Postgraduate Medicine

ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20

The Pharmacology of Topical Analgesics Robert L. Barkin To cite this article: Robert L. Barkin (2013) The Pharmacology of Topical Analgesics, Postgraduate Medicine, 125:sup1, 7-18, DOI: 10.1080/00325481.2013.1110566911 To link to this article: http://dx.doi.org/10.1080/00325481.2013.1110566911

Published online: 16 Jul 2015.

Submit your article to this journal

Article views: 19

View related articles

Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [Umeå University Library]

Date: 19 February 2016, At: 04:24

The Pharmacology of Topical Analgesics

Downloaded by [Umeå University Library] at 04:24 19 February 2016

Robert L. Barkin, PharmD, MBA, FCP 1 1 Professor, Departments of Anesthesiology, Family Medicine, and Pharmacology, Rush University Medical College, Chicago, IL; Clinical Pharmacologist, Department of Anesthesiology, North Shore University Health System Pain Management Centers, Skokie Hospital, Skokie, IL, and Evanston Hospital, Evanston, IL

Abstract: Pain management of patients continues to pose challenges to clinicians. Given the multiple dimensions of pain―whether acute or chronic, mild, moderate, or severe, nociceptive or neuropathic―a multimodal approach may be needed. Fortunately, clinicians have an array of nonpharmacologic and pharmacologic treatment choices; however, each modality must be chosen carefully, because some often used oral agents are associated with safety and tolerability issues that restrict their use in certain patients. In particular, orally administered nonsteroidal antiinflammatory drugs, opioids, antidepressants, and anticonvulsants are known to cause systemic adverse effects in some patients. To address this problem, a number of topical therapies in various therapeutic classes have been developed to reduce systemic exposure and minimize the risks of patients developing adverse events. For example, topical nonsteroidal anti-inflammatory drug formulations produce a site-specific effect (ie, cyclo-oxygenase inhibition) while decreasing the systemic exposure that may lead to undesired effects in patients. Similarly, derivatives of acetylsalicylic acid (ie, salicylates) are used in topical analgesic formulations that do not significantly enter the patient’s systemic circulation. Salicylates, along with capsaicin, menthol, and camphor, compose the counterirritant class of topical analgesics, which produce analgesia by activating and then desensitizing epidermal nociceptors. Additionally, patches and creams that contain the local anesthetic lidocaine, alone or co-formulated with other local anesthetics, are also used to manage patients with select acute and chronic pain states. Perhaps the most common topical analgesic modality is the cautious application of cutaneous cold and heat. Such treatments may decrease pain not by reaching the target tissue through systemic distribution, but by acting more directly on the affected tissue. Despite the tolerability benefits associated with avoiding systemic circulation, topically applied analgesics are associated with application-site reactions in patients, such as dryness, erythema, burning, and discoloration. Furthermore, some adverse events that have been observed in patients may be suggestive of some degree of systemic exposure. This article reviews the mechanisms of action, pharmacokinetics, and tolerability of topical treatments for the management of patient pain. Keywords: pain; analgesics; topical analgesics; nonsteroidal anti-inflammatory drugs; NSAIDs; topical NSAIDs

Introduction

Correspondence: Robert L. Barkin, PharmD, MBA, FCP, North Shore University Health System Pain Management Center, Skokie Hospital, 9701 Knox Ave., Suite 103, Skokie, IL 60076. Tel: 847-933-6974 Fax: 847-933-6044 E-mail: [email protected]

Pain is not only the most common symptom that causes patients to seek medical attention, but also an important source of diagnostic clues for clinicians.1 Classification of pain states on the bases of duration (acute or chronic), intensity (mild, moderate, or severe), and etiology (nociceptive or neuropathic) help guide the clinician’s understanding of a patient’s presenting pain symptoms and inform the decision process for providing appropriate treatment.1 Acute pain is often associated with an identifiable patient injury or inflammation that resolves as the underlying pathology heals. In contrast, chronic pain is generally defined as patient pain that persists beyond the expected healing period and becomes

© Postgraduate Medicine, Volume 125, Issue 4, Suppl 1, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 7 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected]

Downloaded by [Umeå University Library] at 04:24 19 February 2016

Robert L. Barkin

pathological on its own.1 Pain intensity may be quantified on a 0 to 10 numerical scale by patients’ self-rated scores of 1 to 3 (mild pain), 4 to 5 (moderate pain), or $ 6 (severe pain).1 With respect to etiology, pain states are often categorized as neuropathic, nociceptive, or a mixture of the 2.2 Neuropathic pain stems from certain diseases (eg, diabetes, complex regional pain syndrome, multiple sclerosis, or herpes zoster) or injuries (eg, trauma due to surgery) that impact the somatosensory system.2,3 In contrast, nociceptive pain is caused by noxious mechanical, chemical, or thermal stimuli that produce actual tissue damage.2 In patients, such damage stimulates both peripheral inflammation and the release of inflammatory mediators by nociceptive nerve fibers, the peripheral endings of Aδ and C fibers.2 The 4 cardinal signs of inflammation are pain, redness, swelling, and warmth.4 Given the multiple dimensions of pain, the goals for management of patient pain begin with reducing pain sensations and improving a patient’s functional status, mood, and quality of life.1 Accordingly, multidisciplinary approaches are used to achieve these goals, include nonpharmacologic and pharmacologic therapies, which may be used alone or in combination.1 Reductions in patient pain sensation may be achieved through administration of medications that act as analgesics. Analgesics include the opioids, acetaminophen, and antidepressants (ie, tricyclic antidepressants [TCAs]; serotonin-norepinephrine reuptake inhibitors [SNRIs]; serotonin-specific reuptake inhibitors [SSRIs], and anticonvulsants), which reduce activity in pain pathways. Conversely, anti-inflammatory agents (eg, aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs], and corticosteroids) modulate both patient pain and inflammatory pathways, while treatment modalities that work through anesthesia (eg, lidocaine, capsaicin, cold) reduce pain by diminishing sensations.1,5–9 Various opioid and NSAID formulations, as well as acetaminophen have established roles in the management of patients with acute and chronic pain,7 however, oral administration of these agents is known to increase patient risk of experiencing numerous potentially serious adverse events, including gastric bleeding with non-selective NSAIDs, cardiovascular events with selective cyclooxygenase (COX)-2 inhibitors and some non-selective NSAIDs, hepatotoxicity with acetaminophen, and constipation, sedation, nausea, vomiting, hypotension, and respiratory depression with opioids.7 Pain-relieving formulations that use alternate routes of administration (eg, transdermal, rectal, subcutaneous, 8

intranasal, transmucosal, sublingual, and intravenous) have been developed as alternatives to oral administration for producing systemic analgesia in patients.5,7,10 Transdermal patches, for example, have been developed to deliver doses of opioids that are high enough to produce systemic analgesia while bypassing gastrointestinal (GI) absorption, thus potentially lessening the likelihood of adverse events associated with oral administration.5,7,11 In contrast, topical administration is intended to provide the patient with locally effective drug concentrations with a lower degree of systemic exposure and, presumably, a lower risk of systemic adverse effects relative to systemic delivery via oral or transdermal means.11 The skin is the largest, most easily accessible human organ, and has long been considered a viable option for the administration of pharmaceutical agents to treat patient external epidermal conditions, and conditions that affect local subcutaneous tissues, producing systemic effects.12 A topically administered agent with an intended site of action below the surface of the skin must first pass through the thick outer layers of the stratum corneum, which protects the live epidermis from noxious external stimuli.6 Therefore, an agent that is suitable for topical administration should have properties conducive to cutaneous absorption, including hydrophilia, lipophilia, and low molecular weight and volume, characteristics that aid the drug in more efficiently reaching the intended target tissue.12,13 Effective topical agents must also diffuse widely in the stratum corneum and have a low binding potential.12 Agents lacking properties that are conducive to optimal cutaneous absorption may require the addition of a penetration enhancer, such as dimethyl sulfoxide (DMSO), lecithin, or a mixture of ethanol and water.14–16 As noted, it is thought that topical administration of a pharmaceutical agent may have some patient benefits compared with oral administration, including avoiding drug absorption through the GI tract and limiting first-pass metabolism. The degree of systemic exposure observed with topical application is therefore substantially diminished compared with the systemic exposure observed with an orally administered agent, while producing clinically effective concentrations in target tissues.13,17 Importantly, the reduction in exposure attributed to topical administration reduces the risks for the development of tolerability and safety issues associated with substantial patient systemic exposure with some agents prescribed for the treatment of pain.6,17 However, inter-individual variations in skin permeability and the activity of cutaneous enzymes, as well as the differences in absorption rates between healthy

© Postgraduate Medicine, Volume 125, Issue 4, Suppl 1, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected]

Downloaded by [Umeå University Library] at 04:24 19 February 2016

Pharmacology of Topical Analgesics

and diseased skin, may also alter patient exposure to topically applied agents.13,17 Analgesics have many characteristics that are conducive to topical use, including a potential site of action that is in proximity to the affected, painful area and the outer layers of the skin, known as “site-specific activity.” The epidermis contains nociceptors, such as unmyelinated C fibers, that are involved with slow conduction or “second” pain perception, whereas the dermis contains myelinated Aδ fibers that are involved in “first” or “fast” pain perception.6,7 There are a variety of topically applied analgesics from which physicians can choose for managing patient pain.6,18–21 Several treatment guidelines and systematic reviews of topical analgesics have supported the efficacy of these agents for treating a variety of acute and chronic pain syndromes, particularly for patients with risk factors that can compound systemically derived adverse events from the use of orally administered analgesics.22–24 We review the mechanisms of action, pharmacokinetics, and tolerability of several topical formulations of NSAIDs, counter-irritants (eg, capsaicin, salicylates, menthol, and camphor), and sodium/potassiumchannel-blocking anesthetics (eg, lidocaine), along with the application of cold or heat for patient pain management.

Nonsteroidal Anti-inflammatory Drugs

Topical NSAID formulations were, in part, developed to improve upon the safety and tolerability of oral NSAIDs by decreasing systemic exposure (while still producing antiinflammatory analgesic effects) by more directly targeting affected tissues. Topical NSAID formulations, such as ketoprofen, diclofenac, and ibuprofen, have an extensive history of use in the European Union, and, as a result, are recommended by a number of treatment guidelines for managing patients with musculoskeletal pain.19 However, topical NSAID formulations, such as diclofenac sodium 1% gel, diclofenac sodium 1.5% topical solution in 45.5% DMSO, and diclofenac epolamine patch 1.3%, have received regulatory approval for use in the United States (Table 1).25–27

varying degrees. For example, ibuprofen is non-selective and inhibits both COX enzymes to a nearly equivalent degree, while ketoprofen is a more selective COX-1 inhibitor, and diclofenac is more selective for COX-2  inhibition.28 The majority of cells in the body express COX-1, including gastric epithelial cells. As a result, inhibition of COX-1 has been attributed to GI adverse events, including nausea and gastric ulcers, that have been linked to treatment with oral NSAIDs.28 In addition, NSAIDs can have other physiologic effects, such as inhibiting leukotriene synthesis, which may also increase patient risk for GI damage.29 For example, diclofenac is also a putative inhibitor of leukotriene activity.30,31 More specifically induced at the site of tissue inflammation, COX-2 is thought to have greater relevance in regulating the inflammatory processes.27 Consequently, selective COX-2  inhibitors were developed to produce the desired anti-inflammatory and analgesic effects of non-selective NSAIDs, while decreasing but not eliminating the risk of developing GI adverse events associated with non-selective COX inhibitors. 27 Since COX-2 also has substantial expression in cardiovascular tissue, use of the selective COX-2 inhibitors have been linked to patient development of serious cardiovascular safety issues, including stroke and myocardial infarction.27,32 Additionally, the COX enzymes are involved with mediating renal function; therefore, the use of non-selective NSAIDs or selective COX-2  inhibitors can lead to renal toxicity in patients and may not be appropriate for patients with impaired renal functioning (ie, those with a creatinine clearance , 50 mL/min).23,33 There are also considerations for using COX inhibitors in patients who have increased hepatic risk because elevations in liver enzymes have been observed infrequently with the use of NSAIDs.33 As patients age, their overall risk for end-organ damage and the occurrence of comorbidities increase significantly. Therefore, the use of COX inhibitors should only be considered in the elderly when a thorough medical history has been taken and appropriate risk-mitigation and patient monitoring strategies have been implemented.33

Mechanism of Action The anti-inflammatory and subsequent analgesic effects of the NSAID class are primarily driven by the inhibition of the COX enzymes.21,28 By suppressing the activity of COX enzymes, NSAIDs secondarily prevent the formation of prostaglandins and thromboxane, which are responsible for regulating inflammatory processes.28 The COX enzymes exist as 2 major subtypes in humans (ie, COX-1 and COX-2), and NSAIDs inhibit the activity of both COX enzymes to

Pharmacokinetics Topical Compared With Oral NSAID Delivery The pharmacokinetics of topically applied NSAIDs have been evaluated on their own and in comparison with orally administered NSAIDs in numerous studies. An analysis of naproxen, diclofenac, and piroxicam applied topically to rats demonstrated that these drugs only penetrate 3 mm to

© Postgraduate Medicine, Volume 125, Issue 4, Suppl 1, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 9 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected]

Robert L. Barkin

Table 1.  Topical Nonsteroidal Anti-inflammatory Drugs Approved for Use in the United States and European Union Generic Name

Brand Name

Dosing

Availability in US Availability in EU Indication (OTC/Prescription) (OTC/Prescription)

Diclofenac sodium 1.5% w/w topical solution Diclofenac sodium 1% gel

Pennsaid

40 drops, 4 times daily

Prescription

Voltaren Gel

Downloaded by [Umeå University Library] at 04:24 19 February 2016

Diclofenac epolamine 1.3% patch Diclofenac 1.16% gel

2 g for elbow, wrist, hand, Prescription 4 times daily 4 g for knee, ankle, foot; 4 times daily Flector Patch 1 patch (180 mg), Prescription 2 times daily Voltaren Emugel 2–4 g on ∼2.0–2.5 cm, 3 or 4 times daily

Prescription

Prescription/OTC

Diclofenac 4% cutaneous spray solution

KWIS

32–40 mg on 0.8–1.0 cm, 3 times daily

Prescription

Diclofenac 1% gel patch

Voltarol

Prescription

Ibuprofen 5% w/w gel

Nurofen

1 patch per day (140 mg), # 3 days (ankle sprains) or # 14 days (epicondylitis) 50–125 mg on 10–25 cm, # 4 times daily

Ibuprofen 10% w/w gel

Nurofen

50–125 mg on 2–5 cm, # 4 times daily

OTC

Ibuprofen 5% w/w aqueous-alcohol gel

Ibugel

1–2.5 g, # 3 times daily

OTC

Ibuprofen 10% w/w aqueous-alcohol gel

Ibugel

50–125 mg on 2–5 cm, # 3 times daily

Prescription

Ibuprofen 5% cream

Dolgit

50–125 mg on 4–10 cm, 3 or 4 times daily

OTC

Ibuprofen 5% w/w aqueous-cutaneous foam

Ibuleve

1–2 g, 3 or 4 times daily

OTC

OTC

For signs and symptoms of knee OA OA of joints amenable to topical treatment, eg, knees, hands Acute pain due to minor strains, sprains, contusions Local, symptomatic relief of pain/inflammation in tendon, ligament, muscle, and joints trauma (sprains, strains, bruises); localized soft-tissue rheumatism Local, symptomatic relief of mild-to-moderate pain/ inflammation after acute, blunt trauma of small- and mediumsized joints and peri-articular structures Local, symptomatic treatment of pain in epicondylitis, ankle sprain Analgesic/anti-inflammatory for backache, non-serious arthritis, rheumatic and muscular pain, sprains, strains, sports injuries, and neuralgia Relief of pain/inflammation associated with backache, mildto-moderate arthritis, rheumatic and muscular pain, sprains, sports injuries, and neuralgia Treatment of backache, rheumatic and muscular pain, sprains, strains, neuralgia; symptomatic relief of pain due to non-serious arthritis Treatment of backache, rheumatic and muscular pain, sprains, strains, neuralgia; symptomatic relief of pain due to non-serious arthritis Analgesic/anti-inflammatory for relief of symptoms of rheumatic pain; muscular aches and pains; backache; lumbago; fibrositis; strains, sprains, and sports injuries Local relief of pain/inflammation in musculoskeletal conditions— backache, rheumatic, muscular pain, sprains, strains, lumbago, fibrositis, neuralgia; symptomatic relief of pain due to non-serious arthritis

(Continued)

10

© Postgraduate Medicine, Volume 125, Issue 4, Suppl 1, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected]

Pharmacology of Topical Analgesics

Downloaded by [Umeå University Library] at 04:24 19 February 2016

Table 1. (Continued) Generic Name

Brand Name

Dosing

Availability in US Availability in EU Indication (OTC/Prescription) (OTC/Prescription)

Ibuprofen 5% w/w topical spray solution

Ibuspray

1–2 mL (5–10 sprays), 3 or 4 times daily

OTC

Ketoprofen 2.5% w/w gel

Oruvail

2–4 g on 5–10 cm, 2 to 4 times daily

Prescription

Felbinac 3.17% w/w cutaneous foam

Traxam

∼1 g on 4 cm, 2 to 4 times daily

Prescription

Felbinac 3% gel

Traxam

1 g on 2.5 cm, 2 to 4 times daily

Prescription/OTC

Piroxicam 0.5% gel

Feldene

1 g on 3 cm, 3 or 4 times daily

Prescription

Local relief of backache; rheumatic pain; muscular aches, pains, sprains, strains, sports injuries Symptomatic relief of pain in soft-tissue injuries, including sport injuries, sprains, strains, musculotendonitis, swelling, backache, pain Relief of rheumatic pain; pain of non-serious arthritis; soft-tissue injury, such as sprains, strains, contusions Relief of rheumatic pain, pain of non-serious arthritis; soft-tissue injuries such as sprains, strains, contusions Conditions characterized by pain, inflammation, or stiffness

Adapted from Barkin RL, Topical nonsteroidal anti-inflammatory drugs: the importance of drug, delivery, and therapeutic outcome. Am J Ther. [Epub ahead of print] PMID: 2236735417 © 2012, with kind permission from Elsevier. Abbreviations: EU, European Union; OTC, over the counter; US, United States.

4 mm into the dermis.34 Predictably, the application of topical NSAIDs results in relatively minimal systemic exposure, compared with the respective oral administrant. An analysis of the bioavailability of topical ibuprofen 5% gel applied to the thigh suggests that , 1% of a single patient dose is excreted in urine, while almost the entire orally administered dose (∼97%) is excreted through the urine.35 However, the location of the drug application site has been shown to affect the amount of drug that enters patient systemic circulation. Shah et al compared the absorption rate of 1 g of ketoprofen 3% gel (30 mg) applied to the back, arm, and knee in 24 healthy male subjects.36 The authors determined that while application to the back and arm produced comparable patient plasma levels of the drug, exposure following application to the knee was significantly lower than at the other application sites (P , 0.05).36 Comparisons of the pharmacokinetics of topical compared with orally delivered NSAID therapy have demonstrated that patient systemic exposure is substantially lower with topically administered NSAID formulations.37 Diclofenac peak plasma concentrations (Cmax) following the application of 16 g of diclofenac sodium 1% gel to 1 knee, and 48 g to both knees and hands, 4 times daily (n = 39) were found to be 15.0  ng/mL and 53.8  ng/mL, respectively, which were both substantially lower than what was observed with orally dispensed diclofenac 150 mg (2270 ng/mL).38 Similarly, the observed area under the plasma concentration curve (AUC)

values collected from 0 to 24 hours (AUC0–24), for the 16 g (233 ng•h/mL) and 48 g (807 ng•h/mL) topical applications, were substantially lower than orally administered diclofenac (3890 ng•h/mL).38 In contrast, the median time to Cmax was longer for patients given topical diclofenac sodium 1% gel compared with patients treated with oral diclofenac, demonstrating that plasma levels rise more gradually with topically administered formulations, compared with orally administered formulations.38 Similarly, the application of topical ibuprofen 5% gel at a dose of 500 mg (10 g to the back) produced a Cmax of 7100 ng/mL and AUC0–24 of 31 000 ng • h/mL in a study of 18 healthy female subjects. The values were substantially higher than previously reported data but significantly lower than the values observed with orally administered ibuprofen 400 mg (Cmax: 36,700 ng/mL; AUC0–24: 114 000 ng • h/mL).39,40 In a study of 6 healthy women subjects, 20 to 48 years of age, Seth40 used a 200-mg dose of ibuprofen 5% gel and reported a Cmax (1.4 µg/mL) and AUC0-last (12.5 µg h/mL) that were substantially lower than those reported by Kleinbloesem et al (7.1 µg/mL and 31.0 µg h/mL, respectively).39 Similar results have been observed with other topical and oral NSAID formulation comparison. For example, twicedaily application of piroxicam 0.5% gel produced steady-state blood plasma concentrations of 300 to 400 ng/mL, which was equivalent to 5% of the amount observed in blood plasma with a 20-mg daily dose of oral piroxicam.41 The diclofenac

© Postgraduate Medicine, Volume 125, Issue 4, Suppl 1, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 11 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected]

Robert L. Barkin

Downloaded by [Umeå University Library] at 04:24 19 February 2016

epolamine patch 1.3% produces diclofenac Cmax ranging from 0.7 to 6 ng/mL, which was , 1% of the patient exposure observed with an oral dose of diclofenac 50 mg.42 Local Compared With Systemic Drug Concentrations Using Topical NSAIDs Topical NSAID administration is intended to deliver higher local cutaneous drug concentrations relative to plasma concentrations to the patient, and several studies have been conducted to evaluate the degree of local and systemic absorption of drug following topical NSAID administration. In contrast to the relatively low plasma levels associated with the use of topical NSAIDs, substantially greater concentrations at the application site have been reported in several pharmacokinetic studies conducted with various topical NSAIDs. For example, after 3 days of treatment with ibuprofen 5% gel applied to the knee, ibuprofen concentrations in patient subcutaneous tissues were significantly higher than the levels measured in blood plasma (P , 0.05) in a study of 17 patients who required surgery for a degenerative knee disorder.42 Additionally, diclofenac concentrations in patient synovial fluid and blood plasma were measured in 10 patients with bilateral knee joint effusions following the 3-times-daily application of 1 g of diclofenac sodium 1% gel to 1 knee and placebo gel to the contralateral knee.43 On day 4, plasma diclofenac concentrations (40.6 ng/mL) were significantly higher than concentrations in synovial fluid for either the diclofenac-treated knees or the placebo-treated knees (25.5 ng/mL or 21.6 ng/mL, respectively; P , 0.01 vs blood plasma concentrations).43 The relatively small differences between knees treated with the active agent and placebo suggests that the majority (85%) of applied drug reaches the synovial fluid through systemic circulation rather than direct transport or diffusion from the skin to the underlying joint.43 The relative degree of local and systemic exposure of various topically applied NSAID formulations continues to be an active research area.44,45 Recent evidence has suggested that topically administered diclofenac forms a depot in subcutaneous fascia or periarticular tissue, from which the drug may be released into the patient joint and systemic circulation over time.46

Tolerability According to analyses of various topical NSAID formulations (that included diclofenac, eltenac, ibuprofen, and piroxicam), the most frequently occurring adverse events in patients involve the application site, such as dryness, pruritus, and contact dermatitis.47,48 Similarly such large-scale tolerability 12

analyses suggest that topically applied NSAIDs present a lower risk for some of the systemically derived adverse events observed in patients taking oral NSAIDs.19,47,49 Specifically, use of topical NSAIDs has been shown to carry a significantly lower risk of GI adverse events (eg, diarrhea, dyspepsia, upper GI bleeding, and perforation) and acute renal failure in patients, compared to the risk associated with use of oral NSAID therapy.23,47,49,50 There have been calls for conducting similar large-scale studies to assess patient risk for cardiovascular-related adverse events, but certain methodologic issues―such as the necessary length of a study to demonstrate an effect, and the relatively limited patient population―may make it challenging to complete such analyses.51,52

Counterirritants

Counterirritants are broadly characterized as agents that cause irritation or inflammation in one area of the body, yet diminish pain in another area.53 The most commonly used counterirritants—capsaicin, salicylates, menthol, and camphor—are the primary active ingredients for a number of topical analgesic formulations (Table 2).13

Capsaicin Topical capsaicin formulations are developed from the alkaloid extract of hot peppers that underlies their spicy flavor.54 Capsaicin has a long history of use for relieving pain and is available in several over-the-counter (OTC) topical analgesics, usually at concentrations of , 1% (Table 2).13,55 Recently, a prescription patch with an 8% capsaicin concentration (Qutenza®), which is only applied under medical supervision, has received Food and Drug Agency (FDA) approval in the United States for treating postherpetic neuralgia (PHN) and regulatory approval in the European Union for the treatment of nondiabetic neuropathic pain.56,57 The manufacturer of the capsaicin 8% patch has also conducted phase 1 and 2 clinical trials to support the development of a 10% weight/weight (w/w) capsaicin lotion for use in patients with PHN.58,59 Mechanism of Action The analgesic effect of topically applied capsaicin products stems from the initial activation and subsequent desensitization and degeneration of patient epidermal nociceptive nerves.54,60 Specifically, capsaicin selectively stimulates afferent C fibers, which causes an initial release and subsequent depletion of substance P, a neuropeptide that is involved with sensory perception.54,61,62

© Postgraduate Medicine, Volume 125, Issue 4, Suppl 1, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected]

Pharmacology of Topical Analgesics

Table 2.  Commonly Used Topical Counterirritant Formulations Product Icy Hot Balm Ben-Gay Ultra Strength Bengay Patch Salon Patch Qutenza Patch* Mineral Ice Capzasin-HP Flexall Ultra Plus Aspercreme

Ingredients (%) Methyl Salicylate

Menthol

Camphor

29 30

7.6 10 1.4

4

Capsaicin

Trolamine Salicylate

0.025 8 2 0.1 10

16

3.1 10

Downloaded by [Umeå University Library] at 04:24 19 February 2016

*Available only by prescription in the United States and European Union. Reprinted from Stanos SP, Tyburski MD. Minor and short-acting analgesics, including opioid combination products. In: Benzon HT, Rathmell JP, W   u CL, Turk DC, Argoff CE, eds. Raj’s Practical Management of Pain. 4th ed. Philadelphia, PA: Elsevier; 2008: 613–641.13 © 2008, with kind permission from Elsevier.

In a study of patients with diabetic neuropathy, treatment with capsaicin 0.05% cream during an 8-week period caused an initial increase and subsequent decrease in circulating levels of substance P.63 Furthermore, Beydoun et al, using laser-evoked nerve stimulation, demonstrated that a capsaicin 0.75% cream applied to the hand, 3 times daily for 5 weeks, reversibly inhibited signal conduction via Aδ fibers in 5 healthy subjects.64 Capsaicin 0.5% cream has also been shown to inhibit the activity of injected bradykinin, a neuropeptide that is involved in the inflammatory process.65 Studies conducted with the capsaicin 8% patch suggest that the mechanism of action of capsaicin instead involves “defunctionalization” of cutaneous nociceptors, which is mediated by sodium ion channel deactivation. In addition, capsaicin causes a direct desensitization of transient receptor potential vanilloid (TRPV) receptors, which leads to a reversible loss of C fibers.57 After capsaicin application is discontinued, a reinnervation of epidermal nerve fibers and a return of sensation are observed. Following 2 days of capsaicin 0.1% cream application, the density and functional activity of autonomic and sensory nerve fibers generally returned to patient baseline levels within 40 to 50 days for autonomic nerves and within 140 to 150 days for sensory nerve fibers.66 Using a human pain model that involved the application of painful, external stimuli (eg, citric acid, hypertonic saline) to the nasal mucosa of 7 healthy subjects, the administration of a compounded topical capsaicin (50 µL containing 50 mmol of capsaicin) during a period of 5 to 7 days initially produced hyperalgesia that was later followed by analgesia to these stimuli.67 Tolerability Over-the-counter formulations containing , 1% capsaicin have not been shown to cause significant systemically

driven adverse events. Patients using such topical capsaicin formulations experience local discomfort, such as burning, stinging, erythema, and coughing, which have been associated with high rates of treatment discontinuation.54,55 The capsaicin 8% patch is also associated with significant reactions at the application site, including pain, pruritus, and swelling. However, some systemically derived adverse events have been observed; in particular, transient and variable elevations in patient blood pressure have been reported during or shortly following patch application. Therefore, health care professionals should consider a patient’s history of cardiovascular events or poorly controlled hypertension before administering the patch.56 Instructions for use of the capsaicin 8% patch also state that application should only be performed under supervision of a physician; the use of a local anesthetic to manage painful application-site reactions is also recommended.56

Salicylates The salicylates, including methyl salicylate, trolamine salicylate, and oil of wintergreen (a liquid form of methyl salicylate), are used in a number of OTC topical analgesic formulations, such as Icy Hot® and BEN-GAY® (Table 2).13,68 Mechanism of Action The analgesic effect of topical salicylate formulations is incompletely understood, but it is not thought to be a function of COX inhibition. In fact, preclinical data have suggested that the level of COX inhibition associated with topically applied salicylates is as much as 100-fold lower than that for acetylsalicylic acid.21,69 Instead, like other counterirritants, the effect of topical salicylates has been attributed to activation and desensitization of cutaneous nerves. However, the means

© Postgraduate Medicine, Volume 125, Issue 4, Suppl 1, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 13 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected]

Robert L. Barkin

Downloaded by [Umeå University Library] at 04:24 19 February 2016

through which topically applied salicylates produce this effect is incompletely understood as well.13,21 Pharmacokinetics As seen with the use of topically applied NSAIDs, topical salicylate treatment produces drug concentrations in patient tissue that are substantially greater than level of drug seen systemically. Tissue levels of topical salicylates (ie, methyl salicylate 20%, triethanolamine salicylate 10%, and glycol salicylate 7%) have been shown to be approximately 30-fold greater than blood plasma concentrations.70 A trial of 9 healthy subjects showed that 5 g of topical methyl salicylate 30% produced levels of platelet inhibition comparable to the inhibition produced with 162 mg of orally administered aspirin,71 suggesting that topically applied salicylates may have clinically significant pharmacodynamic effects that reflect an equivalence to orally administered aspirin in patients.71 Topically applied salicylic acid has been shown to penetrate patient skin to a depth of 3 mm to 4 mm only,72 and, in similar fashion, only an estimated 12% to 20% of an applied dose of methyl salicylates (12%–50%) entered patient systemic circulation 10 hours after the application of a single dose in a study of 5 subjects.73 However, a pharmacokinetic analysis of 5 g of methyl salicylate 12.5% ointment or trolamine salicylate 10% cream applied twice daily to the same location on the patient’s leg produced Cmax values ranging from 2000 to 6000 ng/mL in a study of 12 healthy subjects; this level of exposure was reached on day 4, following the seventh application.74 Furthermore, the absorption rate of methyl salicylate in patients increased from 15% to 22% between the first and seventh administration, suggesting that exposure increases with repeated applications.74 The absorption rate of methyl salicylate is also affected by the application site; the foot (specifically the plantar, heel, and instep areas) predictably absorbs methyl salicylate more slowly than the abdomen and forearm.73 Tolerability The primary safety concern associated with topically applied salicylates involves intentional and unintentional oral ingestion or excessive topical application by patients, which can produce toxicity and poisoning.21,68,75,76 Symptoms of oral salicylate poisoning include nausea, vomiting, hearing loss, respiratory alkalosis, and metabolic acidosis.75 The appropriate application of topical salicylates is not generally associated with significant local adverse events.53 14

Menthol and Camphor Menthol and camphor are plant-derived compounds that are often used in topical analgesics, either alone or coformulated with salicylates.13 Menthol is described as having a minty taste and smell and is derived from plants in the Mentha genus, which includes peppermint; camphor is developed from the camphor laurel tree and is described as having a sweet smell.13,77,78 Mechanism of Action When applied topically to intact skin, menthol 37.4  mg and camphor 46.8 mg undergo dermal absorption and enter systemic circulation; however, due to their short terminal half-lives, these compounds are unlikely to substantially accumulate.79 Menthol, applied as 1 mL of solution containing 400 mg of 40% L-menthol, may act by diminishing subcutaneous, cold-sensitive C-fiber nociception and activating cold-specific Aδ fibers.80 The analgesic effect of menthol occurs through the blockade of neuronal calcium ion channels by binding to cold- and menthol-sensitive receptors (CMR1) and activating κ-opioid receptors.13,78 The CMR1 belongs to the transient receptor potential (TRP) family of ion channels, which detect heat and cold and are also activated by capsaicin.81 Similar to capsaicin, camphor may produce its analgesic effect by activating and ultimately desensitizing the capsaicin receptor TRPV1, as well as TRPV3, and the garlic receptor, TRPA1.13,77 Tolerability The primary safety issue associated with menthol and camphor use involves oral ingestion of large quantities of these products, leading to the depression of central nervous system function, which is characterized by anxiety, hallucination, and confusion, and can lead to death in more severe cases. Cases of localized burning of the eyes and nose have been reported stemming from accidental application to these areas.79,82

Pharmacologic Agents That Affect Sodium and Potassium

Agents that affect sodium and potassium include local anesthetics that are available in topical formulations, including a lidocaine 5% patch that is available in the United States and a plaster that is available in the European Union; a self-heating patch containing 70 mg each of tetracaine and lidocaine; a eutectic mixture of 2.5% concentrations of lidocaine and prilocaine; and a cream containing 7% concentrations of lidocaine and tetracaine.20,83–87 Although

© Postgraduate Medicine, Volume 125, Issue 4, Suppl 1, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected]

Pharmacology of Topical Analgesics

the majority of these topical lidocaine formulations are used to manage patient pain during minor surgeries and dermatologic procedures, both 5% lidocaine formulations are approved for the treatment of PHN.20,83–87 However, there are some data in the literature suggesting that the lidocaine 5% patch may also be effective for alleviating neuropathic pain associated with other chronic painful diseases, such as diabetes and cancer, and the eutectic mixture of 2.5% lidocaine and prilocaine may also be effective for managing patients with PHN.88–91

Downloaded by [Umeå University Library] at 04:24 19 February 2016

Mechanism of Action The local anesthetics included in topical formulations produce their analgesic effect by disrupting the transmission of pain signals between afferent nerve fibers and the central nervous system. This effect primarily stems from the affinity of these agents for binding to voltage-gated sodium ion channels; however, some local anesthetics also bind to potassium ion channels.92–95 Local anesthetics have varying affinities for each of these receptor sites. For example, using an in vitro animal model, lidocaine was shown to be nonselective for the sodium and potassium ion channels, while tetracaine was found to be more selective for binding to sodium ion channels.95 When local anesthetics bind to these receptor sites they reversibly inhibit neuronal action potential, which prevents the transmission and conduction of nerve impulses.92–95 In addition, some selectivity is observed for the varieties of nerve fibers that are inhibited by these agents. When administered systemically to rats, lidocaine produced a widespread suppression of nerve fiber activity, whereas tocainide more selectively suppressed C-afferent conductivity.92

Pharmacokinetics The maximum depth of skin penetration for lidocainecontaining creams, such as 7% lidocaine/tetracaine and 2.5% lidocaine/tetracaine, is estimated to be 3 mm to 5 mm.83,93 As would be expected when applied topically, significant inter-individual variability in the levels of circulating lidocaine has been observed, which may be a function of variations in cutaneous sites and hepatic enzyme function.96 Following the topical application of 4% lidocaine cream, a minute portion of the applied dose entered systemic circulation and peak plasma concentrations were generally achieved within 90 minutes after application with an occlusive dressing.96 The application of 3 or 4 lidocaine 5% patches daily for 3 days to 20 healthy subjects produced comparable lidocaine Cmax values (130 ng/mL and 153.8 ng/mL, respec-

tively).20,97 Similarly, application of 60 g of lidocaine 2.5%/ prilocaine 2.5% cream to a dermal area measuring ∼400 cm2 for 3 hours produced a lidocaine Cmax of 120 ng/mL and prilocaine Cmax of 70 ng/mL.86 Application of lidocaine 1.5 g/ tetracaine 1.5 g cream for 30 minutes to an area of 400 cm2 produced a lidocaine Cmax of 49 ng/mL and , 0.9 ng/mL for tetracaine.87 Exposure to 2.5% lidocaine/prilocaine and 7% lidocaine/ tetracaine is directly correlated to the duration of application, the surface area that is covered, and the location of the application site.86,87 For example, in 15 healthy volunteers, the application of a lidocaine 5% gel to the forehead produced greater exposure than an equivalent 5% lidocaine gel or patch applied to the torso.98 The effects of lidocaine 2% and tetracaine 2% to 10% topical formulations generally begin 3 to 8 minutes after application and last for 30 to 60 minutes.83 However, concentration and application method can influence the duration of effect; lidocaine 5% formulated with prilocaine 5% applied under an occlusive dressing for 1 hour produced effects that lasted # 2 hours.93

Tolerability The primary safety concern associated with the use of topical anesthetics is the patient risk for systemic toxicity, particularly in the cardiovascular and central nervous systems.83,93,94 However, Ogden et al demonstrated that a topical lidocaine/ tetracaine 7% peel did not produce a significant risk for toxicity—while still producing an analgesic effect—in a population of 36 healthy subjects.99 A systematic literature review has suggested that topical analgesics, such as lidocaine 5% plaster, may be associated with fewer and less clinically significant adverse effects (eg, local skin reactions) than systemic agents (eg, dizziness, fatigue, somnolence).91 Application-site reactions, including skin discoloration and erythema, can occur with the use of 2.5% lidocaine/prilocaine and 7% lidocaine/tetracaine.86,87

Cold and Heat Therapy

The use of cold therapy, generally in the form of ice or cold packs, has become accepted as routine care for soft-tissue injury in patients; however, empiric support is lacking and ice may only be effective if applied immediately following the injury.100,101 Cold therapy can also be used to alleviate patient pain and reduce inflammation after physical therapy sessions.101 Heat therapy is classified by the depth of penetration. Superficial heat is often used to facilitate exercise therapy and usually involves the application of hydrocollator packs at a

© Postgraduate Medicine, Volume 125, Issue 4, Suppl 1, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 15 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected]

Robert L. Barkin

temperature of 65°C to 90°C for 20 to 30 minutes, which generally raises tissue temperature by # 3°C at 1 cm below the surface of the skin.102 Continuous low-level heat may also be used to provide patients with analgesia and decrease muscle stiffness.101 Ultrasound, the most common form of deep heat treatment, uses sound waves to warm deeper tissues.102

West Chester, PA. Funding for this support was provided by Mallinckrodt Inc., the Pharmaceuticals business of Covidien, Hazelwood, MO.

Conflict of Interest Statement

Robert L. Barkin, PharmD, MBA, FCP, discloses no conflicts of interest.

Downloaded by [Umeå University Library] at 04:24 19 February 2016

Mechanism of Action Cold therapy is thought to act by slowing nerve conduction velocity (ie, by producing cold-induced neuropraxia), which produces an analgesic effect by reducing muscle spindle activity, and by producing vasoconstriction, which slows blood flow and reduces swelling.101,102 In contrast, the effectiveness of heat therapy is thought to be primarily driven by vasodilation, which increases the delivery of nutrients, leukocytes, and antibodies to the affected tissue.101,102 Additionally, patient benefit may stem from increased peripheral nerve fiber conductivity, relaxation of muscle fibers, and reductions in muscle spasms.101,102 As a result, heat therapy is often used in conjunction with stretching and rehabilitation therapy.102

Tolerability Patient tolerability issues, such as frostbite, burning, and nerve damage, have been observed after excessive icing. Acute hemorrhage and edema may result from excessive heat applied to a musculoskeletal injury.100–102 Ice should be applied 3 to 4 times daily for # 30 minutes at a time.101,102

Conclusion

Topical analgesics have been developed to deliver relatively higher local concentrations at the application site relative to systemic concentrations. Direct relief may provide additional benefits for treating patients with acute and chronic pain conditions when topical analgesics are used on their own or adjunctively with other agents. Topical analgesics may be particularly useful as components of a multimodal pain management regimen for patients at risk for safety and tolerability issues associated with oral analgesic therapy, which has been highlighted in recent treatment guidelines and systematic reviews. Future research is required to more clearly define the broader pharmacodynamic effects of topical analgesics.

Acknowledgments

Technical editorial and medical writing support for the preparation of this manuscript was provided by Dennis Stancavish, MA, Synchrony Medical Communications, LLC, 16

References

1. Cohen SP, Raja SN. Pain. In: Goldman L, Schafer AI, eds. Goldman’s Cecil Medicine. 24th ed. Philadelphia, PA: Elsevier Saunders; 2012:133–140. 2. Mirchandani A, Saleeb M, Sinatra R. Acute and chronic mechanisms of pain. In: Vadivelu N, Urman RD, Hines RL, eds. Essentials of Pain Management. New York, NY: Springer; 2011:45–54. 3. Treede RD, Jensen TS, Campbell JN, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology. 2008;70(18):1630–1635. 4. Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 2011;31(5):986–1000. 5. Power I. An update on analgesics. Br J Anaesth. 2011;107(1):19–24. 6. Stanos SP. Topical agents for the management of musculoskeletal pain. J Pain Symptom Manage. 2007;33(3):342–355. 7. Zhou YL. Principles of pain management. In: Daroff RB, Fenichel GM, Jankovic J, Mazziotta JC, eds. Bradley’s Neurology in Clinical Practice. Volume I: Principles of Diagnosis and Management. 6th ed. Philadelphia, PA: Elsevier Saunders; 2012:783–801. 8. Berger JM, Zaghi S. Nonopioid analgesics in pain management. In: Vadivelu N, Urman RD, Hines RL, eds. Essentials of Pain Management. New York, NY: Springer; 2011:117–150. 9. Pincus MR, Abraham NZ. Toxicology and therapeutic drug monitoring. In: McPherson RA, Pincus MR, eds. Henry’s Clinical Diagnosis and Management by Laboratory Methods. 22nd ed. Philadelphia, PA: Elsevier Saunders; 2011:329–364. 10. Sprix (ketorolac tromethamine) Nasal Spray [package insert]. Shirley, NY: American Regent, Inc; 2011. 11. Argoff CE. Topical analgesics: a review of recent clinical trials and their application to clinical practice. Adv Stud Med. 2003;3 (7A):S642–S647. 12. Wiechers JW. The barrier function of the skin in relation to percutaneous absorption of drugs. Pharm Weekbl Sci. 1989;11(6):185–198. 13. Stanos SP, Tyburski MD. Minor and short-acting analgesics, including opioid combination products. In: Benzon HT, Rathmell JP, Wu CL, Turk DC, Argoff CE, eds. Raj’s Practical Management of Pain. 4th ed. Philadelphia, PA: Elsevier; 2008:613–641. 14. Gurtovenko AA, Anwar J. Modulating the structure and properties of cell membranes: the molecular mechanism of action of dimethyl sulfoxide. J Phys Chem B. 2007;111(35):10453–10460. 15. Conte A, Ronca G. Petrini M, Mautone G. Effect of lecithin on epicutaneous absorption of diclofenac epolamine. Drugs Exp Clin Res. 2002;28(6):249–255. 16. Kurihara-Bergstrom T, Knutson K, DeNoble JL, Goates CY. Percutaneous absorption enhancement of an ionic molecule by ethanol-water systems in human skin. Pharm Res. 1990;7(7):762–766. 17. Barkin RL. Topical nonsteroidal anti-inflammatory drugs: the importance of drug, delivery, and therapeutic outcome. Am J Ther. 2012 Feb 22 [Epub ahead of print] PMID: 22367354. 18. Altman RD, Barthel HR. Topical therapies for osteoarthritis. Drugs. 2011;71(10):1259–1279. 19. Haroutiunian S, Drennan DA, Lipman AG. Topical NSAID therapy for musculoskeletal pain. Pain Med. 2010;11(4):535–549. 20. Lidoderm (lidocaine patch 5%) [package insert]. Chadds Ford, PA: Endo Pharmaceuticals Inc; 2010.

© Postgraduate Medicine, Volume 125, Issue 4, Suppl 1, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected]

Downloaded by [Umeå University Library] at 04:24 19 February 2016

Pharmacology of Topical Analgesics 21. Altman R, Barkin RL. Topical therapy for osteoarthritis: clinical and pharmacologic perspectives. Postgrad Med. 2009;121(2):139–147. 22. Altman RD. New guidelines for topical NSAIDs in the osteoarthritis treatment paradigm. Curr Med Res Opin. 2010;26(12):2871–2876. 23. Evans JM, McGregor E, McMahon AD, et  al. Non-steroidal antiinflammatory drugs and hospitalization for acute renal failure. QJM. 1995;88(8):551–557. 24. Roelofs PD, Deyo RA, Koes BW, Scholten RJ, van Tulder MW. Nonsteroidal anti-inflammatory drugs for low back pain: an updated Cochrane Review. Spine. 2008;33(16):1766–1774. 25. Voltaren Gel (diclofenac sodium topical gel) 1% [package insert]. Chadds Ford, PA: Endo Pharmaceuticals Inc; 2009. 26. Pennsaid (diclofenac sodium topical solution) 1.5% w/w [package insert]. Hazelwood, MO: Mallinckrodt Brand Pharmaceuticals, Inc; 2010. 27. Flector Patch (diclofenac epolamine topical patch) 1.3% [package insert]. Bristol, TN: King Pharmaceuticals, Inc; 2009. 28. Grosser T, Smyth E, FitzGerald GA. Anti-inflammatory, antipyretic, and analgesic agents; pharmacotherapy of gout. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011:959–1004. 29. Brune K. Safety of anti-inflammatory treatment—new ways of thinking. Rheumatology. 2004;43(suppl 1):i16–i120. 30. Kothari HV, Lee WH, Ku EC. An alternate mechanism for regulation of leukotriene production in leukocytes: studies with an anti-inflammatory drug, sodium diclofenac. Biochim Biophys Acta. 1987;921(3):502–511. 31. Gan TJ. Diclofenac: an update on its mechanism of action and safety profile. Curr Med Res Opin. 2010;26(7):1715–1731. 32. Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest. 2006;116(1):4–15. 33. Barkin RL, Beckerman M, Blum SL, Clark FM, Koh EK, Wu DS. Should nonsteroidal anti-inflammatory drugs (NSAIDs) be prescribed to the older adult? Drugs Aging. 2010;27(10):775–789. 34. Singh P, Roberts MS. Skin permeability and local tissue concentrations of nonsteroidal anti-inflammatory drugs after topical application. J Pharmacol Exp Ther. 1994;268(1):144–151. 35. Tegeder I, Muth-Selbach U, Lötsch J, et al. Application of microdialysis for the determination of muscle and subcutaneous tissue concentrations after oral and topical ibuprofen administration. Clin Pharmacol Ther. 1999;65(4):357–368. 36. Shah AK, Wei G, Lanman RC, Bhargava VO, Weir SJ. Percutaneous absorption of ketoprofen from different anatomical sites in man. Pharm Res. 1996;13(1):168–172. 37. Vaile JH, Davis P. Topical NSAIDs for musculoskeletal conditions: a review of the literature. Drugs. 1998;56(5):783–799. 38. Kienzler J-L, Gold M, Nollevaux F. Systemic bioavailability of topical diclofenac sodium gel 1% versus oral diclofenac sodium in healthy volunteers. J Clin Pharmacol. 2010;50(1):50–61. 39. Kleinbloesem CH, Ouwerkerk M, Spitznagel W, Wilkinson FE, Kaiser RR. Pharmacokinetics and bioavailability of percutaneous ibuprofen. Arzneimittelforschung. 1995;45(10):1117–1121. 40. Seth PL. Percutaneous absorption of ibuprofen from different formulations. Comparative study with gel, hydrophilic ointment and emulsion cream. Arzneimittelforschung. 1993;43(8):919–921. 41. Feldene Gel (piroxicam) [summary of product characteristics]. Hertzliya Pituach, Israel: Pfizer Pharmaceuticals Israel Ltd; 2009. 42. Dominkus M, Nicolakis M, Kotz R, Wilkinson FE, Kaiser RR, Chlud K. Comparison of tissue and plasma levels of ibuprofen after oral and topical administration. Arzneimittelforschung. 1996;46(12):1138–1143. 43. Radermacher J, Jentsch D, Scholl MA, Lustinetz T, Frölich JC. Diclofenac concentrations in synovial fluid and plasma after cutaneous application in inflammatory and degenerative joint disease. Br J Clin Pharmacol. 1991;31(5):537–541. 44. Tse S, Powell KD, MacLennan SJ, et al. Skin permeability and pharmacokinetics of diclofenac epolamine administered by dermal patch in Yorkshire-Landrace pigs. J Pain Res. 2012;5:401–408.

45. Komatsu T, Sakurada T. Comparison of the efficacy and skin permeability of topical NSAID preparations used in Europe. Eur J Pharm Sci. 2012:47(5):890–895. 46. Herndon CM. Topical delivery of nonsteroidal anti-inflammatory drugs for osteoarthritis. J Pain Palliative Care Pharmacother. 2012; 26(1):18–23. 47. Roth SH, Fuller P. Diclofenac topical solution compared with oral diclofenac: a pooled safety analysis. J Pain Res. 2011;4:159–167. 48. Lin J, Zhang W, Jones A, Doherty M. Efficacy of topical non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis: meta-analysis of randomised controlled trials. Br Med J. 2004;329(7461):324. 49. Taylor RS, Fotopoulos G, Maibach H. Safety profile of topical diclofenac: a meta-analysis of blinded, randomized, controlled trials in musculoskeletal conditions. Curr Med Res Opin. 2011;27(3):605–622. 50. Evans JM, McMahon AD, McGilchrist MM, et al. Topical non-steroidal anti-inflammatory drugs and admission to hospital for upper gastrointestinal bleeding and perforation: a record linkage case-control study. Br Med J. 1995;311(6996):22–26. 51. Barkin RL. Reducing cardiovascular risks of nonsteroidal antiinflammatory drugs by using topical formulations. Am J Cardiol. 2009; 104(9):1315. 52. Dawson B, Trapp RG. Study designs in medical research. In: Dawson B, Trapp RG, eds. Basic and Clinical Biostatistics. 4th ed. New York, NY: McGraw-Hill; 2004. http://www.accessmedicine.com/content. aspx?aID=2046062. Accessed June 25, 2012. 53. Mason L, Moore RA, Edwards JE, McQuay HJ, Derry S, Wiffen PJ. Systematic review of efficacy of topical rubefacients containing salicylates for the treatment of acute and chronic pain. Br Med J. 2004;328(7446):995. 54. Rains C, Bryson HM. Topical capsaicin: a review of its pharmacological properties and therapeutic potential in post-herpetic neuralgia, diabetic neuropathy and osteoarthritis. Drugs Aging. 1995;7(4):317–328. 55. Mason L, Moore RA, Derry S, Edwards JE, McQuay HJ. Systematic review of topical capsaicin for the treatment of chronic pain. Br Med J. 2004;328(7446):991. 56. Qutenza (capsaicin) 8% patch [package insert]. San Mateo, CA: NeurogesX, Inc; 2009. 57. Anand P, Bley K. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br J Anaesth. 2011;107(4):490–502. 58. A study to investigate the tolerability and effects on epidermal nerve fiber density of multiple low-concentrations of NGX-1998 in healthy volunteers. ClinicalTrials.gov. http://clinicaltrials.gov/ ct2/show/NCT00912262?term=NGX+1998&rank=2. Accessed February 6, 2013. 59. Study of NGX-1998 for the treatment of postherpetic neuralgia. ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/NCT01228838?t erm=NGX+1998&rank=1. Accessed February 6, 2013. 60. Nolano M, Simone DA, Wendelschafer-Crabb G, Johnson T, Hazen E, Kennedy WR. Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation. Pain. 1999;81(1–2):135–145. 61. Baron R. Capsaicin and nociception: from basic mechanisms to novel drugs. Lancet. 2000;356(9232):785–787. 62. Simone DA, Nolano M, Johnson T, Wendelschafer-Crabb G, Kennedy WR. Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: correlation with sensory function. J Neurosci. 1998;18(21): 8947–8959. 63. Forst T, Pohlmann T, Kunt T, et al. The influence of local capsaicin treatment on small nerve fibre function and neurovascular control in symptomatic diabetic neuropathy. Acta Diabetol. 2002;39(1):1–6. 64. Beydoun A, Dyke DB, Morrow TJ, Casey KL. Topical capsaicin selectively attenuates heat pain and Aδ fiber-mediated laser-evoked potential. Pain. 1996;65(2–3):189–196. 65. Crimi N, Polosa R, Maccarrone C, Palermo B, Palermo F, Mistretta A. Effect of topical application with capsaicin on skin responses to bradykinin and histamine in man. Clin Exp Allergy. 1992;22(10):933–939.

© Postgraduate Medicine, Volume 125, Issue 4, Suppl 1, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 17 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected]

Downloaded by [Umeå University Library] at 04:24 19 February 2016

Robert L. Barkin 66. Gibbons CH, Wang N, Freeman R. Capsaicin induces degeneration of cutaneous autonomic nerve fibers. Ann Neurol. 2010;68(6):888–898. 67. Geppetti P, Tramontana M, Del Bianco E, Fusco BM. Capsaicindesensitization to the human nasal mucosa selectively reduces pain evoked by citric acid. Br J Clin Pharmacol. 1993;35(2):178–183. 68. Gordon RR. Poisoning by oil of wintergreen. Br Med J. 1968;1 (5594):769. 69. Furst DE. Are there differences among nonsteroidal antiinflammatory drugs? Comparing acetylated salicylates, nonacetylated salicylates, and nonacetylated nonsteroidal antiinflammatory drugs. Arthritis Rheum. 1994;37(1):1–9. 70. Cross SE, Anderson C, Roberts MS. Topical preparation of commercial salicylate esters and salts using human isolated skin and clinical microdialysis studies. Br J Clin Pharmacol. 1998;46(1):29–35. 71. Tanen DA, Danish DC, Reardon JM, Chisholm CB, Matteucci MJ, Riffenburgh RH. Comparison of oral aspirin versus topical applied methyl salicylate for platelet inhibition. Ann Pharmacother. 2008;42(10):1396–1401. 72. Singh P, Roberts MS. Dermal and underlying tissue pharmacokinetics of salicylic acid after topical application. J Pharmacokinet Biopharm. 1993;21(4):337–373. 73. Roberts MS, Favretto WA, Meyer A, Reckmann M, Wongseelashote T. Topical bioavailability of methyl salicylate. Aust N Z J Med. 1982;12 (3):303–305. 74. Morra P, Bartle WR, Walker SE, Lee SN, Bowles SK, Reeves RA. Serum concentrations of salicylic acid following topically applied salicylate derivatives. Ann Pharmacother. 1996;30(9):935–940. 75. Chan TY. The risk of severe salicylate poisoning following the ingestion of topical medicaments or aspirin. Postgrad Med J. 1996;72 (844):109–112. 76. Davies MG, Briffa DV, Greaves MW. Systemic toxicity from topically applied salicylic acid. Br Med J. 1979;1(6164):661. 77. Xu H, Blair NT, Clapham DE. Camphor activates and strongly desensitizes the transient receptor potential vanilloid subtype 1 channel in a vanilloid-independent mechanism. J Neurosci. 2005;25 (39):8924–8937. 78. Galeotti N, Mannelli LDC, Mazzanti G, Bartolini A, Ghelardini C. Menthol: a natural analgesic compound. Neurosci Lett. 2002;322 (3):145–148. 79. Martin D, Valdez J, Boren J, Mayersohn M. Dermal absorption of camphor, menthol, and methyl salicylate in humans. J Clin Pharmacol. 2004;44(10):1151–1157. 80. Wasner G, Schattschneider J, Binder A, Baron R. Topical menthol—a human model for cold pain by activation and sensitization of C nociceptors. Brain. 2004;127(pt 5):1159–1171. 81. McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature. 2002;416(6876):52–58. 82. Manoguerra AS, Erdman AR, Wax PM, et al. Camphor poisoning: an evidence-based practice guideline for out-of-hospital management. Clin Toxicol. 2006;44(4):357–370. 83. Catterall WA, Mackie K. Local anesthetics. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011:623–643. 84. Versatis (lidocaine 5% medicated plaster [package leaflet]. Aachen, Germany: Grünenthal GmbH; 2012.

18

85. Synera (lidocaine 70  mg/tetracaine 70  mg topical patch) [package insert]. Salt Lake City, UT: ZARS Pharma, Inc; 2010. 86. EMLA (lidocaine and prilocaine) [package insert]. Schaumburg, IL: APP Pharmaceuticals, LLC; 2008. 87. Pliaglis (lidocaine and tetracaine) Cream 7%/7% [package insert]. Fort Worth, TX: Galderma Laboratories, LP; 2007. 88. Podichetty VK, Reddy A. Acupuncture, transcutaneous electrical nerve stimulation, and topical analgesics. In: Walsh TD, Caraceni AT, Fainsinger R, et al, eds. Palliative Medicine. Philadelphia, PA: Saunders; 2009:1398–1404. 89. Litman SJ, Vitkum SA, Poppers PJ. Use of EMLA cream in the treatment of post-herpetic neuralgia. J Clin Anesth. 1996;8(1):54–57. 90. Attal N, Brasseur L, Chauvin M, Bouhassira D. Effects of single and repeated applications of a eutectic mixture of local anaesthetics (EMLA) cream on spontaneous and evoked pain in post-herpetic neuralgia. Pain. 1999;81(1–2):203–209. 91. Wolff RF, Bala MM, Westwood M, Kessels AG, Kleijnen J. 5% lidocaine-medicated plaster in painful diabetic peripheral neuropathy (DPN): a systematic review. Swiss Med Wkly. 2010;140(21–22): 297–306. 92. Woolf CJ, Wiesenfeld-Hallin Z. The systemic administration of local anaesthetics produces a selective depression of C-afferent fibre evoked activity in the spinal cord. Pain. 1985;23(4):361–374. 93. Morgan GE Jr, Mikhail MS, Murray MJ. Local anesthetics. In: Morgan GE Jr, Mikhail MS, Murray MJ, eds. Clinical Anesthesiology. 4th ed. New York, NY: McGraw-Hill; 2006. 94. Katzung BG, White PF. Local anesthetics. In: Katzung BG, Masters SB, Trevor AJ, eds. Basic and Clinical Pharmacology. 11th ed. New York, NY: McGraw-Hill; 2009. 95. Brau ME, Vogel W, Hempelmann G. Fundamental properties of local anesthetics: half-maximal blocking concentrations for tonic block of NA+ and K+ channels in peripheral nerve. Anesth Analg. 1998; 87(4):885–889. 96. Oni G, Brown S, Burrus C, et al. Effect of 4% topical lidocaine applied to the face on the serum levels of lidocaine and its metabolite, monoethylglycinexylidide. Aesthetic Surg J. 2010;30(6):853–858. 97. Gammaitoni AR, Davis MW. Pharmacokinetics and tolerability of lidocaine patch 5% with extended dosing. Ann Pharmacother. 2002;36(2):236–240. 98. Campbell BJ, Rowbotham M, Davies PS, Jacob P III, Benowitz NL. Systemic absorption of topical lidocaine in normal volunteers, patients with post-herpetic neuralgia, and patients with acute herpes zoster. J Pharm Sci. 2002;91(5):1343–1350. 99. Ogden L, Love G, Basta S. Systemic exposure to lidocaine and tetracaine is low after an application of a lidocaine 7%-tetracaine 7% peel in adults. Int J Dermatol. 2008;47(1):87–90. 100. Collins NC. Is ice right? Does cryotherapy improve outcome for acute soft tissue injury? Emerg Med J. 2008;25(2):65–68. 101. Nadler SF. Nonpharmacologic management of pain. J Am Osteopath Assoc. 2004;104(11 suppl 8):S6–S12. 102. McLean JP, Chimes GP, Press JM, Hearndon ML, Willick SE, Herring SA. Basic concepts in biomechanics and musculoskeletal rehabilitation. In: Fishman SM, Ballantyne JC, Rathmell JP, eds. Bonica’s Management of Pain. 4th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2010.

© Postgraduate Medicine, Volume 125, Issue 4, Suppl 1, July 2013, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected]

The pharmacology of topical analgesics.

Pain management of patients continues to pose challenges to clinicians. Given the multiple dimensions of pain--whether acute or chronic, mild, moderat...
502KB Sizes 5 Downloads 6 Views