Center for Sensory-Motor Interaction (SMI), Laboratory for Musculoskeletal Pain and Motor Control, Aalborg University, Denmark

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1 14RC2 Assessment and mechanisms of musculo-skeletal pain Thomas Graven-Nielsen, Lars Arendt-Nielsen Center for Sensory-Motor Interaction (SMI), Laboratory for Musculoskeletal Pain and Motor Control, Aalborg University, Denmark Monday, June :30-12:15 Room: Ballroom 1 This Refresher Ccourse will provide information on definitions and methodologies for assessing pain in humans and how different mechanisms can be evaluated quantitatively in healthy volunteers and in pain patients. Another target is experimental muscle pain assessment in proof-of-concept studies of new compounds to screen for potential efficacy in musculo-skeletal pain. The focus will, in particular, be on activation and assessment of the peripheral and central pathways related to musculoskeletal structures. This will deal with the basic neurophysiological and biochemical aspects of the transduction, transmission, and processing of nociceptive information from musculo-skeletal tissue under normal conditions and conditions with peripheral or central sensitisation. Furthermore, the application of the assessment methodologies in patients with chronic musculo-skeletal pain provides information about the mechanisms underlying generalised hyperalgesia and generates information needed to develop new rational pain management regimes. Introduction Musculo-skeletal pain is a major clinical problem, and further insight into the peripheral and central neurobiological mechanisms is required to improve understanding, diagnosis and therapy. This presentation will focus on the manifestations of musculo-skeletal pain and methods for assessing potentially involved mechanisms. Musculo-skeletal pain is described as a cramp-like, diffuse aching pain in the muscle, pain referred to distant somatic structures, and modifications in the superficial and deep tissue sensitivity in the painful areas [1, 2]. These manifestations are different from pain arising from superficial structures, which is normally localised around the injury with a burning and sharp quality. Pain localization is poor in deep tissue, and it is difficult to differentiate pain arising from muscle, tendons, ligaments, and bones as well as from joints and their capsules. Referral of muscle pain is typically described as a sensation from deep structures in contrast to visceral referred pain that is both superficially and deeply located. The sensation of acute musculo-skeletal pain is the result of the activation of group III (Aδ-fibre) and group IV (C-fibre) polymodal deep-tissue nociceptors [1]. The nociceptors can be sensitised by release of neuropeptides from the nerve endings. This may eventually lead to hyperalgesia and central sensitisation of dorsal horn neurones manifested as prolonged neuronal discharges, increased responses to defined noxious stimuli, response to non-noxious stimuli, and expansion of the receptive field [1]. The neurobiological mechanisms involved in muscle pain are often difficult to resolve from clinical studies due to great variability between patients, which may be caused by different pain intensities and duration of their pain condition. Human experimental pain models applied to healthy volunteers are one potential strategy to investigate aspects of the mechanisms involved in muscle pain. Experimental muscle pain research involves two separate disciplines: 1. standardized activation of the nociceptive system, and 2. quantitative assessment of the evoked sensory and motor responses. One important advantage of experimental muscle pain studies is that the cause-effect relationship is known. In this situation healthy volunteers transiently become patients with a well-defined muscle pain where the sensory manifestations can be assessed. Moreover, experimental techniques may be used as biomarkers in clinical studies to quantify the sensitivity of the nociceptive system in pain patients and in pharmacological studies. In recent years, there has been an increased interest in using experimental tools for assessing muscle pain in proof-of-concept studies of new compounds to screen for potential efficacy in musculoskeletal pain

2 Experimental techniques to assess mechanisms underlying musculo-skeletal hyperalgesia, temporal summation and referred pain are described below, as these reflect different fundamental manifestations of peripheral and central sensitisation. Muscle pain assessment The assessment of muscle pain is based on psychophysical, electrophysiological, and imaging techniques but only psychophysical methods will be described here. Psychophysical determinations can be divided into response-dependent and stimulus-dependent methods. The response-dependent methods are constructed by a series of fixed stimulus intensities and by applying a score to each stimulus. The score can be a visual analogue scale (VAS), verbal descriptor scale, magnitude estimation, or cross-modality match. The VAS, verbal descriptor scales, McGill Pain Questionnaire and similar scales and questionnaires may be very helpful for the assessment of perceived intensity and quality [3]. The stimulus-dependent methods are based on adjustment of the stimulus intensity until a pre-defined response, typically a threshold (such as, detection, pain, or tolerance) is reached. Stimulus-response functions are more informative than a threshold determination as supra-threshold response characteristics can be derived from the data. For example, the differentiation between low and high intensity stimuli is clearly evaluated by stimulus-response functions. Nevertheless, the stimulus-response function can often be established with stimulus intensities around the pain threshold, and therefore both assessment methods are needed. Assessments of the sensory aspects involve both the evaluation of the localized muscle pain and of the somatic structures related to the referred pain area - the ongoing pain intensity and the sensitivity must be described for both areas. Verbal assessments of the experienced musculoskeletal pain intensity and other subjective characteristics of the muscle pain are obviously needed in any clinical and experimental muscle pain study. The pain intensity is usually scored in a continuous mode on an electronic VAS to characterize the time profile of experimental muscle pain. Pain sensitivity assessments For assessment of deep-tissue pain sensitivity, there are several methods for stimulating the nociceptors and evoking experimental pain. The endogenous techniques induce muscle pain by natural stimuli, for example by ischaemia or by exercise. The exogenous techniques are external interventions, such as electrical stimulation of muscle afferents or injection of algesic substances. In general, the endogenous experimental techniques induce pain in muscles and other somatic structures, which may be used in studies requiring a tissue-unspecific deep pain assessment. Manually applied pressure stimulation (pressure algometry) to induce pain from deep structures has been extensively used and validated [4]; variability may be reduced by computer-controlled stimulation, which also allows establishment of the stimulus response function of the somato-sensory sensitivity [5]. Pressure algometry assesses a relatively small volume of tissue. Instead, a larger volume can be assessed by computer-controlled cuff-algometry technique. The pain intensity related to inflation of a tourniquet applied around an extremity is used to establish stimulus-response curves, and deep-tissue sensitivity can be assessed [6]. Recently cuff-algometry has been used for quantifying the pain sensitivity in the lower legs of fibromyalgia patients, and significantly lower pain thresholds and tolerances were found in patients compared with controls [6]. The pressure pain sensitivity is a combined measure of cutaneous and deep tissue mechano-sensitivity. However, group III and IV afferent fibres from musculo-skeletal tissue are involved in the sensation evoked by pressure stimulation [5]. Deep-tissue pain can be induced by injection of a variety of substances such as hypertonic saline, glutamate, capsaicin, and acidic saline [2]. Intramuscular injection of hypertonic saline is a widely used model because it is reliable and safe and induces a short lasting pain (5-10 min; Figure 1A). The mechanism of referred pain has been extensively investigated after intramuscular injections of hypertonic saline into the tibialis anterior muscle; referred pain is typically reported in the ankle area in healthy subjects (Figure 1B). Receptor types such as the transient receptor potential vanilloid 1 (TRPV1), stretch-inactivated channel, and acid-sensing ion channel (ASIC) receptors have been identified and are probably involved in the transduction process of chemically induced muscle pain

3 Less used in clinical settings are ischaemic exercise, powerful exercise, and non-mechanical external stimuli (such as thermal, electrical) which have been shown to induce muscle pain in humans [2]. Figure 1 A VAS (cm) Healthy subject Musculoskeletal pain patient Injection site Local pain B Control C Musculoskeletal pain patients Time (min) Referred pain The typical pain intensity (A) and distribution (B) and after intramuscular injection of hypertonic saline into the tibialis anterior muscle. Healthy subjects report pain around the injection site and often referred pain to the ankle area. The visual analogue scale (VAS) is anchored by 0 indicating no pain and 10 indicate maximal pain. C: Typical examples of expanded referred pain patterns in musculoskeletal pain patients due to saline-induced muscle pain in the tibialis anterior muscle. The pain intensity is also often increased in pain patients compared with healthy control subjects. Musculo-skeletal hyperalgesia Tender points are anatomically determined soft-tissue body sites where, among other criteria, the patients must be sensitive to a 4-kg pressure at 11 out of 18 points to follow the American College of Rheumatology criteria for fibromyalgia [7]. Trigger points are localised hardening of muscle tissue which is hypersensitive and located in a tense band of muscle fibres [8]. In contrast to tender points, pressure stimulation on trigger points is typically characterised by referral of pain. Pressure algometry has been widely used to assess trigger and tender point sensitivity in musculo-skeletal pain patients [9]. Provided proper standardisation is used, pressure pain thresholds are generally considered an improvement over the manual palpation technique. Nonetheless, the co-location of manually detected tender points and reduced pressure pain thresholds are weak when assessed in healthy subjects [10]. The sensitisation of deep-tissue nociceptors is the best established peripheral mechanism for the subjective tenderness and pain during movement of a damaged muscle. The sensitised nociceptors have not only a lowered mechanical excitation threshold, but also exhibit larger responses to noxious stimuli [1]. If the muscle lesion is extensive, large amounts of endogenous algesic agents will be released which could lead to direct excitation of nociceptors resulting in spontaneous pain. In widespread-pain conditions the involvement of peripheral sensitisation is probably not the primary mechanism for the widespread deep-tissue hyperalgesia; in fibromyalgia, for example, it is likely that the generalised hyperalgesia is explained by central sensitisation. Interestingly, a thorough examination for trigger points in fibromyalgia patients revealed a higher frequency of trigger points in patients compared with controls [11]. This indicates that the central sensitisation results in more trigger points, which in turn may generate larger (widespread) pain areas - 3 -

4 Temporal summation The facilitated pain response to sequential stimuli of equal strength is defined as temporal summation and mimics the initial phase of the wind-up process measured in animal dorsal horn neurons [12]. To elicit temporal summation, a stimulus is repeated at constant intervals, for example - five times with a frequency of 1 Hz, at constant intensity. The intensity of the five stimuli is increased gradually until the subject feels an increase in pain perception during the repeated stimulation. Temporal summation of musculo-skeletal pain has been assessed by intramuscular electrical stimulation, focused ultrasound, or sequential injections of algesic substances. Repeated tapping on a muscle by a pressure probe has also been used to assess the efficacy of temporal summation, and temporal summation was found to be more potent for deep tissue stimulation compared with skin stimulation. The facilitated degree of temporal summation indicates an enhanced central integrative mechanism (central sensitisation). Therefore, facilitated temporal summation of pain in patients with chronic musculo-skeletal pain might suggest the involvement of central sensitisation [13, 14]. In line, temporal summation to pressure stimulation was facilitated in delayed onset muscle soreness in healthy subjects [15] indicating an inclusion of central changes in delayed onset muscle soreness. The threshold for the withdrawal reflex during repeated stimulation is significantly lower in fibromyalgia and whiplash patients compared with healthy controls, indicating central sensitisation in these patients [16]. Facilitated temporal summation might explain the pain after minimal ongoing nociceptive input arising from minimally damaged tissues or even after innocuous stimulation; an attractive explanation for those cases with pain, but without clear evidence of tissue damage. Referred pain Pain perceived at a site adjacent to, or at a distance from, the site of origin is defined as referred pain. It is mainly visceral and musculo-skeletal pain conditions that are accompanied by local or referred pain. Referred pain is probably a combination of central processing and peripheral input as it is possible to induce referred pain in limbs with complete sensory loss resulting from an anaesthetic block. 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. Central sensitisation may be involved in the mechanism of referred pain. A complex network of extensive collateral synaptic connections for each muscle afferent fibre onto multiple dorsal horn neurones is assumed [1]. Under normal conditions, the afferent fibres have fully functional synaptic connections with dorsal horn neurons, as well as latent synaptic connections to other neurones within the same region of the spinal cord. Following ongoing strong noxious input, latent synaptic connections become operational, thereby allowing for the convergence of input from more than one source. The area of the referred pain is correlated with the intensity of the muscle pain, and the appearance of referred pain is delayed by s compared with local muscle pain [17], indicating an involvement of a time-dependent process; perhaps the unmasking of new synaptic connections, in the neural mediation of referred pain. The frequency of referred pain from prolonged mechanical stimulation on the anterior tibial muscle is significantly higher than for brief stimulation, again indicating the time dependency of referred pain [18]. Moreover, saline-induced referred pain occurred less frequently in healthy subjects treated with ketamine compared with a placebo treatment [19], indicating the involvement of central sensitisation. Substantial clinical knowledge exists on the patterns of referred muscle pain from various skeletal muscles and after the activation of trigger points in myofascial pain patients. Typically, the referral of muscle pain is described as a sensation from deep structures in contrast to visceral referred pain that is both superficially and deeply located. The pattern and size of referral seem to be changed in other chronic musculo-skeletal pain conditions, for example fibromyalgia patients experience greater pain and larger referred areas after hypertonic saline-induced muscle pain compared with matched controls [13]. Interestingly, these manifestations were present in lower limb muscles where the patients typically do not experience ongoing pain. Normally, pain from the tibialis anterior is projected distally to the ankle and only rarely proximally. In fibromyalgia syndrome patients, substantial proximal spread of the experimentally-induced referred pain areas was found. Enlarged referred pain areas in pain patients suggest that the efficacy of central processing is increased (central sensitisation). Moreover, the expansion of referred pain areas in fibromyalgia patients was partly inhibited by ketamine, which is an NMDA receptor antagonist and thus inhibits central sensitisation [20]. Extended referred pain areas from the tibialis anterior muscle (Figure 1C), indicating central sensitisation, have also been shown in patients suffering from several other chronic musculo-skeletal pain conditions [12]

5 There are no definitive models explaining the transition from localised pain due to tissue challenges (such as damage) to widespread pain conditions. It is likely that that the initial excitation and sensitisation of nociceptors due to tissue damage will cause sufficient nociceptive input to the central pain systems to cause central sensitisation of dorsal horn neurones or at higher brain centres. Ultimately, this sensitisation sequel will lead to widespread pain conditions. In full-blown widespread pain conditions further studies are still required to establish if the peripheral nociception is needed to maintain the pain. Conclusion A significant part of the manifestations of deep-tissue pain (such as tenderness and referred pain) in chronic musculo-skeletal disorders may be results of peripheral and central sensitisation. Reliable methods for quantitative induction and assessment of musculoskeletal hyperalgesia, referred pain, temporal summation, and muscle sensitivity are available. From a mechanistic point of view sensory assessment procedures can provide complementary clinical information and give qualified clues to revise and optimise treatment regimes. Key learning points Quantitative assessment of musculoskeletal pain in humans provides: knowledge (biomarkers) on specific pain mechanisms involved; and facilitates targeted treatment and prevention according to involved mechanisms. Peripheral sensitisation in musculoskeletal pain involves: increased sensitivity of deep-tissue nociceptors; and is important for deep tissue hyperalgesia and soreness. Central sensitisation in musculoskeletal pain: increases sensitivity of central mechanisms (for example, expanded receptive fields); is important for widespread pain and hyperalgesia (for example, expansion of referred pain areas); and is important for the transition from acute localised pain to chronic widespread pain. References 1. Mense S, Simons DG. Muscle pain. Understanding its nature, diagnosis, and treatment. Philadelphia: Lippincott Williams & Wilkins, Graven-Nielsen T. Fundamentals of muscle pain, referred pain, and deep tissue hyperalgesia. Scandinavian Journal of Rheumatology 2006; 35(Suppl 122): Gracely RH. Studies of pain in human subjects. In: McMahon SB, Koltzenburg M, eds. Textbook of Pain, 5th edn. Elsevier, Churchill Livingstone, 2006: Jensen K, Andersen HØ, Olesen J, Lindblom U. Pressure-pain threshold in human temporal region. Evaluation of a new pressure algometer. Pain 1986; 25: Graven-Nielsen T, Mense S, Arendt-Nielsen L. Painful and non-painful pressure sensations from human skeletal muscle. Experimental Brain Research 2004; 159: Jespersen A, Dreyer L, Kendall S, et al. Computerized cuff pressure algometry: A new method to assess deep-tissue hypersensitivity in fibromyalgia. Pain 2007; 131: Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis & Rheumatism 1990; 33: Simons DG, Travell JG, Simons L. Myofascial pain and dysfunction. The trigger point manual. Philadelphia: Lippincott, Williams & Wilkins, Carli G, Suman AL, Biasi G, Marcolongo R. Reactivity to superficial and deep stimuli in patients with chronic musculoskeletal pain. Pain 2002; 100: Andersen H, Ge H-Y, Arendt-Nielsen L, Danneskiold-Samsøe B, Graven-Nielsen T. Increased trapezius pain sensitivity is not associated with increased tissue hardness. Journal of Pain (in press). 11. Ge HY, Nie H, Madeleine P, Danneskiold-Samsøe B, Graven-Nielsen T, Arendt-Nielsen L. Contribution of the local and referred pain from active myofascial trigger points in fibromyalgia syndrome. Pain 2009; 147:

6 12. Arendt-Nielsen L, Graven-Nielsen T. Translational aspects of musculoskeletal pain: from animals to patients. In: Graven-Nielsen T, Arendt-Nielsen L, Mense S, eds. Fundamentals of Musculoskeletal Pain IASP Press, 2008: Sörensen J, Graven-Nielsen T, Henriksson KG, Bengtsson M, Arendt-Nielsen L. Hyperexcitability in fibromyalgia. Journal of Rheumatology 1998; 25: Staud R, Cannon RC, Mauderli AP, Robinson ME, Price DD, Vierck CJ. Temporal summation of pain from mechanical stimulation of muscle tissue in normal controls and subjects with fibromyalgia syndrome. Pain 2003; 102: Nie H, Arendt-Nielsen L, Madeleine P, Graven-Nielsen T. Enhanced temporal summation of pressure pain in the trapezius muscle after delayed onset muscle soreness. Experimental Brain Research 2006; 170: Banic B, Petersen-Felix S, Andersen OK, et al. Evidence for spinal cord hypersensitivity in chronic pain after whiplash injury and in fibromyalgia. Pain 2004; 107: Graven-Nielsen T, Arendt-Nielsen L, Svensson P, Jensen TS. Stimulus-response functions in areas with experimentally induced referred muscle pain - a psychophysical study. Brain Research 1997; 744: Gibson W, Arendt-Nielsen L, Graven-Nielsen T. Referred pain and hyperalgesia in human tendon and muscle belly tissue. Pain 2006; 120: Schulte H, Graven-Nielsen T, Sollevi A, Jansson Y, Arendt-Nielsen L, Segerdahl M. Pharmacological modulation of experimental phasic and tonic muscle pain by morphine, alfentanil and ketamine in healthy volunteers. Acta Anaesthesiologica Scandinavica 2003; 47: Graven-Nielsen T, Kendall SA, Henriksson KG, et al. Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients. Pain 2000; 85: