In the latest installment in our series on opioid-free pain care, Sergey Motov talks about the expanding role of topical analgesics. Interview by Nick Genes, MD, PhD.
Nicholas Genes: There’s this perception—among patients and even among emergency physicians—that pain requires pills, or if it’s bad enough, an IV. I’m not sure where that comes from, but I sense it. And yet, topical analgesics work well for a variety of conditions and usually carry fewer side effects.
Sergey Motov: Yes, topical analgesics represent an attractive option for managing a variety of acute painful conditions that are underutilized in the ED. These include musculoskeletal pain such as sprains, strains, overuse injuries, contusions, and tendinopathies, as well as acute neuropathic pain like post-herpetic neuralgia, burns, and even acute flares of RA and OA [1-5]. The analgesic efficacy of topical preparations is comparable to their oral equivalents and for certain painful syndromes even to parenteral equivalents but without systemic adverse effects. Of note, topical NSAIDs in particular have the ability to accumulate in cartilages/meniscus with a concentration four to seven times higher than in plasma and in tendons with concentration 100-fold higher than in systemic circulation [1,2]. You’re getting efficient and painless medication delivery, reduced side effects, and improved patients’ adherence and acceptance. In addition, topical agents avoid first-pass metabolism, so you get direct access to the target site, short-lived and minimal adverse effects, and the ease of dose termination [1,2].
Genes: So are topical analgesics for everyone, or should I focus on a certain kind of patient?
Motov: Well, according to McCarberg et al., topical analgesic therapies are particularly useful in patients with more than one chronic condition and older patients because we want to limits the potential for systemic drug–drug interactions. We also think about topical agents for patients with cardiovascular and gastrointestinal risk factors that limit the use of oral NSAIDs and patients with renal or hepatic dysfunction (because they have impaired systemic drug metabolism and clearance) .
Genes: When I’m recommending these drugs to patients, I find myself saying things like, “the medication finds its way in and acts directly on the pain.” My understanding of their mechanism of action really isn’t much more sophisticated than that. But how do these drugs work – what’s really going on?
Motov: Structurally, topical analgesics are embedded in the delivery agent (vehicle) medium that has both hydrophilic and hydrophobic elements. This allows for maximum penetration through the stratum corneum of the skin, and ends up targeting cutaneous nociceptors (unmyelinated C-nerve fibers) [1,2]. The systemic concentration of topical analgesics is minimal. Peak plasma levels range from 0.2% to 8% of the oral route, and systemic absorption rate is just 3% to 5% of the oral route .
Genes: And the different kinds of medication delivered topically – how do the patches help the process?
Motov: Lidocaine formulations, such as the 5% lidocaine patch, alleviate pain (primarily neuropathic pain) by decreasing ectopic discharges from injured cutaneous nerves and nociceptors and blocking voltage-gated sodium channels. The patch has two layers. The outer layer (flannel backing) releases the medication over 12 hours, and the inner layer has a 5% lidocaine suspended in adhesive material. The maximum number of patches to be used at a single time is two, though there are reports of safe use up to four patches [1,2]. Similarly, topical diclofenac epolamine 1.3%, known as Flector Patch, can be placed over the site of a sprain, strain, or contusion. The patch contains an outer layer of polyester felt and an inner adhesive layer that contains 1.3% of diclofenac epolamine imbedded in polymeric hydrogel. The felt backing prevents drying of the hydrogel layer and hydrates the area of skin covered by the patch. The hydrogel enhances the absorption of the medication, allowing release over 12 hours [1,2,5,6]. There are different types of topical analgesics that exist: Gels and Liquids (diclofenac sodium 1% gel (Voltaren Gel, diclofenac sodium topical solution 1.5% with dimethyl sulfoxide (Pennsaid)); Patches (lidocaine 5% patch, diclofenac epolamine patch 1.3% (Flector)); and Creams and Ointments (Lidocaine cream 3%-5%, Lidocaine/Prilocaine cream 2.5%, and Lidocaine ointment 5%) [1,2].
Genes: I see you don’t have BenGay on that list. I recall a salicylate poisoning case about a decade ago. Is the risk not worth the benefit? Do topical NSAIDs or lidocaine post similar risks, if used excessively?
Motov: Topical NSAIDs (not salicylate containing) have not yet been reported in the literature as a cause of death or major adverse effects in adult patients. There are case reports of fatal cardiac arrhythmias and intractable seizures in pediatric patients from ingesting lidocaine creams or patches. However, for adult patients who follow the directions, risks of major side effects are negligible. As an example, lidocaine 5% patch contains 700mg of lidocaine, however, after 12 hours of application to an injured area, about 660 mg still remains in the patch, as the systemic absorption is very low. So even simultaneous application of four patches for 12 hours will keep an adult outside of the toxic range of Lidocaine. However, ingestions, applying the patches to mucosal surfaces, or putting heating pads over these patches will lead to overdoses and potentially bad outcomes. Several topical menthol or methylsalicylate patches are available over the counter, and are safe and effective when used according to package directions. IcyHot is 7.5% menthol; Salonpas is 10% methyl salicylate and 3% menthol; BenGay Original contains 18.3% methylsalicylate and 16% menthol. These agents should not be used with heating pads, because the heat causes systemic absorption. One case report described local skin necrosis and interstitial nephritis from topical methylsalicylate and menthol. Over-use of topical patches or lotions can result in salicylism and menthol toxicity. Also, BenGay should be kept away from children as its oral ingestion can have dire consequences.
Genes: Okay. Let’s dive into the literature on these drugs’ efficacy for specific indications.
Motov: Topical NSAIDs are primarily used for acute musculoskeletal pain (sprain, strain, overuse injuries, contusions, tendinopathies) and exacerbations of osteoarthritis. These meds are available topically as creams, gels, patches, plasters, and solutions with Diclofenac, Ketoprofen, Ibuprofen, and Methylsalicylate being most commonly used [5-7]. When it comes to reporting adverse effects, the most common for topical NSAIDs include pruritus, erythema, and skin rash [5-6]. Topical NSAIDs were found to be superior to placebo for patients with acute pain related to minor sports injuries, and the lack of systemic side effects and minor side effects were comparable to placebo [7-12]. A meta-analysis of 26 randomized controlled trials with nearly 3000 patients demonstrated analgesics superiority of topical NSAIDs in comparison to placebo with NNT of 3.8 (19/26 trials). What’s more, in three trials, topical NSAIDs had compared similarly to oral NSAIDs.
Ketoprofen has been found to be most effective topical analgesic in acute pain, with lack of systemic and local adverse effects . A Cochrane systematic review of 61 randomized controlled trials compared topical NSAIDs to placebo, and active treatment groups showed significantly higher rates of clinical success (more participants with at least 50% pain relief) than matching topical placebos with diclofenac, ibuprofen, and ketoprofen gel formulations providing the best results .
When deciding whether or not to prescribe oral NSAID, the fact that topical NSAIDs often work just as well as oral really ought to be a consideration in the ED.
When it comes to chronic (neuropathic) pain, the administration of topical NSAIDs for two weeks resulted in lower overall visual pain score and a decrease in burning pain in comparison to placebo group [12,13]. A systematic review and meta-analysis of 14 randomized controlled trials demonstrated significantly better pain relief (defined as reduction of pain by 50% at two weeks) in patients receiving topical NSAIDs than a placebo group, with 6% of patients in both groups experiencing minor local side effects .
Genes: So Ketoprofen gel works well, but I can’t find it on GoodRx.com, and the other topical NSAIDs (Voltaren, Pennsaid) are somewhat expensive ($25-$50 a tube for Voltaren, $100-200 or so for Pennsaid). What’s your strategy?
Motov: This is the painful reality in the US: Very effective and safe analgesics are not covered by majority of insurance companies, and the sale price is unaffordable by the majority of patients that I see in my ED (and probably in all EDs across the country). My strategy is to make a reasonable effort to see if a patient’s insurance covers any of the topical NSAIDs, and if not, to recommend the use of methysalicylate-containing OTC preparations (BenGay, IcyHot) or to prescribe lidocaine-containing topical formulary (patches, creams, ointments).
Genes: Turning to the evidence for lidocaine…
Motov: In an acute pain setting, an application of 5% lidocaine to the area of intact skin of patients with acute herpetic neuralgia resulted in significantly greater overall pain relief and intensity (in comparison to placebo) at rest and movement with minimal rates of AE . An application of topical lidocaine patch to patients with acute and subacute low back pain for six weeks demonstrated significant decrease in daily pain intensity at weeks two and six, with less pain interference with quality of life at weeks two and six, and satisfaction of treatment in nearly 60% of patients .
In patients with chronic neuropathic pain (post-herpetic neuralgia (PHN) and diabetic peripheral neuropathy (DPN)), administration of 5% Lidocaine patch in comparison to Pregabalin resulted in higher pain intensity response, longer lasting analgesia, greater patient’s satisfaction and lack of systemic adverse effects in patients with PHN and similar analgesic efficacy in patients with DPN [16,17]. Similarly, an application of 5% lidocaine patch for an average of six weeks to patients with refractory peripheral neuropathic pain conditions with reported intolerable side effects or inadequate pain relief with antidepressant, anticonvulsant, antiarrhythmic, and opioids resulted in moderate-to-better pain relief in 81% of patients with mild skin irritation experienced by one patient .
Genes: Topical lidocaine patches are expensive, too (GoodRx coupons take it to $100 for 30 patches). I’ve heard you can give a patient some viscous lidocaine, gauze, and a tegederm. Is that a strategy?
Motov: The fact that a lidocaine 5% patch is insanely expensive and is not covered by majority of insurance companies is mind-boggling. You can try to get a pre-authorization, but the only indication allowed is neuropathic pain, and this is hard to do from the ED. But, fortunately for us, the lidocaine 4% patch is widely available over-the-counter in major drug stores (Walmart, Target, Walgreens, CVS) and online (Amazon). The price for six patches ranges from few dollars to $11-12 dollars. On Amazon, you can get 60 patches for $6. And I bet the 4% patch as effective as 5%.
In regards to viscous lidocaine, gauze and tegederm, you can use it to numb the skin before laceration repair or IV insertion if you are out of EMLA or LET. This formulary works best on mucosal membranes (mouth, throat), and I would not recommend its use for dermal applications. The 2% lidocaine cream/ointment is a viable alternative to 5% patch, although it may not result in similar amount of lidocaine being delivered to the injured tissues.
Genes: Let’s talk about everyone’s favorite, capsaicin. Patients look at me funny when I say I’m giving them something derived from a chili pepper. When should I reach for capsaicin instead of a topical NSAID or lidocaine?
Motov: Capsaicin is a natural alkaloid that is extracted from hot chili peppers. It is available in multiple over-the-counter formulations (gels, creams, liquids, lotions, and transdermal patches) and concentrations, ranging from 0.025% to 0.15%. The indications of its use include backache, strains, sprains, bruises, cramps, arthritis, or diabetic neuropathy. The 8% capsaicin patch (only by prescriptions) is approved for post-herpetic neuralgia pain. One of most distressing side effects of topical capsaicin is an intense burning and pain at the application site that is experienced by 80% of patients and forces about 40% of patients to stop the treatment . Some sources even recommend pre-treating a skin with topical lidocaine before applying capsaicin!
A systematic review of topical capsaicin for treatment of chronic pain that included nine randomized controlled trials with over 1000 patients demonstrated overall good analgesics efficacy (defined as NNT for 50% of pain reduction) for neuropathic and musculoskeletal pain with NNT of 5.7 and 8.1, respectively. However, 35% of those patients experienced local skin irritation .
Genes: Anyone handling capsaicin should be careful, correct? I washed my hands after applying it to a patient, but later when I rubbed my eye I felt a horrible burn. It only lasted a few seconds, but it was memorable. I went from thinking that I’d need to activate sick call, to thinking I was going to die.
Motov: The burning from capsaicin really is unbearable when it gets into eyes and mucous membranes. Your story with your eye is not uncommon. I once read about a guy applying capsaicin, then later using the bathroom to urinate without thoroughly cleaning his hands. You can imagine what he went through!
For applications of capsaicin-containing creams or ointments, you must use gloves. After applying patch, wash your hands with warm water and soap. Should intense burning occur at the site of application, promptly remove the capsaicin and liberally cover the affected area with ice cream, yogurt, cottage cheese, or milk. Yes, it sounds strange, but that’s the recommendation.
Genes: So when treating zoster, have some dairy products close by. Got it. What other take-home points are you suggesting?
Motov: To sum everything up, topical analgesics are invaluable in providing safe and effective pain relief for ED patients with a variety of acute and chronic painful conditions. The role of topical meds in alleviating pain becomes even more important when patients can’t tolerate oral or IV analgesics due to co-morbidities or potentially severe drug-drug interactions. ED clinicians should consider utilizing topical analgesics in daily practice whether alone or as a part of multimodal pain relief approach.
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