Pain, Allodynia, and Serum Serotonin Level in Orofacial Pain of Muscular Origin
Malin Ernbarg, DDS Aims: This study was conducted to int^estigate the serum level of Graduate Student serotonin (S-S-HT) in patients with temporomandibuiar disorders Department of Clinical Oral Physiology (TMD) of muscular origin, ie. localized myalgia, and to compare it to that found in healthy individuals and patients with fibromyal- Britt Hedenberg-Magnusson, DDS gia- A second aim was to investigate the association between S-S- Graduate Student HT and pam parameters. Methods: Twenty patients with localized Department of Clinical Oral Physiology myalgia participated in the study. Twenty age- and gender- matched healthy individuals and twenty patients with fibromyal- Per Alstergren, DDS gia served as controls. The participants were examined clinically Graduate Student Department of Clinical Oral Physiology as to the condition ofthe temporomandibuiar region and S-S-HT. Results: The levels of S-5-HT did not differ significantly between Thomas Lundeberg, MD, PhD the groups. However, in patients with localized myalgia there was Associate Professor a negative correlation between S-5-HT and tenderness of the tem- Department of Piiysiology and poromandibuiar muscles. Conclusion: The results of this study Pharmacology indicate that allodynia of orofacial muscles in patients with TMD is significantly related to S-5-HT concentration- Sigvard Kopp, DDS, PhD i OROFAC PAIN \999;U--S6-62. Professor Department of Clinical Oral Physiology Keywords: fibromyalgia, allodynia, local myalgia, serotonin, Karolinska Institutet temporomandibuiar disorders Stockholm, Sweden
Correspondence to: Dr Malin Ernberg Department of Clinical Oral Physiology School of Dentistry Box 4064, S-141 04Huddinge, Sweden E-mail: [email protected]
ain in the orofacial muscles is a common reason for patients to seek treatment at pain clinics. Many of these patients suf- Pfer from temporomandibuiar disorders (TMD), while some patients witb orofacial muscle pain suffer from fibromyalgia. Temporomandibuiar disorders of muscular origin are character- ized by localized myalgia and tenderness to palpation, with or without referral of pain to other regions,'-^ The etiology and pathophysiology is unclear, but it has for a long time been assumed to develop after overloading of muscles because of, eg, nocturnal bruxism and ensuing muscle ischemia.^''' Sleep distur- bance, depression, and headache are commonly associated with chronic localized myalgia.''^ Fibromyalgia is characterized by gen- eralized muscle pain and tenderness, muscle stiffness, and fatigue.^ Sleep disturbances, headache, and depression are also frequent symptoms in fibromyalgia. For research purposes, the criteria of the American College of Rheumatology for classifying fibromyal- gia are the most often used.^ These criteria include widespread pain for more than 3 months and tenderness to palpation on at least 11 of 18 specific bilateral points.
56 Volume 13, Number 1, 1999 Ernberg et al
Table 1 Age, Gender, and Duration of Local and General Symptoms in Study Participants
Patients with Patiencs with Healthy localized myalgia fibromyalgia individuals Age (y) tmean ± SEM) 46 ±4 Gender (maie/femaie) 4/16 0/20 Duration of locai symptoms (y) 7± 1 Cmsan ± SEM) duration of general symptoms Cy) — (mean ± SEM)
There is evidence that serotonin (5-HT) is individuals with regional musculoskeletal pain involved in the pathophysiology of chronic myal- and pain-free individuals. gia. Moldofsky and "Warsh^ reported an inverse To the knowledge of the authors, there are no association between plasma tryptophan (a precur- studies of the level of S-5-HT in patients with sor to 5-HT) levels and the level of pain reported TMD of muscular origin. The first aim of this by patients with fibromyalgia. Yunus et al'" found study was therefore to investigate the level of a reduced level of plasma tryptophan and a S-5-HT m patients with chronic locali/,ed myalgia decreased transport ratio of tryptophan across the of the temporomandibuiar region and to compare hlood-brain barrier in fibromyalgia. Russell et al' ' it to that found in healthy individuals and patients found that 5-hydroxyindoleacetic acid, tbe with fibromyalgia. Tbe second aim was to investi- metabolite of 5-HT, was decreased in tbe cere- gate tbe association between the level of S-5-HT brospinal fluid of patients with fibromyalgia. and pain parameters. Furthermore, the serum level of 5-HT (S-5-HT) has been reported to be lower in patients witb fibromyalgia than in healthy control patients.^^ Materials and Methods Recently, Wolfe et aF investigated the level of S-5- HT in a population survey. In agreement with pre- Subjects vious studies, they found a lower level of S-5-HT in patients with fibromyalgia compared to pain- Twenty consecutive patients with localized myal- free individuals. They also found a positive corre- gia (four men and sixteen women) and 20 consec- lation hetween the level of S-5-IIT and tender utive patients with fibromyalgia (all women) who point count as well as depression score, which had been referred to the department of Clinical contradicts previous findings.^'^^'^- This also con- Oral Physiology because of orofacial pain of mus- tradicts reports that 5-HT re-uptake inhibitors cular origin participated in the study (Table 1). have been effective in alleviating pain and tender- The authors intended to match the patients with ness in some patients with fibromyalgia and that fibromyalgia to the patients with localized myalgia they can have a positive effect on the patient's regarding age and gender but were unable to find well-being.^'" While the role of blood 5-HT in any men with fihromyalgia. The patients were first fibromyalgia and tension-type headache^'' as well given a brief clinical examination to determine as in rheumatoid arthritis'-''-^ has been investi- whether they fulfilled the inclusion criteria. These gated frequently, its role in TMD of muscular ori- were pain from the temporomandibuiar region for gin remains unknown. Only a few studies seem to at ieast 3 months and tenderness of the orofacial have addressed this subject. Among them, the muscles to digital palpation. For the patients study of Sharav et al,'^ which investigated the inciuded in the fibromyalgia group, fibromyalgia effect of amitriptyline hydrochloride on chronic was diagnosed according to the criteria of the facial pain of musculoskeletal origin, found that American College of Rheumatology,^ Exclusion the drug was more effective than a placebo in criteria were general inflammatory connective tis- reducing pain, and that it did so independently of sue disease (eg, rheumatoid arthritis) or symptoms its antidepressant action. Wolfe et aF could not that could be related to disease in other orofacial detect any difference in S-5-HT between areas (eg, temporomandibuiar joints, toothache,
Joumal of Orofacial Pain 57 Ernberg et al neuralgia). Four of the patients with fibromyalgia defined as the level of pressure at which the patient were taking antidepressants; one was taking reported that the pain became intolerable. The citalopram, one was taking clomipramine, and sum of the PPT and PPTL values from tbe right two were taking amitriptyline hydrochloride, and left side was calculated for each patient and A group of 20 healthy individuals who partici- referred to as PPT^„^ and PPTL^„^, pated on a voluntary basis were also included in Blood Examination. A sample of 28 mL of the study. They were age- and gender-matched to venous blood was collected from each patient. The the patients with localized myalgia and had no erythrocyte sedimentation rate, C-reactive protein, pain in the temporomandibular region. hemoglobin, rheumatoid factor, and antinuclear The method? and selection of patients were antibodies were analyzed. This was done partly to approved by the local ethical committee at Hud- detect any undiscovered systemic connective tissue dinge Hospital, Karolinska Institutet, Stockholm disease. The thrombocyte particle concentration (151/93). All individuals gave their verbal consent. was also analyzed, since platelets are the main source of 5-HT in blood serum and therefore Methods could be expected to influence the level of S-5-HT, Another sample of 2 mL was collected from each Assessment of Fain. A 10-cm visual analogue scale participant for analysis of the level of S-5-HT, This (VAS) with endpoiots marked by "no pain" and blood sample was left at room temperature for 1 "worst pain ever experienced" was used to assess hour to coagulate and then was cold centrifuged the greatest degree of pain from the orofacial (4°C, 1700 G) for 30 minutes. Approximately 200 region experienced during the last week. The |iL of the supernatant was then pipetted into a patients with fibromyalgia were asked to assess polystyrene tube and kept frozen at -22°C until their general pain on a VAS in a similar way and analysis. To exclude any risk of interference with vi'ere interrogated about pain experienced in cer- the analysis of 5-HT, patients were asked to avoid tain musculoskeletal body regions. These regions tryptophan-rich food (eg, banana, pineapple, were: neck, arm, elbow, buttocks, knee, and ankle. tomato, and chocolate) for 24 hours before the The sum of affirmative answers (maximum of 6) examination. Because of the diurnal variation of S- was referred to as the number of pamful body 5-HT,'^ all blood samples were collected in the regions. morning. Clinical Examination. Routine methods of clini- Biochemical Anaiysis. The level of S-5-HT was cal examination of the temporomandibular system analyzed by a commercially available competitive were used.'" The degree of tenderness to digital enzyme immunoassay kit (No. 0642, Immunotech palpation was assessed over the superficial mas- Internationai), Tbe kit bas a sensitivity of 0.09 seter, anterior temporal, temporal tendon mser- ng/mL and is applicable at concentrations between tion, lateral pterygoid, media! pterygoid, and 0,28 and 35.2 ng/mL, According to the manufac- trapezius, A 4-gradc scale, modified after Russell turer, the intraassay coefficient of variation varies e[ al'^ was used (0 = no tenderness, 1 = mild ten- between 7.9% and 9,4%, and the interassay coeffi- derness, 2 = moderate tenderness with a pain cient of variation varies between 6.2% and 9.9%. reflex, and 3 = marked tenderness with a defensive withdrawal reflex). The sum of tenderness grades, Statistics with a maximum of 36, was calculated for each patient and is referred to as the tendet point mdex Tbe Kolmogorov-Smirnov test for continuous vari- (fpij.is -pj^g pressure pain threshold (PPT) and ables was used to test tbe normality of tbe vari- pressure pain tolerance level (PPTL) were assessed ables. One-way analysis of variance (ANOVA) (kPa) with an algometer (Pain Diagnostics and with the Tukey test for pairwise multiple compari- Thermography) over the most tender point on the son as an ad hoc test was used to test the signifi- 2 superficial masseter muscles. These muscles were cance of the differences between groups regarding chosen since they are easily examined and are normally distributed variables. One-way ANOVA often tender upon digital palpation in patients on ranks with Dunn's method for pairwise multi- with TMD. The algometer had a blunt rubber ple comparison as an ad hoc test or the Mann- recording tip 10 mm in diameter. The pressure rate Whitney U test was used to test the significance of used was approximately 50 kPa/s, The PPT was differences between groups regarding nonnormally defined as the level of pressure at which the patient distributed variables or variables on an ordinal reported that the sensation of pressure changed to scale, Pearson's product-moment correlation pain. At a subsequent recording tbe PPTL was analysis was used to test tbe relationship between
58 Volume 13, Number 1, 1999 Ernberg et al
S-5-HT and clinical variables except for data on an ordinal scale (VAS and TPl], which were tested 200- with Spearman's ranked correlation test. All tests were 2-tailed and the significance level was set at P<0.05. Î Results 150- 4
S-5-H T ( 11 Serum Level of 5-HT 11
The levels of S-5-HT are shown in Fig 1. In the group with localized myalgia the S-5-HT ranged between 14 and 299 ng/mL, in the group with 100- fihromyalgia it ranged hetween 6 and 306 ng/mL, LM FM HI and in the group of healthy individuals it ranged hetween IS and 33S ng/mL. There was no signifi- cant difference in S-5-HT level between the Fig 1 Plot shows the tnean serum level (ng/mL, ± SEM) groups. When the 4 fibromyalgia patients who of serotonin (S-5-HT) in patients with localized myalgia were under medication with antidepressant drugs and fibromyaigia of the temporomandibular region and were excluded, still no significant difference was in healthy individuals. There were 20 subjects in each found between groups. group. The mean S-5-HT (± SEM) was 137 ± 17 ng/mL in the patients with localized tnyalgia, 131 ± 17 ng/mL in the patients with fibromyalgia, and 149 ± 20 ng/mL Assessment of Pain in the healthy individuals, LM - patients with localized myalgia; EM = patients with fibromyalgia; Hi - healthy The VAS score in the group with localized myalgia individuals. ¡median and interquartile range] was 6 ± 2; in the group with fibromyalgia it was 5 + 3. The differ- ence between these patient groups was significant (P < 0,05, Mann-Whitney U test). The general VAS in the group with fibromyalgia was 6 ± 4, Blood Variables and the number of painful body regions was 5*1. Two patients with localized myalgia had slightly Assessment of Tenderness increased erythrocyte sedimentation rates (47 and 40 mm/h, respectively). One of the patients was a The assessments of muscle tenderness are shown in 72-year-old female with a present inflammation of Table 2. The TPl was similar in both patient the urinary tract; the other was a 56-year-old male groups and lower than in the group with healthy who had had otitis. It is unlikely that their symp- individuals. The difference between groups was toms from temporomandibular muscles were a significant (P < 0.001). Multiple comparison result of these infections, since the pain was pre- according to Dunn's test sbowed that both patient sent before the onset of the infections. Further- groups differed from the healthy individuals more, their symptoms did not increase during (P < 0,05) but there was no difference between the infection and persisted after they were cured. A patient groups. 45-year-old female patient with localized myalgia Both PPT and PPTL were lower in the patient tested positive for antinuclear antibodies (ANA) groups than in the healthy individuals, with the but had no rheumatic disease. The thrombocyte lowest values found in the patients with fibromyal- particle concentration was within tbe normal gia. The 3 groups differed regarding range for all patients in both patient groups and (P < 0,001), but not as regards PPT^^n,- showed no correlation to S-5-HT. comparison according to Tukey showed that there were significant differences between all 3 groups Correlations 005) Several significant correlations were found. In the group with localized myalgia tbere was a negative correlation between S-5-HT and TPl (r = -0 57
Journal of Orofacial Pair 59 Ernberg et si
Table 2 Clinical Characteristics of Study Participants Patients with Patients with Healthy localized myalgia fibromyalgia individuals
TPi 10-36) (median ± \QP) 12 ± 8 13±7 2±3 PPTj^^ ii
Fig 2 Scatter plot shows the correlation between the Fig .Î Scatter plot shows the correlation between the serum level (ng/mL) of serotonin (S-5-HT) and the ten- 5erum level (ng/mL) of serotonin (S-5-HT) and the num- der point index (TPI) of temporomandibuiar muscles in her of painful hody regions in patients with fihromyal- patients witb localized myalgia of the temporomandibu- gia of the temporomandibuiar region (r = -0.55, n = 16, iar region (j- =-0.57, n = 20, P< 0.01). P<0.05).
n = 20, P < 0.01; Fig 2). In the group with was a significant correlation between low fibromyalgia there was a negative correlation S-5-HT and high TPI of temporomandihular mus- between S-5-HT and the number of painful muscu- cles, which indicates that S-5-HT has a consider- ioskeletal body regions ir = -0.55, n = 16, P < 0,05; able influence on tenderness to digital palpation or Fig 3) and a positive correlation between S-5-HT local allodynia in this patient group. This remark- {r = 0.49, n = 19, P < 0.05; Fig 4). able finding indicates that central mechanisms are involved in the modulation of allodynia in chronic TMD of muscular origin. It also supports the the- Discussion ory that pathologic alterations of the antinocicep- rive system may lead to allodyniar" Furthermore, The main result of our study is the finding of an the finding may explain why some patients with association between low S-5-HT level and local localized myalgia report improvement in their con- allodynia of temporomandibuiar muscles in dition when using serotonin reuptake inhibitors.^^ patients with chronic TMD of muscular origin. To This result, however, contradicts the finding'-' of our knowledge, this has not been reported previ- an association between high S-5-HT and allodynia ously. In the patients with localized myalgia there of the temporomandibuiar joint in patients with
60 Volume 13, Number 1, 1999 Ernberg et al seropositive rheumatoid arthritis. Tbe reason for this difference is unclear, hut might be due to the 700-1 pathophysiologic differences between these 2 patient categories as well as between ¡oints and 600- muscles. 500. In tbe patients with fihromyalgia, significant CL • 400- correlations were found between low S-5-HT and E a high number of painful musculoskeletal body 300- regions, and between low S-J-HT and low PPTL. •_ These findings concur with the previous studies by CL 200- Moldofsky and Warsh,'' Russell et al," and Stratz 100- et al,'' but contradict the study by Wolfe et aP regarding tenderness. It Is difficult to explain these 0- conflicting results. Flowever, the study by Wolfe et 0 100 200 300 al' was performed in an epidemiologic population survey, while our study was performed on patients S-5-HT (ng/mL) attending treatment. Thete is reason to believe that the intensity and character of pain differs between Fig 4 Scatter plot sbows the correlation between the these populations. serum level (ng/mL) of serotonin (S-5-HT) and the pres- Our study showed no significant difference in S- sure pain tolerance level (PPTL^,,_,,; in kPa) in patients 5-HT between the groups. In all 3 groups the vari- with fibromyalgia of the temporomandibuiar region [r = ation in S-5-HT was large, and we found localized 0.49, n= 19, P< 0.05). myalgia and fihromyalgia patients with high S-S- HT levels and healthy individuals with low S-5- HT. Regarding localized myalgia, our results in this particular aspect agree with those of Wolfe et al,' who found no difference m S-5-HT between could be tbat there is an increased binding of 5-HT patients witb regional chronic musculoskeletal to receptors for pain and allodynia/hyperalgesia in pain and pain-free individuals in a population sur- patients with chronic myalgia and tbat this condi- vey. On tbe other hand, our results disagree witb tion is associated witb low S-5-HT. many reports of a reduced blood serotonin level in It was our intention to match tbe healthy indi- patients with fibromyalgia.^''''"'- The levels of S-5- viduals and tbe patients witb fibromyalgia to the HT in our study are also similar to those found by patients witb localized myalgia regarding both age Alstergren et aP^ in a group of patients with and gender, but we were unable to find any men rheumatoid artbritis. with fibromyaigia. There was, however, no Since low S-5-HT may he a result of fewer significant difference in age and duration of local platelets per volume of blood, we also measured the symptoms between the 2 patient groups. We con- tbrombocyte particle concentration in the patients. sider the difference in local pain (VAS) between In both patient groups the values were within tbe the patient groups to be clinically insignificant and normal range, and no correlation to the S-5-HT was we therefore consider the groups comparable, found. Consequently, it is unUkely that this factor Tbe PPT and PPTL of the masseter muscles viJcre influenced our results or that the thrombocyte parti- lower in the patients witb fibromyalgia than in the cle concentration influences S-5-HT. Four patients patients with localized myalgia. Even tbougb the with fibromyalgia were taking antidepressant medi- difference regarding the PPT was only close to sta- cation. Therefore, we also investigated whether a tistical significance, the finding is in agreement significant difference in S-5-HT between groups with previous studies/'-''^^ Tbese findings may could be found when these patients were excluded. reflect an increased sensitivity to mechanical stim- However, no significant difference was found. uli In general in patients with fibromyalgia, as has It is puzzling that we found no difference in been suggested previously.^'^^ S-5-HT between groups but at the same time The results of this study indicate that allodynia found significant correlations in the patient groups of orofacial muscles in chronic TMD is signifi- between allodynia/hyperalgesia of the temporo- cantly related to S-5-HT concentration. mandibuiar muscles and low S-5-HT. The patients with the lowest S-5-HT thus showed the greatest degree of muscle tenderness. One explanation
Journal of Orofacial Pain 61 Emberg et al
Acknowledgments 10. Yunus MB, Dailey JW, Aldag JC, Masi AT, Jobe PC. Plasma tryptophan and other a mino acids in primary fibromyalgia: A controlled study. J Rheumatol 1992il9:90-94. We wish to thank Kan Eriksson, Maria Kvarnströtn, and 11. Rubsell IJ, Vacroy H, Javors M, Nyberg F, Cerebrospinal Guiiilla Hoverbrandt for their skillful laboratory work and fluid biogeiiic amine metabolites in fibromyalgia/fibrositis Ebba Lagerkrans and Karin Ringstróm for general assistance syndrome and rheumatoid arthritis. Arthritis Rheum atid blood sampling. ¡992;35:5S0-5S6. Thib study was supported by grants from Faculty of 12. Stratz T, Samborski W, Hrycaj P, Pap T, Mackiewicz S, Odontology at Karolinska Instirutet, the Swedish Dental Mennet P, Müller W. Die serotoninkonzentration im Society, the Swedish Medical Research CoLincil (B94-24X- serum bei patienten mit generalisierter tendomyopathie 10416-02B), and Signe and Reiiibold Sund Foundalion. ¡fibtomyalgie) und chronischer polyarthritis. Med Klin
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