**1. Introduction**

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage [1]. It can be associated with inflammation of soft tissue surrounding the dental implant and crestal bone loss (CBL); also called peri-implantitis [2]. A systematic review reported that the evaluation of self-perceived pain (SPP) is also a diagnostic parameter of peri-implantitis besides other diagnostic criteria such as CBL, bleeding on probing (BOP), probing depth (PD), and suppuration [3]. Furthermore, the International Congress of Implantologists (ICOI) also suggested SPP to be utilized as a diagnostic parameter for implant failure and periimplantitis [4] The numeric pain rating scale (NPRS), developed by Downie et al. [5], is a valid and reliable scale often utilized to examine the SPP in subjects with musculoskeletal diseases, for instance, osteoarthritis [6]. The NPRS has also been utilized to evaluate links with dental implant surgeries [7].

**Citation:** Alshahrani, F.A.; Alqarawi, F.K.; Alqutub, M.N.; AlMubarak, A.M.; AlHamdan, E.M.; Al-Saleh, S.; Ahmad, P.; Vohra, F.; Abduljabbar, T. Association of Self-Rated Pain with Clinical Peri-Implant Parameters and Cytokine Profile in Smokers and Never Smokers with and without Peri-Implantitis. *Appl. Sci.* **2021**, *11*, 5559. https://doi.org/10.3390/ app11125559

Academic Editor: Mary Anne Melo

Received: 6 May 2021 Accepted: 26 May 2021 Published: 16 June 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

The abutment screw loosening or failure is a rare, but very unpleasant failure. Several studies have reported that, after dental implant osseointegration, abutment screw loosening seems to be the most frequent issue linked with implants [8–11]. Many factors contribute to the etiology of these technical failures, such as fabrication failures, non-passive fit of the suprastructures, improper placement technique, fatigue, excessive occlusal load, and the utilization of unfavorable components including copy products [12]. A few reports suggest that most of the failures are related to the suprastructure rather than to the dental implants themselves [13].

Cigarette smoking is a well-established predisposing factor for both peri-implant and periodontal soft tissue inflammation; [14] and CBL surrounding dental implants and natural teeth [15]. One justification in this aspect might be that the generation and deposition of advanced glycation end products (AGEs) in the periodontal tissues is increased by cigarette smoking [16]. The linkage of AGEs with their receptors (RAGE), inflammatory cytokines including matrix metalloproteinase (MMP)-1, interleukin (IL)-8, and tumor necrosis factor-alpha (TNF-α) are generated by human gingival fibroblasts that stimulate inflammation [17]. Furthermore, collagen degradation is increased by cigarette smoking via influencing tissue inhibitors of metalloproteinases [18]. Moreover, the RAGE's expression in the gingival tissues is upregulated; the production of reactive oxygen species (ROS) is stimulated by metabolites of nicotine, i.e., nornicotine which damages the periodontal tissues. Besides contributing to delayed periodontal wound healing, these variables might also compromise peri-implant tissue healing. The destructive inflammatory cytokines cause deteriorating clinical peri-implant parameters including plaque index (PI), PD, gingival index (GI), elevated CBL on the distal and mesial aspects of the dental implant. If untreated, implant failure may be caused [19]. Alqahtani et al. [20] evaluated the clinical peri-implant parameters and levels of cotinine in peri-implant crevicular fluid (PICF) of thirty-five never-smokers and thirty-five tobacco smokers. The findings reported that cotinine levels and peri-implantitis in the PICF were considerably lower in never smokers as compared to tobacco smokers. Furthermore, studies have suggested that nicotine harms human periodontal ligament cells and gingival fibroblasts by increasing the generation of inflammatory mediators and compromising cellular proliferation [21,22]. Regardless of its harmful effects on peri-implant and periodontal health, cigarette smoking is not an absolute contraindication to dental implant treatment [23].

To date, no study has reported the association between PICF levels of TNF-α, MMP-1, and IL-8 with clinic-radiographic peri-implant parameters (PI, PD, BOP, and CBL) along with SPP among patients with peri-implantitis. In the current study, it is hypothesized that clinical and radiographic peri-implant parameters along with pain scores are worse and the levels of TNF-α, MMP-1, and IL-8 in the PICF are higher in cigarette smokers with peri-implantitis in comparison with never-smokers with peri-implantitis. The present study aimed to assess the association between SPP, clinical and radiographic peri-implant parameters, and levels of PICF TNF-α, MMP-1, and IL-8 among cigarette smokers and never smokers with and without peri-implantitis.

#### **2. Materials and Methods**

#### *2.1. Ethical Considerations*

This study was submitted, reviewed, and approved by King Saud University, Riyadh, Saudi Arabia (UDRC/019-12). After reading the informed consent document, written in simple Arabic and English, all the volunteering participants provided written informed consent. The ethical standards of the 1964 Helsinki declaration and national and/or institutional research committee were strictly followed while performing all the procedures. All the participants were aware that they had the right to withdraw at any time throughout the study course without any indirect or direct consequences.
