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Increased muscle pain sensitivity in patients with tension-type headache
Pain 129 (2007) 113–121 www.elsevier.com/locate/pain
Increased muscle pain sensitivity in patients with tension-type headache Peter T. Schmidt-Hansen a,b,*, Peter Svensson c,d,e, Lars Bendtsen b, Thomas Graven-Nielsen f, Flemming W. Bach g b
a Department of Neurology, Viborg Hospital, Denmark Danish Headache Center and Department of Neurology, University of Copenhagen, Glostrup Hospital, Glostrup, Copenhagen, Denmark c Department of Clinical Oral Physiology, Dental School, University of Aarhus, Denmark d Department of Maxillofacial Surgery, Aarhus University Hospital, Denmark e Center for Sensory-Motor Interaction, Aalborg University, Denmark f Department of Health Science and Technology, Center for Sensory-Motor Interaction, Aalborg University, Denmark g Danish Pain Research Center and Department of Neurology, Aarhus University Hospital, Denmark
Received 25 June 2006; received in revised form 8 September 2006; accepted 28 September 2006
Abstract Nociceptive mechanisms in tension-type headache are poorly understood. The aim was to investigate the pain sensitivity of pericranial muscles and a limb muscle in patients with tension-type headache. Experimental muscle pain was induced by standardized infusions of 0.5 ml of 1 M hypertonic saline into two craniofacial muscles (anterior temporalis (TPA) and masseter (MAS)) and a limb muscle (anterior tibial (TA)) in 24 frequent episodic tension-type headache patients (FETTH), 22 chronic tension-type headache patients (CTTH) and 26 age and gender matched healthy subjects. Headache patients were examined twice, both on days with and on days without headache. The pressure pain thresholds (PPTs) were determined before and after infusions. The subjects continuously reported intensity of saline-induced pain on an electronic visual analogue scale (VAS) and the perceived area of pain was drawn on anatomical maps. Headache patients demonstrated significantly lower PPTs, higher saline-evoked VAS pain scores and greater pain areas than healthy subjects at all the tested muscle sites (P < 0.05). There was a significant gender difference for the PPTs in all three groups of participants (P < 0.05) and for VAS pain scores in the CTTH patients (P < 0.05). There was no difference in pain sensitivity between FETTH and CTTH or between patients with or without headache. In conclusion, the present study demonstrates the presence of generalized pain hypersensitivity both in FETTH and CTTH compared to controls which is unrelated to actual headache status and extends to include responses to longer-lasting stimuli which are clinically highly relevant. Gender differences in deep pain sensitivity seem to be a consistent finding both in healthy controls and patients with tension-type headache. Ó 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. Keywords: Experimental muscle pain; Tension-type headache; Referred pain; Pain assessment; Pressure algometry; Central sensitization; Muscular hyperalgesia
1. Introduction Abbreviations: TPA, anterior temporalis muscle; MAS, masseter muscle; TA, anterior tibial muscle; FETTH, frequent episodic tensiontype headache; CTTH, chronic tension-type headache; PPT, pressure pain threshold; VAS, visual analogue scale; TTH, tension-type headache. * Corresponding author. Tel.: +45 4323 2062; fax: +45 4323 3839. E-mail address: [email protected] (P.T. Schmidt-Hansen).
The pathophysiology of tension-type headache (TTH) is largely unknown despite intense research efforts (Olesen, 1991; Jensen, 1999; Bendtsen, 2000; Goadsby and Boes, 2002; Vandenheede and Schoenen, 2002). Nociceptive processes in craniofacial muscles are believed to play a role in development and
0304-3959/$32.00 Ó 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2006.09.037
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maintenance of tension-type headache (TTH) (Jensen et al., 1998; Mense et al., 2001), but also sensitization of neurons in the central nervous system may be of major importance (Olesen, 1991; Jensen et al., 1993; Langemark et al., 1993; Bendtsen et al., 1996; Vandenheede and Schoenen, 2002). Little is, however, known about differences in pain sensitivity and manifestations of pain in different craniofacial muscles. Mense et al. (2001) suggested that focal tender points in the muscle tissue, the so-called trigger points, could represent an important key to understand the symptomatology of TTH. Numerous techniques exist for experimental pain testing (Arendt-Nielsen, 1997; Ashina et al., 2003; Svensson and Ashina, 2005), but in particular intramuscular infusions of hypertonic saline and other algogenic substances have been used to study somatosensory and motor manifestations of longer-lasting muscle pain (Kellgren, 1938; Jensen and Norup, 1992; Stohler and Lund, 1994; Mork et al., 2004). The main advantage of these methods is the specific stimulation of muscular tissue without a major contribution from subcutaneous and cutaneous tissues. The International Headache Society subdivides tension-type headache into a frequent episodic type (FETTH) and a chronic type (CTTH) on the basis of whether headache is present at least 1 but less than 15 days per month or present 15 days per month or more (2004). In the present study TTH was further subdivided into FETTH and CTTH with ongoing headache (FETTH+, CTTH+) and without ongoing headache (FETTH , CTTH ) to clarify whether the pain responsiveness was dependent on the actual headache status. The primary aim of the present study was to apply a validated and reproducible experimental technique with painful infusions of hypertonic saline into two craniofacial muscles (Schmidt-Hansen et al., 2006) and a leg muscle in patients with FETTH and CTTH, to test if there would be differences between the groups of headache patients and controls in relation to absence or presence of headache. The secondary aim was to test if there were differences in pain sensitivity between the craniofacial muscles and the leg muscle in patients with FETTH and CTTH compared to controls, to test if the headache patients had a generalized hypersensitivity. These findings could contribute to the development of a standardized technique of experimental pain investigation in tension-type headache patients.
(6 male and 18 female) with a mean age of 38.9 ± 11.7 (SD) years, 22 chronic tension-type headache patients (CTTH) (7 male and 15 female) with a mean age of 39.7 ± 15.1 (SD) years were examined twice. Twenty-six healthy volunteers (11 male and 15 female) with a mean age of 37.2 ± 10.6 (SD) were examined in the same way. All the patients had had the actual condition of FETTH or CTTH for at least 12 months. Patients were included if they fulfilled the diagnostic criteria for FETTH or CTTH according to the International Classification of Headache Disorders 2nd Edition (ICHD-II) 2004. Controls had to report frequency of any kind of headache <0.5 day per month during the last 12 months. All participants had a general neurological examination and none of the participants had focal neurological signs. FETTH and CTTH patients were allowed to have occasional migraine, but it should be less frequent than their TTH. No further records were made concerning the occurrence of migraine in the patients. FETTH and CTTH patients were examined on two different days; one day virtually free of tension-type headache (FETTH ; CTTH ) with an intensity of headache pain, for the last 24 h, of <3 on a visual analogue scale (VAS), where 0 = no pain and 10 = worst imaginable pain and no intake of analgesics for at least 24 h, and another day with tensiontype headache (FETTH+; CTTH+) with an intensity of headache pain P3 during the last 24 h. The female participants were not tested in any particular phase of their menstrual cycle due to the relatively small number of participants and the minor effect of menstrual cycle on pain sensitivity (Dao and LeResche, 2000). The same investigator (PTSH) examined all the subjects. The local Ethics Committee in Viborg and Nordjyllands Counties approved the experiments and informed consent was obtained from all participants. The study was conducted in accordance with the Declaration of Helsinki. 2.2. Experimental design
2. Methods and materials
The sequence and side of infusions into the three test muscles were randomized in the two experimental sessions in a balanced order. The sequence of the muscles examined was written on cards, which the subjects drew before the first session. The experiments took place with the subjects in a semi-supine position in a dental chair. At the first session FETTH and CTTH registered the localization of their habitual pain on a standard map of the face and the habitual intensity of their headache pain on a 0–10 cm VAS. Afterwards pressure pain threshold (PPT) in the test muscle was determined. Then the infusion of hypertonic saline was started and the subjects continuously reported the perceived pain intensity on an electronically 0–10 cm VAS. Immediately after return of VAS pain score to 0, the PPT was determined again, and the subjects drew the perceived area of pain on anatomical maps of the head, face or lower limbs. The same sequence was repeated after 15 min in the next test muscle. All the three muscle sites were examined in each of the two sessions, which lasted about 1–112 h.
2.1. Participants
2.3. Infusion of hypertonic saline
The participants were recruited by advertising in local papers as well as in the neurological department. A total of 24 frequent episodic tension-type headache patients (FETTH)
The methodology has been described in detail previously (Graven-Nielsen et al., 1997; Schmidt-Hansen et al., 2006). In brief, infusion of hypertonic saline was done using a comput-
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er-controlled syringe pump (IVAC, model 770) with a plastic syringe. A tube (IVAC G30303, extension set with polyethylene inner line) was connected from the syringe to the stainless disposable needle (27 G, 40 mm). A total volume of 0.5 ml hypertonic saline (5.8% = 1 M) was infused over 20 s in each of the following three muscles: (1) anterior part of the temporalis (TPA) muscle in the muscle belly about 4 cm behind and 5 cm above the commissure of the eyelids, (2) masseter (MAS) muscle in the belly midway between the anterior and posterior and superior and inferior borders and about 5 cm behind the commissure of the lips, (3) anterior tibial (TA) muscle about 10 cm below the caput fibulae in the middle of the muscle belly. The infusion site in the three test muscles relied on identification of anatomical landmarks and was preceded by careful manual palpation of the muscle and its borders during voluntary contractions. The perceived pain intensity of the hypertonic saline infusions was scored on a 0–10 cm electronic VAS where 0 indicated, ‘‘no pain’’ and 10 ‘‘worst imaginable pain’’. VAS data were sampled every 5 s and stored on a computer. The area under the VAS pain curve (VAS-AUC), maximum pain (VAS-peak), and onset and offset of pain were calculated from the VAS data. The subjects then drew the distribution of pain on anatomical maps of the lateral aspect of the head. The circumference was digitized with an ACECAD D9000+ digitizer and the area calculated in arbitrary units (Sigma-Scan, Jandel Scientific, Canada). 2.4. Pressure pain thresholds The PPT was defined as the amount of pressure applied by a handheld algometer (Somedic AB, Sweden) that the subjects first perceived as painful, i.e., the transition from a feeling of pressure to a painful sensation (Svensson et al., 1995). When a painful sensation was experienced the subjects pressed a button and the pressure value was stored on the display. The increase in pressure rate was manually controlled with use of
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visual feedback and aimed at 40 kPa/s. The area of the probe was 1 cm2. Measurements of PPTs were performed on maximally relaxed muscles perpendicular to the surface after careful palpations of the muscle. PPT was determined as the mean of three recordings with at least 30-s intervals. 2.5. Statistics The PPT and VAS pain data are presented in box plots with medians and ranges. The pain areas are presented as means with standard of the mean (SEM). Analysis of variance (ANOVA) for repeated measures was used to compare PPT baseline values, PPT post injection values, VAS pain data and pain areas between the different muscles (TPA, MAS, TA). The groups (FETTH, CTTH, controls) and subgroups (FETTH , FETTH+, CTTH , CTTH+) and gender (males, females) were compared with separate ANOVAs. Post hoc comparisons tests were performed with the use of LSD (Least significant difference) tests. P < 0.05 was considered significant.
3. Results All 72 subjects completed the planned sessions including three infusions, which were always associated with a distinct sensation of deep, diffuse, moderate to intense levels of pain. 3.1. Habitual pain There was no difference between FETTH and CTTH in habitual headache pain intensity scored on a VAS (ANOVA, F = 0.20; P = 0.66) (Fig. 1). The drawings of habitual pain demonstrated a pattern of pain local-
Fig. 1. FETTH and CTTH subjects drew their habitual pain on standard anatomic maps. The results from the entire group of subjects are superimposed on a standard drawing.
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ized over the entire visceral cranium, predominantly localized in the frontal and neck regions in both FETTH and CTTH with no difference in area of habitual pain between the two groups (ANOVA, F = 0.05; P = 0.83) (Fig. 1). 3.2. Pressure pain threshold 3.2.1. PPT baseline PPT baseline values were significantly different between control, FETTH and CTTH (ANOVA: F = 15.16, P < 0.001) and post hoc analysis showed significantly higher values in the control group than in FETTH (LSD: P < 0.001) and CTTH (LSD: P < 0.001) but no differences between FETTH and CTTH (Fig. 2a). PPT baseline values were significantly different between the control group compared with FETTH , FETTH+, CTTH and CTTH+ (ANOVA: F = 7.64; P < 0.001). Post hoc analyses showed significantly higher values in the control group than in each of the four groups: FETTH , FETTH+, CTTH and CTTH+ (LSD: P < 0.001 in each of the groups) but no
differences between FETTH , FETTH+, CTTH and CTTH+ (Fig. 2a). These findings were consistent for each of the muscles. Thus PPT baseline values were significantly different between the control group compared with FETTH , FETTH+, CTTH and CTTH+ (ANOVA: anterior temporalis muscle, F = 3.2; P < 0.01; masseter muscle, F = 6.84; P < 0.001 and anterior tibial muscle F = 5.1; P < 0.001). Post hoc analyses showed significantly higher values in the control group than in each of the four groups: FETTH , FETTH+, CTTH and CTTH+ (LSD: P < 0.007 in each of the groups for all muscles) but no differences between FETTH , FETTH+, CTTH and CTTH+. 3.2.2. PPT post injection PPT post injection values were significantly different between control, FETTH and CTTH (ANOVA: F = 14.29, P < 0.001) and post hoc analysis showed significantly higher values in the control than in FETTH (LSD: P < 0.001) and CTTH (LSD: P < 0.001), but no differences between FETTH and CTTH (Fig. 2b).
Fig. 2. (a) Box plots to the left show PPT baseline in controls, FETTH , FETTH+, CTTH and CTTH+ subjects in the three muscles: TPA, MAS and TA. Box plots to the right show PPT baseline on the pooled muscle data in controls, FETTH , FETTH+, CTTH and CTTH+ subjects divided into females and males. (b) Box plots to the left show PPT post injection in controls, FETTH , FETTH+, CTTH and CTTH+ subjects in the three muscles: TPA, MAS and TA. Box plots to the right show PPT post injection on the pooled muscle data in controls, FETTH , FETTH+, CTTH and CTTH+ subjects divided into females and males.
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PPT post injection values were significantly different between the control group compared with FETTH , FETTH+, CTTH and CTTH+ (ANOVA: F = 7.24; P < 0.001). Post hoc analyses showed significantly higher values in the control group than in each of the four groups: FETTH , FETTH+, CTTH and CTTH+ (LSD: P < 0.001 in each of the groups) but no differences between FETTH , FETTH+, CTTH and CTTH+ (Fig. 2b). These findings were consistent for each of the muscles. Thus PPT post injection values were significantly different between the control group compared with FETTH , FETTH+, CTTH and CTTH+ (ANOVA: anterior temporalis muscle, F = 3.2: P < 0.02; masseter muscle, F = 7.6; P < 0.001 and anterior tibial muscle F = 3.8; P < 0.005). Post hoc analyses showed significantly higher values in the control group than in each of the four groups: FETTH , FETTH+, CTTH and CTTH+ (LSD: P < 0.03 in each of the groups for all muscles) but no differences between FETTH , FETTH+, CTTH and CTTH+. 3.3. Perceived pain intensity VAS AUC scores were significantly different between controls, FETTH and CTTH (ANOVA: F = 37.96, P < 0.001) and post hoc analysis showed significantly lower values in the control group than in FETTH (LSD: P < 0.001) and CTTH (LSD: P < 0.001) but no difference between FETTH and CTTH (LSD: P > 0.87). VAS AUC scores were significantly different in the control group compared with FETTH , FETTH+, CTTH and CTTH+ (ANOVA: F = 19.43; P < 0.001). Post hoc analyses showed significantly lower values in the control group than in each of the four groups: FETTH (LSD: P < 0.001), FETTH+ (LSD: P < 0.001), CTTH (LSD: P < 0.001) and CTTH+ (LSD: P < 0.001) but no difference in between FETTH ,
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FETTH+, CTTH and CTTH+ (LSD: 0.18 < P < 0.84) (Fig. 3). These findings were consistent for each of the muscles. Thus VAS AUC scores were significantly different between the control group compared with FETTH , FETTH+, CTTH and CTTH+ (ANOVA: anterior temporalis muscle, F = 6.5: P < 0.001; masseter muscle, F = 9.8; P < 0.001 and anterior tibial muscle F = 8.3; P < 0.001). Post hoc analyses showed significantly higher values in the control group than in each of the four groups: FETTH , FETTH+, CTTH and CTTH+ (LSD: P < 0.03 in each of the groups for all muscles) but no differences between FETTH , FETTH+, CTTH and CTTH+. 3.4. Perceived pain areas The sizes of the drawn areas were significantly different between the control group, FETTH and CTTH, (ANOVA: F = 6.20, P < 0.002) and post hoc analysis showed significantly lower values in the control group than in FETTH (LSD: P < 0.02) and CTTH (LSD: P < 0.001) but no difference between FETTH and CTTH (LSD: 0.23 < P). The sizes of the drawn areas were significantly different in the control group compared with FETTH , FETTH+, CTTH and CTTH+ (ANOVA: F = 3.12; P < 0.02). Post hoc analyses showed significantly lower values in the control group than in CTTH (LSD: P < 0.003) and CTTH+ (LSD: P < 0.01), but no significant difference between the control group and FETTH (LSD: P < 0.07) and FETTH+ (LSD: P < 0.07). No significant difference could be detected between FETTH , FETTH+, CTTH and CTTH+ (LSD: 0.29 < P < 0.99) (Fig. 4a). Analysis of the results in the anterior temporalis muscle showed significantly difference between the control group compared with FETTH , FETTH+, CTTH
Fig. 3. Boxplots to the left show VAS AUC in controls, FETTH , FETTH+, CTTH and CTTH+ subjects in the three muscles: TPA, MAS and TA. Box plots to the right show VAS AUC on the pooled muscle data in controls, FETTH , FETTH+, CTTH and CTTH+ subjects divided into females and males.
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Fig. 4. (a) Size of areas of referred pain after intramuscular saline injection. Controls, FETTH , FETTH+, CTTH and CTTH+ subjects drew their referred pain on standard anatomic maps and the results from each of the groups are superimposed on standard drawings according to muscle: TPA, MAS and TA. Boxplots to the left show areas of referred pain in controls, FETTH , FETTH+, CTTH and CTTH+ subjects in the three muscles: TPA, MAS and TA. Box plots to the right show area of referred pain on the pooled muscle data in controls, FETTH , FETTH+, CTTH and CTTH+ subjects divided into females and males. (b) Localization of areas of referred pain after intramuscular saline injection. Illustrates the drawings of pain localization after pain induction in the different groups of participants, where the results of all the participants in each group are shown on the same figure.
and CTTH+ (ANOVA: F = 3.0: P < 0.02). Post hoc analyses showed significantly higher values in the control group than in three of the four groups: FETTH , CTTH and CTTH+ (LSD: P < 0.04) whereas no difference was found between control and FETTH+. No differences were found between FETTH , FETTH+, CTTH and CTTH+. No differences were found between the control group compared with FETTH , FETTH+, CTTH and CTTH+ in the masseter muscle or in the anterior tibial muscle.
P < 0.01, MAS: F = 9.22; P < 0.001, TA: F = 11.03; P < 0.001). Females had significantly higher VAS AUC scores in all muscles (ANOVA: TPA: F = 5.10; P < 0.001, MAS: F = 7.70; P < 0.001, TA: F = 6.84; P < 0.001). Females had significantly higher area of referred pain in the TPA (ANOVA: F = 2.99; P < 0.01) and the TA (ANOVA: F = 3.42; P < 0.01), but no difference could be detected between the genders in the area of referred pain in the MAS.
3.5. Gender differences
3.6. Localization of perceived pain areas
Females had significantly lower PPT baseline values than males in all muscles (ANOVA: TPA:: F = 3.07;
Visual inspection of the pain drawings clearly demonstrated similarities in the location and spread of pain in
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all the groups of participants, as well as in the FETTH /FETTH+ and CTTH /CTTH+ (Fig. 4b). 4. Discussion The present study is the first to provide a standardized description of the pain patterns and pain sensitivity following intramuscular infusion of hypertonic saline into two craniofacial muscles and a limb muscle in FETTH and CTTH compared to controls. Furthermore, it is the first description of a comparison of experimentally induced deep muscular pain in FETTH and CTTH on days with headache compared to days without headache. There were significant differences in PPTs and VAS pain scores between FETTH/CTTH and controls not only in the pericranial muscles, but, importantly, also in the limb muscle. No differences could be detected between FETTH and CTTH, between FETTH /FETTH+ or between CTTH /CTTH+. These findings strongly suggest an enhanced general sensitivity in patients with frequent episodic and chronic tension-type headache unrelated to actual headache status. We cannot completely exclude bias from interferent concurrent migraine in some patients and control persons. However, our inclusion criteria ensured, that for headache patients, TTH was the clearly dominating condition. 4.1. Pressure pain thresholds Pressure pain thresholds are often used in studies on tension-type headache conditions as a quantitative measure of muscle sensitivity (Jensen et al., 1993; Bendtsen et al., 1996). The present results are in accordance with previous findings where an increased sensitivity to pressure pain has been demonstrated in FETTH and CTTH compared to controls (Bendtsen, 2000; Mork et al., 2003). A generalized, central sensitization has been suggested to account for these findings (Bendtsen, 2000). The present results are in contrast to a few studies that could not detect a difference in pain sensitivity between controls and CTTH (Jensen et al., 1993; de Tommaso et al., 2003). However, these studies included a small number of subjects increasing the risk for type 2 errors (for a review see Bendtsen and Treede, 2005). The present results convincingly demonstrate the generalized increased pain sensitivity not only in CTTH but also in FETTH. A minor caveat to this statement is the fact, that examinations of all participants were made without blinding of the diagnoses and actual headache status. This may have introduced the risk of bias. However, both the psychophysical recordings (PPDTs) and self-reported measures (VAS pain and perceived pain areas) showed very robust and consistent differences between controls and patients. To our understanding, the lack of blinding
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of the examiner is not likely to explain such marked differences. From a clinical point of view it is important to recognize that there are muscle specific differences in PPTs in healthy controls thus standardization of manual palpation procedures may require a grading of the pressure applied to the muscle. The PPTs and pain tolerance thresholds in addition to pressure controlled palpation (Bendtsen et al., 1994) provide useful information on the pain sensitivity to phasic stimuli lasting seconds, however, more tonic stimuli lasting several minutes may better mimic clinical pain conditions (Stohler and Kowalski, 1999) and allow description of spread and referral of pain (Stohler and Lund, 1994). 4.2. Pain evoked by hypertonic saline Kellgren (1938) was the first to use injection of hypertonic saline into deep tissues to study spread and referral of pain. Graven-Nielsen et al. (1997) showed that the volume of infused saline influenced the VAS pain scores, but that no spatial summation was found. SchmidtHansen et al. (2006) found reproducible patterns of referred pain mappings, PPT and VAS pain scores, when 0.2 ml of 1 M saline was infused into the masseter muscle (MAS) and the anterior part of the temporal muscle (TPA). The occurrence of referral of pain from the TPA has been found to be dependent on the perceived intensity of pain (Kellgren, 1938). Mense et al. (2001) described how muscle inflammation in experimental animals elicits severe sensitization of neurons of adjacent spinal segments. Injection of 0.5 ml of 1 M saline into the TPA, the MAS and the TA causes local moderate to severe pain sustained for several minutes. This model may mimic the clinic situation of sustained pain better than very short-lasting models of pain induction, thus making it a possible model for the study of referred pain. 4.3. Gender differences in deep pain Recent studies have shown gender differences in perceived pain intensity and pain areas following glutamate injections into MAS (Svensson et al., 2003). Also the frequency of referred pain following hypertonic saline injections into the anterior temporalis muscle has been shown to be sex-dependent with more women reporting referred pain (Jensen and Norup, 1992). The present study demonstrated sex differences for PPT measures, where women reported significantly lower values than males in all muscles. VAS AUC in response to the saline injections was also significantly bigger in females than males. Areas of referred pain were found significantly larger in females than in males in the TPA and the TA muscles. Thus, we demonstrate gender specific differences
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in deep muscle pain sensitivity in patients with tensiontype headache, which may help to explain why more women than men suffer from this disorder and from other types of chronic myofascial pain. 4.4. Central sensitization It is an ongoing debate, whether central or peripheral mechanisms are the most important in tension-type headache. It has been demonstrated that central mechanisms play an important role in CTTH (Bendtsen, 2000; Ashina et al., 2004; Ashina et al., 2005) and this evidence was further supported and extended in the present study. Previous studies have found normal general pain sensitivity but increased pericranial muscular tenderness in episodic TTH (for a review see Bendtsen and Treede, The Headaches 2005) and it has been hypothesized that prolonged nociceptive input was responsible for central sensitization and conversion from infrequent to chronic headache. However, in the studies mentioned above also patients who had infrequent headache episodes were included. With the recent headache classification it has been possible to subdivide ETTH into infrequent and frequent subforms, and one previous study (Mork et al., 2003) has reported increased general pain sensitivity in FETTH patients. This was supported in the present study. Strength of the present study was that we for the first time have demonstrated similar patterns of pain in FETTH and CTTH. This is important, because it indicates that FETTH and CTTH are part of a continuum and not separate entities. Thus, the central mechanisms play a role already in the frequent episodic forms of TTH, indicating that these aspects should be considered when treating these patients as well as when developing procedures that prevent the conversion to the chronic form. It is striking finding that a generalized sensitization has been found in the TTH patients, including the altered pain response in the TA. It has been hypothesized that the drawn areas could be representative of a central component of the pain modulation, reflecting an increase in cortical receptive fields. The present study neither supports nor falsifies this. Nevertheless, it supports the hypothesis of a generalized up-regulation of pain sensitivity in patients with frequent headaches. This could be explained by central sensitization induced by prolonged nociceptive input from pericranial muscles, by deficient descending inhibition or by a combination of these factors (Bendtsen, 2000). In conclusion, the present study demonstrates that both FETTH and CTTH patients have a generalized muscular hyperalgesia compared to controls, which is unrelated to actual headache status. Gender differences in deep pain sensitivity seem to be a consistent finding both in healthy controls and patients with tension-type headache.
Acknowledgements Vestdansk Sundhedsvidenskabeligt Forskningsforum, Department of Neurology, Viborg Hospital, Denmark, Rosa and Asta Jensens Fond, Danish Pain Research Center, Denmark, Center for Sensory-Motor Interaction, Aalborg University, Denmark, Danish Headache Center and Department of Neurology, University of Copenhagen, Glostrup Hospital, Denmark, and the Danish Headache Society supported the present study.
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P.T. Schmidt-Hansen et al. / Pain 129 (2007) 113–121 Kellgren JH. Observations on referred pain arising from muscle. Clin Sci 1938;3:175–90. Langemark M, Bach FW, Jensen TS, Olesen J. Decreased nociceptive flexion reflex threshold in chronic tension-type headache. Arch Neurol 1993;50:1061–4. Mense S, Simons DG, Russell IJ. Muscle pain: understanding its nature, diagnosis, and treatment. Baltimore: Lippincott Williams & Wilkins; 2001. Mork H, Ashina M, Bendtsen L, Olesen J, Jensen R. Induction of prolonged tenderness in patients with tension-type headache by means of a new experimental model of myofascial pain. Eur J Neurol 2003;10:249–56. Mork H, Ashina M, Bendtsen L, Olesen J, Jensen R. Possible mechanisms of pain perception in patients with episodic tensiontype headache. A new experimental model of myofascial pain. Cephalalgia 2004;24:466–75. Olesen J. Clinical and pathophysiological observations in migraine and tension-type headache explained by integration of vascular, supraspinal and myofascial inputs. Pain 1991;46:125–32. Schmidt-Hansen PT, Svensson P, Jensen TS, Graven-Nielsen T, Bach FW. Patterns of experimentally induced pain in pericranial muscles. Cephalalgia 2006;26:568–77.
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Stohler CS, Kowalski CJ. Spatial and temporal summation of sensory and affective dimensions of deep somatic pain. Pain 1999;79:165–73. Stohler CS, Lund JP. Effects of noxious stimulation of the jaw muscles on the sensory experience of volunteer human subjects In: Stohler CS, Carlson DS, editors. Biological and psychological aspects of orofacial pain. Craniofacial growth series, vol. 29. Center for human growth and development. The University of Michigan, Ann Arbor; 1994. p. 55–73. Svensson P, Ashina M. Human studies of experimental pain from muscle. In: Olesen J, Goadsby PJ, Ramadan N, Tfelt-Hansen P, Welch KMA, editors. The headaches. 3rd ed. Philadelphia: Lippincott Williams Wilkins; 2005. p. 635–9. Svensson P, Arendt-Nielsen L, Nielsen H, Larsen JK. Effect of chronic and experimental jaw muscle pain on pain-pressure thresholds and stimulus–response curves. J Orofac Pain 1995;9:347–56. Svensson P, Cairns BE, Wang K, Hu JW, Graven-Nielsen T, Arendt-Nielsen L, et al. Glutamate-evoked pain and mechanical allodynia in the human masseter muscle. Pain 2003;101: 221–7. Vandenheede M, Schoenen J. Central mechanisms in tension-type headaches. Curr Pain Headache Rep 2002;6:392–400.
Increased muscle pain sensitivity in patients with tension-type headache Peter T. Schmidt-Hansen a,b,*, Peter Svensson c,d,e, Lars Bendtsen b, Thomas Graven-Nielsen f, Flemming W. Bach g b
a Department of Neurology, Viborg Hospital, Denmark Danish Headache Center and Department of Neurology, University of Copenhagen, Glostrup Hospital, Glostrup, Copenhagen, Denmark c Department of Clinical Oral Physiology, Dental School, University of Aarhus, Denmark d Department of Maxillofacial Surgery, Aarhus University Hospital, Denmark e Center for Sensory-Motor Interaction, Aalborg University, Denmark f Department of Health Science and Technology, Center for Sensory-Motor Interaction, Aalborg University, Denmark g Danish Pain Research Center and Department of Neurology, Aarhus University Hospital, Denmark
Received 25 June 2006; received in revised form 8 September 2006; accepted 28 September 2006
Abstract Nociceptive mechanisms in tension-type headache are poorly understood. The aim was to investigate the pain sensitivity of pericranial muscles and a limb muscle in patients with tension-type headache. Experimental muscle pain was induced by standardized infusions of 0.5 ml of 1 M hypertonic saline into two craniofacial muscles (anterior temporalis (TPA) and masseter (MAS)) and a limb muscle (anterior tibial (TA)) in 24 frequent episodic tension-type headache patients (FETTH), 22 chronic tension-type headache patients (CTTH) and 26 age and gender matched healthy subjects. Headache patients were examined twice, both on days with and on days without headache. The pressure pain thresholds (PPTs) were determined before and after infusions. The subjects continuously reported intensity of saline-induced pain on an electronic visual analogue scale (VAS) and the perceived area of pain was drawn on anatomical maps. Headache patients demonstrated significantly lower PPTs, higher saline-evoked VAS pain scores and greater pain areas than healthy subjects at all the tested muscle sites (P < 0.05). There was a significant gender difference for the PPTs in all three groups of participants (P < 0.05) and for VAS pain scores in the CTTH patients (P < 0.05). There was no difference in pain sensitivity between FETTH and CTTH or between patients with or without headache. In conclusion, the present study demonstrates the presence of generalized pain hypersensitivity both in FETTH and CTTH compared to controls which is unrelated to actual headache status and extends to include responses to longer-lasting stimuli which are clinically highly relevant. Gender differences in deep pain sensitivity seem to be a consistent finding both in healthy controls and patients with tension-type headache. Ó 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. Keywords: Experimental muscle pain; Tension-type headache; Referred pain; Pain assessment; Pressure algometry; Central sensitization; Muscular hyperalgesia
1. Introduction Abbreviations: TPA, anterior temporalis muscle; MAS, masseter muscle; TA, anterior tibial muscle; FETTH, frequent episodic tensiontype headache; CTTH, chronic tension-type headache; PPT, pressure pain threshold; VAS, visual analogue scale; TTH, tension-type headache. * Corresponding author. Tel.: +45 4323 2062; fax: +45 4323 3839. E-mail address: [email protected] (P.T. Schmidt-Hansen).
The pathophysiology of tension-type headache (TTH) is largely unknown despite intense research efforts (Olesen, 1991; Jensen, 1999; Bendtsen, 2000; Goadsby and Boes, 2002; Vandenheede and Schoenen, 2002). Nociceptive processes in craniofacial muscles are believed to play a role in development and
0304-3959/$32.00 Ó 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2006.09.037
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maintenance of tension-type headache (TTH) (Jensen et al., 1998; Mense et al., 2001), but also sensitization of neurons in the central nervous system may be of major importance (Olesen, 1991; Jensen et al., 1993; Langemark et al., 1993; Bendtsen et al., 1996; Vandenheede and Schoenen, 2002). Little is, however, known about differences in pain sensitivity and manifestations of pain in different craniofacial muscles. Mense et al. (2001) suggested that focal tender points in the muscle tissue, the so-called trigger points, could represent an important key to understand the symptomatology of TTH. Numerous techniques exist for experimental pain testing (Arendt-Nielsen, 1997; Ashina et al., 2003; Svensson and Ashina, 2005), but in particular intramuscular infusions of hypertonic saline and other algogenic substances have been used to study somatosensory and motor manifestations of longer-lasting muscle pain (Kellgren, 1938; Jensen and Norup, 1992; Stohler and Lund, 1994; Mork et al., 2004). The main advantage of these methods is the specific stimulation of muscular tissue without a major contribution from subcutaneous and cutaneous tissues. The International Headache Society subdivides tension-type headache into a frequent episodic type (FETTH) and a chronic type (CTTH) on the basis of whether headache is present at least 1 but less than 15 days per month or present 15 days per month or more (2004). In the present study TTH was further subdivided into FETTH and CTTH with ongoing headache (FETTH+, CTTH+) and without ongoing headache (FETTH , CTTH ) to clarify whether the pain responsiveness was dependent on the actual headache status. The primary aim of the present study was to apply a validated and reproducible experimental technique with painful infusions of hypertonic saline into two craniofacial muscles (Schmidt-Hansen et al., 2006) and a leg muscle in patients with FETTH and CTTH, to test if there would be differences between the groups of headache patients and controls in relation to absence or presence of headache. The secondary aim was to test if there were differences in pain sensitivity between the craniofacial muscles and the leg muscle in patients with FETTH and CTTH compared to controls, to test if the headache patients had a generalized hypersensitivity. These findings could contribute to the development of a standardized technique of experimental pain investigation in tension-type headache patients.
(6 male and 18 female) with a mean age of 38.9 ± 11.7 (SD) years, 22 chronic tension-type headache patients (CTTH) (7 male and 15 female) with a mean age of 39.7 ± 15.1 (SD) years were examined twice. Twenty-six healthy volunteers (11 male and 15 female) with a mean age of 37.2 ± 10.6 (SD) were examined in the same way. All the patients had had the actual condition of FETTH or CTTH for at least 12 months. Patients were included if they fulfilled the diagnostic criteria for FETTH or CTTH according to the International Classification of Headache Disorders 2nd Edition (ICHD-II) 2004. Controls had to report frequency of any kind of headache <0.5 day per month during the last 12 months. All participants had a general neurological examination and none of the participants had focal neurological signs. FETTH and CTTH patients were allowed to have occasional migraine, but it should be less frequent than their TTH. No further records were made concerning the occurrence of migraine in the patients. FETTH and CTTH patients were examined on two different days; one day virtually free of tension-type headache (FETTH ; CTTH ) with an intensity of headache pain, for the last 24 h, of <3 on a visual analogue scale (VAS), where 0 = no pain and 10 = worst imaginable pain and no intake of analgesics for at least 24 h, and another day with tensiontype headache (FETTH+; CTTH+) with an intensity of headache pain P3 during the last 24 h. The female participants were not tested in any particular phase of their menstrual cycle due to the relatively small number of participants and the minor effect of menstrual cycle on pain sensitivity (Dao and LeResche, 2000). The same investigator (PTSH) examined all the subjects. The local Ethics Committee in Viborg and Nordjyllands Counties approved the experiments and informed consent was obtained from all participants. The study was conducted in accordance with the Declaration of Helsinki. 2.2. Experimental design
2. Methods and materials
The sequence and side of infusions into the three test muscles were randomized in the two experimental sessions in a balanced order. The sequence of the muscles examined was written on cards, which the subjects drew before the first session. The experiments took place with the subjects in a semi-supine position in a dental chair. At the first session FETTH and CTTH registered the localization of their habitual pain on a standard map of the face and the habitual intensity of their headache pain on a 0–10 cm VAS. Afterwards pressure pain threshold (PPT) in the test muscle was determined. Then the infusion of hypertonic saline was started and the subjects continuously reported the perceived pain intensity on an electronically 0–10 cm VAS. Immediately after return of VAS pain score to 0, the PPT was determined again, and the subjects drew the perceived area of pain on anatomical maps of the head, face or lower limbs. The same sequence was repeated after 15 min in the next test muscle. All the three muscle sites were examined in each of the two sessions, which lasted about 1–112 h.
2.1. Participants
2.3. Infusion of hypertonic saline
The participants were recruited by advertising in local papers as well as in the neurological department. A total of 24 frequent episodic tension-type headache patients (FETTH)
The methodology has been described in detail previously (Graven-Nielsen et al., 1997; Schmidt-Hansen et al., 2006). In brief, infusion of hypertonic saline was done using a comput-
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er-controlled syringe pump (IVAC, model 770) with a plastic syringe. A tube (IVAC G30303, extension set with polyethylene inner line) was connected from the syringe to the stainless disposable needle (27 G, 40 mm). A total volume of 0.5 ml hypertonic saline (5.8% = 1 M) was infused over 20 s in each of the following three muscles: (1) anterior part of the temporalis (TPA) muscle in the muscle belly about 4 cm behind and 5 cm above the commissure of the eyelids, (2) masseter (MAS) muscle in the belly midway between the anterior and posterior and superior and inferior borders and about 5 cm behind the commissure of the lips, (3) anterior tibial (TA) muscle about 10 cm below the caput fibulae in the middle of the muscle belly. The infusion site in the three test muscles relied on identification of anatomical landmarks and was preceded by careful manual palpation of the muscle and its borders during voluntary contractions. The perceived pain intensity of the hypertonic saline infusions was scored on a 0–10 cm electronic VAS where 0 indicated, ‘‘no pain’’ and 10 ‘‘worst imaginable pain’’. VAS data were sampled every 5 s and stored on a computer. The area under the VAS pain curve (VAS-AUC), maximum pain (VAS-peak), and onset and offset of pain were calculated from the VAS data. The subjects then drew the distribution of pain on anatomical maps of the lateral aspect of the head. The circumference was digitized with an ACECAD D9000+ digitizer and the area calculated in arbitrary units (Sigma-Scan, Jandel Scientific, Canada). 2.4. Pressure pain thresholds The PPT was defined as the amount of pressure applied by a handheld algometer (Somedic AB, Sweden) that the subjects first perceived as painful, i.e., the transition from a feeling of pressure to a painful sensation (Svensson et al., 1995). When a painful sensation was experienced the subjects pressed a button and the pressure value was stored on the display. The increase in pressure rate was manually controlled with use of
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visual feedback and aimed at 40 kPa/s. The area of the probe was 1 cm2. Measurements of PPTs were performed on maximally relaxed muscles perpendicular to the surface after careful palpations of the muscle. PPT was determined as the mean of three recordings with at least 30-s intervals. 2.5. Statistics The PPT and VAS pain data are presented in box plots with medians and ranges. The pain areas are presented as means with standard of the mean (SEM). Analysis of variance (ANOVA) for repeated measures was used to compare PPT baseline values, PPT post injection values, VAS pain data and pain areas between the different muscles (TPA, MAS, TA). The groups (FETTH, CTTH, controls) and subgroups (FETTH , FETTH+, CTTH , CTTH+) and gender (males, females) were compared with separate ANOVAs. Post hoc comparisons tests were performed with the use of LSD (Least significant difference) tests. P < 0.05 was considered significant.
3. Results All 72 subjects completed the planned sessions including three infusions, which were always associated with a distinct sensation of deep, diffuse, moderate to intense levels of pain. 3.1. Habitual pain There was no difference between FETTH and CTTH in habitual headache pain intensity scored on a VAS (ANOVA, F = 0.20; P = 0.66) (Fig. 1). The drawings of habitual pain demonstrated a pattern of pain local-
Fig. 1. FETTH and CTTH subjects drew their habitual pain on standard anatomic maps. The results from the entire group of subjects are superimposed on a standard drawing.
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ized over the entire visceral cranium, predominantly localized in the frontal and neck regions in both FETTH and CTTH with no difference in area of habitual pain between the two groups (ANOVA, F = 0.05; P = 0.83) (Fig. 1). 3.2. Pressure pain threshold 3.2.1. PPT baseline PPT baseline values were significantly different between control, FETTH and CTTH (ANOVA: F = 15.16, P < 0.001) and post hoc analysis showed significantly higher values in the control group than in FETTH (LSD: P < 0.001) and CTTH (LSD: P < 0.001) but no differences between FETTH and CTTH (Fig. 2a). PPT baseline values were significantly different between the control group compared with FETTH , FETTH+, CTTH and CTTH+ (ANOVA: F = 7.64; P < 0.001). Post hoc analyses showed significantly higher values in the control group than in each of the four groups: FETTH , FETTH+, CTTH and CTTH+ (LSD: P < 0.001 in each of the groups) but no
differences between FETTH , FETTH+, CTTH and CTTH+ (Fig. 2a). These findings were consistent for each of the muscles. Thus PPT baseline values were significantly different between the control group compared with FETTH , FETTH+, CTTH and CTTH+ (ANOVA: anterior temporalis muscle, F = 3.2; P < 0.01; masseter muscle, F = 6.84; P < 0.001 and anterior tibial muscle F = 5.1; P < 0.001). Post hoc analyses showed significantly higher values in the control group than in each of the four groups: FETTH , FETTH+, CTTH and CTTH+ (LSD: P < 0.007 in each of the groups for all muscles) but no differences between FETTH , FETTH+, CTTH and CTTH+. 3.2.2. PPT post injection PPT post injection values were significantly different between control, FETTH and CTTH (ANOVA: F = 14.29, P < 0.001) and post hoc analysis showed significantly higher values in the control than in FETTH (LSD: P < 0.001) and CTTH (LSD: P < 0.001), but no differences between FETTH and CTTH (Fig. 2b).
Fig. 2. (a) Box plots to the left show PPT baseline in controls, FETTH , FETTH+, CTTH and CTTH+ subjects in the three muscles: TPA, MAS and TA. Box plots to the right show PPT baseline on the pooled muscle data in controls, FETTH , FETTH+, CTTH and CTTH+ subjects divided into females and males. (b) Box plots to the left show PPT post injection in controls, FETTH , FETTH+, CTTH and CTTH+ subjects in the three muscles: TPA, MAS and TA. Box plots to the right show PPT post injection on the pooled muscle data in controls, FETTH , FETTH+, CTTH and CTTH+ subjects divided into females and males.
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PPT post injection values were significantly different between the control group compared with FETTH , FETTH+, CTTH and CTTH+ (ANOVA: F = 7.24; P < 0.001). Post hoc analyses showed significantly higher values in the control group than in each of the four groups: FETTH , FETTH+, CTTH and CTTH+ (LSD: P < 0.001 in each of the groups) but no differences between FETTH , FETTH+, CTTH and CTTH+ (Fig. 2b). These findings were consistent for each of the muscles. Thus PPT post injection values were significantly different between the control group compared with FETTH , FETTH+, CTTH and CTTH+ (ANOVA: anterior temporalis muscle, F = 3.2: P < 0.02; masseter muscle, F = 7.6; P < 0.001 and anterior tibial muscle F = 3.8; P < 0.005). Post hoc analyses showed significantly higher values in the control group than in each of the four groups: FETTH , FETTH+, CTTH and CTTH+ (LSD: P < 0.03 in each of the groups for all muscles) but no differences between FETTH , FETTH+, CTTH and CTTH+. 3.3. Perceived pain intensity VAS AUC scores were significantly different between controls, FETTH and CTTH (ANOVA: F = 37.96, P < 0.001) and post hoc analysis showed significantly lower values in the control group than in FETTH (LSD: P < 0.001) and CTTH (LSD: P < 0.001) but no difference between FETTH and CTTH (LSD: P > 0.87). VAS AUC scores were significantly different in the control group compared with FETTH , FETTH+, CTTH and CTTH+ (ANOVA: F = 19.43; P < 0.001). Post hoc analyses showed significantly lower values in the control group than in each of the four groups: FETTH (LSD: P < 0.001), FETTH+ (LSD: P < 0.001), CTTH (LSD: P < 0.001) and CTTH+ (LSD: P < 0.001) but no difference in between FETTH ,
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FETTH+, CTTH and CTTH+ (LSD: 0.18 < P < 0.84) (Fig. 3). These findings were consistent for each of the muscles. Thus VAS AUC scores were significantly different between the control group compared with FETTH , FETTH+, CTTH and CTTH+ (ANOVA: anterior temporalis muscle, F = 6.5: P < 0.001; masseter muscle, F = 9.8; P < 0.001 and anterior tibial muscle F = 8.3; P < 0.001). Post hoc analyses showed significantly higher values in the control group than in each of the four groups: FETTH , FETTH+, CTTH and CTTH+ (LSD: P < 0.03 in each of the groups for all muscles) but no differences between FETTH , FETTH+, CTTH and CTTH+. 3.4. Perceived pain areas The sizes of the drawn areas were significantly different between the control group, FETTH and CTTH, (ANOVA: F = 6.20, P < 0.002) and post hoc analysis showed significantly lower values in the control group than in FETTH (LSD: P < 0.02) and CTTH (LSD: P < 0.001) but no difference between FETTH and CTTH (LSD: 0.23 < P). The sizes of the drawn areas were significantly different in the control group compared with FETTH , FETTH+, CTTH and CTTH+ (ANOVA: F = 3.12; P < 0.02). Post hoc analyses showed significantly lower values in the control group than in CTTH (LSD: P < 0.003) and CTTH+ (LSD: P < 0.01), but no significant difference between the control group and FETTH (LSD: P < 0.07) and FETTH+ (LSD: P < 0.07). No significant difference could be detected between FETTH , FETTH+, CTTH and CTTH+ (LSD: 0.29 < P < 0.99) (Fig. 4a). Analysis of the results in the anterior temporalis muscle showed significantly difference between the control group compared with FETTH , FETTH+, CTTH
Fig. 3. Boxplots to the left show VAS AUC in controls, FETTH , FETTH+, CTTH and CTTH+ subjects in the three muscles: TPA, MAS and TA. Box plots to the right show VAS AUC on the pooled muscle data in controls, FETTH , FETTH+, CTTH and CTTH+ subjects divided into females and males.
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Fig. 4. (a) Size of areas of referred pain after intramuscular saline injection. Controls, FETTH , FETTH+, CTTH and CTTH+ subjects drew their referred pain on standard anatomic maps and the results from each of the groups are superimposed on standard drawings according to muscle: TPA, MAS and TA. Boxplots to the left show areas of referred pain in controls, FETTH , FETTH+, CTTH and CTTH+ subjects in the three muscles: TPA, MAS and TA. Box plots to the right show area of referred pain on the pooled muscle data in controls, FETTH , FETTH+, CTTH and CTTH+ subjects divided into females and males. (b) Localization of areas of referred pain after intramuscular saline injection. Illustrates the drawings of pain localization after pain induction in the different groups of participants, where the results of all the participants in each group are shown on the same figure.
and CTTH+ (ANOVA: F = 3.0: P < 0.02). Post hoc analyses showed significantly higher values in the control group than in three of the four groups: FETTH , CTTH and CTTH+ (LSD: P < 0.04) whereas no difference was found between control and FETTH+. No differences were found between FETTH , FETTH+, CTTH and CTTH+. No differences were found between the control group compared with FETTH , FETTH+, CTTH and CTTH+ in the masseter muscle or in the anterior tibial muscle.
P < 0.01, MAS: F = 9.22; P < 0.001, TA: F = 11.03; P < 0.001). Females had significantly higher VAS AUC scores in all muscles (ANOVA: TPA: F = 5.10; P < 0.001, MAS: F = 7.70; P < 0.001, TA: F = 6.84; P < 0.001). Females had significantly higher area of referred pain in the TPA (ANOVA: F = 2.99; P < 0.01) and the TA (ANOVA: F = 3.42; P < 0.01), but no difference could be detected between the genders in the area of referred pain in the MAS.
3.5. Gender differences
3.6. Localization of perceived pain areas
Females had significantly lower PPT baseline values than males in all muscles (ANOVA: TPA:: F = 3.07;
Visual inspection of the pain drawings clearly demonstrated similarities in the location and spread of pain in
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all the groups of participants, as well as in the FETTH /FETTH+ and CTTH /CTTH+ (Fig. 4b). 4. Discussion The present study is the first to provide a standardized description of the pain patterns and pain sensitivity following intramuscular infusion of hypertonic saline into two craniofacial muscles and a limb muscle in FETTH and CTTH compared to controls. Furthermore, it is the first description of a comparison of experimentally induced deep muscular pain in FETTH and CTTH on days with headache compared to days without headache. There were significant differences in PPTs and VAS pain scores between FETTH/CTTH and controls not only in the pericranial muscles, but, importantly, also in the limb muscle. No differences could be detected between FETTH and CTTH, between FETTH /FETTH+ or between CTTH /CTTH+. These findings strongly suggest an enhanced general sensitivity in patients with frequent episodic and chronic tension-type headache unrelated to actual headache status. We cannot completely exclude bias from interferent concurrent migraine in some patients and control persons. However, our inclusion criteria ensured, that for headache patients, TTH was the clearly dominating condition. 4.1. Pressure pain thresholds Pressure pain thresholds are often used in studies on tension-type headache conditions as a quantitative measure of muscle sensitivity (Jensen et al., 1993; Bendtsen et al., 1996). The present results are in accordance with previous findings where an increased sensitivity to pressure pain has been demonstrated in FETTH and CTTH compared to controls (Bendtsen, 2000; Mork et al., 2003). A generalized, central sensitization has been suggested to account for these findings (Bendtsen, 2000). The present results are in contrast to a few studies that could not detect a difference in pain sensitivity between controls and CTTH (Jensen et al., 1993; de Tommaso et al., 2003). However, these studies included a small number of subjects increasing the risk for type 2 errors (for a review see Bendtsen and Treede, 2005). The present results convincingly demonstrate the generalized increased pain sensitivity not only in CTTH but also in FETTH. A minor caveat to this statement is the fact, that examinations of all participants were made without blinding of the diagnoses and actual headache status. This may have introduced the risk of bias. However, both the psychophysical recordings (PPDTs) and self-reported measures (VAS pain and perceived pain areas) showed very robust and consistent differences between controls and patients. To our understanding, the lack of blinding
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of the examiner is not likely to explain such marked differences. From a clinical point of view it is important to recognize that there are muscle specific differences in PPTs in healthy controls thus standardization of manual palpation procedures may require a grading of the pressure applied to the muscle. The PPTs and pain tolerance thresholds in addition to pressure controlled palpation (Bendtsen et al., 1994) provide useful information on the pain sensitivity to phasic stimuli lasting seconds, however, more tonic stimuli lasting several minutes may better mimic clinical pain conditions (Stohler and Kowalski, 1999) and allow description of spread and referral of pain (Stohler and Lund, 1994). 4.2. Pain evoked by hypertonic saline Kellgren (1938) was the first to use injection of hypertonic saline into deep tissues to study spread and referral of pain. Graven-Nielsen et al. (1997) showed that the volume of infused saline influenced the VAS pain scores, but that no spatial summation was found. SchmidtHansen et al. (2006) found reproducible patterns of referred pain mappings, PPT and VAS pain scores, when 0.2 ml of 1 M saline was infused into the masseter muscle (MAS) and the anterior part of the temporal muscle (TPA). The occurrence of referral of pain from the TPA has been found to be dependent on the perceived intensity of pain (Kellgren, 1938). Mense et al. (2001) described how muscle inflammation in experimental animals elicits severe sensitization of neurons of adjacent spinal segments. Injection of 0.5 ml of 1 M saline into the TPA, the MAS and the TA causes local moderate to severe pain sustained for several minutes. This model may mimic the clinic situation of sustained pain better than very short-lasting models of pain induction, thus making it a possible model for the study of referred pain. 4.3. Gender differences in deep pain Recent studies have shown gender differences in perceived pain intensity and pain areas following glutamate injections into MAS (Svensson et al., 2003). Also the frequency of referred pain following hypertonic saline injections into the anterior temporalis muscle has been shown to be sex-dependent with more women reporting referred pain (Jensen and Norup, 1992). The present study demonstrated sex differences for PPT measures, where women reported significantly lower values than males in all muscles. VAS AUC in response to the saline injections was also significantly bigger in females than males. Areas of referred pain were found significantly larger in females than in males in the TPA and the TA muscles. Thus, we demonstrate gender specific differences
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in deep muscle pain sensitivity in patients with tensiontype headache, which may help to explain why more women than men suffer from this disorder and from other types of chronic myofascial pain. 4.4. Central sensitization It is an ongoing debate, whether central or peripheral mechanisms are the most important in tension-type headache. It has been demonstrated that central mechanisms play an important role in CTTH (Bendtsen, 2000; Ashina et al., 2004; Ashina et al., 2005) and this evidence was further supported and extended in the present study. Previous studies have found normal general pain sensitivity but increased pericranial muscular tenderness in episodic TTH (for a review see Bendtsen and Treede, The Headaches 2005) and it has been hypothesized that prolonged nociceptive input was responsible for central sensitization and conversion from infrequent to chronic headache. However, in the studies mentioned above also patients who had infrequent headache episodes were included. With the recent headache classification it has been possible to subdivide ETTH into infrequent and frequent subforms, and one previous study (Mork et al., 2003) has reported increased general pain sensitivity in FETTH patients. This was supported in the present study. Strength of the present study was that we for the first time have demonstrated similar patterns of pain in FETTH and CTTH. This is important, because it indicates that FETTH and CTTH are part of a continuum and not separate entities. Thus, the central mechanisms play a role already in the frequent episodic forms of TTH, indicating that these aspects should be considered when treating these patients as well as when developing procedures that prevent the conversion to the chronic form. It is striking finding that a generalized sensitization has been found in the TTH patients, including the altered pain response in the TA. It has been hypothesized that the drawn areas could be representative of a central component of the pain modulation, reflecting an increase in cortical receptive fields. The present study neither supports nor falsifies this. Nevertheless, it supports the hypothesis of a generalized up-regulation of pain sensitivity in patients with frequent headaches. This could be explained by central sensitization induced by prolonged nociceptive input from pericranial muscles, by deficient descending inhibition or by a combination of these factors (Bendtsen, 2000). In conclusion, the present study demonstrates that both FETTH and CTTH patients have a generalized muscular hyperalgesia compared to controls, which is unrelated to actual headache status. Gender differences in deep pain sensitivity seem to be a consistent finding both in healthy controls and patients with tension-type headache.
Acknowledgements Vestdansk Sundhedsvidenskabeligt Forskningsforum, Department of Neurology, Viborg Hospital, Denmark, Rosa and Asta Jensens Fond, Danish Pain Research Center, Denmark, Center for Sensory-Motor Interaction, Aalborg University, Denmark, Danish Headache Center and Department of Neurology, University of Copenhagen, Glostrup Hospital, Denmark, and the Danish Headache Society supported the present study.
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