Evaluating Noninvasive Pulsed Electromagnetic Field Therapy for Joint and Soft Tissue Pain Management: A Prospective, Multi-center, Randomized Clinical Trial

Abstract

Introduction

Strategies to reduce pharmacologic use for pain are needed. Pulsed electromagnetic field (PEMF) therapy is a noninvasive, nonpharmacologic treatment for pain that modifies nitric oxide signaling to improve healing. This study examined whether PEMF decreased pain and pharmacologic use vs. standard-of-care (SOC) treatment for joint and soft tissue pain.

Methods

This prospective, randomized controlled trial enrolled 120 patients presenting with joint or soft tissue pain at five orthopedic clinic sites. The PEMF group self-administered daily therapy from a commercially available device and the SOC group received standard treatment daily as prescribed by the clinician. Patients recorded their pain level, pharmacologic usage, and adverse events daily for 14 days. After 14 days, patients in the SOC group were given the option to crossover to PEMF therapy and continue for 16 days. The study was overseen by an independent clinical research organization. It was hypothesized that PEMF would be superior to SOC for pain management.

Results

PEMF treatment provided significant analgesic benefits compared to SOC. Complete data was collected for 91 patients, 48 from the PEMF group and 43 from the SOC group. The least squares mean pain score change from baseline was − 1.8 (a 36% reduction) for the PEMF group, significantly surpassing − 0.46 (a 10% reduction) for the SOC group (p < 0.0001). Pharmacologic usage decreased from 40 to 18% for the PEMF group (a 55% reduction), while the SOC group decreased from 40 to 35% (a 12% reduction). In the crossover subgroup, patients experienced an additional 18% decrease in pain score and 63% decrease in pharmacologic use after switching from SOC to PEMF treatment.

Conclusions

PEMF was significantly more effective than SOC at managing pain and reducing pharmacologic use. PEMF therapy should be considered for noninvasive, nonpharmacologic management of joint and soft tissue pain.

Trial Registration

ClinicalTrials.gov ID NCT05244187.

Plain Language Summary

Noninvasive pulsed electromagnetic field (PEMF) therapy has been in clinical use for several decades. PEMF targets the source of joint and soft tissue pain by activating the nitric oxide cascade. Clinical outcomes have varied, perhaps due to the differences in the devices and signals used. This study aimed to evaluate outcomes for a Food and Drug Administration (FDA)-cleared, commercially available PEMF system (Orthocor Active System) on a total of 120 patients compared to a clinician-prescribed standard of care. The results of this study showed that PEMF therapy was safe and led to significant reductions in pain and medication use compared to the standard of care for joint and soft tissue pain. PEMF should be considered for noninvasive and nonpharmacologic management of joint and soft tissue pain.

Key Summary Points

Why carry out this study?

This study evaluated a 27.12-MHz pulsed electromagnetic field (PEMF) for soft tissue and joint pain relief as an option to reduce pain intensity and oral pharmacologic use.

It was hypothesized that optimized PEMF would be superior to standard-of-care (SOC) treatment for pain management.

What was learned from the study?

PEMF therapy was significantly more effective at managing pain and reducing pharmacologic use than SOC treatment.

After 14 days of use, PEMF reduced pain by 36% and medication use by 55%, compared to SOC treatment which reduced pain by 10% and medication use by 12%.

In the crossover subgroup, patients experienced an additional 18% decrease in pain score and 63% decrease in pharmacologic use after switching from SOC to PEMF treatment.

The tested 27.12-MHz PEMF system was effective at reducing pain and pharmacologic use and should be considered for the management of joint and soft tissue pain.

Introduction

An estimated 20% of adults (50 million) in the United States experience chronic pain daily, while 8% (19.6 million) experience high-impact chronic pain which limits work or life activities frequently [1]. The United States Department of Health and Human Services recommends a collaborative, multimodal treatment plan implemented by a diverse team that avoids opiates and uses nonpharmacologic pain treatments when clinically indicated [2]. Chronic use of opiates causes tolerance and may lead to addiction, while chronic use of other pain medications can have systemic adverse effects, including hepatotoxicity, renal toxicity, and increased risk of bleeding.

One example of locally targeted nonpharmacologic treatment is pulsed electromagnetic field (PEMF) therapy, sometimes referred to as pulsed radiofrequency energy or pulsed shortwave diathermy. Recent meta-analyses have shown PEMF to be effective for treating osteoarthritis [3–5], osteoporosis [6], and back pain [7–9], but the PEMF signals and treatment parameters included in these studies are often heterogeneous and not optimized. The goal of this study was to evaluate a specific PEMF therapy device for the treatment of pain, to demonstrate that the improvements are greater with optimized signal parameters and show that the specific results can be generalized to patients presenting with non-specific joint pain.

PEMF is a low-level, time-varying electromagnetic field that penetrates superficial soft tissue, helping to accelerate the body’s natural anti-inflammatory and recovery responses. PEMF accelerates the binding of calcium ions (Ca²⁺) to calmodulin (CaM), which stimulates the anti-inflammatory nitric oxide (NO) cascade (Fig. 1) [10–12]. When produced in short bursts by endothelial nitric oxide synthase (eNOS), NO acts as a vasodilator, aiding healing by increasing blood and lymphatic flow [11]. Additionally, these short bursts of NO decrease inflammation by down-regulating interleukin-1 beta (IL-1β) leading to cyclooxygenase-2 (COX-2) inhibition and decreased production of prostaglandins [13]. PEMF targets a small treatment area, allowing effective pain and inflammation reduction in that tissue without the risk of systemic side effects, such as those associated systemic pain medication. The mechanism for PEMF may be compared to COX-2 specific nonsteroidal anti-inflammatory drugs (NSAIDs) celecoxib (Celebrex^®) and rofecoxib (Vioxx^®), except the local application prevents the cardiotoxic and bleeding effects associated with those drugs.

Fig. 1.

Overview of the pulsed electromagnetic field (PEMF) mechanism of action. PEMF increases calcium (Ca²⁺) binding to calmodulin (CaM), which stimulates endothelial nitric oxide synthase (eNOS) to produce nitric oxide (NO) in short bursts that activate anti-inflammatory signal cascades. This results in dilation of lymph and blood vessels, release of growth factors, lower concentrations of interleukin-1β (IL-1β), and inhibition of cyclooxygenase-2 (COX-2)

The Orthocor Active System is a portable, battery-powered, targeted PEMF therapy system that the Food and Drug Administration (FDA) cleared for commercial use. In addition to PEMF, the system provides heat from single-use, air-activated OrthoPods. The PEMF therapy consists of a 27.12-MHz carrier signal with 2-ms pulses at 2 Hz. These signal parameters are believed to target soft tissue while allowing time for cell recovery between pulses. The joint-specific wrap holds the device in place over the treatment area, such as the ankle, back, knee, wrist, elbow, shoulder, foot, hip, or neck (Fig. 2).

Fig. 2.

Examples of the Orthocor Active System Knee and Wrist devices and an OrthoPod heat pack

In previous clinical studies, PEMF devices have been shown to reduce pain and provide lasting relief without the use of pharmacologic interventions or invasive procedures. A study of 34 patients with early knee osteoarthritis showed a significant 60% reduction in the mean pain score for PEMF compared to sham [10]. Another study of 33 patients with knee osteoarthritis showed 62% reduction in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score and 43% decrease in pain after 2 weeks of treatment with the PEMF device used in this study [14].

The current study sought to further elucidate the clinical impact of a commercially available, nonpharmacologic PEMF pain management system on a larger patient population. The hypothesis was that PEMF therapy would be more effective than standard-of-care treatment (SOC) for joint and soft tissue pain management.

Methods

The primary objective of this study was to compare pulsed electromagnetic field (PEMF) therapy to standard-of-care (SOC) treatment for joint and soft tissue pain management, assessed by pain score on the Mankoski scale and pain medication use. Patients who presented to orthopedic clinic sites with soft tissue or joint pain (ankle, back, knee, wrist, elbow, shoulder, foot, hip, or neck) were screened and enrolled after providing written informed consent. Patients were randomized by an independent clinical research organization (CRO) using 1:1 consecutive alternating allocation independent of clinic site or diagnosis. This study was not blinded. The primary safety endpoint was the number of adverse events and the primary efficacy endpoint was the pain score change from baseline.

This study was conducted at five participating orthopedic clinic sites in the United States of America over 11 months. The sample size of 45 per group was based on the comparison of two proportions, with baseline proportion of 70% for the experimental treatment, assuming a 50% response for SOC, a 10% non-inferiority margin, 90% power, and 95% confidence. The protocol was approved by Advarra IRB and managed by the independent CRO MEDIcept. This study was conducted according to the World Medical Association Declaration of Helsinki and conforms to the ICMJE Recommendations and CONSORT guidelines [15]. Patients provided written informed consent. There was no interim analysis or data preview until the database was locked.

Inclusion criteria were patients with pain in superficial soft tissue or minor muscular and joint aches and pains presenting to the treating clinician at an orthopedic clinic who were willing and able to provide informed consent. Exclusion criteria were patients with active medical implants, implanted metallic leads, current or expected use of opioids, known or expected pregnancy, open wounds in the area of application, inability to sense heat, poor circulation or heart disease, diabetes, age under 18 or open bone growth plates, enrollment in another study, incarceration, and unwillingness or inability to provide informed consent, use the prescribed treatment, or compete the daily pain assessments. Participating patients were given a free PEMF device as compensation for study participation.

Patients in the PEMF group self-administered daily treatment per the instructions for use included with the device, which consisted of a 2-h therapy session that provided PEMF for the first and last 30 min and heat therapy for the entire duration. Patients in the SOC group received only self-administered standard treatment daily as prescribed by the clinician, such as NSAIDs, ice, and physical therapy. Patients recorded their pain score using the Mankoski scale [16], pharmacologic usage, and adverse events daily for 14 days in an electronic diary managed by the CRO. After completing 14 days of treatment, all patients in the SOC group were given the option to crossover to use the Orthocor Active System for an additional 16 days of treatment. Patients who did not comply with the protocol for device use or daily data reporting were withdrawn from the study and replaced.

The statistical analysis was conducted per the plan set forth in the protocol. The primary efficacy analysis was to fit a regression model to the change from baseline in the daily pain score. The regression model included the treatment arm as the main factor and the demographic variables (age, gender, race) and the visit variable as covariates. After normality assessment, a first-order autoregressive covariance matrix was used to model the correlation among repeated measures for the same subject. The model was used to calculate the least squares (LS) mean difference between the PEMF and SOC groups.

Results

A total of 120 patients were enrolled and placed into treatment groups, 59 into the PEMF group and 61 into the SOC group (Fig. 3). General health data, including demographics, pre-existing medical conditions, and concomitant medication use, were recorded and analyzed from all 120 enrolled patients. During the 14 days of treatment, two patients withdrew consent and 27 had incomplete daily diary entries, leaving 91 patients with complete pain score data, 48 using PEMF and 43 receiving SOC treatment. From the SOC group, 19 patients elected to continue in the crossover arm, of which 18 patients completed the additional 16 days.

Fig. 3.

A total of 120 patients were enrolled in this trial and randomized into the pulsed electromagnetic field (PEMF) and standard-of-care (SOC) groups

The most common sites of pain for enrolled patients were the knee at 43%, the foot at 22%, shoulder at 15%, and ankle at 11%. The clinician ensured patients met inclusion and exclusion criteria but was not required to record a primary diagnosis for the source of pain. Of the 52% of enrolled patients with a recorded primary diagnosis, 61% were osteoarthritis; 28% were soft tissue issues such as bursitis, strain, or tear; 6% were surgery; 3% were chronic pain; and 1% each were spondylosis and avascular necrosis. Non-opioid pain medication was prescribed for 16% of patients. Patients self-reported medication use and concomitant medical diagnoses, which were primarily non-orthopedic medical conditions such as hypertension, high cholesterol, anemia, thyroid disorders, and sleep apnea. Age, gender, and race were similar in the PEMF and SOC groups (Table 1).

Table 1.

Demographic information

	Enrolled	Analyzed (complete data)
		Total	PEMF	SOC
	(N = 120)	(N = 91)	(N = 48)	(N = 43)
Age
Mean ± SD	55 ± 16	54 ± 16	54 ± 16	55 ± 16
Gender
Female	65% (78)	66% (60)	71%	60%
Male	35% (42)	34% (31)	29%	40%
Racea
Black or African American	31% (37)	36% (33)	32%	40%
American Indian or Alaskan Native	0.8% (1)	– (0)	–	–
Asian	5.8% (7)	5.6% (5)	8.2%	2.3%
White	59% (71)	56% (51)	53%	58%
Other	5.8% (7)	3.3% (3)	6.1%	–

PEMF pulsed electromagnetic field, SOC standard of care, SD standard deviation

^aIf patient specified two races, they were counted as 1 for both

Normality testing of the pain score data with Mauchley’s test indicated that the assumption of sphericity was violated, however Levene’s test showed significantly different variance for only one of the 15 repeated measures, with p = 0.034 for the day 6 pain score. After Greenhouse–Geisser sphericity correction, the p value remained < 0.001 for the repeated measures model, demonstrating that the deviation from normality did not significantly affect the analysis.

Only patients with complete results were used in the statistical analysis. This is justified because the LS mean for the population of patients with some data − 1.3 ± 0.242 (− 1.8 to − 0.8) was nearly identical to the population with complete data − 1.3 ± 0.249 (− 1.8 to − 0.9), reported as mean difference ± standard error (95% confidence interval).

The baseline pain score was similar for both groups, 5.0 ± 1.5 for the PEMF group and 4.9 ± 1.6 for the SOC group, reported as mean ± SD (Fig. 4). After 1 day of treatment, there was a mean change in pain score of − 1.1 for the PEMF group (a 22% reduction from baseline, paired t test p < 0.001) compared to − 0.14 for the SOC group (a 2% reduction from baseline, paired t test p = 0.50). This trend continued through day 14 with the PEMF group scores approximately 1–1.5 points lower than the SOC group. On day 14, the change from baseline was − 2.1 (42% reduction) for the PEMF group and − 0.67 (a 14% reduction) for the SOC group. The least-squares (LS) mean difference between the PEMF and SOC groups was significant (p < 0.0001).

Fig. 4.

Average pain data for the PEMF (n = 48) and SOC (n = 43) groups (error bars show standard error)

PEMF provided a significant analgesic benefit compared to SOC (Table 2). The PEMF group exhibited an LS mean change from baseline in pain score of − 1.8 (a 36% reduction, 95% CI − 2.1 to − 1.5) over days 1–14, surpassing the SOC group change of − 0.46 (a 10% reduction, 95% CI − 0.83 to − 0.10). The LS mean difference of − 1.3 (95% CI − 1.8 to − 0.85) between the two groups was significant (p < 0.0001), showing a 26% greater decrease in pain for the PEMF group. No significant differences were observed based on demographic variables.

Table 2.

LS mean analysis for patients with complete data

Change from baseline	PEMF (N = 48)	SOC (N = 43)
LS mean (SE)	− 1.8 (0.17)	− 0.46 (0.18)
95% CI for LS mean	[− 2.1, − 1.5]	[− 0.83, − 0.10]
LS mean difference (SE)	− 1.3 (0.25)
p value	< 0.0001
95% CI for LS mean difference	[− 1.8, − 0.85]

PEMF pulsed electromagnetic field, SOC standard of care, LS least squares, SE standard error, CI confidence interval

The incidence of adverse events in this study was notably low, with only four of 120 patients (3.3%, two from each group) experiencing any adverse events. The two adverse events in the PEMF group were tingling and discomfort related to the fit of the wrap. The two adverse events in the SOC group were shoulder pain and fatigue. There were no reports of serious adverse events or unanticipated adverse device effects.

Pharmacologic usage was calculated as the percentage of patients that used pain medication on a given day (Fig. 5). The mean percentage during treatment (days 1–14) was then calculated to compare the two groups. At baseline, 40% of the patients in each group reported pharmacologic use. During treatment, mean pharmacologic usage was 18% for the PEMF group, compared to 35% for the SOC group (t test p < 0.001). The decrease from baseline was 55% for the PEMF group compared to 12% for the SOC group.

Fig. 5.

Pharmacologic use, or percentage of patients who used pain medication on a specific day (dashed lines show mean for days 1–14)

Similar results were seen for the subgroup of SOC patients that chose to cross over to PEMF use. Mean pain scores for the crossover patients changed by − 0.38 from baseline (a 7.9% reduction) with SOC treatment from day 1–14, then changed by an additional − 0.86 (an additional 18% reduction) with PEMF treatment, for a total change of − 1.2 from baseline (a 25% reduction) from day 15–30 with PEMF therapy (Fig. 6). Mean pain scores were significantly lower after crossover (paired t test p < 0.001).

Fig. 6.

Average pain data for crossover patients, who received SOC treatment for days 1–14 and PEMF therapy after crossover on days 15–30 (error bars show standard error)

The subgroup of SOC patients who elected to cross over had a higher baseline medication use of 67% compared to 40% for the entire SOC group, but no other differences were noted. For the crossover subgroup, mean ± SD pharmacologic use was virtually unchanged from 67% at baseline to 65 ± 7% with SOC treatment (Fig. 7). With PEMF therapy, mean pharmacologic use dropped to 23 ± 6%. The decrease from baseline was 2.4% for SOC treatment compared to an additional 63% with PEMF therapy. Pharmacologic usage was significantly lower after crossover (paired t test p = 0.002).

Fig. 7.

Pharmacologic usage for crossover patients, who received SOC treatment for days 1–14 and PEMF therapy after crossover on days 15–30 (pre- and post-crossover means are shown with dashed lines)

Discussion

The PEMF therapy used in this study reduced pain and medication use significantly more than SOC treatment. The pain scores for the PEMF group were significantly lower than the SOC group for any given day of the trial (paired t tests p < 0.001). The consistency of the pain scores in the PEMF group for the last 10 days suggests the decreased pain would continue with sustained treatment. Many patients requested to continue PEMF treatment after the study period was completed. The minimal occurrence of minor adverse events in the PEMF group (N = 2 matching the incidence in the SOC group) reinforces the safety profile of the Orthocor device.

Pharmacologic use by patients was recorded as an additional outcome measurement to account for a potential confounding variable responsible for reduced pain scores. A decrease in pharmacologic use indicates a decrease in perceived pain above and beyond the pain score reduction. The drop in pharmacologic use matched or exceeded the decrease in pain score for all analyzed populations. In the PEMF group, mean pharmacologic use dropped by more than half (55%), compared with 12% in the SOC group. The decrease in pharmacologic use was nearly equal to the decrease in pain scores for the SOC group (12% and 10%, respectively), but the reduction in pharmacologic use was greater than the decrease in pain score for the PEMF group (55% and 36% respectively). It was hypothesized that reduced pain would lead to less pharmacologic use, but the effect was stronger than expected. This suggests that PEMF reduced pain to a level that was tolerable without pharmacologic use.

The subgroup of SOC patients who chose to crossover to PEMF treatment had a similar decrease in pain with a more pronounced reduction in medication use. The crossover subgroup experienced a decrease from baseline in pain of 8% while receiving SOC treatment, with an additional 18% decrease while receiving PEMF therapy. Medication use decreased by 2.4% with SOC treatment, with an additional nearly two-thirds (63%) decrease while receiving PEMF therapy. Some of the benefit may have been carryover from the initial SOC treatment, but the inflection in pain score slope (Fig. 6) and stepwise decrease in pharmacologic use (Fig. 7) demonstrate that PEMF was more effective than SOC for these patients. The higher pharmacologic use in the crossover subgroup compared to the overall SOC group (67% compared to 40%) and marked pharmacologic use decrease suggest that PEMF was effective at treating cases of pain that were refractory to medication and other SOC treatments.

The Mankoski pain scale was chosen because it has concrete descriptions for each level of pain. For example, at the Mankoski pain score of 7 it is difficult to concentrate or sleep, stronger painkillers (codeine, hydrocodone) are only partially effective, and only the strongest painkillers (oxycodone, morphine) are effective in relieving pain. The choice of the Mankoski pain scale made the differences in pain smaller, adding rigor to the study design. In a study with 200 veterans, the Mankoski pain scale was preferred by the patients over three other pain scales (Faces Scale, Visual Analog Scale, and Numeric Rating Scale), with good correlation between all scales [16].

One limitation of this study was the length of follow-up. Another study with a longer follow-up period would provide insight into the sustainability of the benefit from PEMF therapy. The diversity of ailments for which the patients sought pain relief or lack of characterization of their condition (intensity, type, duration) was a limitation. However, the broad inclusion criteria allow the results to be applied more broadly to clinical practice. Providing devices free of charge may have introduced bias into the study. Lack of blinding was also a limitation.

The Orthocor Active System used in this study has a distinctive therapy that combines targeted PEMF and heat to treat joint and soft tissue pain. The PEMF signal consists of a pulse-modulated 27.12-MHz carrier signal inductively coupled to the treatment area. This frequency is in one of the radio bands approved for medical device use and is effective at penetrating soft tissue and “carrying” the treatment signal deep into tissue to effectively treat inflammation. The modulation pulses are 2 ms in duration which was empirically optimized to efficiently cause local cellular effects with low magnetic flux intensities. The pulses are delivered at a rate of 2 Hz, which allows recovery of the tissue during the 500-ms pause before the next pulse is delivered. These targeted PEMF parameters were developed and optimized through years of in vitro, preclinical, and clinical research [10–13]. Additional research is needed to bring the characterization of the Ca²⁺-modulated NO cascade on par with the well-understood Na⁺ and K⁺ channel stimulation parameters. This would allow PEMF treatment parameters to be further refined.

Targeted PEMF systems with a pulse-modulated carrier frequency must be differentiated from devices that use a TENS-like signal output. TENS-like PEMF devices do not have a carrier frequency to penetrate tissue, but rather use fixed or variable short pulses of 0.1–1 ms at a higher pulse rate of 10–1000 Hz. TENS-like PEMF parameters have been optimized to simulate sensory nerves through connected electrodes rather than the inductively coupled magnetic signals used in targeted PEMF therapy.

This study is in line with a growing body of clinical evidence, with recent systematic reviews and meta-analyses showing PEMF is an effective treatment for osteoarthritis [3–5], osteoporosis [6], and back pain [7–9]. A meta-analysis that pooled data from 15 trials (1078 patients) found that PEMF, compared to placebo in patients with osteoarthritis, improved pain, stiffness, and function [3]. Another meta-analysis pooled data from 19 trials on osteoporosis (1303 patients) and determined that PEMF combined with conventional medications, compared with conventional medications alone, increased bone mineral density (BMD), improved chemical markers (ALP, BSAP, and osteocalcin), and decreased pain [6]. A meta-analysis reviewing PEMF treatment for patients with low back pain pooled data from 14 trials (618 patients) and found that PEMF decreased pain compared to placebo or other therapy [7].

While these meta-analyses are positive and confirm the potential of PEMF therapy, there is heterogeneity in the included PEMF signals and treatment parameters. For example, the Yang meta-analysis of PEMF treatment of osteoarthritis included frequencies from 4 Hz to 6.8 MHz [3]. This signal range includes a wide variety of signals that may not all be effective and does not include the 27.12-MHz PEMF studied here. The results in the present study compare favorably with previous studies. Furthermore, this study included many differing causes of joint and soft tissue pain, suggesting that PEMF may be used more generally for pain management.

Conclusions

Pulsed electromagnetic field therapy from the Orthocor Active System was significantly more effective than standard-of-care treatment at reducing joint and soft tissue pain and reducing pharmacologic use. PEMF therapy reduced pain by 36% compared to 10% for SOC treatment. Pharmacologic use decreased by 55% with PEMF compared to 12% with SOC. The crossover subgroup experienced an additional 18% reduction in pain with PEMF on top of the 8% reduction from SOC treatment and an additional 63% reduction in pharmacologic use after beginning PEMF therapy. This study validates the safety and efficacy of a proprietary PEMF system as a noninvasive and nonpharmacologic intervention for joint and soft tissue pain management.

Declarations

Conflict of Interest

Dr. Paci holds an  equity stake in Caerus Corporation through an LLC. David Maravelas is employed by Caerus Corporation. No one from Caerus Corporation had direct contact with the patients, role in collecting data, or access to the data until after the database was locked by MEDIcept. Joshua G Hackel, Sunny Gupta, Taylor North, and Adelina Paunescu declare that they have no competing interests. Taylor North and Adelina Paunescu have changed their affiliation since the completion of this manuscript. Taylor North completed his fellowship at The Andrews Institute for Orthopaedics and Sports Medicine and now works in Orthopedics and Sports Medicine at the Mayo Clinic Health System in Eau Claire, WI, USA. Adelina Paunescu is now Head of Clinical Research at Fractyl Health, Burlington, MA, USA.

Ethical Approval

The protocol was approved by Advarra IRB with approval number Pro00059447 and managed by the independent clinical research organization (CRO) MEDIcept. This study was conducted according to the World Medical Association Declaration of Helsinki and conforms to the ICMJE Recommendations and CONSORT guidelines [15]. Patients provided written informed consent.