Sage Journals: Discover world-class research

Abstract

A new experimental human model of myofascial pain using intramuscular infusion of a combination of bradykinin, serotonin (5-hydroxytryptamine), histamine, and prostaglandin E₂ was applied to patients with episodic tension-type headache (ETTH) in order to examine pain perception. Fifteen patients with ETTH and 15 healthy controls completed the randomized, balanced, double-blinded, placebo-controlled study. Pain intensity, punctate hyperalgesia and allodynia, and pain quality were recorded. The combination induced a moderate and prolonged pain in both patients (median 51 min) (P = 0.001) and controls (median 22 min) (P = 0.001). Patients reported more pain than controls both after the combination (P = 0.045) and after placebo (P < 0.001). The McGill pain score [PRI(R)] was significantly higher in patients (P = 0.002) and in controls (P = 0.001), whereas pain quality and hyperalgesia were similar after the combination compared with placebo in the two groups. Due to side-effects nine subjects did not complete the study. The increased pain response, but similar qualitative pain perception, in ETTH patients may be explained by sensitization of peripheral nociceptors even though central mechanisms may also be involved.

Keywords

5-Hydroxytryptamine bradykinin histamine human experimental muscle pain

Introduction

Myofascial factors may play a major role in the pathophysiology of tension-type headache (TTH) (1, 2). Thus, the most prominent abnormal finding in patients with TTH is increased pericranial myofascial tenderness by palpation (3, 4), and this tenderness is positively correlated to intensity and frequency of headache (5). Only few experimental human models have been developed to examine myofascial mechanisms in TTH (6–11). Improved models of myofascial pain are needed to increase the present knowledge of its aetiology, evolution and treatment. TTH is extremely prevalent since 40–74% of the population has experienced this type of headache in the last year (12, 13). In addition to high personal costs, this disorder also results in substantial socio-economic costs as TTH mostly affects people of working age (14, 15).

Tenderness and pain may be due to release of endogenous substances in myofascial tissues sensitizing and exciting peripheral nociceptors (16–20). A characterization of the neurobiological basis of human muscle pain may therefore be of clinical importance in TTH.

Recently, we demonstrated that infusion of a combination of bradykinin (Bk), serotonin [5-hydroxytryptamine (5-HT)], histamine (His), and prostaglandin E₂ (PGE₂) into the trapezius muscle of healthy subjects produced a prolonged, local and moderate pain and tenderness while single substances or combinations of two or three substances induce only mild and momentary pain and tenderness (21). The trapezius muscle was chosen because this muscle is one of the most tender muscles in TTH (4, 5), and the localization and size of the muscle also make it suitable for examination. The aim of the present study was to apply this experimental human model to patients with episodic tension-type headache (ETTH) in order to examine the pain intensity and to elucidate possible pathophysiological mechanisms in TTH.

Material and methods

Subjects

Nineteen patients with a diagnosis of frequent ETTH and 20 healthy subjects were included (Table 1). The patients were recruited from the out-patient Headache Clinic at Glostrup Hospital and the headache was diagnosed according to the criteria of the Inter-national Headache Society (22) and verified by a 4-week headache diary prior to inclusion (23). Inclusion criteria for patients were 8–15 days of TTH/4 weeks, and a total tenderness score (TTS) (24) of at least 8 (maximum possible score of 48) and a local tenderness score (LTS) of at least 2 (on a scale from 0 to 3) on the non-dominant trapezius muscle on the day of inclusion. Healthy subjects were not allowed to have more than 1 day of TTH per 4 weeks. All subjects underwent a full physical and neurological examination including a screening for depression [Major (ICD-10) Depression Questionnaire (25)] prior to participation in the study. Exclusion criteria for participants were: history of migraine or other primary headaches; allergy; serious somatic or psychiatric disorders including depression; use of any kind of daily medication (except for oral contraceptives); excessive use of analgesics (use of > 50 g of aspirins per month or equivalent); pregnancy or breast feeding; abnormal physical or neurological examination. Examinations were performed on headache-free days and subjects were not allowed to take analgesics or any other medication except for contraceptives 24 h prior to examination.

Table 1

Demographic data

	Patients		Healthy controls
	Included∗	Completed†	Included∗	Completed†
No of subjects	19	15	20	15
Male/female	5/14	5/10	6/14	4/11
Age, years	34 (27–41)	34 (28–42)	29 (24–40)	27 (24–38)
Headache days/28 days	11 (10–13)	11 (10–13)	<1	<1
Headache duration, years	15 (10–20)	16 (10–23)	–	–
Local tenderness score	2 (2–2)	1 (0–3)	0 (0–1)	0 (0–1)
Total tenderness score	12 (9–17)	10 (3–15)	0 (0–0)	1 (0–4)

∗

Data observed on the day of inclusion to study.

†

Data observed on the day of examination.

Median values are given with quartiles within parentheses.

All participants gave written informed consent to participate in the study, which was conducted in accordance with the Declaration of Helsinki and approved by the local Ethics Committee.

Preparations

Combination of endogenous substances

The combination has previously been described in detail (21). Briefly, 1 ml of the combination contained 92 nmol of Bk (Sigma, Vallensbaek Strand, Denmark), 156 nmol of 5-HT (All Bright, Vallensbaek Strand, Denmark), 130 nmol of His (Unikem, Copenhagen, Denmark), and 1.95 nmol of PGE₂ (Bie & Berntsen, Roedovre, Denmark). Initially, Bk, 5-HT, and His were diluted with isotonic saline (9 mg/ml), whereas PGE₂ was dissolved in ethanol (0.043%) and then diluted in isotonic saline. Bk and PGE₂ were stored at − 20 °C, and 5-HT and His were stored at 5 °C. Immediately before infusion Bk and PGE₂ were thawed and mixed with 5-HT and His.

Placebo

Isotonic saline containing ethanol in the same concentration as in the combination (0.007%) was used as placebo.

Experimental design

In a balanced, double-blinded, and placebo-controlled trial subjects were randomized to receive intramuscular infusions of 1 ml of the combination and 1 ml of the placebo. Each infusion was given over 10 min, and the two sessions were separated by at least 2 weeks. Infusions were given in a standardized anatomical point at the centre of the descending part of the non-dominant trapezius muscle midway between the spinal process of the seventh cervical vertebra and the acromion. The infusions were carried out by a syringe pump (Graseby 3400) using a 5-ml plastic syringe (Becton Dickenson, Broendby, Denmark). A tube (Medex; Simonsen & Weel, Copenhagen, Denmark) was connected from the syringe to the disposable EMG-needle (27 G and 25 mm; Judex, Aalborg, Denmark), that was connected to an electromyograph (Counterpoint; Dantec, Copenhagen, Denmark) to ensure intramuscular infusion.

Pain assessment

The recordings were performed by the same observer (a trained technician, H.A.), who was blinded with respect to substances and with respect to patients and controls.

Pain

Pain intensity was assessed on a 100-mm visual analogue scale (VAS) where 0 corresponded to no pain and 100 mm to the worst imaginable pain (26). The pain intensity was recorded at baseline (0 min) and every minute during infusion and until 5 min after stopping infusion, then every 5 min until 30 min, and at 45, 60, 90, 120 min, and 24 h after start of infusion.

Cutaneous hyperalgesia

Punctate hyperalgesia was assessed by gently pricking the skin at approximately 5-mm intervals with a needle (Microlance, 18GI½; BD Medical Systems, Drogheda, Ireland), and defined as a change of sensation into more pain. Allodynia was assessed by gently stoking the skin with a cotton swap, and was defined as a change of perception of stimuli into pain. Boarders of hyperalgesia were determined by slowly moving along 8 radians from well outside the area of hyperalgesia towards the standard point. These borders were marked and the eight points were mapped on transparent plastic and connected, whereafter size of the area was calculated (27). If changes were not reported in all eight directions the area was defined as 0 in the statistical calculations. Recordings were made at 0, 15, 30, 60, 120 min, and 24 h after start of infusion.

Pain quality

Pain quality was scored on a Danish version of the McGill Pain Questionnaire (28). Pain rating index [PRI(R)] based on numerical values assigned to each word descriptor and calculated as outlined by Melzack (29), number of words chosen (NWC), and most frequently used words were determined (29). Pain index was scored on a 5-point scale where 1 corresponded to mild, 2 to discomfort, 3 to distressing, 4 to horrible, and 5 to excruciating (29). Pain quality was determined at 11 (for the period 0–11 min), 60, and 120 min, and 24 h after start of infusion.

Electromyography

Processing of the electrical activity was performed by the Counterpoint programs. The power spectrum of each of the 1-s measurement sessions was calculated for the frequency range 0–1 kHz. The signal was filtered by a 1-kHz filter and the sampling frequency was 2.56 kHz. By means of the disposable EMG needle used for infusion the root mean square (RMS) and mean frequency were measured at baseline and 11 min after start of infusion.

Other parameters

The localization of local pain, projected pain (pain in direct relation to pain at the side of infusion, i.e. local pain) and referred pain (pain at a distant side separated from local/projected pain) was outlined by participants on an anatomical map during the observation period (120 min). Development of wheal and flare were also registered during the observation period.

The presence of pain and tenderness in shoulder or neck region, referred pain, headache and intake of medication were requested in a 24-h diary.

Data analysis and statistics

The standard deviation of pain and tenderness was estimated to 50% and the clinically relevant difference in these parameters was estimated to 50%, power was set to be 80% and the level of significance to 5%. Number of subjects to participate was calculated at 15 in each group (30).

Results are presented as medians and quartiles. Primary efficacy parameter was pain presented by area under the pain curve [area under the pain (VAS)–time (60 min) curve] (AUC_pain) (31) after the combination compared with placebo, and pain after the combination in patients compared with controls. The pain (AUC_pain), maximum pain score (VAS peak) (Max_pain), duration of pain (pain_offset − pain_onset) (Dur_pain), hyperalgesia [area under the hyperalgesia (area of hyperalgesia)–time (60 min) curve] (AUC_hyperalgesia), maximum area of hyperalgesia (Max_hyperalgesia), and duration of hyperalgesia (hyperalgesia_offset − hyperalgesia_onsett), and pain quality [PRI(R), NWC, and pain index] for the combination were compared with placebo by means of Wilcoxon signed rank sum test (paired data). The Wilcoxon signed rank sum test was also used to compare EMG measurements (RMS and mean frequency) before and after infusions in patients and in healthy controls. The Mann–Whitney test (unpaired data) was used to compare data between patients and controls. The McNemar test was used to compare the frequency of development of pain, hyperalgesia, and headache after infusion of the combination to placebo within the two groups, while Fischer's exact test was used to compare these parameters between patients and controls. Five percent was accepted as level of significance. All data were analysed with SPSS software, version 10.0 (SPSS Inc., Chicago, IL, USA).

Results

Fifteen patients and 15 healthy controls completed the study; the demographic data are shown in Table 1. All patients completed the 24-h diary and 10 patients and 10 controls returned for assessment of pain parameters 24 h after the infusion.

Pain

The AUC_pain was significantly increased after infusion of the combination compared with placebo both in the patient group (P = 0.001) and in the control group (P = 0.001). In patients the AUC_pain was significantly higher than in controls after the combination (P = 0.045) and after the placebo (P < 0.001) (Table 2, Fig. 1). However, when the pain induced by the placebo was subtracted from the pain induced by the combination (AUC_combination −AUC_placebo) no significant difference in the reported pain could be detected between patients and controls (P = 0.367). The Max_pain and Dur_pain were significantly increased after infusion of the combination compared with placebo both in patients (P = 0.001 and 0.041, respectively) and in controls (P = 0.001, in both cases). After the combination the Dur_pain was significantly higher in patients compared with controls (P = 0.041), while there was no significant difference in Max_pain in patients compared with controls after the combination (P = 0.161). After placebo the Max_pain and Dur_pain were significantly higher in patients compared with controls (P < 0.001, in both cases) (Table 2, Fig. 1). Pain was present in all subjects (100%) after the combination and was reported within 1–4 min and reached its maximum, Max_pain, within 20 min (median 10 min), in both groups. After the placebo, all patients (100%) and five controls (33%) developed pain within 1–6 min and reached the Max_pain within 13 min (median 8 min in patients and 2 min in controls) in both groups. The frequency of reported pain was not significantly different after the combination compared with placebo in either group or after the combination between groups. No pain was present after 24 h in either group.

Figure 1

Median pain intensity (a) and area under the pain [visual analogue scale (VAS), mm)–time (60 min) curve (AUC_pain) (b) after infusion of the combination of endogenous substances and placebo into the non-dominant trapezius muscle of patients with episodic tension-type headache (ptt) (n = 15) and healthy controls (contr) (n = 15). ∗P ≤ 0.05; ∗∗P ≤ 0.01; ∗∗∗P ≤ 0.001.

Table 2

Pain after infusion of the combination of endogenous substances and placebo into the trapezius muscle of patients with episodic tension-type headache (n = 15) and healthy controls (n = 15)

	Patients	Healthy controls
Pain
AUC_pain (min × mm)
combination	970 (393–2130)	349 (96–613)
	∗∗∗	∗∗∗
placebo	49 (21–712)	0 (0–12)
Max_pain (mm)
combination	49 (30–75)	27 (15–52)
	∗∗∗	∗∗∗
placebo	10 (4–41)	0 (0–2)
Dur_pain (min)
combination	51 (21–104)	22 (16–37)
	∗	∗∗∗
placebo	11 (8–73)	0 (0–5)

Median values are given with quartiles within parentheses.

AUC_pain, Area under the pain [visual analogue scale (VAS)]–time (60 min) curve; Max_pain, maximum pain score (VAS-peak); Dur_pain, duration of pain.

∗

P ≤ 0.05;

∗∗

P ≤ 0.01;

∗∗∗

P ≤ 0.001.

Cutaneous hyperalgesia

No significant differences in the development of punctate hyperalgesia (AUC_hyperalgesia, Max_hyperalgesia, or Dur_hyperalgesia) were detectable when comparing the combination with the placebo or comparing patients with controls (P > 0.100). Ten patients (67%) and eight controls (53%) developed hyperalgesia to pin prick after the combination, and seven (47%) patients and four (27%) controls after placebo. There were no significant differences in frequency of hyperalgesia within or between the two groups. Hyperalgesia developed within 15–60 min (median 27 min) in both groups. No allodynia was found.

Pain quality

Pain was described by words as listed in Table 3. In the period from 0 to 11 min, the total PRI(R), NWC, and the pain index were higher for the combination than for placebo both in the patient group (P = 0.002, 0.002 and 0.001, respectively) and in the control group (P = 0.001, in all cases). Likewise, in PRI(R) subclasses (sensory, affective, miscellaneous, and evaluative) significant differences were found after the combination compared with placebo in patients (P-values 0.019–0.042) and in controls with regard to sensitive, miscellaneous, and evaluative classes (P-values 0.001–0.002), whereas in the affective subclass no significant difference could be detected (P = 0.010). No significant differences in total PRI(R), subclasses of PRI(R), NWC, or pain index were detected after the combination between the two groups. After the placebo significantly higher values of total PRI(R), PRI(R) of the sensitive subclass, NWC, and pain index were found in patients compared with controls after placebo (P = 0.004, 0.002, 0.004 and < 0.001, respectively); no significant differences were found in the remaining subclasses of PRI(R) (Table 3). At 60 min the PRI(R) and NWC were higher in the patient group after infusion of the combination compared with placebo (P = 0.039, and 0.042, respectively) while no differences in pain index were detectable. No further differences were identified within or between the two groups at 60 and 120 min.

Table 3

Pain quality after infusion of the combination of endogenous substances and placebo into the trapezius muscle of patients with episodic tension-type headache (n = 15) and healthy controls (n = 15)

	Patients	Healthy controls
McGill
PRI(R), 0–11 min
combination	14 (7–23)	14 (10–21)
	∗∗	∗∗∗
placebo	7 (1–10)	0 (0–0)
NWC, 0–11 min
combination	7 (4–9)	6 (5–10)	∗∗∗
	∗∗
placebo	4 (2–5)	0 (0–0)
Words used by > 33%
Sensory
combination	Drilling, hot, aching	Hot, tender
placebo	Throbbing, drilling, aching, taut	–
Affective	–	–
Evaluative
combination	Miserable	–
placebo	Annoying	–
Miscellaneous	–	–
Pain index, 0–11 min
combination	4 (3–4)	3 (3–4)
	∗∗∗	∗∗∗
placebo	2 (1–3)	0 (0–0)

Median values are given with quartiles in parentheses.

PRI(R), Pain rating index; NWC, number of words chosen.

∗

P ≤ 0.05;

∗∗

P ≤ 0.01;

∗∗∗

P ≤ 0.001.

Electromyography

In patients, there were no significant changes in RMS and mean frequency after infusion of the combination (P > 0.750) or placebo (P > 0.800). In controls, the RMS was significantly increased (P = 0.031) after infusion of the combination, but not after placebo (P = 0.397). No changes in mean frequency were detected, although a trend to decreased mean frequency (P = 0.064) after the combination compared with baseline was found in controls.

Other parameters

0–2-h observation

All participants developed pain after the combination, and significantly more patients developed pain after the placebo compared with controls (P ≤ 0.001) (Table 4).

Table 4

Percentage distribution of reports of pain, referred pain and tension-type headache after infusion of the combination of endogenous substances and placebo into patients with episodic tension-type headache (n = 15) and healthy controls (n = 15)

	PatientsCombination/ placebo		Controls Combination/ placebo
Acute (0–2 h)
Local pain	100/100	n.s.	100/33	n.s.
Projection of pain	67/20	∗	40/0	n.s.
Referred pain	13/20	n.s.	20/0	n.s.
24-h diary (2–24 h)
Local pain or tenderness	47/33	n.s.	20/7	n.s.
TTH	27/47	n.s.	7/0	n.s.
Completely pain free	47/53	n.s.	73/93	n.s.

TTH, Tension type headache; n.s., not significant.

∗

P ≤ 0.05.

Significantly more patients developed pain projection after the combination compared with the placebo (P = 0.016). No other significant differences were detected in controls or between the two groups (Table 4). The projection was more often proximal in patients compared with controls (Fig. 2). After infusion of the combination 10 patients reported pain projection ipsilaterally: in proximal direction to the neck (n = 9) and retro-auricular region (n = 7) and in distal direction to the shoulder (n = 5). Six controls reported ipsilateral pain projection: in proximal direction to the neck (n = 6) and the retro-auricular region (n = 2) and in distal direction to the shoulder (n = 5). After infusion of the placebo, three patients reported pain projection in proximal direction to the retroauricular region, and two distal to the shoulder.

Figure 2

Distribution of pain after infusion of the combination of endogenous substances in patients with episodic tension-type headache (a) and in healthy controls (b).

No differences in frequency of referred pain were detected within or between the two groups. In two patients referred pain was experienced ipsilaterally after the combination; one subject to the neck and retroauricular region, and in another to the frontal region, whereas three controls reported referred pain ipsilaterally to the neck region. After the placebo, three patients reported referred pain to the ipsilateral retroaucicular region (n = 2) and to the frontal region bilaterally (n = 1), while none in the control group reported projection of the pain or referred pain (Table 4, Fig. 2).

2–24-h diary

After the combination there was no increase in reports of TTH in patients compared with controls (P = 0.165), whereas more patients reported TTH after the placebo compared with controls (P = 0.003). No further significant differences in frequency of TTH or pain and tenderness after infusions were detected within or between the groups (Table 4). Headache in all cases fulfilled the criteria of TTH and was present 3–24 h after the infusions and with a median intensity of 16 mm (6–50 mm) on the VAS scale. Pain and/or tenderness were reported 2–24 h after infusions.

Adverse events

Seven subjects (three patients and four healthy controls) were excluded during infusion of the combination and one subject (one healthy control) during infusion of the placebo due to vaso-vagal symptoms appearing between 3 and 6 min after start of the infusions. During infusion of the combination these symptoms appeared in association with a median pain score of 78 mm on VAS (10–100 mm), but during the placebo infusion no pain was reported. Four subjects developed symptoms during their first infusion, and four subjects during their second infusion. Symptoms were sense of heat, dizziness, and nausea, which disappeared spontaneously in all cases within a few minutes after cessation of infusions. One subject was excluded because of universal erythema 14 days after infusion of the placebo and 7 days after initiation of antibiotic treatment of a nail inflammation.

In all subjects redness, but no weal, was observed locally around the needle in direct relation to infusion of both the combination and the placebo, but disappeared completely in all cases within 1 h.

Discussion

In the present study the combination of Bk, 5-HT, His, and PGE₂ induced a prolonged and moderate pain in both ETTH patients (median 51 min) and controls (median 22 min). The induced pain after this combination was significantly more pronounced than the pain induced after placebo in both groups. The results thereby confirm previous results from a pilot study in healthy controls (21). To our knowledge, only one human model of myofascial pain using naturally occurring endogenous substances has previously been applied to patients (20). In this study injections of 2000 nmol of 5-HT induced mild and brief pain in healthy subjects, but in contrast to the present study injections of 0.2–2000 nmol of 5-HT into the painful masseter muscles of fibromyalgia patients did not produce more pain compared with either baseline or saline. Our present and previous (21) findings indicate that a combination of several substances, i.e. an ‘inflammatory soup’ (32), is needed to induce a clinically relevant and prolonged pain in both myofascial pain patients and healthy controls.

The ETTH patients reported more pain than controls not only after the combination but also after the placebo. The pronounced pain sensitivity in patients may reflect increased excitability or a prior sensitization of peripheral myofascial afferents, possibly caused by local release of endogenous substances in tender muscles (18). Impaired supraspinal descending inhibition (33) or increased excitability at the spinal/trigeminal level because of prolonged activation of primary sensory afferents in the tender muscles may, however, also contribute to the increased sensitivity in patients (34). This is supported by studies in animals showing that decreased supraspinal descending inhibition (35) and central sensitization (36) may contribute to increased pain perception.

However, punctate hyperalgesia was found only in some individuals and no statistical differences were found after the combination or between the groups. Likewise, no allodynia was found. These results indicate that the hypersensitivity to the present infusions in patients may be a peripheral phenomenon (37–41). Furthermore, unchanged mechanical pain thresholds on the finger and in the temporal region in either group after infusion of the combination (42) indicate that peripheral mechanisms may be responsible for the increased pain response in patients.

When we subtracted the pain induced by the placebo procedure from the pain induced by the combination no differences between the two groups could be detected. Thus, patients presented a stronger reaction to both the endogenous substances (chemical stimuli) and to the non-specific stimuli (the placebo and mechanical stimuli) compared with healthy controls. In agreement with this, we found lower pressure pain thresholds in the patients than in controls at baseline, as reported elsewhere (42). In line with the present results, infusion of hypertonic saline has been reported to produce more pain in patients with chronic myofascial pain (fibromyalgia and whiplash) than in healthy controls (43, 44), although there was no placebo control in these studies.

Both patients and controls used ‘stronger’[PRI(R) (total and subclasses) and pain index] and more words after the combination compared with placebo. The values of the PRI(R) (in total and in subclasses), pain index, and number of words used were nevertheless similar after the combination in the two groups. Moreover, the PRI(R) was similar to the PRI(R) in previous acute experimental pain studies (45), and to menstrual pain (29), while it was less pronounced compared with the chronic low back pain and masseter pain or cancer pain (29, 46, 47). The present data may therefore indicate that ETTH patients and healthy controls have a qualitatively similar experience of pain, in contrast to the quantitative experience of pain, which was more pronounced in patients.

A tendency to more proximal distribution of pain in patients compared with healthy subjects was observed. This observation is in agreement with observations in chronic myofascial pain patients (48, 49) and experimental controlled pain studies of chronic pain patients (43, 44). Proximal distribution of pain possibly reflects central sensitization (50, 51) but the number of patients in the present study was too low to make firm conclusions. However, central sensitization may play a role in these patients since their mechanical pain thresholds were decreased compared with thresholds in controls at baseline (42), and the finding may therefore not be a specific reaction to the combination. Referred pain was seen in 13–20% of patients both after the combination and after placebo, as well as in controls after the combination, whereas no referral of pain was seen in controls after placebo. The frequency of referral of pain is similar to reports of referred pain in healthy controls after stimulation with endogenous substances (19), but less pronounced compared with reports of evoked referred pain in other models of myofascial pain (52–54). Differences in quality and intensity of evoked pain responses in the different models might explain these variable results (55, 56). In TTH prolonged myofascial pain and tenderness are supposed to be responsible for the pain. After 10 min of intramuscular infusion of nociceptive substances referred pain and post-experimental headache were similar in patients and controls. Since for ethical reasons more prolonged infusions are not possible, the present model is probably not an experimental model of headache but rather an experimental model of myofascial pain.

In the present study EMG parameters were not affected in the patients after infusion of the combination, and it is therefore unlikely that concomitant electrical muscular activity was responsible for their increased pain response. In contrast, the increase in amplitude in healthy controls may indicate a normal muscular reaction which may be abolished or suppressed in ETTH patients, possibly as a long-term adaptation to myofascial pain (57).

The present experimental human model of myofascial pain using a combination of endogenous substances induces a prolonged (median 51 min in patients and 22 min in healthy controls) and moderate pain in both patients with ETTH and healthy subjects, and thereby represent a very valuable experimental human pain model which can be used for future pharmacological testing. Patients with ETTH showed a higher sensibility to applied stimuli, but pain quality was similar compared with healthy controls. Moreover, referred pain and punctate hyperalgesia and allodynia were no more frequently found in patients compared with controls. These results may indicate a peripheral increased excitability or sensitization in ETTH patients. However, involvement of central mechanisms may also be present, since clinical signs and pain thresholds were lower in ETTH compared with healthy controls.

Footnotes

Acknowledgements

We thank technician Hanne Andresen for helpful technical assistance during the data collection, and pharmacist Trine Schnor (The Central Pharmacy, Copenhagen Community Hospital Services) for preparation and testing of substances.

References

Jensen

. Pathophysiological mechanisms of tension-type headache: a review of epidemiological and experimental studies. Cephalalgia 1999; 19: 602–21.

Bendtsen

. Central sensitization in tension-type headache – possible pathophysiological mechanisms. Cephalalgia 2000; 20: 486–508.

Langemark

Olesen

. Pericranial tenderness in tension headache. A blind, controlled study. Cephalalgia 1987; 7: 249–55.

Bendtsen

Jensen

Olesen

. Decreased pain detection and tolerance thresholds in chronic tension-type headache. Arch Neurol 1996; 53: 373–6.

Jensen

Rasmussen

Pedersen

Olesen

. Muscle tenderness and pressure pain thresholds in headache. A population study. Pain 1993; 52: 193–9.

Gannon

Haynes

Cuevas

Chavez

. Psychophysiological correlates of induced headaches. J Behav Med 1987; 10: 411–23.

Ashton-Miller

McGlashen

Herzenberg

Stohler

. Cervical muscle myoelectric response to acute experimental sternocleidomastoid pain. Spine 1990; 15: 1006–12.

Göbel

Cordes

. Circadian variation of pain sensitivity in pericranial musculature. Headache 1990; 30: 418–22.

Haynes

Gannon

Bank

Shelton

Goodwin

. Cephalic blood flow correlates of induced headaches. J Behav Med 1990; 13: 467–80.

10.

Martin

Marie

Nathan

. Psychophysiological mechanisms of chronic headaches: investigation using pain induction and pain reduction procedures. J Psychosom Res 1992; 36: 137–48.

11.

Jensen

Olesen

. Initiating mechanisms of experimentally induced tension-type headache. Cephalalgia 1996; 16: 175–82.

12.

Rasmussen

Jensen

Schroll

Olesen

. Epidemiology of headache in a general population – a prevalence study. J Clin Epidemiol 1991; 44: 1147–57.

13.

Schwartz

Stewart

Simon

Lipton

. Epidemiology of tension-type headache. JAMA 1998; 279: 381–3.

14.

Rasmussen

Jensen

Olesen

. Impact of headache on sickness absence and utilisation of medical services: a Danish population study. J Epidemiol Community Health 1992; 46: 443–6.

15.

Schwartz

Stewart

Lipton

. Lost workdays and decreased work effectiveness associated with headache in the workplace. J Occup Environ Med 1997; 39: 320–7.

16.

Mense

Meyer

. Bradykinin-induced modulation of the response behaviour of different types of feline group III and IV muscle receptors. J Physiol 1988; 398: 49–63.

17.

Jensen

Tuxen

Pedersen-Bjergaard

Jansen

Edvinsson

Olesen

. Pain and tenderness in human temporal muscle induced by bradykinin and 5-hydroxytryptamine. Peptides 1990; 11: 1127–32.

18.

Mense

. Nociception from skeletal muscle in relation to clinical muscle pain. Pain 1993; 54: 241–89.

19.

Babenko

Graven-Nielsen

Svensson

Drewes

Jensen

Arendt-Nielsen

. Experimental human muscle pain and muscular hyperalgesia induced by combinations of serotonin and bradykinin. Pain 1999; 82: 1–8.

20.

Ernberg

Lundeberg

Kopp

. Pain and allodynia/hyperalgesia induced by intramuscular injection of serotonin in patients with fibromyalgia and healthy individuals. Pain 2000; 85: 31–9.

21.

Mørk

Ashina

Bendtsen

Olesen

Jensen

. Experimental pain and tenderness following infusion of endogenous substances in man. Eur J Pain 2003; 7: 145–53.

22.

Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8: 29–34.

23.

Russell

Rasmussen

Brennum

Iversen

Jensen

Olesen

. Presentation of a new instrument: the diagnostic headache diary. Cephalalgia 1992; 12: 369–74.

24.

Bendtsen

Jensen

Olesen

. Pressure-controlled palpation: a new technique which increases the reliability of manual palpation. Cephalalgia 1995; 15: 205–10.

25.

Bech

Wermuth

. Applicability and validity of the major depression inventory in patients with Parkinson's disease. Nord J Psychiatry 1998; 52: 305–9.

26.

Price

McGrath

Rafii

Buckingham

. The validation of visual analogue scales as ratio scale measures for chronic and experimental pain. Pain 1983; 17: 45–56.

27.

Simone

Baumann

LaMotte

. Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin. Pain 1989; 38: 99–107.

28.

Drewes

Helweg-Larsen

Petersen

Brennum

Andreasen

Poulsen

McGill Pain Questionnaire translated into Danish: experimental and clinical findings. Clin J Pain 1993; 9: 80–7.

29.

Melzack

. The McGill Pain Questionnaire: major properties and scoring methods. Pain 1975; 1: 277–99.

30.

Altmann

. Clinical trials. In: Altmann

, editor. Practical statistics for medical research, 1st edn . London: Chapman & Hall, 1991: 440–77.

31.

Matthews

JNS

Altman

Campbell

Royston

. Analysis of serial measurements in medical research. Br Med J 1990; 300: 230–5.

32.

Handwerker

Ringkamp

Schmelz

. Neurophysiological basis for chemogenic pain and itch. In: Boivie

Hansson

Lindblom

, editors. Touch, temperature, and pain in health and disease: mechanisms and assessments, progress in pain research and management, Vol. 3. Seattle: IASP Press, 1994: 195–206.

33.

Langemark

Bach

Jensen

Olesen

. Decreased nociceptive flexion reflex thresholds in chronic tension-type headache. Arch Neurol 1993; 50: 1061–4.

34.

Bendtsen

Jensen

Olesen

. Qualitatively altered nociception in chronic myofascial pain. Pain 1996; 65: 259–64.

35.

Fields

Basbaum

. Central nervous system mechanisms of pain modulation. In: Wall

Melzack

, editors. Textbook of pain, 3rd edn. Edinburgh: Churchill Livingstone, 1994: 243–57.

36.

Woolf

. Windup and central sensitization are not equivalent. Pain 1996; 66: 105–8.

37.

LaMotte

Shain

Simone

Tsai

E-FP

. Neurogenic hyperalgesia: psychophysical studies of underlying mechanisms. J Neurophysiol 1991; 66: 190–211.

38.

Kolzenburg

Lundberg

LER

Torebjörk

. Dynamic and static components of mechanical hyperalgesia in human hairy skin. Pain 1992; 51: 207–19.

39.

LaMotte

Lundberg

LER

Torebjörk

. Pain, hyperalgesia and activity in nociceptive c units in humans after intradermal injection of capsaicin. J Physiol 1992; 448: 749–64.

40.

Torebjörk

Lundberg

LER

LaMotte

. Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J Physiol 1992; 448: 765–80.

41.

Treede

R-D

Cole

. Dissociated secondary hyperalgesia in a subject with a large-fibre sensory neuropathy. Pain 1993; 53: 169–74.

42.

Mørk

Ashina

Bendtsen

Olesen

Jensen

. 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.

43.

Sörensen

Graven-Nielsen

Henriksson

Bengtsson Arendt-Nielsen

. Hyperexcitability in fibromyalgia. J Rheumatol 1998; 25: 152–5.

44.

Johansen

Graven-Nielsen

Olesen

Arendt-Nielsen

. Generalised muscular hyperalgesia in chronic whiplash syndrome. Pain 1999; 83: 229–34.

45.

Graven-Nielsen

McArdle

Phoenix

Arendt-Nielsen

Jensen

Jackson

, In vivo model of muscle pain: quantification of intramuscular chemical, electrical, and pressure changes associated with saline-induced muscle pain in humans. Pain 1997; 69: 137–43.

46.

Reading

. A comparison of the McGill Pain Questionnaire in chronic and acute pain. Pain 1982; 13: 185–92.

47.

Stohler

Kowalski

. Spatial and temporal summation of sensory and affective dimensions of deep somatic pain. Pain 1999; 79: 165–73.

48.

Travell

Simons

. ‘Trapezius muscle’. In: Travell

Simons

, ediroes. Myofascial pain and dysfunction. The trigger point manual. Baltimore/London: Williams & Wilkins, 1983: 183–201.

49.

Lous

. The importance of referred pain in myogenic headache. Headache 1976; 16: 119–22.

50.

Cook

Woolf

Wall

McMahon

. Dynamic receptive field plasticity in rat spinal cord dorsal horn following c-primary afferent input. Nature 1987; 325: 151–3.

51.

Hoheisel

Mense

Simons

X-M

. 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 1993; 153: 9–12.

52.

Graven-Nielsen

Arendt-Nielsen

Svensson

Jensen

. Stimulus-response functions in areas with experimentally induced referred muscle pain – a psychophysical study. Brain Res 1997; 744: 121–8.

53.

Laursen

Graven-Nielsen

Jensen

Arendt-Nielsen

. Quantification of local and referred pain in humans induced by intramuscular electrical stimulation. Eur J Pain 1997; 1: 105–13.

54.

Witting

Svensson

Gottrup

Arendt-Nielsen

Jensen

. Intramuscular and intradermal injection of capsaicin: a comparison of local and referred pain. Pain 2000; 84: 407–12.

55.

Graven-Nielsen

Arendt-Nielsen

Svensson

Jensen

. Experimental muscle pain: a quantitative study of local and referred pain in humans following injection of hypertonic saline. J Musculoskel Pain 1997; 5: 49–69.

56.

Graven-Nielsen

Arendt-Nielsen

Svensson

Jensen

. Quantification of local and referred muscle pain in humans after sequential i.m. injections of hypertonic saline. Pain 1997; 69: 111–7.

57.

Lund

Donga

Widmer

Stohler

. The pain-adaptation model: a discussion of the relationship between chronic musculoskeletal pain and motor activity. Can J Physiol Pharmacol 1991; 69: 683–94.

Possible Mechanisms of Pain Perception in Patients with Episodic Tension-Type Headache. A New Experimental Model of Myofascial Pain

Abstract

Keywords

Introduction

Material and methods

Subjects

Preparations

Combination of endogenous substances

Placebo

Experimental design

Pain assessment

Pain

Cutaneous hyperalgesia

Pain quality

Electromyography

Other parameters

Data analysis and statistics

Results

Pain

Cutaneous hyperalgesia

Pain quality

Electromyography

Other parameters

0–2-h observation

2–24-h diary

Adverse events

Discussion

Footnotes

Acknowledgements

References