Considered from another perspective, the interaction effects suggest that certain temperamental traits are risk factors for substance use when parental monitoring is low, but not when it is high. Either interpretation is consistent with the findings and points to a similar conclusion about how temperament and parenting work together to increase risk for early substance use. Being raised in a home with a perception of minimal monitoring by parents may be a more salient risk factor for substance use for those adolescents with dispositional proclivities toward substance use, and possessing a disposition toward substance use may be a stronger risk factor when youth do not believe they are closely monitored by their parents. The broader developmental consideration is that temperamental factors and family variables should be considered jointly in models that attempt to understand early risk for substance use. Although the current study was notable for its multi-informant longitudinal design, and for the size and ethnic composition of the sample, there are limitations that merit consideration. For instance, our ability to detect effects for surgency was hampered by the low reliability of the scale in the 5th grade; thus, results involving surgency should be interpreted with caution. Also, we relied exclusively on youth reports of their substance use, intentions, and expectancies. However, intentions and expectancies are inherently subjective variables and are thus best assessed via self-report. Likewise,vertical farming market focal youth might be in the best position to report on their actual use given understandable motivations to hide substance use from parents, teachers, and other potential informants.
In closing, we found evidence from a longitudinal study of Mexican-origin youth that temperament and parental monitoring assessed in 5th grade are prospectively related to substances use outcomes in 9th grade. These findings are important because they suggest that theoretical models concerning the influence of temperament on substance use can be applied to adolescents of Mexican origin. Indeed, we suspect that factors like temperament and parental monitoring have transcontextual validity to the extent that they are risk factors for early substance use for a diverse range of youth. Of particular importance, we also found that relatively high levels of perceived monitoring might attenuate some of the risks associated with dispositional tendencies toward substance use. Although the current results should be replicated, we suggest that future intervention and prevention efforts could be enhanced by attending to individual differences in temperament. Such attention might be especially important when considering efforts to increase parental monitoring. Neuropathic pain, caused by a lesion or disease affecting the somatosensory nervous system,1 has a considerable impact on patients’ quality of life, and is associated with a high economic burden on the individual and society.Epidemiological surveys have shown that many patients with neuropathic pain do not receive appropriate treatment for their pain.This may be due to lack of diagnostic accuracy and relatively ineffective drugs, but also insufficient knowledge about effective drugs and their appropriate use in clinical practice.Evidence-based recommendations for the pharmacotherapy of neuropathic pain are therefore essential. Over the past 10 years, a few recommendations have been proposed for pharmacotherapy of neuropathic pain or specific neuropathic pain conditions, such as painful diabetic neuropathies and postherpetic neuralgia. In the interim, new pharmacological therapies and high-quality clinical trials have appeared.
Previously hidden and unpublished large trials can now be identified on the web , which, together with analysis of publication bias, may limit the risk of bias in reporting data. Furthermore, prior recommendations sometimes came to discrepant conclusions because of inconsistencies in methods used to assess the quality of evidence . In order to address these inconsistencies, the Grading of Recommendations Assessment, Development, and Evaluation was introduced in 2000 and has received widespread international acceptance. All these reasons justify an update of evidence-based recommendations for the pharmacotherapy of neuropathic pain. The present work aimed to update the recommendations of the Special Interest Group on Neuropathic Pain of the International Association for the Study of Pain on the systemic and topical pharmacological treatments of neuropathic pain.Non-pharmacological management such as neurostimulation techniques were beyond the scope of this work We conducted a systematic review and meta-analysis of randomised controlled trials of all drug treatments for neuropathic pain published since 1966 and of unpublished trials with available results, and assessed publication bias. We used GRADE to rate the quality of evidence and the strength of recommendations. The systematic review of the literature compiled with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statements.We used a standardized review and data extraction protocol . The full reports of randomised, controlled, double-blind studies published in peer-reviewed journals between 1966 and April 2013 were identified using searches of PubMed/Medline, the Cochrane Central Register of Controlled Trials, and Embase. Additional papers were identified from published reviews and the reference lists of selected papers. The target population was patients of any age with neuropathic pain according to the IASP definition; this included postherpetic neuralgia, diabetic and non-diabetic painful polyneuropathy, postamputation pain, post-traumatic/postsurgical neuropathic pain including plexus avulsion and complex regional pain syndrome type II , central post-stroke pain, spinal cord injury pain, multiple sclerosis-associated pain. Neuropathic pains pertaining to multiple aetiologies were also considered. Neuropathic pain associated with nociceptive components was included provided that the primary outcome was neuropathic pain. Conditions such as complex regional pain syndrome type I, low back pain without radicular pain, fibromyalgia, and atypical facial pain were not included because they do not fulfill the current definition of neuropathic pain.
Trigeminal neuralgia was considered separately because of generally distinct response to drug treatment.The interventions were systemic or topical treatments with at least 3 weeks duration of treatment. Single-administration treatments with long-term efficacy were included if there was a minimum follow-up of 3 weeks. Studies using intramuscular, intravenous,vertical farming pros and cons or neuraxial routes of administration and preemptive analgesia studies were excluded . Randomised, double-blind, placebo-controlled studies with parallel group or crossover study designs that had at least 10 patients per arm were included. Enriched-enrolment, randomised withdrawal trials were summarised separately. Studies published only as abstracts were excluded. Double-blind active comparator trials of drugs generally proposed as first or second-line treatments were included. The study outcome was based on the effect on the primary outcome measure, e.g. neuropathic pain intensity. Studies in which the primary outcome included a composite score of pain and paraesthesia or paraesthesia only were not included. Studies were assessed for methodological quality using the five-point Oxford Quality Scale by two independent authors . Here, a minimum score of 2 out of 5 was required for inclusion.We also assessed serious risk of bias relating to lack of allocation concealment, incomplete accounting of outcome events, selective outcome reporting, stopping early for benefit, use of invalidated outcome measures and carryover effects in crossover trials. The results of the database and registry search are shown in figure 1. In total, 191 published articles and 21 unpublished studies were included in the quantitative synthesis. Study characteristics are summarised in appendices 4 and 5. In addition, five published and 12 unpublished studies were retrieved between April 2013 and January 2014 . Thus, a total of 229 articles/studies were included. References are presented in appendix 7. Eligible studies investigated tricyclic antidepressants , serotonin- noradrenaline reuptake inbibitor antidepressants, other antidepressants, pregabalin, gabapentin/ gabapentin extended release and enacarbil, other antiepileptics, tramadol, opioids, cannabinoids, lidocaine 5% patch, capsaicin 8% patch and cream, subcutaneous BTX-A, NMDA antagonists, mexiletine, miscellaneous topical, newer systemic drugs, and combination therapies. Fifty-five percent of the trials were conducted in diabetic painful polyneuropathy or postherpetic neuralgia. NNT and NNH could be calculated in 77% of published placebo-controlled trials. There was generally no evidence for efficacy of particular drugs in specific conditions. Therefore these recommendations apply to neuropathic pain in general. However, they may not be applicable for trigeminal neuralgia, for which we could extract only one study complying with our inclusion criteria. We therefore recommend referring to previous specific guidelines regarding this condition.Few studies included cancer-related neuropathic pain; the recommendations for the use of opioids may be different in certain cancer populations. Similarly these recommendations do not apply to acute pain or acute pain exacerbation. Treatment of neuropathic pain in children is a neglected area.However, none of the studies assessed pediatric neuropathic pain, and the present guidelines therefore only apply to adults. Details regarding GRADE recommendations and practical use are provided in tables 2, 3 and appendix 10. Few relevant trials appeared since our meta-analysis, but none affected the recommendations . TCAs, SNRI antidepressants duloxetine and venlafaxine, pregabalin, gabapentin and gabapentin ER/enacarbil have strong GRADE recommendations for use in neuropathic pain and are proposed as first-line, with caution regarding most TCAs .
Tramadol, lidocaine patches and high-concentration capsaicin patches have weak GRADE recommendations for use and are proposed as generally second-line. Topical treatments are recommended for peripheral neuropathic pain with presumed local pain generator. In select circumstances, e.g when there are concerns due to side effects or safety of first-line treatments, particularly in frail and elderly patients, lidocaine patches may be considered as first-line. Strong opioids and BTX-A have weak GRADE recommendations for use and are recommended as third-line. Prescription of opioids should be strictly monitored particularly for patients requiring high dosages .Tapentadol, other antiepileptics, capsaicin cream, topical clonidine, SSRI antidepressants, NMDA antagonists and combination therapy have inconclusive GRADE recommendations. Combination of pregabalin/gabapentin and duloxetine/TCAs may be considered as an alternative to increasing dosages in monotherapy for patients unresponsive to monotherapy with moderate dosages . Cannabinoids and valproate have weak recommendations against their use in neuropathic pain and levetiracetam and mexiletine have strong recommendations against their use .The present manuscript presents the revised NeuPSIG recommendations for the pharmacotherapy of neuropathic pain based on an updated systematic review and meta analysis of systemic or topical drug treatments. We used the GRADE systemto assess the quality of evidence for all treatments, and the recommendations comply with the AGREE II guidelines. The present recommendations are driven by drug treatments rather than by the aetiology of pain, akin to prior NeuPSIG recommendations.Neuropathic pain is increasingly recognised as a specific multi-aetiology entity across neuropathic syndromes.In accordance with previous reports24 results of our meta-analysis show that the efficacy of systemic drug treatments is generally not dependent on the aetiology of the underlying disorder . Side effects may, however, to some degree depend on the aetiology, eg, drugs with CNS-related side effects may be less tolerated in patients with CNS lesions.Pain due to HIV-related painful polyneuropathy and radiculopathy seems more refractory than other pain conditions in our meta-analysis. This may be due to large placebo responses in HIV-related neuropathy trials,a distinct clinical phenotype in subgroups of patients with radiculopathy,or psychological/psychosocial comorbidites, often neglected in large trials. Topical agents have no known relevance for use in central neuropathic pain, and this is clearly stated in our recommendations. The strengths of this systematic review and meta-analysis are the analysis of publication bias and unpublished trials. Publication bias may be present if studies with positive results are published while those with no data or negative results are not.It may lead to major overestimation of efficacy in therapeutic studies.Our results showed that the effect sizes estimated from studies published in peer-reviewed journals were higher than those estimated from studies available in open databases. This finding emphasises the need for searching these databases in systematic reviews. Analysis of further publication bias suggested a limited overstatement of overall efficacy of drug treatments , although available methods to assess publication bias have limitations.Here, we found that high concentration capsaicin patches were the most susceptible to publication bias, ie, a new study with less than 400 participants with no effect may increase the NNT to an unacceptable level. This supports the robustness of a meta-analysis taking into account unpublished trials, and suggests that effect sizes were overestimated in previous meta analyses of pharmacotherapy for neuropathic pain. Results of quantitative data for individual drugs, showing NNT for 50 % pain relief ranging from around 4 to 10 across most positive trials, emphasizes the overall modest study outcomes in neuropathic pain. Inadequate response of neuropathic pain to drug therapy constitutes a highly unmet need and may have substantial consequences in terms of psychological or social adjustment.However these results may also reflect insufficient assay sensitivity of clinical trials of neuropathic pain.