Similarities in stress physiology among patients with chronic pain and headache disorders: evidence for a common pathophysiological mechanism?

Totally, 44 healthy control subjects [35 women (mean age 39.7 years) and 9 men (36.6 years)] and 92 patients belonging to one of four diagnostic groups participated in this study. A total of 22 patients had migraine, 20 women (39.8 years) and 2 men (45.0 years), and 13 of these patients had aura preceding the headache. Eighteen patients had TTH, including nine women (33.8 years) and nine men (35.7 years). Twelve of the TTH patients had chronic TTH (daily headache) and six had episodic TTH (three patients reported 4–7 headache days per month and three patients reported 7–14 headache days per month). A total of 23 female patients were diagnosed with FMS (48.3 years), and 29 female patients (41.1 years) had SNP. Detailed subject and headache history data are shown in Table 1 (one migraine patient reported some attacks of short duration). Patients were diagnosed after an interview and physical examination by a neurologist or a specialist in physical medicine and rehabilitation. Headache diagnoses were made according to the International Headache Society classification of headache from 1988 [35]. Migraineurs with TTH more than 7 days per month were excluded. FMS patients were included if they fulfilled the 1990 American College of Rheumatology criteria (ACR criteria) for FMS [36]. SNP patients were included if they reported SNP (more than 3 months during previous year) with local tenderness or pain. SNP patients were included even if they reported pain in other body regions, as long as pain in the shoulder and neck region was their main problem. No SNP patients fulfilled the ACR criteria for FMS.

Control subjects did not suffer from headache or musculoskeletal pain for more than 1 day per month. Exclusion criteria were: neoplastic disease, hypertension, infectious disease, metabolic, endocrine or neuromuscular diseases, significant psychiatric disorders, connective tissue disorder, tendinitis, recent significant accident or injury, pregnancy, daily medication with neuroleptics, antiepileptics, Ca²⁺-blockers, β-blockers, antidepressants and significant associated diseases affecting either the heart, lungs, cerebrovascular system, or the central or peripheral nervous system. The project was approved by the regional ethics committee. All participants gave written informed consent and received NOK 500 (USD 75) for transport expenses and inconvenience. The participants were provided with written information concerning the aim of the study prior to the day of the stress test. The aim of studying pain and headache was mentioned, but the information focused on the practical details of the procedure. Upon arrival on the test day, subjects went through a structured interview concerning headaches and musculoskeletal complaints (distribution, severity and duration). These data have been presented elsewhere and are not included in the present study [16, 17, 32‐34].

Autonomic activity was measured indirectly by continuous recording of non-invasive finger BP (Portapres, TNO Biomedical Instrumentation, Amsterdam, The Netherlands) [37] and skin BF in the thumbs (Moorlab, time constant 0.02 s, low-pass filter 22 kHz; Moor Instruments Ltd., Devon, England). The BP cuffs were mounted on the intermediate phalanx on the left middle and ring fingers. Finger skin BF was measured bilaterally with the electrodes (fibre separation 0.5 mm) placed on the volar side of the distal phalanx (pulp) of the thumbs. The average from the left and right thumb was used for analysis, because a significant side difference was not found. Signals were sampled at 200 Hz. Heart rate (HR) and BP were calculated with the Beatscope 1.0 software (TNO, Amsterdam, The Netherlands). Muscular activity was recorded with surface electromyography (EMG) bilaterally in the trapezius, splenius, temporalis and frontalis muscles, as described in a previous paper [16, 17]. Because we previously did not find differences in muscular activity between the controls and patients, these variables were not included in the statistical analyses in the present study. Respiration was recorded with a thermistor (Embla S-AF-010, Flaga, Reykjavik, Iceland) below the nose with active elements in each nostril and in front of the mouth, but respiration frequency was not analysed in this study due to technical difficulties (seven controls, eight migraine patients, two TTH patients, one FMS patient and two SNP patients had corrupted respiration rate data).

The subjects were seated in an ordinary office chair without armrests and performed a two-choice reaction-time test presented on a PC monitor for 60 min [38]. The test involved a grid (seven columns by five rows) in which a large and a small square were placed randomly [39]. The subject was then presented with a suggestion on how to move the small square to superimpose it on the large square (for instance, “two up, four right”), and the subjects responded by pressing either “right” or “wrong” on a panel before them with their right index or ring finger, respectively. Then the positions of the squares were changed and a new suggestion was displayed. The subjects were instructed to carry out the assignment as fast and correctly as possible, and the computer provided feedback on performance by informing whether the answer was correct or not and how fast the trial was performed (very slow, slow, normal, fast or very fast) [40]. The “normal” response for each subject was determined as the mean response time during a 5-min trial period. The subjects were acclimated to the lab environment for 30 min, during which the procedure was explained and the recording equipment was mounted. The recording started with 5 min uninstructed rest (UIR, baseline) followed by 5 min active, instructed rest with visual EMG feedback (FB). FB data were not included in the statistical analysis because we believe that UIR probably is a more realistic “real-life” baseline. The cognitive task was then performed for 1 h (800–1,500 trials), followed by 30 min recording during rest (recovery period). The subjects were asked to relax while seated and to move as little as possible during the recovery period. After the baseline and FB periods, at 10-min intervals during the cognitive task, and at 10-min intervals during the recovery period, the subjects were asked to mark on a 100 mm visual analogue scale (VAS) their level of pain with endpoints “no pain” and “worst imaginable pain”. Pain was reported bilaterally in the trapezius, splenius, temporalis and frontalis areas. No patient had to be excluded because of headache attacks during the test. Venous blood was sampled before the test (immediately after the interview was concluded) and immediately after the stress period (after 60 min). Blood sample data will not be reported in this paper.

Some subjects had partly missing data due to technical difficulties: two controls, two migraine patients and four SNP patients had corrupted BP and HR data during the test and recovery period, and one patient with TTH had corrupted BP, HR, BF and pain data during the recovery period.

Mean values for systolic blood pressure (SBP), diastolic blood pressure (DBP), HR and finger BF were calculated for the UIR period, and for each 10-min interval throughout the stressful task and recovery period. The pain variable used was defined as the maximal pain reported at the eight muscle locations (trapezius, splenius, temporalis and frontalis muscles; left and right side) at each 10-min interval. These data were used in statistical ANOVA models.

Baseline values were compared among the groups with Student’s two-group t test. Repeated measures ANOVA time × group interaction was used to explore differences in response and recovery patterns between groups. It was the potential differences in response and recovery patterns to the stressor, which was of interest in the present study, and not differences in absolute levels, hence we report time × group interaction, F and P values. Three different models with selected dependent variables were applied to explore different parts of the stress response and recovery profile. To examine how the novelty of the stressor influenced the subjects, the first 10 min and the baseline were compared in an F₂-model [SBP, DBP, HR and BF: y = (baseline (UIR), 0–10 min); pain: y = (0, 10 min)]. This was described as the early (acute) stress response. After the first 10 min, it was assumed that the novelty aspect of the stressor was gone, and we examined how the subjects adapted to the stressor with an F₆ model with six repeated dependent variables [SBP, DBP, HR and BF: y = (0–10, 10–20, 20–30, 30–40, 40–50, 50–60 min); pain: y = (10, 20, 30, 40, 50, 60 min)] to examine how the subjects adapted to the stressor. This was described as the adaptation response to stress. An F₃-model with three dependent variables [y = (65–75, 75–85, 85–95 min)] was used to examine how the subjects recovered from the stressor. For pain, recovery was evaluated with an F₄-model with four dependent variables [y = (65, 75, 85, 95 min). An F₄-model instead of an F₃-model was necessary for the pain variable to cover the same time frame as the physiological variables, since pain was measured every 10 min and not as an average of continuously measured 10-min intervals. The ANOVA models were corrected for non-sphericity by reduced degrees of freedom with Huyhn–Feldts method. In the present study, we report differences in migraine and TTH patients compared to FMS and SNP patients. Differences in TTH patients compared to migraine patients and healthy controls, and differences in FMS patients compared to SNP patients and healthy controls have been reported in previous papers [16, 17, 32‐34].

As FMS and SNP and, to some extent, TTH are associated with chronic pains, and based on observations made in earlier studies, it was of interest to compare subjects with chronic pain (12 chronic TTH, FMS and SNP patients) against subjects with episodic or no pain (controls, migraine and six episodic TTH patients). The basis for this grouping was that the episodic pain patients are pain-free most of the time. It was also of interest to investigate whether headache patients as a group were different from patients with musculoskeletal pains. Therefore, F₂, F₆ and F₃/F₄ analyses were performed both on chronic pain patients versus non-chronic/healthy subjects, and on headache patients versus musculoskeletal pain patients.

As our general statistical strategy involves a large number of comparisons, some might argue that there is a need for a multiple-comparison adjustment to control for type I errors. We chose not to do this, as this would create other problems, such as an increase in type II errors [41, 42]. Also, as the study was considered to be mainly hypothesis-generating and not so much hypothesis-controlling, we believe that findings worthy of further research might be missed by applying too rigid criteria to the statistical analyses. A two-tailed significance level of <0.05 was considered significant in the statistical analyses. P values within a range of 0.05–0.10 were defined as trends.