Exercise is the first-line treatment for knee osteoarthritis (KOA). Cryotherapy is used to control pain and inflammation, but robust evidence on its benefits is lacking.
ObjectiveAnalyze the additional effects of cryotherapy, when associated with an exercise protocol, on pain, function, and quality of life in people with KOA.
MethodsA randomized controlled trial with sham and control groups, concealed allocation, blinded assessors, and intention-to-treat analysis. Individuals (n = 120) aged from 40 to 75, with knee pain ≥ 4 cm on 10 cm visual analog scale, and radiographic diagnosis of grade 2 or 3 (Kellgren and Lawrence) were included and divided into 3 groups (n = 40 per group): Exercise; Exercise + Cryotherapy; Exercise + Sham Cryotherapy Treatment was delivered 3 times per week for 8 weeks (24 sessions). Primary outcome was pain intensity (Visual Analog Scale). Secondary outcomes were physical function [Western Ontario and McMaster Universities (WOMAC)] and functional tests: 30-second sit-to-stand test, stair climbing test, 40-meter fast walking test, and quality of life [36-item Short Form Health Survey (SF-36)].
ResultsAt post-intervention, for pain at rest, there were no between-group differences: Exercise vs. Exercise + Cryotherapy (mean difference, MD = -0.46 [confidence interval, 95 % CI: -1.97, 1.05]), Exercise vs. Exercise + Sham (MD = -1.27 [95 % CI: -2.78, 0.23]), Exercise + Cryotherapy vs. Exercise + Sham (MD = -0.82 [95 % CI: -2.32, 0.69]). At follow-up period, the results also did not show between-group differences (p > 0.05).
ConclusionResults showed the beneficial effects of exercise in the treatment of KOA, without additional effects of cryotherapy.
Knee osteoarthritis (KOA) is a clinical chronic and progressive condition,1 according to the Global Burden of Diseases from 2020, 595 million people live with some form of osteoarthritis, with the knee joint being the most affected.2 KOA prevalence is related to increased obesity and higher life expectance.1 The pathophysiology of KOA is a dynamic process,1 initially characterized by an imbalance between repair and damage mechanisms affecting joint structures (e.g. bones, cartilage, tendons, and ligaments).3,4 This process may be triggered by various factors, including mechanical, inflammatory, and metabolic alterations.1,5 As the disease progresses, the composition of the articular cartilage is altered, compromising its structural integrity.5 The most common signs and symptoms of this disease are pain, knee morning stiffness <30 min, physical function limitations, such as difficulty walking, sitting, and performing self-care activities, and reduced quality of life.1 Pain is the primary symptom driving clinical decision-making,6 and its management is associated with high socioeconomic costs.7
The clinical practice guidelines (OARSI)8 and (EULAR)9 recommend a combination of non-pharmacological and pharmacological strategies to improve clinical symptoms and increase the quality of life in individuals with KOA. Among the non-pharmacological treatment options, physical exercise, patient education, and weight loss (for overweight or obese individuals) constitute the first-line treatment approach for KOA.7,10
Strategies that reduce pain and can be combined with exercise have great potential for managing skeletal muscle disorders. Cryotherapy is also a non-pharmacological intervention commonly used to reduce pain and inflammatory processes in skeletal muscle disorders.11 Furthermore, cryotherapy is a low-cost and easily to apply resource, that can be used isolated or in combination with physical exercise.12 Cryotherapy was effective in reducing the local inflammation, with less migration of leukocytes and proinflammatory cytokines,13,14 as well as higher protection of the neuromuscular junction in animal models with induced KOA.15
Clinical recommendations for the use of cryotherapy in KOA remain controversial. While some guidelines conditionally recommend cryotherapy for managing KOA,8,16 others either do not mention or do not recommend it.9,17 Barriers to making consistent recommendations include methodological issues in studies, such as the lack of concealed allocation and the absence of blinded assessors, which increase the risk of bias.18,19 Additionally, the wide range of applications, short-term effects, and variability in technique reported in the literature, contribute to the difficulty in providing a clear recommendation.16
Thus, this superiority randomized controlled trial aimed to evaluate the additional effects of cryotherapy combined with an exercise protocol on pain intensity, physical function, and quality of life in individuals with knee osteoarthritis. We hypothesized that the group receiving Exercise + Cryotherapy would show better outcomes compared to Exercise and Exercise + Sham Cryotherapy groups.
MethodsThis study followed the recommendations for Clinical Trial Interventions (OARSI guidelines) and Template for Intervention Description and Replication (TIDier).3,20 It was previously registered with Clinical Trial (Register Number: NCT03360500). The results were reported according to Consolidated Standards of Reporting Trials (CONSORT) for randomized trials of non-pharmacological treatments,21 and it was previously registered and approved by the Institutional Human Ethics Committee of the Universidade Federal de São Carlos, São Carlos, São Paulo, Brazil. The protocol of this study was previously published, and more details about the methodology can be accessed elsewhere.22
DesignThis is a sham-controlled randomized clinical trial. Verbal and written information about the benefits and harms of the intervention was given to the participants and, they signed the consentient term that was previously approved by the Ethics Committee.
Sample sizeAs previously published,22 we aimed to detect a minimum clinical important difference (MCID) of 1.75 cm on the Visual Analogue Scale (0–10 cm), for knee pain (primary outcome)23 and an MCID of 30 points, in the general score of the WOMAC questionnaire (secondary outcome).24 Thus, the sample size (N) calculation was based on an analysis of covariance adjusting for baseline outcome scores, assuming a standard deviation of 2.0 for pain and 45 points for WOMAC, with a statistical power of 80 %, and a significance level of 5 %. The analysis indicated that 37 volunteers were needed in each group. Considering a sample loss of 10 %, 40 participants were recruited for each group, totaling 120 participants.
ParticipantsParticipants were recruited through public announcements on social media, local advertisements, and by contacting a list of participants at our research group. Initially, those interested in participating underwent a remote assessment via telephone. If the eligibility criteria were met, an in-person assessment was scheduled to confirm the eligibility criteria and clinical assessment. Eligible participants underwent a lateral, anteroposterior, and axial radiography of both knees to determine de KOA structure severity at the University Hospital. The diagnosis of KOA was based on the clinical and radiographic criteria of the American College of Rheumatology (ACR)25 and all participants had to present grades 2 or 3, according to the Kellgren and Lawrence criteria, in at least one compartment of the knee joint.3
Participants of both sexes, aged between 40–75 years, who engaged in moderate to intense physical exercise for <45 min per week,26 with body mass index (BMI) < 35 kg/m2, and reported knee pain intensity ≥ 4 cm on the 10 cm visual analog scale in the previous week3 were included in the study. Exclusion criteria were having undergone physical therapy in the last 3 months, having received joint infiltration in the last 6 months, having decompensated cardiovascular complications, neurological disorders, or other rheumatologic conditions, having undergone hip, knee, or ankle surgery, or having any other chronic condition that leads to chronic pain. Individuals with allergies or contraindications to the use of cryotherapy were also excluded.
RandomizationThe randomization sequence was provided by a computer program (www.randomization.com) and carried out by a researcher who had no contact with the participants. The allocation was made in opaque and sealed envelopes, and it was stored in a central location. The researcher responsible for randomization also informed the group allocation of each participant to the responsible physiotherapist on the first day of intervention. This researcher was not involved in any other study procedures. This information was added in the randomization section.3
Eligible participants were allocated into 3 groups: 1- Exercise; 2- Exercise+ Cryotherapy (Exercise + Cryo) and 3- Exercise and Sham Cryotherapy (Exercise + Sham).
InterventionsThe participants underwent a group exercise intervention, combined or not with a cryotherapy session, in a physiotherapy clinic at Universidade Federal de São Carlos, São Carlos, São Paulo, Brazil, for 8 weeks, 90 min per session, 3 times a week, on non-consecutive days, totalizing 24 sessions. Two physical therapists delivered the intervention. Prior to the study, they received 10 h of scientific and clinical training on knee osteoarthritis, including instruction on how to apply the protocol and cryotherapy interventions. All randomized participants performed the same exercise protocol. According to randomization, after each session, they received 20 min of local cryotherapy or sham cryotherapy on the most affected knee. The group that did not receive the additional intervention remained lying down for the same period.
Exercise protocolThe 8-week supervised exercise protocol was developed following recommendations for non-pharmacological interventions in individuals with knee osteoarthritis.7,27 The protocol was divided into 2 phases of 4 weeks of progressive exercise, 3 times a week, in non-consecutive days. The intensity of the exercises was controlled individually, respecting the conditioning of each participant. The volitional interruption method was used to achieve the benefits of resistance training.28 All participants started without external resistance, and the loads were gradually increased (by 1 kg for free weight or elastic band resistance), until the participant was able to perform 12 repetitions adequately, without interruption due to muscle fatigue.28 Load adjustments were not made in every session, but were made according to participant perception. In case of missed sessions, it was not possible to reschedule the intervention. However, participants were instructed to use the same load as in the previous session or reduce it in case of repeated absences.
Cryotherapy and sham protocolThe cryotherapy protocol consisted of local application of cryotherapy, with bags of crushed ice, covering the entire joint of the most affected knee, for 20 min. Participants were positioned in the supine position, with their knees extended and their legs relaxed. The surface of the joint was covered with damp gauze (45 × 50 × 0.01 cm) to protect the skin from the cold. Subsequently, two plastic bags (24 × 34 × 0.08 cm), with 1 kg of crushed ice each, were positioned covering the entire joint and stabilized by an elastic band.29
The sham cryotherapy session adopted the same protocol described above. However, the plastic bags were filled with 1 kg of dry sand each, positioned on the most affected knee, and stabilized by an elastic band. The cryotherapy and sham cryotherapy protocols were based on a previously accepted methodology developed by our research group.30
AssessmentsThe assessments were conducted by two physical therapists, both doctoral students, who were “blinded” to the participant group allocation. To avoid bias, they were previously trained to follow a standardized script that described the general objective of the study and how to perform the assessment and functional measurements. The initial assessment (A1) was carried out one week before the intervention period and the second assessment (A2) was carried out after a short period after the last session (between 1 and 3 days after). To assess the residual effects of the intervention, follow-up assessments were carried out at 3 months (A3) and 6 months (A4) after the end of the intervention period. Each volunteer was assessed by the same physiotherapist.
Outcome measuresPrimary outcomeThe primary outcome was pain intensity assessed by the Visual Analogue Scale (VAS), at rest and after each physical functional test. This self-reported pain outcome is a valid and reliable measure for individuals with KOA.31
Secondary outcomeTo assess physical function and problems associated with KOA, the Western Ontario and McMaster Universities (WOMAC) questionnaire translated and validated in Brazilian Portuguese was used.32 The 36-item Short Form Health Survey, validated in Brazilian Portuguese was used to assess physical function quality of life in terms of social and emotional aspects.33 Three functional tests were performed to evaluate physical function: 30 s chair stand test, stair climb test, and 40 m fast-paced walk test.34 These tests are core assessment measures of physical function and are well established for the population with KOA, with reliability, validity, and ability to detect clinical changes.
Statistical analysisThe data were analyzed descriptively, using measures of central tendency and variability. Analyzes were performed by a biostatistician blinded to the patient allocation group, using commercial software SPSS (V.22.0; SPSS). The Kolmogorov - Smirnov test was applied to assess the normality of data distribution (p > 0.05). A two-way analysis of variance (ANOVA two-way) was conducted for the primary outcome (pain at rest) and secondary outcomes. The outcomes assessment periods (baseline and follow-up of 3 and 6 months) were used as a within-subject factor and the intervention groups as between-subject factors. Additionally, an intention-to-treat analysis was performed for all randomized participants. All missing data were imputed using the expectation-maximization method.25 MCID or minimal detectable difference (MDD) were also used to help interpret the results.35
ResultsA total of 354 participants were contacted for initial assessment. After applying the eligibility criteria and diagnostic examination to confirm knee osteoarthritis, 120 particpants were randomized and included in the 3 intervention groups (40 participants each). All participants received the intervention they were originally allocated. Most variables were normally distributed at baseline, including age, BMI, pain at rest, pain after physical tests, physical tests, WOMAC domains and SF-36 domains.
Adherence to the exercise protocol was monitored through attendance diaries. The Exercise + Cryotherapy group attended a mean of 17.85 sessions (SD = 5.65), corresponding to an attendance rate of 74.4 %. The Exercise + Sham Cryotherapy group attended a mean of 19.95 sessions (SD = 4.20), with an attendance rate of 83.1 %. The Exercise group attended a mean of 19 sessions (SD = 5.09), corresponding to an attendance rate of 79.2 %. When considering all participants, the overall mean attendance was 19.08 sessions (SD = 5.09), with an overall attendance rate of 79.5 %.
The detailed flow diagram with the participation of volunteers in each stage of the clinical trial is represented in Fig. 1.
Table 1 shows the baseline clinical and anthropometric characteristics of the three groups. Participants were similar for baseline outcomes. The mean age was 60.6 years (SD ± 8.1), BMI 29.7 kg/m2 (SD ± 2.3), and most of the participants were female (65 %).
Baseline characteristics of participants with knee osteoarthritis (KOA).
Data expressed as mean ± standard deviation and number (percentage). BMI: body mass index.
Table 2 presents the results for primary and secondary outcomes for each group in the four evaluation periods. There were no group x time interactions (p > 0.05) for any outcome. After an 8-week intervention, the three groups had a significant clinically improvement for both primary and secondary outcomes. In the follow-up period of 3 and 6 months, the benefits of the intervention were maintained compared to baseline (A1), however, they tended to worsen when compared to the post-intervention assessment (A2).
Outcome measures over time according to group allocation from an intention-to-treat analysis.
Data expressed as mean ± standard deviation (SD).
a. Visual Analogue Scale (VAS 0–10 cm); higher scores indicate worse pain intensity. Minimal Clinically Important Difference (MCID) for pain = 1.75 cm.
b. Western Ontario and McMaster Universities (WOMAC) score, range 0–96; higher scores indicate worse pain, stiffness, and physical function; MCID = 30 units.
c. Total number of repetitions within 30 s; MCID = 2 to 3 repetitions.
d. Time (seconds); Minimal Detectable Difference (MDD) for stair climb test = 5.5 s.
e. Speed (meters/seconds); MCID = 0.2 to 0.3 m/s.
f. 36-item short-form questionnaire (SF-36), range 0–100; higher scores indicate better health; MDD = 10 points.
For pain at rest, the results indicated that the group that received Exercise + Cryotherapy 3 times a week for 8 weeks did not have greater improvements than the Exercise and Exercise + Sham Cryotherapy groups. Although a greater reduction on pain was observed after the 30-second chair stand test for the Exercise + Sham Cryotherapy compared to the Exercise group, at the 3-month follow-up (−1.570, 95 % CI −2.75 to −0.4), this difference did not reach the MCID. Table 3 shows the overall between-group comparison results.
Estimated mean differences between groups for all outcomes at post-intervention and follow-up evaluations.
Data expressed as adjusted mean differences between groups (95 % confidence interval), p < 0.05.
⁎ Negative values indicate a better mean in the second-mentioned group.
⁎⁎ Positive values indicate a better mean in the first-mentioned group. No differences were found (p > 0.05).
a. Visual Analogue Scale (VAS 0–10 cm); higher scores indicate worse pain intensity. Minimal Clinically Important Difference (MCID) for pain = 1.75 cm.
b. Western Ontario and McMaster Universities (WOMAC) score, range 0–96; higher scores indicate worse pain, stiffness, and physical function; MCID = 30 units.
c. Total number of repetitions within 30 s; MCID = 2 to 3 repetitions.
d. Time (seconds); Minimal Detectable Difference (MDD) for stair climb test = 5.5 s.
e. Speed (meters/seconds); MCID = 0.2 to 0.3 m/s.
f. 36-item short-form questionnaire (SF-36), range 0–100; higher scores indicate better health; MDD = 10 points.
Overall, for secondary outcomes, the results from Table 3 show that there was no difference between the groups (p > 0.05). Also, the higher improvement of the total WOMAC score found for the Exercise + Sham Cryotherapy group compared to Exercise + Cryotherapy, at the 6-month follow-up (−15.16, 95 % CI −24.71 to −5.6) did not reach the MCID.
DiscussionThe results of this clinical trial indicate that adding cryotherapy after a supervised exercise protocol for individuals with KOA for 8 weeks did not provide additional beneficial effects with respect to the exercise alone on pain intensity, function, and quality of life. Therefore, the study hypothesis was not confirmed. However, the three groups showed significant clinical improvements in all outcomes after the intervention period. The results of this study bring a new scientific contribution to the effects of cryotherapy in KOA management.
A recent systematic review about the effects of cryotherapy for individuals with KOA,18 shows a lack of scientific evidence on this topic, with studies with low methodological quality, and higher risk of bias, due to the lack of concealed allocation and small sample size. Although the included studies in the review have presented positive results regarding the use of cryotherapy, the analysis of its clinical effects in the treatment of KOA remains uncertain.18 The present study was designed to minimize the methodological bias identified in this review,18 ensuring concealed allocation, adequate sample size calculation and blinding of the evaluated team and statistical analysis.
In the present study, cryotherapy was used for eight weeks, associated with an exercise protocol, considered the first-line treatment approach for KOA,7,10 as recommended by the main clinical practice guidelines (OARSI8 and EULAR9). Another randomized clinical trial,30 showed that the effects of cryotherapy applied once a day, for 4 consecutive days, in individuals with KOA, were also not superior when compared to sham cryotherapy, for pain, physical function, and quality of life of individuals with KOA. The isolated and short-term use of cryotherapy in the study by Dantas et al. can be considered a limitation, as it is not a usual and recommended clinical practice in the management of chronic musculoskeletal conditions, such as KOA.
A recent study,36 which associated cryotherapy with a home exercise protocol for eight weeks, showed that the effects of cryotherapy associated with exercise were superior to the group that did only home-based exercises and the group that did usual physical therapy, for pain, stiffness, and physical function assessed by WOMAC and, in balance assessed by the Time Up and Go test. However, the study has some limitations, such as the lack of details about the sample size calculation, which was small, there was no information about the blinding of evaluators and biostatisticians, in relation to group allocation, and the absence of a control group for the compression force, promoted by the material used during the stabilization of the gel packs. It is known that compression alone can promote pain relief and improve physical function and quality of life, similar to cryotherapy.30 Our study controlled the compression effect on cryotherapy sessions, with the sham cryotherapy group, showing that neither cryotherapy nor compression led to additional improvement in individuals with KOA when compared to the group that performed exercise only.
Physical exercise is a non-pharmacological treatment widely recommended for KOA management,7,10,37 with efficacy on pain intensity modulation, improvement of quality of life and physical function,38 results related to the neurophysiological, psychological, and cognitive alterations.39 In our exercise protocol, we implemented a gradual progression of weight, adjusting it based on individual perceived effort and exercise complexity. According to Booth et al.40 considering these aspects increases adherence to training and prevents episodes of hyperalgesia in people with chronic musculoskeletal pain. Our participants completed at least 20 training sessions, and their benefits were maintained at follow-up compared to baseline, similar to other studies that also showed the beneficial effects of physical exercise on KOA.7,10,37 However, these benefits were reduced at 3 and 6-month follow-up, when compared to the post-intervention evaluation, possibly due the effects of detraining, as presented in previous studies.41–43 Moreover, WOMAC global score had a significant difference between the sham and cryotherapy groups at A4, however, this positive result may have been influenced by the sample size loss and intention to treat approach.
A dropout higher than 10 % in the follow-up periods is a limitation of this study. While the post-intervention dropout rate was moderate, a higher attrition was observed at the 3- and 6-month follow-up assessments. This represents a limitation of the study, and results from follow-up time points should be interpreted with caution. Although the absence of blinding of therapists and participants, regarding the intervention applied, can be considered a limitation, in general, this type of blinding is not possible to be carried out in thermotherapy protocols.
The main clinical implication of our findings is that exercise remains the core component of knee osteoarthritis management, and the addition of cryotherapy did not enhance the effects of the intervention. Thus, based on these results, the routine use of cryotherapy following an exercise intervention to improve treatment outcomes in knee osteoarthritis is not recommended.
Future studies could investigate whether home-based cryotherapy (e.g. applied daily or whenever pain occurs) combined with exercise produces superior outcomes compared to only exercise and sham interventions. Additionally, strategies to minimize attrition, particularly during follow-up, should be considered. Offering transportation reimbursements and the opportunity to participate in health education programs (such as nutritional guidance, sleep hygiene, and quality-of-life improvement) after completing the final assessment may reduce loss to follow-up. Lastly, researchers should systematically monitor and report reasons for dropout to better understand both the interventions and individual factors influencing participant retention.
ConclusionCryotherapy sessions applied three times per week after supervised exercise protocol for 8 weeks did not promote additional improvement in pain intensity, physical function, and quality of life in individuals with KOA.
Ethical approvalThe study was approved by the Ethics Committee of the Universidade Federal de São Carlos, São Carlos, São Paulo, Brazil (65966617.9.0000.5504) and registered with Clinicaltrials.gov (NCT03360500).
Financial supportThis study was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), funding the PhD fellowship of Julya Perea (Grant number: 2022/03302-7). Tania de Fatima Salvini is a Researcher of the Conselho Nacional de Desenvolvimento Científico e Tecnológico- CNPq (Process number: 302169/2018-0). The funding agencies had no role in design and conduct of the study, acquisition, management, analysis, interpretation of data, writing of the manuscript or the decision to submit the manuscript for publication, and do not own ultimate authority over any of these activities.
The authors declare no competing interests.
The authors thank the funding agencies FAPESP, and CNPq for financing support for the research project and the volunteers for their participation.
