Pharmacologic Management Part 1: Better-Studied Neuropathic Pain Diseases

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1 PAIN MEDICINE Volume 5 Number S Pharmacologic Management Part 1: Better-Studied Neuropathic Pain Diseases Misha-Miroslav Backonja, MD,* Jordi Serra, MD *University of Wisconsin Hospital and Clinics, Madison, Wisconsin; Neuropathic Pain Unit, Hospital General de Catalunya, Barcelona, Spain ABSTRACT Neuropathic pain impacts millions of people in the United States and around the world. Patients experience one of many symptoms, such as pain, paresthesia, dysesthesia, hyperalgesia, and allodynia, for many years because of unavailable or inadequate treatment. One of the major challenges in treating patients with neuropathic pain syndromes is a lack of consensus concerning the appropriate first-line treatment options for conditions associated with neuropathic pain, including postherpetic neuralgia, diabetic peripheral neuropathy, and trigeminal neuralgia. This review summarizes the published results of randomized trials involving treatment for neuropathic pain conditions. Anticonvulsants, such as gabapentin, carbamazepine, and lamotrigine, and tricyclic antidepressants, including amitriptyline and desipramine, have demonstrated efficacy in relieving pain associated with postherpetic neuralgia, diabetic peripheral neuropathy, and trigeminal neuralgia, in several studies. However, the lack of head-to-head comparison studies of these agents limits the conclusions that can be reached. Clinicians who must make decisions regarding the care of individual patients may find some guidance from the number of randomized trials with a positive outcome for each agent. Using quality-of-life study outcomes, treatment strategies must encompass the impact of therapeutic agents on the comorbid conditions of sleep disturbance and mood and anxiety disorders associated with neuropathic pain. Looking to the future, emerging therapies, such as pregabalin and newer N-methyl-D-aspartate receptor blockers, may provide physicians and patients with new treatment options for more effective relief of pain. Key Words. Neuropathic Pain; Diabetic Peripheral Neuropathy (DPN); Postherpetic Neuralgia (PHN); Trigeminal Neuralgia (TGN); Anticonvulsants; Tricyclic Antidepressants. Introduction It is estimated that over 4 million people in the United States suffer from neuropathic pain [1], which is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system by the International Association for the Study of Pain [2]. A more specific definition calls for pain that is the result of injury to the nervous system, peripheral, central, or both, and manifests with positive and negative sensory phenomena [3]. Lesions that originate in the peripheral or central Reprint requests to: Dr. Jordi Serra, Neuropathic Pain Unit, Hospital General de Catalunya, c. Gomera s/n, Sant Cugat del Vallès, Barcelona, Spain. Tel: ; Fax: ; jserrac@meditex.es. nervous system may manifest as different neuropathic pain syndromes, depending on the anatomic location and type of impairment. Noncancer neuropathic pain syndromes are listed in Table 1. Patients with neuropathic pain experience a combination of positive and negative sensory, motor, and autonomic signs and symptoms. Positive sensory symptoms include pain, paresthesia (abnormal sensation, either evoked or spontaneous), dysesthesia (evoked or spontaneous unpleasant, abnormal sensation), hyperalgesia (increased response to a normally painful stimulus), and allodynia (painful response to a nonnoxious stimulus). Negative sensory symptoms involve a loss of sensitivity to stimulation in general and painful stimuli in particular (hypoes- American Academy of Pain Medicine /04/$15.00/S28 S28 S47

2 Pharmacologic Management Part 1 Table 1 Peripheral Central Noncancer neuropathic pain syndromes Complex regional pain syndrome (type I and II) Posttraumatic nerve injury Radiculopathy HIV sensory neuropathy Diabetic peripheral neuropathy Phantom limb pain Postherpetic neuralgia Trigeminal neuralgia Central poststroke pain Multiple sclerosis pain Spinal cord injury pain Adapted with permission from Dworkin [90]. thesia and hypoalgesia, respectively) [4]. Often, these symptoms of neuropathic pain are chronic and endure for many years with either no treatment or inadequate treatment [5]. A survey conducted by the American Pain Society in 1998 found that most people with chronic pain had been experiencing pain for over 5 years, that approximately one third of chronic pain sufferers rated their pain as the worst pain one can possibly imagine, and that many chronic pain sufferers had to visit more than one doctor in an effort to gain relief from their pain [6]. Despite the large number of people who are affected by neuropathic pain and the degree of suffering they endure, there does not appear to be consensus regarding the best way to treat the more commonly encountered neuropathic pain conditions [7]. No one therapeutic drug class or agent has been proven to be effective for all patients with neuropathic pain from a given etiology. Identification of an effective pharmacologic regimen for a specific patient is further complicated by the fact that a particular pain symptom may be produced by different mechanisms and that one underlying mechanism may manifest as several different symptoms [8,9]. Theoretically, the ability to identify the mechanism(s) underlying a patient s pain would enable the clinician to target pharmacologic treatment based on a drug s mechanism of action [10]. Currently, patients with neuropathic pain are often treated with agents such as nonsteroidal anti-inflammatory drugs, which do not have proven efficacy in relieving neuropathic pain, or are treated with inappropriately low doses of agents that have demonstrated efficacy. In addition, as Nicholson and Verma discuss elsewhere in this issue, an understanding of the impact of comorbid conditions on pain and the effect of pain treatment on comorbidities is a key component in the successful management of patients with neuropathic pain [11]. In this first part of our review of the pharmacologic management of neuropathic pain, we discuss three of the better-studied neuropathic pain conditions postherpetic neuralgia (PHN), diabetic peripheral neuropathy (DPN), and trigeminal neuralgia (TGN) by examining published reports of clinical trials to draw conclusions from the available data. Methods This review is not intended to be a complete, systematic analysis of all available data concerning the treatment of these three neuropathic pain conditions. Rather, it provides a summary of published data from well-designed, randomized trials. We discuss several selected studies within the context of each specific neuropathic pain syndrome, highlighting those that have a quantitatively measured effect on the treatment of specific neuropathic pain symptoms or quality-of-life parameters. We have excluded open-label studies, case studies, unpublished data, and study results reported only in abstracts or poster presentations. Postherpetic Neuralgia S29 Disease Overview The varicella zoster virus that causes chicken pox can remain latent in sensory ganglia for many years following the original infection [12]. Each year in the United States, reactivation of this virus manifests as herpes zoster (i.e., shingles) in an estimated 800,000 people [13]. During the acute phase of herpes zoster, a painful rash usually forms along a single dermatome related to the affected dorsal root or cranial nerve ganglion [12]. The rash and severe pain associated with herpes zoster usually lasts less than 4 weeks [14]. However, a common sequela of herpes zoster is PHN, a condition in which pain along the involved nerve territory persists for a prolonged period after the acute rash resolves. Evidence suggests that the pathogenesis of PHN involves both peripheral and central mechanisms that change over time, such as irritable peripheral nociceptors and central sensitization [9,15]. People 50 years of age and older are most likely to develop PHN following herpes zoster, and this painful condition can severely impact all aspects of life, including mood, sleep, physical activity, appetite, social activity, and the performance of necessary functions of daily living [13]. Therefore, the identification of an appropriate treatment to optimize outcome is essential.

3 S30 Backonja and Serra Treatment Options Published data from randomized trials assessing the effect of various pharmacotherapeutic agents on pain in patients with PHN are summarized in Table 2 and discussed briefly below. The most commonly studied therapeutic classes in PHN are anticonvulsants and antidepressants; however, many other systemic and topical agents, including vincristine and magnesium sulfate, have also been investigated. Anticonvulsants The efficacy of anticonvulsants in relieving the pain associated with PHN has been demonstrated in several randomized, placebo-controlled trials. For example, Rice et al. [16] and Rowbotham et al. [17] demonstrated that gabapentin, at doses of 1,800 mg/day, 2,400 mg/day, and 3,600 mg/day, was significantly better than placebo at reducing pain in patients with PHN (P < 0.01 for 1,800-mg and 2,400-mg doses [16]; P < for 3,600-mg dose) [17]. In both of those studies, improvements in quality-of-life parameters were significantly greater in gabapentin-treated patients compared with patients who received placebo, including vitality (P < 0.05), mental health (P < 0.05) [16], sleep interference (P < 0.001) [17], mood, depression, anger, fatigue (P < for each), and confusion (P = 0.01) [17]. The mechanisms by which gabapentin alleviates neuropathic pain have not been fully elucidated. Gabapentin binds to the a 2 d subunit of neurotransmitter-gated calcium ion channels [18]; however, ongoing research suggests other mechanisms may be involved [19]. Tricyclic Antidepressants Tricyclic antidepressants (TCAs) are prescribed frequently for the treatment of PHN. In 1982, Watson et al. demonstrated the efficacy of amitriptyline, versus placebo, in significantly (P ) reducing pain in patients with PHN, specifically paroxysmal, lancinating pain [20]. Subsequent studies found that amitriptyline was more effective in relieving PHN-related pain than lorazepam [21], fluphenazine [22], and maprotiline [23]. However, nortriptyline was as effective as amitriptyline in ameliorating neuropathic pain in patients with PHN [24], and other TCAs, such as desipramine, also have demonstrated efficacy [25]. Indeed, Raja et al. found no significant difference between pain relief with nortriptyline or desipramine and that seen with opioids in patients with PHN [26]. Inhibiting the reuptake of norepinephrine and serotonin is how TCAs exert their effect. In general, the most common adverse events observed during treatment with these agents include sedation, anticholinergic effects (i.e., dry mouth, constipation), and hypotension. However, amitriptyline, clomipramine, and imipramine, which inhibit both norepinephrine and serotonin reuptake, have worse side-effect profiles than agents such as desipramine and nortriptyline that act on serotonin only [27]. Opioids Controversy exists concerning the use of opioids to treat neuropathic pain. Although some pain specialists believe that opioids are either ineffective or effective only at doses that cause intolerable side effects, others feel that it is possible to achieve pain relief while maintaining an acceptable side-effect profile [28]. Significant decreases in pain scores have been noted in patients with PHN during treatment with opioids [26,29]. Oxycodone in extended-release form was significantly more effective than placebo at relieving allodynia (P = ) and paroxysmal pain (P = ) in patients with PHN [29]. However, oxycodone had no effect on mood and depression, and adverse events included constipation, nausea, and sedation. Extended-release morphine was associated with less cognitive side effects than nortriptyline, and it was preferred by patients over nortriptyline [26]. Tramadol, a centrally acting analgesic, although chemically different from the opioids, has been shown to be effective in relieving the pain associated with PHN. Tramadol was also shown to be more effective than placebo in decreasing visual analog scale (VAS) pain scores (P < 0.05), and patients in the tramadol group in that study required less rescue medication (P < 0.05) than those given placebo [30]. Topical Agents The 5% lidocaine patch, a local anesthetic, has been shown to reduce the pain and allodynia associated with PHN in several randomized studies [31 33], possibly by reducing ectopic activity in the involved sensory nerves, and by providing a physical barrier to mechanical stimulation from contact with clothing, etc. [31,32]. In one study, involving 96 patients with PHN, the lidocaine patch was significantly more effective in relieving neuropathic pain than a vehicle patch (P = 0.043), and significant benefits were experienced by patients with nonallodynic pain (P = 0.022) and patients with sharp, hot, dull, and deep pain (P = 0.013) [33]. In a similar study, the only side effect reported was a mild redness at the

4 Pharmacologic Management Part 1 S31 Table 2 Pharmacotherapy of PHN Study Patients Treatment Outcomes Adverse events/withdrawals Randomized, double-blind, placebo-controlled trials Boureau et al., Pts with PHN Tramadol 400 mg/d (N = 63) Mean pain intensity was No difference in rates of AEs, 2003 [30] (N = 125) ( 300 mg/d if 75 y or older) significantly lower in the tramadol (29.7%) vs placebo or placebo (N = 62) 6 wks tramadol group than in the (31.8%) or total AEs, placebo group (P < 0.05) and tramadol (31) vs placebo required less rescue medication (28) (P < 0.05) Dowd et al., Pts with PHN Vincristine 0.01% (N = 11) or Pain scores were significantly No neurological deficits or 1999 [91] (N = 20) placebo (saline, N = 9) lower in both groups on Day 20 changes in blood profiles administered by vs baseline. Pain relief was were detected in either iontophoresis over 1 h daily moderate or greater in 40% of group 20 days vincristine-treated patients and 55% of placebo-treated pts Dworkin et al., Pts with PHN Pregabalin, 600 mg/d (N = 59) Pregabalin vs placebo Withdrawals due to AEs: 2003 [37] (N = 173) if creatinine clearance demonstrated significantly pregabalin 32% vs placebo >60 ml/min or 300 mg/d greater decreases in pain (end 5%; AEs, pregabalin vs (N = 30) if creatinine point mean pain scores 3.60 vs placebo: dizziness, 28% vs clearance ml/min, or 5.29, P = ) and sleep 12%; somnolence, 25% vs placebo (N = 84) 8 wks interference (P = ) 7%; peripheral edema, 19% vs 2%; amblyopia, 11% vs 1%; dry mouth, 11% vs 2%; abnormal gait, 8% vs 1%; headache, 8% vs 8%; ataxia, 7% vs 0%; confusion, 7% vs 0%; diarrhea, 7% vs 5%; speech disorder, 6% vs 0% Galer et al., Pts with PHN 5% lidocaine patch vs vehicle Lidocaine patch improved pain NA 2002 [33] (N = 96) patch 3 wks qualities as measured by NPS to a greater extent than vehicle patch (P = 0.043) Graff-Radford Pts with PHN Pts randomly assigned to 1 of Statistically significant decrease G2 (amitriptyline and et al., 2000 (N = 49) 4 groups: G1, amitriptyline; in pain (measured by VAS) fluphenazine) had the [22] G2, amitriptyline and compared with baseline highest incidence of fluphenazine; G3, occurred in G1 and G2 sleepiness and G1 fluphenazine; G4, active (P < and P = 0.04, (amitriptyline) had the highest placebo, 8 wks respectively) incidence of dry mouth Rice et al., Pts with PHN Gabapentin, 1,800 mg/d Differences in pain scores vs AEs: dizziness and 2001 [16] (N = 334) (N = 115), gabapentin, baseline were -34.5% (1,800-mg somnolence, particularly 2,400 mg/d (N = 108), or dose), -34.4% (2,400-mg dose), during titration phase placebo (N = 111) 7 wks and -15.7% (placebo). Both (with dose titration during first 2 wks) gabapentin doses were significantly better than placebo (P < 0.01 for each dose) Rowbotham Pts with PHN Gabapentin maximum dose: Reduction in pain scores Withdrawals: 13.3% with et al., 1998 (N = 229) 3,600 mg/d (range: 1,200 significantly greater with gabapentin; 9.5% with [17] 3,600 mg/d, N = 113) or gabapentin vs placebo (from placebo; AEs: somnolence, placebo (N = 116) 8 wks; 6.3 to 4.2 points vs 6.5 to 6.0 dizziness, ataxia, peripheral dose titration during first points, respectively, P < 0.001) edema, and infections were 4 wks more frequent with gabapentin than placebo Serpell et al., Pts with Gabapentin, 900 mg/d (titrated Gabapentin demonstrated Withdrawals: gabapentin, 2002 [39] various over 3 days), with escalation greater improvement in pain 32 pts; placebo, 41 pts; AEs, symptoms to 1,800 mg/d or 2,400 mg/d, score than placebo (21% vs gabapentin vs placebo: (N = 307), for a total of 8 wks (N = 153), 14%, P = 0.048) dizziness, 24% vs 8%; PHN or placebo (N = 152) somnolence, 14% vs 5%; (43/307) infection, 9% vs 13%; headache, 9% vs 14%; nausea, 9% vs 9%; flu syndrome, 7% vs 5%; abdominal pain, 7% vs 4%; accidental injury, 6% vs 5%; diarrhea, 5% vs 4% Watson et al., Pts with PHN Capsaicin 0.075% cream vs Capsaicin resulted in greater AEs: burning and stinging at 1993 [35] (N = 143) placebo (vehicle) cream decrease in pain than placebo application site in 60% of (measured by VAS) at 2 wks pts using capsaicin and (19% vs 0.4%, P < 0.05) and 33% using placebo 6 wks (P = 0.032). Long-term follow up ( 2 years, N = 77) showed clinical benefit in 86% of patients

5 S32 Backonja and Serra Table 2 Continued Study Patients Treatment Outcomes Adverse events/withdrawals Randomized, double-blind, placebo-controlled, crossover trials Baranowski Pts with PHN Pts received each of the Ongoing pain (measured by VAS) No pts at the lower dose et al., 1999 (N = 24) following IV infusions over was significantly reduced after reached toxic plasma levels; [92] 2 h 1 wk apart: placebo all infusions (P < 0.05); dynamic however, several pts at the (normal saline), lidocaine pressure-evoked pain was higher dose did reach toxic 1 mg/kg, and lidocaine significantly reduced by both levels. Thus, the lower doses 5 mg/kg lidocaine infusions (P < 0.05, may be considered safe for each dosage level); area of allodynia declined with lidocaine 1 and 5 mg/kg (P < 0.05 and P < 0.001, respectively) Brill et al., Pts with PHN Magnesium sulphate, 30 mg/kg, Mean pain score decreased from No side effects were 2002 [93] (N = 7) IV, or saline 6.7 to 1.9 at 30 minutes reported during treatment posttreatment with magnesium with magnesium sulphate sulphate. Pain scores were significantly lower with magnesium sulphate than with placebo at 20 and 30 minutes (P = 0.016) De Benedittis Pts with PHN Pts had 1 of 4 suspension/ Only aspirin was significantly Mild cutaneous rash in 1 pt and (N = 22) diethyl ether solutions superior to placebo for reduction each with indomethacin and Lorenzetti, AHN applied to affected areas in in pain (based on VAS score) diclofenac 1996 [94] (N = 15) a randomized order on 4 from baseline (P < 0.05) and different days. Median duration of pain (P < 0.01). doses of active suspensions: Good-to-excellent results were aspirin 1,000 mg; reported in >81% of PHN pts indomethacin 75 mg; with topical aspirin suspension diclofenac 100 mg; lactose was used for placebo Galer et al., Pts with PHN Topical 5% lidocaine patch vs Primary end point was time to Withdrawals: 1 pt suffered a 1999 [31] (N = 33) placebo (vehicle) patch for exit, i.e., pts were allowed stroke prior to receiving 2 14 days, depending on to discontinue treatment if pain study medication; 1 pt increase in pain; then relief diminished. Median time withdrew during placebo patients crossed over to to exit was significantly better period because of increased alternative treatment with lidocaine than placebo pain and insomnia; 1 pt (14 d vs 3.8 d, P < 0.001). stopped placebo because Lidocaine patch was preferred of red, irritated skin; AEs by 78.1% of pts vs 9.4% for placebo (P < 0.001) were mild or moderate; application site reaction redness/rash reported in 9 pts with lidocaine patch and 11 pts with placebo patch Kishore- Pts with PHN Desipramine (mean dose: Pain relief with desipramine was Withdrawals: 8 pts because of Kumar et al., (N = 26) 167 mg/d) or placebo significantly greater from weeks AEs or intercurrent medical 1990 [25] 6 wks; then pts crossed 3 to 6 than with placebo illnesses; AEs: desipramine: over to alternative treatment (P < 0.001) syncope, 1 pt; left bundle branch block, 1 pt; jitteriness and atypical chest pain, 1 pt; fever, 1 pt; and vertigo, 1 pt; placebo: vertigo and nausea, 1 pt; skin rash, 1 pt; unsteadiness + mental fogginess, 1 pt Max et al., Pts with PHN Amitriptyline ( mg/d), Moderate or greater pain relief AEs: dry mouth, sedation, 1988 [21] (N = 58) lorazepam (0.5 6 mg/d), or was reported by 47% of pts dizziness; occurred with placebo (lactose) 2 wks; with amitriptyline, 16% of pts both active treatments followed by 1-wk washout; with placebo, and 15% of then crossed to alternative pts with lorazepam treatment Nelson et al., Pts with DPN Oral dextromethorphan (mean Dextromethorphan did not reduce Withdrawals: 5 PHN pts due 1997 [95] (N = 14) dose in PHN: 439 mg/d) or pain in pts with PHN to a to sedation, ataxia and and with placebo 6 wks followed by greater extent than placebo confusion, and (unrelated) PHN 1-wk washout; then crossed (P = 0.72) 6th cranial nerve palsy (N = 18) over to alternative treatment

6 Pharmacologic Management Part 1 S33 Table 2 Continued Study Patients Treatment Outcomes Adverse events/withdrawals Raja et al., Pts with PHN Each pt was scheduled to Greater mean decreases in pain Withdrawals: opioids, 20 pts; 2002 [26] (N = 76) undergo three treatment ratings on a 0 10 scale were TCA = 6 pts; placebo, 1 pt periods (8 wks each) in achieved with TCAs (1.4) and (P < 0.01); AEs: random order: opioid (mean with opioids (1.9) than with constipation, nausea, dose: morphine 91 mg or placebo (0.2, P < 0.001) dizziness, drowsiness, loss methadone 15 mg); TCA of appetite, and dry mouth (mean dose nortriptyline 89 mg or desipramine 63 mg); and placebo Rowbotham Pts with PHN Pts randomly assigned (as to Pain intensity reductions AEs: bruising and pain upon et al., 1996 (N = 35) session order) to four 12-h significantly greater with patch removal, 1 pt; mild [32] long treatment sessions: lidocaine patch than with vehicle skin reddening, 2 pts (1 pt 5% lidocaine patch (2 patch (P < to P = at each with lidocaine and sessions), vehicle patch, individual time points) and with vehicle patch) and observations only observation only (P = to P = at individual time points); pain reductions significantly greater with vehicle patch than with observation only at 2-h (P = 0.016) and 6-h (P = 0.041) time points Sang et al., Pts with DPN Median doses for pts with PHN Mean reductions in pain intensity AEs included sedation (71%, 2002 [38] (N = 23) were: dextromethorphan in pts with PHN were 6% with 63%, and 38%), dry mouth and with 400 mg/d, memantine dextromethorphan, 2% with (30%, 21%, and 25%), and PHN 35 mg/d, or lorazepam memantine, and 0% GI distress (17%, 0%, and (N = 21) (active placebo) 1.2 mg/d with lorazepam 0%) for dextromethorphan, memantine, and lorazepam, respectively Watson et al., Pts with PHN Pts randomly assigned to Amitriptyline was significantly AEs resulting in withdrawal: 1992 [23] (N = 35) amitriptyline or maprotiline. better than maprotiline at amitriptyline: dry mouth Median dose of both agents relieving pain as measured by combined with constipation, was 100 mg/d 5 wks; VAS score (P < 0.01) sedation, dizziness, lethargy, followed by 2-wk washout then crossed over to alternative treatment mouth ulcers, and nausea (1 pt each); maprotiline: dry mouth and nausea, nausea and vomiting, restless legs (1 pt each) Watson et al., Pts with PHN Amitriptyline, mg/d, Changes in VAS scores Withdrawal: 1 pt because 1982 [20] (N = 24) increased to median dose demonstrated that amitriptyline of erythema multiforme; of 75 mg, or placebo 3 wk; was superior to placebo in AEs: dry mouth, 16 pts; followed by a 1- to 2-wk relieving pain (P ) drowsiness, 4 pts; washout, then pts crossed over to alternative treatment Watson and Pts with PHN Oxycodone, 10 mg (increased Reduction in pain was significantly Withdrawals: 6 pts with Babul, 1998 (N = 50) to a maximum of 30 mg), or better with oxycodone than with oxycodone; 5 pts with [29] placebo every 12 h 4 wks, placebo (P = ) placebo; AEs with followed by crossover to the alternative treatment constipation, 2 pts; increased breast size, 1 pt; rash, 1 pt oxycodone: constipation, 5 pts; nausea, 4 pts; sedation, 3 pts Watson et al., Pts with PHN Amitriptyline or nortriptyline, No difference between the two Withdrawals: 2 pts left due to 1998 [24] (N = 33) 10 mg ( 65 y of age), or drugs in any pain parameter AEs (1 pt taking nortriptyline 20 mg (<65 y of age), with experienced increased pain dosage increases 5 wks; followed by 2-wk washout, then crossed over to alternative treatment fever, epigastric pain, bad dreams, and perspiration; 1 pt taking amitriptyline experienced slurred speech and urinary retention) Abbreviations: AEs = adverse events; AHN = acute herpetic neuralgia; d = day; GI = gastrointestinal; h = hour; min = minute; NA = not available; NPS = Neuropathic Pain Scale; pts = patients; wk = week; y = year.

7 S34 application site of the patch in patients who used either the lidocaine patch or the vehicle patch [31]. Reduction in pain, as measured on a VAS, has also been observed with the topical agent capsaicin. Capsaicin binds to receptors (VR1/TRPV1) on subpopulations of sensory nociceptive C or Ad fibers. Initially, capsaicin causes pain by initiating nociceptor firing, resulting in increased sensitivity to painful thermal and mechanical stimuli. An analgesic effect follows the painful experience as prolonged exposure to capsaicin desensitizes nociceptive terminals through partial or complete degeneration of axon terminals or the neuron [34]. However, the initial burning and stinging at the application site may be intolerable to some patients [35]. Emerging Treatment Regimens Pregabalin, a new a 2 d ligand with analgesic, anxiolytic, and anticonvulsant activities, is currently being investigated for use in the treatment of neuropathic pain [36]. Dworkin et al. reported the results of a randomized, double-blind study involving 173 patients with PHN [37]. Patients treated with pregabalin (600 mg/day or 300 mg/day based on creatinine clearances of >60 ml/minute or ml/minute, respectively) had a significantly lower mean pain score than patients who received placebo (3.60 vs 5.29, P = ), and 50% of the pregabalin-treated patients reported a 50% reduction in mean pain scores, compared with only 20% of patients who received placebo (P = 0.001). Compared with patients in the placebo group, pregabalin-treated patients also experienced significantly greater improvements in sleep (P = ). Side effects associated with pregabalin included dizziness, somnolence, peripheral edema, and dry mouth. In most cases, side effects were of mild to moderate intensity. Sang et al. investigated the use of dextromethorphan and memantine, low-affinity N- methyl-d-aspartate (NMDA) antagonists, in the treatment of neuropathic pain in patients with DPN and PHN [38]. In patients with PHN, the mean reduction in pain intensity from baseline was 7% with dextromethorphan, 2% with memantine, and 0% with lorazepam (active placebo). Although these results were not statistically significant, 29% of patients with PHN had moderate or better pain relief with dextromethorphan, as did 12% with memantine. Adverse events with dextromethorphan and memantine included sedation, dry mouth, and gastrointestinal distress. Backonja and Serra Non Disease-Specific Trials: Anticonvulsant Serpell et al. [39] conducted a study designed to assess the impact of gabapentin on specific neuropathic pain symptoms in patients with various neuropathic pain conditions. Evidence suggests that neuropathic pain symptoms reflect an underlying pathophysiology and, therefore, may respond to the same pharmacologic agents regardless of etiology. Of the 307 patients enrolled in that study, 43 had PHN. Although data for patients with PHN were not reported specifically, overall, higher percentages of gabapentin-treated patients, than patients in the placebo group, experienced improvements in allodynia (23% vs 15%), shooting pain (32% vs 24%), burning pain (23% vs 15%), and hyperalgesia (26% vs 17%), although no clear inference on specific mechanisms that responded better to gabapentin could be established. The most common adverse events observed with gabapentin treatment in those studies were somnolence, dizziness, ataxia, peripheral edema, and infections. Number Needed to Treat The importance of data generated from clinical studies is that the knowledge gained can be translated to clinical practice. Thus, clinicians who are making decisions about the management of individual patients need to have a measurement of treatment effect. This enables clinicians to evaluate the results of various clinical trials that have different end points and use different statistical analytic methods. The number needed to treat (NNT), which indicates the number of patients that would have to be treated in order to obtain a positive therapeutic response, or to prevent one untoward event, is calculated as the reciprocal of the absolute risk reduction, that is, the difference between event rates in the treatment and placebo groups [40]; for example NNT = 1/(response rate to treatment) (response rate to placebo). However, when making clinical decisions based on NNT values, certain caveats should be considered pooled NNT values are not adjusted for study quality or size; different studies use different outcome measures; there can be differences in clinical settings or patient characteristics; and there may be secular trends in incidence or morality [41]. Collins et al. analyzed data from randomized trials to calculate NNT values for anticonvulsants and antidepressants used to treat neuropathic pain in patients with PHN [42]. They determined that the NNT to obtain a 50% pain relief in one

8 Pharmacologic Management Part 1 patient is 3.2 for anticonvulsants and 2.1 for antidepressants. Sindrup and Jensen reported NNT values of 2.3 for TCAs, 2.5 for oxycodone, and 5.3 for capsaicin in PHN [43]. Number Needed to Harm The number needed to harm (NNH) indicates the number of patients that would need to be treated in order for one patient to have an adverse event. Calculation of the NNH uses the same basic equation as for the NNT, that is, NNH = 1/(adverse event rate to treatment) (adverse event rate of placebo). In a report by Collins et al. [42], NNH data were pooled for both PHN and DPN in a comparison of antidepressants (TCAs and selective serotonin reuptake inhibitors [SSRIs]) with placebo. TCAs were found to have an NNH value of 14 for major adverse events while SSRIs were shown to be no different than placebo. Although there were no NNH anticonvulsant data available for major adverse events, for minor adverse events, the NNH for gabapentin and phenytoin were 2.6 and 3.2, respectively [42]. Clinical Experience PHN can be very disabling for patients who are predominantly elderly. In contrast to results from clinical trials, TCAs are rarely effective in relieving PHN pain and associated symptoms in the clinical setting. Gabapentin and newer anticonvulsants, most of which have not been studied as well as gabapentin, provide much more dramatic pain relief in a larger number of patients with less side effects than TCAs. Patient Case An 89-year-old retired nurse with PHN of 2 years duration who was treated with topical capsaicin and oral amitriptyline experienced many side effects from these two treatments. Pain was interfering with her activities of daily living, especially since she was the one who had to take care of her older blind sister. Once started on gabapentin at doses of 400mg twice daily and 600mg at bedtime, she was able to resume activities at the level prior to her initial shingles outbreak. The residual pain was treated with the lidocaine patch. Diabetic Peripheral Neuropathy Disease Overview An estimated 17 million people in the United States have diabetes [44], and approximately 20 24% of them suffer from DPN [13], primarily a distal, symmetrical, axonal-sensory neuropathy, S35 usually involving first the feet and legs and then the hands [45]. The pathophysiology of DPN is not fully understood, nor is the mechanism underlying the painful symptoms, but it is probably hyperexcitable axon membranes that play a pivotal role. Animal and human models have suggested that edema of the endoneurium [46], oxidative injury and apoptosis of dorsal root ganglion neurons [47], and abnormal expression of sodium channels in dorsal root ganglions following nerve injury [48] may be involved. Patient-related factors affecting the development of DPN include poor glycemic control, age at diagnosis, and the duration of diabetes with both the incidence and prevalence of DPN increasing over the years [49]. Twenty-five years after a diagnosis of diabetes, almost 50% of patients have DPN [49]. People with DPN describe their pain as burning, electric, or sharp. They may also refer to a dull or aching pain. The pain associated with DPN interferes with the ability to enjoy life because all aspects of life are affected, including work, sleep, social activities, recreation, and mobility [45]. Treatment Options Many treatment options for DPN have been investigated; however, most randomized studies have involved anticonvulsants and TCAs (Table 3), and these agents have been successful in reducing pain for many patients. Anticonvulsants Carbamazepine was one of the first anticonvulsant agents to be used in the treatment of DPN [50]. Carbamazepine has a membrane-stabilizing effect in injured nerves and has been shown to decrease ectopic discharges by acting on voltage-sensitive sodium channels in animal models [51]. The efficacy of carbamazepine in relieving DPN-related pain was confirmed in early trials [52]. More recently, carbamazepine was found to be as effective as a combination of nortriptyline and fluphenazine in improving pain and paresthesias associated with DPN [53]. Data from randomized trials also have shown that anticonvulsants, such as gabapentin [54 56] and lamotrigine [57], can significantly decrease the pain of DPN, as measured by daily pain scores, McGill Pain Questionnaire scores, and numerical pain scales. Backonja et al. [54] demonstrated that gabapentin, at doses of 900 3,600 mg/day, was significantly better than placebo in reducing DPNrelated pain (P < 0.001), improving comorbid sleep disturbances (P < 0.05), and improving quality of

9 S36 Backonja and Serra Table 3 Pharmacotherapy of DPN Study Patients Treatment Outcomes Adverse events/withdrawals Randomized, double-blind, placebo-controlled trials Backonja Pts with DPN Gabapentin (titrated from Mean daily pain score at end of Withdrawals: gabapentin, 14 pts; et al., 1998 (N = 165) 900 to 3600 mg/d or study was significantly lower placebo, 16 pts; AEs, gabapentin [54] MTD, N = 84) or for gabapentin-treated pts vs placebo: dizziness, 24% vs placebo (N = 81) than for placebo-treated pts 4.9%; somnolence, 23% vs 6%; 8 wks (3.9 vs 5.1, P < 0.001). confusion, 8% vs 1.2% Capsaicin Pts with DPN or Capsaicin 0.075% Physician s global evaluation Withdrawals: capsaicin, 38 pts; Study radiculopathy (N = 138) or placebo scale, decrease in pain placebo, 20 pts; AEs, capsaicin Group, (N = 252) (N = 139) 8 wks intensity, and improvement vs placebo: burning, 63% vs 1991 [72] in pain relief were all 17%; cough-sneezing, 11% vs significantly greater in the 1.4%; irritation, 6.5% vs 0.7%; capsaicin group than in the rash-erythema, 7.2% vs 2.9% placebo group (P < 0.05 for all) Eisenberg Pts with DPN Lamotrigine (titrated from Daily NPS score was decreased Withdrawals: lamotrigine, 2 pts with et al., 2001 (N = 59) 25 to 400 mg/d, N = 29) in lamotrigine-treated pts from rash; placebo, 2 pts (impotence [57] or placebo (N = 30) 6.4 to 4.2 and from 6.5 to and diarrhea, 1 pt each); AEs, 6 wks 5.3 in placebo group (P < lamotrigine vs placebo: nausea for lamotrigine doses of 4 pts each; epigastric pain, 3 vs 200, 300, and 400 mg) 1 pt; headache, 2 pts each; drowsiness, 1 vs 4 pts; dizziness, 3 vs 4 pts Ertas et al., Pts with DPN Levodopa, 100 mg, plus Decreases in VAS scores of the AEs: no pts experienced AEs 1998 [96] (N = 25) benserazide, 25 mg active-treatment group were during the 4-wk follow-up tid, 28 d (N = 14), or placebo (N = 11) significantly greater than those of the placebo-treatment group at weeks 2, 3, and 4 (P = 0.048, P = 0.019, and P = 0.005, respectively) Gimbel et al., Pts with DPN CR oxycodone, 10-mg CR oxycodone significantly Withdrawals due to AEs: CR 2003 (N = 159) tablet every 12 h better at relieving pain than oxycodone, 7 pts; placebo, 4 pts; [67] (increased every 3 d placebo (P = 0.002); daily AEs with CR oxycodone vs to maximum of 6 pain intensities for Days placebo: constipation, 42% vs tablets [60 mg] every were 4.1 and 5.3, 14%; somnolence, 40% vs 1%; 12 h (N = 82) or respectively nausea, 36% vs 8%; dizziness, placebo (N = 77) 32% vs 10%; pruritus, 24% vs 8%; vomiting, 21% vs 3%; dry mouth, 16% vs 3% Harati et al., Pts with DPN Tramadol, 50 mg/d, Tramadol was significantly AEs with tramadol: nausea, 1998 [70] (N = 131) titrated to 200 mg/d, better at reducing pain than constipation, headache, and Days 1 14, and to placebo (P < 0.001) somnolence 400 mg/d maximum, Days (N = 65), or placebo (N = 66) qid 42 days Oskarsson Pts with DPN Mexiletine, 225 mg/d Mexiletine 675 mg/d was AEs with mexiletine were GI 1997 [71] (N = 126) (N = 31), 450 mg/d significantly better at reducing complaints, 7 pts, and one of (N = 33), or 675 mg/d nighttime pain (P < 0.03) and each of the following: dry mouth, (N = 31), vs placebo sleep disturbances (P < 0.05) thrombosis in lower limb, allergic (N = 31) than placebo reaction, and tachycardia Ruhnau et al., Pts with DPN Thioctic acid (TA), 600 mg TA was significantly better than No AEs reported during study 1999 [97] (N = 24) tid (N = 12), or placebo placebo in improving (N = 12) 3 wks symptoms (P = 0.021) Serpell et al., Pts with various Gabapentin, 900 mg/d Gabapentin demonstrated Withdrawals: gabapentin, 32 pts; 2002 [39] symptoms (titrated over 3 days), greater improvement in pain placebo, 41 pts; AEs, gabapentin (N = 307), with escalation to score than placebo (21% vs vs placebo: dizziness, 24% vs with DPN 1,800 mg/d or 14%, P = 0.048) 8%; somnolence, 14% vs 5%; (N = 7/307) 2,400 mg/d for a total infection, 9% vs 13%; headache, of 8 wks (N = 153) or 9% vs 14%; nausea, 9% vs 9%; placebo (N = 152) flu syndrome, 7% vs 5%; abdominal pain, 7% vs 4%; accidental injury, 6% vs 5%; diarrhea, 5% vs 4% Watson et al., Pts with painful CR oxycodone, 20 mg/d CR oxycodone resulted in Withdrawals: CR oxycodone, 7 pts; 2003 [69] DPN (N = 45) (maximum of 80 mg/d, significantly greater placebo, 1 pt; AEs, CR titrated every 2 7 days), improvements in pain intensity oxycodone vs placebo: nausea, or active placebo (VAS and categorical scores) 70% vs 36%; somnolence, 39% (benztropine 0.25, 0.5, (P = ) and pain relief vs 50%; constipation, 57% vs 0.75, 1 mg; maximum (P ) compared with 18%; dry mouth, 13% vs 55% of 2 mg/d) placebo

10 Pharmacologic Management Part 1 S37 Table 3 Continued Study Patients Treatment Outcomes Adverse events/withdrawals Ziegler et al., Pts with DPN 3 treatment groups: AA After 7 months, total symptom Withdrawals: 34 pts dropped out 1999 [98] (N = 509) (N = 167): a-lipoic acid, scores (pain, burning, during the IV phase and 92 pts 600 mg/d IV 3 wks, paresthesias, and numbness) dropped out during the oral followed by a-lipoic were not significantly phase; AEs: rates were similar in acid, 600 mg tid orally different among the three the three treatment groups 6 months; AP treatment groups (N = 174): a-lipoic acid, 600 mg/d IV 3 wks, followed by placebo, tid orally 6 months; PP (N = 168): placebo IV once daily 3 wks, followed by placebo orally tid 6 months Randomized, double-blind, crossover trials Chadda and Pts with DPN Diphenylhydantoin, Diphenylhydantoin resulted in No significant AEs were observed Mathur, (N = 40) 100 mg, or placebo tid significantly greater 1978 [99] 2 wks; Group A improvements in pain (Group received A, P < 0.02; Group B, P < 0.01) diphenylhydantoin then and paresthesia (Group A, placebo; Group B P < 0.05; Group B, P < 0.02) received placebo then vs placebo diphenylhydantoin Gomez-Perez Pts with DPN Nortriptyline-fluphenazine Both treatments significantly AEs included dry mouth, dizziness, et al., 1996 (N = 16) vs carbamazepine 30 reduced pain and constipation, nausea, and [53] days followed by paresthesia by 49%; no epigastric pain 2 4 wks washout, significant difference between then crossed over to the two treatment groups alternative treatment Gorson et al., Pts with DPN Gabapentin, 900 mg/d Mean reduction in McGill Pain AEs with gabapentin included: 1999 [55] (N = 40) (N = 19), or placebo Questionnaire score was 8.9 drowsiness, 6 pts; fatigue, 4 pts; (N = 21) 6 wks points with gabapentin and and imbalance, 3 pts followed by 3-wk 2.2 points with placebo washout, then pts (P = 0.03) crossed over to alternative treatment Kvinesdal Pts with DPN Imipramine (50 mg/d Seven pts treated with AEs: dizziness, 2 pts, 1 withdrew; et al., 1984 (N = 12) 1st wk then 100 mg/d) imipramine reported dry mouth, 9 pts, imipramine; 1 pt, [61] or placebo 5 wks; improvement vs no pts treated placebo; impaired micturition, then pts crossed over with placebo (P < 0.02) 2 pts, imipramine to alternative treatment Max et al., Pts with DPN Desipramine, Moderate relief was experienced Withdrawals: 2 pts each during 1991 [63] (N = 24) mg/d, or by 11 pts with desipramine desipramine and placebo active placebo and 2 pts with placebo; phases; AEs: dry mouth, (benztropine mg/d) reduction in mean pain sedation, insomnia, constipation, 6 wks; then crossed intensity score was significantly orthostatic symptoms, over to alternative better with desipramine than palpitations, increased sweating treatment with placebo (P < 0.01) Max et al., Pts with DPN Two separate studies Moderate or greater pain relief Withdrawals due to AEs: 1992 [59] (N = 79) were performed (mean was reported by pts in all amitriptyline: confusion, 2 pts; daily dose): desipramine groups: amitriptyline, 74%; orthostatic hypotension, fatigue, (111 mg) vs amitriptyline desipramine, 61%; fluoxetine, malaise, hypomania, and rash, (105 mg) and fluoxetine 48%; and placebo, 41% 1 pt each; desipramine: rash, (40 mg) vs active 3 pts; orthostatic hypotension, placebo (benztropine); bundle-branch block, tremor, each study drug was and fever, 1 pt each; fluoxetine: given for 6 wks followed orthostatic hypotension, rash, by 2-wk washout; then and headache, 1 pt each; pts crossed over to placebo: fatigue and chest pain, alternative treatment 1 pt each Max et al., Pts with DPN Amitriptyline ( mg 23/29 patients reported less AEs, amitriptyline: dry mouth, 1987 [60] (N = 37) capsules) vs active pain with amitriptyline, one sedation, dizziness, constipation, placebo (benztropine patient had less pain with depression, tinnitus, urinary 1 mg) 6 wks; then placebo, and five reported hesitancy, urinary frequency, crossed over to similar levels of pain with the jitteriness, leg weakness, muscle alternative treatment two treatments (P < ) cramps, unsteadiness, and itching; placebo: dry mouth, sedation, dizziness, urinary hesitancy, urinary frequency, hypnagogic hallucinations, and nausea

11 S38 Backonja and Serra Table 3 Continued Study Patients Treatment Outcomes Adverse events/withdrawals Morello et al., Pts with DPN Gabapentin, Pain relief with gabapentin and Withdrawals: gabapentin, 1 pt; 1999 [56] (N = 28) mg/d, or amitriptyline was not amitriptyline, 3 pts; AEs: sedation, amitriptyline mg/d significantly different (P = 0.26) dry mouth, dizziness, postural 6 wks followed by hypotension, weight gain, ataxia, 1-wk washout; then pts and lethargy; with the exception crossed over to of weight gain, there were alternative treatment similar incidences with both treatments Rull et al., Pts with DPN Carbamazepine, 600 mg/d, Pain relief occurred in 28 pts AEs: mild somnolence and 1969 [50] (N = 30) or placebo 2 wks; dizziness; cutaneous rash then pts crossed over resulted in two discontinuations to alternative treatment Sang et al., Pts with DPN Median doses for pts Mean reductions in pain AEs included sedation (71%, 63%, 2002 [38] (N = 23) and with DPN were: intensity in pts with DPN were and 38%), dry mouth (30%, 21%, with PHN dextromethorphan, 33% with dextromethorphan, and 25%), and GI distress (N = 21) 400 mg/d, memantine, 17% with memantine, and (17%, 0%, and 0%) for 55 mg/d, or lorazepam 16% with lorazepam dextromethorphan, memantine, (active placebo), and lorazepam, respectively 1.8 mg/d Saudek et al., Pts with DPN Phenytoin, 100 mg tid, No difference was found AEs with phenytoin included: 1977 [100] (N = 12) or placebo, alternating between phenytoin and ataxia, blurry vision, dizziness, wks 23 wks each placebo in symptoms or pain rash Sindrup et al., Pts with DPN Pts crossed over to VAS scores demonstrated AEs: imipramine was associated 1990 [64] (N = 29) paroxetine, 40 mg/d, significantly better effect with with significantly higher imipramine, 50 or paroxetine and imipramine incidences of dry mouth, 75 mg/d, or placebo than with placebo (P = dizziness, and palpitations for 2 wks each and P = , respectively); imipramine had a significantly better effect than paroxetine (P = ) Sindrup et al., Pts with DPN Pts crossed over to Clomipramine resulted in Both clomipramine and desipramine 1990 [62] (N = 26) clomipramine (50 or significantly greater pain were associated with more AEs 75 mg/d), desipramine reduction than placebo than placebo (P < 0.05); most (50 or 200 mg/d), or (P < 0.05) common AEs included: dry placebo for 2 wks each mouth, sweating, orthostatic dizziness, and fatigue Sindrup et al., Pts with DPN Citalopram, 40 mg/d, or Citalopram resulted in AEs occurred more frequently with 1992 [65] (N = 17) placebo 3 wks significantly greater citalopram than with placebo followed by 1-wk improvements in symptoms (P = 0.03) washout; then pts compared with placebo as crossed over to measured by pts self-reports alternative treatment (P = 0.007) Sindrup et al., Pts with DPN Tramadol, mg/d, Pain (P = 0.001) and paresthesia Withdrawals: 11 pts; AEs: there was 1999 [68] (N = 45) or placebo 4 wks (P = 0.001) ratings were a significantly higher incidence followed by 1-wk significantly lower with of AEs with tramadol than with washout; then pts tramadol than with placebo placebo, including tiredness, crossed over to dizziness, dry mouth, sweating, alternative treatment and constipation Sindrup et al., Pts (N = 40); Venlafaxine, 225 mg, The sum of individual pain AEs were similar with all three 2003 [66] pts with DPN imipramine, 150 mg, scores during treatment wk 4 treatments; there were higher (N = 15) or placebo 4 wks; was lower with venlafaxine incidences of dry mouth and then pts crossed over (80% of baseline score; sweating with imipramine and to alternative P = 0.006) and imipramine tiredness with venlafaxine treatment 4 wks; (77%; P = 0.001) than with then crossed over placebo (100%) to final treatment Wilton, 1974 Pts with DPN Carbamazepine, 200 mg Carbamazepine decreased pain AEs were mild and transient and [52] (N = 40) tid, or placebo 1 wk; significantly better than were reported by 25 pts on then pts crossed over placebo at Days 10 and 14 carbamazepine and 2 pts on to alternative treatment (P < 0.05 each) placebo Abbreviations: AEs = adverse events; CR = controlled release; d = day; GI = gastrointestinal; IV = intravenous; MTD = maximum tolerated dose; NPS = numerical pain scale; pts = patients; qid = 4 times per day; tid = 3 times per day; wk = week.

12 Pharmacologic Management Part 1 life as measured by the Short Form-36 Quality of Life Questionnaire (bodily pain, P = 0.01; mental health, P = 0.03; and vitality, P = 0.001). Similarly, Eisenberg et al. found that lamotrigine-treated patients (200, 300, or 400mg/day) experienced a significantly greater reduction in pain than patients treated with placebo (P < 0.001) [57]. However, neither lamotrigine nor placebo caused a significant change in the results of the McGill Pain Questionnaire, the Beck Depression Inventory, or the Pain Disability Index. Adverse events with these two medications were similar in both studies, with nausea being the most commonly observed adverse event. However, the use of lamotrigine has been associated with serious rashes, including Stevens-Johnson syndrome (incidence of 0.3% when used as adjunctive therapy in epilepsy) that may require discontinuation of medication and hospitalization [58]. Tricyclic Antidepressants Amitriptyline [59,60], imipramine [61], clomipramine [62], and desipramine [62,63] have been shown to produce significantly greater reductions in the pain associated with DPN than placebo or other antidepressants. Amitriptyline reduced lancinating pain [60], and imipramine improved pain, paresthesias, dysesthesias, and numbness [61]. The use of TCAs may be limited by intolerable anticholinergic side effects, including dry mouth, dizziness, hypotension, constipation, and urinary retention. Among the first-generation TCAs, desipramine has been associated with the least anticholinergic and sedative effects [63]. Selective Serotonin Reuptake Inhibitors and Serotonin-Norepinephrine Reuptake Inhibitors Several SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been investigated in neuropathic pain conditions. The SSRIs, such as paroxetine [64] and citalopram [65], and SNRIs, such as venlafaxine [66], have all produced significantly greater pain reductions than placebo in patients with DPN (P = , P = 0.007, P = 0.006, respectively). Although venlafaxine was significantly better than placebo at relieving paroxysms (P = 0.015), constant pain (P = ), and pressure-evoked pain (P = 0.011), it was not better than imipramine [66]. In general, SSRIs possess a more tolerable side-effect profile than TCAs, with nausea and tiredness reported most frequently [66]. Opioids Opioids can also ameliorate pain in patients with DPN [67,68]. Gimbel et al. [67] demonstrated the S39 efficacy of controlled-release oxycodone in a placebo-controlled study involving 159 patients with DPN-related pain (average daily pain ratings were 4.1 and 5.3, for controlled-release oxycodone and placebo, respectively, P = 0.002). In a separate placebo-controlled study, controlled-release oxycodone resulted in significantly greater improvements in pain intensity, mean daily pain, steady pain, and brief pain versus active placebo (benztropine, P = for all) [69]. Tramadol was also studied for pain associated with DPN in a randomized placebo-controlled study. By completion of the trial (day 42) and at an average dose of 210 mg/day, tramadol was found to be significantly more effective (P < 0.001) than placebo; with a pain score that was 0.8 lower (1.4 vs 2.2, final pain scores for tramadol and placebo, respectively) [70]. Another study using tramadol involved 45 patients with neuropathic pain of various etiologies [68]. Tramadol significantly improved neuropathic pain symptoms, including paresthesia (P = 0.001), and touch-evoked pain (P = 0.001). Adverse events most commonly experienced with opioids include constipation, somnolence, nausea, dizziness, vomiting, and dry mouth [67,68]. Others Mexiletine and capsaicin have shown promise in treating DPN. Mexiletine, an antiarrhythmic, was shown to be effective in an insulin-treated population (N = 126). Significant reductions in nighttime pain and sleep disturbances were seen in patients taking the highest dose of mexiletine (675 mg/day) [71]. Topical preparations, such as capsaicin, were also shown to be effective in a diabetic cohort. Capsaicin was compared with a vehicle cream (placebo) and was shown to be statistically more effective in a physician s global evaluation (P < 0.05), percent improvement (P < 0.05), and percent relief (P < 0.05) [72]. However, burning and stinging may be intolerable in patients using capsaicin [35]. Emerging Treatment Regimens In patients with DPN, Sang et al. investigated the use of dextromethorphan and memantine, lowaffinity NMDA antagonists, in the treatment of neuropathic pain in these patients [38]. In patients with DPN, the mean reduction in pain intensity from baseline was 33% with dextromethorphan, 17% with memantine, and 16% with lorazepam (active placebo). Although these results were not statistically significant, 68% of patients with DPN had moderate or better pain relief with dextromethorphan, as did 47% with memantine.