Our purposes in this study were: (1) to determine the reproducibility of previous findings that showed the unique biochemical milieu of substances associated with pain and inflammation in an active MTP in the upper trapezius muscle, and (2) to compare the similarity of analyte levels sampled from the biochemical milieu in the upper trapezius of subjects with active, latent, and no MTPs with those levels in a remote uninvolved site in the upper medial gastrocnemius muscle.
Discussion
We have confirmed that biochemicals associated with pain and inflammation are elevated in soft tissue in the vicinity of active MTPs. The concentrations of these biochemicals, including protons (equivalent to inverse pH), bradykinin, SP, CGRP, TNF-α, IL-1β, 5-HT, and norepinephrine differentiate the active group from the latent and normal groups. Two additional analytes not previously sampled, IL-6 and IL-8, were also significantly higher in the active group.
We have also shown that the concentrations of these biochemicals in the upper trapezius, adjacent to active MTPs, differ quantitatively from the remote, uninvolved site we chose in the gastrocnemius muscle. There are also consistent differences in the biochemical milieu among active, latent, and normal groups in the gastrocnemius. This suggests that substances associated with pain and fatigue are not limited to local areas of MTPs or a single anatomic locus.
These findings suggest that subjects with active MTPs have a greater presence of inflammatory mediators, neuropeptides, catecholamines, and cytokines within the local milieu of the trigger point. The elevated levels of these sensitizing substances and a higher proton concentration (lower pH) in the active MTP support Simons’ integrated hypothesis
1- Simons D.G.
- Travell J.G.
- Simons L.S.
Travell and Simons’ myofascial pain and dysfunction: the trigger point manual. Vol 1. Upper half of body.
of an area of relative local ischemia and hypoxia compared to latent and normal muscle.
According to the integrated hypothesis, “… a central MTrP [myofascial trigger point] has multiple muscle fibers with endplates releasing excessive acetylcholine, and it shows histopathological evidence of regional sarcomere shortening.”
12Review of enigmatic MTrPs as a common cause of enigmatic musculoskeletal pain and dysfunction.
(p100) Sarcomere shortening requires high oxygen to maintain continuous muscle contractile activity. The combination of this increased metabolic demand and the ischemia from compromised circulation caused by increased tension of the involved sarcomeres could account for the severe local hypoxia. Consequently, the relative ischemia and hypoxia would cause the elevated levels of sensitizing substances we found in active MTPs. Furthermore, relatively higher levels of these substances in active MTPs help explain the local tenderness and referred pain of active MTPs.
12Review of enigmatic MTrPs as a common cause of enigmatic musculoskeletal pain and dysfunction.
Issberner et al
13- Issberner U.
- Reeh P.W.
- Steen K.H.
Pain due to tissue acidosis: a mechanism for inflammatory and ischemic myalgia?.
showed a positive correlation between pain and local acidity. An acidic milieu alone (without muscle damage) is sufficient to cause profound changes in the properties of the “pain matrix” such that alterations in pH would be sufficient to modify the threshold sensitivity of the nociceptor. An acidic pH stimulates the production of bradykinin during local ischemia and inflammation; therefore, a local acidic milieu may explain the pain associated with an active MTP.
Mechanical hyperalgesia is a hallmark of an MTP. Ongoing nociceptive activity, however, is not necessary to cause mechanical hyperalgesia. In a rat model,
14- Sluka K.A.
- Kalra A.
- Moore S.A.
Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia.
repeated injections of acidic saline boluses into 1 gastrocnemius muscle produced bilateral, long-lasting mechanical hypersensitivity (ie, hyperalgesia) of the paw. Furthermore, the study found that the persistent mechanical hyperalgesia was not caused by muscle tissue damage and was not maintained by continued nociceptive input from the site of muscle injury.
14- Sluka K.A.
- Kalra A.
- Moore S.A.
Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia.
This model clearly demonstrates that secondary mechanical hyperalgesia may be maintained by neuroplastic changes in the central nervous system (eg, in spinal dorsal neurons and thalamic neurons).
14- Sluka K.A.
- Kalra A.
- Moore S.A.
Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia.
Hong et al
15- Hong C.Z.
- Torigoe Y.
- Yu J.
The localized twitch responses in responsive bands of rabbit skeletal muscle are related to the reflexes at spinal cord level.
suggest that an integrative mechanism at the spinal cord level in response to sensitized nociceptors has a role in development of active MTPs and should be considered in any pathogenetic hypotheses.
In an expansion of Simons’ integrated hypothesis
1- Simons D.G.
- Travell J.G.
- Simons L.S.
Travell and Simons’ myofascial pain and dysfunction: the trigger point manual. Vol 1. Upper half of body.
, Gerwin et al
16- Gerwin R.D.
- Dommerholt J.
- Shah J.P.
An expansion of Simons’ integrated hypothesis of trigger point formation.
postulate that the acidic pH may also modulate the motor endplate by inhibiting acetylcholinesterase. This would result in an increased concentration of acetylcholine at the synaptic cleft that would lead to sarcomere contraction and formation of a taut band.
We found significantly elevated levels of SP and CGRP in the vicinity of the active MTPs. The orthodromic and antidromic release of these substances is greatly increased in response to nociceptor activation, (eg, by H
+ and bradykinin binding to their matched receptors).
17Retrograde signaling in the nervous system: dorsal root reflexes.
This dynamic phenomenon may lead to neuroplastic changes in the dorsal horn and profound changes in neuronal activity and the perception of pain.
The goal of trigger point needling of the active MTP is to elicit multiple LTRs.
4Myofascial pain syndromes and their evaluation.
, 18- Dommerholt J.
- Mayoral O.
- Grobli C.
Trigger point dry needling.
In our active group, SP and CGRP were the only 2 analytes for which concentrations during the recovery period (post) after the LTR were significantly below their concentrations at baseline (pre). This corresponds with the commonly observed decrease (at least temporarily) in pain and local tenderness after the release of an MTP by needling. Physiologically, this may be caused by interference with nociceptor membrane channels or transport mechanisms associated with a briefly augmented inflammatory response. The levels of these analytes may also fall because of a local increase in blood flow. Additional study of these analytes would be needed to explain the nature of this phenomenon.
SP causes mast cell degranulation with the release of histamine, serotonin, and upregulation of both proinflammatory (eg, TNF-α, IL-6) and anti-inflammatory cytokines (eg, IL-4, IL-10). TNF-α is the only cytokine prestored in the mast cell and is released immediately after mast cell degranulation. TNF-α stimulates norepinephrine production. We found significantly elevated levels of serotonin and norepinephrine in subjects with active MTPs. The increased levels of norepinephrine may be associated with increased sympathetic activity in the motor end plate region.
Levels of TNF-α and IL-1β were significantly elevated in the trapezius of subjects with active MTPs. In a rat model, TNF-α produces a time- and dose-dependent muscle hyperalgesia within several hours after injection into the gastrocnemius or biceps brachii muscles. This hyperalgesia was completely reversed by systemic treatment with the nonopioid analgesic metamizol.
19- Schafers M.
- Sorkin L.S.
- Sommer C.
Intramuscular injection of tumor necrosis factor-alpha induces muscle hyperalgesia in rats.
Furthermore, TNF-α did not cause histopathologic tissue damage or motor dysfunction. One day after injection of TNF-α, there were elevated levels of CGRP, nerve growth factor, and prostaglandin E
2 in the muscle. Therefore, TNF-α and other proinflammatory cytokines such as IL-1β may have a role in the development of muscle hyperalgesia, and the targeting of proinflammatory cytokines might be beneficial for the treatment of muscle pain syndromes.
19- Schafers M.
- Sorkin L.S.
- Sommer C.
Intramuscular injection of tumor necrosis factor-alpha induces muscle hyperalgesia in rats.
This may depend, however, on the time course of the injury and inflammatory response. Hoheisel’s data
20- Hoheisel U.
- Unger T.
- Mense S.
Excitatory and modulatory effects of inflammatory cytokines and neurotrophins on mechanosensitive group IV muscle afferents in the rat.
suggest that TNF-α has a dual action when released intramuscularly. Specifically, “… it suppresses neuronal hyperexcitability early after release but contributes to neuronal hyperexcitability in a later phase.”
20- Hoheisel U.
- Unger T.
- Mense S.
Excitatory and modulatory effects of inflammatory cytokines and neurotrophins on mechanosensitive group IV muscle afferents in the rat.
(p174)We found significantly elevated levels of IL-6 and IL-8 in the trapezius of the active group. IL-6 has both pro- and anti-inflammatory effects and like TNF-α, IL-1β, and IL-8, it produces a dose- and time-dependent mechanical hypernociception in rats. Cytokines and chemokines play a crucial role in mediating inflammatory and neuropathic pain in rat models of tissue injury. Furthermore, the cascade of cytokines released follows 2 distinct pathways with different final mediators (ie, prostanoids and sympathetic amines). For example, “… TNF-α, IL-6, and IL-1β sequentially precede the release of prostanoids to induce hypernociception in rats.”21(p123)
Conversely, the chemokine IL-8 participates in a separate (ie, cyclo-oxygenase [COX] independent) pathway and coordinates the sympathetic components of the inflammatory hypernociception after tissue injury. Moreover, IL-8 induces a dose- and time-dependent mechanical hypernociception. Elevated levels of IL-8 in active MTPs may mediate inflammatory hypernociception, muscle tenderness, and pain through this pathway, which is inhibited by β adrenergic receptor antagonists; COX inhibitors, however, do not inhibit this pathway.
21- Verri W.A.
- Cunha T.M.
- Parada C.A.
- Poole S.
- Cunha F.Q.
- Ferreira S.H.
Hypernociceptive role of cytokines and chemokines: targets for analgesic drug development?.
Analysis of samples taken from both muscles found that all analyte concentrations in the trapezius of the actives were generally higher than concentrations in their gastrocnemius muscles. There were fewer differences in the latent group and almost none in the normal group. The differences between the active and the other groups in the trapezius were more dramatic (ie, greater slope of the curve and higher peak and amplitude) than the differences in the gastrocnemius muscle. Concentrations in the gastrocnemius measurements remained relatively constant over the 10-minute sampling period.
The striking differences between analyte concentrations in the trapezius versus gastrocnemius muscles might be explained by several inherent muscle properties and functions. The trapezius and gastrocnemius have different muscle fiber types, mechanical properties, functions, and structures. Given the nature and density of the gastrocnemius muscle, analyte concentration locally may be insufficient to generate a noxious stimulus sufficient to produce a substantial rise in inflammatory analytes. Additionally, the trapezius is among the muscles most commonly affected by MPS because of its unique antigravity function. This puts it at high risk for overuse and susceptibility to irritation.
The trapezius and gastrocnemius muscles demonstrate different responses to needle insertion. The reaction during the pre-time level also suggests sensitivity to the needle, with the actives having the largest response, the latents a smaller response, and the normals having the least response to needle insertion. Additionally, the gastrocnemius muscles of all groups showed the least response to needle insertion. This may be associated with hyperirritability of the trapezius muscle in people with active MTPs, which is not evident in normals or in the gastrocnemius muscle.
Concentrations at the post-time level represent a recovery phase after a rapid drop in analyte levels associated with needle advancement. We thought that gastrocnemius concentrations would represent baseline levels for unaffected muscle and that post-trapezius data would trend toward these unaffected muscle levels. This was not the case in the trapezius of the actives, where all analytes except CGRP remained significantly higher than in the gastrocnemius in the recovery phase (post-level, approximately 5 minutes after needle advancement) (see
table 1). This suggests that the muscle with an active MTP is more biochemically reactive to needle perturbation than latent or normal muscle tissue.
Although there were no trigger points in the upper medial gastrocnemius, our results indicate that even in this muscle, analyte levels were always significantly higher in the active group than in the normal group and generally higher than in the latent group. This suggests that analyte abnormalities may not be limited to local areas of active (painful) MTPs in the upper trapezius, but are present in unaffected muscles remote from the active MTP, although at a lower level than in the trapezius. The slightly elevated analyte levels in the gastrocnemius may be a widespread phenomenon in the active group. This may be related to a central sensitization in the active group, which lowers the threshold to stimuli and leads to a higher sensitivity to mechanical stimuli at the gastrocnemius, or to a systemic susceptibility to inflammation. There is a possibility that widespread elevation of analytes is a precursor to development of active (painful) MTPs. Conversely, people who are predisposed to develop active MTPs might have elevated baseline levels in muscles throughout their bodies. An ongoing natural history study could determine whether the relatively elevated analyte levels in the gastrocnemius in the active group follow the development of an active MTP, or if there is a baseline low-level elevation of these analytes that precedes the development of an active MTP.
We believe that further research in this area should include studying the natural history of subjects with normal muscle and those with MTPs. This type of research will determine whether MTPs resolve spontaneously or evolve into the active forms from latent or normal conditions. Microdialysis sampling of the levels of inflammatory mediators, neuropeptides, catecholamines, pro-inflammatory cytokines, and other substances (eg, anti-inflammatory cytokines, peripheral opioids) may lead to an improved biochemical characterization of the MTP and identify people who are at risk for developing persistent symptoms. Furthermore, discovering whether and which measurable substances are predictive of pain could lead to focused therapies.
Study Limitations
There are several limitations to this study. First, the sample size was small. Because of this, statistical power was low, which would result in an increased probability of a type II error. A type II error, however, can only occur when findings do not achieve significance, so we could not have made this error. Further, we used conservative analysis (Bonferroni adjustment) to minimize type I error (ie, inappropriate significant differences), and we are therefore confident that our differences are real.
The depth of needle penetration was not standardized intersubject or within subjects because a stylus was not used. There was, however, a consistent initial end point in all groups, as determined by a change in tissue resistance at needle contact with the muscle. A consistent second end point for the active and latent groups was determined by the LTR and was approximated in the normal group as closely as possible.
We studied only 2 muscles. There is a possibility that other muscles might provide different findings. We believe, however, that the trapezius and gastrocnemius muscles are reasonable models for more generalized conclusions.
The physical findings and symptoms still may have some degree of clinical variance, as evidenced by the subject who was disqualified post hoc. There may be many different, and as yet undetermined, physiologic or pharmacologic phenomena present, and future studies will need to be specifically designed to seek these answers.