Background: Axial low back pain (LBP) is a leading cause of disability worldwide, affecting 65-80% of US adults throughout their lifetime. Lumbar facet joint arthritis (FJA) is a primary cause of LBP, with patients experiencing loss of cartilage, joint space, and ultimately, painful inflammation of surrounding tissues. First-line treatment includes use of NSAIDs; however, chronic anti-inflammatory use often leads to GI and renal toxicity side effects. Cetylated Fatty Acids (CFAs), defined as fatty acids esterified with cetyl alcohol, have likewise been shown to decrease production of inflammatory mediators (i.e. B4, IL-6, TNF-a), with limited documented side effects. The purpose of this study is to evaluate CFA supplementation, consisting of an oral gel with transdermal patch system, on FJA-related low back pain. We hypothesize CFA supplementation will reduce patient outcomes of both LBP and reported disability, with minimal adverse effects.

Methods: A total of 28 patients (17 male, 11 female) were recruited to the study, with an average age of 61.8 (±17.2) years and BMI of 24.7 kg/m²(±3.9). All patients over 21 years of age with the following inclusion criteria were enrolled: axial back pain from facet degenerative joint disease (>3 months of duration). Exclusion criteria included: patients on narcotic pain medication, current use of pain patch (lidocaine), pregnancy or breastfeeding, and LBP from traumatic injury. Subjects were given a 4-week supply of CFA intervention, consisting of an oral supplement gel twice per day with 8-hr transdermal patch. The primary outcome was to measure patient physical disability using pre- and post-RMDQ scores. Secondary outcomes included pain, using NPRS scale, adverse effects, and reported outcomes.

Results: After four weeks of supplementation, preliminary analysis determined a statistically significant reduction in both RMDQ Disability scores (p-value=0.002) and NPRS Reported Pain values (p-value=0.04) (Table I). Notably, 21.4% of patients reported skin irritation to the transdermal patch and 10.7% of patients reported general GI upset or diarrhea over the trial period. Four patients were excluded from the study, two patients due to non-compliance and two patients due to unrelated hospitalization, and therefore not included in the final analysis.

Conclusion: The study found that a combined 4-week oral and transdermal CFA system did significantly reduce patient reported disability and pain outcomes. Interestingly, over 25% of patients experienced mild to moderate GI and skin irritation side effects from intervention. While necessary follow-up studies, including a larger cohort and control group, are to be pursued, CFA supplementation shows potential in improving LBP and overall function for patients.

Keywords: low back pain, facet joint arthritis, cetylated fatty acids, clinical outcomes, disability

LBP, low back pain; CFA, Cetylated fatty acids; FJA, facet joint arthritis; NSAIDs, Non-steroidal anti-inflammatory drugs; RMDS, Roland Morris Disability Questionnaire; NPRS, Numeric Pain Rating Scale; GI, Gastrointestinal; IL-6, Interleukin 6; MCP-6, Monocyte chemoattractant 6; TNF-a, Tumor necrosis factor; FBSS, Failed Back Surgery Syndrome

Axial low back pain (LBP) is a leading cause of disability worldwide, affecting as many as 65-80% of US adults throughout their lifetime.^1,2 Chronic LBP can be defined as pain lasting longer than 12 weeks, typically following an acute episode, with plausible sources of pain including spinal stenosis, disc herniation, and lumbar facet joint arthritis (FJA).³ Facet, or Zygapophyseal, joints are true synovial joints covered by hyaline articular cartilage with arthritis of these regions involves loss of cartilage, leading to decreased synovial fluid, loss of joint space, boney hypertrophy, and ultimately, painful inflammation of surrounding tissues.^4,5 Due to the high prevalence of facet joint arthritis (40-85%), and resulting symptoms, determining appropriate treatment is essential.⁶ Currently, there is ambiguity surrounding treatment recommendations and efficacy for patients with facet joint arthritis.⁷ First-line treatment includes conservative physical therapy and exercise, followed by the use of anti-inflammatory pharmaceuticals, often in the form of NSAIDs.⁸ NSAIDs have demonstrated significant results in pain reduction but often lead to GI and renal toxicity side effects with chronic use, and may even inhibit synthesis of cartilage matrix.^9,10 Opioids can be used in severe arthritic cases but are not recommended to treat chronic pain due to addiction, altered brain morphology, and lack of long-term efficacy.^11,12 In patients unresponsive to conservative methods, lumbar fusion is traditionally used to combat degenerative disease and bolster motion preservation.¹³ However, surgical interventions have high risks of complications, such as Failed Back Surgery Syndrome (FBSS), internal fixation loosening, and infection, offering an opportunity to determine safer, effective treatment options.^13–15

In recent years, Cetylated Fatty Acids (CFAs), defined as fatty acids esterified with cetyl alcohol, were used to treat sports-related and arthritic disorders.¹⁶ As seen in stem cell and mouse models, CFAs decrease the production of inflammatory mediators such as leukotriene B4, IL-6, MCP-1, and TNF-a, as well as reduce degrading enzymes, triggered apoptosis, and signal transduction.^16–19 Studies utilize a range of CFA mediums, mainly through topical creams, oral and capsule supplementation, in various conditions, such as athletic pubalgia, osteoarthritis of the knee, and myofascial pain syndrome of the neck.^{16–18,20,21} However, there are limited study designs utilizing transdermal delivery systems, similar to a lidocaine patch, which may address GI side effects and poor compliance.^23–25 In addition, CFAs have not been used in the treatment of FJA of the spine. Therefore, this study seeks to evaluate the CFA Cetlier system, consisting of oral supplementation and transdermal patch delivery, on patients with axial facet joint arthritic back pain.

A total of 28 patients (17 male, 11 female) were recruited to the study, with an average age of 61.8 (±17.2) years and BMI of 24.7 kg/m²(±3.9). All patients over 21 years of age with the following inclusion criteria were enrolled: axial back pain from facet degenerative joint disease (>3 months of duration). Exclusion criteria included: patients on narcotic pain medication, current use of pain patch (lidocaine), pregnancy or breastfeeding, and LBP from traumatic injury. Subjects were given a 4-week supply of CFA intervention, consisting of an oral supplement gel twice per day with 8-hr transdermal patch. The primary outcome was to measure patient physical disability using pre- and post-RMDQ scores. Secondary outcomes included pain, using NPRS scale, adverse effects, and reported outcomes. The hypothesis of the study is that a 4 week supplementation with the Cetilar Back Pain System will act synergistically to reduce axial back pain from facet degenerative joint disease as measured by the Roland Morris Disability questionnaire (RMDQ) as well as the Numeric Pain Rating Scale (NPRS). This was an IRB approved, prospective, single-center cohort study conducted at a single institution (ISRCNT30329617) and conducted in accordance with Good Clinical Practice guidelines and the principles outlined in the Declaration of Helsinki. Written informed consent was obtained from all patients prior to enrolling.

Study population

A total of 28 patients were recruited to the study. All patients over 21 years of age with the following inclusion criteria were enrolled: axial back pain from facet degenerative joint disease (>3 months of duration). The exclusion criteria included: Patients currently on narcotic pain medication, Patients using a pain patch (lidocaine), Patients unwilling to follow study protocol, Patients that are pregnant or currently breastfeeding and patients with low back pain from a traumatic injury. Since the above conditions could mask back pain or result in it they were removed from the study to accurately observe progression of axial back pain from facet degenerative joint disease. Patients were instructed to continue the treatments they have been utilizing without adding anything new except the CFAs.

Intervention

Subjects were given 6 packs of Pharma Nutra Cetilar CFA patch (Via Delle Lenze, 216/b - 56122 Pisa). Ingredients include CFAs of vegetable origin, acrylate copolymer, menthol. Patients were instructed to apply 1 patch over the indicated spinal area of concern, 8 hours daily for 30 consecutive days. Additionally, Subjects were given 3 boxes of Pharma Nutra Cetilar Oro oral suspension food supplement with CFAs (Via Delle Lenze, 216/b - 56122 Pisa). Ingredients include purified water, stabilizer, glycerol, Lipocet, sucrose esters of fatty acids, flavorings, thickener, xanthan gum, preservatives, potassium sorbate, sodium benzoate, acidifier, citric acid, antioxidant, rosemary extracts, sweetener, sucralose. Patients were instructed to take 1 sachet (800 mg) twice a day for 30 consecutive days (1.60 g daily).

Patient evaluation

The primary outcome of the study was patient physical disability measured using the RMDQ scores. Secondary outcome was patient pain measured using the NPRS and any adverse events. At the time of enrollment, RMDQ and NPRS were collected via paper documents. At the end of 30 consecutive days, patients were contacted via email and/or phone and were asked to complete RMDQ and NPRS and report adverse effects.

The normality of the distributions of continuous variables was assessed using the Jarque-Bera test. Continuous variables were represented as mean ± standard deviation. A two-tailed paired t-test was performed to compare mean baseline RMDQ and NPRS scores to mean scores after 30 days of intervention. A nonparametric Wilcoxon-Mann-Whitney test was used for data that did not follow a normal distribution. The Minimally Clinically Important Difference (MCID) for the RMDQ at 30 days was calculated using the proven 30% reduction from baseline to signify clinical improvement.²⁶ A chi-squared test was performed to compare the demographics of responders and non-responders. A p-value below 0.05 was considered significant. The statistical analysis was carried out using Microsoft Excel Version 16.80.1.

Twenty-eight patients were enrolled in the study (Figure 1). Two patients discontinued the intervention, due to unrelated hospitalizations, 1 patient was non-compliant with taking the supplementation, and 1 patient failed to complete the surveys. A total of 24 patients were included in the final analysis. Participants’ ages ranged from 32 to 89 (61.75±17.23) with 39% identifying as female. The average BMI of participants was 24.72 (± 3.85) (Table 1). The baseline RMDQ Disability scores significantly decreased from 8.21 ± 4.96 to 4.30 ± 3.60 after 30 days of CFA supplementation (p = 0.002) (Table 2 & Figure 2). Likewise, there was a statistically significant decline in NPRS Reported Pain values from pre-baseline scores (5.95 ± 2.2) to post- intervention scores (4.52 ± 2.66) (p = 0.04). NPRS worst scores decreased from pre-CFA supplementation (8.60±1.34) to post-supplementation (6.20±2.59) (p=0.05) (Table 2). There was also a statistically significant decline in NPRS current scores declining from pre (5.95±2.27) to post (4.52±2.66) (p=0.04). Notably, NPRS best scores did not show a significant decrease, with slight increase from pre (3.20 ± 0.25) to post (3.40 ± 2.19) due to patient response variation. Patients were separated into responders (75.0%) and non-responders (25.0%) (Figure 3) based on whether they fulfilled the MCID criteria for clinical improvement after 30 days. The baseline characteristics (i.e. BMI, height, weight, age) of responders and non-responders were compared. However, no significant differences were found between both groups. Adverse side effects were additionally gathered throughout the study for patients who contacted the research team and as a survey question at the end of the study. Notably, 21.4% of patients reported skin irritation to the transdermal patch and 10.7% of patients reported general GI upset or diarrhea over the trial period.

Figure 1 Consort flow diagram of study design

Figure 2 Baseline vs. Final RMDQ Scores.

Notes: Box and Whisker Plot for baseline and final (30-day) RMDQ scores. Figure shows a statistically significant decline from baseline to final scores (p-value: 0.002).

Figure 3 Non-Responders vs. Responders.

Notes: Bar graph comparing the percentage of responders (75%) to non-responders (25%). Categories were established based on MCID calculated by 30% reduction quota in RMDQ scores.

From our understanding, this trial is the only current study utilizing novice CFAs to treat facet joint arthritis symptoms. The study found that a dual patch and oral supplementation of CFAs for 30 days reduced patient disability and improved function, as indicated by a statistically significant reduction in RMDQ scores. The severity of chronic pain was also reduced, shown by the statistically significant reduction of NPRS from baseline to post-intervention scores. Using the MCID criteria for further clinical evaluation, 75% of participants were determined responders and 25% were determined non-responders, or those who did not show a 30% reduction in RMDQ baseline scores. As FJA is a multifactorial condition, this response rate signifies the difficulty in treating this complex disease state. While 10.7 - 21.4% of patients experienced adverse side effects (i.e. GI upset, skin irritation), participants were able to continue using the products. Through these findings, CFAs prove to be an effective treatment option for pain and disability management regarding FJA back pain with less extensive side effects when compared to other substances, such as NSAIDs and Opioids. To properly discuss CFAs, we must frame the results of our study in the scope of current FJA treatment protocol. Regarding clinical work-up, a new patient with acute onset LBP is evaluated via a clinical history, physical exam, and “Red Flag” criteria, such as neurological manifestations or extra-vertebral causes.²⁷ If a patient is determined to have non-specific LBP, counseling and pharmacotherapy is initiated, with de-escalation of treatment following remission of symptoms after 2-6 weeks. However, up to 65% of patients do not experience remission and engage in chronic pharmacotherapy, with first line therapy being Non-Steroidal Inflammatory Drugs (NSAIDs), and second most commonly prescribed opiates.^3,4,27 A 2023 Cochrane meta-analysis review on treatment options for LBP revealed NSAIDs as having a small pain and disability reduction when compared to placebo (95% CI, -10.98 to -3.61).²⁶ Muscle relaxants similarly showed small reduction with notable no significant evidence for paracetamol, opioids, or antidepressants.

With NSAIDs emerging as the mainstay treatment option, it is important to consider adverse effects. In a similar meta-analysis study, 54.3% of patients in the chronic NSAID cohort reported mild-moderate adverse effects, 65.7% in the opioid group, and 15.5% in muscle relaxant group, as compared to 0% in non-pharmaceutical cohorts (i.e. education, heat wrap).²⁷ In addition, both NSAID and opioid groups were noted to have three severe adverse events. Patients in the chronic NSAIDs cohort reported a wide range of adverse effects, including renal toxicity, thrombotic cardiac events, GI erosions and ulcers.^9,10,27,28 Regarding opioids, prescription of such treatment for chronic pain has both declined and been discouraged due to new data on altered neurologic effects, such as hyperalgesia, depression and anxiety, high rates of abuse and dependence, and the fervent opioid epidemic.^11,12 Similar to NSAIDs and opiates, the usage of CFAs did show short term improvement in both pain and disability (i.e. NPRS, RMDQ scores respectively). While we cannot speak to the long-term effects of supplementation, 75% of patients were considered as clinical responders. 10.7% of patients experienced GI upset, including diarrhea or discomfort, and 21.4% experienced dermal irritation to the patch, none of which were life threatening. Patients in our study did not experience as significant or severe side effects as those of opiates and NSAIDs, similar to previous CFA studies. Thus, CFAs demonstrate great potential in both treating symptoms of FJA as a no harm first line treatment. There are several limitations to this study. The first includes a lack of control group with subjects receiving a placebo treatment, such as sugar gel with placebo patch. Although a comparison between CFA and control was not within the aim of the study, a control group would have allowed our group to determine the extent of placebo effect and should be pursued in future trials. Similarly, the study did not have blinding of the physicians or patients. The lack of blinding has potential to impact results and should be considered in future trials. In addition, the study design was conducted at a single center with sample size constraints, which cannot be representative of the entire population. Inclusion of patients from various centers and demographics would reduce error, prevent bias, increase statistical power and offer more accurate clinical results.

A follow up at a later time period would help our team draw additional conclusions regarding CFAs efficacy in the chronic pain and disability management resulting from lumbar facet arthritis. In conclusion, the dual oral and patch supplementation of CFA for a period of 30 consecutive days in patients with low back facet joint arthritis demonstrated a reduction in disability and pain symptoms with varying side effects. CFA supplementation could be a promising solution to improve low back functionality in patients with chronic low back pain as a first line treatment, though further clinical trials need to be conducted.

Our team would like to acknowledge Hospital for Special Surgery for approval and support to conduct this clinical trial at a single-institution in New York City, NY. We would like to express gratitude towards all members of the research team, under lead PI Dr. Vijay Vad, for successful completion of the study. No additional funding from third-party sources regarding this study.

We further confirm that any aspect of the work covered in this manuscript that has involved patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript. Study reviewed and approved by Hospital for Special Surgery ethics board, conducted via WCG & WIRB, trusted partner and IRB reviewal board for institution.

The authors declares that there are no conflicts of interest.

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