Central Sensitization in Fibromyalgia and Other Musculoskeletal Disorders

Transcription

1 Central Sensitization in Fibromyalgia and Other Musculoskeletal Disorders Lars Arendt-Nielsen, PhD* and Thomas Graven-Nielsen, PhD Address *Laboratory for Human Experimental Pain Research, Center for Sensory-Motor Interaction, Aalborg University, Fredrik Bajers Vej 7, Building D3, DK-9220 Aalborg, Denmark. Current Pain and Headache Reports 2003, 7: Current Science Inc. ISSN Copyright 2003 by Current Science Inc. Muscle hyperalgesia and referred pain play an important role in chronic musculoskeletal pain. New knowledge on the involved basic mechanisms and better methods to assess muscle pain in the clinic are needed to revise and optimize treatment regimens. Increased muscle sensitivity is manifested as pain evoked by a normally non-nociceptive stimulus (allodynia), increased pain intensity evoked by nociceptive stimuli (hyperalgesia), or increased referred pain areas with associated somatosensory changes. Some manifestations of sensitization, such as expanded referred muscle pain areas in patients with chronic musculoskeletal pain, can be explained from animal experiments showing extrasegmental spread of sensitization. An important part of the pain manifestations (eg, tenderness and referred pain) related to chronic musculoskeletal disorders may result from peripheral and central sensitization, which may play a role in the transition from acute to chronic pain. Introduction It generally is accepted that pain from deep tissues constitutes a special diagnostic and therapeutic challenge; further insights into the peripheral and central neurobiologic mechanisms are necessary to improve diagnosis and management strategies. The focus of this paper is to discuss the possible mechanisms underlying muscle pain and hyperalgesia in humans and how these mechanisms can be assessed quantitatively under experimental conditions in healthy volunteers or in patients suffering from chronic musculoskeletal pain. Paradoxically, most experimental pain research has been on cutaneous pain, although cutaneous pain is less important than deep tissue pain. In contrast to sharp, localized characteristics of cutaneous pain, muscle pain is described as aching and cramping with diffuse localization. Kellgren [1] was one of the pioneers to experimentally study the diffuse characteristics of muscle pain and the actual locations of referred pain to selective activation of specific muscle groups. Firm neurophysiologically based explanations for referred pain do not exist, but it has been shown that wide dynamic-range neurons and nociceptivespecific neurons in the spinal cord and in the brain stem receive convergent afferent input from the mucosa, skin, muscles, joints, and viscera. This may cause misinterpretation of the afferent information coming from muscle afferents and reaching higher levels in the central nervous system; therefore, it may be one reason for the diffuse and referred characteristics. The sensation of acute muscle pain is the result of activation of group-iii (Aδ-fiber) and group-iv (C-fiber) polymodal muscle nociceptors. The nociceptors can be sensitized by the release of neuropeptides from the nerve endings. This eventually may lead to central hyperexcitability of dorsal horn neurons manifested as prolonged neuronal discharges, increased responses to defined noxious stimuli, response to non-noxious stimuli, and expansion of the receptive field [2]. Therefore, it is likely that muscular hyperalgesia plays an important role for muscle pain disorders. Extensive animal experiments have supported this notion by showing that hyperexcitability of dorsal horn neurons may be a possible cause for muscular hyperalgesia and referred pain [2]. Little basic information is available in humans on the peripheral neuronal correlate of muscle nociceptor sensitization and only few microneurographic studies have been published [3,4]. This is because of difficulties in recording and directly activating the muscle nociceptors. Therefore, other more indirect, but still quantitative techniques are needed. Quantitative sensory testing may help to assess muscle pain and, hence, muscle hyperalgesia. Muscle Hyperalgesia and Referred Pain Many clinical studies report increased sensitivity to painful stimuli of deep tissues within [5 12] and outside [6 8,11,13] muscle pain areas in patients compared with control subjects. Peripheral mechanisms (sensitization of receptors) may explain deep tissue hyperalgesia; however, modulation of somatosensory sensitivity at referred sites without obvious tissue pathologies is mediated by central mechanisms. This is evident because anesthetizing the referred area does not abolish the referred muscle pain totally [14,15 ].

2 356 Fibromyalgia Referred pain has been known and described for more than a century and has been used extensively as a diagnostic tool in the clinic. Head [16] initially used the term referred tenderness and pain in Pain from deep structures such as muscles, joints, ligaments, tendons, and viscera is described typically as diffuse and difficult to locate precisely in contrast to superficial types of pain (eg, skin and mucosal pains) [2,17,18]. Thus, the perceived localization of deep pain may be different from the original source of pain. Pain located to the source of pain is termed local pain or primary pain; pain felt in a different region away from the source of pain is termed referred pain or heterotopic pain [17] (Fig. 1). A clear distinction between spread of pain and referred pain is not possible; these phenomena also may share common pathophysiologic mechanisms. A typical localization of referred pain from experimental muscle pain induced in the tibialis anterior muscle is shown in Figure 2. In addition to the distribution of experimental muscle pain, different pain intensity profiles can be obtained from various experimental models. Inman and Saunders [19] systematically investigated the distribution of referred pain in relation to the activated muscle groups. Based on their observations, it was suggested that referred pain followed the distribution of sclerotomes (muscle, fascia, and bone) more frequently than the classical dermatomes [20] (Fig. 1). The somatosensory sensitivity changes in referred pain areas have been studied thoroughly. In experimentally induced (intramuscular injection of 6% saline) referred pain areas, Kellgren [1] found tenderness to pressure; however, most of the later studies have not been able to reproduce this finding. Similarly, skin sensitivity in the referred pain area has been reported to depend on the stimulus modality tested [21 23]. Increased visual analog scale (VAS) response to electrical cutaneous stimulation and decreased sensitivity to radiant heat or pinprick stimulation have been reported in referred pain areas [21,22]. This modality-specific somatosensory change found in the referred muscle area is similar to findings in secondary hyperalgesic areas of the skin after injury (Fig. 3). Several neuroanatomic and neurophysiologic theories regarding the appearance of referred pain have been suggested, basically stating that nociceptive dorsal horn or brain stem neurons receive convergent inputs from various tissues; therefore, higher centers cannot identify the actual input source correctly. Most recently, the models have included newer theories in which sensitization of dorsal horn and brain stem neurons plays a central role. Similar sensitization may be involved in deep tissue hyperalgesia at a site distant from the pain locus. The association between referred pain and the degree of sensitization seems evident because a correlation between the degree of pain/nociception and referred pain areas are found in many studies. Peripheral sensitization Experimental findings Sensitization of muscle nociceptors may explain deep tissue hyperalgesia because this phenomenon decreases the mechanical excitation threshold and increases responses to noxious stimuli. Experimentally, this has been seen as decreased pressure pain thresholds after intramuscular injections of capsaicin [24]. Muscle hyperalgesia also can be induced by combined intramuscular injections of 5-hydroxytyramine (serotonin) and bradykinin [25]. Thus, peripheral serotonergic receptors could be involved in the regulation of musculoskeletal pain disorders. The ionotropic and metabotropic glutamate receptors are other receptor types, which are found on peripheral unmyelinated sensory afferents in the skin [26,27]. Intramuscular injections of glutamate produce muscle hyperalgesia to pressure stimuli in humans [28]. There is some evidence from behavioral studies that glutamate and substance P work synergistically to sensitize primary afferents [29]. Therefore, it is conceivable that glutamate-induced mechanical sensitization of muscle afferents may, in part, result from the actions of released neuropeptides such as substance P (Fig. 2). An experimental study [10] found increased tenderness assessed by pressure algometry, which was observed after the jaw muscle had been exposed to experimental muscle pain (hypertonic saline). Moreover, pain thresholds to intramuscular electrical stimulation are significantly lower in muscles 24 hours after they have been exposed to hypertonic saline [30]. Another model on deep tissue hyperalgesia is the soreness developed after eccentric muscle work (delayed onset of muscle soreness), with peak soreness and hyperalgesia after 24 to 48 hours [31 35] (Fig. 2). A feature of delayed onset of muscle soreness is no pain at rest; however, pain is evoked by muscle function and during palpation (ie, allodynia/hyperalgesia). An example of delayed-onset muscle soreness is deep tissue pain in wrist extensors, with characteristics similar to lateral epicondylalgia [36]. Clinical findings Mechanical stimuli have been used extensively to assess the sensitization of myofascial tissues in humans such as tender points, fibromyalgia, work-related myalgia, myofascial pain, strain injuries, myositis, chronic fatigue syndrome, arthritis/orthoses, and other muscle/tendon/ joint inflammatory conditions [37]. The most widely used technique is pressure algometry [37 39]. Pressure pain thresholds and tolerance thresholds are recorded by increasing the pressure intensity with a constant rate until the patient detects the actual threshold. Pressure algometry is recommended as one of the diagnostic procedures for the evaluation of patients with tensiontype headache (Headache Classification Committee, 1988). Methodologic concerns such as short-term and

3 Central Sensitization in Fibromyalgia Arendt-Nielsen and Graven-Nielsen 357 Figure 2. An example of normal and abnormal referred pain patterns. The normal referred pattern after a bolus injection of hypertonic saline in the anterior tibialis muscle is projected around the ankle joint. In patients with chronic musculoskeletal pain (eg, fibromyalgia), the same injection causes a highly abnormal referred pain pattern in which the pain also is seen to spread in the proximal direction. Figure 1. The pain intensity ratings related to the local and referred muscle pain after intramuscular injection of a bolus of hypertonic saline (0.5 ml, 6%) in a healthy control subject. long-term reproducibility [37 45], influence of pressure rates and muscle contraction levels [43,46,47], and examiner expectancy [48] have been addressed carefully. With proper standardization, pressure pain thresholds generally are considered to be an improvement on the manual palpation technique. Stimulus-response functions can provide more information than a threshold because sensitization to low and high intensities can be assessed. A shift in parallel towards the left together with an increased slope has been found in patients with myofascial pain [10]. After anesthetizing the muscle, the curve was shifted towards the right with reduced slope [10]. Likewise, capsaicin-induced muscular hyperalgesia in healthy control subjects produced a characteristically left-shift in the stimulus response (pressurepain curves) assessed by cuff-algometry [49]. Referred pain and central sensitization Experimental findings Referred pain likely is a combination of central processing and peripheral input because it is possible to induce referred pain to the limbs with complete sensory loss as a result of spinal injury [50] or an anesthetic block [15,51]. Figure 3. A comprehensive assessment of muscle pain includes investigation of the local pain sensitivity and an investigation of the somatosensory changes in the referred pain area. The investigation should use a multimodal sensory testing approach (tactile, thermal, electrical) to characterize possible modality-specific hypoalgesia or hyperalgesia. However, the involvement of peripheral input from the referred pain area is unclear because anesthetizing this area shows inhibitory or no effects on the referred pain intensity [14,50 54]. Central sensitization may be involved in the generation of referred pain. Animal studies show a development of new or an expansion of existing receptive fields by noxious muscle stimuli [55 57]. Recordings from a dorsal horn neuron with a receptive field located in the biceps femoris muscle show new receptive fields in the tibialis anterior muscle and at the foot after intramuscular injection of bradykinin into the tibialis anterior muscle [56]. In the context of referred pain, the unmasking of new receptive fields as a result

4 358 Fibromyalgia of central sensitization could mediate referred pain [2]. The time needed for this sensitization process may explain the delay between the appearance of local and referred pain [21]. Referred pain has been suggested to be the phenomenon of secondary hyperalgesia in deep tissue. A number of studies have found that the area of the referred pain correlated with the intensity of the muscle pain [19,54,58 61], which parallels the observations for cutaneous secondary hyperalgesia in which the hyperalgesic area is related to the capsaicin-induced pain intensity [62]. This type of plasticity of the central nervous system also may alter somatosensory sensitivity and account for deep tissue hyperalgesia. In referred areas of experimentally induced muscle pain, Kellgren [1] and Feinstein et al. [51] found tenderness to pressure, but Steinbrocker et al. [63] did not. Similarly, different findings on skin sensitivity in the referred pain area have been reported depending on the stimulus modality tested [21,22,24,51,64]. Increased VAS response to electrical cutaneous stimulation and decreased sensitivity to radiant heat stimulation have been reported in referred pain areas [21]. This modality-specific somatosensory change found in the referred muscle area is similar to findings in secondary hyperalgesic areas of the skin. The authors found hyperalgesia to pressure distal to the referred pain area produced by experimental pain induced in the tibialis anterior muscle [65]. The referred hyperalgesic area was innervated by the deep peroneal nerve, which also innervates the tibialis anterior muscle. This suggests involvement of summation between muscle afferents and the somatosensory afferents from the hyperalgesic area eventually facilitated by central sensitization (Fig. 3). Central sensitization of dorsal horn or brain stem neurons initiated by nociceptive activity from muscles may explain the expansion of pain with referral to other areas and likely hyperalgesia in these areas. However, facilitated neurons cannot 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. Moreover, the authors found that salineinduced muscle pain resulted in deep tissue hypoalgesia in extrasegmental areas (including the area of referred pain) distant from the pain focus [66,67]. Therefore, descending inhibitory mechanisms may mask any eventual increases in somatosensory sensitivity caused by experimental pain. Clinical findings Substantial clinical knowledge exists regarding the patterns of referred muscle pain from various skeletal muscles and after activation of trigger/tender points [68 70]; this aspect will not be covered further. However, relatively few clinical studies have aimed to study central sensitization in combination with chronic musculoskeletal pain. A number of recent studies have provided the first evidence of central sensitization in chronic musculoskeletal pain. In patients with fibromyalgia, intramuscular electrical stimulation has been used to assess the efficacy of temporal summation of painful muscle stimuli. Temporal summation was found to be more pronounced in the patients compared with control subjects [71]. The increased efficacy of temporal summation in patients with fibromyalgia has been reproduced with cutaneous heat stimulation [72 ]. Temporal summation of pain stimuli applied to the skin, joints, and muscles was most pronounced for muscle tissue [73], which illustrates the importance of testing the temporal summation from deep tissue (this may be affected specifically by central sensitization in musculoskeletal pain conditions). Facilitated temporal summation in patients with pain suggests that the efficacy of central processing is increased (central sensitization) in these patients. Moreover, the exaggerated temporal summation was partly inhibited by ketamine, (an N-methyl-D-aspartate antagonist) targeting central sensitization in patients with fibromyalgia [74 ]. Further evidence of central sensitization in chronic musculoskeletal pain is seen by enlarged referred pain areas. Sörensen et al. [71] found that fibromyalgic patients experienced stronger pain and larger referred areas after intramuscular injection of hypertonic saline. The most interesting aspect was that these manifestations were present in lower limb muscles in which the patients normally do not experience ongoing pain. It could be argued that the subjective pain ratings and drawings could be a result of hypervigilance, but the expanded referred pain areas in fibromyalgia patients recently have been shown to be reduced by ketamine, targeting central sensitization [74 ]. Pain from the tibialis anterior normally is projected distally to the ankle, never proximally. Substantial proximal spread of the referred areas was found in the patients. This corresponds to basic neurophysiologic experiments in rats, in which dorsal horn neuron recordings from various spinal segments were investigated before and after muscle inflammation [56]. In these experiments, the inflammation caused a proximal spread of hyperexcitability, which explains the clinical findings. Similar findings of enlarged referred pain areas from the tibialis anterior muscle has been shown in patients suffering from chronic whiplash pain [75 ]. The increased areas of referred pain were especially found in the neck/shoulder region (painful region) and in distant areas in which the patient does not normally experience pain (ie, lower leg). Central sensitization in patients with whiplash also is suggested based on increased sensitivity to intramuscular electrical stimulation of the tibialis anterior muscle compared with healthy subjects [76]. These findings could partly be a manifestation of central sensitization of second-order neurons, but suggest that more generalized pathologic mechanisms also are involved in the whiplash syndrome. One possibility that explains the widespread changes could be a decreased efficacy of endogenous pain inhibitory systems or even increased action of descending facilitatory pathways. In patients

5 Central Sensitization in Fibromyalgia Arendt-Nielsen and Graven-Nielsen 359 suffering from chronic osteoarthritic knee pain [77 ], extended areas of saline-induced referred pain has been found. This indicates that noxious joint input to the central nervous system may facilitate the referred pain mechanisms possibly resulting from central sensitization. Similarly, in patients with myofascial temporomandibular pain, enlarged pain areas were found with painful injections of hypertonic saline into the masseter muscle [78]. Enlarged referred pain areas also were found after visceral stimulation in patients with chronic visceral pain. Leffler et al. [79 ] assessed the somatosensory function in referred pain in patients with long-term trapezius myalgia. Hyperalgesia to pressure and hypoalgesia to light mechanical stimulation were found in the referred pain area, suggesting a modality or tissue-specific change of the somatosensory function similar to previous experimental findings [21]. However, in patients with lateral epicondylalgia, only hypoalgesia to light mechanical stimulation was found in the referred pain area produced by muscle contractions [79 ]. A factor that may influence the somatosensory changes is the duration of habitual pain. The patients in whom referred hyperalgesia was found on average had experienced pain for 6 years [80]; however, on average, the patients had pain for 6 months in the study and hyperalgesia was not detected [81]. Similarly, increased sensitivity to pressure in a nonpainful area was found in patients with rheumatoid arthritis who were suffering for more than 5 years in contrast to patients who experienced pain for less than 1 year [79 ]. This fits well with the concept of central sensitization because a certain period of nociceptive input is needed to induce central sensitization. Widespread pain in musculoskeletal pain disorders frequently is initiated by localized deep pain, indicating the development of central sensitization over time. Another manifestation of central sensitization may be the number of palpable trigger points. The authors found a significantly higher number of these points in lower limb muscles in patients suffering from knee osteoarthritis compared with control subjects [82]. In accord, it was found that patients with multiregional musculoskeletal pain who had a low number of trigger points showed a dysfunction of the nociceptive system that was more severe in patients with a higher number of trigger points [83]. The presence of central sensitization may facilitate low-intensity input (possibly muscle allodynia) and result in the experience of pain when a possible latent trigger point is activated. This also may be one of the reasons why a localized painful condition can spread and become generalized. Conclusions An important part of the pain manifestations (eg, tenderness and referred pain) related to chronic musculoskeletal disorders may result from peripheral and central sensitization. Better assessment of the mechanisms involved in chronic musculoskeletal pain may provide qualified clues to revise and optimize treatment regimens. Some manifestations of sensitization, such as expanded referred muscle pain areas in patients with chronic musculoskeletal pain, can be explained from animal experiments showing extrasegmental spread of sensitization. Acknowledgment The Danish National Research Foundation and the Danish Research Council are acknowledged for supporting the time spent by the authors to write this paper. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Kellgren JH: Observation on referred pain arising from muscle. Clin Sci 1938, 3: Mense S: Referral of muscle pain. 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Wright A, Graven-Nielsen T, Davies I, Arendt-Nielsen L: Temporal summation of pain from skin, muscle and joint following nociceptive ultrasonic stimulation in humans. Exp Brain Res 2002, 144: Graven-Nielsen T, Kendall SA, Henriksson KG, et al.: Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients. Pain 2000, 85: The exaggerated referred pain areas evoked by hypertonic saline and facilitated temporal summation to intramuscular electrical stimulation previously found in patients with fibromyalgia (71) was pharmacologically decreased by ketamine (an NMDA-antagonist), which targeted central sensitization. The facilitated mechanisms for referred pain and temporal summation were reduced by ketamine compared with placebo, which strongly indicates involvement of central sensitization in fibromyalgia. 75. Johansen MK, Graven-Nielsen T, Olesen AS, Arendt-Nielsen L: Generalized muscular hyperalgesia in chronic whiplash syndrome. Pain 1999, 83: Assess referred pain pattern to intramuscular infusion of hypertonic saline and the muscle sensitivity to pressure in areas within and outside the region involved in the whiplash trauma. Hyperalgesia to pressure and enlarged referred pain areas were found in patients with chronic whiplash syndrome compared with control subjects within and outside the traumatized area suggesting central sensitization. 76. Curatolo M, Petersen-Felix S, Arendt-Nielsen L, et al.: Central hypersensitivity in chronic pain after whiplash injury. Clin J Pain 2001, 17: Bajaj P, Bajaj P, Graven-Nielsen T, Arendt-Nielsen L: Osteoarthritis and its association with muscle hyperalgesia: an experimental controlled study. Pain 2001, 93: This study shows that persistent joint chronic nociceptive input can facilitate the central processing of muscle nociceptive input in humans. Muscle sensitivity and referred pain pattern were assessed in patients with knee osteoarthritis by intramuscular infusion of hypertonic saline into the tibialis anterior muscle. Increased pain intensity and enlarged pain areas were found in patients versus control subjects, suggesting involvement of central sensitization. 78. Svensson P, List T, Hector G: Analysis of stimulus-evoked pain in patients with myofascial temporomandibular pain disorders. Pain 2001, 92: Leffler AS, Kosek E, Lerndal T, et al.: Somatosensory perception and function of diffuse noxious inhibitory controls (DNIC) in patients suffering from rheumatoid arthritis. Eur J Pain 2002, 6: This study describes the influence of ongoing rheumatoid arthritic pain, with two different disease durations, on somatosensory sensitivity and descending inhibitory pain control mechanism. In addition to hyperalgesia to pressure over the painful joint, widespread hyperalgesia to pressure also was found in the patient group with the longest disease duration compared with control subjects. The descending inhibitory control of pain was not affected in any of the patient groups compared with control subjects. The widespread hyperalgesia to pressure detected in the group with long-term pain conditions indicated development of central sensitization. 80. Leffler AS: Pain influences somatosensory perception: an experimental and clinical study [PhD Thesis]. Stockholm: Karolinska Institute and Hospital; Leffler AS, Kosek E, Hansson P: The influence of pain intensity on somatosensory perception in patients suffering from subacute/chronic lateral epicondylalgia. Eur J Pain 2000, 4: Bajaj P, Bajaj P, Graven-Nielsen T, Arendt-Nielsen L: Trigger points in patients with lower limb osteoarthritis. JMusculoskel Pain 2001, 9: Carli G, Suman AL, Biasi G, Marcolongo R: Reactivity to superficial and deep stimuli in patients with chronic musculoskeletal pain. Pain 2002, 100: