Effectiveness of Curcumin in Reducing Self-Rated Pain-Levels in the Orofacial Region: A Systematic Review of Randomized-Controlled Trials

The aim was to systematically review randomized controlled trials (RCTs) that assessed the effectiveness of curcumin in reducing self-rated pain levels in the orofacial region (OFR). The addressed focused question was “Is curcumin effective in reducing self-rated pain levels in the OFR?”. Indexed databases (PubMed (National Library of Medicine), Scopus, EMBASE, MEDLINE (OVID), and Web of Science) were searched up to and including February 2022 using different keywords. The inclusion criteria were (a) original studies (RCTs) in indexed databases; and (b) studies assessing the role of curcumin in the management of pain in the OFR. The risk of bias was assessed using the Cochrane risk of bias tool. The pattern of the present systematic review was customized to primarily summarize the pertinent information. Nineteen RCTs were included. Results from 79% of the studies reported that curcumin exhibits analgesic properties and is effective in reducing self-rated pain associated with the OFR. Three studies had a low risk of bias, while nine and seven studies had a moderate and high risk of bias, respectively. Curcumin can be used as an alternative to conventional therapies in alleviating pain in the OFR. However, due to the limitations and risk of bias in the aforementioned studies, more high-quality RCTs are needed.


Introduction
Pain in the orofacial region (OFR) is often described as pain perception of musculoskeletal, neurovascular, or neuropathic origin [1]; however, it also encompasses pain in dental and mucosal tissues caused by infection or inflammation [2,3]. Secondary etiological risk factors of orofacial pain (OFP) include nerve trauma, neurovascular disorders, and temporomandibular joint or muscular disorders [4]. In the United States, nearly 22% of individuals experience OFP in some capacity during any given 6-month period [5] with females and younger individuals between 15 and 45 years of age being most susceptible to OFP [5,6]. Multi-faceted pathophysiology and psychosocial comorbidity often challenges the correct diagnosis and management of OFP. Traditionally, OFP is treated using (a) medications such as non-steroidal anti-inflammatory drugs, local anesthetics, muscle relaxants, endocannabinoids, anti-convulsants, and antidepressants [7][8][9]; (b) oral appliances such as occlusal splints [10]; (c) massage therapy [11]; and (d) diode-laser therapy [12].
Complementary alternate medications (CAM) are usually derived from medicinal plants and are perceived to have no undesirable side effects compared with synthetic pharmacological drugs [13][14][15]. Patients often use CAM for the relief of pain including OFP [13,16]. Curcumin, a naturally occurring flavonoid [17] chemically denoted as (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), has two aromatic O-methoxy phenolic components, a β-dicarbonyl group, and a seven-carbon linker containing two enone groups [18]. It is a major constituent of several herbs including turmeric [17], which is a common Indian spice and is also consumed when health-related curcumin effects are desired [19,20]. Most turmeric extracts contain three major curcuminoids, including curcumin (60-70%), demethoxycurcumin (20-27%), and bisdemethoxycurcumin (10-15%), along with many other less abundant secondary metabolites [21,22]. Throughout the literature, there is currently a generalized lack of distinction between curcumin and turmeric, with many studies using the terms interchangeably [23,24]. It has been reported that even doses up to 12 g/day are safe [25]; however, curcumin exhibits poor bioavailability due to poor absorption, low intrinsic activity, and a high rate of metabolism and excretion [21,26]. Despite lower bioavailability, it has been reported that curcumin exhibits antioxidant, analgesic, and anti-inflammatory properties [17,27]. Therapeutic effects of curcumin have been assessed with regard to many diseases including cancer, diabetes mellitus, arthritis, neurological diseases, and Crohn's disease [26,[28][29][30][31][32]. Moreover, curcumin has been reported to exhibit anti-cariogenic and immunomodulatory characteristics [33,34]. In a randomized controlled trial (RCT), the efficacy of a curcumin-based gel was compared with a non-eugenol dressing in reducing post-operative pain following periodontal flap surgery in patients with periodontitis [35]. The study concluded that the curcumin-based gel is as effective as a non-eugenol dressing in promoting periodontal healing after flap surgery, and can therefore be used as a substitute form of periodontal post-operative dressing [35]. Similarly, results from another RCT showed that post-operative pain (assessed using the numeric rating scale [NRS]) after surgical extraction of impacted third molars (ITM) is significantly less among individuals who consume curcumin compared with patients using mefenamic acid (MA) [24]. Nevertheless, it has also been proposed that curcumin is not superior to MA in terms of reducing post-operative pain after surgical extraction of ITM [36]. This suggests that there is controversy regarding the effectiveness of curcumin in reducing pain in the OFR. Following a vigilant review of pertinent indexed literature, the authors observed that there are no studies that have systematically reviewed the effectiveness of turmeric and turmeric products in the management of pain in the OFR.
With this background, the aim of the present study was to systematically review RCTs that assessed the effectiveness of curcumin in reducing pain levels in the OFR.

Ethical Approval
In the present study, pertinent indexed literature was reviewed. In this context, prior approval from an institutional review board/committee was not required.

Focused Question, PICO, and PRISMA
The focused question "Is turmeric effective in reducing self-rated pain levels in the OFR?" was addressed using the Population, Intervention, Control, and Outcomes guidelines where P = Patients with pain in the OFR, I = management of pain with curcumin, C = pain management using sources other than curcumin or no treatment, and O = reduction in self-rated pain levels in the OFR. The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were used during the literature search [37]. The protocol for the present systematic review was registered with PROSPERO (CRD42021278739).

Eligibility Criteria
The inclusion criterion was (a) RCTs in indexed databases that investigated the role of curcumin in the management of pain in the OFR. Commentaries, case reports, case series, letters to the Editor, and review articles (narrative and systematic) were excluded.

Data Sources and Search Strategy
The indexed databases (PubMed (National Library of Medicine), Scopus, EMBASE, MEDLINE (OVID), and Web of Science) were electronically searched without language and/or time barriers up to and including February 2022. A customized search strategy was developed by one author (BS): "[(pain) AND (curcumin OR turmeric) AND (orofacial OR face OR facial OR dental OR oral mucosa OR tooth OR teeth OR maxilla OR mandible OR temporomandibular joint)]". The titles and abstracts of identified studies using the aforementioned search strategy were independently screened by two authors (BS, ER). The full texts of pertinent studies were independently reviewed, and reference lists of the relevant studies were hand-searched for any additional studies. The guidelines of the preferred reporting outcomes for systematic reviews and meta-analysis (PRISMA) were used during the literature search [38]. Disagreements in the study selection process were resolved via discussion.

Risk of Bias Assessment
The risk of bias (RoB) in the included studies was assessed using the Cochrane RoB tool [56]. The following parameters were used to assess the RoB: (a) Random sequence generation; (b) allocation concealment; (c) selective reporting (based on the availability of pre-specified primary and secondary outcomes); (d) blinding of investigators and participants; (e) blinding of outcome assessment; (f) incomplete outcome data; and (g) other bias due to problems not covered in the study. The RoB in each category was assessed as "low-risk", "high-risk", or "unclear-risk", with the last category indicating either lack of information or uncertainty over the potential for bias [56]. Based on the criteria, each study was determined to have either a low, moderate, or high overall RoB.
In studies by Maulina et al. [24] and Lone et al. [40], pain in the OFR was associated with the extraction of impacted mandibular third molars and alveolar osteitis (AO), respectively. One study evaluated pain from healing extraction sockets in type II diabetics [55]. Two studies examined pain from periodontal flap surgery [35,51]. Four studies [39,45,52,53] evaluated the effect of turmeric on pain from recurrent aphthous stomatitis (RAS) and six studies [43,[46][47][48][49][50] reported its effect on pain from oral lichen planus (OLP).  In the study by Mansourian et al. [41], pain in the OFR was associated with graft vs. host disease. In the study by Nakao and colleagues, oral pain in patients after head and neck radiotherapy was assessed [42], while chemotherapy-induced oral mucositis with and without head and neck radiotherapy was assessed by Kia et al. [44]. These results are shown in Table 1.

Outcomes of Included Studies
In ten of the studies, pain scores of test and control subjects were directly compared to baseline [24,39,42,43,45,48,50,[52][53][54]; in nine studies, it was found that pain scores were significantly reduced compared to baseline in both curcumin groups and control groups that were administered an active substance [24,39,43,45,48,50,[52][53][54], while in one study comparing curcumin to a placebo, pain scores were not significantly different from baseline for either test or control groups in patients undergoing head and neck radiotherapy [42]. In contrast, Kia et al. [44] found that curcumin nanomicelle capsules were more effective compared to a placebo in reducing oral pain scores in patients undergoing chemotherapy either with or without head and neck radiotherapy. Anil et al. [51] also found pain scores to be significantly decreased in subjects receiving a curcumin mucoadhesive film vs. a placebo film after undergoing periodontal flap surgery. Eleven studies compared curcumin therapy with corticosteroid therapy for pain reduction [39,41,43,[45][46][47][48][49][50]52,53]; seven of these found no significant difference between pain scores with curcumin therapy as compared to corticosteroid therapy, showing similar efficacy in pain reduction with either therapy [39,41,43,45,46,48,53]. Two of these studies compared combined corticosteroid and curcumin therapy vs. curcumin therapy alone and found that topical curcumin with corticosteroid had a significantly greater effect on reducing pain scores than curcumin alone [49] or corticosteroid therapy alone [47]. One study found that corticosteroid therapy reduced self-rated pain scores more rapidly as compared to curcumin therapy [52], while another study found that combined curcumin and corticosteroid therapy showed no difference in reduction of pain scores compared to corticosteroid therapy alone [50]. Srivastava and colleagues [54] measured pain scores with the use of curcumin and clove oil lozenges in test subjects compared to intralesional infiltration of dexamethasone and hyaluronidase in controls and found both groups revealed the absence of pain associated with the lesion after 3 months; however, no difference between the results of the two groups was noted.
Two studies found a statistically significant result when comparing subjects' need for NSAID analgesics as a rescue drug in the curcumin group as compared to control groups after periodontal flap surgery, with curcumin test groups requiring fewer analgesic tablets compared with groups receiving placebo with COE-pak [35,51]. In addition, the study by Maulina and colleagues [24] discovered that patients in the curcumin test group experienced significantly lower pain scores compared to the controls using mefenamic acid and concluded that systemic curcumin was an effective agent for the management of inflammatory pain after the extraction of third molars [24]. In the study by Lone et al., a topical turmeric dressing showed a greater efficacy in resolving alveolar osteitis symptoms, with test subjects experiencing symptoms for a significantly different number of days than control subjects using a Zinc oxide eugenol (ZOE) dressing [40]. It was also found by Mugilan and colleagues [55] that pain scores were significantly lower following tooth extraction on the seventh day in the group receiving the curcumin dressing compared to no dressing in diabetic patients (Tables 4 and 5).

Authors et al. Main Outcomes Conclusions
Deshmukh et al. [39] • Test group ↓ vs. baseline * • Control group ↓ vs. baseline • Test group = control group at any time point measured Curcumin gel showed a similar efficacy to triamcinolone gel in the treatment of minor RAS.
Nakao et al. [42] • Test group = control (placebo) groups = baseline Turmeric in oral gel does not effectively relieve oral pain after head and neck radiotherapy.
Kia et. al. [43] • Test group ↓ vs. baseline • Control group ↓ vs. baseline • Test group = control group at any time point measured Systemic curcumin showed a similar efficacy to systemic prednisone in the treatment of OLP.
Kia et. al. [46] • Test group = control group at any time point measured Topical curcumin showed a similar outcome to topical triamcinolone in the treatment of OLP.
Naik et al. [47] • Control group ↓ vs. test group Topical curcumin with prednisone is more effective than topical curcumin alone in the treatment of OLP.
Nosratzehi et al. [48] • Topical curcumin with prednisolone is significantly more effective in reducing pain compared to topical curcumin alone in the treatment of OLP.
Raman et al. [52] • Test group ↓ vs. baseline • Control group ↓ vs. baseline • Significantly more subjects had alleviation of pain symptoms in the control group on the first, second, third, fourth and fifth days compared to the test group Triamcinolone paste reduces self-rated pain scores from recurrent aphthous ulcers more rapidly as compared to curcumin gel.
Kia et al. [45] • Test group ↓ vs. baseline • Control group ↓ vs. baseline • Test group = control group on the first, fourth, seventh or tenth days 5% Curcumin in orabase is as effective as 0.1% triamcinolone in reducing pain from aphthous ulcers.
Halim et al. [53] • Test group ↓ vs. baseline • Control group ↓ vs. baseline • Test group = control group on the first and fifth days of treatment Turmeric powder and 0.1% triamcinolone had similar efficacy in reducing pain from aphthous ulcers.
Kia et al. [44] • Test group ↓ vs. control (placebo) group at week 7 in patients with and without head and neck radiotherapy • Test group ↓ vs. control (placebo) group in second, fourth and seventh weeks compared to placebo in patients receiving chemotherapy only Curcumin capsules were effective in decreasing pain in patients undergoing chemotherapy either with or without head and neck radiotherapy.  Table 5. Main outcomes and conclusions of studies with curcumin-combination-treated study groups.

Authors et al. Main Outcome Conclusions
Maulina et al. [24] • Test group ↓ vs. baseline * • Control group ↓ vs. baseline • Test group ↓ vs. baseline Curcumin with amoxicillin is more effective for pain management after exodontia than mefenamic acid with amoxicillin.
Lone et. al. [40] • Number of days that subjects experienced symptoms of alveolar osteitis was significantly less in test vs. control groups Curcumin dressing with mustard oil showed greater efficacy at subsiding symptoms of alveolar osteitis compared to ZOE dressing.
Amirchaghmaghi et al. [50] • Anil et al. [51] • Test group ↓ vs. control group for several time points measured • The number of analgesics required by the test group was significantly less than that needed by the control (placebo) group Curcumin mucoadhesive film showed greater analgesic properties in the presence of an amoxicillin regimen as compared to placebo for periodontal post-surgical pain control.
Mugilan et al. [55] • Test group ↓ vs. control group on the 7th day Curcumin oral gel dressing post-extraction in diabetic patients showed slightly greater potential for pain reduction in the presence of a hifenac and novamox regimen.
Mansourian et al. [41] • Pain scores were not significantly different between test and control groups at any time point measured.
Curcumin gel showed a similar efficacy to triamcinolone gel in the presence of systemic prednisone and cyclosporine for the treatment of GVHD.
=: Pain scores not significantly different; ↓: Pain scores significantly reduced; ZOE: Zinc-oxide eugenol. OLP: Oral lichen planus. * The term "baseline" is used to describe pain levels at the beginning of the trials.
The RoB has been described as a deviation or systematic error in the reported results [62]. In other words, the RoB is useful in estimating the extent to which the study design and methodology minimize potential biases [62]. In general, many RCTs had moderate and low RoB [35,39,41,42,45,46,51,54,55]. However, some studies presented with high RoB [24,40,[47][48][49]52,53]. For instance, Maulina et al. [24] reported that the operator who performed the extraction of impacted third molars was blinded to the medications prescribed to patients, and both medications (curcumin and MA) looked alike; however, the authors also stated that patients in the test groups received two capsules of curcumin to manage post-operative pain compared with the control group, in which the patients orally ingested one MA tablet. Another factor that possibly biased the outcomes of the RCTs [24,35,[39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55] assessed is the wide variation in the follow-up duration, which ranged from 1 day to nearly 3 months after treatment.

Conclusions
Preliminary data suggest that curcumin can be used as an alternative to conventional therapies in alleviating pain in the OFR. However, due to the limitations and risk of bias in the aforementioned studies, high-quality RCTs with a lower risk of bias are needed to further investigate curcumin use in pain management in the OFR prior to consideration for widespread clinical use.

Institutional Review Board Statement:
The present study is a systematic review and was therefore exempted from prior approval from an Institutional Review Board.