Pharmacological Management of Neuropathic Pain in Older Adults: An Update on Peripherally and Centrally Acting Agents

Vol. 38 No. 2S August 2009 Journal of Pain and Symptom Management S15 Special Article Pharmacological Management of Neuropathic Pain in Older Adults: An Update on Peripherally and Centrally Acting Agents Brian E. McGeeney, MD, MPH Pain Management Group, Neurology Department, Boston University School of Medicine, Boston, Massachusetts, USA Abstract The burden of neuropathic pain in older adults is great and the practitioner is challenged to reduce symptoms and improve quality of life. Many common neuropathic pain syndromes are more prevalent in the older population, and older adults also carry greater sensitivity to certain side effects. The health care professional should have a thorough familiarity with all medications available to treat this difficult group of disorders. J Pain Symptom Manage 2009;38:S15eS27. Ó 2009 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Anticonvulsants, neuropathic pain, older adults, pain treatment guidelines, topical analgesics Introduction While nociceptive pain results from the activation of pain receptors, neuropathic pain is the result of dysfunction or a lesion within the peripheral or central nervous system (PNS and CNS, respectively) (Fig. 1). 1 Many of the conditions and diseases that can lead to neuropathic pain, such as postherpetic neuralgia (PHN) and diabetic peripheral neuropathy (DPN), are more prevalent in older adults than within younger cohorts. 2 One of the most common painful neuropathies is acute radiculopathy, which is particularly prevalent in older individuals because the prevalence of one of the contributing Address correspondence to: Brian E. McGeeney, MD, MPH, Department of Neurology, C329, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA. E-mail: bmcg@bu.edu Accepted for publication: May 20, 2009. Ó 2009 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. factors, intervertebral disc degeneration, increases linearly with age. 3 In addition, neuropathic pain associated with cancer and spinal cord injury is very common, in addition to painful alcoholic peripheral neuropathy. 4 A study of persons who chronically abused alcohol found that 16% had polyneuropathy symptoms, whereas 48% had signs suggestive of polyneuropathy based on abnormal electroneurographic results. 5 Pain syndromes linked with multiple sclerosis have been historically under-recognized, possibly because of the high variability between patients and lack of clinical signs. Such syndromes are caused by CNS demyelinating lesions. 4,6 Establishing adequate relief of neuropathic pain for older adult patients is associated with particular challenges, such as the amount of concurrent medication use. Clinicians treating older adults must be aware of the potential for drug-drug interactions and carefully 0885-3924/09/$esee front matter doi:10.1016/j.jpainsymman.2009.05.003

S16 McGeeney Vol. 38 No. 2S August 2009 Fig. 1. Different types of pain and their causes. The types of pain are categorized by symptoms/sign constellations based on the classifications proposed by Siddall, Taylor, and Cousins for spinal cord injury. 1 consider the target(s) of the drugs prescribed. Older individuals are prone to an exaggerated response to CNS-active drugs. 7 Patients taking centrally acting agents, such as antidepressants or anticonvulsants, typically have less of a side effect burden when the medications are not combined with other drugs that also have central effects. For patients prescribed agents that enter the CNS, clinicians should be particularly cognizant of changes in cognitive function and gait disturbances, in addition to constipation. Especially within older adult populations, side effects of drugs are common, whereas the efficacy of analgesics can be variable or delayed and dosing regimens can be complicated. In addition, aging is associated with important pharmacokinetic changes that include a reduction in the excretory capacity of the kidneys and liver function changes. 8 Furthermore, physiological differences, such as changes in gastrointestinal motility and blood flow, affect drug handling by the body, and drug distribution can be affected by lower plasma albumin levels and total body water differences, along with increased body fat/lean ratios. 8 As primary care physicians (PCPs) commonly provide the core care for older adult patients, these professionals need to be adept at assessing neuropathic pain, making diagnoses, and establishing a pain plan with appropriate medication(s). Establishing reasonable goals with the patient, such as lessening pain and improving function, reducing stress, and improving the overall quality of life is critical. For more challenging patients, including those with an unclear diagnosis, referrals may be made to a wide variety of medical specialists, such as neurologists, psychiatrists, physical therapists, and interventional pain specialists (Fig. 2). 9 If a patient has a sufficiently complicated presentation, his or her care should be coordinated by a specialist rather than a PCP. There are many pharmacological choices available for treating neuropathic pain (see Table 3 of the article by Dr. Fine), and many of the first-line agents have similar efficacies in controlled trials, making the choice of a therapy less straightforward. 10 Therefore, analgesics are often chosen based on their safety, tolerability, drug interactions, and cost; clinical study evidence on typical therapeutics taken for neuropathic pain will be provided herein. Although many agents are used off-label when prescribed for neuropathic pain, there are several that have pain indications. Lidocaine patch 5%, gabapentin, and pregabalin are indicated for treatment of pain associated with PHN, whereas pregabalin and duloxetine have been approved by the U.S. Food and Drug Administration (FDA) to treat painful DPN. Carbamazepine is indicated for the treatment of trigeminal neuralgia; topiramate and valproate are indicated for migraine prophylaxis. Although tricyclic antidepressants, oxcarbazepine, and lamotrigine are used to relieve neuropathic pain, they do not have FDA approval for this use. Less commonly used, and

Vol. 38 No. 2S August 2009 Management of Neuropathic Pain in Older Adults S17 Fig. 2. A model for the collaboration, referral, and care of complex pain patients. 9 also lacking neuropathic pain FDA treatment indications, are phenytoin, phenobarbital, levetiracetam, and zonisamide. The most current guidelines on treating neuropathic pain were published in 2007 through an international collaborative effort under the auspices of the International Association for the Study of Pain (IASP). These recommendations advocate the use of topical lidocaine (such as the lidocaine patch 5%), secondary amine tricyclic antidepressants, selective serotonin and norepinephrine reuptake inhibitors, calcium channel ligands (gabapentin and pregabalin), and tramadol as first-line agents for managing neuropathic pain, as well as opioid agonists in certain clinical circumstances (Table 1). 11 In 2005, an Table 1 First-Line Options for Treating Neuropathic Pain 10 Calcium channel a2-d ligands Gabapentin a Pregabalin a Secondary amine tricyclic antidepressants Nortriptyline Desipramine SSNRIs Duloxetine a Venlafaxine Topical lidocaine a Tramadol SSNRI ¼ selective serotonin and norepinephrine reuptake inhibitor. a FDA-approved for a neuropathic pain indication. international group proposed a treatment algorithm for managing peripheral neuropathic pain based on randomized, double-blind, placebo-controlled trial evidence and the calculated numbers needed to treat (NNT) (Table 2). 12 Therapeutic gain/effect measure is the difference in effect between active and placebo in a clinical trial, the reciprocal of which is the NNT. The therapeutic gain and the NNT describe the benefit of a medicine specifically because of the biological effect, in contrast to the percentage of patients that respond to treatment in a clinical trial, which includes beneficial effects because of both the therapy and other nonspecific factors, such as the patient s natural history and expectations. Note that the given confidence intervals (CIs) are smaller for those agents that have been better studied, reflecting a higher confidence in the NNT. The available evidence on therapeutic effects for treating central pain is especially limited and, therefore, not particularly useful for guiding or formulating a treatment regimen. The recommended method for treating neuropathic pain begins with prescribing topical lidocaine for PHN and focal neuropathy, whereas for other types of pain, considering whether the patient has any contraindications for taking tricyclic antidepressants and prescribing them if appropriate. 13 If the patient presents with a comorbidity that precludes them from taking tricyclic antidepressants (as is often the case with older adults), gabapentin or pregabalin should be considered next; however, venlafaxine and

S18 McGeeney Vol. 38 No. 2S August 2009 Table 2 NNTs for Analgesics Classified by Neuropathic Pain Type 11 Medication Number of Trials Peripheral Pain (95% CI) Central Pain (95% CI) Cannabinoids 2 crossover, 2 parallel ND 6.0 (3.0e718) Capsaicin 11 parallel 6.7 (4.6e12) ND Gabapentin and Pregabalin 4 crossover, 13 parallel 4.0 (3.6-5.4) NA NMDA antagonists 5 crossover, 2 parallel 5.5 (3.4e14) ND Opioids 6 crossover, 2 parallel 2.7 (2.1e3.6) ND SNRIs 2 crossover, 3 parallel 5.1 (3.9e7.4) ND Topical lidocaine 4 crossover 4.4 (2.5e17) ND Tramadol 1 crossover, 2 parallel 3.9 (2.7e6.7) ND TCAs 16 crossover, 4 parallel 2.3 (2.1e2.7) 4.0 (2.6e8.5) ND ¼ no studies done; NA ¼ dichotomized data not available; NMDA ¼ N-methyl-D-aspartic acid; SNRIs ¼ serotonin noradrenaline reuptake inhibitors. duloxetine may be better options, as they are typically better tolerated by older adults. If the neuropathic pain is still not adequately controlled, opioids, including tramadol, are then considered. There have been new developments in the field regarding the management of PHN, which is one of the more common neuropathic pain conditions that also has a bigger impact on older than younger adults. PHN is a potentially debilitating neuropathic complication of acute herpes zosterda disease caused by the varicella virus. 14 Breakout of the varicella virus, which originated as a systemic infection (chicken pox), can occur locally when previously dormant virus in a sensory ganglion becomes reactivated and involves the corresponding dermatome (shingles). Increasing age enhances the risk of developing herpes zoster (after infection with varicella). 15 In addition, individuals older than 50 years are at highest risk of developing PHN after zoster; the overall prevalence of PHN is 0.7 cases per 1,000 people. 16 Moreover, the potential for severe consequences increases with age; compared with children, older adults are 12 times more likely to be hospitalized because of a herpes zoster outbreak. 17 Hallmarks of PHN are both steady and intermittent pain, as well as allodyniadpain provoked by innocuous stimuli. 14 Allodynia may affect as many as 90% of patients with PHN. 18 The American Academy of Neurology published guidelines regarding the treatment of PHN in 2004. 19 Gabapentin, pregabalin, opioids, and lidocaine patch 5% were recommended as first-line agents for managing PHN pain, as well as tricyclic antidepressants for younger individuals. Guidelines compiled by the European Federation of Neurological Societies recommended topical lidocaine as a first-line treatment for PHN, especially for older adults who are more susceptible to side effects and often require polypharmacy. 20 In addition, for individuals 60 years of age or older, a live attenuated virus (booster) vaccine has recently become available, which reduces the chance of a zoster outbreak, and consequently PHN, by more than 50%. A double-blind, randomized, placebo-controlled trial of 38,546 adults 60 years of age or older demonstrated that the use of the zoster vaccine reduced the incidence of PHN by 66.5% (P < 0.001) and herpes zoster by 51.3% (P < 0.001). 21 This booster shot has been recommended and indicated for older adults aged 60 years or more who are not immunocompromised to prevent the development of zoster and PHN. 22 Oral Pharmacological Options for Treating Neuropathic Pain in Older Adults Antidepressant Agents Duloxetine was approved to treat DPN in September 2004 by the U.S. FDA and then approved in late 2007 in Canada for the same indication; the agent also has indications for major depressive disorder, generalized anxiety disorder, fibromyalgia, and in some countries, stress urinary incontinence. 23 Duloxetine induces analgesia through enhancement of the body s natural central antinociceptive systems. Duloxetine is a serotonin and norepinephrine reuptake inhibitor, 24 with similarities to venlafaxine; however, it more potently and specifically targets only serotonin and norepinephrine reuptake systems. 25 The agent is taken once daily and is weight neutral,

Vol. 38 No. 2S August 2009 Management of Neuropathic Pain in Older Adults S19 meaning it is not associated with changes in body weight. 23 Duloxetine is metabolized by the CYP1A2 and CYP2D6 class of cytochrome P450 enzymes, and thus, caution should be exercised when coadministered with inhibitors of these enzymes or drugs that are metabolized primarily by these metabolic pathways. Additionally, duloxetine should not be prescribed for patients who have heavy alcohol intake. 23 Most of duloxetine is plasma protein-bound; hence, coadministration with another highly protein-bound drug could potentially result in adverse reactions. 23 Anecdotally, duloxetine is better tolerated than tricyclic antidepressants, and overall, studies in older adults have not indicated any significant differences in safety, effectiveness, or pharmacokinetics (C max ) compared with younger participants. Thus, dosage adjustment based on the age of the patient is not necessary. Calcium Channel a 2 d Ligands The anticonvulsant agents gabapentin and pregabalin have more similarities than differences; they both bind with high affinity to the a 2 d-1 subunit of certain voltage-gated calcium channels. 26e28 This interaction inhibits calcium currents, and it is thought to, thereby, reduce allodynia in a dose-dependent manner with chronic usage, 26e28 and likely mediates the drugs anticonvulsant, analgesic, and anxiolytic effects. 29 Gabapentin and pregabalin are alkylated structural analogs of g-aminobutyric acid (GABA); 30 yet, neither compound interacts with GABA A or GABA B receptors. 28,31 Both compounds are excreted in the urine primarily unchanged. 32 An important difference between the two members of the gabapentinoid family is bioavailability; while the amount of gabapentin absorbed is dose dependent, pregabalin has a linear profile and is more than 90% bioavailable between doses of 25 mg and 300 mg (single dose). 32,33 With gabapentin administered at low doses, high bioavailability is observed, but the fraction of dose absorbed decreases with increasing doses from 60% to 27% over the range of 100e1600 mg (single dose), 34 because of the saturatable uptake of the compound. 35 Compromised renal function associated with aging has been linked to reduced oral clearances of both gabapentin and pregabalin; therefore, dose reductions may be required for older adults. 33,34 Pivotal studies have demonstrated the efficacy of the two gabapentinoids for neuropathic pain using randomized and placebo-controlled designs. A 30% reduction in pain scores has generally been found to be a meaningful abatement in pain to patients; 62% and 65% of the study participants with DPN given 300 mg or 600 mg/day of pregabalin, respectively, reported this clinically important improvement rate, compared with 33% of patients given placebo. 36 Also, a higher proportion of pregabalin-treated patients reported a 50% reduction in pain: 46% in the 300 mg/day and 48% in the 600 mg/day pregabalin groups, compared with 18% in the placebo cohort. 36 In addition, a study of patients with PHN demonstrated that significantly more patients within both pregabalin groups (26% given the 150 mg dose; 28% given the 300 mg dose) had a 50% or greater decrease in mean pain scores from baseline to endpoint than in the placebo (10%) group (P ¼ 0.006 and P ¼ 0.003, respectively). 37 Although direct comparisons between gabapentin and pregabalin cannot be made without a head-to-head trial, a study of patients with PHN-administered gabapentin reported similar efficacies to those just discussed: 32% of the gabapentin 1800 mg treatment group and 34% the gabapentin 2,400 mg group showed a 50% or greater reduction in mean pain scores between baseline and the end of treatment compared with 14% of the placebo-treated patients (P ¼ 0.001). 38 Several pharmacokinetic properties of gabapentin and pregabalin are particularly suited to use in older adult populations; they have few drug-drug interactions, less than 3% plasma protein binding, no hepatic metabolism, and 5- to 7-hour half-lives. 33,34 Routine monitoring of clinical laboratory parameters is not necessary for the safe use of either gabapentinoid. 33,34 Dizziness, somnolence, and/or peripheral edema are not uncommon side effects with these agents, 37,39 although side effects may increase with concomitant use of other centrally acting agents. These agents have a beneficial effect on sleep architecture because of enhancement of the most restorative periods of sleep; 37,40 hence, off-label use of pregabalin or gabapentin as a single dose at bedtime has been used clinically.

S20 McGeeney Vol. 38 No. 2S August 2009 The U.S. FDA issued a new warning on the use of anticonvulsants and suicidal ideation based on the clinical trial results of 11 agents, including approximately 200 trials. 41 Most of the anticonvulsants considered were associated with suicidal ideation behavior; 140 events were noted, with patients receiving antiepileptic drugs having approximately twice the risk of suicidal behavior or ideation compared with patients receiving placebo. 41 It may be hypothesized that patients with a depressive disorder are more likely to experience this behavior. An estimated 2 per 1,000 more patients in the drugtreatment groups experienced suicidality than in the placebo groups; 41 hence, these agents should still be considered part of the pain management armamentarium. However, clinicians should be cognizant of this newly recognized side effect and share this information with their patients taking anticonvulsants. Table 3 Examples of Opioid Therapeutic Options for Treating Neuropathic Pain Morphine Immediate-release Controlled-release Oxycodone Immediate-release Controlled-release Codeine Immediate-release Methadone Hydromorphone Immediate-release Fentanyl Transdermal patch Oral transmucosal Buccal tablet Oxymorphone Immediate-release Extended-release Opioids Trials of oral opioid agents have demonstrated benefit for managing various peripheral and central neuropathic pains for up to eight weeks (the length of the clinical trials). 11 The magnitude of their efficacy is at least as great as nonopioid alternatives; however, they are often only used in select clinical circumstances for several reasons. 11 Treatment with opioids is associated with a higher frequency of side effects than tricyclic antidepressants (TCAs) or gabapentin in head-to-head studies. 11 Chronic opioid use can be associated with often under-recognized consequences, such as hypogonadism, sexual dysfunction, and immunologic changes. 42 Furthermore, tolerance development can be associated with hyperalgesia, and diversion and misuse are other potential negative outcomes of chronic opioid use, even in older adults. Overall, the safety of long-term opioid use has not been established adequately. A Cochrane Database of Systematic Reviews in 2007 found that intermediate-term studies (8e70 days) of opioids for treating neuropathic pain demonstrated significant efficacy over placebo to an extent that is likely to be clinically important. 43 Importantly, the reported side effects, although common, were not found to be life-threatening. There are several opioid analgesics that can be prescribed to manage neuropathic pain, many available in multiple formulations (Table 3). Some clinicians believe that the naturally occurring opioids, morphine and codeine, are less well tolerated by older adults than the synthetic options, and small doses of methadone can be useful for treating neuropathic pain, including in older adults; new delivery methods for fentanyl, such as the buccal tablet and a transmucosal formulation, may be more useful for treating cancer pain than neuropathic pain. Both oxymorphone and oxycodone can be well tolerated by older adults. The newest addition to the opioid armamentarium, oxymorphone, is another synthetic alternative with stronger potency than morphine or oxycodone, and a more rapid onset. 44,45 Oxymorphone has demonstrated efficacy in studies of chronic low back pain 46e48 and osteoarthritis (OA) of the hip and knee, with nearly all studies conducted in populations whose mean age was between w50 and 60 years of age. 49e51 In particular, a one-year study established the effectiveness and safety of oxymorphone extendedrelease (ER) in an older population (mean [standard deviation]: 60.0 years 10.1). 51 At least 80% of these patients with moderate-to-severe chronic osteoarthritis pain rated their satisfaction with oxymorphone as excellent, very good, or good at each assessment. 51 Notably, in older adults, plasma levels of oxymorphone

Vol. 38 No. 2S August 2009 Management of Neuropathic Pain in Older Adults S21 ER were about 40% higher than in younger subjects, and thus, should be administered with smaller initial dosages and titrated with caution. 52 Also, oxymorphone must be used with caution in patients who are sensitive to CNS depressants, such as those with cardiovascular, pulmonary, renal, or hepatic disease. 52 Of importance for patients who require polypharmacydas is often the case in older adultsdoxymorphone ER exhibits minimal potential for causing metabolic drug-drug interactions mediated by the cytochrome P450 enzymes CYP2C9 or CYP3A4. 53 Tramadol Tramadol is a weak m-opioid agonist that also inhibits the reuptake of norepinephrine and serotonin. Randomized controlled trials of tramadol have been conducted that have demonstrated efficacy in treating neuropathic pain, 54 including PHN, 55 painful DPN, 56 osteoarthritis, 57 and low back pain. 58 Of particular note, a 2007 publication described the results of a double-blind trial of 1,020 older adult patients with osteoarthritis of the knee or hip, who were given once-daily tramadol (300 mg) or placebo. 59 The study found that the 300 mg tramadol cohort had significantly lower mean pain intensity scores compared with placebo (P < 0.04), as well as a significant improvement from baseline to the final visit in overall sleep quality (P ¼ 0.037) because of lessening of pain-related sleep disturbances. 59 The availability of this once-daily ER formulation of tramadol can be useful to increase patient adherence to the dosing schedule. However, anecdotal reports indicate that tramadol is not typically well tolerated in the older adult population, and occasionally, an individual very sensitive to tramadol can be dizzy for a day from a single 50 mg dose. The most common side effects associated with tramadol are somnolence, dizziness, nausea, and orthostatic hypotension. 59 In addition, similar to many agents that target the CNS, tramadol can cause cognitive impairment and gait disturbances in older adults. Although uncommon, tramadol use can be associated with seizures, 59 especially when taken daily in combination with TCAs. Tramadol is indicated for treatment of moderate to moderately severe pain in adults at up to 400 mg/day, 60 but a cautionary approach when there is concern for developing side effects can lead to a limit of 200 mg/day. Tricyclic Antidepressants TCAs provide analgesia by multiple mechanisms, but primarily by inhibiting the reuptake of norepinephrine and serotonin, and thereby enhancing the descending antinociceptive systems in the CNS. TCAs have been recommended as first-line agents for managing neuropathic pain by current guidelines, 11,20 and can be particularly beneficial for patients with insomnia and/or depression. However, for older adult patients, the guidelines offer the caveat that TCAs can induce or exacerbate cognitive impairment and gait disturbances, and thereby increase their risk of falling. In addition, before beginning TCA treatment, an electrocardiogram is recommended for patients over 40 years of age; then treatment may be initiated with a low dose (10e25 mg) and slowly titrated upwards every few days until the patient s pain is adequately managed or until side effects become a burden. 61 Notably, the dosing for neuropathic pain and depression are not equivalent. The tolerability of TCAs greatly varies across individuals, although split dosing can reduce side effects, as can coadministration with opioids. Also, TCAs can cause toxicity when coadministered with agents that inhibit cytochrome P450 2D6, such as selective serotonin reuptake inhibitors (SSRIs). Furthermore, the American Geriatric Society has recommended that the tertiary amine amitriptyline should not be prescribed for patients older than 60 years because of the analgesic side effect burden, including disturbances in cardiac conduction, orthostatic hypotension, and acute angle closure glaucoma. 61,62 While tachycardia is a relatively common side effect of TCAs, orthostatic hypotension is more likely in older adult populations, and is often underrecognized. Other anticholinergic side effects (which are more prevalent with tertiary amines) include dry mouth, constipation, blurred vision, urinary problems, and erectile dysfunction. 63 Still, the secondary amines, nortriptyline and desipramine, can be safely used for treating pain in older adults in moderate doses; desipramine can have a stimulating effect in patients who have drowsiness issues. 64

S22 McGeeney Vol. 38 No. 2S August 2009 Topical Treatments for Managing Neuropathic Pain Capsaicin Cream Caterina et al. 65 cloned the specific receptor activated by capsaicin in 1997, thereby laying the groundwork for characterizing the molecular events underlying the sensation of pain associated with capsaicin. The capsaicin receptor, called the transient receptor potential V1, responds both to capsaicin and temperatures above a threshold of 41 to 42 C, as well as a multitude of painful physical and chemical stimuli and inflammatory mediators. Multiple inflammatory receptor systems within sensory neurons can sensitize these neurons through intracellular signaling pathways. 66 The resulting phenotype is one associated with thermal hyperalgesiad oversensitivity to heatdthereby shifting the threshold of receptor activation to normal body temperature, leading to inflammatory pain. Early open-label studies indicated that capsaicin could be beneficial for treating neuropathic pain; this finding was strengthened by the results of two randomized, double-blind trials of 0.075% capsaicin cream for treatment of PHN. 67,68 Still, a meta-analysis of trials on the effectiveness of topical capsaicin indicated that, although the treatment afforded greater pain relief than placebo for DPN (odds ratio [OR]: 2.74; 95% CI: 1.73e4.32) and OA (OR: 4.36; 95% CI: 2.77e6.88), the results for PHN were less persuasive. Typically, topical capsaicin formulations have very high concentrations so that over multiple applications, sensory neurons become desensitized and receptor activation is blocked from other stimuli as well. 69 The burning sensation associated with the sensitization phase can be a difficult side effect to overcome and can limit its use. Because of the lag time before a beneficial effect is felt, pain with sudden onset is not amenable to capsaicin treatment; rather, the agent is more suited for chronic pain conditions and probably best as a co-analgesic to achieve satisfactory pain relief. In addition, the cost of this nonprescription analgesic can be prohibitive for some patients. Topical capsaicin has been recommended by both the American College of Rheumatology subcommittee 70 and the European League Against Rheumatism for managing short-term chronic low back pain, 71 as well as treatment of pain relatedtohandandkneeoa. 72,73 Topical Lidocaine The lowered threshold for sensing pain observed in many chronically painful conditions, as well as a model of chronic inflammation, have been linked to the upregulation of voltage-gated sodium channels in peripheral sensory neurons with abnormally high rates of spontaneous firing. 74,75 Lidocaine functions as a sodium channel blocker, and thereby reduces the ectopic impulses in afferent fibers to provide pain relief. 76 A commercially prepared, cream-based, eutectic mixture of 2.5% lidocaine and 2.5% prilocaine with efficacy in reducing chronic neuropathic pain is available in the United States. 77,78 This formulation of lidocaine is well tolerated and typically has mild-to-moderate side effects limited to the application site. In contrast to the rare but serious adverse events associated with compounded local anesthetics (toxicity), this anesthetic cream has demonstrated efficacy and safety in both young cohorts and older adult patients. 79 Although a number of topical treatments have been used to manage neuropathic pain, the most commonly used topical analgesic is the lidocaine patch 5%. Current guidelines created by the European Federation of Neurological Societies as well as an international collaborative body of the experts assembled by the IASP recommend the lidocaine patch 5% as first-line therapy for treating localized neuropathic pain, especially for older adults. 11,20 The lidocaine patch 5% provides pain relief by the targeted peripheral analgesic, lidocaine, and by providing a mechanical barrier that reduces allodynia. 80,81 The pioneering, randomized, double-blind study of 35 patients with PHN conducted in the mid-1990s found significantly reduced pain intensities in the lidocaine patch 5% group compared with participants in the vehicle-only cohort, from four to 12 hours after application. 82 More recently, a threeweek, vehicle-controlled trial of 96 participants with PHN demonstrated that lidocaine patch 5% significantly relieved pains not associated with allodynia (P ¼ 0.022), and those described as hot, dull, sharp, and/or deep (P ¼ 0.013). 83 In 2006, a head-to-head randomized study compared the lidocaine patch 5% with 500 mg naproxen taken twice daily for the

Vol. 38 No. 2S August 2009 Management of Neuropathic Pain in Older Adults S23 relief of pain associated with carpal tunnel syndrome. 84 Relative to baseline measurements, significant reductions in pain were achieved by both cohorts (P < 0.001 for the lidocaine group; P ¼ 0.004 for the naproxen group); however, a lack of a placebo group in the design precluded the comparison of natural histories between treatment groups. All side effects noted for both cohorts were mild to moderate in nature; application site sensitivity was the most common side effect noted within the lidocaine patch 5% group. Moreover, the safety and tolerability of the lidocaine patch 5% was specifically investigated in a pharmacokinetic study that measured the peak plasma concentrations of the lidocaine attained after the simultaneous application of four patches, changed every 24 or 12 hours over three days. 85 Even when these high amounts of lidocaine patches were applied, the peak plasma concentrations observed (186 and 225 ng/ml, respectively) were approximately 12%e15% of the lidocaine levels associated with cardiac activity and 4%e5% of that connected with toxicity. Because of the minimal risk of systemic side effects or drug-drug interactions associated with lidocaine patch 5% therapy, it is a good option for older adult patients. 85 Still, appropriate caution should be taken with patients who have severe hepatic disease, as they could be at risk of accumulating concerning levels of lidocaine from the patch s topical application. No dose adjustments are required for patients with renal or hepatic dysfunction. Clinically, the length and timing of lidocaine patch use should be optimized for each individual based on his or her needs and the characteristics of his or her pain. The patch can be cut to shape as needed and applied to intact, allodynic skin without causing further pain. Although the analgesic is indicated for 12-hour application followed by 12 hours without the patch, it can be safely applied for longer periods to continue to provide analgesia. Notably, approximately 95% of the medication remains in the patch after 12 hours of use. Topical Nonsteroidal Anti-Inflammatory Drugs NSAIDs provide analgesia by reversibly inhibiting cyclooxygenase (COX), an enzyme responsible for synthesizing prostaglandins. These commonly prescribed oral medications account for nearly one-fourth of all adverse events reported. 86 In contrast, topical formulations of NSAIDs have a lowered risk of systemic adverse effects, because much lower peak plasma concentrations (less than 10% of oral levels, ranges from 0.2% to 8.0%) are obtained from application despite local therapeutic levels (according to a study of oral vs. topical ibuprofen). 87 Topical NSAIDs are commonly used in Europe for treating neuropathic pain and patients appear to benefit, although the literature has conflicting evidence supporting and repudiating its use. In the United States, diclofenac sodium is available as a topical patch for acute pain due to minor strains, sprains, and contusions, and as a topical gel that is indicated for OA pain. Other Agents Although the following medications can be used as second-line options in certain circumstances, primarily the following agents are considered third-line alternatives for treating neuropathic pain: the anticonvulsant agentsdcarbamazepine, lamotrigine, oxcarbazepine, topiramate, and valproic acid; the antidepressantsdbupropion, citalopram, and paroxetine; mexiletine; N-methyl-D-aspartic acid receptor antagonists; and the topical agent capsaicin. 11 Carbamazepine has been used for treating neuropathic pain since 1962 88 and still remains useful, particularly for trigeminal neuralgia where it is, notably, a first-line agent. The dose of carbamazepine generally needs to be adjusted in the two- to three-month period after initiation of treatment, because carbamazepine induces its own metabolism through hepatic enzyme autoinduction. 89 This is not the case with oxcarbazepine. 90 In addition, the epoxide metabolite of carbamazepine has CNS-toxic effects, thereby limiting its dose; oxcarbazepine does not have this metabolite, contributing to better tolerability. 90 Some data and anecdotal reports support the use of oxcarbazepine as an option for treating central neuropathic pain, although further supportive trial evidence is needed. 91 Notably, in the aging population, oxcarbazepine attains higher plasma concentrations than the same dose given to younger individuals, potentially because of reduced clearance. 8

S24 McGeeney Vol. 38 No. 2S August 2009 Evidence does not support the use of SSRIs, NSAIDs, COX-2 inhibitors, topiramate, propoxyphene, or meperidine for treating neuropathic pain in older adults, 4 although there are exceptionsdnsaids can be an option for older adult patients presenting with inflammatory neuropathic pain, such as radiculopathy, and SSRIs can be a useful alternative for older pain patients with comorbid depression. Conclusions Aging causes physiological alterations to the liver, kidney, blood, and fat, which result in different drug-metabolism pharmacokinetics and necessitate the optimization of medicines for older adults. Therefore, it is important to appropriately adjust medication types and dosages to account for these changes, as well as effects from other comorbidities and/or drug-drug interactions. Several recommendations from organizations and collaborative efforts of experts are available to guide clinicians in treating neuropathic pain. Also, topical agents provide a useful option in a population particularly prone to side effects, and often in need of adjunctive agents beyond oral treatments. References 1. Siddall PJ, Taylor DA, Cousins MJ. Classification of pain following spinal cord injury. Spinal Cord 1997;35(2):69e75. 2. Bennett GJ. Neuropathic pain: new insights, new interventions. Hosp Pract (Minneap) 1998; 33(10):95e98. 101e104, 107e110. 3. Kalichman L, Hunter DJ. The genetics of intervertebral disc degeneration. Familial predisposition and heritability estimation. Joint Bone Spine 2008; 75(4):383e387. 4. Galluzzi KE. Managing neuropathic pain. J Am Osteopath Assoc 2007;107(10 Suppl. 6):ES39eES48. 5. Vittadini G, Buonocore M, Colli G, et al. Alcoholic polyneuropathy: a clinical and epidemiological study. Alcohol Alcohol 2001;36(5):393e400. 6. Konig FB, Wildemann B, Nessler S, et al. Persistence of immunopathological and radiological traits in multiple sclerosis. Arch Neurol 2008;65(11): 1527e1532. 7. Barton C, Sklenicka J, Sayegh P, et al. Contraindicated medication use among patients in a memory disorders clinic. Am J Geriatr Pharmacother 2008; 6(3):147e152. 8. Perucca E. Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age. Clin Pharmacokinet 2006;45(4):351e363. 9. American Pain Society. Pain control in the primary care setting. Glenview, IL: American Pain Society, 2006. 10. Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003;60(11):1524e1534. 11. Dworkin RH, O Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007; 132(3):237e251. 12. Finnerup NB, Otto M, Jensen TS, et al. An evidence-based algorithm for the treatment of neuropathic pain. MedGenMed 2007;9:36. 13. Finnerup NB, Otto M, McQuay HJ, et al. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 2005;118(3):289e305. 14. Dworkin RH, Portenoy RK. Pain and its persistence in herpes zoster. Pain 1996;67(2e3):241e251. 15. Gnann JW Jr, Whitley RJ. Clinical practice. Herpes zoster. N Engl J Med 2002;347(5):340e346. 16. Khaliq W, Alam S, Puri N. Topical lidocaine for the treatment of postherpetic neuralgia. Cochrane Database Syst Rev 2007;(2):CD004846. 17. Edmunds WJ, Brisson M, Rose JD. The epidemiology of herpes zoster and potential cost-effectiveness of vaccination in England and Wales. Vaccine 2001;19(23e24):3076e3090. 18. Bowsher D. Pain, sensory change, and allodynia in postherpetic neuralgia. In: Watson CPN, Gershon AA, eds, 2nd rev ed., Herpes zoster and postherpetic neuralgia, Vol. 11 The Netherlands: Elsevier Science B.V., 2001: 143e147. 19. Dubinsky RM, Kabbani H, El-Chami Z, et al. Practice parameter: treatment of postherpetic neuralgia: an evidence-based report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2004;63(6):959e965. 20. Attal N, Cruccu G, Haanpaa M, et al. EFNS guidelines on pharmacological treatment of neuropathic pain. Eur J Neurol 2006;13(11):1153e1169. 21. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005; 352(22):2271e2284. 22. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2008;57(RR-5):1e30.

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