Mechanisms and Management of Pain for the Physical Therapist Second Edition by Kathleen A. Sluka

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CHAPTER 4 Motor Control and Pain Paul W. Hodges People can move differently in the presence of pain, when threatened by pain, after resolution of pain, or as a precursor to pain. In each scenario there could be relevance for such changes to be assessed and addressed with treatment. At first glance many changes appear straightforward, reasonable, and beneficial to the individual—for example, avoidance of full weight-bearing and dorsiflexion of the ankle during walking after an acute ankle sprain, co- contraction of trunk muscles to limit spine movement after provocation of pain [26], and so on. Yet these changes could equally be part of the problem—for example, increased muscle activation predicts recurrence of low back symptoms [8]. Changes could also be both beneficial and problematic; that is, changes that are logical in the early phase to protect a painful segment could become problematic for other body regions or problematic for the region it aims to help —for example, walking with external rotation of the leg after spraining an ankle would protect the injured ligament in the early phase by reducing the demand for ankle dorsiflexion, but would increase the demand for movement of proximal segments, and in the long term could lead to limited ankle mobility. Changes in motor control are not straightforward and not well explained by current theories. Motor control refers to all of the motor, sensory, and information-processing elements associated with generation of motor functions [61]. Differences in any (or all) of these elements may be present in an individual with present, previous, or threatened pain. For the patient in pain, consideration of motor control may be critical for recovery, and to address these issues may be a major element of intervention. This chapter provides an overview of the contemporary view of motor control changes in pain, possible mechanisms, and potential benefits of treatments that aim to change the way a patient moves. HOW DOES MOTOR CONTROL RELATE TO 96

PAIN? Early theories proposed a simplistic relationship between pain and motor control: that pain would lead to either inhibition of muscle activity [75] or “spasm” [56]. This evolved into theories that predicted both inhibition and facilitation of muscle. The “pain adaptation” theory proposes inhibition of muscles producing a painful movement and facilitation of muscles that oppose it [43]. As many clinical and experimental observations do not align with these predictions of stereotypical response to pain, newer theories propose a more variable response that depends on the individual, the task, and the context [30,31,50]. However, fundamental to the changes in motor control in “pain” is the realization that there are several discrete, but interconnected, contexts in which changes/differences can be interpreted. In the contemporary clinical and experimental literature, there are four major ways in which changes in motor control are considered in conjunction with nociception/pain/injury and/or anticipation of pain/injury (Fig. 4-1): 1. Suboptimal movement/motor control as a precursor to injury and pain [8,57]; 2. Impaired movement/motor control as a consequence of interference by actual or threatened injury and/or pain [27,62]; 3. Modification of movement/motor control for protection of the painful/injured/threatened region [31]; and 4. Modified movement/motor control explained by a conditioned association with pain [49,51]. Each alternative may be associated with unique modifications of motor function, unique mechanisms, and unique outcomes for the health of the individual. Of course they may overlap—an adaptation to protect could be a precursor for other problems; and adaptation to protect could become conditioned. Each alternative may have different implications for management; different strategies may be required to change control, and whether or not it is beneficial to change control may depend on the underlying basis for the change. Each option requires consideration. 97

FIGURE 4-1 Interaction between pain and movement, and possible treatment targets. Pain and movement interact according to four hypotheses that are not mutually exclusive. Pain and/or injury (or threatened pain/injury) may change motor control by interference with motor output (negative) or by initiation of a protective solution (positive, in the short term). Movement may continue to be painful by suboptimal loading of tissues or if movement is conditioned to provoke pain in the absence of nociceptive input. Suboptimal loading of the injured or other tissues may lead to the onset of pain, or may be the result of pain interference or a negative consequence of the protective response. Different treatments (Tx), highlighted in colored boxes, may be required to target the different features that link pain and movement. Suboptimal Tissue-Loading Hypothesis An individual may move/align his or her body or activate muscles in a manner that loads his or her tissues suboptimally (Fig. 4-2). This could be an initial precursor to development of pain/injury in the first instance [8,57], or a factor in its recurrence [24]. The fundamental basis of this hypothesis is that suboptimal tissue loading leads to excitation of nociceptive afferents (with or without tissue injury) and, ultimately, pain. Such process could be enhanced if the peripheral tissues or the neural pathways are sensitized by peripheral or central 98

sensitization, such that less input is required to initiate nociceptive discharge or activate the pain network. In this case repeated exposure to the suboptimal loading mechanism may provoke pain. Single loading events with high force (e.g., slip or trip), unexpected force, or high loading in suboptimal positions induce tissue injury, nociceptive activation, and pain [5]. In these situations movement/motor control may be optimal but loading exceeds the capacity of the tissues. On the other hand, the view that accumulation of load over time from adoption of a strategy that loads the tissues suboptimally is less well defined or accepted. This concept has been proposed for many years (e.g., reference [17]), but empirical evidence has been limited. Many examples are cited in the clinical literature, such as “poor” posture/alignment (e.g., sitting in an end-range posture [11]), movement with poor alignment of the axis of rotation (e.g., axis of rotation of glenohumeral joint during shoulder motion [2]), or poor coordination of motion between adjacent segments (e.g., early motion of the spine, before the hip in leg movement tasks [60]; modified “start position” such as motion of the glenohumeral joint from a suboptimal position of rotation [47]). The primary argument against this proposal is that there are many people who use strategies that are deemed “negative,” but are pain/injury free, and therefore questioning the relationship to nociceptive input/pain/injury. The counterargument is that for a specific movement/loading strategy to cross the “threshold” and induce nociceptive input/pain/injury there must be sufficient “exposure” [13]; whereas high forces can exceed tissue tolerance with as few repetitions as one, low forces may require repeated exposure over an extended period to exceed the threshold. Add to this potential individual variation in the resilience of tissues and psychosocial context, and the equation between loading strategy and pain/injury becomes complex. Furthermore, there will not one but multiple different loading strategies that could be problematic (e.g., sitting more flexed or more extended both present in people with pain [11]). Taken together, it is not surprising that not all individuals with a specific posture/alignment, movement, or muscle activation pattern present with injury and pain. Multiple factors must converge to exceed the threshold of tissue tolerance. 99

FIGURE 4-2 Suboptimal tissue-loading hypothesis. Whether loading of tissues exceeds the threshold for tissue health depends on the interaction between load amplitude and the exposure (frequency and duration). Tolerance may also depend on individual variation in tissue type/resilience. Suboptimal loading may take many forms. Although suboptimal loading may lead to initial onset of injury and pain, it may not be necessary for the maintenance of pain. Why are suboptimal loading strategies adopted? Multiple theories have been presented. Some examples are as follows: • Habit—habitual use of a specific pattern of movement, posture, or muscle activation; • Environmental factors—poor posture motivated by a chair design, use of a computer [63]; modified hip mobility secondary to sustained periods sitting in posterior tilt; • Functional factors—asymmetrical muscle development from frequent exposure to asymmetrical task (tennis playing [72]; cricket fast bowling [21]) leading to adoption of such patterns in other tasks; • Presumed benefit—adoption of a posture or movement in response to information that this is beneficial (sitting with excessive thoracolumbar extension as the perceived ideal posture [9]); • Energy minimization—adoption of posture or movement that are supported by passive resistance rather than muscle activity (e.g., standing in hip adduction supported by iliotibial band tension [22]); • Previous exposure to pain/injury—motor adaptation induced by 100

pain/injury may remain [29,44] (see sections “Pain/Injury Interference Hypothesis” and “Protective Response Hypothesis” below). This latter item is a rising theory in clinical management of pain—that an individual who has recovered from injury/painful event may have initially developed a modified motor control strategy in response to the event (pain may have motivated the change), but the adaptation may persist beyond the recovery of pain (although pain is a motivator to change, relief of pain does not necessarily motivate resolution to a “normal”/“optimal” motor pattern). In this case suboptimal loading secondary to the modified motor behavior could become a risk factor for the recurrence of pain. Some evidence exists. For instance, individuals who fail to recover the size of the multifidus muscle after an acute episode of back pain have a greater risk for recurrence of symptoms [24]. Regardless of the explanation for the adoption of a suboptimal motor control strategy, the assumption is that maintained “use” of the strategy continues to suboptimally load the tissues leading to nociceptor discharge. In the presence of peripheral or central sensitization, this would be amplified such that less stimulus/loading is required to activate the nociceptors (peripheral sensitization), or the signal may be amplified centrally (central sensitization)—the threshold for “pain” may be lowered or non-nociceptive afferent input activates the “pain” network [79]. It is critical to recognize that the relationship between nociceptive input and pain is not linear. Nociceptive input is neither sufficient nor required to maintain pain (see section “Conditioned Response Hypothesis” below). Normal sensation may be perceived as painful—either because of sensitization [79] or conditioned association with the pain experience [49]. Thus, experience of pain does not necessarily mean that loading is abnormal or that nociceptors have been activated. Furthermore, the intensity of pain does not accurately reflect the extent to which tissue is suboptimally loaded. The major consequence of this nonlinearity and the physiology of the pain network is that although modified movement may have initiated the pain experience, it may not be the reason it is maintained. If suboptimal tissue loading continues to activate nociceptors, then changing movement to optimize the loading may be relevant for symptom recovery. However, because of the nonlinearity of the relationship between pain and loading, rehabilitation of movement patterns may not lead to symptom recovery, or may lead to recovery but not for the reasons presumed to be responsible. 101

Pain/Injury Interference/Inaccuracy Hypothesis In addition to the potential for suboptimal motor control to lead to pain and injury, pain and injury clearly change motor control. Although from one perspective this may be viewed as a “protective” solution to reduce potential for pain and/or injury (see section “Protective Response Hypothesis” below), from another, injury/nociceptive discharge/pain or even the threat/anticipation of these, may change motor behavior in a manner that interferes with behavior leading to inaccuracy and does not necessarily serve an obvious role in protection. These mechanisms may act at any level of the nervous system (Fig. 4-3). Nociceptive or non-nociceptive afferent input from injured tissue may directly influence excitability of motoneurons. Although nociceptive input is often presumed to have an inhibitory input to motoneurons, animal studies show that activation of nociceptive afferents in animals lead to both inhibitory and excitatory potentials on motoneurons [41]. The net effect is not straightforward, and both increased and reduced excitability has been shown in animal (increased discharge of masseter motorneurons after mustard oil application in rats [64]) and human studies (increased excitability of biceps motoneurons with hypertonic saline injection [46]). Non-nociceptive afferent input, via interneurons, can inhibit and facilitate motoneurons. Reflex inhibition (sometimes referred to as “arthrogenic” inhibition) is independent of the effects “pain” and commonly inhibits extensor muscles (inhibited quadriceps muscle after knee injury [14,62]) with concurrent facilitation of flexor muscles (hamstrings [14]). This is argued to explain many changes in motor control after acute injury, including early atrophy of the multifidus muscle in acute back pain [25,27]. Disrupted peripheral sensory function can also interfere with motor control. Many possibilities exist. For instance, direct injury to a mechanoreceptor or the tissue within which the sensory receptor is located (e.g., muscle, ligament, joint capsule) will modify afferent input [12,54]. Depending on the extent of injury and the availability of other sensory information to compensate, this would compromise the awareness of position and movement. Nociceptive input and local chemical changes (e.g., local inflammation) can alter muscle spindle sensitivity [65]. Supraspinal motor and sensory mechanisms are also possible contributors. Acute nociceptive input and injury changes excitability of sensory and motor areas [42,59,69]. More sustained symptoms are related to changes in organization of the motor [66,67] and sensory [19] cortices. How these changes 102

may relate to modified motor function and whether this equates to “interference” or “protective” function, or both, remains unclear. Some data show compromised corticospinal inputs to specific muscles (e.g., hypertonic saline injection leads to reduced excitability of inputs to transversus abdominis, which is considered important for fine-tuning of spine motion [69]), but enhanced excitability of inputs to other muscles involved in protective responses (e.g., obliquus externus abdominis [69]). FIGURE 4-3 Pain/injury interference/inaccuracy hypothesis. Pain and injury may interfere with motor output at any level of the sensorimotor system. The sensorimotor system occupies a substantial area of the nervous system, and different regions contribute to different features of motor function, broadly according to the detail in the figure. Pain and injury have been shown to have effects on motor output at each of the sites highlighted. At these sites, 103

nociceptive or non-nociceptive afferent input, or descending input from higher centers (molded by beliefs, attitudes, and expectations) may compromise the quality of motor control, leading to interference with function, or suboptimal loading of tissues. There is also extensive evidence of muscle changes (atrophy, muscle fiber- type changes, fatty infiltration, connective tissue changes [3,15,25,28]) associated with pain/injury. Although chronic changes in muscle may have a straightforward mechanism related to disuse [1], the nature of changes and the underlying mechanisms in acute and subacute periods are debated [3,25]. Recent work proposes different mechanisms with different time courses: reflex inhibition in the early phase; a possible role for inflammatory system in the intermediate period; and disuse in the chronic phase [28]. Regardless of the mechanism, and despite the “intention” of the nervous system to perform a specific motor function, the muscle apparatus may not be able to meet this demand. Regardless of the mechanism, the maladaptive effect of pain/injury on motor output may compromise function, may predispose to further pain/injury, or may be an epiphenomenon (i.e., change in motor function that is present but with no direct relevance for persistence or recurrence of pain). To counteract interference/inaccuracy it may be necessary to target the stimulus for the effect (e.g., joint swelling), the outcome of the interference (e.g., reflex inhibition), or both. Protective Response Hypothesis In the context of acute pain, the basic premise of the adaptation in motor control is that it serves to protect the tissues from further pain and/or injury (Fig. 4-4). In response to information regarding threat to the tissues (activation of nociceptive afferents by mechanical, thermal, or chemical stimulus) the nervous system generates a pain response (based on interpretation of the meaning of the threat) and generates an output to remove or reduce the threat. This can involve responses that range from simple, stereotypical flexor withdrawal reflex to a complex and flexible adaptation involving multiple body segments. Pain alerts the individual to the threat of pain and motivates the individual to change behavior to reduce the threat. It is through the motor system that behavior is changed, in conjunction with autonomic (e.g., increased heart rate; decreased peripheral vascular resistance) and other changes, to remove the threat. Early theories of stereotypical motor adaptation to pain were consistent with 104

this hypothesis—to increase muscle activity to limit motion [56], or inhibit agonist activity and facilitate antagonist activity during voluntary movement [43]. In both cases the objective is protection, but through predictable changes in muscle activation. Although logical and supported by some evidence, the complexity of the human body means that changes in pain are rarely stereotypical [31]. For instance, when back pain is simulated by noxious stimulation to the back muscles, there is profound interindividual variation; although almost all individuals had a net increase in muscle activity and estimated spine stability, the change in pattern of muscle activity to achieve this varied [26]. More recent theories aim to account for variation observed experimentally and clinically [30,31,50]. These theories propose that the adaptation pain (1) changes motor function across a spectrum of alternatives from subtle redistribution of activity within or between muscles, to complete avoidance of movement, activity, or participation; (2) varies between individuals and tasks; (3) serves the overall aim, at least in the short term, to protect the painful or threatened body part from actual or anticipated pain or injury and has “real” or perceived short-term benefit; (4) has potential long-term consequences if it is maintained, excessive, or inappropriate; and (5) has multiple potential mechanisms at various levels of the nervous system that are influenced by biological, psychological, and social aspects of pain [30,31]. 105

FIGURE 4-4 Protective response hypothesis. The logical response to pain and/or injury (or the threat of pain and/or injury) is to protect the injured/painful/threatened body region. This adaptation varies between individuals and tasks and can take many forms. Although logical in the short term, if sustained, the protective response can lead to further pain and injury of the same body region or other regions (e.g., adjacent joints) as a result of suboptimal loading. Protection of the injured/painful/threatened body region may be achieved by many different responses. These could include (but are not limited to) increased stiffness to limit movement (e.g., splinting back muscles to limit spine movement [39]); decreased force amplitude (e.g., limping to limit force applied to injured ankle); changed force direction (e.g., change in direction of knee extension force to modify pressure on infra-patellar fat pad [71]); redistribution of activity within [70] and between [34] muscles to reduce muscle stress; avoidance of movement or function (e.g., bed rest); or avoidance of participation (e.g., work absenteeism). The specific solutions selected by the nervous system 106

to reduce threat will depend on many features that may vary between individuals and may not be constant within individuals. Factors that could influence the selection motor adaptation include the body region affected, the biomechanical options available to enable adaptation but maintain completion of the task, neuromuscular options available for adaptation (e.g., it may not be possible to redistribute activity between muscles in all contexts [35]), cognitive- emotional/psychosocial features (e.g., perceived consequences of unsuccessful adaptation; prior experience), or external demands (e.g., motivation to maintain behavior such as completion of a marathon). In general it is assumed that some adaptations will be stereotypical and triggered with short latency from the exposure to threat (e.g., flexion withdrawal reflex [78]), but some will be learned over time (Bergin et al., unpublished data, 2015). Through trial and error, movement will adapt to “find” a solution that is less provocative or less injurious. Trial-to-trial variation in movement performance may subserve this search. Although some data show increased variation during pain [45,48], this is not universal [4] and different individuals may resolve to a new solution in different ways (Bergin et al., unpublished data, 2015). Recognizing that the response to protect the tissues may also be linked to threat, anticipation, or fear is also important. In this case an individual may adopt a protective solution when one is not needed (fear of injury/pain when there is no real threat to the tissues) or a protective solution that exceeds that required to protect the tissues. A large literature related to fear avoidance (e.g., references [74,76]) that interleaves with this aspect of the interaction between pain/injury and motor control exists. In this context protective adaptation in terms of avoidance of activity or participation may be prevalent. Although there is clear short-term advantage to adaptation, there may be long-term consequences [31]. Although the adapted motor behavior may reduce the actual or perceived threat to the tissues, it may also abnormally load the tissues of that or other body regions. If maintained, this could lead to further/additional problems. For instance, later relaxation of abdominal muscle activation after release of a load from the trunk (which could be interpreted to represent greater protection) is related to greater risk of a new back pain episode [8], and longer duration of co-contraction of medial knee muscles during gait in knee osteoarthritis is related to more rapid cartilage loss over time [32]. Thus, the protective response may underpin suboptimal loading, which leads to further pain of the affected or other body regions. In this case threat to the tissues was the motivator to change behavior in the first instance. If the protective response is maintained beyond when it is necessary, is in excess of what is necessary, or is 107

inappropriate, then resolution of symptoms may require reduction/removal of the protective response. Conditioned Response Hypothesis Recent emphasis has been placed on a fourth aspect of the relationship between movement/motor control and pain, which argues that an individual with pain may learn to associate movement with pain via a process of classical conditioning (Fig. 4-5) [49], in which movement produces pain by way of a learned association, without the requirement for ongoing nociceptor discharge from the tissues. This has also been referred to in terms of pain “memories” [51]. The process of association of pain with movement is thought to occur via process identical to that which induced Pavlov’s dog to salivate (conditioned response) in response to ringing of a bell (conditioned stimulus) after it had been presented concurrently with the smell of meat (unconditioned stimulus) [55]. Movement may initially be provocative of symptoms because of nociceptor activation due to tissue loading (with or without sensitization). Over time, via a process of classical conditioning, pain (the conditioned response) may be experienced in association with movement (the conditioned stimulus), in the absence of nociceptive discharge (the unconditioned stimulus). An individual may continue to experience pain with movement, in the absence of input from the peripheral tissues and may continue to use or even enhance an adapted motor behavior (see section “Protective Response Hypothesis” above). Some evidence for the association of movement with pain (e.g., when individuals with neck pain are provided feedback that indicates more movement than is actually performed, pain is experienced earlier in the actual range [23]) exists. Treatment in the case of conditioning would require attempts to extinguish the association between movement and pain. 108

FIGURE 4-5 Conditioned response hypothesis. Via a process of classical conditioning repeated, simultaneous exposure of an individual to movement and pain (initially from nociceptor input) can lead to the movement being experienced as painful, despite the absence of nociceptor activation. This can lead to pain interference and protective responses, despite the absence of actual threat to the tissues from the movement. Integration of Hypotheses The four hypotheses to explain the interaction between pain/injury and motor control are not mutually exclusive; in fact, it is likely that the changes in motor control identified in association with pain/injury can only be understood by considering the interaction between these options (Fig. 4-1). It is likely that all coexist, but explain different aspects of the change in motor control in the presence of pain. The mix of mechanisms active in an individual will vary, the manner in which they are expressed will vary, and this will most likely change over time. Each has clear implications for treatment, and the potential success of an intervention is likely to depend on identification of the mechanism underpinning the motor control change and finding a treatment to target it. CONSIDERATION OF MOTOR CONTROL IN THE TREATMENT OF PEOPLE IN PAIN 109

Different mechanisms will require different treatments. Some basic concepts are as follows: 1. If motor strategy leads to suboptimal loading of tissues, then training the individual to change strategy to a more optimal solution to load tissues in a healthy manner may be helpful. 2. If pain and/or injury interfere with movement, then treatments that target the interference and counteract the effects/consequences of interference are likely to be required. 3. If a protective motor adaptation is greater than is necessary or sustained beyond the time that it is necessary with subsequent suboptimal loading of the tissues, then training is likely to be required to resolve/reduce the motor adaptation to load the tissues in a more healthy manner and to restore activity and participation. 4. If movement is conditioned to induce pain, then interventions to extinguish the conditioning would be required. Treatment of an individual is likely to require consideration of a combination of the concepts. Each requires further brief consideration. Options to Train Optimal Loading and Resolve Excessive Protection If suboptimal loading of tissues (as a precursor to pain/injury or secondary to a protective reaction or pain/injury interference) continues to contribute to the persistence of symptoms or contributes to development of related secondary changes (e.g., new problems in adjacent body regions), treatment strategies to retrain motor control may be required. Multiple treatment options may be available. Options include “skill learning” or “motor relearning” to specifically target the feature of motor control that is considered to underpin the suboptimal loading [33], generic training that aims to change motor function without specific attention to individual features [7], or strategies to automatically modify motor function [6]. Motor learning that targets specific features of motor control require detailed assessment of an individual’s motor control and development of a clinical rationale for the relationship to symptom behavior. In general the approach proceeds with cognitive modification of a movement, posture/alignment, or muscle activation strategy, followed by practice in a range of environments to 110

ensure integration of the new solution in function, utilizing motor learning principles [18,20]. This process can be facilitated by identification of clinical subgroups of patients that can assist with prioritization of treatment [40,53]. Multiple programs have been described to train motor function in this manner for the back [33,52,57], neck [38], and peripheral joints [58]. Generic training program may aim to encourage adoption of movement strategies that are considered “healthy” without detailed specific attention to an individual presenting movement behavior. Although some clinicians apply these interventions in a more individualized manner, typical examples could be ball exercises, many Pilates programs, and generic core stability exercises. Some clinical approaches to modification of movement strategies rely on techniques to “automatically” change motor control. A range of clinical techniques is common in clinical practice. These may include application of tape, manipulative therapy, dry-needling, and so forth. In many cases the results are variable and the efficacy is unclear. Options to Target Interference and Counteract the Effects of Interference Strategies to overcome interference are those that target the mechanisms of interference or its outcome. For instance, reflex inhibition is likely to be best managed by treatments that reduce the stimulus (e.g., reduce intra-articular swelling) and target activation of the muscle affected by inhibition to counteract atrophy [25] and so forth. Identification of the stimulus for the interference is likely to aid optimization of treatment efficacy. Stimuli could include maintained nociceptive and non-nociceptive afferent input, inflammation, and so forth. Counteracting the effects of interference is unlikely to be achieved through generic strength training and is likely to require specific training to target a change in muscle activation pattern, alignment, or movement. Options to address interference can be targeted at any level of motor system. Interventions may be targeted at the muscle (activation, specific strength training), the spinal cord (facilitation/inhibition of excitability), and supraspinal features (e.g., somatosensory awareness, motor map). Options similar to those described above to counteract suboptimal loading are likely to apply. Options to Extinguish Conditioning If movement is conditioned to induce pain, treatment should aim to extinguish 111

the conditioning [51]. Experience with painfree movement is the crux of this approach. This might be achieved through exercise combined with pain neuroscience education [51], but may be enhanced by training with virtual movement, where movement is perceived without any actual movement [23]. Current work is underway by several groups to identify methods to optimize this approach. Evidence of Efficacy It is unlikely that the blanket application of any solution to people with pain will be effective, and outcome is likely to be optimized if right treatment targeted to the right patient at the right time. Features of motor control can be changed with treatment. This includes changes in posture [16], sensory function [36], and muscle activation in trials of neck pain [37], back pain [68], and knee pain [10]. Some evidence exists of a relationship between changes in motor control and changes in clinical symptoms. But not all data are supportive [77]. Considering that intervention that targets features of motor control are unlikely to be required or beneficial by all individuals with pain is critical. Most systematic reviews of treatment of musculoskeletal conditions show that exercise is effective, but with limited effect size [73]. Key issues with interpretation of the literature are that many clinical trials treat all individuals with a similar intervention, systematic reviews generally group interventions together despite vastly different mechanisms, and most clinical trials include individuals in a nonspecific manner. Few attempts have been made to match the right treatment to the right patient at the right time, and this is likely to be critical considering the complex mix of mechanisms that link pain/injury and motor control. Substantial work still remains to be done. CONCLUSION This chapter has outlined four different viewpoints that are necessary to consider the changes in motor control that present of pain and/or injury. These viewpoints are clearly interrelated and all are needed to explain different aspects of the changes in motor control that present in an individual. Each mechanism has implications for selection of treatment, and there is potential for gains in efficacy of interventions if this interaction can be understood such that the right treatment is applied to the right patient at the right time. 112

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64. Sunakawa M, Chiang CY, Sessle BJ, Hu JW. Jaw electromyographic activity induced by the application of algesic chemicals to the rat tooth pulp. Pain 1999;80(3):493–501. 65. Thunberg J, Ljubisavljevic M, Djupsjöbacka M, Johansson H. Effects on the fusimotor-muscle spindle system induced by intramuscular injections of hypertonic saline. Exp Brain Res 2002;142(3):319–26. 66. Tsao H, Danneels LA, Hodges PW. ISSLS prize winner: smudging the motor brain in young adults with recurrent low back pain. Spine 2011;36(21):1721–7. 67. Tsao H, Galea MP, Hodges PW. Reorganization of the motor cortex is associated with postural control deficits in recurrent low back pain. Brain 2008;131(pt 8):2161–71. 68. Tsao H, Hodges PW. Immediate changes in feedforward postural adjustments following voluntary motor training. Exp Brain Res 2007;181(4):537–46. 69. Tsao H, Tucker KJ, Hodges PW. Changes in excitability of corticomotor inputs to the trunk muscles during experimentally-induced acute low back pain. Neuroscience 2011;181:127–33. 70. Tucker K, Butler J, Graven-Nielsen T, Riek S, Hodges P. Motor unit recruitment strategies are altered during deep-tissue pain. J Neurosci 2009;29(35):10820–6. 71. Tucker KJ, Hodges PW. Changes in motor unit recruitment strategy during pain alters force direction. Eur J Pain 2010;14(9):932–8. 72. Van Dillen LR, Sahrmann SA, Caldwell CA, McDonnell MK, Bloom N, Norton BJ. Trunk rotation- related impairments in people with low back pain who participated in 2 different types of leisure activities: a secondary analysis. J Orthopedic Sports Phys Ther 2006;36(2):58–71. 73. van Middelkoop M, Rubinstein SM, Verhagen AP, Ostelo RW, Koes BW, van Tulder MW. Exercise therapy for chronic nonspecific low-back pain. Best Pract Res Clin Rheumatol 2010;24(2):193–204. 74. Vlaeyen JW, Linton SJ. Fear-avoidance and its consequences in chronic musculoskeletal pain: a state of the art. Pain 2000;85(3):317–32. 75. Wang K, Arima T, Arendt-Nielsen L, Svensson P. EMG-force relationships are influenced by experimental jaw-muscle pain. J Oral Rehabil 2000;27(5):394–402. 76. Wideman TH, Asmundson GGJ, Smeets RJEM, Zautra AJ, Simmonds MJ, Sullivan MJL, Haythornthwaite JA, Edwards RR. Re-thinking the fear avoidance model: toward a multidimensional framework of pain-related disability. Pain 2013;154(11):2262–5. 77. Wong AY, Parent EC, Funabashi M, Kawchuk GN. Do changes in transversus abdominis and lumbar multifidus during conservative treatment explain changes in clinical outcomes related to nonspecific low back pain? A systematic review. J Pain 2014;15(4):377 e1–377 e35. 78. Woolf CJ. Long-term alterations in the excitability of the flexion reflex produced by peripheral tissue injury in the chronic decerebrate rat. Pain 1984;18(4):325–43. 79. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain 2011;152(3, suppl):S2–S15. 116

CHAPTER 5 Individual Differences and Pain Variability Laura A. Frey Law and Steve Z. George Pain is both a diagnostic and a prognostic indicator. For example, knee pain may be the first indication of osteoarthritis. However, the experience of pain can vary considerably among individuals with osteoarthritis. For example, severity of knee pain and severity of osteoarthritic radiographic findings are not well correlated. Indeed, physical therapists commonly observe variability among individuals, finding that some patients are more or less sensitive to apparently similar pathology or painful stimuli. Individual differences in pain sensitivity result in variability in the pain experience at the group or population level. This chapter will explore selected clinically relevant factors that contribute to this interindividual variability. Pain variability can be observed under clinical and experimental conditions, with each condition providing a unique perspective on the pain experience. Variability of pain in clinical pain conditions can be challenging to assess as it may be confounded by the duration of the disease process, the severity of the underlying injury, the effects of previous treatment, and the use of varying coping strategies. Experimental models provide a means to study standard nociceptive stimuli across individuals to better delineate factors that contribute to pain variability. These models also allow for assessment of different components of the pain experience that may or may not be readily available in clinical settings. Pain sensitivity can be evaluated in two basic ways: (1) applying a constant noxious stimulus across individuals to assess differences in pain response; and (2) applying varying levels of noxious stimuli to assess a given pain response (i.e., threshold, tolerance, or some other predefined pain response). Increasingly, quantitative sensory testing (QST) is used in both research and clinical environments to determine pain threshold, tolerance, and responses to standard stimuli across multiple nociceptive modalities. These assessments allow for group comparisons to be made, to compare individual responses with normative values, or to predict patient outcomes. The use of both experimental pain models in healthy subjects and QST in patient populations has 117

increased our understanding of the extent of, and factors contributing to, variability in pain sensitivity. Specific examples of interindividual pain variability from experimental conditions can be seen in Fig. 5-1. Fig. 5-1 depicts pain sensitivity, using both a constant stimulus (panel A, acidic intramuscular infusion) and a variable stimulus (panel B, pressure pain threshold), in a cohort of healthy subjects. The wide range of responses using both models provides a clear indication of the variability of the pain experience, even under controlled circumstances involving healthy subjects. As defined by the International Association for the Study of Pain (IASP), pain is an unpleasant sensory and emotional experience related to actual or potential tissue damage. Pain sensitivity may depend on a myriad of factors (Fig. 5-2). Accordingly, a single factor is unlikely to explain the total variance in pain sensitivity. Further, these factors—sex, race, genetics, and psychological factors —are likely to interact in complex ways, making simple conclusions on the specific effect of a particular factor challenging. In this chapter, we will highlight the current status of the research on pain variability, acknowledging the inherent intricacies of the subject. We will discuss several sources of interindividual pain variability, considering studies of both clinical and experimental pain. We will focus on factors that have relevance to most clinical situations involving physical therapy: men versus women, ethnicity or race; psychological factors, age-related considerations, and heritability or genetics. 118

FIGURE 5-1 The distribution of (A) peak pain ratings (Borg CR10 scale) during intramuscular infusion of acidic phosphate buffer (pH 5.2) and (B) pressure pain thresholds (30 kPa/s) for 155 healthy subjects receiving these stimuli to the anterior tibialis (reanalyzed from Frey Law [20] and unpublished data). Both pain assessments showed nonnormal distributions and extensive variability with coefficients of variation (SD/mean) of 61.2% and 50.2% for panels (A) and (B), respectively. 119

FIGURE 5-2 Schematic representation of multiple interacting factors that may influence an individual’s perception of pain. (Modified and adapted from Berkley et al. [4] and Greenspan et al. [35].) Pain sensitivity can be specific to the nature of the underlying stimulus; someone particularly sensitive to heat pain may not be sensitive to cold pain or deep-tissue pressure pain, and vice versa [38,43,56]. Additionally, pain sensitivity may depend on the nature of the measure; for example, pain threshold may vary considerably, whereas tolerance to the same pain stimulus may be relatively consistent across individuals or vice versa. Thus, caution should be used when considering which factors influence pain sensitivity—they may not generalize across all situations. Although one commonly hears a patient or his or her clinician indicate the patient has a “high” or “low” pain threshold or tolerance, this is an overly simplistic judgment. A therapist needs to understand that an individual is not likely to be equally sensitive to all possible noxious stimuli, and may be particularly sensitive to cold, pressure, or even exercise- induced pain, for example. SEX AND GENDER Although the terms sex and gender are often used interchangeably, we will define sex as the biological distinction between men and women, whereas 120

gender will be used to distinguish among social, cultural, or behavioral roles and expectations typically associated with men (e.g., masculinity) and women (e.g., femininity) [4,35,69]. Although sex and gender are frequently correlated, they are not synonyms. Our discussion will include both studies that have investigated sex differences and those that have taken into consideration the underlying gender roles. Sex is one of the easiest individual differences to classify, and more information is available on differences in pain between men and women than on differences related to gender role. Sex Differences—Clinical Pain Numerous clinical pain conditions are more prevalent in women, but some diagnoses are more frequently seen in men (see Tables 5-1 and 5-2) [3,35]. Several chronic musculoskeletal pain conditions commonly treated by physical therapists occur more frequently in women, such as: fibromyalgia, osteoarthritis (after age 45), temporomandibular joint disorder, and carpal tunnel syndrome [3,35]. However, not well understood is why these conditions may occur preferentially in women or whether women display greater pain sensitivity then men for similar diagnoses. In a review of multiple common recurrent pain conditions (headache, facial, back, musculoskeletal, and abdominal), women generally reported higher intensity, longer duration, and more frequent pains than men [82]. Similarly, women reported higher knee pain than men, after controlling for severity of radiographic knee osteoarthritis, particularly for the less severe (Kellgren–Lawrence grades <3) conditions [31]. However, in other studies, no sex differences in pain intensity were reported in chronic musculoskeletal pain conditions [22,68], but women reported a larger anatomical distribution of pain [22]. Further, no sex differences were noted in pain intensity ratings or medication use in cancer patients [81] or after oral surgery [43]. In fact, in a cohort of patients with acute and subacute low back pain, men reported higher pain intensity in comparison with women [23]. The mixed findings in observed clinical male–female differences may be related to differences in underlying pathology or tissue damage, peripherally or centrally mediated pain signal processing, or from biases in pain report or health care utilization. However, men and women use similar pain rating schemas [19], indicating that observed sex differences are not likely simply due to pain report bias. Thus, sex differences in clinical pain may be complex and vary by condition. 121

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Sex Differences—Experimental Pain Results from human studies using experimental pain models are also mixed when it comes to sex differences. Pressure or mechanical pain has shown the most consistent and largest effect sizes for male–female differences. In a meta- analysis of a total of 22 studies on sex differences to experimental stimuli, Riley et al. [64] found that women had lower pressure pain thresholds with a moderate effect size (Cohen’s d = 0.59) and lower pressure pain tolerance with a large effect size (d = 1.18). Women also displayed lower thresholds for thermal pain (d = 0.46), electrical pain (d = 0.59), and ischemic pain (d = 0.18) [64]. Tolerance measures were also typically lower for women, but the effect size varied more between stimuli. The largest effect size was observed for pressure pain, but smaller effect sizes were observed for thermal pain (d = 0.09), electrical pain (d = 0.64), and ischemic pain (d = 0.16) [64]. More recently, Racine et al. [60] similarly concluded, from a meta-analysis of 122 publications, that sex differences are not consistent across multiple experimental pain modalities. However, both meta-analyses concurred that women exhibit greater sensitivity to thermal and pressure pain. Studies reporting pain ratings to a consistent algesic stimulus, such as pain with thermal probe at a set temperature, exercise-induced pain, or intramuscular infusions, have observed both elevated [20,40,43,44] and equal [10,20,41,43] pain responses in women compared with men. It has been suggested that women may exhibit greater centrally mediated pain responses. Women have typically reported higher rates of temporal summation in response to thermal [18,29,70] and mechanical stimuli [72]. Temporal summation is the increased pain response to a consistent stimulus over time and is believed to be related to the central processing of pain at the spinal cord level. Higher rates of temporal summation are indicative of “amplification” of pain, and may be associated with the development of chronic pain syndromes. Referred pain and secondary mechanical hyperalgesia in the referred pain region, additional forms of centrally mediated pain, have also been observed more frequently in women than men [20,62]. However, no sex differences in secondary hyperalgesia have been noted with cutaneous heat and capsaicin pain models [41]. Collectively, these studies suggest that central processing of pain may differ between women and men, such that women have equal or higher pain sensitivity and may be at higher risk for the amplification of nociceptive signals. Numerous studies have investigated the potential effect of the menstrual cycle in women on pain sensitivity. Contradictory reports reveal this issue is far from well understood. In one meta-analysis of 16 studies, women were least sensitive (i.e., had the highest thresholds) to pressure pain, cold pain, thermal 123

heat pain, and ischemic muscle pain during the follicular phase (days 6–11, immediately after the menstrual phase), with small to moderate effect sizes (Cohen’s d = 0.34–0.48) [65]. However, in a subsequent review by Sherman and LeResche [73], the addition of different studies, coupled with inconsistencies in classifying menstrual phases in the prior studies, led to their conclusion that currently “little evidence” existed for menstrual cycle influences on experimentally evoked pain [73]. Similarly, in a recent review by Bartley and Fillingim [1], they acknowledge that studies in this area are limited by methodological weaknesses. Thus, future studies may still alter our understanding of the hormonal influences on pain sensitivity in women. The experimental literature consistently suggests that women have equal or higher pain sensitivity than men, suggesting differences in peripheral sensitivity and central processing. However, the peripheral and centrally mediated sex differences may not be uniform across modalities or pain experiences. The studies outlined above, both clinical and experimental, do not account for gender or psychosocial factors, potentially important confounds. Gender Gender roles, which are influenced not only by the biological orientation of the individual, but also by social, cultural, and behavioral factors, have the potential to influence pain perception. Stereotypical gender roles suggest that men should have higher pain tolerance than women. This body of literature is much smaller than the previously reviewed literature related only to sex differences. However, there is some evidence to suggest gender influences pain perception, independent of biological orientation. Measurement of gender roles is not as simple as determining biological orientation, but self-report questionnaires can be used. Several approaches to measure gender roles have been reported specifically in relation to pain, such as the Gender Roles Expectations of Pain (GREP), a measure that considers the influence of socially learned responses to pain for men and women [69], and the Extended Personal Attributes Questionnaire, which includes a measure of perceived masculinity/femininity. Others have assessed how strongly individuals associate with their ideal gender group [59]. In several experimental pain models, gender roles and expectations mediate observed sex differences. Willingness to report pain (on the GREP questionnaire) was found to be more meaningful than sex differences in explaining temporal summation [70]. This factor also added additional meaning to the sex differences in tolerance, threshold, and unpleasantness ratings to cold stimuli [90]. Similarly, 124

masculinity/femininity scores partially mediated the sex differences observed in a cold pressor task [79]. Participants with a strong gender group identity displayed large male–​female differences for both hypothetical and electrically stimulated pain tolerance ratings, whereas men and women with low gender group identity reported similar tolerances [59]. Finally, when gender roles are manipulated, men and women have equal tolerance to cold stimuli [67], which suggests previously observed sex differences may be partially due to social expectations. Bartley and Fillingim [1] indicated that psychosocial factors and coping strategies may differ between men and women, thereby contributing to sex differences in pain. This is supported by a subsequent study that found thermal pain threshold was greater in women [40], but largely explained by sex differences in ratings of pain-related fear (see section “Psychological Factors” later in this chapter). These various factors may be associated with gender roles, but have yet to be fully examined. Gender roles have not been well explored in clinical settings. Women are more likely to seek medical attention and report health care complaints [50], although these results could spring from either sex or gender differences. However, a large cross-cultural study of multiple health complaints in adolescents suggests social gender roles could be contributing to these differences because they varied considerably between cultures [80]. The sex differences in recurring health complaints were generally small in 11-year-olds, but increased substantially by age 15 in some countries. This finding may be due to physiological changes with maturation, but may also be evidence for increased influence of social roles and expectations. In summary, although gender roles are likely to influence clinical pain, the relationship is not well understood. ETHNICITY AND RACE The terms ethnicity and race are often used interchangeably. However, for the purposes of this chapter, we will define ethnicity as belonging to a group of people who share a common background related to social, cultural, language, and geographical factors [61]. In contrast, the term race will be used to describe group membership on the basis of physical differences, although a strong social contribution to determination of race is acknowledged [47]. For example, the National Institutes of Health considers Caucasian, African American, and Asian 125

to be races, whereas Hispanic is considered an ethnicity. Similarly to sex and gender, both race and ethnicity can be confounded by additional complex social and cultural roles and expectations. Determination of ethnicity and race most commonly relies on subject self-report, and our discussion will focus on such studies that used this methodology for identification, as opposed to genetic definitions using ancestry markers. Next to sex, ethnicity and race are probably one of the most common differences identified during clinical encounters. Clinical Pain Several studies have reported on ethnic and racial differences in the clinical pain experience, with varied results. For example, migraine headache is more prevalent in Caucasians than in either African Americans or Asians; however, African Americans report higher migraine pain intensities [76]. African Americans generally report greater pain than ​Caucasians across the life span and across various patient populations [14,34], but inconsistencies are also observed. African Americans, compared with Caucasians, report greater pain with temporomandibular disorders [88], greater pain after surgery to correct scoliosis [87], and higher pain with lower experimental pain tolerance with chronic pain conditions [14]. Native Americans also have a higher prevalence of chronic pain compared with non-Hispanic White Americans overall in a review of 12 studies [42]. But this racial group has not been well studied historically. Further complicating the issue, racial/ethnic associations with affective pain and disability ratings may differ from sensory–discriminative pain intensity ratings. For example, although African American subjects reported higher pain intensity from migraine headaches, their reports of pain disability were lower when compared with Caucasian subjects [76]. In another study, African Americans reported higher levels of pain unpleasantness, emotional distress, and pain behavior, despite similar pain intensities [66]. The inconsistency in these results may be due to other confounding factors such as sex, socioeconomic status, or pain location. When study participants are matched by sex, educational level, work status, duration of pain, and location of pain, similar levels of pain intensity, unpleasantness, and interference with activities are noted across the racial and ethnic groups [16]. However, higher pain intensity occurs in African Americans even when investigators control for age and socioeconomic status [76]. Overall, racial disparities in pain reporting as well as in pain treatment have been consistently documented [34]. Accordingly, Green et al. [34] suggest that greater education and training in racial and ethnic factors is warranted for all health care professionals. 126

Experimental Pain The difficulty in comparing clinical pain conditions between ethnic and racial groups has led to interest in determining experimental pain sensitivities in both healthy and pain populations [6]. In a small sample of healthy college students, African American subjects had lower tolerance and higher ratings of unpleasantness to heat stimuli [15]. In a larger sample of college students, African American subjects had lower tolerance to heat, cold pressor and ischemic pain when compared with Caucasians [6]. However, only for heat stimuli were the differences in pain intensity and unpleasantness ratings significantly higher for African Americans [6]. These results were largely supported in a follow-up study, with Hispanic subjects also exhibiting lower tolerance to heat and cold when compared with non-​Hispanic Caucasian subjects [61]. Although relatively little information is available involving additional races, African Americans, Hispanic and Asian Americans all had shorter withdrawal times and higher pain ratings than European Americans during the cold pressor task [43]. However, in a heat pain task, only Asian Americans displayed greater pain ratings at each temperature tested compared with African Americans, European Americans, and Hispanics [43]. Racial and ethnic differences may be more pronounced for experimental pain assessments than observed in clinical pain conditions. This statement is supported by an interesting study combining experimental and clinical pain models in patients seeking treatment for chronic pain conditions. Although African Americans reported both higher clinical pain intensity and disability ratings and lower experimental pain tolerance [14], the differences in clinical pain were smaller than the differences in experimental pain tolerance. Further, QST measurements and clinical pain reports in patients with knee osteoarthritis both showed greater pain and pain sensitivity in African Americans than in non- Hispanic Whites [9]. However, after controlling for education and annual income, the clinical pain racial differences diminished, but the QST pain sensitivity differences remained. This finding suggests larger racial differences with experimentally induced pain as compared with clinical pain. In addition to experimental pain sensitivity studies, racial and ethnic differences in endogenous pain inhibition have been reported. Diffuse noxious inhibitory control (DNIC, see Chapter 3) represents an endogenous descending inhibition system, in which the application of a painful conditioning stimulus evokes a generalized analgesia, inhibiting pain from a noxious test stimulus. This phenomenon is also referred to as “pain inhibits pain.” Using a DNIC 127

protocol, one study found that non-Hispanic Caucasians had greater reduction in electrically induced pain following ischemic pain, when compared with ​African Americans, suggesting Caucasians may have greater descending pain inhibition than African Americans [7]. PSYCHOLOGICAL FACTORS Negative Emotionality, Pain Catastrophizing, and Fear of Pain Various approaches have been used to investigate psychological traits (enduring dimensions of psychological individual differences) and states (temporary or transient dimensions of psychological individual differences). Trait individual differences can be classified in many ways, but hierarchical structures have been increasingly recognized. These include traditional higher-order personality dimensions, such as neuroticism and extraversion; trait and mood scales, such as negative and positive affect or trait anxiety; and various dispositional or vulnerability scales, such as pain catastrophizing or pain-related fear. This section will focus on what we believe to be of most relevance for pain-related constructs—personality traits, negative emotionality, pain catastrophizing, and pain-related fear. Personality traits have been characterized using several models, but the two most consistently described traits are neuroticism (also referred to as negative emotionality) and extraversion. Neuroticism is associated with anxious, worrisome, overly emotional, moody, and negative thoughts, feelings, and behaviors. Extraversion is associated with sociable, optimistic, excitement- craving, and easygoing traits. Neuroticism and extraversion are highly correlated with negative and positive affect, respectively; however, they are not opposites of each other [84]. For example, individuals can be high in both neuroticism and extraversion. Many personality assessment instruments are available, ranging from the100-item Eysenck Personality Questionnaire (EPQ) to the 10-item Positive and Negative Affect Schedule (​PANAS) [84]. Pain catastrophizing is a negative cognitive style, which at the extreme includes feelings and beliefs that the pain experienced is beyond the control of the individual and will inevitably result in the worst possible outcome. Pain catastrophizing is believed to be a multidimensional construct comprised of magnification, rumination, and helplessness or pessimism. The Pain Catastrophizing Scale (PCS) is one example of a measure of pain catastrophizing 128

[77]. Example statements include: “I feel I can’t go on, it’s awful and I feel that it overwhelms me, and I anxiously want the pain to go away.” Another commonly used instrument is the Catastrophizing Scale of the Coping Strategies Questionnaire (CSQ) [71]. Pain-related fear can also be measured in multiple ways. The Fear of Pain Questionnaire-III (FPQ) is a self-report measure of anticipated fear for hypothetical situations that assesses severe pain (e.g., “breaking your neck”), minor pain (e.g., “having a muscle cramp”), and medical or procedure-related pain (e.g., “having a tooth pulled”) [52]. A high score on the FPQ indicates a high level of pain-related fear. The Fear-Avoidance Beliefs Questionnaire (FABQ) assesses pain-related fear associated with clinical pain conditions, specifically addressing fear-avoidance beliefs of physical activity [83]. A practical example is an individual with an elevated FABQ score would be hesitant to resume therapeutic exercise in response to shoulder pain, believing such activity would result in reinjury. Pain-related fear may depend on an individual’s prior pain experiences, present stress level, pain behavior, and certain personality traits. Clinical Pain Negative emotionality and its related subfacets have been associated with chronic pain perception, such that patients who express greater negative emotionality are more likely to report more health complaints and chronic pain conditions [32,53,85]. Similarly, pain catastrophizing and pain-related fear are associated with poorer function and greater pain in patient populations, such as those with osteoarthritis [75], shoulder pain [28], or fibromyalgia [33,37]. However, these cross-sectional studies are unable to clarify whether the poor health and chronic pain led to greater negative affect or vice versa. Additional prospective research suggests pain-related fear and catastrophizing can predict greater pain and poorer outcomes in patient populations. Preoperative pain catastrophizing was the best predictor of poor self-reported function 6 months after total knee replacement in a prospective study of 140 patients [63]. Patients with elevated pain-related fear and catastrophizing measures at the acute stage of low back pain were more likely to have greater disability for up to 6 months [25,58], and at 1 year [5]. However, elevated pain-related fear (as measured on the FABQ) was predictive of work status at 1 year when examined in isolation, but only pain centralization was predictive when several factors were considered simultaneously [86]. Finally, changes in pain catastrophizing were predictive of subsequent changes in pain in 129

57 patients with fibromyalgia [8], but not vice versa, suggesting the psychological factor preceded the change in pain. Collectively, these studies suggest a temporal relationship such that pain-related fear and pain catastrophizing at symptom onset are precursors of reports of greater pain and disability even 6–12 months later. Thus, they may be viewed as predictors of poor outcome and should be considered when looking at risk factors for chronicity. Experimental Pain A large body of literature has compared psychosocial individual differences in relation to experimental cutaneous pain. Higher self-reports of negative emotionality, anxiety, pain catastrophizing, and fear of pain are associated with lower pain thresholds, lower pain tolerance, and higher pain sensory and affective ratings [13,36]. For example, using the cold pressor task, fear of pain was a unique predictor of pain tolerance and intensity [23,39], whereas in another study only pain quality was predicted by pain-related fear and catastrophizing [48]. In patients with low back pain, fear avoidance was related to initial heat pain ratings, whereas catastrophizing was related to temporal summation, that is, the increase in pain ratings when the heat was maintained [29]. Fig. 5.3 shows an example of the association between fear of pain and heat pain ratings in an experimental pain condition. Higher pain ratings were positivity correlated with FPQ scores when a 49°C thermal stimulus was applied to the trunk in healthy individuals (S. George, unpublished data). Although few studies exist involving experimental deep-tissue pain, temporomandibular muscle pain responses were partially explained by negative affect during hypertonic saline infusion [91]. Further, fear of pain and pain catastrophizing are predictive of pain intensity, evoked pain, development of kinesophobia, and shoulder disability in studies using the delayed onset muscle soreness (DOMS) model [26,27,57]. Similarly, using an intramuscular infusion model of pain, individuals with the highest negative emotionality traits reported greater primary pain, greater mechanical hyperalgesia, and were twice as likely to experience referred pain than those with low negative emotionality traits [49]. 130

FIGURE 5-3 Fear of pain is associated with numerical experimental pain ratings on a scale of 0–100 (r = 0.47, P < 0.01) in response to 49°C stimuli to the trunk. Fear of pain was measured with the Fear of Pain Questionnaire-III (FPQ). In summary, both clinical and experimental studies consistently support the association between pain or disability outcomes and negative temperament, pain catastrophizing, and pain-related fear. Furthermore, patients with low back pain differentially respond to rehabilitation on the basis of their fear-avoidance beliefs [21,24], suggesting patients’ psychological traits may have important consequences on pain and disability and may affect the clinician’s choice of treatment. GENETICS AND HERITABILITY The genetic influence on pain is challenging to study, in part because of difficulties in defining pain phenotypes. Sivert [74] defines a pain phenotype as “a measure that directly or indirectly reflects the processing of parts or the whole of the pain system, excluding tissue pathology and pain expression.” However, tissue pathology is often a confounding factor in clinical pain phenotypes. The question arises, what constitutes a “pain gene”? Is a gene that is linked to osteoarthritis a pain gene or simply a gene linked to tissue pathology? There can 131

be several different pain phenotypes that may be impacted by a genetic factor, such as pain intensity, pain quality, pain duration, mechanical hyperalgesia, measures of centrally mediated pain facilitation or inhibition, or even response to pain treatment. Accordingly, the investigations of the genetic contributions to pain variability are still in their infancy and will likely continue to evolve. Heritability has been traditionally investigated using twin studies (identical vs. fraternal twins) or family-based linkage studies to determine the underlying genetic versus environmental factors contributing to a disease. A recent meta- analysis of twin studies on clinical pain conditions reported estimates of 33–53% heritability for migraine and 30–38% heritability for back pain [55]. In clinical populations, it is challenging to differentiate the heritability of the underlying pathology as opposed to the heritability of experiencing pain. However, the authors specifically noted that one study, finding a common factor to explain nearly half the risk of developing pain at different musculoskeletal sites [89] and thus varied underlying pathological conditions, suggests that the genetic influence is likely to be primarily on pain processing. Although few twin studies have examined pain sensitivity specifically, one study involving experimentally evoked pain (cold pressor and thermal heat) demonstrated that genetics accounted for roughly 60% of the variance in cold pressor pain, but only 26% of the variance in heat pain [58].These twin studies collectively suggest that genetic factors can play an important role in pain sensitivity, but they may not influence different nociceptive stimuli or pain conditions equally. Whereas twin studies have been used for some time to investigate the general heritability of various conditions, association studies investigating the links between specific genotype variations and pain phenotypes are increasingly common. The human genetic code was mapped only relatively recently, allowing researchers to examine single nucleotide polymorphisms (SNPs), that is, variations in the alleles G, C, T, A at a specific location on a gene. This advance has promoted rapidly evolving research on specific genetic variability as a contributing factor to various forms of pathology and disease. For example, 11% of the variance in a combined measure of overall pain sensitivity results from variations in a single gene [12]. Genetic influences on phenotypes can involve complex interactions between multiple genes and the environment. Accordingly, large sample sizes are typically needed to determine significant associations between genotype and pain phenotypes. To maximize statistical power and minimize false positives, multiple candidate pain genes have been identified and prioritized for use in association studies [2]. The criteria for prioritizing candidate pain genes for human association studies are: (1) adequate evidence supporting the gene’s role 132

in pain processing, (2) genetic variation frequent enough to affect clinical manifestation, and (3) a high likelihood that genetic variation affects protein function. Also gaining popularity are genome-wide association studies, which examine associations between phenotypes (e.g., pain) and SNPs sampled from across the entire human genome. Both approaches are likely to advance our understanding of the genetic influences on pain in the coming decades. Several lines of evidence now support the underlying hypothesis that genotype influences pain perception. Three examples of high-priority genes that have been linked to pain perception in humans include the catecholamine-o-methyltransferase gene (COMT), the transient receptor potential subtype 1 gene (TRPV1), and the µ- opioid receptor gene (OPRM1). The COMT gene is important for the enzymatic breakdown of catecholamines—hormones released during physiological stress— such as epinephrine, norepinephrine, and dopamine. Thus, the COMT gene is likely involved in pain by altering the expression of the enzyme involved in the degradation of these substances. TRPV1, also known as the vanilloid receptor, is a membrane channel receptor found in both the peripheral and central nervous system. This receptor is activated by various nociceptive stimuli such as low pH, heat, and capsaicin (hot peppers), and is thus likely to be involved in pain transmission. OPRM1 is a μ-opioid receptor that is involved in the analgesic response to opioid drugs. The OPRM1 gene is believed to be important in the variability of opioid response to medication and in the endogenous opioid mechanisms that serve to inhibit pain. These examples were selected only to highlight several genes that have been investigated in the literature, and are not meant to represent a systematic or comprehensive review of all pain-related genes. Clinical Pain Genetic studies involving clinical pain patients are only beginning to emerge. For example, in patients undergoing shoulder surgery, postsurgical pain at 3–5 months was associated with variations in the COMT gene with interactions with psychological traits [27]. The GCH1 gene (which governs the expression of guanosine triphosphate cyclohydrolase I, an enzyme involved in catecholamine production) was associated with pain reports following diskectomy for radiculopathy [78]. As would be expected, the OPRM1 gene was associated with the morphine (an opioid) dose needed for pain control in patients with cancer pain [46]. 133

Experimental Pain In healthy subjects, the COMT gene has been linked to pain perception and heterogeneity using thermal, mechanical, and ischemic experimental pain stimuli [11,12]. A study of muscle pain using the hypertonic saline model found that COMT was associated with cortical imaging of μ-opioid receptor binding, suggesting that this gene plays an important role in pain perception [91]. Additionally, the β-adrenergic receptors 2 and 3 genes (ADRB2 and ADRB3) may also be important in mediating catecholamine levels, ultimately influencing pain sensitivity [54]. The TRPV1 gene influences cold cutaneous pain, but not noxious heat in humans [44]. The OPRM1 gene is associated with higher pressure pain thresholds [17] and with decreased event-related potentials from a pain stimulus [51] in healthy volunteers. AGE The effect of age on pain variability can be difficult to assess because several of the previously discussed factors (physiological, psychological, and social) may vary from youth through adulthood, and potentially on into older adult years. Although we have attempted to discuss several of these separately, considering them as a function of age has value for the clinician. A review of the literature including over 140 citations on age-related effects on pain concluded that thresholds were more frequently elevated (showing less sensitivity to pain) in older adults. However, the review found that age-related effects can vary with modality (thermal and mechanical more than electrical), location (distal more than proximal), and temporal/spatial characteristics [30]. It is less clear whether systematic changes in suprathreshold pain perception occur with aging. It is possible that older individuals may have a reduced region between pain awareness (threshold) and pain tolerance. Accordingly, advancing age may result in greater central sensitization, as determined by measures of temporal summation and secondary mechanical hyperalgesia, and less ability to endogenously inhibit pain, suggesting that older adults may experience greater pain sensitivity. Collectively, all of these changes result in nervous system adaptations that may delay initial onset of pain reports but take a longer time to resolve than younger adults [30]. 134

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