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Spatial Pain Propagation Over Time Following Painful Glutamate Activation of Latent Myofascial Trigger Points in Humans
The Journal of Pain, Vol 13, No 6 (June), 2012: pp 537-545 Available online at www.jpain.org and www.sciencedirect.com
Spatial Pain Propagation Over Time Following Painful Glutamate Activation of Latent Myofascial Trigger Points in Humans Chao Wang,*,y Hong-You Ge,* Jos e Miota Ibarra,*,z Shou-Wei Yue,y Pascal Madeleine,* and Lars Arendt-Nielsen* *Laboratory for Musculoskeletal Pain and Motor Control, Center for Sensory-Motor Interaction (SMI), Department of Health Science and Technology, Aalborg University, Aalborg, Denmark. y Department of Physical Medicine & Rehabilitation, Qilu Hospital, Medical School of Shandong University, Jinan, China. z Nursing and Physiotherapy School, Department of Nursing and Physiotherapy, University of Castilla-La Mancha, Toledo, Spain.
Abstract: The aim of this present study was to test the hypothesis that tonic nociceptive stimulation of latent myofascial trigger points (MTPs) may induce a spatially enlarged area of pressure pain hyperalgesia. Painful glutamate (.2 mL, 1M) stimulation of latent MTPs and non-MTPs in the forearm was achieved by an electromyography-guided procedure. Pain intensity (as rated on the visual analog scale [VAS]) and referred pain area following glutamate injections were recorded. Pressure pain threshold (PPT) was measured over 12 points in the forearm muscles and at the mid-point of tibialis anterior muscle before and at .5 hour, 1 hour, and 24 hours after glutamate injections. The results showed that maximal pain intensity, the area under the VAS curve, and referred pain area were significantly higher and larger following glutamate injection into latent MTPs than non-MTPs (all, P < .05). A significantly lower PPT level was detected over time after glutamate injection into latent MTPs at .5 hour (at 4 points), 1 hour (at 7 points), and 24 hours (at 6 points) in the forearm muscles. However, a significantly lower PPT was observed only at 24 hours after glutamate injection into non-MTPs in the forearm muscles (at 4 points, P < .05) when compared to the pre-injection PPT. PPT at the mid-point of the tibialis anterior was significantly decreased at 1 hour only as compared to the pre-injection PPT in both groups (< .05). The results of the present study indicate that nociceptive stimulation of latent MTPs is associated with an early onset of locally enlarged area of mechanical hyperalgesia. Perspective: This study shows that MTPs are associated with an early occurrence of a locally enlarged area of pressure hyperalgesia associated with spreading central sensitization. Inactivation of MTPs may prevent spatial pain propagation. ª 2012 by the American Pain Society Key words: Glutamate, myofascial trigger points, nociception, pain propagation, pressure pain threshold.
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yofascial pain syndrome due to myofascial trigger points (MTPs) can be acute or chronic, regional or generalized.21 Recent studies support the role of active MTPs in the induction and/or maintenance of not
Received December 9, 2011; Revised January 26, 2012; Accepted March 1, 2012. Supported by a grant from the Danish Working Environment Authority (‘‘Undersøgelse af manifestationer, arsagsmekanismer samt progression af smerter hos computerbrugere’’ project). The authors have no conflict of interest to report. Address reprint requests to Lars Arendt-Nielsen, Center for SensoryMotor Interaction, Department of Health Science and Technology, Aalborg University, Fredrik Bajers Vej 7 D-3, DK-9220, Aalborg, Denmark. E-mail: [email protected] 1526-5900/$36.00 ª 2012 by the American Pain Society doi:10.1016/j.jpain.2012.03.001
only regional pain conditions, such as headache,9 low back pain,30 temporomandibular pain disorders,10 and chronic pelvic pain syndrome,3 but also generalized pain syndromes, such as fibromyalgia12,15,18 and whiplash syndromes.11,26 These results suggest that active MTPs may be a strong link between localized regional pain and generalized pain conditions. It is suggested that active MTPs as ongoing nociceptive stimuli may contribute to the spatial pain propagation and/or widespread pain in musculoskeletal pain conditions.17 Chronic widespread pain may be related to multiple peripheral and central pain mechanisms.25 Of particular importance in central pain mechanisms is the contribution of central sensitization to the development of chronic widespread pain,46 as compared to a limited or 537
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ceiling effect of descending inhibition mechanisms in humans.19,33 MTPs have the potential to induce central sensitization,37,47and central sensitization in fibromyalgia is maintained by muscle afferent input43 and especially by active MTPs.1 Clinically, it is the active, but not latent, MTPs that are responsible for patients’ spontaneous pain (local and/or referred pain). Characteristics common for both active and latent MTPs are the tenderness spot on a taut muscle band, local twitch response upon palpation and/or dry needling, and the existence of spontaneous electrical activity with intramuscular needle electromyographic (EMG) examination when the muscle is at rest.22,40 To mimic active MTPs, algesic substance glutamate44 has been used to activate latent MTPs and induce local and/or referred pain in healthy humans.8,14 Studies have shown that glutamate, but not hypertonic saline, can increase mechanical pain sensitivity when injected into the muscle.12,24,44 Therefore, we hypothesized that glutamate injection into latent MTPs may induce a locally enlarged area of mechanical hyperalgesia as compared to non-MTPs, in addition to the induction of central sensitization.47 However, direct evidence is lacking for the spatial and temporal propagation of pressure hyperalgesia caused by MTPs in humans. Topographical pressure pain threshold (PPT) mapping has recently been used to identify MTPs in the infraspinatus and temporalis9,13 and to assess spatial distribution of mechanical pain sensitivity of the trapezius muscle6,15 and forearm muscles.39 Further, the pattern of topographical PPT mapping changes over time following eccentric5 and concentric exercise19 of the trapezius muscle and eccentric exercise of the forearm muscles.7 PPT mapping in the forearm reflects the pressure pain sensitivity of 3 extensor muscles.7,39 Thus, topographical PPT mapping in the forearm may provide a window to observe spatial and temporal patterns of pressure pain sensitivity across these 3 extensor muscles following activation of a latent MTP in 1 of the muscles. Thus, the aim of this study is to simultaneously assess the changes in spatial (localized and generalized) and temporal development of pressure pain sensitivity following painful glutamate stimulation of latent MTPs in the forearm.
Methods Subjects Thirteen healthy subjects (10 males and 3 females; mean age, 24.5 6 2.6 years), with no signs or symptoms of musculoskeletal pain, were recruited through notices at Aalborg University campus and volunteered for this study. This study was approved by the local Ethics Committee (N-20100048) and conducted in accordance with Helsinki Declaration. Informed consent was obtained from all subjects.
Experimental Protocol Each subject participated in a 2-session study in which glutamate was injected into a latent MTP and a non-MTP in the extensor digitorum communis with an interval
Myofascial Trigger Points and Pain Propagation of 24 hours between sessions; based on the previous results, generalized sensitization lasts up to 30 minutes following sustained mechanical stimulation of latent MTPs.47 The forearm muscles were divided into 12 points forming a 3 4 matrix (4 points in the lateral part, 4 points in the middle, and 4 points in the interior part), outlined in previous studies,7,39 but the matrix was moved 2 cm distal to the lateral epicondyle in the current study to include all points in the muscle belly but not tendon tissue. Briefly, 2 cm distal to the lateral epicondyle was taken as the reference point (point 5). A line downward from the lateral epicondyle was set as the central column of the map. The rest of the 3 points in the middle are separated by 2 cm (point nos. 6, 7, and 8). These 4 points were used to define the remaining 2 columns of the matrix. The remaining points were symmetrically located 2 cm lateral (point nos. 1 to 4) and 2 cm interior (point nos. 9 to 12) to each respective point in the middle. Point nos. 1 to 4 corresponded to the muscle belly of the extensor carpi radialis brevis, point nos. 5 to 8 to the muscle belly of the extensor digitorum communis, and point nos. 9 to 12 to the location of the muscle belly of the extensor carpi ulnaris muscle (Fig 1). The subjects were asked to lie down on a bed, and their forearms were exposed and supported with a suitable pillow to keep the forearms relaxed. A latent MTP was identified and marked in the extensor digitorum communis, and a non-MTP was then identified and marked at approximately the mirror location of the latent MTP on the opposite side of the extensor digitorum communis. The side of the forearm was randomized for the identification of a latent MTP. A latent MTP was confirmed by a taut muscle band, local twitch response, and most tender point with or without referred pain upon digital palpation and reconfirmed by the presence of spontaneous electrical activity with intramuscular EMG. A non-MTP was defined if there were no characteristics of a latent MTP by digital palpation and reconfirmed by the absence of spontaneous electrical activity with intramuscular EMG. An EMGguided injection was then undertaken (detailed later). A bolus of glutamate (.2 mL, 1M) was then injected into a latent MTP or a non-MTP in a randomized order. Subjects were asked to rate the pain intensity in real time on an electronic visual analog scale (VAS 0–10 cm, Aalborg University) starting from intramuscular needle insertion and recorded for 8 minutes. 0 represents no pain and 10 the most pain imaginable. Maximal pain intensity and the area under the VAS curve were extracted for further analysis. The EMG-guided injection needle was removed at the end of the VAS recording. The referred pain pattern was drawn by the subjects on an anatomic map after each EMG-guided injection, and the referred pain area was calculated with VistaMetrix software (VistaMetrix 1.36; SkillCrest, LLC, Tucson, AZ) by an experimenter (C.W.) blinded to the MTP type. PPT measurement blinded to the MTP type was taken at 12 points in the forearm under investigation and the midpoint of the tibialis anterior muscle contralateral to the injection side before and .5 hour, 1 hour, and 24 hours after injection (detailed later).
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1 second. The EMG-guided injection needle was advanced slowly by the experimenter (J.M.I.) into latent MTPs with spontaneous electrical activity or into nonMTPs without spontaneous electrical activity.
Assessment of PPT PPT was measured at the different measurement points in the forearm muscles and the middle of tibalis anterior muscle by a handheld pressure algometer (Algometer type 2; Somedic, Sollentuna, Sweden) before and .5 hour, 1 hour, and 24 hours after injection. The pressure algometer is equipped with a 1-cm2 rubber-tipped plunger mounted on a force transducer and was used to measure the PPT. Each point was repeated 2 times, and averages of the 2 repetitions were used for analysis. The pressure was increased at a rate of 30 kPa/second until the subject detected the pain threshold or until the pressure applied reached an upper limit of 800 kPa.
Statistical Analysis
Figure 1. Representation of the 12 points forming a 3 4 matrix in the forearm.
EMG-Guided Intramuscular Injection Following identification of a latent MTP and a nonMTP, the skin area around the marked position of a latent MTP or a non-MTP was then shaved and cleaned with isopropyl alcohol. One pair of bipolar surface EMG electrodes (Neuroline 720-01-k; Ambu, ølstykke, Denmark; intra-electrode distance of 2 cm) was placed 2 cm distal to the marked position. The surface electrodes were used to ensure that the forearm muscles were relaxed prior to injection of glutamate and to monitor the EMG activity after injection. A reference surface electrode was placed 2 cm lateral to the marked position. A ground tape electrode was then wrapped around the ankle. The EMG-guided injection needle (Neuroline Inoject, 35 .4 mm, Ambu) was first connected to an extension tube (15 cm, filling volume .2 mL) and then to a syringe (1 mL in volume). The syringe was pre-filled with .4 mL glutamate, which resulted in .2 mL in the extension tube and an injection of .2 mL of glutamate into a latent MTP or a non-MTP. The extension tube and the syringe were fixed to the skin to prevent displacement of the EMG-guided injection needle during injection. The total time for each injection was manually controlled for 10 6
Statistical analysis in the current study was made with Statistica software (v.8.0, StatSoft, Inc., Uppsala, Sweden). A paired t-test was used to compare the difference in maximal pain intensity, area under the VAS curve, and referred pain area between latent MTPs and non-MTPs. A Fisher exact test was used to compare the difference in the occurrence of referred pain and in the proportion of points with decreased PPT between latent MTPs and non-MTPs following glutamate injection. Three-way (latent MTPs and non-MTPs, measurement points, time) repeated measures analysis of variance (ANOVA) was used to compare the differences in PPT levels among 12 measurement points in the forearm muscles before and .5 hour, 1 hour, and 24 hours after glutamate injection into latent MTPs or non-MTPs. Two-way repeated measures (latent MTPs and non-MTPs, time) ANOVA was used to compare the differences in PPT levels in the middle of tibialis anterior muscle before and .5 hour, 1 hour, and 24 hours after glutamate injection into latent MTPs or non-MTPs. Values in the text and figures are expressed as standard error of the mean (SEM). Significance level was set at P < .05.
Results Local and Referred Pain Induced by Glutamate Injection Latent MTPs were found at the upper and middle parts of the extensor digitorum communis in every subject: a latent MTP was located between point no. 5 and point no. 6 in 8 subjects and between point no. 6 and point no. 7 in 5 subjects. The depth of EMG needle insertion was estimated to be 1 6 .2 cm until a latent MTP (spontaneous electrical activity) was found. Local muscle pain was evoked in all 13 subjects by glutamate injections into latent MTPs or non-MTPs in the extensor digitorum communis. A higher maximal pain intensity was induced by glutamate injection into latent MTPs than
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into non-MTPs (t = 6.26, P < .001, Fig 2A), and so was the area under the VAS curve (t = 5.39, P < .001, Fig 2B). Referred pain was induced in 10 out of 13 subjects following glutamate injection into latent MTPs. Muscle pain was referred to the dorsal forearm in 4 subjects, to the dorsal and ventral aspects of the elbow in 1 subject, to the shoulder in 3 subjects, and to the ventral wrist and palm in 2 subjects (Fig 3A). Referred pain was induced in 7 out of 13 subjects following glutamate injection into non-MTPs. Referred pain was observed to the dorsal forearm in 5 subjects and to the dorsal and ventral aspects of the elbow in 2 subjects (Fig 3B). Pain referral to the other limbs or body sites was not reported by the subjects in both groups. There was no significant difference in the occurrence of referred pain between the latent MTP (77%) and non-MTP (58%) groups (P > .05). However, the referred pain area induced from latent MTPs was significantly larger than from non-MTPs (t = 2.46, P < .05, Fig 4).
PPT Changes Over Time in the Forearm Following Glutamate Injection A three-way ANOVA revealed a significant difference in PPT among different measurement points (F = 33.6, P = 0 .001) and a significant difference in PPT over time after glutamate injection (F = 3.33, P = .02). There was also significant interaction (F = 2.77, P = .04) between groups (latent MTPs and non-MTPs) and time, ie, changes in PPT over time were different between the latent MTP and non-MTP groups. However, neither significant difference was found in PPT between latent MTPs and non-MTPs (F = .32, P = .5), nor were there significant interactions among groups, measurement points, and time (F = .52, P = .98). Topographical pressure pain sensitivity maps at 12 points were demonstrated before and .5 hour, 1 hour, and 24 hours after glutamate injection into latent MTPs
Myofascial Trigger Points and Pain Propagation (Fig 5A) and non-MTPs (Fig 5B). The enlarged area with decreased PPT was seen earlier after glutamate injection into latent MTPs (at .5 hour) than into non-MTPs (at 1 hour). Within the latent MTP groups, there was a statistically significant difference in PPT among measurement points (F = 16.96, P < .001) and a significant difference in PPT over time (F = 17.69, P < .001). However, not all the measurement points followed the same trend of changes in PPT over time (F = .82, P = .74). PPT levels at measurement point nos. 1, 2, 4, and 5 were all significantly lower than the point nos. 8, 10, and 12 before glutamate injection (all, P <.05). PPT levels at measurement point nos. 3, 6, and 7 were also all significantly lower than at point no. 12 before glutamate injection (all, P < .05). Post hoc analysis for the factor of points and time showed that a significantly lower PPT level was detected at 5 measurement points (nos. 1, 2, 3, 10, and 12) at .5 hour postglutamate injection into latent MTPs compared with the pre-injection level (all, P < .001), and again PPT levels at 7 measurement points (nos. 2, 6, 7, 8, 9, 10, and 12) at 1 hour post-glutamate injection into latent MTPs were lower than pre-injection levels (all, P < .001). A significant reduction was also found in PPT at 6 points (nos. 2, 3, 6, 8, 10, and 12) at 24 hours post-glutamate injection into latent MTPs when compared with pre-injection (all, P < .001, Fig 6A). Within the non-MTP groups, there were significant changes in PPT among measurement points (F = 26.16, P < .001) and a significant difference in PPT over time (F = 7.4, P < .001). However, there were no significant interactions in PPT between measurement points and time (F = .54, P = .98). PPT levels at measurement point nos. 1 and 2 were all significantly lower than at point nos. 8, 10, 11, and 12 before glutamate injection (all, P < .05). PPT levels at measurement point nos. 3 and 6 were also all significantly lower than at point nos. 11 and 12 before glutamate injection (all, P < .05). Post hoc analysis for
Figure 2. Higher maximal pain intensity (A) and area under the VAS (B) following glutamate injection into latent MTP than into non-MTP. *Indicates P < .05.
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Figure 4. Larger referred pain area following glutamate injection into latent MTP than non-MTP. *Indicates P < .05.
hour (0/12) (P < .05) and but not at 24 hours for latent MTPs (6/12) and non-MTPs (4/12) (P > .05).
PPT Changes at the Mid-point of the Tibialis Anterior Muscle Following Glutamate Injection Significant difference in PPT over time (F = 3.21, P = .034) was observed. However, there was no significant difference (F = 1.56, P = .23) in PPT level between latent MTPs and non-MTPs. No significant interaction (F = 2.07, P = .12) in PPT was found between groups (latent MTPs and non-MTPs) and time. The average PPT values from both groups reached the lowest level (F = 3.21, P = .034) 1 hour post-glutamate injection as compared to other time points (300 6 8 kPa pre-, 294 6 8 kPa .5 post-, 267 6 8 kPa 1 hour post-, and 277 6 8 kPa 24 hours post-glutamate injections).
Discussion The present study demonstrated that painful glutamate injection into latent MTPs induced an early occurrence of locally enlarged area of pressure hyperalgesia associated with spreading central sensitization. The results suggest that MTPs may contribute to spatial pain propagation and the development of generalized pressure hyperalgesia.
injection into latent MTP (A) and non-MTP (B). Note: no referred pain on the right arm in the non-MTP group.
Local and Referred Muscle Pain From Nociceptive Stimulation of Latent MTPs
the factors of points and time showed that a significant decrease was found in PPT at 4 points (nos. 2, 4, 5, and 6) at 24 hours only post-glutamate injection into nonMTPs when compared with pre-injection (all, P > .001, Fig 6B). In summary, more points with significantly decreased PPT were observed at .5 hour (4/12) and 1 hour (7/12) after glutamate injection into latent MTPs than into non-MTPs at .5 hour (0/12) (P < .05) and 1
Higher local maximal pain intensity and the area under the VAS curve were found following glutamate injection into latent MTPs than into non-MTPs, suggesting increased nociceptor sensitivity at MTPs. These results are consistent with previous studies using glutamate14 and hypertonic saline34 injections and mechanical stimulation47 of latent MTPs. Local muscle pain is known to be associated with the activation of muscle nociceptors. Activation of muscle nociceptors would induce referred pain mediated via spinal and supraspinal mechanisms,4,27 and the maintenance of referred muscle pain
Figure 3. Overall referred pain patterns following glutamate
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Figure 5. PPT topographical maps before and .5 hour, 1 hour, and 24 hours following glutamate injection into latent MTP (A) and non-MTP (B) in the forearm. The PPT data were interpolated using inversed distance interpolation by a factor of 2 with Franke and Nielson weightings5,6,9 to display the topographical pressure pain distribution. Units on axis are in mm. An early occurrence of enlarged area of mechanical hyperalgesia is seen at .5 hour and maximized at 1 hour in the MTP group (see text for detail).
usually depends on ongoing noxious inputs from the site of primary muscle pain.38 Similar occurrence of referred pain following intramuscular injection of glutamate into latent MTPs and non-MTPs suggests that the dose of .2 mL, 1M glutamate is adequate for the activation of normal muscle nociceptors. A larger referred pain area in the latent MTP group than in the normal muscle point group (non-MTP) following the same nociceptive stimulation consolidates the concept that muscle nociceptors at latent MTPs are sensitized (peripheral sensitization)16 and, in addition, could indicate a subclinical manifestation of central sensitization as larger referred pain areas are seen in, eg, fibromyalgia15 or whiplash32 patients with central sensitization.
MTPs Contribute to the Induction of Spatial Pain Propagation In the current study, multiple points covering several muscles in the forearm were observed to show decreased PPT levels .5 hour and 1 hour after glutamate injection into latent MTPs, but not into non-MTPs, while a similar number of points showed decreased PPTs 24 hours after glutamate injection into both latent MTPs and nonMTPs. These spatial and temporal patterns of PPT changes are clearly demonstrated also by PPT mapping.
These results indicate that MTPs are associated with an early occurrence of a locally enlarged area of pressure hyperalgesia. The locally enlarged area of mechanical hyperalgesia, which covers the innervation zone of C5 to C8, may represent a net effect of spinal sensitization .5 hour post-glutamate injection into latent MTPs. This result corresponds to the multisegmental propagation of nociceptive activity within the spinal cord in the spatial and temporal dimensions in animals following deep tissue nociception.31 Following tissue damage, increased responses to nociceptive stimuli as well as expansion of the receptive field are also observed within 30 to 60 minutes after injury in animals.29,45 The generalized sensitization is evident in the current study by both decreased PPT in the extrasegmental level and the larger number of points with decreased PPTs in the forearm. However, PPTs in the forearm were not significantly different between .5 hour (spinal sensitization) and 1 hour (generalized sensitization) post-glutamate injection into latent MTPs, indicating that the effect of generalized sensitization induced by short-term nociception may be not as strong as sustained nociception in chronic musculoskeletal pain conditions, where central sensitization is associated with decreased pressure hyperalgesia.1,2,15,43 Nevertheless, these results suggest that
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Figure 6. PPT at 12 points in the forearm .5 hour, 1 hour, and 24 hours following glutamate injection into latent MTP (A) and non-MTP (B). *Indicates significant lower levels of PPT .5 hour, 1 hour, and 24 hours post-glutamate injection as compared with the pre-injection.
central sensitization contributes significantly to the spatial pain propagation. It should be mentioned that a relatively low PPT value measured at the mid-point of the tibialis anterior muscle is shown in this study as compared to our previous study.47 This phenomenon may reflect generalized post-glutamate injection sensation, which can last up to 24 hours, or the effects of seasonal bicycling by subjects. A caution should also be given to the results, in that there was no significant interaction between 3 factors—group, time, and measurement points in the forearm—though there was significant interaction between groups (latent MTPs and non-MTPs) and time. Therefore, it is the inclusion of the factor of points into the analysis that makes the interaction among the 3 factors insignificant. The insignificant interaction among the 3 factors may partly be due to the heterogeneity of PPT changes among different points following glutamate injection: not all the points follow the similar pattern of PPT changes over time. It is also interesting to note that glutamate injection into non-MTPs induced a delayed onset (24 hours
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post-injection) of mechanical hyperalgesia in an enlarged area covering C5 to C6 segments, indicating the involvement of spinal sensitization but not generalized sensitization, which happened 1 hour following glutamate injection. Similarly, when the effect of generalized sensitization was not obvious 24 hours following glutamate injection into latent MTPs, the enlarged area of mechanical hyperalgesia remained. Thus, spinal sensitization may contribute to the maintenance of pain propagation following deep tissue nociception in humans. The spatial and temporal profiles of mechanical pain intensity following nociceptive stimulation of latent MTPs in the current study support the hypothesis that MTPs contribute to the induction of spatial pain propagation mediated by spinal and supraspinal (generalized) sensitization mechanisms. Consistent with our previous results,8 the occurrence of a locally enlarged area of mechanical hyperalgesia associated with MTPs in the current study is of clinical significance in that an active MTP can increase the mechanical sensitivity of other latent MTPs (satellite and/or attachment) in the same and nearby muscles and may thus predispose these latent MTPs to become active in response to various perpetuating factors. This result is consistent with an experimental muscle pain model of nerve growth factor injected into the muscle showing spreading pressure hyperalgesia in the shoulder muscles.20 Spreading sensitization may contribute to the existence of multiple active MTPs in a single muscle15 or in several functionally related muscles9 in chronic musculoskeletal pain conditions. Thus, inactivation of MTPs may prevent and/or reverse the development of spatial pain propagation in chronic musculoskeletal pain conditions. And indeed, inactivation of MTPs has been shown to be associated with attenuation of central sensitization36 and induction of spinal inhibition.41,42 Further, consecutive anesthetic injections into active MTPs significantly decrease mechanical hyperalgesia and painful areas in both localized pain condition of migraine23 and generalized pain conditions of fibromyalgia1 and whiplash syndrome.11 Mechanisms of pain propagation due to MTPs are not fully understood. Other mechanisms, such as interaction between MTPs (MTP network),17 sympathetic hyperactivity,48 and disordered motor control strategy,28,35 may also contribute to spatial propagation, which deserves further evaluation.
Limitations First, the current study employs an acute stimulation of latent MTPs in healthy subjects; thus, the spatial extent of decreased PPT may be smaller than that in chronic musculoskeletal pain patients where central sensitization has already existed. Second, the sample size may not be large enough to detect group difference, although it is large enough to detect the differences in PPT over time. The heterogeneity of PPTs at 12 points may further limit group difference. Third, the 24-hour interval between 2 injections in the current crossover study might produce a carryover effect
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because of the previous glutamate injection that induced central sensitization that lasted 24 hours, thus limiting the detection of significant differences in data analysis and low PPT values from healthy people. Last, latent MTPs are stimulated by the algesic substance glutamate in the current study; the effects of stimulation of latent MTPs by other algesic substances, such as hypertonic saline, merit further evaluation.
Conclusions
References
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The results of the present study suggest that MTPs are associated with an early manifestation of local and spreading pressure hyperalgesia. Peripheral sensitization and central sensitization contribute to spatial mechanical pain propagation. Inactivation of MTPs may prevent local pain conditions from developing into generalized central sensitization.
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5. Binderup AT, Arendt-Nielsen L, Madeleine P: Pressure pain threshold mapping of the trapezius muscle reveals heterogeneity in the distribution of muscular hyperalgesia after eccentric exercise. Eur J Pain 14:705-712, 2010 6. Binderup AT, Arendt-Nielsen L, Madeleine P: Pressure pain sensitivity maps of the neck-shoulder and the low back regions in men and women. BMC Musculoskelet Disord 11:234, 2010 ndez-Carnero J, Binderup AT, Ge HY, Fernandez-de7. Ferna las-Penas C, Arendt-Nielsen L, Madeleine P: Pressure pain sensitivity mapping in experimentally induced lateral epicondylalgia. Med Sci Sports Exerc 42:922, 2010 8. Fernandez-Carnero J, Ge HY, Kimura Y, Fernandez-de-LasPenas C, Arendt-Nielsen L: Increased spontaneous electrical activity at a latent myofascial trigger point after nociceptive stimulation of another latent trigger point. Clin J Pain 26: 138-143, 2010 ndez-de-las-Pen ~ as C, Caminero AB, Madeleine P, 9. Ferna Guillem-Mesado A, Ge HY, Arendt-Nielsen L, Pareja JA: Multiple active myofascial trigger points and pressure pain sensitivity maps in the temporalis muscle are related in women with chronic tension type headache. Clin J Pain 25: 506, 2009 ndez-de-Las-Pen ~ as C, Gala n-del-Rıo F, Alonso10. Ferna nez-Garcıa R, Arendt-Nielsen L, Svensson P: Blanco C, Jime Referred pain from muscle trigger points in the masticatory and neck-shoulder musculature in women with temporomandibular disoders. J Pain 11:1295-1304, 2010 11. Freeman MD, Nystrom A, Centeno C: Chronic whiplash and central sensitization; an evaluation of the role of a myofascial trigger points in pain modulation. J Brachial Plex Peripher Nerve Inj 4:2, 2009
17. Ge HY, Fernandez-de-Las-Penas C, Yue SW: Myofascial trigger points: Spontaneous electrical activity and its consequences for pain induction and propagation. Chin Med 6:13, 2011 18. Ge HY, Wang Y, Fernandez-de-Las-Penas C, GravenNielsen T, Danneskiold-Samsoe B, Arendt-Nielsen L: Reproduction of overall spontaneous pain pattern by manual stimulation of active myofascial trigger points in fibromyalgia patients. Arthritis Res Ther 13:R48, 2011 19. Ge HY, Nie H, Graven-Nielsen T, Danneskiold-Samsøe B, Arendt-Nielsen L: Descending pain modulation and its interaction with peripheral sensitization following sustained isometric muscle contraction in fibromyalgia. Eur J Pain, 2011 Jun 28 [Epub ahead of print] 20. Gerber RK, Nie H, Arendt-Nielsen L, Curatolo M, GravenNielsen T: Local pain and spreading hyperalgesia induced by intramuscular injection of nerve growth factor are not reduced by local anesthesia of the muscle. Clin J Pain 27: 240-247, 2011 21. Gerwin RD: Classification, epidemiology, and natural history of myofascial pain syndrome. Curr Pain Headache Rep 5:412-420, 2001 22. Gerwin R: Myofascial pain syndrome: Here we are, where must we go. J Musculoskelet Pain 18:329-347, 2010 23. Giamberardino MA, Tafuri E, Savini A, Fabrizio A, Affaitati G, Lerza R, Di Ianni L, Lapenna D, Mezzetti A: Contribution of myofascial trigger points to migraine symptoms. J Pain 8:869-878, 2007 24. Graven-Nielsen T, Babenko V, Svensson P, ArendtNielsen L: Experimentally induced muscle pain induces hypoalgesia in heterotopic deep tissues, but not in homotopic deep tissues. Brain Res 787:203-210, 1998
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25. Graven-Nielsen T, Arendt-Nielsen L: Assessment of mechanisms in localized and widespread musculoskeletal pain. Nat Rev Rheumatol 6:599-606, 2010
37. Niddam DM, Chan RC, Lee SH, Yeh TC, Hsieh JC: Central representation of hyperalgesia from myofascial trigger point. Neuroimage 39:1299-1306, 2008
26. Herren-Gerber R, Weiss S, Arendt-Nielsen L, PetersenFelix S, Stefano GD, Radanov BP, Curatolo M: Modulation of central hypersensitivity by nociceptive input in chronic pain after whiplash injury. Pain Med 5:366-376, 2004
38. Rubin TK, Gandevia SC, Henderson LA, Macefield VG: Effects of intramuscular anesthesia on the expression of primary and referred pain induced by intramuscular injection of hypertonic saline. J Pain 10:829-835, 2009
27. Hoheisel U, Mense S, Simons DG, Yu XM: Appearance of new receptive fields in rat dorsal horn neurons following noxious stimulation of skeletal muscle: A model for referral of muscle pain? Neurosci Lett 153:9-12, 1993
ndez-de-las-Pen ~ as C, Ortega39. Ruiz-Ruiz B, Ferna Santiago R, Arendt-Nielsen L, Madeleine P: Topographical pressure and thermal pain sensitivity mapping in patients with unilateral lateral epicondylalgia. J Pain 12:1040-1048, 2011
28. Hoyle JA, Marras WS, Sheedy JE, Hart DE: Effects of postural and visual stressors on myofascial trigger point development and motor unit rotation during computer work. J Electromyogr and Kinesiol 21:41-48, 2011 29. Ikeda H, Stark J, Fischer H, Wagner M, Drdla R, Jager T, Sandkuhler J: Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science 312:1659-1662, 2006 30. Itoh K, Katsumi Y, Kitakoji H: Trigger point acupuncture treatment of chronic low back pain in elderly patients– a blinded RCT. Acupunct Med 22:170, 2004 31. Jongen JL, Pederzani T, Koekkoek SK, Shapiro J, van der Burg J, De Zeeuw CI, Huygen FJ, Holstege JC: Autofluorescent flavoprotein imaging of spinal nociceptive activity. J Neurosci 30:4081-4087, 2010 32. Kosek E, Januszewska A: Mechanisms of pain referral in patients with whiplash associated disorder. Eur J Pain 12: 650-660, 2008 33. Lannersten L, Kosek E: Dysfunction of endogenous pain inhibition during exercise with painful muscles in patients with shoulder myalgia and fibromyalgia. Pain 151:77-86, 2010 34. Li LT, Ge HY, Yue SW, Arendt-Nielsen L: Nociceptive and non-nociceptive hypersensitivity at latent myofascial trigger points. Clin J Pain 25:132-137, 2009 35. Lucas KR, Rich PA, Polus BI: Muscle activation patterns in the scapular positioning muscles during loaded scapular plane elevation: The effects of Latent Myofascial Trigger Points. Clin Biomech 25:765-770, 2010 36. Niddam DM, Chan RC, Lee SH, Yeh TC, Hsieh JC: Central modulation of pain evoked from myofascial trigger point. Clin J Pain 23:440, 2007
40. Simons DG: Review of enigmatic MTrPs as a common cause of enigmatic musculoskeletal pain and dysfunction. J Electromyogr Kinesiol 14:95-107, 2004 41. Srbely JZ, Dickey JP, Lowerison M, Edwards AM, Nolet PS, Wong LL: Stimulation of myofascial trigger points with ultrasound induces segmental antinociceptive effects: A randomized controlled study. Pain 139:260-266, 2008 42. Srbely JZ, Dickey JP, Lee D, Lowerison M: Dry needle stimulation of myofascial trigger points evokes segmental antinociceptive effects. J Rehabil Med 42:463-468, 2010 43. Staud R, Nagel S, Robinson ME, Price DD: Enhanced central pain processing of fibromyalgia patients is maintained by muscle afferent input: A randomized, double-blind, placebo-controlled study. Pain 145:96-104, 2009 44. Svensson P, Cairns BE, Wang K, Hu JW, Graven-Nielsen T, Arendt-Nielsen L, Sessle BJ: Glutamate-evoked pain and mechanical allodynia in the human masseter muscle. Pain 101: 221-227, 2003 45. Woolf CJ: Evidence for a central component of postinjury pain hypersensitivity. Nature 306:686-688, 1983 46. Woolf CJ: Central sensitization: Implications for the diagnosis and treatment of pain. Pain 152(Suppl 1):S2-S15, 2011 47. Xu YM, Ge HY, Arendt-Nielsen L: Sustained nociceptive mechanical stimulation of latent myofascial trigger point induces central sensitization in healthy subjects. J Pain 11: 1348-1355, 2010 48. Zhang Y, Ge HY, Yue SW, Kimura Y, Arendt-Nielsen L: Attenuated skin blood flow response to nociceptive stimulation of latent myofascial trigger points. Arch Phys Med Rehabil 90:325-332, 2009
Spatial Pain Propagation Over Time Following Painful Glutamate Activation of Latent Myofascial Trigger Points in Humans Chao Wang,*,y Hong-You Ge,* Jos e Miota Ibarra,*,z Shou-Wei Yue,y Pascal Madeleine,* and Lars Arendt-Nielsen* *Laboratory for Musculoskeletal Pain and Motor Control, Center for Sensory-Motor Interaction (SMI), Department of Health Science and Technology, Aalborg University, Aalborg, Denmark. y Department of Physical Medicine & Rehabilitation, Qilu Hospital, Medical School of Shandong University, Jinan, China. z Nursing and Physiotherapy School, Department of Nursing and Physiotherapy, University of Castilla-La Mancha, Toledo, Spain.
Abstract: The aim of this present study was to test the hypothesis that tonic nociceptive stimulation of latent myofascial trigger points (MTPs) may induce a spatially enlarged area of pressure pain hyperalgesia. Painful glutamate (.2 mL, 1M) stimulation of latent MTPs and non-MTPs in the forearm was achieved by an electromyography-guided procedure. Pain intensity (as rated on the visual analog scale [VAS]) and referred pain area following glutamate injections were recorded. Pressure pain threshold (PPT) was measured over 12 points in the forearm muscles and at the mid-point of tibialis anterior muscle before and at .5 hour, 1 hour, and 24 hours after glutamate injections. The results showed that maximal pain intensity, the area under the VAS curve, and referred pain area were significantly higher and larger following glutamate injection into latent MTPs than non-MTPs (all, P < .05). A significantly lower PPT level was detected over time after glutamate injection into latent MTPs at .5 hour (at 4 points), 1 hour (at 7 points), and 24 hours (at 6 points) in the forearm muscles. However, a significantly lower PPT was observed only at 24 hours after glutamate injection into non-MTPs in the forearm muscles (at 4 points, P < .05) when compared to the pre-injection PPT. PPT at the mid-point of the tibialis anterior was significantly decreased at 1 hour only as compared to the pre-injection PPT in both groups (< .05). The results of the present study indicate that nociceptive stimulation of latent MTPs is associated with an early onset of locally enlarged area of mechanical hyperalgesia. Perspective: This study shows that MTPs are associated with an early occurrence of a locally enlarged area of pressure hyperalgesia associated with spreading central sensitization. Inactivation of MTPs may prevent spatial pain propagation. ª 2012 by the American Pain Society Key words: Glutamate, myofascial trigger points, nociception, pain propagation, pressure pain threshold.
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yofascial pain syndrome due to myofascial trigger points (MTPs) can be acute or chronic, regional or generalized.21 Recent studies support the role of active MTPs in the induction and/or maintenance of not
Received December 9, 2011; Revised January 26, 2012; Accepted March 1, 2012. Supported by a grant from the Danish Working Environment Authority (‘‘Undersøgelse af manifestationer, arsagsmekanismer samt progression af smerter hos computerbrugere’’ project). The authors have no conflict of interest to report. Address reprint requests to Lars Arendt-Nielsen, Center for SensoryMotor Interaction, Department of Health Science and Technology, Aalborg University, Fredrik Bajers Vej 7 D-3, DK-9220, Aalborg, Denmark. E-mail: [email protected] 1526-5900/$36.00 ª 2012 by the American Pain Society doi:10.1016/j.jpain.2012.03.001
only regional pain conditions, such as headache,9 low back pain,30 temporomandibular pain disorders,10 and chronic pelvic pain syndrome,3 but also generalized pain syndromes, such as fibromyalgia12,15,18 and whiplash syndromes.11,26 These results suggest that active MTPs may be a strong link between localized regional pain and generalized pain conditions. It is suggested that active MTPs as ongoing nociceptive stimuli may contribute to the spatial pain propagation and/or widespread pain in musculoskeletal pain conditions.17 Chronic widespread pain may be related to multiple peripheral and central pain mechanisms.25 Of particular importance in central pain mechanisms is the contribution of central sensitization to the development of chronic widespread pain,46 as compared to a limited or 537
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ceiling effect of descending inhibition mechanisms in humans.19,33 MTPs have the potential to induce central sensitization,37,47and central sensitization in fibromyalgia is maintained by muscle afferent input43 and especially by active MTPs.1 Clinically, it is the active, but not latent, MTPs that are responsible for patients’ spontaneous pain (local and/or referred pain). Characteristics common for both active and latent MTPs are the tenderness spot on a taut muscle band, local twitch response upon palpation and/or dry needling, and the existence of spontaneous electrical activity with intramuscular needle electromyographic (EMG) examination when the muscle is at rest.22,40 To mimic active MTPs, algesic substance glutamate44 has been used to activate latent MTPs and induce local and/or referred pain in healthy humans.8,14 Studies have shown that glutamate, but not hypertonic saline, can increase mechanical pain sensitivity when injected into the muscle.12,24,44 Therefore, we hypothesized that glutamate injection into latent MTPs may induce a locally enlarged area of mechanical hyperalgesia as compared to non-MTPs, in addition to the induction of central sensitization.47 However, direct evidence is lacking for the spatial and temporal propagation of pressure hyperalgesia caused by MTPs in humans. Topographical pressure pain threshold (PPT) mapping has recently been used to identify MTPs in the infraspinatus and temporalis9,13 and to assess spatial distribution of mechanical pain sensitivity of the trapezius muscle6,15 and forearm muscles.39 Further, the pattern of topographical PPT mapping changes over time following eccentric5 and concentric exercise19 of the trapezius muscle and eccentric exercise of the forearm muscles.7 PPT mapping in the forearm reflects the pressure pain sensitivity of 3 extensor muscles.7,39 Thus, topographical PPT mapping in the forearm may provide a window to observe spatial and temporal patterns of pressure pain sensitivity across these 3 extensor muscles following activation of a latent MTP in 1 of the muscles. Thus, the aim of this study is to simultaneously assess the changes in spatial (localized and generalized) and temporal development of pressure pain sensitivity following painful glutamate stimulation of latent MTPs in the forearm.
Methods Subjects Thirteen healthy subjects (10 males and 3 females; mean age, 24.5 6 2.6 years), with no signs or symptoms of musculoskeletal pain, were recruited through notices at Aalborg University campus and volunteered for this study. This study was approved by the local Ethics Committee (N-20100048) and conducted in accordance with Helsinki Declaration. Informed consent was obtained from all subjects.
Experimental Protocol Each subject participated in a 2-session study in which glutamate was injected into a latent MTP and a non-MTP in the extensor digitorum communis with an interval
Myofascial Trigger Points and Pain Propagation of 24 hours between sessions; based on the previous results, generalized sensitization lasts up to 30 minutes following sustained mechanical stimulation of latent MTPs.47 The forearm muscles were divided into 12 points forming a 3 4 matrix (4 points in the lateral part, 4 points in the middle, and 4 points in the interior part), outlined in previous studies,7,39 but the matrix was moved 2 cm distal to the lateral epicondyle in the current study to include all points in the muscle belly but not tendon tissue. Briefly, 2 cm distal to the lateral epicondyle was taken as the reference point (point 5). A line downward from the lateral epicondyle was set as the central column of the map. The rest of the 3 points in the middle are separated by 2 cm (point nos. 6, 7, and 8). These 4 points were used to define the remaining 2 columns of the matrix. The remaining points were symmetrically located 2 cm lateral (point nos. 1 to 4) and 2 cm interior (point nos. 9 to 12) to each respective point in the middle. Point nos. 1 to 4 corresponded to the muscle belly of the extensor carpi radialis brevis, point nos. 5 to 8 to the muscle belly of the extensor digitorum communis, and point nos. 9 to 12 to the location of the muscle belly of the extensor carpi ulnaris muscle (Fig 1). The subjects were asked to lie down on a bed, and their forearms were exposed and supported with a suitable pillow to keep the forearms relaxed. A latent MTP was identified and marked in the extensor digitorum communis, and a non-MTP was then identified and marked at approximately the mirror location of the latent MTP on the opposite side of the extensor digitorum communis. The side of the forearm was randomized for the identification of a latent MTP. A latent MTP was confirmed by a taut muscle band, local twitch response, and most tender point with or without referred pain upon digital palpation and reconfirmed by the presence of spontaneous electrical activity with intramuscular EMG. A non-MTP was defined if there were no characteristics of a latent MTP by digital palpation and reconfirmed by the absence of spontaneous electrical activity with intramuscular EMG. An EMGguided injection was then undertaken (detailed later). A bolus of glutamate (.2 mL, 1M) was then injected into a latent MTP or a non-MTP in a randomized order. Subjects were asked to rate the pain intensity in real time on an electronic visual analog scale (VAS 0–10 cm, Aalborg University) starting from intramuscular needle insertion and recorded for 8 minutes. 0 represents no pain and 10 the most pain imaginable. Maximal pain intensity and the area under the VAS curve were extracted for further analysis. The EMG-guided injection needle was removed at the end of the VAS recording. The referred pain pattern was drawn by the subjects on an anatomic map after each EMG-guided injection, and the referred pain area was calculated with VistaMetrix software (VistaMetrix 1.36; SkillCrest, LLC, Tucson, AZ) by an experimenter (C.W.) blinded to the MTP type. PPT measurement blinded to the MTP type was taken at 12 points in the forearm under investigation and the midpoint of the tibialis anterior muscle contralateral to the injection side before and .5 hour, 1 hour, and 24 hours after injection (detailed later).
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1 second. The EMG-guided injection needle was advanced slowly by the experimenter (J.M.I.) into latent MTPs with spontaneous electrical activity or into nonMTPs without spontaneous electrical activity.
Assessment of PPT PPT was measured at the different measurement points in the forearm muscles and the middle of tibalis anterior muscle by a handheld pressure algometer (Algometer type 2; Somedic, Sollentuna, Sweden) before and .5 hour, 1 hour, and 24 hours after injection. The pressure algometer is equipped with a 1-cm2 rubber-tipped plunger mounted on a force transducer and was used to measure the PPT. Each point was repeated 2 times, and averages of the 2 repetitions were used for analysis. The pressure was increased at a rate of 30 kPa/second until the subject detected the pain threshold or until the pressure applied reached an upper limit of 800 kPa.
Statistical Analysis
Figure 1. Representation of the 12 points forming a 3 4 matrix in the forearm.
EMG-Guided Intramuscular Injection Following identification of a latent MTP and a nonMTP, the skin area around the marked position of a latent MTP or a non-MTP was then shaved and cleaned with isopropyl alcohol. One pair of bipolar surface EMG electrodes (Neuroline 720-01-k; Ambu, ølstykke, Denmark; intra-electrode distance of 2 cm) was placed 2 cm distal to the marked position. The surface electrodes were used to ensure that the forearm muscles were relaxed prior to injection of glutamate and to monitor the EMG activity after injection. A reference surface electrode was placed 2 cm lateral to the marked position. A ground tape electrode was then wrapped around the ankle. The EMG-guided injection needle (Neuroline Inoject, 35 .4 mm, Ambu) was first connected to an extension tube (15 cm, filling volume .2 mL) and then to a syringe (1 mL in volume). The syringe was pre-filled with .4 mL glutamate, which resulted in .2 mL in the extension tube and an injection of .2 mL of glutamate into a latent MTP or a non-MTP. The extension tube and the syringe were fixed to the skin to prevent displacement of the EMG-guided injection needle during injection. The total time for each injection was manually controlled for 10 6
Statistical analysis in the current study was made with Statistica software (v.8.0, StatSoft, Inc., Uppsala, Sweden). A paired t-test was used to compare the difference in maximal pain intensity, area under the VAS curve, and referred pain area between latent MTPs and non-MTPs. A Fisher exact test was used to compare the difference in the occurrence of referred pain and in the proportion of points with decreased PPT between latent MTPs and non-MTPs following glutamate injection. Three-way (latent MTPs and non-MTPs, measurement points, time) repeated measures analysis of variance (ANOVA) was used to compare the differences in PPT levels among 12 measurement points in the forearm muscles before and .5 hour, 1 hour, and 24 hours after glutamate injection into latent MTPs or non-MTPs. Two-way repeated measures (latent MTPs and non-MTPs, time) ANOVA was used to compare the differences in PPT levels in the middle of tibialis anterior muscle before and .5 hour, 1 hour, and 24 hours after glutamate injection into latent MTPs or non-MTPs. Values in the text and figures are expressed as standard error of the mean (SEM). Significance level was set at P < .05.
Results Local and Referred Pain Induced by Glutamate Injection Latent MTPs were found at the upper and middle parts of the extensor digitorum communis in every subject: a latent MTP was located between point no. 5 and point no. 6 in 8 subjects and between point no. 6 and point no. 7 in 5 subjects. The depth of EMG needle insertion was estimated to be 1 6 .2 cm until a latent MTP (spontaneous electrical activity) was found. Local muscle pain was evoked in all 13 subjects by glutamate injections into latent MTPs or non-MTPs in the extensor digitorum communis. A higher maximal pain intensity was induced by glutamate injection into latent MTPs than
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into non-MTPs (t = 6.26, P < .001, Fig 2A), and so was the area under the VAS curve (t = 5.39, P < .001, Fig 2B). Referred pain was induced in 10 out of 13 subjects following glutamate injection into latent MTPs. Muscle pain was referred to the dorsal forearm in 4 subjects, to the dorsal and ventral aspects of the elbow in 1 subject, to the shoulder in 3 subjects, and to the ventral wrist and palm in 2 subjects (Fig 3A). Referred pain was induced in 7 out of 13 subjects following glutamate injection into non-MTPs. Referred pain was observed to the dorsal forearm in 5 subjects and to the dorsal and ventral aspects of the elbow in 2 subjects (Fig 3B). Pain referral to the other limbs or body sites was not reported by the subjects in both groups. There was no significant difference in the occurrence of referred pain between the latent MTP (77%) and non-MTP (58%) groups (P > .05). However, the referred pain area induced from latent MTPs was significantly larger than from non-MTPs (t = 2.46, P < .05, Fig 4).
PPT Changes Over Time in the Forearm Following Glutamate Injection A three-way ANOVA revealed a significant difference in PPT among different measurement points (F = 33.6, P = 0 .001) and a significant difference in PPT over time after glutamate injection (F = 3.33, P = .02). There was also significant interaction (F = 2.77, P = .04) between groups (latent MTPs and non-MTPs) and time, ie, changes in PPT over time were different between the latent MTP and non-MTP groups. However, neither significant difference was found in PPT between latent MTPs and non-MTPs (F = .32, P = .5), nor were there significant interactions among groups, measurement points, and time (F = .52, P = .98). Topographical pressure pain sensitivity maps at 12 points were demonstrated before and .5 hour, 1 hour, and 24 hours after glutamate injection into latent MTPs
Myofascial Trigger Points and Pain Propagation (Fig 5A) and non-MTPs (Fig 5B). The enlarged area with decreased PPT was seen earlier after glutamate injection into latent MTPs (at .5 hour) than into non-MTPs (at 1 hour). Within the latent MTP groups, there was a statistically significant difference in PPT among measurement points (F = 16.96, P < .001) and a significant difference in PPT over time (F = 17.69, P < .001). However, not all the measurement points followed the same trend of changes in PPT over time (F = .82, P = .74). PPT levels at measurement point nos. 1, 2, 4, and 5 were all significantly lower than the point nos. 8, 10, and 12 before glutamate injection (all, P <.05). PPT levels at measurement point nos. 3, 6, and 7 were also all significantly lower than at point no. 12 before glutamate injection (all, P < .05). Post hoc analysis for the factor of points and time showed that a significantly lower PPT level was detected at 5 measurement points (nos. 1, 2, 3, 10, and 12) at .5 hour postglutamate injection into latent MTPs compared with the pre-injection level (all, P < .001), and again PPT levels at 7 measurement points (nos. 2, 6, 7, 8, 9, 10, and 12) at 1 hour post-glutamate injection into latent MTPs were lower than pre-injection levels (all, P < .001). A significant reduction was also found in PPT at 6 points (nos. 2, 3, 6, 8, 10, and 12) at 24 hours post-glutamate injection into latent MTPs when compared with pre-injection (all, P < .001, Fig 6A). Within the non-MTP groups, there were significant changes in PPT among measurement points (F = 26.16, P < .001) and a significant difference in PPT over time (F = 7.4, P < .001). However, there were no significant interactions in PPT between measurement points and time (F = .54, P = .98). PPT levels at measurement point nos. 1 and 2 were all significantly lower than at point nos. 8, 10, 11, and 12 before glutamate injection (all, P < .05). PPT levels at measurement point nos. 3 and 6 were also all significantly lower than at point nos. 11 and 12 before glutamate injection (all, P < .05). Post hoc analysis for
Figure 2. Higher maximal pain intensity (A) and area under the VAS (B) following glutamate injection into latent MTP than into non-MTP. *Indicates P < .05.
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Figure 4. Larger referred pain area following glutamate injection into latent MTP than non-MTP. *Indicates P < .05.
hour (0/12) (P < .05) and but not at 24 hours for latent MTPs (6/12) and non-MTPs (4/12) (P > .05).
PPT Changes at the Mid-point of the Tibialis Anterior Muscle Following Glutamate Injection Significant difference in PPT over time (F = 3.21, P = .034) was observed. However, there was no significant difference (F = 1.56, P = .23) in PPT level between latent MTPs and non-MTPs. No significant interaction (F = 2.07, P = .12) in PPT was found between groups (latent MTPs and non-MTPs) and time. The average PPT values from both groups reached the lowest level (F = 3.21, P = .034) 1 hour post-glutamate injection as compared to other time points (300 6 8 kPa pre-, 294 6 8 kPa .5 post-, 267 6 8 kPa 1 hour post-, and 277 6 8 kPa 24 hours post-glutamate injections).
Discussion The present study demonstrated that painful glutamate injection into latent MTPs induced an early occurrence of locally enlarged area of pressure hyperalgesia associated with spreading central sensitization. The results suggest that MTPs may contribute to spatial pain propagation and the development of generalized pressure hyperalgesia.
injection into latent MTP (A) and non-MTP (B). Note: no referred pain on the right arm in the non-MTP group.
Local and Referred Muscle Pain From Nociceptive Stimulation of Latent MTPs
the factors of points and time showed that a significant decrease was found in PPT at 4 points (nos. 2, 4, 5, and 6) at 24 hours only post-glutamate injection into nonMTPs when compared with pre-injection (all, P > .001, Fig 6B). In summary, more points with significantly decreased PPT were observed at .5 hour (4/12) and 1 hour (7/12) after glutamate injection into latent MTPs than into non-MTPs at .5 hour (0/12) (P < .05) and 1
Higher local maximal pain intensity and the area under the VAS curve were found following glutamate injection into latent MTPs than into non-MTPs, suggesting increased nociceptor sensitivity at MTPs. These results are consistent with previous studies using glutamate14 and hypertonic saline34 injections and mechanical stimulation47 of latent MTPs. Local muscle pain is known to be associated with the activation of muscle nociceptors. Activation of muscle nociceptors would induce referred pain mediated via spinal and supraspinal mechanisms,4,27 and the maintenance of referred muscle pain
Figure 3. Overall referred pain patterns following glutamate
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Figure 5. PPT topographical maps before and .5 hour, 1 hour, and 24 hours following glutamate injection into latent MTP (A) and non-MTP (B) in the forearm. The PPT data were interpolated using inversed distance interpolation by a factor of 2 with Franke and Nielson weightings5,6,9 to display the topographical pressure pain distribution. Units on axis are in mm. An early occurrence of enlarged area of mechanical hyperalgesia is seen at .5 hour and maximized at 1 hour in the MTP group (see text for detail).
usually depends on ongoing noxious inputs from the site of primary muscle pain.38 Similar occurrence of referred pain following intramuscular injection of glutamate into latent MTPs and non-MTPs suggests that the dose of .2 mL, 1M glutamate is adequate for the activation of normal muscle nociceptors. A larger referred pain area in the latent MTP group than in the normal muscle point group (non-MTP) following the same nociceptive stimulation consolidates the concept that muscle nociceptors at latent MTPs are sensitized (peripheral sensitization)16 and, in addition, could indicate a subclinical manifestation of central sensitization as larger referred pain areas are seen in, eg, fibromyalgia15 or whiplash32 patients with central sensitization.
MTPs Contribute to the Induction of Spatial Pain Propagation In the current study, multiple points covering several muscles in the forearm were observed to show decreased PPT levels .5 hour and 1 hour after glutamate injection into latent MTPs, but not into non-MTPs, while a similar number of points showed decreased PPTs 24 hours after glutamate injection into both latent MTPs and nonMTPs. These spatial and temporal patterns of PPT changes are clearly demonstrated also by PPT mapping.
These results indicate that MTPs are associated with an early occurrence of a locally enlarged area of pressure hyperalgesia. The locally enlarged area of mechanical hyperalgesia, which covers the innervation zone of C5 to C8, may represent a net effect of spinal sensitization .5 hour post-glutamate injection into latent MTPs. This result corresponds to the multisegmental propagation of nociceptive activity within the spinal cord in the spatial and temporal dimensions in animals following deep tissue nociception.31 Following tissue damage, increased responses to nociceptive stimuli as well as expansion of the receptive field are also observed within 30 to 60 minutes after injury in animals.29,45 The generalized sensitization is evident in the current study by both decreased PPT in the extrasegmental level and the larger number of points with decreased PPTs in the forearm. However, PPTs in the forearm were not significantly different between .5 hour (spinal sensitization) and 1 hour (generalized sensitization) post-glutamate injection into latent MTPs, indicating that the effect of generalized sensitization induced by short-term nociception may be not as strong as sustained nociception in chronic musculoskeletal pain conditions, where central sensitization is associated with decreased pressure hyperalgesia.1,2,15,43 Nevertheless, these results suggest that
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Figure 6. PPT at 12 points in the forearm .5 hour, 1 hour, and 24 hours following glutamate injection into latent MTP (A) and non-MTP (B). *Indicates significant lower levels of PPT .5 hour, 1 hour, and 24 hours post-glutamate injection as compared with the pre-injection.
central sensitization contributes significantly to the spatial pain propagation. It should be mentioned that a relatively low PPT value measured at the mid-point of the tibialis anterior muscle is shown in this study as compared to our previous study.47 This phenomenon may reflect generalized post-glutamate injection sensation, which can last up to 24 hours, or the effects of seasonal bicycling by subjects. A caution should also be given to the results, in that there was no significant interaction between 3 factors—group, time, and measurement points in the forearm—though there was significant interaction between groups (latent MTPs and non-MTPs) and time. Therefore, it is the inclusion of the factor of points into the analysis that makes the interaction among the 3 factors insignificant. The insignificant interaction among the 3 factors may partly be due to the heterogeneity of PPT changes among different points following glutamate injection: not all the points follow the similar pattern of PPT changes over time. It is also interesting to note that glutamate injection into non-MTPs induced a delayed onset (24 hours
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post-injection) of mechanical hyperalgesia in an enlarged area covering C5 to C6 segments, indicating the involvement of spinal sensitization but not generalized sensitization, which happened 1 hour following glutamate injection. Similarly, when the effect of generalized sensitization was not obvious 24 hours following glutamate injection into latent MTPs, the enlarged area of mechanical hyperalgesia remained. Thus, spinal sensitization may contribute to the maintenance of pain propagation following deep tissue nociception in humans. The spatial and temporal profiles of mechanical pain intensity following nociceptive stimulation of latent MTPs in the current study support the hypothesis that MTPs contribute to the induction of spatial pain propagation mediated by spinal and supraspinal (generalized) sensitization mechanisms. Consistent with our previous results,8 the occurrence of a locally enlarged area of mechanical hyperalgesia associated with MTPs in the current study is of clinical significance in that an active MTP can increase the mechanical sensitivity of other latent MTPs (satellite and/or attachment) in the same and nearby muscles and may thus predispose these latent MTPs to become active in response to various perpetuating factors. This result is consistent with an experimental muscle pain model of nerve growth factor injected into the muscle showing spreading pressure hyperalgesia in the shoulder muscles.20 Spreading sensitization may contribute to the existence of multiple active MTPs in a single muscle15 or in several functionally related muscles9 in chronic musculoskeletal pain conditions. Thus, inactivation of MTPs may prevent and/or reverse the development of spatial pain propagation in chronic musculoskeletal pain conditions. And indeed, inactivation of MTPs has been shown to be associated with attenuation of central sensitization36 and induction of spinal inhibition.41,42 Further, consecutive anesthetic injections into active MTPs significantly decrease mechanical hyperalgesia and painful areas in both localized pain condition of migraine23 and generalized pain conditions of fibromyalgia1 and whiplash syndrome.11 Mechanisms of pain propagation due to MTPs are not fully understood. Other mechanisms, such as interaction between MTPs (MTP network),17 sympathetic hyperactivity,48 and disordered motor control strategy,28,35 may also contribute to spatial propagation, which deserves further evaluation.
Limitations First, the current study employs an acute stimulation of latent MTPs in healthy subjects; thus, the spatial extent of decreased PPT may be smaller than that in chronic musculoskeletal pain patients where central sensitization has already existed. Second, the sample size may not be large enough to detect group difference, although it is large enough to detect the differences in PPT over time. The heterogeneity of PPTs at 12 points may further limit group difference. Third, the 24-hour interval between 2 injections in the current crossover study might produce a carryover effect
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because of the previous glutamate injection that induced central sensitization that lasted 24 hours, thus limiting the detection of significant differences in data analysis and low PPT values from healthy people. Last, latent MTPs are stimulated by the algesic substance glutamate in the current study; the effects of stimulation of latent MTPs by other algesic substances, such as hypertonic saline, merit further evaluation.
Conclusions
References
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