Immediate pain alleviation in oral mucositis and other oral ulcerative diseases through photobiomodulation therapy: the preemptive treatment concept.

OBJECTIVE: Photobiomodulation (PBM) therapy is recommended by multiple international societies for managing oral mucositis (OM). These recommendations are based on extensive evidence. However, the search for an optimal PBM protocol continues. This mapping review focuses on a novel aspect of PBM therapy which is the immediate effect on pain levels associated with oral ulcerative conditions. DATA SOURCES: This literature review systematically compiles and evaluates the evidence about OM, alongside other oral ulcerative conditions, as the protocols that achieved pain relief for these oral conditions may have potential applicability to OM management. The scientific database used was PubMed. CONCLUSION: Whereas most of the randomized controlled trials about PBM therapy for OM and other ulcerative oral diseases reported delayed pain relief, certain PBM therapy protocols reported immediate pain relief. The results of this review highlight the concept of preemptive PBM therapy, in which PBM therapy is delivered early in the development of OM throughout the oncotherapy and may achieve immediate pain relief consistently in most of the patients and close to a negligible pain level. PBM therapy, as a powerful non-pharmacologic tool for immediate pain relief, has a great beneficial value in patients suffering from OM and other painful oral ulcerative diseases such as recurrent aphthous stomatitis and chronic graft-versus-host disease.

Perforating dental implants and maxillary sinus pathology.

OBJECTIVES: To study the association between perforation dental implants into the maxillary sinus cavity and the development of sinus pathology. METHODS: We retrospectively examined 3732 computerized tomography (CT) scans to detect maxillary implants. The detected scans were grouped based on apparent or lack of perforated dental implants in the maxillary sinus (study and control group, respectively). Clinical data was gathered including the CT indication, patients' demographics, comorbidities and medications, implant features, and the radiographic appearance of the maxillary sinuses. We conducted a logistic regression to identify risk factors to develop radiopaque thickening in the sinuses. RESULTS: Included in the study were 198 patients with 719 maxillary implants; of these, 236 and 483 implants were in the study and control groups, respectively. Sinus opacification was associated with implants' perforations (p < 0.001), diameter, and side and place (p < 0.05). Implants' perforation (OR = 3.679; 95% CI = 1.891-7.157) and diameter (OR = 1.608; 95% CI = 1.067-2.424), sinus floor augmentation (OR = 2.341; 95% CI = 1.087-5.042), male gender (OR = 2.703; 95% CI = 1.407-5.192), and smoking (OR = 6.073; 95% CI = 2.911-12.667) were associated with ipsilateral sinus fullness. CONCLUSIONS: A first large study on the association between maxillary dental implant and sinus pathology. Dental implant perforation is associated with sinus opacification. Considering dental implant diameter, rather than vertical depth of penetration into the sinus, as an important criterion when examining perforated dental implants necessitates a new approach to clinical decision-making.

Immunotherapy-Related Oral Adverse Effects: Immediate Sequelae, Chronicity and Secondary Cancer.

(1) Background: Immunotherapy-related adverse effects (irAEs) have been reported to manifest in oral tissues, mainly as lichenoid and non-lichenoid lesions and salivary gland dysfunction; however, the characterization of oral irAEs and their clinical impact is limited. (2) Methods: This is a retrospective clinical chart review of 14 patients with oral irAEs, describing the impact of the oral irAEs in terms of the immediate effect, treatment, chronicity of the irAEs and the development of oral cancer. (3) Results: Common symptoms were pain and dry mouth, causing no-to-severe pain and/or dry mouth sensation. The immediate sequala ranged from sensitivity to certain foods up to elimination of oral intake. Treatment included conventional palliation techniques with or without systemic steroids. Discontinuation of the immunotherapy agents was required in 6 patients. Innovative treatment modalities included photobiomodulation for oral mucosal pain relief, and salivary gland intraductal irrigations for relief of salivary gland hypofunction. Late sequala included the development of proliferative leukoplakia and oral cancer. (4) Conclusions: Patients treated with immunotherapy may develop debilitating oral irAEs. They should be followed for oral involvement so treatment may be initiated when the symptoms are mild to avoid discontinuation of the immunotherapy. Patients that develop oral lichenoid lesions should receive long-term follow-up, as they may have higher risk for oral cancer.

Clinical use of photobiomodulation for the prevention and treatment of oral mucositis: the real-life experience of MASCC/ISOO members.

AIM: To assess clinical use and patient outcome of photobiomodulation (PBM) for oral mucositis (OM) prevention and treatment among specialized practitioners. METHODS: A poll was emailed to the members of the Mucositis Study Group of MASCC/ISOO. The PBM parameters used by the respondents were analyzed using exploratory statistical methods to identify combinations of PBM parameters (patterns) that characterize the variance in the protocols (principal component analysis). RESULTS: Responses were received from 101 MSG members, with 78 providing analyzable data. Most of the responders were dental practitioners or oral medicine specialists. PBM was used by 59% of the responders for OM or targeted therapy stomatitis. Technical parameters varied widely. Most responders used wavelengths ∼650 nm intra-orally. The spot-size and distance from the tissue were the main factors driving the variation. All PBM users noted that PBM relieved pain, either immediately or a delayed effect. High likelihood of pain relief (measured as responder's report of pain relief in 67-100% of patients) was reported by 22% and 19% of PBM users for immediate pain relief and delayed pain relief, respectively. The most common reported barriers to using PBM were financial considerations, time constraints, lack of training or experience and concern about the potential for malignant transformation or increased risk of cancer recurrence. CONCLUSIONS: The use of PBM for OM prevention or treatment is in early phases of adoption in practices, facing some obstacles to implement it. A wide variation in technical parameters was found. Nonetheless, responses indicate that PBM provided pain relief.

High-power laser photobiomodulation therapy for immediate pain relief of refractory oral mucositis.

PURPOSE: We aimed to evaluate the efficacy of high-power (class IV) laser photobiomodulation (PBM) therapy for immediate pain relief due to oral mucositis (OM) refractory to recommended first-line therapy. METHODS: This retrospective study included 25 cancer patients with refractory chemotherapy- or radiotherapy-induced OM (16 and 9 patients, respectively) that were treated for pain relief with an intraoral InGaAsP diode laser (power density = 1.4 W/cm2 ). Pain was self-assessed immediately before and after laser treatment using a 0-to-10 numeric rating scale ([NRS], "0" = no pain, "10" = intolerable pain). RESULTS: Patients reported an immediate decrease in pain following 94% (74 of 79) of the PBM sessions, in 61% (48 sessions) the pain reduction was over 50%, and in 35% (28 sessions) the initial pain was completely eliminated. There were no reports of increased pain post-PBM. For chemotherapy and radiotherapy-treated patients, mean reduction in pain NRS post-PBM was 4.8 ± 2.5 (p < 0.001) and 4.5 ± 2.8 (p = 0.001), indicating a post-PBM reduction of 72% and 60% of the initial pain level, respectively. The analgesic benefit of PBM remained for a mean of 6.0 ± 5.1 days. One patient reported a transient burning sensation after one PBM session. CONCLUSIONS: High-power laser PBM may provide nonpharmacologic, patient-friendly, long-lasting, rapid pain relief for refractory OM.

Dental tourism and the risk of barotrauma and barodontalgia.

Background and aim Dental tourism, which reflects the provision of health care services abroad, also includes a travelling component. Air travel after dental intervention may cause barotrauma and barodontalgia. This paper aimed to provide guiding principles regarding the minimal time interval between dental procedures and air travel to prevent these adverse effects.Methods A literature search was performed to reveal information with regards to complications related to flights following dental treatments. There is little research in this area and most of it has been conducted on the military aircrew population, which has different characteristics of flight and personnel than civilian commercial flights.Results The recommended time of flying is one week after most dental intervention and six weeks after a sinus lift procedure. The minimal time required between a procedure and flight is 24 hours after restorative treatment, 24-48 hours after simple extraction, 72 hours after nonsurgical endodontic procedure, surgical extraction, and implant placement, and at least two weeks after sinus lift procedure.Conclusions The provided guidelines may serve as a starting point for the clinician's decision-making. The tailoring of an individual treatment plan to the patient should take into consideration the patient's condition, dental procedure, complications and flight characteristics. Further research based on commercial flights is needed to formulate more accurate guidelines for the civilian population.

Clinicians' experience with topical benzydamine and morphine for the management of oral mucositis: adverse effects and barriers.

INTRODUCTION: Among the evidence-based agents outlined in the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) mucositis guidelines, benzydamine and morphine are advised for the management of oral mucositis (OM) in certain cancer patients. This study is aimed to collect information from a group of highly experienced healthcare professionals in the field of oral mucositis about their clinical experience with these agents. METHODS: A survey questionnaire about the clinical experience with topical benzydamine and morphine to manage oral mucositis and their related adverse effects (AEs) was electronically distributed to the members of the Mucositis Study Group of MASCC/ISOO. RESULTS: Eighty-eight entries were recorded (response rate 25%), and 54 entries submitted complete questionnaires about the drug-related AE (completion rate 65%) and were used for the data analysis. Of the respondents, 44% and 27.7% prescribed benzydamine and morphine to manage their patients' oral mucositis, respectively. Lack of availability in the respondent's country was the common reason for not prescribing benzydamine and morphine (18.9% and 5.4%, respectively); however, a large portion of the respondents indicated that 'another reason' stopped them from prescribing these agents (51.3% and 73%, respectively). AEs to benzydamine or morphine were observed by 25.9% and 12.9% of respondents, respectively, with mild numbness and tingling as the most common drug-related AE for both agents. CONCLUSION: The use of topical benzydamine and morphine for the management of OM varies between countries. While relatively common, the AEs related to these agents are mild. Mitigating the barriers for prescribing them may increase their use.

Photobiomodulation therapy in management of cancer therapy-induced side effects: WALT position paper 2022.

Disclaimer: This article is based on recommendations from the 12th WALT Congress, Nice, October 3-6, 2018, and a follow-up review of the existing data and the clinical observations of an international multidisciplinary panel of clinicians and researchers with expertise in the area of supportive care in cancer and/or PBM clinical application and dosimetry. This article is informational in nature. As with all clinical materials, this paper should be used with a clear understanding that continued research and practice could result in new insights and recommendations. The review reflects the collective opinion and, as such, does not necessarily represent the opinion of any individual author. In no event shall the authors be liable for any decision made or action taken in reliance on the proposed protocols. Objective: This position paper reviews the potential prophylactic and therapeutic effects of photobiomodulation (PBM) on side effects of cancer therapy, including chemotherapy (CT), radiation therapy (RT), and hematopoietic stem cell transplantation (HSCT). Background: There is a considerable body of evidence supporting the efficacy of PBM for preventing oral mucositis (OM) in patients undergoing RT for head and neck cancer (HNC), CT, or HSCT. This could enhance patients' quality of life, adherence to the prescribed cancer therapy, and treatment outcomes while reducing the cost of cancer care. Methods: A literature review on PBM effectiveness and dosimetry considerations for managing certain complications of cancer therapy were conducted. A systematic review was conducted when numerous randomized controlled trials were available. Results were presented and discussed at an international consensus meeting at the World Association of photobiomoduLation Therapy (WALT) meeting in 2018 that included world expert oncologists, radiation oncologists, oral oncologists, and oral medicine professionals, physicists, engineers, and oncology researchers. The potential mechanism of action of PBM and evidence of PBM efficacy through reported outcomes for individual indications were assessed. Results: There is a large body of evidence demonstrating the efficacy of PBM for preventing OM in certain cancer patient populations, as recently outlined by the Multinational Association for Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). Building on these, the WALT group outlines evidence and prescribed PBM treatment parameters for prophylactic and therapeutic use in supportive care for radiodermatitis, dysphagia, xerostomia, dysgeusia, trismus, mucosal and bone necrosis, lymphedema, hand-foot syndrome, alopecia, oral and dermatologic chronic graft-versus-host disease, voice/speech alterations, peripheral neuropathy, and late fibrosis amongst cancer survivors. Conclusions: There is robust evidence for using PBM to prevent and treat a broad range of complications in cancer care. Specific clinical practice guidelines or evidence-based expert consensus recommendations are provided. These recommendations are aimed at improving the clinical utilization of PBM therapy in supportive cancer care and promoting research in this field. It is anticipated these guidelines will be revised periodically.

The broadening scope of oral mucositis and oral ulcerative mucosal toxicities of anticancer therapies.

Oral mucositis (OM) is a common, highly symptomatic complication of cancer therapy that affects patients' function, quality of life, and ability to tolerate treatment. In certain patients with cancer, OM is associated with increased mortality. Research on the management of OM is ongoing. Oral mucosal toxicities are also reported in targeted and immune checkpoint inhibitor therapies. The objective of this article is to present current knowledge about the epidemiology, pathogenesis, assessment, risk prediction, and current and developing intervention strategies for OM and other ulcerative mucosal toxicities caused by both conventional and evolving forms of cancer therapy.

The Impact of Expectation for Pain Relief on Orofacial Pain Treatment Outcomes.

Aims: To examine the effects of expectations for pain relief on the objective and subjective outcome of chronic orofacial pain (OFP) treatment. Materials and Methods: Sixty individuals referred to the Orofacial Pain Clinic at the Hebrew University-Hadassah School of Dental Medicine between 2015 and 2017 with OFP reported their expectation for pain relief upon initial consultation. They were also interviewed by telephone after treatment and asked to recall their expectations, referred to as "recalled expectations" (RE). Correlations between RE and treatment success were calculated from pain diaries, and from subjective pain improvement rates (PIR) reported by the patients. Results: 21 males (35.0%) and 39 females (65%), mean age of 46.90 ± 15.77 years and mean pain duration of 49.07 ± 51.95 months participated in the study. All participants rated their expectations as "10" on a 0 to 10 scale during their first visit. RE did not correlate with diary ratings, (P = 0.773) but inversely correlated (-0.3) with PIR (P = 0.020) treatment outcomes. Conclusions: Expectations for pain relief, reported as 10 on a 0-10 scale during the first appointment, may reflect the patient's desire for complete relief of their pain rather than their expectations. Clinicians should therefore be aware of the need for clear communication and wording when examining for expectations. Inverse correlation between recalled expectations and subjective outcome may be due to the nature of recalled expectations when patients already knew their treatment outcomes, and may be explained by the concept of cognitive dissonance.

Long-term dental implications of infant oral mutilation: a case series.

Infant oral mutilation (IOM) is a ritual ceremony practised mostly in African cultures, in which the primary tooth bud of the deciduous canine is extracted. Complications and risks of IOM include pain, heavy bleeding and infection that may deteriorate to life-threating conditions. The main long-term consequence of IOM is future dental abnormalities. The scientific literature lacks in-depth analyses of the dental sequelae of this practice among adults who underwent it, and particularly of the aspect of dental treatment. Eight new cases of IOM are presented in this case series, with emphasis on dental diagnosis and treatment modalities. We describe different outcomes of this practice, such as enamel hypoplasia and crown deformations with later necrosis and infection of the root canal system, severe discolouration, immature root apex, impaction of a canine, failure of development and missing lower permanent incisors and canines, an odontoma-like structure, severe periodontal defect and root dilaceration. Familiarity with the practice of IOM is vital in order to identify its manifestations and arrive at the correct diagnosis and optimal course of treatment.

Oral white lesion in patients post-hematopoietic stem cell transplantation: a case series demonstrating the diagnostic dilemma.

The current National Institutes of Health (NIH) consensus paper excluded "white hyperkeratotic plaque" from the diagnostic criteria for oral chronic graft-versus-host disease (cGVHD) in order to ensure malignant transformation is not overlooked. Therefore, an isolated oral white plaque is recommended to be subjected to biopsy and pathologic examination. The cases described in this paper shed a new light on the clinical approach to oral white plaque post-hematopoietic stem cell transplantation. The objectives of this article are to demonstrate that a white plaque does not contradict a diagnosis of oral cGVHD, and to highlight the clinical considerations for taking a biopsy.

Standardization of terminology, imaging features, and interpretation of CBCT sialography of major salivary glands: a clinical review.

Sialography combined with cone beam computerized tomography (sialo-CBCT) is an imaging technique that demonstrates the ductal system of the major salivary glands and allows evaluation of gland function. This review describes the sialo-CBCT technique, terminology, common pitfalls and limitations, as well as radiographic features and suggested pathogenicity of various salivary gland disorders, based on 1,758 sialo-CBCT examinations conducted over the last decade in one institution, and the current literature. The adoption of standardized terminology is proposed to prevent miscommunication, facilitate formulation of differential diagnoses, and thereby promote patient management: (1) Sialo-CBCT requires specific training, and operator experience is required for adequate glandular filling with minimal extravasation; (2) Limit injection-to-scan time to avoid pre-mature emptying; (3) The sialo-CBCT report should include a description of the morphology of the primary duct as well as the secondary, tertiary, and descending branches, the maximal branching level, the presence of sialectasis, overall glandular size, and parenchymal findings; (4) Functional evaluation is based on assessment of iodine clearance in the post evacuation image; (5) Sialectasis and ductopenia are the main findings in Sjogren syndrome and recurrent juvenile parotitis; (6) Sialodochitis with or without fillings defects or hyperdense calcifications characterize obstructive sialadenitis and sialolithiasis; (7) The findings following radioactive-iodine-induced damage are similar to obstructive sialadenitis, with atrophy in late stages; (8) In chronic graft-versus-host disease (cGVHD), variable presentations of ductopenia, sialectasis, and sialodochitis may be evident; (9) The red flags indicating a space-occupying lesion include areas of no filling, splaying of ducts, and primary duct deviation.

Oral Graft-Versus-Host Disease: A Pictorial Review and a Guide for Dental Practitioners.

INTRODUCTION: Graft-versus-host disease (GVHD) is a complication of haematopoietic stem cell transplantation (HSCT). GVHD may also develop following solid transplants or blood transfusions if white blood cells are transferred. GVHD affects multiple organs, including the oral tissues. OBJECTIVE: This pictorial review provides a background of GVHD to dental practitioners, describes the most common oral manifestations of GVHD and highlights the main treatment modifications needed to deliver dental care to patients with GVHD. METHODS: A narrative review enhanced with clinical photographs. RESULTS: Acute GVHD may manifest in the oral mucosa; however, it often develops immediately following HSCT when routine dental treatment is postponed. Chronic GVHD may manifest in the oral mucosa, the salivary glands and the musculoskeletal compartment. It may indirectly affect the teeth and the oral flora, putting the patient at risk for infections. Importantly, GVHD poses an increased risk for oral cancer. CONCLUSION: GVHD has a wide range of oral manifestations, some of which may affect dental treatment.

Photobiomodulation (low-level laser) therapy for immediate pain relief of persistent oral ulcers in chronic graft-versus-host disease.

PURPOSE: To determine the immediate pain-relieving effect of photobiomodulation therapy (PBMt) in patients with oral ulcers of chronic graft-versus-host disease (cGVHD) refractory to first line therapy with topical corticosteroids. METHODS: This retrospective study included all patients who underwent PBMt for pain relief of refractory oral cGVHD lesions. PBMt was applied using an intraoral approach to all sites with mucosal lesions, using a 940 nm InGaAsP diode laser device, with the following parameters: pulsed modulation (duty cycle of 50%), power 0.7 W, illuminated spot size 7.1 cm2, irradiance 98.6 mW/cm2, and irradiation time 90 s per point. Pain was self-assessed using a 0-to-10 scale immediately before and after PBMt. RESULTS: Data from eleven patients with a total of 56 PBMt sessions were analyzed. In 48 (85.7%) sessions, the patients reported less pain immediately after treatment, with a reduction of ≥ 50% of the initial pain level in 43 (76.8%) sessions. Mean pre- and post-treatment pain levels were 5.20 ±2.7 and 1.38 ±2.1, respectively (p < 0.001), i.e., a post-treatment reduction of 73.4% of the initial pain level. The benefits of the treatment remained for a mean of 6.50 ±5.4 days (range of 2 to 14 days). No adverse effects were reported. CONCLUSIONS: PBMt seems to be a promising treatment modality for refractory oral cGVHD lesions as a rapid pain reliever with relatively long-lasting effects.

Supportive care of cancer patients with a self-applied photobiomodulation device: a case series.

PURPOSE: Oral mucositis (OM) and prolonged wound healing are common side-effects of cancer treatments. Photobiomodulation (PBM), previously called low-level laser, is currently part of the official guideline for OM prevention. However, all the PBM protocols relate to office-based devices, operated by professional health caregivers, requiring frequent applications. In the following case series, we present our experience with a self-applied consumer home-use PBM device for supportive care. METHODS: Five patients receiving cancer treatment presented at the clinic (female:male 3:2, 55-76 years old) with OM grade 3/4 (n=2), post-surgical non-healing wounds (n=3), and dermatitis (n=1). The PBM treatment (808 nm, 250 mW peak power, 15KHz, 5 J/min, ray size 4.5×1.0cm2) was self-applied by the patients. The protocol included extra/intra-oral applications, over the wound bed/margins and adjacent lymph nodes. RESULTS: The treatment was found effective for resolving OM with rapid pain relief and accelerated healing in post-operative wounds and dermatitis, without reported adverse events. Patients found routine easy to follow and painless, and the protocol was easily integrated as an adjuvant treatment to standard care at the clinic or home while not requiring additional time from the staff. CONCLUSIONS: Side-effects induced by cancer therapy have a detrimental effect on the patient's well-being and may delay or even prevent the patients from completing treatment regimens. PBM is already an established tool for supportive treatment in cancer patients. The advent of a self-applied personal PBM treatment with easy-to-apply protocols for a variety of side-effects makes this technology an important accessible and safe supportive care option.

Pain characteristics in medication-related osteonecrosis of the jaws.

PURPOSE: To characterise pain from medication-related osteonecrosis of the jaws (MRONJ) and the effects of antimicrobial treatment on it. METHODS: Data from files of patients diagnosed with MRONJ according to the position paper of the American Association of Oral and Maxillofacial Surgeons (2014) and Multinational Association of Supportive Care in Cancer and American Society of Clinical Oncology (2019) were collected retrospectively, including gender, age, primary disease, bone-modifying agents (BMAs)/anti-angiogenics, administration route, involved jaw, location, and exposure size. The patients were treated according to the abovementioned position papers' recommendations, i.e. all patients who suffered from pain were staged as 2 or 3 and treated with systemic amoxicillin, or doxycycline or clindamycin in case of sensitivity, and local antiseptic and hygiene instructions. RESULTS: Data from 77 MRONJ patients (aged 65.09 ± 11.9 years old) were analysed. Most (90.1%) received bisphosphonates for cancer (79%) and osteoporosis (17%). A total of 67.5% experienced pain; 36.5% had moderate-to-severe pain. Female gender was significantly associated with the presence of pain (p = 0.002). Osteonecrosis lesions after dento-alveolar surgery had a higher risk of pain development than spontaneous lesions (p = 0.045). Medical and oncologic background, type of pharmacotherapy, lesion size, and location were not associated with pain levels. Worse initial pain was significantly associated with better relief following MRONJ treatment (p = 0.045). Meaningful pain reduction (≥ 50%) was significantly correlated with initial pain severity (p = 0.0128, OR = 4.75). CONCLUSIONS: Pain from infection and inflammation often accompanies MRONJ. The presence of pain is correlated with longer BMAs pre-therapy and if surgery preceded the MRONJ. Persistency of the mild pain together with a resistance to common antimicrobial treatment, although not complete, is a feature that MRONJ pain shares with neuropathic-"like" pain, and requires further study and consideration during treatment.

MASCC/ISOO clinical practice guidelines for the management of mucositis: sub-analysis of current interventions for the management of oral mucositis in pediatric cancer patients.

OBJECTIVE: The aim of this sub-analysis was to highlight the MASCC/ISOO clinical practice guidelines for the management of oral mucositis (OM) in pediatric patients and to present unique considerations in this patient population. METHODS: This sub-analysis of the pediatric patient population is based on the systematic review conducted by the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISSO) published in 2019/2020. Studies were scored and assigned a level of evidence based on previously published criteria. Data regarding adverse effects and compliance was collected from the original publications. RESULTS: A total of 45 papers were included and assessed in this sub-analysis, including 21 randomized controlled trials (RCTs). Chewing gum was demonstrated to be not effective in preventing OM in pediatric cancer patients in 2 RCTs. The efficacy of all other interventions could not be determined based on the available literature. CONCLUSION: There is limited or conflicting evidence about interventions for the management of OM in pediatric cancer patients, except for chewing gum which was ineffective for prevention. Therefore, currently, data from adult studies may need to be extrapolated for the management of pediatric patients. Honey and photobiomodulation therapy in this patient population had encouraging potential. Implementation of a basic oral care protocol is advised amid lack of high level of evidence studies.