Referred Muscle Pain: Basic and Clinical Findings

Acute pain and long-term pain originating from deep somatic structures represent a major part of pain complaints in many patients. Deep pain is a diagnostic and therapeutic problem, and further insights into the peripheral and central neurophysiologic mechanisms are necessary to improve diagnosis and therapy. Systematic studies of referred pain from muscles may help to reveal such mechanisms. The focus of this paper is discussion of the possible mechanisms behind pain referred from muscles. Paradoxically, a large amount of experimental pain research has been obtained from studies of cutaneous pain. Cutaneous pain varies from deep pain in many ways. Typically, it is described as a localized sharp or burning pain and is rarely (if ever) referred to other somatic structures. Conversely, deep pain often is described as a diffuse, dull pain, with frequent referral to distant sites.1 Referred pain has been known and described for more than a century, and it has been used extensively as a diagnostic tool in the clinical setting. Head2 initially used the term "referred tenderness and pain" in 1893. However, other clinicians had reported the phenomenon previously (for a review, see Bonica1). Since then, it has been used to describe pain perceived at a site adjacent to or at a distance from the site of origin. The taxonomy committee of the International Association for the Study of Pain has not defined the term; however, several authors have defined it in different ways. In this paper, we will use the definition "pain felt at a site remote from the site of origin/stimulation." Several neuroanatomic and physiologic theories regarding the appearance of referred pain have been suggested, and they state that nociceptive dorsal horn and brain stem neurons receive convergent inputs from various tissues; therefore, higher centres cannot identify correctly the actual input source. Most recently, the models have included newer theories in which plasticity of dorsal horn and brainstem neurons plays a central role. During the past decades, a systematic attempt to chart referred musculoskeletal pain areas in humans has been made.3 Some of these findings have been reproduced in experimental muscle pain studies in humans.4-15 BASIC ASPECTS Clinical versus experimental studies regarding referred pain Further basic research of all aspects of referred pain is needed to obtain a better understanding of pain pathologies related to deep somatic structures. Clinical research and, in particular, research of pain, often are confounded by many factors that make it difficult to look at specific aspects of the disease. Experimental models seem to be good alternatives. Human experimental pain research classically involves two separate topics: (1) standardized activation of the nociceptive system and (2) measurements of the evoked responses (for a review, see Arendt-Nielsen16). The ultimate goal of advanced human experimental pain research is to obtain a better understanding of mechanisms involved in pain transduction, transmission, and perception under normal and pathophysiologic conditions. Hopefully, this can give more insight regarding the mechanisms underlying referred pain and provide better characterization, prevention, and management of pain. Experimental studies are useful in basic research because they can be standardized by using healthy individuals, allow a study with few confounding factors, and studies can 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 perception that is difficult to quantify and to validate in the clinical setting. In experimental pain, the researchers have the possibility to control stimulus intensity, duration, and modality. Furthermore, the psychophysical-evoked responses can be assessed quantitatively (using, for example, visual analog scores) or qualitatively (using, for example, the McGill Pain Questionnaire). Stimulus-response relations, being of great value in, for example, pharmacologic research, can also be investigated. Disadvantages of experimental models are the short-lasting acute stimuli, which may not parallel long-term clinical pain. The psychological involvement may also be limited in experimental models; therefore, the stimuli may not mimic clinical pain sufficiently. Therefore, multimodality experimental pain stimuli may be recommended for assessment of pharmacologic interventions.16-18 A multimodal sensory test regime also should be used when hyper-/hypoalgesia is assessed in referred pain areas. Muscle pain Various methods can be used to induce experimental muscle pain. Usually, the methods are classified in two groups: (1) endogenous (without external stimuli); and (2) exogenous (external stimuli) methods.17 Human endogenous methods (e.g., ischemia and exercise) are characterized by high response rate and are suitable for studying general pain states. However, they have the disadvantage of involving several or all muscle groups within the region investigated, and often pain from other somatic tissues cannot be excluded.17,19 Finally, endogenous methods are not suitable to induce referred pain. Therefore, we will concentrate on exogenous models in this paper. Referred muscle pain using algogenic substances A number of exogenous methods have been used to induce experimental human muscle pain. The most commonly used method is intramuscular infusion of hypertonic saline (6%). Kellgren and Lewis introduced the method in 1938,20,21 and intramuscular infusion of hypertonic saline subsequently has been used extensively.4-6,11-15,22-31 A variety of parameters have been shown 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, the mechanisms responsible for the excitation of nociceptive activity shortly after the infusion are still unknown. A direct excitation of afferents because of osmotic difference has been proposed, although other mechanisms can not be excluded.32 Referred pain is felt in structures at a distance from the infusion site, and it appears with a delay of approximately 20 seconds in comparison with local pain5(Fig. 1). This referred pain is characterized as being diffuse and unpleasant.4FIG. 1: The distribution of local and referred muscle pain after continuous (10 seconds, 10 Hz) electrical stimulation of the anterior tibialis muscle in 10 healthy individuals.Infusion of hypertonic saline has several advantages. It is easy and safe to use, and it induces local and referred muscle pain in most individuals (40-85%), depending on the actual muscle of injection.4-6,11,12,14 The disadvantage of this muscle pain model is the relatively long-lasting pain (several minutes) after a bolus infusion.4,5,6,10,17,31 In recent years, more potent algogenic substances have been tested as muscle pain models. Bradykinin,33-37 serotonin,35-37 capsaicin,38-40 and substance P35-37 have been used separately or in combination to induce muscle pain. This model combining different algogenic substances has been a promising model for deep tissue hyperalgesia. One study has shown referred pain after subsequent intramuscular injections of serotonin and bradykinin was used.35 Referred muscle pain using electrical stimulation Intramuscular electrical stimulation (IMES) of muscle tissue has been used in various experimental and clinical settings. Intramuscular electrical stimulation offers an advantage in that it can induce referred muscle pain in an on-and-off manner. It is an easy method to use, and a high incidence of local (94%) and referred (78%) pain is induced.7 In our studies of IMES, we used 10-Hz stimulation for at least 10 seconds to generate referred muscle pain (Fig. 2).FIG. 2: Schematic illustration of the ongoing local and referred pain after infusion of hypertonic saline into the tibialis anterior muscle. There is a short delay between onset of local and referred pain.Intramuscular electrical stimulation has been used to assess somatosensory sensibility by determining various thresholds (e.g., of sensation and of pain). Vecchiet et al.41 found a significantly lower pain threshold in muscle, subcutis, and skin of patients with chronic fatigue syndrome in comparison with healthy controls, which indicated hypersensitivity to painful stimulation in this group of patients. In a recent study, IMES was used to evaluate the effect of ketamine on muscle pain induced using single electrical stimulation in comparison with repeated (temporal summation) electrical stimulation for patients with fibromyalgia. A significant increase in the pain summation threshold to repeated IMES was found during the ketamine infusion.42 Referred pain after IMES appears with different delays in the various studies7-10 that range from immediately after the referred pain occurs to a delay of 43 seconds on average. A difference in stimulus intensities could account for the variances of referred pain onset.7 A more consistent delay of referred pain onset is characteristic for hypertonic saline experiments.6 The reason for the difference in time delay between the two models could be due to different excitation mechanisms of the nociceptive afferents and/or because of central mechanisms (temporal summation or hyperexcitability). However, IMES has a shortcoming in comparison with hypertonic saline in that it bypasses the sensory nerve endings, which makes investigations of receptor transduction mechanisms impossible. Significantly higher stimulus intensity is necessary to elicit referred pain in comparison with local pain, and a significantly positive correlation has been found among the stimulus intensity and the local pain and referred pain intensity ratings.7 This is in accordance with previous experimental and clinical studies5,6,23,43,44 and studies that used direct intraneural electrical stimulation of muscle nociceptive afferents.38,43,45 Spatial summation is a well-described feature in many experimental pain models of cutaneous pain,46 deep pain,6,38,45 and visceral pain.47,48 The mechanism responsible for spatial summation observed most likely is an additional recruitment of nociceptor units,49 which results in an increased barrage to dorsal horn and brain-stem neurons and, consequentially, increased local pain and referred pain. Significant correlations between the size of local pain and referred pain areas and the local sensation/pain and referred sensation/pain intensity ratings have been demonstrated.7 Similar observations have been detected in studies in which sequential infusions of hypertonic saline into a muscle resulted in an increasing number of individuals experiencing referred pain and increasing areas of referred pain,5 and in which intraneural electrical stimulation of muscle afferents at a constant frequency and intensity evoked an expansion of the projected pain area over time.38 Increased nociceptive input to the dorsal horn or brainstem neurons, which generates an expansion of receptive fields,50,51 may be responsible for the expansion of referred areas detected during increased intramuscular stimulation.7 Manifestation of referred muscle pain Inman and Saunders systematically investigated the distribution of referred pain in relation to the activated muscle groups.52 Based on their observations, they suggested that referred pain followed the distribution of sclerotomes (muscle, fascia, and bone) more frequently than it followed the classical dermatomes.53 Sensory manifestations of clinical and experimental muscle pain are seen as diffuse aching pain in the muscle, pain referred to distant somatic structures, and modifications in superficial and deep tissue sensibility in the painful areas.1,6,20 These manifestations differ from cutaneous pain, which normally is superficial and localized around the injury and has a sharp and burning quality.1,4 Referred pain and sensibility changes in the painful structures have been known for many years,20,24 but the neural mechanisms responsible for these phenomena are not understood fully. Referred muscle pain probably involves a central neurobiological mechanism because it is possible to induce referred pain to limbs with complete sensory loss using an anesthetic block.24 However, the lack of peripheral input from the referred pain area seems to decrease the referred pain intensity,8 which suggests that the peripheral input from the referred pain area is involved but not a necessary condition for referred pain. Hypothetically, convergence of nociceptive afferents on dorsal horn neurons may mediate referred pain, but studies by Hoheisel and Mense54 showed a rare convergence of muscle afferents and other deep tissue afferents, such as muscle, although Sessle et al.55 showed an extensive convergence between both deep and superficial afferents in the craniofacial region. Central hyperexcitability may modulate the manifestation of referred pain. Animal studies have found a development of new receptive fields via noxious muscle stimuli.56-58 Recordings from a dorsal horn neuron with a receptive field located in the biceps femoris muscle indicated new receptive fields in the tibialis anterior muscle and in the paw after intramuscular injection of bradykinin into the tibialis anterior muscle.58 In the context of referred pain, revealing new receptive fields could be the mechanism behind referred pain because of central hyperexcitability.59 Forming of new receptive fields has been suggested to be the phenomenon of secondary hyperalgesia in deep tissue.59 Similar findings are shown in humans after intradermal injection of capsaicin in which a rapid development of central hyperexcitability (seen as secondary cutaneous hyperalgesia) is found. The time needed for revealing (in the range of seconds) may account for the time delay between local pain and the development of referred pain4 and for the increased number of individuals developing referred pain during repeated hypertonic saline infusions5 or tonic infusion.14 Several studies have found that the area of the referred pain correlated with the intensity6,7,52,60 and duration38 of the muscle pain, which parallels the observations for cutaneous secondary hyperalgesia. Chronic musculoskeletal pain has been shown to respond better to treatment using NMDA-receptor antagonists (ketamine) than to conventional morphine management,61 which indicates the role of central hyperexcitability in these patients, with the reason being that NMDA-antagonists in animal studies, in experimental studies, and in clinical studies are found to inhibit wind-up and hyperalgesia. Therefore, it is reasonable to propose that muscle pain conditions59 may evoke central hyperexcitability, which may play an important role in long-term musculoskeletal pain syndromes (e.g., whiplash62). The relation between temporal summation and central hyperexcitability may be shown by the progressive spread of pain during tonic intramuscular infusion of hypertonic saline.14 From studies on cutaneous hyperalgesia,47 central summation of nociceptive input from muscles and referred pain areas is expected to be exaggerated in musculoskeletal pain conditions if central hyperexcitability is involved. Infusions of hypertonic saline have shown larger referred pain areas in fibromyalgia patients than in controls, and also proximal referral of pain was found in the patients, but not in controls.61 This may reflect central hyperexcitability in fibromyalgia patients as hypertonic saline is infused into muscles with no clinical muscle pain.61 Moreover, the gain of temporal summation was increased in fibromyalgia patients as the pain threshold for repeated intramuscular electrical stimulation and not single stimulation was decreased in fibromyalgia patients compared to controls.61 In a recent study, a similar manifestation of enlarged referred pain areas to intramuscular injection of hypertonic saline was found in chronic pain patients after whiplash injuries.62 Preliminary data63 from temporomandibular pain patients show that such enlarged areas also can be manifested in the orofacial region. Similarly, enlarged referred pain areas also are found after visceral stimulation in patients with chronic visceral pain. Hyperalgesia related to referred muscle pain The somatosensory sensibility in the referred pain area may provide additional information about the mechanisms involved in generation of referred pain. It is accepted that muscle pain can result in hyperalgesia in the referred somatic structures. The somatosensory sensibility is affected by saline-induced muscle pain in cutaneous and deep structures in the area of local and referred pain. During saline-induced pain, the deep tissue sensibility may increase,12,24,27,64 decrease,65 or remain unaffected5 in the local and referred muscle pain area. Increased VAS response to electrical cutaneous stimulation and decreased sensibility to radiant heat stimulation have been reported in referred pain areas.5 This modality-specific somatosensory change found in the referred muscle area is similar to findings in secondary hyperalgesic areas of the skin. The mechanisms of sensibility changes may be of peripheral origin or of central origin. Infiltration of the muscle tissue by anesthetics 30 minutes after injection of hypertonic saline completely reverses the cutaneous and muscular hyperalgesia.27 The effect of a peripheral block on the hyperalgesia27 suggests that the hyperalgesia is caused by maintained peripheral input which is also a necessary condition for referred pain.5,20 Alternatively, the mechanisms responsible for deep and cutaneous hyperalgesia after muscle pain may be caused by central hyperexcitability. Central hyperexcitability of dorsal horn and brainstem neurons initiated by nociceptive activity from muscles may explain the expansion of pain with referral to other areas, and it probably also explains hyperalgesia in these areas. However, facilitated neurons do not account for the decreased sensation to certain sensory stimuli in the referred area. Descending inhibitory control of the dorsal horn neurons may explain the decreased response to additional noxious stimuli in the referred pain area. Recently, we found that saline-induced muscle pain resulted in deep-tissue hypoalgesia in extra segmental areas (including the area of referred pain) distant from the pain focus.13,66 In addition, segmental inhibition at the spinal cord or brainstem level may contribute to the decreased sensibility. Modulation of referred pain During the past century, several theories on the origin of referred pain have been suggested (see later in this paper). To illuminate possible mechanisms of referred pain, a number of case reports and experiments regarding the effect of anesthetizing the referred pain area have been published. Often, when referred visceral pain has been investigated, contradictory results have been shown. Weiss and Davies67 published the first large study. They found that patients with various diseases (e.g., angina pectoris, pleuritis, stomach ulcer, chronic cholecystitis, salpingitis, and kidney stones) experienced pain at structures (most often the skin) located at a distance from the affected organ(s), which could have been partially and, in some cases, completely abolished by infiltrating the area using a local anesthetic. Conversely, Wollard et al.68 found minor or no changes of referred pain intensity in an anesthetized skin area. Furthermore, Kellgren20 did not see a decrease in referred pain intensity when he anesthetized areas to which saline-induced muscle pain was referred. Several explanations regarding the divergent results obtained when an area of referred pain is anesthetized have been offered: (1) the variation in the number of structures (skin, subcutis, fascia, muscle, tendons, ligaments, and bone) anesthetized. This is likely a major bias because referred pain areas and, especially visceral referred pain, tend to be located in the deep tissues in which complete anesthesia of a referred pain area is difficult; (2) the duration and level of local pain; (3) the site of the local pain (skin, viscera, and deep structures); (4) whether sensory changes (hypersensitivity) occur at the referred pain site. The IMES technique recently has been used to investigate systematically the effect of anesthetizing the referred areas. In a placebo-controlled experiment,8 an eutectic mixture of local anesthetics was applied to the skin lying over the referred pain area. Reduction of the referred pain intensity by 22.7% was shown in the local anesthetic group in comparison with the placebo group. A similar result has been reported when ethyl chloride was sprayed onto the saline-induced referred pain area, which greatly reduced referred pain.69 This suggests that referred pain to some degree is dependent on spontaneous input from cutaneous receptors. Although cutaneous nociceptors do not exert resting activity,70 a reduction of activity from other skin receptors (e.g., thermal receptors and possibly low-threshold mechano-receptors) could explain the finding. To completely block all afferents from the referred pain area two techniques have been used: (1) differential nerve blocking with an inflated tourniquet between the site of stimulation and the corresponding distal referred area;9 and (2) intravenous regional analgesia (IVRA).9 Interestingly, the referred pain intensity was reduced by 40.2% while myelinated nerve fiber was which suggests that referred pain has a peripheral with myelinated nerve fiber the nerve fiber was referred pain still studies in which the input from the referred area has been completely have reported similar Therefore, seems to that referred pain, to some on an peripheral with some spontaneous mechanisms for referred pain The mechanisms responsible for referred pain referral to adjacent are not known in Several theories have been suggested and will be These theories have been for visceral pain, for muscle pain or for and, as are very The Based on the of and that from different tissues onto spinal neurons (Fig. The of this is that the nociceptive activity from the spinal cord is as originating from other structures. This could explain the segmental of referred muscle pain and the increased referred pain intensity when local muscle pain was However, it not explain the delay in the development of referred pain after local referred pain has not been shown to be a phenomenon (e.g., muscle pain in the anterior muscle pain in the part of the but the condition has not been However, muscle pain can be referred to the and pain can be referred to the muscles. Finally, the threshold for local and referred muscle pain is The different possible mechanisms of referred pain. horn neurons are shown as and the changes in the dorsal The to the in the of the is from and was also by the of and that and that input to the spinal cord an focus in the spinal cord This focus make other somatic inputs in an and, in some cases, be perceived to be referred pain. The was not because it did not visceral pain. In recent years, however, of an focus has under The somatosensory sensibility changes reported in referred pain areas could in part be by similar mechanisms in the dorsal horn and brainstem neurons and the delay in appearance of referred pain shown in various could also be because the of central may The of afferents from two different tissues has been suggested as an of referred Although of nociceptive afferents from different tissues and and and it is that these of neurons are Moreover, a time delay in the appearance of referred pain, different thresholds for local and referred muscle pain, and somatosensory sensibility changes in referred pain area cannot be by this The hyperexcitability experimental and clinical studies (see previous have some of anesthetizing the referred pain therefore, referred pain may likely not be by a central although the central is to be the most The theories lack some of the referred pain previously described in this Recently, suggested an especially from a regarding referred muscle pain, that is known as the (Fig. Recordings from a dorsal horn neuron in have that noxious stimuli to a receptive field in a muscle within minutes at a distance from the receptive The appearance of two new receptive fields could that convergent afferents on the dorsal horn neuron may be by noxious stimuli from muscle and this of convergence could as referred pain. observations from the group have shown that substance from the of afferents plays a role in the in the dorsal Furthermore, an expansion of the receptive fields proximal to the normal receptive field was found in a study in which experimental was and, of antagonists to different receptors is in the induced The of this is in with several of the of referred muscle pain on stimulus and a delay in appearance of referred pain in comparison with local pain). The proximal appearance of receptive of as referred pain, is in to the reports from a of the referred pain studies, healthy Clinical studies regarding the spread of induced referred pain in patients with whiplash syndrome and fibromyalgia have shown proximal and distal referral of In study have we seen proximal spread of referred muscle pain in a few healthy after intramuscular injection of A possible of the in these observations could be that an ongoing pain is necessary to have a barrage or to induce a state of hyperexcitability in the spinal This results in proximal and distal referral in comparison with the distal referral in healthy The hyperexcitability is on animal studies in which receptive fields within This not with the development of referred pain in which occurs within However, we that the of between dorsal horn neurons is To explain the referred pain, which could not be mechanisms that could mimic the mechanisms seen in the dorsal horn or brainstem can not be the of local and referred muscle pain is not performed in the and techniques and be possible to the underlying nociceptive responsible for referred pain in The suggested that referred pain as a summation of input from the area and the referred pain area within neurons in the and not in the spinal cord (Fig. A recent study of referred pain in that applied has shown several that on different and Referred muscle pain has some The size of referred pain is related to the intensity and duration of pain. summation is a potent mechanism for generation of referred muscle pain. Central hyperexcitability is important for the of referred pain. with chronic musculoskeletal have enlarged referred pain areas to experimental spread of referred muscle pain is seen in patients with chronic musculoskeletal pain and very seen in healthy specific somatosensory changes occur in referred areas, which the of using a multimodal sensory test regime for Human experimental pain research has new to study referred pain quantitatively in and patients. Clinical studies and pharmacologic of induced referred pain may contribute with additional information regarding the underlying mechanisms. and understanding of referred pain mechanisms and related hyperalgesia may help to and to pain management and clinical The authors The for the time to this paper, and for for

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