topical agents for the management of musculoskeletal pain › wp-content › uploads ›...

342 Journal of Pain and Symptom Management Vol. 33 No. 3 March 2007

Special Article

Topical Agents for the Managementof Musculoskeletal PainSteven P. Stanos, DOChronic Pain Care Center, Rehabilitation Institute of Chicago, and Department of Physical Medicine

and Rehabilitation, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA

AbstractThe recent recognition of the magnitude of cardiovascular risk of both nonselectivenonsteroidal anti-inflammatory drugs and COX-2 selective inhibitors, in addition to thepersistent concerns about the use of opioids, has brought increased attention to nonsystemic,topical analgesics. These agents have a favorable safety profile and there is increasingevidence indicating their efficacy for a variety of pain disorders. The use of topical analgesicsin the treatment of the most prevalent musculoskeletal pain syndromes is described, witha focus on mechanisms for drug delivery and clinical trials data. J Pain SymptomManage 2007;33:342e355. � 2007 U.S. Cancer Pain Relief Committee. Published byElsevier Inc. All rights reserved.

Key WordsCounterirritants, local anesthetics, musculoskeletal pain, topical analgesics

IntroductionMusculoskeletal pain encompasses a wide

spectrum of disorders from simple ligamen-tous injuries (e.g., ankle sprains) to intra-articular disorders (e.g., osteoarthritis andrheumatoid arthritis), muscle pain syndromes(e.g., myofascial pain and fibromyalgia), andvarious spine-related neck and low back condi-tions (e.g., disc degeneration, disc herniation,facet arthropathies, and spondylosis). Thesedisorders are highly prevalent and exacta huge toll in terms of individual quality oflife and cost to society. Topical analgesics

Address reprint requests to: Steven P. Stanos, DO, Reha-bilitation Institute of Chicago, Chronic Pain CareCenter, 1030 North Clark Street, Suite 320, Chicago,IL 60610, USA. E-mail: [email protected]

Accepted for publication: November 28, 2006.

� 2007 U.S. Cancer Pain Relief CommitteePublished by Elsevier Inc. All rights reserved.

may provide a safe and effective therapeuticapproach for some musculoskeletal pains.

EpidemiologyLow back pain (LBP) and osteoarthritis are

the most common musculoskeletal disorders.LBP creates a significant burden on societydue to its high prevalence (17.6% within theU.S. work force)1 and consequent economicimpact (estimated to exceed $50 billion).2

LBP is the most reported musculoskeletalpain3 and as many as 84% of adults will experi-ence LBP in their lifetime.4 When chronic, thecomplex pathophysiology, often involving bothmusculoskeletal and neuropathic compo-nents, may cause the management of LBP tobe notoriously challenging.

Osteoarthritis affects more than 20 millionAmericans between the ages of 25 years and75 years5 and is predicted to become the

0885-3924/07/$esee front matterdoi:10.1016/j.jpainsymman.2006.11.005

mailto:[email protected]

Vol. 33 No. 3 March 2007 343Topical Agents for Musculoskeletal Pain

fourth leading cause of disability by the year2020, worldwide.3 Over the course of the dis-ease progression, joints undergo degenerationof articular cartilage, osteophyte formation,and subchondral bone sclerosis.5 Nerve fiberslocalize densely within bone, and chronicpain is thought to arise from sensitized noci-ceptors that become exposed due to the ero-sion of articular cartilage.6

Numerous other musculoskeletal pains areprevalent. Ankle sprain alone has an incidenceof 52.7 per 10,000, according to a study con-ducted in the United Kingdom.7 Bone painmay result from metastatic cancer, orthopedicsurgery, and traumatic injuriesdpotentially af-fecting many people. Although the majority ofthese injuries are benign and self-limiting,many patients may experience intermittent ormore persistent pain and/or loss of function,both of which adversely affect a patient’s gen-eral quality of life.8

The Biology of Pain: Pathologicvs. Physiologic Pain

In a healthy individual, pain may be definedas a complex sensory experience associatedwith actual or potential tissue damage.9 Injuryin the periphery induces keratinocytes andblood vessels in the dermis to release excit-atory factors, such as prostaglandins, substanceP (SP), and calcitonin gene-related peptide,which bind to receptors on nociceptive fibersand cause depolarization. These unspecial-ized, peripheral nerve fibersdC and Ad poly-modal nociceptorsdcan be stimulated bynoxious thermal, chemical, and mechanical in-puts. They transmit signals from the peripheryvia the dorsal horn to higher cerebral struc-tures.10 Generally, the intensity, localization,and timing of the initiating stimuli are re-flected in the level of the neuronal signal.11

In contrast, with inflamed tissue, an externalstimulus is not required to generate signaltransduction and transmission to the dorsalhorn. This hypersensitivity, seen in diseaseslike osteoarthritis, can be inhibited by a num-ber of different pharmacologic agents, suchas nonsteroidal anti-inflammatory drugs(NSAIDs), opioids, and cannabinoids.11

Topical Drug DeliveryControversy regarding postmarketing ad-

verse event (AE) data and a re-examinationof coxib and traditional NSAID safety studiesignited intense debate within both popularand medical media starting from the end of2004 and still ongoing currently.12 Certainly,the debates brought the issue of pharmaco-therapy safety to the forefront, and conse-quently may have positively affected theprescribing habits of clinicians. Hence, healthcare providers and the pharmaceutical indus-try are currently reassessing the potential anal-gesic and additional safety advantages of oneof the oldest routes of delivery, topical applica-tion.13 Potentially, topical agents can achievea similar efficacy to oral formulations withoutthe associated systemic side effects. Some evi-dence has shown that topically deliveredagents can accumulate to therapeutic concen-trations within the local tissues to which theyhave been applied while maintaining low se-rum levels. Potentially, lowering the systemiclevels of medications reduces the associatedrisk of organ or tissue toxicity; a more com-plete list of the benefits and limitations of der-mal and transdermal delivery systems14e32 arelisted in Table 1.

Topical agents comprise a growing part ofthe over-the-counter analgesic market, as wellas a smaller evolving niche market of com-pounding pharmacies in the United Statesand Europe. Topical medications for pain ac-counted for 6.1% of the U.S. analgesic marketin 2000.33 Yet, an email survey in 2002 con-ducted by the American Society of RegionalAnesthesia and Pain Medicine indicated thatonly 27% of clinicians prescribe compoundedtopical analgesics, despite the perception that43� 3% of treated patients respond favorablyto topical agents, with an average of 47� 3%pain relief and few side effects.34

Topical vs. TransdermalThe terms ‘‘topical’’ and ‘‘transdermal’’ are

sometimes used interchangeably, although im-portant differences need to be considered.Both delivery methods must transverse thestratum corneumdthe major barrier to de-livering treatment.6 Transdermal methodsdeliver medication through percutaneous ab-sorption, with the goal of achieving

344 Vol. 33 No. 3 March 2007Stanos

therapeutic systemic levels of active drug com-parable to oral medications. Transdermalpharmacotherapies can be, and often are, ad-ministered distal to the site of injury (i.e., sus-tained release nicotine and clonidine patchesand long-acting fentanyl delivery systems),and typically deliver therapy over an extendedperiod of time after a slow onset of action. Incontrast, topical agents use cutaneous deliveryto specifically target the site of application.The sites of action for topical agents are thesoft tissues and peripheral nerves underlyingthe site of application.13 Serum levels generallyremain relatively low, and consequently, sys-temic side effects or drug-drug interactionsare more unlikely.13

The vehicle in which the active ingredi-ent(s) are delivered can affect the skin pene-tration depth and absorption rate into theepidermis.13 The penetration of topical modal-ities is limited by the stratum corneumdadense layer of flattened keratinocytes that

Table 1Benefits and Limitations of Analgesia

by Cutaneous Delivery

Benefits Limitations

� First passmetabolism and othervariables associated withthe gastrointestinal tract(such as pH and gastricemptying time) areavoided.15e17

� Reduced side effects, andthe minimization of drugconcentration peaks andtroughs in the blood.17,18

� Ease of dose terminationin the event of untowardside effects.� Delivery can be sustained

and controlled over aprolonged period.19,20

� Direct access to thetarget site.13,14

� Convenient and painlessadministration.15,16

� Improved patientacceptance and adherenceto therapy.21e23

� Ease of use may reduceoverall health treatmentcosts.24

� Provides a viablesolution for treatmentwhen oral dosingis not feasible(i.e., in unconscious ornauseated patients.)17

� Diffusion acrossthe stratum corneumonly occurs formolecules <500 Da.25

� Topical agentsmust have bothaqueous and lipidsolubility.26

� Both intra- andinterindividualvariability in thepermeabilityof skin, as well asdifferences betweenhealthy and diseasedskin, causes variableefficacy.27,28

� Skin enzymes can causemetabolism beforecutaneous absorption,reducing the potencyof the drug.29

� Localized skinirritation, suchas erythema, can becommon.30e32

Adapted from Ref. 14.

shelters the live epidermis (Fig. 1).6,14 Oncepast this relatively impermeable barrier, anal-gesics may access the unmyelinated C-fibersand encounter the predominant keratinocytesand melanocytes of the epidermal layer. Belowthe epidermis, the dermal layer also containsnociceptive fibers, along with fibroblasts, con-nective tissue, blood vessels, hair follicles,and glands. Collectively, the nerves present inthe epidermis and dermis are referred to asthe cutaneous nociceptors.6

Animal models have suggested that the vari-ability in transcutaneous absorption rates be-tween topical agents is likely derived fromtheir ability to negotiate the superficialskin.35 Ideally, a topical agent will have a lowmolecular weight (<500 Da)14 and have bothhydrophobic features in order to transversethe stratum corneum and hydrophilic charac-teristics to penetrate the predominantly aque-ous epidermis.35,36 Furthermore, ex vivostudies of human skin tissue indicate that non-physiological pHs of the vehicle can reducethe skin penetration of an agent, while occlu-sion of the skin surface can have a beneficialimpact on drug delivery.36

Several delivery agents have been engi-neered to increase the bioavailability of topi-cally delivered analgesics. For example,lecithin organogels are biocompatible jelly-like phases, composed primarily of hydratedphospholipids and organic liquid, which havebeen used to deliver NSAIDs and other treat-ments for muscle spasm, cancer, and brux-ism.37 Also, lecithin, pluronic gel, andisopropyl palmitate (called pluronic lecithinorganogel-PLO) have been combined to cre-ate a colloidal gel used to topically deliverNSAIDs.38 Additionally, polyethylene glycoland limonene39 have been used as topical pen-etration enhancers, increasing the absorptionrate of NSAIDs by up to 75-fold.36 Datingback as far as a century ago, the delivery of top-ical therapeutics was ameliorated by nonphar-macologic methods, such as iontophoresis.14

This method uses a low-level current to en-hance the permeability of a topically appliedagent. Finally, patch preparations and ‘‘plas-ters’’ incorporate adhesive cloth disposable sys-tems and may offer additional benefit to moretraditional topical creams, gels, or solutions,given their potential to deliver medication ata continuous rate.40


Hair shaft

Dermal papillae

Hair follicle

Hair root

Artery

Vein

Pacinian corpuscle

Root hair plexus

Adipose tissue

Eccrine sweat gland

Hypodermis

Reticular layerPapillary layer

Pore

Meissner’scorpuscle

Stratumbasale

Stratumspinosum

Stratumgranulosum

Stratumlucidum

Stratumcorneum

Deeper tissueNonsteroidalanti-inflammatoryagents (NSAIDs)

SystemicOpioidsAntidepressants

LocalAnesthetics

Free nerveending

Sebaceous(oil) gland

Arrector pilimuscleSensorynerve fiber

Fig. 1. Anatomy and physiology of the skin with the potential targets or sites of action of selected analgesics.Adapted from Ref. 14.

Although analgesics have been the mostthoroughly studied in controlled trials of alltypes of agents delivered topically, anestheticsand counterirritants can be administered topi-cally as well. In fact, some of the oldest topicalmedicines may have been counterirritantsdmild or moderate noxious agents that suppressthe perception of pain.13 Anesthetic agentshave evolved considerably for the treatmentof musculoskeletal pain, too. Some examplesof commercially available products andpharmacy-compounded agents are listed inTable 2.

Topical Treatment Options: ClinicalTrial EvidenceNonsteroidal Anti-Inflammatory Drugs

Topical NSAIDs have been more widely usedand studied in Europe than in the UnitedStates. Research primarily conducted inEurope has suggested several potential peri-pheral mechanisms of analgesic activity, in-cluding the inhibition of prostaglandinsynthesis, the lipoxygenase pathway, and

excitatory amino acids, as well as modulationof G-protein mediated signal transduction.13

A large variety of topical formulations ofNSAIDs are available commercially, includingthe agents listed in Table 3.35

Pharmacokinetic data suggest that topicallyapplied NSAIDs can result in enhanced local

Table 2Examples of Topical Agents for the Treatment

of Musculoskeletal Pain and PrescribingConsiderations

CommerciallyAvailable Products

Pharmacy-CompoundedPreparations

Examples Capsaicin Alpha-2 agonists2.5% lidocaine/

2.5% prilocaineAnticonvulsantsLocal anesthetics

Lidocainepatch 5%

NMDA antagonistsNSAIDs

Doxepin OpioidsTCAs

Considerations � Consistency ofpreparation

� Potential variabilityof preparation

� Establishedsafety and efficacy(FDA approval)

� Lack of controlledtrials


concentrations without significant toxic sys-temic levels. Heyneman et al. summarizedboth single- and multiple-dose NSAID absorp-tion studies.36 Collectively, the studies indi-cated that following topical administration ofNSAIDs, peak plasma levels were less than10% of the concentrations obtained fromoral dosing (range, 0.2%e8.0%). As the totalsystemic absorption from topical applicationis only 3%e5% of the oral route, systemic tox-icity from topical NSAIDs are correspondinglyrare. Also, the length of time before Cmax isachieved following topical application rangedfrom 2.2 to 23 hours, approximately 10 timeslonger than the time required for the equiva-lent oral dose. Topical NSAIDs achievesteady-state generally within 2e5 days of re-peated application.36

Penetration studies also indicate that topi-cally applied NSAIDs reach therapeutic con-centrations below the site of application.36 Atwo-way crossover design assessed the levels ofsubcutaneous absorption and muscle absorp-tion of 800 mg of oral ibuprofen or 16 g of5% ibuprofen gel administered to the thigh.41

Microdialysis probes inserted 25e30 mm intothe muscle found average values of 63.5�90.3 ng h mL�1 and 213.4� 117.2 ng h mL�1

of ibuprofen for the topical and oral routes, re-spectively. The ibuprofen concentrations inthe dermis were 22.5-fold greater when deliv-ered topically; the mean values of ibuprofenin the subcutaneous tissue were 731.2�605.0 ng h mL�1 and 176.6� 122.9 ng h mL�1

for the topical and oral routes, respectively.41

Another study of 100 patients consideredthe ketoprofen concentrations in the intra-articular tissues following a single applicationof a 30 mg plaster, multiple applications of

Table 3Topical NSAIDs

Formulation Active Ingredient

Ointment IndomethacinCream Diclofenac, ibuprofen, benzydamine,

salicylic acidSpray IndomethacinPatch/plaster Diclofenac, flurbiprofenGel Piroxicam, diclofenac, felbinac,

ketoprofen, indomethacin,ibuprofen, salicylic acid, eltenac

Drops Ketorolac, flurbiprofen, suprofen,diclofenac

Foam Ketoprofen, felbinac

Reprinted with permission from Ref. 35.

plasters over a five-day period, or a 50 mgoral dose.42 The median Cmax values for topicaland oral administration were 568.9 ng/g and85.7 ng/g in the cartilage, respectively (a 6.8-fold difference). In contrast, the plasma valueswere 18.7 ng/ml for topically administered ke-toprofen and 2,595.3 ng/ml for the oral route.Overall, when applied topically, the ketopro-fen levels were 30-fold greater in the cartilagethan in the plasma.42

Relative to any other topically administereddrug, the largest amount of clinical evidencehas been accumulated for NSAIDs.13 A meta-analysis by Moore et al. considered 86 random-ized, placebo-controlled trials of NSAIDs fortreatment of pain conditions; 10,160 patientswere included.43 The effectiveness measurenearest to one week following the start of treat-ment for acute conditions, such as soft tissuetrauma, sprains, and strains, and the two-week measure for chronic pain conditions,such as osteoarthritis and tendonitis, wereused in the meta-analysis. Overall, the numberneeded to treat (NNT) was 3.9 for acute painconditions, more specifically: 2.6 for ketopro-fen, 3.0 for felbinac, 3.5 for ibuprofen, and4.2 for piroxicam (benzydamine and indo-methacin had efficacies comparable to pla-cebo). For chronic pain conditions, the NNTwas 3.1 and ranged between 2.7 and 3.8. Fur-thermore, for all pain conditions studied, top-ical NSAIDs rarely induced local skin reactions(3.6%) and more rarely had any adverse sys-temic effects (<0.5%).43 Similarly, a smallermeta-analysis of 26 double-blind, placebo-controlled trials by Mason et al., found thattopical NSAID treatment was safe and effectivefor acute pain, following one week ofapplication.44

Another meta-analysis of randomized, con-trolled trials by Lin et al. assessed the efficacyof topical NSAIDs relative to placebo or oralformulations for the treatment of osteoarthri-tis.45 Compared to placebo, a positive treat-ment effect was observed only during Weeks1 and 2 of treatment; reported pooled treat-ment effect sizes for pain relief were 0.41(95% confidence interval [CI], 0.16e0.66)and 0.40 (95% CI, 0.15e0.65) for each week,respectively. In contrast, even in the firstweek, topical NSAIDs were found inferior tooral versions for improving pain and function,and topical agents induced more local side


effects as well. The authors concluded that notrial evidence has supported the benefit ofNSAIDs over placebo for treating osteoarthritisafter two weeks of application, and even sug-gested that the current practice guidelines onosteoarthritis that advocate the use of topicalNSAIDs46e48 should be revised.45 However,two recent, randomized, controlled trials ofa topical diclofenac solution for the treatmentof pain from knee osteoarthritis reported ben-efit following four and 12 weeks of applica-tion.49,50 Measured by Western Ontario andMcMaster Universities Osteoarthritis Indexscores, the study group had a 42.9% decreasein pain relative to baseline following fourweeks, and a 45.7% decrease after 12 weeks,compared to a respective 26.9% and 33.3% de-crease in pain by the vehicle-control groups.Measurements of physical function, stiffness,and pain on walking indicated similar benefitof the topical diclofenac over placebo in bothstudies. Likely due to the skin penetration en-hancer, dimethyl sulfoxide, 30 of the 84 pa-tients in the four-week study group and 68 of164 patients in the 12-week study group re-ported skin irritation (typically dryness), lead-ing to the discontinuation of five patients ineach of the treatment groups.49,50

Various novel NSAID patches or plastershave been developed, conferring a more con-stant delivery of a standardized dose of analge-sic (although individual skin variability affectsthe actual amount absorbed). A study by Galeret al. used a multicenter, randomized, paralleldesign to assess the efficacy of a topicaldiclofenac patch for treatment of pain fromsports-related soft tissue injuries, such assprains, strains, or contusions.51 A diclofenacepolamine 1.3% or placebo patch was appliedtwice daily on 222 patients for two weeks. Thestudy group achieved statistically significantpain intensity differences from placebo duringclinic visits on Day 3 (P¼ 0.036) and Day 14(P # 0.044) following treatment initiation,but not on Day 7. Forty percent of participantsgiven placebo reported AEs, while 34% ofstudy group patients reported side effects.51

A similar study comparing a diclofenac patchto placebo for patients with traumatic bluntsoft tissue injury found that the analgesic con-ferred a significantly beneficial effect over pla-cebo (P< 0.0001), as measured by tendernessproduced by pressure.52 Also, the time

required to reach pain resolution at the siteof injury was significantly shorter for the studygroup (P< 0.0001). The study and controlgroups experienced a similar frequency ofAEs, most commonly local cutaneous reac-tions.52 Finally, a placebo-controlled study ofpatients with pain due to ankle sprain assessedthe analgesia achieved by the application ofa 100 mg topical ketoprofen patch overa two-week period.8 There were significantlyfewer observations of spontaneous pain forthe study group compared to the controlgroup during all visits (Days 3e4, Day 7� 1,and Day 14� 2). Most notably, there wasa 49.9� 20.2 mm (�73%) decrease in painfrom baseline at Day 7� 1 for patients giventhe ketoprofen patch, compared to a37.6� 24.3 mm (�57%) decrease among thepatients given a placebo patch. The intergroupdifference in pain relief was significant(P¼ 0.0007), but the difference in AEs wasnot. Thirty-one percent of the study group and24% of the control group experienced AEs.8

Nitroglycerin (NTG)Topically applied NTG has been studied for

localized treatment of musculoskeletal pain.NTG may be converted to an anti-inflammatoryagentdnitric oxide (NO)dthat is released en-dogenously by activated macrophages.53 Treat-ment-generated NO may modulate theinflammatory process, as well as produceanalgesia through mechanisms directed at noci-ceptors, similar to the activity of cholinergicdrugs.53 For example, acetylcholine is a cholin-ergic agent that can induce analgesia by stimu-lating the release of NO, leading to anelevation of 3050 cyclic guanidine monophos-phate concentration in nociceptors.

A randomized, double-blind, placebo-controlled trial evaluated a 5 mg NTG patchfor relief of shoulder pain when applied dailyover a three-day period. While no change inpain intensity was observed in the controlgroup, after 48 hours the NTG group reporteda significant decrease in pain intensity frombaseline, on a 0e10 analog scale (2� 0.3;P< 0.003). Two of 10 patients in the treatmentgroup experienced headache.53 Paoloni et al.examined the use of topical NO for the treat-ment of chronic extensor tendinosis in a ran-domized, placebo-controlled trial. Comparedto the placebo group, patients in the NO


group reported significantly reduced elbowpain while active at two weeks (P< 0.05), re-duced extensor tenderness at six and 12 weeks(P< 0.05), and an increase in wrist extensorstrength at 24 weeks (P< 0.05).54

Local AnestheticsTopical anesthetics likely provide pain relief

by reducing ectopic discharges from superficialsomatic nerves.13 A number of mechanisms thatcontribute to peripheral sensitization may bedecreased by topical anesthetics.55 Experimentsthat have used complete Freund’s adjuvant toinduce inflammation have shown a correlationbetween the upregulation of tetrodotoxin-resistant, voltage-gated sodium channels andan inflammatory state.56,57 As sodium channelsplay a fundamental role in the excitability ofneurons, alterations in their expression levelsor function can lead to the neuronal hyperexcit-ability observed in many types of chronic painconditions.58 Additionally, pharmacotherapieswhich block sodium channels have been shownto provide effective analgesia for the manage-ment of some types of chronic pain.58

The lidocaine patch 5% likely reduces theectopic transmission of pain signals to the dor-sal horn of the spinal cord by inhibiting abnor-mal sodium channels in dermal nociceptorsresiding in the area of the localized pain.59

The current basic mechanistic understandingof osteoarthritis suggests that pain is theresult of a chronic inflammatory state in in-tra-articular joints. Blocking upregulatedsodium channels in inflamed tissues from in-ducing aberrant transmissions may provideanalgesia.60 A two-week pilot study tested theability of the lidocaine patch 5% to provide an-algesia for 20 patients with knee osteoarthritis.At the completion of the trial, statistically sig-nificant improvements were observed for allWestern Ontario and McMaster Universitiessubscale scores of pain, as well as the compos-ite index (P< 0.01). Also, 84% of the patientsreported the achievement of moderate-to-complete global pain relief, while 90% ofthe patients had no observed erythema. How-ever, due to the lack of controls and small sam-ple size, further randomized, controlled trialswere recommended.59

Another open-label study used the Neuro-pathic Pain Scale to assess the analgesiaachieved by the application of the lidocaine

patch 5% for 100 patients with knee osteoar-thritis.61 All four composite measures weresignificantly improved (P< 0.001) followingtwo weeks of treatment. No treatment-relatedAEs were reported in the group given lido-caine patch 5% monotherapy.61

Finally, an open-label study of 137 patientswith knee osteoarthritis considered the use ofthe lidocaine patch 5% as add-on therapy toa stable analgesic regimen (e.g., acetamino-phen, NSAIDs, COX-2 inhibitors, tramadol,opioids).62 Following two weeks of treatmentonce daily with the lidocaine patch 5%, aver-age pain intensity scores decreased by 29%(4.2� 2.2) compared to baseline scores(5.9� 1.5; P< 0.001). Also, Brief Pain Inven-tory measurements of pain interference onquality of life decreased from 37.2� 13.7 atbaseline to 23.5� 15.1 at Week 2 (P< 0.001).Fourteen patients experienced treatment-related side effects that included headache(n¼ 4), dermatitis (n¼ 3), and taste distur-bance (n¼ 2). Although there were no seriousAEs reported, five patients discontinuedtreatment.62

Open-label trial evidence has suggested thatthe lidocaine patch 5% may be beneficial forpatients experiencing LBP as well. A six-week,nonrandomized trial conducted by Gimbelet al. considered the patch’s effectiveness foracute/subacute (<3 months, n¼ 21), short-term chronic (3e12 months, n¼ 33), orlong-term chronic (>12 months, n¼ 77)LBP.63 Compared to baseline, significant re-ductions in pain intensity were reported by pa-tients within all three categories, at both twoand six weeks (P # 0.007). Overall, 25 patientsreported treatment-related AEs; 20 of thoseAEs were mild-to-moderate in severity.63 A sim-ilarly designed study of 71 patients also foundsignificant improvement measured by the Neu-ropathic Pain Scale composite at Weeks 2 and6 (P< 0.001).1 Eleven patients reported der-mal side effects, while five patients reportedsystemic side effects (dizziness and nausea).1

Topical CounterirritantsCounterirritants, such as capsaicin, cam-

phor, menthol, and garlic, are a category ofanalgesics that excite and subsequently desen-sitize nociceptive sensory neurons.64 Althoughmany of the members of this group have hada long history of common medical use, it was


not until recently that their molecular mecha-nisms of action were elucidated. All of thesepungent plant derivatives act on the recentlyelucidated transient receptor potential (TRP)superfamily, a group of structurally similarion channels, such as TRPV1 (also called vanil-loid receptor subtype 1), TRPV3, TRPM8, andTRPA1.65 The superfamily is activated bycapsaicin, camphor, menthol, and garlic,respectively64 (Fig. 2). These thermosensitivereceptors detect a wide range of temperaturesranging from noxious heat to extreme cold, aswell as other stimuli, including acidic pH,lipids, changes in extracellular osmolarityand/or pressure, and depletion of intracellu-lar Ca2þ stores (Fig. 3).6,66 These proteins areexpressed in primary sensory neurons as wellas other tissues. Upon the activation of TRP re-ceptors, the release of calcitonin gene-relatedpeptide, SP, and other inflammatory neuro-transmitters are induced; hence, producinglocal irritation and inflammation.67 This canlead to two types of desensitization: 1) acuteor ‘‘pharmacologic’’ desensitization character-ized by a diminished response during a constantagonist application, and 2) over a longer pe-riod, tachyphylaxis or ‘‘functional’’ desensitiza-tion characterized by a reduction in responseafter many stimulations.64

As early as the 19th century, the selective ef-fects of capsaicin on sensory nerve fibers wererecognized.6 The spicy ingredient in chili pep-pers has been used to relieve neuropathicpain, uremic pruritus, and bladder overactivity,as well as for providing analgesia.68 Currently,nonprescription creams, lotions, and patchescontaining 0.025%e0.075% capsaicin byweight for treatment of musculoskeletal andneuropathic pains are available.69 When

applied topically, capsaicin has a biphasic phar-macologic effect on sensory neurons. The firstphase is characterized by the excitation and ac-tivation of TRPV1, while the second phase pro-duces analgesia from the depletion ofpronociceptive transmitters, including SP.70

There is significant pain, burning, itching,and cutaneous vasodilatation experiencedupon initial application due to excitation andsensitization of cutaneous C- and A-fiber noci-ceptors; however, the repeated application ofcapsaicin leads to the persistent desensitiza-tion of nociceptors during Phase 2.71

A systematic review of topical capsaicin forthe relief of musculoskeletal pain pooled theresults of three double-blind, placebo-controlled trials, summing up to 368 patientsin total.72 After four weeks of treatment withcapsaicin 0.025% or plaster, the mean re-sponse rate (the percentage of patients withat least 50% pain relief) was 38% (range,34%e42%), while the placebo response ratewas 25% (range, 17%e37%). The NNT was8.1 and approximately one-third of the pa-tients experienced local, treatment-relatedAEs.72 An older meta-analysis also reportedthat capsaicin cream provided better pain re-lief for osteoarthritis than placebo (odds ra-tio¼ 4.36; 95% CI¼ 2.77-6.88).73 However,products with low concentrations of capsaicinrequire multiple applications to provoke thedesensitization of nerves,68 and often contam-inate the patient’s personal surroundings(bed, contact lenses, etc.).6 Those hindrances,along with the side effect of burning and painupon application, reduce patient adherenceand concomitantly, the efficacy of the treat-ment.6,68 Yet due to the reversible desensitiza-tion of nociceptive C-fibers and lack of

Fig. 2. TRP family receptors and their thermosensitivity (adapted from Ref. 69).


Brain: burning pain sensation

Temperature>43ºC

Endogenous/exogenousagonists:

anandamide , 12-hydroxyeicosatetraenoic acid,

N-oleoyldopamine,capsaicin, resiniferatoxin,

olvanil, DA-5016, SDZ 249-665, civamide, and

camphor

Spinal cord

Sensory neuron

Peripheral nerve

Action potential

Intracellular Ca2+ signal and depolarization

Cell membrane

Ca2+

Na+

AcidosispH<6

H+O

O

HO

NH

Fig. 3. Acute activation of the TRPV1 receptor leads to local intracellular calcium signals and the sensation ofheat or burning pain. TRPV-transient receptor potential vanilloid. Reprinted with permission from Ref. 6.

systemic side effects, topical capsaicin was rec-ommended by the European League AgainstRheumatism (EULAR) in 2003 for the treat-ment of knee osteoarthritis.47

The potent analog of capsaicin, resinifera-toxin (RTX), is an extract from the resin ofthe Euphorbia cactus.6 RTX induces a slower de-polarization and influx of Ca2þ into C-fibers74

and induces less pain upon application.68 De-spite some promising clinical trial results fortreating detrusor hyperreflexia and bladderhyperreflexia,68 RTX has not been approvedfor use within the United States.

Camphor is derived from the wood of thecamphor laurel tree (Cinnamomum camphora)and historically, the sweet-smelling compoundhas had many medicinal uses, including as a de-congestant, cough suppressant, and antipruriticagent.64 Over-the-counter camphor-containingbalms have also been used to provide analgesia.Recent research has implicated three receptorsin camphor’s mechanism of action, TRPV3, thecapsaicin receptordTRPV1, and the garlicreceptordTRPA1.64

The analgesic capacity of the compounds ingarlic (allicin and diallyl disulfide) have notbeen well-explored, although they have beenoften used to treat hypertension, high bloodcholesterol, and thrombosis.67 Allicin anddiallyl disulfide both bear a structural resem-blance to the components in mustard plantswhich induce pain and inflammationdisothio-cyanates. Likewise, recent research has indi-cated that mustard and garlic depolarizesensory neurons specifically through activationof the TRPA1 receptor to elicit inflammatorypain.67,75

In contrast, mentholdthe component thatconfers mint smell and flavor to the Menthaspeciesdis often included in eutectic formula-tions of local anesthetic agents.76 Anecdotally,menthol induces tingling and cooling sensa-tions when applied topically. Menthol gener-ates analgesia through its Ca2þ channelblocking activity. In addition to bindingTRPM8,65,69 menthol binds k-opioid receptors,and possibly engenders analgesia throughboth mechanisms.76 Animal studies have


demonstrated that menthol can confer analge-sia following both noxious thermal and chem-ical stimuli.76 Furthermore, similar to otherterpenes, menthol is an effective topical per-meation enhancer for water-soluble drugs,such as the antidepressant, imipramine.77

Another type of counterirritant is topical ru-befacients containing salicylates. Although, ithas been postulated that analgesia is conferredby a mode different than that of NSAIDs, asyet, salicylates have an unidentified mecha-nism of action.78 Despite this, salicylates areoften found in many topical preparations.Randomized, clinical trial data describing theefficacy of salicylates for pain relief have beensystematically reviewed by Mason et al.78 Onlythree double-blind, placebo-controlled trialshave been published that consider the use oftopical salicylates for the treatment of acutemusculoskeletal pain. The study groups ex-hibited significantly better pain reductionsthan placebo (relative benefit¼ 3.6, 95% CI,2.4e5.6; NNT¼ 2.1, range, 1.7e2.8). Al-though the long-term efficacy data and thereporting of AEs were poor for chronic muscu-loskeletal pain, the information from six dou-ble blind, placebo-controlled trials indicateda relative benefit over control of 1.5 (range,1.3e1.9; NNT 5.3, range, 3.6e10.2).78

Other counterirritants often found in over-the-counter analgesic preparations includemarsh tea, peppermint oil, and poison ivy. Arandomized, controlled trial explored the useof a topical homeopathic gel that includedthe ingredients, Symphytum officinale (comfrey),Rhus toxicodendron (poison ivy), and Ledum pal-ustre (marsh tea) for the management of kneeosteoarthritis pain.79 The 86 patients that com-pleted the trial in the homeopathy groupreported a reduction in pain of 16.5 mm byvisual analogue scale, compared to an8.1 mm pain reduction by the 86 patients inthe piroxicam group. The difference betweenthe treatment groups was 8.4 mm (95% CI,0.8e15.9). Twelve patients within the homeop-athy group and 16 patients within the NSAIDgroup experienced an AE, causing five andnine patients, respectively, to withdraw fromthe study.79

Other AgentsHeat wraps are a popular therapy for back

pain, and the treatment has been

recommended by practice guidelines in boththe United States and the United Kingdomfor management of acute LBP.80 A random-ized, single-blind clinical trial compareda group of 113 patients treated with a 40�Cheat wrap for 8 hours per day to patients givenone of the two most common oral, nonpre-scription drugs in the United States: acetamino-phen (4,000 mg/day; n¼ 113) or ibuprofen (1,200 mg/day;n¼ 106).80 Significantly better mean pain reliefwas obtained by the heat-wrap therapy groupon Day 1, and then again by Days 3e4 (extendedmean pain relief¼ 2.61, compared to 1.68 foribuprofen, P¼ 0.0001 and 1.95 for acetamino-phen, P¼ 0.0009). Furthermore, lateral trunkmobility and disability significantly improvedfor the heat-wrap therapy group relative to thecomparators.80 Another randomized, controlledtrial also found better functional outcomes forpatients treated with low-level heat wraps thanfor the control group.81 Combining heat wrapswith directional, preference-based exercise fur-ther reduced disability scores after a week oftreatment to nearly half those of either therapyalone.81

For thousands of years, medicinal leecheshave been used for the treatment of variousdiseases, and more recently have offereda novel option for the treatment of venouscongestion in plastic surgery82,83 and inchronic musculoskeletal disorders.84 Leeches,Hirudo medicinalis, purportedly have biologi-cally active, anti-inflammatory and anticoagu-lant mediators within their saliva.85 Ina recent study, 24 patients with osteoarthritisof the knee were locally administered four tosix leeches for approximately 70 minutes,and compared with 27 patients treated witha 28-day regimen of topical diclofenac gel(300 mg, twice a day).84 The mean reductionin pain observed within the leech therapygroup was 53.5� 13.7 at baseline and19.3� 12.2 at Day 7. Compared with the diclo-fenac group (51.5� 16.8 at baseline and42.4� 19.27 at Day 7), there was a significantbetween-group difference (�23.9; CI, �32.8to �15.1; P< 0.001). However, 17 of the 24 pa-tients administered leeches experienced localitching, while none of the patients given topi-cal NSAIDs reported pruritus.84

Although the evidence-based literature indi-cates that systemic opioids are effective at


providing analgesia for a variety of painful con-ditions, topical preparations of opioids havenot been well-explored, with the exception ofsome studies of relief from painful skin ul-cers.86,87 Potentially, the local application ofopioids could minimize systemic side effects,such as sedation, respiratory depression, andnausea.88 A 2005 study followed three patientsadministered topical morphine in PLO gel forrelief of chronic arthritis pain.89 A satisfactorylevel of pain control was reported, althoughlikely due to the systemic absorption of theopioid, as indicated by urinalysis results.89 Fur-thermore, an animal study indicated potentialsynergy between topical lidocaine and topicalopioids.88 Possibly, combining different drugclasses to create a topical preparation that tar-gets multiple peripheral sites may enhance theanalgesia obtained. Preliminary results in ananimal model suggest that combining topicalmorphine with topical cannabinoid may im-prove the antinociceptive effects that areachieved, while reducing central nervous sys-tem exposure to opioid.90 Other precursoryresults suggest that topical cannabinoid prepa-rations may buffer emerging pain signals at pe-ripheral sites via CB1 receptors, while avoidingthe dysphoric side effects and abuse potentialof central-acting cannabinoid agents.91 Thispromising research could lead to the develop-ment of another agent in the armamentariumof topical analgesics.

ConclusionRecent research has significantly evolved our

understanding of the diverse mechanisms bywhich topical preparations induce analgesia.Many topical agents have significantly less sys-temic AEs than oral pharmacotherapies, whileproviding effective pain relief. In particular,topical NSAIDs have demonstrated benefitfor treating pain from acute and chronic mus-culoskeletal conditions, while topical lidocainehas provided effective peripheral analgesia forlocalized pain associated with joint and lowback ailments. Also, clinicians should becomefamiliar with over-the-counter topical prepara-tions for analgesia, as they are often used andcan contain ingredients with analgesic mecha-nisms supported by evidence in the literature.Furthermore, maintaining an understanding

of topical delivery systems, as new ones are de-veloped and others optimized, will be impor-tant to providing continuing best practice forpatients requiring diverse, multimodal optionsfor managing their pain.

References1. Galer BS, Gammaitoni AR, Oleka N, Jensen MP,

Argoff CE. Use of the lidocaine patch 5% in reduc-ing intensity of various pain qualities reported bypatients with low-back pain. Curr Med Res Opin2004;20(Suppl 2):S5eS12.

2. Luo X, Pietrobon R, Sun SX, Liu GG, Hey L.Estimates and patterns of direct health careexpenditures among individuals with back pain inthe United States. Spine 2004;29(1):79e86.

3. Woolf AD, Pfleger B. Burden of major musculo-skeletal conditions. Bull World Health Organ 2003;81(9):646e656. Epub 2003, Nov 2014.

4. Walker BF. The prevalence of low back pain:a systematic review of the literature from 1966 to1998. J Spinal Disord 2000;13(3):205e217.

5. Moskowitz RW, Holderbaum D. Clinical and lab-oratory findings in osteoarthritis. In: Koopman WJ,ed. Arthritis and allied conditions, 14th ed. Phila-delphia: Lippincott Williams & Wilkins, 2001:2216e2243.

6. Bley KR. Recent developments in transient re-ceptor potential vanilloid receptor 1 agonist-basedtherapies. Expert Opin Investig Drugs 2004;13(11):1445e1456.

7. Bridgman SA, Clement D, Downing A, et al.Population based epidemiology of ankle sprains at-tending accident and emergency units in the WestMidlands of England, and a survey of UK practicefor severe ankle sprains. Emerg Med J 2003;20(6):508e510.

8. Mazieres B, Rouanet S, Velicy J, Scarsi C,Reiner V. Topical ketoprofen patch (100 mg) forthe treatment of ankle sprain: a randomized,double-blind, placebo-controlled study. Am J SportsMed 2005;33(4):515e523.

9. Basbaum AI, Jessell TM. The perception ofpain. In: Kandel ER, Schwartz JH, Jessell TM, eds.Principles of neural science, 4th ed. New York:The McGraw-Hill Companies, 2000: 472e479.

10. Millan MJ. The induction of pain: an integrativereview. Prog Neurobiol 1999;57(1):1e164.

11. Kidd BL, Urban LA. Mechanisms of inflamma-tory pain. Br J Anaesth 2001;87(1):3e11.

12. Grosser T, Fries S, FitzGerald GA. Biological ba-sis for the cardiovascular consequences of COX-2 in-hibition: therapeutic challenges and opportunities.J Clin Invest 2006;116(1):4e15.


13. Galer BS. Topical medications. In: Loeser JD,Butler SH, Chapman CR, Turk DC, eds. Bonica’smanagement of pain, 3rd ed. Philadelphia: Lippin-cott Williams & Wilkins, 2001: 1736e1742.

14. Brown MB, Martin GP, Jones SA, Akomeah FK.Dermal and transdermal drug delivery systems: cur-rent and future prospects. Drug Deliv 2006;13(3):175e187.

15. Cleary GW. Transdermal delivery systems; a med-ical rationale. In: Shah VP, Maibach HI, eds. Topicaldrug bioavailability, bioequivalence, and penetra-tion. New York: Plenum Press, 1993: 17e68.

16. Henzl MR, Loomba PK. Transdermal delivery ofsex steroids for hormone replacement therapy andcontraception. A review of principles and practice.J Reprod Med 2003;48(7):525e540.

17. Kornick CA, Santiago-Palma J, Moryl N,Payne R, Obbens EA. Benefit-risk assessment oftransdermal fentanyl for the treatment of chronicpain. Drug Saf 2003;26(13):951e973.

18. Cramer MP, Saks SR. Translating safety, efficacyand compliance into economic value for controlledrelease dosage forms. Pharmacoeconomics 1994;5(6):482e504.

19. Varvel JR, Shafer SL, Hwang SS, Coen PA,Stanski DR. Absorption characteristics of transder-mally administered fentanyl. Anesthesiology 1989;70(6):928e934.

20. Yang SI, Park HY, Lee SH, et al. Transdermaleperisone elicits more potent and longer-lastingmuscle relaxation than oral eperisone. Pharmacol-ogy 2004;71(3):150e156.

21. Payne R, Mathias SD, Pasta DJ, et al. Quality oflife and cancer pain: satisfaction and side effectswith transdermal fentanyl versus oral morphine.J Clin Oncol 1998;16(4):1588e1593.

22. Jarupanich T, Lamlertkittikul S, Chandeying V.Efficacy, safety and acceptability of a seven-day,transdermal estradiol patch for estrogen replace-ment therapy. J Med Assoc Thai 2003;86(9):836e845.

23. Archer DF, Cullins V, Creasy GW, Fisher AC.The impact of improved compliance with a weeklycontraceptive transdermal system (Ortho Evra) oncontraceptive efficacy. Contraception 2004;69(3):189e195.

24. Frei A, Andersen S, Hole P, Jensen NH. A oneyear health economic model comparing transder-mal fentanyl with sustained-release morphine inthe treatment of chronic noncancer pain. J PainPalliat Care Pharmacother 2003;17(2):5e26.

25. Bos JD, Meinardi MM. The 500 Dalton rule forthe skin penetration of chemical compounds anddrugs. Exp Dermatol 2000;9(3):165e169.

26. Yano T, Nakagawa A, Tsuji M, Noda K. Skin per-meability of various non-steroidal anti-inflammatorydrugs in man. Life Sci 1986;39(12):1043e1050.

27. Southwell D, Barry BW, Woodford R. Variationsin permeability of human skin within and betweenspecimens. Int J Pharm 1984;18:299e309.

28. Larsen RH, Nielsen F, Sorensen JA, Nielsen JB.Dermal penetration of fentanyl: inter- and intraindi-vidual variations. Pharmacol Toxicol 2003;93(5):244e248.

29. Steinstrasser I, Merkle HP. Dermal metabolismof topically applied drugs: pathways and models re-considered. Pharm Acta Helv 1995;70(1):3e24.

30. Hogan DJ, Maibach HI. Adverse dermatologicreactions to transdermal drug delivery systems.J Am Acad Dermatol 1990;22(5 Pt 1):811e814.

31. Carmichael AJ. Skin sensitivity and transdermaldrug delivery. A review of the problem. Drug Saf1994;10(2):151e159.

32. Murphy M, Carmichael AJ. Transdermal drugdelivery systems and skin sensitivity reactions. Inci-dence and management. Am J Clin Dermatol 2000;1(6):361e368.

33. Datamonitor. United Statesdanalgesics. NewYork, NY. Reference code 72e751. Available from.www.datamonitor.com. Accessed January 28, 2007.

34. Ness TJ, Jones L, Smith H. Use of compoundedtopical analgesicsdresults of an Internet survey.Reg Anesth Pain Med 2002;27(3):309e312.

35. Vaile JH, Davis P. Topical NSAIDs for musculo-skeletal conditions. A review of the literature. Drugs1998;56(5):783e799.

36. Heyneman CA, Lawless-Liday C, Wall GC. Oralversus topical NSAIDs in rheumatic diseases: acomparison. Drugs 2000;60(3):555e574.

37. Kumar R, Katare OP. Lecithin organogels asa potential phospholipid-structured system for topi-cal drug delivery: a review. AAPS PharmSciTech2005;6(2):E298eE310.

38. Franckum J, Ramsay D, Das NG, Das SK.Pluronic lecithin organogel for local delivery ofanti-inflammatory drugs. Int J PharmaceuticalCompounding 2004;8(2):101e105.

39. Yamane MA, Williams AC, Barry BW. Terpenepenetration enhancers in propylene glycol/waterco-solvent systems: effectiveness and mechanism ofaction. J Pharm Pharmacol 1995;47(12A):978e989.

40. Assandri A, Canali S, Giachetti C. Local tolera-bility and pharmacokinetic profile of a newtransdermal delivery system, diclofenac hydroxye-thylpyrrolidine plaster. Drugs Exp Clin Res 1993;19(3):89e95.

41. Tegeder I, Muth-Selbach U, Lotsch J, et al. Ap-plication of microdialysis for the determination ofmuscle and subcutaneous tissue concentrations af-ter oral and topical ibuprofen administration. ClinPharmacol Ther 1999;65(4):357e368.

42. Rolf C, Engstrom B, Beauchard C, Jacobs LD,Le Liboux A. Intra-articular absorption and distribu-tion of ketoprofen after topical plaster application

http://www.datamonitor.com


and oral intake in 100 patients undergoing kneearthroscopy. Rheumatology (Oxford) 1999;38(6):564e567.

43. Moore RA, Tramer MR, Carroll D, Wiffen PJ,McQuay HJ. Quantitative systematic review of topi-cally applied non-steroidal anti-inflammatory drugs.Br Med J 1998;316(7128):333e338.

44. Mason L, Moore RA, Edwards JE, Derry S,McQuay HJ. Topical NSAIDs for acute pain: a meta-analysis. BMC Fam Pract 2004;5:10.

45. Lin J, Zhang W, Jones A, Doherty M. Efficacy oftopical non-steroidal anti-inflammatory drugs in thetreatment of osteoarthritis: meta-analysis of rando-mised controlled trials. Br Med J 2004;329(7461):324.

46. Scott DL, Shipley M, Dawson A, et al. The clin-ical management of rheumatoid arthritis and osteo-arthritis: strategies for improving clinicaleffectiveness. Br J Rheumatol 1998;37(5):546e554.

47. Jordan KM, Arden NK, Doherty M, et al.EULAR recommendations 2003: an evidence basedapproach to the management of knee osteoarthritis.Report of a Task Force of the Standing Committeefor International Clinical Studies Including Thera-peutic Trials (ESCISIT). Ann Rheum Dis 2003;62(12):1145e1155.

48. American College of Rheumatology Subcom-mittee on Osteoarthritis Guidelines. Recommenda-tions for the medical management ofosteoarthritis of the hip and knee: 2000 update.Arthritis Rheum 2000;43(9):1905e1915.

49. Bookman AA, Williams KS, Shainhouse JZ. Ef-fect of a topical diclofenac solution for relievingsymptoms of primary osteoarthritis of the knee:a randomized controlled trial. CMAJ 2004;171(4):333e338.

50. Roth SH, Shainhouse JZ. Efficacy and safety ofa topical diclofenac solution (pennsaid) in the treat-ment of primary osteoarthritis of the knee: a ran-domized, double-blind, vehicle-controlled clinicaltrial. Arch Intern Med 2004;164(18):2017e2023.

51. Galer BS, Rowbotham M, Perander J, Devers A,Friedman E. Topical diclofenac patch relieves mi-nor sports injury pain: results of a multicenter con-trolled clinical trial. J Pain Symptom Manage 2000;19(4):287e294.

52. Predel HG, Koll R, Pabst H, et al. Diclofenacpatch for topical treatment of acute impact injuries:a randomised, double blind, placebo controlled,multicentre study. Br J Sports Med 2004;38(3):318e323.

53. Berrazueta JR, Losada A, Poveda J, et al. Suc-cessful treatment of shoulder pain syndrome dueto supraspinatus tendinitis with transdermal nitro-glycerin. A double blind study. Pain 1996;66(1):63e67.

54. Paoloni JA, Appleyard RC, Nelson J,Murrell GA. Topical nitric oxide application in the

treatment of chronic extensor tendinosis at theelbow: a randomized, double-blinded, placebo-controlled clinical trial. Am J Sports Med 2003;31(6):915e920.

55. Jensen TS, Gottrup H, Kasch H, et al. Has basicresearch contributed to chronic pain treatment?Acta Anaesthesiol Scand 2001;45(9):1128e1135.

56. Gould HJ 3rd, England JD, Liu ZP, Levinson SR.Rapid sodium channel augmentation in response toinflammation induced by complete Freund’s adju-vant. Brain Res 1998;802(1e2):69e74.

57. Gould HJ 3rd, Gould TN, Paul D, et al. Develop-ment of inflammatory hypersensitivity and augmen-tation of sodium channels in rat dorsal root ganglia.Brain Res 1999;824(2):296e299.

58. Lai J, Porreca F, Hunter JC, Gold MS. Voltage--gated sodium channels and hyperalgesia. AnnuRev Pharmacol Toxicol 2004;44:371e397.

59. Galer BS, Sheldon E, Patel N, et al. Topical lido-caine patch 5% may target a novel underlying painmechanism in osteoarthritis. Curr Med Res Opin2004;20(9):1455e1458.

60. Amir R, Argoff CE, Bennett GJ, et al. The role ofsodium channels in chronic inflammatory and neu-ropathic pain. J Pain 2006;7(5 Suppl 3):S1eS29.

61. Gammaitoni AR, Galer BS, Onawola R,Jensen MP, Argoff CE. Lidocaine patch 5% and itspositive impact on pain qualities in osteoarthritis:results of a pilot 2-week, open-label study usingthe Neuropathic Pain Scale. Curr Med Res Opin2004;20(Suppl 2):S13eS19.

62. Burch F, Codding C, Patel N, Sheldon E. Lido-caine patch 5% improves pain, stiffness, and physi-cal function in osteoarthritis pain patients. Aprospective, multicenter, open-label effectivenesstrial. Osteoarthr Cartil 2004;12(3):253e255.

63. Gimbel J, Linn R, Hale M, Nicholson B. Lido-caine patch treatment in patients with low backpain: results of an open-label, nonrandomized pilotstudy. Am J Ther 2005;12(4):311e319.

64. Xu H, Blair NT, Clapham DE. Camphor activatesand strongly desensitizes the transient receptorpotential vanilloid subtype 1 channel in a vanilloid-independent mechanism. J Neurosci 2005;25(39):8924e8937.

65. Tominaga M, Caterina MJ. Thermosensationand pain. J Neurobiol 2004;61(1):3e12.

66. Gunthorpe MJ, Benham CD, Randall A,Davis JB. The diversity in the vanilloid (TRPV) re-ceptor family of ion channels. Trends PharmacolSci 2002;23(4):183e191.

67. Bautista DM, Movahed P, Hinman A, et al. Pun-gent products from garlic activate the sensory ionchannel TRPA1. Proc Natl Acad Sci USA 2005;102(34):12248e12252.


68. Szallasi A. Vanilloid (capsaicin) receptors inhealth and disease. Am J Clin Pathol 2002;118(1):110e121.

69. McKemy DD, Neuhausser WM, Julius D. Identi-fication of a cold receptor reveals a general role forTRP channels in thermosensation. Nature 2002;416(6876):52e58.

70. Szallasi A, Blumberg PM. Vanilloid (capsaicin)receptors and mechanisms. Pharmacol Rev 1999;51(2):159e212.

71. Carpenter SE, Lynn B. Vascular and sensory re-sponses of human skin to mild injury after topicaltreatment with capsaicin. Br J Pharmacol 1981;73(3):755e758.

72. Mason L, Moore RA, Derry S, Edwards JE,McQuay HJ. Systematic review of topical capsaicinfor the treatment of chronic pain. Br Med J 2004;328(7446):991.

73. Zhang WY, Li Wan Po A. The effectiveness oftopically applied capsaicin. A meta-analysis. Eur JClin Pharmacol 1994;46(6):517e522.

74. Robbins W. Clinical applications of capsaici-noids. Clin J Pain 2000;16(2 Suppl):S86eS89.

75. Bautista DM, Jordt SE, Nikai T, et al. TRPA1mediates the inflammatory actions of environmen-tal irritants and proalgesic agents. Cell 2006;124(6):1269e1282.

76. Galeotti N, Di Cesare Mannelli L, Mazzanti G,Bartolini A, Ghelardini C. Menthol: a natural anal-gesic compound. Neurosci Lett 2002;322(3):145e148.

77. Jain AK, Thomas NS, Panchagnula R. Transder-mal drug delivery of imipramine hydrochloride. I.Effect of terpenes. J Control Release 2002;79(1e3):93e101.

78. Mason L, Moore RA, Edwards JE, et al. System-atic review of efficacy of topical rubefacients con-taining salicylates for the treatment of acute andchronic pain. Br Med J 2004;328(7446):995.

79. van Haselen RA, Fisher PA. A randomizedcontrolled trial comparing topical piroxicam gelwith a homeopathic gel in osteoarthritis of theknee. Rheumatology (Oxford) 2000;39(7):714e719.

80. Nadler SF, Steiner DJ, Erasala GN, et al. Contin-uous low-level heat wrap therapy provides more effi-cacy than ibuprofen and acetaminophen for acutelow back pain. Spine 2002;27(10):1012e1017.

81. Mayer JM, Ralph L, Look M, et al. Treatingacute low back pain with continuous low-level heatwrap therapy and/or exercise: a randomized con-trolled trial. Spine J 2005;5(4):395e403.

82. Daane S, Zamora S, Rockwell WB. Clinical useof leeches in reconstructive surgery. Am J Orthop1997;26(8):528e532.

83. Gideroglu K, Yildirim S, Akan M, Akoz T. Imme-diate use of medicinal leeches to salvage venouscongested reverse pedicled neurocutaneous flaps.Scand J Plast Reconstr Surg Hand Surg 2003;37(5):277e282.

84. Michalsen A, Klotz S, Ludtke R, et al. Effective-ness of leech therapy in osteoarthritis of the knee:a randomized, controlled trial. Ann Intern Med2003;139(9):724e730.

85. Markwardt F. Pharmacology of hirudin: onehundred years after the first report of the anticoag-ulant agent in medicinal leeches. Biomed BiochimActa 1985;44(7e8):1007e1013.

86. Porzio G, Aielli F, Verna L, et al. Topical mor-phine in the treatment of painful ulcers. J PainSymptom Manage 2005;30(4):304e305.

87. Gallagher RE, Arndt DR, Hunt KL. Analgesic ef-fects of topical methadone: a report of four cases.Clin J Pain 2005;21(2):190e192.

88. Kolesnikov YA, Chereshnev I, Pasternak GW.Analgesic synergy between topical lidocaine andtopical opioids. J Pharmacol Exp Ther 2000;295(2):546e551.

89. Wilken M, Ineck JR, Rule AM. Chronic arthritispain management with topical morphine: case se-ries. J Pain Palliat Care Pharmacother 2005;19(4):39e44.

90. Yesilyurt O, Dogrul A, Gul H, et al. Topical can-nabinoid enhances topical morphine antinocicep-tion. Pain 2003;105(1e2):303e308.

91. Dogrul A, Gul H, Akar A, et al. Topical cannabi-noid antinociception: synergy with spinal sites. Pain2003;105(1e2):11e16.

topical agents for the management of musculoskeletal pain › wp-content › uploads ›...

Documents