The effectiveness of the information‐motivation model and domestic brushing with a hypochlorite‐based formula on peri‐implant mucositis: A randomized clinical study

Abstract Objective Management of mucositis is essential for the long‐term maintenance of dental implants. This study determined the efficacy, in terms of clinical parameters, of an adjunctive domiciliary agent paired with non‐surgical periodontal therapy (NSPT) for patients with peri‐implant mucositis. Materials and methods Patients involved in a periodontal maintenance program were randomly distributed to the domestic use of a chlorhexidine toothpaste and mouthwash (control) or a hypochlorite‐based formula brushing solution (test) after diagnosis of peri‐implant mucositis. A modified approach towards NSPTwas performed after 10 days of domestic use of the assigned maintenance product in both groups. Clinical and patient‐related outcomes were recorded during a 90‐day follow‐up period. Results Forty patients completed the three‐month study (20 patients per group). Both groups showed relevant clinical and patient outcome improvements after the NSPT (T2) and between T1 and T2 (p < 0 0.01), except for PPD. For the test group, the clinical improvement was significantly greater than that for the control group at the seventh‐day evaluation (T1) in the gingival index (0–3) and FMBS (%). Favorable outcomes were maintained during the entire follow‐up period. Conclusion The present study showed that the modified NSPT paired with the domestic use of nitradine‐based formula helps resolve peri‐implant mucositis and that nitradine might represent an alternative to chlorhexidine in these cases. Clinical relevance The gold standard for nonsurgical maintenance is full‐mouth disinfection. A previous decontamination of the oral cavity with chlorhexidine or nitradine domiciliary for 10 days could reduce plaque and inflammation, resulting in a painless operative session. This protocol may help reduce airborne contamination and the risk of cross‐infection, and during the pandemic, the protocol is safer for clinicians. In the same clinical cases, nitradine may be more efficient than chlorhexidine, and the former has no side effects such as discolouration.

well tolerated by patients and is associated with less bleeding and less need for anesthesia when compared with standard FMD (Marconcini et al., 2019).
A preoperative rinse with an antimicrobial agent such as chlorhexidine is recommended in surgical periodontal treatment protocols (Quirynen et al., 2000;Zhao et al., 2020). Nevertheless, chlorhexidine has several side effects; thus, new decontaminating products such as NitrAdine ® are emerging in dental practice (Slot et al., 2014).
Its anti-biofilm mode of action is based on a combination of surfactant-induced protein denaturation and slow release of a nontoxic concentration of hypochlorite (0.02%) effective versus microorganisms including bacteria, fungi, and viruses (Glass et al., 2004).
PerioTabs ® is classified as medical device class I in the European Union (Patent pending EP15798353.7 and US 15/526,247) with no side effects reported (no teeth discolouration, corrosion, or burning sensations), and it is used for decontamination purposes in different oral care-related issues (Vento-Zahra et al., 2011). This antimicrobial product has been proven useful in different clinical scenarios (Coenye et al., 2008;Goguta et al., 2021).
This randomized controlled clinical study evaluated the clinical efficacy of full-mouth decontamination paired with 10-day brushing with the PerioTabs ® brushing solution versus the use of chlorhexidine toothpaste combined with chlorhexidine mouthwash. The null hypothesis was that no significant clinical differences exist between chlorhexidine and PerioTabs ® when combined with full-mouth decontamination.

| Study design
This study was a randomized controlled clinical trial with a threemonth follow-up period. Eligible patients were enrolled from those attending the Tuscan Stomatologic Institute (Lido di Camaiore, Italy)for regular implant maintenance protocols-that eventually presented with peri-implant mucositis. Ethical approval was granted by Saint Camillus International University of Health Sciences (UniCamillus, Rome), number 6/2020 (Protocol: "Studio clinico sull'efficacia della motivazione all'igiene orale domiciliare mediante un dispositivo medico in pazienti con mucosite perimplantare"). All patients signed written informed consent at the time of enrolment in the study following the 2008 Helsinki Declaration, updated in 2013.

| Inclusion and exclusion criteria
The main inclusion criterion was the presence of ≥1 endosseous dental implant with clinical and radiographic signs of peri-implantitis and/or peri-implant mucositis around one or more implants per patient. Peri-implant mucositis was identified through a visual examination of edema and inflammation, with peri-implant probing pocket depth (PPD) ≥ 5 mm and the presence of suppuration or bleeding upon probing. Peri-implantitis was identified through observation of bleeding and/or suppuration upon probing, combined with a PPD ≥5 mm and bone loss ≥2 mm from the marginal bone level (MBL) at implant loading (Dietrich et al., 2019).
The following inclusion criteria were adopted: implant function time ≥ 1 year, patients aged 18 years or older, patients exhibiting good general health with no systemic disorders that might affect implant health (such as uncontrolled diabetes, cardiovascular events, or immunodeficiency), patients able to comply with the study protocol, and willingness to adhere to the hygiene instructions. Exclusion criteria were alcohol or drug abuse; regular drug use of bisphosphonates; use of non-steroidal or steroidal anti-inflammatory medication, daily antacid therapy, selective serotonin reuptake inhibitors, and other therapies that might affect implant health; smoking more than 10 cigarettes; pregnancy; lactation; previous periodontitis treatment within the last 6 months; radiotherapy to the head or neck; and current chemotherapy. Subjects exhibiting at least one of these criteria were excluded from the present study. Full medical and dental histories were recorded, along with an oral examination.

| Main variables
The main variables are as follows: • Gingival index (GI): average full mouth score (ranging from 0 to 3); • Mean pocket probing depth (PPD): average full mouth score (expressed in mm); • Recession (Rec): average full mouth score (expressed in mm); • Full-mouth bleeding score (FMBS): average full mouth score (expressed in %); • Modified plaque index (MPI) by Mombelli (1987) for dental implant scales as follows: 0 = no plaque, 1 = plaque at the cervical margin difficult to be seen, 2 = plaque can be seen by the naked eye, 3 = abundance of soft matter; • Modified sulcus bleeding index (MSBI) for dental implant scales as follows: 0 = no bleeding when periodontal probe is passed along the gingival margin, 1 = isolated bleeding spots visible, 2 = blood forms a confluent red line on the gingival margin, 3 = heavy or profuse bleeding; • MBL around dental implants by radiographic assessment; • Pain reported by patients, measured via a visual analogic scale (VAS) with scores ranging from 1 to 10; and • Patients' reported outcome: oral health-related quality of life (OHrQoL), with scores ranging from 0 (good impact) to 5 (negative impact), measured at T0 and T1.

Main intervention: Full-mouth decontamination
Full-mouth decontamination was performed according to the modified approach by Genovesi et al. (2014), which consisted of two appointments: • Baseline: included instruction and motivation with extensive visual explanation of the correct use of antimicrobial domestic products and devices, and • Professional treatment: included one-stage FMD using manual and sonic instruments.

| Randomization and allocation
The patients were randomly allocated to one of two possible treatment groups (20 patients per group) by drawing a card. Sample size estimation was performed according to previously published literature to achieve a significant difference in the longitudinal analysis of implant clinical parameters. The sample size was calculated using a

| Group 2 or control group (C group)
At baseline, the patients were given instructions for the domestic use of a manual toothbrush with chlorhexidine 0.12% toothpaste for 10 days of tooth brushing twice daily (morning and evening). In addition, the patients used a chlorhexidine 0.2% mouth rinse every evening for 10 days. After 1 week, full-mouth decontamination was performed in the same way as in Group 1.

| Timeline
The study comprised one baseline and four follow-up visits defined as follows, as reported in Table 1: T 0 = baseline and oral hygiene instruction session; T 1 = 7 days after the oral hygiene instruction session, full-mouth debridement; T 2 = 10 days after the oral hygiene instruction session and 3 days after full-mouth debridement; T 3 = 30 days after the oral hygiene instruction session; and.
T 4 = 90 days after the oral hygiene instruction session.
The clinical outcomes were evaluated at baseline and at each follow-up visit. Radiological outcome (MBL) was evaluated at baseline and 90 days after the instruction session (T 4 ). The endoral radiographs were standardized using personalized silicone to maintain parallelism, axis, and position .

| Statistical analysis
The clinical parameters were expressed as mean ± standard deviation (SD). Student's t-test for independent samples was used to evaluate the difference between the N and C groups.
Differences were considered statistically significant at p ≤ 0.05.
Statistical analyses were performed using Excel (Microsoft Windows 2020).

| RESULTS
A total of 40 patients with a mean age of 49.8 ± 11.75 years completed the follow-up sessions. The demographic data of both groups (PerioTabs ® and chlorhexidine) are reported in Table 2. No significant differences were observed based on gender, age, or smoking habits (p > 0.05). A total of 70 dental implants were evaluated: 34 implants in the PerioTabs ® group (test group) and 36 in the chlorexidine group (control group).

| Clinical assessment
The mean and standard deviation for each clinical parameter are reported in Table 3. All clinical outcomes significantly improved (p < 0 0.01) between T0 and T1 and between T1 and T2, except for PPD. There were significant differences between the groups in the gingival index (0-3) and FMBS (%) at T1, after the domiciliary use of both products. Patients in the PerioTabs ® group showed the greatest benefit in FMBS (%) from full-mouth NSPT when compared with patients assigned to the chlorhexidine group (p < 0.05) at T2. In addition, 19 patients in the PerioTabs ® group showed signs of gingivitis at T0; this was reduced to five patients at T1, and none at T2. In the chlorhexidine group, 17 patients had gingivitis symptoms at T0, nine at T1, and two at T2. Therefore, it was not possible to analyze the recession.
PPD did not show any differences between the groups and time points. Figures 1 and 2 show the plots of the relative treatment effect for GI and reveal significant differences between the groups at T1.
For FMBS, the figures show differences at T1 and T2. The graphics highlighted at T4 show a slightly greater worsening of these two parameters in the chlorhexidine group.

| Implant sites
The mean and standard deviations for each clinical parameter for dental implants are shown in Table 4. A total of 70 dental implants were evaluated: 34 implants in the PerioTabs ® -group (test group) and 36 in the chlorexidine group (control group). Of the 34 implants evaluated in the PerioTabs ® group, 31 were diagnosed with periimplant mucositis (five patients were smokers) and three with periimplantitis (three patients were smokers). In the chlorhexidine group, 34 implants showed peri-implant mucositis and two implants showed peri-implantitis in two different smoking patients. The main clinical outcomes of implants (mPI and mBI) significantly improved (p < 0 0.01) between T0 and T1 and between T1 and T2, except for PPD, which showed no differences in dental implants.
It was not possible to analyze MBL because no clinical differences were reported after treatment: less than 90 days was not sufficient to highlight significant differences between time points and between groups, and most patients had peri-implant mucositis without any bone involvement. According to the new classification of periodontal and peri-implant disease, after treatment, none of the implants with mucositis required peri-implant surgery in either group during the study's observation period, because no signs of inflammation (bleeding or suppurations) and symptoms worsened. The five implants with peri-implantitis (three of the 33 implants evaluated in the PerioTabs ®group and two implants in the chlorhexidine group) did not present signs of suppuration, and the patients did not report pain; nevertheless, these five implants had no improvements in mBI at T 4 compared with T 0 .
There were significant differences between the groups in mPI (0-3) at T2, with the greatest benefit found in the PerioTabs ® group compared with the chlorhexidine group (p < 0.05).  T A B L E 3 Gingival index (mean value ± SD) mean pocket probing depth (PPD), FMBS (%) and respectively, p-value, p < 0.05 in bold

F I G U R E 2
The full-mouth bleeding scores (%) drop down in both groups, especially in T2 after the professional oral hygiene session. After the domiciliary treatment (T1), the PerioTabs ® group shows a significant reduction in mean value relative to that of the chlorhexidine group

| Patients' reported outcomes
In addition, patient outcomes (VAS and OHrQoL) significantly improved after both types of nonsurgical maintenance protocols (p < 0.001), as reported in Table 5. There were no significant differences between the groups in VAS scale and OHIP-14-score In addition, the clinical parameters around the dental implants (mPI and mBI) significantly improved after only 1 week (T1) and 3 days after the operative session (T2), and no signs of inflammation or pain were reported after treatment. These results indicated that peri-implant mucositis was stabilized, and no implants needed adjunctive surgery after motivation, domestic treatment, and supportive non-surgical therapy. However, all the implants diagnosed with periimplantitis at baseline still presented with bleeding upon probing at the last follow-up visit. This is because frank peri-implantitis is a multifactorial disorder often influenced by systemic conditions, implant mal-positioning, and the type/quality of the prosthetic restoration.
The group using PerioTabs ® showed better clinical outcomes with respect to GI (0-3) at T1 compared with patients assigned to the use of chlorhexidine paste and mouth rinse. Patients in the PerioTabs ® group also showed a greater reduction in FMBS after professional treatment than those in the chlorhexidine group. Other T A B L E 4 Mean value ± SD of modified plaque index (0-3), modified bleeding index (0-3) and respectively, p-value, p < 0.05 is in bold The modified plaque index (mPI, value between 0-3) drops down in both groups, especially in T2 after the professional oral hygiene session. In both groups the plaque grows after the same weeks in T3 and T4. No statistically significant differences are highlighted between the groups, with a p-value <0.05, except for T2 clinical data showed no statistically significant differences between the groups. These findings may be due to the preliminary reduction in The crossover study of Sekino et al. (2004) highlighted that a chlorhexidine mouthwash before surgery could significantly decrease the salivary and tissue bacterial counts and delay plaque formation (Sekino et al., 2004). The substantivity of a 0.2% chlorhexidine mouthwash can have an antibacterial effect for up to 3 h. Subsequently, the microbiota spontaneously recolonized the oral cavity to the baseline level (immediately after the NSPT) (Quintas et al., 2015). The trends seen in the GI and MPI in the present study at T3 and T4 confirm these data and reinforce the notion that the specific individual characteristics of the microbiota could return to the same situation as seen before the stimulus (local antimicrobial substance) was applied, and could even worsen with a major shift in the salivary composition, leading to more acidic conditions and a lower nitrite availability, especially among healthy individuals (Bescos et al., 2020;García-Caballero et al., 2013).
Regarding patient-related endpoints, all patients reported a significant improvement in all outcomes. The pain measured by VAS was improved at seven and 10 days, and the seven-day OHrQoL also showed improvement (Cosola et al., 2018), allowing us to conclude that the benefits of the domestic oral care instructions and the patients' motivation did not only result in an improved anti-plaque effect, but also in their increased well-being (Meza-Mauricio et al., 2018). first seven to 15 days; then, the motivation of the patient needs to be reinforced, and the NSPT is performed at this stage (Genovesi et al., 2014). In this initial seven-to 15-day antimicrobial "shock" therapy, chlorhexidine, particularly used as a mouth rinse, represents the gold standard agent (Zhao et al., 2020). However, since chlorhexidine often induces side effects such as oral mucosa desquamation, tooth staining, and alterations in taste, alternatives might be evaluated. Our study showed that PerioTabs ® can be a valid alternative as an effective initial domestic therapy for MFMD (D'Ercole et al., 2017;Slot et al., 2014).
In this study, no non-desired side effects of PerioTabs ® were observed, whereas two patients in the chlorhexidine group reported burning sensations after the use of chlorhexidine for 10 days. One patient also presented with severe staining of the palatal surfaces of the upper teeth. In addition, although daily preparation of the PerioTabs ® brushing solution by the patient at home required some time and could be considered less consumer-friendly than the use of a simple toothpaste, the patients regarded PerioTabs ® as an actual drug to be taken seriously, and consequently, were highly motivated to follow precisely the directions for use (Coenye et al., 2008;Goguta et al., 2021). In addition, patients preferred the one-step approach of brushing with the PerioTabs ® solution over the two-step approach of chlorhexidine toothpaste and mouthwash.
A common limitation of both PerioTabs ® and chlorhexidine is that they should not be used as long-term preventive therapies. Aerosols represent a major challenge in dental settings, for which a pre-procedural rinse with an antiseptic mouthwash such as chlorhexidine has been proposed (D'Ercole et al., 2017). Therefore, given the properties of the NitrAdine ® , future studies aimed at assessing airborne contamination after dental treatment of patients who have had a pre-operative rinse of PerioTabs ® are recommended (Coenye et al., 2008;Glass et al., 2004). It is also unknown whether the level of gingival inflammation contributes to the bacterial load within aerosol contamination. In this respect, MFMD may offer an interesting approach. Reducing the patient's plaque and inflammation by means of a robust domestic dental hygiene protocol prior to professional treatment could enable clinicians to work more safely with a low level of airborne contamination and a lower production of contaminated aerosol during periodontal debridement.
The findings of the present study indicate that there are alternatives to chlorhexidine for the management of peri-implant mucositis by NSPT. Specifically, PerioTabs ® was found to be associated with reduced pain and dental anxiety, and greater product acceptance, with fewer side effects than chlorhexidine.

ACKNOWLEDGMENTS
The authors acknowledge the director of "Istituto Stomatologico Toscano," Prof. Ugo Covani, who allowed this clinical study and also Dr. ssa Laura Pigozzo and Dott.ssa Silvia Mascarucci who treated some patients enrolled in the study during their post-graduate master degree in "non-surgical periodontal treatment" at the same institute.

CONFLICT OF INTEREST
None declared. Bonyf AG provided all the materials to support the professional and domiciliary treatment of the patients.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.