Summary Background New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and E valuation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis. Methods Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January , 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fi xed-eff ects Mantel-Haenszel method. Findings 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment eff ects. Studies published in peer-reviewed journals reported greater eff ects than did unpublished studies (r² 9·3%, p=0·009). T rial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2–8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5–9·4) for pregabalin; 7·2 (5·9–9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4–19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, fi nal quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These fi ndings permitted a strong recommendation for use and proposal as fi rst-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only. Interpretation Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest effi cacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profi ling probably account for moderate trial outcomes and should be taken into account in future studies. Funding NeuPSIG of the International Association for the Study of Pain.

/pdf/pharmacotherapy-for-neuropathic-pain-in-adults-a-systematic-424rqh29lj.pdf

Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis.

Diabetic neuropathies are the most prevalent chronic complications of diabetes. This heterogeneous group of conditions affects different parts of the nervous system and presents with diverse clinical manifestations. The early recognition and appropriate management of neuropathy in the patient with diabetes is important for a number of reasons: 

1. Diabetic neuropathy is a diagnosis of exclusion. Nondiabetic neuropathies may be present in patients with diabetes and may be treatable by specific measures.

2. A number of treatment options exist for symptomatic diabetic neuropathy.

3. Up to 50% of diabetic peripheral neuropathies may be asymptomatic. If not recognized and if preventive foot care is not implemented, patients are at risk for injuries to their insensate feet.

4. Recognition and treatment of autonomic neuropathy may improve symptoms, reduce sequelae, and improve quality of life.

Among the various forms of diabetic neuropathy, distal symmetric polyneuropathy (DSPN) and diabetic autonomic neuropathies, particularly cardiovascular autonomic neuropathy (CAN), are by far the most studied (1–4). There are several atypical forms of diabetic neuropathy as well (1–4). Patients with prediabetes may also develop neuropathies that are similar to diabetic neuropathies (5–10). Table 1 provides a comprehensive classification scheme for the diabetic neuropathies.

View this table:

Table 1 
Classification for diabetic neuropathies



Due to a lack of treatments that target the underlying nerve damage, prevention is the key component of diabetes care. Screening for symptoms and signs of diabetic neuropathy is also critical in clinical practice, as it may detect the earliest stages of neuropathy, enabling early intervention. Although screening for rarer atypical forms of diabetic neuropathy may be warranted, DSPN and autonomic neuropathy are the most common forms encountered in practice. The strongest available evidence regarding treatment pertains to these forms.

This Position Statement is based on several recent technical reviews, to which the reader is referred for detailed discussion …

/pdf/diabetic-neuropathy-a-position-statement-by-the-american-2213pwegte.pdf

Diabetic Neuropathy: A Position Statement by the American Diabetes Association

Background
Duloxetine is a balanced serotonin and noradrenaline reuptake inhibitor licensed for the treatment of major depressive disorders, urinary stress incontinence and the management of neuropathic pain associated with diabetic peripheral neuropathy. A number of trials have been conducted to investigate the use of duloxetine in neuropathic and nociceptive painful conditions. This is the first update of a review first published in 2010.

Objectives
To assess the benefits and harms of duloxetine for treating painful neuropathy and different types of chronic pain.

Search methods
On 19th November 2013, we searched The Cochrane Neuromuscular Group Specialized Register, CENTRAL, DARE, HTA, NHSEED, MEDLINE, and EMBASE. We searched ClinicalTrials.gov for ongoing trials in April 2013. We also searched the reference lists of identified publications for trials of duloxetine for the treatment of painful peripheral neuropathy or chronic pain.

Selection criteria
We selected all randomised or quasi-randomised trials of any formulation of duloxetine, used for the treatment of painful peripheral neuropathy or chronic pain in adults.

Data collection and analysis
We used standard methodological procedures expected by The Cochrane Collaboration.

Main results
We identified 18 trials, which included 6407 participants. We found 12 of these studies in the literature search for this update. Eight studies included a total of 2728 participants with painful diabetic neuropathy and six studies involved 2249 participants with fibromyalgia. Three studies included participants with depression and painful physical symptoms and one included participants with central neuropathic pain. Studies were mostly at low risk of bias, although significant drop outs, imputation methods and almost every study being performed or sponsored by the drug manufacturer add to the risk of bias in some domains. Duloxetine at 60 mg daily is effective in treating painful diabetic peripheral neuropathy in the short term, with a risk ratio (RR) for ≥ 50% pain reduction at 12 weeks of 1.73 (95% CI 1.44 to 2.08). The related NNTB is 5 (95% CI 4 to 7). Duloxetine at 60 mg daily is also effective for fibromyalgia over 12 weeks (RR for ≥ 50% reduction in pain 1.57, 95% CI 1.20 to 2.06; NNTB 8, 95% CI 4 to 21) and over 28 weeks (RR 1.58, 95% CI 1.10 to 2.27) as well as for painful physical symptoms in depression (RR 1.37, 95% CI 1.19 to 1.59; NNTB 8, 95% CI 5 to 14). There was no effect on central neuropathic pain in a single, small, high quality trial. In all conditions, adverse events were common in both treatment and placebo arms but more common in the treatment arm, with a dose-dependent effect. Most adverse effects were minor, but 12.6% of participants stopped the drug due to adverse effects. Serious adverse events were rare.

Authors' conclusions
There is adequate amounts of moderate quality evidence from eight studies performed by the manufacturers of duloxetine that doses of 60 mg and 120 mg daily are efficacious for treating pain in diabetic peripheral neuropathy but lower daily doses are not. Further trials are not required. In fibromyalgia, there is lower quality evidence that duloxetine is effective at similar doses to those used in diabetic peripheral neuropathy and with a similar magnitude of effect. The effect in fibromyalgia may be achieved through a greater improvement in mental symptoms than in somatic physical pain. There is low to moderate quality evidence that pain relief is also achieved in pain associated with depressive symptoms, but the NNTB of 8 in fibromyalgia and depression is not an indication of substantial efficacy. More trials (preferably independent investigator led studies) in these indications are required to reach an optimal information size to make convincing determinations of efficacy.

Minor side effects are common and more common with duloxetine 60 mg and particularly with 120 mg daily, than 20 mg daily, but serious side effects are rare.

Improved direct comparisons of duloxetine with other antidepressants and with other drugs, such as pregabalin, that have already been shown to be efficacious in neuropathic pain would be appropriate. Unbiased economic comparisons would further help decision making, but no high quality study includes economic data.

Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia.

BACKGROUND: Neuropathic pain (NeP), redefined as pain caused by a lesion or a disease of the somatosensory system, is a disabling condition that affects approximately two million Canadians.

/pdf/pharmacological-management-of-chronic-neuropathic-pain-2cdb1zsh5n.pdf

Pharmacological management of chronic neuropathic pain: Revised consensus statement from the Canadian Pain Society

Neuropathic pain is caused by disease or injury of the nervous system and includes various chronic conditions that, together, affect up to 8% of the population. A substantial body of neuropathic pain research points to several important contributory mechanisms including aberrant ectopic activity in nociceptive nerves, peripheral and central sensitization, impaired inhibitory modulation, and pathological activation of microglia. Clinical evaluation of neuropathic pain requires a thorough history and physical examination to identify characteristic signs and symptoms. In many cases, other laboratory investigations and clinical neurophysiological testing may help identify the underlying etiology and guide treatment selection. Available treatments essentially provide only symptomatic relief and may include nonpharmacological, pharmacological, and interventional therapies. Most extensive evidence is available for pharmacological treatment, and currently recommended first-line treatments include antidepressants (tricyclic agents and serotonin-norepinephrine reuptake inhibitors) and anticonvulsants (gabapentin and pregabalin). Individualized multidisciplinary patient care is facilitated by careful consideration of pain-related disability (eg, depression and occupational dysfunction) as well as patient education; repeat follow-up and strategic referral to appropriate medical/surgical subspecialties; and physical and psychological therapies. In the near future, continued preclinical and clinical research and development are expected to lead to further advancements in the diagnosis and treatment of neuropathic pain.

Neuropathic Pain: Principles of Diagnosis and Treatment

This multicentre, double-blind, parallel-group study in diabetic peripheral neuropathic pain addressed whether, in patients not responding to standard doses of duloxetine or pregabalin, combining both medications is superior to increasing each drug to its maximum recommended dose. For initial 8-week therapy, either 60 mg/day duloxetine (groups 1, 2) or 300 mg/day pregabalin (groups 3, 4) was given. Thereafter, in the 8-week combination/high-dose therapy period, only nonresponders received 120 mg/day duloxetine (group 1), a combination of 60 mg/day duloxetine and 300 mg/day pregabalin (groups 2, 3), or 600 mg/day pregabalin (group 4). Primary outcome (Brief Pain Inventory Modified Short Form [BPI-MSF] 24-hour average pain change after combination/high-dose therapy) was analyzed comparing combination (groups 2, 3 pooled) with high-dose monotherapy (groups 1, 4 pooled). Secondary end points included response rates, BPI-MSF severity items, and comparison of duloxetine and pregabalin in BPI-MSF average pain. Eight hundred four patients were evaluated for initial therapy and 339 for combination/high-dose therapy. There were no significant differences between combination and high-dose monotherapy regarding BPI-MSF average pain (mean change: combination: -2.35; high-dose monotherapy: -2.16; P = 0.370) and most secondary end points, which, however, consistently favoured combination therapy. Fifty-percent response rates were 52.1% for combination and 39.3% for high-dose monotherapy (P = 0.068). In exploratory analyses of the initial 8-week therapy uncorrected for multiple comparisons, 60 mg/day duloxetine was found superior to 300 mg/day pregabalin (P < 0.001). Both drugs and their combination were well tolerated. Although not significantly superior to high-dose monotherapy, combination therapy was considered to be effective, safe, and well tolerated.

Duloxetine and pregabalin: high-dose monotherapy or their combination? The "COMBO-DN study"--a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain.

Sensory profiles are heterogeneous in neuropathic pain disorders, and subgroups of patients respond differently to treatment. To further explore this, patients in the COMBO-DN study were prospectively assessed by the Neuropathic Pain Symptom Inventory (NPSI) at baseline, after initial 8-week therapy with either duloxetine or pregabalin, and after subsequent 8-week combination/high-dose therapy. Exploratory post hoc cluster analyses were performed to identify and characterize potential subgroups through their scores in the NPSI items. In patients not responding to initial 60 mg/d duloxetine, adding 300 mg/d pregabalin for combination treatment was particularly effective regarding the dimensions pressing pain and evoked pain, whereas maximizing the duloxetine dose to 120 mg/d appeared more beneficial regarding paresthesia/dysesthesia. In contrast, adding 60 mg/d duloxetine to 300 mg/d pregabalin in case of nonresponse to initial pregabalin led to numerically higher decreases in all NPSI dimensions/items compared to maximizing the pregabalin dose to 600 mg/d. Cluster analysis revealed 3 patient clusters (defined by baseline scores for the 10 NPSI sensory items) with different pain profiles, not only in terms of overall pain severity, but also across NPSI items. Mean Brief Pain Inventory average pain improved in all clusters during combination/high-dose therapy. However, in patients with severe pain, the treatment effect showed a trend in favor of high-dose monotherapy, whereas combination therapy appeared to be more beneficial in patients with moderate and mild pain (not significant). These complementary exploratory analyses further endorse the idea that sensory phenotyping might lead to a more stratified treatment and potentially to personalized pain therapy.

Neuropathic pain phenotyping as a predictor of treatment response in painful diabetic neuropathy: Data from the randomized, double-blind, COMBO-DN study

Alberto Lledo

Papers

Duloxetine and pregabalin: high-dose monotherapy or their combination? The "COMBO-DN study"--a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain.

Neuropathic pain phenotyping as a predictor of treatment response in painful diabetic neuropathy: Data from the randomized, double-blind, COMBO-DN study

Are there different predictors of analgesic response between antidepressants and anticonvulsants in painful diabetic neuropathy