Joint European Academy of Neurology-European Pain Federation-Neuropathic Pain Special Interest Group of the International Association for the Study of Pain guidelines on neuropathic pain assessment.

BACKGROUND AND PURPOSE: In these guidelines, we aimed to develop evidence-based recommendations for the use of screening questionnaires and diagnostic tests in patients with neuropathic pain (NeP). METHODS: We systematically reviewed studies providing information on the sensitivity and specificity of screening questionnaires, and quantitative sensory testing, neurophysiology, skin biopsy, and corneal confocal microscopy. We also analysed how functional neuroimaging, peripheral nerve blocks, and genetic testing might provide useful information in diagnosing NeP. RESULTS: Of the screening questionnaires, Douleur Neuropathique en 4 Questions (DN4), I-DN4 (self-administered DN4), and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) received a strong recommendation, and S-LANSS (self-administered LANSS) and PainDETECT weak recommendations for their use in the diagnostic pathway for patients with possible NeP. We devised a strong recommendation for the use of skin biopsy and a weak recommendation for quantitative sensory testing and nociceptive evoked potentials in the NeP diagnosis. Trigeminal reflex testing received a strong recommendation in diagnosing secondary trigeminal neuralgia. Although many studies support the usefulness of corneal confocal microscopy in diagnosing peripheral neuropathy, no study specifically investigated the diagnostic accuracy of this technique in patients with NeP. Functional neuroimaging and peripheral nerve blocks are helpful in disclosing pathophysiology and/or predicting outcomes, but current literature does not support their use for diagnosing NeP. Genetic testing may be considered at specialist centres, in selected cases. CONCLUSIONS: These recommendations provide evidence-based clinical practice guidelines for NeP diagnosis. Due to the poor-to-moderate quality of evidence identified by this review, future large-scale, well-designed, multicentre studies assessing the accuracy of diagnostic tests for NeP are needed.

Wellness of patients with chronic pain is not only about pain intensity.

OBJECTIVE: Attaining good outcomes in the management of chronic pain remains a clinical challenge. This study aimed to investigate the relationships between - and the contribution of - pain and related conditions to the wellness of these patients. DESIGN: A secondary analysis of database of patients with chronic pain treated with medical cannabis (MC) to carry out a one-year prospective follow-up study was conducted. Questionnaires were completed before (T0 ), six (T6 ), and twelve (T12 ) months after MC initiation. Data included patients' demographics and questionnaires related to three latent factors: pain intensity measures, related conditions (catastrophizing, sleep disturbance, anxiety, and depression), and wellness parameters (quality-of-life, disability, subjective-health-state). Weighted average of the observed variables (WOBs) were calculated for each latent factor. Longitudinal structural equation modeling (SEM) and mediation analyses were performed to identify predictors and interrelations between the WOBs, respectively. RESULTS: Participants included 510 patients. All variables were significantly improved from T0 to T6 and T12 . SEM revealed that related conditions, and to a lesser extent pain, predicted wellness at T0 , T6 , and T12 (related conditions: ß0  = 0.55, p < 0.001; ß6  = 0.54, p < 0.001; and ß12  = 0.51, p < 0.001; pain: ß0  = 0.42, p < 0.001; ß6  = 0.18, p < 0.001; and ß12  = 0.25, p < 0.001). Mediation analyses demonstrated that the effect of WOB-related conditions was greater than WOB-pain on wellness. CONCLUSION: Wellness of patients with chronic pain can be determined not only by pain itself but even more so by the severity of related conditions. Thus, considering a broad spectrum of pain measures and related conditions seems relevant for improving the wellness of patients with chronic pain.

Feasibility of Magnetic Resonance-Guided High-Intensity-Focused Ultrasound (MRgHIFU) Ablation of Stump Neuromas for the Relief of Chronic Postamputation Neuropathic Pain.

Up to 70% of limb amputees develop chronic postamputation neuropathic pain (CPANP) which includes phantom pain and residual limb neuropathic pain due to neuroma formation. CPANP often requires invasive procedures aimed at neuroma ablation. Five amputees received 6 noninvasive magnetic resonance-guided high-intensity-focused ultrasound MRgHIFU treatments ExAblate®, Insightec, Tirat-Carmel, Israel). Although ablative temperature (>65°C) at the neuroma was reached in only 1 patient, pain intensity dropped from 5.7 at baseline to 4.3 and back to 5.6 at 3 and 6 month follow-up. Post-treatment bone necrosis was demonstrated in 1 patient. Although no firm conclusion about the effectiveness of MRgHIFU for CPANP could be drawn, further studies are warranted.

Specific phytocannabinoid compositions are associated with analgesic response and adverse effects in chronic pain patients treated with medical cannabis.

Medical cannabis (MC) treatment for chronic pain is increasing, but evidence regarding short- and long-term efficacy and associated adverse effects (AEs) of the different cannabis plant components is limited. Most reports focus on two phytocannabinoids, (-)-Δ9-trans-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). This study, aimed to identify patterns of phytocannabinoid compositions associated with MC treatment response and with related AEs. Participants in this multicenter prospective cohort were patients with chronic non-cancer pain that were prescribed MC by physicians. Data was collected before MC treatment, at one month (short-term) and at 12 months (long-term). Simultaneously, liquid chromatography mass spectrometry identification and quantification of phytocannabinoids from the cultivars were performed. The monthly dose of each phytocannabinoid for each patient was z-scaled and clustered into ten groups to assess the difference in analgesic treatment response (≥30%/50% pain intensity reduction) and AEs rates. We identified ten clusters that had similar analgesic treatment response rates. However, there were significant differences in AEs rates both at short- and long-term. We identified specific phytocannabinoid compositions that were associated with overall AEs rates (5% compared to 53% at short-term and 44% at long-term) and with specific AEs rates such as MC related central nervous system, gastrointestinal and psychological AEs. To conclude, Evaluating only Δ9-THC or CBD is insufficient to find associations with MC related AEs. Therefore, comprehensive profiling of phytocannabinoids is needed to discover associations to related AEs and help physicians prescribe safer cannabis with less AEs while still relieving pain.

Teaching During the COVID-19 Pandemic: The Experience of the Faculty of Medicine at the Technion-Israel Institute of Technology.

BACKGROUND: The coronavirus disease-2019 (COVID-19) pandemic forced drastic changes in all layers of life. Social distancing and lockdown drove the educational system to uncharted territories at an accelerated pace, leaving educators little time to adjust. OBJECTIVES: To describe changes in teaching during the first phase of the COVID-19 pandemic. METHODS: We described the steps implemented at the Technion-Israel Institute of Technology Faculty of Medicine during the initial 4 months of the COVID-19 pandemic to preserve teaching and the academic ecosystem. RESULTS: Several established methodologies, such as the flipped classroom and active learning, demonstrated effectiveness. In addition, we used creative methods to teach clinical medicine during the ban on bedside teaching and modified community engagement activities to meet COVID-19 induced community needs. CONCLUSIONS: The challenges and the lessons learned from teaching during the COVID-19 pandemic prompted us to adjust our teaching methods and curriculum using multiple online teaching methods and promoting self-learning. It also provided invaluable insights on our pedagogy and the teaching of medicine in the future with emphasis on students and faculty being part of the changes and adjustments in curriculum and teaching methods. However, personal interactions are essential to medical school education, as are laboratories, group simulations, and bedside teaching.

[TEACHING INTERNAL MEDICINE IN THE SHADOW OF THE COVID-19 OUTBREAK - THE EXPERIENCE OF THE TECHNION FACULTY OF MEDICINE].

INTRODUCTION: The clerkship of internal medicine is pursued in the 2nd semester of the 4th year at the Technion Medical School. Following the COVID-19 outbreak, frontal and bedside teaching was interrupted. Therefore, we decided to provide distant teaching until having the opportunity to resume clinical bedside teaching. A team of tutors composed a course of weekly units, each week assigned to a different subject in internal medicine. A total of 120 students were divided into 15 groups of 8 students, each group guided by a personal tutor. The format of each unit included online pretest, clinical virtual cases and two separate 2 hour ZOOM sessions with the tutor. The pretest was based on 1-3 chapters from Harrison's Internal Medicine textbook, 20th edition, and consisted of both clinical reasoning and knowledge questions. During ZOOM sessions with the tutor, the students practiced clinical problem solving. In addition, all the students were granted free access to the commercial "Aquifer" case-based virtual course for more practice. The students' feedback at the end of the learning period revealed that, although frustrated in being away from the clinics, the overall level of satisfaction from the course was good (rated 5 or 4/5 by 65% of responders) and the time was used efficiently. In conclusion, the students received a positive proactive learning experience of both theoretical aspects and clinical reasoning skills in internal medicine. There is no doubt that bedside teaching in medicine is invaluable and can't be replaced by any other means, however, given the circumstances, our format provided a reasonable temporary alternative.

Cannabis treatment in hospitalized patients using the SYQE inhaler: Results of a pilot open-label study.

OBJECTIVE: The objectives were to evaluate the, usability, feasibility of use, satisfaction, and safety of the Syqe Inhaler Exo (Syqe Inhaler), a metered dose, Pharmacokinetics-validated, cannabis inhaler device in a cohort of hospitalized patients that were using medical cannabis under license as a part of their ongoing medical treatment. METHOD: Before and after inhaling from the Syqe Inhaler, participants were asked to fill a questionnaire regarding pain reduction on a visual analog scale from 0 to 10 and, if relevant, reduction in chemotherapy-induced nausea and vomiting and/or spasticity. A patient satisfaction questionnaire and a usability questionnaire were filled in following the last use. Prescribed treatment included 4 daily doses of 500 µg tetrahydrocannabinol each delivered from 16 mg cannabis flos per inhalation plus up to an additional four SOS (distress code for more doses of cannabis) doses. RESULT: Daily cannabis dose consumed during hospitalization with the Syqe Inhaler was 51 mg (20-96) versus 1,000 mg (660-3,300) consumed prehospitalization. Patients were easily trained and continued to use Syqe Inhaler for the duration of their hospitalization (5 [3-7] days). Pain intensity 30-60 minutes following inhalations was reported to be significantly lower than preinhalation 4 [1-5] versus 7 [2-9]). Participants ranked their satisfaction with Syqe Inhaler as 6 (5-7). Three participants reported mild cough, which resolved spontaneously. SIGNIFICANCE OF RESULTS: Cannabis inhalation by combustion is not feasible for hospitalized patients. The use of Syqe Inhaler during hospitalization yielded high levels of patients and staff satisfaction with no complications.

Anchoring the Numeric Pain Scale Changes Pain Intensity Reports in Patients With Chronic But Not With Acute Pain.

BACKGROUND: Despite enormous differences between acute and chronic pain, the numeric pain scale (NRS) is commonly used in pain research and clinical practice for assessing the intensity of both acute and chronic pain. The use of this scale has been challenged as it may fail to accurately reflect the pure intensity of chronic pain. AIM: To compare the effect of anchoring the NRS on the intensity of pain reported by patients with acute vs. chronic pain. METHODS: Patients with acute postoperative or chronic pain (n = 100/group) were requested to rate their: current clinical pain intensity on an NRS from 0 to 100; the intensity of an anchoring pain event on the same scale; and subsequently to rate again their current pain intensity while making reference to the reported intensity of the pain event. The magnitude of correction was compared between the 2 groups. RESULTS: The anchoring pain was rated identically between the groups. However, following anchoring, patients with chronic pain made a significantly larger correction of their pain intensity than did those with acute pain (mean ± standard deviation = 9 ± 9, median [interquartile range] = 10 [0 to 10] vs. 3 ± 7, 0 [0 to 5], respectively; P < 0.0001). More patients in the chronic pain group corrected their pain intensity. Logistic regression showed that chronic pain and female gender significantly increased the likelihood of making the correction (chronic pain: odds ratio 7.2, 95% confidence interval 3.5 to 15.1, P < 0.0001; female gender: odds ratio 2.8, 95% confidence interval 1.4 to 5.5, P < 0.0001). CONCLUSION: The results suggest that anchoring the NRS can potentially improve the accuracy of reported chronic pain intensity.

Opioid-Induced Constipation and Bowel Dysfunction: A Clinical Guideline.

OBJECTIVE: To formulate timely evidence-based guidelines for the management of opioid-induced bowel dysfunction. SETTING: Constipation is a major untoward effect of opioids. Increasing prescription of opioids has correlated to increased incidence of opioid-induced constipation. However, the inhibitory effects of opioids are not confined to the colon, but also affect higher segments of the gastrointestinal tract, leading to the coining of the term "opioid-induced bowel dysfunction." METHODS: A literature search was conducted using Medline, EMBASE, and EMBASE Classic, and the Cochrane Central Register of Controlled Trials. Predefined search terms and inclusion/exclusion criteria were used to identify and categorize relevant papers. A series of statements were formulated and justified by a comment, then labeled with the degree of agreement and their level of evidence as judged by the Strength of Recommendation Taxonomy (SORT) system. RESULTS: From a list of 10,832 potentially relevant studies, 33 citations were identified for review. Screening the reference lists of the pertinent papers identified additional publications. Current definitions, prevalence, and mechanism of opioid-induced bowel dysfunction were reviewed, and a treatment algorithm and statements regarding patient management were developed to provide guidance on clinical best practice in the management of patients with opioid-induced constipation and opioid-induced bowel dysfunction. CONCLUSIONS: In recent years, more insight has been gained in the pathophysiology of this "entity"; new treatment approaches have been developed, but guidelines on clinical best practice are still lacking. Current knowledge is insufficient regarding management of the opioid side effects on the upper gastrointestinal tract, but recommendations can be derived from what we know at present.

Back Pain with Leg Pain.

PURPOSE OF REVIEW: The clinical diagnostic dilemma of low back pain that is associated with lower limb pain is very common. In relation to back pain that radiates to the leg, the International Association for the Study of Pain (IASP) states: "Pain in the lower limb should be described specifically as either referred pain or radicular pain. In cases of doubt no implication should be made and the pain should be described as pain in the lower limb." RECENT FINDINGS: Bogduks' editorial in the journal PAIN (2009) helps us to differentiate and define the terms somatic referred pain, radicular pain, and radiculopathy. In addition, there are other pathologies distal to the nerve root that could be relevant to patients with back pain and leg pain such as plexus and peripheral nerve involvement. Hence, the diagnosis of back pain with leg pain can still be challenging. In this article, we present a patient with back and leg pain. The patient appears to have a radicular pain syndrome, but has no neurological impairment and shows signs of myofascial involvement. Is there a single diagnosis or indeed two overlapping syndromes? The scope of our article encompasses the common diagnostic possibilities for this type of patient. A discussion of treatment is beyond the scope of this article and depends on the final diagnosis/diagnoses made.

The effect of hydromorphone therapy on psychophysical measurements of the descending inhibitory pain systems in patients with chronic radicular pain.

OBJECTIVE: Conditioned pain modulation (CPM) and offset analgesia (OA) are considered to represent paradigms of descending inhibitory pain modulation in humans. This study tested the effects of hydromorphone therapy on descending inhibitory pain modulation, as measured by changes from baseline in the magnitudes of CPM and OA. DESIGN: Prospective evaluation. SETTING: Institute of Pain Medicine, Rambam Health Care Campus. SUBJECTS: Patients with chronic radicular pain. METHODS: Thirty patients received 4 weeks of oral hydromorphone treatment at an individually titrated dose (mean ± standard deviation dose of 11.6 ± 4.8 mg/day). CPM and OA were assessed before and after hydromorphone treatment. CPM was assessed by subtracting the response to a painful phasic heat stimulus administered simultaneously with a conditioning cold pain stimulus, from the response to the same heat stimulus administered alone. The OA paradigm consisted of a three-temperature stimuli train (T1 = 49°C [5 seconds], T2 = 50°C [5 seconds], and T3 = 49°C [20 seconds]). The magnitude of OA was quantified by subtracting minimal pain scores obtained during T3 from the maximal pain scores obtained during T2. RESULTS: CPM scores changed from a baseline of 17.7 ± 20.6 to 21 ± 20.4 following treatment, and OA scores changed from 7.8 ± 20.5 to 9.7 ± 14.6. Wilcoxon signed rank test indicated that these changes were not significant (CPM: P = 0.22; OA: P = 0.44). McNemar test revealed that the percentage of patients who exhibited a change in the direction of CPM or OA in response to hydromorphone treatment was not significant (CPM: P = 0.37; OA: P = 0.48). CONCLUSIONS: These results suggest that the descending inhibitory pain modulation, as manifested in humans by CPM and OA, is unlikely to be mediated by hydromorphone therapy.

Alterations in pain response are partially reversed by methylphenidate (Ritalin) in adults with attention deficit hyperactivity disorder (ADHD).

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is characterized by dysregulation of sensory processing and neurobiology of dopamine. Although cumulative evidence suggests that dopamine is involved in pain processing, pain perception in ADHD subjects and the effect of dopamine agonists such as methylphenidate (MP, Ritalin) on it have rarely been studied. AIMS: The aims of this study were to (1) psychophysically assess sensitivity to pain in ADHD subjects as compared to controls and (2) examine the effects of MP on pain response in ADHD subjects. METHODS: Thirty subjects with ADHD and 30 age- and gender-matched controls participated in a preliminary trial. Pain threshold, intensity, and tolerance in response to cold pain stimulation were measured for both groups (ADHD with no treatment). In addition, the ADHD group was reassessed following a single dose of MP treatment. RESULTS: The ADHD subjects "without MP" in comparison with controls displayed significantly shorter cold pain threshold (2.8 ± 2.1 vs. 5.8 ± 2.5 seconds, respectively, P < 0.001) and cold tolerance (21.8 ± 22.3 vs. 62.8 ± 59.8 seconds, respectively P < 0.001). No differences in pain intensities between the groups were found. Following MP treatment, both cold threshold and tolerance in the ADHD subjects increased significantly compared to those with no treatment (3.6 ± 2.5 seconds, P = 0.011, and 46.4 ± 53.3 seconds, P < 0.001, respectively). CONCLUSIONS: These results suggest that adults with ADHD are more sensitive to pain compared with controls and that MP may exert antinociceptive properties in these subjects. Randomized, controlled trials are warranted to verify these findings.

Measuring the Intensity of Chronic Pain: Are the Visual Analogue Scale and the Verbal Rating Scale Interchangeable?

OBJECTIVES: The 0 to 100 mm visual analogue scale (VAS) and the five-category verbal rating scale (VRS) are commonly used for measuring pain intensity. An open question remains as to whether these scales can be used interchangeably to allow comparisons between intensities of pain in the clinical setting or increased statistical power in pain research. METHODS: Seven hundred and ninety-six patients were requested to rate the present intensity of their chronic pain on the two scales. Spearman's rank correlation coefficients between VAS and VRS were calculated. For testing interchangeability, VAS was transformed into a discrete ordinal scale by dividing the entire VAS into five categories, either equidistantly (biased) or using frequency distributions of VAS (unbiased). We used Goodman-Kruskal's gamma and Wilson's e measures of ordinal association quantified the relationships between the transformed VAS and VRS scores and Svensson method to evaluate agreement between biased and unbiased discrete VAS and VRS scales. RESULTS: Average VAS and VRS scores were 76 ± 18 mm and "severe," respectively. Spearman's rank correlation coefficient values between continuous VAS and VRS were 0.77 to 0.85. Goodman-Kruskal's gamma ordinal associations between discrete VAS and VRS were 0.82 to 0.92 and 0.90 to 0.98 for the biased and unbiased VAS, respectively. Wilson's e measures were 0.51 to 0.61 and 0.54 to 0.65, accordingly. Svensson analysis showed low probability of agreement between both biased (0.66 to 0.76) and unbiased (0.75 to 0.82) VAS and VRS. DISCUSSION: Regardless of the relatively high Spearman correlations between original VAS and VRS, the low ordinal association and low probability of agreement between discrete VAS and VRS suggest that they are not interchangeable. Therefore, VAS and VRS should not be used interchangeably in the clinical setting or for increased statistical power in pain research.

Drug combinations in the treatment of neuropathic pain.

Pharmacotherapy, the main treatment option for neuropathic pain, remains a major clinical challenge. The most commonly studied drug classes in the context of neuropathic pain-antidepressants, anticonvulsants, and opioids-have only limited efficacy and frequent dose-limiting adverse effects. Yet, most guidelines recommend monotherapy as the first line of neuropathic pain treatment. Recent understanding of neuropathic pain pathophysiology suggests that multiple mechanisms, both at the peripheral and the central nervous system levels, underlie neuropathic pain, pointing to the possibility that targeting multiple mechanisms simultaneously can improve treatment outcome. A few clinical trials using various drug combinations for neuropathic pain have already been published but yielded inconsistent results, partially due to methodological problems associated with the conduction of such trials. Nonetheless, combination therapy remains an intriguing treatment option for neuropathic pain, awaiting future high-quality validating trials.

Cannabis oil extracts for chronic pain: what else can be learned from another structured prospective cohort?

Introduction: The use of medicinal cannabis for managing pain expands, although its efficacy and safety have not been fully established through randomized controlled trials. Objectives: This structured, prospective questionnaire-based cohort was aimed to assess long-term effectiveness and safety of cannabis oil extracts in patients with chronic pain. Methods: Adult Israeli patients licensed to use cannabis oil extracts for chronic pain were followed prospectively for 6 months. The primary outcome measure was change from baseline in average weekly pain intensity, and secondary outcomes were changes in related symptoms and quality of life, recorded before treatment initiation and 1, 3, and 6 months thereafter. Generalized linear mixed model was used to analyze changes over time. In addition, "responders" (≥30% reduction in weekly pain at any time point) were identified. Results: The study included 218 patients at baseline, and 188, 154, and 131 at 1, 3, and 6 months, respectively. At 6 months, the mean daily doses of cannabidiol and Δ9-tetrahydrocannabinol were 22.4 ± 24.0 mg and 20.8 ± 30.1 mg, respectively. Pain decreased from 7.9 ± 1.7 at baseline to 6.6 ± 2.2 at 6 months (F(3,450) = 26.22, P < 0.0001). Most secondary parameters also significantly improved. Of the 218 participants, 24% were "responders" but could not be identified by baseline parameters. "Responders" exhibited higher improvement in secondary outcomes. Adverse events were common but mostly nonserious. Conclusion: This prospective cohort demonstrated a modest overall long-term improvement in chronic pain and related symptoms and a reasonable safety profile with the use of relatively low doses of individually titrated Δ9-tetrahydrocannabinol and cannabidiol.

Challenges in Implementing Guideline on Integrative Oncology and Pain: The Israeli Perspective.

CONTEXT AND OBJECTIVES: To explore the feasibility of implementing the joint guideline on integrative medicine for pain management in oncology, published by the Society for Integrative Oncology (SIO) and the American Society of Clinical Oncology (ASCO), for integrative oncology (IO) services in supportive and palliative care. METHODS: A qualitative research methodology was co-designed by the SIO-ASCO guideline committee, with the Society for Complementary Medicine, Israel Medical Association (IMA). A questionnaire with five open-ended questions exploring barriers and enablers to implementing the guideline was distributed to chairs and board members of nine IMA-affiliated medical societies; four deans of Israeli medical schools; and nurses from the Israeli Society for Oncology Nursing. Respondent narratives were qualitatively analyzed using ATLAS.Ti software for systematic coding. RESULTS: Questionnaires were completed by 52 physicians and nurses from medical oncology, hematology, gynecological oncology, pediatric oncology, palliative medicine, pain, family medicine, internal medicine, and integrative medicine. The SIO-ASCO guidelines were endorsed by nine IMA-affiliated societies. The domains identified included the importance of guideline implementation in clinical practice; barriers and facilitators to implementation; practical aspects required for this implementation (e.g., IO training); clinical indications for referral; budget-related issues; and clinical and administrative models enabling practical implementation of the guideline. CONCLUSION: We found across-the-board consensus among the nine IMA-affiliated societies supporting the current guideline. This, while identifying potential facilitators and barriers in order to address the implementation of the SIO-ASCO guideline recommendations.

Opioids for neuropathic pain.

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 3, 2006, which included 23 trials. The use of opioids for neuropathic pain remains controversial. Studies have been small, have yielded equivocal results, and have not established the long-term profile of benefits and risks for people with neuropathic pain. OBJECTIVES: To reassess the efficacy and safety of opioid agonists for the treatment of neuropathic pain. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (to 24th October 2012), MEDLINE (1966 to 24th October 2012 ), and EMBASE (1980 to 24th October 2012) for articles in any language, and reference lists of reviews and retrieved articles. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in which opioid agonists were given to treat central or peripheral neuropathic pain of any etiology. Pain was assessed using validated instruments, and adverse events were reported. We excluded studies in which drugs other than opioid agonists were combined with opioids or opioids were administered epidurally or intrathecally. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and included demographic variables, diagnoses, interventions, efficacy, and adverse effects. MAIN RESULTS: Thirty-one trials met our inclusion criteria, studying 10 different opioids: 23 studies from the original 2006 review and eight additional studies from this updated review.Seventeen studies (392 participants with neuropathic pain, average 22 participants per study) provided efficacy data for acute exposure to opioids over less than 24 hours. Sixteen reported pain outcomes, with contradictory results; 8/16 reported less pain with opioids than placebo, 2/16 reported that some but not all participants benefited, 5/16 reported no difference, and 1/16 reported equivocal results. Six studies with about 170 participants indicated that mean pain scores with opioid were about 15/100 points less than placebo.Fourteen studies (845 participants, average 60 participants per study) were of intermediate duration lasting 12 weeks or less; most studies lasted less than six weeks. Most studies used imputation methods for participant withdrawal known to be associated with considerable bias; none used a method known not to be associated with bias. The evidence, therefore, derives from studies predominantly with features likely to overestimate treatment effects, i.e. small size, short duration, and potentially inadequate handling of dropouts. All demonstrated opioid efficacy for spontaneous neuropathic pain. Meta-analysis demonstrated at least 33% pain relief in 57% of participants receiving an opioid versus 34% of those receiving placebo. The overall point estimate of risk difference was 0.25 (95% confidence interval (CI) 0.13 to 0.37, P < 0.0001), translating to a number needed to treat for an additional beneficial outcome (NNTB) of 4.0 (95% CI 2.7 to 7.7). When the number of participants achieving at least 50% pain relief was analyzed, the overall point estimate of risk difference between opioids (47%) and placebo (30%) was 0.17 (95% CI 0.02 to 0.33, P = 0.03), translating to an NNTB of 5.9 (3.0 to 50.0). In the updated review, opioids did not demonstrate improvement in many aspects of emotional or physical functioning, as measured by various validated questionnaires. Constipation was the most common adverse event (34% opioid versus 9% placebo: number needed to treat for an additional harmful outcome (NNTH) 4.0; 95% CI 3.0 to 5.6), followed by drowsiness (29% opioid versus 14% placebo: NNTH 7.1; 95% CI 4.0 to 33.3), nausea (27% opioid versus 9% placebo: NNTH 6.3; 95% CI 4.0 to 12.5), dizziness (22% opioid versus 8% placebo: NNTH 7.1; 95% CI 5.6 to 10.0), and vomiting (12% opioid versus 4% placebo: NNTH 12.5; 95% CI 6.7 to 100.0). More participants withdrew from opioid treatment due to adverse events (13%) than from placebo (4%) (NNTH 12.5; 95% CI 8.3 to 25.0). Conversely, more participants receiving placebo withdrew due to lack of efficacy (12%) versus (2%) receiving opioids (NNTH -11.1; 95% CI -20.0 to -8.3). AUTHORS' CONCLUSIONS: Since the last version of this review, new studies were found providing additional information. Data were reanalyzed but the results did not alter any of our previously published conclusions. Short-term studies provide only equivocal evidence regarding the efficacy of opioids in reducing the intensity of neuropathic pain. Intermediate-term studies demonstrated significant efficacy of opioids over placebo, but these results are likely to be subject to significant bias because of small size, short duration, and potentially inadequate handling of dropouts. Analgesic efficacy of opioids in chronic neuropathic pain is subject to considerable uncertainty.  Reported adverse events of opioids were common but not life-threatening. Further randomized controlled trials are needed to establish unbiased estimates of long-term efficacy, safety (including addiction potential), and effects on quality of life.

The individual and societal burden of chronic pain in Europe: the case for strategic prioritisation and action to improve knowledge and availability of appropriate care.

BACKGROUND: Chronic pain is common in Europe and elsewhere and its under treatment confers a substantial burden on individuals, employers, healthcare systems and society in general. Indeed, the personal and socioeconomic impact of chronic pain is as great as, or greater, than that of other established healthcare priorities. In light of review of recently published data confirming its clinical and socioeconomic impact, this paper argues that chronic pain should be ranked alongside other conditions of established priority in Europe. We outline strategies to help overcome barriers to effective pain care resulting in particular from deficiencies in education and access to interdisciplinary pain management services. We also address the confusion that exists between proper clinical and scientific uses of opioid medications and their potential for misuse and diversion, as reflected in international variations in the access to, and availability of, these agents. DISCUSSION: As the economic costs are driven in part by the costs of lost productivity, absenteeism and early retirement, pain management should aim to fully rehabilitate patients, rather than merely to relieve pain. Accredited education of physicians and allied health professionals regarding state-of-the-art pain management is crucial. Some progress has been made in this area, but further provision and incentivization is required. We support a tiered approach to pain management, whereby patients with pain uncontrolled by non-specialists are able to consult a physician with a pain competency or a specialist in pain medicine, who in turn can recruit the services of other professionals on a case-by-case basis. A fully integrated interdisciplinary pain service should ideally be available to patients with refractory pain. Governments and healthcare systems should ensure that their policies on controlled medications are balanced, safeguarding public health without undue restrictions that compromise patient care, and that physician education programmes support these aims. SUMMARY: Strategic prioritization and co-ordinated actions are required nationally and internationally to address the unacceptable and unnecessary burden of uncontrolled chronic pain that plagues European communities and economies. An appreciation of the 'return on investment' in pain management services will require policymakers to adopt a long-term, cross-budgetary approach.

Anti tumor necrosis factor - alpha adalimumab for complex regional pain syndrome type 1 (CRPS-I): a case series.

BACKGROUND AND AIMS: Evidence suggests tumor necrosis factor-alpha (TNF-α) mediates, at least in part, symptoms and signs in complex regional pain syndrome (CRPS). Here, we present a case series of patients with CRPS type 1, in whom the response to the anti-TNF-α adalimumab was assessed. METHODS: Ten patients with CRPS type 1 were recruited. Assessments were performed before treatment, at 1 week, and 1, 3, and 6 months following 3 biweekly subcutaneous injections (40 mg/0.8 mL) adalimumab (Humira(®) ) and included the followings: Pain intensity using a 0-10 cm visual analog scale; the Short Form of the McGill Pain Questionnaire; the Beck Depression Inventory; the SF-36 questionnaire and mechanical and thermal thresholds (Von frey hair and Thermal Sensory Analyzer, respectively). In addition to the description of individual patient responses, both intention to treat (ITT) and per-protocol (PP) analyses were performed for the entire group. RESULTS: Three subgroups of patients were identified (3 patients in each): "nonresponders", "partial responders", and "robust responders" in whom improvement in almost all parameters was noted. Both the ITT and PP analyses demonstrated only a trend toward improvement in mechanical pain thresholds following treatment (ITT χ² = 13.83, P = 0.008; PP χ² = 10.29, P = 0.036). CONCLUSION: These results suggest adalimumab, and possibly other anti-TNF-α, can be potentially useful in some (although not in all) patients with CRPS type 1. These preliminary results along with the growing body of evidence which points to the involvement of TNF-α in the pathogenesis of CRPS justify further studies in this area.

Evaluating Sex Differences in Efficacy, Safety and Pharmacokinetics in Patients Treated with Cannabis by a Metered-Dose Inhaler.

BACKGROUND: Clinical studies on medical cannabis (MC) treatment have shown sex-related differences, including higher susceptibility to adverse events among women and greater analgesia among men. Here, we used the Syqe metered-dose inhaler (MDI) and a single chemovar to analyze sex differences. METHODS: A total of 1249 Israeli chronic pain patients were assessed for pain intensity, sleep and adverse events (AEs) over 240 days. RESULTS: Following the first two weeks, no significant sex differences were found in the effectiveness or safety of MC treatment (p > 0.05). Inhaled Δ9-THC doses did not vary significantly between sexes (p > 0.05) except in the first month of treatment. Pain reduction and sleep improvement were similar for both sexes (p > 0.05). The overall rate of AEs was equal and relatively low at 10% (n = 65, 10% of women and n = 60, 10% of men; χ2 (1) = 0.05, p = 0.820). A secondary analysis of pharmacokinetic data showed no significant differences between sexes in Δ9-THC and its metabolite pharmacokinetics, cardiovascular measures, or AE severity (p > 0.05). CONCLUSIONS: Uniform MC treatment via the Syqe MDI showed no sex differences in short-term effectiveness, safety and pharmacokinetics, nor in long-term effects, under "real-life" conditions. These findings provide insights into MC treatment which may inform clinical practice and policy-making in the field.