Drugs Aging DOI 10.1007/s40266-014-0218-9

LEADING ARTICLE

Topical Analgesics for Neuropathic Pain in the Elderly: Current and Future Prospects Jana Sawynok

Ó Springer International Publishing Switzerland 2014

Abstract Neuropathic pain (NeP) is a significant medical and socioeconomic burden with limited therapeutic options. Elderly patients exhibit a higher incidence of several NeP conditions and pose a particular challenge due to age-related pharmacokinetic and pharmacodynamic issues, comorbid conditions, and polypharmacy, as well as frailty and cognitive decline. Topical analgesics are of interest because of their comparable efficacy to oral agents, good tolerability and safety, and potential to be add-on therapies to oral treatments. In recent years, two topical formulations for NeP have been approved (5 % lidocaine medicated plaster, 8 % capsaicin patch) but are not available in all countries. There are controlled trials and a growing body of open-label reports on their use in clinical care. Some studies provide a post hoc analysis of data in relation to older age (C65 years), which is useful. The body of evidence relating to topical investigational agents is growing and involves controlled trials as well as individual cases. The largest single body of information is for topical ketamine, administered either alone or combined with other agents (particularly amitriptyline), and some large randomized controlled trials report efficacy. Other large trials involve topical clonidine and further ketamine combinations. Compounding analgesics involves challenges, including uncertain composition (two to five ingredients are used) and concentrations (range 0.5–5 %), as well as the heterogeneity of data that support choices. Nevertheless, case reports and acceptable response rates in larger cohorts are intriguing, and this area merits further investigation in controlled settings as well as continued documentation of clinical experiences. J. Sawynok (&) Department of Pharmacology, Dalhousie University, Halifax, NS B3H 4R2, Canada e-mail: [email protected]

Key Points The pharmacological management of neuropathic pain in the elderly involves unique challenges, and this area merits direct attention to further inform treatment options. In recent years, two topical formulations have been approved for some forms of neuropathic pain, although these are not available in all countries. Ongoing exploration of topical formulations of investigational agents, using a variety of trial designs, provides promising lead information relating to additional potential treatment options.

1 Introduction Neuropathic pain (NeP) is defined as pain occurring as a direct consequence of a lesion or disease affecting the somatosensory system [1]. NeP can be caused by trauma, metabolic changes, ischemic events, drug or chemotherapy toxic events, infective agents, immune-mediated events, and genetic variations. It includes focal peripheral neuropathies (e.g. post-herpetic or post-traumatic neuralgias), generalized or polyneuropathies (e.g. metabolic disorders, drug or toxin-induced neuropathy), lesions to the central nervous system (e.g. spinal cord injury, multiple sclerosis, vascular lesions to brainstem and thalamus), complex disorders (e.g. complex regional pain syndrome), and mixed pain syndromes (e.g. chronic low back pain with radiculopathy) [2, 3]. Characteristic features include negative signs and symptoms (hypoesthesia, hypoalgesia),

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spontaneous pain/sensations (burning pain, paroxysmal pain, paresthesia), and hyperalgesia (in response to mechanical or thermal stimulation), and different aspects are attributed to distinct mechanisms [3–5]. Both peripheral mechanisms (involving sensory nerve endings and dorsal root ganglia) and central mechanisms (involving the dorsal spinal cord, supraspinal projection, and bulbospinal modulation pathways) are implicated in generating NeP [3–5]. Topical analgesics are drugs applied locally to the surface of the skin (usually as patches, gels, or creams) with local actions in the tissue on sensory nerve endings and adjacent cellular structures such as immune cells and keratinocytes. They differ from transdermal analgesics, where drugs are absorbed into the systemic circulation and act at remote sites within the central nervous system (e.g. fentanyl, buprenorphine). Topical analgesics, as a drug class, are of interest due to their low systemic drug levels and minimal systemic side effects and drug interactions [6, 7], and these properties make them attractive options for the elderly, either as monotherapies or as potential add-on therapies to oral analgesics. Topical non-steroidal antiinflammatory drugs (NSAIDs) are recommended for the treatment of osteoarthritis [8, 9], and may be of particular use in the elderly due to their comparable efficacy to oral NSAIDs but better tolerability [10, 11]. Topical analgesics are also emerging as a useful class of agents for the treatment of NeP [12, 13], and applications for the elderly are now being considered. The purpose of this article is to consider challenges of NeP in the elderly, the evidence for approved topical analgesics, and the evidence and challenges relating to topical investigational or compounded agents with implications for pain management in the elderly.

2 Prevalence of Neuropathic Pain A recent systematic review of epidemiological studies of NeP published to the end of 2012 is available [14]. The prevalence of chronic pain with NeP characteristics depends on methods used to derive the information and ranged from 3.3 to 17.9 %, but best estimates were 7–10 % [14]. These numbers are similar to those reported in an earlier synthesis of epidemiological data (6–8 %) [15]. Several studies have considered the prevalence of NeP throughout the lifespan, and age generally C50 years is a risk factor [16–20]. NeP is associated with poor general health, impaired quality of life, and significant healthcare costs [21–23]. The most common individual NeP conditions are postherpetic neuralgia (PHN), painful diabetic peripheral neuropathy (DPN), and trigeminal neuralgia (TGN) [14]. These conditions have incidence rates of PHN 3.9–42.0

per 100,000 person-years (PY), PDN 15.3–72.3 per 100,000 PY, and TGN 12.6–28.9 per 100,000 PY; less common conditions are glossopharyngeal neuralgia with an incidence rate of 0.2–0.4 per 100,000 PY, and phantom limb pain with 0.8–1.5 per 100,000 PY [14]. With age, generally C50 years but especially C60 years, the prevalence of PHN and DPN increases markedly [24–28]. TGN and other facial neuralgias occur throughout adulthood and also increase with age, but more gradually [24– 26].

3 Management of Neuropathic Pain in the Elderly With advancing age, and especially in those considered to be older or elderly (C65 years), increasing numbers of health conditions develop. By age 75–80 years, many exhibit chronic illness, often multiple illnesses, and increasing frailty. Persistent or chronic pain ([3 or 6 months) is common, and the assessment and pharmacological management of chronic pain in the elderly represent distinct fields of investigation [29–32]. Principles for pain management in the elderly are derived from evidencebased sources, but a limitation is that while older people are included in many chronic pain studies, few trials focus specifically on older cohorts or conduct subgroup analyses according to age [29–32]. Several factors require consideration: (1) clinical manifestations of pain can be complex and confounded by comorbidities, (2) older individuals may under-report pain due to appraisal factors (attitudes, beliefs) or cognitive impairment, (3) polypharmacy is common and can lead to poor adherence and increased likelihood of drug interactions, (4) there are age-related differences in pharmacokinetics of drugs (decreased absorption, altered distribution due to altered composition of body compartments, decreased hepatic metabolism and renal clearance), (5) older individuals are more likely to experience medication-related adverse effects (pharmacodynamics), especially those due to central nervous system actions. Systemic pharmacotherapy for NeP includes antidepressants (tricyclic antidepressants [TCAs], serotonin noradrenaline reuptake inhibitors), anticonvulsants, opioids, and adjuvant analgesics [33–36]. Antidepressants and gabapentinoids (TCAs, duloxetine, venlafaxine, gabapentin, pregabalin) are considered first-line therapies, while tramadol and other opioids are second-line options. A diverse class of agents known as adjuvants (lamotrigine and other anticonvulsants, cannabinoids, ketamine, botulinum toxin) were still finding their place in guidelines published up to 2010, were generally considered as third-line options [33– 36], and continue to be explored [37, 38]. TGN is treated with carbamazepine and oxcarbazepine as first-line agents,

Topical Analgesics for Neuropathic Pain in the Elderly

with baclofen, pregabalin, and other agents as secondary options [39, 40]. Glossopharyngeal neuralgia is treated as for TGN, while trigeminal NeP is managed with general NeP options [40]. In the elderly, systemic treatment of NeP requires more careful dosing (usually lower), titration (usually slower), and monitoring (for efficacy, adverse effects) than in younger patients due to drug factors (altered pharmacokinetics and pharmacodynamics) and patient factors (comorbidities, polypharmacy, frailty) [41, 42]. Despite the availability of several options, treatment of NeP is not optimal, as medications provide only a partial effect and adverse effects can limit dose escalation, resulting in suboptimal dosing. An often quoted perspective is that B50 % experience satisfactory pain relief, and side effects are common [43]. To address this limitation, combinations of different drug classes are being explored, with the rationale that augmented analgesia may occur due to different mechanisms (synergy or additivity) but side effects may differ (drugs represent different classes) and be within tolerable limits. Combinations include oral formulations of first-line agents (e.g. gabapentin/pregabalin ? nortriptyline) or first- and second-line agents (e.g. gabapentin/amitriptyline ? opioid), and some trials show superiority of combinations over monotherapy [44, 45]. Additional lines of exploration involve comparisons of low-dose combinations (duloxetine ? pregabalin) with high-dose monotherapy, as this may improve tolerability [46]. Oral combination therapies involving drugs with adverse central nervous system effects (e.g. sedation, dizziness, effects on cognition) require particular attention in the elderly. Because of the good tolerability of topical analgesics compared with oral medications, this class of agents represents a rational and potentially viable approach to combination therapy.

4 Topical Analgesics and Pain in the Elderly 4.1 5 % Lidocaine Medicated Plaster Topical 5 % lidocaine medicated plaster (5%LMP) is approved for use in the USA (since 1999), the UK (since 2007), and several European, Latin American, and Middle Eastern countries for treatment of PHN [47–49]. The 10 9 14 cm plaster consists of a lidocaine-containing hydrogel, with a liner and backing; up to three plasters are recommended for daily application (maximum of 12 h); approximately 3 % reaches the systemic circulation, and low systemic exposure makes pharmacokinetic drug interactions unlikely. While not specifically approved for other conditions, 5%LMP exhibits efficacy in several forms of NeP, but such trials are generally small, or are open-

label or case studies, and use in these conditions requires further validation [49–51]. Topical 5%LMP is considered a first-line therapy for PHN [33, 34, 36], and both placebo-controlled and effectiveness trials support its use for this indication [48, 49, 52– 55]. Localized NeP, which is consistent and circumscribed areas of pain, accounts for approximately 60 % of NeP (range 32–83; 83 % for PHN) [56] and is considered to predispose to better outcomes with 5%LMP [57, 58]. Anatomical location also can be a factor, as perceived benefits of 5%LMP in PHN when applied to the head, trunk, or extremities can be similar, but it is better tolerated at latter sites [59]. When applied for extended intervals, 5%LMP provides long-term pain relief for PHN and other conditions in a proportion of those who initially respond [60, 61]. 5%LMP produces effects comparable to oral firstline treatments for PHN and is well tolerated compared with such treatments in both direct and indirect comparisons [55, 62]. 5%LMP is considered cost effective for PHN compared with gabapentin and pregabalin in several different countries [63]. 5%LMP also exhibits efficacy in DPN [64]. PHN is more common in the elderly (Sect. 2), and treatment guidelines emphasize the use of 5%LMP for the elderly [33, 34]. The mean age of those who participate in PHN trials can be 64–74 years [52–55, 61], and results of such trials are applicable to elderly populations. Some studies have performed subgroup analysis of those aged C70 years in relation to the general study population [65, 66]. In a pragmatic trial examining use of 5%LMP in those in whom prior PHN treatment was inadequate, not tolerated, or contraindicated, Cle`re et al. [65] reported a reduction in concomitant medications (especially TCAs and step 3 analgesics) in both the general study population and the elderly group, and considered improved polymedication status and good tolerability as support for the use of 5%LMP in the elderly. Delorme et al. [66] noted similar response rates and good tolerability in the overall study population and the C70 years subgroup in an open-label effectiveness trial of refractory mixed NeP conditions (76 % due to conditions other than PHN). A recent study examined cognitive function in elderly patients (mean age 73 years) with PHN treated with oral medications or 5%LMP, and reported better cognitive outcomes with 5%LMP than with oral medications [67]. These specific observations in older populations support general treatment guideline recommendations regarding the use of topical analgesics in the elderly. No single pharmacological approach is universally effective for NeP. The responder rate for 5%LMP for PHN is 52–66 % [53–55] and similar to that observed with oral PHN treatment in a direct comparison [55]. For those with an inadequate response to monotherapy (oral or topical), a

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combination 5%LMP ? oral medication can provide further pain relieving effects [68]. The merit of considering a topical analgesic in combination with a suboptimal oral medication is that improved efficacy can be observed without necessarily adding to the adverse effect burden, and this issue is particularly relevant to elderly populations. Another benefit of adding LMP to an ongoing oral therapy is the potential for a reduction in oral medications (analgesic sparing effect) in both general populations and elderly patients, which can lead to fewer adverse effects and improved quality of life [65]. 4.2 Topical Capsaicin Topical formulations of low-concentration capsaicin creams (0.025–0.075 %) have been available for musculoskeletal pain and NeP since the early 1980s [69]. There are a limited number of trials of such creams for NeP [70], and while there is some evidence of efficacy of 0.075 % compared with placebo, there is considerable trial heterogeneity and this precludes pooled analysis; furthermore, application site reactions occur and there is concern over the ability to blind studies [71]. Low-concentration creams are regarded as third-line options for NeP in treatment guidelines and algorithms [33, 34, 36]. A high-concentration capsaicin patch (8 % in an adhesive layer, NGX-4010) was approved for use for PHN in the USA and for peripheral NeP (non-diabetic) in several EU countries in 2009 [69, 70, 72]. The patch is generally applied for 30 or 60 mins (depending on the site), and application site reactions (most common are pain, erythema, edema, pruritus) are managed with topical local anesthetics (applied prior to patch application), cooling (following patch application), and oral analgesics (as needed). In controlled studies, the 8 % capsaicin patch has been compared with an ultra-low-concentration patch (0.04 %), which permits blinding, and significantly reduces pain due to PHN compared with that control condition [73– 76]. Meta-analysis of PHN data indicates significant reductions in pain 2–12 weeks following patch application, with a C30 % pain reduction in 44 % of patients and complete pain relief in 7–11 %; the mean onset time was 3.4 days, with a mean duration of analgesia of 5 months [77]. The 8 % capsaicin patch also reduces pain due to HIV-associated neuralgia, with similar response rates (41 % for C30 % pain reduction, 7 % for complete pain relief) but varied onset time (6.5 days) and duration (3 months) [77, 78]. An integrated analysis of tolerability indicates that nearly all tolerate NGX-4010 to C90 % of the treatment duration; 54–64 % used medications for application-related pain, and a similar incidence of medication use occurred with repeat applications (up to four times) [79].

Additional information on experiences using the 8 % capsaicin patch for NeP is now available following use in clinical settings involving more varied etiology, although PHN and mononeuropathy are the majority conditions. Treede et al. [80] report on 189 patients (287 patch applications) with mixed NeP, with 174 follow-ups to 12 weeks; they report a responder rate of 38 % for C30 % pain reduction, with similar outcomes at 1, 4, and 12 weeks; efficacy was maintained in the subgroup that underwent repeat treatments. Wagner et al. [81] report on 68 patients (96 patch applications); 53 had follow-up data to 8 weeks and exhibited an overall responder rate of 70 % for C30 % pain reduction, and 57 % for C50 % reduction. The authors speculate that the higher response rates they observed compared with controlled trials may reflect optimized patch application technique (included bandaging, sandbagging to optimize dermal contact). Importantly, there was a significant reduction in concomitant oral pain medications for NeP following patch treatment [81]. A further management perspective on experiences with [200 patients noted that, although generally recommended in product prescribing information, pretreatment with topical local anesthetics may not always be necessary, cooling measures after application are the most practical and beneficial for reducing site discomfort, and only a minimal number of patients require oral analgesics for application site pain [82]. Supporting this observation, a study directly comparing tolerability and efficacy of the 8 % capsaicin patch for those pretreated with topical lidocaine (with systemic co-treatment) reported similar outcomes in the two groups [83]. Factors considered to be positive predictors for treatment success are positive symptoms, a single NeP condition, and a definite NeP diagnosis [82]. Information on sensory profiles was considered potentially helpful in making predictions, but remains to be validated [80]. The use of the 8 % capsaicin patch may be limited by time (2 h needed for treatment) and cost, although it has been proposed that, with further experience, physician supervision may not be necessary [84]. A cost-effectiveness assessment for PHN indicates a similar cost for the capsaicin patch in relation to topical 5%LMP [85]. The mean age of participants in individual controlled trials for PHN ranges from 70 to 74 years, with a mean of 70.8 (standard deviation [SD] 11.7) years [77, 78]. One integrated analysis considered age ranges, and indicated that 75 % of patients were aged C65 years, with 42 % aged C75 years [79]. Results of these studies are clearly relevant to elderly populations. Additional post hoc agerelated comparisons (e.g. outcomes in those aged \65 or 70 and aged C65 or 70 years) are possible on these datasets, as has been done for studies of topical NSAIDs [10, 11] and topical 5%LMP [65, 66]. Polypharmacy is

Topical Analgesics for Neuropathic Pain in the Elderly

common in the elderly, and some reported observations are relevant to this issue. An integrated analysis of responses to the capsaicin patch in controlled trials compared results in those taking concomitant oral NeP medications and those who were not (mean age 70–71 years), and noted a significant effect in both groups, although those not using systemic medications reported an overall greater pain reduction (36.5 vs. 26.1 %) [86]. An observational study of oral analgesic medication use before and after application of the capsaicin patch for mixed NeP in clinical practice indicates that oral pain medications (opioids, anticonvulsants, antidepressants) were discontinued by 55–57 % and reduced in a further 11–18 %; however, the mean age of 59.9 (SD 13.3) years in that study was lower than in the PHN studies, reflecting the more diverse pain etiology [81]. Additional analysis of oral medication use before and after use of the capsaicin patch, which is stratified for age, especially in observational trials of clinical practice where oral medications do not need to remain constant due to protocol issues, will provide valuable further information on management of NeP in the elderly. 4.3 Topical Investigational Agents Topical analgesics involve an additional diverse class of agents that are classified according to other indications (e.g. antidepressants) or according to their mechanism of action. These agents are not currently approved for use, are collectively considered as investigational agents, and include experimental and compounded agents. Several recent reviews have specifically considered topical analgesics, including investigational agents, for NeP [12, 13, 87, 88]. Table 1 lists agents that have been reported to produce analgesia in NeP conditions. It illustrates (1) the diversity of pharmacological agents used, (2) the diversity of conditions in which they are applied (the neuropathic component is not well defined in several instances), and (3) the heterogeneity of the nature of the evidence that is available. Several comments can be made regarding this diverse dataset. (1) Randomized controlled trials (RCTs). The number of RCTs for compositions for particular NeP conditions is limited but growing. While many individual trials are small and exploratory and involve N B 30 per group, several trials now involve N C 75 per group [89– 93]. In smaller trials, post-treatment reductions in pain are observed with the topical regimen, but control groups are comparable. Some larger RCTs report significant differences from placebo in the overall group [92] or in a prominent subset (those responding to topical capsaicin) [90], or an overall trend but significant effects in specific subscales [89]. (2) Case and case series reports. Such

reports are limited by the lack of controls and uncertain generalizability, but their merit is that they often report on instances in which oral medications have been inadequate for pain control (topical analgesic used as add-on therapy) or are not well tolerated (topical analgesic used as an alternative therapy). Several individual case reports for a particular condition have been followed by a retrospective analysis of a larger number of patients. Retrospective case series analyses indicate response rates of 41 % for some relief (C30 % reduction; N = 12) [94], 24–54 % for substantial (C50 % reduction) and 62–85 % for some pain relief (N = 13–36) [95–99], or 73 % with some benefit (N = 11) [98]. (3) Challenges of drug combinations. A large number of potential agents can be applied topically, as indicated in reviews that focus on compounded agents for NeP [13, 99]. However, the optimal composition (combinations of two to five different agents are used) and concentration (concentrations of 0.5–5 % are mainly used; 10 % is sometimes used, but at this concentration there can be concerns regarding systemic effects) is not clear. At times, prior experience (cases) informs choices, but at other times, there is little rationale for choosing particular ingredients in a combination other than potential efficacy based on mechanism of action. The relative lack of systemic absorption and safety of this approach provides a useful buffer for this exploration. Continued documentation of clinical experiences using this approach is needed. The largest dataset for a single agent applied topically is for ketamine, which has been examined, either alone or in combination with other agents, in 13 RCTs (N = 1,733), five open trials (N = 133), four retrospective studies (N = 76), and 12 case/series reports (N = 32) [87, 88]. Several cases indicate some efficacy for ketamine 0.5–5 %, but no controlled clinical trial for NeP has reported significant reductions in pain compared with placebo at these concentrations [100–102]. Topical ketamine 10 % reduced aspects of evoked pain in a clinical population in one experimental trial [103]. Ketamine combined with amitriptyline (0.5–1 ? 2 % or 2 ? 4 %) is the combination for which there is the most information; this produces a response rate of 62–85 % for some pain relief in NeP conditions in case series reports (N = 13–36) [95–97] and a 52 % response rate (N = 129/250) in the screening stages of an enriched enrolment trial of PHN [104]. In a comparative RCT, ketamine combined with amitriptyline produced a significant analgesic effect in PHN, similar to that observed with oral gabapentin [92]. In other controlled trials, ketamine and amitriptyline did not produce a significant effect compared with placebo in DPN [93] or chemotherapy-induced peripheral neuropathy (although the taxane subgroup showed a significant difference compared with the non-taxane subgroup) [91].

J. Sawynok Table 1 Topical agents reported to produce analgesia in neuropathic pain conditions in controlled trials, case series reports, and individual cases Drug class, specific agents

NeP condition

Type of evidence (N)

Vasodilators (± other agents) Isosorbide dinitrate (spray)

DPN

RCT (22)

Glyceryl dinitrate (spray)

DPN

RCT (131)

Isosorbide dinitrate ? capsaicin ? lidocaine

NeP

Cases (2)

Lidocaine (spray)

PSPT

RCT (31)

Lidocaine (spray)

PHN

RCT (24)

DPN

RCT (179)

Doxepin (± capsaicin)

Mixed NeP

RCT (240)

Amitriptyline

Mixed NeP

RCTs (35)

Local anesthetics

a-AR agonist Clonidine Antidepressants

NMDA-R antagonist Ketamine

SMP

Cases (5)

PHN

Cases (23)

PHN

RCT (12)

CRPS

Cases (7)

CRPS

RCT (20)

DPN

RCT (17)

Mixed NeP

RCTs (20)

Lumbar radiculopathy

Case (1)

Nerve entrapment

Case (1)

Combinations with ket Ket ? amitriptyline

Mixed NeP

RCTs (152)

Ket ? amitriptyline

CIPNa

RCT (462)

Ket ? amitriptyline

PHNa

RCT (360)

Ket ? amitriptyline

DPNa

RCT (226)

Ket ? amitriptyline

Rectal, genital, perineal

Cases (13)

Ket ? amitriptyline

Pain erythromelalgia

Cases (36)

Ket ? amitriptyline

Pruritis (including NeP)

Cases (27)

Ket ? amitriptyline ? baclofen

CIPN

RCT (208)

Ket ? amitriptyline ? lidocaine

Radiation skin reaction

Open label (16)

Ket ? lidocaine

Mixed NeP

Cases (11)

Ket ? clonidine ? gabapentin

CIPN

Case (1)

Ket ? ketoprofen

Chronic pain (NeP [ MSK)

Cases (55)

Ket ? lidocaine ? clonidine ? ketoprofen

PHN, pruritis

Case (1)

Ket ? amitriptyline ? baclofen ? gabapentin

Pudendal neuralgia

Case (1)

Ket ? carbamazepine ? lidocaine ?

Orofacial NeP

Cases (39)

Gallium maltolate

PHN

Case (1)

Peppermint oil

PHN

Case (1)

Menthol

NeP

Cases (8)

ketoprofen ? gabapentin Other

(1) Content is summarized from recent reviews [12, 13, 87, 88]. (2) Agents are administered as creams or gels, except where indicated (spray). (3) In some conditions, the neuropathic component is not well defined a-AR a-adrenergic receptor, CIPN chemotherapy-induced peripheral neuropathy, CRPS complex regional pain syndrome, DPN painful diabetic peripheral neuropathy, ket ketamine, MSK musculoskeletal, NeP neuropathic pain, NMDA-R N-methyl-D-aspartate receptor, PHN post-herpetic neuralgia, PSPT post-surgical, post-traumatic, RCT randomized controlled trial, SMP sympathetically maintained pain a

Indicates additional data that are now available [91–93]

With respect to topical investigational agents in the elderly, some cases refer to those aged C65 years [13, 98], but there has been no systematic exploration of this issue. However, in some larger trials, 20–25 % of

participants are aged C65 years [92, 93], and post hoc analysis of this subgroup is possible and would provide useful information. With some trials, older age ([80 years) is an exclusion criterion [90]; this would

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influence the proportion of participants in an older age stratification analysis.

5 Summary and Perspective Pain medicine has now reached a point where there is discussion on limitations of current medications for chronic pain. This includes recognizing limitations of RCT trial designs (which are controlled and serve a regulatory process as well as clinical practice) along with the importance of pragmatic trials (which are more heterogeneous and serve clinical practice) [105]. For NeP in particular, there has been a general recognition of limitations with reports that B50 % experience substantial pain relief and that side effects from oral medications are common [43]. Other perspectives indicate the number-totreat values for oral treatments are 4–6, with specific benefits in only up to 25 % of patients [106]. Some considerations of this limited success posit expecting analgesic failure, along with the need to consider additional treatment options [107]. With such failure rates, there is the need for a broad range of drug options in order to have a better chance of success. The best order in which to use drugs is not always clear, but it has been noted that success can be determined within the first few weeks, and outcomes at these times can be predictive of longer-term outcomes [107]. Topical analgesics provide an additional class of agents that can be considered as analgesic options; their merit is systemic safety, but their limitation is response rate and unclear place in algorithms. The number of approved topical analgesics for NeP (lidocaine, capsaicin) is limited, and these options are not available in all countries. There is ongoing interest in, and a growing body of information on, investigational or experimental agents, where the rationale for use is plausible peripheral mechanisms of action. The largest body of such information relates to ketamine, which is administered either alone or in combination with other agents (particularly amitriptyline). There are also large RCTs for topical clonidine and additional combinations involving ketamine combined with other agents (amitriptyline, baclofen). This information provides additional treatment options, as well as potentially leading to the approval of future new topical analgesics. Post hoc analysis of analgesic trials stratified in relation to older age represents a pragmatic layer of information, and would be helpful for informing treatment choices in the elderly. Perspectives on topical analgesics in relation to the elderly are summarized as follows.

Summary of perspectives on topical analgesics and relevance to the elderly 1) Topical analgesics are effective in a proportion of those with neuropathic pain, and can produce a degree of analgesia that is comparable with that of oral agents. 2) Topical analgesics are well tolerated, with adverse effects being mainly due to localized skin reactions. Low systemic levels occur following topical administration, and do not contribute to systemic adverse effects or drug interactions. 3) Topical analgesics may be used as alternative analgesics (when systemic analgesics are not tolerated) or as add-on analgesics when an oral agent produces a partial effect (their addition does not increase the side effect burden). 4) Only a limited number of topical analgesics are currently approved, but there is interest in investigational agents that recruit several potential mechanisms of action, and additional options may become available. 5) Several studies include those aged C65 years, and there is some post hoc stratification of outcomes in relation to younger age and those aged C65 years. Additional pragmatic analysis of this kind is feasible and is encouraged. 6) Topical analgesics have the potential to contribute to improved pain management in the elderly based on their efficacy, adverse effect profile, potential for use as add-on therapies, and potential for oral analgesic-sparing effects with ensuing reduction in adverse effects.

Acknowledgments No sources of funding were used to support the preparation of this article. Disclaimer The author has received license fees from EpiCept (now Immune Pharmaceuticals Inc.).

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