with FGID, and in other chronic painsyndromes.86 95 96

Abnormal EPM in FGID by brain imagingfMRI and positron emission tomography studieshave been pivotal in elucidating the brain areas and

networks activated during pain, discomfort andcognition-related tasks in health and FGID.However, the experimental context and studydesign require a critical interpretation regardingapplicability to clinical situations. An in-depthreview of these imaging studies is beyond the scopeof this specialised paper and the reader is referred toexcellent recent publications.97e102 Several fMRIand positron emission tomography studies withcognitive and sensory manipulation have showndifferences in activation between patients with IBSor FD and healthy subjects in brain regions associ-ated with EPM.103e105 In brain imaging studies,function is frequently ascribed to different regionsand changes in activation are taken to implyparallel changes in function, with the accompa-nying risk of reverse inferencing.102 Aue et al, ina useful paper on this topic, suggest that investi-gators do not assume any invariant relationshipsbut instead expect to have to marshal empiricalevidence to support fMRI claims.106 In thiscontext, a minority of imaging investigations wereconcerned specifically with modulation of experi-mental pain, and no formal imaging studies ofclinical IBS or FD pain exist to the best of ourknowledge. Consequently, we will first summarisethe indirect evidence regarding pain modulation inFGID and then examine the studies with specificmanipulation of pain modulation during imaging.In studies of rectal distension, pain or discomfort,

patients with IBS have fairly variable differences inactivated brain regions compared with controls,generally comprising divisions of the prefrontalcortex, anterior cingulate cortex (ACC), mid-cingu-late cortex (MCC), insula, amydala, hypothalamusand brainstem nuclei (figure 7).44 45 107e110 Many ofthese areas are implicated in pain processing aswell as in cognitive and emotional processing. Aclear distinction between different psychologicalmodulatory regions (eg, for emotion and cognition)is problematic in healthy controls, but even more soin patients with FGIDs who have additionalpsychological dysfunction.11 107 111 112 Activationdifferences in these regions have been variouslyinterpreted as abnormal function either in the painfacilitatory or the inhibitory pathways. While thedescribed areas are part of the recognised modula-tory network, current mechanistic studies do notdelineate distinct facilitatory and inhibitory path-ways but indicate that the balance of modulation isregulated largely within the same circuits.3 Some ofthe seemingly discrepant fMRI results may beexplained by paradigm-related differences inbalance or gain within the same network ratherthan different circuitry. The modulatory balance islikely to be set by cognitive factors very relevant inIBS, such as expectation, anxiety, learning processesand association.10 12 107 108 It should furtherbe cautioned that the functioning of pain modula-tory mechanisms at below-pain (ie, discomfort)intensity is presently unclear.Hypotheses for CNS as well as peripheral aeti-

ologies exist in FGID, and there is supportiveevidence for both in fMRI studies. Top-down

Box 3 Methods of assessing endogenous pain modulation

< Sensory testing using heterotopic stimulationdthat is, two simultaneous anddistant painful stimulations (eg, rectal distension and thermal handstimulation).

< Stepwise limb immersion and withdrawal from thermal water stimulus.< Manipulation of pain processing by cognitive or emotional inputdfor

example, by variation of expectation (placebo/nocebo), suggestion, distrac-tion, stress or anxiety.

< Brain imaging with fMRI or PET during modulation of pain.< Brain and spinal electrical activity changes during modulation of paindfor

example, cerebral evoked potentials.

Figure 5 Model for testing endogenous pain modulation using heterotopic stimulation.Heterotopic stimulation denotes modulation of a primary pain stimulus by a seconddistant (heterotopically applied) painful stimulus. The change in primary pain stimulusintensity is the outcome measure. The graph shows typical results for pain intensity ofprimary pain alone (red bar), pain intensity of primary pain together with heterotopicstimulus (yellow bar) and the pain intensity decrease due to the heterotopic stimulus(green bar).

−10−20−30

010203040506070

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modulatory dysfunction in IBS, corresponding toattentional and cognitive changes such as hyper-vigilance and increased symptom-directed anxiety,is visible in the abnormal prefrontal cortex activa-tion patterns.113 The diminished prefrontal activa-tion often demonstrated in IBS is also associatedwith negative emotions and increased pain.12 114

The success of hypnosis in IBS may reflect a modu-latory effect with increased prefrontal activationfeeding into the downstream modulatory areas,resulting in distancing from the emotional impactof pain and in pain reduction.115e117 On the otherhand, there is also evidence in imaging studies ofincreased intestinal (peripheral) sensory input dueto sensitisation or subcortical facilitation in IBS.Thus, with identical rectal stimulus intensity, brainactivation in the early pain processing areas wasgreater in IBS than in controls whereas, in subjectiverating-matched stimulation, there were only minoractivation differences in these areas between subjectgroups.45 118 Several recent interesting studies haveexamined the linkage between the main painprocessing centres in IBS using connectivity anal-ysis.108 119 120 However, owing to the absence ofadequate control groups, they can only provideindirect evidence of any disease-related changes inmodulation and will not be considered here.

Brain activation differences during a sensorystimulus between patients with IBS and controlsare frequently ascribed to abnormal endogenoussensory inhibition. While associations are possiblein these studies with generally smaller numbers ofsubjects, certain caveats need to be mentioned asthe associations between imaging and function areunlikely to be linear for several reasons: thecomplex relationship between neuronal activation,perception and BOLD fMRI signal change; theinvolvement of the same brain centres in bothinhibitory and facilitatory actions; and a shiftingmodulatory balance with chronic input. Further-more, many of the classic modulatory brain centresare also extensively involved in regulation of non-nociceptive functions. To address these issues,several studies have included paradigms activelyengaging quantifiable pain modulation duringimaging. These paradigms include attentional andemotional modulation, placebo and nocebo proce-dures and the above-described heterotopic stimu-lation. All of these procedures significantly andquantifiably alter pain intensity but, nonetheless,they bear the limitations inherent in the applica-tion of acute experimental procedures to a chronicdisease setting. We will consider the relevantstudies relating to IBS below.

Brain imaging during activation of EPM byheterotopic stimulation in IBSHeterotopic stimulation has demonstratedabnormal pain modulation in IBS and, consistentwith this, concurrent brain imaging has shownaberrant brain activation in areas associatedwith thecognitive and emotional modulation of pain (figures8 and 9).44 45 75 114 121e123 The processing seen in theclassic modulatory regions during effective paininhibition in controls contrasts with the increasedactivations in the so-called ‘fear and threat’ networkin IBS during pain facilitation or decreased

Figure 6 Endogenous modulation of (A) visceral pain (rectal pain) and (B) somatic pain(hand pain) using heterotopic foot stimulation in healthy controls (n¼69) and patientswith irritable bowel syndrome (n¼84). Decreased pain inhibition or pain facilitation wasseen in patients with irritable bowel syndrome compared with the consistent inhibition incontrols. (C) Pain modulation differs significantly between individuals of differentethnicities (rectal pain, n¼69). Means and 95% CIs are shown. Reproduced withpermission from Wilder-Smith and Robert-Yap.75

Figure 7 Brain and brainstem areas showing mostconsistent activation differences between patients withirritable bowel syndrome and healthy controls during imagingstudies of rectal pain or discomfort. ACC, anterior (posterior-anterior) cingulate cortex; AMY, amygdala; HYP, hypothal-amus; INS, insula; MCC, middle cingulate cortex; PAG, ????;PFC, prefrontal cortices.

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inhibition. Moreover, the diminished endogenouspain inhibition in patients with IBS correlated withthe activation changes in the key pain processingareas and also with the presence of somatic andvisceral hyperalgesia.44 45 Analysis of functionalbrain connections during pain modulation inducedby heterotopic stimulation showed top-downcontrol of cortical brain areas over key brainstemmodulatory areas in healthy controls but a reversedbottom-up direction of control in patients withIBS.121 The predominantly quantitative rather thanqualitative activation differences in IBS imagingstudies may well be due to a shifted gain within themodulatory balance in these central control areas, ashas been demonstrated in various forms of chronicpain in animals by Vanegas and Schaible.19 Insummary, current pain modulation brain imagingstudies support the presence of abnormal EPM inIBS. We are not aware of any brain imaging studiesduring explicit modulation of pain in FD.

Brain imaging during psychological modulation ofpain and IBSThe individual experience of pain is powerfullyinfluenced by cognitive and emotional mechanismssuch as the expectation and desire of pain relief(placebo), the expectation of pain (nocebo),memory, reward and mood.124 125 Expectation mayexplain up to 50% of the variation in painratings.125 Placebo and nocebo effects appear torepresent a continuous spectrum of responsesrather than qualitatively different mechanisms.126

This balance between hypo- and hyperalgesia, orinhibition and facilitation, is predominantly regu-lated by endogenous opioid and cholecystokininsystems.127 Cholecystokinin is implicated inhyperalgesia mediated in the PAG, counter-balancing opioid-induced analgesia, and also in thepathogenesis of IBS.128e132

Brain imaging studies with placebo in healthyindividuals have shown a correlation between thedegree of expected pain relief and brain activationin main modulatory (especially opioidergic)areas.14 50 52 101 133e136 However, dopaminergicreward pathways in the basal ganglia also accountfor approximately 25% of the variance of placeboresponses.54 Placebo analgesia manipulates activityin cortical and subcortical regions key to thecognitive and emotional modulation of pain.Importantly, the anticipation of pain and ofnocebo-induced hyperalgesia activated very similarbrain regions.15 16 136e140 The overlap in brainareas activated during cognitively-induced paininhibition and pain enhancement again suggestsa modulation executed within an overlappingfunctional network.Comparatively few brain imaging data have been

published examining cognitive and emotionaleffects on pain in FGID. However, these modula-tory mechanisms are of particular relevance inFGID, where memory of abuse, somatisation,negative mood, symptom-related anxiety, selectiveattention and hypervigilance are implicated inpathogenesis and where expectation and placebo

Figure 8 Brain and brainstem areas showing mostconsistent activations in patients with irritable bowelsyndrome (red) and healthy controls (blue) in imagingstudies during activation of pain modulation usingheterotopic stimulation. ACC, anterior cingulate cortex;AMY, amygdala; DBS, dorsal brainstem (periaqueductalgrey); HIP, hippocampus; INS, anterior insula; PAR,parietal cortex; PCC, posterior cingulate cortex; dlPFC,dorsolateral prefrontal cortex; mPFC, dorsolateralprefrontal cortices; RVM, rostroventral medulla; S1,primary somatosensory cortex; THAL, thalamus.

Figure 9 Brain functional MRI showing regions activated during endogenous painmodulation by heterotopic stimulation (painful rectal distension with foot cold pain) inhealthy controls (left column) and patients with irritable bowel syndrome (right column).Reproduced with permission from Song et al.44

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responses are considered elevated.107 109 141 Inpatients with IBS the history of abuse was associ-ated with activation differences compared withcontrols in distinct subregions of the cingulatecortex during rectal distension.142 In a separatestudy, increased anxiety during expectation ofa rectal distension in patients with IBS correlatedwith an absence of deactivation in arousal networkregions, especially the dorsal brainstem.110 There-fore, although associations between psychologicalprocesses, gastrointestinal sensory function andsymptoms have been shown in patients with FGIDduring functional brain imaging, most studieshave been performed in uncontrolled settings inIBS.107 118 143e146 Rectal placebo with the sugges-tion of enhanced analgesia in IBS reduced bothrectal distension pain ratings and brain activationsin divisions of the insula and ACC compared withrectal distension alone.143 Functional connectivityanalysis yielded differences in the direction ofinfluence within modulatory areas with placebo.120

Further controlled studies are needed to bettercharacterise the psychological modulation of painin FGID and visceral pain in general.

THERAPEUTIC IMPLICATIONS OF EPM IN FGIDThe descending pain modulatory pathways can bemanipulated with a wide range of medications

including opioidergic, serotoninergic, noradrenergic,dopaminergic and non-steroidal anti-inflammatorydrugs.40 78 147 Given the close integration ofcognitive, emotional and modulatory processes, itwould be expected that behavioural and cognitivetreatments exert their principal effects via themodulatory pathways. Indeed, imaging andpsychophysical data provide correspondingsupportive evidence for placebo and nocebo studies,and data emerging from trials of hypnosis, cogni-tive behavioural therapy, mindfulness and dynamicpsychotherapy indicate that their potential effec-tiveness in the treatment of FGID may be viathe modulatory networks.125 128 148e151 Thereare therefore considerable pharmacological andnon-pharmacological therapeutic possibilities ofmanipulating EPM that deserve further explorationwith high-quality studies.

CONCLUSIONS AND FUTURE DIRECTIONSThere is increasing evidence for abnormal EPM inIBS and FGID, with a shift in balance from inhi-bition towards facilitation. EPM may be part of thebody’s integrated and dynamic homoeostaticresponse and probably explains some of the relatedchanges in other regulatory systems in FGID suchas autonomic function, immune, cognitive andgastrointestinal motility changes. Both top-down(ie, CNS dysfunction) and bottom-up (ie, spinaland peripheral immune activation) could reset EPM(figure 10). Undoubtedly, the very loose pheno-typical definition of FGID encompasses differentsubgroups of pathologies, however disorderedfunction of a central regulator of homoeostaticfunctions would go far in explaining some of thedivergent manifestations. As Sherrington suggestedin 1900: ‘Pain is a curiously imperative occurrencethat co-opts descending bulbospinal neurons tomake necessary adjustments to sensory, autonomicand motor functions’.152

Brain imaging is increasingly defining thepredominant structures involved in the modulationof pain. The pathways and centres governing thebalance between pain inhibition and facilitationlargely overlap. Future imaging studies shouldtherefore include conditions allowing quantifica-tion of inhibitory and facilitatory components.Comparisons between healthy controls andpatients with FGID incorporating the assessmentof peripheral, spinal and supraspinal modulationduring placebo and nocebo manipulation arenecessary to further define the aberrant painmodulation in FGID.

Competing interests None.

Provenance and peer review Commissioned; externally peerreviewed.

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Figure 10 Factors potentially driving changes in endogenous pain modulation invisceral pain syndromes. Shifted modulatory balance may act as a central mechanism inchronic pain syndromes and may predict an individual’s pain sensitivity.

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disordersof pain in functional gastrointestinal The balancing act: endogenous modulation

Clive H Wilder-Smith

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