Abstract

Neuropathic pain often imposes a substantial and unrelenting burden on those individuals who have it; single-agent analgesics typically only reduce pain at best. Worldwide, five sets of treatment recommendations offer insight into managing neuropathic pain, including two European guidelines, one Canadian, one Latin American, and another constructed under the auspices of the International Association for the Study of Pain (IASP). The analgesics common to these guidelines are topical lidocaine, secondary amine tricyclic antidepressants, serotonin and norepinephrine dual reuptake inhibitors, calcium channel α2-δ ligands, tramadol, and opioid antagonists. Still, significant knowledge gaps in the treatment of neuropathic pain conditions have hampered the development of algorithms and multimodal approaches. As the evidence base expands, the addition of new comparative trial data will further refine the development of new guidance for clinical management of neuropathic pain. New alternatives for managing neuropathic pain, such as the high-concentration capsaicin patch, will enlarge the treatment armamentarium and potentially impact therapeutic guidelines.

Introduction

Neuropathic pain has recently been redefined from the International Association for the Study of Pain (IASP) 1994 definition to “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system [1].” This type of pain is estimated to affect millions of people worldwide [2]. Neuropathic pain is known to negatively impact all aspects of function and substantially reduce health-related quality of life [3,4]. Furthermore, randomized controlled trials (RCTs) have shown that successful therapies for neuropathic pain are able to provide benefit at best for only half of those treated, and of those who receive benefit, often only partial pain relief is attained [5]. Hence, neuropathic pain imposes a substantial, often unrelenting burden on those who are affected.

Guideline Recommendations on Treating Peripheral Neuropathic Pain

The current literature has five sets of recommendations regarding the treatment of neuropathic pain, including two European guidelines [6–8], one Canadian [9], one Latin American [10], and another constructed under the auspices of the IASP [2]. The Neuropathic Pain Special Interest Group formed by the IASP recommends four first-line agents: topical lidocaine, secondary amine tricyclic antidepressants (TCAs: nortriptyline, desipramine), serotonin and norepinephrine dual reuptake inhibitors (SNRIs: milnacipran, duloxetine, venlafaxine), and calcium channel α2-δ ligands (gabapentin, pregabalin); and two second-line options that are also considered first-line in select clinical circumstances: tramadol and opioids (e.g., morphine, oxycodone, methadone) [2]. However, they do not offer any advice on the effectiveness of combining agents or in which order they should be implemented. A 2010 review of the new RCT evidence in the literature since the publication of the 2007 IASP guidelines noted that with new positive data on combination therapies, future guidelines on neuropathic pain may recommend a new multimodal treatment paradigm [5]. Also, new data on selective serotonin reuptake inhibitors (SSRIs: paroxetine, citalopram) for treating neuropathic pain in combination with known clinical benefits of the agents, such as greater safety against overdose than TCAs and lack of dose titration, may lead to a re-evaluation of its place in the treatment armamentarium [5].

In contrast, the European Federation of Neurological Societies (EFNS) guidelines consider each type of neuropathic pain etiology separately, individually describing the studies and recommending treatments for each condition [8]. They note, however, that the analgesics used to relieve neuropathic pain generally have similar efficacies across various conditions, with the exception of trigeminal neuralgia, chronic radiculopathy, and HIV neuropathy [8]. Only lamotrigine and capsaicin patches were found to be even moderately effective in treating HIV-associated neuropathic pain [8]. Similar to the IASP guidelines, the EFNS recommends TCAs (25–150 mg/day), pregabalin (150–600 mg/day), and gabapentin (1,200–3,600 mg/day) as first-line options for managing various painful neuropathic conditions (with the exception of trigeminal neuralgia). In the 2010 update to the EFNS guidelines, duloxetine (60–120 mg/day) and venlafaxine (150–225 mg/day) are newly recommended as first-line agents for treating diabetic peripheral neuropathy (DPN), while lidocaine patch 5% (3/day, maximal dose) is listed as a first-line approach to managing postherpetic neuralgia (PHN). This diverges from other guidelines in that the recommendations for these last 3 agents are restricted only to treating the listed, neuropathic pain conditions. As with the IASP recommendation, tramadol (200–400 mg/day) is listed as a second-line agent, however, opioids are only considered second- or third-line options, similar to the Canadian guidelines [9], because of long-term safety concerns. In addition, the 2010 guidelines, which include 64 new RCTs since January 2005, newly recommend capsaicin as a first-line analgesic for PHN and also recommend TCA-gabapentin or gabapentin-opioid combination therapies [8]. Still, the EFNS 2009 task force noted that more large-scale comparative studies are still needed [8].

Meanwhile, the European guideline by Finnerup et al. subdivides neuropathic pain types into “central” and “peripheral”[6]. According to these guidelines, peripheral neuropathic pain due to PHN or focal neuropathy should be treated with the lidocaine patch 5%. In the circumstance where this patch does not provide pain relief or for other types of peripheral neuropathic pain, a TCA or SNRI can be prescribed, unless contraindicated. For patients for whom TCAs are contraindicated, a voltage-gated calcium channel blocker is recommended, such as gabapentin or pregabalin. In cases where there still is no pain resolution, tramadol or opioids are suggested.

The Latin American guidelines also subdivide neuropathic pain into categories and then outline specific treatment algorithms for each type [10]. The subdivisions of neuropathic pain are localized peripheral neuropathies, diffuse peripheral neuropathies, central neuropathies, combined nonmalignant pain, mixed cancer pain, and trigeminal neuralgia. Although similar to other guidelines, the Latin American recommendations are tailored for the medical practices of the regions, which have, for example, different drug availabilities. In particular, access to opioids is limited [10]. Additionally, these guidelines stress the value of addressing multiple therapeutic targets via combination analgesic regimens to enhance outcomes with pharmacotherapies that often are unable to completely abate pain as monotherapies.

Differences Among the Guidelines on Treating Peripheral Neuropathic Pain

Overall, there are few differences among the pharmacologic guidelines for treating neuropathic pain. The differences that exist stem from areas of controversy in the management of neuropathic pain. For example, the IASP Neuropathic Pain Special Interest Group, the Canadian Pain Society, and the Latin American experts regarded peripheral neuropathic pain as a single treatment category. In contrast, the EFNS split peripheral neuropathic pain into different conditions, such as PHN and painful polyneuropathy (the latter includes diabetic neuropathy). Both the Canadian and European guidelines incorporate rankings of efficacy of the various agents based on number-needed-to-treat (NNT) data, whereas the Latin American recommendations have a stepwise approach to implementing therapy, so it is clear what to do next when an agent fails to provide adequate pain relief. Despite these minimal differences, the five guidelines are consistent with each other. Indeed, a 2009 review of the current guidelines has outlined these differences in a table format, and they are relatively insignificant (Table 1) [11]. The consensus guidelines, with the exception of those compiled by the Latin American experts, are not applicable to pediatric patients or those with trigeminal neuralgia. Moreover, they do not make recommendations for fibromyalgia or irritable bowel syndrome, conditions that may begin as visceral pain and then evolve into neuropathic pain.

Table 1

Comparison of neuropathic pain treatment guidelines, excluding trigeminal neuralgia*[11]

Medication Class Neuropathic Pain Special Interest Group Guidelines Canadian Pain Society Guidelines European Federation of Neurological Societies Guidelines 
Tricyclic antidepressants First line First line First line for PPN, PHN, and CP 
Calcium channel α2-δ ligands (gabapentin and pregabalin) First line First line First line for PPN, PHN, and CP 
SSNRIs (duloxetine and venlafaxine) First line Second line Second line for PPN 
Topical lidocaine First line for localized peripheral NP Second line for localized peripheral NP First line for PHN if small area of pain/allodynia 
Opioid analgesics Second line except in selected circumstances Third line Second-third-line for PPN, PHN, and CP 
Tramadol Second line except in selected circumstances Third line Second-third-line for PPN and PHN 
Medication Class Neuropathic Pain Special Interest Group Guidelines Canadian Pain Society Guidelines European Federation of Neurological Societies Guidelines 
Tricyclic antidepressants First line First line First line for PPN, PHN, and CP 
Calcium channel α2-δ ligands (gabapentin and pregabalin) First line First line First line for PPN, PHN, and CP 
SSNRIs (duloxetine and venlafaxine) First line Second line Second line for PPN 
Topical lidocaine First line for localized peripheral NP Second line for localized peripheral NP First line for PHN if small area of pain/allodynia 
Opioid analgesics Second line except in selected circumstances Third line Second-third-line for PPN, PHN, and CP 
Tramadol Second line except in selected circumstances Third line Second-third-line for PPN and PHN 
*

Only medications considered first or second line in 1 of the guidelines are presented.

Opioid analgesics and tramadol were considered first-line options in the following circumstances: for the treatment of acute NP, episodic exacerbations of severe NP, neuropathic cancer pain, and during titration of a first-line medication in patients with substantial pain.

CP = central pain; NP = neuropathic pain; PHN = postherpetic neuralgia; PPN = painful polyneuropathy; SSNRIs = selective serotonin and norepinephrine reuptake inhibitors.

Reprinted from O'Connor AB, Dworkin RH. Treatment of neuropathic pain: An overview of recent guidelines. American Journal of Medicine 2009;122(suppl 10):S22–32, with permission from Elsevier.

Gaps and Flaws in the Evidence Base for Treating Peripheral Neuropathic Pain

There are several gaps in the evidence supporting the current guidelines for treating neuropathic pain. First of all, most of the pharmacotherapy trials have investigated patients with either PHN or painful DPN for treatment periods of only 6 to 12 weeks at the longest. Yet, there are many patients who suffer from pain due to other neuropathic pain conditions who may not necessarily benefit from the same regimens that are efficacious for PHN or DPN. These other conditions include complex regional pain syndrome (CRPS), spinal cord injury, cancer invasion of nerve structures, and surgery- or chemotherapy-induced peripheral neuropathy. This raises several important concerns. First of all, it may be inappropriate to extrapolate the results from an RCT of one neuropathic pain condition to the treatment of another neuropathic pain condition, although this is frequently done clinically. Notably, RCTs of several neuropathic pain conditions have been negative for TCAs, and negative results have been observed in RCTs of gabapentin for treating HIV- and chemotherapy-induced peripheral neuropathy as well as CRPS, and yet these medications are still prescribed clinically for these conditions [2,6]. This illustrates that even when studies assessing patient responsiveness have negative results, some patients can still derive benefit from the therapy in question, as there is a high degree of variability in how people respond. Also, therapies can have different and, moreover, beneficial effects when combined with other agents. Table 2 describes a situation where patients with neuropathic cancer pain have been unresponsive to TCAs but derive benefit from gabapentin [11]. Yet, TCAs continue to be used clinically in combination with gabapentin or pregabalin. Indeed, license is often taken to try agents despite negative data from some studies. A 2009 systematic review considered the evidence and noted considerable gaps in the evidence for treating neuropathic pain with anticonvulsants [12]. For example, the majority of studies of cancer-related neuropathy, as well as phantom limb pain, have negative results.

Table 2

Summary of the results of randomized clinical trials involving first- and second-line medications for patients with neuropathic pain*[11]

 Antidepressants
 
Calcium Channel Ligands
 
Topical
 
Opioid Receptor Agonists
 
Pain Condition Tricyclic Antidepressants Duloxetine Venlafaxine Gabapentin Pregabalin Lidocaine Patch 5% Opioid Analgesics Tramadol 
Peripheral NP         
  Painful DPN Positive Positive Positive Both Both — Positive Positive 
  PHN Positive — Negative Positive Both Positive Positive Positive 
  Painful polyneuropathy Positive — Positive Positive — Positive Positive Positive 
  Phantom limb pain Negative — — Both — — Positive Positive 
  Postmastectomy pain Positive — Negative — — — — — 
  Guillain-Barré syndrome — — — Positive — — — — 
  Neuropathic cancer pain Negative — — Positive — — — — 
  Complex regional pain syndrome (type I) — — — Negative — — — — 
  Chronic lumbar root pain Negative — — — — — Negative — 
  Chemotherapy-induced neuropathy Negative — — Negative — — — — 
  HIV neuropathy Negative — — Negative — — — — 
Central NP         
  Central post-stroke pain Positive — — — Positive — — — 
  Spinal cord injury pain Negative — — Positive Positive — — — 
 Antidepressants
 
Calcium Channel Ligands
 
Topical
 
Opioid Receptor Agonists
 
Pain Condition Tricyclic Antidepressants Duloxetine Venlafaxine Gabapentin Pregabalin Lidocaine Patch 5% Opioid Analgesics Tramadol 
Peripheral NP         
  Painful DPN Positive Positive Positive Both Both — Positive Positive 
  PHN Positive — Negative Positive Both Positive Positive Positive 
  Painful polyneuropathy Positive — Positive Positive — Positive Positive Positive 
  Phantom limb pain Negative — — Both — — Positive Positive 
  Postmastectomy pain Positive — Negative — — — — — 
  Guillain-Barré syndrome — — — Positive — — — — 
  Neuropathic cancer pain Negative — — Positive — — — — 
  Complex regional pain syndrome (type I) — — — Negative — — — — 
  Chronic lumbar root pain Negative — — — — — Negative — 
  Chemotherapy-induced neuropathy Negative — — Negative — — — — 
  HIV neuropathy Negative — — Negative — — — — 
Central NP         
  Central post-stroke pain Positive — — — Positive — — — 
  Spinal cord injury pain Negative — — Positive Positive — — — 
*

“Positive” indicates that ≥1 trial demonstrated statistically significant pain relief for the primary outcome (compared with placebo); “negative” indicates that ≥1 trial failed to demonstrate statistically significant pain relief for the primary outcome (compared with placebo); and “both” indicates that ≥1 trial was positive and ≥1 trial was negative. Not all medications were tested in every NP condition.

Trial only included patients with allodynia.

DPN = diabetic painful neuropathy; HIV = human immunodeficiency virus; NP = neuropathic pain; PHN = postherpetic neuralgia.

Reprinted from O'Connor AB, Dworkin RH. Treatment of neuropathic pain: An overview of recent guidelines. American Journal of Medicine 2009;122(suppl 10):S22–32, with permission from Elsevier.

Another important issue is the lack of long-term data. For most therapies used for neuropathic pain, the effects of using them for longer than 3 months are undocumented [5], with the exception of lidocaine patch 5% for treating PHN (N = 249, for 24 months) [13], duloxetine for managing DPN (N = 237, for 12 months) [14], and pregabalin (N = 81, for up to 15 months in 3-month cycles) [15]. Also, few head-to-head RCTs compare different treatments for neuropathic pain or combination therapies, which is a major limitation when developing treatment algorithms. Lastly, because of differences in study designs, it is often difficult to compare results from different RCTs even when the patients have the same condition.

When direct comparisons of drug efficacies are unavailable, an alternative approach is to estimate their relative efficacies by calculation of NNTs [6]. Indeed, to make comparisons among the efficacies of different treatments, NNT data were utilized in both the Canadian and European guidelines on treating neuropathic pain [6,9]. NNTs are calculated by taking the inverse of the difference between the efficacy of the responder and the placebo. For example, calculating the NNT from a trial wherein 60% of the participants achieved a 50% reduction in pain, and 30% of the placebo group reported 50% pain relief, 0.30 is subtracted from 0.60. Then, the inverse of the difference is taken (1/0.3), yielding an NNT of 3.3. In this example, for every three patients treated clinically, there will be one who attains an efficacy of 50% pain relief. In the literature, an NNT of two to six is considered strong support for using a particular agent in the treatment of neuropathic pain. Still, an NNT within this range does not always translate clinically into reliable beneficial results. For example, both valproate and TCAs have sufficient NNTs supporting their use for treating neuropathic pain, with a 2.8 for the former (range of 2.1–4.2) and 3.1 for the latter (2.7–3.7) [6]. Yet, clinical experience has shown that the agents often do not provide good results for patients with neuropathic pain.

At the heart of the difficulty in ranking and comparing therapies for treating neuropathic pain are the changes in study design over the years. For example, older RCTs of TCAs implemented crossover designs, while newer studies of antineuropathic agents use parallel-group research designs. This causes significant problems in result interpretation across trials. Furthermore, as adherence can be reduced within patient populations because of the side effects frequently observed, recent trials have used a run-in period to increase adherence to treatment. Also, to be included in a trial, a moderate baseline pain severity is generally required. These strategies have been recently implemented and were not part of study designs 10 years before, making a decision tree based on NNT values difficult to accept.

Also, the outcome measures used currently differ from those studied previously: older pain studies would rely solely on visual analogue scale (VAS) scores, while newer studies also include a patient's impression of global improvement. It has now become standard practice for pain studies to include—in addition to those first two measures—a functionality measure (SF-36) and a quality-of-life improvement tool. Indeed, the parameters for efficacy have become more stringent over the years, and the evolution of study design has complicated the comparison of the efficacy of treatments studied at different time periods.

Another concern involves the more recent use of a statistical method called baseline-observation-carried-forward, versus the latest-observation-carried-forward used in older studies. The difference in the methods involves using the pain score noted when the patient first enters the study vs using the last observed pain rating from the study. These different variables can cause difficulties in analyzing results across studies. The use of NNT and number-needed-to-harm (NNH) assessments in the guidelines issued by the EFNS and the Canadian Pain Society enhance the comparisons of the treatments therein [7,9]. Regardless, ignoring response to placebos, most trials of efficacious treatments have found that 50% of patients achieve satisfactory pain relief (∼30%) [11]. A 30% improvement in pain has been shown to correlate to a noticeable effect clinically [16].

N-Methyl-d-aspartate acid (NMDA) antagonists such as ketamine or mementine are not considered in any of the current guidelines for treating neuropathic pain, as there are no RCTs available with evidence on the safety and efficacy of their use.

A Rational Strategy for Treating Neuropathic Pain

Often reliable rankings of medications are not available, so other approaches must be undertaken in a rational strategy for prescribing, particularly for the ∼50% of patients who are nonresponsive to treatment with the analgesics that are initially prescribed. First, the potential for adverse effects should be weighed when prescribing medications. In this regard, amitriptyline is less recommended due to its anticholinergic side effects and blockade of baroreceptor reflexes in favor of other medications that are less likely to induce sedation and produce the aforementioned side effects. Furthermore, analgesics with fewer systemic effects, such as topical agents (e.g., lidocaine patch 5%), may be chosen before an anticonvulsant for localized neuropathic pain (e.g., DPN).

Treatments that are able to treat multiple comorbidities are advantageous. For example, the TCA nortriptyline can also reduce insomnia, a common consequence of pain. Consequently, for a patient who will be treated with a TCA and also experience insomnia, nortriptyline may be a better choice than desipramine. The risk of drug–drug interactions, overdose, or abuse affects the choice of analgesic. The cytochrome P450 enzyme system metabolizes many endogenous and exogenous substances, including 40% to 50% of all medications [17]. Drugs that are metabolized through this system may be prone to more interactions in patients taking multiple medications. Indeed, TCAs, anticonvulsants, nonsteroidal anti-inflammatory drugs (NSAIDs), and most opioids (with the exception of morphine, hydromorphone, oxymorphone, and tapentadol) have the potential to induce or inhibit CYP450 enzymes, and thus can be prone to drug–drug or drug–disease interactions [18–20]. Drugs that prolong the QTC interval also have an increased risk of inducing a drug–drug interaction. For example, methadone can interact with calcium channel blockers, TCAs, and some antibiotics. Finally, cost can be another important element to consider when choosing medications, as individual patients can be limited by insurance coverage and financial resources [5].

There are other sources of insight into managing the ∼50% of patients who are nonresponsive to the initial analgesic they are given. In the last 2 years, several studies comparing the efficacy of available treatments with combination therapy have been published. The first of these was conducted by Ian Gilron and colleagues who found that the coadministration of gabapentin with morphine provided better analgesia at lower doses than either agent alone at higher doses [21]. The patients studied in this RCT had DPN or PHN, and their most frequently observed adverse effects from treatment were constipation, dry mouth, and sedation. A subsequent publication of another RCT indicated that combinations of nortriptyline and gabapentin were more efficacious than either monotherapy for treating neuropathic pain.

Other new studies have investigated the efficacy of a single analgesic compared with a different single agent. For example, an RCT of acute pain due to herpes zoster (which has the potential to evolve into persistent pain) found that controlled-release oxycodone has the potential to produce better pain control compared with gabapentin; furthermore, gabapentin did not yield significantly better pain relief than placebo [22]. In another RCT with a 4-week comparative phase, patients with PDN or PHN were treated with either lidocaine patch 5% or pregabalin [23]. Both treatment groups had significant reductions in pain scores and allodynia, with an overall response rate of 65.3% in the lidocaine group and 62.0% in the pregabalin group. However, the incidences of drug-related adverse effects were notably different, with 3.9% in the lidocaine patch 5% group and 39.2% in the pregabalin cohort. Moreover, the related treatment discontinuations were 1.3% and 20.3%, respectively [23]. The topical agent was associated with 10-fold fewer adverse events than the central-acting analgesic and, as a corollary, the number of treatment-related discontinuations was significantly lower in the lidocaine patch 5% group.

Alternative Approaches and New Therapies for Managing Peripheral Neuropathic Pain

When intensive pharmacological therapy is implemented without adequate results, alternative therapies can be considered. A task force assembled by the EFNS reviewed the literature published between 1968 and 2006 on neurostimulation therapy for treating neuropathic pain [24]. Good evidence supports the use of neurostimulation for reducing pain associated with failed back surgery syndrome (FBSS) and CRPS I, albeit the evaluations did not extend beyond 6 months. Positive results for studies of CRPS II, peripheral nerve injury, DPN, PHN, brachial plexus lesion, amputation (stump and phantom pains), and partial spinal cord injury suggest that neurostimulation could benefit those conditions as well; however, further comparative trials are needed for confirmation [24]. Motor cortex stimulation may be useful for central post-stroke pain and neuropathic facial pain. Additionally, practice parameters issued in the United States support the use of spinal cord stimulation techniques for treating neuropathic pain in patients who have failed other forms of therapy [25].

A study published in January 2010 considered the use of spinal cord stimulation for FBSS, using the outcome of workers' compensation. A prospective population cohort was divided into three groups: 1) 51 patients administered spinal cord stimulation following referral from a pain specialist; 2) 39 patients who attended a pain clinic but did not receive spinal cord stimulation; and 3) 68 control patients who were not seen at a pain clinic and did not receive spinal cord stimulation [26]. Data on the participants were collected at 6, 12, and 24 months after enrollment. Less than 10% of any of the patients in the study achieved satisfactory pain relief. The outcome of the patients who received spinal cord stimulation did not significantly differ from those who received treatment through the pain clinic, and no better effectiveness was attained from spinal cord stimulation therapy compared with alternative treatments, particularly past 6 months [26].

Still, an editorial by Dr Wasan noted potentially important differences between the study groups [27]. Notably, the spinal cord stimulation group tended to have more severe pain for a longer period of time and worse baseline functioning, as may be expected considering that referrals for this type of therapy only occur after multiple other treatments fail. The authors of the study attempted to correct for this difference by manipulating the variables in the statistical management of the data. However, separating the variability in the treatment response due to spinal cord stimulation is limited by the interrelationships between important variables in the data and is not always successful, particularly in light of the sample size and the multiplicity of issues with which the patients presented. Another equally important issue was the use of composite pain reduction, function, and opioid consumption for the primary outcome analysis. Patients presenting with FBSS not only had leg pain but also low back pain, which is often refractory to spinal cord stimulation therapy. The pain scores and opioid consumption could have remained high because spinal cord stimulation is not highly effective at relieving low back pain. The authors did not differentiate between the types of pain that failed to respond to therapy. Also, the analysis of those patients within the spinal cord stimulation group included those who had a trial but were not given an implant (47%). The low rate of implantation suggests that the study suffered from poor patient selection. Indeed, issues with study enrollment are also indicated by the low mental health scores of all the study groups. In line with clinical experience, the study results do indicate that those with unilateral radicular pain, better baseline functioning, and better mental health appear to have the best outcomes with spinal cord stimulation therapy.

Other than invasive techniques, there are several other options for those patients who do not find adequate relief from traditional analgesics. Novel treatments highlighted in the 2010 review of the literature on new RCT data following the publication of the 2007 IASP guidelines on treating neuropathic pain consider evidence on botulinum toxin, high-concentration capsaicin patch, and lacosamide [5]. One of the oldest medicines, the “heat” component in chili peppers, capsaicin, has a new presentation. An 8% capsaicin dermal patch was recently developed specifically for treating neuropathic pain. The patch has been studied in a 12-week RCT in 402 patients with PHN [28]. A single 60-minute application of the patch led to sustained pain relief, and the only adverse events observed were those localized to the application site [28]. Indeed, the safety of repeated applications of the patch was assessed over a year-long period, during which only localized skin reactions such as erythema, edema, and pain were noted [29]. Furthermore, an RCT involving healthy volunteers assessed the safety of the 8% capsaicin patch over 24 weeks. At 1 week following application of the patch, an 80% reduction in nerve fiber density was noted, but 24 weeks later these fibers had nearly all regenerated [30]. The patch has also been used to relieve other painful conditions, such as DPN and HIV-associated distal sensory neuropathy, with a surface area as big as 1,120 cm2 (33 × 33 cm) [31].

Botulinum toxin type A has been formulated recently for single intradermal application. In an RCT of 29 patients, doses of 20 to 190 units were injected into sites of focal peripheral neuropathic pain with significant and persistent responses from 2 weeks up to 14 weeks following administration [32]. The adverse effects of the intradermal injection were limited to localized pain upon application. In another RCT of botulinum toxin A, pain associated with DPN was significantly reduced (a decrease of at least 30%) in 44.4% of the 18 patients who completed the trial [33]. After an intradermal injection of the toxin, reductions in pain on VAS were noted at 1 week, 4 weeks (P = 0.014), 8 weeks (P = 0.039), and 12 weeks (P = 0.024) [33]. It has been suggested that the mechanism of analgesia provided by botulinum toxin involves preferential blocking of neurotransmitter release and transient receptor potential vanilloid subfamily, member 1 (TRPV1) receptor signaling in C-fibers, thereby reducing neurogenic inflammation and increasing heat pain threshold [34]. A 2010 evidence-based review of the published data on botulinum toxin reported that the current studies are as yet inconclusive, and larger studies are needed to establish the use of the therapy for treating neuropathic pain [35].

New drugs have also been developed with potential benefits for treating neuropathic pain. Lacosamide is a new anticonvulsant medication approved for use as an adjunctive treatment for partial-onset seizures. It has undergone investigations for use as an analgesic, but these studies have not led to approval by either the US Food and Drug Administration or the European Medicines Agency for an indication of pain [5]. Although the mechanism of analgesic action has not been established, in vitro studies suggest a dual effect involving the selective enhancement of slow activation of voltage-gated sodium channels along with binding to the collapsin response mediator protein 2 (CRPM2) [36]. CRPM2 is involved in the downregulation of a subunit of the NMDA receptor—a key modulator of the transmission of pain. Daily doses of as much as 400 mg lacosamide were associated with at least a 30% reduction in pain from DPN in 58% of the treatment group vs 46% of the placebo group in an 18-week RCT [37]. Side effects observed in the study were akin to those frequently seen with other anticonvulsants: dizziness, nausea, tremors, headache, and fatigue [37]. A 2-year open-label extension of this trial found that 68% of patients initiated with a 100 mg/day regimen of lacosamide and then slowly titrated to as much as 400 mg/day achieved a positive response and chose to continue with their treatment [38].

Tapentadol is another new analgesic with a dual mode of action: agonism of the µ opioid receptor and inhibition of norepinephrine reuptake [39]. It has been studied for treating inflammatory and neuropathic pain, including DPN. The potency of tapentadol is 2- to 3-fold lower than morphine; however, the development of tolerance in animal models is significantly slower than observed with morphine [40].

Conclusions

The current guidelines for treating neuropathic pain facilitate the implementation of therapy. The recommendations also provide a preliminary outline of the current gaps in the knowledge, suggesting areas that need further investigation in order to improve patient care. However, the guidelines do not address the options for patients who have failed single-agent pharmacological therapy, and the use of combination therapy has not been adequately considered. Moreover, the guidelines do not contain a sufficient analysis of the literature on interventional techniques for the management of patients who have not responded to pharmacological therapies.

Acknowledgments

Publication of this supplement was made possible through an educational grant from Endo Pharmaceuticals Inc. The author wishes to thank Rebecca A. Bachmann, PhD, for assistance in the search of the literature and in preparation of this manuscript.

Disclosures

The author has no financial disclosures to report.

References

1
Treede
RD
Jensen
TS
Campbell
JN
et al
Neuropathic pain: Redefinition and a grading system for clinical and research purposes
.
Neurology
 
2008
;
70
(
18
):
1630
5
.
2
Dworkin
RH
O'Connor
AB
Backonja
M
et al
Pharmacologic management of neuropathic pain: Evidence-based recommendations
.
Pain
 
2007
;
132
(
3
):
237
51
.
3
Turk
DC
Audette
J
Levy
RM
Mackey
SC
Stanos
S
.
Assessment and treatment of psychosocial comorbidities in patients with neuropathic pain
.
Mayo Clin Proc
 
2009
;
85
(
suppl 3
):
S42
50
.
4
Doth
AH
Hansson
PT
Jensen
MP
Taylor
RS
.
The burden of neuropathic pain: A systematic review and meta-analysis of health utilities
.
Pain
 
2010
;
149
(
2
):
338
44
.
5
Dworkin
RH
O'Connor
AB
Audette
J
et al
Recommendations for the pharmacological management of neuropathic pain: An overview and literature update
.
Mayo Clin Proc
 
2010
;
85
(
suppl 3
):
S3
14
.
6
Finnerup
NB
Otto
M
McQuay
HJ
et al
Algorithm for neuropathic pain treatment: An evidence based proposal
.
Pain
 
2005
;
118
(
3
):
289
305
.
7
Attal
N
Cruccu
G
Haanpaa
M
et al
EFNS guidelines on pharmacological treatment of neuropathic pain
.
Eur J Neurol
 
2006
;
13
(
11
):
1153
69
.
8
Attal
N
Cruccu
G
Baron
R
et al
EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision
.
Eur J Neurol
 
2010
;
17
(
9
):
1113
e88
.
9
Moulin
DE
Clark
AJ
Gilron
I
et al
Pharmacological management of chronic neuropathic pain—consensus statement and guidelines from the Canadian Pain Society
.
Pain Res Manag
 
2007
;
12
(
1
):
13
21
.
10
Acevedo
JC
Amaya
A
Casasola Ode
L
et al
Guidelines for the diagnosis and management of neuropathic pain: Consensus of a group of Latin American experts
.
J Pain Palliat Care Pharmacother
 
2009
;
23
(
3
):
261
81
.
11
O'Connor
AB
Dworkin
RH
.
Treatment of neuropathic pain: An overview of recent guidelines
.
Am J Med
 
2009
;
122
(
suppl 10
):
S22
32
.
12
Goodyear-Smith
F
Halliwell
J
.
Anticonvulsants for neuropathic pain: Gaps in the evidence
.
Clin J Pain
 
2009
;
25
(
6
):
528
36
.
13
Hans
G
Sabatowski
R
Binder
A
et al
Efficacy and tolerability of a 5% lidocaine medicated plaster for the topical treatment of post-herpetic neuralgia: Results of a long-term study
.
Curr Med Res Opin
 
2009
;
25
(
5
):
1295
305
.
14
Raskin
J
Smith
TR
Wong
K
et al
Duloxetine versus routine care in the long-term management of diabetic peripheral neuropathic pain
.
J Palliat Med
 
2006
;
9
(
1
):
29
40
.
15
Stacey
BR
Dworkin
RH
Murphy
K
et al
Pregabalin in the treatment of refractory neuropathic pain: Results of a 15-month open-label trial
.
Pain Med
 
2008
;
9
(
8
):
1202
8
.
16
Farrar
JT
Young
JP
Jr
LaMoreaux
L
Werth
JL
Poole
RM
.
Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale
.
Pain
 
2001
;
94
(
2
):
149
58
.
17
Rogers
JF
Nafziger
AN
Bertino
JS
Jr
.
Pharmacogenetics affects dosing, efficacy, and toxicity of cytochrome P450-metabolized drugs
.
Am J Med
 
2002
;
113
(
9
):
746
50
.
18
Stamer
UM
Stuber
F
.
Genetic factors in pain and its treatment
.
Curr Opin Anaesthesiol
 
2007
;
20
(
5
):
478
84
.
19
Kadiev
E
Patel
V
Rad
P
et al
Role of pharmacogenetics in variable response to drugs: Focus on opioids
.
Expert Opin Drug Metab Toxicol
 
2008
;
4
(
1
):
77
91
.
20
Tzschentke
TM
De Vry
J
Terlinden
R
et al
Tapentadol hydrochloride
.
Drugs Future
 
2006
;
31
(
12
):
1053
61
.
21
Gilron
I
Bailey
JM
Tu
D
et al
Morphine, gabapentin, or their combination for neuropathic pain
.
N Engl J Med
 
2005
;
352
(
13
):
1324
34
.
22
Dworkin
RH
Barbano
RL
Tyring
SK
et al
A randomized, placebo-controlled trial of oxycodone and of gabapentin for acute pain in herpes zoster
.
Pain
 
2009
;
142
(
3
):
209
17
.
23
Baron
R
Mayoral
V
Leijon
G
et al
Efficacy and safety of 5% lidocaine (lignocaine) medicated plaster in comparison with pregabalin in patients with postherpetic neuralgia and diabetic polyneuropathy: Interim analysis from an open-label, two-stage adaptive, randomized, controlled trial
.
Clin Drug Investig
 
2009
;
29
(
4
):
231
41
.
24
Cruccu
G
Aziz
TZ
Garcia-Larrea
L
et al
EFNS guidelines on neurostimulation therapy for neuropathic pain
.
Eur J Neurol
 
2007
;
14
(
9
):
952
70
.
25
North
R
Shipley
J
Prager
J
et al
Practice parameters for the use of spinal cord stimulation in the treatment of chronic neuropathic pain
.
Pain Med
 
2007
;
8
(
suppl 4
):
S200
75
.
26
Turner
JA
Hollingworth
W
Comstock
BA
Deyo
RA
.
Spinal cord stimulation for failed back surgery syndrome: Outcomes in a workers' compensation setting
.
Pain
 
2010
;
148
(
1
):
14
25
.
27
Wasan
AD
.
Spinal cord stimulation in a workers' compensation population: How difficult it can be to interpret a clinical trial
.
Pain
 
2010
;
148
(
1
):
3
4
.
28
Backonja
M
Wallace
MS
Blonsky
ER
et al
NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: A randomised, double-blind study
.
Lancet Neurol
 
2008
;
7
(
12
):
1106
12
.
29
Simpson
DM
Gazda
S
Brown
S
et al
Long-term safety of NGX-4010, a high-concentration capsaicin patch, in patients with peripheral neuropathic pain
.
J Pain Symptom Manage
 
2010
;
39
(
6
):
1053
64
.
30
Kennedy
WR
Vanhove
GF
Lu
SP
et al
A randomized, controlled, open-label study of the long-term effects of NGX-4010, a high-concentration capsaicin patch, on epidermal nerve fiber density and sensory function in healthy volunteers
.
J Pain
 
2010
;
11
(
6
):
579
87
.
31
Noto
C
Pappagallo
M
Szallasi
A
.
NGX-4010, a high-concentration capsaicin dermal patch for lasting relief of peripheral neuropathic pain
.
Curr Opin Investig Drugs
 
2009
;
10
(
7
):
702
10
.
32
Ranoux
D
Attal
N
Morain
F
Bouhassira
D
.
Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain
.
Ann Neurol
 
2008
;
64
(
3
):
274
83
.
33
Yuan
RY
Sheu
JJ
Yu
JM
et al
Botulinum toxin for diabetic neuropathic pain: A randomized double-blind crossover trial
.
Neurology
 
2009
;
72
(
17
):
1473
8
.
34
Gazerani
P
Pedersen
NS
Staahl
C
Drewes
AM
Arendt-Nielsen
L
.
Subcutaneous botulinum toxin type A reduces capsaicin-induced trigeminal pain and vasomotor reactions in human skin
.
Pain
 
2009
;
141
(
1–2
):
60
9
.
35
Qerama
E
Fuglsang-Frederiksen
A
Jensen
TS
.
The role of botulinum toxin in management of pain: An evidence-based review
.
Curr Opin Anaesthesiol
 
2010
;
23
(
5
):
602
10
.
36
Perucca
E
Yasothan
U
Clincke
G
Kirkpatrick
P
.
Lacosamide
.
Nat Rev Drug Discov
 
2008
;
7
(
12
):
973
4
.
37
Wymer
JP
Simpson
J
Sen
D
Bongardt
S
.
Efficacy and safety of lacosamide in diabetic neuropathic pain: An 18-week double-blind placebo-controlled trial of fixed-dose regimens
.
Clin J Pain
 
2009
;
25
(
5
):
376
85
.
38
Shaibani
A
Biton
V
Rauck
R
Simpson
J
.
Long-term oral lacosamide in painful diabetic neuropathy: A two-year open-label extension trial
.
Eur J Pain
 
2009
;
13
(
5
):
458
63
.
39
Schroder
W
Vry
JD
Tzschentke
TM
Jahnel
U
Christoph
T
.
Differential contribution of opioid and noradrenergic mechanisms of tapentadol in rat models of nociceptive and neuropathic pain
.
Eur J Pain
 
2010
;
14
(
8
):
814
21
.
40
Tzschentke
TM
Christoph
T
Kogel
B
et al
(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): A novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties
.
J Pharmacol Exp Ther
 
2007
;
323
(
1
):
265
76
.