Effects of S 38093, an antagonist/inverse agonist of histamine H3 receptors, in models of neuropathic pain in rats

Abstract

Background

Histamine H3 receptors are mainly expressed on CNS neurons, particularly along the nociceptive pathways. The potential involvement of these receptors in pain processing has been suggested using H3 receptor inverse agonists.

Methods

The antinociceptive effect of S 38093, a novel inverse agonist of H3 receptors, has been evaluated in several neuropathic pain models in rat and compared with those of gabapentin and pregabalin.

Results

While S 38093 did not change vocalization thresholds to paw pressure in healthy rats, it exhibited a significant antihyperalgesic effect in the Streptozocin-induced diabetic (STZ) neuropathy model after acute and chronic administration and, in the chronic constriction injury (CCI) model only after chronic administration, submitted to the paw-pressure test. Acute S 38093 administration at all doses tested displayed a significant cold antiallodynic effect in a model of acute or repeated administration of oxaliplatin-induced neuropathy submitted to cold tail immersion, cold allodynia being the main side effect of oxaliplatin in patients. The effect of S 38093 increased following chronic administration (i.e. twice a day during 5 days) in the CCI and STZ models except in the oxaliplatin models where its effect was already maximal from the first administration The kinetics and size of effect of S 38093 were similar to gabapentin and/or pregabalin. Finally, the antinociceptive effect of S 38093 could be partially mediated by α2 adrenoreceptors desensitization in the locus coeruleus.

Conclusions

These results highlight the interest of S 38093 to relieve neuropathic pain and warrant clinical trials especially in chemotherapeutic agent-induced neuropathic pain.

Significance

S 38093, a new H3 antagonist/inverse agonist, displays antiallodynic and antihyperalgesic effect in neuropathic pain, especially in oxaliplatin-induced neuropathy after chronic administration. This effect of S 38093 in neuropathic pain could be partly mediated by α2 receptors desensitization in the locus coeruleus.

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Multidisciplinary Evaluation Leads to the Decreased Utilization of Lumbar Spine Fusion: An Observational Cohort Pilot Study

Study Design. Observational cohort pilot study. Objective. To determine the impact of a multidisciplinary conference on treatment decisions for lumbar degenerative spine disease. Summary of Background Data. Multidisciplinary decision making improves outcomes in many disciplines. The lack of integrated systems for comprehensive care for spinal disorders has contributed to the inappropriate overutilization of spine surgery in the United States. Methods. We implemented a multidisciplinary conference involving physiatrists, anesthesiologists, pain specialists, neurosurgeons, orthopaedic spine surgeons, physical therapists, and nursing staff. Over 10 months, we presented patients being considered for spinal fusion or who had a complex history of prior spinal surgery. We compared the decision to proceed with surgery and the proposed surgical approach proposed by outside surgeons with the consensus of our multidisciplinary conference. We also assessed comprehensive demographics and comorbidities for the patients and examined outcomes for surgical patients. Results. A total of 137 consecutive patients were reviewed at our multidisciplinary conference during the 10-month period. Of these, 100 patients had been recommended for lumbar spine fusion by an outside surgeon. Consensus opinion of the multidisciplinary conference advocated for nonoperative management in 58 patients (58%) who had been previously recommended for spinal fusion at another institution (χ 2  = 26.6; P < 0.01). Furthermore, the surgical treatment plan was revised as a product of the conference in 28% (16 patients) of the patients who ultimately underwent surgery (χ 2  = 43.6; P < 0.01). We had zero 30-day complications in surgical patients. Conclusion. Isolated surgical decision making may result in suboptimal treatment recommendations. Multidisciplinary conferences can reduce the utilization of lumbar spinal fusion, possibly resulting in more appropriate use of surgical interventions with better candidate selection while providing patients with more diverse nonoperative treatment options. Although long-term patient outcomes remain to be determined, such multidisciplinary care will likely be essential to improving the quality and value of spine care. Level of Evidence: 3

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Is the Number of Different MRI Findings More Strongly Associated With Low Back Pain Than Single MRI Findings?

Study design. A cross-sectional and longitudinal analysis using two different datasets. Objective. To investigate if the number of different magnetic resonance imaging (MRI) findings present is more strongly associated with low back pain (LBP) than single MRI findings. Summary of Background Data. Most previous studies have investigated the associations between single MRI findings and back pain rather than investigating combinations of MRI findings. If different individuals have different pathoanatomic sources contributing to their pain, then combinations of MRI findings may be more strongly associated with LBP. Methods. This study used data from two previous studies that investigated the association between single MRI findings and LBP. One study was a cross-sectional population cohort of 412 people of 40 years; the second was a longitudinal cohort of 76 people recently recovered from LBP who were followed for 12 months. The outcome for the cross-sectional study was presence of LBP during the last year. The outcome for the longitudinal study was days to recurrence of activity limiting LBP. In both datasets, we created an aggregate score of the number of different MRI findings present in each individual and assessed the relationship between this aggregate score and LBP. Results. The risk of LBP outcome increased with increasing numbers of different MRI findings. Compared with those with no MRI findings, those with three MRI findings were at substantially greater risk of LBP in the last year (odd ratio = 14.1; 95% confidence interval, 4.32–49.47) in the cross-sectional study, or of future recurrence of LBP (hazard ratio = 12.2; 95% confidence interval 1.26–118.21) in the longitudinal study. Conclusion. The aggregate MRI score was more strongly associated with LBP outcomes than single MRI findings in both datasets. Further investigation of this approach is indicated. Level of Evidence: 2

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Does Familial Aggregation of Chronic Low Back Pain Affect Recovery?: A Population-Based Twin Study

Study Design. Longitudinal twin-cohort study. Objective. To investigate the effect familial aggregation of chronic low back pain (LBP) has on the recovery from chronic LBP. Summary of Background Data. LBP is a worldwide problem, with pain and disability often becoming chronic. Genetics and familial behaviors could significantly affect the recovery from chronic LBP but have not been extensively investigated. Methods. A total of 624 Spanish twins from the Murcia Twin Registry reported experiencing chronic LBP within the past 2 years during the 2009/11 data collection wave and were followed up in 2013. Familial aggregation of chronic LBP was determined by the co-twin experiencing chronic LBP within the past 2 years at baseline. Twins reporting LBP “within the past 4 weeks” at follow-up were considered to have not recovered. Results. There were 455 twins with available data on LBP at follow-up and available data on LBP from their co-twin at baseline. Twins with an affected co-twin at baseline were significantly more likely to have not recovered from chronic LBP at follow-up (odds ratio [OR] = 1.6, 95% confidence interval [CI]: 1.0–2.4, P = 0.046). This relationship was stronger for monozygotic twins (OR = 2.5, 95% CI: 1.3–4.8, P = 0.006) (n = 172) but disappeared when considering only dizygotic twins (OR = 1.1, 95% CI: 0.6–2.0, P = 0.668) (n = 283). Sibling-relative recurrence risk (λs) was 1.2 for the total sample, 1.5 for monozygotic twins, and 1.1 for dizygotic twins. Conclusion. Having a sibling with chronic LBP at baseline increased the likelihood of LBP at follow-up by 20%, with this likelihood increasing to 50% if the sibling was an identical twin. These results are novel and highlight the important influence genetics have on people's recovery from chronic LBP. Information regarding the presence of chronic LBP within a family is easy to obtain and has the potential to inform clinicians on which patients are less likely to recover when treatment implementation is not considered. Level of Evidence: 3

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A Profile of Low Back Pain: Treatment and Costs Associated With Patients Referred to Orthopedic Specialists in Sweden

Study Design. Analysis of Swedish national and regional register data. Objectives. The aim of this study was to characterize healthcare resource utilization, productivity loss, and costs of patients with low back pain (LBP) with or without leg pain, who have been referred from primary care settings to orthopedic specialist care. Summary of Background Data. Register data on outpatient and inpatient care, work absence, drug prescriptions, socioeconomics, and mortality were extracted for patients visiting orthopedic specialists for LBP in the Swedish region Västra Götaland (1.6 million inhabitants in 2015) in 2008 to 2011 (4 years). Methods. Patients were followed with regard to resource use and costs during “LBP episodes,” defined as the time period from the first visit to an orthopedic specialist (“index-point”) until the last observed resource use registered with an LBP diagnosis. Patients were also followed during fixed time periods of 2 years before and 2 years after the index-point. Results. In total, 16,329 LBP episodes were identified (13,931 unique patients), in six diagnosis groups. Mean societal cost per LBP episode was estimated at €6466 (SD 21,884), where indirect cost constituted 74% and half of the 26% remaining direct costs were owing to hospital inpatient care. Patients underwent surgery in 10% of the episodes (n = 1583). Cost per LBP episode varied between diagnosis groups, with a range of €18,668 to €40,774 in episodes with surgery and €978 to €10,379 in episodes without surgery. Assessment of the fixed time period of 2 years before and after index-point showed that costs increased gradually during the year before in all groups and declined the year after in all groups. Conclusion. The marked decline in total costs the year after referral to an orthopaedic specialist indicates that the treatment provided, regardless of treatment, has an effect and also likely improves the quality of life for the patient. Level of Evidence: 4

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Measurement Properties of the Scoliosis Research Society Outcomes Questionnaire in Adolescent Patients With Spondylolisthesis

Study Design. Prospective validation of the Scoliosis Research Society Outcomes Questionnaire French-Canadian version (SRS-22fv) in adolescent patients with spondylolisthesis. Objective. To determine the measurement properties of the SRS-22fv. Summary of Background Data. The SRS-22 is widely used for the assessment of health-related quality of life in adolescent idiopathic scoliosis (AIS) and other spinal deformities. Spondylolisthesis has an important effect on quality of life. The instrument was previously used in this population, although its measurement properties remained unknown. We aim to determine its reliability, factorial, concurrent validity, and its discriminant capacity in an adolescent spondylolisthesis population. Methods. The SRS-22fv was tested in 479 subjects (272 patients with spondylolisthesis, 143 with AIS, and 64 controls) at a single institution. Its reliability was measured using the coefficient of internal consistency, concurrent validity by the short form-12 (SF-12v2 French version) and discriminant validity using multivariate analysis of variance, analysis of covariance, and multivariate linear regression. Results. The SRS-22fv showed a good global internal consistency (spondylolisthesis: Cronbach α = 0.91, AIS: 0.86, and controls: 0.78) in all its domains for spondylolisthesis patients. It showed a factorial structure consistent with the original questionnaire, with 60% of explained variance under four factors. Moderate to high correlation coefficients were found for specifically corresponding domains between SRS-22fv and SF-12v2. Boys had higher scores than do girls, scores worsened with increasing age and body mass index. Analysis of covariance showed statistically significant differences between patients with spondylolisthesis, patients with AIS, and controls when controlling for age, sex, body mass index, pain, function, and self-image scores. In the spondylolisthesis group, scores on all domains and mean total scores were significantly lower in surgical candidates and in patients with high-grade spondylolisthesis. Low to moderate ceiling effects were shown in function (1.1%), self-image (10.7%), and pain (13.6%). Conclusion. The SRS-22fv can discriminate between healthy and spondylolisthesis subjects. It can be used in spondylolisthesis patients to assess health-related quality of life. Level of Evidence: 4

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Explaining How Cognitive Behavioral Approaches Work for Low Back Pain: Mediation Analysis of the Back Skills Training Trial

Study Design. This is secondary research examining the longitudinal mediation effect within a structural equation model. Objective. To identify possible mechanisms that mediate the effects of a cognitive behavioral approach upon disability and pain in low back pain patients. Summary of Background Data. Cognitive behavioral interventions (CBIs) can improve pain and disability in low back pain (LBP) but the mechanisms of action are unclear. We used data from a large randomized controlled trial to investigate mediators of the treatment effect of CBI. Methods. Pain self-efficacy, fear avoidance, and physical and mental functioning were selected as candidate mediators based on the theoretical rationale of the intervention. The primary treatment outcomes were the Roland Morris Questionnaire (RMDQ) and the modified Von Korff scale (MVK pain and disability) at 12 months. We used structural equation models to estimate the contribution of mediators. All models were tested for goodness-of-fit using χ 2 , Root Mean Square Error of Approximation, Adjusted Goodness of Fit Index, and Bentler Comparative Fit Index. Results. We included 701 adults with LBP. The average RMDQ score at baseline for those on the intervention arm was 8.8 (Standard Deviation 5.0). The intervention was effective in reducing disability and pain at 12 months. Change in mental functioning was not a significant mediator. Changes to pain self-efficacy, fear avoidance, and physical functioning were causal mediators of the treatment effect at 12 months (RMDQ b= –0.149, P < 0.001; MVK-pain b = –0.181, P < 0.001 and MVK-disability b = –0.180, P < 0.001). Overall, the SEM model exceeded the threshold for acceptable goodness-of-fit. Conclusion. Fear avoidance and self-efficacy were important causal mediators of the cognitive behavioral treatment effect. Self-assessed change in physical function was a causal mediator but mental functioning was not. This suggests people need to experience meaningful change in physical function and beliefs but not in mental functioning associated with LBP, to achieve a treatment benefit. Level of Evidence: 2

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