Abstract
The aim of the present preliminary study was to investigate the effectiveness of an avocado–soybean unsaponifiable extract (ASU) in patients with arthralgia and osteoarthritis of the temporomandibular joint (TMJ). A randomized, double-blind, placebo-controlled trial was carried out. Fourteen women diagnosed with arthralgia and osteoarthritis of the TMJ using the Research Diagnostic Criteria for Temporomandibular Disorders were included in the statistical analysis. The women were allocated randomly to two groups: ASU group and placebo group. Pain was measured using a visual analogue scale and pressure algometer. Mandibular function was evaluated through measurement of mandibular movements. Quality of life was measured using the Oral Health Impact Profile (OHIP-14). The medication (ASU capsules or placebo capsules) was used for 4 months and the total follow-up was 6 months. Those taking the ASU extract had a decrease in pain symptoms and an improvement in quality of life. Moreover, a significant reduction in the use of rescue medication was found in the ASU group compared to the placebo group. This preliminary study provides strong evidence of the effectiveness of an avocado–soybean unsaponifiable extract in patients with degenerative joint diseases and arthralgia in the TMJ. Further studies with larger samples should be performed.
Temporomandibular disorders (TMD) are an important public health problem, with a prevalence rate of approximately 10% among adults. The three most common characteristics of TMD are pain, joint sounds, and limited jaw function. Pain is the most typical symptom and is generally aggravated during chewing or other jaw functions.
Despite the numerous systems employed for the diagnosis of TMD, only two are used widely: the guidelines of the American Academy of Orofacial Pain, and the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). The RDC/TMD currently represent the most often employed examination protocol and the diagnosis is established based on patient history and a physical examination. The RDC/TMD have been employed in both clinical and epidemiological studies and demonstrate a high degree of reliability. This assessment tool allows the classification of TMD into three groups: group I, muscle disorders; group II, disc displacement; group III, arthralgia and joint degeneration (osteoarthritis and osteoarthrosis).
Attempts to improve and develop the diagnostic index culminated in the 2014 publication of the Diagnostic Criteria of Temporomandibular Disorders (DC/TMD) by Schiffman et al. Significant changes have occurred in respect to the ease of implementation as well as the application of the examination, with particular improvements in the validation project referring to painful diagnosis (i.e., myalgia and arthralgia) and disc displacement without reduction or mouth opening limitations. However, other internal disorders (group II, DC/TMD) and degenerative processes of the temporomandibular joint (TMJ) (group III, DC/TMD) maintain low sensitivity, indicating an inability to validate the detection of true illness, even using the DC/TMD.
Use of the DC/TMD, however, was not feasible in the present study as they were published after the study had been started. Furthermore, the diagnosis of degenerative joint disease is characterized by the deterioration of tissue with concomitant bone changes in the condyle and/or articular eminence. According to Schiffman et al., it is necessary that at least one of the following situations exists, regardless of the RDC/TMD: (1) Clinical history: patient report of any noise present in the TMJ during jaw movement or function in the last 30 days, or patient report of any noise occurring during the examination. (2) Clinical examination: crackling detected during one of the jaw movements or during palpation of opening, closing, or lateral protrusion. (3) Imaging: confirmation of subchondral cysts, erosions, condylar flattening, generalized sclerosis, or osteophytes.
Most cases of TMD have a diagnosis of muscle pain, followed by conditions related to the joint disc. A smaller number of patients are categorized in group III (arthralgia, osteoarthritis and osteoarthrosis), and cases of multiple diagnoses in the same patient are uncommon.
Osteoarthritis and osteoarthrosis (OA) are the most common joint disorders and are characterized by the loss of cartilage in areas with increased load, the formation of bone burs, sclerosis, and subchondral cysts, associated with local inflammation. Both quantitative and qualitative changes occur in the cartilage matrix. The prevalence of joint degeneration increases with age and can have a strong psychological impact, thereby affecting quality of life. The treatment of OA has not yet been fully established and studies on arthropathies of the TMJ require a greater degree of scientific evidence.
Some slow-acting drugs have proven to be effective at alleviating the symptoms of OA, such as glucosamine sulphate, chondroitin sulphate, and avocado–soybean unsaponifiable extract (ASU). ASU appears to have anabolic, anti-catabolic, and anti-inflammatory effects on chondrocytes. Its actions include the protection of cartilage (inhibiting interleukin 1 effects and collagenase, as well as the destruction of proteoglycan, phospholipids, and cartilage), an anti-inflammatory effect (inhibiting prostaglandin E2, cyclooxygenase A2, and nitric oxide), and the stimulation of cartilage on chondrocytes and synoviocytes (proteoglycan synthesis and synovial fluid). At the clinical level, ASU reduces pain and stiffness while improving joint function, resulting in a decreased dependence on analgesics. However, there are no studies published in the literature on the use of ASU for the treatment of degenerative diseases of the TMJ.
Thus, the aim of this preliminary study was to investigate the clinical effects of ASU in patients with arthralgia and degenerative diseases of the TMJ.
Patients and methods
Study design, location, and sample selection
A prospective, randomized, placebo-controlled, double-blind clinical trial was performed with independent samples. Participants were recruited based on voluntary presentation to the Brazilian public healthcare system and referral to the School of Dentistry of the University of Pernambuco with a complaint of orofacial pain between September 2012 and August 2013. This study received approval from the human research ethics committee of the study university. The participants underwent a simplified clinical examination, as described by Fonseca et al. The following variables were evaluated: pain in the TMJ for more than 3 months, pain upon palpation of the TMJ, joint sounds during mandibular function (clicking and/or crepitation), limited mouth opening (<40 mm), limited mandibular lateral movements and protrusion (<8 mm), and 2–9 points on an 11-point visual analogue scale (VAS) for pain.
Based on the initial screening, 137 individuals (116 women and 21 men) were assessed according to Axis II of the RDC/TMD. Those with myofascial pain were excluded and only those categorized in group III (arthralgia (IIIa), osteoarthritis (IIIb), and osteoarthrosis (IIIc)) were included. A simultaneous diagnosis of disc displacement with reduction (IIa of group II, RDC/TMD) was permitted. As symptoms of TMD were more prevalent among females, the decision was made to include women only in the sample. Figure 1 displays a flowchart of the selection process.
The following were exclusion criteria: polyarthritis, rheumatological condition, muscle disorder without a joint component, VAS score outside the normality curve, missing teeth or poorly adapted dentures/dentures in poor condition, currently pregnant, other orofacial pain, history of facial trauma, use of non-steroidal anti-inflammatory drugs (NSAIDs), and non-participation in any of the phases of the study.
After application of the eligibility criteria, 19 women were included in the study and signed a statement of informed consent. The participants were allocated randomly ( www.random.org ) to either the experimental group (ASU) or the control group (placebo). The experimental group were given unsaponifiable oil extract consisting of 200 mg of soybean oil and 100 mg of avocado oil in capsule form (Flexi-Smart 300 mg; Smart City, Smart Nutrition Ltd, Luxemburg) and the placebo group were given capsules containing 10 mg of starch. The placebo capsules were identical to the ASU capsules in shape, size, and colour.
The participants were instructed to take one capsule daily with the main meal for four consecutive months; they returned to the clinic every 2 weeks to receive further capsule supplies. The total follow-up period was 6 months. The participants were requested to abstain from the use of anti-inflammatory agents, anxiolytic drugs, bite plates, and speech therapy exercises for 2 weeks prior to the study, as well as throughout the study period. Those who required complementary drug therapy during the study due to pain could use a rescue drug (acetaminophen 750 mg at a maximum daily dose of 3 g divided into four administrations).
Evaluations
Jaw function assessments (measurements of maximum mouth opening without assistance, protrusion, and lateral mandibular movements) were performed with a calibrated digital calliper by a single examiner. The findings were recorded in millimetres. Pain intensity was measured using a VAS. In addition, a digital algometer (FPX10 Algometer, 5 × 0.005 kgf; Wagner Instruments, Greenwich, CT, USA) with a tip measuring 1 cm 2 was used to measure the pressure necessary to cause pain. The site of choice was the lateral ligament of the TMJ, which was identified through palpation during mandibular movements. The readings were expressed in kilogram force (kgf/cm 2 ). All readings were taken by a single examiner who had undergone training. Pressure was increased at a rate of 2 kgf/cm 2 every 10 s.
Quality of life was evaluated using the simplified Oral Health Impact Profile (OHIP-14), which is composed of 14 items distributed equally among seven subscales: functional limitation, physical pain, psychological discomfort, physical disability, psychological disability, social disability, and handicap. Each item has five response options scored from 0 to 4 points, with higher scores indicating a greater negative impact on quality of life.
Evaluations were performed at baseline (T0), 30 days after initiating treatment (T30), 90 days after initiating treatment (T90), 120 days after initiating treatment (T120 – end of treatment), and 180 days after initiating treatment (T180 – 2 months after the end of treatment). The OHIP-14 was administered at T0 and T180 ( Table 1 ).
| Variable | Time, in days | ||||
|---|---|---|---|---|---|
| T0 | T30 | T90 | T120 | T180 | |
| Pain intensity (VAS/algometer) | ✓ | ✓ | ✓ | ✓ | ✓ |
| Jaw function | ✓ | ✓ | ✓ | ✓ | ✓ |
| Quality of life | ✓ | ✓ | |||
| Side effects | ✓ | ✓ | ✓ | ✓ | |
Statistical analysis
Descriptive statistics were expressed as the mean and standard deviation (SD). The Kolmogorov–Smirnov test was employed to determine the distribution of the continuous variables. The Mann–Whitney test was used for comparisons between groups. The non-parametric Wilcoxon test was used for comparisons within the same group over time. Results were considered significant when the P -value was <0.05. GraphPad Prism 5 software (GraphPad Software Inc., San Diego, CA, USA) was used for all statistical analyses.
Results
Fourteen women with similar characteristics participated in the present study. Table 2 shows the distribution of the participants according to age and diagnosis. Mean age was 42.85 ± 14.55 years in the placebo group and 43.14 ± 15.34 years in the ASU group.
| Variable | Group | |
|---|---|---|
| Placebo | ASU | |
| Mean age (SD), years | 42.85 (14.55) | 43.14 (15.34) |
| Age group, n (%) | ||
| <39 years | 3 (42.9) | 3 (42.9) |
| ≥40 years | 4 (57.1) | 4 (57.1) |
| Total | 7 (100) | 7 (100) |
| RDC/TMD, n (%) | ||
| Arthralgia | 2 (28.6) | 1 (14.3) |
| Osteoarthritis | 1 (14.3) | 1 (14.3) |
| Arthralgia/osteoarthritis | 1 (14.3) | 3 (42.9) |
| Arthralgia/DDR | 3 (42.9) | 1 (14.3) |
| Osteoarthritis/DDR | 0 (0) | 1 (14.3) |
| Total, n (%) | 14 (100) | |
A statistically significant reduction in the VAS pain score was found in both groups beginning at T30. A significant difference between the two groups was found only at T120 ( P = 0.04), favouring the ASU group. Maximum mouth opening, protrusion, and right/left lateral excursion were within the range of normality and no statistically significant differences were found between the groups ( Table 3 ).
| Variable | Time | P -value * | |||||||
|---|---|---|---|---|---|---|---|---|---|
| T0 | T30 | T90 | T120 | T180 | P 1 | P 2 | P 3 | P 4 | |
| Pain VAS | |||||||||
| Placebo | 7.1 (1.2) | 5.1 (1.9) | 4.8 (2.1) | 4.1 (1.9) | 3.5 (1.9) | NS | NS | NS | 0.02 |
| ASU | 7.4 (0.7) | 5.1 (1.4) | 3.4 (1.9) | 1.7 (1.9) | 1.5 (1.2) | NS | 0.02 | 0.02 | 0.02 |
| P -value † | 0.8 | 0.8 | 0.2 | 0.04 | 0.07 | ||||
| MMO (mm) | |||||||||
| Placebo | 50.2 (12.2) | 49.2 (13.2) | 49.5 (11.0) | 49.4 (12.1) | 49.5 (12.3) | 0.5 | 0.8 | 0.6 | 0.7 |
| ASU | 42.2 (5.9) | 43.2 (6.1) | 45.5 (6.6) | 46.7 (6.7) | 48.4 (8.3) | 0.8 | 0.6 | 0.2 | 0.1 |
| P -value † | 0.1 | 0.2 | 0.3 | 0.4 | 0.5 | ||||
| Protrusion (mm) | |||||||||
| Placebo | 6.8 (2.2) | 6.8 (2.9) | 7.0 (2.3) | 7.4 (2.0) | 7.2 (2.1) | 1.0 | 0.7 | 0.2 | 0.4 |
| ASU | 5.5 (1.2) | 6.0 (2.0) | 6.4 (1.6) | 6.5 (1.5) | 7.0 (1.2) | 0.5 | 0.08 | NS | NS |
| P -value † | 0.2 | 0.6 | 0.6 | 0.4 | 0.9 | ||||
| Right lateral excursion (mm) | |||||||||
| Placebo | 6.7 (3.0) | 6.2 (2.6) | 6.8 (2.7) | 6.8 (2.5) | 6.7 (2.8) | 0.3 | 0.7 | 1.0 | 1.0 |
| ASU | 6.8 (1.0) | 7.1 (1.8) | 7.4 (1.9) | 7.2 (2.3) | 7.8 (2.1) | 0.7 | 0.3 | 1.0 | 0.08 |
| P -value † | 0.6 | 0.6 | 1.0 | 0.8 | 0.7 | ||||
| Left lateral excursion (mm) | |||||||||
| Placebo | 8.5 (2.2) | 6.8 (2.1) | 7.1 (1.4) | 7.4 (1.9) | 7.2 (1.6) | 0.05 | 0.08 | 0.08 | 0.05 |
| ASU | 7.2 (2.2) | 7.5 (2.8) | 8.1 (2.3) | 7.7 (2.2) | 8.4 (2.2) | 0.7 | 0.5 | 0.8 | 0.1 |
| P -value † | 0.3 | 0.6 | 0.5 | 0.9 | 0.3 | ||||
| Algometer, right side (kgf/cm 2 ) | |||||||||
| Placebo | 1.04 (0.33) | 1.04 (0.29) | 1.10 (0.27) | 1.07 (0.28) | 1.14 (0.21) | 1.0 | 0.3 | 0.9 | 0.2 |
| ASU | 0.99 (0.29) | 1.09 (0.30) | 1.13 (0.31) | 1.37 (0.37) | 1.47 (0.36) | 0.1 | 0.1 | NS | NS |
| P -value † | 0.8 | 0.7 | 0.7 | 0.3 | 0.1 | ||||
| Algometer, left side (kgf/cm 2 ) | |||||||||
| Placebo | 1.10 (0.33) | 1.03 (0.24) | 1.00 (0.22) | 1.00 (0.18) | 1.07 (0.19) | 1.0 | 0.4 | 0.2 | 0.9 |
| ASU | 1.07 (0.39) | 1.11 (0.48) | 1.20 (0.33) | 1.37 (0.38) | 1.45 (0.38) | 0.4 | 0.3 | 0.1 | 0.03 |
| P -value † | 0.9 | 0.9 | 0.2 | 0.07 | 0.05 | ||||
| Algometer, more symptomatic side (kgf/cm 2 ) | |||||||||
| Placebo | 0.89 (0.21) | 0.96 (0.25) | 0.99 (0.25) | 0.95 (0.26) | 1.03 (0.20) | 0.06 | 0.12 | 0.61 | 0.17 |
| ASU | 0.94 (0.27) | 1.02 (0.26) | 1.15 (0.33) | 1.40 (0.34) | 1.47 (0.36) | NS | NS | NS | 0.01 |
| P -value † | 0.56 | 0.70 | 0.30 | 0.02 | 0.02 | ||||
| Use of rescue drug (days) | |||||||||
| Placebo | – | 8.57 (4.69) | 4.28 (3.82) | 3.42 (3.31) | 4.85 (5.55) | – | 0.13 | 0.01 | 0.17 |
| ASU | – | 5.57 (3.74) | 2.00 (1.83) | 0.71 (1.25) | 0.57 (0.98) | – | NS | 0.03 | 0.03 |
| P -value † | – | 0.2 | 0.2 | 0.1 | 0.02 | – | |||
* P 1 = T0 vs. T30; P 2 = T0 vs. T90; P 3 = T0 vs. T120; P 4 = T0 vs. T180. Paired Wilcoxon test for comparisons among evaluation times and corrected by Bonferroni test.
† Placebo vs. ASU. Mann–Whitney test for comparisons between groups.
No significant differences between groups were found in the algometer readings on the right side. In the intra-group analysis, significant increases in the pain threshold on the right side were found in the ASU group between T0 and T120, and between T0 and T180; however, the difference was not significant after Bonferroni test correction. On the left side, the difference between groups was significant only at 6 months after the onset of treatment ( P = 0.03). In the comparison of the more symptomatic joint, significant differences were found between the groups after 4 months of treatment (T120, P = 0.02; T180, P = 0.02) ( Table 3 ; Fig. 2 ).
A significant difference between groups was found regarding the use of the rescue drug (acetaminophen) at T180. In the intra-group analysis, a significant reduction in the use of the rescue drug was found in the ASU group between T30 and T120 ( P = 0.03) ( Table 3 ). Regarding the total use of the rescue drug, the placebo group took a significantly greater amount in comparison to the ASU group ( P = 0.02) ( Fig. 3 ).
None of the participants reported any side effects of the medication. One patient in the placebo group reported gastrointestinal discomfort lasting 36 h at 15 days prior to the end of the treatment period and was instructed to cease taking the capsules. A subsequent investigation suggested that the discomfort stemmed from the patient’s diet, as other members of the family also reported the same symptom.
Table 4 displays the OHIP-14 scores at T0 and T180. No significant differences between groups were found at baseline. At T180, the ASU group exhibited significantly greater improvements (lower scores) over the placebo group regarding the physical pain, psychological discomfort, and physical disability subscales ( P < 0.05). In the intra-group analysis, the ASU group exhibited significant improvements on five of the seven subscales between T0 and T180, whereas the placebo group exhibited a significant improvement only on the social disability subscale ( P = 0.01). Nonetheless, the total OHIP-14 score demonstrated improvements in both groups ( Fig. 4 ).
| T0 | T180 | Placebo | ASU | |||||
|---|---|---|---|---|---|---|---|---|
| Functional limitation | Placebo | 5.42 ± 1.61 | Placebo | 4.28 ± 0.95 | T0 | 5.42 ± 1.61 | T0 | 3.85 ± 2.61 |
| ASU | 3.85 ± 2.61 | ASU | 2.85 ± 2.61 | T180 | 4.28 ± 0.95 | T180 | 2.85 ± 2.61 | |
| P -value * | 0.36 | P -value * | 0.32 | P -value † | 0.20 | P -value † | 0.05 | |
| Physical pain | Placebo | 6.85 ± 0.89 | Placebo | 6.00 ± 1.41 | T0 | 6.85 ± 0.89 | T0 | 6.28 ± 1.60 |
| ASU | 6.28 ± 1.60 | ASU | 3.28 ± 1.49 | T180 | 6.00 ± 1.41 | T180 | 3.28 ± 1.49 | |
| P -value * | 0.59 | P -value * | 0.01 | P -value † | 0.21 | P -value † | 0.02 | |
| Psychological discomfort | Placebo | 6.28 ± 1.79 | Placebo | 6.42 ± 1.90 | T0 | 6.28 ± 1.79 | T0 | 6.00 ± 2.51 |
| ASU | 6.00 ± 2.51 | ASU | 2.85 ± 1.57 | T180 | 6.42 ± 1.90 | T180 | 2.85 ± 1.57 | |
| P -value * | 1.00 | P -value * | 0.009 | P -value † | 1.00 | P -value † | 0.03 | |
| Physical disability | Placebo | 5.00 ± 2.70 | Placebo | 4.00 ± 1.00 | T0 | 5.00 ± 2.70 | T0 | 5.42 ± 2.50 |
| ASU | 5.42 ± 2.50 | ASU | 1.71 ± 1.49 | T180 | 4.00 ± 1.00 | T180 | 1.71 ± 1.49 | |
| P -value * | 0.84 | P -value * | 0.01 | P -value † | 0.26 | P -value † | 0.02 | |
| Psychological disability | Placebo | 5.42 ± 1.71 | Placebo | 4.57 ± 2.22 | T0 | 5.42 ± 1.71 | T0 | 4.57 ± 2.50 |
| ASU | 4.57 ± 2.50 | ASU | 2.28 ± 1.49 | T180 | 4.57 ± 2.22 | T180 | 2.28 ± 1.49 | |
| P -value * | 0.55 | P -value * | 0.06 | P -value † | 0.17 | P -value † | 0.05 | |
| Social disability | Placebo | 5.71 ± 1.97 | Placebo | 3.85 ± 1.77 | T0 | 5.71 ± 1.97 | T0 | 5.14 ± 2.34 |
| ASU | 5.14 ± 2.34 | ASU | 2.57 ± 1.71 | T180 | 3.85 ± 1.77 | T180 | 2.57 ± 1.71 | |
| P -value * | 0.69 | P -value * | 0.21 | P -value † | 0.01 | P -value † | 0.02 | |
| Handicap | Placebo | 4.14 ± 2.79 | Placebo | 2.57 ± 2.14 | T0 | 4.14 ± 2.79 | T0 | 5.42 ± 1.98 |
| ASU | 5.42 ± 1.98 | ASU | 2.42 ± 1.51 | T180 | 2.57 ± 2.14 | T180 | 2.42 ± 1.51 | |
| P -value * | 0.44 | P -value * | 0.94 | P -value † | 0.22 | P -value † | 0.03 | |
| Total | Placebo | 38.86 ± 8.39 | Placebo | 31.71 ± 8.20 | T0 | 38.86 ± 8.39 | T0 | 36.71 ± 10.45 |
| ASU | 36.71 ± 10.45 | ASU | 18.00 ± 6.75 | T180 | 31.71 ± 8.20 | T180 | 18.00 ± 6.75 | |
| P -value * | 0.84 | P -value * | 0.005 | P -value † | 0.02 | P -value † | 0.01 | |
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