RESEARCH IDEAS

Trigger Points and Central Modulation—A New Hypothesis
Mark J. L. Hocking, BVSc

ABSTRACT. Objective: A new hypothesis is proposed to explain the pathogenesis, symptomatology, and treatment of the trigger points [TrPs], which define the myofascial pain syndrome [MPS]. Hypothesis: TrPs are formed due to sustained α-motoneuron plateau depolarization, which is maintained by one of two different central nervous system [CNS] mechanisms. “Antecedent” TrPs are formed in withdrawal reflex agonist muscles due to central sensitization of the C fiber nociceptive withdrawal reflex [NWR], visceromotor reflex [VMR], or nociceptive jaw-opening reflex [NJOR]. “Consequent” TrPs result in withdrawal reflex antagonist muscles due to compensatory reticulospinal or reticulo-trigeminal motor facilitation. Afferent nociceptive signals arise from both latent and active TrPs. However, latent TrPs are not spontaneously painful, because of complete inhibition of nociceptive transmission at the spinal cord or trigeminal nucleus [SC/TN] levels. Marked SC/TN sensitization [especially with a reduced antinociceptive functional reserve] may overwhelm the brainstem antinociceptive mechanism, going beyond the MPS into the generalized allodynia of the fibromyalgia syndrome [FMS]. The principal brainstem nuclei involved in TrP sensory and motor modulation have other diverse homeostatic roles; therefore TrP-induced brainstem dysfunction may contribute to the pathogenesis of a variety of sensory, motor, and autonomic disorders. Treatment involves noxious stimulus-induced transient inhibition of the CNS mechanisms that sustain TrPs. This allows stretching of the contractured muscle fibers to resolve the TrP local energy crisis, and to reverse muscle nociceptor and CNS sensitization. Conclusion: This hypothesis proposes that TrPs result in the muscles due to sustained αmotoneuron plateau depolarization. Descending inhibition normally ensures that most TrPs remain latent, but FMS may result if this inhibitory mechanism is overwhelmed. KEYWORDS. Myofascial pain syndrome, trigger points, central sensitization, ventromedial medulla, descending modulation

INTRODUCTION In this paper I propose a new hypothesis for the pathophysiology of trigger points [TrPs]. As

a veterinarian who frequently treats the TrPs of dogs, I cannot reconcile some of my clinical observations with current TrP hypotheses. These observations include the following: first, the

Mark J. L. Hocking, BVSc, Gladesville Veterinary Hospital, Gladesville NSW, Australia. Address correspondence to: Mark J. L. Hocking, BVSc, Gladesville Veterinary Hospital, 449 Victoria Road, Gladesville NSW 2111, Australia. E-mail: mark.j.hocking@hotmail.com Journal of Musculoskeletal Pain, Vol. 18(2), 2010 Available online at www.informaworld.com/WJMP 2010 Informa Healthcare USA, Inc. All rights reserved. doi: 10.3109/10582452.2010.483964

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most clinically relevant TrPs [those that restrict stride and distort posture] are found predominantly in flexor muscles. Second, after treatment of all TrPs in a lame limb, the lameness will sometimes shift to another limb. Third, despite it being obvious that not all canine TrPs are active [multiple TrPs are usually found in the lame limb and TrPs are also typically found in the non-lame limbs], it is normally impossible to determine which TrPs in a lame limb are active and which are latent. All TrPs feel similar, palpation elicits similar pain reactions, and appropriate stimulation induces a similar local twitch response. I have brought together relevant information from numerous sources in an effort to explain my observations. These sources include the human TrP literature [readers are referred to Travell and Simons (1) and Mense and Simons (2) for a comprehensive TrP review] and published pain and other neurophysiological experimental research. My hypothesis attempts to explain the pathogenesis, symptomatology, and treatment of TrPs in both humans and other vertebrates. It may also help to solve the larger puzzle of pain and provide insight into the pathogenesis of a variety of other incompletely understood sensory, motor, and autonomic disorders. Fundamental Trigger Point Pathophysiological Mechanism I propose that TrPs do not form due to a critical abnormality of neuromuscular function at the motor endplate of an extrafusal skeletal muscle fiber (3), but are the result of the chronic expression of an intrinsic α-motoneuron property, the plateau potential. A plateau potential is a sustained partial depolarization of an αmotoneuron that may persist for at least several seconds after synaptic excitation has reduced or ceased (4). α-Motoneurons may exhibit the intrinsic membrane property of bistability, where they are stable at either of two different membrane potentials: a less excitable, more hyperpolarized state and a more excitable, partially depolarized plateau state (5, 6). Repeated plateau potential activation leads to α-motoneuron warm-up, where there is a decreased threshold for, and increased duration of, plateau potentials (7). Sustained partial depolarization of the α-motoneuron increases the release of acetylcholine packets at the motor endplate. This man-

ifests electrically as endplate noise, which can be recorded by needle electromyogram at the active locus of a TrP. I propose that centrally maintained αmotoneuron plateau depolarization, rather than an intrinsic disorder of the motor endplate, is the fundamental pathophysiological mechanism which perpetuates the local muscle contracture associated with a TrP. Warm up of α-motoneuron plateau depolarization is maintained by one of two different central nervous system [CNS] mechanisms, resulting in two essentially different types of TrPs, which I call “antecedent” and “consequent” TrPs. Antecedent TrPs are sustained by central sensitization of the C fiber polysynaptic withdrawal reflexes: the NWR, the VMR, and the NJOR. Antecedent TrPs are formed in withdrawal reflex agonist muscles, which are generally, but not exclusively, flexor muscles. Consequent TrPs are sustained by tonic reticulospinal or reticulo-trigeminal facilitation of plateau potentials in withdrawal reflex antagonist α-motoneurons. Consequent TrPs are formed in withdrawal reflex antagonist muscles, which are generally, but not exclusively, extensor muscles. Pathophysiology of Antecedent Trigger Points The withdrawal reflexes are complex polysynaptic reflexes, mediated by spinal cord or trigeminal nucleus [SC/TN] neural circuitry that facilitate either rapid withdrawal from a potentially damaging acute stimulus or ongoing immobilization of an injured area to prevent further damage and allow healing. Activation of the NWR typically results in simultaneous contraction of ipsilateral limb flexor muscles and reciprocal inhibition of ipsilateral limb extensor muscles to effect the withdrawal. Simultaneous contraction of contralateral limb extensors and reciprocal inhibition of contralateral limb flexors may also result via the interconnected crossed extensor reflex mechanism to prevent the animal from overbalancing. The VMR is another spinal reflex that may also cause contraction of skeletal muscles but as a result of visceral afferent, rather than somatic or cutaneous afferent noxious input. The NJOR leads to contraction of jaw opening muscles and reciprocal inhibition of jaw closing muscles as a result of orofacial noxious input.

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I suggest that sustained stimulation of peripheral nociceptors for cutaneous, somatic, or visceral C afferent neurons is a precondition for the formation of antecedent TrPs. Such sustained noxious stimulation may result from traumatic injury, inflammatory disease, or sensitization of nociceptors in other TrPs. Only ongoing C fiber-mediated nociceptive transmission to the SC/TN leads to central sensitization of the above-mentioned withdrawal reflex mechanisms, resulting in sustained efferent αmotoneuron activation of agonist muscles and simultaneous inhibition of antagonist muscles. The reflex response to C nociceptor input is a low level of muscular contraction, compared to the reflex response to myelinated afferent input that is monitored with most methods of behavioral observation or standard electromyographic recording (8). Central sensitization is a process that results in an increase in efficiency of synaptic transmission between neurons and an increased excitability and prolonged discharge [plateau depolarization] of postsynaptic neurons following certain forms of repeated or sustained synaptic excitation. Prolonged noxious stimulation that activates C afferent neurons leads to SC/TN central sensitization at the various synapses of the activated polysynaptic withdrawal reflex mechanism/s [e.g., in the SC, plateau potentials can be evoked by primary sensory afferents in both dorsal horn [DH] neurons and motoneurons (9)] (10–12). Sustained application of an appropriate nociceptive conditioning stimulus, even at low levels, is sufficient to maintain DH central sensitization (13). Dorsal horn central sensitization leads to an enhanced pain sensation [secondary hyperalgesia] and reduced pain threshold [allodynia]. The synaptic and postsynaptic mechanisms of central sensitization are complex, but it is clear that they result in plateau depolarization of the postsynaptic neuron due to progressive activation of L-type calcium channels (10, 12, 14). Facilitation of the C fiber withdrawal reflexes due to SC/TN central sensitization both predisposes to antecedent TrP formation and helps perpetuate these TrPs. The NWR persists during sleep (15), so ongoing activation of the NWR may maintain antecedent TrPs indefinitely. Lamina V wide dynamic range [WDR, convergent, multireceptive] SC/TN neurons are likely to be critically involved in the pathogenesis of antecedent TrPs. Lamina V WDR neu-

rons may show graded responses to innocuous and noxious mechanical stimuli, noxious heat, noxious cold, and noxious muscle or visceral stimuli (16). They respond to repetitive C fiber activation with a windup discharge [central sensitization] and are intercalated in the withdrawal reflex pathway (16, 17). I propose that warm up of α-motoneuron plateau depolarization, which is maintained by central sensitization of the C fiber withdrawal reflexes, leads to an ongoing low-level increase in acetylcholine packet release at the motor endplates of both active and latent antecedent TrPs. The axons of α-motoneurons in the plateau state exhibit a low-level increase in electroneurogram activity, most visible when action potentials are blocked (6), which closely resembles recordings by needle electromyogram of endplate noise from the active locus of a TrP. The low-amplitude motor endplate potentials of endplate noise cause ongoing partial depolarization of the postjunctional membrane and subsequent focal sustained contractile activity of the muscle sarcomeres in the immediate vicinity of the motor endplate zone (18). Persistent contractile activity of these sarcomeres leads to a local energy crisis, as explained by the current energy crisis hypothesis. This states that ongoing contraction squeezes shut the capillaries that supply the nutritional and oxygen needs of that region, which simultaneously has an increased metabolic demand (19). The severe but local energy crisis leads to a failure of relaxation of the sarcomeres [a contracture] due to an inadequate local supply of adenosine triphosphate, which is required by the Ca2+ pump that returns calcium ions to the sarcoplasmic reticulum to terminate contractile activity (19). Histopathologically, the localized contracture of a segment of muscle fiber around the motor endplate appears as a contraction knot (20). Each motoneuron controls between 300 muscle fibers and 1,500 muscle fibers in postural and limb muscles (21), so central facilitation of αmotoneuron discharge would predispose to the simultaneous formation of multiple contraction knots. If contraction knots develop in enough muscle fibers, a palpable nodule and restriction in stretch range of motion of the muscle would result. I propose that sustained low-level motoneuronal activity is sufficient to maintain the TrP local energy crisis and muscle fiber contracture for an indefinite period.

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The energy crisis and profound hypoxia that develop around the motor endplate zone of a skeletal muscle containing a TrP lead to sensitization of local nociceptors, as nociceptive sensory nerves [and small blood vessels and postganglionic sympathetic nerves] are normally part of the same neurovascular bundle that includes the motor nerve (22). I propose that afferent nociceptive signals arise from sensitized local muscle nociceptors in both latent and active TrPs. I suggest that concurrent alteration of local sympathetic neuronal activity, which leads to vasodilation in the vicinity of a TrP, is a mechanism that has evolved to counter the microvascular compromise and marked hypoxia that occur within a TrP. This altered sympathetic neuronal activity can explain both the adjacent thermographic hotspot and outer shell of increased oxygen tension associated with a TrP (23). As the sensitized type IV [C fiber] muscle nociceptors within antecedent TrPs contribute further to C fiber nociceptive afferent input and induce further withdrawal reflex central sensitization, antecedent TrPs may self-perpetuate long after the initiating noxious stimulus has ceased. Muscle C fibers are more effective than cutaneous C fibers at inducing prolonged facilitation of the NWR (24). By increasing the NWR central sensitization, antecedent TrPs may lead to the formation of other TrPs in synergistic [flexor] muscles and also cause ongoing reciprocal inhibition and motor dysfunction of antagonist [extensor] muscles. The involvement of the sensitized NWR mechanism in the pathogenesis of antecedent TrPs can explain the reported clinical observation of shortened, hyperexcitable agonist, and functionally weakened antagonist muscles [e.g., tight iliopsoas/tensor fasciae latae and weak gluteal muscles (25)]. Sustained partial depolarization of the αmotoneurons that supply affected muscle fibers influences, but does not prevent, normal action potential stimulation of muscular contraction. Electromyographically, a muscle containing a TrP shows an absence of motor unit action potentials at rest, but an increased responsiveness when the muscle is voluntarily contracted and loaded (26). Supraspinal centers are critically involved in descending modulation [a shifting balance between facilitation and inhibition] of the withdrawal reflex mechanisms, SC/TN central

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sensitization, and ascending nociceptive transmission. Only in the presence of sufficient descending facilitatory command does input from muscle or joint flexor reflex afferents activate α-motoneurons (27, 28). The activation of the NWR by noxious stimulation anywhere on a limb does not lead to one stereotypical muscular response. The NWR mechanism has a modular organization [the cutaneous receptive field for each limb muscle, or few synergistic muscles, corresponds to the skin area withdrawn upon contraction of the effector muscle[s] when the limb is in the standing position (29)], so ongoing noxious stimulation of different areas would result in antecedent TrP formation in different combinations of agonist muscles. Noxious stimulation of some limb areas results in the NWR-mediated contraction of ipsilateral extensor muscles (29). Withdrawal reflex mechanisms develop in utero. The reflex responses of neonates are exaggerated compared to adults, and the NWR synaptic connections are fine-tuned over the postnatal period, with a depression of the overall response and an individuation and restriction of the response to an isolated withdrawal movement (30). The lamina V WDR neurons that are intercalated in the withdrawal reflex pathway and are thought to play a major role in pain are organized musculotopically, rather than somatotopically, during development by movement-induced patterns of primary afferent activity (16). Ascending Nociceptive Transmission At the SC/TN DH, nociceptive information from muscle is transmitted from primary afferent neurons to second-order neurons, which then project to supraspinal centers (31). Almost all postsynaptic projection neurons with input from nociceptive muscle afferents also process information from other receptors in other tissues (31). The WDR neurons, which may respond to noxious or innocuous input from cutaneous, somatic, or visceral receptors, include both neurons that project in ascending pathways and interneurons involved in polysynaptic reflexes (32). Within the SC DH, nociceptive information from the viscera, skin, and other organs is subject to extensive processing by a diversity of mechanisms, which may enhance or inhibit its transfer to higher centers (33).

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Nociceptive signals may be transmitted to a wide variety of supraspinal centers via multiple parallel ascending pathways (31, 34). Many projection pathways decussate at the ventral commissure, before ascending on the contralateral side of the SC (31, 34). It is likely that the properties and terminations of the nociceptive impulse-carrying ascending projections [i.e., the fiber type, terminal topographic organization, number of synapses crossed, and function of contacted postsynaptic neurons] help to decode the character and physiological effects of pain. Muscle [TrP] pain is typically conducted slowly, poorly localized, and may lead to considerable disruption of homeostasis (35). This is probably because of substantial transmission through unmyelinated axons, less distinct topographic organization of terminals, polysynaptic projection to cerebral centers, and termination at diverse brainstem centers [which mediate the physiological response to pain]. Supraspinal Modulation I propose that brainstem, especially medullary, centers are integrally involved in the pathophysiology of TrPs and now consider these supraspinal mechanisms. A highly interconnected complex of brainstem nuclei facilitates or inhibits ascending sensory [including nociceptive] and descending motor and autonomic transmission, predominantly via projections to the SC/TN. Supraspinal centers that are critically involved in the descending modulation of pain include the brainstem noradrenergic nuclei [A5, locus ceruleus, A7 nuclei] and the medullary reticular formation and raphe nuclei [especially the rostral ventromedial medulla/ventromedial medulla [RVM/VMM] and the caudal medullary subnucleus reticularis dorsalis [SRD, dorsal reticular nucleus]] (33, 36). These brainstem centers project to the SC/TN DH, where the ascending nociceptive signal may be enhanced or inhibited [bidirectionally modulated]. These centers may also modulate pain-related responses via ascending projections (36). Under resting conditions, descending inhibition dampens excessive sensitivity to noxious stimulation (33). This role may be counterbalanced by descending facilitation, which enhances the signal to noise ratio for the per-

ception of noxious stimuli (33). Activation of a single supraspinal pain modulatory center may, via contrasting mechanisms, simultaneously trigger both descending inhibition and facilitation of nociception (33). Ordinarily, the output of brainstem nociceptive inhibitory neurons is greater than the output of brainstem nociceptive facilitatory neurons, but this balance is labile (37) and may be shifted in either direction by internal or external factors. Therefore, these centers usually maintain a resting level of nociceptive inhibitory tone [reversible SC block typically results in an increased responsiveness of nociceptive DH neurons (38, 39)]. However, pain inhibitory mechanisms may be intensified either endogenously, e.g., during sleep, stress-induced analgesia, exercise-induced analgesia, and attentional modulation of pain, or exogenously, e.g., during stimulation-induced analgesia and after pharmaceutical administration. The balance may be shifted under other circumstances [injury, illness, stress, fatigue] to facilitate ascending nociceptive transmission. I propose that afferent nociceptive signals arise from both latent and active TrPs, but the signals from latent TrPs are completely inhibited at the SC/TN DH by tonically active descending antinociceptive mechanisms mediated by these brainstem centers [so latent TrPs are clinically quiescent with respect to spontaneous pain, but may show all the other clinical characteristics of active TrPs (40)]. That is, despite the existence of a continuum of nociceptor sensitization between latent and active TrPs, only active TrPs are spontaneously painful because the signal from latent TrPs is actively blocked before reaching consciousness [unless the latent TrP is palpated or its nociceptive signal is otherwise augmented]. The level of descending antinociceptive tone is probably primarily regulated by the brainstem pain modulatory centers in direct response to the intensity of the incoming ascending nociceptive signal. The Ventromedial Medulla The VMM contains an important cluster of nuclei that are involved in both the facilitation and inhibition of sensory [including nociceptive], autonomic, and motor functions. These nuclei include the midline raphe nuclei [nucleus raphe magnus [NRM], nucleus raphe obscurus

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[NRO], and nucleus raphe pallidus [NRP]] and the adjacent reticular formation nuclei [nucleus reticularis gigantocellularis, nucleus reticularis magnocellularis [NRMC, nucleus reticularis gigantocellularis pars alpha] and nucleus reticularis paragigantocellularis lateralis] (33, 41–43). I propose that the VMM is critically involved in both facilitation and inhibition of TrP formation and TrP nociception, as well as in the treatment of TrPs. Neurons in the VMM mostly provide direct descending projections to all levels of the SC/TN, but those in different areas of the VMM have preferential projections through different spinal funiculi and preferential laminar destinations. Cells in the rostrally located NRM, NRMC, and nucleus reticularis paragigantocellularis lateralis [RVM] tend to project through the dorsolateral funiculus to target the DH, those in the rostral part of the NRP/NRO project via the lateral funiculus to target the intermediate horn [including the intermediolateral cell column], and those in the caudal NRP/NRO project through the ventrolateral and ventral funiculi to target the ventral horn (43). I suggest that the primary function of the VMM is to regulate SC/TN neuronal and reflex excitability. By altering the excitability of neurons at the SC/TN level, neurons in the VMM may simultaneously facilitate and inhibit ascending noxious and innocuous sensory transmission and facilitate and inhibit descending autonomic and motor activity. Because of this bidirectional influence on the excitability of neurons at all segmental levels and in all laminae of the SC/TN [and at brainstem somatic and autonomic motor nuclei], the VMM has been reported to be involved in the regulation of very diverse bodily functions. Reported functions of the VMM include nociceptive and innocuous sensory modulation; modulation of locomotion and basal muscle tone; modulation of autonomic activity [heart rate, blood pressure, respiration, thermoregulation, digestion, micturition, and sexual function]; regulation of cortical arousal and sleep; control of SC/TN central sensitization and reflex activity [including the NWR]; and supply of neurotransmitters to spinal and supraspinal sites (42–45). The VMM contains a mixed population of neurons that have either phasic or tonic and facilitatory or inhibitory effects on sensory [including nociceptive], autonomic, and motor

functions at the SC/TN level. Pharmacological or electrical stimulation of the RVM can produce either facilitation or suppression of nociception or motor activity, depending on the subgroups of neurons activated and the state of the sleep/wake cycle at the time of stimulation (44). Several overlapping classification systems of the RVM neurons have been described, which depend on different in vivo/in vitro characteristics. The RVM neurons can be broadly divided into phasically active non-serotonergic neurons and tonically active serotonergic neurons. The non-serotonergic RVM neurons include on-, off-, and neutral-cells. These neurons have an irregular discharge pattern and/or a high mean discharge rate (41). The RVM onand off-cells have been shown to phasically modulate nociceptive transmission in opposite directions in the anesthetized rat. The on-cells facilitate nociceptive transmission, are directly inhibited by µ-opioids, and their activity is thought to be facilitatory [or in fact obligatory] for certain types of persistent pain (46). The off-cells are thought to have a net inhibitory effect on ascending nociceptive transmission and are indirectly activated by µ-opioids (45). In the anesthetized rat, on- and off-cells discharge in bursts that are timed reciprocally (43). The RVM on- and off-cells are likely to rapidly enhance and inhibit, respectively, the nocifensive reflex responses to repeated noxious stimulation (47, 48). Most studies report that a minority of spinally projecting VMM neurons is serotonergic (43, 49). Morphologically distinct serotonergic VMM neurons are typically active in a tonic manner [they have a slow and steady, but not necessarily regular discharge] (41, 50). The serotonergic RVM cells are not likely to play a role in phasic nociceptive modulation, but instead are likely to serve a tonic function, perhaps modulating nociceptive transmission in accordance with changing behavioral or social states (50). As with the RVM non-serotonergic neurons, different subclasses of the RVM serotonergic neurons may facilitate or inhibit nociceptive transmission at the SC/TN DH (50, 51). The NRM and NRMC serotonergic neurons are the major source of serotonin in the SC/TN DH (50). I propose that an inhibitory subclass of the RVM serotonergic neurons is the cell type primarily responsible for the complete inhibition of nociceptive signals that arise from latent

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TrPs, although RVM off-cells, SRD neurons, and brainstem noradrenergic neurons may also inhibit TrP pain. As TrPs accumulate and ascending nociceptive transmission intensifies, the “tonic” inhibitory activity of these serotonergic neurons increases, and as TrPs are treated, this antinociceptive activity reduces so that only the most sensitized TrPs are consciously perceived to be painful [active]. Descending pathways may modulate nociceptive transmission at the DH via an interaction with primary afferent terminals, ascending projection neurons, intrinsic excitatory and inhibitory interneurons, and the terminals of other descending pathways (33). The VMM may suppress [or in some circumstances facilitate] both the NWRs [including the C fiber NWR (52) and the VMR (53)] and SC/TN central sensitization, and therefore inhibit [or facilitate] the formation of antecedent TrPs. The VMM may modulate the C fiber withdrawal reflexes by acting on sensory, interneuronal, and motor components of the SC/TN reflex arcs. The RVM is involved in inhibitory feedback mechanisms that counteract the windup [central sensitization] phenomenon and trigger long periods of inhibition (52). Transection of the ipsilateral dorsolateral funiculus removes the RVM-mediated descending inhibition of multireceptive [WDR] spinal neurons and disproportionately prolongs the after-discharge [sensitization] component of their response to noxious stimulation (39). The RVM may also facilitate the development and maintenance of SC/TN sensitization [SC transection or inactivation of the RVM attenuates secondary hyperalgesia and central sensitization in several models of persistent pain (54)]. The VMM receives projections from suprabulbar motor facilitatory and inhibitory areas, and plays an important role in the modulation of phasic [locomotion] and tonic [basal muscle tone] motor activity (44). The RVM facilitates and inhibits visceral nociceptive transmission at the DH (55). The VMM might facilitate or inhibit most autonomic functions by modulating descending output as well as somatovisceral and viscerosomatic reflexes [including the VMR]. This modulation of autonomic function is possible because the VMM projects, via monosynaptic and disynaptic routes, to preganglionic sympathetic and parasympathetic neurons that, after synapsing, target most autonomic tissues (43).

The Ventromedial Medulla and Sleep Some VMM neurons might aid in the production of a coherent behavioral state, such as waking, slow wave sleep [SWS], or paradoxical sleep [PS], rapid eye movement sleep], by specifically reconfiguring the sensitivity of spinal circuits to external and internal stimuli (43). The VMM neurons are involved in the modulation of many sleep-related functions, including sensory modulation [including antinociception], PS muscle tone suppression [atonia], visceral and somatic reflex modulation, and cortical arousal control. The spontaneous activity of the RVM neurons alters across the sleep–wake cycle [most noxious on-, neutral- and unclassified neurons are wake-active, having a higher discharge rate during waking than in SWS, whereas most off-cells are SWS-active, showing a higher firing rate in SWS than during waking (56)]. The off-cell activity during sleep has been proposed to suppress the alerting reaction evoked by external stimulation, thereby allowing an animal to maintain the sleep state (45). The serotonergic NRM neurons discharge at their highest rates during active waking, at progressively decreasing rates during quiet waking, and SWS, and are almost silent during PS (57). Lower levels of the VMMderived serotonin in the SC/TN during SWS [in comparison to waking] would explain the disinhibition of motor withdrawals from noxious stimulation during SWS [rats have an enhanced paw withdrawal from noxious heat during SWS compared with waking] (15, 43). During PS, RVM neuronal activity contributes to muscle atonia by causing hyperpolarization of the cranial and spinal motoneurons (44, 58). Conservation and replenishment of brainstem serotonin is likely to be an essential role of sleep [especially PS, when brainstem serotonergic neuronal activity is the lowest]. Sensory Gating The VMM may modulate [facilitate or inhibit] ascending transmission of innocuous tactile and thermal, as well as noxious, sensory information at the SC/TN DH level (45). The activity of the SC/TN WDR neurons [which have cutaneous, somatic, and visceral receptive fields] is profoundly influenced by the RVM descending modulation (59). I

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propose that a tonic level of descending inhibition helps regulate the differential perception of cutaneous, somatic, and visceral sensory input. Wide dynamic-range neurons are likely to be preferentially activated by cutaneous input, with lesser sensitivity to somatic input and least to visceral input. Tonically active descending inhibition more strongly inhibits DH WDR neuronal responses to deep somatic [muscle, tendon, joint] input in comparison to cutaneous input (60). Different spinal projection patterns of C fibers arising from different peripheral tissues would be a factor in this variable WDR neuronal activation and also contribute to the difficulty in localizing muscle and visceral pain. Cutaneous fibers have the most focused and dense spinal projections, visceral afferents have the most wide-ranging and diffuse projections, and those innervating muscles are intermediate in their spinal projections (61). Therefore, the RVM descending modulation usually allows cutaneous sensation, some somatic, and no visceral sensation. However, changes in the RVM descending inhibition or facilitation of [or central sensitization of] the WDR neuronal activity can alter the perception of noxious or innocuous sensation from these sources. Pathophysiology of Consequent Trigger Points Having considered the pathophysiology of antecedent TrPs, I now consider the pathophysiology of consequent TrPs. I propose that consequent TrPs are formed due to tonic reticulospinal or reticulo-trigeminal facilitation of plateau potentials in the withdrawal reflex antagonist αmotoneurons. Consequent TrPs develop in withdrawal reflex antagonist muscles, which are generally, but not exclusively, extensor muscles. I suggest that this facilitatory mechanism evolved to augment posture, counteract C fiber withdrawal reflex reciprocal inhibition of antagonist muscles, and counteract postural changes induced by antecedent TrPs. As with sensory transmission at the DH, it is likely that different subclasses of the VMM neurons mediate either phasic or tonic and facilitatory or inhibitory modulation of α-motoneuron activity at the ventral horn. I propose that tonic activity of the VMM serotonergic neurons, which typically facilitates extensor motor activity [and extensor α-motoneuron plateau depolarization] and suppresses flexor activity,

predisposes to consequent TrP formation. This tonic activity may change in magnitude or direction under certain circumstances [injury, illness, stress, fatigue, and sleep], which would disinhibit flexor motor activity and predispose to antecedent TrP formation. Microstimulation of different sites in the medullary reticular formation predominantly leads to ipsilateral limb flexion, contralateral limb extension, and ipsilateral head turning (62). I propose that these asymmetric motor effects counteract contralateral noxious stimulationinduced spinal reflexes [NWR and crossed extensor reflex] and thus help to maintain posture. Descending facilitation of motor activity may lead to reciprocal effects on ipsilateral flexor and extensor muscles, and opposite reciprocal effects on contralateral flexor and extensor muscles by acting on segmental [including commissural] spinal interneuron circuits. The tonically active VMM serotonergic neurons, which project to the SC, facilitate postural muscle tone (63). Rats with denervation of descending serotonergic and noradrenergic pathways do not show impairment of general motor ability but show a tendency to less erect posture (64). Fatigue may have a prominent CNS component, reflecting a disfacilitation of motor output [the activity of medullary [NRO, NRP] serotonergic neurons decreases steadily as a cat fatigues during prolonged treadmill locomotion] (65). In the case of the NJOR, the jaw closing muscles are the antagonists that would be reciprocally inhibited during sensitization of the reflex and so reticulo-trigeminal motor facilitation would predispose to consequent TrP formation in these muscles. Serotonin of supraspinal origin [of which the VMM is the major source] shifts α-motoneurons from the stable hyperpolarized state, with little or no neuronal activity, to the stable partially depolarized plateau state, with tonic neuronal activity (6). After acute SC transection [when brainstemderived neuromodulators are lost], motoneurons caudal to the injury lose [albeit temporarily] their ability to produce plateau potentials (66). Brainstem Pain Modulatory Center Sensitization and Dysfunction I propose that as TrPs accumulate and the level of DH central sensitization and ascending nociceptive transmission increase, the

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activity of the brainstem pain modulatory centers increases concurrently, so that pain from only the most sensitized TrPs is perceived [active TrPs], while most, if not all, TrPs remain latent. Long-term noxious stimulation is characterized by a progressive reinforcement in mechanisms of descending inhibition, reflecting the recruitment of descending pathways originating in the RVM and noradrenergic nuclei, and this enhancement of descending inhibitory “tone” counterbalances excessive nociceptive input and mitigates pain (33). It has been suggested that “[d]ue to the progressive exhaustion or dysregulation of descending inhibition, to its limited efficacy, or to a loss of responsiveness of downstream mechanisms mediating its effects, descending inhibition may be unable to combat long-term painful states” (33). I propose that the formation of large numbers of TrPs may overwhelm the anti-nociceptive reserve of the brainstem pain modulatory centers. This is especially likely when the simultaneous formation of many TrPs [through generalized noxious stimulation and immobility] leaves less time for pain modulatory center functional adaptation. Any genetic weakness, nutritional deficiency, or metabolic disturbance affecting relevant neurotransmitter or neuronal activity would lessen the brainstem pain modulatory center functional reserve and lower the threshold for, and increase the severity of, dysfunction-related symptoms. Because many, often co-localized, neurotransmitters and receptor types are probably involved in TrP antinociception, the neurotransmitter/receptor couple with the least functional reserve [the “weakest link”] would fail first. Failure of different neurotransmitter/receptor couples, with differing actions, could manifest as a variety of overlapping sensory, motor, and autonomic disorders with associated myalgia. Disorders I consider it likely that TrP formation, TrPmaintained SC/TN central sensitization, and subsequent sensitization and disequilibration of VMM and other supraspinal pain modulatory center functions are important factors in the pathogenesis of a wide variety of idiopathic or incompletely understood disorders. These disorders could include localized, regional, and gen-

eralized pain disorders and disorders of sleep, mood, development, and motor and autonomic functions. There is wide acceptance that individual muscle active TrPs commonly contribute to a variety of local or referred, chronic or episodic pain disorders. As any skeletal muscle can develop TrPs (67), TrPs may cause pain to be perceived almost anywhere in the body. Pain may arise directly from sensitized nociceptors within TrPs, from nerves entrapped by TrP taut bands, and from nociceptors in other nonmuscular tissues affected by TrP-induced muscular tension [including enthesopathy]. TrPs, instead of occurring singly or randomly, are normally found in patterned regional or generalized groupings [with active TrPs far less common than latent TrPs (67)]. A regional myofascial pain syndrome [MPS] typically involves one [or up to a few] active TrPs, as well as multiple latent TrPs, in the affected region [as well as latent TrPs in other regions]. Regional pain disorders in which TrPs may play a fundamental role include tension-type headache, frozen shoulder, and nonspecific neck and low back pain [currently up to 90 percent of human low back pain cases are labeled as nonspecific, in which no specific pathophysiological mechanism can be identified (68)]. In addition, TrPs may act as a factor in the etiology of osteoarthritis by increasing mechanical joint wear due to joint compression [if TrPs occur in transarticular muscles] and postural change, as well as by altering regional sympathetic reflex activity. The MPS would be accompanied by central sensitization at both SC/TN and brainstem pain modulatory center levels, although in most cases any resulting brainstem dysfunction would be comparatively mild. The formation of large numbers of TrPs [sequentially or more particularly simultaneously], especially when there is a lesser brainstem antinociceptive reserve, may overwhelm the brainstem’s capacity for descending nociceptive inhibition and lead to generalized pain disorders, including fibromyalgia syndrome [FMS]. Generalized TrP pain disorders involve not only pain arising directly from TrPs but also generalized hyperalgesia and allodynia, due to the resulting SC/TN central sensitization and overwhelmed descending antinociceptive mechanism. Generalized TrP pain disorders are typically more prevalent in females than males [adult women

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are four to seven times more likely to have FMS than adult men (69)]. This is likely due to a lower rate of serotonin synthesis in the female brain [the mean rate of serotonin synthesis in the human brain has been found to be 52 percent higher in normal males than in normal females (70)]. In most patients, chronic localized or regional muscle pain precedes the development of FMS, which is associated with longstanding or permanent central sensitization of the DH WDR neurons and disinhibition of pain due to impaired endogenous descending pain modulation (71). There are measurable alterations in the NWR in headache (72), FMS (73), and other pain disorders. Central sensitization of the NWR, maintained by afferent input from TrPs, would result in ongoing reflex inhibition of antagonist [extensor] motor activity and reflex facilitation of agonist [flexor] motor activity. This motor disturbance and associated postural change lead to an augmentation of compensatory reticulospinal facilitation of extensor motor activity and inhibition of flexor activity. Marked sensitization and subsequent dysfunction of brainstem motor modulatory centers, due to overwhelming numbers of TrPs, would lead to a weakening of this compensatory mechanism and a worsening of posture. The resulting disfacilitation of motor output would also contribute to fatigue. I have suggested that altered sympathetic neuronal activity in the vicinity of a hypoxic TrP results in compensatory vasodilation. A regional or generalized MPS could result in sufficient vasodilation to alter thermoregulation and thermal tolerance. TrPs may directly induce visceral disturbance and dysfunctions by somatovisceral [reflexive] mechanisms (74). Dysfunction of brainstem pain modulatory centers due to overwhelming TrP nociception may contribute to the development of other [often concomitant] autonomic disturbances, including alterations to heart rate, respiration, blood pressure, micturition, sexual function, and thermoregulation. Most patients with persistent TrP pain have difficulty in sleeping and show abnormal sleep patterns when monitored in a sleep laboratory (75). The pain of active TrPs may lead to attentional disruption of sleep. In addition, TrP nociception-induced VMM neuronal dysfunction may contribute to insomnia, nonrestorative sleep, and attenuation of sleep muscle atonia.

The VMM serotonergic neuronal sensitization and subsequent dysfunction, due to overwhelming TrP nociception, may also be a factor in the etiology of certain mood disorders that are associated with low serotonin levels and somatization. Although somatic changes are generally considered to be a consequence of psychiatric illness, it is possible that in some cases bodily changes actually precede and contribute to the neuronal dysregulation that leads to mood disorders, such as clinical depression and anxiety. The nociception-induced brainstem pain modulatory center dysfunction could then amplify the somatization through disequilibration of sensory, motor, and autonomic functions. It is well established that depression occurs more frequently in individuals with a variety of chronic pain syndromes [including FMS, chronic musculoskeletal pain, and headache] than in those without pain (76, 77). Patients with major depression have increased sensitivity to deep somatic pain and reduced sensitivity to phasic cutaneous pain (77). The VMM serotonergic neuronal dysfunction and compensatory enhanced phasic antinociceptive mechanisms could explain these abnormal sensitivities. Ontogenetically, TrPs may arise when the neural and reflexive mechanisms underlying their development are sufficiently organized. This is likely to occur in utero. Perinatal development of a generalized MPS would result in SC/TN central sensitization [including αmotoneuron plateau depolarization], significant changes in muscle tone, and interference with the normal postnatal tuning of reflexes and maturation of motor control. Appropriate postnatal tuning of the NWR system also depends on the normal functioning of supraspinal centers [neonatal SC transection results in the persistence of neonatal reflex patterns in adult rats] (78). It is possible that the developmental motor dysfunction of spastic cerebral palsy may result from the perinatal development of generalized [or significant regional] MPS, as well as from perinatal damage to supraspinal reflex tuning centers. If the generalized MPS arose later in infancy when reflexes were already tuned and the motor cortices were organized, such developmental disturbance of motor function would not result. It could be that TrP formation in juveniles may be an important etiological factor in the development of later osteoarthritis due to

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the susceptibility of rapidly growing joints to disturbance. Treatment of Trigger Points I propose that most of the generally accepted treatments for TrPs in fact involve the strong and transient inhibition of the CNS mechanisms that sustain the α-motoneuron plateau depolarization, which perpetuates TrPs. This inhibition of the centrally sensitized C fiber withdrawal reflexes or reticulospinal/reticulo-trigeminal motor facilitation is predominantly mediated by brainstem centers and is induced by a variety of noxious counter-stimulation techniques. Noxious stimulus-induced suppression of the C fiber withdrawal reflexes involves activation of descending inhibitory mechanisms mediated by various brainstem nuclei [primarily the nuclei of the VMM but also other centers, including the SRD]. Sham-operated rats [with an intact neuraxis] show a strong noxious stimulusinduced inhibition of the C fiber NWR, which lasts about 20 minutes (52). Spinalization or caudal medullary transection prevents the noxious stimulus-induced inhibition of the NWR and instead leads to a long-lasting facilitation of the reflex (79). This indicates that supraspinal centers mediate the noxious inhibitory control [although the inhibition is effected at SC level]. Inactivation of the entire RVM profoundly reduces the noxious stimulus-induced inhibition of the C fiber NWR but does not block this inhibition completely (52). This indicates that the RVM and other supraspinal centers mediate the NWR inhibition. The SRD mediates diffuse noxious inhibitory controls, a mechanism in which most WDR and some nociceptive-specific neurons, at all segmental levels of the SC/TN DH, can be strongly inhibited by noxious stimulation of any part of the body [apart from the excitatory receptive field of the inhibited neuron] (32, 80, 81). It has been shown that diffuse noxious inhibitory controls operate in normal human subjects, with painful heterotopic conditioning stimuli inducing simultaneous depression of the sensation of pain and the NWR evoked by electrical stimulation of the sural nerve (82). Neurons that exhibit bistable behavior can be switched between the two stable levels of excitability by short-lasting excitatory or inhibitory

input (6). The brainstem-mediated inhibition of SC/TN neuronal activity involves several mechanisms, including hyperpolarization of the postsynaptic neuronal membrane (58, 83, 84). Strong activation of descending inhibition would temporarily reduce α-motoneuron activity by shifting the motoneuron membrane potential from the more excitable, partially depolarized plateau state to the less excitable, hyperpolarized state. Temporary hyperpolarization of previously partially depolarized α-motoneurons removes the low-grade efferent stimulus that helps perpetuate both antecedent and consequent TrPs. Although contractured muscle is highly resistant to stretch, this temporary suppression of neural mechanisms that maintain the TrP local energy crisis causes interruption of the actin–myosin interaction, which allows stretching of the contractured muscle fibers to full length. At full stretch range of motion, overlap between myofibril actin and myosin molecules is greatly reduced, which reduces muscle contractile activity and energy consumption to almost zero and restores blood perfusion and oxygenation via decompression of the local capillary bed (85). This normalization of local perfusion reverses the TrP local energy crisis and muscle nociceptor sensitization. Reversal of TrP muscle nociceptor sensitization reduces withdrawal reflex afferent activity, which helps to reverse central sensitization of the SC/TN [including withdrawal reflex central sensitization]. By diminishing NWR sensitization, appropriate treatment of antecedent TrPs counters further facilitation of withdrawal reflex agonist muscle activity, which limits TrP recurrence in the treated muscle and propagation of TrPs to synergistic muscles. Treatment of antecedent TrPs also reverses NWR reciprocal inhibition of antagonist extensor muscles. For example, treatment of TrPs in the hip flexors often improves the strength and reduces the inhibition of the antagonist gluteal muscles (25). However, inappropriate treatment of the more frequently painful consequent TrPs alone [and not the antecedent TrPs] exacerbates the main antecedent TrP problem and postural disturbance. Subsequent pain relief is not long-lasting, because compensatory reticulospinal motor facilitation persists. Treatment of the most sensitized TrPs in the body [active TrPs] decreases ascending nociceptive transmission, which lowers the pain threshold by reducing brainstem pain modulatory

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center descending antinociceptive tone. This frequently causes the next most sensitized latent TrP to become painful [become active]. When an active “TrP has been successfully eliminated, the pain pattern may shift to that of an earlier, key TrP which also must be inactivated” (86). As TrPs are sequentially treated, there is a gradual reduction in the modulatory output from the VMM and other brainstem pain modulatory centers, lessening the central sensitization of these nuclei and allowing a gradual normalization of any central sensitization-related dysfunction. Because of the sensory, motor, and autonomic modulatory roles of the nuclei involved in TrP antinociception, treatment of TrPs may lead to an improvement in a variety of sensory, motor, and autonomic dysfunctions. Systematic treatment of active and latent TrPs may therefore lead to an amelioration, or in some cases cure, of a variety of pain disorders and some disorders where pain is not prominent, by causing a shift toward homeostasis of brainstem pain modulatory center, SC/TN, muscle nociceptor, and muscular function. There are a wide variety of traditional and modern techniques that have been used [knowingly or unknowingly] to prevent or treat TrPs in humans. Preventative techniques usually involve regular stretching of the muscles and most treatment methods involve noxious counterstimulation [with increased effect if immediately followed by stretching]. Noxious counter-stimulation techniques used to treat and control the pain of TrPs involve stimulation of nociceptors that are usually local [within the TrP or the overlying skin] but are sometimes well distant to the TrP. It is likely that strong segmental noxious stimulation causes the most profound inhibition of the CNS mechanisms that perpetuate TrPs. Such noxious stimulation often induces a spinal reflex-mediated local twitch response of the muscle containing the TrP during treatment. Noxious counter-stimulation techniques are of variable efficacy. The most efficacious counter-stimulation techniques used to treat TrPs include pressure release, superficial and deep dry needling, TrP injection, vapocoolant skin stimulation, and low-frequency transcutaneous electrical nerve stimulation [over the TrP]. The efficacy of cutaneous counter-stimulation techniques [superficial dry needling and vapocoolant application] indicates that TrP treatment in-

volves CNS mechanisms and does not necessitate physical damage to the affected area of muscle. Less efficacious counter-stimulation techniques may treat some TrPs, but their main effect on TrPs involves the activation of descending antinociceptive mechanisms that help to control pain. Traditional noxious counter-stimulation techniques involve the application of noxious temperature [thermal pools, saunas, moxibustion], massage [many cultures have their own form], and needle insertion [acupuncture]. More recently devised counter-stimulation techniques include spinal manipulation [chiropractic], soft tissue manipulation [osteopathy], conventional transcutaneous electrical nerve stimulation, mechanical vibration, and therapeutic ultrasound. Injection of botulinum A toxin [Botox] into TrPs is an effective treatment but at the expense of post-injection muscle function. Botox injection into TrP-active loci totally destroys endplate function, effectively denervating those muscle fibers (87). No other pharmaceuticals are reported to be useful in the treatment of TrPs, although a variety of pharmaceuticals can reduce the peripheral and central sensitization that predispose to TrP formation and provide some TrP pain relief. Because full lengthening of a muscle markedly reduces energy consumption and restores perfusion, stretching also plays a crucial role in the prevention of TrPs. In the incipient stage of energy deficit prior to contracture or after a TrP is treated, regular stretching of the muscle should prevent a TrP from forming or reforming. Daily passive stretch exercise (88) protects against the formation of TrPs and maintains flexibility. The prevention of TrPs helps to explain the utility of traditional systematic stretching techniques, such as yoga and tai chi, as well as regular exercise. Lack of stretching during prolonged immobility, accompanied by ongoing noxious stimulation, strongly predisposes to TrP formation. Evolutionary Development The neural mechanisms responsible for TrP formation, nociception, and antinociception are primitive and are likely to occur, with varying degrees of complexity, in all vertebrate species. In many cases the same neurotransmitter acting on the same receptor type exhibits opposite

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effects on nociception at brainstem and SC level, which suggests that brainstem pain modulatory mechanisms may have started to develop at the earliest differentiation of the neuraxis into brain and SC. There would presumably be a strong evolutionary selection pressure acting to refine these neural mechanisms to provide the optimum balance between nociception and antinociception, so that only the most relevant [severe] pain signals are perceived and the rest inhibited before reaching consciousness. Over the course of evolution, an ever more complex and finely tuned nociceptive control system has presumably developed to give animals the greatest chance of survival to reproductive age. Now there are a multitude of neurotransmitters and other mediators involved in the transmission and modulation of nociceptive processing in the DH and higher centers (33). The development of an upright stance during human evolution would have required an augmentation of the reticulospinal motor modulatory mechanisms that maintain posture and counter the NWR. This evolutionary adaptation would explain the frequent localization of active TrPs on the posterior extensor aspect of the human torso.

are involved in the way I propose would require considerable research effort. Some appropriate further investigations could include the following:
• Investigating whether plateau depolarization of α-motoneurons is responsible for the endplate noise detectable at the active locus of a TrP, by making concurrent electrophysiological recordings at axon and motor endplate levels. • If so, testing whether these partially depolarized α-motoneurons become hyperpolarized during the treatment of a TrP by making similar electrophysiological recordings during the treatment. • Investigating whether two main types of TrPs [antecedent and consequent] exist, e.g., by comparing the efficacy of treating TrPs in anterior flexor muscles versus posterior extensor muscles in human nonspecific neck or low back pain. • Testing whether central sensitization of the C fiber withdrawal reflexes is involved in the pathogenesis of antecedent TrPs, by measuring a reduction in the amplitude of the C fiber NWR several days after methodical treatment of antecedent TrPs. • Verifying whether SC/TN and brainstem pain modulatory center sensitization is associated with MPS and is reversible upon treatment of most TrPs, e.g., by measuring sensitization indicators in cerebrospinal fluid or using advanced imaging techniques such as positron emission tomography [PET] or functional magnetic resonance imaging [fMRI]. • Investigating whether TrP-induced CNS sensitization and dysfunction are involved in the pathogenesis of a variety of disorders, including FMS and depression [this could be done by comparing the response of a population of affected patients to methodical treatment of latent and antecedent TrPs versus control treatments, e.g., treatment of active TrPs only]. • Investigating if brainstem-mediated antinociceptive mechanisms completely inhibit the nociceptive signals from latent TrPs, so that only active TrPs are spontaneously painful, by systematically treating human or canine TrPs in three body quadrants and determining whether

Suggestions for Further Research Reliable localization or treatment of TrPs requires cooperation and communication between the [human or companion animal] patient and the practitioner. Although treatment of TrPs is possible under sedation or general anesthesia, reduced or absent vocal or gestural feedback makes it considerably more difficult to ascertain that a TrP has been located and has responded appropriately to treatment. Methodical treatment of most TrPs, as would be required to validate certain parts of this hypothesis, would be very difficult, if not impossible, with laboratory animals such as rodents and rabbits. The need for cooperation and communication is likely to make dogs and humans the most useful subjects for TrP research. Many of the neuronal mechanisms that I suggest are involved in the pathogenesis and treatment of TrPs have been individually described through neurophysiological research on humans or laboratory animals. However, confirming that these mechanisms

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pain results in the nontreated quadrant [with lameness being an indicator of spontaneous pain in a dog]. Experimental Design I now outline the design of a specific prospective randomized controlled clinical trial that could be undertaken to test whether two main types of TrPs [antecedent and consequent] exist. I hypothesize that in cases of human nonspecific low back pain, treatment of all TrPs in anterior lumbar and hip flexor muscles would provide larger and more persistent improvements in measured pain and health status outcomes than treatment of all TrPs in posterior lumbar and hip extensor muscles. Adult patients [aged between 18 and 70 years] with chronic [persisting for more than three months] nonspecific low back pain [pain of the low back, either with or without leg pain, which is not associated with major trauma, spinal stenosis, radiculopathy, or other specific cause] would be eligible for inclusion in the trial. Patients having received any prior treatment would be eligible for inclusion, but pregnant or obese patients whose anterior lumbar muscle TrPs could not be safely or effectively treated would be excluded. Patients would be randomly assigned to one of two treatment groups. Subjects in the index group would receive treatment of all latent and active TrPs in the lumbar and hip flexor muscles [quadratus lumborum, iliopsoas, rectus abdominis, abdominal obliques, gluteus medius/minimus anterior part, sartorius, rectus femoris, tensor fasciae latae, pectineus, adductor longus/brevis, and gracilis]. Subjects in the control group would receive treatment of all latent and active TrPs in the lumbar and hip extensor muscles [longissimus thoracis, spinalis thoracis, iliocostalis lumborum, lumbar multifidi, gluteus maximus, gluteus medius/minimus posterior part, biceps femoris long head, semitendinosus, semimembranosus, and adductor magnus posterior part]. Any localized tender spot in a taut muscle band, with or without patient pain recognition, which shows a slow crescendo and then rapid decrescendo in pain intensity upon application of constant non-ischemic digital pressure, would be defined as a TrP. In both the groups, each TrP would be treated using

such digital pressure constantly applied until the pain intensity rapidly diminishes [after approximately one minute] and the treated muscle would then be gently stretched to full length. During each treatment session this process would be repeated on each TrP in the target flexor or extensor muscles in the index or control groups, respectively, until no further TrPs could be found in the target muscles. In both index and control groups, a treatment session would be given on weeks 1, 2, 4, and 8. Subjects would be blinded to the study hypothesis. Any concomitant therapy should be avoided or minimized. I propose that the outcomes to be evaluated shall include pain, back-specific health status, generic health status, lost working days due to back pain, and patient satisfaction (89). Validated pain and health status measures that could be used to evaluate primary outcomes include a 100-point visual analog pain scale to assess overall back pain and the Roland–Morris Disability Questionnaire (90) to assess back-specific health status. These measures would be assessed for each subject prior to each of the four treatment sessions and then at months 4, 6, 9, and 12. Whether each subject achieves a 30 percent minimal clinically important improvement (89) in each pain or health status score, compared to the baseline, would be calculated at each of the subsequent seven assessments. At each assessment, any difference in the percentage of subjects in the index or control groups that make such an improvement in each outcome measure would be analyzed for statistical significance. I predict that a higher proportion of subjects in the index group will make minimal clinically important improvements in measured pain and health status outcomes. I also predict that such improvements in measured outcomes will persist at more subsequent assessments of the index group. The sample size required to achieve statistical significance would be best determined through a pilot study, although I estimate that a sample of 60 to 100 subjects in each group would be sufficient. CONCLUSION In this paper I have proposed a new hypothesis for the pathophysiology of TrPs, i.e., TrPs result from nociception-induced CNS plasticity, rather

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than from an intrinsic disorder of the motor endplate. If this hypothesis is correct, it will justify an increased emphasis on the prevention of TrPs by regular systematic stretching and a more methodical approach to treatment, with targeting of antecedent and latent TrPs. However, only with an improved understanding of underlying pathophysiology will there be a general acceptance of the importance of TrPs and better management of the MPS and other disorders. Declaration of interest: The author reports no conflict of interest. The author alone is responsible for the content and writing of this paper. REFERENCES
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Submitted: June 26, 2008 Revision Accepted: April 8, 2009

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