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J Muscoskeletal Pain Downloaded from by Prof. Maria Adele Giamberardino on 01/01/11 For personal use only.

Visceral Referred Pain
Maria Adele Giamberardino Giannapia Affaitati Raffaele Costantini

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 superficial 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 significantly enhanced [“viscero-visceral hyperalgesia”]. In this case, treatment of one visceral condition significantly 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 reflexes 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 difficult in the elderly, increasing the risks in life-threatening conditions. Some of the contributing mechanisms may include age-related impaired A-Delta fiber 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. D’Annunzio” Foundation, Department of Medicine and Science of Aging, “G. D’Annunzio” University of Chieti, Chieti, Italy. Raffaele Costantini, Institute of Surgical Pathology, “G. D’Annunzio” 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: Journal of Musculoskeletal Pain, Vol. 18(4), 2010 Available online at © 2010 Informa Healthcare USA, Inc. All rights reserved. doi: 10.3109/10582452.2010.502624


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). which varies and is organ-specific. True visceral pain is always transitory. 5–7). On the whole. are only a few examples of this variegated reality (1). after which the phase of referral occurs. increases with their repetition. IBS. for example. Visceral referred pain is. with a threshold decrease indicating hyperalgesia. Clinical Presentation of Visceral Referred Pain The very first phase of painful episodes from internal organs is similar in any visceral pain condition: a vague and poorly defined sensation felt at the midline. Henry Head [1893] labelled this phenomenon “referred pain. In urinary calculosis. abdominal pain from irritable bowel syndrome [IBS]. Hyperalgesia is already detectable after a few visceral pain episodes. The profile of referred hyperalgesia has been assessed by using these different procedures in patients with different pathologies of internal organs.e. starting in the skeletal muscle layer. only appears in the case of painful visceral diseases. and in 90 percent of the cases persists for months–years after elimination of the urinary stone (10). the mechanisms behind visceral referred pain are fundamentally the same whatever the viscus in question. Maria Adele Giamberardino on 01/01/11 For personal use only. For muscle and subcutis. together with a reduction of cutaneous electrical pain thresholds and muscle pressure pain thresholds in the referred J Muscoskeletal Pain Downloaded from informahealthcare. gallbladder disease. For skin. . based on the findings of clinical and experimental studies in the field. lowest abdominal quadrants for the reproductive organs. accompanied by marked neurovegetative reactions and emotional signs [true visceral pain] (4). 3). Clinical manoeuvres reveal the hypersensitivity in an “on-off” manner. vigorous pain reaction by the subject upon firm manual compression of the muscle tissue.404 JOURNAL OF MUSCULOSKELETAL PAIN INTRODUCTION Pain originating in internal organs is amongst the most frequent forms of pain experienced by individuals in the course of life. 2. urinary calculosis. left chest area/arm/forearm for the heart.g. lumbar region/flank for the urinary tract. in fact. especially in women. Patients with acute appendicitis show increased ratings to pinprick and thermal stimuli. and endometriosis (5. This paper is intended to highlight the clinical profile of referred pain from viscera and its current interpretation. for instance. the results of these studies indicate that referred visceral hyperalgesia. and outlasts not only the spontaneous pain but often also the presence of the primary pain trigger in the internal organ. Visceral pain has the distinctive feature of being perceived in areas of the body located at a distance from the diseased organs. upper right abdominal quadrant for the biliary tract. scratching of a needle point over an area of altered dermographic reactivity of the skin. is accentuated in extent by the repetition of the episodes. Instrumental procedures involve pain threshold measurement to different stimuli. While the patterns of referral vary from organ to organ. perceived in somatic areas of the body wall located in the same neuromeric field as the organ in question. lumbar muscle hyperalgesia appears soon after the first one or two colics. The hyperalgesia can be detected by clinical means and precisely quantified instrumentally. independently of their organic or dysfunctional nature. dysmenorrhea. coronary artery disease. electrical [impulses delivered through needle electrodes]. e. lasting from minutes to hours. and chemical [injections of algogenic substances of progressively increasing concentrations] stimuli are usually employed..” a painful sensation reported in a region other than that in which the noxious stimulation takes place. Cardiac pain from coronary heart disease. mechanical [pressure and pinch algometer]. is detectable between the painful episodes. In acute inflammatory visceral by Prof. Secondary hyperalgesia [increased sensitivity to painful stimuli/decreased pain threshold] most often takes place in the referred areas. as are the rules to be applied when interpreting the various modalities of its clinical presentation (2. 7–10). mostly involving the skeletal muscle layer. i. the referred hyperalgesia tends to also involve the superficial somatic tissues. pinch palpation of the subcutis. or pelvic pain from the reproductive area. thermal stimulation [thermal algometer] is also used in addition to mechanical [von Frey hairs] and electrical [impulses delivered through surface electrodes] stimuli (1.. urinary and biliary colics from calculosis.

Thus. the hypersensitivity appears normalized after cholecystectomy (12). urinary colic pain. The electrical and pressure pain thresholds are lower in the referred pain area in patients compared with the same area in healthy controls (11). rather than isolated acute episodes. .Giamberardino et al. has been shown to significantly improve typical symptoms from the other. With the notable rise in life expectancy in the past hundred years. Experimental Visceral Referred Pain Visceral referred pain has been investigated not only in the clinical context. due to which the patient experiences an enhancement of both spontaneous referred pain and referred hyperalgesia (2). that while the hyperalgesia tends to decrease with the progressive fading of the activity of the visceral trigger [though remaining still significant]. Similar to the hyperalgesia. during which a subgroup of them had not complained of further colics. If the affected viscera share at least part of their central sensory projection. have also been quantified via ultrasounds in patients with symptomatic urinary and biliary calculosis (1. are needed to leave persistent hyperalgesic traces in the referred area. as in colics. These consist of an increased thickness of the subcutaneous tissue and a decreased thickness of the muscle [tendency to muscle atrophy]. present significantly more anginal attacks. 4. the referred trophic changes would rather seem an on-off phenomenon. A decrease has also been shown of urinary pain/referred lumbar hyperalgesia after hormonal treatment of dysmenorrhea or laser treatment of endometriosis. 9). the hyperalgesia was accentuated while in the asymptomatic subgroup it diminished. 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. Patients with concomitant coronary heart disease and gallbladder calculosis. however. 14). the trophic changes do not. These changes. a different finding from the above-reported results on the persistence of some degree of hyperalgesia after stone elimination in urinary colics. with respect to one condition only (9. “Viscerovisceral hyperalgesia” has important therapeutic implications. not only does hyperalgesia take place but trophic changes are also frequently observed. It has been shown. 7). heat. Maria Adele Giamberardino on 01/01/11 For personal use only. and single and repeated cutaneous electrical stimulation in the referred pain area and in the contralateral control area of the abdomen. while another subgroup had continued to present colics. 405 abdominal pain area [McBurney’s point] versus the contralateral control area. In the areas of referred visceral pain. and somatic abdomino-pelvic/lumbar hyperalgesia [in the areas of referred pain from the uterus and from the urinary tract]. and somatic abdominal/pelvic hyperalgesia [in the areas of referral from the uterus and from the intestine] than dysmenorrhea or IBS only (2. trophic changes remained unaltered in both (7). in contrast. This outcome probably indicates that repeated painful visceral inputs. but also in experimental controlled studies in both humans and J Muscoskeletal Pain Downloaded from informahealthcare. while hormonal treatment of dysmenorrhea reduces referred pain and hyperalgesia from IBS (4). as well as a decrease in menstrual pain and referred abdomino-pelvic hyperalgesia after urinary stone elimination following lithotripsy (1. In acute cholecystitis patients show hypersensitivity to pinprick. In the symptomatic subgroup. detectable clinically by pinch palpation. effective treatment of one condition. patients with dysmenorrhea/endometriosis combined with urinary calculosis [common projection between uterus and upper urinary tract: T10-L1] have increased menstrual pain. the so-called phenomenon of “viscero-visceral hyperalgesia” may take by Prof. it is increasingly common in clinics for a patient to present with more than one visceral pain condition simultaneously. pressure. 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. for instance. cold. a reduction of IBS symptoms with appropriate diet has also been shown to improve spontaneous pain and referred hyperalgesia from dysmenorrhea. Similarly. Women with dysmenorrhea plus IBS [common projection between uterus and colon: T10-L1] have more menstrual pain. Similarly. while referred hyperalgesia appears strictly modulated by the painful input from the viscera. they appear only in the case of painful visceral conditions. 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. intestinal pain. 14). 13). However. in fact.

mimicking women’s pelvic inflammatory pain. a result indicating central sensitization phenomena (19. as shown by a significant increase in withdrawal responses to application of von Frey hairs to the abdomen (33). 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). Electrophysiological. the first experimental evidence of trophic changes in sites of referred pain from viscera (29. Inflammation of the uterus in female rats elicits not only spontaneous pain behavior but also referred hyperalgesia in the ipsilateral flank muscles. assessed by recording withdrawal reactions to application of mechanical and thermal stimuli or by measuring vocalization thresholds to different stimuli [mechanical. etc. 30). in fact. immunohistochemical. Experimental inflammation of the bladder in rats and mice also produces referred hyperalgesia to various stimuli in the tail. . 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). electrical]. 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). 15–17). with a post-stone decrease in vocalization thresholds to electrical muscle stimulation significantly more pronounced than in rats with a stone only or rats with sham-endometriosis plus stone.406 JOURNAL OF MUSCULOSKELETAL PAIN animal models. Human studies have been conducted in healthy volunteers by applying controlled stimuli of different nature to various internal organs (6. regarded as a reliable index of perceived pain in animals (21). 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 inflammation of the organs [“visceral hyperalgesia”]. For instance. as shown by a significant reduction of vocalization thresholds to electrical muscle stimulation.. Various animal models have also been set up to study referred phenomena from viscera (21). The combination of an artificial ureteric stone with experimental emdometriosis in female rats produces particularly pronounced algogenic effects. the areas of referred muscle hyperalgesia are also the site of neurogenic plasma extravasation in the skin. caudal abdomen or hindlimb (25–28). Similar to what is observed in humans. Prolonged nociceptive electrical stimulation or formation of an artificial 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]. In these studies. In calculosis rats. as testified by a significant decrease in vocalization thresholds to electrical muscle stimulation.e. and genetic investigations performed on these and other animal models of visceral nociception have allowed J Muscoskeletal Pain Downloaded from informahealthcare. anatomical. or spasmolytics (22. tramadol. mechanical. mimicking the “viscerovisceral hyperalgesia” observed in women with urinary calculosis and endometriosis. and electrical stimulation of the oesophagus after chemical sensitization resulted in a significant increase in the referred pain areas in human volunteers. repeated filling 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).com by Prof. an enhancement is. In this model. In the mouse. 20). i. Maria Adele Giamberardino on 01/01/11 For personal use only. observed not only of the spontaneous pain behavior from both the ureter and the reproductive area but also of the referred lumbar muscle hyperalgesia. nonsteroidal anti-inflammatory drugs [NSAIDs]. treatment of only one condition in this model relieves symptoms from the other. 23). The parameter monitored has mostly been referred deep and/or superficial hyperalgesia. contractions of abdomen. metamizol. the extent of this threshold decrease is proportional to the amount of spontaneous pain behavior and is dose-dependently reduced by treatment with morphine. Some examples are here provided. In this model. stretching.] and referred abdominal hyperalgesia. pharmacological. 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. since vocalization is a highly integrated test. chemical stimulation of the colon evokes dose-dependent visceral pain behaviors [licking of abdomen.

J Muscoskeletal Pain Downloaded from informahealthcare. 34. 39). needed to fully characterize the central components of referred phenomena in viscero-visceral hyperalgesia. Along with viscero-somatic convergence. This involves phenomena of increased spontaneous activity in viscero-somatic convergent neurons. When the nociceptive input from the affected internal organ is particularly strong. The mechanisms so far described seem. and N-methylD-aspartate receptors are assumed to play an important role in this central process (34). 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 central effect of even normal sensory inputs coming from the somatic area of referral would be facilitated [convergence-facilitation theory] (22. for example. Maria Adele Giamberardino on 01/01/11 For personal use only.” in modern terms.and smallcaliber primary afferent fibers and enlarged receptive field areas (36). especially the trophic changes which cannot be accounted for on the basis of central mechanisms only.. indeed. 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). then the pain will be felt in these regions of the body rather than in the heart. where they can release neurotransmitters or alter the excitability of sensory terminals related to the referred area. such as the model of artificial ureteric calculosis. 34). triggered by the afferent barrage from one visceral organ. “Central sensitization” accounts in part for the referred hyperalgesia that so often accompanies visceral pain states. bladder. increased excitability of viscero-visceralsomatic convergent by Prof. Thus. 407 several hypotheses on the pathophysiology of referred phenomena to be tested in standardized experimental contexts (22. via dorsal root reflexes 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]. Central sensitization has. an “irritable focus. prolonged or repetitive. however. not sufficient to explain in full the phenomena that take place in the visceral referred pain areas. however. 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). With hyperactivity and hyperexcitability of viscero-somatic convergent neurons induced by the massive afferent visceral barrage. experimental evidence exists for viscerovisceral convergence in the CNS. 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). as well as to investigate the possible contribution by other mechanisms. a state of “central sensitization”. .Giamberardino et al. 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. but also contribute to the phenomenon via dorsal root reflexes which are conducted centrifugally out to peripheral sensory endings. The brain receives information from both internal organs and somatic areas through the same sensory channel. and uterine cervix (13. could mediate the increased reactivity to impulses from the second visceral organ and the somatic area of referral (1. if neurons with inputs from cardiac nociceptors have receptive fields in the left thorax and left arm. an increase in neuronal response evoked by large. is secondarily set off in the spinal cord. vagina. between the gallbladder and heart. Central changes after noxious visceral input can also induce the release of vasoactive peptides from fine afferents in peripheral tissues not affected by the original cause. The pattern of referral will be determined by the pattern of viscero-somatic convergence so that. in which the rats display hypersensitivity of the oblique musculature ipsilat- eral to the implanted ureter (37). between colon/rectum. Further experiments are.g. 38. in fact. 35). 2). in fact. e. been documented in electrophysiological studies in animal models of referred muscle hyperalgesia from viscera.

Studies in experimental animal models also confirm a reduction of visceral pain expression with the aging process. with advancing age. This hypothesis would also fit 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. as efferent branch of the reflex. in turn responsible for sensitization of nociceptors locally. substance P or calcitonin gene-related peptide] (48). cFos activation was found in the spinal cord not only in sensory neurons but also in motoneurons. involving sensory fibers from the internal organ. . as shown by a decreased pain behavior in aged rats with artificial ureteral calculosis with respect to young rats [unpublished observation]. Reflex arc activations have been claimed to be contributing mechanisms also to the skin/subcutis hyperalgesia. The pathophysiology of the decreased expression of referred visceral pain in older age is being actively investigated. fibers. nonhyperalgesic muscle. compared to less than five percent of younger adults (46). for example. some of the contributing mechanisms may include impaired A-Delta fiber function and a reduction in the content and turnover of neurotransmitter systems known to be involved in nociception [e. In the same model. In this case. This phenomenon of silent or atypical presentation of ischemic heart disease makes diagnosis in the elderly more difficult. and somatic efferences to the skeletal muscle. This phenomenon paradoxically occurs when an increase is observed. collagen. in the elderly. a reflex arc activation has been postulated. this pressure being an expression of the resistance that solid structures of the tissue offer to atmospheric pressure. Atherosclerosis. 43). Also. Also worth mentioning is the higher prevalence. which could contribute to the hyperalgesia and in the long run also to the decreased thickness of the tissue. 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. and acute referred pain in particular.. The exact nature of referred trophic changes in the subcutis remains to be determined. This augmentation in pressure would be motivated by an increase in subcutis interstitial jaluronic acid (7). About 45 percent of older adults with appendicitis do not have referred lower right quadrant pain as a presenting symptom. Visceral Referred Pain as a Function of Age The aging process is associated with a lesser expression of visceral pain in general. which has definitely been associated with an impaired pain perception (49). based on the clinical observation of the reduction of referred superficial sensory changes in patients after blocking of the sympathetic efferences toward the referred area. the efferent branch of the reflex would be represented by sympathetic efferences toward the superficial somatic tissues. Experimental support for this theory has been provided by studies in the rat model of referred muscle hyperalgesia from artificial 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. of medical conditions. and intercellular gel. 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). This hypothesis. 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). of a number of pathologic conditions that are potentially algogenic for viscera (44). 42).g. 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 by Prof. Further studies on bioptic tissue samples will be needed to clarify this issue. significantly more on the affected side (41. Since compression on the thickened tissue does not leave the typical depression of edema due to interstitial fluid accumulation [“fovea”]. elderly patients affected with these conditions are at a highest risk of presenting with painless diseases J Muscoskeletal Pain Downloaded from informahealthcare. as afferent branch of the reflex. Thus. such as hypertension or diabetes. The extent of change in these indices was proportional to the degree of visceral pain behavior and referred hyperalgesia recorded in the animals. still needs to be confirmed experimentally in standardized conditions (2. Maria Adele Giamberardino on 01/01/11 For personal use only.408 JOURNAL OF MUSCULOSKELETAL PAIN Regarding the skeletal muscle.

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