Miroslav Backonja

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.

NeuPSIG guidelines on neuropathic pain assessment

&NA; This is a revision of guidelines, originally published in 2004, for the assessment of patients with neuropathic pain. Neuropathic pain is defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system either at peripheral or central level. Screening questionnaires are suitable for identifying potential patients with neuropathic pain, but further validation of them is needed for epidemiological purposes. Clinical examination, including accurate sensory examination, is the basis of neuropathic pain diagnosis. For more accurate sensory profiling, quantitative sensory testing is recommended for selected cases in clinic, including the diagnosis of small fiber neuropathies and for research purposes. Measurement of trigeminal reflexes mediated by A‐beta fibers can be used to differentiate symptomatic trigeminal neuralgia from classical trigeminal neuralgia. Measurement of laser‐evoked potentials is useful for assessing function of the A‐delta fiber pathways in patients with neuropathic pain. Functional brain imaging is not currently useful for individual patients in clinical practice, but is an interesting research tool. Skin biopsy to measure the intraepidermal nerve fiber density should be performed in patients with clinical signs of small fiber dysfunction. The intensity of pain and treatment effect (both in clinic and trials) should be assessed with numerical rating scale or visual analog scale. For future neuropathic pain trials, pain relief scales, patient and clinician global impression of change, the proportion of responders (50% and 30% pain relief), validated neuropathic pain quality measures and assessment of sleep, mood, functional capacity and quality of life are recommended.

external validation of Iasp diagnostic criteria for Complex Regional Pain Syndrome and proposed research diagnostic criteria

Recent work in our research consortium has raised internal validity concerns regarding the current IASP criteria for Complex Regional Pain Syndrome (CRPS), suggesting problems with inadequate sensitivity and specificity. The current study explored the external validity of these IASP criteria for CRPS. A standardized evaluation of signs and symptoms of CRPS was conducted by study physicians in 117 patients meeting IASP criteria for CRPS, and 43 patients experiencing neuropathic pain with established non-CRPS etiology (e.g. diabetic neuropathy, post-herpetic neuralgia). Multiple discriminant function analyses were used to test the ability of the IASP diagnostic criteria and decision rules, as well as proposed research modifications of these criteria, to discriminate between CRPS patients and those experiencing non-CRPS neuropathic pain. Current IASP criteria and decision rules (e.g. signs or symptoms of edema, or color changes or sweating changes satisfy criterion 3) discriminated significantly between groups (P < 0.001). However, although sensitivity was quite high (0.98), specificity was poor (0.36), and a positive diagnosis of CRPS was likely to be correct in as few as 40% of cases. Empirically-based research modifications to the criteria, which are more comprehensive and require presence of signs and symptoms, were also tested. These modified criteria were also able to discriminate significantly, between the CRPS and non-CRPS groups (P < 0.001). A decision rule, requiring at least two sign categories and four symptom categories to be positive optimized diagnostic efficiency, with a diagnosis of CRPS likely to be accurate in up to 84% of cases, and a diagnosis of non-CRPS neuropathic pain likely to be accurate in up to 88% of cases. These results indicate that the current IASP criteria for CRPS have inadequate specificity and are likely to lead to overdiagnosis. Proposed modifications to these criteria substantially improve their external validity and merit further evaluation.

Complex regional pain syndrome: are the IASP diagnostic criteria valid and sufficiently comprehensive?

This is a multisite study examining the internal validity and comprehensiveness of the International Association for the Study of Pain (IASP) diagnostic criteria for Complex Regional Pain Syndrome (CRPS). A standardized sign/symptom checklist was used in patient evaluations to obtain data on CRPS-related signs and symptoms in a series of 123 patients meeting IASP criteria for CRPS. Principal components factor analysis (PCA) was used to detect statistical groupings of signs/symptoms (factors). CRPS signs and symptoms grouped together statistically in a manner somewhat different than in current IASP/CRPS criteria. As in current criteria, a separate pain/sensation criterion was supported. However, unlike in current criteria, PCA indicated that vasomotor symptoms form a factor distinct from a sudomotor/edema factor. Changes in range of motion, motor dysfunction, and trophic changes, which are not included in the IASP criteria, formed a distinct fourth factor. Scores on the pain/sensation factor correlated positively with pain duration (P<0. 001), but there was a negative correlation between the sudomotor/edema factor scores and pain duration (P<0.05). The motor/trophic factor predicted positive responses to sympathetic block (P<0.05). These results suggest that the internal validity of the IASP/CRPS criteria could be improved by separating vasomotor signs/symptoms (e.g. temperature and skin color asymmetry) from those reflecting sudomotor dysfunction (e.g. sweating changes) and edema. Results also indicate motor and trophic changes may be an important and distinct component of CRPS which is not currently incorporated in the IASP criteria. An experimental revision of CRPS diagnostic criteria for research purposes is proposed. Implications for diagnostic sensitivity and specificity are discussed.

NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomised, double-blind study

BACKGROUND The limitations of current treatments for postherpetic neuralgia (PHN) have led to the investigation of localised, non-systemic alternatives. NGX-4010, a high-concentration (8%) capsaicin dermal patch, was developed to treat patients with neuropathic pain. We report the results of a randomised, double blind, 12-week study of the efficacy and safety of one application of NGX-4010 in patients with PHN. METHODS In this multicentre, double-blind, parallel-group trial, 402 patients were randomly assigned to one 60-min application of NGX-4010 (640 microg/cm(2) [8% capsaicin]) or a low-concentration capsaicin control patch (3.2 microg/cm(2) [0.04% capsaicin]). Patients were aged 18-90 years, had had postherpetic neuralgia for at least 6 months, and had an average baseline numeric pain rating scale (NPRS) score of 3 to 9. The primary efficacy endpoint was percentage change in NPRS score from baseline to weeks two to eight. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00115310. FINDINGS Patients who were randomly assigned to NGX-4010 (n=206) had a significantly greater reduction in pain during weeks two to eight than did patients who had the control patch (n=196). The mean changes in NPRS score were -29.6%vs -19.9% (difference -9.7%, 95% CI -15.47 to -3.95; p=0.001). 87 (42%) patients who received NGX-4010 and 63 (32%) controls had a 30% or greater reduction in mean NPRS score (odds ratio [OR] 1.56, 95% CI 1.03 to 2.37; p=0.03). The patients who had NGX-4010 had significant improvements in pain during weeks two to 12 (mean change in NPRS score -29.9%vs -20.4%, difference -9.5, -15.39 to -3.61; p=0.002). Transient blood pressure changes associated with changes in pain level were recorded on the day of treatment, and short-lasting erythema and pain at the site of application were common, self-limited, and generally mild to moderate in the NGX-4010 group and less frequent and severe in the controls. INTERPRETATION One 60-min application of NGX-4010 provided rapid and sustained pain relief in patients with postherpetic neuralgia. No adverse events were associated with treatment except for local reactions at the site of application and those related to treatment-associated pain.

Complex regional pain syndrome: are there distinct subtypes and sequential stages of the syndrome?

&NA; This study tested for evidence supporting the clinical lore of three sequential stages of complex regional pain syndrome (CRPS) and examined the characteristics of possible CRPS subtypes. A series of 113 patients meeting IASP criteria for CRPS underwent standardized history and physical examinations to assess CRPS signs and symptoms in four domains identified in previous research: pain/sensory abnormalities, vasomotor dysfunction, edema/sudomotor dysfunction, and motor/trophic changes. K‐Means cluster analysis was used to derive three relatively homogeneous CRPS patient subgroups based on similarity of sign/symptom patterns in these domains. The resulting CRPS subgroups did not differ significantly regarding pain duration as might be expected in a sequential staging model. However, the derived subgroups were statistically‐distinct, and suggested three possible CRPS subtypes: (1) a relatively limited syndrome with vasomotor signs predominating, (2) a relatively limited syndrome with neuropathic pain/sensory abnormalities predominating, and (3) a florid CRPS syndrome similar to ‘classic RSD’ descriptions. Subtype 3 showed the highest levels of motor/trophic signs and possible disuse‐related changes (osteopenia) on bone scan, despite having directionally the briefest pain duration of the three groups. EMG/NCV testing suggests that Subtype 2 may reflect CRPS‐Type 2 (causalgia). Overall, these results are consistent with limited previous work that argues against three sequential stages of CRPS. However, several distinct CRPS subtypes are suggested, and these could ultimately have utility in targeting treatment more effectively.

Usefulness and limitations of quantitative sensory testing: Clinical and research application in neuropathic pain states

a Dept. of Neurosurgery, Pain Center, Karolinska University Hospital and Dept. of Molecular Medicine and Surgery, Section of Clinical Pain research, Karolinska Institutet, 171 76 Stockholm, Sweden b Department of Neurology H6/570, University of Wisconsin Hospital, Madison, WI 53792, USA c INSERM U-792, CHU Ambroise Pare, APHP, Boulogne-Billancourt F-92100, France d Université Versailles-Saint-Quentin, Versailles F-78035, France

Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus

Summary Standards for conducting quantitative sensory testing (QST), which is a psychophysical method used to quantify somatosensory function in response to controlled stimuli in healthy subjects and patients, is discussed, and recommendations on the basis of current status of QST are presented. ABSTRACT Quantitative sensory testing (QST) is a psychophysical method used to quantify somatosensory function in response to controlled stimuli in healthy subjects and patients. Although QST shares similarities with the quantitative assessment of hearing or vision, which is extensively used in clinical practice and research, it has not gained a large acceptance among clinicians for many reasons, and in significant part because of the lack of information about standards for performing QST, its potential utility, and interpretation of results. A consensus meeting was convened by the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain (NeuPSIG) to formulate recommendations for conducting QST in clinical practice and research. Research studies have confirmed the utility of QST for the assessment and monitoring of somatosensory deficits, particularly in diabetic and small fiber neuropathies; the assessment of evoked pains (mechanical and thermal allodynia or hyperalgesia); and the diagnosis of sensory neuropathies. Promising applications include the assessment of evoked pains in large‐scale clinical trials and the study of conditioned pain modulation. In clinical practice, we recommend the use QST for screening for small and large fiber neuropathies; monitoring of somatosensory deficits; and monitoring of evoked pains, allodynia, and hyperalgesia. QST is not recommended as a stand‐alone test for the diagnosis of neuropathic pain. For the conduct of QST in healthy subjects and in patients, we recommend use of predefined standardized stimuli and instructions, validated algorithms of testing, and reference values corrected for anatomical site, age, and gender. Interpretation of results should always take into account the clinical context, and patients with language and cognitive difficulties, anxiety, or litigation should not be considered eligible for QST. When appropriate standards, as discussed here, are applied, QST can provide important and unique information about the functional status of somatosensory system, which would be complementary to already existing clinical methods.

Interventional management of neuropathic pain: NeuPSIG recommendations

&NA; Neuropathic pain (NP) is often refractory to pharmacologic and noninterventional treatment. On behalf of the International Association for the Study of Pain Neuropathic Pain Special Interest Group, the authors evaluated systematic reviews, clinical trials, and existing guidelines for the interventional management of NP. Evidence is summarized and presented for neural blockade, spinal cord stimulation (SCS), intrathecal medication, and neurosurgical interventions in patients with the following peripheral and central NP conditions: herpes zoster and postherpetic neuralgia (PHN); painful diabetic and other peripheral neuropathies; spinal cord injury NP; central poststroke pain; radiculopathy and failed back surgery syndrome (FBSS); complex regional pain syndrome (CRPS); and trigeminal neuralgia and neuropathy. Due to the paucity of high‐quality clinical trials, no strong recommendations can be made. Four weak recommendations based on the amount and consistency of evidence, including degree of efficacy and safety, are: 1) epidural injections for herpes zoster; 2) steroid injections for radiculopathy; 3) SCS for FBSS; and 4) SCS for CRPS type 1. Based on the available data, we recommend not to use sympathetic blocks for PHN nor radiofrequency lesions for radiculopathy. No other conclusive recommendations can be made due to the poor quality of available data. Whenever possible, these interventions should either be part of randomized clinical trials or documented in pain registries. Priorities for future research include randomized clinical trials, long‐term studies, and head‐to‐head comparisons among different interventional and noninterventional treatments.

A Multicenter, Randomized, Double-Blind, Controlled Study of NGX-4010, a High-Concentration Capsaicin Patch, for the Treatment of Postherpetic Neuralgia

OBJECTIVES To confirm the efficacy, tolerability, and safety of NGX-4010, an 8% capsaicin dermal patch (capsaicin 640 µg/cm(2) ), in patients with postherpetic neuralgia (PHN). PHN is a chronic pain disorder that can be difficult to treat and for which current treatment options are often limited by poor tolerability. DESIGN A total of 418 patients were randomized to receive a single 60-minute application of NGX-4010 or a 0.04% capsaicin control patch (3.2 µg/cm(2) ) in a multicenter, double-blind, confirmatory, phase 3 study. PATIENTS Patients were 18-90 years old with a diagnosis of PHN, pain for at least 6 months, and an average baseline Numeric Pain Rating Scale (NPRS) score of 3-9. OUTCOME MEASURES The primary efficacy end point was the percentage change in NPRS score from baseline to weeks 2-8. RESULTS NGX-4010 recipients had a significantly greater mean reduction from baseline in pain during weeks 2-8 compared with the control group (32.0% vs 24.4%; P=0.011). A ≥ 30% reduction in mean NPRS scores was achieved in 46% of NGX-4010 recipients compared with 34% of controls (P=0.02). Pain was significantly lower in NGX-4010 recipients than controls by week 2, and greater pain reduction was maintained throughout the remaining 12-week study period. Most treatment-emergent adverse events were application site specific (notably erythema and pain), transient, and generally mild to moderate in severity. CONCLUSIONS In patients with PHN, a single 60-minute application of NGX-4010 produced significant reduction in pain that was maintained over a 12-week period.