Significant differences in application method, the duration of the studies, tested agents, and numerous other factors preclude drawing definitive conclusions based on the included trials. Each study employed a distinct compound, which can be generally divided into three groups: (1) analgesic substances: aceclofenac gel, indomethacin gel, Theraflex-TMJ topical cream with methyl salicylate [35,39,41], (2) cannabidiol (CBD) [33,34], and (3) warming ointments: capsaicin cream, bee venom, Ping-On with peppermint oil and menthol [36,37,38,40]. Each of these preparations exerts a different therapeutic mechanism.

Analgesics exhibit anti-inflammatory effects, proven through many years of use, which involve inhibiting the production of COX by inhibiting the metabolism of arachidonic acid [42]. Their topical application limits undesirable effects in the form of digestive or cardiovascular system problems, depending on the affinity for a specific COX subtype [42,43].

Another substance used was CBD, which is a substance found in cannabis, classified as an organic compound [44]. Despite being an isomorph of THC and showing activity on the same pathway, it does not have psychoactive properties [45]. Many authors have demonstrated its antinociceptive and anti-inflammatory properties [46,47,48,49]. In addition, they have also been demonstrated with topical, not systemic, applications [50,51]. Although, referring to Pastina et al. [52], CBD is ineffective in reducing muscle pain when applied locally.

The final group comprises warming agents, representing a form of physiotherapy rather than traditional pharmacology. This approach carries a significant advantage due to minimal metabolic requirements and reduced side-effect risk. In addition, general warming of a given area can be easily applied in the case of pain, using, for example, hot compresses. It leads to muscle relaxation, pain reduction, and increased blood flow [53].

Another noteworthy aspect of individual studies is the variability in application techniques. Even the same substances were administered in other ways, for example, CBD [33,34]. In some cases, this may increase or eliminate the share of manual activities in pain reduction.

While some authors recommended the application of products only until complete absorption for several dozen seconds [34,39,40], others extended this period to several minutes with the use of circular movements as an additional massage [37,38], and others kept the preparation on the skin for up to 2 h [36]. Some of the researchers used the ultrasound technique [35,41].

However, the application used has visible side effects. In Ramakrishnan et al.’s study [35], the participants in the placebo group achieved a lower VAS score than those in the study group. The same situation occurred with the second author, who used the ultrasound method. The duration of Soon-Moon et al.’s study was much shorter, only 2 days. The baseline values in the case of both authors are not very similar for the placebo and study groups (6.40 vs. 4.68 and 6.03 vs. 4.96), which does not facilitate the analysis and makes it difficult to compare them rationally. Evidence indicates the effectiveness of ultrasound therapy as monotherapy in reducing pain [54]. However, some authors did not demonstrate such effectiveness but recommend considering its use in combination with other common modalities [55].

A comparison of the VAS values from day zero and after 14–15 days revealed a significant reduction in pain levels (p < 0.05) in studies providing standard deviations. The largest percentage reduction in the values was obtained by Nitecka-Buchta et al. [34]. These authors used CBD in a concentration of 1.46%. In contrast, another study by Walczyńska-Dragon et al. [33] employed higher concentrations of CBD (5% and 10%) but did not achieve a similar reduction in pain. This could probably be related to the method and place of application of the administered substances. The intergroup differences in the study by Walczyńska-Dragon et al. [33] indicate that higher concentrations of CBD produce a more substantial therapeutic effect. The imperceptible advantage of higher concentrations over lower ones may indicate a lack of a simple linear dose-effect correlation. The absence of this correlation may also indicate that lower concentrations are sufficient to achieve the desired therapeutic effects or that some pain components limit the benefit at higher doses and are insensitive to CBD. Alternatively, the observed differences may be due to random statistical factors between studies. Moreover, the interpretation of CBD dosing across studies is limited by inconsistent reporting of formulation strength. Although the Nitecka-Buchta et al. [34] formulation’s recipe could imply a 4% CBD content, the authors state that it contains ~1.46% CBD, which we adopted. The Walczyńska-Dragon et al. [33] study reports 5% and 10% gels, though with minor internal inconsistencies in per-dose amounts. These discrepancies, combined with the lack of pharmacokinetic data, prevent meaningful assessment of dose–response patterns and underscore the need for clearer formulation reporting in future trials.

After analyzing the reduction in pain intensity on the VAS, the next parameter assessed was mouth-opening range. Normal mouth opening varies among populations, but the critical functional value is 35–40 mm [26,56]. In case of unavailability of measurement devices, we can use three fingers of the patient (index, middle, and ring) for the assessment. The patient tries to open the mouth as much as possible and place these fingers in the mouth [57]. TMD is often accompanied by opening limitations and other occlusal disorders, such as catching and locking of the jaw [58]. Patients with TMJ disorders have a reduced range of motion in this joint compared to non-TMD patients [59]. Such disorders can be caused by muscle damage from dental injections, excessive chewing, yawning, and prolonged dental procedures, which lead to the development of myalgia, resulting in limited opening [58].

A detailed functional evaluation (mandibular abduction) was conducted by two research teams using warming agents [38,40]. Li et al. [38] obtained a greater increase in values for the Ping-On group, even though the duration of therapy was the same and amounted to 4 weeks. This may be related to the method of application, in which Li et al. [38] extended the application time to several minutes, compared to Winocur et al. [40], who recommended application only until complete absorption. Studies indicate the high effectiveness of physiotherapy in reducing trismus [60]. This is a probable reason for the better results obtained by one of the authors, indicating its greater contribution, which was also confirmed by reductions in the limitation of mandibular abduction in the case of placebo groups.

Given the promising effects observed in improving mandibular function and in reducing pain, it is also important to consider the broader context of local therapies for musculoskeletal pain. As indicated in the review by Derry et al. [61], local treatment can be as effective as oral treatment for acute musculoskeletal pain, with a significantly reduced risk of adverse effects. In another review by Derry et al. [62], the effectiveness of local therapy for chronic pain caused by osteoarthritis—a condition with similar characteristics to TMD—is emphasized. Therefore, this review fits perfectly into the treatment needs of patients with TMD but does not fill the gaps regarding other methods of local drug administration and modifications of the structures of drugs used, briefly discussed below.

Ionophoresis is a physiotherapeutic treatment using electrical current, which is used to introduce drugs into deep tissues [63]. The mechanism involves the introduction of a positively charged drug near the anode and moving within the electric field towards the cathode [64]. The best effects are elicited when the molecules are small and hydrophilic [65]. It is better than typical applications and delivers 10-2000 times more hydrophilic molecules to the skin [66]. Compared to other methods, iontophoresis has many advantages, such as safety, simplicity of use, and high transdermal efficiency [65]. It would be helpful to use this method, which has been known for decades, to maximize the effect of transdermal drug delivery to the masticatory system. Zuo et al. [67] demonstrated increased effectiveness of transdermal administration of NSAIDs such as ibuprofen and indomethacin (whose effect was studied by Soon-Moon Shin et al. [41]). This indicates both the gaps in the existing literature and the possibilities of using this method of drug administration in the treatment of TMD.

While ionophoresis is an advanced technique to improve transdermal delivery, it is essential to consider the broader principles and challenges related to transdermal drug administration. Transdermal drug administration has many advantages, including avoiding the first-pass effect, eliminating adverse effects from the gastrointestinal tract, and eliminating interactions with food or oral medications [68]. Due to the structure of the skin, lipophilic, nonpolar, and low molecular weight molecules (<500 Da) penetrate it to the greatest extent [68]. Even though the drug will present one of the above features, it may turn out to be insufficient, so there is a need to modify the structure, select the form, or use vesicles to maximize its effect. However, this route of administration may also have numerous disadvantages, such as allergic cutaneous reactions and localized irritation, which may cause systemic reactions and problems related to the time of drug penetration [69]. Continuous research is being conducted around the world on modifying the structures of selected substances to improve their therapeutic possibilities in the above method of administration.

An example of the modification of the structure of the introduced molecule is the use of prodrugs. In this technique, the drug is introduced in an inactive, more hydrophobic form [70], which makes it easier to overcome the skin barrier, and then undergoes metabolism and enzymatic conversion towards the active form [71]. Another method based on the modification of the drug structure is the use of vesicles. Depending on the main component, different types are used here, such as liposomes, ethosomes, transfersomes, niosomes, and phytosomes [68,72], Although nanovesicles have great potential, their use also has limitations, such as their instability, low drug loading, control of particle size, and short half-life [73]. Another goal of increasing drug absorption may be stratum corneum (SC) modification, which may increase their permeability [72]. This involves the use of occlusive dressings or absorption promoters [68]. Occlusive dressing and patches placed on the skin block the possibility of water evaporating from its surface and consequently increase the hydration of the SC. This method is particularly useful in the case of hydrophilic drugs. It also leads to increased blood flow in the vessels and an increase in temperature, which also results in increased permeability for drugs [70,74,75].

The carrier and type of preparation are also worth attention. As indicated by Derry et al. [61], the best formulation for administering analgesic medication in local therapy is a gel. In this form, diclofenac, ibuprofen, and ketoprofen have shown the greatest effectiveness.

Although promising results have been obtained, especially for CBD, current evidence does not allow for the formulation of strong clinical recommendations. Nevertheless, in the case of patients with contraindications to systemic therapy, local therapy and local application of drugs should be considered as one of the stages of multi-level pain treatment in TMD. The use of local therapy, which is a combination of selected substances with an appropriately selected method of application, is a safe and effective alternative to systemic treatment, especially in patients with contraindications to the use of NSAIDs, in the elderly, with diseases of the gastrointestinal tract or cardiovascular system. Such treatment increases the patient’s acceptability, reducing adverse effects.

Despite the lack of sufficient standardization of results, the review shows that the effectiveness of therapy can be enhanced by the appropriate pharmaceutical form, application technique, and individualization of treatment, as well as the proper selection of the active substance. The fact that different groups of drugs with varying mechanisms of action demonstrate the effectiveness of action indicates the possible personalization of treatment depending on the characteristics of symptoms and patient preferences. However, due to the methodological diversity of studies, their limitations, and the constant lack of clear guidelines, clinical decisions should be made individually based on the safety of the therapy and the doctor’s experience.

The search conducted in the presented review utilized an extensive query and integrated six databases, which is a positive aspect of the entire review and allows for a thorough assessment of the studied topic. No time limits were introduced either.

However, only the English-language literature was assessed, which could lead to the omission of studies from other regions of the world and a limitation of the available data. Due to the diversity of available data, direct comparison of results was not possible. Limitations stem from differences in treatment duration, drug administration methods, and the wide variety of substances used, including differences in pharmacodynamics, formulation, and mechanisms of action. This led to the inability to extend statistical analysis and the need to employ narrative analysis in selected cases.

The available clinical trials remain small, short in duration, and methodologically heterogeneous, with very limited documentation of safety outcomes. These issues further constrain the strength of the evidence and reinforce the need for more rigorous and standardized investigations.

Therefore, future studies should use standardized formulations, dosing methods, and outcome measures to enable clearer comparisons across treatments. Longer follow-up, systematic safety reporting, and trials directly comparing different drug classes and carriers are needed to identify the most effective and clinically meaningful approaches to percutaneous therapy in TMD.