In explaining the local nature of MPS TrPs, Simons (1990, 2008) suggests that the damage to the muscle occurs primarily at the motor endplates, creating an energy crisis at the TrP. He suggests that this crisis occurs from grossly abnormal increase in acetylcholine release at the endplate and generation of numerous miniature endplate potentials, resulting in an increase in energy demand, sustained depolarizaton of the postjunction membrane, and mitochondrial changes. Other studies also support this proposed mechanism. For example, Hubbard and Berkoff (1993) found spontaneous EMG activity at the TrP (Hubbard and Berkoff 1993). EMG characteristics of the local twitch response are generated locally without input from the CNS (Hong 1994; Hong and Torigoe 1994).

Histologic studies also provide some support for this mechanism. They have shown myofibrillar lysis, moth eaten fibers, and ragged red type I fibers with deposition of glycogen and abnormal mitochondria but little evidence of cellular inflammation hypothesis (Bengtsson et al. 1986b; Yunus et al. 1986). Studies of muscle energy metabolism found a decrease in the levels of ATP, ADP, and phosphoryl creatine and abnormal tissue oxygenation in muscles with TrPs (Bengtsson et al. 1986a). El-Labban and colleagues demonstrated that TMJ ankylosis will result in degenerative changes in masseter and temporalis muscles (El-Labban et al. 1990). These studies suggest that localized progressive increases in oxidative metabolism and depleted energy supply in type I fibers may result in abnormal muscle changes that initially include reactive dysfunctional changes to muscle fiber type I and surrounding connective tissue but eventually may involve degenerative changes and increased connective tissue in the muscle.

The resulting metabolic by-products of this damage can result in peripheral sensitization of nociceptors the muscle, fatigue (Mao et al. 1993). Muscle strain may lead to localized progressive increases in oxidative metabolism, particularly in muscle fiber type I with depleted energy supply, increased metabolic by-products, and resultant muscle nociception at the periphery. This is supported by our recent findings that MPS TMD subjects present higher salivary and serum oxidative stress levels (8-hydroxydeoxyguanosine (8-OHdG), malondialdehyde (MDA), and total antioxidant status (TAS)) in comparison to controls (Rodriguez de Sotillo et al. 2011).

It is unknown what specific mediators are involved in this sensitization, but these may include high potassium concentration and hyperpolarization outside the muscle due to K  +  pump damage, high calcium concentration from damage to the sarcoplasmic reticulum, or inflammatory mediators from tissue damage. Localized tenderness and pain in the muscle involve type III and IV muscle nociceptors and has shown to be activated by noxious substances including K+, bradykinin, ­histamine, or prostaglandins that can be released locally from the damage and trigger tenderness (Fricton 2004; Kniffki et al. 1978; Mense 1993). It is important to note the K+ activated a higher percent of type IV muscle nociceptors than other agents, providing support for the idea that localized increases in K+ at the neuromuscular junction may be responsible for sensitization of nociceptors. This peripheral sensitization is thought to play a major role in local tenderness and pain, which together with central sensitization produces hyperalgesia in patients with persistent muscle pain, particularly in TMD affecting masticatory and cervical muscles (Dubner 61; Fernandez-de-Las-Penas et al. 2010; Fricton 2004).

The afferent inputs from type III and IV muscle nociceptors in the body are transmitted to the CNS through cells such as those of the lamina I, V, and possibly IV of the dorsal horn on the way to the cortex, resulting in perception of local pain (Dubner and Bennett 1983; Sessle 1995b, 1995a). In the trigeminal system, these afferent inputs project to the second order neurons in the brain stem regions including the superficial lamina of trigeminal subnucleus caudalis as well as its more rostral lamina such as interpolaris and oralis (Sessle 1995b). These neurons can then project to neurons in higher levels of the CNS such as the thalamus, cranial motor nuclei, or the reticular formation (Sessle 1995a). In the thalamus, the ventro basal complex, the posterior group of nuclei, and parts of the medial thalamus are involved in receiving and relaying somatosensory information. These inputs can also converge with other visceral and somatic inputs from tissues such as the joint or skin and be responsible for referred pain perception (Fricton 2004; Melzack 1981).

Both FMS and MPS TMD need to be considered as a primary disorder of central pain perception. Although nociceptive input from the periphery does occur, it has been shown to be modified by multiple factors in its transmission to the CNS. For example, low- and high-intensity electrical stimulation of sensory nerves or noxious stimulation of sites remote from the site of pain will suppress nociceptive responses of trigeminal brain stem neurons and related reflexes (Kashima et al. 1999). This provides support that afferent inputs can be inhibited by multiple peripherally or centrally initiated alterations in neural input to the brain stem through various treatment modalities such as cold, heat, analgesic medications, massage, muscular injections, and transcutaneous electrical stimulation (Melzack 1981). For example, Kashima et al. (1999) found increased pain sensitivity of the upper extremities of TMD patients with myalgia to experimentally evoked noxious stimulation, suggesting the possibility of central sensitization. Ta et al. (2002) studied 32 TMJ implant patients and found an altered sensitivity to sensory stimuli, a higher number of tender points with a diagnosis of FMS, increased self-report of chemical sensitivity, higher psychologic distress, and significantly lower functional ability (Fricton 2004).

Likewise, persistent peripheral or central nociceptive activity can result in an increase in abnormal neuroplastic changes in cutaneous and deep neurons. These neuroplastic changes may include prolonged responsiveness to afferent inputs, increased receptive field size, and spontaneous bursts of activity (Guilbaud 1991; Dubner 1992). Thus, peripheral inputs from muscles may also be facilitated or accentuated by multiple peripherally or centrally initiated alterations in neural input with further sustained neural activity such as persistent joint pain, sustained muscle activity habits or postural tension, or CNS alterations such as depression and anxiety that can support the central sensitization further perpetuating the problem. This sensitization may be subserved by a number of neuropeptides, including substance P, glutamate, serotonin, dopamine, norepinephrine, and endorphins. Reduced CSF levels of the major metabolites of serotonin, dopamine, and norepinephrine were found in FMS patients indicating a low turnover of these neurotransmitters. Conversely, elevated levels of substance P and glutamate were present in the CSF (Russell et al. 1994; Sarchielli et al. 2007). Furthermore, the combination of elevated glutamate and substance P and reduced serotonin supports a role for central amplification in the pain transmission and perception of patients with FMS (Vaeroy et al. 1988; Russell 1989). Moreover, researchers also found that CSF levels of two neurotrophins, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), were elevated in patients with FMS (Giovengo et al. 1999; Laske et al. 2007; Sarchielli et al. 2007). The increased levels of NGF and BDNF correlated with increased CSF glutamate levels of FMS patients. These researchers speculated that NGF acted indirectly to increase BDNF expression, which then modulated N-methyl-D-aspartate (NMDA) receptor activity (which is essential in both initiating and maintaining activity-dependent central amplification) to increase the excitatory amino acids glutamate and aspartate, supporting the involvement of a central mechanism in the pathophysiology of FMS (Fricton 2004; Laske et al. 2007).

Central pain amplification is well known to cause hyperalgesia (increased pain from normally painful stimuli), allodynia (pain from normally nonpainful stimuli), and referred pain (Meeus and Nijs 2007). Central pain amplification has also been supported by preclinical studies, where several animal models reproducing widespread, long-lasting hyperalgesia or allodynia have been developed to model FMS muscle pain (DeSantana and Sluka 2008; Nagakura et al. 2009). Increased glutamate and aspartate release in the mice spinal cord followed the injection of acidic saline to the gastrocnemius muscle, which correlated with hyperalgesia development in the paw (Skyba et al. 2005; Sluka et al. 2001). This hyperalgesic effect was reversed by NMDA and non-NMDA receptor antagonists, suggesting that elevated glutamate played a role in mechanical hyperalgesia (Skyba et al. 2002). Inhibitors of adenylate cyclase or protein kinase A have also been found to reverse the mechanical hyperalgesia and allodynia (Hoeger-Bement and Sluka 2003). In addition, acid-sensing ion channels (ASICs) located on afferent fibers, which respond to pH changes, can also be involved in the mechanical hyperalgesia induced by acidic saline injections in mice. This hyperalgesia has been prevented by pretreatment of the muscle with a nonselective ASIC antagonist, suggesting a role for ASICs in the development of central amplification (Sluka et al. 2003, 2007). Consequently, ASICs may be another therapeutic target for FMS pain therapy. ASICs are also important targets in neuropathic pain models, in which the role of central amplification has been well established (Poirot et al. 2006).

There is also evidence that patients with FMS may have abnormalities associated with the immune system that may distinguish FMS from MPS patients, and support the more systemic nature of FMS. Several studies have found that most patients with chronic fatigue and immune dysfunction syndrome (CFIDS) fulfill the criteria for FMS and that they may have several serum abnormalities of immune function (Komaroff and Goldenberg 1989; Moldofsky 2001; Russell 1989). The clinical overlap between these conditions may reflect a shared underlying pathophysiologic basis involving dysregulation of the hypothalamic-pituitary-adrenal stress hormone axis in predisposed individuals (Fricton 2004).

These biochemical changes underlie an integrated “central biasing mechanism” in the CNS that will dampen or accentuate peripheral input (Melzack 1971, 1981). This mechanism may explain many of the characteristics of MPS TMD and FMS including the broad regions of pain referral, the recruitment of additional muscles in chronic cases, the inter-relationship between muscle and joint pain, and the ability of many treatments including pharmacological approaches, spray and stretch modalities, massage therapy, and TrP injections to reduce the pain for longer than the duration of action (Fricton 2004).

Several studies indicated a deficiency of diffuse noxious inhibitory control (DNIC) in subjects with TMD and FMS. DNIC involves testing the pain threshold at baseline, followed by administering a painful stimulus that leads to an analgesic effect, presumably by activating endogenous analgesic systems (Dadabhoy et al. 2008). Deficient DNIC was found in four cross-sectional studies among TMD and FM patients (Julien et al. 2005; Kosek et al. 1996b; Lautenbacher and Rollman 1997; Maixner et al. 1995).

Treatment of TMD can range from simple cases with transient mild pain and fatigue to complex cases involving multiple pain locations and many interrelating contributing factors including the presence of FMS. The difficulty in management of both disorders lies in the critical need to match the level of complexity of the management program with the complexity of the patient. Failure to address the entire problem, including all involved muscles and joints, concomitant diagnoses including FMS, and contributing factors may lead to failure to improve the pain, improve function, and perpetuation of the problem. Many authors have found success in treatment of both TMD and FMS using a wide variety of techniques such as exercise, trigger point injections, vapocoolant spray and stretch, TENS, biofeedback, postural correction, tricyclic antidepressants, muscle relaxants, pregabulin, nonsteroidal anti-inflammatories, and other medications, as well as addressing perpetuating factors (Fricton and Dall’ Arancio 1994; Fricton 2004; Goldenberg 2002; Travell 1998).

Although there are no controlled studies examining progression of chronic pain syndromes, results from clinical studies reveal that many patients with TMD and FMS have seen many clinicians and received numerous medications and multiple other singular treatments for years without receiving more than temporary improvement. In one study of 164 TMD patients, the mean duration of pain was 5.8 years for males and 6.9 years for females with a mean of 4.5 past clinicians seen for the study (Fricton and Haley 1982). Patients with TMD and FMS have a worse prognosis (only 5% sustained remission after treatment) than those without FMS.

These and other studies of chronic pain suggest that regardless of the pathogenesis of muscular pain, a major characteristic of some of these patients is the failure of traditional approaches to completely resolve the problem. Each clinician confronted with a patient with chronic TMD and FMS needs to recognize that there is no single treatment that is effective and only by addressing the whole problem can you maximize the potential for a successful outcome. Treating only those patients whose complexity matches the treatment strategy available to the clinician can improve success. Simple cases with minimal behavioral and psychosocial involvement can typically be managed by a single clinician. Complex TMD patients, particularly those who also have FMS should be managed within an interdisciplinary pain clinic setting that uses a team of clinicians to address different aspects of the problem in a concerted fashion (Fricton 2004).

Management includes exercises, direct therapy to muscles, and reduction of all contributing factors. The short-term goal is to restore normal function of muscles and joints, posture, and full joint range of motion with exercises and muscle therapy. This is followed in the long term with a regular muscle stretching, postural, conditioning, and strengthening exercise program as well as control of contributing factors. Long-term control of pain depends on patient education, self-responsibility, and development of long-term doctor–patient relationships. This often requires shifting the paradigms implicit in patient care (Table 24.2). The difficulty in long-term management often lies not in treating the muscle and joints, but rather in the complex task of changing the identified contributing factors since they can be integrally related to the patient’s attitudes, lifestyle, and social and physical environment. Interdisciplinary teams integrate various health professionals in a supportive environment to accomplish both long-term treatment of illness and modification of these contributing factors. Many approaches such as habit reversal techniques, biofeedback, and stress management have been used to achieve this within a team approach (Fricton 2004).