Local Tramadol Improves the Anesthetic Success in Patients with Symptomatic Irreversible Pulpitis: A Meta-Analysis

Symptomatic irreversible pulpitis is a painful clinical condition with a broad inflammatory component. Dental anesthesia in these patients is affected by the inflammatory process, reporting a high incidence of anesthesia failure. The aim of this systematic review and meta-analytical evaluation was to determine the effect of pre-treatment with tramadol in patients with symptomatic irreversible pulpitis, as well as for pain control and adverse effects. This study was registered in PROSPERO (ID: CRD42021279262). PubMed was consulted to identify clinical investigations comparing tramadol and placebo/local anesthetics in patients with symptomatic irreversible pulpitis. Data about the anesthesia, pain control, and adverse effects were extracted. Both the anesthetic success index and the adverse effects of local tramadol and placebo were compared with the Mantel–Haenszel test and odds ratio. Data analysis showed that the local administration of tramadol increased the anesthetic success rate when compared to placebo in patients with symptomatic irreversible pulpitis (n = 228; I2 = 0; OR = 2.2; 95% CIs: 1.30 to 3.79; p < 0.004). However, local administration of tramadol increased the risk of adverse effects when compared to placebo/local anesthetics (n = 288; I2 = 0; OR = 7.72; 95% CIs: 1.37 to 43.46; p < 0.02). In conclusion, this study shows that the local administration of tramadol increases the anesthetic success index when compared to placebo in patients with symptomatic irreversible pulpitis.


Introduction
Patients with symptomatic irreversible pulpitis (SIP) face an inflammatory condition with moderate to severe pain that must be treated as a dental emergency. In addition, these patients have pain during root canal treatment due to the anesthetic agents' present difficulty to carry out dental pulp anesthesia [1][2][3].
Non-steroidal anti-inflammatory drugs (NSAIDs) [4] and glucocorticosteroids [5], as well as, to a lesser extent, opioid analgesics have been used to improve the anesthetic success in patients with SIP [6][7][8]. These kinds of drugs suppress the inflammatory process-NSAIDs and glucocorticosteroids- [4,5] or, in the case of opioid analgesics, hyperpolarize the membranes of the nerve fibers-a traditional opioid mechanism of action-which would translate into a decrease in the perception of pain [9][10][11][12]. In both cases, the goal of the preoperative administration of a drug would be to obtain deeper anesthesia to treat patients with this clinical condition [4,5,[9][10][11][12].
In this regard, the opioid analgesic most often used in patients with SIP has been tramadol, which has been used in some clinical trials for improving anesthesia success and for postoperative pain control [13][14][15][16][17][18]. However, the efficacy of tramadol in the dental field has been questioned because no benefits were found when compared to NSAIDs after third molar surgery. Furthermore, tramadol increases the number of adverse effects in comparison to NSAIDs [19].
Tramadol binds to µ-opioid receptors and inhibits monoamine reuptake to exert its therapeutic effect and side effects. Compared to other opioids, it has a low potential for abuse and a low incidence of adverse effects [20]. It has rapid absorption and distribution with maximum serum concentration reached after 2 h [21]. It is metabolized in the liver and its main route of excretion is the kidneys. A small amount of tramadol crosses the placental barrier, and, similarly, a small portion of the drug is excreted in breast milk [21,22]. Several local mechanisms of action of tramadol have been demonstrated, which could be the key to understanding the effect in patients with SIP [17]. An anesthetic effect due to sodium channel blockade [23,24], an anti-nociceptive effect due to potassium channel blockade [23,25] and analgesia acting on peripheral opioid receptors [23,[26][27][28] are the local mechanisms that could be involved in the increased efficacy of anesthetic blockade in patients with SIP.
For this reason, we conducted this systematic review and meta-analytic evaluation (SRME) to determine anesthetic success when using tramadol as a pretreatment in patients with SIP, as well as pain control and adverse effects.

Study Design
This SRME was completed at the Instituto de Investigación en Ciencias Médicas from the Centro Universitario de los Altos of the Universidad de Guadalajara following PRISMA guidelines [29,30] and it has a record in the National Institute for Health Research from the University of York (PROSPERO ID: CRD42021279262).

Information Search
The keywords used to perform the PubMed searches and identification of published articles were: "tramadol", "symptomatic irreversible pulpitis", "active dental pain", "dental pain", "endodontic treatment", and "root channel therapy". In the same way, three screens were employed: 1. Control: a placebo group or a local anesthetic group. Outcomes: anesthetic success, anesthesia depth, anesthetic time, pain intensity, rescue analgesic intake, and adverse effects.

Exclusion Criteria
Clinical studies reporting a loss to follow-up of more than 20%. High risk of bias according to the Cochrane Collaboration's risk-of-bias tool.

Extraction of Information
Article ID data, experimental design, treatment groups, size sample (n), dose and route of administration, anesthetic success index, anesthesia depth, anesthetic time, pain intensity, rescue analgesic intake, and adverse effects were obtained.
Aksoy and Ege published two articles using local tramadol in patients with SIP in 2020. These reports were placed with a lowercase letter to identify them in this SRME ("Aksoy and Ege, 2020a" [13] and "Aksoy and Ege, 2020b" [14]).
Two independent clinical researchers made the bias measurement and data extraction. The differences between them were decided by a third investigator, only when necessary.

Statistical Analysis
The review management 5.3 software for Windows from the Cochrane Library (London, UK) was used for data analysis. Both anesthetic success index and adverse effects of local tramadol versus placebo/local anesthetic were compared with the Mantel-Haenszel test and odds ratio (OR). Data inconsistency was analyzed with the I 2 test. Furthermore, the funnel plots were employed to assess the publication bias of the included clinical studies. A p-value ≤ of 5% (0.05), with an OR ≥ 1 within a 95% confidence interval (CIs), was considered a statistical difference [32,[35][36][37][38].

Search and Measurement of Bias
The initial PubMed search showed a total of 104 articles using tramadol in dentistry, of which six articles compared tramadol and placebo/local anesthetics in patients with SIP ( Figure 1). Moreover, all clinical investigations had a low risk of bias according to the bias tool used ( Figure 2).

Quantitative Evaluation
The evaluation of the anesthesia success rate of submucosal tramadol versus placebo was performed with four clinical investigations (n = 228) [13,[15][16][17]. Data analysis showed that the local administration of tramadol increased the anesthetic success rate when compared to placebo/local anesthetics in patients with SIP (n = 228; I 2 = 0; OR = 2.2; 95% CIs: 1.30 to 3.79; p < 0.004; Figure 3). Table 1. Identification of study, study design, treatments (n), patients, dental procedure, clinical evaluation, and conclusion of the included studies.

ID Study and, Study Design Treatments (n) Details of Patients, Dental Procedure, and Evaluation Conclusions
Aksoy and Ege, 2020a [13]. Randomized, double-blind, parallel, clinical study.  The adverse effects assessment of local tramadol and placebo was made using data from five clinical trials (n = 288) [13,[15][16][17]. In this regard, nine patients who were given local tramadol presented adverse effects, while in the placebo/local anesthetics group no patients reported adverse effects (n = 288; I 2 = 0; OR = 7.72; 95% CIs: 1.37 to 43.46; p < 0.02; The adverse effects assessment of local tramadol and placebo was made using data from five clinical trials (n = 288) [13,[15][16][17]. In this regard, nine patients who were given local tramadol presented adverse effects, while in the placebo/local anesthetics group no patients reported adverse effects (n = 288; I 2 = 0; OR = 7.72; 95% CIs: 1.37 to 43.46; p < 0.02; Figure 4). The adverse effects assessment of local tramadol and placebo was made using data from five clinical trials (n = 288) [13,[15][16][17]. In this regard, nine patients who were given local tramadol presented adverse effects, while in the placebo/local anesthetics group no patients reported adverse effects (n = 288; I 2 = 0; OR = 7.72; 95% CIs: 1.37 to 43.46; p < 0.02; Figure 4).

The Publication Bias
The publication bias of the published clinical investigations was evaluated using the data of anesthetic success ( Figure 5A) [13,[15][16][17] and pain control ( Figure 5B) [13][14][15][16][17] of tramadol and placebo/local anesthetic in patients with SIP. In both cases, the data fell within the funnel plot, indicating a low risk of publication bias.

The Publication Bias
The publication bias of the published clinical investigations was evaluated using the data of anesthetic success ( Figure 5A) [13,[15][16][17] and pain control ( Figure 5B) [13][14][15][16][17] of tramadol and placebo/local anesthetic in patients with SIP. In both cases, the data fell within the funnel plot, indicating a low risk of publication bias.

Discussion
The most important clinical result of this SRME was that the local administration of tramadol increases the anesthetic success index when compared to placebo/local anes-

Discussion
The most important clinical result of this SRME was that the local administration of tramadol increases the anesthetic success index when compared to placebo/local anesthetic in patients with SIP. Moreover, according to the findings of this SRME, local tramadol increases the risk of adverse effects in comparison to placebo. We consider that the risk/benefit balance justifies the use of local tramadol as the high anxiety, severe pain, and suffering that patients with this clinical condition [1][2][3]. We could consider the use of local tramadol as an experimental procedure rarely used in daily practice. Generating more information on the efficacy or otherwise of tramadol in patients with SIP could help introduce or rule out this pharmacological procedure.
The bias tool showed that only one global and individual indicator, detection bias, was rated at medium risk of bias (blinding of outcome assessment), while the rest of the indicators showed a low risk of bias ( Figure 2). In addition, the publication bias of the included studies using tramadol to improve dental anesthesia in patients with SIP was low because all points (representing each individual study) on the funnel plot are within the limits that make up the graph. Only 1/4 of the published studies using tramadol to improve dental anesthesia showed positive results and three clinical trials found no statistical difference between tramadol and placebo/local anesthetic. In other words, most of the published reports present negative results [39][40][41].
The local administration of tramadol in dentistry has been shown to improve the anesthetic and analgesic effects of different agents [42]. In this regard, tramadol has been used as a local anesthetic for dental extraction of upper teeth and it is recommended when patients cannot receive a conventional anesthetic agent [43]. Moreover, the local administration of tramadol increased the anesthetic activity of 4% articaine and 1:100,000 adrenaline following third molar removal [44,45]. However, these findings are different from those reported by Ceccheti et al., 2014, who found that submucosal tramadol improved analgesia but did not extend the anesthetic activity of mepivacaine 2%-1:20,000 levonorfedrine after third molar surgery [46]. Additionally, it has been reported that submucosal tramadol increased anesthesia depth by 2% mepivacaine with 1:100,000 adrenaline in healthy teeth [47]. Moreover, the submucosal administration of tramadol and oral ketorolac produced a better analgesic effect than oral ketorolac plus submucosal placebo after third molar surgery [48]. In addition, the local application of tramadol was effective for pain control after third molar surgery [49]. In this SRME, only one clinical trial reported an increase in the anesthetic time of mepivacaine by using local tramadol in patients with SIP [17].
One point that strongly draws attention to tramadol is the action that this drug induced on a peripheral nerve, a local anesthetic-like effect. Tsai et al., 2001, reported that the local administration of tramadol on the sciatic nerve blocks the spinal somatosensory potentials in rodents [50]. Altunkaya and collaborators evaluated the anesthetic activity of tramadol in different clinical procedures-cutaneous lesions surgery and tendon repair surgery-and concluded that tramadol has an anesthetic action similar to prilocaine 2% [51] or lidocaine with epinephrine [52]. Moreover, tramadol presents additional mechanisms, as explained in the introduction [23][24][25][26][27][28]. All these mechanisms of anesthetic and anti-nociceptive action of tramadol could be acting on specific receptors in the dental pulp to improve the local anesthetic effect in patients with SIP.
The adverse effects of tramadol have been evaluated in other systematic reviews and meta-analyses. Tsaousi et al., 2020 found a negligible association of adverse effects after local administration of tramadol in children undergoing tonsillectomy [53]. In this sense, Mattar et al., 2019, carried out the evaluation of analgesia and adverse effects of tramadol during a diagnostic outpatient's hysteroscopy and reported that the pooled analysis showed no increase in the risk of minor adverse effects, such as nausea, vomiting, and bradycardia [54]. Moreover, Isiordia-Espinoza et al., 2014, informed that tramadol increased the risk of adverse effects on the nervous system as nausea and dizziness when compared to NSAIDs after third molar surgery [19]. In this SRME, 9/144 patients in the tramadol group had a significantly increased risk of adverse effects when compared to the control group. Nausea and dizziness were the adverse effects reported by patients receiving tramadol in the clinical trials included in this SRME. However, the upper ICs is wide, which could indicate that the significant data did not have great relevance, despite the OR obtained.
The adherence to international guidelines for conducting this SRME, the use of studies with a low risk of bias, and the low heterogeneity of the data are the main strengths of this study. However, some weaknesses were detected, for example, the low number of studies detected, a relatively small sample size, the different doses of tramadol used, the different methods employed to assess the same variable (i.e., the pain intensity was evaluated with the 100 mm VAS in some clinical trials and in other studies with the 170 mm Heft-Parker VAS), and the lack of reported data as the standard deviation, which avoids a study being included in the pooled analysis.
The most important finding of this SRME was that when pooled analysis of these data was performed, the anesthetic success rate showed a statistical difference in favor of local administration of tramadol versus placebo/local anesthetics in patients with SIP, highlighting two important aspects: the increase in the sample size and the power of the statistical tests ( Figure 3).
In conclusion, this SRME demonstrates that the administration of submucosal tramadol increases the anesthetic success rate with minor adverse effects in comparison to placebo/local anesthetics in patients with SIP undergoing root channel treatment.