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Gatto MR. Cordaro M. Checchi L. Pain management generally consists of nonsteroidal anti-inflammatory drug NSAIDs , but due to the important side effects related to its use, Palmitoylethanolamide PEA has been taken into consideration. PEA acts as an endogenous agent with anti-inflammatory effect, it also has an analgesic effect starting from the fourth day of treatment.


A case series analysis was retrospectively conducted in order to assess if the association of PEA and Celecoxib, a cyclooxygenase-2 inhibitor, provides a quicker reduction of pain. Maximum mouth opening was also recorded. Since there are currently no disease-modifying agents to treat OA, management of pain by pharmacology, physiotherapy [6], laser therapy [7] and, in few cases, surgical joint treatment, is recommended. Some studies have shown that short-term within a month Paracetamol treatment fails to reduce OA pain to minimal clinically importance levels [8,9]. Although NSAIDs provide excellent pain control for arthritis patients, NSAIDs overuse has been associated with increased risks of gastrointestinal complications [10,11] and cardiovascular events [12] which can limit their prolonged use, therefore innovative therapeutic strategies are needed.

Celecoxib, a cyclooxygenase-2 COX-2 inhibitor, seems to be as effective as Ibuprofen in reducing symptoms associated with knee osteoarthritis with a significant difference from placebo group [13]. Due to the pleiotropic role of endocannabinoids eCB in the pathogenesis of chronic diseases associated with inflammation and pain [14,15], Palmitoylethanolamide PEA , a chemical analog of the anandamide AEA [16], but without central psychotropic effect, has been considered. PEA has been reported to exert anti-inflammatory and analgesic effects in experimental models of both acute and chronic pain and in several human pathological painful conditions [17,18].

A total lack of side effects seems to be ascribed to m- and um-PEA [23,24,25,26], suggesting its potential role for chronic pain treatment. The aim of this case series is to describe whether the short-term combined therapy of Celecoxib and um-PEA decreases the intensity of pain in patients affected by OA and arthralgia of TMJ. Inclusion criteria were the presence of arthralgia and OA, with pain lasting over 4 months and pain intensity greater than 60 on a Visual Analog Scale VAS.

In order to confirm the clinical diagnosis, T1- and T2-weighted magnetic resonance imaging MRI have been performed on each patient by the same radiologist, using the same device to detect anatomical changes of both hard and soft tissues. An informed consent of 12 patients selected was obtained in accordance with guidelines of the Helsinki Declaration [29].

Two patients with synovitis were included in the group. Pain Assessment : All patients received a days diary including for each day a VAS scale to fill in; they were instructed to report current pain level in the evening by putting a mark at the level that best represented their pain at the time of assessment, as described by Huskisson [30]. Maximum Active Mouth Opening Evaluation : The maximum active mouth opening ROM was registered at baseline and at the seventh and fourteenth day of treatment; a mean of three mouth-opening trials was quantified each time.

The vertical distance between edge of the maxillary and mandibular incisors was measured by a ruler and recorded in millimeters.

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Treatment schedule : All selected patients underwent treatment with um-PEA mg Normast , Epitech Group Spa once a day, plus Celecoxib mg Celebrex , Pfizer in the morning and mg in the evening for the first four days and afterwards they were instructed to continue the treatment with mg um-PEA daily for two weeks. Every patient was requested to report any adverse effects during treatment by means of a questionnaire.

They were also advised to immediately suspend the treatment in case of pain in the stomach or tachycardia. Statistical Analysis : Hypothesizing that the expected SD within each group was equal to 0. Data relative to twelve patients affected by osteoarthrosis or synovitis were included in the analysis.

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Average pain intensity score decreased from After the first four days of treatment an important decrease of mean VAS values was observed and then the only administration of um-PEA allowed a reduction of pain intensity to not clinically relevant levels at the end of the two weeks. Figure 1. Moreover, an improvement of mean ROM after the treatment was observed: going from Figure 2.

None of the participants reported any side effect related to the treatment. A major concern in the pharmacological management of in these patients is the risk of side effects related with chronic NSAIDs use [32]; as well as the risk of drug interactions especially in aged patients. In , Ouanounou et al. In this case series, we reported that um-PEA, in combination with Celecoxib for few days, provokes an immediate decrease of pain and improves temporomandibular functions in TMJ-OA patients.

We already reported a pain relief associated with TMJ-OA in patients receiving m-PEA [27], but during the first four days no significant results were reported.

The current study extends this previous work by suggesting that the combination of um-PEA and Celecoxib for few days at the beginning of the treatment, causes quicker decrease in pain intensity and improves TMJ function without any side effect. These results can be related to the different mode of action of the two PEA formulations and to the different target of the medications used. The current findings are also consistent with a recent meta-analysis of randomized controlled trials by Xu et al.

This treatment was associated with acceptable adverse effects. Interestingly, Celecoxib has been also reported to have an effect on decreasing neuroinflammation in an experimental model of Alzheimer disease [35] and this could explain the significant effects obtained. PEA demonstrated a significant efficacy in reducing the hyperalgesic component of neuropathic pain, modulating the activity of mast cells [36]. Moreover, a study carried out using male rats demonstrated to exert superior anti-inflammatory action by orally administered, micronized m-PEA and ultra-micronized um- PEA, versus that of no-micronized PeaPure [17].

The main limitations of this study are the lack of a placebo and control group, the small sample size and the short observation period; which may be addressed in future research. Even though these findings should be confirmed in a double-blind study, still of a remarkable importance is the pain-relieving effect obtained with the association of um-PEA and Celecoxib in so short time, combined to the total lack of side effects, providing additional rationale for using PEA treatment in the context of TMJ-OA pain.

In order to rapidly reduce pain and determine a higher improvement in ROM, the association of um-PEA and Celecoxib in the first four days should be administered. Due to the lack of side effects, this can be considered an effective and safe treatment.

TMJ Exercises #1

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Nicot and co-workers stated that dento-facial deformities are dysmorpho-functional disorders involving the TMJ. Many investigators have reported a TMJ improvement in dysfunctional subjects with malocclusion after orthodontic or combined orthodontic and surgical treatment particularly for the relief of pain. In particular, few studies have highlighted the demographic and clinical predictors of response to surgical treatment.

To-date, no genetic factor has yet been identified as a predictor of response to surgical treatment.

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Conversely, the heterozygous genotype AT was identified as a risk factor of TMD with respect to the rest of the population. All these elements are particularly important to bring new screening strategies and tailor future treatment. The authors concluded that the findings of this study helped to identify sub-populations at high risk of developing post-operative temporomandibular disorders after orthognathic surgery procedures. Moreover, they stated that many other genes of interest could be potential factors influencing the dysfunctional response to orthognathic surgery, particularly genes of the Opera cohort.

Yilmaz and colleagues noted that TMJ internal derangement TMJ ID is a multi-factorial complex disease characterized by articular disc degeneration. Matrilin-3 is a cartilage and bone-specific adaptor protein, and amino-acid substitutions in the protein are associated with skeletal diseases and joint disorders. These researchers further analyzed exon 2 by DNA sequencing to determine the sequence of these variants.

Melis and Di Giosia performed a review of the literature of published articles assessing the role of genetic factors in the etiology of TMDs. A PubMed search was carried out by looking for all controlled clinical trials related to the topic and limiting the search to English language and humans. The references from the studies included and those from review articles were also examined for further relevant papers.

Temporomandibular Disorders

A total of 1, articles were first identified, 24 of which were considered relevant to the topic; 2 other papers were found while searching the references. While TMD signs and symptoms' co-occurrence was not found in subjects within the same family, many gene polymorphisms were shown to be associated with a higher or lower risk of TMD. Such genes were mainly related to serotonin activity and metabolism, T-cell receptor pathway, catecholamine activity and metabolism, estrogen activity, folate metabolism, glutathione activity, ANKH gene, major histocompatibility complex, extracellular matrix metabolism, genes studied in the orofacial pain prospective evaluation risk and assessment OPPERA study, and related to cytokines activity and metabolism.

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The authors concluded that this new understanding of the pathophysiology of TMD can lead to a different treatment approach by identifying the subjects at higher risk for this pathology, and possibly by creating new drugs targeted at interfering with the expression of the genes that enhance such risk. In a case-control study, Harmon and colleagues examined the relationship between omentin-1 levels and painful TMD.

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  4. Levels of omentin-1 in stored blood plasma samples were measured by using an enzyme linked immune-sorbent assay ELISA. Models were adjusted for study site, age, sex, and body mass index BMI. The authors concluded that circulating levels of omentin-1 were significantly lower in painful TMD cases than controls, suggesting that TMD pain is mediated by inflammatory pathways. Eligible studies were selected based on inclusion criteria and included English language, peer-reviewed publications of RCTs comparing BTX versus any alternative intervention or placebo.

    Quality assessment and data extraction were done according to the Cochrane risk of bias tool and recommendations. The entire systematic search and selection process was done independently by 2 reviewers. A total of 5 relevant study trials were identified, involving participants; 2 trials revealed a significant between-group difference in myofascial pain reduction, another trial that compared BTX with fascial manipulation showed equal effectiveness of pain relief on TMDs, while the remaining 2 trials showed no significant difference between the BTX and placebo groups.