Topical Analgesics: Pharmacology and Clinical Applications

Abstract

Pain is a leading reason for seeking medical care, necessitating accurate diagnosis and appropriate analgesic treatment. When oral administration is impractical due to nausea, vomiting, difficulty swallowing, or gastrointestinal issues, or when pain is localized, topical analgesics offer an effective alternative for managing both acute and chronic pain conditions, including osteoarthritis and neuropathic pain. These agents, such as nonsteroidal anti-inflammatory drugs, lidocaine, and capsaicin, can provide pain relief while minimizing systemic side effects. Technological advances, such as nanocarriers and microneedles, aim to improve efficacy but face challenges like cost and toxicity. Here, the authors explore the pharmacology and clinical efficacy of topical analgesics, providing recommendations for their use in pain management.

Topical analgesics effectively manage pain while minimizing systemic side effects, benefiting patients with localized pain or gastrointestinal issues. Advances in drug delivery may improve efficacy but require further research.

Pain is the primary reason patients seek medical attention.¹ Accurately diagnosing and treating the specific type of pain with appropriate pain medications is essential to provide analgesia. Pain management involves not only selecting the appropriate analgesic but also determining the optimal route of administration. Oral administration can be challenging in some cases due to swallowing difficulties or gastrointestinal issues that affect drug absorption. In other cases, pain is strictly localized. For these patients, topical analgesics offer a suitable alternative. Although designed for localized pain relief, they are also effective in managing a range of painful conditions. These include acute pain, such as strains, muscle aches, and sprains, as well as chronic inflammatory pain, such as osteoarthritis-related pain, and neuropathic pain, including postherpetic neuralgia and pain from diabetic peripheral neuropathy.² The spectrum of analgesics suitable for topical pain management encompasses nonsteroidal anti-inflammatory drugs (NSAIDs), the local anesthetic lidocaine, and other substances such as capsaicin, a vanilloid, a voltage gated channel blocker, and transient receptor potential vanilloid 1 channel (TRPV1) agonist. Topical analgesics can be similarly effective to oral analgesics, but they can bypass the risk of systemic adverse effects and problems associated with systemic absorption, metabolization and elimination. They can be beneficial for patients with impaired drug absorption from the gastrointestinal tract or other gastrointestinal issues such as nausea/vomiting or difficulty swallowing.

The pharmacologic treatment of neuropathic pain remains particularly challenging due to the limited effectiveness of current therapies and the distinct mechanisms compared to acute and inflammatory pain.³ Topical analgesics, such as high-concentration lidocaine and capsaicin patches, have also found application and are recommended as potential therapeutics in the treatment of peripheral neuropathic pain.^4,5 Here, we review pharmacology and efficacy of topical analgesics to provide recommendations for their application.

Challenges of Substance Transport across the Skin

The skin, our body’s largest organ, acts as a crucial barrier against external threats. Its outermost layer, the stratum corneum, comprises multiple layers of dead skin cells (corneocytes). These cells are formed through a process called cornification.⁶ The stratum corneum consists of 10 to 20 layers of these cornified cells embedded in a hydrophobic lipid–protein matrix. The stratum corneum’s resistance to penetration poses a significant challenge for drug delivery.⁷ To address this challenge, specific drug formulations are designed to facilitate the passage of medication through the skin barrier. There are three primary pathways for crossing the stratum corneum: (1) through the hydrophobic intercellular lipid–protein matrix, (2) through the intracellular space of corneocytes, or (3) via hair follicles, sebaceous glands, and sweat glands (transappendageal route).⁸

The second (intracellular) route is particularly challenging due to the differing physicochemical properties between the lipophilic cell membrane and the hydrophilic intracellular environment, making it difficult for substances to traverse all layers.⁹ Various strategies exist to enhance drug absorption through the skin, including microemulsion and liposomal systems.

For example, dimethyl sulfoxide enhances topical drug absorption by disrupting the lipid matrix of the stratum corneum, creating pathways for deeper drug penetration. As both a solvent and carrier, it increases drug solubility and thermodynamic activity to aid diffusion.¹⁰ However, high concentrations can cause skin irritation, so formulations must balance its permeation-enhancing effects with safety considerations.¹¹

Topical creams improve drug absorption by incorporating chemical permeation enhancers like ethanol or propylene glycol, which disrupt the stratum corneum to facilitate diffusion. They often include colloidal carriers such as liposomes or nanoemulgels to encapsulate drugs, enhance solubility, and promote deeper penetration. Additionally, creams provide sustained drug release while balancing efficacy and minimizing skin irritation.^8,10,12

Hydrogels are polymeric networks that absorb and retain large amounts of water, whereas emulsion gels consist of a gel matrix with dispersed emulsion droplets. Hydrogels primarily focus on swelling and environmental responsiveness, while emulsion gels are designed for the encapsulation and controlled release of hydrophilic or hydrophobic compounds. Hydrogels are widely applied in biomedical and environmental fields, whereas emulsion gels are commonly used in food, pharmaceuticals, and cosmetics.^13–15

Topical plasters, such as lidocaine medicated plasters, deliver drugs locally by adhering to the skin and gradually releasing the active ingredient into the targeted area. In contrast, topical patches release medication that penetrates the skin and enters the bloodstream, producing systemic effects.¹⁶

Pharmacologic Aspects of Topical Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used worldwide, primarily for treating inflammatory pain. However, their use is often restricted due to their tendency to cause gastrointestinal injury.¹⁷ Topical NSAIDs deliver effective drug levels to the affected area while minimizing the amount of drug entering the bloodstream and causing related adverse events. Topically applied NSAIDs are usually used for the treatment of musculoskeletal pain, mainly after injuries, soft tissue pain, and rheumatic diseases (table 1). Similar to systemic administration, topical NSAIDs inhibit the cyclooxygenase 2–dependent synthesis of proinflammatory and proalgesic prostaglandins. This prevents the activation of prostaglandin receptors and the subsequent sensitization of ion channels in peripheral nerves² (fig. 1). Topical NSAIDs are available in various formulations. For instance, diclofenac can be found as a hydrogel, emulsion gel, or patch (diclofenac hydroxyethyl pyrrolidine). Additionally, it is available as a solution combined with dimethyl sulfoxide.¹⁸

Table 1.

Indications for Various Topical Analgesics (FDA)

Drug (Class)	Agents and Formulations	Indication(s) (FDA)
Topical NSAIDs	Various, e.g., Diclofenac gel (1% w/w) Diclofenac solution (1.5–2% w/w) Diclofenac patch (1.3% w/w) Ketoprofen gel (2.5% w/w) Piroxicam gel (0.5% w/w)	Acute pain, osteoarthritis-induced pain
Capsaicin	Low-dose cream or gel (0.025% w/w; 0.075% w/w) High-dose patch (8% w/w)	Low dose: acute pain High-dose patch:  • Postherpetic neuralgia  • Diabetic peripheral neuropathy
Lidocaine	Low dose cream, gel, and ointments in various strengths and in combination with prilocaine (2.5%/2.5% w/w) High-dose patch (5% w/w)	Low dose: acute pain High-dose patch: postherpetic neuralgia

FDA, U.S. Food and Drug Administration (Silver Spring, Maryland); NSAID, nonsteroidal anti-inflammatory drug.

Fig. 1.

Schematic depiction of the mechanism of action of topical analgesics. Nonsteroidal anti-inflammatory drugs (NSAIDs), capsaicin, and lidocaine act locally. COX-2, cyclooxygenase-2; Na_(v), voltage-gated sodium channel; TRPV1, transient receptor vanilloid 1 channel.

One key question in the pharmacologic use of topical NSAIDs is whether a fraction of the applied drugs can enter the bloodstream and act systemically. This was investigated by several clinical studies. In a randomized, three-way crossover design study, participants received either an oral treatment or topical diclofenac sodium gel. The gel was applied in doses of 4 g to one knee four times daily (total daily dose, 16 g) or 4 g to each knee plus 2 g to both hands four times daily (total daily dose, 48 g). Mean plasma concentrations of diclofenac were approximately 17 times lower with topical administration than with oral treatment, and peak concentrations were approximately 150-fold lower. Likewise, only oral therapy was associated with treatment-related gastrointestinal adverse events.¹⁹ Similar results are observed with other topical NSAIDs. Leppert et al. conclude that the blood serum concentration of an NSAID that was applied topically reaches only up to 15% of the concentration achieved after systemic administration.²⁰ These results show that a portion of topically applied NSAIDs can enter the bloodstream and have a systemic effect. However, the concentrations in the plasma remain significantly lower as compared to those achieved with oral NSAIDs.

Assessing the Analgesic Efficacy of Topical NSAIDs

The analgesic efficacy of topical NSAIDs has been evaluated in several studies. In 2017, Derry et al.² conducted a meta-analysis of existing Cochrane reviews and concluded that the evidence from these studies ranged from moderate to high quality. Risk of bias was defined as variations in efficacy at specific doses resulting from differences in formulations and compounds, as well as factors such as short or inadequate trial durations, incomplete outcome data, lack of blinding, insufficient allocation concealment, and small sample sizes. For acute musculoskeletal pain, topical diclofenac emulgel had the lowest number needed to treat (NNT) of 1.8 for 50% pain reduction (95% CI, 1.5 to 2.1), followed by ketoprofen gel (NNT, 2.5; 95% CI, 2.0 to 3.4) and piroxicam gel (NNT, 4.4; 95% CI, 3.2 to 6.9). Diclofenac plaster showed similar efficacy to piroxicam gel (fig. 2; table 2). There is a lack of conclusive evidence for the efficacy of other NSAIDs.^2,21

Fig. 2.

Relative evidence of analgesic efficacy of topical nonsteroidal anti-inflammatory drugs (NSAIDs) in acute pain (A, blue bars) and of topical NSAIDs, capsaicin, and lidocaine in osteoarthritis-induced (OA) pain (B, yellow bars). Quality of evidence for efficacy ranges from very low to high and was collected from several sources.^2,20–26

Table 2.

Overview of the Different Topical Analgesics that Are Discussed in This Article, as Well as Their Mechanisms of Action, Indications, and Relative Efficacy

Substance	Analgesic Mechanism of Action	Indication	Evidence for Analgesic Efficacy	References
Topical diclofenac	COX-2 inhibiton, reduction of inflammatory hyperalgesia	1. Acute musculoskeletal pain 2. Osteoarthritis-induced inflammatory pain	Moderate–high Moderate	2,21 22–24
Topical ketoprofen	COX-2 inhibiton, reduction of inflammatory hyperalgesia	1. Acute musculoskeletal pain 2. Osteoarthritis-induced inflammatory pain	Moderate–high Moderate	2,21 22–24
Topical piroxicam	COX-2 inhibiton, reduction of inflammatory hyperalgesia	1. Acute musculoskeletal pain 2. Osteoarthritis-induced inflammatory pain	Moderate Low	2,21 22–24
Topical capsaicin, low-dose	Activation of TRPV1 in nociceptors, causing desensitization	1. Osteoarthritis-induced inflammatory pain 2. Neuropathic pain (PHN, DPN)	Low Very low	25 27
Topical capsaicin, high-dose	Activation of TRPV1 in nociceptors, causing defunctionalization and subsequent resprouting of regenerated nerve fibers	1. Osteoarthritis-induced inflammatory pain 2. Neuropathic pain (PHN, DPN)	Low Low–moderate	25 4,5,28
Topical lidocaine, low-dose	Inhibition of voltage-gated sodium channels (Na(v)s) in peripheral nerves	1. Osteoarthritis-induced inflammatory pain 2. Neuropathic pain (PHN, DPN)	Low Very low	20,26 4,5,29
Topical lidocaine, high-dose	Inhibition of voltage-gated sodium channels (Na(v)s) in peripheral nerves	1. Osteoarthritis-induced inflammatory pain 2. Neuropathic pain (PHN, DPN)	Low–moderate Low	20,26 4,5,29

COX-2, cyclooxygenase-2; DPN, diabetic peripheral neuropathy; PHN, postherpetic neuralgia; TRPV1, transient receptor vanilloid 1 channel. Data were collected from several sources.^2,4,20–33

For chronic pain associated with osteoarthritis, the primary outcome was defined as at least a 50% reduction in pain. The authors concluded that topical diclofenac preparations are effective for moderate osteoarthritis-induced pain, with an NNT of 5.0 (95% CI, 3.7 to 7.4) for long-term use, but less than 6 weeks. Ketoprofen used during a period of 6 to 12 weeks has an NNT of 6.9 (95% CI, 5.4 to 9.3), and topical diclofenac preparations during the same period have an NNT of 9.8 (95% CI, 7.1 to 16). An interesting general observation is that topical NSAID creams and plasters had higher NNTs as compared to gel or emulgel formulations, suggesting that gels are more effective than creams and plasters (fig. 2; table 2).^2,22

Several studies have confirmed the accumulation of NSAIDs in target tissues.³⁴ For example, Efe et al. investigated diclofenac concentrations in the synovial tissue and synovial fluid of patients with joint effusion. These patients were randomized to apply diclofenac sodium 4% spray gel to their knees either two or three times daily during a 3-day treatment period. The authors found that diclofenac concentrations were 10 to 20 times higher in the synovial tissue as compared to the synovial fluid and blood plasma.³⁵

Two meta-analyses conclude that topical NSAIDs may be considered safe in the treatment of osteoarthritis pain. Risk of bias was defined as described in “Assessing the Analgesic Efficacy of Topical NSAIDs.” Unlike oral NSAIDs, topical NSAIDs are not associated with gastrointestinal adverse events, and there was no significant difference in the odds ratio for gastrointestinal disorders between topical NSAIDs and placebo.^23,24

In summary, the analgesic efficacy of topical NSAIDs has been assessed in multiple studies. For acute musculoskeletal pain, diclofenac emulgel had the lowest NNT of 1.8, followed by ketoprofen gel and piroxicam gel. For chronic osteoarthritis pain, there is evidence that topical diclofenac and ketoprofen are effective for moderate pain but with higher NNTs than for acute pain. There is not much evidence to support the efficacy of topical salicylate and other NSAIDs. An interesting observation is that gels seem to be more effective than creams and plasters. Additionally, NSAIDs were found to accumulate significantly more in synovial tissue as compared to synovial fluid and blood plasma. Meta-analyses suggest that topical NSAIDs are safe for treating osteoarthritis pain and do not cause gastrointestinal adverse events, unlike oral NSAIDs.

Exploring the Pharmacology of Topical Capsaicin

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), the active ingredient in chili peppers from the genus Capsicum, acts as an agonist of the TRPV1 in sensory neurons. This interaction increases the channel’s open probability, causing calcium influx and depolarization, which may trigger action potentials.³⁶ A recent publication identified molecular signatures of human nociceptors and highlighted species differences that may have led to previous misconceptions of neuronal subpopulations. TRPV1 is expressed by around 50% of human sensory neurons, so capsaicin is addressing a large fraction of peripheral nerve fibers.³⁷ Physiologically, TRPV1 acts as a sensor for noxious heat, and its activation is associated with heat and burning pain. As a chemical agonist, capsaicin produces similar sensations when applied topically.³⁸

Capsaicin acts as a local analgesic. Low-concentration (less than 1% [w/w]) capsaicin induces transient analgesia through desensitization or tachyphylaxis, a process that transiently reduces the activity of the capsaicin receptor TRPV1.³⁹ In contrast, high-concentration capsaicin treatment (more than 5% [w/w]) leads to a process termed “defunctionalization” in which the nociceptors are more damaged by the excessive TRPV1-mediated calcium influx. This calcium overload causes mitochondrial dysfunction, activation of calpains, degradation of the cytoskeleton, and ablation of axonal nerve fibers. Although damaging the nerve fibers, this high-concentration capsaicin treatment can lead to a long-lasting analgesia⁴⁰ (fig. 1). After these processes, resprouting of regenerated nerve fibers can occur. These newly regenerated nerve fibers can then “replace” the hypersensitive fibers that had been ablated and can restore their physiologic activity and function.⁴¹ These mechanisms have only recently been identified and have led to the development of topical high-dose capsaicin for the treatment of persistent pain. Today, a skin patch 8% (w/w) (Qutenza, Grünenthal GmbH, Germany) containing 179 mg capsaicin is approved for the treatment of postherpetic neuralgia and for diabetic peripheral neuropathy of the feet⁴² (table 1). The capsaicin 8% patch reduces epidermal nerve fiber density by 80% after 1 week. By week 12, this reduction diminishes to approximately 20%, with near-complete recovery observed by week 24.⁴³

Capsaicin also causes the release of somatostatin, an antinociceptive neuropeptide, which might contribute to TRPV1-independent capsaicin-induced desensitization.⁴⁴

Evaluating the Analgesic Efficacy of Topical Capsaicin in Chronic Pain

The efficacy of capsaicin is highly variable, with high NNTs indicating rather low overall effectiveness. A meta-analysis indicates that low-concentration (0.025%) topical capsaicin may be effective for osteoarthritis-related pain.²⁵ However, there is no current evidence to support the efficacy of capsaicin cream at this concentration for treating neuropathic pain.^27,45 The primary outcome in these studies was defined as at least a 50% reduction in pain. Risk of bias was defined as incomplete outcome data, lack of blinding, insufficient allocation concealment, small sample sizes, and insufficient random sequence generation.²⁷

In contrast, there is evidence for the efficacy of high-concentration topical capsaicin for chronic neuropathic pain in adults. As mentioned in the previous section, a skin patch containing 8% (w/w) is approved for the treatment of postherpetic neuralgia and for diabetic peripheral neuropathy and may be efficient in HIV neuropathy as well.²⁸ Topical capsaicin should be applied only to intact skin, not to open wounds, burns, or broken or inflamed skin, avoiding contact with the eyes.

For the treatment of diabetic peripheral neuropathy, capsaicin has been reported to provide analgesic effects comparable to duloxetine, pregabalin, or gabapentin.⁴⁶ Unlike these oral medications, which are significantly associated with increased risks of dizziness, somnolence, and treatment discontinuation compared to placebo, the capsaicin patch does not carry these risks.⁴⁶ Similar results were reported from two small open-label single-center studies with patients suffering from chemotherapy-induced peripheral neuropathy, which is a major side effect of various cytostatic drugs,⁴⁷ and another trial with patients suffering from phantom limb pain. In all three cases, the high-dose capsaicin patch was positively assessed for pain reduction.^48–51 However, the small cohort sizes do not provide sufficient evidence for its general recommendation.

These effects suggest that the mechanism of defunctionalization is necessary for analgesic efficacy in neuropathic pain states, and that desensitization or tachyphylaxis from low concentrations of topical capsaicin is insufficient for long-term pain relief.

Despite these encouraging reports, the efficacy of topical high-dose capsaicin for the relief of neuropathic pain is quite low. A meta-analysis conducted by the International Association for the Study of Pain (Washington, D.C.) Neuropathic Pain Special Interest Group (NeuPSIG) concludes that the NNT for high-concentration capsaicin patches in neuropathic pain states is 10.6 (95% CI, 7.4 to 18.8) and the most recent study gives it a weak recommendation for use as second-line therapy for peripheral neuropathy.^4,5 Additionally, the most recent Cochrane report concluded that the quality of evidence is low,²⁸ emphasizing the need for more randomized controlled trials with larger patient cohorts to evaluate the analgesic potential of high-concentration topical capsaicin in various chronic and neuropathic pain conditions. Aside from temporary local reactions at the application site, such as procedural pain and erythema, there are no significant safety concerns related to skin exposure to capsaicin. Concerning adverse events and safety, clinical studies have not observed long-term damage to sensory nerve fibers. Instead, sensory function and epidermal nerve fiber reinnervation have been shown to return after 24 weeks in clinical trials.^43,52 It is important to note that capsaicin provides analgesia for neuropathic pain only when hyperalgesia is mediated and maintained by TRPV1-positive epidermal nerve fibers. Capsaicin selectively ablates TRPV1-positive nerve fibers while preserving the function of TRPV1-negative fibers, thereby maintaining protective cutaneous sensation.^40,52

In summary, high-dose topical capsaicin is recommended as a second-line treatment for postherpetic neuralgia and diabetic peripheral neuropathy, supported by moderate evidence (fig. 3; table 2). In cancer pain, topical capsaicin can be used as coanalgesic when a neuropathic component contributes to the pain. For nonneuropathic cancer pain, capsaicin is not recommended.⁵⁴ Currently there is no evidence to support recommending low-dose capsaicin for analgesic therapy.

Fig. 3.

Relative evidence of analgesic efficacy of topical capsaicin or lidocaine patch in neuropathic pain states for postherpetic neuralgia (PHN, red bars) and diabetic peripheral neuropathy (DPN, yellow bars). Quality of evidence for efficacy ranges from very low to high and was collected from several sources.^4,27–33,53

Mechanisms of Action of Topical Lidocaine

Lidocaine was discovered at the Institute of Chemistry at Stockholm University (Stockholm, Sweden) and was the first local anesthetic with an amino amide structure. Its primary mechanism of action is in reducing the open probability of voltage-gated sodium channels, particularly Na_(v)1.7 and Na_(v)1.8, in peripheral nerves²⁶ (fig. 1). Although lidocaine can also affect the activity of other ion channels such as hyperpolarization-activated cyclic nucleotide-gated channels and neurotransmitter receptors when applied systemically,⁵⁵ it is unclear whether these effects contribute significantly to peripheral analgesia of topical applications.

Lidocaine is absorbed well and rapidly from mucous membranes and from injection sites, but poorly from intact skin. Like NSAIDs, it requires a formulation that allows it to penetrate through the stratum corneum. Lidocaine can be applied as cream, gel, foam spray, and solution for short‐term analgesia. However, its most widespread application for the treatment of neuropathic pain is an adhesive patch with the dimensions 10 × 14 cm, containing 5% (w/w) lidocaine.^29,56

Each 5% lidocaine plaster contains 700 mg lidocaine, for which a maximum of three plasters applied simultaneously for 12 h is allowed. Pharmacokinetic analyses revealed that only 3 ± 2% of this maximum recommended dose is systemically absorbed, which minimizes the risk of systemic adverse events. When absorbed, lidocaine primarily binds to alpha-1-acid glycoprotein and likely diffuses passively across the placental and blood–brain barriers. Lidocaine is metabolized in the liver to nonactive metabolites that are excreted by the kidneys with an elimination half-life of 7.6 h.²⁶

Effectiveness of Topical Lidocaine in Pain Management

Topical lidocaine is widely used for various pain conditions due to its limited absorption and relative lack of systemic adverse effects, making it an attractive option for many vulnerable patients. For acute pain in superficial surgical procedures, such as minor skin excisions or painful biopsies, lidocaine-containing creams like EMLA can be used. EMLA cream consists of lidocaine and prilocaine in a 1:1 ratio (25 mg each per gram) combined with a thickener (carboxypolymethylene), an emulsifier (polyoxyethylene fatty acid esters), and water. This formulation creates a eutectic oil-in-water emulsion, allowing the lidocaine and prilocaine to remain in liquid form at room temperature. Adverse events are generally mild and localized, typically involving minor allergic reactions.^20,26

A higher-concentration patch containing 5% lidocaine (w/w) can be applied to the painful area for 12 h per day, followed by a 12-h break. The maximum dose is three patches within a 24-h period. As with the capsaicin patch, topical lidocaine should be applied only to intact skin, not to open wounds, burns, or broken or inflamed skin, avoiding contact with the eyes, and the patch should cover the entire painful area. Although primarily indicated for postherpetic neuralgia (table 1), it may also be effective for carpal tunnel syndrome, diabetic peripheral neuropathy, and osteoarthritis-induced pain.^26,57

For neuropathic pain, lidocaine patches were previously recommended as a first-line treatment alongside tricyclic antidepressants, pregabalin, and gabapentin. However, the most recent meta-analysis by NeuPSIG and a Cochrane review found low effect sizes and low-quality evidence for the efficacy of topical lidocaine.²⁹ As a result, NeuPSIG no longer recommends lidocaine patches as a first-line treatment for neuropathic pain and instead gives it a weak recommendation. However, due to its good safety profile, high patient values and preferences, and positive results from initial short-term studies, they still propose topical lidocaine as a second-line treatment for peripheral neuropathic pain (fig. 3; table 2).^4,5

Due to its safety profile and favorable risk-to-benefit ratio, topical lidocaine could be an excellent alternative on its own or as an addition to systemic medications and nonpharmacologic approaches for optimized pain management and multimodal analgesia. However, more evidence is needed to support its analgesic efficacy. Like capsaicin, there is a growing need for more randomized controlled trials with larger patient cohorts to evaluate the analgesic potential of high-concentration topical lidocaine in various chronic and neuropathic pain conditions. In the management of cancer pain, topical lidocaine can be used as a coanalgesic in the form of either high-dose patches or low-dose local anesthetic creams. However, similar to capsaicin, topical lidocaine is not recommended as main analgesic for the treatment of nonneuropathic cancer pain, as opioids remain the most effective analgesics for this specific type of pain.⁵⁴

Other Potential Topical Analgesics

Many other analgesics are formulated for topical use, including extemporaneously prepared or “special” formulations. While some of these have been tested only in animal models, others have been described in patient case studies in the literature and should be mentioned, despite not being discussed in this review. For instance, topical gabapentin has been evaluated for treating vulvodynia. Although the results appear promising, the evidence is inconclusive due to small sample sizes and the concurrent use of other pain treatments, making it difficult to recommend topical gabapentin for this condition.⁵⁸

Another topical formulation is a cream combining the muscle relaxant baclofen, the tricyclic antidepressant amitriptyline, and sometimes the N-methyl-d-aspartate antagonist ketamine. This mixture has been investigated for treating various neuropathic pain conditions.

Mechanistically, amitriptyline can inhibit voltage-gated sodium channels, particularly Na(v)1.7 currents, in sensory neurons, which may reduce neuronal excitation, depolarization, and the likelihood of generating action potentials.⁵⁹ Baclofen acts as an agonist at peripheral γ-aminobutyric acid type B receptors but may also activate tetraethylammonium-sensitive potassium channels, which could contribute to its analgesic effect.⁶⁰ The analgesic effects of ketamine are primarily attributed to its noncompetitive channel-blocking action on N-methyl-d-aspartate receptors.⁶¹

A double-blind, placebo-controlled trial involving 208 patients examined a topical baclofen/amitriptyline/ketamine combination for chemotherapy-induced peripheral neuropathy and found no difference to placebo treatment.⁶² Likewise, a large phase III randomized, placebo-controlled trial that involved 462 patients suffering from chemotherapy-induced peripheral neuropathy and tested a formulation of 2% ketamine plus 4% amitriptyline applied as a topical cream could not see any improvement on 6-week chemotherapy-induced peripheral neuropathy scores.⁶³ A meta-analysis on this topic concludes that, despite several case reports and small trials suggesting benefits for neuropathic pain patients, there is currently insufficient evidence to support the use of these creams for treating neuropathic pain in patients.⁶⁴

The neurotoxin botulinum toxin type A is recommended by NeuPSIG as third-line therapy for specialist use in peripheral neuropathic pain. It is injected subcutaneously or intradermally at a dose of 50 to 200 U to the painful area every 3 months.⁵⁷ A recent review concludes that botulinum toxin type A has therapeutic value in refractory neuropathic pain or idiopathic trigeminal neuralgia. When patients are stratified, those who respond best appear to be individuals with thermal sensitivity in the affected area, as well as those experiencing evoked and deep pain with pain paroxysms.⁶⁵

Moreover, several reports describe the use of topical ambroxol for treating neuropathic pain of various etiologies.^66,67 Apart from its oral use as a mucolytic, ambroxol can inhibit voltage-gated sodium channels in sensory neurons.⁶⁸ While these findings are promising, there is currently insufficient evidence to recommend ambroxol as a treatment option for neuropathic pain.

In summary, several other topical formulations may provide analgesic effects and could be considered for the treatment of neuropathic pain. However, there is currently insufficient evidence to support their use. Further randomized clinical trials with well-characterized and stratified patient populations are needed to conclusively evaluate their potential analgesic efficacy.

Conclusions and Future Directions

As described herein, topical analgesics are valuable for managing various pain conditions, as they bypass gastrointestinal side effects and are suitable for patients with swallowing difficulties. In the case of topical analgesics like NSAIDs, lidocaine, and capsaicin, only a small fraction of the applied substance is absorbed systemically, which helps minimize systemic adverse events and enhances their tolerability. Several technological advancements could enhance the efficacy and safety profile of topical analgesics in the near future and should be highlighted.

Technological Improvements of Topical Analgesic Delivery

As we have discussed, a fraction of the administered dose of topical analgesics can be absorbed into the systemic circulation, potentially increasing the risk of adverse effects that topical application aims to avoid. Although systemic concentrations are typically low, it is essential to optimize the application of topical drugs. This ensures effective penetration through the stratum corneum while maintaining localized action and minimizing entry into the bloodstream. There are several technological improvements that may help to improve skin penetration. These include nanocarriers, such as liposomes, nanoemulsions, and lipid nanoparticles, but also other carriers, such as microsponges, ionic liquids, and deep eutectic solvents.^8,12 They can be combined with active application modes, such as radiation or microneedle injections.⁸ These innovative formulation strategies may improve drug transport and pharmacokinetics of topical analgesics.

For instance, a diclofenac microemulsion was tested in a small prospective observational study with 11 patients, of whom 9 reported at least a 50% reduction in pain on a visual analog scale.⁶⁹ While these results are promising, the small cohort size limits the ability to draw definitive conclusions about the efficacy of the diclofenac microemulsion.

Despite their potential, these technological advancements also have certain disadvantages, including high material and production costs as well as the risk of potential toxicity.⁸ Additionally, delivery and targeted release of large molecules, such as peptides and proteins without systemic uptake, remain a challenge with these methods. In the context of personalized medicine, it may also be necessary to tailor delivery strategies and doses to the patient’s specific skin type and unique requirements.¹²

In summary, numerous novel and promising topical drug delivery systems have been developed that could be useful for the delivery of analgesics. However, further research is needed to establish their efficacy and safety.

Pain management is a complex process that requires careful selection of analgesics and their routes of administration to address both acute and chronic conditions effectively. Topical analgesics offer promising alternatives to oral medications for acute, inflammatory, and neuropathic pain, particularly for patients with gastrointestinal issues or those at risk of systemic side effects. Further research into innovative delivery systems is crucial to optimize their use and to improve safety and efficacy.

Literature Search Strategy

For our analysis, we conducted a search of the PubMed and Cochrane databases using the keywords “topical analgesics,” “transdermal analgesics,” “topical NSAIDs,” “topical lidocaine,” and “topical capsaicin,” in combination with terms such as “peripheral neuropathic pain,” “diabetic peripheral neuropathy,” “neuropathic pain,” “acute pain,” “osteoarthritis-induced pain,” and “inflammatory pain.” Additionally, we combined our search with the terms “review” and “Cochrane review.” These keywords were combined with Boolean operators such as “AND” and “OR.”

Inclusion criteria were English language publications in peer-reviewed journals that investigate topical analgesics. While all search results were initially considered, the review prioritized publications published after 2010. Studies were excluded if they were case reports, included fewer than 10 participants, or investigated systemic analgesic therapies or genetic disorders.

Research Support

This work was supported by the German Research Foundation (Bonn, Germany), grants SFB1039 A09 and Z01, from the Fraunhofer Foundation Project (Munich, Germany): Neuropathic Pain, and the Fraunhofer Cluster of Excellence for Immune-Mediated Diseases. This work was also supported by Leistungszentrum Innovative Therapeutics (TheraNova) funded by the Fraunhofer Society and the Hessian Ministry for Science and the Arts (Wiesbaden, Germany).

Competing Interests

Dr. Rice declares the following competing interests: Imperial College Consultants, paid consultancy work; in the last 36 months from Lateral Pharma, Confo, Astra Zeneca, and Combigene; grants and studentships from UKRI (Medical Research Council and BBSRC), Versus Arthritis, Alan and Sheila Diamond Trust, Royal British Legion, European Commission, Ministry of defense, Dr Jennie Gwynn Bequests, British Pain Society, and Royal Society of Medicine; International Association for the Study of Pain: travel expenses in connection with duties as president; honoraria and speaking engagements: University of California-San Franciso, Royal Marsden Hospital, Royal Pharmaceutical Society (BNF), Malaysian Society of Anaesthetists, and Pain Association of Singapore; lecture: MD Anderson Cancer Center, Bioevents, Medicines and Healthcare Products Regulatory Agency, Hospital for Special Surgery/Cornell University, USA, 57th Congress of Japanese Society of Pain Clinicians, United Arab Emirates University, and Korean Pain Society. The other authors declare no competing interests.