This was a randomised, open, crossover trial of 3 weeks duration (7 weeks in both periods included) to test the efficacy of WBC as adjuvant therapy for the control of pain and impact of disease in patients with FM. The study protocol and materials were approved by the Clinical Research Ethics Committee of the Hospital Puerta de Hierro of Madrid (TIME-CRY-2015-01, V04 JULIO 2016-Meeting 2016-07-11).
Eligible patients were recruited consecutively from participating general practices. Selection criteria included: age between 25 and 80 years old; diagnosis of FM according to ACR criteria ; more than 1 year from diagnosis; lack of response or partial response to previous treatment; in case of women, commitment not to get pregnant during the study. Participants were excluded if they had cardiovascular or psychiatric comorbidity, cold intolerance, changes in pharmacological or non-pharmacological treatment during the study—including treatment changes at baseline—or a body temperature over 37.5 °C.
After inclusion, subjects were randomly assigned to a sequence starting by WBC or control using a randomization scheme generated through the http://www.randomization.com website .
Patients on WBC group were treated on alternate days during 3 weeks. At each session, patients were introduced in Cryosense TCT™ cabins during 3 min, where temperatures reached − 196 °C—the evaporation point of liquid nitrogen—. After ten sessions, patients underwent a 1-week washout period to eliminate any possible residual effect of the previous application of WBC. Subsequently, the groups were inverted; those initially treated with WBC became controls and vice versa (Fig. 1). In addition, patients maintained current treatment (pain-killers on a regular basis) without modification during the duration of the study.
Trial main endpoints were changes in pain, assessed by a 10 cm visual analogue scale (VAS), and in impact of disease, assessed by the Fibromyalgia Impact Questionnaire (FIQ) . As secondary endpoint, changes in the severity of the disease were tested, assessed by the Combined Index of Severity of Fibromyalgia (ICAF) , and on the SF-36. The FIQ is a self-administered questionnaire that tests the ability to perform large muscle tasks, difficulty with work, pain, fatigue, morning tiredness, stiffness, anxiety and depression; it contains ten items with a range of scores from 0 to 100, with higher score indicating greater impact.
On the other hand, ICAF is a tool for assessing the severity of FM based on its most prevalent clinical manifestations, resulting in a total score of the severity where higher scores represent greater importance of the condition and its consequences in the patient’s life. The ICAF questionnaire also provides information on emotional, physical, and of coping (active and passive) aspects of the patient. The emotional factor emphasizes the role of emotional aspects such as anxiety and depression; the physical factor assesses pain, fatigue, sleep quality and functional ability; active coping includes positive coping strategies, and passive coping identifies a group of particularly severe patients. The ICAF contains 59 items and its score ranges from 0 to 84, with higher values indicating greater severity .
All patients were assessed after 22 and 50 days from period start—visits 3 and 6, corresponding to the evaluation of the first and second periods, respectively—(see Table 1 at supplementary material for an outline of study procedures and assessments).
Secondary endpoints were 50% reduction of pain at days 10 and 22, and changes in quality of life (SF-36) .
A sample size of 60 participants was deemed sufficient to detect a significant treatment group difference on pain VAS, accounting for a dropout rate of 20% (power 80% and alpha level of 0.05).
The sample was described by summary statistics (mean and standard deviation, frequencies and percentages). Differences between groups at baseline (visit 1 and visit 4, or baseline after washout) were tested with Student’s t or Mann–Whitney U tests, depending on the distribution of continuous variables, and Chi square for qualitative variables. Normality was tested with the Kolmogorov–Smirnov test.
Within-group differences in outcome measures by time were assessed using repeated measures ANOVA.
Sequence and period effects were evaluated. The comparison of response in terms of ∆VAS pain and ∆FIQ, and of the secondary outcomes, between treatment groups was carried out using Student’s t or Mann–Whitney U tests, depending on the distribution of the respective variables, with an intention to treat approach.
Finally, and to take account possible differences in baseline between both study groups, multiple linear regression was used. Models were constructed using the outcome measures as dependent variables, and treatment group, controlling for variables with significant baseline differences (complete model), as independent variables. Backward stepwise regression was used for modelling variables selection with successive elimination of those without confounding effect. Comparison of models was performed by information measures, Akaike information criteria (AIC), and Bayesian information criteria (BIC). The final models were the most parsimonious and with the lowest values on information criteria.