OTHER SOFT TISSUE DISORDERS

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Visceral Referred Pain

ABSTRACT. Objectives: The perception of pain in regions other than the affected organ is the rule in visceral nociception. This paper reviews the current knowledge about modalities of clinical presentation and pathophysiological mechanisms of visceral referred pain, based on the results of clinical and experimental studies. Findings: Visceral referred pain occurs in somatic areas neuromerically connected with the affected organs where secondary hyperalgesia takes place mostly in deep body wall tissues, extending to supercial layers in repetead/prolonged visceral processes. When two internal organs sharing part of their central sensory projection are affected, visceral pain and referred hyperalgesia from each organ are signicantly enhanced [viscero-visceral hyperalgesia]. In this case, treatment of one visceral condition signicantly improves symptoms from the other. Referred phenomena are mainly sustained by central sensitization processes, involving viscero-somatic or viscerovisceral-somatic convergent neurons, as shown by electrophysiological studies in animal models. A contribution by viscero-somatic reexes is also present, which would account for the trophic changes of deep body wall tissues that often accompany the hyperalgesia. The expression of visceral referred pain is reduced with the aging process, which renders diagnosis more difcult in the elderly, increasing the risks in life-threatening conditions. Some of the contributing mechanisms may include age-related impaired A-Delta ber function and a reduction in the content and turnover of neurotransmitter systems involved in nociception. Conclusions: Visceral referred pain and accompanying phenomena are being increasingly understood as regards their pathophysiology. This opens new avenues for treatment strategies that are more mechanism-based and not purely symptomatic. KEYWORDS. peralgesia Visceral referred pain, hyperalgesia, central sensitization, viscero-visceral hy-

Maria Adele Giamberardino and Giannapia Affaitati, Ce.S.I, G. DAnnunzio Foundation, Department of Medicine and Science of Aging, G. DAnnunzio University of Chieti, Chieti, Italy. Raffaele Costantini, Institute of Surgical Pathology, G. DAnnunzio University of Chieti, Chieti, Italy. Address correspondence to: Maria Adele Giamberardino, MD, Pathophysiology of Pain Laboratory, via Carlo de Tocco n. 3, 66100 Chieti, Italy, Phone: +39-0871-358070, Fax: +39-0871-541207. E-mail: [email protected] Journal of Musculoskeletal Pain, Vol. 18(4), 2010 Available online at www.informaworld.com/MUP 2010 Informa Healthcare USA, Inc. All rights reserved. doi: 10.3109/10582452.2010.502624

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INTRODUCTION Pain originating in internal organs is amongst the most frequent forms of pain experienced by individuals in the course of life. Cardiac pain from coronary heart disease, urinary and biliary colics from calculosis, abdominal pain from irritable bowel syndrome [IBS], or pelvic pain from the reproductive area, especially in women, are only a few examples of this variegated reality (1). Visceral pain has the distinctive feature of being perceived in areas of the body located at a distance from the diseased organs. Henry Head [1893] labelled this phenomenon referred pain, a painful sensation reported in a region other than that in which the noxious stimulation takes place. While the patterns of referral vary from organ to organ, the mechanisms behind visceral referred pain are fundamentally the same whatever the viscus in question, as are the rules to be applied when interpreting the various modalities of its clinical presentation (2, 3). This paper is intended to highlight the clinical prole of referred pain from viscera and its current interpretation, based on the ndings of clinical and experimental studies in the eld. Clinical Presentation of Visceral Referred Pain The very rst phase of painful episodes from internal organs is similar in any visceral pain condition: a vague and poorly dened sensation felt at the midline, accompanied by marked neurovegetative reactions and emotional signs [true visceral pain] (4). True visceral pain is always transitory, lasting from minutes to hours, after which the phase of referral occurs, which varies and is organ-specic. Visceral referred pain is, in fact, perceived in somatic areas of the body wall located in the same neuromeric eld as the organ in question, for example, left chest area/arm/forearm for the heart, lumbar region/ank for the urinary tract, upper right abdominal quadrant for the biliary tract, lowest abdominal quadrants for the reproductive organs. Secondary hyperalgesia [increased sensitivity to painful stimuli/decreased pain threshold] most often takes place in the referred areas, starting in the skeletal muscle layer, and extending upward to the overlying subcutis

and skin especially in the case of recurrent and/or prolonged visceral stimuli [referred pain without and with hyperalgesia] (5). The hyperalgesia can be detected by clinical means and precisely quantied instrumentally. Clinical manoeuvres reveal the hypersensitivity in an on-off manner, i.e., vigorous pain reaction by the subject upon rm manual compression of the muscle tissue, pinch palpation of the subcutis, scratching of a needle point over an area of altered dermographic reactivity of the skin. Instrumental procedures involve pain threshold measurement to different stimuli, with a threshold decrease indicating hyperalgesia. For muscle and subcutis, mechanical [pressure and pinch algometer], electrical [impulses delivered through needle electrodes], and chemical [injections of algogenic substances of progressively increasing concentrations] stimuli are usually employed. For skin, thermal stimulation [thermal algometer] is also used in addition to mechanical [von Frey hairs] and electrical [impulses delivered through surface electrodes] stimuli (1, 2, 57). The prole of referred hyperalgesia has been assessed by using these different procedures in patients with different pathologies of internal organs, e.g., coronary artery disease, gallbladder disease, IBS, urinary calculosis, dysmenorrhea, and endometriosis (5, 710). On the whole, the results of these studies indicate that referred visceral hyperalgesia, mostly involving the skeletal muscle layer, only appears in the case of painful visceral diseases, independently of their organic or dysfunctional nature. Hyperalgesia is already detectable after a few visceral pain episodes, is accentuated in extent by the repetition of the episodes, and outlasts not only the spontaneous pain but often also the presence of the primary pain trigger in the internal organ. In urinary calculosis, for instance, lumbar muscle hyperalgesia appears soon after the rst one or two colics, increases with their repetition, is detectable between the painful episodes, and in 90 percent of the cases persists for monthsyears after elimination of the urinary stone (10). In acute inammatory visceral pain, the referred hyperalgesia tends to also involve the supercial somatic tissues. Patients with acute appendicitis show increased ratings to pinprick and thermal stimuli, together with a reduction of cutaneous electrical pain thresholds and muscle pressure pain thresholds in the referred

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abdominal pain area [McBurneys point] versus the contralateral control area. The electrical and pressure pain thresholds are lower in the referred pain area in patients compared with the same area in healthy controls (11). In acute cholecystitis patients show hypersensitivity to pinprick, heat, cold, pressure, and single and repeated cutaneous electrical stimulation in the referred pain area and in the contralateral control area of the abdomen. However, the hypersensitivity appears normalized after cholecystectomy (12), a different nding from the above-reported results on the persistence of some degree of hyperalgesia after stone elimination in urinary colics. This outcome probably indicates that repeated painful visceral inputs, as in colics, rather than isolated acute episodes, are needed to leave persistent hyperalgesic traces in the referred area. With the notable rise in life expectancy in the past hundred years, it is increasingly common in clinics for a patient to present with more than one visceral pain condition simultaneously. If the affected viscera share at least part of their central sensory projection, the so-called phenomenon of viscero-visceral hyperalgesia may take place, due to which the patient experiences an enhancement of both spontaneous referred pain and referred hyperalgesia (2). Patients with concomitant coronary heart disease and gallbladder calculosis, for instance, present signicantly more anginal attacks, biliary colics and referred muscle hyperalgesia in the chest area and right upper abdominal quadrant than patients with one condition only [common sensory projection between heart and gallbladder: T5] (4, 13). Women with dysmenorrhea plus IBS [common projection between uterus and colon: T10-L1] have more menstrual pain, intestinal pain, and somatic abdominal/pelvic hyperalgesia [in the areas of referral from the uterus and from the intestine] than dysmenorrhea or IBS only (2, 14). Similarly, patients with dysmenorrhea/endometriosis combined with urinary calculosis [common projection between uterus and upper urinary tract: T10-L1] have increased menstrual pain, urinary colic pain, and somatic abdomino-pelvic/lumbar hyperalgesia [in the areas of referred pain from the uterus and from the urinary tract], with respect to one condition only (9, 14). Viscerovisceral hyperalgesia has important therapeutic implications; effective treatment of one condition, in fact, has been shown to signicantly improve typical symptoms from the other. A re-

duction has been observed of angina pain/chest hyperagelsia after cholecystectomy and of biliary pain and hyperalgesia in the upper right abdominal quadrant after cardiac revascularization. A decrease has also been shown of urinary pain/referred lumbar hyperalgesia after hormonal treatment of dysmenorrhea or laser treatment of endometriosis, as well as a decrease in menstrual pain and referred abdomino-pelvic hyperalgesia after urinary stone elimination following lithotripsy (1, 4, 9). Similarly, a reduction of IBS symptoms with appropriate diet has also been shown to improve spontaneous pain and referred hyperalgesia from dysmenorrhea, while hormonal treatment of dysmenorrhea reduces referred pain and hyperalgesia from IBS (4). In the areas of referred visceral pain, not only does hyperalgesia take place but trophic changes are also frequently observed. These consist of an increased thickness of the subcutaneous tissue and a decreased thickness of the muscle [tendency to muscle atrophy]. These changes, detectable clinically by pinch palpation, have also been quantied via ultrasounds in patients with symptomatic urinary and biliary calculosis (1, 7). Similar to the hyperalgesia, they appear only in the case of painful visceral conditions. It has been shown, however, that while the hyperalgesia tends to decrease with the progressive fading of the activity of the visceral trigger [though remaining still signicant], the trophic changes do not. Patients with symptomatic gallbladder calculosis presenting both hyperalgesia and trophic changes in the upper right abdominal quadrant [cystic point] in basal conditions were reevaluated after a period of six months, during which a subgroup of them had not complained of further colics, while another subgroup had continued to present colics. In the symptomatic subgroup, the hyperalgesia was accentuated while in the asymptomatic subgroup it diminished; in contrast, trophic changes remained unaltered in both (7). Thus, while referred hyperalgesia appears strictly modulated by the painful input from the viscera, the referred trophic changes would rather seem an on-off phenomenon. Experimental Visceral Referred Pain Visceral referred pain has been investigated not only in the clinical context, but also in experimental controlled studies in both humans and

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animal models. Human studies have been conducted in healthy volunteers by applying controlled stimuli of different nature to various internal organs (6, 1517). In these studies, the distribution of the evoked pain was characterized and the phenomenon was also shown of the enlargement of the referred areas after sensitization of the viscera due to repeated stimulation or experimental inammation of the organs [visceral hyperalgesia]. For instance, repeated lling of the urinary bladder in female volunteers progressively increased the physiological and perceptual responses to pain and the extent of the referred somatic areas (18), continuous electrical stimulation of the gut provoked a progressive enlargement of the referred pain area as the duration of the stimulation was increased from 30 to 120 seconds (15) and thermal, mechanical, and electrical stimulation of the oesophagus after chemical sensitization resulted in a signicant increase in the referred pain areas in human volunteers, a result indicating central sensitization phenomena (19, 20). Various animal models have also been set up to study referred phenomena from viscera (21). The parameter monitored has mostly been referred deep and/or supercial hyperalgesia, assessed by recording withdrawal reactions to application of mechanical and thermal stimuli or by measuring vocalization thresholds to different stimuli [mechanical, electrical], since vocalization is a highly integrated test, regarded as a reliable index of perceived pain in animals (21). Some examples are here provided. Prolonged nociceptive electrical stimulation or formation of an articial stone in one ureter in rats produces not only behavioral signs indicative of direct visceral pain but also referred hypersensitivity of the ipsilateral oblique musculature [L1], as shown by a signicant reduction of vocalization thresholds to electrical muscle stimulation. In calculosis rats, the extent of this threshold decrease is proportional to the amount of spontaneous pain behavior and is dose-dependently reduced by treatment with morphine, tramadol, metamizol, nonsteroidal anti-inammatory drugs [NSAIDs], or spasmolytics (22, 23). The combination of an articial ureteric stone with experimental emdometriosis in female rats produces particularly pronounced algogenic effects. In this model, mimicking the viscerovisceral hyperalgesia observed in women with

urinary calculosis and endometriosis, an enhancement is, in fact, observed not only of the spontaneous pain behavior from both the ureter and the reproductive area but also of the referred lumbar muscle hyperalgesia, with a post-stone decrease in vocalization thresholds to electrical muscle stimulation signicantly more pronounced than in rats with a stone only or rats with sham-endometriosis plus stone. Similar to what is observed in humans, treatment of only one condition in this model relieves symptoms from the other, i.e., treatment of endometriosis before stone formation [with NSAIDs or tramadol] prevents the enhancement of pain behavior from the ureter [ureteral crises and referred lumbar muscle hyperalgesia] (24). Experimental inammation of the bladder in rats and mice also produces referred hyperalgesia to various stimuli in the tail, caudal abdomen or hindlimb (2528). Inammation of the uterus in female rats elicits not only spontaneous pain behavior but also referred hyperalgesia in the ipsilateral ank muscles, as testied by a signicant decrease in vocalization thresholds to electrical muscle stimulation. In this model, mimicking womens pelvic inammatory pain, the areas of referred muscle hyperalgesia are also the site of neurogenic plasma extravasation in the skin, the rst experimental evidence of trophic changes in sites of referred pain from viscera (29, 30). Neurogenic plasma extravasation in L5 to S2 dermatomes [primarily in L6 and S1] has also been documented in male rats after experimental prostatitis [chemical irritation of the prostate] and in rats receiving bladder irritation (31). Chronic pancreatitis induced in rats by pancreatic infusion of trinitrobenzene sulfonic acid produces increased sensitivity to mechanical probing of the abdomen [referred hyperalgesia] in addition to increased sensitivity to noxious electrical stimulation of the pancreas (32). In the mouse, chemical stimulation of the colon evokes dose-dependent visceral pain behaviors [licking of abdomen, stretching, contractions of abdomen, etc.] and referred abdominal hyperalgesia, as shown by a signicant increase in withdrawal responses to application of von Frey hairs to the abdomen (33). Electrophysiological, pharmacological, anatomical, immunohistochemical, and genetic investigations performed on these and other animal models of visceral nociception have allowed

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several hypotheses on the pathophysiology of referred phenomena to be tested in standardized experimental contexts (22, 34, 35). Pathophysiology of Visceral Referred Pain The referral of visceral sensations to areas of the body away from the injured organ has been interpreted as the consequence of convergence of somatic and visceral afferent information onto the same sensory neurons. The brain receives information from both internal organs and somatic areas through the same sensory channel, but would attribute the origin of the sensation to the somatic domain because of mnemonic traces of previous experiences of somatic pain, more numerous in percentage than those of visceral pain in the course of life [convergence-projection theory]. The pattern of referral will be determined by the pattern of viscero-somatic convergence so that, for example, if neurons with inputs from cardiac nociceptors have receptive elds in the left thorax and left arm, then the pain will be felt in these regions of the body rather than in the heart. Considerable experimental evidence is in support of this interpretation as numerous studies have described viscero-somatic convergent neurons in the spinal cord and other regions of the CNS (34). When the nociceptive input from the affected internal organ is particularly strong, prolonged or repetitive, an irritable focus, in modern terms, a state of central sensitization, is secondarily set off in the spinal cord. This involves phenomena of increased spontaneous activity in viscero-somatic convergent neurons, an increase in neuronal response evoked by large- and smallcaliber primary afferent bers and enlarged receptive eld areas (36). Central sensitization accounts in part for the referred hyperalgesia that so often accompanies visceral pain states. With hyperactivity and hyperexcitability of viscero-somatic convergent neurons induced by the massive afferent visceral barrage, in fact, the central effect of even normal sensory inputs coming from the somatic area of referral would be facilitated [convergence-facilitation theory] (22, 34). Central sensitization has, indeed, been documented in electrophysiological studies in animal models of referred muscle hyperalgesia from viscera, such as the model of articial ureteric calculosis, in which the rats display hypersensitivity of the oblique musculature ipsilat-

eral to the implanted ureter (37), and N-methylD-aspartate receptors are assumed to play an important role in this central process (34). A similar mechanism has been hypothesized for referred hyperalgesia in the case of concurrent algogenic conditions from two internal organs sharing at least part of their central sensory projection [viscero-visceral hyperalgesia] (1). Along with viscero-somatic convergence, in fact, experimental evidence exists for viscerovisceral convergence in the CNS, e.g., between the gallbladder and heart, between colon/rectum, bladder, vagina, and uterine cervix (13, 38, 39). Thus, increased excitability of viscero-visceralsomatic convergent neurons, triggered by the afferent barrage from one visceral organ, could mediate the increased reactivity to impulses from the second visceral organ and the somatic area of referral (1, 2). Preliminary electrophysiological studies in the animal model of referred hyperalgesia from endometriosis plus ureteral calculosis have provided evidence for a higher level of sensitization of sensory neurons receiving input from the hyperalgesic muscle with respect to rats with sham endometriosis plus ureteral calculosis and rats with calculosis only (4). Further experiments are, however, needed to fully characterize the central components of referred phenomena in viscero-visceral hyperalgesia, as well as to investigate the possible contribution by other mechanisms. Central changes after noxious visceral input can also induce the release of vasoactive peptides from ne afferents in peripheral tissues not affected by the original cause, via dorsal root reexes conducted antidromically from the spinal cord (40). The central changes produced by the visceral input could thus not only be responsible per se for the secondary hyperalgesia [increased responsiveness of sensitized viscerosomatic convergent neurons to painful stimuli in the somatic area of referral], but also contribute to the phenomenon via dorsal root reexes which are conducted centrifugally out to peripheral sensory endings, where they can release neurotransmitters or alter the excitability of sensory terminals related to the referred area. The mechanisms so far described seem, however, not sufcient to explain in full the phenomena that take place in the visceral referred pain areas, especially the trophic changes which cannot be accounted for on the basis of central mechanisms only.

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Regarding the skeletal muscle, a reex arc activation has been postulated, involving sensory bers from the internal organ, as afferent branch of the reex, and somatic efferences to the skeletal muscle, as efferent branch of the reex. This hypothesis would also t with the clinical observation that the area of pain referral from viscera is often the site of sustained muscle contraction (5). The activation of somatic efferences would thus produce sustained contraction in the skeletal muscle, in turn responsible for sensitization of nociceptors locally, which could contribute to the hyperalgesia and in the long run also to the decreased thickness of the tissue. Experimental support for this theory has been provided by studies in the rat model of referred muscle hyperalgesia from articial ureteric calculosis in which positivity was found of a number of ultrastructural indices of contraction in the hyperalgesic muscle ipsilateral to the affected ureter at lumbar level but not in the contralateral, nonhyperalgesic muscle. The extent of change in these indices was proportional to the degree of visceral pain behavior and referred hyperalgesia recorded in the animals. In the same model, cFos activation was found in the spinal cord not only in sensory neurons but also in motoneurons, signicantly more on the affected side (41, 42). Reex arc activations have been claimed to be contributing mechanisms also to the skin/subcutis hyperalgesia. In this case, the efferent branch of the reex would be represented by sympathetic efferences toward the supercial somatic tissues. This hypothesis, based on the clinical observation of the reduction of referred supercial sensory changes in patients after blocking of the sympathetic efferences toward the referred area, still needs to be conrmed experimentally in standardized conditions (2, 43). The exact nature of referred trophic changes in the subcutis remains to be determined, but the fact that these tend to persist almost unaltered for a long time after cessation of the painful episodes could indicate some structural tissue alteration which is liable to become permanent in spite of resolution of the visceral condition. Since compression on the thickened tissue does not leave the typical depression of edema due to interstitial uid accumulation [fovea], it has been hypothesized that the thickening is due to an increase in solid tissue pressure that is exerted on the points of contact of the cells, bers, collagen, and intercellular gel, this pressure being an

expression of the resistance that solid structures of the tissue offer to atmospheric pressure. This augmentation in pressure would be motivated by an increase in subcutis interstitial jaluronic acid (7). Further studies on bioptic tissue samples will be needed to clarify this issue. Visceral Referred Pain as a Function of Age The aging process is associated with a lesser expression of visceral pain in general, and acute referred pain in particular. This phenomenon paradoxically occurs when an increase is observed, with advancing age, of a number of pathologic conditions that are potentially algogenic for viscera (44). Atherosclerosis, for example, increases exponentially with age but is not accompanied by a parallel increase in manifestations of ischemic pain from internal organs: silent cardiac ischemia and painless myocardial infarction become more frequent in older age (45). This phenomenon of silent or atypical presentation of ischemic heart disease makes diagnosis in the elderly more difcult. About 45 percent of older adults with appendicitis do not have referred lower right quadrant pain as a presenting symptom, compared to less than ve percent of younger adults (46). Also, visceral referred pain associated with various types of malignancy is reported to be much less intense in adults of advanced age than in younger adults (47). Studies in experimental animal models also conrm a reduction of visceral pain expression with the aging process, as shown by a decreased pain behavior in aged rats with articial ureteral calculosis with respect to young rats [unpublished observation]. The pathophysiology of the decreased expression of referred visceral pain in older age is being actively investigated, some of the contributing mechanisms may include impaired A-Delta ber function and a reduction in the content and turnover of neurotransmitter systems known to be involved in nociception [e.g., substance P or calcitonin gene-related peptide] (48). Also worth mentioning is the higher prevalence, in the elderly, of medical conditions, such as hypertension or diabetes, which has denitely been associated with an impaired pain perception (49). Thus, elderly patients affected with these conditions are at a highest risk of presenting with painless diseases

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of internal organs, a circumstance that should always be kept in mind clinically to avoid not only misdiagnosis but mostly underestimation of potentially life-threatening visceral events. CONCLUSION Referred pain and hyperalgesia from internal organs have been known for a long time clinically, but their precise assessment in patients and investigation of their pathophysiological mechanisms in standardized conditions in both human and animal models have been performed in relatively recent times. The controlled studies carried out in the past few decades have now allowed a considerable advancement in the understanding of these phenomena. Though a number of questions still remain open in the eld, such as the precise identication of mechanisms beyond viscero-visceral hyperalgesia, the information so far available represents an important basis for the institution of therapeutic regimens that are more mechanism-based and not merely symptomatic in patients affected with such an important and frequent form of suffering as visceral pain. Declaration of interest: The author reports no conict of interest. The author alone is responsible for the content and writing of this paper. REFERENCES
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