Involvement of the opioid system and BDNF in neuroplastic alterations occurring in neuropathic pain conditions

Chronic pain affects one in five adults, reducing quality of life and increasing risk of developing co-morbidities such as depression. Neuropathic pain results by lesions to the nervous system that alter its structure and function leading to spontaneous pain and amplified responses to noxious and innocuous stimuli. The Opioid System is probably the most important system involved in control of nociceptive transmission. Dynorphin and nociceptin systems have been suggested key mediators of some neuropathic pain aspects. An important role also for BDNF has been recently suggested since its involvement in the peripheral and central sensitization phenomena is known. We studied neuroplastic alterations occurring in chronic pain in mice subjected to the chronic constriction injury (CCI). We investigated gene expression alterations of both BDNF and Opioid System at spinal level at different intervals of time. A transient upregulation of pBDNF and pDYN was observed in spinal cord, while increasing upregulation of ppN/OFQ was found in the DRGs of injured mice. Development of neuropathic behavioral signs has been observed in ICR/CD-1 and BDNF+/+ mice, subjected to CCI. A different development of these signs was observed in BDNF+/-. We also studied gene expression changes of investigated systems in different brain areas fourteen days after surgery. We found pBDNF, pDYN, pKOP, ppN/OFQ and pNOP gene expression alterations in several areas of CCI mice. In the same brain regions we also determined bioactive nociceptin peptide levels, and elevated N/OFQ levels were observed in the amygdala area. Histone modifications studies have been performed in BDNF and DYN gene promoters of CCI animal spinal cord showing selected alterations in pDYN gene promoter. In addition, a preliminary characterization of the innovative NOP-EGFP mice was performed. Overall, our results could be useful to understand which and how neuropeptidergic systems are involved in neuroplastic mechanism occurring in neuropathic pain.

Hip arthroscopy after previous surgical hip dislocation for femoroacetabular impingement

PURPOSE: The purpose of this study was to examine whether arthroscopic adhesiolysis can relieve symptoms of patients with persistent pain after open surgical hip dislocation for femoroacetabular impingement syndrome without osseous or cartilaginous alterations. METHODS: This study comprised 16 consecutive patients (6 men and 10 women; mean age, 33.5 years [range, 19 to 60 years]) with persistent pain without osseous or cartilaginous alterations after surgical hip dislocation for the treatment of femoroacetabular impingement. At index surgery, all patients had osteochondroplasty of the head-neck junction and resection of the acetabular rim with reattachment of the labrum in 9 cases. All patients had preoperative magnetic resonance imaging-arthrogram and were treated with arthroscopy of the hip. RESULTS: At arthroscopy, all reattached labra were stable. In the cases without preservation of the labrum at the index operation, the joint capsule was attached at the level of the acetabular rim and synovitis was noticed. All patients had adhesions between the neck of the femur and joint capsule or between the labrum and capsule. In 3 patients the arthroscopic procedure was technically limited by massive thickening of the capsule. Overall, 81% of patients (13/16) showed less pain or were pain-free. The Merle d'Aubigné score improved from 13 points preoperatively to 16 points at the last follow-up. CONCLUSIONS: Persistent pain after surgical dislocation of the hip without evidence of cartilaginous and osseous alterations could result from intra-articular adhesions. Hip arthroscopy after previous surgery can be demanding because of scarring. If the adhesions can be released, good results can be achieved. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Influence of preoperative functional status on outcome after total hip arthroplasty

BACKGROUND: International registries with large, heterogeneous patient populations provide excellent research opportunities for studying factors that influence treatment outcomes after total hip arthroplasty. In the present study, we used a European multinational database to investigate whether there is an association between three functional variables (preoperative pain, mobility, and motion) and functional outcome. METHODS: We performed a retrospective cohort study on preoperative and follow-up clinical data that were prospectively entered into the International Documentation and Evaluation System European hip registry between 1967 and 2002. The inclusion criteria for this study were an age of more than twenty years, an underlying diagnosis of osteoarthritis, and a Charnley class-A functional designation at the time of surgery. A total of 12,925 patients (13,766 total hip arthroplasties) who met these criteria were entered into the analysis. Three functional variables (pain, mobility, and motion) that were assessed preoperatively were evaluated postoperatively at various follow-up examinations for a maximum of ten years. RESULTS: Six thousand four hundred and one patients could walk longer than ten minutes preoperatively; of these, 57.1% had a walking capacity of more than sixty minutes at the time of the most recent follow-up. In comparison, 6896 patients had a preoperative walking capacity of less than ten minutes and only 38.9% of these patients could walk more than sixty minutes at the time of the most recent follow-up. The difference was significant (p < 0.01). Similarly, 10,375 patients had a preoperative hip flexion range of >70 degrees ; of these, 74.7% had a flexion range of >90 degrees at the time of the most recent follow-up. In comparison, 2793 patients had a preoperative hip flexion range of <70 degrees and only 62.6% of these patients had a flexion range of >90 degrees at the time of the most recent follow-up. The difference was also significant (p < 0.01). Lasting, complete, or almost complete pain relief was achieved by >80% of the patients following total hip arthroplasty regardless of their preoperative categorization of pain. CONCLUSIONS: Patients with poor preoperative walking capacity and hip flexion are less likely to achieve an optimal outcome with regard to walking and motion. In contrast, there is no correlation between the preoperative pain level and pain alleviation, which is generally good and long-lasting after total hip arthroplasty.

Doxycycline for osteoarthritis of the knee or hip

BACKGROUND: Osteoarthritis is a chronic joint disease that involves degeneration of articular cartilage. Pre-clinical data suggest that doxycycline might act as a disease-modifying agent for the treatment of osteoarthritis, with the potential to slow cartilage degeneration. OBJECTIVES: To examine the effects of doxycycline compared with placebo or no intervention on pain and function in patients with osteoarthritis of the hip or knee. SEARCH STRATEGY: We searched CENTRAL ( The Cochrane Library 2008, issue 3), MEDLINE, EMBASE and CINAHL up to 28 July 2008, checked conference proceedings, reference lists, and contacted authors. SELECTION CRITERIA: We included studies if they were randomised or quasi-randomised controlled trials that compared doxycycline at any dosage and any formulation with placebo or no intervention in patients with osteoarthritis of the knee or hip. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate. We contacted investigators to obtain missing outcome information. We calculated differences in means at follow-up between experimental and control groups for continuous outcomes and risk ratios for binary outcomes. MAIN RESULTS: We found one randomised controlled trial that compared doxycycline with placebo in 431 obese women. After 30 months of treatment, clinical outcomes were similar between the two treatment groups, with a mean difference of -0.20 cm (95% confidence interval (CI) -0.77 to 0.37 cm) on a visual analogue scale from 0 to 10 cm for pain and -1.10 units (95% CI -3.86 to 1.66) for function on the WOMAC disability subscale, which ranges from 17 to 85. These differences correspond to clinically irrelevant effect sizes of -0.08 and -0.09 standard deviation units for pain and function, respectively. The difference in changes in minimum joint space narrowing was in favour of doxycycline (-0.15 mm, 95% CI -0.28 to -0.02 mm), which corresponds to a small effect size of -0.23 standard deviation units. More patients withdrew from the doxycycline group compared with placebo due to adverse events (risk ratio 1.69, 95% CI 1.03 to 2.75). AUTHORS' CONCLUSIONS: The symptomatic benefit of doxycycline is minimal to non-existent. The small benefit in terms of joint space narrowing is of questionable clinical relevance and outweighed by safety problems. Doxycycline should not be recommended for the treatment of osteoarthritis of the knee or hip.

Arthroscopic versus open cam resection in the treatment of femoroacetabular impingement

PURPOSE The purpose of this study was to evaluate if osseous correction of the femoral neck achieved arthroscopically is comparable to that achieved by surgical dislocation. METHODS We retrospectively analyzed all patients who were treated with hip arthroscopy or surgical dislocation for cam or mixed type femoroacetabular impingement (FAI) in our institution between 2006 and 2009. Inclusion criteria were complete clinical and radiologic documentation with standardized radiographs. Group 1 consisted of 66 patients (49 female patients, mean age 33.8 years) treated with hip arthroscopy. Group 2 consisted of 135 patients (91 male patients, mean age 31.2 years) treated with surgical hip dislocation. We compared the preoperative and postoperative alpha and gamma angles, as well as the triangular index. Mean follow-up was 16.7 months (range, 2 to 79 months). RESULTS In group 1, the mean alpha angle improved from 60.7° preoperatively to 47.8° postoperatively (P < .001) and the mean gamma angle improved from 47.3° to 44.5° (P < .001). Over time, the preoperative mean alpha angle increased from 56.3° in 2006 to 67.5° in 2009, whereas the postoperative mean alpha angle decreased from 51.2° in 2006 to 47.5° in 2009. In group 2, the mean alpha angle improved from 75.3° preoperatively to 44.8° postoperatively (P < .001), and the mean gamma angle improved from 65.1° to 52.2° (P < .001). Arthroscopic revision of intra-articular adhesions was performed in 4 patients (6.1%) in group 1 and 16 patients (12%) in group 2. Three patients (2.2%) in group 2 underwent revision for nonunion of the greater trochanter. CONCLUSIONS Osseous correction of cam-type FAI with hip arthroscopy is comparable to the correction achieved by surgical hip dislocation. There is a significant learning curve for hip arthroscopy, with postoperative osseous correction showing improved results with increasing surgical experience. LEVEL OF EVIDENCE Level III, retrospective comparative study.

Overview of Treatment Options, Clinical Results, and Controversies in the Management of Femoroacetabular Impingement

The surgical management of symptomatic femoroacetabular impingement (FAI) generally is indicated after the failure of a trial of nonsurgical treatment. Surgical planning includes an assessment of the labrochondral pathology as well as of the acetabular and proximal femoral bony deformity. Advanced articular cartilage disease generally is associated with poorer outcomes. Surgical hip dislocation and hip arthroscopy have been used, with favorable early outcomes and low complication rates. Careful patient selection is important in predicting the success of the surgical management of symptomatic FAI. A trial of nonsurgical management generally is recommended, but limited information exists regarding its success. The early outcomes of both open and arthroscopic surgical techniques demonstrate significant improvement in most patients, with relatively low rates of complications. Because poorer clinical outcomes are associated with more advanced articular cartilage degeneration, improved strategies for the earlier identification and disease staging of symptomatic patients may enhance the long-term outcomes of both nonsurgical and surgical management.

Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain

Peripheral neuropathic pain is a disabling condition resulting from nerve injury. It is characterized by the dysregulation of voltage-gated sodium channels (Navs) expressed in dorsal root ganglion (DRG) sensory neurons. The mechanisms underlying the altered expression of Na(v)s remain unknown. This study investigated the role of the E3 ubiquitin ligase NEDD4-2, which is known to ubiquitylate Navs, in the pathogenesis of neuropathic pain in mice. The spared nerve injury (SNI) model of traumatic nerve injury-induced neuropathic pain was used, and an Na(v)1.7-specific inhibitor, ProTxII, allowed the isolation of Na(v)1.7-mediated currents. SNI decreased NEDD4-2 expression in DRG cells and increased the amplitude of Na(v)1.7 and Na(v)1.8 currents. The redistribution of Na(v)1.7 channels toward peripheral axons was also observed. Similar changes were observed in the nociceptive DRG neurons of Nedd4L knockout mice (SNS-Nedd4L(-/-)). SNS-Nedd4L(-/-) mice exhibited thermal hypersensitivity and an enhanced second pain phase after formalin injection. Restoration of NEDD4-2 expression in DRG neurons using recombinant adenoassociated virus (rAAV2/6) not only reduced Na(v)1.7 and Na(v)1.8 current amplitudes, but also alleviated SNI-induced mechanical allodynia. These findings demonstrate that NEDD4-2 is a potent posttranslational regulator of Na(v)s and that downregulation of NEDD4-2 leads to the hyperexcitability of DRG neurons and contributes to the genesis of pathological pain.

Use of a hand-assisted laparoscopic surgical technique for closure of an extensive mesojejunal rent in a horse

CASE DESCRIPTION A 7-year-old 573-kg (1,261 -lb) Swiss Warmblood gelding was evaluated because of signs of acute abdominal pain. CLINICAL FINDINGS Physical examination revealed a markedly distended abdomen with subjectively reduced borborygmi in all abdominal quadrants. A large, gas-distended viscus was present at the pelvic brim preventing complete palpation of the abdomen per rectum. Ultrasonographic evaluation could not be safely performed in the initial evaluation because of severe signs of abdominal pain. TREATMENT AND OUTCOME Ventral midline celiotomy was performed, and right dorsal displacement of the ascending colon was corrected. Progressive signs of abdominal pain after surgery prompted repeat ventral midline celiotomy, and small intestinal incarceration in a large, radial mesojejunal rent was detected. The incarceration was reduced, but the defect was not fully accessible for repair via the celiotomy. Repair of the mesenteric defect was not attempted, and conservative management was planned after surgery; however, signs of colic returned. A standard laparoscopic approach was attempted from both flanks in the standing patient, but the small intestine could not be adequately mobilized for full evaluation of the rent. Hand-assisted laparoscopic surgery (HALS) allowed identification and reduction of jejunal incarceration and repair of the mesenteric rent. Although minor ventral midline incisional complications were encountered, the horse recovered fully. CLINICAL RELEVANCE HALS techniques should be considered for repair of mesenteric rents in horses. In the horse of this report, HALS facilitated identification, evaluation, and repair of a large radial mesenteric rent that was not accessible from a ventral median celiotomy.

Long-term injury induced plasticity in {\it Aplysia\/} neurons: Behavioral, electrophysiological, and morphological studies

Nerve injury is known to produce a variety of electrophysiological and morphological neuronal alterations (reviewed by Titmus and Faber, 1990; Bulloch and Ridgeway, 1989; Walters, 1994). Determining if these alterations are adaptive and how they are activated and maintained could provide important insight into basic cellular mechanisms of injury-induced plasticity. Furthermore, characterization of injury-induced plasticity provides a useful assay system for the identification of possible induction signals underlying these neuronal changes. Understanding fundamental mechanisms and underlying induction signals of injury-induced neuronal plasticity could facilitate development of treatment strategies for neural injury and neuropathic pain in humans.^ This dissertation characterizes long-lasting, injury-induced neuronal alterations using the nervous system of Aplysia californica as a model. These changes are examined at the behavioral, electrophysiological, and morphological levels. Injury-induced changes in the electrophysiological properties of neurons were found that increased the signaling effectiveness of the injured neurons. This increase in signalling effectiveness could act to compensate for partial destruction of the injured neuron's peripheral processes. Recovery of a defensive behavioral response which serves to protect the animal from further injury was found within 2 weeks of injury. For the behavioral recovery to occur, new neural pathways must have been formed between the denervated area and the CNS. This was found to be mediated at least in part by new axonal growth which extended from the injured cell back along the original pathway (i.e. into the injured nerve). In addition, injury produced central axonal sprouting into different nerves that do not usually contain the injured neuron's axons. This could be important for (i) finding alternative pathways to the periphery when the original pathways are impassable and (ii) the formation of additional synaptic connections with post-synaptic targets which would further enhance the signalling effectiveness of the injured cell. ^

Exercise for osteoarthritis of the hip.

BACKGROUND Current international treatment guidelines recommending therapeutic exercise for people with symptomatic hip osteoarthritis (OA) report are based on limited evidence. OBJECTIVES To determine whether land-based therapeutic exercise is beneficial for people with hip OA in terms of reduced joint pain and improved physical function and quality of life. SEARCH METHODS We searched five databases from inception up to February 2013. SELECTION CRITERIA All randomised controlled trials (RCTs) recruiting people with hip OA and comparing some form of land-based therapeutic exercise (as opposed to exercises conducted in water) with a non-exercise group. DATA COLLECTION AND ANALYSIS Four review authors independently selected studies for inclusion. We resolved disagreements through consensus. Two review authors independently extracted data, assessed risk of bias and the quality of the body of evidence for each outcome using the GRADE approach. We conducted analyses on continuous outcomes (pain, physical function and quality of life) and dichotomous outcomes (proportion of study withdrawals). MAIN RESULTS We considered that seven of the 10 included RCTs had a low risk of bias. However, the results may be vulnerable to performance and detection bias as none of the RCTs were able to blind participants to treatment allocation and, while most RCTs reported blinded outcome assessment, pain, physical function and quality of life were participant self reported. One of the 10 RCTs was only reported as a conference abstract and did not provide sufficient data for the evaluation of bias risk.High-quality evidence from nine trials (549 participants) indicated that exercise reduced pain (standardised mean difference (SMD) -0.38, 95% confidence interval (CI) -0.55 to -0.20) and improved physical function (SMD -0.38, 95% CI -0.54 to -0.05) immediately after treatment. Pain and physical function were estimated to be 29 points on a 0- to 100-point scale (0 was no pain or loss of physical function) in the control group; exercise reduced pain by an equivalent of 8 points (95% CI 4 to 11 points; number needed to treat for an additional beneficial outcome (NNTB) 6) and improved physical function by an equivalent of 7 points (95% CI 1 to 12 points; NNTB 6). Only three small studies (183 participants) evaluated quality of life, with overall low quality evidence, with no benefit of exercise demonstrated (SMD -0.07, 95% CI -0.23 to 0.36). Quality of life was estimated to be 50 points on a norm-based mean (standard deviation (SD)) score of 50 (10) in the general population in the control group; exercise improved quality of life by 0 points. Moderate-quality evidence from seven trials (715 participants) indicated an increased likelihood of withdrawal from the exercise allocation (event rate 6%) compared with the control group (event rate 3%), but this difference was not significant (risk difference 1%; 95% CI -1% to 4%). Of the five studies reporting adverse events, each study reported only one or two events and all were related to increased pain attributed to the exercise programme.The reduction in pain was sustained at least three to six months after ceasing monitored treatment (five RCTs, 391 participants): pain (SMD -0.38, 95% CI -0.58 to -0.18). Pain was estimated to be 29 points on a 0- to 100-point scale (0 was no pain) in the control group, the improvement in pain translated to a sustained reduction in pain intensity of 8 points (95% CI 4 to 12 points) compared with the control group (0 to 100 scale). The improvement in physical function was also sustained (five RCTs, 367 participants): physical function (SMD -0.37, 95% CI -0.57 to -0.16). Physical function was estimated to be 24 points on a 0- to 100-point scale (0 was no loss of physical function) in the control group, the improvement translated to a mean of 7 points (95% CI 4 to 13) compared with the control group.Only five of the 10 RCTs exclusively recruited people with symptomatic hip OA (419 participants). There was no significant difference in pain or physical function outcomes compared with five studies recruiting participants with hip or knee OA (130 participants). AUTHORS' CONCLUSIONS Pooling the results of these 10 RCTs demonstrated that land-based therapeutic exercise programmes can reduce pain and improve physical function among people with symptomatic hip OA.

Studies on behavioral regulations of morphine tolerance in rats

Opioids remain the drugs of choice in chronic pain treatment, but opioid tolerance, defined as a decrease in analgesic effect after prolonged or repeated use, dramatically limits their clinical utility. Opioid tolerance has classically been studied by implanting spinal catheters in animals for drug administration. This procedure has significant morbidity and mortality, as well as causing an inflammatory response which decreases the potency of opioid analgesia and possibly affects tolerance development. Therefore, we developed and validated a new method, intermittent lumbar puncture (Dautzenberg et al.), for the study of opioid analgesia and tolerance. Using this method, opioid tolerance was reliably induced without detectable morbidity. The dose of morphine needed to induce analgesia and tolerance using this method was about 100-fold lower than that required when using an intrathecal catheter. Only slight inflammation was found at the injection site, dissipated within seven mm. ^ DAMGO, an opioid μ receptor agonist, has been reported to inhibit morphine tolerance, but results from different studies are inconclusive. We evaluated the effect of DAMGO on morphine tolerance using our newly-developed ILP method, as well as other intrathecal catheter paradigms. We found that co-administration of sub-analgesic DAMGO with morphine using ILP did not inhibit morphine tolerance, but instead blocked the analgesic effects of morphine. Tolerance to morphine still developed. Tolerance to morphine can only be blocked by sub-analgesic dose of DAMGO when administered in a lumbar catheter, but not in cervical catheter settings. ^ Finally, we evaluated the effects of Gabapentin (GBP) on analgesia and morphine tolerance. We demonstrated that GBP enhanced analgesia mediated by both subanalgesic and analgesic doses of morphine although GBP itself was not analgesic. GBP increased potency and efficacy of morphine. GBP inhibited the expression, but not the development, of morphine tolerance. GBP blocked tolerance to analgesic morphine but not to subanalgesic morphine. GBP reversed the expression of morphine tolerance even after tolerance was established. These studies may begin to provide new insights into mechanisms of morphine tolerance development and improve clinical chronic pain management. ^

Why does low dose morphine augment fentanyl analgesia?

Opioids dominate the field of pain management because of their ability to provide analgesia in many medical circumstances. However, side effects including respiratory depression, constipation, tolerance, physical dependence, and the risk of addiction limit their clinical utility. Fear of these side effects results in the under-treatment of acute pain. For many years, research has focused on ways to improve the therapeutic index (the ratio of desirable analgesic effects to undesirable side effects) of opioids. One strategy, combining opioid agonists that bind to different opioid receptor types, may prove successful.^ We discovered that subcutaneous co-administration of a moderately analgesic dose of the mu-opioid receptor (MOR) selective agonist fentanyl (20μg/kg) with subanalgesic doses of the less MOR-specific agonist morphine (100ng/kg-100μg/kg), augmented acute fentanyl analgesia in rats. Parallel [35S]GTPγS binding studies using naïve rat substantia gelatinosa membrane treated with fentanyl (4μM) and morphine (1nM-1pM) demonstrated a 2-fold increase in total G-protein activation. This correlation between morphine-induced augmentation of fentanyl analgesia and G-protein activation led to our proposal that interactions between MORs and DORs underlie opioid-induced augmentation. We discovered that morphine-induced augmentation of fentanyl analgesia and G-protein activity was mediated by DORs. Adding the DOR-selective antagonist naltrindole (200ng/kg, 40nM) at doses that did not alter the analgesic or G-protein activation of fentanyl, blocked increases in analgesia and G-protein activation induced by fentanyl/morphine combinations. Equivalent doses of the MOR-selective antagonist cyprodime (20ng/kg, 4nM) did not block augmentation. Substitution of the DOR-selective agonist SNC80 for morphine yielded similar results, further supporting our conclusion that interactions between MORs and DORs are responsible for morphine-induced augmentation of fentanyl analgesia and G-protein activation. Confocal microscopy of rat substantia gelatinosa showed that changes in the rate of opioid receptor internalization did not account for these effects.^ In conclusion, fentanyl analgesia augmentation by subanalgesic morphine is mediated by increased G-protein activation resulting from functional interactions between MORs and DORs, not changes in MOR internalization. Additional animal and clinical studies are needed to determine whether side effect incidence changes following opioid co-administration. If side effect incidence decreases or remains unchanged, these findings could have important implications for clinical pain treatment. ^

Recovery from Pediatric Brain Injury: A Preliminary Comparison of Longitudinal Data on Psychological Symptomology and Mental Health Treatment

Objective: To document the course of psychological symptomology, mental health treatment, and unmet psychological needs using caregiver reports in the first 18 months following pediatric brain injury (BI). Method: Participants included 28 children (aged 1-18 years) who were hospitalized at a children's hospital's rehabilitation unit. Caregiver reports of children's psychological symptoms, receipt of mental health treatment, and unmet psychological needs were assessed at one month, six months, 12 months, and 18 months post-BI. Results: Caregivers reported a general increase in psychological symptoms and receipt of mental health treatment over the 18 months following BI; however, there was a substantial gap between the high rate of reported symptoms and low rate of reported treatment. Across all four follow-up time points there were substantial unmet psychological needs (at least 60% of sample). Conclusions: Findings suggest that there are substantial unmet psychological needs among children during the first 18 months after BI. Barriers to mental health treatment for this population need to be addressed.

Analgesia epidural no tratamento da dor oncológica : caso clínico

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014