The Clinical Journal of Pain 17:11–19 © 2001 Lippincott Williams & Wilkins, Inc., Philadelphia Referred Muscle Pain: Basic and Clinical Findings *Lars Arendt-Nielsen, Dr.Med.Sci., Ph.D., and *†Peter Svensson, Dr.Odont, Ph.D. *Laboratory for Experimental Pain Research, Center for Sensory-Motor Interaction, Aalborg University, Aalborg, Denmark; †Department of Prosthetic Dentistry and Stomatognathic Physiology, Dental School, University of Aarhus, Aarhus, Denmark Key Words: Muscle Pain—Referred p
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  Referred Muscle Pain: Basic and Clinical Findings *Lars Arendt-Nielsen, D r . M ed . S ci ., P h . D ., and *†Peter Svensson, D r . O dont , P h . D . *Laboratory for Experimental Pain Research, Center for Sensory-Motor Interaction, Aalborg University, Aalborg, Denmark;†Department of Prosthetic Dentistry and Stomatognathic Physiology, Dental School, University of Aarhus, Aarhus, Denmark  Key Words: Muscle PainReferred painExperimentalHyperexcitability Acute pain and long-term pain srcinating from deepsomatic structures represent a major part of pain com-plaints in many patients. Deep pain is a diagnostic andtherapeutic problem, and further insights into the periph-eral and central neurophysiologic mechanisms are nec-essary to improve diagnosis and therapy. Systematicstudies of referred pain from muscles may help to revealsuch mechanisms. The focus of this paper is discussionof the possible mechanisms behind pain referred frommuscles.Paradoxically, a large amount of experimental painresearch has been obtained from studies of cutaneouspain. Cutaneous pain varies from deep pain in manyways. Typically, it is described as a localized sharp orburning pain and is rarely (if ever) referred to other so-matic structures. Conversely, deep pain often is de-scribed as a diffuse, dull pain, with frequent referral todistant sites. 1 Referred pain has been known and described for morethan a century, and it has been used extensively as adiagnostic tool in the clinical setting. Head 2 initially usedthe term “referred tenderness and pain” in 1893. How-ever, other clinicians had reported the phenomenon pre-viously (for a review, see Bonica 1 ). Since then, it hasbeen used to describe pain perceived at a site adjacent toor at a distance from the site of srcin. The taxonomycommittee of the International Association for the Studyof Pain has not defined the term; however, severalauthors have defined it in different ways. In this paper,we will use the definition “pain felt at a site remote fromthe site of srcin/stimulation.”Several neuroanatomic and physiologic theories re-garding the appearance of referred pain have been sug-gested, and they state that nociceptive dorsal horn andbrain stem neurons receive convergent inputs from vari-ous tissues; therefore, higher centres cannot identify cor-rectly the actual input source. Most recently, the modelshave included newer theories in which plasticity of dor-sal horn and brainstem neurons plays a central role. Dur-ing the past decades, a systematic attempt to chart re-ferred musculoskeletal pain areas in humans has beenmade. 3 Some of these findings have been reproduced inexperimental muscle pain studies in humans. 4–15 BASIC ASPECTSClinical versus experimental studies regardingreferred pain Further basic research of all aspects of referred pain isneeded to obtain a better understanding of pain patholo-gies related to deep somatic structures. Clinical researchand, in particular, research of pain, often are confoundedby many factors that make it difficult to look at specificaspects of the disease. Experimental models seem to begood alternatives.Human experimental pain research classically in-volves two separate topics: (1) standardized activation of the nociceptive system and (2) measurements of theevoked responses (for a review, see Arendt-Nielsen 16 ).The ultimate goal of advanced human experimental painresearch is to obtain a better understanding of mecha-nisms involved in pain transduction, transmission, and Address correspondence and reprint requests to Dr. Lars Arendt-Nielsen, Aalborg University, Center for Sensory-Motor Interaction,Laboratory for Experimental Pain Research, Fredrik Bajers Vej 7,D3, DK-9220 Aalborg, Denmark. Address electronic mail to  The Clinical Journal of Pain 17: 11–19 © 2001 Lippincott Williams & Wilkins, Inc., Philadelphia 11  perception under normal and pathophysiologic condi-tions. Hopefully, this can give more insight regarding themechanisms underlying referred pain and provide bettercharacterization, prevention, and management of pain.Experimental studies are useful in basic research becausethey can be standardized by using healthy individuals,allow a study with few confounding factors, and studiescan be performed during very standardized conditions. 16 Studies of clinical pain are limited by bias because of cognitive, emotional, and social aspects of the disease.Pain is a multidimensional and highly individualized per-ception that is difficult to quantify and to validate in theclinical setting. In experimental pain, the researchershave the possibility to control stimulus intensity, dura-tion, and modality. Furthermore, the psychophysical-evoked responses can be assessed quantitatively (using,for example, visual analog scores) or qualitatively (us-ing, for example, the McGill Pain Questionnaire). Stimu-lus-response relations, being of great value in, for ex-ample, pharmacologic research, can also be investigated.Disadvantages of experimental models are the short-lasting acute stimuli, which may not parallel long-termclinical pain. The psychological involvement may alsobe limited in experimental models; therefore, the stimulimay not mimic clinical pain sufficiently. Therefore, mul-timodality experimental pain stimuli may be recom-mended for assessment of pharmacologic interven-tions. 16 – 18 A multimodal sensory test regime also shouldbe used when hyper-/hypoalgesia is assessed in referredpain areas. Muscle pain Various methods can be used to induce experimentalmuscle pain. Usually, the methods are classified in twogroups: (1) endogenous (without external stimuli); and(2) exogenous (external stimuli) methods. 17 Human endogenous methods (e.g., ischemia and ex-ercise) are characterized by high response rate and aresuitable for studying general pain states. However, theyhave the disadvantage of involving several or all musclegroups within the region investigated, and often painfrom other somatic tissues cannot be excluded. 17,19 Fi-nally, endogenous methods are not suitable to inducereferred pain. Therefore, we will concentrate on exog-enous models in this paper. Referred muscle pain using algogenic substances A number of exogenous methods have been used toinduce experimental human muscle pain. The mostcommonly used method is intramuscular infusion of hypertonic saline (6%). Kellgren and Lewis introducedthe method in 1938, 20,21 and intramuscular infusion of hypertonic saline subsequently has been used exten-sively. 4 – 6,11 – 15,22 – 31 A variety of parameters have beenshown to correlate with the infusion of hypertonic saline(e.g., saline concentration, infusion rate and pressure,and amount of saline infused). 4,29,32 Nevertheless, themechanisms responsible for the excitation of nociceptiveactivity shortly after the infusion are still unknown. Adirect excitation of afferents because of osmotic differ-ence has been proposed, although other mechanisms cannot be excluded. 32 Referred pain is felt in structures at adistance from the infusion site, and it appears with adelay of approximately 20 seconds in comparison withlocal pain 5 (Fig. 1). This referred pain is characterized asbeing diffuse and unpleasant. 4 Infusion of hypertonic saline has several advantages. Itis easy and safe to use, and it induces local and referredmuscle pain in most individuals (40 – 85%), depending onthe actual muscle of injection. 4 – 6,11,12,14 The dis-advantage of this muscle pain model is the relativelylong-lasting pain (several minutes) after a bolusinfusion. 4,5,6,10,17,31 In recent years, more potent algogenic substances havebeen tested as muscle pain models. Bradykinin, 33 – 37 se-rotonin, 35 – 37 capsaicin, 38 – 40 and substance P 35 – 37 havebeen used separately or in combination to induce musclepain. This model combining different algogenic sub-stances has been a promising model for deep tissue hy- FIG. 1. The distribution of local and referred muscle pain aftercontinuous (10 seconds, 10 Hz) electrical stimulation of the an-terior tibialis muscle in 10 healthy individuals. ARENDT-NIELSEN AND SVENSSON 12 The Clinical Journal of Pain, Vol. 17, No. 1, 2001  peralgesia. One study has shown referred pain after sub-sequent intramuscular injections of serotonin and brady-kinin was used. 35 Referred muscle pain using electrical stimulation Intramuscular electrical stimulation (IMES) of muscletissue has been used in various experimental and clinicalsettings. Intramuscular electrical stimulation offers anadvantage in that it can induce referred muscle pain in anon-and-off manner. It is an easy method to use, and ahigh incidence of local (94%) and referred (78%) pain isinduced. 7 In our studies of IMES, we used 10-Hz stimu-lation for at least 10 seconds to generate referred musclepain (Fig. 2).Intramuscular electrical stimulation has been used toassess somatosensory sensibility by determining variousthresholds (e.g., of sensation and of pain). Vecchiet etal. 41 found a significantly lower pain threshold inmuscle, subcutis, and skin of patients with chronic fa-tigue syndrome in comparison with healthy controls,which indicated hypersensitivity to painful stimulation inthis group of patients. In a recent study, IMES was usedto evaluate the effect of ketamine on muscle pain in-duced using single electrical stimulation in comparisonwith repeated (temporal summation) electrical stimula-tion for patients with fibromyalgia. A significant increasein the pain summation threshold to repeated IMES wasfound during the ketamine infusion. 42 Referred pain after IMES appears with different de-lays in the various studies 7 – 10 that range from immedi-ately after the referred pain occurs to a delay of 43 sec-onds on average. A difference in stimulus intensitiescould account for the variances of referred pain onset. 7 Amore consistent delay of referred pain onset is charac-teristic for hypertonic saline experiments. 6 The reasonfor the difference in time delay between the two modelscould be due to different excitation mechanisms of thenociceptive afferents and/or because of central mecha-nisms (temporal summation or hyperexcitability). How-ever, IMES has a shortcoming in comparison with hy-pertonic saline in that it bypasses the sensory nerve end-ings, which makes investigations of receptor transductionmechanisms impossible.Significantly higher stimulus intensity is necessary toelicit referred pain in comparison with local pain, and asignificantly positive correlation has been found amongthe stimulus intensity and the local pain and referred painintensity ratings. 7 This is in accordance with previousexperimental and clinical studies 5,6,23,43,44 and studiesthat used direct intraneural electrical stimulation of muscle nociceptive afferents. 38,43,45 Spatial summation is a well-described feature in manyexperimental pain models of cutaneous pain, 46 deeppain, 6,38,45 and visceral pain. 47,48 The mechanism re-sponsible for spatial summation observed most likely isan additional recruitment of nociceptor units, 49 whichresults in an increased barrage to dorsal horn and brain-stem neurons and, consequentially, increased local painand referred pain.Significant correlations between the size of local painand referred pain areas and the local sensation/pain andreferred sensation/pain intensity ratings have been dem-onstrated. 7 Similar observations have been detected instudies in which sequential infusions of hypertonic salineinto a muscle resulted in an increasing number of indi-viduals experiencing referred pain and increasing areasof referred pain, 5 and in which intraneural electricalstimulation of muscle afferents at a constant frequencyand intensity evoked an expansion of the projected painarea over time. 38 Increased nociceptive input to the dor-sal horn or brainstem neurons, which generates an ex-pansion of receptive fields, 50,51 may be responsible forthe expansion of referred areas detected during increasedintramuscular stimulation. 7 Manifestation of referred muscle pain Inman and Saunders systematically investigated thedistribution of referred pain in relation to the activatedmuscle groups. 52 Based on their observations, they sug-gested that referred pain followed the distribution of sclerotomes (muscle, fascia, and bone) more frequentlythan it followed the classical dermatomes. 53 Sensory manifestations of clinical and experimentalmuscle pain are seen as diffuse aching pain in themuscle, pain referred to distant somatic structures, andmodifications in superficial and deep tissue sensibility inthe painful areas. 1,6,20 These manifestations differ fromcutaneous pain, which normally is superficial and local-ized around the injury and has a sharp and burning qual-ity. 1,4 Referred pain and sensibility changes in the pain- FIG. 2. Schematic illustration of the ongoing local and referredpain after infusion of hypertonic saline into the tibialis anteriormuscle. There is a short delay between onset of local and re-ferred pain. REFERRED MUSCLE PAIN: BASIC AND CLINICAL FINDINGS 13 The Clinical Journal of Pain, Vol. 17, No. 1, 2001  ful structures have been known for many years, 20,24 butthe neural mechanisms responsible for these phenomenaare not understood fully.Referred muscle pain probably involves a central neu-robiological mechanism because it is possible to inducereferred pain to limbs with complete sensory loss usingan anesthetic block. 24 However, the lack of peripheralinput from the referred pain area seems to decrease thereferred pain intensity, 8 which suggests that the periph-eral input from the referred pain area is involved but nota necessary condition for referred pain. Hypothetically,convergence of nociceptive afferents on dorsal horn neu-rons may mediate referred pain, but studies by Hoheiseland Mense 54 showed a rare convergence of muscle af-ferents and other deep tissue afferents, such as muscle,although Sessle et al. 55 showed an extensive conver-gence between both deep and superficial afferents in thecraniofacial region. Central hyperexcitability may modu-late the manifestation of referred pain. Animal studieshave found a development of new receptive fields vianoxious muscle stimuli. 56 – 58 Recordings from a dorsalhorn neuron with a receptive field located in the bicepsfemoris muscle indicated new receptive fields in the tibi-alis anterior muscle and in the paw after intramuscularinjection of bradykinin into the tibialis anterior muscle. 58 In the context of referred pain, revealing new receptivefields could be the mechanism behind referred pain be-cause of central hyperexcitability. 59 Forming of new re-ceptive fields has been suggested to be the phenomenonof secondary hyperalgesia in deep tissue. 59 Similar find-ings are shown in humans after intradermal injection of capsaicin in which a rapid development of central hy-perexcitability (seen as secondary cutaneous hyperalge-sia) is found. The time needed for revealing (in the rangeof seconds) may account for the time delay between localpain and the development of referred pain 4 and for theincreased number of individuals developing referred painduring repeated hypertonic saline infusions 5 or tonicinfusion. 14 Several studies have found that the area of the referredpain correlated with the intensity 6,7,52,60 and duration 38 of the muscle pain, which parallels the observations forcutaneous secondary hyperalgesia. Chronic musculoskel-etal pain has been shown to respond better to treatmentusing NMDA-receptor antagonists (ketamine) than toconventional morphine management, 61 which indicatesthe role of central hyperexcitability in these patients,with the reason being that NMDA-antagonists in animalstudies, in experimental studies, and in clinical studiesare found to inhibit wind-up and hyperalgesia. Therefore,it is reasonable to propose that muscle pain conditions 59 may evoke central hyperexcitability, which may play animportant role in long-term musculoskeletal pain syn-dromes (e.g., whiplash 62 ). The relation between temporalsummation and central hyperexcitability may be shownby the progressive spread of pain during tonic intramus-cular infusion of hypertonic saline. 14 From studies oncutaneous hyperalgesia, 47 central summation of nocicep-tive input from muscles and referred pain areas is ex-pected to be exaggerated in musculoskeletal pain condi-tions if central hyperexcitability is involved. Infusions of hypertonic saline have shown larger referred pain areasin fibromyalgia patients than in controls, and also proxi-mal referral of pain was found in the patients, but not incontrols. 61 This may reflect central hyperexcitability infibromyalgia patients as hypertonic saline is infused intomuscles with no clinical muscle pain. 61 Moreover, thegain of temporal summation was increased in fibromy-algia patients as the pain threshold for repeated intramus-cular electrical stimulation and not single stimulationwas decreased in fibromyalgia patients compared to con-trols. 61 In a recent study, a similar manifestation of enlargedreferred pain areas to intramuscular injection of hyper-tonic saline was found in chronic pain patients afterwhiplash injuries. 62 Preliminary data 63 from temporo-mandibular pain patients show that such enlarged areasalso can be manifested in the orofacial region. Similarly,enlarged referred pain areas also are found after visceralstimulation in patients with chronic visceral pain. Hyperalgesia related to referred muscle pain The somatosensory sensibility in the referred pain areamay provide additional information about the mecha-nisms involved in generation of referred pain. It is ac-cepted that muscle pain can result in hyperalgesia in thereferred somatic structures.The somatosensory sensibility is affected by saline-induced muscle pain in cutaneous and deep structures inthe area of local and referred pain. During saline-inducedpain, the deep tissue sensibility may increase, 12,24,27,64 decrease, 65 or remain unaffected 5 in the local and re-ferred muscle pain area.Increased VAS response to electrical cutaneous stimu-lation and decreased sensibility to radiant heat stimula-tion have been reported in referred pain areas. 5 This mo-dality-specific somatosensory change found in the re-ferred muscle area is similar to findings in secondaryhyperalgesic areas of the skin.The mechanisms of sensibility changes may be of pe-ripheral srcin or of central srcin. Infiltration of themuscle tissue by anesthetics 30 minutes after injection of hypertonic saline completely reverses the cutaneous andmuscular hyperalgesia. 27 The effect of a peripheral block on the hyperalgesia 27 suggests that the hyperalgesia is ARENDT-NIELSEN AND SVENSSON 14 The Clinical Journal of Pain, Vol. 17, No. 1, 2001
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