Recent Progress in Gels for Neuropathic Pain

Neuropathic pain is a complex and debilitating condition that affects millions of people worldwide. While several treatment options are available, they often have limited efficacy and are associated with adverse effects. In recent years, gels have emerged as a promising option for the treatment of neuropathic pain. Inclusion of various nanocarriers, such as cubosomes and niosomes, into gels results in pharmaceutical forms with higher drug stability and increased drug penetration into tissues compared to products currently marketed for the treatment of neuropathic pain. Furthermore, these compounds usually provide sustained drug release and are biocompatible and biodegradable, which makes them a safe option for drug delivery. The purpose of this narrative review was to provide a comprehensive analysis of the current state of the field and identify potential directions for future research in the development of effective and safe gels for the treatment of neuropathic pain, ultimately improving the quality of life for patients suffering from neuropathic pain.


Introduction
Neuropathic pain (NeP) is caused by damage or dysfunction of the nervous system, which can result in abnormal sensory processing and pain signals being sent to the brain [1]. Its etiology is complex, involving nerve damage or injury (owing to trauma, surgery, infection, or diseases, such as diabetes, multiple sclerosis, or HIV), compression or entrapment of nerves (e.g., in carpal tunnel syndrome or herniated discs), and diseases affecting the nervous system (as in stroke, spinal cord injury, or Parkinson's disease) [2].
It may also be the result of exposure to chemotherapy or radiation therapy or of the administration of certain medications (e.g., antivirals or anticonvulsants) [3]. Independent of the etiology, negative (deficits of different somatosensory qualities) and positive (paresthesia and dysesthesia, paroxysmal pain, and ongoing superficial pain) sensory symptoms coexist in NeP [4]. Stimulus-evoked symptoms such as hyperalgesia and allodynia may occur in addition to spontaneous pain and are rarely the only pain manifestation [4].
An increasing trend in the prevalence of NeP is reported: 10% in 2017 vs. 5% in 2008, in the US [5]. Furthermore, a recent study approximated that about 15% of nursing home residents in the US suffer from NeP [6]. A recent research showed that the aged-standardized prevalence of chronic polyneuropathy is 3.3% for the European Union, 3.0% for the United States, and 2.3% for the world population and is expected to increase by ±25% in the next 20 years based on the expected age distributions [7]. Furthermore, in the young population, the incidence of diabetic neuropathy ranges from 2.6% to 11% and cardiac autonomic neuropathy from 4% to 39% of the patients with type 2 diabetes. Thus, diabetic neuropathy and cardiac autonomic neuropathy are the most common forms of neuropathy in adolescents and young adults [8].
The symptoms of NeP can be debilitating and have a significant impact on a person's quality of life [4]. In patients with chronic neuropathic pain, physical and mental health declines more than in those with other types of chronic pain [9,10]. This highlights the Drug combinations (gabapentin/opioids or gabapentin/tricyclic antidepressants) are recommended to those patients who are partial responders to analgesic monotherapy [24]. Furthermore, for the first time, EFNS recommends cannabinoids in neuropathic pain in refractory cases [20].
Even though individual agents within the TCA (tricyclic antidepressants), SNRI, and gabapentinoid groups have similar efficacy in neuropathic pain, their adverse effect profile is different [32]. Patients with preexisting constipation, urinary retention, or orthostatic hypotension may show a lower tolerability for TCAs. In addition, cognitive impairment, gait disturbances, and falls may occur, especially in the elderly population [27,34]. On the other hand, the side effects of SNRIs and sodium channel blockers, such as nausea, tiredness, and vertigo, may be intolerable for patients with similar preexisting symptoms [27]. Patients with comorbidities causing peripheral edema should cautiously use gabapentinoids as they can also induce peripheral edema [27].
The average duration for a treatment to show efficacy is approximately 12 weeks. Neuropathic pain treatment should be administered for at least 12 weeks before being evaluated and considered ineffective, appropriate, or intolerable [27]. Regardless of each medication's unique side effect profile, vertigo, somnolence, and tiredness are common in oral therapeutic regimens, while application site reactions occur in topical medication. A summary of the pharmacological therapeutic options is given in Table 1. Considering that the therapeutic options for treating neuropathic pain have limited effectiveness in relieving pain and numerous side effects, few drugs with novel mechanisms of action are under clinical development for the treatment of this pathology [35], including selective sodium blocking agents such as Nav1.7 antagonists [36], angiotensin type II (EMA) [37], TPRV1, and nerve growth factor antagonists [35]. However, it will take some time before new therapies will be available.
Therefore, developing topical preparations, such as gels, containing substances known to be effective against NeP represents an attractive option as they would provide a faster onset of action, targeted delivery, improved adherence, a lower risk of gastrointestinal side effects, flexibility in dosing, and reduced drug interactions.

Development of Analgesic-Containing Gels Useful for NeP
Over the past decade, several types of gels containing analgesics for NeP therapy have been developed, based on the properties of the active substances for drug delivery applications (Table 2). Such gels are based on natural polymers such as chitosan or gelatin, which provide excellent biocompatibility and biodegradability [38]. These gels can be cross-linked with a variety of agents, such as glutaraldehyde, genipin, or sodium tripolyphosphate, to improve their mechanical and swelling properties [39]. Another type of hydrogel is based on synthetic polymers, such as polyethylene glycol or polyvinyl alcohol, which provide tunable properties and controlled drug release capabilities [40]. Furthermore, they can be modified with various functional groups to enhance their stability and biocompatibility. The incorporation of the active substances into these hydrogels can be achieved by different methods, such as physical entrapment, covalent bonding, or electrostatic interactions.
Understanding and optimizing these factors can improve the overall effectiveness of such treatments. Some of these preparations have shown promising analgesic effects after transdermal or subcutaneous delivery in animals, and thus, they might offer an improved therapeutic outcome in NeP.

Capsaicin
In clinical practice, capsaicin is primarily used as a topical analgesic to treat neuropathic pain. Capsaicin has also been studied for its potential therapeutic effects in other conditions, including osteoarthritis, psoriasis, gastritis, and migraines, although more research is needed to determine its efficacy and safety in these areas [64].
Regarding the currently authorized products containing capsaicin, they include prescription patches of 8%. Usually, transdermal capsaicin implies the use of up to 4 patches for 30-60 min once every 3 months. Overuse of capsaicin patches can lead to severe skin irritation or other side effects. In vitro data demonstrate that the release rate of capsaicin from patches is linear over the duration of application, and approximately 1% of the amount of capsaicin is absorbed into the layers of the epidermis and dermis during an 1-hour application [65]. Several creams containing capsaicin exist worldwide as supplements [66]. Capsaicin cream, available as over-the-counter products with 0.025-0.1% concentrations, with 0.1% considered high potency, can be applied up to four times a day. Although burning, stinging, or itching may occur, these sensations diminish over time [67].
Capsaicin-containing gels have been extensively studied in the last decade. Most of the studies used natural polymers such as chitosan [68], alginate [69], or gelatin [70] to develop capsaicin-containing hydrogels. Several synthetic polymers, including polyethylene glycol (PEG) and polyvinyl alcohol (PVA), were also used. The incorporation of capsaicin into the hydrogels was achieved by different methods, such as physical mixing and more recently, by encapsulation. The release profile of capsaicin from the gels varied depending on the type of polymer and the method of incorporation.
Older studies investigated the formulation of hydrogels containing capsaicin through physical mixing. Wang et al. [71] investigated the in vitro and in vivo skin absorption of capsaicin from chitosan/carboxymethylcellulose-based hydrogels and compared it with that of commercialized creams containing capsaicin. Drug partition between the skin and the gel matrix was critical in the permeation process. As expected, the in vitro permeation of capsaicin from the tested gels is depended on the physicochemical nature and the concentration of the polymer used. Thus, adding the nonionic polymer Pluronic (Plo) F-127 to the gels produced a delayed release of capsaicin. On the other hand, a higher capsaicin permeation rate was obtained in in vitro studies with cationic chitosan and anionic carboxymethyl cellulose hydrogels than with cream bases. In a dose-dependent manner, the cream produced skin erythema in vivo. However, the dose-dependence was not observed in gels which had a lower irritative effect than commercially available cream [71].
Peng et al. [72] designed and investigated the transdermal controlled release of cubic phase gels containing capsaicin. Release studies demonstrated that cubic phase gels imprint a sustained system for capsaicin, the release rate being affected by the initial water content, distribution of capsaicin in the lipid bilayers, and cubic phase gel swelling.
Capsaicin-loaded 1% nanolipoidal carriers (NLCs) were designed to increase permeation and provide analgesic and anti-inflammatory effects with reduced skin irritation [73]. These NLCs and gels with capsaicin-loaded NLCs demonstrated sustained release, noncytotoxic properties, enhanced penetration, and improved pain threshold in a dose-dependent manner, while inhibiting inflammation more effectively than conventional preparations. Reduced skin irritation suggests NLCs as a potential carrier for topical delivery of capsaicin in pain and inflammation therapy [73].
Aylang et al. [74] extracted a natural β-chitin-protein complex film from waste shells of Ensis spp. After production and physicochemical characterization of the film, capsaicin was loaded. The loading capacity was 5.79%, and over a period of 120 h capsaicin remained stable with a sustained release rate. Maximum release of capsaicin was recorded as 50.49% (48 h) for pH 4.0, 59.81% (72 h) for pH 5.5, and 59.02% (96 h) for pH 7.4.
Another study developed and characterized a chitosan-based hydrogel containing capsaicinoids-loaded nanocapsules for topical delivery. Several chitosan hydrogels were prepared to determine the optimal composition. The most suitable gel contained the lowest amount of lactic acid (1.5%) and an intermediate amount of chitosan (3.5%), ensuring a pH of 4.34 ± 0.11. After 30 days of storage, the gel exhibited a slight increase in consistency and a decrease in the flow index and pH [68].
Peng et al. used phytantriol-and GMO-based cubosomes as a targeted, sustained transdermal delivery system for capsaicin [75]. Their skin retention of capsaicin (4.32 ± 0.13 µg) was higher than that of capsaicin cream (0.72 ± 0.13 µg). The cubosomes were stable under strong light and high temperatures for up to 10 days and caused minimal irritation. Phytantriol-containing cubosomes exhibited higher permeation and more sustained skin retention of the drug than GMO-based cubosomes and the cream.
To conclude, the newly synthesized gels showed a release rate ranging from 12.96% to 81% of capsaicin and improved skin permeation of the drug. Furthermore, the encapsulation of capsaicin in nanocarriers reduces the irritative effect.

Tramadol
The physicochemical characteristics of tramadol presented in Table 1 make it suitable for incorporation in gels.

Gels for Transdermal Use
Shah et al. [18] investigated the possibility of transdermal delivery of tramadol using a proniosomes-based gel formulation and evaluated its therapeutic potential in vivo. Surfactant-based colloidal drug carriers such as niosomes and their hybrids (proniosomes) effectively transport larger drug quantities to the skin, enabling controlled release for systemic absorption [76]. Dry proniosomes formulations are converted to niosomes after the hydration [76]. For example, the proniosomes embedded in a suitable gel form niosomes by absorbing water [18]. Niosomes increase drug permeation as they overcome the barrier properties of skin and form a drug depot [77]. The formula with the best drug release, stability, and transdermal efficacy contained 100 mg tramadol hydrochloride, 1800 mg Span 80, 1800 mg lecithin, and 200 mg cholesterol [18] Natori et al. [78] developed a tramadol-containing hydrogel film composed of 20% (w/w) hydroxypropyl methylcellulose (HPMC), which was obtained by irradiation with electron beams. This formula presented similar transparency and elasticity as commercially available dressings. Various electron beam doses imprinted differences in release and permeation rate from hydrogel films containing tramadol; thus, hydrogel films irradiated at 50 kGy showed enhanced release than those irradiated at 30 kGy.
For effective pain management, tramadol-hydrochloride-encapsulated transethosomes were formulated by cold method with different lipoidal carrier systems. A total of 12 formulations were prepared, formulations being designed by using ethanol, edge activator (Span 20 and Cremophor EL-35), and phospholipids (soya lecithin, l-α phosphatidylcholine from egg yolk). The highest encapsulation efficiency was observed for the transethosomes obtained using Cremophor EL-35 0.5% as an edge activator. Their average size ranged between 149.34 and 198.10 nm. As the concentration of edge activator in the formulation increased, the vesicular size decreased. Lecithin-based formulations exhibited a higher particle size and higher viscosity [79].

Gels for Parenteral Use
Hydrogels have emerged as a promising material for parenteral drug delivery due to their ability to absorb large quantities of water while maintaining a three-dimensional network structure. The highly hydrated nature of hydrogels allows them to mimic the extracellular matrix of tissues, promoting biocompatibility and reducing immune reactions [80]. Additionally, hydrogels can be created to respond to various stimuli, such as pH, temperature, and enzymatic activity, enabling controlled drug release [81]. Moreover, the unique physicochemical properties of hydrogels, such as their high water content and tunable mechanical properties, make them ideal candidates for encapsulating and delivering a wide range of therapeutics, including tramadol [82].
Barati et al. [83] developed a chitosan-based thermoresponsive in situ gel-forming formulation with tramadol purposive for subcutaneous injection. Their clear advantage, compared to oral formulations, consists in providing a depot for slow release of the drug over an extended period of time at the site of the injection over 8 h. Furthermore, adding pentasodium triphosphate (TPP) to the formula resulted in the formation of spherical nanocavities in the homogenous containing gel structure, resulting in a higher percentage of the cumulative release than the formula without TPP. The nanostructures were not present in the sol state. They appeared when the sol-gel transition occurred, leading to the emergence of a new concept: pro-nanogels.
Dos Santos et al. studied PL-based binary hydrogels composed of PL 407 and PL 188 [82]. A minimal PL concentration of 35% formed thermo-reversible gels. Drugmicelle interaction studies showed PL 407-PL 188 binary systems with drug partitioning into micelles. The presence of tramadol hydrochloride increased enthalpy variation values during the sol-gel transition phase. Rapid hydrogel dissolution reached 80-90% in 24 h. Tramadol incorporation into the binary system prolonged analgesic effects, extending release for 48-72 h after subcutaneous injection.

Gabapentin
Topical administration of gabapentin is associated with minor adverse effects [84]. Therefore, topical formulations are being developed. However, gabapentin has some physicochemical characteristics that may make it difficult to incorporate into gels, as shown in Table 1 [44].
Despite challenges, successful incorporation of gabapentin into gels has been reported. One clinical trial reported that a 6% gabapentin cream effectively ameliorates vulvodynia [85]. A 10% w/w topical gabapentin gel applied thrice daily significantly reduced allodynia and hyperalgesia in a rat sciatic nerve constriction model without motor impairment [86]. The same pharmaceutical form also attenuated cisplatin-induced neuropathic allodynia and heat-hypoalgesia [87].
Martin et al. [88] prepared and evaluated several formulations of gabapentin, including preformulated oil-in-water bases and Carbopol-based hydrogels with permeation enhancers. To prevent crystallization, a maximum of 6% (w/w) gabapentin was incorporated within all Carbopol ® hydrogels. The 5% (w/w) DMSO Carbopol ® gels were stable for at least 3 months under ambient conditions.
A new gabapentin formulation was recently developed-chitosan-g-poly(acrylic acidco-acrylamide) hydrogel composite-containing gabapentin and evaluated at different pH, temperature, and time intervals for drug delivery and controlled release of gabapentin. The research showed a maximum encapsulation of 64% and a drug loading efficiency of the hydrogel of 71% and that the formula imprinted a sustained-release manner of the drug from the hydrogel. In the first 2 h, 90% of the total gabapentin was released according to the dual temperature and pH-responsive hydrogel composite release study [89].
At 25 • C and 40 • C, the potency of gabapentin in Lipoderm cream highly increased after 28 and 90 days, respectively. In contrast, gabapentin has deteriorated in Emollient cream. At 25 • C, the drug combined with Lipoderm cream did not show changes in organoleptic properties for up to 28 days, but physical changes were observed in other bases. Gabapentin was recrystallized from Versabase gel and Emollient cream within 14 days.
Another study formulated and characterized gabapentin-encapsulated elastic liposomes and compared their efficiency in transdermal delivery of gabapentin with that of the compounded gabapentin-based Plo lecithin organogel. Gabapentin liposomescontaining gel had a significantly slower release rate compared to the Plo lecithin organogel (12 h vs. 4 h). Moreover, after 24 h, liposomes highly increased the percutaneous penetration of gabapentin through the porcine skin leading to greater concomitant drug concentrations compared to the Plo lecithin organogel [91].

Pregabalin
Currently, there are no authorized topical formulas containing pregabalin. Oral formula has side effects which include dizziness, sleepiness, dry mouth, and blurred vision, among others [92]. Topical formulas could reduce systemic drug exposure and penetration into the brain, minimizing the occurrence of CNS-mediated side effects [93].
Four pregabalin preparations for transdermal application were developed in a recent study [94]: 0.4% aqueous solution, Plo lecithin organogel, hydrophilic cream, and lipophilic cream. The organogel had the highest permeability, followed by the aqueous solution, while creams showed no permeation. Pregabalin was distributed into the dermis 1 h after the application of the organogel. Furthermore, in vivo testing using a mouse model of diabetic neuropathy demonstrated that only the organogel had a significant analgesic effect. This study demonstrated for the first time that pregabalin reached the dermis following topical application of a Plo lecithin-based organogel formulation.
Arafa et al. [92] prepared mucoadhesive topical gels with pregabalin alone or encapsulated in niosomes. Higher cholesterol ratios increased pregabalin entrapment efficiency, as increasing the concentration of cholesterol inhibits the conversion of the gel into liquid and enhances the encapsulation of hydrophilic drugs. Furthermore, the formula with the highest cholesterol content showed the lowest percent of drug release. HPMC and carbopol hydrogel formulations showed a higher release rate (91.2 ± 0.05%) of PG compared to niosomal PG formulations.
Cevik et al. [95] reported a novel method for synthesizing pH-responsive composite hydrogels using visible light. The pH-responsive layer is formed using poly(methacrylic acid-g-ethylene glycol) [P(MAA-g-EG)] as the macromer, eosin Y as the photoinitiator, and triethanolamine as the co-initiator. The three types of hydrogels, plain, [P(MAA-g-EG)], and P(MAA-g-EG) hydrogels, varied with the composition of the hydrogel prepolymer and the photoinitiation mechanism, with those formed under visible light preserving their integrity better than the ones formed under UV light. Therefore, cross-linked styrenebutadiene-styrene particles enhance the integrity of the hydrogel. Furthermore, in vitro fibroblast viability assay and in vivo implantation experiments indicated the hydrogels were nontoxic and nonirritant.
Another study evaluated different formulas of emulgels-containing pregabalin using Carbopol 940 and other polymers. The best drug release rate was achieved with Carbopol 940 0.4% and HPMC K15M 0.4%, offering rapid analgesic effects while avoiding pregabalin's CNS-mediated side effects [93].
Thus, optimized gel formulations containing pregabalin resulted in a significant release rate of up to 90% and an improved skin permeation for up to 240 h.

Amitriptyline
Oral amitriptyline can cause serious side effects [50]; therefore, developing topical formulas with amitriptyline for treating NeP is of great interest. However, no registered topical formulas exist currently. This may be due to the inconsistent results seen in clinical studies. Several clinical studies reported no analgesic efficacy of amitriptyline in patients with neuropathy when topically administered as 5% or lower concentration formulas [96]. Furthermore, most of these studies do not report the used formulation. Ho et al. [97] reported the use of a Plo lecithin organogel formulation. Despite reducing pain intensity, topical lidocaine induced minimal clinical improvement, whereas placebo and topical amitriptyline were ineffective. No rationale was given to justify the use of Plo. However, studies using higher concentrations of amitriptyline (10%) reported a more consistent analgesic effect [19].
Conversely, Shakshuki et al. [98] evaluated amitriptyline hydrochloride (1%, 5%, and 10%) compounded with three different bases: Lipoderm base, Emollient Cream, and Mediflo 30 Plo lecithin organogel. Mean cumulative release after 24 h from the 10% formulation was significantly higher from the Mediflo Plo lecithin organogel than from the Lipoderm base or Emollient Cream: 53.2% vs. 23.9% and 41.8%, respectively. The authors had an extremely important observation: Amitriptyline released from formulas containing less than 1% of active substance did not permeate through the artificial skin membrane. A similar observation was made for the 5% Mediflo Plo lecithin organogel. Furthermore, despite having the highest amitriptyline release rate, 10% Mediflo Plo lecithin had the lowest permeation over 24 h. Amitriptyline 5% in Lipoderm base had the highest flux-this indicates that using a more lipophilic base may be a more suitable choice for creating topical amitriptyline preparations due to its high lipid content and lipophilic properties. By containing a high percentage of lipids, such as isopropyl myristate and caprylic/capric triglyceride, which are highly lipophilic, Lipoderm can improve the solubility and permeability of lipophilic drugs [99]. Another suggestion would be using a pH adjuster. Amitriptyline is a weak base, and its solubility increases at acidic pH. Thus, an appropriate pH adjuster may be used to adjust the pH of the gel to a range where amitriptyline is more soluble.

Other Substances
Despite not being included in the therapy guidelines for NeP, some reports indicate that the use of topical preparations containing other substances may be useful in the treatment of pain.
Ketamine is primarily used for anesthesia and pain relief. In recent years, it has also gained interest as a treatment for depression, posttraumatic stress disorder, and other psychiatric conditions. The mechanism of action of ketamine is complex and not yet fully understood. It is an N-methyl-D-aspartate receptor antagonist, and it seems it can also act on other receptors in the brain, such as the dopamine and serotonin receptors. Ketamine is typically administered intravenously, and its use is associated with several side effects, including dissociative effects, hallucinations, and changes in blood pressure and heart rate. Therefore, topical formulations may be a great alternative [52]. Wang et al. [52] developed a ketamine-loaded PL F127 stabilized reduced graphene oxide hydrogel for sustained transdermal drug delivery. Adding Plo F127 stabilized reduced graphene oxide sustaining the release of ketamine due to unique π-π stacking interaction. The ex vivo release study showed sustained release of ketamine from hydrogel compared to the control hydrogel, consistent with the results of the in vivo tail-flick evaluation, in which ketamine-loaded reduced graphene oxide had a significantly prolonged analgesic effect (24 h) compared to the ketamine control hydrogel (4 h). Baclofen interacts with two types of receptors, gamma amino butyric acid A and B, inhibiting chemokine-induced chemotaxis [100]. Adverse effects following oral administration include muscle weakness, nausea, somnolence, and paresthesia and affect between 25% and 75% of patients [56].
In a study, a topical gel containing baclofen niosomes was developed by adjusting the ratios between various nonionic surfactants (Span 60, 40), cholesterol, and chargeinducing agents. The entrapment efficiency of the formulations ranged from 4.37% to 80.31%. Encapsulating the drug into niosomes allowed sustained and controlled drug release. The incorporation of free baclofen and two niosomal baclofen formulations into Carbopol 934 led to faster permeation than Pluronic F127. In vivo examination revealed no significant analgesic differences between baclofen niosomal gel and marketed baclofen tablets after 24 h [100].
Baclofen-containing hydrogels with controlled release were prepared using different hydrophilic polymers. A total of 18 formulations were prepared and evaluated. The topical baclofen gels showed good physical properties, and the optimized formulations were stable at room temperature [101].
Another study formulated baclofen-loaded Eudragit ® RL100 nanoparticles by nanoprecipitation method. After characterization, particle size decreased with increasing Eudragit ® RL100, and the smallest size was observed in formulas containing an organic phase (acetone: methanol) in a 1:3 ratio. The highest encapsulation efficiency occurred with the highest baclofen-loaded Eudragit ® RL100 concentration and the same organic phase ratio [102].
Topically administered nonsteroidal anti-inflammatory drugs reduce proinflammatory PGs by inhibiting cyclooxygenase COX-2, interfering with the nociceptive pathway [103]. Conventional topical preparations are not effective in NeP. However, newer formulations have optimized characteristics. Furthermore, long-term oral administration of NSAIDs can cause gastrointestinal symptoms ranging from vague complaints to duodenal ulcer symptoms.
Naproxen was investigated in a formula using glycofurol as a vehicle-based gel and three various gelling agents (Carbopol 974P, Gantrez AN 119, and polyvinylpyrollidone K30). Skin permeation rates and lag times were evaluated to obtain the best gel formulation. Permeability parameters, steady-state flux, permeability coefficient, and penetration index, showed an increase in optimized formulation containing 2% Transcutol as permeation enhancer. On the other hand, optimized novel glycofurol-based gel formulation showed no topical adverse effects in the skin irritation test. Glycofurol-based gel seems to ensure dermal and transdermal delivery of naproxen and may be used for water-insoluble drugs [104].
As a new approach for delivering therapeutic agents, researchers developed supramolecular hydrogels using small peptides conjugated with NSAIDS. The conjugation did not disrupt the binding of naproxen to COX-2. The presence of D-tyrosine on the D-peptide improved the activity and selectivity of naproxen no matter where the position of naproxen was on the side chain. Furthermore, the conjugation of naproxen greatly reduced its binding to COX-1, which in theory, would diminish the associated adverse gastrointestinal and renal effects [105].
Tryptophan N-capped dipeptides with naproxen were prepared using C-terminal dehydroamino acids. The hydrogels consisted of networks of micro/nanosized fibers formed by peptide self-assembly driven by aromatic group stacking interactions. Hydrophobic peptides (containing C-terminal dehydrophenylalanine) formed more elastic gels at lower critical gelation concentrations and revealed irreversible breakup, while gels with C-terminal dehydroaminobutyric acid and dehydroalanine showed structural recovery and partial healing of the elastic properties. Therefore, these hydrogels are promising drug-nanocarrier candidates [106].
A topical microemulsion-based hydrogel containing ibuprofen was prepared and evaluated. The optimum formulation contained 3% ibuprofen, 6% ethyl oleate, 30% Tween 80/ PG (2:1), and water and showed a high permeation rate of 38.06 µg cm −2 h −1 in vitro using porcine skins. Xanthan gum was used as a gel matrix, for increasing viscosity. The studied microemulsion-based hydrogel presented good stability, being a promising vehicle for topical delivery of ibuprofen [107].
Mauri et al. evaluated the covalent tethering of ibuprofen to a hydrogel matrix via esterification. The COX inhibitory activity of ibuprofen was not affected after the modification of the terminal carboxyl group, ensuring a therapeutic effect that is comparable to that of its salt form. As a result of chemical functionalization, ibuprofen can be given in the form of its free carboxylic acid instead of its sodium salt, which provides a viable alternative. The free carboxylic acid form of ibuprofen is more soluble and diffuses more quickly than the salt form. By incorporating an ibuprofen-diol derivative into the hydrogel formulation, a more sustained release profile was achieved compared to the salt form. These ibuprofen-functionalized hydrogels could be used as injectable tools due to their sol-gel transition, which enables localized drug release and presents promising possibilities for in situ treatments [108].
Using chitosan, lipids, gum arabic, and polyvinyl alcohol, six formulations containing ibuprofen were prepared through ionic interaction, maturation, and freeze-thaw methods. The results showed that the lipid-conjugation-based hydrogel exhibited a higher conjugation efficiency and prolonged drug release than control. Furthermore, ibuprofen effectively reduced LPS-induced PGE2 synthesis [109].
Water-swollen hydrogels transferred to pH 5.8 or 8.0 phosphate buffer or NaCl solutions showed release driven by competition with environmental ions, sustaining the release process for minimum 24 h for ibuprofen and almost 1 week for diclofenac owing to the remaining hydrophobic interactions and the high polymer density induced by poly(hydroxyethyl methacrylate) [110].
Another study analyzed hydrogel films loaded with ibuprofen using water-soluble polysaccharides such as cellulose sulfate, chitosan sodium, and tripolyphosphate via self-assembly method. The hydrogels formed a dense regularly shaped network due to polyelectrolyte complex formation via electrostatic interaction. Loading and encapsulation efficiency were 43.15 ± 4.88% and 60.65 ± 4.68%, respectively. The hydrogel films showed a sustained release profile during 1440 min test using mice skin [39].

Associations of Analgesic Substances
The combination of two or more therapeutic agents can be more effective considering the wide variety of pathophysiological mechanisms involved in the development and progression of neuropathic pain. A topical combination of baclofen, amitriptyline, and ketamine was evaluated in a double-blind, placebo-controlled trial, including patients with chemotherapy-induced peripheral neuropathy. The active formulation contained 40 mg of amitriptyline, 20 mg of ketamine, and 10 mg of baclofen in pluronic lecithin organogel and was applied twice a day for 4 weeks (a teaspoonful of gel to each affected area). Although improvements in sensory pain and motor scale were observed, they were not statistically significant, and no adverse effects or systemic toxicity were reported [96].
In an uncontrolled trial, Uzaraga et al. [111] assessed the efficacy of a topical treatment consisting in an amitriptyline 2%, ketamine 1%, and lidocaine 5% (AKL) containing gel in radiation-induced dermatitis and neuropathic pain. The gel was given to 60 individuals, three times per day until 2 weeks post-radiotherapy. A patient assessment was performed every 2-5 days during radiotherapy and at 2 and 6 weeks postradiotherapy. Pain was assessed using the University of Washington neuropathic pain scale. After AKL gel application, a reduction in pain intensity and other symptoms was recorded at 30 min and 2 weeks posttreatment compared to baseline, but fatigue and skin irritation occurred at the application site.
A study case reported the effectiveness of the amitriptyline and ketamine containing gel in a patient with erythromelalgia. Over the next 2 weeks, the patient described "very promising results", with a 60% decrease in pain intensity, primarily burning pain. This patient did not respond previously to oral paracetamol, NSAIDs, gabapentin, and amitriptyline [112]. These clinical trials support the idea of using topical preparations instead of oral therapy.
The method of preparation and the functional excipients used to obtain all these gels are presented in Table 3. As the local conditions within the tissue or cellular environment (pH, temperature) where the gel is applied can influence the efficacy and function of the gel, when available we also included such details in Table 3.

Rate of release 33%
Cubic phase gels based on the ternary phase diagram of the monooleate-propylene glycol-water system offer transdermal controlled release of capsaicin. After 108 h, around 30% of capsaicin was released from the gels.  Phytantriol forms cubosomes determining a sustained release of capsaicine (longer than that of on-market products). Cubosomes formulations induced no obvious irritation to the skin.
[75] The tramadol-containing gel showed a higher analgesic efficacy than oral tramadol tablets in acetic-acid-induced abdominal writhing test in rats. The new formula presented an enhanced release and skin permeation compared to standard formulations. The amount of tramadol released from the hydrogel film and the amount of skin permeation increased by changing the electron dose.
[78] Chitosan extends the release of drug compared to tramadol-containing gel. Prehydrated and non-prehydrated membranes had similar gabapentin permeability, but prehydrated ones showed less variability. [88]

Substance
Gel Type

Role of Agents Parameter
Advantages of the New Formulation in the Treatments of Neuropathic Pain

References
Gabapentin Hydrogel

Conclusions and Perspectives
Management of NeP is often challenging and may require a multimodal approach involving early diagnosis, psychological therapy, as well as treatment to relieve symptomatic pain [113]. According to the latest guidelines, oral therapies are used as first-line therapies for the treatment of NeP [114], with topical therapies being the second line owing mostly to low efficacy. Furthermore, oral analgesics are often associated with high toxicity.
Gels represent a promising platform for transdermal drug delivery due to their unique physicochemical properties. Gels can provide a sustained drug release, improved bioavailability, and controlled delivery of drugs through the skin. The high water content of gels allows for better hydration of the stratum corneum, which can increase the permeability of the skin and enhance drug absorption [115]. In addition, gels can be designed to adhere to the skin, minimizing drug loss due to rubbing or sweat [116]. The gel matrix can also protect the drug from degradation and improve its stability during storage and transport [66]. Transdermal delivery systems prevent the occurrence of adverse effects by preventing peak and trough plasma concentrations and decreasing drug accumulation [67].
Over the years, several studies investigated the development of gels with capsaicine, amitryptiline, gapabentin, pregabalin, tramadol, and ketamine to be used in the treatment of NeP [117].
In recent years, different new forms of gels with therapeutic agents useful for NeP have been discovered and tested. Nanoemulsion containing capsaicin, proniosomes gel formulation containing tramadol, tramadol hydrochloride encapsulated transethosomes, chitosan-g-poly(acrylic acid-co-acrylamide) hydrogel composite containing gabapentin, pluronic lecithis organogel formulation containing pregabalin, Mediflo pluronic lecithin organogel containing amitriptyline, and ketamine-loaded Pluronic ® F127 stabilized reduced graphene oxide hydrogel for sustain drug delivery via transdermal route are among the pharmaceutical gels characterized, tested for the analgesic effect in vivo in preclinical or clinical studies and demonstrating a real potential to replace oral therapy.
The recent developments made in the formulation of gels containing analgesics include: • incorporation of vesicular carriers, such as niosomes, transethosomes, and cubosomes, with enhanced skin penetration and drug delivery compared to conventional liposomes [118]. These carriers protected the encapsulated drug from degradation and acted as local reservoirs of the drug. All the included studies revealed that the utilization of vesicular carriers as drug delivery systems enables a profound interaction with the skin layers, leading to sustained and efficient drug release for a wide range of drugs. However, a better understanding of this interaction would allow further optimization of the formulas. • use of in situ gel-forming formulations which also ensured a prolonged and constant drug release. Furthermore, thermoresponsive polymers that can undergo a reversible sol-gel transition in response to temperature changes have been used in the preparation of injectable gels for drug delivery. In situ cross-linking was used as a trigger to stimulate this transformation. • use of multicomponent gels that contain more than one type of polymer. They offer better mechanical stability and tunable properties. • co-delivery of multiple drugs in a single gel formulation can improve treatment efficacy and reduce side effects.
Our investigation encountered several inherent limitations due to the heterogeneous nature of the study designs evaluated. For instance, disparate methodologies were employed to quantify drug release rates and skin permeation profiles, potentially leading to inconsistent results. Furthermore, although several gels were developed, they were not tested in preclinical or clinical studies. Thus, it is difficult to evaluate their real analgesic utility. We consider that creating uniform protocols of evaluation of drug release for gels and performing an appropriate preclinical and clinical assessment of these products would provide the very much needed scientific base for identifying new gels useful in the therapy of NeP.
In conclusion, recent advances in the formulation of analgesic gels have brought about significant improvements in drug delivery systems for pain management. The development of new gelling agents, additives, and drug delivery technologies has led to enhanced solubility, bioavailability, and controlled release of analgesics, resulting in better pain relief and improved patient compliance. Additionally, the development of personalized medicine and the exploration of nonopioid analgesics in gel formulations offer new directions for future research. While there are still challenges to be overcome, such as ensuring safety and addressing the need for targeted drug delivery, the progress made in recent years provides a strong foundation for the continued development of advanced analgesic gel formulations.
Author Contributions: Conceptualization, S.N.; data curation, C.P.; writing-original draft preparation, C.P.; writing-review and editing, A.Z. All authors have read and agreed to the published version of the manuscript.
Funding: This work was co-financed by the European Social Fund, through the Operational Program Human Capital, project number POCU/993/6/13/154722.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: All data generated or analyzed during this study are included in this published article.

Conflicts of Interest:
The authors declare no conflict of interest.