Musculoskeletal pain is an extensive societal challenge, due to the large population affected, an increased expected life span, and the lack of efficient prevention and treatment modalities. Globally, approx. 1.3 billion cases of musculoskeletal disorders were reported in the Global Burden of Disease Study 2017, with a higher point prevalence in women than in men, and 95% of prevalent cases were disorders frequently associated with pain such as low back pain (LBP), neck pain, osteoarthritis, rheumatoid arthritis, and other rheumatologic conditions.197 As a condition, it represents a major source of socioeconomic burden due to increased healthcare utilisation and lost productivity, not to mention the distress caused for patients and relatives. Information regarding peripheral and central neurophysiological mechanisms is essential to improve diagnosis and therapy. A major knowledge gap is the mechanistic interplay in the transition from acute to chronic clinical pain, and from phasic (seconds) and tonic (minutes) pain to long-term pain (days/weeks) in experimental conditions. The overarching theory is that musculoskeletal pain mechanisms are facilitated because of the continuous peripheral nociceptive barrage, and neuroplastic manifestations may cause a change in symptomatology from localised pain and hyperalgesia to expanded pain areas with widespread hyperalgesia.
Based on the clinical manifestations of musculoskeletal pain, the aim of this review was to present the translational aspects of deep-tissue nociception, the unique distribution of musculoskeletal pain and hyperalgesia, disturbed antinociceptive and pronociceptive modulatory mechanisms, and adaptations of cortical circuitry in musculoskeletal pain. The translational findings are outlined with emphasis on provoking and probing the pain system in human experimental and clinical settings (Fig. 1). Although important for musculoskeletal pain, psychological and motor control aspects are not within the scope of this review.
1.1. Clinical manifestations of musculoskeletal pain
Musculoskeletal pain is frequently expressed as a tight, drilling, diffuse, and radiating sensation with pain referrals away from the pain origin, as well as localised and widespread deep-tissue hyperalgesia.76,77,160 Deep-tissue pain is therefore difficult to distinguish among pain from various tissues such as muscle, bones, tendons, ligaments, and joints. Nonetheless, joint pain is often more localised than myalgia, and bone pain is frequently worse at night but less affected by movements in contrast to, for example, myalgia and joint pain. Deep-tissue hyperalgesia and especially referred pain are unique characteristics for musculoskeletal pain. Clinical cases with referred pain can be patients with hip osteoarthritis presenting with pain referred to the thigh or knee joint, cervical spondylosis may give referred pain to arm muscles, and lateral elbow pain is sometimes referred from the shoulder region in cases with tendinitis of the supraspinatus muscle. There is often a discrepancy between the degree of tissue damage and the pain intensity, for example, significant joint degeneration in osteoarthritis is not necessarily painful in all patients,61 illustrating that other mechanisms are likely in play. Musculoskeletal pain is categorised as localised, regional, or widespread. Localised pain is found in, e.g., joint pain such as patellofemoral or osteoarthritis pain, whereas localised tenderness and referred pain caused by active myofascial trigger points in the myofascial pain syndrome is an example of a regional muscle pain. Examples of widespread musculoskeletal pain are, for example, fibromyalgia and whiplash-associated disorders.
Musculoskeletal pain is defined as nociceptive, and recently, the nociplastic category was instated which may include the widespread musculoskeletal pain conditions where a pain origin cannot be determined. Neuropathic conditions affecting deeper structures are often neglected, although the German Research Network on Neuropathic Pain includes 1 parameter assessing the deep-tissue pain sensitivity.194 A major challenge is to classify musculoskeletal pain with nociceptive, neuropathic, and nociplastic mechanistic characteristics.215
1.2. Translational findings on deep-tissue nociception
Free nerve endings located around vascular structures and in connective tissue are the basic construct for muscle nociceptors. Polymodal muscle nociceptors related with group III and IV (Aδ and C) afferent nerve fibres can be predominately excited by strong (noxious) mechanical or chemical stimulation, and this is presumably associated with perception of acute muscle pain.161
Provocation of experimental muscle pain in humans has been standardised over the past years. Using physiological stimuli such as exercise or ischemia will endogenously induce muscle pain, whereas external stimuli (eg, injection of algesic substances or intramuscular electrical stimulation) may be used to target specific tissues in a more intensive manner. Pressure stimulation is frequently used to induce deep-tissue pain and to assess the pain sensitivity. Manual pressure algometry (Fig. 2A) has been validated, although its variability can be reduced by computer-controlled pressure stimulation, which also allows better standardisation of suprapain threshold (eg, tolerance) assessments and establishing stimulus-response functions.85 Cuff algometry is a user-independent alternative to pressure algometry compensating for the limited amount of tissue strained and the manual rate of pressure application in manual pressure algometry (Fig. 2B). Using cuff algometry, the pain intensity is related to the computer-controlled inflated pressure in a tourniquet mounted around an extremity.191 This approach is superior for stimulating deeper tissue than, for example, single-point pressure algometry,146 and the user-independent cuff algometry demonstrates good to excellent reliability.86 Cuff algometry has also been translated to preclinical settings where the firing rates of deep dorsal horn wide-dynamic-range neurons were recorded in rats during inflation of the cuff to a comparable pressure intensity as inducing pain in humans (Fig. 2D).47 Generally, the pressure pain sensitivity is higher in women compared with men86,221 and decreases with age for pressure algometry,221 whereas it increases for cuff algometry probably because of the larger volume assessed.86
Tonic conditions of experimental muscle pain for several minutes can be induced by intramuscular injections of algesic substances (eg, hypertonic saline). Strong excitation of group III and IV muscle afferent nerve fibres by intramuscular injection of hypertonic saline was demonstrated in animals in contrast to similar stimulations of the thick, fast afferent fibres32 as well as strong excitation of dorsal horn neurons.97 Other examples of algesic substances relevant for provocation of tonic muscle pain include acidic buffers, glutamate, capsaicin, and bradykinin shown to excite thin muscle afferent fibres in animal studies; for review ref. 76. Kellgren initiated in the late 1930s case studies on muscle pain distribution by injection of hypertonic saline,115 which later were followed by larger studies,53,76,79–81,84,102,120,207 and also with other substances. For instance, intramuscular injection of capsaicin induced an intense pain sensation,16,17,39,40,82,193,226,227,259,261,263 which also was used in case studies using microneurography to verify excitation of thin muscle nerve fibres in humans.148 Similarly, tonic pain by glutamate injections has been extensively used.4,16,31,33,34,60,214,236 Moreover, intramuscular infusion of acidic buffered solutions induce pain, although with low to moderate intensity,57,66,260 and interestingly, in animal studies, repeated injections of acidic saline have shown bilateral hyperalgesia.224 Heated isotonic saline injected into muscle tissue may also induce pain.78,193 Although not consistent, some algesic-induced tonic muscle pain models (eg, glutamate) provoke more pain in women compared with men.34,76
1.2.2. Joint and bone
Group II to IV afferent nerves fibres (Aβ, Aδ, and C fibres) innervate the joint.204 All joint structures are generally innervated by free nerve endings (group III and IV), although not the cartilage. In ligaments and in the fibrous capsule, corpuscular endings related to group II fibres have been found. In humans, excitation of joint nociceptors can be performed by arthroscopic mechanical stimulations,55 electrical needle stimulation,104 or focused ultrasound stimulation.267 Inflammation and triggering of autoimmune reactions are however counterindicative of intra-articular stimulation of joint nociceptors in human trials. However, external pressure stimulation has been used for assessing differences in pain sensitivity across the joint structure.14 Other modalities for exciting joint nociceptors in humans include, for example, intradiscal pressure provocation,206 external facet joint pressure stimulation,216 electrical facet joint stimulation,175 and infrapatellar fat pad injections of hypertonic saline.27,111
Fundamental mechanisms in bone pain studied by Mantyh et al. showed that mineralised bone, periosteum, and marrow are innervated by thin afferent sensory fibres.145,147 The most densely innervated tissue is the periosteum, whereas the bone marrow holds the largest number of sensory fibres. In the bone marrow, nociceptors respond to high intraosseous pressure.168 In humans, an immediate sharp pain with the highest pain sensitivity was found with direct stimulation of the periosteum compared with similar stimulations of fascia, tendon, and ligaments, and muscle as the least sensitive.101 In line with this, stimulating the surface of the human periosteum by injection of hypertonic saline elicits more pain than intramuscular injections.79 Mechanical impact stimulation has also been used for induction of experimental bone pain in humans.62
1.2.3. Connective tissue
In animal connective tissue such as tendon and fascia, innervation of nerve endings of group III and IV afferents has been reported.9,239 In the animal thoracolumbar fascia, location of calcitonin gene-related peptide and substance P-containing free nerve endings illustrate that the outer part is densely innervated. Similar findings were made in a human study239 suggesting the relevance of fascia in LBP conditions. Electrophysiological studies of thin sensory afferent fibres in fascia have reported responses to heat, mechanical, and chemical nociceptive stimulations.238
Experimental pain provocation techniques directed toward tendon, fascia, and ligaments have been targeted in experimental human pain studies.73,74,101,115,180,205,223 Compared with saline-induced muscle pain, the saline-induced pain in ligaments and tendon showed more excessive pain.72,101 Interestingly, saline-induced muscle pain was less intense compared with similar injections of hypertonic saline in fascia.73 In line with this, hypertonic saline injected into the tendon–bone junction induced more pain compared with in the tendon and muscle belly,72 and differences among the pain sensitivity between different tendons have also been shown.102 Nerve growth factor (NGF) injections into facia compared with muscle caused more long-term hyperalgesia.48,262 These differences in pain sensitivity between various types of connective tissues challenge the notion of clinical muscle pain per se because it likely has many constituents.
1.3. Unique pain distribution of musculoskeletal pain
Referred pain is defined as pain perceived at a distant site or adjacent to the origin of localised pain, although the localised pain is not necessarily perceived. A challenge with the referred pain concept is the manifestations of pain spreading to a larger region; in such cases, local pain is fused with the referred pain, but this does not exclude involvement of the central mechanism for pain referral. Referred pain from deep tissue is often felt in other deep structures, which is a contrast to visceral pain referral, which is felt both deep and/or superficially. Referred pain has mainly been studied when provoked from muscle tissue,76 but tendon and ligaments may also induce large pain areas likely accommodating referred pain54,72,102; in particular, injection of hypertonic saline into the long posterior sacroiliac ligament induced large referred pain areas perceived in the low back and down to the lower leg (Fig. 3A).180
Interesting studies have demonstrated that it is possible to perceive referred pain from areas with a completely effective regional anaesthetic block when stimulating outside the blocked region.135 Such findings suggest that a central mechanism is likely involved in the perception of referred pain. Nonetheless, the peripheral sensory information transmitted from the referred pain area might have a role in the intensity of referred pain because it is either reduced or unaffected when referred pain is induced in an area that is completely numb.76
A likely mechanism for pain referral relates to sensitisation and the synaptic connections of dorsal horn neurons.95 Afferent fibres from, for example, different muscles have functional synaptic connections with dorsal horn neurons and latent synaptic connections to other neurons within the same region of the spinal cord.95 The latent synaptic connections become active after persistent and strong noxious input, and this may allow convergence of input from more than one source. Several features of referred pain may support the above mechanism based on latent synaptic connections. For instance, there is a correlation between the muscle pain intensity and area of referred pain, there is a delay in the appearance of referred pain (approx. 20-40 seconds) from perception of local muscle pain,76 and the frequency of referred pain is higher after prolonged mechanical painful stimulation compared with a brief mechanical painful stimulation at the same intensity.72 Such manifestations could indicate a time-dependent mechanism for referred pain such as unmasking of latent synaptic connections.95 Interestingly, the frequency of referred pain was significantly reduced in healthy participants treated with ketamine (an N-methyl-d-aspartate receptor antagonist targeting sensitisation) compared with opioid and placebo treatment,208 again suggesting involvement of sensitisation of a central mechanism.
The classical demonstration of referred pain is performed by saline-induced pain in the brachioradialis muscle causing referred pain to the wrist (Fig. 3B), likewise from the tibialis anterior muscle to the ankle (Fig. 3C), and from the infraspinatus muscle to the shoulder (Fig. 4A).76 Tonic pressure pain stimulation on the tibialis anterior muscle90 or the infraspinatus muscle (Fig. 4B and C)53 has demonstrated similar pain referral patterns to the ankle as well as shoulder and arm, respectively. Remarkably, assessing the referred pain area after 1 day with a long-term muscle pain model resulted in enlarged pain areas (Fig. 4D), supporting the involvement of sensitisation (due to long-term pain) in the mechanism of referred pain.53,90. Recent studies have also shown that asymptomatic participants, who have had a painful joint-related trauma or fracture, have larger referred pain areas directing towards the previously injured but now asymptomatic joint (Fig. 4E),51,52,179 and this may indicate a mechanism underlying ’memory’ in the spatial mapping of pain.
Clinically, pain referral patterns after trigger point activation in patients with myofascial pain have been thoroughly mapped.219 There is notable similarity between pain referral patterns after trigger point activation (palpation) in the tibialis anterior muscle or the brachioradialis muscle in patients with myofascial pain and after intramuscular injection of hypertonic saline in muscles without trigger points,76 indicating that referred pain is a normal finding in healthy participants, whereas the development of trigger points in patients is pathological.
Compared with healthy control participants, several chronic musculoskeletal pain groups (eg, LBP, osteoarthritis, fibromyalgia, and whiplash-associated disorders) show enlarged referred pain areas after saline-induced pain in the tibialis anterior muscle.19,120,176,228 The pressure-induced referred pain from the infraspinatus muscle53 may be more applicable in clinical settings, and with this approach, expanded pain areas were recently demonstrated in patients with whiplash-associated disorders compared with controls.43 Expanded saline-induced referred pain areas in patients with chronic musculoskeletal pain may suggest sensitisation of the referred pain mechanism, and interestingly, the enlargement of referred pain was reduced by ketamine in patients with fibromyalgia.81
1.4. Hyperalgesia in musculoskeletal pain
1.4.1. Localised hyperalgesia
Trauma is frequently associated with localised soreness because of release of multiple endogenous substances sensitising deep-tissue nociceptors.159 Sensitised deep-tissue nociceptors cause an increased response to mechanical noxious stimuli (hyperalgesia) and/or decreased excitation thresholds (allodynia) for mechanical stimulation. Hyperalgesia and allodynia have not been mechanistically separated within musculoskeletal pain research, and in this review, hyperalgesia will unify both concepts.
Short-term deep-tissue hyperalgesia has been induced by injection of capsaicin and glutamate, whereas saline-induced pain does not.76 To mimic the clinical persistent pain conditions better, we have developed new models provoking pain and hyperalgesia for several days up to 10 to 15 days. Using eccentric muscle training (lengthening muscle contractions) will typically induce hyperalgesia and low to moderate pain during function with a maximum pain intensity appearing 1 to 2 days after the exercise.53,73,153,193,222,269 Animal studies have found that intramuscular endogenous NGF may be fundamental for the delayed-onset muscle soreness induced by eccentric training.166,247 Intramuscular NGF injections do not excite dorsal horn neurons but rather subthreshold excitatory potentials and sensitisation after 1 day, which is opposite to the effects of intramuscular injections of hypertonic saline,97,237 and hyperexcitability of dorsal horn neurons is more pronounced after 2 NGF injections.96 This is in line with findings in human studies where intramuscular NGF injections do not provoke immediate pain at injection but rather hyperalgesia and pain the subsequent days, and often repeated NGF injections are used for this prolonged pain model (Fig. 5).4,5,7,28,36,45,46,59,68,90,122,152,153,170,199,209,213,229,230,234,235,257,262,269 Similarly, injection of NGF into the infrapatellar fat did not evoke pain at injection but rather hyperalgesia after 1 day.165 More intense NGF-induced muscle pain and hyperalgesia have been reported in women compared with men, and expression of N-methyl-D-aspartate receptors on peripheral nerve fibres may partly explain the long-term hyperalgesia and pain, particularly in women.4,5,266
A clinical example of localised hyperalgesia is myofascial trigger points in patients with myofascial pain where discrete sites of hyperalgesic loci are found by palpation in taut bands of muscle fibres.160 Quantifying the pressure pain sensitivity above trigger points may be performed by pressure algometry. However, the coexistence of hyperalgesic trigger points assessed by palpation and pressure algometry is generally poor.8 Subsequently, we have developed pressure algometry methods mimicking pressure palpation by adding rotation and vibration to the pressure probe during pressure stimulation, demonstrating a better detection of deep-tissue hyperalgesia.1
Hyperalgesia assessed by pressure algometry across painful structures is regularly reported, for example, in patients with painful knee and hip osteoarthritis compared with asymptomatic controls14,87,103,188 as well as in patients with patellofemoral pain,99,100 LBP,156 neck pain,42 and lateral epicondylalgia.163,222 Detailed analysis of multiple pressure pain assessment sites around the osteoarthritis knee joint demonstrates that not all sites are equally hyperalgesic and interestingly not clearly correlated to MRI-verified synovitis.188 After intra-articular injection of analgesia and steroid into the osteoarthritic knee, the peripatellar pressure hyperalgesia was reduced.110 By contrast, by provoking pain in the infrapatellar fat pad by injecting hypertonic saline, hyperalgesia was found around the knee in patients already receiving osteoarthritic pain relief by intra-articular analgesia and steroid,111 as well as in healthy participants.108 These findings suggest a clear link between ongoing local pain processes and the localised hyperalgesia. The degree of peripatellar pressure hyperalgesia in patients with osteoarthritis was associated with the severity of knee pain,14,87,188 suggesting that the pressure stimulation targets the clinically sensitised structures or perhaps more likely that facilitated central mechanisms (eg, spatial summation) result in hyperalgesia also in tissue not directly affected by the disease.
1.4.2. Spreading and widespread hyperalgesia
Hyperalgesia to pressure outside a painful locus has been demonstrated in conditions where there is no reason to believe that systemic sensitisation of peripheral nociceptors has occurred. In patients with knee and hip osteoarthritic pain compared with control participants, pain thresholds assessed by pressure algometry were reduced at the lower leg and on the arm (ie, distant from the painful joint).14,87,103,131 Similarly, cuff algometry used to record the cuff pressure pain thresholds on the legs in patients with knee and hip osteoarthritis showed hyperalgesia compared with asymptomatic controls.87,103,184 Interestingly, the distant hyperalgesia is not normalised when patients with osteoarthritis still have pain even after a revision total knee replacement220 in contrast to the normalisation seen in patients who experience a significant pain reduction after total knee replacement.87 Spreading hyperalgesia has also been reported in several other conditions, for example, patients with patello-femoral pain,99,100 LBP,156,176 neck pain,42 lateral epicondylalgia,106,163 and partly in the recovery phase from a tibial fracture.134 In systemic rheumatologic diseases such as rheumatoid arthritis, pressure pain thresholds are reduced in patients compared with controls, both at the painful joint and occasionally outside.109,136,144
The spreading hyperalgesia and its temporal characteristics suggest that central mechanisms are sensitised by the nociceptive drive from the painful structure. The spreading hyperalgesia may require pain over a longer time because 10 minutes of electrical stimulation of the lumbar facet joints did not cause any distant pressure hyperalgesia,175 whereas it was found after 2 days with exercise-induced LBP in healthy controls158 and during the pain flare, but not without, in patients with recurrent LBP.156 In NGF-induced long-term pain models, spreading hyperalgesia outside the injection site has also been shown 1 day or more after the NGF injection.7,90,229,262
Compared with asymptomatic controls, widespread hyperalgesia assessed by manual pressure algometry at different body sites is found in patients with fibromyalgia69,70,75,228 and whiplash pain.43,114,120,231 Cuff algometry studies have demonstrated similar hyperalgesic findings in patients with chronic widespread pain.58,75,107,138 Here, the aetiology is less understood, but mechanisms other than sensitisation of central mechanisms due to a peripheral nociceptive drive are assumed.
1.5. Pronociceptive modulatory mechanisms in musculoskeletal pain
Modulatory pain mechanisms acting pronociceptively or antinociceptively can be assessed by dynamic sensory testing of deep structures. The outcome is less affected by baseline pain sensitivity because the resulting parameter is a relative effect within the same individual.
Temporal summation of pain (TSP) is a pronociceptive mechanism, with wind-up of dorsal neuronal activity as the assumed spinal correlate and assessed as the amount of pain increase when repeating phasic noxious stimulation with the same intensity but sufficiently fast. This has been assessed extensively by heat, laser, pinprick, and electrical stimulation on the skin. The first attempt to study TSP in deep tissue was performed by fast repeated intramuscular injections of hypertonic saline inducing progressively increasing pain.80 Later, electrical stimulation using intramuscular needle electrodes was used where the pain perception for 1 stimulation was lower compared with, for example, 5 stimulations of the same intensity.13,81 Computer-controlled single-point pressure stimulation repeated 10 times (eg, 1-second stimulation and 1-second pause) provokes a progressive increase in the perceived pain intensity compared with the first stimuli and with a slower repetition protocol.2,170 Using the advantage of stimulating a large tissue volume (ie, reducing variability), repeated cuff stimulations can also be used to assess TSP (Fig. 2C) with a higher degree of TSP in women compared with men.86,142
1.5.1. Facilitated summation of pain in patients with musculoskeletal pain
Enhanced TSP suggests a facilitated central integrative mechanism. Assessing the span in pain thresholds to single and repeated intramuscular electrical stimulations demonstrated facilitated TSP in patients with fibromyalgia compared with controls, and this facilitation was normalised by low-dose ketamine.81 Similarly, in patients with fibromyalgia and whiplash, the electrical threshold evoking the withdrawal reflex to sequential stimulation on the skin is lower compared with controls, indicating a facilitated central mechanism.21
Temporal summation of pain after repeated pressure stimulation to the knee and lower leg was facilitated in patients with knee osteoarthritis compared with controls and even more facilitated in patients with high clinical pain scores compared with moderate pain scores.14 Using cuff algometry at the legs, facilitated TSP compared with asymptomatic controls has been demonstrated, for example, in patients with knee131,184 and hip103 osteoarthritic pain, in adolescents with patellofemoral pain,99 in young females with chronic patellofemoral pain and those who recovered from adolescent patellofemoral pain,100 during the pain flare in patients with recurrent LBP,156 and in patients with fibromyalgia.75 Moreover, increased TSP was reported in patients with neck pain and LBP with radiating pain patterns compared with localised pain patterns253 and in patients with osteoarthritis undergoing a revision total knee replacement with postoperative pain compared with similar patients without postoperative pain.220 In a meta-analysis across 27 LBP studies, we found facilitated TSP assessed with various modalities, although without differences between acute/recurrent and chronic pain conditions.157 Nonetheless, increased TSP was associated with longer symptom duration in axial spondyloarthritis164 and knee osteoarthritis,14 suggesting that the sensitisation is a time-dependent process. Interestingly, a human model of experimental knee pain (saline-induced pain in the infrapatellar fat pad) caused facilitated TSP to repeated pressure stimulation applied locally and to knee-related muscles.108 Overall, most studies suggest that facilitated TSP is a state phenomenon, as also found in patients with recurrent LBP where facilitated temporal summation is found during a pain flare and not in a pain-free period.156
Spatial summation of musculoskeletal pain has been studied by relating the difference in pain thresholds with different sized pressure stimulation probes171 and inflation of 1 vs 2 cuffs.191 The cuff-induced spatial summation of pain was higher in women compared with men,137 and in patients with knee osteoarthritic pain, spatial summation of pain assessed on the lower leg was facilitated compared with pain-free controls and this was normalised after total knee replacement.87 In line with this, facilitated spatial summation assessed on the arm with cuff algometry has been found in patients with lateral epicondylalgia.106
1.5.2. Musculoskeletal pain summation as a predictor for pain progression
A high degree of TSP assessed by manual pinprick stimulation before total knee joint replacement was associated with the postoperative (12 months) pain intensity185,189 and similarly was found in another study when cuff algometry-assessed TSP was combined with other central pain mechanisms assessed at baseline.186 Moreover, in patients with osteoarthritis, facilitated TSP recorded at baseline was associated with less analgesia after treatment with nonsteroidal anti-inflammatory drugs11 combined with paracetamol.187 In other pain interventions, facilitated TSP at pretreatment was associated with poor outcomes. For example, facilitated TSP at baseline in adolescents with patellofemoral pain was associated with less improvement in pain intensity after several weeks of activity (sport) modification.99 Furthermore, pain management by physical activity in LBP resulted in pain flares in patients with baseline facilitated TSP.254 The predictive value of TSP can also be found in experimental studies. Exercise-induced LBP inducing moderate pain for several days did not facilitate the TSP when assessed on the legs, but interestingly, the baseline degree of TSP was associated with the pain intensity of the experimentally induced LBP158 and similarly when provoking long-term pain in the calf muscle.127
In summary, summation of pain often assessed distant to the pain locus is generally facilitated in musculoskeletal pain conditions compared with asymptomatic controls or compared with pain-free periods in the same individuals, suggesting that this is a state of the pain system, although with an important prognostic value for pain persistence and treatment outcome. However, the TSP may also hold some trait characteristics of the pain system because it also predicts the degree of experimental long-term pain conditions in otherwise asymptomatic controls.
1.6. Antinociceptive modulatory mechanisms in musculoskeletal pain
Contrasting pronociceptive mechanisms, conditioned pain modulation and exercise-induced hypoalgesia have antinociceptive descending modulatory characteristics, and if dysfunctional, spinal mechanisms may become hyperexcitable causing, for example, widespread hyperalgesia.
1.6.1. Antinociceptive effects on musculoskeletal pain sensitivity
Based on animal work, the term diffuse noxious inhibitory control (DNIC) was originally used to describe an inhibitory spino–bulbar–spinal loop where noxious stimulation of an extremity led to reduced firing of dorsal horn wide-dynamic-range neurons in response to concurrent noxious stimulation of a heterotopic site.26 The perceptual correlate of DNIC may in part be assessed by the psychophysical protocol, conditioned pain modulation (CPM), where a painful test stimulus is applied before and during or immediately after a painful conditioning stimulus applied heterotopically to the test stimulus.192,268 The CPM effect is the decreased pain perception of the test stimulus (or the increase in pain threshold) because of the conditioning stimulus. The descending control is under strong cortical influence22,178 and factors such as distraction, expectation, anxiety, and emotional states may affect the CPM magnitude, and therefore, DNIC is only a partial reflection of CPM. There is a wealth of preclinical studies on the descending pain modulatory systems,23,24,129 describing its function and pharmacology mainly within neuropathic pain and only few on musculoskeletal pain models.
The descending inhibitory effect on musculoskeletal pain perception has been studied with different test stimulus modalities (often pressure or cuff algometry), and the conditioning stimulus is typically a tonic mechanical stimulus (eg, pressure) or the cold-pressor stimulus (ie, ice water). In a cohort study with approx. 2000 participants, pressure pain thresholds were increased compared with baseline when applying the cold-pressor test as conditioning, although approx. 10% of participants did not show a reduction of pressure pain thresholds.221 The CPM effect was higher in women than men,221 which may link with the higher prevalence of musculoskeletal pain in women. A user-independent methodology for musculoskeletal CPM assessment is available, where cuff algometry on the test leg is used to record cuff pain thresholds (test stimulus) and on the contralateral extremity another cuff is automatically inflated providing a painful conditioning during which the cuff algometry on the test leg is repeated (Fig. 6A).83 We have recently demonstrated the translational value of cuff algometry for CPM assessment where the response of deep dorsal horn wide-dynamic-range neurons to cuff stimulation was reduced when applying a contralateral noxious cuff conditioning (Fig. 6B and C).47 Methodological parameters regarding the CPM assessments by cuff algometry have been studied demonstrating fair reliability83 and robustness of fast repetitions of the CPM assessment92 as well as effects of stress and attention.93,94 A meta-analysis showed that the intersession reliability for CPM assessments was fair when using pressure modalities for both test and conditioning173 and similarly was reported in a systematic review.116
1.6.2. Reduced antinociceptive effects in patients with musculoskeletal pain
A reduced CPM effect has been reported in a meta-analysis across different groups of patients with chronic pain compared with controls.139 In another meta-analysis, CPM was impaired in patients with LBP compared with controls, and the magnitude of impairment was higher in patients with chronic vs acute/recurrent LBP.157 Moreover, reduced CPM was found in patients with knee87 and hip124 osteoarthritis compared with controls, in patients with knee osteoarthritis undergoing a revision total knee replacement with postoperative pain compared with patients without postoperative pain,220 as well as in patients with fibromyalgia123 and whiplash-associated disorder compared with controls.43,169 By contrast, several studies have not demonstrated a significant reduced CPM effect in patients with osteoarthritic pain.103,131,185,186 Using cuff algometry for CPM assessment in other patients with musculoskeletal pain, impaired CPM was found in adolescents with patellofemoral pain compared with controls,99 in young females with chronic patellofemoral pain compared with those who recovered from adolescent patellofemoral pain,100 and in patients with recurrent LBP in periods with and without pain compared with controls.156 Fair to say, other musculoskeletal pain conditions have reported mixed CPM effects, for example, in patients with temporomandibular disorder pain.125,177 In an animal model of osteoarthritis, the descending inhibitory control was not affected in the early phase but rather attenuated in the late stage of osteoarthritis,143 which seems to mimic some of the clinical findings. However, in a cancer bone pain model, the descending control was impaired in the early phase and normalised in the later phase.128
Mixed effects have been reported on the effects of treatment on CPM. A meta-analysis showed no significant change in CPM before and after treatment in patients with knee osteoarthritis, although the degree of CPM normalisation was correlated with the treatment-related pain reduction.174 By contrast, a meta-analysis showed CPM improvement by physical therapy in patients with chronic musculoskeletal pain.18 Thus, the musculoskeletal nociceptive drive may maintain the impaired descending inhibitory control, and an efficient treatment of the nociceptive drive could explain normalisation of the CPM effects. There also exist examples of increased CPM efficacy, for example, in participants completely recovered from an ankle fracture and now asymptomatic compared with participants who have not experienced an ankle trauma.179
A major question relates with how much and how long the duration of pain is needed before a CPM impairment occurs. Tonic saline-induced muscle pain or cold-pressor pain as conditioning induced generally a higher CPM effect in men compared with women, but interestingly, when applying the 2 conditioning stimuli at the same time, a less CPM effect was observed in men.15 In a later study where a pain model was applied to the arm for 1 hour, it was demonstrated that the CPM assessed by cuff algometry on the legs was impaired, and immediate experimental reduction or facilitation of the arm pain did not change the CPM attenuation, suggesting some plasticity of the descending control system.91 Nonetheless, although long-term pain was maintained for 1 day, the CPM effect progressed towards a normalisation suggesting that the healthy descending control is adaptive.91 Similarly, in a model of experimental LBP, for several days, the CPM was not significantly affected.158
Of note, better characterisation may be obtained when combining pronociceptive and antinociceptive mechanisms. Integration of several mechanistic-based parameters (pain sensitivity, TSP, and CPM) was useful for characterising individuals with osteoarthritic pain as highly sensitised.12 Similarly, in a large cohort of patients with chronic musculoskeletal pain, impaired CPM combined with facilitated TSP was associated with widespread pain.248 The complementary role of CPM and TSP is also shown in an experimental study where painful conditioning mainly reduced the pain response to the first stimulation applied during TSP assessment.98
Like the CPM protocol, exercise-induced hypoalgesia is reflected in changed pain sensitivity caused by aerobic and resistance exercise. In the healthy population, hypoalgesia generally occurs after exercise.167 In patients with chronic musculoskeletal pain, exercise-induced hypoalgesia was intact in several patient cohorts, but impaired exercise-induced hypoalgesia or even hyperalgesia has also been reported in other patients with musculoskeletal pain.252 In patients with widespread pain, reduced efficacy of exercise-induced hypoalgesia has also been found compared with controls.225,243 The nontrivial part of exercise in chronic musculoskeletal pain is the potential pain flare that may reduce the degree of exercise-induced hypoalgesia, for example, in patients with LBP.254 Moreover, in healthy controls, pressure pain thresholds at the head and neck increased when doing repeated arm abductions (ie, exercise-induced hypoalgesia), but in patients with neck pain, pressure pain thresholds were gradually reduced and pain increased.42 Recently, reduced exercise-induced hypoalgesia was found in healthy participants exposed to a long-term neck pain model.44 Interestingly, exercise-induced hypoalgesia caused a reduction of the CPM effect.6 By contrast, however, the reduction in pressure pain sensitivity due to a cold-pressor conditioning (ie, CPM) and due to exercise (ie, exercise-induced hypoalgesia) was not significantly correlated.251 Still, in patients with chronic musculoskeletal pain having high pain sensitivity compared with low pain sensitivity, impaired CPM and attenuated exercise-induced hypoalgesia were found.250 Such findings suggest that shared inhibitory pathways are recruited in exercise-induced hypoalgesia and CPM.
1.6.3. Reduced antinociceptive effects as a predictor for pain progression in musculoskeletal pain
The prognostic value of an impaired CPM effect in musculoskeletal pain conditions is less convincing. In a small study, the CPM effect in patients with knee osteoarthritic pain before total knee replacement correlated with the pain reduction recorded 6 months after the surgery.249 However, larger cohort studies in patients with osteoarthritis could not demonstrate a predictive value of impaired CPM per se on chronic postoperative pain.103,131,185,186 Combining mechanistic pain parameters in the analysis may improve the predictive value. For instance, in pain patients with knee osteoarthritis having impaired CPM and facilitated TSP before total knee replacement, less pain relief was found after 1 year.186
1.7. Cortical manifestations of prolonged and persistent musculoskeletal pain
Chronic musculoskeletal pain is associated with structural and functional cortical reorganisation and maladaptive neuroplasticity.130 Early pioneering studies demonstrated reorganisation of the primary somatosensory cortex in patients with chronic LBP65 and similar findings have been reported subsequently.126 Moreover, reorganisation of the motor cortex was thoroughly studied in LBP.232,245,246 In the progression from acute to chronic LBP, the cortical representation shifts from sensory discriminative/nociceptive to emotional circuits.10,89,211 As an example, in patients with chronic LBP, the power of gamma oscillations in the prefrontal region reflected the variation in ongoing pain intensity.154 Moreover, the dynamics of specific brain networks (particularly the default mode network) were changed in patients with LBP and osteoarthritic pain, compared with controls, and such modifications correlated with pain duration.20 Similarly, in a large cohort of patients with LBP, connectivity between sensorimotor, salience, and default mode networks was increased compared with controls, with some connections particularly influenced by pain catastrophizing.119 In line, disruption of whole-brain and local functional connectivity was shown in patients with osteoarthritic pain,25 and various knee osteoarthritis phenotypes were associated with the power of oscillations in different cortical regions.218 Although, the dynamic changes in connectivity within and between regions are important for chronic pain,118 the following sections will focus on the immediate cortical changes in musculoskeletal pain.
1.7.1. Somatosensory cortical effects of tonic musculoskeletal pain models
Early studies demonstrated that a capsaicin-induced tonic muscle pain evoked similar resting-state electroencephalographic topography patterns as a control injection, but the painful condition resulted in a decreased power of alpha (parietal) and increased power of beta (global) oscillations,40 where the increased power of beta oscillations was in contrast to a similar intradermal pain model.39 Using a repeated tonic muscle pain model (5 injections of hypertonic saline provoking relatively low-intensity pain that gradually declined over repetitions), the power of alpha oscillations was reduced in the first 2 pain epochs, whereas the beta oscillations gradually increased during the 5 pain epochs.38 The decreased alpha power was not found if participants were presented to an aversive auditory stimulus, suggesting that the pain effect was not due to a general arousal.37 Similarly, saline-induced tonic muscle pain caused decreased alpha power with a reduced effect if a simultaneous placebo condition was introduced141 and increased gamma power in case of moderate-intensity compared with low-intensity saline-induced muscle pain.140 However, if saline-induced muscle pain was maintained on a steady pain intensity for 5 minutes before electroencephalography was recorded, a long-lasting increase in delta and alpha power was found, possibly illustrating a decreased excitability of the somatosensory cortex.183 The different findings in alpha power changes in tonic muscle pain models may relate to the required cognitive processing and attention, where the capsaicin pain model induces an immediate high-intensity pain profile, and the saline-induced pain is steadier. Recently, painful cuff pressure stimulation maintained for 3 minutes compared with nonpainful cuff pressure evoked an increased global electroencephalographic power in several regions (eg, contralateral anterior cingulate cortex, primary somatosensory cortex, dorsolateral prefrontal cortex, and posterior parietal cortex), where the increase in the alpha power may be a result of increased cortical inhibition by the deep-tissue pain.258
The cortical excitability in tonic pain models has also been studied by sensory-evoked potentials in electroencephalographic recordings after electrical stimulation of peripheral nerves. Inhibition of early sensory-evoked potentials was found after tonic chemically induced muscle pain, with lasting depression several minutes after the pain vanished.195,196,198,202
1.7.2. Somatosensory cortical effects of long-term musculoskeletal pain models
The initial transition to chronic pain has been studied by long-term muscle pain models. Reduction of the frontal N30 sensory-evoked potential and facilitation of the parietal P45 peak were recorded after 4 to 5 days with NGF-induced muscle pain152,153 and similar P45 facilitation was found after days with delayed-onset muscle soreness.151,153 Such manifestations are interesting because these electroencephalographic recordings are performed in participants with daily pain but in resting situations without pain flares, thus differing from tonic muscle pain models. Using a long-term pain model (exercise-induced muscle pain), increased alpha power was found within 12 hours, but at peak pain (36 hours), no significant changes in the alpha oscillations were observed.190 These findings suggest that the long-term musculoskeletal pain models also involve cortical adaptations linked with the required cognitive and attentional demands.
Muscle pain for 1 to 2 weeks induced by NGF injections demonstrated a negative correlation between the sensorimotor peak alpha frequency of the electroencephalography at baseline and the experimental muscle pain intensity (slow peak alpha frequency associated with higher muscle pain intensity), but the peak alpha frequency was not significantly affected in the 2-week observation period.68 Using a combined model of exercise-induced muscle pain and NGF-induced muscle pain, a slowing of the peak alpha frequency was demonstrated during the days with pain, but in contrast to Furman et al.,68 the subgroup with the highest perceived muscle pain intensity was associated with faster peak alpha frequency at baseline.150 So far, the peak alpha frequency is still to be recorded in patients with musculoskeletal pain and further clarified as other studies have shown a positive172 and negative67 correlation between the tonic thermal-induced pain intensity and the peak alpha frequency before pain induction.
1.7.3. Corticomotor excitability in musculoskeletal pain models
Motor-evoked potentials by transcranial magnetic stimulation have been used to assess corticomotor excitability in musculoskeletal pain conditions.56,201,246 A meta-analysis showed that the corticomotor excitability was depressed during and after induction of tonic deep-tissue pain.30 The post-pain corticomotor depression seems robust because motor cortex activation by movement203 or a working memory task (engaging prefrontal and premotor cortices) did not affect the depression,133 although premotor cortex activation (by action observation and motor imagery tasks) may counteract the pain-induced corticomotor depression.132
In a series of studies, corticomotor excitability was studied in the progression of long-term pain models. In the first studies, facilitated motor-evoked potentials152,153 and expansion of the motor maps (area of the motor cortex inducing a motor-evoked potential when doing transcranial magnetic stimulation) were found during the days of peak NGF-induced muscle pain.152,153,199 However, other studies demonstrated that motor maps were reduced in the days after NGF-induced muscle pain,46 and the reduction was correlated with less motor variability during pain.233 Moreover, reduced motor maps in NGF-induced long-term pain were found with higher experimental pain intensity, and lower pain causes motor map expansion.210 Interestingly, the group showing motor map expansion also had lower corticomotor excitability at baseline, suggesting that they are flexible towards pain-related changes.
A meta-analysis found that corticomotor disinhibition assessed by transcortical magnetic stimulation is generally found in patients with chronic pain but most pronounced in patients with neuropathic pain.181 Similar findings have been reported in patients with osteoarthritic pain217 and fibromyalgia.162 Likewise, in a long-term muscle pain model, reduced intracortical inhibition and increased intracortical facilitation were found accompanying the expanded motor maps,199 suggesting that such cortical disinhibition is a relatively fast change.
1.7.4. Cortical adaptability in musculoskeletal pain
The fundamental principle that the brain can adapt during various conditions, including musculoskeletal pain, has resulted in studies focusing on mechanisms that support adaptability in the human brain, and a basic construct defined as “homeostatic plasticity” is needed to keep stability in neural networks.29,113 For instance, the homeostatic modulation may be assessed in the motor cortex when 2 blocks of anodal transcranial direct current stimulation (tDCS) and a block of no stimulation in-between are delivered in a priming test paradigm.242,264,265 In patients with chronic LBP, such homeostatic modulation was impaired compared with controls,240 indicating reduced adaptability. Using a long-term muscle pain model in healthy participants, the peak impairment of the homeostatic modulation was found after few days of ongoing muscle pain,241 suggesting that as pain manifests, the neuroplastic adaptability reduces.
Overall, the neuroplastic capacity may be an important factor in musculoskeletal pain, both as a trait and state. In a study using NGF-induced muscle pain, Seminowicz et al.212 found that a relative slow baseline peak alpha frequency combined with reduced motor maps when having musculoskeletal pain partly discriminated the most pain-sensitive participants from more tolerant participants. In patients with subacute LBP compared with controls, early sensory-evoked potentials from electrical stimulation on the back were depressed, and the motor maps were reduced.41 By contrast, less discrete motor maps for back muscles were found in patients with recurrent244 and chronic200 LBP compared with asymptomatic controls. Measures recorded in the acute pain phase of LBP may also represent an epiphenomenon, but the reduced sensory-evoked potentials were demonstrated as causative of chronic pain after 6 months in contrast to the changes in the motor mapping.105 Such data indicate that the cortical sensory-discriminative function is impaired in candidates vulnerable to developing chronic musculoskeletal pain. How this links with the sensory-discriminative function in painful stimulations is unknown, although previous studies demonstrated augmented nociceptive-evoked potentials (short latency) in patients with chronic LBP49 and fibromyalgia50 compared with controls.
1.7.5. Noninvasive brain stimulation in musculoskeletal pain
The cortical manifestations in musculoskeletal pain and, in particular, the predictive characteristics open a therapeutic window for noninvasive neuromodulatory approaches. Generally, noninvasive brain stimulation (NIBS), such as repetitive transcranial magnetic stimulation (rTMS) and tDCS, has demonstrated efficiency and has been used for peripheral neuropathic pain and migraine. So far, the clinical evidence for NIBS in musculoskeletal pain is sparse. The modulatory effects on the cortical excitability have been demonstrated with anodal tDCS256 and high-frequency rTMS182 causing increased excitability while cathodal tDCS reduced the excitability.255
A recent meta-analysis showed that NIBS increased pain thresholds in healthy participants when pooling studies of rTMS and tDCS of the primary motor cortex, but for individual analysis of rTMS and tDCS, this was not significant.71 Relevant for deep-tissue pain, anodal motor cortex tDCS inconsistently increased pressure pain thresholds in healthy participants.63,64,112,256 By contrast, the pressure pain thresholds in healthy participants increased after daily sessions of high-frequency rTMS on the left dorsolateral prefrontal cortex.149 Another approach is the high-density tDCS, where one or more cortical regions can be targeted. In a large sham-controlled design with daily anodal tDCS applied to the primary motor cortex, dorsolateral prefrontal cortex, or both combined, the pain sensitivity (eg, pressure pain thresholds) was not affected in healthy participants.121
With anodal high-density tDCS applied daily on 3 consecutive days to the primary motor cortex and dorsolateral prefrontal cortex in participants exposed to the long-term NGF-induced muscle pain model, some antihyperalgesic effects were observed.122 Moreover, in a sham-controlled design, the long-term muscle pain intensity induced by intramuscular NGF injections was reduced by daily high-frequency rTMS sessions targeting the left dorsolateral prefrontal cortex209 as well as reversing the pain-induced pressure hyperalgesia and exerting opposing effects on both cortical somatosensory excitability and corticomotor excitability (Fig. 7).152 In a similar long-term pain model, analgesia was demonstrated after high-frequency rTMS to the primary motor cortex but interestingly without any effects on the corticomotor excitability.35 Across different types of patients with chronic pain, NIBS generally increased pain thresholds.71 However, in patients with musculoskeletal pain, only few studies exist, for example, in patients with osteoarthritic pain, active compared with sham anodal tDCS to the primary motor cortex reduced the pressure pain sensitivity,3 and in patients with fibromyalgia, anodal tDCS caused a lasting pain reduction after 10 daily treatment sessions.117
Studies of NIBS on pronociceptive modulatory mechanisms are rare. However, the CPM effects were generally increased by rTMS and tDCS of the primary motor cortex both in healthy participants and patients with chronic pain.71 Beneficial effects of tDCS were found for CPM assessed by pressure pain thresholds in healthy participants63,64 and in patients with osteoarthritis.3 In a long-term pain model (capsaicin), CPM assessed by cuff algometry was reduced in parallel with reduced corticomotor excitability in the sham tDCS, whereas the CPM and corticomotor excitability were not significantly affected on active anodal high-density tDCS to the motor network.88 One hypothesis could be that neuroplastic manifestations are needed before tDCS will be efficient, as also evident in another study where tDCS in patients with LBP having low pain severity had no effect on the pain sensitivity or CPM.155
2. Conclusion and future directions
Musculoskeletal pain biomarkers are differentially affected depending on the pain duration and change in the continuum from short-term to chronic pain (Fig. 8): (1) Provoked pain is localised and referred initially, whereas spreading and extended when chronic. (2) Deep-tissue hyperalgesia is localised initially and spreading or widespread when chronic. (3) The pronociceptive modulation has a normal gain initially and a facilitated gain when chronic. (4) The antinociceptive modulation is more variable but seems to provide an inhibitory function initially, with reduced inhibitory efficacy when chronic. (5) Cortical circuitries demonstrate adaptations initially, whereas reorganised and less adaptive when chronic. Overall, a trait of the musculoskeletal pain system being more vulnerable to persistent pain could be hypothesised as (1) having spinal neuronal mechanisms which become easily sensitised and (2) having less neuroplastic capacity, ie, being less flexible when a cortical adaptive response is normally requested and thus affecting the downstream control of the spinal excitability. A similar hypothesis could be proposed for chronic pain (sensitised spinal mechanism and reduced neuroplastic capacity). Although not covered in this review, the lack of adaptability may even extend to psychological and motor control concepts in musculoskeletal pain. Currently, both hypotheses are not fully supported but may facilitate novel treatment modalities, for example, using NIBS to modulate the neuroplastic capacity in musculoskeletal pain conditions.
Conflict of interest statement
NociTech (cuff algometry) is partly owned by Aalborg University. The author has no conflicts of interest to declare.
Colleagues at the Center for Neuroplasticity and Pain (CNAP, Aalborg University, Denmark), in particular Prof. Lars Arendt-Nielsen, and external collaborators are greatly acknowledged for their contributions to the studies presented here.
Research funding: Center for Neuroplasticity and Pain (CNAP) is supported by the Danish National Research Foundation (DNRF121).
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