Lidocaine is available in a 5% preparation (gel, cream, or patch) and 8% spray. The 5% lidocaine patch is approved for first-line use in Post-Herpetic Neuralgia (PHN). The patch, worn for 12 hours out of every 24 hours, relieves dynamic allodynia to mechanical stimulation in PHN patients. 5% topical lidocaine also alleviates post-surgical neuropathy, carpal tunnel syndrome, and diabetic- and cancer-related neuropathies. In a randomized control trial (RCT), seven days of administration of a 5% lidocaine patch produced 50% relief from ongoing pain in patients with focal peripheral neuropathy of varying etiologies. With a number needed to treat (NNT) of 4.4 (95% CI 2.5-17.5), the efficacy was comparable to other systemic agents like gabapentin and TCAs [7]. 5% topical lidocaine formulations also relieve pain associated with complex regional pain syndrome (CRPS – type II), neuropathy after surgeries such as amputation, thoracotomy and mastectomy, carpal tunnel syndrome, idiopathic sensory polyneuropathy, intercostal, ilioinguinal and myofascial neuralgia, neuromas, meralgia paresthetica, diabetic neuropathy, and cancer-related neuropathy [8-10]. The analgesic effects of topical lidocaine depend on peripheral actions, as typically, only 3% of the drug penetrates the systemic circulation. Its long-term use in localized neuropathic pain provides sustained pain relief, only causing brief, reversible erythema and no systemic side effects [11].

Other topical local anesthetics include combinations of lidocaine with tetracaine (7% each in a cream), lidocaine with tetracaine (70 mg each in a self-heating patch), and lidocaine with prilocaine (2.5% each in an EMLA cream). These preparations are commonly used to treat patients with acute pain. Topical EMLA cream alleviates the pain of facial and perineal lacerations [12,13]. The cream is also effective as an analgesic for wound-related pain associated with chronic leg ulcers [14].

Capsaicinoids

Capsaicinoids, which include drugs like capsaicin, zucapsaicin, olvanil and resiniferatoxin, act by binding to the transient receptor potential vanilloid 1 (TRPV1), activating a non-selective cation channel expressed on nociceptors. While this activation causes the initial release of various neuropeptides, repeated application, or single exposure to high concentrations, of capsaicin causes over-stimulation followed by desensitization of TRPV1, depletion of neuropeptides, and a reversible degeneration of sensory terminals. The outcome is a reduced or lost function of nociceptors that produces hypoalgesia.

Capsaicin and its synthetic cis isomer, zucapsaicin, have been used clinically as topical analgesics. Low-concentration (0.025-0.075 %) capsaicin creams, gels, and patches are available over the counter to treat localized neuropathic pain but are not much more effective than placebo treatments [15]. Yet, low-dose topical capsaicin is clinically approved to treat knee osteoarthritis [16]. A 0.025% capsaicin cream used four times daily produces clinically significant pain alleviation in these patients (effect size: 0.41, 95% CI 0.17-0.64) [17].

A high-concentration (8%) capsaicin patch produces analgesic effects in cancer Chemotherapy-Indued Peripheral Neuropathy (CIPN), HIV-neuropathy, neuropathic back pain, Painful Diabetic Neuropathy (PDN), PHN, and post-traumatic neuropathy. A single treatment with an 8% capsaicin patch produced significant pain relief in post-herpetic neuralgia at 2 to 12 weeks with an NNT of 10 (95% CI 6.3-28) to obtain 30% pain reduction [18]. Similarly, the patch produced analgesia in painful HIV-neuropathy lasting 2 to 12 weeks with an NNT of 11 (95% CI 6.2-47) for 30% analgesia. Patients with mixed localized neuropathic pain received more significant relief from allodynia with an 8% capsaicin patch than oral pregabalin [19].

While low-concentration formulations of capsaicin need repeated administration for effective pain reduction, a single 3060 min application of the 8% capsaicin patch produces analgesic effects lasting up to 3 months [18]. Local reactions like burning pain, erythema, swelling, and pruritus after the topical treatment are more frequent and severe with these high-concentration patches. Thus, an 8% capsaicin patch treatment should be conducted in the presence of a healthcare professional. The adverse effects can be managed by pretreatment with local anesthetics or cooling after patch application. Even at low concentrations, capsaicin causes a reversible degeneration of sensory and autonomic intraepidermal nerve fibers (IENFs) [20].

Zucapsaicin is a synthetic cis isomer of capsaicin with a similar mechanism of action but produces fewer adverse local reactions. The 0.075% zucapsaicin (civamide) cream alleviated pain and physical dysfunction in patients with knee osteoarthritis in a 12-week-long multicenter RCT [21]. No measurable systemic absorption of the drug was detected, and local reactions like burning and rash occurred in only 5% of the patients. In an openlabel trial, a 12-month long-term continuation of treatment with 0.075% zucapsaicin produced a 34% reduction of osteoarthritic pain score from baseline. The synthetic vanilloid olvanil is nonpungent and appears to desensitize TRPV1 channels without initially activating and sensitizing nociceptors [22]. Olvanil and resiniferatoxin, which have pungent effects like capsaicin, have not been tested in humans but produce analgesic effects in laboratory animals [22,23].

Anticonvulsants

Like local anesthetics, most anticonvulsant drugs reduce sodium channel activity, but unlike local anesthetics, they produce a use-dependent reduction of sodium channels. In this manner, they target abnormal or excessive neuronal activity without significantly impacting normal activity [24]. Anticonvulsant drugs have not been used topically in sufficient studies and are not approved for neuropathic pain patients. Recently, however, a few studies suggest promising topical use of anticonvulsant drugs for neuropathic pain. Phenytoin reduces the amplitude of action potentials at sodium-dependent channels by enhancing their steady-state inactivation [24]. Topical 5-10% phenytoin effectively reduced neuropathic pain in a case series of 70 patients [25]. Another use-dependent sodium channel blocker, ambroxol, is more selective for TTX-resistant sodium channels, including NaV1.8 and NaV1.9, expressed on nociceptors [26]. A recent study showed that 20% topical ambroxol effectively relieved pain in 7 patients with traumatic neuropathic pain, including patients resistant to the analgesic effects of 5% lidocaine or 8% capsaicin [26]. Gabapentin is another anticonvulsant; in this case, one that binds to the α2δ subunits of calcium channels, reducing calcium currents and nerve injury-induced trafficking of calcium channels [27]. Topical 6% gabapentin reduced pain in 18 of 23 patients with PHN, CRPS, PDN, trigeminal neuralgia, and other neuropathic pain syndromes [28]. Due to the use-dependent nature of these agents and the considerable reduction of systemic side effects or adverse events associated with their topical application, topically administered anticonvulsant drugs may prove helpful in treating neuropathic pain.

Topical Analgesics that Target Peripheral Sources of Pathology

NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) produce anti-inflammatory and analgesic effects by reversibly inhibiting the cyclooxygenase-dependent metabolism of arachidonic acid into various inflammatory mediators, including prostaglandins and prostacyclin. Topical NSAIDs reduce the sensitization of peripheral nociceptors by inflammatory mediators that underlies acute and chronic inflammatory and musculoskeletal pain. As these inflammatory mediators are mechanistically involved in numerous acute and chronic inflammatory conditions, NSAID use is directly aimed at key peripheral sources of pathology. NSAIDs reduce the sensitization of nociceptors induced by these mediators [29]. Several topical NSAIDs are effective in acute pain conditions, including sprains, muscle and joint strains, and overuse injuries. However, since these same inflammatory mediators play a role in developing and maintaining neuropathic pain [29], it is not surprising that recent studies have shown that topical NSAIDs also produce analgesic effects in patients with neuropathies. Thus, 1.5-5% diclofenac relieved pain in patients with PHN, CRPS, and orofacial neuropathic pain [30,31]. Aspirin, ibuprofen, and ketoprofen are combined with other topical drugs to treat neuropathic pain of varying etiologies, including PHN and radiculopathy [29].

In a recent systematic review, topical diclofenac gel (1.2-2.3% Emulgel) produced a 50% reduction in acute musculoskeletal pain with an NNT of 1.8 (95% CI 1.5-2.1) [32]. For topical ketoprofen gel, the NNT was 2.5 (95% CI 2.0-3.4), and that of topical ibuprofen gel was 3.9 (95% CI 2.7-6.7). The treatments were given at least once daily for up to seven days. NNT calculations for each topical preparation included 2-5 RCTs with 240-350 participants in moderate to high-quality studies. A slightly lower efficacy was found for plaster preparations of diclofenac and ketoprofen in patients with acute musculoskeletal pain with NNTs between 3.2 and 8.2. The topical use of NSAIDs was associated with mild and transient local irritation with erythema and pruritus, but not at a higher frequency than their placebo counterparts. Systemic adverse effects are rare, as plasma concentrations of NSAIDs after topical administration is less than 5% of the level attained through systemic routes [32].

Topical administration of diclofenac and ketoprofen produces analgesia in chronic musculoskeletal pain, including knee osteoarthritis. In studies with this condition, treatment with topical diclofenac gel or solution achieved at least a 50% reduction in pain after 6 to 12 weeks, yielding an NNT of 9.8 (95% CI 7.116). The NNT for topical ketoprofen gel was 6.9 (95% CI 5.49.3). These values come from a recent Cochrane systematic review meta-analysis that included 4-6 moderate quality trials with more than 5,000 patients [33]. The efficacy of topical NSAIDs was also studied in non-musculoskeletal chronic pain conditions. An RCT in a small cohort of patients with PHN and complex regional pain syndrome (CRPS) showed that a 1.5% topical solution of diclofenac significantly improved self-reported pain [31].

Nitrates

Nitrates like glyceryl trinitrate (GTN) and isosorbide dinitrate are agents that release nitric oxide (NO) and produce vasodilation by increasing guanylate cyclase levels in vascular smooth muscle [34]. Although these types of agents are typically associated with ischemic pain, such as angina [35], there is evidence that their topical application produces analgesia in various pain conditions [36], including neuropathic, where there is evidence of endoneurial ischemia [37]. NO donors achieve analgesia by acting on ATP-sensitive K+ channels and may potentiate the actions of opioids [36]. There is growing evidence for the analgesic effects of topical nitrates in pain conditions like CRPS, PDN, and musculoskeletal pain due to tendinopathies [38-40]. GTN spray given for four weeks significantly reduced pain scores compared to placebo in a group of 50 patients with PDN enrolled in a doubleblind crossover RCT. The NNT was calculated to be 4 (95% CI 2–7) [40]. Similarly, topical GTN patches used in patients with acute shoulder tendinopathies reduced pain intensity, though its long-term benefit could not be determined [39]. Headaches are a common side-effect of systemic absorption of nitrates and can occur after topical treatment with GTN.

Clonidine

Clonidine is a presynaptic α2-adrenergic agonist used systemically or transdermally as an antihypertensive agent. Clonidine also has analgesic effects when administered topically [41]. Its analgesic mechanisms may depend on alleviating microvascular dysfunction by inhibiting vasoconstrictive norepinephrine (NE) released from peripheral sympathetic terminals innervating the microvasculature [42]. It may also reduce nociceptor hyperexcitability by directly activating α2adrenergic and I2-imidazoline receptors on nerve fibers [43] or reducing abnormal excitability of nociceptors after downregulating adenylate cyclase [44]. Topical clonidine (cream, gel, or patch) reduces pain associated with PHN, PDN, trigeminal neuralgia, and CRPS [43,45].

Topical clonidine relieves PDN, as demonstrated by a metaanalysis of two studies that resulted in an NNT of 8.88 (95% CI 4.3-50) to obtain a 30% reduction in pain [42]. The studies of nearly 350 patients examined the analgesic effect of 0.1-0.2% clonidine gel applied to both feet 2-3 times daily for 8-12 weeks. The limited efficacy of topical clonidine in PDN has led to its recommended use only when alternative treatment options have been exhausted due to inefficacy, contraindications, and side effects. Topical clonidine lacks undesirable adverse effects like dry mouth, sedation, and hypotension that occur with its systemic administration [42].

N-methyl-D-aspartate (NMDA) antagonists

NMDA antagonists, including ketamine, dextromethorphan, and memantine, are given systemically for chronic pain but are not widely used because of significant side effects and adverse events, including psychomimetic effects, dizziness, sedation, loss of appetite, and nausea [46]. Glutamate is released from the peripheral terminals of nociceptive afferents and acts on various glutamatergic receptors, including NMDA receptors found on peripheral nociceptor terminals [47], which are upregulated in response to injury [48]. This provides the basis for the topical use of NMDA antagonists for neuropathic pain. Various open trials and randomized controlled trials (RCTs) demonstrate topical ketamine, as a cream, ointment, or gel (either alone or with other agents), is effective for neuropathic pain (including PDN, PHN) and CRPS at various concentrations (0.5-20%). However, not all RCTs have supported the enthusiastic evidence of open trials [49]. Generally, these concentrations do not result in significant adverse effects or detectable plasma levels of drugs or metabolites [50]. As ketamine is a non-selective agent with additional actions on calcium channels, and cholinergic, monoaminergic, and opioidergic receptors, it will be essential to determine whether more selective agents produce similar effects on neuropathic pain when given topically. Although a topical patch containing dextromethorphan and other agents is available, it has not been studied in neuropathic pain patients [51].

Topical Therapeutics that Activate Inhibitory Systems

Opioids

The three major classes of opioid receptors (µ,δ, and κ) are all present on sensory nerve endings and various immune and skin cells. They may be upregulated in painful pathological conditions [52]. Opioid receptors are coupled to Gi and Go proteins that inhibit adenylyl cyclase and modulate ion channels, resulting in inhibitory effects on pain transmission in nociceptors [52]. However, few studies have assessed the impact of topical opioid drugs on chronic pain, except for painful skin ulcers and mouth sores associated with chemotherapeutics [53]. In the studies, gel formulations of morphine and diamorphine alleviated pain in palliative care patients with pressure ulcers. While a systematic review concluded that evidence for the analgesic effects of peripherally injected opioids was weak [54], the potential use of topical opioids for chronic inflammatory and neuropathic pain remains untested.

Cannabinoids

Cannabinoid receptors are present on peripheral nerve terminals, keratinocytes, and immune cells in the skin [55]. Their activation inhibits cutaneous nociceptors by reducing adenylate cyclase, mitogen-activated protein kinase, and flux through various ion channels [55]. There is preliminary evidence for the topical analgesic use of cannabinoids in neuropathic pain. In patients with symptomatic peripheral neuropathy of varying etiologies, an RCT assessing topical treatment with cannabidiol oil administered for four weeks revealed a significant reduction in pain [56]. Similarly, a four-week-long open-label topical treatment with a cream containing the cannabinoid receptor agonist Npalmitoylethanolamine alleviated pain in patients with postherpetic neuralgia [57].

Topical cannabidiol has reduced pain and promoted healing in a case series of pediatric patients with the blistering skin disorder epidermolysis bullosa [58]. Similarly, topical application of medical cannabis reduced pain by over 30% in a prospective case series of patients with pyoderma gangrenosum. This ulcerative inflammatory skin condition produces intense, opioid-resistant pain [59].

GABA agonists

Agents acting as agonists at the GABA-B receptor produce inhibitory effects on synaptic transmission by increasing the intracellular influx of K+ and decreasing the influx of Ca2+ ions [60]. Until recently, the GABA-B agonist baclofen is often combined with other topical agents [8]. However, recent studies demonstrate the analgesic effects of topical 2-5% baclofen for chronic pain associated with either acromegaly or herniated lumbar discs [61,62]. As these reports were both case studies, the burden of evidence awaits controlled clinical trials and systematic reviews, as yet not completed.

Antidepressants

Various studies have suggested that antidepressant drugs often prescribed orally for neuropathic pain may produce analgesia when applied topically. Antidepressants, such as amitriptyline and doxepin, have multiple peripheral effects, including actions on opioid, cholinergic, histaminergic, and adenosine receptors, as well as various ion channels [64]. Limited studies have indicated analgesic effects of topical 1-10% amitriptyline and 3-5% doxepin in neuropathic pain and CRPS [63,64]. However, a recent systematic review concluded there was weak evidence for the analgesic effects of topical amitriptyline. Low doses of amitriptyline produced little or no effect. In contrast, high doses indicated analgesic effects, but in poorly controlled case studies, analgesia was accompanied by side effects or adverse events likely caused by systemic absorption [65].

Topical combinations

Topical combinations of analgesics may produce greater efficacy due to their potential to impact multiple pathological processes. The most studied topical analgesic combination for chronic pain comprises the antidepressant amitriptyline and the NMDA receptor antagonist ketamine. While amitriptyline has multiple peripheral effects, including actions on opioid, cholinergic, histaminergic, and adenosine receptors, and various ion channels, ketamine blocks the glutaminergic N-methyl-Daspartate (NMDA) receptors with additional actions on calcium channels, and cholinergic, monoaminergic and opioid receptors. Ketamine also induces NO synthesis, increasing vasodilation and reducing pro-inflammatory cytokines [65].

RCTs that investigated the singular use of either agent to treat chronic pain conditions have produced mixed results giving inconsistent indications for their analgesic efficacy [50,64]. Nonetheless, a two-week-long treatment with the topical combination of amitriptyline 2% and ketamine 1% produced a 33% reduction in average daily pain in an RCT of patients with PHN [65]. Furthermore, a double-blind RCT that compared this topical combination to oral gabapentin in PHN has revealed that four weeks of the topical combination treatment produced comparable pain-relieving effects to gabapentin with no significant difference in analgesic efficacy [65]. Similarly, a double-blind RCT indicated a combination of ketamine (1.5%) and amitriptyline (3%) with the addition of baclofen (0.75%) in pluronic lecithin organogel reduced symptoms of tingling, cramping and burning pain in the hands of patients with chemotherapy-induced painful neuropathy [66].

Compounding amitriptyline or ketamine with various drugs such as lidocaine, gabapentin, pregabalin, baclofen, or clonidine adds to the suppression of excitation, or the enhancement of inhibition, already produced by these two agents. Importantly, as the penetration of these agents into the systemic circulation is typically so low it is undetectable after topical administration, concerns about adverse systemic drug-drug interactions are not warranted. Thus, multimodal drug combinations, which would be inconceivable for systemic therapy, are generally perfectly safe in topical drug compounding [67-69].

Topical Therapeutics for the Mucosal Tissue

Given the relative ease of drug absorption at these sites, painful pathologies of mucosal tissues are sensitive to topical analgesics. Oral mucositis after chemotherapy is commonly treated with topical morphine mouth rinse (0.1-0.2%) and gel (0.1 %) [53]. Orofacial neuropathic pain, pulpitis, and chemotherapyinduced mucositis are effectively treated with oral (lozenge, gum, mouthwash, gel, etc.) therapies, including 0.01-0.25% capsaicin, 2% amitriptyline, 0.2% topical clonidine, and 5% ketamine [70]. Topical steroids in pastes, ointments, and mouthwashes relieve pain due to aphthous ulcers [73]. Local anesthetics gels and creams have also demonstrated efficacy in relieving mild-to-moderate pain of oral mucosal lesions caused by trauma and ulceration [71].

For pain pathologies in the rectal, genital, and perineal areas, including vulvodynia, proctodynia, and pudendal neuralgia, topical agents 1–2.5% amitriptyline (alone or combined with other agents), 2–6% gabapentin and 2% ketamine are effective [70].

Current Advancements in Topical Analgesics

Research efforts to develop effective topical therapeutics for acute and chronic pain are ongoing. New topical formulations of local anesthetics, NSAIDs, and capsaicin with an improved constitution and dosing are being investigated in clinical trials for different pain conditions. More interestingly, novel therapeutics like funapide (XEN402), a selective NaV1.7/1.8 channel antagonist, are being investigated to treat PHN.

Recent studies demonstrate synergistic analgesic effects are produced in animal models of CRPS and neuropathic pain using combinations of agents that target more specific pathophysiological mechanisms associated with these conditions. Deep tissue and/ or endoneurial microvascular dysfunction contributes to the pathophysiology of CRPS and neuropathic pain [72]. Reducing microvascular dysfunction using topical combinations of nitric oxide donors or α2-adrenergic agonists (which increase thermoregulatory blood flow) with type IV phosphodiesterase (PDE) inhibitors (which increase nutritive blood flow) produces synergistic analgesic effects in animal models of CRPS and neuropathic pain [73,74]. Thus, topical combinations of α2adrenergic agonists (clonidine and apraclonidine) or NO donors (linsidomine, S-nitroso-N-acetylpenicillamine) with PDE inhibitors (pentoxifylline and lisofylline) produce analgesic effects that are much greater than the analgesic effects of the individual agents given on their own. Given that the anti-allodynic effects of these treatments are paralleled by their anti-ischemic effects, it suggests their synergistic analgesic effects may depend partly on disease-modifying actions. One such combination, clonidine + pentoxifylline, produces significantly greater analgesic effects than either of the single agents in a surrogate of neuropathic pain (postcapsaicin ischemia-induced pain) in healthy human volunteers [75].

Another potential for advancement in topical analgesics can come through using analgesic combinations in the form of co-drugs, drug-drug salts, co-crystals, and ionic liquids. These preparations are made by pairing multi-targeted analgesic agents based on therapeutic complementarity and physicochemical properties to achieve better solubility and bioavailability. While co-drugs are conjugates typically bound together by covalent chemical bonds, drug-drug salts, co-crystals, and hydrates are crystalline compounds of two or more active drugs linked by ionic or hydrogen bonds. Ionic liquids are salts in liquid form. The synthesis of such analgesic combinations has been reported and constitutes agents with local anesthetic, anti-inflammatory, antidepressant, and opioid activities. Some examples are lidocaineibuprofen, lidocaine-etodolac, lidocaine-aspirin, aspirin-tramadol, and celecoxib-tramadol all pending investigations as topical analgesic formulations [76,77]. Recent studies also show that salts or co-crystals of vasodilatory pharmaceuticals with antioxidant nutraceuticals are analgesic in animal models of models of neuropathic pain and CRPS [78,79].

Acknowledgments

T.J.C. has received grant support from CIHR, NSERC, FRQS-QPRN, and the Louise and Alan Edwards Foundation. O.A.F. received studentships from the Louise and Alan Edwards Foundation and the MUHC Research Institute.

References

1. Stanos S (2020) Topical analgesics. Phys Med Rehabil Clin N Am 31: 233-244.
2. Derry S, Moore RA, Rabbie R (2016) Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev 4: CD007400.
3. National Clinical Guideline Centre (UK) (2014) Osteoarthritis: Care and Management in Adults. National Institute for Health and Care Excellence, London, UK.
4. Harden RN, Oaklander AL, Burton AW, Perez RS, Richardson K, et al. (2013) Complex regional pain syndrome: practical diagnostic and treatment guidelines, 4th edition. Pain Med 14: 180-229.
5. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, et al. (2015) Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 14: 162-173.
6. Tverdohleb T, Candido KD, Knezevic NN (2019) Topical Medications. In Pain: A Review Guide. Abd-Elsayed A, Ed, Springer International Publishing: Cham, Switzerland, pp: 293-296.
7. Davies PS, Galer BS (2004) Review of lidocaine patch 5% studies in the treatment of post-herpetic neuralgia. Drugs 64: 937-947.
8. Casale R, Symeonidou Z, Bartolo M (2017) Topical treatments for localized neuropathic pain. Curr Pain Headache Rep 21: 15.
9. Baron R, Allegri M, Correa-Illanes G, Baron R, Allegri M, et al. (2016) The 5% lidocaine-medicated plaster: Its inclusion in international treatment guidelines for treating localized neuropathic pain, and clinical evidence supporting its use. Pain Ther 149-169.
10. Mick G, Correa-Illanes G (2012) Topical pain management with the 5% lidocaine medicated plaster--a review. Curr Med Res Opin 28: 937951.
11. Wilhelm IR, Tzabazis A, Likar R, Sittl R, Griessinger N (2010) Longterm treatment of neuropathic pain with a 5% lidocaine medicated plaster. Eur J Anaesthesiol 27: 169-173.
12. Park SW, Oh TS, Choi JW, Eom JS, Hong JP, et al. (2015) Topical EMLA cream as a pretreatment for facial lacerations. Arch Plast Surg 42: 28-33.
13. Abbas AM, Mohamed AA, Mattar OM, El Shamy T, James C, et al. (2020). Lidocaine-prilocaine cream versus local infiltration anesthesia in pain relief during repair of perineal trauma after vaginal delivery: a systematic review and meta-analysis. J Matern Fetal Neonatal Med 33: 1064-1071.
14. Purcell A, Buckley T, King J, Moyle W, Marshall AP (2020) Topical analgesic and local anesthetic agents for pain associated with chronic leg ulcers: A systematic review. Adv Skin Wound Care 33: 240-251.
15. Derry S, Moore RA (2012) Topical capsaicin (low concentration) for chronic neuropathic pain in adults. Cochrane Database Syst Rev 9: CD010111.
16. Kolasinski SL, Neogi T, Hochberg MC, Oatis C, Guyatt G, et al. (2020) 2019 American College of Rheumatology/Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Rheumatol 72: 220-233.
17. Persson M, Stocks J, Walsh DA, Doherty M, Zhang W (2018) The relative efficacy of topical nonsteroidal anti-inflammatory drugs and capsaicin in osteoarthritis: a network meta-analysis of randomised controlled trials. Osteoarthritis Cartilage 26: 1575-1582.
18. Derry S, Rice AS, Cole P, Tan T, Moore RA (2017) Topical capsaicin (high concentration) for chronic neuropathic pain in adults. Cochrane Database Syst Rev 1: CD007393.
19. Cruccu G, Nurmikko T, Ernault E, Riaz FK, McBride WT, et al. (2018) Superiority of capsaicin 8% patch versus oral pregabalin on dynamic mechanical allodynia in patients with peripheral neuropathic pain. Eur J Pain 22: 700-706.
20. Nolano M, Simone DA, Wendelschafer-Crabb G, Johnson T, Hazen E, et al. (1999) Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation. Pain 81: 135-145.
21. Schnitzer TJ, Pelletier J-P, Haselwood DM, Ellison WT, Ervin JE, et al. (2012) Civamide cream 0.075% in patients with osteoarthritis of the knee: A 12-week randomized controlled clinical trial with a longterm extension. J Rheumatol 39: 610-620.
22. Alsalem M, Millns P, Altarifi A, El-Salem K, Chapman V, et al. (2016) Anti-nociceptive and desensitizing effects of olvanil on capsaicininduced thermal hyperalgesia in the rat. BMC Pharmacol Toxicol 17: 31-41.
23. Kissin I (2008) Vanilloid-induced conduction analgesia: selective, dose-dependent, long-lasting, with a low level of potential neurotoxicity. Anesth Analg 107: 271-281.
24. Matsuki N, Quandt FN, Ten Eick RE, Yeh JZ (1984) Characterization of the block of sodium channels by phenytoin in mouse neuroblastoma cells. J Pharmacol Exp Ther 228: 523-530.
25. Kopsky DJ, Keppel Hesselink JM (2018) Phenytoin cream for the treatment for neuropathic pain: Case series. Pharmaceuticals (Basel) 11: 53.
26. Kern KU, Weiser T (2015) Topical ambroxol for the treatment of neuropathic pain. An initial clinical observation. Schmerz 29: S89-S96.
27. Patel R, Dickenson AH (2016) Mechanisms of the gabapentinoids and α2δ-1 calcium channel subunit in neuropathic pain. Pharmacol Res Perspect 4: e00205.
28. Hiom S, Patel GK, Newcombe RG, Khot S, Martin C (2015) Severe postherpetic neuralgia and other neuropathic pain syndromes alleviated by topical gabapentin. Br J Dermatol 173: 300-302.
29. Ma W, St-Jacques B, Duarte PC (2012) Targeting pain mediators induced by injured nerve-derived COX2 and PGE2 to treat neuropathic pain. Expert Opin Ther Targets 16: 527-540.
30. Plaza-Villegas F, Heir G, Markman S, Khan J, Noma N, et al. (2012) Topical pregabalin and diclofenac for the treatment of neuropathic orofacial pain in rats. Oral Surg Oral Med Oral Pathol Oral Radiol 114: 449-456.
31. Ahmed SU, Zhang Y, Chen L, Cohen A, St Hillary K, et al. (2015) Effect of 1.5% topical diclofenac on clinical neuropathic pain. Anesthesiology 123: 191-198.
32. Derry S, Moore RA, Gaskell H, McIntyre M, Wiffen PJ (2015) Topical NSAIDs for acute musculoskeletal pain in adults. Cochrane Database Syst Rev 6: CD007402.
33. Derry S, Wiffen PJ, Kalso EA, Bell RF, Aldington D, et al. (2017) Topical analgesics for acute and chronic pain in adults - an overview of Cochrane Reviews. Cochrane Database Syst Rev 5: CD008609.
34. Mitchell JA, Ali F, Bailey L, Moreno L, Harrington LS (2008) Role of nitric oxide and prostacyclin as vasoactive hormones released by the endothelium. Exp Physiol 93: 141-147.
35. Nossaman VE, Nossaman BD, Kadowitz PJ (2010) Nitrates and nitrites in the treatment of ischemic cardiac disease. Cardiol Rev 18: 190-197.
36. McCleane G (2007) Topical analgesics. Anesthesiol Clin 25: 825-839.
37. Lim TK, Shi XQ, Johnson JM, Rone MB, Antel JP, et al. (2015) Peripheral nerve injury induces persistent vascular dysfunction and endoneurial hypoxia contributing to the genesis of neuropathic pain. J Neurosci 35: 3346-3359.
38. Groeneweg, G Niehof S, Wesseldijk F, Huygen FJ, Zijlstra FJ (2008) Vasodilative effect of lsosorbide dinitrate ointment in complex regional pain syndrome type 1. Clin J Pain 24: 89-92.
39. Cumpston M, Johnston RV, Wengier L, Buchbinder R (2009) Topical glyceryl trinitrate for rotator cuff disease. Cochrane Database Syst Rev 3: CD006355.
40. Agrawal RP, Choudhary R, Sharma P, Sharma S, Beniwal R, et al. (2007) Glyceryl trinitrate spray in the management of painful diabetic neuropathy: a randomized double blind placebo controlled crossover study. Diabetes Res Clin Pract 77: 161-167.
41. Sawynok J (2003) Topical and peripherally acting analgesics. Pharmacol Rev 55: 1-20.
42. Serednicki WT, Wrzosek A, Woron J, Garlicki J, Dobrogowski J, et al. (2022) Topical clonidine for neuropathic pain in adults. Cochrane Database Syst Rev 5: CD010967.
43. Khan ZP, Ferguson CN Jones RM (1999) Alpha-2 and imidazoline receptor agonists their pharmacology and therapeutic role. Anaesthesia 54: 146-165.
44. Lavand’homme PM, Ma W, De Kock M, Eisenach JC (2002) Perineural alpha(2A)-adrenoceptor activation inhibits spinal cord neuroplasticity and tactile allodynia after nerve injury. Anesthesiology 97: 972-980.
45. Leppert W, Malec-Milewska M, Zajaczkowska R, Wordliczek J (2018) Transdermal and topical drug administration in the treatment of pain. Molecules 23: 681.
46. Cvrcek P (2008) Side effects of ketamine in the long-term treatment of neuropathic pain. Pain Med 9: 253-257.
47. Miller KE, Hoffman EM, Sutharshan M, Schechter R (2011) Glutamate pharmacology and metabolism in peripheral primary afferents: physiological and pathophysiological mechanisms. Pharmacol Ther 130: 283-309.
48. Carlton SM, Coggeshall RE (1999) Inflammation-induced changes in peripheral glutamate receptor populations. Brain Res 820: 63-70.
49. Sawynok J (2014) Topical and peripheral ketamine as an analgesic. Anesth Analg 119: 170-178.
50. Kopsky DJ, Hesselink JMK, Bhaskar A, Hariton G, Romanenko V, et al. (2015) Analgesic effects of topical ketamine. Minerva Anesthesiol 81: 440-449.
51. Pickering G, Martin E, Tiberghien F, Delorme C, Mick G (2017) Localized neuropathic pain: an expert consensus on local treatments. Drug Des Devel Ther 11: 2709-2718.
52. Bigliardi PL, Tobin DJ, Gaveriaux-Ruff C, Bigliardi-Qi M (2009) Opioids and the skin – where do we stand? Exp Dermatol 18: 424-430.
53. LeBon B, Zeppetella G, Higginson IJ (2009) Effectiveness of topical administration of opioids in palliative care: A systematic review. J Pain Symptom Manage 37: 913-917.
54. Picard PR, Tramer MR, McQuay HJ, Moore RA (1997) Analgesic efficacy of peripheral opioids (all except intra-articular): a qualitative systematic review of randomised controlled trials. Pain 72: 309-318.
55. Guindon J, Beaulieu P (2009) The role of the endogenous cannabinoid system in peripheral analgesia. Curr Mol Pharmacol 2: 134-139.
56. Xu DH, Cullen BD, Tang M, Fang Y (2020) The Effectiveness of topical cannabidiol oil in symptomatic relief of peripheral neuropathy of the lower extremities. Curr Pharm Biotechnol 21: 390-402.
57. Phan NQ, Siepmann D, Gralow I, Ständer S (2010) Adjuvant topical therapy with a cannabinoid receptor agonist in facial post-herpetic neuralgia. J Dtsch Dermatol Ges 8: 88-91.
58. Chelliah MP, Zinn Z, Khuu P, Teng JMC (2018) Self-initiated use of topical cannabidiol oil for epidermolysis bullosa. Pediatr Dermatol 35: e224-227.
59. Maida V, Corban J (2007) Topical medical cannabis: A new treatment for wound pain - three cases of pyoderma gangrenosum. J Pain Sympt Manage 54: 732-736.
60. Reis GM, Duarte ID (2006) Baclofen, an agonist at peripheral GABAB receptors, induces anti-nociception via activation of TEA-sensitive potassium channels. Br J Pharmacol 149: 733-739.
61. Kopsky DJ, Hesselink JMK (2013) Neuropathic pain as a result of acromegaly, treated with topical baclofen cream. J Pain Symptom Manag 46: e4-e5.
62. Kopsky DJ, Hesselink JMK, Casale R (2015) Walking with neuropathic pain: paradoxical shift from burden to support? Case Rep Med 2015: 764950.
63. Kopsky DJ, Hesselink JM (2012) High doses of topical amitriptyline in neuropathic pain: two cases and literature review. Pain Pract 12: 148-153.
64. Thompson DF, Brooks KG (2015) Systematic review of topical amitriptyline for the treatment of neuropathic pain. J Clin Pharm Ther 40: 496-503.
65. Sawynok J, Zinger C (2016) Topical amitriptyline and ketamine for post-herpetic neuralgia and other forms of neuropathic pain. Expert Opin Pharmacother 17: 601-609.
66. Barton DL, Wos EJ, Qin R, Mattar BI, Green NB, et al. (2011) A doubleblind, placebo-controlled trial of a topical treatment for chemotherapyinduced peripheral neuropathy: NCCTG trial N06CA. Supportive Care Cancer 19: 833-841.
67. Zur E (2014) Topical treatment of neuropathic pain using compounded medications. Clin J Pain 30: 73-91.
68. Sawynok J (2014) Topical analgesics for neuropathic pain: preclinical exploration, clinical validation, future development. Eur J Pain 18: 465481.
69. Safaeian P, Mattie R, Hahn M, Plastaras CT, McCormick ZL (2016) Novel treatment of radicular pain with a multi-mechanistic combination topical agent: A case series and literature review. Anesth Pain Med 6: e33322.
70. Coderre TJ (2018) Topical drug therapeutics for neuropathic pain.Expert Opin Pharmacother 19: 1211-1220.
71. Coderre TJ, Bennett GJ (2010) A hypothesis for the cause of complex regional pain syndrome-type I (reflex sympathetic dystrophy): pain due to deep-tissue microvascular pathology. Pain Med 11: 1224-1238.
72. Ragavendran JV, Laferrière A, Xiao WH, Bennett GJ, Padi SS, et al. (2013) Topical combinations aimed at treating microvascular dysfunction reduce allodynia in rat models of CRPS-I and neuropathic pain. J Pain 14: 66-78.
73. Laferrière A, Abaji R, Tsai CY, Ragavendran JV, Coderre TJ (2014) Topical combinations to treat microvascular dysfunction of chronic postischemia pain. Anesth Analg 118: 830-840.
74. Ragavendran JV, Laferrière A, Bennett GJ, Ware MA, Gandhi W, et al. (2016) Effects of topical combinations of clonidine and pentoxifylline on capsaicin-induced allodynia and postcapsaicin tourniquet-induced pain in healthy volunteers: a double-blind, randomized, controlled study. Pain 157: 2366-2374.
75. Robertson JJ (2016) Managing pharyngeal and oral mucosal pain. Curr Emerg Hosp Med Rep 4: 57-65.
76. Gascon N, Almansa C, Merlos M, Miguel Vela J, Encina G, et al. (2019) Co-crystal of tramadol-celecoxib: preclinical and clinical evaluation of a novel analgesic. Expert Opin Invest Drugs 28: 399-409.
77. Shamshina JL, Barber PS, Rogers RD (2013) Ionic liquids in drug delivery. Expert Opin Drug Deliv 10: 1367-1381.
78. Fulas OA, Laferrière A, Ayoub G, Gandrath D, Mottillo C, et al. (2020) Drug-Nutraceutical Co-Crystal and Salts for Making New and Improved Bi-Functional Analgesics. Pharmaceutics 12: 1144.
79. Fulas OA, Laferrière A, Coderre TJ (2021) Novel Co-crystal of Pentoxifylline and Protocatechuic Acid Relieves Allodynia in Rat Models of Peripheral Neuropathic Pain and CRPS by Alleviating Local Tissue Hypoxia. ACS Chem Neurosci 12: 3855-3863.