Topical Drug Delivery in the Treatment of Pain

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (10 February 2023) | Viewed by 43578

Special Issue Editor


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Guest Editor
Laboratory of Quality of Life Research, Poznan University of Medical Sciences, 61-701 Poznan, Poland
Interests: pain; topical administration; adverse effects; analgesics; treatment

Special Issue Information

Dear Colleagues,

The comprehensive treatment of pain is multidimodal, with pharmacotherapy playing a key role. This Themed Issue “Topical Drug Delivery in the Treatment of Pain” is aimed at presenting current knowledge on analgesics administered by topical routes for healthcare professionals dealing with patients with pain.

Nonsteroidal anti-inflammatory drugs applied topically are the main mechanism of action and are based on a high concentration in the structures of the joint and a provision of local anti-inflammatory effects. Topically administered drugs such as lidocaine and capsaicin in patches, capsaicin in cream, EMLA cream, and creams containing antidepressants, i.e., doxepin, and amitriptyline act mainly locally in tissues through receptors and/or ion channels. Topically administered opioids are characterized by a lower risk of addiction compared to systemic routes. Topical routes offer some advantages over systemic analgesic administration. Analgesics administered topically have a much better profile for adverse effects as they relieve local pain with minimal systemic effects.

Prof. Wojciech Leppert
Guest Editor

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Keywords

  • adverse effects
  • analgesia
  • analgesics
  • pain
  • topical administration

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Published Papers (10 papers)

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Research

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18 pages, 5036 KiB  
Article
Topical Delivery of Ketorolac Tromethamine via Cataplasm for Inflammatory Pain Therapy
by Zhiyuan Hou, Qiang Wen, Wenhu Zhou, Peng Yan, Hailong Zhang and Jinsong Ding
Pharmaceutics 2023, 15(5), 1405; https://doi.org/10.3390/pharmaceutics15051405 - 4 May 2023
Cited by 9 | Viewed by 2594
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely used in the treatment of inflammatory pain, such as in osteoarthritis. Ketorolac tromethamine is considered to be an NSAID with strong anti-inflammatory and analgesic potency, however, traditional applications, such as oral administration and injections, often induce [...] Read more.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely used in the treatment of inflammatory pain, such as in osteoarthritis. Ketorolac tromethamine is considered to be an NSAID with strong anti-inflammatory and analgesic potency, however, traditional applications, such as oral administration and injections, often induce high systemic exposure, leading to adverse events such as gastric ulceration and bleeding. To address this key limitation, herein we designed and fabricated a topical delivery system for ketorolac tromethamine via cataplasm, which is based on a three-dimensional mesh structure formed by the cross-linking of dihydroxyaluminum aminoacetate (DAAA) and sodium polyacrylate. The viscoelasticity of the cataplasm was characterized by rheological methods and exhibited a “gel-like” elastic property. The release behavior showed a Higuchi model characteristic with a dose dependence. To enhance the skin permeation, permeation enhancers were added and screened utilizing ex vivo pig skin, in which 1,2-propanediol was found to have the optimal permeation-promoting effect. The cataplasm was further applied to a rat carrageenan-induced inflammatory pain model, which showed comparable anti-inflammatory and analgesic effects with oral administration. Finally, the biosafety of the cataplasm was tested in healthy human volunteers, and reduced side effects were achieved as compared to the tablet formulation, which can be ascribed to less systemic drug exposure and lower blood drug concentrations. Therefore, the constructed cataplasm can reduce the risk of adverse events while maintaining efficacy, thus serving as a better alternative for the treatment of inflammatory pain, including osteoarthritis. Full article
(This article belongs to the Special Issue Topical Drug Delivery in the Treatment of Pain)
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15 pages, 2135 KiB  
Article
Enhancing Intradermal Delivery of Lidocaine by Dissolving Microneedles: Comparison between Hyaluronic Acid and Poly(Vinyl Pyrrolidone) Backbone Polymers
by Delly Ramadon, Lissa Florencia Putri Sutrisna, Yahdiana Harahap, Kurnia Sari Setio Putri, Fathin Ulayya, Pietradewi Hartrianti, Qonita Kurnia Anjani and Ryan F. Donnelly
Pharmaceutics 2023, 15(1), 289; https://doi.org/10.3390/pharmaceutics15010289 - 14 Jan 2023
Cited by 17 | Viewed by 4349
Abstract
Lidocaine hydrochloride (LiH), an amide-type local anesthetic agent, is commonly used in dermatological procedures. LiH is categorized as a BCS (biopharmaceutics classification system) class III group, which has high solubility and poor permeability. It should be noted that, in this context, LiH is [...] Read more.
Lidocaine hydrochloride (LiH), an amide-type local anesthetic agent, is commonly used in dermatological procedures. LiH is categorized as a BCS (biopharmaceutics classification system) class III group, which has high solubility and poor permeability. It should be noted that, in this context, LiH is intended as a local anesthetic, so the level of LiH in systemic circulation should be minimized to avoid toxicity and unwanted side effects such as hypotension and bradycardia. This study aimed to formulate and evaluate LiH-loaded dissolving microneedles (DMNs) with different polymer bases. Moreover, an in vitro permeation study using Franz diffusion cells and in vivo study were also performed. LiH-loaded DMNs were prepared using polymer groups of poly(vinyl pyrrolidone) (PVP-K30) and hyaluronic acid (HA). DMNs were created using the micro-molding method with centrifugation. The formulations selected based on the evaluation were F3 (HA 10%) and F5 (PVP-K30 25%). Based on the in vitro permeation study, the amount of drug permeated and deposited in the skin at F3 (HA 10%) was 247.1 ± 41.85 and 98.35 ± 12.86 μg, respectively. On the other hand, the amount of drug permeated and deposited in the skin at F5 (PVP-K30 25%) was 277.7 ± 55.88 and 59.46 ± 9.25 μg, respectively. Our in vivo drug-permeation study showed that only one rat from the PVP-K30 polymer group—with a concentration of 150.32 ng/mL—was detected on rat plasma. Therefore, LiH can be formulated into a DMN and can be deposited in the skin with a safe concentration of the drug permeating into systemic circulation. Full article
(This article belongs to the Special Issue Topical Drug Delivery in the Treatment of Pain)
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16 pages, 2319 KiB  
Article
In Silico Simulation of the Systemic Drug Exposure Following the Topical Application of Opioid Analgesics in Patients with Cutaneous Lesions
by Maksim Khotimchenko, Victor Antontsev, Kaushik Chakravarty, Hypatia Hou and Jyotika Varshney
Pharmaceutics 2021, 13(2), 284; https://doi.org/10.3390/pharmaceutics13020284 - 21 Feb 2021
Cited by 7 | Viewed by 2457
Abstract
The use of opioid analgesics in treating severe pain is frequently associated with putative adverse effects in humans. Topical agents that are shown to have high efficacy with a favorable safety profile in clinical settings are great alternatives for pain management of multimodal [...] Read more.
The use of opioid analgesics in treating severe pain is frequently associated with putative adverse effects in humans. Topical agents that are shown to have high efficacy with a favorable safety profile in clinical settings are great alternatives for pain management of multimodal analgesia. However, the risk of side effects induced by transdermal absorption and systemic exposure is of great concern as they are challenging to predict. The present study aimed to use “BIOiSIM” an artificial intelligence-integrated biosimulation platform to predict the transdermal disposition of opioid analgesics. The model successfully predicted their exposure following the topical application of central opioid agonist buprenorphine and peripheral agonist oxycodone in healthy human subjects with simulation of intra-skin exposure in subjects with burns and pressure wounds. The predicted plasma levels of analgesics were used to evaluate the safety of the therapeutic pain control in patients with the dermal structural impairments caused by acute (burns) or chronic cutaneous lesions (pressure wounds) with topical opioid analgesics. Full article
(This article belongs to the Special Issue Topical Drug Delivery in the Treatment of Pain)
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16 pages, 4606 KiB  
Article
Novel Fluorinated Poly (Lactic-Co-Glycolic acid) (PLGA) and Polyethylene Glycol (PEG) Nanoparticles for Monitoring and Imaging in Osteoarthritis
by Luana Zerrillo, Karthick Babu Sai Sankar Gupta, Fons A.W.M. Lefeber, Candido G. Da Silva, Federica Galli, Alan Chan, Andor Veltien, Weiqiang Dou, Roberta Censi, Piera Di Martino, Mangala Srinivas and Luis Cruz
Pharmaceutics 2021, 13(2), 235; https://doi.org/10.3390/pharmaceutics13020235 - 7 Feb 2021
Cited by 12 | Viewed by 4541
Abstract
Polymeric nanoparticles (NPs) find many uses in nanomedicine, from drug delivery to imaging. In this regard, poly (lactic-co-glycolic acid) (PLGA) and polyethylene glycol (PEG) particles are the most widely applied types of nano-systems due to their biocompatibility and biodegradability. Here we developed novel [...] Read more.
Polymeric nanoparticles (NPs) find many uses in nanomedicine, from drug delivery to imaging. In this regard, poly (lactic-co-glycolic acid) (PLGA) and polyethylene glycol (PEG) particles are the most widely applied types of nano-systems due to their biocompatibility and biodegradability. Here we developed novel fluorinated polymeric NPs as vectors for multi-modal nanoprobes. This approach involved modifying polymeric NPs with trifluoroacetamide (TFA) and loading them with a near-infrared (NIR) dye for different imaging modalities, such as magnetic resonance imaging (MRI) and optical imaging. The PLGA-PEG-TFA NPs generated were characterized in vitro using the C28/I2 human chondrocyte cell line and in vivo in a mouse model of osteoarthritis (OA). The NPs were well absorbed, as confirmed by confocal microscopy, and were non-toxic to cells. To test the NPs as a drug delivery system for contrast agents of OA, the nanomaterial was administered via the intra-articular (IA) administration method. The dye-loaded NPs were injected in the knee joint and then visualized and tracked in vivo by fluorine-19 nuclear magnetic resonance and fluorescence imaging. Here, we describe the development of novel intrinsically fluorinated polymeric NPs modality that can be used in various molecular imaging techniques to visualize and track OA treatments and their potential use in clinical trials. Full article
(This article belongs to the Special Issue Topical Drug Delivery in the Treatment of Pain)
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18 pages, 2352 KiB  
Article
Rheological and Drug Delivery Characteristics of Poloxamer-Based Diclofenac Sodium Formulations for Chronic Wound Site Analgesia
by Jackson Russo, Jennifer Fiegel and Nicole K. Brogden
Pharmaceutics 2020, 12(12), 1214; https://doi.org/10.3390/pharmaceutics12121214 - 15 Dec 2020
Cited by 30 | Viewed by 3495
Abstract
Chronic wounds are a significant and growing health problem, and clinical treatment is often a painful experience. A topical dosage form would be optimal to treat this pain. Poloxamer 407, a thermosensitive polymer that is a liquid at low temperatures but gels at [...] Read more.
Chronic wounds are a significant and growing health problem, and clinical treatment is often a painful experience. A topical dosage form would be optimal to treat this pain. Poloxamer 407, a thermosensitive polymer that is a liquid at low temperatures but gels at higher temperatures, is well suited to administer topical analgesics to chronic wound sites. The goal of this study was to evaluate the gelation and drug delivery properties of poloxamer 407 gels containing diclofenac sodium for potential use in chronic wound analgesic delivery. The gelation properties of poloxamer formulations were evaluated rheologically. Drug delivery properties of poloxamers loaded with diclofenac sodium were evaluated using snakeskin dialysis membranes, intact porcine ear skin, and porcine ear skin impaired via tape stripping. A commercial gel product and a solution of diclofenac sodium in water were used as control formulations. Poloxamer concentration and gelation temperature varied inversely, and the addition of higher concentrations of diclofenac sodium correlated to significant increases in poloxamer gelation temperature. Poloxamer solutions were effective in limiting the permeation of diclofenac sodium through membranes with impaired barrier properties, and delivery of diclofenac sodium from poloxamer 407 did not vary significantly from delivery observed from the commercial gel product. The amount of drug delivered in 24 h did not change significantly with changes in poloxamer 407 concentration. The results of this study indicate that poloxamer 407 may be a useful formulation component for administration of an analgesic product to a chronic wound site. Full article
(This article belongs to the Special Issue Topical Drug Delivery in the Treatment of Pain)
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16 pages, 2758 KiB  
Article
Drug-Nutraceutical Co-Crystal and Salts for Making New and Improved Bi-Functional Analgesics
by Oli Abate Fulas, André Laferrière, Ghada Ayoub, Dayaker Gandrath, Cristina Mottillo, Hatem M. Titi, Robin S. Stein, Tomislav Friščić and Terence J. Coderre
Pharmaceutics 2020, 12(12), 1144; https://doi.org/10.3390/pharmaceutics12121144 - 26 Nov 2020
Cited by 7 | Viewed by 3181
Abstract
The discovery and development of effective analgesics is greatly lagging behind the steadily rising prevalence of chronic pain. Currently prescribed analgesics for chronic pain are lacking in efficacy mainly due to their narrowly-targeted mechanism of action. Driving neuronal hyperexcitability that underlies symptoms of [...] Read more.
The discovery and development of effective analgesics is greatly lagging behind the steadily rising prevalence of chronic pain. Currently prescribed analgesics for chronic pain are lacking in efficacy mainly due to their narrowly-targeted mechanism of action. Driving neuronal hyperexcitability that underlies symptoms of chronic pain are multiple non-neuronal processes, among which are tissue hypoxia and oxidative stress. Here we demonstrate the design, synthesis, and activity of new multi-component bi-functional analgesic crystalline solids, co-crystals, and salts, based on pairing of vasodilatory anti-hypoxic drugs pentoxifylline, clonidine and linsidomine with antioxidant nutraceuticals protocatechuic acid, α-lipoic acid, and caffeic acid. After validation, chemical and structural characterization of these novel salts and co-crystals, topical formulations of the products were tested in a rat model of complex regional pain syndrome. Analgesic effects achieved with the salts and co-crystal exceeded the efficacy and/or potency of constituent compounds indicating that more effective, advanced analgesics can readily be developed by careful pairing of compounds that simultaneously target multiple neural and non-neural processes driving chronic pain. Full article
(This article belongs to the Special Issue Topical Drug Delivery in the Treatment of Pain)
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Review

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17 pages, 1881 KiB  
Review
Natural Herbal Non-Opioid Topical Pain Relievers—Comparison with Traditional Therapy
by Dalia M. Kopustinskiene, Urte Bernatonyte, Yuliia Maslii, Nataliia Herbina and Jurga Bernatoniene
Pharmaceutics 2022, 14(12), 2648; https://doi.org/10.3390/pharmaceutics14122648 - 29 Nov 2022
Cited by 7 | Viewed by 4653
Abstract
Pain is the predominant symptom of many clinical diseases and is frequently associated with neurological and musculoskeletal problems. Chronic pain is frequent in the elderly, causing suffering, disability, social isolation, and increased healthcare expenses. Chronic pain medication is often ineffective and has many [...] Read more.
Pain is the predominant symptom of many clinical diseases and is frequently associated with neurological and musculoskeletal problems. Chronic pain is frequent in the elderly, causing suffering, disability, social isolation, and increased healthcare expenses. Chronic pain medication is often ineffective and has many side effects. Nonsteroidal over-the-counter and prescription drugs are frequently recommended as first-line therapies for pain control; however, long-term safety issues must not be neglected. Herbs and nutritional supplements may be a safer and more effective alternative to nonsteroidal pharmaceuticals for pain management, especially when used long-term. Recently, topical analgesic therapies have gained attention as an innovative approach due to their sufficient efficacy and comparatively fewer systemic side effects and drug–drug interactions. In this paper, we overview the main natural herbal pain relievers, their efficacy and safety, and their potential use as topical agents for pain control. Although herbal-derived medications are not appropriate for providing quick relief for acute pain problems, they could be used as potent alternative remedies in managing chronic persistent pain with minimal side effects. Full article
(This article belongs to the Special Issue Topical Drug Delivery in the Treatment of Pain)
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24 pages, 1498 KiB  
Review
Transient Receptor Potential Channels: Important Players in Ocular Pain and Dry Eye Disease
by Darine Fakih, Tiffany Migeon, Nathan Moreau, Christophe Baudouin, Annabelle Réaux-Le Goazigo and Stéphane Mélik Parsadaniantz
Pharmaceutics 2022, 14(9), 1859; https://doi.org/10.3390/pharmaceutics14091859 - 2 Sep 2022
Cited by 17 | Viewed by 3613
Abstract
Dry eye disease (DED) is a multifactorial disorder in which the eyes respond to minor stimuli with abnormal sensations, such as dryness, blurring, foreign body sensation, discomfort, irritation, and pain. Corneal pain, as one of DED’s main symptoms, has gained recognition due to [...] Read more.
Dry eye disease (DED) is a multifactorial disorder in which the eyes respond to minor stimuli with abnormal sensations, such as dryness, blurring, foreign body sensation, discomfort, irritation, and pain. Corneal pain, as one of DED’s main symptoms, has gained recognition due to its increasing prevalence, morbidity, and the resulting social burden. The cornea is the most innervated tissue in the body, and the maintenance of corneal integrity relies on a rich density of nociceptors, such as polymodal nociceptor neurons, cold thermoreceptor neurons, and mechano-nociceptor neurons. Their sensory responses to different stimulating forces are linked to the specific expression of transient receptor potential (TRP) channels. TRP channels are a group of unique ion channels that play important roles as cellular sensors for various stimuli. These channels are nonselective cation channels with variable Ca2+ selectivity. TRP homologs are a superfamily of 28 different members that are subdivided into 7 different subfamilies based on differences in sequence homology. Many of these subtypes are expressed in the eye on both neuronal and non-neuronal cells, where they affect various stress-induced regulatory responses essential for normal vision maintenance. This article reviews the current knowledge about the expression, function, and regulation of TRPs in ocular surface tissues. We also describe their implication in DED and ocular pain. These findings contribute to evidence suggesting that drug-targeting TRP channels may be of therapeutic benefit in the clinical setting of ocular pain. Full article
(This article belongs to the Special Issue Topical Drug Delivery in the Treatment of Pain)
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11 pages, 287 KiB  
Review
Efficacy and Safety of Topical Morphine: A Narrative Review
by Krzysztof Nosek, Wojciech Leppert, Łukasz Puchała and Krzysztof Łoń
Pharmaceutics 2022, 14(7), 1499; https://doi.org/10.3390/pharmaceutics14071499 - 19 Jul 2022
Cited by 9 | Viewed by 4078
Abstract
Background. Opioids are the cornerstone of the therapy used in both acute and chronic pain syndromes to treat pain of moderate to severe intensity. The knowledge that opioid receptors also occur in other tissues outside the central nervous system has created a possibility [...] Read more.
Background. Opioids are the cornerstone of the therapy used in both acute and chronic pain syndromes to treat pain of moderate to severe intensity. The knowledge that opioid receptors also occur in other tissues outside the central nervous system has created a possibility for the topical use of opioids. Thus, local analgesia may be obtained without systemic adverse effects. Methods. A narrative review of scientific papers discussing the topical use of morphine was conducted. For this purpose, the PubMed, Google Scholar, Cochrane Library, and Mendeley databases were searched. Results. The current knowledge on topical morphine does not allow for its recommended use in everyday medical practice, but suggests it may be effective, particularly in the treatment of ulcers and erosions of inflammatory etiology and painful skin lesions including persistent post-mastectomy pain due to breast cancer. Conclusions. Topical morphine has its place beside other analgesics. An important issue is the practical possibility to meet the demand for topical formulations, which is limited by technical difficulties. Full article
(This article belongs to the Special Issue Topical Drug Delivery in the Treatment of Pain)
37 pages, 1127 KiB  
Review
Topical Treatments and Their Molecular/Cellular Mechanisms in Patients with Peripheral Neuropathic Pain—Narrative Review
by Magdalena Kocot-Kępska, Renata Zajączkowska, Joanna Mika, David J. Kopsky, Jerzy Wordliczek, Jan Dobrogowski and Anna Przeklasa-Muszyńska
Pharmaceutics 2021, 13(4), 450; https://doi.org/10.3390/pharmaceutics13040450 - 26 Mar 2021
Cited by 29 | Viewed by 9219
Abstract
Neuropathic pain in humans results from an injury or disease of the somatosensory nervous system at the peripheral or central level. Despite the considerable progress in pain management methods made to date, peripheral neuropathic pain significantly impacts patients’ quality of life, as pharmacological [...] Read more.
Neuropathic pain in humans results from an injury or disease of the somatosensory nervous system at the peripheral or central level. Despite the considerable progress in pain management methods made to date, peripheral neuropathic pain significantly impacts patients’ quality of life, as pharmacological and non-pharmacological methods often fail or induce side effects. Topical treatments are gaining popularity in the management of peripheral neuropathic pain, due to excellent safety profiles and preferences. Moreover, topical treatments applied locally may target the underlying mechanisms of peripheral sensitization and pain. Recent studies showed that peripheral sensitization results from interactions between neuronal and non-neuronal cells, with numerous signaling molecules and molecular/cellular targets involved. This narrative review discusses the molecular/cellular mechanisms of drugs available in topical formulations utilized in clinical practice and their effectiveness in clinical studies in patients with peripheral neuropathic pain. We searched PubMed for papers published from 1 January 1995 to 30 November 2020. The key search phrases for identifying potentially relevant articles were “topical AND pain”, “topical AND neuropathic”, “topical AND treatment”, “topical AND mechanism”, “peripheral neuropathic”, and “mechanism”. The result of our search was 23 randomized controlled trials (RCT), 9 open-label studies, 16 retrospective studies, 20 case (series) reports, 8 systematic reviews, 66 narrative reviews, and 140 experimental studies. The data from preclinical studies revealed that active compounds of topical treatments exert multiple mechanisms of action, directly or indirectly modulating ion channels, receptors, proteins, and enzymes expressed by neuronal and non-neuronal cells, and thus contributing to antinociception. However, which mechanisms and the extent to which the mechanisms contribute to pain relief observed in humans remain unclear. The evidence from RCTs and reviews supports 5% lidocaine patches, 8% capsaicin patches, and botulinum toxin A injections as effective treatments in patients with peripheral neuropathic pain. In turn, single RCTs support evidence of doxepin, funapide, diclofenac, baclofen, clonidine, loperamide, and cannabidiol in neuropathic pain states. Topical administration of phenytoin, ambroxol, and prazosin is supported by observational clinical studies. For topical amitriptyline, menthol, and gabapentin, evidence comes from case reports and case series. For topical ketamine and baclofen, data supporting their effectiveness are provided by both single RCTs and case series. The discussed data from clinical studies and observations support the usefulness of topical treatments in neuropathic pain management. This review may help clinicians in making decisions regarding whether and which topical treatment may be a beneficial option, particularly in frail patients not tolerating systemic pharmacotherapy. Full article
(This article belongs to the Special Issue Topical Drug Delivery in the Treatment of Pain)
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