Lymphocyte subsets in peripheral blood of patients with moderate-to-severe versus mild plaque psoriasis

In several studies peripheral blood T-cells have been quantified, yet few data are available on lymphocyte subsets in moderate-to-severe psoriasis (in terms of extent and activity of lesions) versus mild psoriasis. The objective is to compare lymphocyte subsets in peripheral blood of patients with moderate-to-severe disease (PASI-score ≥12) to patients with mild disease (PASI-score <12) and to healthy subjects. By means of flow cytometry method, lymphocytes in peripheral blood of 27 patients with psoriasis and 10 healthy controls were characterized. The absolute number of total lymphocytes was markedly decreased in patients with moderate-to-severe psoriasis as compared to patients with mild disease and normal subjects. Cellcounts of all analysed subsets were found to be increased in more severe psoriasis, except for CD8+CD45RO+ cells. The under-representation of CD8+CD45RO+ cells is compatible with the dynamics of acquired immunity, which requires a time log after the relapse of the lesions to differentiate from CD45RA+ naive cells.
Introduction
Psoriasis is a common inflammatory skin disease characterized by hyperproliferation of keratinocytes. It is a well established fact that T-cells play an important role in the pathogenesis of psoriasis [6, 9]. Indeed, treatments such as anti-CD4 [5, 15, 19], anti-CD11 [5, 13] and anti-CD25 [13], targeting at specific T-cells, have shown to be effective in psoriasis. Several T-cell subsets seem to play a primary role. Major classes are CD4+, CD8+, CD45RO+ and CD45RA+ T-cells. Recently, NK-T cells have been suggested to play an additional role in the regulation of immunity, through the release of cytokines [3, 14, 16]. NK-T cells are cells bearing both T cell receptors as well as natural killer-cell specific receptors such as CD161. It has been shown that circulating NK-T cells are significantly reduced in some autoimmune diseases [8, 17].
The large body of research on the role of T-cells in psoriasis has been focused on lesional T-cells. This has resulted in the hypothesis that there is a final common pathway responsible for the development of chronic plaque psoriasis, which may involve specific antigen recognition by T-cells that results in stimulation of keratinocyte proliferation. In psoriasis, CD4+ cells seem to be important mainly in the early phase of plaque development. These cells are found predominantly in the upper dermis, whereas CD8+ cells have proven to be relevant during chronic phases and are found predominantly in the epidermis [21], although others have found a more early involvement of CD8+ T-cells in the development of psoriatic plaques [22]. A large number of activated T-cells have been shown in clinically involved skin of psoriatic patients, but also uninvolved skin contains a significant number of T-cells. In healthy skin, however, T-cells can hardly be found. It has been suggested that circulating T-cells are activated and subsequently recruited from the circulation during the development of psoriatic plaques [2, 10].
Several studies have investigated peripheral blood T-cells of psoriatic patients [1–3, 7, 10, 12, 14, 20, 21]. These studies indicated that the total amount of T-cells in patients is comparable or slightly increased as compared to that found in normal subjects. No relevant differences have been shown with respect to total T-cell counts and T-cell subsets including CD4+, CD8+, CD45RO+ and CD45RA+ cell counts. Only few studies comprise a comparison between mild and more severe forms of psoriasis, using clinical severity indicators such as the Psoriasis Area and Severity Index (PASI-score) [4, 18].
The present study compares specific circulating lymphocyte subsets in patients with mild psoriasis, patients with moderate-to-severe psoriasis and normal subjects.
Materials and methods
Patients and controls
Fifteen patients with moderate-to-severe psoriasis vulgaris (12 male and three female aged 19–66, mean age 46.2 years) and 12 patients with mild psoriasis (seven male and five female, aged 34–72, mean age 52.8 years) from our outpatient department participated in this study. Mean PASI-scores in both groups were 20.97 ± 2.55 (mean ± SEM) and 6.11 ± 1.27, respectively. Patients were classified into one of both groups based on their PASI-score. We considered all patients with a PASI-score <12 as having a “mild”, and all patients with a PASI >12 as having a “moderate-to-severe” psoriasis [4, 18].
Patients were free of any systemic therapy for at least 4 weeks and did not use any topical therapy in the last 2 weeks. Peripheral blood was obtained from all subjects with their written informed consent.
Control samples were collected from 10 healthy volunteers without any history or signs of skin disease (four male and six female aged 24–49, mean age 33.8 years).
Preparation of PBMC’s
For each patient, the exact amount of blood withdrawn was determined by measuring the height of the column of blood in the tube, which was subsequently converted to the corresponding volume in microliter.
PBMC’s were isolated from heparinized blood by density centrifugation on polyester gel (Becton Dickinson Vacutainer™ CPT™, Franklin Lakes NJ, USA). After filtering through a 70 μm cellstrainer, cells were washed twice.
For flow cytometry, single-cell suspensions (concentration 5 × 105 cells ml−1) were stained in 1% fetal calf serum in phosphate-buffered saline (PBS) at concentrations recommended by the manufacturer. Additionally, 450 μl propidium iodide (PI) in PBS was added to each sample in order to exclude non-viable cells from analysis.
The following monoclonal antibodies were used: fluorescein isothiocyanate (FITC)-conjugated anti-CD4, FITC-conjugated anti-CD8, phycoerythrin (PE)-conjugated anti-CD4, PE-conjugated anti-CD8, PE-conjugated anti-CD94 and PE-conjugated anti-CD161 (all from Immunotech, Marseille, France), as well as FITC-conjugated anti-CD45RA (Becton Dickinson, San Jose, CA, USA) and FITC-conjugated anti-CD45RO (DAKO, Glostrup, Danmark).
Flowcytometric analysis
Cells were analyzed with an EPICS Elite flow cytometer (Coulter, Luton, UK), using the forward scatter as a discriminator. Lymphocytes were identified by gating on CD45 and side and forward scatter properties. All samples were processed within 18 h of phlebotomy.
The following (combinations of) PE and FITC-conjugated reagents were used to determine the expression of each antigen or antigen combination on lymphocytes derived from peripheral blood: CD4+ (marker for T-helper cells), CD8+ (marker for cytotoxic T cells), CD45RA+ (marker for naïve T-cells), CD45RO+ (marker for memory T-cells), CD94+ (marker for NK-cells, T cells), CD161+ (marker for NK-cells, T-cells with memory phenotype), CD4+ CD45RA+, CD4+ CD45RO+, CD8+ CD45RA+, CD8+ CD45RO+, CD8+ CD94+ and CD8+CD161+.
Determination of absolute numbers of lymphocytes
Enumeration of positive cells was performed by adding Flow Count Beads (Beckman Coulter, Fullerton, CA, USA) to the cell suspension of PBMCs. An automatic stop after a defined amount of beads was programmed on the flow cytometer. Absolute counts of lymphocyte subsets per blood sample were calculated by determining the ratio of the beads to the cell population and then multiplying this ratio by the number of beads in the tube. By dividing this count by the amount of microliters in the tube, a relative absolute lymphocyte count in cells μl−1 blood withdrawn was obtained. Analysis was performed with Verity software.
Ratios for CD4+/CD8+ cells, CD45RO+/CD45RA+ cells, CD4+CD45RO+/CD4+CD45RA+ cells and CD8+CD45RO+/CD8+CD45RA+ cells were calculated afterwards, with data derived from this analysis.
Statistical analysis
Data-entry and analysis was performed using Statistica 6.0 software. Means and standard deviations were calculated for each parameter and were tested with one-way ANOVA. Differences were considered statistically significant at p < 0.05.
Results
In total, 27 patients with psoriasis and 10 normal subjects without signs or symptoms of skin disease were included in the present study. Table 1 summarizes the demographic details and psoriasis related characteristics of the patients with moderate-to-severe psoriasis, patients with mild psoriasis and normal subjects. Four out of 12 patients with mild psoriasis had shown a minimal increase in the extent of lesions; in the others the skin abnormalities were stable. With respect to the 15 patients with moderate-to-severe-psoriasis, 12 had an increase of the extent of lesions during the previous 4 weeks, whereas the other three had been stable.
Table 1Demographic and psoriasis related characteristics of patient and subjects participating in the study (mean ± SEM)Moderate-to-severe psoriasisMild psoriasisNormal subjectsDemographicsAge (years)46.2 ± 3.4552.8 ± 3.4933.8 ± 3.1Male:female ratio 12:37:54:6Psoriasis related characteristicsPASI-score 20.97 ± 2.556.11 ± 1.27NADuration (years)16.7 ± 2.722.2 ± 2.5NA
Total cell counts
The total amount of gated cells (per microliter blood withdrawn) in normal subjects was 2,220 ± 301 cells μl−1 (mean ± SEM). The cell-count in mild psoriasis was 1,923 ± 230 cells μl−1. In contrast, patients with moderate-to-severe psoriasis had cell counts of 498 ± 95 cells μl−1. No statistically significant difference was observed between normal subjects and patients with mild psoriasis. However, a highly significant difference (p < 0.0001) was observed between mild and severe psoriasis. The CD4+/CD8+ ratios in all three groups were in the same range, meaning no shift occurred in the distribution of these subgroups of peripheral blood lymphocytes.
The total number of lymphocytes, and the CD4+ and CD8+ counts of the patients with moderate-to-severe disease were also routinely measured at the GLP certified Central Haematology Laboratory in our hospital, in which the whole blood lysing method is the standard. Comparison of both methods reveals an acceptable resemblance in results, with lower counts of maximum 10%.
Lymphocyte subsets
Lymphocyte subsets as a percentage of total gated cells are summarized in Fig. 1. CD4+, CD8+, CD45RA+ and CD45RO+ cells are increased in patients with severe psoriasis as compared to patients with mild psoriasis and normal subjects (p < 0.0001 in all cases).
Fig. 1CD4, CD8, CD45RO and CD45RA subpopulations, expressed as a percentage of total lymphocyte counts. Comparison between normal subjects, patients with mild- and patients with moderate-to-severe psoriasis. (*: p < 0.0001)
No significant differences were observed between patients with mild psoriasis and normal subjects.
Double labeling of lymphocytes revealed that the percentages of CD4+CD45RO+, CD4+CD45RA+ and CD8+CD45RA+ cells were significantly increased in moderate-to-severe versus mild psoriasis (p < 0.001 in all cases), whereas the percentage of CD8+CD45RO+ cells was not increased significantly (Fig. 2). Cell ratios for CD4+/CD8+ cells, CD45RO+/CD45RA+ cells, CD4CD45RO+/CD4CD45RA+ cells and CD8CD45RO+/CD8CD45RA+ cells are summarized in Fig. 3.
Fig. 2Expression of CD4+CD45RO+, CD4CD45RA+, CD8+CD45RO+ and CD8CD45RA+ cells, as percentage of the total amount of lymphocytes, in three subgroups: moderate-to-severe psoriasis, mild psoriasis and normal subjects (*: p < 0.001)Fig. 3Ratios of CD4/CD8, CD45RO+/CD45RA+, CD4CD45RO+/CD4CD45RA+ and CD8CD45RO+/CD8CD45RA+ in normal subjects, mild and moderate-to-severe psoriasis (*: p < 0.05)
Lymphocytes expressing NK cell receptors
CD94+ and CD161+ cells, expressed as a percentage of total cells were increased in patients with moderate-to-severe psoriasis, as compared to patients with mild psoriasis and normal subjects (p < 0.05 and p < 0.001, respectively). Figure 4 summarizes these observations. Again no statistically significant differences were observed between normal subjects and patients with a mild form of psoriasis.
Fig. 4CD94 and CD161 subpopulations, expressed as a percentage of total lymphocyte counts. Comparison between normal subjects, patients with mild- and patients with moderate-to-severe psoriasis (*: p < 0.05 and p < 0.001 respectively)
With respect to double stained cells, we observed an increase in the expression of both CD8+CD94+ cells as well as CD8+CD161+ cells (markers for NK T subpopulations) in patients with a more extensive form of psoriasis, expressed as a percentage of the total amount of cells, as compared to patients with mild psoriasis and normal subjects (p < 0.008 and p < 0.009, respectively, results shown in Fig. 5).
Fig. 5Cellcounts of CD8+CD94+ and CD8+CD161+ cells as percentage of total lymphocytes (*: p < 0.009)
Correlation between PASI-score and lymphocyte subsets and cells expressing NK receptors
Linear regression analysis revealed no significant correlation between the individual PASI-scores and the quantifications of lymphocyte subsets or cells with NK-cell receptors. Correlation analysis between disease activity and peripheral lymphocytes did not reveal a difference between patients with spreading lesions and those with stable plaque psoriasis.
Discussion
The results of this study show marked differences in absolute cellcounts between the three patient groups. Our main goal was to investigate whether there is a difference in the occurrence of biomarkers on circulating lymphocytes in mild psoriasis versus more severe forms of the disease. One of the criteria to qualify for a treatment with major systemic therapies such as a biological is often a minimum PASI-score of 12 [4, 18]. We were interested whether this cut-off point also implies a differentiation between mild versus moderate/severe psoriasis in terms of T-cell and NKT-cell subsets. The results of the present study have shown us that there are indeed marked differences between mild psoriasis and the more severe forms of disease defined by cut-off point PASI 12.
A decrease of total lymphocyte counts, as percentage of PBMC, and an increase in the percentage of CD4+CD45RO+ cells in patients with moderate-to-severe psoriasis has been reported before [10]. These patients (32 subjects) had an average PASI of 25.7 (10–48), and all had had an exacerbation following infection. Patients had a mixed morphology, from guttata psoriasis to chronic plaque psoriasis. In the same study, however, a decrease in the amount of CD4+ cells was described, which is in contrast with the findings in our study. Other authors have reported no significant difference in total T-cells as percentage of PBMC counts between patients with psoriasis and normal subjects [3]. These patients (14 subjects) had an average PASI of 23.5 ± 10.6. However, no information was given whether these patients had relapsing psoriasis. In the present study, the patients with severe psoriasis had an extension of lesions during the wash out period (average increase in PASI: 4.9). Therefore, the severity in our patients not only comprises the extent of lesions but also activity of lesions with progression and therefore, approaches the characteristics of the patients reported by Lecewicz-Torún et al. [10], who also reported a decrease of T-cells in peripheral blood in psoriasis (expressed as percentage of total PBMC). The decrease of lymphocyte counts, expressed as a percentage, in peripheral blood in patients with moderate-to-severe psoriasis is the reverse of the substantial accumulation of lymphocytes in psoriatic skin. The most likely explanation for this paradox is an increased influx of cells into the skin of patients with severe disease. Further studies, in which simultaneous measurements of lesional and circulating T cells will be performed, need to be carried out to support this hypothesis.
A striking observation is the increased percentage of both CD4+ cells and CD8+ cells in patients with moderate-to-severe psoriasis as compared to mild psoriasis and normal subjects, without a change in CD4/CD8 ratio. So far, reports on the CD4+/CD8+ ratio in psoriasis have been at variance [10, 11].
With respect to the double labeled lymphocytes, both the percentage of CD4+CD45RO+ cells as well as the percentage of CD4+CD45RA+ cells is increased in patients with moderate-to-severe psoriasis, in contrast to the absolute decrease of total lymphocytes. The relative count of both subsets is increased, whereas their ratio shows a tendency to decrease (p = 0.0509). Thus, with increasing severity of disease, the increase in CD4+CD45RA+ cells seems to exceed the increase in CD4+CD45RO+ cells. An explanation for this phenomenon is the preferential migration of CD4+CD45RO+ cells into lesional skin in extensive disease, resulting in a relative decrease of this subset of CD4+ lymphocytes in peripheral blood. This hypothesis supports earlier studies where CD4+CD45RO+ cells have been shown to be the major players in psoriatic plaques. Indeed, CD4+ cells appear in a very early phase of the psoriatic process. In a previous study, CD4+ cells have been detected in the distant uninvolved skin of patients with active psoriasis [22]. The percentage of CD8+CD45RO+ cells in patients with moderate-to-severe psoriasis approached the percentages in patients with mild psoriasis and normal subjects, in contrast with the CD8+CD45RA+ cells, which did show a significant increase in peripheral blood. The impressive under-representation of CD8+CD45RO+ lymphocytes as compared to CD8+CD45RA+ lymphocytes in moderate to severe psoriasis suggests a preferential influx of CD8+CD45RO+ cells into the skin. Both CD8+ cells, as well as CD45RO+ cells are abundantly present in psoriatic lesional skin. Previously, we have shown that in the outer margin of the spreading psoriatic plaque the number of CD8+ cells and CD45RO+ cells were increased [22]. Therefore, the relative under-representation in peripheral blood of CD45RO+ cells, in particular the CD8+ CD45RO+ cells, most likely reflect the influx of these cells into the skin in patients with moderate-to-severe psoriasis in an active phase of disease. However, further studies are needed to support this hypothesis. Lymphocyte counts, preferably T-cells, in skin as well as in the peripheral blood should be monitored during a longer period of time, e.g., during exacerbation and during disease-free intervals. The CD8+CD94+ cells and CD8+CD161+ cells show a marked increase in patients with moderate-to-severe psoriasis as compared to mild psoriasis and normal subjects. The increases of these lymphocytes expressing NK receptors in peripheral blood are accompanied with increases of these cells in the psoriatic lesion.
The results of the present study suggest that in peripheral blood of patients with moderate-to-severe psoriasis, in contrast to the vast presence of T-cells in skin lesions, the absolute lymphocyte counts are profoundly decreased, without any change of CD4/CD8 ratio. The relative under-representation of CD45RO+ cells, as compared to CD45RA+ cells, in peripheral blood most likely results from a massive influx of memory effector T-cells into the psoriatic lesions in an active phase of disease. Both in blood and skin of patients with moderate-to-severe psoriasis the percentages of CD94+ and CD161+ cells are increased. These results are compatible with the functions of these cells. CD45RO+ cells differentiate from CD45RA+ cells and represent acquired immunity, whereas NK-T cells are able to act without prior sensitization, representing innate immunity [3]. In further research, more selective lymphocyte markers are required in order to investigate the role of peripheral blood T-cells in the pathogenesis of psoriasis, and correlation studies between peripheral blood T-cells and T-cells in skin are required in order to understand the dynamics of compartmentalization of T-cell subsets belonging to either the acquired or the innate immunity system in psoriasis.

lymphocytes
peripheral blood
psoriasis
t cells
severity of disease


Progressive improvement of impaired visual acuity during the first year after transsphenoidal surgery for non-functioning pituitary macroadenoma

Objective Improvement of visual field defects continues even years after the initial surgical treatment. Because this process of continuing improvement has not been documented for visual acuity, we audited our data to explore the pattern of recovery of visual acuity until 1 year after transsphenoidal surgery for non-functioning pituitary macroadenoma.
Introduction
Non-functioning pituitary macroadenomas (NFMA) are the most prevalent macroadenomas [1, 2]. Patients with NFMA mainly present with decreased visual acuity, visual field defects and hypopituitarism, caused by mass effects of the tumor [3–5]. Transsphenoidal surgery is the treatment of choice, resulting in improvement of visual field defects in 75–100% of all patients [3–5]. Accordingly, visual acuity improves in the majority of patients [6–10], although visual field defects and visual acuity may worsen in a limited number of patients after surgery [6, 7, 9, 10].
The process of visual fields recovery starts directly after surgery and can already be documented on the second postoperative day [11]. This process of recovery is probably due to restoration of the velocity of conduction. However, improvement of visual field defects continues even years after the initial surgical treatment [12, 13]. Although a reduced visual acuity is correlated with the extent of visual field defects [13, 14], postoperative changes in visual acuity do not parallel changes in visual fields in every case [6].
To our knowledge, the process of gradual visual improvement, has only been observed for visual field defects, but not for visual acuity [12]. This is, however, clinically relevant, since improvement of minor visual field defects can occur unnoticed, whereas improvement in visual acuity is almost invariably noticed, and can potentially overcome thresholds to previous impairments in daily life. We therefore audited our data to explore the pattern of recovery of visual acuity until 1 year after transsphenoidal surgery for non-functioning pituitary macroadenoma.
Patients and methods
Patient selection
Forty-three patients, mean age 56 ± 14 years, were included in this retrospective analysis. In order to obtain a homogenous cohort for assessment, the inclusion criteria were the following:Compression of the optic chiasm on MRI by the pituitary tumor prior to surgeryTranssphenoidal surgery for non-functioning pituitary macroadenoma (diameter > 1 cm) for decompression of the optic chiasmAssessment of visual acuity at least once before surgery, and at least twice in the first year after surgeryThe availability of two postsurgical MR scans, within a time frame of maximal 3 months of the ophtalmological assessments
We did not restrict the inclusion criteria to patients with visual field defects, but also included patients with clear compression of the optic chiasm without decreased visual function, for two reasons. First, we were interested in the pattern of change in visual function prior to surgery. Second, it is, at least theoretically, possible that in patients with compression of the optic chiasm, surgical treatment may decrease visual function. To overcome the potential effect of postoperative tumor-regrowth on visual outcome, patients were excluded from analysis if the 1 year post-operative scans revealed growth of residual tumor.
For complete assessment, we reviewed the patient records of all departments involved in the treatment of NFMA (Endocrinology, Neurosurgery, Ophthalmology). Endocrine (pituitary function) and ophthalmologic data (visual acuity and visual fields) were assessed before surgery, 3 and 12 months after surgery. An MRI was performed before surgery, 3–6 months and 12–15 months after surgery. Transsphenoidal surgery was performed by one of two neurosurgeons
Corrected visual acuity was determined by the Snellen chart [15, 16] and was scored for both eyes. Visual fields were assessed by Humphrey perimetry in all patients. Goldman perimetry was used as an additional tool to assess peripheral visual field defects. To increase the reliability of the visual field testing, assessment of the visual fields, and thereby also visual acuity, was preferably performed twice prior to surgical treatment. However, surgical treatment was not delayed due to double ophthalmologic testing in patients with severe impaired visual acuity.
Definitions
The diagnosis of non-functioning pituitary macroadenoma was based on two criteria: the presence of a pituitary macroadenoma (>1 cm) on MRI, and the absence of overproduction of any of the pituitary hormones. In all cases the diagnosis was histologically confirmed. Tumor size was classified according to Hardy [17]. Tumor extension was classified as suprasellar (Hardy II0, A, B, C) or parasellar/infrasellar (Hardy IID,E, Hardy III0-E and Hardy IV0-E).
In all patients, visual acuity was scored on a scale between 0 and 1.25. Visual field defects were scored semi-quantitative and classified as mild, moderate or severe. Visual field defects were classified as mild, if there were peripheral defects in only one quadrant. Defects were classified as moderate if the upper quadrants were affected, whereas in combined upper and lower quadrant field defects, these were classified as severe.
Growth hormone (GH) deficiency was defined as an insufficient rise in GH levels (absolute value < 3 μg/l) after stimulation during an insulin tolerance test (ITT). When secondary amenorrhoea was present for more than 1 year premenopausal women were defined as LH/FSH deficient. Postmenopausal women were defined as LH/FSH deficient, when gonadotropin levels were below the normal post-menopausal range (LH < 10 U/l, FSH < 30 U/l). In men, LH/FSH deficiency was defined, as a testosterone level below the reference range (8.0 nmol/l). TSH deficiency was defined as a total or free T4 level below the reference range. ACTH deficiency was defined as a basal cortisol level at 8.00 AM of <0.12 μmol/l and/or an insufficient increase in cortisol levels (absolute value < 0.55 μmol/l) after an ITT.
Statistical analysis
The paired t-test was used for paired samples. SPSS software version 12.0 (SPSS Inc., Chicago, IL, USA) was used. A P-value of <0.05 was considered statistically significant.
Results
Preoperative patient characteristics (Table 1)
Forty-three patients, 51% male, were included in this study. Radiological imaging by MRI revealed a macroadenoma in all patients, with suprasellar extension in 100% and parasellar/infrasellar extension in 42% of cases. Hypopituitarism was present in 79% of all patients, and panhypopituitarism in 23%.
Table 1Patient characteristics before transsphenoidal surgeryMale/female22/21Age (years ± SD)56 ± 14Visual acuity Right eye (mean ± SD)0.65 ± 0.37Left eye (mean ± SD)0.60 ± 0.32Visual field defectsSevere60%Moderate17%Mild14%None9%Pituitary functionGH deficiency76%LH/FSH deficiency69%ACTH deficiency43%TSH deficiency36%Panhypopituitarism23%MRI characteristicsSuprasellar extension100%Infrasellar/parasellar extension42%
Pre-operative assessment of visual function (Table 1)
Visual fields were normal in 4 patients. Transsphenoidal surgery in these patients was performed because compression of the optic chiasm was evident on the MR scan (n = 4). In these 4 patients visual acuity was at least 1.0 for both eyes. Of all patients with visual field defects 60% were classified as severe, 17% as moderate, and 14% as mild. Mean visual acuity was 0.65 ± 0.37 for the right eye, 0.60 ± 0.32 for the left eye.
Visual acuity was assessed twice before surgery in 34 patients (79% of total). The median time between the first and the second pre-surgical assessment was 4 weeks (range 1–45). No significant decrease in visual acuity was observed within this time period. The mean visual acuity for the two pre-surgical assessments was: 0.65 ± 0.37 vs. 0.66 ± 0.38 (right eye), and 0.60 ± 0.32 vs. 0.62 ± 0.33 (left eye). Moreover, no decrease in visual acuity was observed in patients (n = 13) with a time interval of >8 weeks between the first and the second pre-surgical assessment. In 4 of these patients there were no visual field defects.
Surgical treatment
All patients were treated by transsphenoidal surgery. Repeat surgery within 6 months after initial treatment was performed twice (large residual tumor mass (n = 1) and persisting liquor leakage (n = 1)). Repeat surgery was performed by transcranial approach.
Transsphenoidal surgery was followed by radiotherapy in 10 patients in order to prevent recurrence. Patients received 40 Gy (n = 5) or 46 Gy (n = 5).
Three months postoperative assessment of visual function
After transsphenoidal operation in patients with preoperative visual field defects improvement was observed in 60% and normalization of the visual fields in 30%. In 1 patient there was a slight increase in visual field defects.
Visual acuity improved significantly 3 months after transsphenoidal surgery (Fig. 1). The mean visual acuity increased from 0.65 ± 0.37 to 0.75 ± 0.36 (P < 0.01) (right eye), and from 0.60 ± 0.32 to 0.82 ± 0.30 (P < 0.01) (left eye).
Fig. 1The pattern of improvement of visual acuity after transsphenoidal surgery for non-functioning pituitary macroadenomas (n = 43)
One-year postoperative assessment of visual function
One year after initial surgical therapy visual field defects showed continuous improvement in 36% of patients, compared to early postoperative results. In 80% of them, this improvement was accompanied by continuous improvement of visual acuity.
In 56% of all patients (n = 24) visual acuity shows continuing improvement until 1 year after surgery. In 8 of them, this improvement was not accompanied by further improvement of visual field defects. Visual acuity was improved 1 year after transsphenoidal surgery compared to the 3 months postoperative values (Fig. 1). The mean visual acuity increased from 0.75 ± 0.36 to 0.82 ± 0.34 (P < 0.05) (right eye), and from 0.82 ± 0.30 to 0.88 ± 0.27 (P < 0.05) (left eye).
Discussion
The main aims of surgery in non-functioning pituitary macroadenoma are restoration of visual acuity and visual field defects by decompression of the optic chiasm. Nonetheless, our data indicate that there is no necessity for immediate decompression, since postponement of surgery for several weeks did not result in deterioration of visual acuity. Moreover, in this series of 43 patients, we demonstrated a continuing improvement of visual acuity until 1 year after transsphenoidal surgery.
There is a significant correlation between the severity of visual loss prior to surgery and persisting visual field defects [9, 13, 14]. In our patients in whom visual acuity was assessed twice before surgery, no decrease of visual acuity was observed with a median time interval between two measurements of 4 weeks. This indicates that postponing surgery for 1 month does not negatively influence visual outcome, which is in line with the slow growth pattern of non-functioning adenomas [4]. Nonetheless, the delay of surgery should not unnecessarily be prolonged because a significant, inverse, correlation between visual outcome and the prolonged duration of symptoms has been reported [9]. Moreover, especially in patients with rapid loss of visual function or decreased visual acuity due to apoplexy, urgent surgical intervention is indicated.
The initial event in the pathogenesis of decreased visual function in pituitary macroadenomas is compression of the optic chiasm. Nerve compression leads to decreased conduction and to demyelination. In an experimental setting, the process of demyelination after nerve compression has been observed even after 2 days [18, 19]. In case of continuous nerve compression remyelination can be observed after several weeks, although remyelinated fibers do not seem to reach normal thickness and organization structure, and complete demyelinated fibers co-exist [18, 19]. Re-myelinated fibers restore conduction, at least partially, even if the causative nerve lesion is still existing [20, 21]. The improvement of visual dysfunction after surgical treatment is supposed to consist of two, or probably even three, phases [12]. There is an early phase, comprising the first hours and days after surgery. In this early fast phase, the improvement is caused by decompression of the visual pathways, leading to a restoration of signal conduction. Visual recovery has been demonstrated in the first days after surgical treatment [11, 12]. The second phase, i.e., delayed recovery, is pathophysiologically caused by restoration of axonal transport and remyelination, and based on remyelination of the optic nerve vessels. This phase of delayed recovery may last for several years [12, 13]. A precise boundary between the end of the fast phase of recovery and the start of the delayed recovery seems to be artificial, because these two phases reflect different pathophysiological mechanisms, which may co-exist for a certain time-period. The contribution of the first phase of recovery might be larger, given the fact that more than 50% of eventual recovery takes place within the first 3 months after surgery [13].
It is already known that visual acuity improves in the first months after surgical treatment [6–10] and that the improvement of visual field defects is a continuing process for at least 1 year [12, 13]. Kerrison et al. [12] showed progressive improvement of visual fields even more than 2 years after surgical decompression of the optic chiasm. However, they did not demonstrate this same pattern of recovery for visual acuity. This might be due to the relative small number of patients during prolonged follow-up. In the present study we demonstrate that also improvement of visual acuity continued 1 year after surgical treatment.
The clinical consequences of the delayed phase of recovery for both visual field defects and visual acuity are obvious. Follow-up of patients after surgical treatment for pituitary macroadenomas should include ophthalmologic assessment within several weeks after surgery, as well as subsequent assessments after one and 2 years, in order to estimate the final effect of surgery on visual function. Moreover, patients should be told that visual function can continue to improve, at least until 1 year after surgery. The relevance of these findings are obvious and is of importance to all patients, given the impact of a decreased visual acuity as an independent predictor for a decreased quality of life [22, 23]. Moreover, these data are essential in order to evaluate potential effects of recurrent pituitary adenomas on visual function.
Ten patients in our series received postoperative radiotherapy. However, it is unlikely that this treatment affected the results of our study. In a series reported by Gnanalingham et al. [13], in which 34% of all patients received postoperative radiotherapy, persistent improvement of visual field defects was documented even years after surgical therapy. In another series of 21 patients, 2 years after pituitary irradiation, there were no cases of radiation-induced visual field or visual acuity deterioration [24].
In conclusion, this study demonstrates that the improvement of visual acuity, after transsphenoidal treatment for non-functioning pituitary macroadenomas, consists of both an early and a delayed phase of recovery. After initial post-surgical recovery, a progressive delayed improvement of visual acuity at least until 1 year after transsphenoidal surgery, is likely to occur.

visual acuity
surgery
non-functioning macroadenoma


Effectiveness of Massage Therapy for Chronic, Non-malignant Pain: A Review

Previous reviews of massage therapy for chronic, non-malignant pain have focused on discrete pain conditions. This article aims to provide a broad overview of the literature on the effectiveness of massage for a variety of chronic, non-malignant pain complaints to identify gaps in the research and to inform future clinical trials. Computerized databases were searched for relevant studies including prior reviews and primary trials of massage therapy for chronic, non-malignant pain. Existing research provides fairly robust support for the analgesic effects of massage for non-specific low back pain, but only moderate support for such effects on shoulder pain and headache pain. There is only modest, preliminary support for massage in the treatment of fibromyalgia, mixed chronic pain conditions, neck pain and carpal tunnel syndrome. Thus, research to date provides varying levels of evidence for the benefits of massage therapy for different chronic pain conditions. Future studies should employ rigorous study designs and include follow-up assessments for additional quantification of the longer-term effects of massage on chronic pain.
Introduction
Massage therapy has been defined as soft-tissue manipulation by trained therapists for therapeutic purposes (1). Massage therapy has a long history, being first described in China during the second century B. C. and soon thereafter in India and Egypt (1). More recently, massage therapy has been administered using mechanical devices in addition to hands-on treatment by therapists. Massage can be applied to single or multiple body parts or to the entire body. There are many different types of massage therapy including Swedish massage, Shiatsu, Rolfing, reflexology and craniosacral therapy. Most of the published trials on massage therapy have utilized Swedish or Swedish-type massage.
Despite the growing popularity of massage, there is inconsistent empirical support for its effectiveness in chronic pain. Although the effects of massage therapy on chronic pain has been the subject of prior reviews (described subsequently), most of these reviews have focused on a single chronic pain condition and the level of supportive evidence appears to vary greatly, depending on the particular pain condition investigated. This review aims to bring together the existing data on the effectiveness of massage therapy for a wide range of chronic, non-malignant pain conditions. (Evidence regarding the effects of massage on acute pain is reviewed under ‘Meta-Analysis—Massage Therapy Effects on Pain. Chronic pain has been defined by the International Association for the Study of Pain (IASP) as continuous or recurrent pain that persists for longer than the normal time of healing, generally about 3 months (2). It is hoped that by providing an overview of the field, gaps in extant research may be identified in order to inform future clinical trials.
Typically, massage is viewed as adjunctive therapy to help prepare the patient for exercise or other interventions, and is rarely administered as the main treatment (3). Following the methodology of the Cochrane Collaboration, the focus of this review will be on those studies in which massage for pain relief is delivered alone rather than as part of a treatment package, since it is difficult to draw conclusions regarding the effectiveness of massage when multiple treatments are involved. In addition, the emphasis of this review will be on randomized, controlled trials (RCTs) or quasi-RCTs of massage therapy. As noted above, the main purpose of this article is to provide a broad overview of extant literature on the application of massage to a wide range of chronic pain conditions. Prior reviews have typically focused on a single pain complaint, even though many chronic pain patients present with multiple pain conditions. Thus, the current review summarizes the findings of existing reviews and meta-analyses as well as key individual studies that have appeared since the publication of these comprehensive reviews. Although this approach is limited as it depends heavily on the methodology used in extant reviews and the quality of the methodology likely varied across reviews, it was considered the most feasible approach in order to synthesize the large number of studies examining massage for a broad array of chronic pain conditions.
This review is organized as follows. First, empirical findings of effectiveness are presented according to the type of chronic pain condition examined; each of these sections concludes with a summary statement of the level of evidence for the specific pain condition studied. (A summary table of the overall findings is also presented in Table 6.) It should be noted that a review of the findings from the handful of studies on mixed chronic pain problems is also included. Second, the results of a meta-analysis of massage therapy for pain complaints are discussed. This study was unusual in that it examined massage therapy effects across a number of pain complaints. The review concludes with a summary of the findings across the various chronic pain conditions, together with a discussion of putative mechanisms, clinical implications and recommendations for future trials.
Methods
The PubMed, PsychInfo, CINAHL, and Cochrane Library databases searched up to July 2006 using the keywords ‘massage’, ‘pain’, ‘analgesia’ and ‘analgesics’. As noted above, the focus of this article is to provide a comprehensive overview of the evidence regarding massage therapy for chronic, non-malignant pain. Thus, due to the large number of trials uncovered using the present search strategy, reviews by the Cochrane Collaboration and other authors were used where applicable to identify relevant trials. Primary studies that were excluded by the Cochrane group or others due to methodological or other limitations were therefore not included in the present review. However, findings from relevant primary studies that had been published since these reviews appeared were included. Only those chronic, non-malignant pain conditions that had been examined by at least one controlled trial were included in this review. The studies included in this review focused on adult participants; the application of massage therapy for chronic pain in children has been discussed in a prior review (4,5). The study findings are summarized in Tables 1–6. Mean reductions in the main pain outcome measure are shown in the Tables. Since the most commonly used pain outcome measure was a visual analog scale or VAS rating of pain intensity, means for this outcome are reported whenever possible.
Table 1.Summary of results for studies included in the Cochrane Review on massage therapy (MT) for low back painStudynPain durationControl conditionsOutcomesFindings (Mean reduction in pain)Hsieh et al. (1992) (6)**63Not statedSpinal manipulation (SM); Corset (CT);TranscutaenousOswestry Low Back Pain Q’aireSM (20) > MT (9.2)    muscular stimulation (TMS)Roland-Morris Activity Scale(SM = CT) > MT; SM > TMSCherkin et al. (2001) (11)**26261%=Acupuncture (AC); Self-care education (SC)Symptom scale (0–10)MT (2.6) > SC (1.5)>1 year1 year F/UMT (3.0) = SC (2.3); MT > AC (1.7)Roland Disability ScaleMT > SC; MT > AC1 year F/UMT = SC; MT > ACUse of Medications (1 year F/U)MT > SC; MT > ACSF-12 (Physical Health)MT > SC1 year F/UMT = SC = ACSF-12 (Mental Health)MT > SC; MT > AC1 year F/UMT = SC = ACHernandez-Reif et al.24Not stated but >6 mProgressive muscle relaxation (PMR)VAS pain intensity (0–10)MT (3.9) > PMR (1.6)    (2001) (10)*McGill Pain QuestionnaireMT = PMRRange of Motion (ROM)MT > PMRHoehler et al. (1981) (13)*9548–52% < 1 mSMPatient-rated pain (unspecified scale)MT = SM17–29% > 6 mStraight-leg raiseMT = SMPope et al. (1994) (7)**16429% < 6 mSM; TMS; CTVAS pain intensity (0–10)MT (17.2) = SM (24.1) = TMS (9.6) = CT (15.9)35% = 6–12 mROM (flexion/extension)MT = SM = TMS = CT36% > 2 yearsMaximum voluntary extension effortMT = SM = TMS = CTSorensen fatigue testMT = SM = TMS = CTGodfrey et al. (1984) (12)*81Not stated but <14 daysSM; Low-level electrical stimulation (LES)Pain, stiffness, tenderness (0–4)MT = SM = LESDaily activities (0–4)MT = SM = LESSelf-reported limitations due to painMT = SM = LESFingertip flexion testMT = SM = LESMelzack et al. (1983) (14)**41Mean = 36.2 wksTranscutaneous electrical nerve stimulation (TENS)McGill Pain Questionnaire (PRI)TENS (85%) > MT (38%) (>50% reduction on PRI)Straight-leg raiseTENS > MTBack FlexionTENS = MTPreyde et al. (2000) (9)**98Mean range = 12.0–14.8 wksSoft-tissue manipulation (STM); Exercise (EX);Roland Disability QuestionnaireCMT (5.9) > EX (0.3), SL (0.4); STM (5.2) > EX, SLSham laser therapy (SL)1 month F/UCMT (6.8) > EX (1.5), SL (0.7); (STM (5.7) = EX) > SLNote: Above were compared with Comprehensive Massage Therapy (CMT) which included STM and EXLumbar ROMCMT = STM = EX = SLNote: **denotes high quality study per Cochrane review (3); *denotes low quality study per Cochrane review (3). The Hsieh and Pope studies reported findings from the same trial.
Table 2.Summary of findings for studies on massage therapy (MT) for headache painStudy and type of headachenPain durationComparison conditionsOutcomesFindings (Mean reduction in pain)Nilsson et al. (1997) (17)*Cervicogenic Headaches54Not statedSpinal manipulation (SM)    but ≥3 mNOTE: The above was compared with MT plus placeboVAS pain intensity (0–10)SMT (17.0) > MT (4.2)LaserHeadache durationSMT > MTWylie et al. (1997) (18)Migraine and67Mean = 10.2AcupuncturePain total index (hours × severity)    Tension-type    yearsNOTE: The above was comparedMigraineMT (171.7) > AC (128.0)    with MT plus relaxationTension-typeMT (217.0) = AC (119.5)Both groups combinedMT = ACHeadache index (number × severity)MigraineMT > ACTension-typeMT = ACBoth groups combinedMT = ACMigraine DaysMT = ACHanten et al. (1999) (20)65Not statedResting position (RP); No treatment (CON)Tension-typeNOTE: The above was compared with CV-4 techniqueVAS pain intensity (0–10)MT (19.3) > [RP (11.2) = CON (7.8)]VAS pain affect (0–10)MT > (RP = CON)Note: *this study was included in the Cochrane review of non-invasive physical treatments for chronic/recurrent headache (15).
Table 3.Summary of findings for studies on massage therapy (MT) for neck and shoulder pain and carpal tunnel syndromeStudy and type of painnPain durationComparison conditionsOutcomesFindings (Mean reduction in pain)Irnich et al. (2001) (28)VAS pain intensity (0–100)AC (17.3) > MT (3.1); AC = SLA (11.4)Neck pain17721.5–22.6% > 5 yearsAcupuncture (AC);3 month F/UAC (15.0) = MT (8.1); AC = SLA (11.2)Sham laserRange of Motion (ROM)AC > MT; AC = SLA    acupuncture (SLA)3 month F/UAC = MT; AC = SLAPressure pain threshold (algometer)AC = MT; AC = SLA3 month F/UAC = MT; AC = SLASpontaneous pain (7 point scale)AC = MT; AC = SLA3 month F/UAC > MT; AC = SLAMotion-related pain (7-point scale)AC > MT; AC > SLA3 month F/UAC > MT; AC = SLAGlobal complaints (7-point scale)AC > MT; AC > SLA3 month F/UAC > MT; AC = SLAHealth-related quality of life (SF-36)AC = MT; AC = SLA3 month F/UAC = MT; AC = SLADyson-Hudson et al. (2001) (24)Shoulder pain18Mean range = 13.4–16.2 yearsACWheelchair user's shoulder pain indexAC (23.3) = MT (21.7)ROMAC = MTMok and Woo (2004) (25)Shoulder pain102Not statedNo treatment control (CON)VAS pain intensity (unspecified scale)MT (14.6) > CON (0.2)State anxiety (STAI)MT > CONHeart rateMT > CONSystolic blood pressureMT > CONDisastolic blood pressureMT > CONvan den Dolder (2003) (27)Shoulder pain29Mean range = 26–30 weeksCONMcGill Pain QuestionnaireVAS pain intensity (0–10)MT (26.6) > CON (0.1)Present Pain Intensity (PPI) scaleMT = CONVerbal descriptorsMT > CONFunctional DisabilityMT > CONROMMT > CONField (2004) (32)Carpal Tunnel16Mean = 6.7 yearsCONVAS pain intensity (0–10)MT (3.2) > CON (.08)    SyndromeGrip StrengthMT > CONState anxiety (STAI)MT > CONProfile of Mood States — DepressionMT > CONPhysician assessed CTS symptomsMT > CON
Table 4.Summary of findings for studies on massage therapy (MT) for fibromyalgiaStudynPain durationComparison conditionsOutcomesFindings (Mean reduction in pain)Sunshine et al.30Not statedTranscutaneous electricalImmediate post-session    (1996) (33)    stimulation (TENS); Sham TENS (STENS)State anxiety (STAI)MT = TENS; TENS, MT > STENSProfile of Mood States (POMS) — DepressionMT = TENS; TENS, MT > STENSSalivary cortisolMT = TENS; TENS, MT > STENSPre- Post TreatmentSelf-Report Interview — Pain (unspecified scale)MT (3.3) > TENS (0.2); STENS (1.6)StiffnessMT > TENS; STENSFatigueMT > TENS; STENSSleepMT > TENS; STENSDolorimeter testMT > TENS; STENSPhysician assessment of conditionMT = TENS; TENS, MT > STENSDepression (CES - D)MT = TENS = STENSField et al.20Mean years inProgressive muscleImmediate post-session(2002) (34)    treatment = 9.2    relaxation (PMR)STAIMT = PMRPOMS – DepressionMT = PMRPre- Post TreatmentVAS pain intensity (0–10)MT (2.3) > PMR (1.4)VAS fatigue (0–10)MT > PMRVAS stiffness (0–10)MT > PMRPhysician assessment of conditionMT > PMRNumber of tender pointsMT > PMRCES - DMT > PMRBratttberg (1999) (35)4886% > 5 years;No treatment control (CON)VAS pain intensity (0–100)MT (26.3) > CON (1.4)50% > 10 yearsDisability rating indexMT = CONSleep disturbance (0–5)MT = CONHospital anxiety and depression scaleAnxietyMT = CONDepressionMT > CONAlnigenis et al. (2001) (36)37Mean range = 5–10.4 yearsUsual care (UC);Arthritis impact measurement scaleUC plus phone calls (UCP)Pain (0–10)MT (0.9) = UC (1.0) = UCP (0.3)Rheumatology attitudes indexMT = UC = UCPCES-DMT = UC = UCPQuality of well being scaleMT = UC = UCP
Table 5.Summary of findings for studies on massage therapy (MT) for mixed chronic painStudynPain durationComparison conditionsOutcomesFindings (Mean reduction in pain)Walach et al. (2003) (37)29Not stated but > 6 monthsUsual care (UC)Pain intensity (1–9 point scale)MT (1.0) > UC (0.1)Profile of Mood States (tiredness)MT > UCCES-DMT > UCState anxiety (STAI)MT > UCFrankfurt body concept scalesMT = UCHasson et al.129Not statedProgressive MusclePain (unspecified scale)(2004) (38)but > 3 monthsRelaxation (PMR)Post-treatmentMT (14.5) > PMR (2.1)3 month F/UMT (.03) = PMR (1.3)Mental energy (unspecified scale)Post-treatmentMT > PMR3 month F/UMT = PMRSelf-perceived health status (5-point scale)Post-treatmentMT > PMR3 month F/UMT = PMRPlews-Ogan et al. (2005) (39)30Not stated but > 3 monthsMindfulness-based stress reductionVAS pain unpleasantness ratings (0–10)MT (2.9) > UC (.13); MBSR (.7) = UC(MBSR); UC1 month F/UMT = MBSR = UCSF-12 physical healthMT = MBSR = UC1 month F/UMT = MBSR = UCSF-12 mental healthMT = MBSR = UC1 month F/UMBSR > UC; MBSR = MT
Table 6.Summary of overall findingsType of painNumber of studiesResults (number of studies)Quality ranking (global assessment of quality)Low back pain8MT > relaxation (1), education (1), acupuncture (1)1 (good)MT = corsets (2), exercise (1)MT < spinal manipulation (4), TENS (1)Shoulder pain3MT > acupuncture (1), no treatment (2)2 (moderate)Headache pain3MT > rest for migraine (1) and tension-type (1)3 (moderate)MT < spinal manipulation for cervicogenic (1)Fibromyalgia4MT > TENS (1), relaxation (1)4 (preliminary)MT = no treatment (1), usual care (1)Mixed chronic pain3MT > usual care (1)5 (preliminary)MT = relaxation (1), meditation and usual care (1)Neck pain1MT = acupuncture (1)6 (preliminary)Carpal tunnel1MT > no treatment (1)7 (preliminary)Note: Quality Ranking refers to the overall ranking of the quality of the literature on the effectiveness of massage therapy for each chronic pain condition relative to the other chronic pain conditions discussed in this review.
Results
Empirical Findings
Massage Therapy for Low Back Pain
The Cochrane Collaboration recently published a report on the use of massage therapy for non-specific low back pain (LBP) (3). Their comprehensive review included studies published until May 2001 and was substantively amended at the end of January 2002. The review included randomized or quasi-randomized trials testing the use of any type of massage (using hands or mechanical device) as an intervention for LBP. The Cochrane review identified nine publications which reported the results of eight randomized trials (Table 1 for detailed information). Note that the studies by Hsieh et al. (6) and Pope et al. (7) listed in Table 1 reported results from the same trial. One study was in German (8) (results not shown in Table 1) and the remainder were in English. Numerous studies were excluded from the review; many studies were excluded because massage was tested within a treatment package combined with various other therapies. Standardized criteria were applied to the included studies to assess methodological quality. For the eight trials, five were judged to be of high methodological quality (denoted as ** in Table 1) and three were deemed to be of low quality (denoted * in Table 1).
In one study (9), massage was compared with a placebo (sham laser). Massage was found to be superior to the placebo treatment. In the other seven trials, massage was compared with various active treatments. These studies showed that massage was superior to relaxation (10), acupuncture (11) and education (11); massage was equal to corsets (6,7) and exercises (9); massage was inferior to spinal manipulation (6,7,12,13) and transcutaneous electrical nerve stimulation (TENS) (14). The single German study showed that acupressure/pressure point massage techniques provided more pain relief than classical (Swedish) massage (8).
Beneficial Effects for Subacute and Chronic Non-specific Low Back Pain
The Cochrane review concluded that massage therapy may be beneficial for patients with subacute and chronic non-specific LBP, particularly when combined with exercises and education. They also noted that the results of one high quality study showed that the benefits of massage last as long 1 year following the end of active treatment (11). The benefit obtained from massage exceeded that achieved from relaxation, education or acupuncture. However, the beneficial effects may be less than that provided by spinal manipulation or TENS. The Cochrane Review noted that there is insufficient evidence regarding the effects of massage on acute back pain and on specific forms of massage for chronic LBP.
Although the Cochrane review represents a synthesis of the most rigorous trials to date examining massage for LBP, it should be noted that the review based their conclusions on a relatively small number of studies. For example, their conclusions regarding the superiority of massage to relaxation and acupuncture were based on only a single study each, and therefore await further confirmation in future trials. On the other hand, the studies included in the review demonstrated therapeutic effects for massage that exceeded or equaled those obtained from various active treatment conditions. This level of evidence is more encouraging than that obtained from trials showing that massage is superior to no treatment or waitlist control.
Pain Management for Headaches from Massage Therapy
The Cochrane Collaboration also published a recent review of non-invasive physical treatments for chronic/recurrent headache (15). This review included studies published until November 2002 and was substantively updated in May 2004. The review studied five types of headaches (i.e. migraine, tension-type, cervicogenic, mixed tension-type and migraine and post-traumatic headache), and a broad range of treatments were examined. Of the 22 studies that met inclusion criteria, only one trial, reported in two studies (16,17) examined the impact of massage on headaches. In this trial, massage plus placebo laser was compared with spinal manipulation for cervicogenic headache. The findings of this study indicated that spinal manipulation was superior to massage for headache pain intensity, headache duration and medication use (Table 2). The Cochrane review concluded that there is moderate evidence that massage plus placebo laser is inferior to spinal manipulation for pain intensity and duration in relation to cervicogenic headache.
The Cochrane review did not include the results of Wylie and colleagues (18) compared massage and relaxation to acupuncture for headache pain in patients with migraine or combined headache and patients with tension-type headaches. Patients received six sessions lasting 45 min. For the massage and relaxation condition, it is unclear how much of each session was devoted to relaxation which included muscle and breathing exercises as well as visualization techniques. All patients exhibited significant decreases in pain total index (PTI; monthly number of headache hours multiplied by severity) and headache index (HI; monthly number of attacks multiplied by severity). For patients with tension-headaches (n = 40), there was no difference in pain outcomes based on intervention type. However, for patients with migraines (n = 27), those who received massage had significantly lower PTI and HI scores than those who received acupuncture (Table 2). The number of migraine days did not vary across treatments. These findings suggest that massage may be superior to acupuncture for migraine headaches. But, because massage was combined with relaxation and other self-help techniques, it is not possible to draw definitive conclusions regarding the specific effects of massage based solely on these findings.
Craniosacral therapy is based on the notion that movement restrictions in the cranial structures of the skull adversely impact rhythmic impulses conveyed through the cerebral spinal fluid from the cranium to the sacrum (19). Thus, craniosacral therapy is a form of massage that uses gentle pressure on the plates of the patient's skull. Few controlled studies have been conducted on craniosacral therapy and a recent review concluded that there is insufficient evidence to support the effectiveness of this approach (19). One study, not included in the review, examined the CV-4 craniosacral technique on tension-type headaches (20). The CV-4 technique moves with the narrowing and widening of the skull, or the cranial rhythm; the basis of the technique is the compression of the fourth ventricle. Sixty patients were randomly allocated to one of three conditions: (i) a 10 min session during which multiple still points were induced by the CV-4 technique; (ii) a 10 min session during which the head and neck were positioned according to the resting position technique; (iii) a 10 min no treatment control. Immediately following treatment, the CV-4 group reported less pain intensity and pain affect than the control group; there were no differences between the resting position group and controls.
Moderate Evidence for Cranioscaral Massage in Managing Tension-Type Headache Pain
There have been surprisingly few published RCT's on massage therapy for headache pain. The single study included in the Cochrane review of non-invasive treatments for recurrent/chronic headache found that spinal manipulation resulted in greater pain reduction than massage plus sham laser for cervicogenic headache. One other study reported that massage may be more beneficial than acupuncture for migraine headaches but that both approaches were equally effective for tension-type headaches. A single study found that craniosacral therapy led to superior pain reduction compared with rest positioning and no intervention for tension-type headaches. This latter study using CV-4 technique was included in a recent review of manual therapies for tension-type headaches (21). The review authors gave this study a score of 6 out of 10 possible points for methodological quality, suggesting that there is moderate evidence from this trial that the CV-4 technique exerts a beneficial effect on pain related to tension-type headaches. As noted in the review, given that headaches are among the most common problems seen in medical practice (22), there is an urgent need to establish the effectiveness of manual therapies, including massage in the treatment of headache pain. The review also noted that not only is tenderness of the pericranial myofascial tissues one of the prominent features of tension-type headache, myofascial tissues may play an important role in the genesis of such headaches (23). Because the aim of soft tissue manipulation is to alter mechanical stress caused by myofascial tissue disorders, the review concluded that massage techniques may therefore be an effective therapy for tension-type headaches. However, further large-scale studies are needed before conclusions regarding the effectiveness of massage for tension-type or other types of headaches can be drawn.
Shoulder Pain — Moderate Support for the Use of Massage Therapy
Three analyses examined the effects of massage for shoulder pain. The first study compared acupuncture to Trager Psychophysiological Integration (a form of massage) in 18 patients with chronic shoulder pain who used manual wheelchairs as their primary means of mobility (24). Each patient received 10 treatments over 5 weeks; the acupuncture sessions lasted approximately 20–30 min and the Trager sessions lasted approximately 45 min. By 5-week follow-up, both groups exhibited improvements in pain and range of motion (see Table 3); there were no significant differences between groups. The study authors concluded that both acupuncture and Trager were effective for shoulder pain in wheelchair users. In their meta-analysis of massage therapy effects (discussed subsequently) this study was included as evidence supporting the benefits of massage on the delayed assessment of pain (i.e. pain that is assessed following a period after which no treatment is delivered).
Mok and Woo (25) analyzed hospitalized stroke patients with shoulder pain who were randomly assigned to receive slow-stroke back massage (SSBM) (26) or no intervention control. SSBM was administered for 10 min before bedtime for seven consecutive days. Patients who received SSBM experienced decreases in pain, anxiety, heart rate and blood pressure, compared with no such changes in controls (see Table 3). Another study (27) compared patients with shoulder pain who received six 15–20 min sessions of massage over two weeks (n = 15) to a waitlist control (n = 14). Patients who received massage improved significantly in functional disability, pain, and range of motion, whereas the control group evidenced no changes on these outcomes (Table 3).
These results provide moderate support for the use of massage for shoulder pain. However, the patient characteristics varied greatly across studies (e.g. stroke patients; wheelchair users) suggesting that generalizability of the findings may be limited. Moreover, with the exception of Mok and Woo (25) these studies had small sample sizes and only the study by Dyson-Hudson et al. (24) included a follow-up assessment. Finally, two of these studies compared massage with no treatment control. Additional studies are needed to determine whether massage therapy leads to improvements in shoulder pain when controlling for non-specific effects of treatment (e.g. increased clinician time/attention). Replication of these findings of these three studies in larger samples and with longer follow-up evaluation periods is warranted.
Comparison with Acupuncture for Neck Pain
Another group (28) examined patients with chronic neck pain randomly assigned to one of the following conditions: acupuncture (n = 56), massage (n = 60), ‘sham’ laser acupuncture (n = 61). Patients received five 30-min treatments over 3 weeks. For the main outcome, pain VAS (0–100) ratings, acupuncture was superior to massage, but no different than sham laser immediately after treatment. However, by 3-month follow-up, there were no differences between acupuncture and massage or between acupuncture and sham laser (Table 3). Among the secondary measures, acupuncture showed more improvement than massage across most measures assessed immediately post-treatment. Nevertheless by 3-month follow-up, acupuncture was superior to massage only on spontaneous pain, global complaints and motion-related pain.
Effectiveness of Massage Therapy for Neck Pain Remains Unclear
The authors of the previous work concluded that acupuncture appears to be effective in the short-term for chronic neck pain, it should be noted that by the 3-month follow-up, acupuncture was no more effective than massage or sham laser acupuncture on most outcome measures. Unfortunately, the study did not include direct comparisons between the massage and sham laser conditions. Therefore, it is not possible to determine whether massage was superior to a placebo condition. An unpublished master's thesis (29) has been cited in a recent meta-analysis as providing support for the longer-term effects of massage on pain (30). These studies were included in a very recent Cochrane Review on massage for mechanical neck disorders (31), which also included a broad array of interventions such as traditional Chinese massage, ischemic compression, self-administered ischemic pressure using a J-knob cane, and occipital release, among others. The review authors noted that many of these approaches were of questionable value. The review concluded that no practice recommendations could be made since the effectiveness of massage for neck pain remains unclear.
Preliminary Support for Pain Relief in Carpal Tunnel Syndrome
Patients with carpal tunnel syndrome (CTS) were randomly assigned to either a 4-week course of massage therapy or usual care (32). The massage group received a 15-min massage once a week from a massage therapist and were also taught self-massage to be done daily at home prior to bedtime. The massage group evidenced improvements in pain, grip strength, anxiety and depression compared with no such improvements in the control group (Table 3). Physician assessments of carpal tunnel symptoms also indicated significant improvements in the massage group versus no change in the control group.
The findings of this single study provide preliminary support for the application of massage to CTS. However, the sample size was very small, and it is unclear whether the physicians assessing the patients were aware of group assignment. Moreover, it is unclear to what extent patients practiced self-massage at home and whether the amount of massage administered was related to treatment response. Further work with larger samples and more rigorous study methodology are needed to determine the effectiveness of massage therapy for CTS.
Equivocal Support for Analgesic Effects in Fibromyalgia
The effects of massage therapy on fibromyalgia have been examined in four investigations. Two of these studies were conducted by Tiffany Field and colleagues. In the first study (33), women with fibromyalgia were randomly assigned to receive massage, TENS or sham TENS for 30 min twice a week for 5 weeks. Immediately following treatment on the first and last days, the massage therapy group evidenced reductions in anxiety, depression and salivary cortisol. The TENS group experienced the same improvements but only on the last day. The sham TENS groups demonstrated no such improvements. By the end of treatment, the massage therapy group reported less pain, stiffness, fatigue and difficulty sleeping (as assessed via interviews), as well as improvements in dolorimeter test value and physician's assessment of clinical condition (Table 4). The TENS group improved on this latter measure only. Limitations of this study include inadequate information regarding the interview items. Moreover, it was unclear whether interviewers and physicians were blind to patient group assignment.
The Field group (34) also randomly assigned fibromyalgia patients to receive either massage therapy or progressive muscle relaxation (PMR) for 30 min twice a week for 5 weeks. Both groups reported reductions in anxiety and depression immediately following treatment on the first and last days. By the end of treatment, the massage group evidenced significant reductions in self- and physician-assessed pain and symptoms, as well as reductions in the number of tender points and substance P levels (Table 4). No significant improvements were seen in the PMR group.
Brattberg (35) randomly allocated patients with fibromyalgia to massage therapy or no treatment control. The massage group received 15 massages of indeterminate length over 10 weeks. Comparisons immediately post-treatment revealed greater improvements in pain, depression and quality of life in the massage group relative to controls, but no differences in disability, sleep disturbance or anxiety (Table 4). Brattberg maintained that there was a 37% reduction in pain following the massage treatment but that 30% of the improvement in pain had disappeared by 3-month follow-up and 90% of the reduction in pain was gone by the 6 month follow-up. Thus, it appears that the benefits of massage for fibromyalgia do not persist over the longer-term after the termination of active treatment. Brattberg recommended that following an initial treatment of 15 sessions, maintenance therapy may be instituted (e.g. once or twice per month).
Another study randomly assigned 37 patients with fibromyalgia to one of three conditions: massage, usual care, usual care with follow-up phone calls from a nurse (36). The massage group received 10 treatments of indeterminate length over 24 weeks.
Unfortunately, only 16 patients completed the full study protocol (six patients in the each of the two usual care groups and four patients in the massage group). Although the massage group showed a trend towards greater improvement in pain and self-efficacy for managing their condition, there were no between-group differences by the end of treatment (Table 4), likely due to the small cell sizes.
Summary — Massage Therapy for Fibromyalgia
The evidence supporting the use of massage for fibromyalgia is mixed. Whereas the Field group has found that massage leads to improvements in pain and symptoms compared with relaxation (33) or TENS (34), their work suffers from methodological limitation such as small sample size, inadequate blinding of assessors and an absence of follow-up assessments. The two other studies found either no benefits for massage (36) or only short-term benefits that eroded over time (35). Replication of the positive results reported by the Field group in an independent research group would increase confidence in their findings.
Application to Mixed Chronic Pain Conditions
Whereas the majority of existing trials of massage therapy have examined patients with discrete chronic pain syndromes, three studies have investigated the impact of massage on patients with a variety of chronic pain complaints. Walach and colleagues (37) conducted a randomized controlled trial comparing massage therapy (10–20 min sessions administered twice weekly for 5 weeks) to usual care for patients with various chronic pain symptoms (i.e. lower back, neck, shoulders, headaches). By 3-month follow-up, patients who received massage reported less pain, depression, anxiety and tiredness relative to controls (Table 5). However, the study authors noted that their study was limited due to lack of equivalence across groups on demographic characteristics. Moreover, it is unclear whether the groups were similar in terms of the type of pain complaints represented or important clinical characteristics such as the duration and/or severity of pain.
Another study randomly assigned patients with chronic pain to receive either massage or relaxation (listening to a PMR tape recording) (38). The massage group received 6–10 sessions lasting 30 min each; patients were treated 1–3 times per week. The relaxation group listened to the audiotape twice a week for 5 weeks. Although the massage group evidenced improvements in pain, mental energy and self-perceived health status compared with the relaxation group immediately following treatment, by 3-month follow-up, there were no differences between groups.
In a third analysis, patients with chronic musculoskeletal pain were randomly assigned to mindfulness-based stress reduction (MBSR), massage or usual care (UC) (39). MBSR involved 8 weekly 2.5-h sessions in a group format, with audiotaped meditation exercises assigned as daily home practice. The massage group received 1-h massage once per week for 8 weeks. At post-treatment, the massage group reported less pain unpleasantness and improved mental health compared with the usual care group. However, by 1-month follow-up, there were no differences among the groups in pain intensity or pain unpleasantness (Table 5).
Moderate Support for Short-term Benefits of Massage Therapy for Mixed Chronic Pain Conditions
These reports provide modest support for the immediate benefits of massage for a variety of chronic pain complaints. However, it appears that these treatment gains were not maintained following the end of active treatment. A potential difficulty with such studies including heterogeneous pain complaints is ensuring that treatment and control conditions are equivalent on key clinical and demographic characteristics. On the other hand, evidence of therapeutic effects across a variety of pain conditions supports the generalizability of the findings to a potentially broader group of patients. Future studies incorporating samples with mixed chronic pain conditions may also examine which types of pain conditions may benefit most from massage therapy in order to promote a more targeted approach to treatment.
Meta-Analysis — Massage Therapy Effects on Pain
As noted above, the majority of primary analyses and review articles have focused on the application of massage to discrete pain conditions. Moyer and colleagues (30) have published a recent meta-analysis of massage therapy research that examined the effects of massage for a variety of both chronic and acute pain symptoms. Data across trials were aggregated to investigate these effects across pain conditions on the immediate and delayed assessment of pain. According to Moyer et al. (30), immediate assessment of pain pertains to ‘single dose effects’ or short-term effects observed on the same day following massage therapy. The delayed assessment of pain reflects ‘multiple dose effects,’ which refers to outcomes that were assessed at various time points after treatment has been discontinued and following multiple sessions of massage. It should be noted that several of the studies included in this meta-analysis were also included in the Cochrane reviews discussed earlier in this article.
Moyer and colleagues (30) concluded that massage therapy did not exhibit a significant effect on the immediate assessment of pain. The studies included in this category examined a wide range of pain problems ranging from back pain, neck pain, cancer pain, headaches and fibromyalgia, as well as acute pain in relation to surgery and other procedures (e.g. amniocentesis; cardiac catheterization). However, Moyer et al. (30) did conclude that massage evidenced a significant effect for the delayed assessment of pain. They maintained that patients who received a course of massage and were evaluated several days or weeks after the end of active treatment exhibited levels of pain that were on average 62% lower than controls. This conclusion was based on the results of 5 studies—two of these were conducted with patients experiencing LBP (9,11), one was conducted with patients with tendonitis (40), one was conducted with patients experiencing shoulder pain (24) (discussed earlier in this article), and one was an unpublished master's thesis (29) examining patients with neck pain.
It should be noted that the Moyer et al. (30) analysis of the delayed assessment of pain did not include three of the trials discussed earlier in this article that did not find long-term benefits for fibromyalgia (35) and mixed chronic pain (38,39). The latter two studies were published after the Moyer review was completed; it is unclear why the study on fibromyalgia was not included in the meta-analysis. Nevertheless, the rigorous approach employed by Moyer and colleagues, which expressly included the calculation of between-group effect sizes and the aggregation of data across numerous trials lends confidence to their overall conclusion that multiple applications of massage therapy appears to confer lasting benefits on pain. Their work did not however, speak to the time period over which such analgesic effects are maintained, or the rate at which such effects decay. These considerations warrant further examination in additional studies.
Discussion
The existing literature provides varying levels of support for the effectiveness of massage therapy for chronic pain. The most abundant and rigorous evidence was found for the effects of massage on non-specific LBP. The Cochrane Collaboration (3), concluded that massage therapy may be beneficial for patients with subacute and chronic non-specific LBP, especially when combined with exercises and education. Whereas the evidence supporting the application of massage for LBP is fairly robust, there is less support for the use of massage for the other chronic pain conditions reviewed. This review suggests that the level of evidence for massage therapy effects by pain condition is (in order from most to least): LBP, shoulder pain, headache pain, fibromyalgia, mixed chronic pain, neck pain and CTS.
Although shoulder pain has been the subject of only three studies, all of the studies yielded positive outcomes for pain and were methodologically rigorous, with one study including over 100 patients (25). Moreover, one of these studies was cited by Moyer et al. (30) in their meta-analysis indicating that massage therapy demonstrates significant effects on the long-term assessment of pain. Like shoulder pain, massage for headache pain has only been the subject of three studies but the data are somewhat weaker. The Cochrane Collaboration (15) concluded that there is moderate evidence that spinal manipulation is superior to massage plus placebo laser for pain related to cervicogenic headache, although these conclusions were based on the results of a single trial reported in two studies (16,17). Two additional studies provided preliminary evidence for the benefits of massage and craniosacral therapy in the treatment of pain related to migraine headaches (18) and tension-type headaches (20), respectively. However, in the migraine study (18), massage was combined with relaxation and other self-help techniques, making it difficult to draw conclusions regarding the specific effects of massage.
There is considerably less support for the effectiveness of massage therapy in treating the remaining chronic pain conditions. Of the four studies examining massage therapy for fibromyalgia, only two studies, both by the same research group, revealed therapeutic effects (33,34), whereas the other two studies found no benefits (36) or improvements that attenuated over time (35). Thus, there is only modest evidence for the effectiveness of massage for pain related to fibromyalgia. For mixed chronic pain, the three studies to date provide somewhat conflicting findings. Whereas one study found that massage was superior to usual care (37), two other studies found that by follow-up, massage was no better than relaxation (38), mindfulness meditation or usual care (39). Taken together, these studies provide fairly weak support for the application of massage to mixed chronic pain. For neck pain, one trial using conventional massage techniques found that massage was similar to acupuncture by 3-month follow-up. A recent Cochrane review which included a broad array of massage techniques, many of which were considered questionable, reported that no firm conclusions could be drawn regarding the effectiveness of massage for neck pain (31). Only one published trial has investigated massage therapy effects on CTS; this study found that massage was superior to no treatment. Based on these findings, there is only preliminary evidence to support the effectiveness of massage for both neck pain and CTS.
Putative Mechanisms of Massage Therapy for Chronic Pain
The precise mechanism of action in massage therapy is not known. It has been proposed that increased parasympathetic activity (41) and a slowed-down physiological state may underpin the behavioral and physiological processes associated with massage. As discussed by Wright and Sluka (42), massage is thought to induce a variety of positive physiological effects that may contribute to tissue repair, pain modulation, relaxation, and improved mood. For example, these authors point to research showing that massage has beneficial effects on arterial and venous blood flow and edema (43). In addition, they note that vigorous massage has been shown to increase local blood flow and cardiac stroke volume (44), as well as improve lymph drainage (45); massage also appears to have an anticoagulant effect (46). Finally, Wright and Sluka maintain that massage may activate segmental inhibitory mechanisms to suppress pain and that some techniques may activate descending pain inhibitory systems (43), as suggested by gate theory (discussed subsequently).
The main theories regarding the analgesic effects of massage include gate theory, the serotonin hypothesis, and the restorative sleep hypothesis (47). According to gate theory (48), pressure receptors are longer and more myelinated than pain fibers, and thus pressure signals from massage are transmitted faster, closing the gate to pain signals. The serotonin hypothesis maintains that massage increases levels of serotonin, a neurotransmitter that modulates the pain control system (49). The restorative sleep hypothesis holds that because substance P, a neurotransmitter associated with pain is released in the absence of deep sleep, the ability of massage to increase restorative sleep reduces substance P and consequent pain (50). There is little definitive data to support these major theories concerning the mechanisms underlying the analgesic benefits of massage.
Clinical Implications: The Application of Massage Therapy for Chronic Pain
The existing literature suggests that massage therapy may be a useful approach for pain relief in a number of chronic, non-malignant pain conditions, particularly musculoskeletal pain complaints (e.g., shoulder pain, low back pain). Massage is typically administered as adjunct therapy to help prepare the patient for exercise or other interventions and is rarely administered as the main treatment (3). Thus, massage is not usually considered a first line treatment, but rather as a complement to other conventional first line approaches (e.g., physical therapy; medications). It should be noted that the studies reviewed above did not specifically report on findings regarding possible interactions of massage therapy with other CAM or conventional medicine approaches. Nevertheless, the increasing popularity of massage and the fact that it is typically used as an adjunctive approach with other established treatments suggests that massage may be successfully integrated into the treatment of a variety of chronic or recurrent non-malignant pain conditions. The paucity of data on negative side effects pertaining to massage does not necessarily mean that such effects do not exist. Future work should focus on systematically characterizing those patients for whom massage is not indicated.
Future Directions: Critical Issues for Studies on Massage Therapy for Chronic Pain
This review highlights the need for continued rigorous research on the effectiveness of massage therapy for chronic, non-malignant pain conditions. Somewhat surprisingly, this review indicated that very few studies to date have focused on massage for pain related to chronic/recurrent headaches and chronic neck pain. Given that massage promotes relaxation, it would appear to be a particularly appropriate therapy for tension-type headaches as well as migraine related to increased stress. Moreover, at pointed out above, massage therapy may alter the mechanical stress caused by myofascial tissue disorders (21) which have been implicated in tension-type headaches (23). In light of the contradictory findings noted above, future work may also continue to examine massage therapy effects on pain related to fibromyalgia which involves wide-spread, diffuse pain that is often not responsive to traditional approaches.
Numerous methodological problems were noted in the studies reviewed including small sample sizes, lack of equivalence across treatment and control groups, and inadequate blinding of assessors. However, one of the most notable limitations of the literature as a whole is that very few studies included follow-up assessments. As indicated by Moyer et al. (30) in their meta-analysis, the beneficial effects of massage therapy on pain are predominately evidenced after the end of active treatment. They concluded that such delayed effects on pain were substantial, with patients who were evaluated several days/weeks after treatment cessation exhibiting on average 62% less pain than controls and one study on LBP revealed significant benefits from massage persisting 1 year after the cessation of active treatment (11). It should be noted however, that the conclusions by Moyer et al. (30) were based on only 5 studies, suggesting that future trials of massage therapy should include follow-up assessments in order to further quantify such delayed effects. Moreover, additional studies may focus on examining the optimal time periods for the scheduling of ‘booster’ sessions to maintain treatment gains. Previous work has suggested that psychological treatment delivered according to a schedule with increasing time intervals between sessions (e.g. 1, 4, 10 intervening days) is more effective over the long-term compared to a uniform schedule (e.g. 5, 5, 5 intervening days) of treatment delivery (51). Thus, future research may also examine the optimal treatment schedule for delivery of massage therapy with a view to enhancing longer-term analgesic effects.
Limitations of the Current Review and Concluding Statements
The main limitation of the current study is its reliance on existing reviews and meta-analyses. Thus, many of the conclusions drawn in this article are based on the findings of other authors. Relatedly, the soundness of the methodological approach of these existing reviews may have been limited (e.g. due to improper exclusion of specific studies) as well as highly variable across reviews. Nevertheless, the reliance on extant reviews was considered necessary in order to synthesize a vast and diverse literature examining a broad array of chronic pain conditions. Another limitation of the present study is that only those pain conditions that were the subject of at least one controlled trial of massage therapy were included. Thus, not all chronic pain problems were examined in this review. It is possible that positive effects for massage therapy on other chronic pain conditions may have been reported in uncontrolled trials and/or case studies.
In sum, this review identified important areas for future research on the effectiveness of massage therapy for chronic, non-malignant pain. Whereas there is fairly robust support for the analgesic effects of massage for non-specific LBP, there is only moderate support for such effects on shoulder pain and headache pain. Extant literature provides only modest, preliminary support for massage in treating fibromyalgia, mixed chronic pain, neck pain and CTS. One of the most important methodological considerations that should be addressed in future trials is the inclusion of follow-up assessments in order to allow further quantification of the longer-term effects of massage therapy on pain. Another key methodological consideration is the inclusion of comparison conditions that control for non-specific effects including physical contact and therapist time and attention. Moyer et al. (30) in their meta-analysis maintained that their positive findings for delayed assessment of pain are consistent with the notion that massage may promote pain reduction by enhancing restorative sleep. However, they note that data on sleep patterns was not included in the studies reviewed and therefore, this possibility remains to be tested. Thus, the careful consideration of potential mechanisms may inform future research, particularly with respect to the inclusion of key outcome variables as well as the examination of possible moderators and mediators of treatment response. Additional rigorous research is needed to establish massage therapy as a safe and effective intervention for the treatment of chronic, non-malignant pain.

low back pain
headache pain
recurrent pain
musculoskeletal pain
fibroymalgia