Karen Lund

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pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies.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 Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r(2) 9·3%, p=0·009).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.

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.

The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: A randomised, double-blind, placebo-controlled phenotype-stratified study

&NA; The sodium channel blocker oxcarbazepine is efficacious in peripheral neuropathic pain patients, with preserved thermal sensation and some gain of sensory function, that is, the “irritable nociceptor” phenotype. &NA; In neuropathic pain it has been suggested that pain phenotype based on putative pain mechanisms may predict response to treatment. This was a randomised, double‐blind, placebo‐controlled, and phenotype‐stratified study with 2 6‐week treatment periods of oxcarbazepine (1800‐2400 mg) and placebo. The primary efficacy measure was change in median pain intensity between baseline and the last week of treatment measured on an 11‐point numeric rating scale, and the primary objective was to compare the effect of oxcarbazepine in patients with and without the irritable nociceptor phenotype as defined by hypersensitivity and preserved small nerve fibre function determined by detailed quantitative sensory testing. Ninety‐seven patients with peripheral neuropathic pain due to polyneuropathy, surgical or traumatic nerve injury, or postherpetic neuralgia were randomised. The intention‐to‐treat population comprised 83 patients: 31 with the irritable and 52 with the nonirritable nociceptor phenotype. In the total sample, oxcarbazepine relieved pain of 0.7 points (on a numeric rating scale 0‐10; 95% confidence interval [CI] 0.4‐1.4) more than placebo (P = 0.015) and there was a significant interaction between treatment and phenotype of 0.7 (95% CI 0.01‐1.4, P = 0.047). The number needed to treat to obtain one patient with more than 50% pain relief was 6.9 (95% CI 4.2‐22) in the total sample, 3.9 (95% CI 2.3‐12) in the irritable, and 13 (95% CI 5.3‐∞) in the nonirritable nociceptor phenotype. In conclusion, oxcarbazepine is more efficacious for relief of peripheral neuropathic pain in patients with the irritable vs the nonirritable nociceptor phenotype.

Pain relief with lidocaine 5% patch in localized peripheral neuropathic pain in relation to pain phenotype: A randomised, double-blind and placebo-controlled phenotype panel study

Abstract In neuropathic pain with irritable nociceptor (IN) phenotype, upregulation of sodium channels on nociceptors is supposed to be an important pain mechanism that may be targeted by topical sodium channel blockade. This randomised, double-blind, phenotype panel, crossover study with 4-week treatment periods of lidocaine 5% patch and placebo was performed to search for phenotype differences in effect. The primary efficacy measure was the total pain intensity on an 11-point numeric rating scale, and the primary objective was to compare the effect of lidocaine in patients with and without IN phenotype as defined by hypersensitivity and preserved small-fibre function determined by quantitative sensory testing. Forty-six patients with neuropathic pain due to nerve injury or postherpetic neuralgia were randomised. The modified intention-to-treat population comprised 15 patients with irritable nociceptor and 25 patients with nonirritable nociceptor. In the total sample, lidocaine reduced pain by 0.3 numeric rating scale points (95% confidence interval [CI]: 0.1-0.5) and pain-related sleep disturbance by 0.6 points (95% CI: 0.4-0.8) more than placebo (P = 0.007 and P < 0.001) and relieved pain by 0.4 verbal score (−1-5) points more (P = 0.036). For these measures, there was no significant interaction between treatment and phenotype, but there was a significant interaction for pain paroxysms (0.8, 95% CI: 0.4-1.2, P < 0.001) and deep aching pain (0.6, 95% CI: 0.1-1.0, P = 0.013). In conclusion, lidocaine 5% patch had an effect on peripheral neuropathic pain, and it may be most efficacious in patients with IN phenotype. The lack of significant phenotype differences may be caused by too low statistical power.

Randomised controlled trials may underestimate drug effects: balanced placebo trial design.

Background It is an inherent assumption in randomised controlled trials that the drug effect can be estimated by subtracting the response during placebo from the response during active drug treatment. Objective To test the assumption of additivity. The primary hypothesis was that the total treatment effect is smaller than the sum of the drug effect and the placebo effect. The secondary hypothesis was that non-additivity was most pronounced in participants with large placebo effects. Methods We used a within-subject randomised blinded balanced placebo design and included 48 healthy volunteers (50% males), mean (SD) age 23.4 (6.2) years. Experimental pain was induced by injections of hypertonic saline into the masseter muscle. Participants received four injections with hypertonic saline along with lidocaine or matching placebo in randomised order: A: received hypertonic saline/told hypertonic saline; B: received hypertonic saline+lidocaine/told hypertonic saline; C: received hypertonic saline+placebo/told hypertonic saline+pain killer; D: received hypertonic saline+lidocaine/told hypertonic saline+pain killer. The primary outcome measure was the area under the curve (AUC, mm2) of pain intensity during injections. Results There was a significant difference between the sum of the drug effect and the placebo effect (mean AUC 6279 mm2 (95% CI, 4936–7622)) and the total treatment effect (mean AUC 5455 mm2 (95% CI, 4585–6324)) (P = 0.049). This difference was larger for participants with large versus small placebo effects (P = 0.015), and the difference correlated significantly with the size of the placebo effect (r = 0.65, P = 0.006). Conclusion Although this study examined placebo effects and not the whole placebo response as in randomised controlled trials, it does suggest that the additivity assumption may be incorrect, and that the estimated drug effects in randomised controlled trials may be underestimated, particularly in studies reporting large placebo responses. The implications for randomised controlled trials and systematic reviews need to be discussed.

Placebo Effects in Idiopathic and Neuropathic Pain Conditions

The magnitude of placebo analgesia effect appears to be large in chronic pain patients experiencing hyperalgesic states. So far, placebo effects have primarily been investigated in idiopathic pain conditions, such as irritable bowel pain syndrome, but more recently they have also been investigated in neuropathic pain patients, in which the underlying nerve injury is known. Expected pain levels and emotional feelings are central to placebo effects in both types of pain. They appear to help patients to engage in a mindset for pain relief and activate the pain-modulating system. Furthermore, expectations, emotional feelings, and the experience of pain seem to interact over time, thereby maintaining or enhancing the pain-relieving effect. Expectations and emotional feelings also contribute to the effect of active drugs, and recent studies indicate that drug effects and placebo effects interact in ways that may complicate the interpretations of the findings from clinical trials. It is suggested that expectations and emotional feelings may act as additional or alternative measures in the testing of new pharmacological agents, thereby improving the understanding of the interaction between pharmacological effects and placebo effects, which may have far-reaching implications for research and clinical practice.

The magnitude of placebo analgesia effects depends on how they are conceptualized

OBJECTIVE Placebo effects are usually calculated as the difference between placebo treatments and no treatments. Recently, placebo-like effects have been investigated using open and hidden administrations of active treatments. The aim of the study was to directly compare the two types of placebo effects and examine how they are influenced by personality traits. METHODS In a within-subject, randomized, blinded, balanced placebo trial design study with 48 healthy volunteers, we compared placebo and placebo-like effects and tested if expectancy, absorption and suggestibility correlated with these effects. Subjects completed the Tellegen Absorption Scale and the Sensory Suggestibility Scale, and pain was induced by injections of hypertonic saline into the masseter muscle. Participants received four injections of hypertonic saline with lidocaine or matching placebo in randomized order: open treatment, hidden treatment, placebo and control. The placebo effect was defined as the difference in pain between the placebo and the control condition and the placebo-like effect as the difference in pain between the open and hidden condition. RESULTS Placebo effects were significant both in the traditional paradigm: mean placebo effect AUC 1626 mm(2) (95% CI 958-2293) and the open-hidden paradigm: mean placebo-like effect AUC 801 mm(2) (95% CI 134-1469), but there was a significant difference between the magnitude of the two effects (p=0.049). Absorption and suggestibility did not predict the placebo or the placebo-like effect. Estimated expected pain relief correlated with placebo effects but not placebo-like effects. CONCLUSION The magnitude of placebo effects differs depending on how they are conceptualized and calculated.

Placebo responses in patients with peripheral neuropathic pain

Abstract Background and aim Treatment responses during placebo periods in randomized clinical trials (RCTs) are quite often substantial and may impede a positive outcome of the trial. It would therefore be beneficial to gain more knowledge on factors contributing to large placebo responses in RCTs. The aim of the current study was to identify predictors of placebo responses in patients with peripheral neuropathic pain. Hypotheses We hypothesized that a high baseline pain intensity and variability will be predictive of large responses during placebo treatment. Furthermore, we hypothesized that expectation for pain relief, few prior treatments and side effects, low scores of pain catastrophizing, anxiety, depression and the personality trait neuroticism and high levels of positive emotions will be predictors of placebo responses. Methods This study is part of a randomized, double-blind, placebo-controlled, crossover study with the anticonvulsant oxcarbazepine. Pain intensity was registered at baseline and during treatment periods on a numerical rating scale (NRS, 0–10) along with expectation for pain relief (NRS), psychological measures (scores for anxiety, depression, catastrophizing, neuroticism, and positive emotions), prior treatments, and side effects. Results Multiple regression analysis with pain reduction during placebo treatment as the dependent variable and baseline pain, age, gender, and pain duration as explanatory variables was highly significant (R-squared = 0.53, p < 0.001), while other explanatory variables did not reach statistical significance. Further analyses will be carried out. Conclusions Age and gender were not significant predictors of placebo responses in this study. Further results will be presented at the congress. Acknowledgements This study is part of the Innovative Medicines Initiative project EUROPAIN, www.imi.europa.eu.

Sensory phenotypes in patients with peripheral neuropathic pain evaluated with quantitative sensory testing

Abstract Background In patients with neuropathic pain, Quantitative Sensory Testing (QST) can define different sensory phenotypes thought to be related to different underlying mechanisms. One phenotype with abnormal sensitization of cutaneous nociceptors has been termed irritable nociceptors. Methods This study is a part of a randomized, double-blind, placebo controlled, crossover trial with the anticonvulsant oxcarbazepine. The study is ongoing. In this report, baseline QST measures from patients with peripheral neuropathic pain due to either polyneuropathy (PNP) or peripheral nerve injury (PNI) are analyzed. QST evaluates thresholds for cold and heat detection (CDT, WDT), thermal pain (CPT, HPT), vibration (VDT), pin prick, mechanical detection and pressure pain. Furthermore, wind-up ratio and dynamic mechanical allodynia (DMA) are evaluated. Patients with irritable nociceptors are defined as patient with normal CDT and WDT and either mechanical or thermal allodynia or hyperalgesia. Results By March 2012, 28 patients with PNI and 24 with PNP were included. There was no difference in pain duration (66.2 (53.7) vs. 64.0 (43.3) months, p = 0.87) or pain intensity (NRS, 0 10) (6.6 (1.6) vs. 6.3 (1.7), p = 0.54), but patients with PNI were significantly younger (48.8 (15.1) years) compared to patients with PNP (62.4 (8.5) years), p < 0.001. The percentage of irritable nociceptors in the PNI group was 39.3% and in the PNP group 29.2% (p = 0.44). The percentage of patients with DMA was 39.3% and 33.3%, respectively (p = 0.66). Significantly more patients with PNI had thermal allodynia (28.6% vs. 0%, p = 0.005), 6 reported cold allodynia and 4 heat allodynia. Conclusion Preliminary results show that there was no significant difference in percentage of irritable nociceptors between the two groups, but more patients with PNI had thermal allodynia.