Okifuji, Akiko PhD; Turk, Dennis C. PhD; Marcus, Dawn A MD
ACR = American College of Rheumatology, FMS =fibromyalgia syndrome, FMSHA = fibromyalgia with chronicheadaches, FMSONLY = fibromyalgia without chronic headaches, HAONLY = headache with <11 painful tender points, HATP =headache with ≥11 painful tender points, IHS = InternationalHeadache Society, MPI = Multidimensional Pain Inventory, TP =tender point.
Definitive pathophysiologic mechanisms of recurrent headache are unknown in the majority of cases (1, 2). There has been a growing interest in determining the role of abnormality in pain modulation at the peripheral and central levels in the pathophysiology of primary headaches (3, 4). Traditionally, it has been assumed that localized hyperalgesia is particularly important for tension-type headaches. In this view, the mechanism underlying tension-type headaches reflects abnormally elevated levels of muscle tension associated with excessive contraction. It is further postulated that hyperreactivity to emotional stressors results in hypertonia in the pericranial and cervical areas, producing localized hyperalgesia (5). Research evaluating algesic responses in the headache-related regions has generally demonstrated elevated tenderness or pain sensitivity to digital palpation in individuals with recurrent headaches, particularly chronic tension-type headaches, compared with headache-free individuals (4, 6–8).
Recent evidence indicates that hypertonia in cervical and pericranial muscles may be neither specific nor necessary for tension-type headaches (9–13). Moreover, patients with migraine headache commonly exhibit increased tenderness in the cervical area (12, 14). Patients with migraine headaches and those with tension headaches do not exhibit significantly different pressure pain thresholds in the pericranial regions (15). Furthermore, migraineurs are as likely as patients with tension-type headaches to have myofascial trigger points in the cervical or pericranial regions (16). These results suggest that myofascial hyperalgesia needs to be examined not only in tension-type headaches but also other types of recurrent headache disorders.
In addition to the localized, proximal hyperalgesia, patients suffering from recurrent headaches may exhibit more generalized defects in pain modulation. Several studies have shown that headache patients, relative to healthy individuals, exhibit lower thresholds in distal areas for myofascial and visceral nociceptin (6, 17, 18). Accumulated evidence pointing to a serotonin abnormality in headache patients (19) also suggests that generalized abnormality in pain modulation may be involved in the pathophysiology of chronic headache.
Centrally modulated pain dysfunction has also been implicated in other pain syndromes, such as FMS (20, 21). FMS is a generalized musculoskeletal pain disorder with a range of comorbid symptoms including recurrent headaches. In general, the pain thresholds of FMS patients have been shown to be reduced (22, 23). Up to 91% of FMS patients may have a positive history of primary headache (24), and approximately 30% report a concurrent headache disorder (21). Nicolodi and Sicuteri (25) proposed that a serotonergic abnormality may underlie both headache and FMS.
The diagnostic criteria of FMS incorporate the clinical feature of widespread or generalized hyperalgesia. The ACR (21) has proposed two diagnostic criteria for FMS: 1) presence of widespread pain of at least 3 months’ duration and 2) diffuse pain hypersensitivity to digital palpation, defined as reported pain at 11 or more of 18 designated locations or TPs (ie, generalized hyperalgesia). TPs are located at specific sites (eg, greater trochanter, gluteal, occiput, and trapezius). Digital palpation of these points can yield pressure pain sensitivity across multiple body regions, permitting examination of regional as well as generalized hyperalgesia. The interrater reliability of digital TP examination has been demonstrated in several studies (26, 27).
In a previous study, when the TP examination was applied to patients with recurrent headache and those with FMS, the patients with FMS consistently reported greater numbers of positive TPs and greater pain sensitivity even in the trapezius and occipital sites (28). Nevertheless, a substantial number of headache patients did meet the ACR TP criterion for FMS, suggesting the presence of large variability in generalized pain hypersensitivity within the headache population. Because FMS patients are, by definition, positive for hypersensitivity to pressure pain in diffuse bodily areas, they should serve as an adequate comparison group for investigating the presence and extent of generalized hyperalgesia in patients with headaches.
We hypothesized that there are at least two subgroups of headache patients, those for whom there is generalized hyperalgesia and those who have more localized pain hypersensitivity specific to the pericranial and cervical areas. Furthermore, given the lack of diagnostic specificity in localized hyperalgesia (9–13), the distinction based on pain hypersensitivity may be independent of the traditional classification of migraine and tension-type headaches.
The primary purpose of the study described here was to investigate the distinctive factors associated with generalized and regional hyperalgesia in chronic headache sufferers. Specifically, comparisons will be made among four groups of individuals with chronic pain disorders: 1) headache patients who meet the FMS TP criterion (ie, diffuse pain hypersensitivity), 2) headache patients who do not meet the FMS TP criterion, 3) FMS patients with chronic headaches, and 4) FMS patients without primary headaches.
We hypothesized that localized hyperalgesia in the cervical and pericranial regions would be associated with headache disorder. Furthermore, we predicted that FMS patients overall would exhibit a greater degree of generalized hyperalgesia than headache patients. Finally, we expected large variability among individuals in the degree of generalized hyperalgesia within the headache sample. We further expected that there would be a subset of headache patients who would exhibit generalized hyperalgesia in a manner similar to that of FMS patients. This article also includes a description of a preliminary test of the impact of generalized compared with regional hyperalgesia on adaptation among headache patients.
The study included 70 patients with recurrent headaches and 66 patients with FMS who were referred to a university-based pain treatment facility with programs specifically designed to evaluate and treat patients with FMS and chronic headaches. Headache diagnoses were determined by a board-certified neurologist (D.A.M.) using the IHS classification system (29). Headache diagnoses included migraine (63%), tension-type (8%), combined migraine and tension-type (11%), and others (18%). None of the headache patients reported widespread pain of at least 3 months’ duration, one of the two criteria required for the diagnosis of FMS. All FMS patients were diagnosed on the basis of the ACR classification criteria (21). Twenty-three of the 66 FMS patients (35%) reported migraine or tension-type headaches. The mean age of the total sample was 42.17 years (SD = 12.91 years). Mean age for the headache and FMS samples was 36.54 years (SD = 11.31 years) and 48.14 years (SD = 11.85 years), respectively. The majority of patients were female (93%) and married (52%) with at least a high school education (94%).
All patients underwent a standardized TP assessment (28) as a part of the comprehensive medical examination. Using this protocol, a physician palpated 18 (9 bilateral) TPs and three control points in a predetermined order using the thumb of the dominant hand with 4 kg of force (Table 1). Control sites are routinely included in pressure pain sensitivity studies to provide a basis for comparing sensitivity to TP palpation (21, 30). Many FMS patients report some pain in control points when palpated, although their pain sensitivity is significantly lower at these sites than at TP sites (28, 31). After each palpation, patients indicated whether the palpation was painful and the severity of pain on an 11-point scale (0 = no pain, 10 = worst pain). Patients reporting at least 11 TPs as painful were classified as meeting the ACR TP criterion (ie, generalized hyperalgesia).
To address the question of generalized vs. local hyperalgesia, the ACR TPs were subgrouped. Six of the TPs in the cervical areas were aggregated to create a score for regional hyperalgesia, and four TPs in the lumbar areas were aggregated to create an index of distal locations (distal site). In addition, a middle forehead control point (pericranial control site) and two distal control sites (forearm and thumb) were included (Table 2).
After the TP examination, each patient completed the MPI (32), which is used to assess pain severity and psychosocial adaptation by patients to their pain conditions. The MPI has been used widely with headache as well as FMS patients and is reported to have good psychometric properties (33–35). In this study, five scales of the MPI were selected to measure pain adaptation: pain severity, interference, life control, affective distress, and general activity.
Forty percent (28 of 70) of the headache patients rated at least 11 of the 18 TPs as painful, meeting the ACR TP criterion for FMS (generalized hyperalgesia). As noted above, 35% of the FMS patients reported recurrent migraine or tension-type headaches. Thus, there were 28 headache patients meeting the TP criterion (HATP), 42 headache patients who did not meet the TP criterion (HAONLY), 23 FMS patients with chronic headaches (FMSHA), and 43 FMS patients without chronic headaches (FMSONLY).
Group comparisons of demographic variables identified a significant difference in age (F (3,132) = 14.04, p< .001). Post hoc analysis using the Scheffe method further revealed that the patients in the FMSONLY group were significantly older than patients in the other three groups. Age has been reported to be positively related to the number of painful TPs (36). In our sample, age was significantly related to positive TP counts (r= 0.27, p< .01) and average TP pain intensity (r= 0.22, p< .05); thus, it was used as a covariate in subsequent analyses.
The average pain duration was 10.5 years for the total sample (Table 3), and the duration was not significantly different across groups (p= .62). As shown in Table 3, there were no significant group differences in any of the demographic variables (ie, educational levels, employment, and marital status) other than age.
To determine whether specific headache diagnoses were related to generalized hyperalgesia, a χ2 test was used to compare the proportions of patients with migraine, tension-type, combined, and other types of headaches in the HATP and HAONLY groups. The proportions were 69%, 8%, 8%, and 15% in the HATP group and 52%, 8%, 16%, and 24% in the HAONLY group for migraine, tension-type, combined, and other headaches, respectively. The result of the χ2 analysis was not statistically significant (χ2(3) = 2.29).
Mean numbers of positive TPs, adjusted for age, were 14.20 (SE = 0.59) for the HATP group, 4.59 (SE = 0.49) for the HAONLY group, 16.92 (SE = 0.63) for the FMSHA group, and 15.18 (SE = 0.50) for the FMSONLY group. The difference was statistically significant (F (3,132) = 124.92, p< .001). As expected, the post hoc Scheffe analysis revealed that the patients in the HAONLY group exhibited significantly fewer positive TPs compared with the patients in the other three groups (p< .05). There were no other significant group differences. Thus, the TP count reported by the HATP group did not differ from that reported by either of the FMS patients.
The proportions of patients in each of the four patient groups who rated palpation as painful for the cervical TP sites, distal TP sites, and control pericranial and distal sites are described in Figures 1 to 3, respectively. Again, using χ2 analyses, we found significant group differences for all sites (p< .001). Overall, patients in the HATP group were remarkably similar to the two FMS groups in their pain sensitivity at the cervical and all distal locations. At the pericranial control point (middle forehead), however, a large number of patients in the HATP and FMSHA groups reported pain on palpation (61% and 44%, respectively), whereas only 15% of the HAONLY group and 12% of the FMSONLY group had pain at the middle forehead point. There were no significant differences between the HATP and FMSHA groups or between the HAONLY and FMSONLY groups.
Palpation Pain Sensitivity Scores
Table 4 contains the adjusted mean pain sensitivity score for each site for the four patient groups. Multivariate analyses of covariance using age as the covariate were performed on the two sets of TP sites (cervical and distal) and two control sites (pericranial and distal). The first analysis revealed a significant patient group effect (F (3,131) = 42.65, p< .001) but no location or location–by–patient group interaction (F (1,132) = 0.23 and F (3,132) = 1.10, respectively). For the control sites, in addition to the significant patient group effect (F (3,130) = 6.46, p< .001), a significant location effect (F (1,3) = 4.03, p< .05) as well as a significant interaction (F (3,131) = 13.24, p< .001) were obtained.
Post hoc analyses, using the Scheffe method, revealed that no statistical difference in pain sensitivity was found between the HATP and the two FMS groups in the cervical and distal TP sites. However, their algesic responses were significantly greater than those of the HAONLY patients (p< .05). For the pericranial control site, patients in the HATP and FMSHA groups reported significantly greater pressure pain sensitivity than patients in the other two groups (p< .05). FMS patients in general reported greater hyperalgesia than headache patients at the distal control sites (p< .05).
Two simple effect comparisons were conducted to test within-group differences in hyperalgesia to digital palpation between TP sites and control point sites and between pericranial and distal control sites. The first analysis revealed that all groups rated TP sites as significantly more painful than control sites (F (1,131) = 70.54, 9.43, 145.17, and 196.56 for the HATP, HAONLY, FMSHA, and FMONLY groups, respectively; for all, p< .005). However, differences in pain severity at the two control sites varied across the groups. Patients in the HATP group exhibited significantly greater hyperalgesia at the pericranial site than at the distal site (F (1,131) = 29.82, p< .001). The reverse was found in the FMSONLY group (F (1,131) = 8.33, p< .01). The other patients did not display differential pain sensitivity between the two control sites.
Pain Severity and Pain Adaptation
Table 5 presents the age-adjusted means on the MPI scales for each of the four patient groups. Significant group differences were obtained in pain severity (F (1,116) = 4.27, p< .007), interference (F (1,116) = 3.27, p< .02), affective distress (F (1,116) = 3.13, p< .03), and general activity (F (1,116) = 5.50, p< .001) but not in life control (F (1,116) = 0.66). Group contrasts revealed that the differences in the pain, interference, affective distress, and general activity scales were significant between FMS patients and headache patients. The FMS patients reported significantly greater pain, interference, and affective distress and lower levels of activity than the total headache group. There were no differences between the two headache groups or between the two FMS groups on any of the scale scores.
Relationship Between Palpation Pain Sensitivity and Self-Reported Pain Severity
To examine whether the relationship between pain and pain sensitivity varies as a function of group (ie, presence of generalized sensitivity for headache patients and presence of headaches in FMS patients), a series of regression analyses were performed. Pain sensitivity scores for each site were used as the dependent variables. Thus, for each of the four regions, a separate regression equation was estimated for each of the headache and FMS patients. Table 6 includes the results of these analyses. Given the number of analyses, we used Bonferroni’s correction to set p< .002 as the criterion for establishing statistical significance.
By definition, patients in the HATP group and all FMS patients should exhibit elevated pain sensitivity in widespread areas. Thus, we expected to see significant group effects in headache patients but not FMS patients. Indeed, statistically significant group effects were observed only for headache patients in TP pain sensitivity. The presence of generalized hyperalgesia in the headache patients added 37% and 47% to the variance accounting for TP sensitivity in the cervical and distal TP regions, respectively. No group effects were observed in the FMS patients.
We were most interested in examining how the presence of generalized hyperalgesia affected the relationship between TP sensitivity (ie, provoked pain) and self-reported pain severity for pain conditions (ie, general level of pain). The significant incremental value of interaction was obtained only in the headache patients in TP sensitivity of the cervical regions. The interaction added 10% of the variance, totaling 65% of variance with MPI pain severity, the presence of generalized hyperalgesia, and the interaction between these two variables (F (1,51) = 30.76, p< .0001). Separate correlation analyses revealed that the association between MPI pain sensitivity and the TP cervical index was significant only for patients in the HATP group (r= 0.77, p< .001) but not for patients in the HAONLY group (r= 0.26). The differential relationships are graphically presented in Figure 4.
The results of the present study support the view that patients with recurrent headaches show wide variability in pain sensitivity to palpation of both local (ie, pericranial and cervical region) and distal sites (eg, lumbar). The results indicate that a substantial proportion of headache patients exhibit hypersensitivity to pain not just in the local area but also at distal sites. In this heterogeneous sample of headache patients, 40% exhibited generalized hyperalgesia, as defined by the ACR TP criterion for the classification of FMS (21). Interestingly, the elevated pain sensitivity was unrelated to the IHS headache diagnosis. The proportions of patients exhibiting generalized hyperalgesia did not differ across the different headache diagnoses. No other demographic or clinical variables were specific to these headache patients.
The results of this study are in agreement with those of Marlowe (18), who found greater pain sensitivity, regardless of IHS diagnosis, in headache patients than in healthy control subjects. Similarly, there were no differences between migraine patients and tension-type headache patients in the presence of generalized hyperalgesia or in the pain pressure rating at the proximal as well as distal sites. Thus, pressure pain hypersensitivity in the cervical and pericranial area is unlikely to be a marker of a specific type of headache. The results do not support the hypothesis that an abnormality in central mechanisms of pain modulation is prominent in all recurrent headache disorders. However, the majority of headache patients in our sample had a diagnosis of migraine and combined tension-type and migraine headaches. Our results should be considered preliminary and need to be replicated with larger samples of patients with migraine and tension-type headaches.
Research has consistently shown that patients with FMS report greater pain at both TP and control sites than healthy individuals and headache patients and that TPs are likely to be more painful than control points (28, 30, 37). The results of the present study are consistent with these findings. We found that, in general, most patients exhibited greater pressure pain sensitivity at the TPs than at the control sites. However, elevated pain sensitivity in the pericranial control site was found in the headache patients who met the ACR TP criterion, suggesting that pain sensitivity in the cervical and pericranial areas may be particularly important for a subgroup of headache patients. The possible involvement of dysregulated pain modulation in these patients needs to be investigated further.
The results of this study also reveal that generalized hyperalgesia is differentially associated with self-reported severity of pain across pain diagnoses. The relationship between pain sensitivity to digital palpation in the cervical area and self-reported pain severity was significant only for headache patients who exhibited generalized hyperalgesia. This is particularly notable because the two headache groups did not differ in self-reported pain severity. The presence of generalized pain hypersensitivity in headache patients seems to influence the interrelations between severity of usual levels of pain and pain sensitivity in response to palpation in the cervical area.
The significant associations between generalized hyperalgesia and poorer pain adaptation in headache patients also suggest that differential treatments may be appropriate for these patients. Although the exact mechanisms underlying generalized hyperalgesia are not known, research in TP sensitivity suggests that physical deconditioning may play a significant role in generalized hyperalgesia. Sedentary individuals report greater pain sensitivity to TP palpation than do physically active individuals (37). Fitness exercises seem to be more effective than tricyclic antidepressants (eg, amitriptyline) in reducing pain sensitivity of TPs in FMS patients (Okifuji A, Turk DC. Treatment of fibromyalgia syndrome, unpublished manuscript).
When they are prescribed, physical exercises for headache patients are usually limited to the cervical areas and consist primarily of stretching or postural correction. The results of studies evaluating the efficacy of physical exercises for headache patients have reported varying degrees of effectiveness (38–40). It is possible that general fitness programs aiming to improve overall physical conditioning may be particularly effective for headache patients exhibiting generalized hyperalgesia.
Additionally, recent studies examining factors associated with hyperalgesia have implicated several other factors, such as hyporeactive autonomic nervous system (41) and interactive effects of nociceptin and female hormones (42). Nicolodi et al. (24) have reported that FMS and migraine headaches are related to abnormally elevated production of nitric oxide associated with hyperactivity of N-methyl-D-aspartate receptors. Future examinations of these factors may provide a better understanding of the mechanisms underlying hyperalgesia in FMS and some headache patients.
There are several limitations of this study that should be acknowledged. First, we did not address whether elevated pressure pain sensitivity affects physical impairment. For example, cervical range of motion seems to be limited for some, but not all, patients with migraine or tension-type headaches (43, 44). From this study, we cannot determine whether hyperalgesia is related to such physical limitations. Given the profound impact of headache disorders on health care and disability (45), investigation of the relationship between pain modulation and specific physical limitations is desirable.
The standardized TP assessment was conducted as a part of the clinical examination; thus, the examiners could not be blind to patients’ medical diagnoses. Furthermore, no attempts were made to bring patients into the clinic at the time of a symptomatic headache episode. The large variability in TP counts and severity within headache patients suggests that the procedure did not restrict the score distributions. It should be noted, however, that these headache patients were referred because of the recalcitrance of their headaches. On average, they suffered from headaches for more than 10 years. The report of pain severity from the MPI in headache patients averaged around 3.27 on a scale of 0 to 6, suggesting the presence of at least modest pain. No headache patients reported an absence of pain (0 pain). Thus, it seems reasonable to assume that no patients were totally asymptomatic at the time of the evaluation. Another limitation may be that we did not report current use of medications. The patients’ reported levels of pain, however, suggest that better symptom management was indicated. Nevertheless, because of these limitations, our findings should be interpreted as preliminary. The results need to be confirmed in future studies in which the person performing the evaluation is blinded to the pain diagnoses. Furthermore, the patients’ headache status at the time of evaluation should be assessed because it may contribute to the presence of hyperalgesia.
In conclusion, the present study provides support for the role of widespread pain sensitivity in headache patient independent of IHS diagnosis. The heterogeneity of pain sensitivity within headache patients suggests that there may be at least two subtypes of chronic headaches: one with an underlying abnormality in central pain modulation and a second with more localized pain sensitivity. These group differences seem to be independent of headache type. The involvement of abnormal pain modulation, independent of the IHS diagnoses, suggests another factor for consideration in headache classification, presence or absence of generalized hyperalgesia. Moreover, the role of generalized hyperalgesia for a significant minority of headache patients suggests that conditioning exercises might be appropriate adjuncts to traditional interventions.
Preparation of this manuscript was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases Grants R55 AR44230 (A.O.) and R01 AR44724 (D.C.T.), and a grant from the Raymond and Elizabeth Bloch Educational and Charitable Foundation (D.A.M.).
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