Nanna Brix Finnerup

Pharmacologic management of neuropathic pain: evidence-based recommendations.

Abstract Patients with neuropathic pain (NP) are challenging to manage and evidence‐based clinical recommendations for pharmacologic management are needed. Systematic literature reviews, randomized clinical trials, and existing guidelines were evaluated at a consensus meeting. Medications were considered for recommendation if their efficacy was supported by at least one methodologically‐sound, randomized clinical trial (RCT) demonstrating superiority to placebo or a relevant comparison treatment. Recommendations were based on the amount and consistency of evidence, degree of efficacy, safety, and clinical experience of the authors. Available RCTs typically evaluated chronic NP of moderate to severe intensity. Recommended first‐line treatments include certain antidepressants (i.e., tricyclic antidepressants and dual reuptake inhibitors of both serotonin and norepinephrine), calcium channel α2‐δ ligands (i.e., gabapentin and pregabalin), and topical lidocaine. Opioid analgesics and tramadol are recommended as generally second‐line treatments that can be considered for first‐line use in select clinical circumstances. Other medications that would generally be used as third‐line treatments but that could also be used as second‐line treatments in some circumstances include certain antiepileptic and antidepressant medications, mexiletine, N‐methyl‐d‐aspartate receptor antagonists, and topical capsaicin. Medication selection should be individualized, considering side effects, potential beneficial or deleterious effects on comorbidities, and whether prompt onset of pain relief is necessary. To date, no medications have demonstrated efficacy in lumbosacral radiculopathy, which is probably the most common type of NP. Long‐term studies, head‐to‐head comparisons between medications, studies involving combinations of medications, and RCTs examining treatment of central NP are lacking and should be a priority for future research.

Algorithm for neuropathic pain treatment: an evidence based proposal.

&NA; New studies of the treatment of neuropathic pain have increased the need for an updated review of randomized, double‐blind, placebo‐controlled trials to support an evidence based algorithm to treat neuropathic pain conditions. Available studies were identified using a MEDLINE and EMBASE search. One hundred and five studies were included. Numbers needed to treat (NNT) and numbers needed to harm (NNH) were used to compare efficacy and safety of the treatments in different neuropathic pain syndromes. The quality of each trial was assessed. Tricyclic antidepressants and the anticonvulsants gabapentin and pregabalin were the most frequently studied drug classes. In peripheral neuropathic pain, the lowest NNT was for tricyclic antidepressants, followed by opioids and the anticonvulsants gabapentin and pregabalin. For central neuropathic pain there is limited data. NNT and NNH are currently the best way to assess relative efficacy and safety, but the need for dichotomous data, which may have to be estimated retrospectively for old trials, and the methodological complexity of pooling data from small cross‐over and large parallel group trials, remain as limitations.

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

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 Evaluation (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 fixed-effects Mantel-Haenszel method. FINDINGS 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r(2) 9·3%, p=0·009). Trial 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, final 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 findings permitted a strong recommendation for use and proposal as first-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 efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling 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.

The evidence for pharmacological treatment of neuropathic pain.

&NA; Randomized, double‐blind, placebo‐controlled trials on neuropathic pain treatment are accumulating, so an updated review of the available evidence is needed. Studies were identified using MEDLINE and EMBASE searches. Numbers needed to treat (NNT) and numbers needed to harm (NNH) values were used to compare the efficacy and safety of different treatments for a number of neuropathic pain conditions. One hundred and seventy‐four studies were included, representing a 66% increase in published randomized, placebo‐controlled trials in the last 5 years. Painful poly‐neuropathy (most often due to diabetes) was examined in 69 studies, postherpetic neuralgia in 23, while peripheral nerve injury, central pain, HIV neuropathy, and trigeminal neuralgia were less often studied. Tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors, the anticonvulsants gabapentin and pregabalin, and opioids are the drug classes for which there is the best evidence for a clinical relevant effect. Despite a 66% increase in published trials only a limited improvement of neuropathic pain treatment has been obtained. A large proportion of neuropathic pain patients are left with insufficient pain relief. This fact calls for other treatment options to target chronic neuropathic pain. Large‐scale drug trials that aim to identify possible subgroups of patients who are likely to respond to specific drugs are needed to test the hypothesis that a mechanism‐based classification may help improve treatment of the individual patients.

Pharmacotherapy for neuropathic pain in adults

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 Evaluation (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 fixed-effects Mantel-Haenszel method. FINDINGS 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r(2) 9·3%, p=0·009). Trial 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, final 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 findings permitted a strong recommendation for use and proposal as first-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 efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling 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.

Central post-stroke pain: clinical characteristics, pathophysiology, and management

Central post-stroke pain (CPSP) is a neuropathic pain syndrome that can occur after a cerebrovascular accident. This syndrome is characterised by pain and sensory abnormalities in the body parts that correspond to the brain territory that has been injured by the cerebrovascular lesion. The presence of sensory loss and signs of hypersensitivity in the painful area in patients with CPSP might indicate the dual combination of deafferentation and the subsequent development of neuronal hyperexcitability. The exact prevalence of CPSP is not known, partly owing to the difficulty in distinguishing this syndrome from other pain types that can occur after stroke (such as shoulder pain, painful spasticity, persistent headache, and other musculoskeletal pain conditions). Future prospective studies with clear diagnostic criteria are essential for the proper collection and processing of epidemiological data. Although treatment of CPSP is difficult, the most effective approaches are those that target the increased neuronal hyperexcitability.

A classification of chronic pain for ICD-11

Chronic pain has been recognized as pain that persists past normal healing time5 and hence lacks the acute warning function of physiological nociception.35 Usually pain is regarded as chronic when it lasts or recurs for more than 3 to 6 months.29 Chronic pain is a frequent condition, affecting an estimated 20% of people worldwide6,13,14,18 and accounting for 15% to 20% of physician visits.25,28 Chronic pain should receive greater attention as a global health priority because adequate pain treatment is a human right, and it is the duty of any health care system to provide it.4,13 The current version of the International Classification of Diseases (ICD) of the World Health Organization (WHO) includes some diagnostic codes for chronic pain conditions, but these diagnoses do not reflect the actual epidemiology of chronic pain, nor are they categorized in a systematic manner. The ICD is the preeminent tool for coding diagnoses and documenting investigations or therapeutic measures within the health care systems of many countries. In addition, ICD codes are commonly used to report target diseases and comorbidities of participants in clinical research. Consequently, the current lack of adequate coding in the ICD makes the acquisition of accurate epidemiological data related to chronic pain difficult, prevents adequate billing for health care expenses related to pain treatment, and hinders the development and implementation of new therapies.10,11,16,23,27,31,37 Responding to these shortcomings, the International Association for the Study of Pain (IASP) contacted the WHO and established a Task Force for the Classification of Chronic Pain. The IASP Task Force, which comprises pain experts from across the globe,19 has developed a new and pragmatic classification of chronic pain for the upcoming 11th revision of the ICD. The goal is to create a classification system that is applicable in primary care and in clinical settings for specialized pain management. A major challenge in this process was finding a rational principle of classification that suits the different types of chronic pain and fits into the general ICD-11 framework. Pain categories are variably defined based on the perceived location (headache), etiology (cancer pain), or the primarily affected anatomical system (neuropathic pain). Some diagnoses of pain defy these classification principles (fibromyalgia). This problem is not unique to the classification of pain, but exists throughout the ICD. The IASP Task Force decided to give first priority to pain etiology, followed by underlying pathophysiological mechanisms, and finally the body site. Developing this multilayered classification was greatly facilitated by a novel principle of assigning diagnostic codes in ICD-11, termed “multiple parenting.” Multiple parenting allows the same diagnosis to be subsumed under more than 1 category (for a glossary of ICD terms refer to Table ​Table1).1). Each diagnosis retains 1 category as primary parent, but is cross-referenced to other categories that function as secondary parents. Table 1 Glossary of ICD-11 terms. The new ICD category for “Chronic Pain” comprises the most common clinically relevant disorders. These disorders were divided into 7 groups (Fig. ​(Fig.1):1): (1) chronic primary pain, (2) chronic cancer pain, (3) chronic posttraumatic and postsurgical pain, (4) chronic neuropathic pain, (5) chronic headache and orofacial pain, (6) chronic visceral pain, and (7) chronic musculoskeletal pain. Experts assigned to each group are responsible for the definition of diagnostic criteria and the selection of the diagnoses to be included under these subcategories of chronic pain. Thanks to Bedirhan Ustun and Robert Jakob of the WHO, these pain diagnoses are now integrated in the beta version of ICD-11 (http://id.who.int/icd/entity/1581976053). The Task Force is generating content models for single entities to describe their clinical characteristics. After peer review overseen by the WHO Steering Committee,39 the classification of chronic pain will be voted into action by the World Health Assembly in 2017. Figure 1 Organizational chart of Task Force, IASP, and WHO interactions. The IASP Task Force was created by the IASP council and its scope defined in direct consultation of the chairs (R.D.T. and W.R.) with WHO representatives in 2012. The Task Force reports to ... 2. Classification of chronic pain Chronic pain was defined as persistent or recurrent pain lasting longer than 3 months. This definition according to pain duration has the advantage that it is clear and operationalized. Optional specifiers for each diagnosis record evidence of psychosocial factors and the severity of the pain. Pain severity can be graded based on pain intensity, pain-related distress, and functional impairment. 2.1. Chronic primary pain Chronic primary pain is pain in 1 or more anatomic regions that persists or recurs for longer than 3 months and is associated with significant emotional distress or significant functional disability (interference with activities of daily life and participation in social roles) and that cannot be better explained by another chronic pain condition. This is a new phenomenological definition, created because the etiology is unknown for many forms of chronic pain. Common conditions such as, eg, back pain that is neither identified as musculoskeletal or neuropathic pain, chronic widespread pain, fibromyalgia, and irritable bowel syndrome will be found in this section and biological findings contributing to the pain problem may or may not be present. The term “primary pain” was chosen in close liaison with the ICD-11 revision committee, who felt this was the most widely acceptable term, in particular, from a nonspecialist perspective.

Pain and dysesthesia in patients with spinal cord injury: A postal survey.

Study design: A postal survey.Objectives: To assess the prevalence and characteristics of pain and dysesthesia in a community based sample of patients with spinal cord injury (SCI) with special focus on neuropathic pain.Setting: Community. Western half of Denmark.Methods: We mailed a questionnaire to all outpatients (n=436) of the Viborg rehabilitation centre for spinal cord injury. The questionnaire contained questions regarding cause and level of spinal injury and amount of sensory and motor function below this level. The words pain and unpleasant sensations were used to describe pain (P) and dysesthesia (D) respectively. Questions included location and intensity of chronic pain or dysesthesia, degree of interference with daily activity and sleep, presence of paroxysms and evoked pain or dysesthesia, temporal aspects, alleviating and aggravating factors, McGill Pain Questionnaire (MPQ) and treatment.Results: Seventy-six per cent of the patients returned the questionnaire, (230 males and 100 females). The ages ranged from 19 to 80 years (median 42.6 years) and time since spinal injury ranged from 0.5 to 39 years (median 9.3 years). The majority (>75%) of patients had traumatic spinal cord injury. Of the respondents, 77% reported having pain or unpleasant sensations, and 67% had chronic pain or unpleasant sensations at or below lesion. Forty-eight per cent reported that P/D could be evoked by non-noxious stimulation of the skin indicating that allodynia is present in almost half of the patients. Forty-three per cent of respondents took analgesics, 7% received antidepressants or anticonvulsants.Conclusion: This survey suggests that pain and dysesthesia are common and serious complaints in SCI patients. Unexpectedly, only 7% of the patients were treated with drugs considered to be most effective in neuropathic pain. This emphasizes the need for a continued research and education on P/D in SCI.Spinal Cord (2001) 39, 256–262.

Lamotrigine in spinal cord injury pain: a randomized controlled trial

&NA; The objective was to investigate the effectiveness of lamotrigine for the treatment of spinal cord injury pain and clinical signs of neuronal hyperexcitability. Thirty patients with spinal cord injury (SCI) and at or below level neuropathic pain participated in a randomized double blind, placebo‐controlled, crossover trial. A 1‐week baseline period was followed by two treatment periods of 9 weeks duration with lamotrigine slowly increased to a maximum of 400 mg or placebo separated by a 2‐week washout period. The primary outcome measure was the change in median pain score from baseline week to the last week of treatment. Secondary outcome measures included thresholds to standardized sensory stimuli using quantitative sensory testing. Twenty‐two patients completed the trial. We found no statistically significant effect of lamotrigine as evaluated in the total sample. However, in patients with incomplete SCI, lamotrigine significantly reduced pain at or below SCI level. Patients with brush evoked allodynia and wind‐up‐like pain in the area of maximal pain were more likely to have a positive effect to lamotrigine than patients without these evoked pains (7 of 7 vs. 1 of 14). Lamotrigine was generally well tolerated. While this trial showed no significant effect on spontaneous and evoked pain in complete and incomplete spinal cord injury, lamotrigine reduced spontaneous pain in patients with incomplete spinal cord injury and evoked pain in the area of spontaneous pain.

The neuropathic component in persistent postsurgical pain: A systematic literature review☆

Summary The prevalence of persistent postsurgical pain and its neuropathic component varies across surgical procedures. More consistent assessment methodology is recommended for this type of pain. Abstract Persistent postsurgical pain (PPSP) is a frequent and often disabling complication of many surgical procedures. Nerve injury–induced neuropathic pain (NeuP) has repeatedly been proposed as a major cause of PPSP. However, there is a lack of uniformity in NeuP assessment across studies, and the prevalence of NeuP may differ after various surgeries. We performed a systematic search of the PubMed, CENTRAL, and Embase databases and assessed 281 studies that investigated PPSP after 11 types of surgery. The prevalence of PPSP in each surgical group was examined. The prevalence of NeuP was determined by applying the recently published NeuP probability grading system. The prevalence of probable or definite NeuP was high in patients with persistent pain after thoracic and breast surgeries—66% and 68%, respectively. In patients with PPSP after groin hernia repair, the prevalence of NeuP was 31%, and after total hip or knee arthroplasty it was 6%. The results suggest that the prevalence of NeuP among PPSP cases differs in various types of surgery, probably depending on the likelihood of surgical iatrogenic nerve injury. Because of large methodological variability across studies, a more uniform approach is desirable in future studies for evaluating persistent postsurgical NeuP.