Myofascial pain syndrome is an important health problem. It affects a majority of the general population, impairs mobility, causes pain, and reduces the overall sense of well-being. Underlying this syndrome is the existence of painful taut bands of muscle that contain discrete, hypersensitive foci called myofascial trigger points. In spite of the significant impact on public health, a clear mechanistic understanding of the disorder does not exist. This is likely due to the complex nature of the disorder which involves the integration of cellular signaling, excitation-contraction coupling, neuromuscular inputs, local circulation, and energy metabolism. The difficulties are further exacerbated by the lack of an animal model for myofascial pain to test mechanistic hypothesis. In this review, current theories for myofascial pain are presented and their relative strengths and weaknesses are discussed. Based on new findings linking mechanoactivation of reactive oxygen species signaling to destabilized calcium signaling, we put forth a novel mechanistic hypothesis for the initiation and maintenance of myofascial trigger points. It is hoped that this lays a new foundation for understanding myofascial pain syndrome and how current therapies work, and gives key insights that will lead to the improvement of therapies for its treatment.
Myofascial pain is a significant health problem affecting as much as 85% of the general population sometime in their lifetime while the estimated overall prevalence is ~46% [
While myofascial pain syndrome is complex in its presentation, the onset and persistence of myofascial pain syndrome are known to be caused by myofascial trigger points [ What initiates the formation of a myofascial trigger point? What sustains a myofascial trigger point? What causes a myofascial trigger point to be painful? What will make the myofascial trigger point disappear?
Myofascial pain syndrome arises from the muscle and is composed of symptoms from the sensory, motor, and autonomic systems [
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 [
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.
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 [
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 crossbridges 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 crossbridge cycle (i.e., attachment-myofilament sliding-detachment) of all myosin heads in each muscle. The crossbridge 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 crossbridge 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.
Striated muscle generates superoxide as the primary ROS. Superoxide is generated by the addition of a single electron to ground state oxygen [
The most well described source for superoxide production is the mitochondria where superoxide is produced within the electron transport chain (ETC) [
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 [
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 [
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 [
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 [
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
Hypothesized signaling pathways of myofascial trigger points and therapies. A schematic diagram of the mechanism of myofascial trigger points and treatment options. The initiating mechanisms of myofascial trigger points are shown in blue with the downstream events in dark blue. The treatment for myofascial pain is shown in red with the pathways of their action shown in dark red. The arrows indicate how one feature causes another. The square at the ends of lines indicates inhibition of the end feature by the preceding feature. The myofascial trigger point is initiated by a combination of chronic load on the muscle which caused microtubule proliferation which increases ROS production and a decreased ability to remove ROS. The increase of ROS increases ryanodine receptors open probability, hence increasing calcium which results in contraction and deformation of the microtubule network resulting in more ROS production. This is the key positive feedback loop. Psychological stress can contribute to this as it reduces mitochondrial content and increase ROS production in cells. The contraction restricts blood flow resulting in local ischemia/hypoxia that results in muscle damage and the inflammatory response. Pain is caused by the activation of nociceptors by a decreased pH (ASIC channels), increased ROS (TRPV1 channels), and substance P. When depolarized, nociceptive neurons release CGRP which increases the amount of and response to acetylcholine in the neuromuscular junction, which can cause additional contraction. This provided a second positive feedback loop. Treatments such as lidocaine and capsaicin block nociception. Other treatments such as massage and cold laser therapy might increase circulation or reduce oxidative stress. Furthermore, treatments that induce stretching/contraction such as needling, electrical stimulation, stretching, and exercise increase calcium local to high enough concentrations (>10
A clear mechanistic description for the initiation of a myofascial trigger point does not currently exist. Trigger points are thought to occur as a result of muscle overuse or muscle trauma or psychological stress [
Another important consideration is that, in some healthy individuals and athletes, muscle fatigue or trauma does not always result in myofascial trigger points. Instead they can result in stiffness, soreness, and pain that usually resolve themselves after a few days. This also supports a threshold for occurrence and/or possibly a cofactor that promotes the initiation of a myofascial trigger point. Here, clues to the mechanistic events that initiate myofascial trigger points may be gained from our knowledge that comorbid conditions such as aging, disease, and stress increase the incidence of myofascial trigger points. For example, myofascial trigger points are thought to underlie the spontaneous pain patter in individuals suffering from fibromyalgia [
Myofascial trigger points are more common under conditions of psychological stress [
The persistence of myofascial trigger points requires a self-sustaining positive feed-forward process. Simons presented the integrated hypothesis for myofascial trigger points to offer an explanation [
More recently this hypothesis has been expanded by Gerwin and coworkers [
These expanded hypotheses presented in the previous paragraph are based upon experimental and clinical evidence and understanding when possible [
The positive feedback loop in the above mechanism requires that there be sustained stimulation of the muscle motor unit due to increased acetylcholine release and decreased acetylcholinesterase activity. However, it appears that acetylcholine release might not be required for sustaining trigger points. In studies comparing the efficacy of motor nerve block using lidocaine injection compared to intramuscular stimulation using dry needling, the group receiving the intramuscular stimulation showed more than 40% greater improvement than did the lidocaine injection group [
There are several therapies currently used to treat myofascial trigger points including massage, stretching, dry needling/injections, electrical stimulation, cold laser treatment, and ultrasound. There are several massage treatments that relax myofascial trigger points such as passive rhythmic release, active rhythmic release, and trigger point pressure release [
It is widely believed that massage increases blood flow. For example, in one study massage of the lower left extremity in young females increase blood flow in the tibial artery as measured by Doppler ultrasound [
Stretching of muscle involves a series of stretching exercises of the muscle where pain is experienced [
The insertion of a needle (acupuncture) can release a myofascial trigger point if the insertion of a needle into the trigger point elicits a local twitch. This local twitch involves a transient increase in activity in the muscle band containing the trigger point. Furthermore, it is considered to be a spinal reflex since spinal cord transection between the brain and the level of the trigger point does not affect the response [
Electrical stimulation places electrode across the muscle affected by a trigger point and rapidly causes contractions by depolarizing the muscle. The goal of this therapy is to increase the size and frequency of the twitches that could have been elicited by needling [
Cold laser therapy also known as low level light therapy exposes the myofascial trigger point to near infrared light. It has been shown to work clinically reducing pain and rigidity and increasing mobility [
Ultrasound is often used to treat myofascial pain and trigger points. However, the benefits are unclear. While exercise and massage seem to reduce pain and the number and size of myofascial trigger points, conventional ultrasound did not result in pain reduction [
In light of the discussion above, it is clear that the current theory for the mechanisms behind myofascial pain is not sufficient to fully explain the syndrome. As the myofascial trigger point appears central to the onset and persistence of myofascial pain syndrome, we have focused attention on the muscle fiber level in an attempt to reveal new mechanistic insight. Here we present mechanistic findings in muscle that demonstrate how mechanical stress acts to trigger excess calcium release in muscle via a novel mechanotransduction pathway. With this new pathway as a foundation, we put forth a novel mechanistic hypothesis for the initiation and persistence of myofascial trigger points that extends the current theories discussed above.
The essence of this question is what positive feedback mechanisms exist that can sustain a myofascial trigger point once initiated. Based on the models and mechanisms discussed above, the local and persistent hypercontracture of the muscle appears to be critical to the myofascial trigger point. At the cellular level, a persistent neural activation may act to initiate a local and sustained contraction; however, fatigue of the muscle would ensue much as in a highly trained athlete with high motivation that is eventually unable to sustain muscle activity. Rather, the local contracture of the muscle must occur secondary to the normal neuromuscular activation and arise due to regenerative feed-forward processes within the muscle cell. At the most basic level, this situation would necessitate a mechanism that permitted regenerative calcium release within the myofibers that escaped from the normal inhibitory processes that govern central and peripheral muscle fatigue. It would be most practical for this feed-forward mechanism to take advantage of any aberrant activity (contraction dependent mechanical stress, calcium release, and altered metabolic signaling) as an initiation trigger and as a mechanism to sustain its activity.
X-ROS signaling is anewly characterized mechanoactivated ROS-dependent signaling cascade in cardiac and skeletal muscle. In X-ROS signaling mechanical deformation of the microtubule network acts as a mechanotransduction element to activate the NADPH oxidase (NOX2) which produces ROS. The ROS oxidizes RyRs and increases their open probability resulting in increases in Ca2+ release from the sarcoplasmic reticulum. The Ca2+ mobilization resulting from mechanical stretch through this pathway is X-ROS signaling. In heart, X-ROS acts locally to affect the sarcoplasmic reticulum (SR) Ca2+ release channels (ryanodine receptors, ryanodine receptors) and “tunes” excitation-contraction coupling Ca2+ signaling during physiological behavior but can promote Ca2+-dependent arrhythmias during pathology with X-ROS in excess [
The above mechanism purports that excessive contraction dependent stress acts through the microtubule cytoskeletal elements to activate NADPH oxidase to produce ROS. The subsequent ROS sensitization of ryanodine receptors and sarcolemmal calcium influx channels increases myoplasmic calcium concentration and contraction leading to more stretch. Based on this model, one reason why the occurrence of myofascial trigger points may be less common in healthy individuals is due to the absence of the feed-forward trigger, excess microtubules, or NOX2 that serves to generate X-ROS. This hypothesis then proposes that the threshold for developing myofascial pain and myofascial trigger points is lower with the trigger present as a critical amount of X-ROS activity that would serve to lower the threshold for calcium release activation such that spontaneous or regenerative calcium release generation promoted can initiate the contractures which underscore the myofascial trigger point.
Our hypothesis that the microtubule cytoskeleton and X-ROS may play a role in the mechanism of myofascial trigger point came from work that suggests that microtubule proliferation have been associated with either myofascial trigger points or myofascial pain or both. Taxane based chemotherapy, for example, pacilitaxel, is a common therapy for cancer as by increasing microtubules and it blocks the organization of the centrosome and kinetochore thereby inhibiting mitosis [
Myofascial trigger points are thought to occur by muscle injury and muscle overuse [
One intriguing possibility arises. Recently, noninvasive imaging studies using Doppler ultrasound or vibration elastography have been shown effective in detecting myofascial trigger points. Areas associated with myofascial trigger points are hyperechoic under ultrasound imaging having lower vibration amplitude and entropy, respectively, than that of normal muscle [
In addition to the increase of ROS production through the X-ROS mechanism, a reduced ability of the muscle cell to remove ROS most likely also plays a role in the mechanism. In normal stretching of the muscle, reactive oxygen species are removed by the normal homeostatic mechanisms. Superoxide is reduced to hydrogen peroxide by superoxide dismutase. The hydrogen peroxide is removed by catalase or glutathione oxidase and converted to water. The glutathione that is oxidized to glutathione disulfide is converted back to glutathione by glutathione reductase consuming NADPH in the process. The regeneration of NADPH uses the nicotinamide nucleotide transhydrogenase which requires a proton gradient and membrane potential across the mitochondrial inner membrane. The local ischemia that results from the formation of a myofascial trigger point will result in a decrease in mitochondrial membrane potential and increase in extramitochondrial proton concentration (decreased pH) [
As mentioned previously, muscle-damaging exercise and psychological stress play a role in the initiation of myofascial trigger points. This might be due to the reduced ability of the muscle to remove ROS under these conditions. Experimental studies have shown that repeated muscle-damaging exercises results in muscle oxidative stress which includes decreased levels of glutathione and increased levels of its oxidized form, glutathione disulfide [
In summary, we hypothesize that the occurrence of X-ROS is a disease modifier for the development of myofascial trigger point. We propose that the molecular underpinning of the myofascial trigger point involves an increased microtubule density which leads to an increase in NOX2-dependent reactive oxygen species production which in turn lowers the threshold for calcium release and entry in muscle. In the trigger point region there will be increased ROS levels as well as increased calcium levels. In fact, it has been hypothesized that calcium is elevated in myofascial trigger points [
Hypothesized mechanism yielding active and latent trigger points. At the site of the myofascial trigger point, there is restriction of blood flow increasing the proton concentration ([H+]) locally. There is also an increase of local [ROS]. The plot shows the normalized concentrations of these substances as a function of the distance from the trigger point center. As the distance from the trigger point center increases, the levels of [ROS] (blue) decrease more gradually than the levels of [H+] (red). If the nociceptors are located close to the center of the trigger point, they are active as the levels of [ROS] and [H+] protons are high enough to activate the ASIC and TRPV1 channels. If these neurons/receptors are farther away the, trigger point would be latent. Upon palpation the [ROS] increases due to mechanical deformation of the microtubule network and activation of NADPH oxidase and the [ROS] increases (green) so that the nociceptors see sufficient ROS to be activated.
Myofascial trigger points yield pain upon palpation. If they are only painful upon palpation, they are called latent. If they are painful without manipulation they are considered to be active [
The local sustained contraction in a myofascial trigger point can result in restriction of local circulation which can cause the local ischemia/hypoxia and the observed changes caused by it such as increased acid accumulation resulting in a decrease in pH. In experiments in rabbit gastrocnemius muscle, the intracellular pH dropped from 7.0 to 6.6 during 4 hours of ischemia [
As noted above, reactive oxygen species are produced in large amounts as a result of the mechanism of myofascial trigger points. There are several TRP (transient receptor potential) channels that respond to reactive oxygen species including TRPM2, TRPM7, TRPC5, TRPV1, and TRPA1 [
Considering that the two nociceptors above most likely are involved in the sensation of pain in the environment of trigger points, the question arises—why are some trigger points latent and some active? We hypothesize that pain is likely felt with manipulation of trigger points as the cytoskeleton is being stretched and reactive oxygen species production increased activation of more nociceptors. Some trigger points might be active because the local extracellular reactive oxygen species concentration in the location of the TRPV1 receptors is high enough for their activation. This requires that these receptors be close enough to the trigger point (Figure
Hypothesis of how changes to the affected region cause a sustained perturbation yielding a trigged point. Conceptual phase plane diagrams for intracellular [Ca2+] and [ROS]. (a) The [ROS] nullcline (red) intersects the [Ca2+] nullcline (blue) at the steady state value for resting [Ca2+] and [ROS] (black dot). (b) With the changes that occur with microtubule proliferation and reduction in the ability of the myocyte to remove ROS, the [ROS] nullcline shifts to the right higher [ROS] for a given level of [Ca2+] resulting in a higher steady-state [ROS] and [Ca2+].
There are also other receptor channels that are located in the pain sensing neuron that are involved in the sensation of pain in myofascial pain syndrome [
In summary, it appears that myofascial pain is likely due to a combined activation of several ligand gated ion channels in the pain sensing neuron. For example, ASIC3 and TRPV1 open as a result of increased acidity and reactive oxygen species, respectively. Any treatment for pain should address these mechanisms.
This is important for understanding what therapies can be used to treat myofascial trigger points. We can begin by explaining why current therapies work or do not work. The current therapies for myofascial trigger points are described above. These therapies include massage, stretching, dry needling/injection, electrical stimulation, cold laser therapy, and ultrasound. The underlying process with the treatment of trigger points is to temporarily release the trigger points to reduce pain and increase muscle mobility. This is often accomplished by massage, heat (direct or through ultrasound), and needling and injection for persistent trigger points. This is followed by stretching and simulation which essentially exercises the muscle. We hypothesize that the exercise of the muscle most likely starts to remodel the cytoskeleton, including the microtubular network, toward a more normal phenotype. There is also improvement in metabolism possibly by the increased blood flow and increase in mitochondrial content.
Injections of substances such as lidocaine and capsaicin block the activation of the nociceptive neurons. Capsaicin blocks activation of the TRPV1 channels while lidocaine blocks neuron depolarization (Figure
The long-term effects might be from other aspects of the treatments that reduce oxidative stress. For example, some reports indicated that massage increases circulation. If this can restore circulation to an ischemia area, the mitochondria might recover and the removal of reactive oxygen species can be more effective. Massage might also increase mitochondrial biogenesis which can also help to relieve oxidative stress. Cold laser therapy also seems to reduce oxidative stress.
Another commonality between treatments is that there seems to be some sort of stretching involved and perturbation of the NADPH oxidase system. Massage and stretching directly stretch the muscle and can activate NADPH oxidase. Needling requires that a muscle twitch be elicited and electrical stimulation builds upon this by creating repeated strong twitches. This can lead to stretching as well.
Exercise has also been shown to help alleviate myofascial trigger points. During exercise there are transient elevations of calcium that are likely higher at peak than those seen in the muscle during a myofascial trigger point. Calcium-dependent regulator protein inhibited polymerization of microtubules at physiological calcium concentrations [
Exercise also leads to mitochondrial biogenesis [
If the hypothesis that increased microtubule polymerization results in a pathologic increase in reactive oxygen species production through the NAPDH oxidase complex, then treatments that reduce microtubule polymerization should show benefit for treating myofascial trigger points. In fact, administration of colchicine and related compounds seems to reduce myofascial pain. The application of topical thiocolchicoside reduced pain in patients with acute cervical myofascial pain to alleviate back pain in patients [
Recent progress in experimental studies has provided a wealth of information that can be used to gain understanding of the molecular mechanisms of myofascial pain syndrome. Only through improved understanding of the molecular and subcellular pathways behind this disorder can novel therapeutics be discovered. This improved comprehension might also help guide current treatment protocols for optimal benefit. However, many details of the signaling pathways involved remain yet unclear and further study is needed. Finally, the analysis presented here suggests that colchicine is a likely therapeutic that should be explored further as a treatment for myofascial pain.
Acid-sensing ion channel with isoforms ASIC1, ASIC2, ASIC3, and ASIC4
Adenosine triphosphate
Calcitonin gene related peptide
End plate potential
Electron transport chain
Extracellular signal-related kinase
Focal adhesion kinase
Another name for NOX2
Hydrogen peroxide
Miniature end plate potential
Nicotinamide adenine dinucleotide phosphate
NADPH oxidase with isoforms NOX2 and NOX4
Regulatory subunits of NOX2
Regulatory subunits of NOX2
Regulatory subunits of NOX2
Regulatory subunits of NOX2
Phospholipase A2
Ras-related C3 botulinum toxin substrate 1 acting as regulatory subunits of NOX2
A small prokaryotic protein involved in the termination of transcription
Reactive oxygen species
Ryanodine receptor
Ryanodine receptor type 1
Superoxide dismutase
Transient receptor potential channel with isoforms TRPM2, TRPM7, TRPC5, TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, and TRPM8
Xanthine oxidase
Stretch activated ROS production by NOX2 to potential calcium signaling.
The author declares that there is no conflict of interests regarding the publication of this paper.
The author would like to give special thanks to Professor Chris Ward of the University of Maryland School of Medicine for his essential discussions and his comments and suggestions for the paper. The author would also like to thank Siddhartha Sikdar for the discussions on this topic. This work was supported in part by the National Institutes of Health Grants 5R01AR057348 and 5R01HL105239.