DOI: https://doi.org/10.21203/rs.3.rs-2226356/v1
Cetylated fatty acids (CFAs) reduce pain through decreasing production of key mediators. They have been successful in improving many conditions including athletic pubalgia, shoulder tendinopathies, and osteoarthritis, but have never been studied in axial discogenic back pain. This study aims to investigate if short term supplementation of oral CFAs reduces pain and disability in patients with axial discogenic low back pain.
The study included 27 patients with average age 57 ± 16 years diagnosed with axial discogenic low back pain based on axial symptoms of chronic low back pain for more than 3 months. The primary outcome of the study was the Oswestry Disability Index (ODI) score. The secondary outcomes were the Numeric Pain Rating Scale (NPRS) (best, worst, and current pain scores) and adverse events. Clinical evaluations were performed at baseline and after 4-week supplementation period with oral CFAs.
After four weeks of supplementation, analysis determined statistically significant reduction in ODI scores from 24.6% ± 16.0 to 16.2% ± 10.7 (p value = 0.0022). 48% of patients were determined to be responders by fulfilling the calculated Minimal Clinically Important Difference (MCID) for ODI at 4 weeks. NPRS current, worst, and best scores all improved significantly (p-value < 0.05) from baseline to 4 weeks. 11.1% of patients experienced adverse effects, none of which were life threatening.
The use of CFA supplementation reduced axial discogenic low back pain and disability in this prospective study. Further research on the use of this treatment is warranted including randomized controlled trials.
Low back pain is the leading contributor to disability and lost workdays in the United States [1]. There are many causes of low back pain, but the most frequent nonspecific lumbar back pain is discogenic [2]. Axial discogenic back pain entails degeneration of the intervertebral disc without herniation [3]. While spinal surgery is effective for other causes of back pain such a radicular pain, spinal stenosis, spondylolisthesis, and other conditions, it is not a treatment frequently used for axial discogenic back pain [3]. Axial discogenic pain is complex with potential contributions from the intervertebral disc (IVD), ligaments, facet joints, and surrounding musculature, making it very difficult to treat [1, 3]. Due to the frequency of axial discogenic back pain and its impact on the population, determining appropriate treatment is essential.
There is a lack of clarity on treatment recommendations for patients with axial discogenic back pain.8 Conservative management including pharmaceutical therapy is often first-line treatment [4, 5]. Pharmaceutical therapy is often directed at targeting reduction in inflammation. IVDs experience mechanical overload thought to cause increased infiltration of macrophages leading to production of pro-inflammatory mediators [2]. Therefore, NSAIDs are frequently utilized [1]. Anti-inflammatories have demonstrated significant results but come with notable side effects for extended use such as renal toxicity and GI side effects [6]. Opioids can also be used in very severe cases but are largely not recommended due to their risk of dependence and addiction [1]. Surgery, including spinal fusion and total disc replacement, and regenerative medicine are options for patients who do not respond to conservative management [1, 3]. However, surgical options have high risks of complication and regenerative medicine has only been effective in early IVD degeneration [1, 3]. There is still need for treatments that can safely reduce inflammation and pain in patients.
In 2001, cetylated fatty acids (CFA), which are fatty acids esterified with cetyl alcohol, started to be used for sports conditions and arthritis [7–9]. Studies utilized a variety of administration techniques including topical CFA cream, capsule supplementation, and patch formulation [8–15]. They are believed to reduce pain by decreasing secretion of leukotriene B4 from stimulated neutrophils, diminishing the release of IL-1 by monocytes, and reducing production of IL-6, TNF, and MCP-1 [6, 9, 11, 13, 14, 16–19]. In a variety of conditions, including athletic pubalgia, shoulder tendinopathies, osteoarthritis, and myofascial pain syndrome of the neck, fatty acids showed improvement in muscle strength, pain, and range of motion [8–15]. However, CFAs have not been used in the treatment of axial discogenic low back pain. Therefore, we decided to carry out this study evaluating the effects of oral supplementation of cetylated fatty acids on patients with axial discogenic back pain.
The hypothesis of the study is that supplementation with CFAs for 4 weeks will reduce disability as measured by ODI score and pain as measured by NPRS from axial discogenic low back pain. This was an IRB approved prospective, single-center cohort study conducted at a single institution (ISRCTN16509365) and conducted in accordance with Good Clinic Practice guidelines and the principles outlined in the Declaration of Helsinki. Written informed consent was obtained from all patients prior to enrolling.
A total of 36 patients were recruited as participants into the study. Patients over 18 years of age were enrolled if they had all the following inclusion criteria: axial symptoms of CLBP (> 3 months of duration). Exclusion criteria included: patients currently on narcotic pain medication, pregnant or currently breastfeeding, patients with low back pain from traumatic injury, patients currently using a pain patch (e.g lidocaine), concurrent pathology that may contribute to the patient’s axial low back symptoms (e.g., spondylolysis, spondylolisthesis, facet arthropathy), severe lumbar disc degeneration, any peripheral neurological symptom attributed to the intervertebral disc pathology, history of lumbar spine surgery, or history of previous spine trauma. Patients were instructed to continue the treatments they have been utilizing without adding anything new except the CFAs.
Subjects were given 3 bottles of PharmaNutra Lipocet CFAs (Via Delle Lenze, 216/b-56122 Pisa). Ingredients of the CFAs included medium chain triglycerides, cetylated fatty acids (refined olive oil, cetyl myristate, cetyl oleate) with excipients. Patients were instructed to take 2 capsules (300mg CFAs each) twice a day for 4 consecutive weeks (1200mg daily).
The primary outcome of the study was patient disability measured by the Oswestry Disability Index (ODI) scores. The secondary outcomes were Numeric Pain Rating Scale (NPRS) and adverse events. NPRS scores included pain at the worst, pain at the best, and current pain level. At the time of enrollment, ODI and NPRS scores were collected via paper document. At the end of 4 weeks, patients were contacted via phone and/or email. Patients were asked to complete ODI scores, NPRS scores, and adverse events.
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 ODI and NPRS scores to mean scores after 4 weeks. A non-parametric Wilcoxon-Mann-Whitney test was used for data that did not follow a normal distribution. The Minimally Clinically Important Difference (MCID) for ODI at 4 weeks was calculated using a distribution-based method of dividing by two the standard deviation of the mean improvement from baseline. Chi-squared was performed to compare 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 16.63.1.
Thirty-six patients were enrolled in the study (Fig. 1). Two patients were lost to follow up, 2 patients were non-compliant with taking the medication, 1 patient failed to complete the surveys, and 1 patient stopped taking the medication due to concerns about mixing with other medications. A total of 27 patients were included in the final analysis. Participants’ ages ranged from 25 to 83 years (57 ± 16) with 52% identified as female (Table 1). The average BMI of participants was 25.8.
Table 1: Patient Demographics
|
Characteristic |
Study Population (n = 27) |
|
Age (mean ± sd) |
57 ± 16 |
|
BMI (mean ± sd) |
25.8 ± 5.25 |
|
Sex n (%) |
13 (48%) male: 14 (52%) female |
|
Abbreviations: BMI = body mass index (units: kg/m2) |
|
The baseline ODI scores significantly decreased from 24.6% ± 16.0 to 16.2% ± 10.7 after 4 weeks of CFA supplementation (p=0.0022) (Figure 2). NPRS worst scores decreased from pre-CFA supplementation (7.63± 1.71) to post (5.67± 2.13) supplementation (p=0.0006) (Table 2). There was also a statistically significant decline in NPRS current scores declining form pre (4.56± 2.45) to post (2.63± 1.96) (p=0.0015). NPRS best scores decreased from pre-CFA supplementation (2.48± 1.91) to post (1.74± 1.79) supplementation (p=0.0343).
Table 2: PROMs|
Clinical Evaluation |
Baseline |
Final |
P-value |
|
ODI score |
24.6% ± 16.0 |
16.2% ± 10.7 |
0.0022 |
|
NPRS best |
2.48± 1.91 |
1.74± 1.79 |
0.0343 |
|
NPRS worst |
7.63± 1.71 |
5.67± 2.13 |
0.000591 |
|
NPRS current |
4.56± 2.45 |
2.63± 1.96 |
0.00153 |
|
Final = 4 week follow up. Baseline and Final values stated as mean ± sd. P-value = baseline vs. final. A p-value of less than 0.05 was considered significant |
|||
Patients were separated into responders (48.15%) and non-responders (51.85%) (Fig. 3) if they fulfilled MCID for ODI at 4 weeks. The baseline characteristics of responders and non-responders were compared however no significant differences were found between both groups.
Adverse events were gathered throughout the study for patients who contacted the research team and as a survey question at the end of the study. There was a total of 4 patients that presented were adverse events. One patient had mild gastrointestinal upset but continued taking the medication. One patient discontinued the medication after 3 days due to nausea. One reported soreness and shortness of breath after 17 days of supplementation and discontinued its use. One patient reported feeling hand numbness after taking the study medication and discontinued its use after 6 days.
To our knowledge, this is the only study utilizing CFAs for axial discogenic low back pain. This study found that supplementation with 4 weeks of CFAs reduced disability and improved function as measured by a statistically significant reduction in ODI scores. Pain from axial discogenic low back pain was also reduced as shown in the statistically significant reduction of NPRS best, worst, and current scores. NPRS best, worst, and current scores were all taken to attempt to address the critique that NPRS does not address the complexity and changing nature of chronic low back pain. While 48% of patients were responders using MCID for ODI scores, we must consider that axial discogenic low back pain is a complex condition, and this response rate is significant to an issue as difficult to treat. Based on these findings, CFAS could be an alternative for other substances utilized for pain and disability management in axial discogenic low back pain that come with extensive side effects.
It is important to frame the results of our study on CFAs in the scope of the other treatments available. Non-steroidal anti-inflammatory drugs (NSAIDs) and opiates are the most common pharmaceutical options for treating axial discogenic low back pain, with NSAIDs currently as the first line analgesic option [4, 5]. An extensive 2011 Cochrane review meta-analysis on NSAID use for low back pain concluded that NSAIDs have only shown a small impact for treatment of chronic low back pain [4, 5]. When compared to placebo, the pool weighted mean difference was − 12.40 (95% CI: -15.53 to-9.26) in favor of NSAIDs [5]. Overall, NSAIDs were slightly better than placebo at improving pain and disability from chronic low back pain. However, NSAIDs come with significant gastrointestinal side effects; 15–30% of patients on chronic NSAIDs will develop erosions or ulcers according to endoscopy studies [5, 20]. NSAIDs have also shown significant renal toxic and cardio toxic effects at lower rates than gastrointestinal side effects [20].
In comparison, opiates have shown evidence for analgesic effect in short term usage for chronic low back pain [21]. Data on function improvements and long-term effectiveness are unknown [21, 22]. The average pain relief encompassing chronic pain in general was 30%; however, data on long term usage and chronic back pain specifically is still unknown [21]. Use of opioids must be highly regulated as prescriptions for chronic pain are the main contributor to the opioid epidemic [22]. Opiates have high rates of development of abuse and/or dependence, and negative psychological changes including depression and anxiety, and hyperalgesia [22].
Similar to NSAIDs and opiates, there was an improvement in pain and disability in the short term in this study using CFAs. The ODI scores and NPRS of all measures decreased in a statistically significant manner. Around half of patients who received CFAs were considered responders, which was a significant number of patients in comparison. We do not have long term data to compare since our supplementation period was 4 weeks. However, since our study is not a randomized controlled trial, we are not able to make direct comparisons in success between NSAIDs, opiates, and CFAs. Patients in our study did not have the significant side effects of opiates and NSAIDs. In our study, around 10% of patients experienced adverse events, none of which were life threatening. One patient experienced shortness of breath. The patient pursued a cardiac stress test which was negative. We are unsure if this was a result of CFA supplementation or other conditions of the patient. Prior studies utilizing CFAs have supported limited side effects. In comparison with pharmaceutical options, the side effects noted for CFAs are minor. CFAs show strong capabilities as a no harm first line treatment for patients with axial discogenic low back pain.
We are aware that this study has some limitations. First is the lack of a control group with subjects receiving a placebo. A comparison between CFA and placebo was not within the aim of this study, although a placebo arm would have allowed to obtain clearer results and should be pursued in future studies. Similarly, the study did not have blinding of physicians or patients which could impact the results and should be studied. This study was conducted at a single center which cannot be representative of the entire population. Finally, the length of follow up is a limitation. Prior analysis of NSAID usage showed studies utilizing periods ranging from < 2 weeks to > 12 months [4]. While this range is variable, our supplementation for 4 weeks would be considered short-term. A longer term follow up would help to draw conclusions regarding the use of CFAs in the chronic pain and disability resulting from axial discogenic low back pain.
In conclusion, the supplementation of CFA in oral formulation for 4 consecutive weeks in patients with axial discogenic low back reduced disability and pain with minimal adverse effects. Oral CFA supplementation could be a promising solution to improve disability and pain in patients with axial discogenic low back pain as a first line treatment, though further studies need to be conducted.
Ethics approval and consent to participation: All methods were carried out in accordance with relevant guidelines and regulations. All experiment protocols were approved by wcg IRB (study number 13291166). Informed consent was obtained from all subjects
Consent for publication: Not applicable
Availability of data and materials: All data generated or analyzed during this study are included as a supplementary file.
Competing interests: No competing interests to disclose.
Funding: Project received funding from the Vad foundation.
Authors contributions: A.P. prepared figures and wrote the main manuscript text. K.M., A.M-I., and V.V. developed the methodology and oversaw the study. All authors reviewed the manuscript.
Acknowledgements: Not applicable