Central Sensitisation in Fibromyalgia and Other Musculoskeletal Disorders
Lars Arendt-Nielsen
& Thomas Graven-Nielsen
Laboratory for Human Experimental Pain Research
Center for Sensory-Motor Interaction - Department of Health Sciences
and Technology - Aalborg University - Denmark
Abstract
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 optimise treatment regimes. Increased muscle sensitivity is manifested as 1) pain evoked by a normally non-nociceptive stimulus (allodynia), 2) increased pain intensity evoked by nociceptive stimuli (hyperalgesia), or 3) increased referred pain areas with associated somatosensory changes. Some manifestations of sensitisation, such as expanded referred muscle pain areas in chronic musculoskeletal pain patients, can be explained from animal experiments showing extra-segmental spread of sensitisation. An important part of the pain manifestations (e.g., tenderness and referred pain) related to chronic musculoskeletal disorders may be due to peripheral and central sensitisation which play a role in the transition from acute to chronic pain.
Introduction
It is generally accepted that pain from deep tissues constitutes a special diagnostic and therapeutic challenge, and further insights into the peripheral and central neurobiological 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 far 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 study experimentally 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 as well as nociceptive specific 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 and, hence, be one reason for the diffuse and referred characteristics.
The sensation of acute muscle pain is the result of activation of group III (A‰-fibre) and group IV (C-fibre) polymodal muscle nociceptors. The nociceptors can be sensitised by release of neuropeptides from the nerve endings. This may eventually 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 most 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) .
In humans little basic information is available on the peripheral neuronal correlate of muscle nociceptor sensitisation and only a few microneurographic studies have been published (3,4) . The reason is difficulties in recording and directly activating the muscle nociceptors. Other more indirect but still quantitative techniques are therefore needed, and 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, 6, 7, 8, 9, 10, 11, 12) and outside (6, 7, 8, 11, 13) muscle pain areas in patients compared to controls. Peripheral mechanisms (sensitisation of receptors) may explain deep tissue hyperalgesia whereas modulation of somatosensory sensitivity at referred sites without obvious tissue pathologies is mediated by central mechanisms. This is evident, as anaesthetizing the referred area does not abolish totally the referred muscle pain (14,15) .
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 initially used the term referred tenderness and pain in 1893 (16) .
Pain from deep structures such as muscle, joints, ligaments, tendons and viscera, is typically described as diffuse and difficult to locate precisely in contrast to superficial types of pain, e.g., skin and mucosal pains (2,17,18) . Thus the perceived localization of deep pain may be dif-ferent from the original source of pain. Pain located at the source is termed local pain or primary pain whereas pain felt in a different region away from the source of pain is termed referred pain or heterotopic pain (17) . A clear distinction between spread of pain and referred pain is not possible at the moment, and these phenomena may also share common pathophysiological mechanisms. A typical localization of referred pain from experimental muscle pain induced in the tibialis anterior muscle is to ankle. Aside from the distribution of experimental muscle pain, different pain-intensity profiles can be obtained from various experimental models. Inman and Saunders (19) investigated systematically 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) .
The somatosensory sensitivity changes in referred pain areas have been thoroughly stud-ied. In experimentally-induced (intramuscular injection of 6% saline) referred pain areas Kellgren 1 found tenderness to pressure, but not all later studies have been able to reproduce this finding. Similarly, skin sensitivity in the referred pain area has been reported to depend on the stimulus modality tested (21,22,23) . Increased 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.
Several neuroanatomical and neurophysiological theories regarding the appearance of referred pain have been suggested, and basically they state that nociceptive dorsal horn or brain stem neurons receive convergent inputs from various tissues, thus higher centres cannot identify correctly the actual input source. Most recently the models have included newer theories where sensitisation of dorsal horn and brainstem neurons play a central role. Similar sensitisation might be involved in deep tissue hyperalgesia at a site distant from the pain locus. The association between referred pain and degree of sensitisation seems evident as correlation between degree of pain/nociception and referred pain areas are found in many studies.
Peripheral sensitisation
Experimental findings
Sensitisation of muscle nociceptors might explain deep tissue hyperalgesia as this phenomenon decreases the mechanical excita-tion threshold and increases responses to noxious stimuli. Experimentally, this has been seen as a decreased pressure pain thresholds after intramuscular injections of capsaicin (24) . Muscle hyperalgesia can also be induced with combined intramuscular injections of 5-HT and BK (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 behavioural studies that glutamate and substance P work synergistically to sensitise primary afferents (29) . Therefore, it is conceivable that glutamate-induced mechanical sensitisation of muscle afferents may, in part, result from the actions of released neuropeptides such as substance P.
An experimental study (10) found that increased tenderness assessed by pressure algometry 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) .
|
Clinical findings
Mechanical stimuli have been used exten-sively to assess the sensitisation of myofascial tissues in humans such as tender points, fibromyalgia, work-related myalgia, myofacial pain, strain injuries, myositis, chronic fatigue syndrome, arthritis/orthroses, and other mus-cle/tendon/joint inflammatory conditions (for review see (37) ).
The most widely used technique is pressure algometry (37,38,39) . 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 actually recommended as one of the diagnostic procedures for evaluation of patients with tension-type headache (Headache Classification Committee 1988). Methodological concerns like short-term and long-term reproducibility (37,40,41,42,43,44,45) , influence of pressure rates and muscle contraction levels (43,46,47) , and examiner expectancy (48) have all been addressed carefully. Provided proper standardization, pressure pain thresholds are generally considered an improvement on the manual palpation technique.
Stimulus-response functions can provide more information than just a threshold as sensitisation. Both low and high intensities can be assessed, and a parallel shift towards left together with an increased slope has been found in patients with myofacial pain (10) . After anaesthetizing the muscle, the curve shifted towards right with reduced slope (10) . Likewise a clinical study, capsaicin-induced muscular hyperalgesia in healthy subjects produce a characteristical left-shift in the stimulus-response (pressure-pain) curves assessed by cuff-algometry (49) .
Referred pain and central sensitisation
Experimental findings
Referred pain is probably a combination of central processing and peripheral input as it is possible to induce referred pain to limbs with complete sensory loss due to spinal injury (50) or an anaesthetic block (15,51) . However, the involvement of peripheral input from the referred pain area is not clear as anaesthetizing this area shows inhibitory or no effects on the referred pain intensity (14,50,52,53,54) . Central sensitisation may be involved in the generation of referred pain. Animal studies show a development of new and/or expansion of existing receptive fields by noxious muscle stimuli (55,56,57) . 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 i.m. injection of bradykinin into the tibialis anterior muscle (56) . In the context of referred pain, the unmasking of new receptive fields due to central sensitisation could mediate referred pain (2) . The time needed for this sensitisation process might explain the delay between 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 (19,54,58,59,60,61) , which parallels the observations for cutaneous secondary hyperalgesia where the hyperalgesic area is related to the capsaicin-induced pain intensity (62) . This type of plasticity of the central nervous system may also 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. Recently, we 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 peroneous nerve, which also innervates the tibialis anterior muscle. This suggests involvement of summation between muscle afferents and the somatosensory afferents from the hyperalgesic area eventual facilitated by central sensitisation.
Central sensitisation of dorsal horn or brainstem neurons initiated by nociceptive activity from muscles may explain the expansion of pain that refers to other areas and may also explain 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, we found that saline-induced muscle pain resulted in deep tissue hypoalgesia in extrasegmental areas (including the area of referred pain) distant from the pain focus (66,67) . Descending inhibitory mechanisms might, therefore, mask any eventual increase in somatosensory sensitivity caused by experimental pain.
Clinical findings
Substantial clinical knowledge exists concerning the patterns of referred muscle pain from various skeletal muscles and after activation of trigger/tender points (68,69,70) , and this aspect will not be covered further. Relatively few clinical studies have, however, aimed to study central sensitisation in combination with chronic musculoskeletal pain.
|
A number of recent studies have provided the first evidence of central sensitisation in chronic musculoskeletal pain. In fibromyalgia patients, intramuscular electrical stimulation has been used to assess the efficacy of temporal summation of painful muscle stimuli, and temporal summation was more pronounced in the patients compared with control subjects (71) . The increased efficacy of temporal summation in fibromyalgia patients has been reproduced with cutaneous heat stimulation (72) . Interestingly, temporal summation of pain stimuli applied to skin, joint and muscle was most pronounced for muscle tissue (73) . This illustrates the importance of testing the temporal summation from deep tissue as this might specifically be affected by central sensitisation in musculoskeletal pain conditions. Facilitated temporal summation in pain patients suggest that the efficacy of central processing is increased (central sensitisation) in these patients. Moreover, in fibromyalgia patients the exaggerated temporal summation was partly inhibited by ketamine (an NMDA-antagonist) targeting central sensitisation (74) . See figure 1.
Further evidence of central sensitisation in chronic musculoskeletal pain is seen by enlarged referred pain areas. Sörensen et al. (71) found that fibromyalgia patients experienced stronger pain and larger referred areas after intramuscular injection of hypertonic saline. The most interesting aspect was the fact that these manifestations were present in lower limb muscles where the patients normally did not experience ongoing pain. One could argue that the subjective pain ratings and drawings could be a result of hyper vigilance, but the expanded referred pain areas in fibromyalgia patients have recently been shown to be reduced by ketamine targeting central sensitisation (74) . Normally pain from the tibialis anterior is projected distally to the ankle and never proximally. In fibromyalgia patients substantial proximal spread of the referred areas was found. This corresponds to basic neurophysiological experiments in rats, where dorsal horn neurone 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 have been shown in patients suffering from chronic whiplash pain (75) . The increased areas of referred pain were found both in the neck/shoulder region (painful region) and in distant areas in which the patient does not normally experience pain (i.e., lower leg). Central sensitisation in whiplash patients is also suggested based on increased sensitivity to intramuscular electrical stimulation of the tibialis anterior muscle compared to healthy subjects (76) . These findings could, in part, be a manifestation of central sensitisation of second order neurons, but they suggest that more generalized pathological mechanisms are also involved in the whiplash syndrome. One possible explanation for the wide spread changes could be a decreased efficacy of endogenous pain inhibitory systems or even increased action of descending facilitatory pathways. In patients suffering from chronic ostereoarthritic knee pain (77) extended areas of saline-induced referred pain have been found. This indicates that noxious joint input to the central nervous system may facilitate the referred pain mechanisms possibly due to central sensitisation. 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 were also found after visceral stimulation in patients with chronic visceral pain.
Leffler et al. (79) assessed the somatosensory function in referred pain in long-term trapezius myalgic patients. 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 might influence the somatosensory changes is the duration of habitual pain. The patients with referred hyperalgesia had experienced pain for 6 years (80) on average, whereas, in the study where hyperalgesia was not detected (81) , the patients experienced pain for 6 months on average. Similarly, increased sensitivity to pressure in a non-painful area was found in rheumatoid arthritis patients suffering more than 5 years in contrast to patients with pain less than 1 year (79) . This fits well with the concept of central sensitisation, as a certain period of nociceptive input is needed to induce central sensitisation. Interestingly, widespread pain in musculoskeletal pain disorders is frequently initiated by localized deep pain indicating that central sensitisation developped over time.
Another manifestation of central sensitisation may be the number of palpable trigger points. Recently, we found a significantly higher number of these points in lower limb muscles in patients suffering from knee osteoarthritis compared to controls (82) . In accord, multi-regional musculoskeletal pain patients with a low number of trigger points showed a dysfunction of the nociceptive system that was more severe with a higher number of trigger points (83) . The presence of central sensitisation may facilitate low intensity input (could be muscle allodynia) and, hence, result in the experience of pain when a possible latent trigger point is activated. This may also be one of the reasons why a localized painful condition can spread and become generalized.
Conclusion
An important part of the pain manifesta-tions (e.g., tenderness and referred pain) related to chronic musculoskeletal disorders may be due to peripheral and central sensitisation. Better assessment of the mechanisms involved in chronic musculoskeletal pain may provide qualified clues to revise and optimise treatment regimes. Some manifestations of sensitisation, such as expanded referred muscle pain areas in chronic musculoskeletal pain patients, can be explained from animal experiments showing extra-segmental spread of sensitisation.
Acknowledgement
The Danish National Research Foundation and the Danish Research Council are acknowledged for supporting the time spent by the authors to write this paper.
