Systematic review of management of chronic pain after surgery.

BACKGROUND: Pain present for at least 3 months after a surgical procedure is considered chronic postsurgical pain (CPSP) and affects 10-50 per cent of patients. Interventions for CPSP may focus on the underlying condition that indicated surgery, the aetiology of new-onset pain or be multifactorial in recognition of the diverse causes of this pain. The aim of this systematic review was to identify RCTs of interventions for the management of CPSP, and synthesize data across treatment type to estimate their effectiveness and safety. METHODS: MEDLINE, Embase, PsycINFO, CINAHL and the Cochrane Library were searched from inception to March 2016. Trials of pain interventions received by patients at 3 months or more after surgery were included. Risk of bias was assessed using the Cochrane risk-of-bias tool. RESULTS: Some 66 trials with data from 3149 participants were included. Most trials included patients with chronic pain after spinal surgery (25 trials) or phantom limb pain (21 trials). Interventions were predominantly pharmacological, including antiepileptics, capsaicin, epidural steroid injections, local anaesthetic, neurotoxins, N-methyl-d-aspartate receptor antagonists and opioids. Other interventions included acupuncture, exercise, postamputation limb liner, spinal cord stimulation, further surgery, laser therapy, magnetic stimulation, mindfulness-based stress reduction, mirror therapy and sensory discrimination training. Opportunities for meta-analysis were limited by heterogeneity. For all interventions, there was insufficient evidence to draw conclusions on effectiveness. CONCLUSION: There is a need for more evidence about interventions for CPSP. High-quality trials of multimodal interventions matched to pain characteristics are needed to provide robust evidence to guide management of CPSP.

Persistent pain after knee replacement: do factors associated with pain vary with degree of patient dissatisfaction?

OBJECTIVE: Up to 20% of patients experience long-term pain and dissatisfaction following knee replacement. The aim of this study was to investigate factors associated with persistent pain following knee replacement and their implications for patient satisfaction. DESIGN: A case-controlled analysis compared patients with established persistent pain with patients who were pain-free. 2:1 frequency matching for age, gender, time from surgery and prosthesis was performed. 1310 patients were approached and 100 patients with persistent pain and 200 matched pain-free controls were included. Variables assessed included mechanical, biological, psychosocial and generalised factors. RESULTS: The study found that the degree of dissatisfaction experienced by the patient with persistent pain following knee replacement affected the factors associated with pain. In the most dissatisfied patients, pain was associated with instability in the coronal plane (OR 19.8, 95% CI 3.8-104.0), stiffness (OR 6.4, 95% CI 2.3-18.4) and negative social support (OR 3.3, 95% CI 1.1-10.0). In patients who were less dissatisfied, pain was associated with patellofemoral problems (OR 10.3, 95% CI 3.6-29.6), elevated BMI (OR 2.8, 95% CI 1.4-5.7) and reduced local pain thresholds (OR 4.4, 95% CI 2.0-9.6). Depression (OR 13.6, 95% CI 1.9-96.6) and presence of proximal tibial tenderness (OR 23.5 95% CI 7.8-70.7) were strongly associated with pain regardless of level of satisfaction. CONCLUSIONS: Patients with persistent pain after knee replacement are dissatisfied. This study identifies factors associated with the worst pain outcomes, which lead to the greatest levels of dissatisfaction. Particular efforts with a holistic multidisciplinary approach should be focused towards these "red flag" factors in order to minimise persistent pain after knee replacement.

Radiographic landmarks for tunnel placement in reconstruction of the medial patellofemoral ligament.

PURPOSE: To verify the findings of previous studies in confirming radiographic landmarks for the femoral attachment of the medial patellofemoral ligament (MPFL), but also to define radiographic landmarks for the patellar attachment. Assess the effect of limb rotation upon these radiographic landmarks. METHODS: The medial patellofemoral ligament was identified in ten fresh-frozen human cadaveric knees. A headed pin was used to mark the centre of the femoral and patellar attachments. True lateral radiographs were performed followed by lateral radiographs in 10° and 20° of internal and external rotation. Posterior-anterior and proximal-distal position of the headed pin was evaluated. RESULTS: The femoral attachment averaged 3.8 ± 5.0 mm anterior to the posterior femoral cortical line and 0.9 ± 2.4 mm distal to the perpendicular line intersecting the posterior aspect of Blumensaat's line. The patellar attachment averaged 7.4 ± 3.5 mm anterior to the posterior patellar cortical line, 5.4 ± 2.6 mm distal to the perpendicular line intersecting the proximal margin of the patellar articular surface. There was a significant relationship between limb rotation and distance of femoral and patellar attachment from the posterior cortical line (P < 0.0001 and P < 0.0002 respectively). CONCLUSION: Radiographic landmarks for the femoral attachment of the MPFL identified in this study are comparable with other recent work. This study describes new radiographic landmarks for the patellar attachment of the MPFL and highlights that it is essential to acquire true lateral radiographs if these radiographic landmarks are to be interpreted accurately.

Degeneration of neural cells in the central nervous system of mice deficient in the gene for the adhesion molecule on Glia, the beta 2 subunit of murine Na,K-ATPase.

We generated mice, null mutant in the adhesion molecule on glia (AMOG), the beta 2 subunit of the murine Na,K-ATPase gene. These mice exhibit motor incoordination at 15 d of age, subsequently tremor and paralysis of extremities, and die at 17-18 d after birth. At these ages, the mutants have enlarged ventricles, degenerating photoreceptor cells, and swelling and degeneration of astrocytic endfeet, leading to vacuoles adjoining capillaries of brain stem, thalamus, striatum, and spinal cord. In tissue homogenates from entire brains of 16-17-d-old mutants, Na,K-ATPase activity and expression of the beta 1 subunit of the Na,K-ATPase and of the neural adhesion molecules L1, N-CAM, and MAG appear normal. We suggest that the mutant phenotype can be related primarily to reduced pump activity, with neural degeneration as a possible consequence of osmotic imbalance.

An essential role for CD44 variant isoforms in epidermal Langerhans cell and blood dendritic cell function.

Upon antigen contact, epidermal Langerhans cells (LC) and dendritic cells (DC) leave peripheral organs and home to lymph nodes via the afferent lymphatic vessels and then assemble in the paracortical T cell zone and present antigen to T lymphocytes. Since splice variants of CD44 promote metastasis of certain tumors to lymph nodes, we explored the expression of CD44 proteins on migrating LC and DC. We show that upon antigen contact, LC and DC upregulate pan CD44 epitopes and epitopes encoded by variant exons v4, v5, v6, and v9. Antibodies against CD44 epitopes inhibit the emigration of LC from the epidermis, prevent binding of activated LC and DC to the T cell zones of lymph nodes, and severely inhibit their capacity to induce a delayed type hypersensitivity reaction to a skin hapten in vivo. Our results demonstrate that CD44 splice variant expression is obligatory for the migration and function of LC and DC.

The Wilms tumor suppressor gene wt1 is required for development of the spleen.

The Wilms tumor suppressor gene WT1 (wt1 in mouse) is unique among tumor suppressors because, in addition to its involvement in cancer [1] [2] and various other diseases [3] [4] [5] [6], it has an essential role in the development of certain organs. This is revealed by the phenotype of mice with inactivated wt1 alleles [7]. These animals exhibit a complete failure of kidney and gonad development as well as abnormalities of the heart and mesothelial structures. On a C57BL/6 genetic background, wt1(-/-) animals die between day 13.5 (E13.5) and 15.5 (E15.5) of embryonic development [7]. We report here that crossing of the wt1 mutation onto different mouse backgrounds delayed embryonic lethality until birth. In wt1(-/-) mice on these different genetic backgrounds, we observed a dramatic failure of spleen development, in addition to the well characterized phenotypic abnormalities. The spleen anlage formed at around E12 to E13 and involuted by the E15 stage, before the invasion of hematopoietic cells. The absence of proper spleen development in these wt1(-/-) embryos correlated with enhanced apoptosis in the primordial spleen cells. The expression of hox11, a gene that also controls development of the spleen [8] [9], was not altered by the inactivation of wt1. In situ hybridization revealed that the two genes are regulated independently. These findings demonstrate that the penetrance of the wt1(-/-) phenotype depends on the existence of one or more modifier gene(s) and that wt1 plays a pivotal role in the development of the spleen, thereby extending its role in organogenesis.

The casualty profile from the Reading train crash, November 2004: proposals for improved major incident reporting and the application of trauma scoring systems.

OBJECTIVE: To report the casualty profile of the major incident at the Royal Berkshire Hospital, Reading, following the Ufton Nervet Train crash, November 2004. To make further proposals regarding major incident reporting and implementation of trauma-scoring systems. METHOD: Retrospective analysis of emergency department and hospital notes. Calculation of index Injury Severity Score (ISS) and Trauma and Injury Severity Score (TRISS) in all patients. RESULTS: Of 61 casualties, the majority (74%) were seen in the minors area of our emergency department with a mixture of blunt impact and penetrating glass injuries. One died and 16 were admitted. 10% had an ISS >16. All surviving patients had a TRISS predicted probability of survival >90%. CONCLUSION: We propose mandatory major incident reporting within 6 months of a major incident to aid development of a national database. As previously proposed, this will aid education and facilitate future major incident planning. We further propose the widespread use of trauma scoring systems to facilitate comparative analysis between major incidents, perhaps extrapolating this to develop a major incident score.

Inhibition of MT-450 rat mammary tumour growth by antibodies recognising subtypes of blood group antigen B.

Using subtractive immunization to identify cell surface epitopes expressed in a metastasis-specific fashion on cells of the rat MT-W9 mammary carcinoma model, we generated a monoclonal antibody called M-N#1. This antibody binds specifically to metastasizing cells of the MT-W9 series and also to certain other metastasizing rat mammary carcinoma cell lines. We demonstrate that the M-N#1 antibody recognizes a fucosylated N-glycosyl sugar modification, and furthermore show that the epitope specificity of the M-N#1 antibody is for blood group antigen B subtypes 2, 3 and 4 with slight cross-reactivity with blood group antigen A subtype 2. The expression of these carbohydrate epitopes on MT-450 cells is functionally important, because the M-N#1 antibody efficiently inhibits MT-450 tumour growth in spontaneous metastasis assays. These results suggest that expression of the subtypes of blood group antigen B recognized by the M-N#1 antibody does not directly participate in the metastatic cascade but rather confers a growth or survival advantage on the tumour cells.

Interdomain binding mediates tumor growth suppression by the NF2 gene product.

The neurofibromatosis 2 (NF2) tumor suppressor gene encodes an intracellular membrane-associated protein, called merlin (or schwannomin), that belongs to the band 4.1 family of cytoskeleton-associated proteins. Inactivating NF2 mutations occur in several sporadic tumor types and have been linked to the NF2 disease, whose hallmark is the development of bilateral Schwann cell tumors (schwannomas) of the eighth cranial nerve. Two major alternatively spliced NF2 variants are expressed in normal tissues: 'NF2-17' lacking exon 16 and 'NF2-16' that contains exon 16 and encodes a merlin protein truncated at the C-terminus. We report that overexpression of NF2-17 in rat schwannoma cells inhibits their growth in vitro and in vivo, while NF2-16 fails to influence schwannoma growth. Tumor growth inhibition by merlin depends on an interdomain association occurring either in cis or in trans between the N- and C-termini. This association does not occur in the truncated NF2-16 protein nor in a mutant NF2-17 protein lacking C-terminal sequences. These data indicate that merlin has a unique mechanism of tumor suppression, inhibiting cell proliferation via self-association.

Soluble CD44 inhibits melanoma tumor growth by blocking cell surface CD44 binding to hyaluronic acid.

Proteolytic cleavage of the extracellular domain of CD44 from the surface of cells has been observed recently in different cell types. In cell culture supernatants of human melanoma cell lines a 70 kDa soluble CD44 protein (solCD44) was detected at concentrations of 250-300 ng/ml. Protease inhibitor studies revealed that serine proteases and metalloproteases are involved in the cleavage of CD44 from the surface of melanoma cells. To analyse a possible function of soluble CD44 a human malignant melanoma cell line was stably transfected with cDNAs encoding either wild type soluble CD44s or mutated forms with defective HA binding properties (CD44sR41A and CD44sR150A/R154A). Soluble CD44s almost completely inhibited hyaluronic acid binding by melanoma cells, whereas soluble CD44 mutated in the HA binding domain had no effect. When cultivated on hyaluronic acid, melanoma cell proliferation was induced by 30% for both the parental and the control transfected cells. This increase in proliferation was blocked completely in solCD44s-secreting transfectants, whereas solCD44sR41A and solCD44sR150A/R154A-secreting cells again showed hyaluronic acid-induced cell proliferation. These cell lines were subcutaneously injected into MF1 nu/nu mice to compare their growth as tumors in vivo. Compared to tumors derived from parental and control transfected cells, we observed a dramatic reduction of primary tumor growth with solCD44s expressing MM cells. Transfectants expressing solCD44s mutated in the HA binding domain in contrast developed fast-growing primary tumors. These results provide strong evidence that direct solCD44 interactions with hyaluronic acid interfere competitively with processes induced by hyaluronic acid binding to surface CD44. Autocrine, or drug-induced secretion of solCD44 by human melanoma cells may thus exert potent antitumoral effects in vivo.

Induction of tumour hypoxia by a vasoactive agent. A combined NMR and radiobiological study.

The effect of hydralazine treatment on 3 murine tumours (RIF-1, KHT and 16/C) was monitored using 31P-NMR. Changes in the 31P-NMR spectrum are compared with measurements of radiobiological hypoxic fraction (RHF) in the RIF-1 and KHT. Hydralazine is known to reduce temporarily blood flow in experimental tumours, and thus cause a transient increase in the RHF to 100% (in RIF-1 and KHT). This correlates with a decline in energy status as measured by 31P-NMR (i.e. there was an increase in Pi in all three tumours). Time-course data from the RIF-1 and KHT tumours show that maintenance of anaesthesia prolongs the hypoxia induced by hydralazine.

Phase I study of intravenous 4-hydroxyanisole.

4-Hydroxyanisole is a depigmenting agent which has been shown to have activity against malignant melanoma when given intra-arterially in man. An intravenous dose escalation study has been carried out with the aim of obtaining maximum plasma concentrations in a 5 day schedule. 8 patients entered this study which was stopped because of drug toxicity after 3 patients had been treated at the third dose escalation of 15 g/m2. 2 patients had WHO grade 4 liver and one also grade 4 renal toxicity and another had grade 4 haemoglobin toxicity. Extrapolated plateau plasma levels between 112 and 860 mumol/l were obtained, which in vitro studies suggested would be cytotoxic. Hopefully, newer analogues will have a greater specificity for the melanin pathway with less toxicity.

Enhancement of the anti-tumor effect of melphalan in experimental mice by some vaso-active agents.

A comparison is made between the vaso-active agents hydralazine, nifedipine, and verapamil for their ability to increase the anti-tumor effectiveness of melphalan. Treatment of mice with hydralazine (5 mg/kg) 15 mins after melphalan increases by a factor of approximately 2.5 melphalan-induced delay in growth of either the RIF-1 or KHT tumors. Similar enhancements are obtained when measurement is made of the surviving fraction of tumor cells in vitro following treatment in vivo with hydralazine and melphalan. Further, tumor cell kill is also increased when nifedipine is administered with melphalan compared with the effect of melphalan alone. These enhanced effects are observed if the vaso-active agents are given before or after melphalan. Hydralazine (5 mg/kg) induces close to 100% radiobiological hypoxia in the RIF-1 and KHT tumors. In contrast, Nifedipine has no effect on tumor hypoxic fraction at a dose of 10 mg/kg although the anti-tumor effectiveness of melphalan is substantially increased. However, a higher dose of 50 mg/kg nifedipine causes a large increase in tumor hypoxic fraction, an effect that persists for several hours. Verapamil causes no change in the fraction of hypoxic cells in the KHT tumor and increases, only slightly, the anti-tumor effect of melphalan.

Induction of tumour hypoxia post-irradiation: a method for increasing the sensitizing efficiency of misonidazole and RSU 1069 in vivo.

It is known that hydralazine can decrease blood flow to experimental murine tumours. A consequence of this, in the KHT sarcoma, is the induction of close to 100 per cent radiobiological hypoxia, which lasts for nearly 2 h following i.v. injection of 5 mg/kg hydralazine to the mouse. This phenomenon is exploitable in order to increase the apparent sensitizing efficiency of the nitroheterocyclic radiosensitizers, misonidazole and RSU 1069, and is demonstrated using the treatment schedule: sensitizer----60 min----X-rays----1 min----hydralazine. Such a strategy will first take advantage of the radiosensitizing properties of the nitroimidazole, then after irradiation the hydralazine should allow expression of the differential toxicity towards hypoxic cells known to occur with misonidazole and RSU 1069. Misonidazole gives an enhancement ratio (ER) of 1.3 at 100 mg/kg, rising to 2.0 at 1000 mg/kg. Where hydralazine is given after irradiation, no additional cell kill is observed with 1000 mg/kg. In contrast, at lower doses of misonidazole, hydralazine induces a substantial increase in cell killing such that the ER obtained with 100 mg/kg is the same as that achieved with 1000 mg/kg misonidazole when used alone with radiation. Similarly, 20 mg/kg RSU 1069 with radiation followed by hydralazine is equivalent to the radiosensitizing effect of 80 mg/kg RSU 1069 without hydralazine. In addition, doses of RSU 1069 that normally give no radiosensitization (5 or 10 mg/kg) produce substantial increases in cell killing when combined with hydralazine.

The outcome at ten years of lateral closing-wedge high tibial osteotomy: determinants of survival and functional outcome.

The aim of this study was to examine the functional outcome at ten years following lateral closing wedge high tibial osteotomy for medial compartment osteoarthritis of the knee and to define pre-operative predictors of survival and determinants of functional outcome. 164 consecutive patients underwent high tibial osteotomy between 2000 and 2002. A total of 100 patients (100 knees) met the inclusion criteria and 95 were available for review at ten years. Data were collected prospectively and included patient demographics, surgical details, long leg alignment radiographs, Western Ontario and McMaster Universities osteoarthritis index (WOMAC) and Knee Society scores (KSS) pre-operatively and at five and ten years follow-up. At ten years, 21 patients had been revised at a mean of five years. Overall Kaplan-Meier survival was 87% (95% confidence interval (CI) 81 to 94) and 79% (95% CI 71 to 87) at five and ten years, respectively. When compared with unrevised patients, those who had been revised had significantly lower mean pre-operative WOMAC Scores (47 (21 to 85) vs 65 (32 to 99), p < 0.001), higher mean age (54 yrs (42 to 61) vs 49 yrs (26 to 66), p = 0.006) and a higher mean BMI (30.2; 25 to 39 vs 27.9; 21 to 36, p = 0.005). Each were found to be risk factors for revision, with hazard ratios of 10.7 (95% CI 4 to 28.6; pre-operative WOMAC < 45), 6.5 (95% CI 2.4 to 17.7; age > 55) and 3.0 (95%CI 1.2 to 7.6; BMI > 30). Survival of patients with pre-operative WOMAC > 45, age < 55 and BMI < 30 was 97% at five and ten years. WOMAC and KSS in surviving patients improved significantly between pre-operative (mean 61; 32 to 99) and five (mean 88; 35 to 100, p = 0.001) and ten years (mean 84; 38 to 100, p = 0.001). Older patients had better functional outcomes overall, despite their higher revision rate. This study has shown that improved survival is associated with age < 55 years, pre-operative WOMAC scores > 45 and, a BMI < 30. In patients over 55 years of age with adequate pre-operative functional scores, survival can be good and functional outcomes can be significantly better than their younger counterparts. We recommend the routine use of pre-operative functional outcome scores to guide decision-making when considering suitability for high tibial osteotomy.

Medial patellofemoral ligament reconstruction for patellar instability in patients with hypermobility: a case control study.

Hypermobility is an acknowledged risk factor for patellar instability. In this case control study the influence of hypermobility on clinical outcome following medial patellofemoral ligament (MPFL) reconstruction for patellar instability was studied. A total of 25 patients with hypermobility as determined by the Beighton criteria were assessed and compared with a control group of 50 patients who were matched for age, gender, indication for surgery and degree of trochlear dysplasia. The patients with hypermobility had a Beighton Score of ≥ 6; the control patients had a score of < 4. All patients underwent MPFL reconstruction performed using semitendinosus autograft and a standardised arthroscopically controlled technique. The mean age of the patients was 25 years (17 to 49) and the mean follow-up was 15 months (6 to 30). Patients with hypermobility had a significant improvement in function following surgery, with reasonable rates of satisfaction, perceived improvement, willingness to repeat and likelihood of recommendation. Functional improvements were significantly less than in control patients (p < 0.01). Joint hypermobility is not a contraindication to MPFL reconstruction although caution is recommended in managing the expectations of patients with hypermobility before consideration of surgery.

High-energy open tibial fractures in children: treatment with a programmable circular external fixator.

Between 2005 and 2010 ten consecutive children with high-energy open diaphyseal tibial fractures were treated by early reduction and application of a programmable circular external fixator. They were all male with a mean age of 11.5 years (5.2 to 15.4), and they were followed for a mean of 34.5 months (6 to 77). Full weight-bearing was allowed immediately post-operatively. The mean time from application to removal of the frame was 16 weeks (12 to 21). The mean deformity following removal of the frame was 0.15° (0° to 1.5°) of coronal angulation, 0.2° (0° to 2°) sagittal angulation, 1.1 mm (0 to 10) coronal translation, and 0.5 mm (0 to 2) sagittal translation. All patients achieved consolidated bony union and satisfactory wound healing. There were no cases of delayed or nonunion, compartment syndrome or neurovascular injury. Four patients had a mild superficial pin site infection; all settled with a single course of oral antibiotics. No patient had a deep infection or re-fracture following removal of the frame. The time to union was comparable with, or better than, other published methods of stabilisation for these injuries. The stable fixator configuration not only facilitates management of the accompanying soft-tissue injury but enables anatomical post-injury alignment, which is important in view of the limited remodelling potential of the tibia in children aged > ten years. Where appropriate expertise exists, we recommend this technique for the management of high-energy open tibial fractures in children.

Medial patellofemoral ligament reconstruction: a prospective outcome assessment of a large single centre series.

We report a prospective analysis of clinical outcome in patients treated with medial patellofemoral ligament (MPFL) reconstruction using an autologous semitendinosus graft. The technique includes superolateral portal arthroscopic assessment before and after graft placement to ensure correct graft tension and patellar tracking before fixation. Between October 2005 and October 2010, a total of 201 consecutive patients underwent 219 procedures. Follow-up is presented for 211 procedures in 193 patients with a mean age of 26 years (16 to 49), and mean follow-up of 16 months (6 to 42). Indications were atraumatic recurrent patellar dislocation in 141 patients, traumatic recurrent dislocation in 50, pain with subluxation in 14 and a single dislocation with persistent instability in six. There have been no recurrent dislocations/subluxations. There was a statistically significant improvement between available pre- and post-operative outcome scores for 193 patients (all p < 0.001). Female patients with a history of atraumatic recurrent dislocation and all patients with history of previous surgery had a significantly worse outcome (all p < 0.05). The indication for surgery, degree of dysplasia, associated patella alta, time from primary dislocation to surgery and evidence of associated cartilage damage at operation did not result in any significant difference in outcome. This series adds considerably to existing evidence that MPFL reconstruction is an effective surgical procedure for selected patients with patellofemoral instability.