Myofascial Pain Rehabilitation Research Paper
Myofascial pain syndrome arises from the muscle and is composed of symptoms from the sensory, motor, and autonomic systems [5]. Myofascial pain syndrome is caused by myofascial trigger points which are identified by palpation as discrete foci of hyper contracted areas within a muscle. Clinically, myofascial trigger points are defined as active or latent. An active myofascial trigger point is recognized as eliciting spontaneous pain as well as pain, referred pain, and motor or autonomic symptoms on palpation [6]. These include an impaired range of motion, muscle weakness, and loss of coordination. In contrast, latent myofascial trigger points upon palpation/compression cause pain, a local twitch response, and referred pain [7]. In fact they may display all the symptoms of an active trigger point to a lesser degree. For example latent trigger points may have associated autonomic symptoms with pain and their presence results in a limited range of motion, muscle fatigability, and muscle weakness as in the active presentation [8, 9]. This makes latent trigger points a significant concern also.Myofascial Pain Rehabilitation Research Paper
It is important to distinguish between myofascial pain and neuropathic pain. While myofascial pain originates at the muscle, neuropathic pain results from an injury to or malfunction of the peripheral or central nervous system [10]. There are myriad different pain syndromes and chronic pain disorder that fall into the category of neuropathic pain [11]. Myofascial pain, on the other hand, is thought to originate at the trigger point in the taut band of muscle.Myofascial Pain Rehabilitation Research Paper
In order to begin to gain mechanistic insights into the mechanisms of myofascial trigger points, it is helpful to consider aspects of skeletal muscle physiology.
Excitation-Contraction Coupling. Excitation-contraction coupling encompasses the processes involved in the neural activation of the muscle cell to the contraction and subsequent relaxation of the muscle fiber. Skeletal muscle, like cardiac muscle, is called striated muscle because it has a banded appearance within the single myocyte due to repeated pattern of contractile units termed as sarcomeres. Contraction of skeletal muscle is governed by motor neurons and graded by motor units, which are the collection of muscle fibers innervated by a single motor neuron (for review see [12]). At the neuromuscular junction (i.e., the interface between a motor neuron and a single muscle fiber), a motor neuron action potential initiates the release of acetylcholine from the presynaptic nerve terminals. Acetylcholine then diffuses across the synaptic cleft to activate nicotinic acetylcholine receptors in the postsynaptic membrane. Muscle contraction occurs when the summation of acetylcholine receptor activation reaches the threshold to trigger voltage dependent sodium channel activation in the sarcolemma outside the neuromuscular junction and subsequent action potential generation and depolarization of the muscle fiber. The clearance of acetylcholine from the synaptic cleft by acetylcholinesterase resets the process for subsequent activation.Myofascial Pain Rehabilitation Research Paper
The contraction of the muscle fiber is triggered by action potential transmission deep within the muscle fiber through sarcolemmal membrane invagination’s termed as transverse tubules (t-tubules). Anatomic specialization within the t-tubule is seen at the triad where the t-tubule is flanked by the calcium storage organelle, the sarcoplasmic reticulum. The membrane depolarization accompanying the arrival of the action potential at the triadic space within the t-tubule activates voltage dependent L-type calcium channels in the transverse tubular membrane. Type I ryanodine receptors are located in the sarcoplasmic reticulum in close proximity to the L-type channels [13] and physical coupling between the type I ryanodine receptors and the L-type calcium channels (they either directly or through accessory proteins cause the ryanodine receptors to undergo a conformational change and open releasing calcium into the myoplasm) [14].
This transient rise in calcium binds to troponin on the actin thin filament, which relieves the inhibition on actin for binding by the contractile protein myosin. The calcium dependent interaction of actin and myosin occurs through the formation of strongly bound myosin cross bridges to actin. Force is then generated through ATP (adenosine triphosphate) dependent processes. Critical to this process is ATP hydrolysis that provides energy for the enzymatic activity of the myosin head which generates a single articulation of the myosin head and molecular movement of actin past myosin which shortens the sarcomere. The rebinding of a new ATP is then needed to relieve the strongly bound actin and myosin. In this process, muscle shortening occurs at a rate dependent on the speed of myosin’s enzymatic activity and the resultant force and power output is the ensemble of the cross bridge cycle (i.e., attachment-monofilament sliding-detachment) of all myosin heads in each muscle. The cross bridge cycle is therefore calcium and ATP dependent and maintained as long as calcium and ATP remain high in the cytoplasm. In fact, a depletion of ATP while calcium is elevated results in the inability of cross bridge detachment and the formation of the “rigor bond” which leads to the stiffness seen postmortem.
Subsequent to the calcium release into the myoplasm, the sarcoendoplasmic reticulum ATPase (SERCA) works to sequester calcium back into the sarcoplasmic reticulum, again via ATP dependent enzymatic activity. Subsequent to a brief activation (~5 msec) by a single action potential, troponin, SERCA, and a host of other calcium binding proteins compete for calcium such that a brief force transient is realized (i.e., twitch). Grading force production at the single muscle fiber is then produced by delivering action potentials at higher frequencies (i.e., repetitive firing of the motor unit) resulting in pulses of calcium release that progressively increase myoplasmic calcium concentration.Myofascial Pain Rehabilitation Research Paper
Energetics. The molecule ATP is the critical energy source for muscle function. The metabolic processes that generate ATP use carbohydrates fatty acids and sometimes amino acids as their primary substrate (for a review see [15]). Carbohydrates are converted to glucose which enters the glycolysis pathway in the cell cytoplasm. The end product of this process is pyruvate which is converted to acetyl CoA by pyruvate dehydrogenase in the mitochondria. The β-oxidation of fatty acids results in formation of acetyl CoA. Acetyl CoA enters the tricarboxylic acid cycle (Krebs cycle) that takes place in the mitochondria [16]. Amino acids are converted to other tricarboxylic acid cycle intermediates and enter the cycle at different point. The tricarboxylic acid cycle produces the reducing equivalents NADH and FADH2 that enter the electron transport chain. The electron transport chain uses the energy contained in the reducing equivalents to pump protons out of the mitochondria producing an electrochemical gradient (pH gradient and membrane potential) that is used to make ATP [17]. The electron transport chain consumes oxygen during proton pumping resulting in the term oxidative phosphorylation to describe the entire process that transfers the energy in the reducing equivalents to ATP. Hence, the mitochondria in the myocytes provide the ATP needed for contraction. Skeletal muscles contain approximately 1–12% mitochondria by volume depending upon the particular muscle [18, 19]. Muscles with higher energy demand have higher mitochondrial content. For example, the diaphragm which is constantly active has 10–12% mitochondria by volume [18].
Reactive Oxygen Species. Striated muscle generates reactive oxygen species (ROS) which acts which modulates a host of biochemical processes including glucose uptake, gene expression, calcium signaling, and contractility through the targeted modification of specific protein residues. In striated muscle, contractile activity increases ROS signaling which leads to physiologic adaptation; however, in pathological conditions, ROS signaling is often in excess where it contributes to contractile dysfunction and myopathy.Myofascial Pain Rehabilitation Research Paper
Striated muscle generates superoxide as the primary ROS. Superoxide is generated by the addition of a single electron to ground state oxygen [20]. Superoxide is a highly reactive, unstable species that is rapidly converted by superoxide dismutase (SOD) to hydrogen peroxide (H2O2), a weaker but more stable oxidant. H2O2 is highly diffusible within and between cells, activates multiple signaling pathways, and is decomposed by either catalase or glutathione peroxidase to water and oxygen [21, 22].
The most well described source for superoxide production is the mitochondria where superoxide is produced within the electron transport chain (ETC) [23]. Recent work estimates that, at rest, the percentage of the ROS generated by electron flow through the ETC is low (<1%). During sustained vigorous contractile activity, however, where mitochondrial function increases >50-fold, the magnitude of superoxide release is modestly increased [24, 25], only a small amount (~2–4-fold) over resting levels (see [22] for review).Myofascial Pain Rehabilitation Research Paper
Two additional ROS sources are operant in muscle and yet are likely to be of significance only in disease or high stress conditions. The enzyme xanthine oxidase (XO) has been shown to produce superoxide in response to contractile activity in rodent muscle [20, 26]. Available evidence however supports either a vascular source of XO generated superoxide due to contractile shear stress or an increase in XO activity secondary to anaerobic metabolism that increases the availability of XO substrates [26–28]. Superoxide is also produced by phospholipase A2 (PLA2) dependent processes [29] with a Ca2+-independent PLA2 contributing to ROS production under resting conditions [30], whereas a Ca2+-dependent PLA2 may contribute to ROS production during contraction when cytosolic [Ca2+] is elevated [31–33]. While XO or PLA2 sources of ROS are unlikely to play a role in the sustained ROS production at rest or during dynamic contractions, each supports a mechanism to increase superoxide following exhaustive/fatiguing contractions or sustained contractures where anaerobic metabolism predominates.
Recent work in striated muscle by Ward and coworkers and others has implicated nicotinamide adenine dinucleotide phosphate oxidase 2 (NADPH oxidase; NOX) as the major source of superoxide ROS during repetitive contraction [24, 25]. NOX is a multimeric enzymatic complex that generates superoxide by transferring electrons from NADPH to oxygen. Several NOX isoforms are expressed in striated muscle and located within the sarcoplasmic reticulum, the sarcolemma, and the transverse tubules [34, 35]. Striated muscle cells express NOX2 and 4 which each bind p2
, a small subunit essential for enzyme activity [34]. NOX4 is constitutively active and does not require association with regulatory subunits, with regulation thought to occur mainly by changes in expression level. Therefore NOX4 likely contributes to the basal rate of ROS production in the myocyte. In contrast, NOX2 (also known as gp9) is activated by specific agonists (e.g. G-protein coupled receptor agonists such as angiotensin II, growth factors, and cytokines) and mechanical/contractile stress, which induce the association of regulatory subunits (p4, p6, p4Myofascial Pain Rehabilitation Research Paper
, and Rac1) and activation of the enzyme [35, 36].
The mechanosensitivity of NOX2 has recently garnered much attention. The production of reactive oxygen species by NADPH oxidase is regulated by the small Rho like GTPase protein Rac1 [37, 38]. The Rac1 protein activity is regulated by microtubules [39] and the actin cytoskeleton [39]. During mechanical stress such as the stretching/twisting of airway smooth muscle cells, the cytoskeleton deforms and activates Rac1 [40]. This response is disrupted if myosin II tension is blocked with blebbistatin, f-actin is disrupted with cytochalasin D, or the micro tubules are disrupted with colchicine [40]. This mechanism is also present in skeletal muscle where mechanical stretching induces ROS production by NOX2. This mechanoactivation of NOX2 dependent ROS production has been recently shown to be critical to the pathogenic calcium and ROS signaling in Duchenne muscular dystrophy. Relevant hypothesis on mechanoactivated NOX2 dependent ROS production is discussed below.
3. Myofascial Trigger Point Mechanisms
In all cases, myofascial trigger points are associated with areas in muscle that have stiff, tender nodules under palpation. It is believed that this stiffness might arise from hypercontracture of the sarcomere in this area [41, 42]. Histological examination of muscle biopsies from myofascial trigger points reveals structural evidence of muscle hypercontracture consistent with sustained sarcoplasmic reticulum calcium release due to intense neural activation and action potential generation [42]. This is supported by the work identifying trigger points exhibiting spontaneous electrical activity suggesting aberrant action potential generation [43]. Further pathological findings associated with sustained hypercontraction/activity (e.g., sarcomere shortening, protein degradation, and myofiber and mitochondrial swelling) are consistent with metabolic stress and ATP depletion.Myofascial Pain Rehabilitation Research Paper
Sustained contractile activity leading to increased metabolic stress and reduced blood flow is likely the foci for secondary changes that contribute to the persistence of the myofascial trigger point. In addition the sustained contractile activity, metabolic alterations, and cell stress trigger the increased release of myokines, inflammatory cytokines, and neurotransmitters that also undoubtedly contribute to these myofascial trigger points and myofascial pain syndrome. Figure 1 shows the mechanisms of initiation and maintenance myofascial trigger points, how they cause pain, and how current therapies work. These pathways will be explained in the following sections.
Myofascial pain syndrome is a chronic pain condition that tends to result from repetitive movements of a particular muscle. It is a deep, muscle ache or muscle pain that doesn’t go away with rest and can actually feel worse as time goes on. The hallmark sign of this condition is trigger points. These are tough nodules of tissue located deep within the muscle. You may notice them as small lumps, and you may also notice that they elicit strange responses.
Although trigger points hurt when they are pressed on, they do not behave as other tissue that receives pressure. Many patients report feeling pain far away from the trigger point when the nodule is manipulated or activated. This is known as referred pain, and it is a primary differentiation point between myofascial pain and chronic myalgia. Trigger points and referred pain are signs that lead to diagnosis of this rare condition, and the presence of this network of pain receptors often points to a more complicated problem than simple myalgia.Myofascial Pain Rehabilitation Research Paper
What kind of pain results?
Myofascial pain syndrome usually results in deep, aching muscle pain. It is the same feeling you would get from straining a muscle, but it tends to be amplified in the case of this condition. The pain is either more intense or just doesn’t go away. Another important point to consider about the pain is that it is often referred. Myofascial pain means that the connective nerves in the muscle fibers are eliciting pain signals. This is why you have pain in a different area when a trigger point is activated. For this reason, those who have this type of pain can experience pain in the muscle, of course, but they can also feel it as far away as adjacent joints or nearby muscles.