Effects of electroanalgesia on knee osteoarthritis: study protocol for a randomized, triple-blind, placebo-controlled trial

Camila Cadena Almeida, Klaus Porto Azevedo, Tatiana Andrade Cacho, Júlia B. L. Garcia Leal, Geovanna Nascimento Montanini, Danielly Nery T. Silva, Patrícia Azevedo Garcia, Jo?o Luiz Quagliotti Durigan

Muscle Tendon Plasticity Research Group from University of Brasilia, Brasília, Brazil

Abstract

Key words:arthritis; chronic pain; electric stimulation therapy; knee; osteoarthritis; pain; randomized controlled trial; transcutaneous electric nerve stimulation

INTRODUCTION

Patients with osteoarthritis present a significant increase in the number of stiffness and apparently enlarged joints, crepitations, motion restriction, weakness and loss of muscle mass (especially the quadriceps) and pain during walking and when going up or down stairs.1Regarding the non-surgical and nonpharmacological treatments, electrotherapy has a reasonable level of evidence for pain control; however, it is not considered for treatment because of inconsistent results and controversial effects.2Thus, this study aims to verify the efficacy of electroanalgesia, using different currents, for knee osteoarthritis.

METHODS/DESIGN

Study setting and design

All data will be collected at the University of Brasilia facilities, Brasília, Brazil.

Eligibility criteriaInclusion criteria

The inclusion criteria were (1) men and women aged over 60 years who do not exercise regularly - frequency less than 3 times a week,3with a diagnosis of knee osteoarthritis, (2) numerical verbal scale (NVS) with a minimum value of 4, (3) clinical signs of osteoarthritis according to ACR criteria, (4) not having undergone physical therapy in the 3 months prior to the research project, (5) no infiltration with corticosteroid in the knee (6 months prior), (6) no medical restriction that makes it impossible to participate in the proposed evaluations (cardiorespiratory, neurological and/or musculoskeletal changes) and previous knee or hip surgeries.4,5

Exclusion criteria

The exclusion criteria were (1) a score of less than 18 points in the Mini-Mental State Examination,5(2) scores higher than 10 in the 30-item Geriatric Depression Scale (GDS-30),6,7(3) the use of corticosteroids during the study, (4) more than 25% of absences from the total treatment sessions, corresponding to 3 sessions and not being able to attend the replacement sessions that will be offered at the end of the treatment, (5) electrical current intolerance by self-report of discomfort or pain.

Recruitment

The selection of individuals included or excluded from the study will be through a triage done by a physiotherapist in the network of hospitals and health posts. Online disclosure willbe conductedviasocial media in local journals and leaflets will be distributed.

Allocation

Allocation of patients in each type of treatment is secret and random (random.org). That is, the subject being treated does not know which treatment is being applied. For the secret allocation, a person determines the individual's eligibility to participate in the study, while the same person is not aware of the group in which the subject is allocated. The allocation is made with closed opaque envelopes, where the modulator randomizes the individual to a randomly listed treatment list. Only the equipment modulator can know the treatment being applied. The researchers responsible for generating the allocation sequence, enrolling participants, and assigning participants to interventions will be independent.

Blinding

It is a triple-blinded randomized controlled trial. A tripleblinded trial is that neither the evaluators nor those responsible for therapeutic application nor the participant know which group the participant is being allocated. Unblinding will not be permitted during the time of intervention and patient's group only be revealed when all sessions are finished.

Interventions

The equipment used will be the electrical stimulator Neurodyn 2.0 (Ibramed, SP, Brazil) connected to independent cables and those connected to two pairs of self-adhesive electrodes (dimensions = 50 × 50 mm2).

On intervention days with electrotherapy, patients will be in the supine position with a support on the head and knee where they will receive treatment so that it is lightly flexed. Next, the area will be sanitized with alcohol to improve electrical conductivity and the electrodes 5 × 5 cm2will be positioned on each side of the affected knee, and the positioning will be the same for the four groups.

In the protocol of this study, four different types of current will be used in each group: transcutaneous electrical nerve stimulation in Group 1, bipolar interferential current in Group 2, Aussie in Group 3, and placebo in Group 4. The physical parameters in Groups 1 and 2 were 100-Hz pulse frequency, 200-ms pulse length and 20-minute intervention; in Group 3, 100-Hz frequency burst, 4-ms interburst interval and 20-minute intervention; in Group 4, 100-Hz pulse frequency and 20-minute intervention for the first 30 seconds. To maintain stimulation level, an increase in intensity will be performed every 5 minutes.

Placebo electrotherapy will be performed in accordance with the findings of Rakel et al.8They proposed a transitory electrostimulation protocol, which 100% of the researchers and 40% of the subjects were blinded when compared to 0 of the researchers and 21% of the placebo electrotherapy subjects with total absence of current. In this protocol, the transcutaneous electrical nerve stimulation current is active within the first 30 seconds of treatment and it decreases for the next 15 seconds until it stops, with a total time of 20 minutes. The placebo group will be offered the most effective treatment after the end of the collections.

The treatment will be discontinued whenever patients are not able to tolerate the initial or the intensity required during the treatment for a strong but comfortable sensation. To improve adherence, all the beneficial aspects of the intervention will be clarified as the importance of attending every session and their frequency will also be documented.

During treatment, patients are not permitted to attend other physiotherapy intervention such as conventional treatment (exercises, electrotermophoterapy). If they are engaged on regular physical activity, they can continue. Medication use during treatment is allowed whenever they need it and continuous medication will not be prohibited.

Baseline information

Mini-Mental State Examination

All volunteers will respond to the questionnaire on the day of the interview. It was developed by Folstein et al.,9allows the evaluation of cognition and screening of dementia and has the maximum score of 30 points through 6 domains: temporal and spatial orientation (10 points), records (3 points) and calculation (5 points), evocation memory (3 points) and language (9 points).

Geriatric Depression Scale (GDS-30)

All volunteers will respond to the questionnaire on the day of the interview. The GDS-30 is a brief, self-applicable, or applicable questionnaire by a trained professional with a total of 30 items, in which individuals respond as they felt last week using the “yes” or “no” options. Each question contains a response that can indicate depression; and in the case of the patient's choice, a point will be added to the total. Scores from 0 to 4 are considered normal, 5 to 8 indicate mild depression, 9 to 11 moderate depression and 12 to 15 severe depression.10This scale has already been validated for the Brazilian elderly population in an outpatient setting by Louren?o and Veras7and Paradela et al.11

International physical activity questionnaire

All participants will receive the test on the first and last days of research. This questionnaire in the short form evaluates the physical activity performed through a set of domains, including: physical activity during the leisure period; household and gardening activities; physical activity related to work and, finally, physical activity related to transportation. The form evaluates about three specific types of activities carried out in the four domains introduced above. Specific types assessed include walking, moderate- and high-intensity activities. Items were structured to provide separate scores on specific activities. Measurement of the total score requires the sum of the duration (in minutes) and the frequency (days) of the activities. It is also worth mentioning that specific domain estimates cannot be realized.11

Outcome measures

Primary outcome: Pain evaluation

NVS: This scale will be applied to the pain registry on the first and the last days of the data collection. NVS is a wellrecognized instrument to measure the intensity of chronic pain that visually represents the intensity of pain that the individual believes to present.12The scale will be positioned horizontally in front of the individual and will vary from 0 to 10 cm, 0 being the complete absence of pain and 10 being the maximum pain intensity reported by the individual.13This scale will be measured both in the resting condition and during the functional tests.

Pain-pressure threshold: To measure pressure-pain threshold, a mechanical pressure algometer (ITO Co., LTD - Physiotherapy & Rehabilitation, model OE-220, Tokyo, Japan) with contact area of 1 cm2will be used. There will be 3 consecutive measures with an interval of 20 seconds between each in the 12 predetermined points randomly chosen. The average value of the three measurements will then be used. At each point, the pressure pain threshold will be evaluated using the tip of the algometer at a rate of 1 kg/s, perpendicularly. The interval time between each measurement will be taken into account to avoid the temporal summation of cutaneous nociceptors.14The reliability of pressure algometry is high (intraclass correlation coefficient = 0.91 [95% confidence interval (CI) 0.82-0.97]).15

Brief pain inventory: All participants will receive the test on the first and last days of research. The brief pain inventory is a multidimensional questionnaire, validated for the Brazilian population that evaluates the presence of pain. It uses a scale of 0-10 to grade the items: intensity, pain interference to walk, daily activities of the participant, at work, social activities, mood and sleep.16It also includes a body diagram to indicate the location of pain, percentage of pain relief and treatments used for its control.17

Secondary outcomes: Function evaluation and quality of life

Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC): All participants will receive the test on the first and last days of research. WOMAC is a self-report questionnaire, designed to assess the problems experienced by individuals with lower limb osteoarthritis. The score for the items is expressed through a scale in which the classification revolves around: none = 0, low = 1, moderate = 2, severe = 3 and very severe = 4. The maximum score in each section is expressed in percentage, with higher scores indicating greater pain, stiffness and physical dysfunction.18Each point corresponds to a particular dimension (pain, stiffness and physical function). This questionnaire has been translated and validated into the Brazilian Portuguese.19

Total range of motion and painless range of motion: All participants will receive the test on the first and last days of research. For this test, the participants will be in supine position and execute actively knee extension. The range of motion free of pain (P1) will be checked, and then the total range of motion regardless the pain (P2) will be checked. Maximum knee extension free of pain and maximum knee range of motion are P1 and P2, respectively. The exact angle will be measured with a Fleximeter, which will be placed on the ankle for documenting knee extension range of motion (in degrees).

Timed Get-Up-and-Go test: All participants will receive the test on the first and last days of research. This test is used to evaluate the balance of an individual sitting, transferring from sitting to standing, the stability of the walk and changes during gait without any compensatory strategy.20This test includes the following: asking the individual to get up of chair, walk 3 meters turn around go back and sit in the chair once again. It observes the capacity to get up, the balance, the posture the basis of the gait (large or small), the start of the gait (if there is hesitation or freezing), the speed, the size of the step, the symmetry, the balance of the torso and members, the involuntary movement and the ability to go back. The timing of test is particularly useful as predictor of functional independency: timing under 20 seconds are considered normal; and above 30 seconds it is considered as a possible indicative of high risk of falling and functional dependency.21Right after the test, the NVS will be used.

30-second Sit-to-Stand test: All participants will receive the test on the first and last days of research. The sit to stand from a chair is administered using armless chair, and the height of the seat is approximately 43 cm from the floor. The chair has a non-slip rubber underneath it and it is placed by the wall to avoid oscillations. The participant has to sit straight on the chair with the feet apart and aligned with the shoulders and it has to be placed on the floor in an angle slightly behind the knee. To help maintain balance, a foot should be in front the other and the arms crossed on the chest. The test consists of getting up as many times as possible from sitting to standing up during 30 seconds. This test can evaluate a variety of ability levels with scores that go from 0 in those who cannot complete a single one repetition to more than 20 repetitions in those physically well prepared.22The NVS will be used 10 seconds before the end of the test, for 20 seconds.

Stair-ascend test: All participants will receive the test on the first and last days of research. In addition to insert an everyday situation, this test also evaluates muscle strength and balance of the inferior lower member.23The number of steps depends on the environment, but when possible, it is recommended to have 9 steps of 20-cm height with the presence of a handrail. In an adapted way, the participants will receive this test in a two-step ladder in which they go up as they usually do on their daily life and then go down backwards; they do it for nine times. The use of a support is advised by the therapist only when necessary. The NVS is used again when they reach the ground for the last time.

40-meter fast-walk test: All participants will receive the test on the first and last days of research. This test gives a direct measurement of the ability to go through short distances an important activity, but it is frequently limited in individuals with knee osteoarthritis.23This test is carried out by marking a 10-meter hall with two signaling cones positioned 2 meters before and after the route delimited. The participant will be instructed to walk 40 meters (3 turns) as fast as possible and it will be timed and posteriorly converted to speed (m/s). The NVS is used again on last lap.

6-minute walk test: This test requires walking as fast as possible in a 20-meter hall for 6 minutes. It is a simple test in the clinical practice and on continuous daily activities in healthy and non-healthy individuals.24There are a lot of factors that can alter the length walked during the test. Short individuals, advanced age, overweight, female, pulmonary, cardiovascularor musculoskeletal diseases have the tendency to walk less in the test. Male individual using medication to maintain their healthy condition with supplementary oxygen and experienced with test can increase the distance walked.25The NVS is used at the last minute of the test.

Balance platform: All participants will receive the test on the first and last days of research. For the dynamic balance test, the Biodex Balance System Platform (Biodex, Inc., Shirely, NY, USA) will be used. This equipment is constituted by a platform capable of moving in the anteroposterior and laterallateral axes and has the capacity to quantitatively measure the displacements performed by the individuals during the test. The protocol will be the Fall Risk26in which patients will be positioned on the platform in a comfortable position, standing with bipodal support and will try to maintain the balance easy and challenging oscillations in three attempts of 20 seconds each. An evaluator will remain positioned behind the patient to provide security. The NVS will be used 10 seconds before the test ends.

The Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) for quality of life evaluation: All participants will receive the test on the first and last days of research. This scale is a multidimensional quality-of-life questionnaire, strongly related to the presence of pain.27It consists of 36 items grouped into a total of 8 components: functional capacity (10 items), physical aspects (4 items), pain (2 items), general health (5 items), vitality (4 items), social aspects (2 items), emotional aspects (3 items), mental health (5 items), physical aspects (4 items), and a question of comparative evaluation between current health conditions and that of a year ago. It evaluates both negative and positive aspects.28

Participant timeline

Patients will be randomly divided into four groups and will complete the evaluation, treatment, discontinuation and reassessment stages at 1, 3, and 6 months after the start of the study (Figure 1).

Detailed outcome measures thought out the study can be seen in Table 1.

Sample size

The sample size was calculated based on the mean of NVS score for pain previously reported for a similar population of patients with knee osteoarthritis (8.10 ± 1.23 cm).29An assumption was made that a clinically significant change in NVS scores would have to correspond to 30% of the total value and significance level of 0.01 and 95% of power werechosen. These criteria led to an estimated minimum sample size of 25 in each group.30

Figure 1: Study flowchart.

Table 1: Study assessment schedules

Data collection

All data will be collected on the first and the last days of treatment. To improve reliability of measures, the evaluator will be trained and perform an interclass correlation coefficient of algometry and balance evaluation will be performed within 2 days to familiarize with the equipment. All participants who exceed the number of faults will have their data analyzed using the intention-to-treat analysis. All data will be stored in a compressed and digitized form with the leader researcher.

Statistical methods

A descriptive analysis of all variables of the study will be performed, applying measures of central tendency and dispersion, tables and graphs. For the statistical analysis of the homogeneity of the dependent variables, the Levene's test will be applied. Once these assumptions are met, the mixed-analysis of variance (Split-Splot) will be applied to verify the existence of significant differences between the measurements obtained, with Bonferronipost hoctest, at all evaluated moments and among all groups. The level of significance for all tests applied will be 5% and the statistical program will be SPSS (version 18.0; SPSS Inc., Chicago, IL, USA).

Data monitoring

A data monitoring committee will be established to process all data during and after the trial. This committee will be independent from the university financial support and competing interests. The trial will only be terminated if material and personal expenses cannot be supported and this decision has to be approved by all the research group members.

Harms

There are some risks during parts of the treatment, seeing that some of the tests such as painless range of motion. Algometry can cause discomfort and even pain. Some can lead to loss of balance and fall such as Timed Get-Up-and-Go test, 30-second Sit-to-Stand test, balance platform, 40-meter fast-walk test and 6-minute walk test. Others can lead to embarrassment such as GDS-30 and Mini-Mental State Examination. Since the treatment is based on electrotherapy, it may cause some discomfort; the participants maybe have electrical current intolerance. There is the possibility of discomfort given that the participant needs to stay in a certain position for quite a long time. Given all the possible risks, all necessary measures will be taken care of to minimize such risks.

Auditing

The auditing process will be performed by the university ethical research committee every six months. This process is planned jointly by investigators and the study sponsor.

Ethics and dissemination

This research project was already approved by the Ethics and Research Committee of the Faculdade de Ciências da Saúde - CEP/FS of Universidade de Brasília - UnB (CAEE 62256516.2.0000.0030) on July 18, 2017 (Additional file 1), according to Resolution 196/96 of the Conselho Nacional de Saúde (CNS) and registered in the Brazilian Clinical Trials Registry (ReBEC) (RBR-875zsw) on November 24, 2017. All possible changes on study protocol during the trial will be reported to this committee and eligible for approval. For the participation in the research, individuals were informed that they would have to voluntarily sign the informed consent form for the independent evaluator (Additional file 2). No additional consent will be needed. To maintain confidentiality, the name and personal information of all participants will not be revealed to any individual outside the research group. This manuscript was prepared according to Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement (Additional file 3).

The authors declared no conflict of interest. The final dataset will only be available for the research group members. If any harm occurs during the trial, some measures will be taken. At the end of the evaluation, all patients will receive an exercise protocol based on the recommended literature. The communication of the results will be through national and international congresses and scientific journals. Subjects were informed about the research objectives, as well as the benefits, possible risks and procedures contained in the study. All data obtained in the study will remain private and will be used for scientific purposes, protecting the identity of all subjects.

DISCUSSION

We hope this will be an improvement in the timed performance tests, in all the outcomes related with pain, including reported score in the NVS, pain-pressure threshold, reported quality of life and knee function and stiffness. It is also expected to have a better linearity in the findings corresponding to thermography, as well as new studies that may enrich the discussion about the results found here.

TRIAL STATUS

Patients have been recruited since August 2017. Primary outcome measures will be analyzed in June 2020 and the study will be completed in August 2020.

Additional files

Additional file 1: Ethical Approval Documentation (Portuguese).

Additional file 2: Model consent form.

Additional file 3: SPIRIT checklist.

Author contributions

Study concept and design: JLQD, CCA, PAG; principle investigator: CCA; manuscript drafting: CCA, KPA, TAC, JBLGL, GNM and DNTS. All authors gave final approval for publication.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Financial support

None.

Institutional review board statement

The research project was approved by the Ethics and Research Committee of the Faculdade de Ciências da Saúde - CEP/FS of Universidade de Brasília - UnB (CAEE 62256516.2.0000.0030) on July 18, 2017, according to Resolution 196/96 of the Conselho Nacional deSaúde (CNS) and registered in the Brazilian Clinical Trials Registry (ReBEC) (RBR-875zsw) on November 24, 2017.

Declaration of patient consent

The authors certify that they will obtain all appropriate patient consent forms. In the forms the patients will give their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Reporting statement

This manuscript was prepared according to Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement.

Biostatistics statement

The statistical methods of this study were reviewed by the biostatistician of University of Brasilia of Brazil.

Copyright license agreement

The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement

Anonymized individual data will be available immediately after study publication upon request from those who wish to access the data for 5 years. If anonymized data is provided, it should be done so after proposals to cadenacamila@gmail.com. Raw data (including personal information and participant codes) will be stored in a locked cabinet at the University of Brasilia for this time period before being destroyed. Personal results will also be available to participants upon request. If requested, study protocols and outputs of statistical analysis will be available.

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Externally peer reviewed.

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