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Finnerup N.B.,University of Aarhus | Attal N.,French Institute of Health and Medical Research | Attal N.,University of Versailles | Haroutounian S.,University of Washington | And 22 more authors.
The Lancet Neurology | Year: 2015

Background: New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis. Methods: Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fixed-effects Mantel-Haenszel method. Findings: 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r2 9·3%, p=0·009). Trial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2-8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5-9·4) for pregabalin; 7·2 (5·9-9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4-19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, final quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These findings permitted a strong recommendation for use and proposal as first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only. Interpretation: Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling probably account for moderate trial outcomes and should be taken into account in future studies. Funding: NeuPSIG of the International Association for the Study of Pain. © 2015 Elsevier Ltd.


Wrigley P.J.,University of Sydney | Gustin S.M.,University of Sydney | McIndoe L.N.,University of Sydney | Chakiath R.J.,University of Sydney | And 3 more authors.
Pain | Year: 2013

Neuropathic pain remains one of the most difficult consequences of spinal cord injury (SCI) to manage. It is a major cause of suffering and adds to the physical, emotional, and societal impact of the injury. Despite the use of the best available treatments, two thirds of people experiencing neuropathic pain after SCI do not achieve satisfactory pain relief. This study was undertaken in response to a recent clinical trial reporting short-term, clinically significant reductions in neuropathic SCI pain with primary motor cortex transcranial direct current stimulation (tDCS). In this investigation, we aimed to build on this previous clinical trial by extending the assessment period to determine the short-, medium-, and long-term efficacy of tDCS for the treatment of neuropathic pain after SCI. We found that, contrary to previous reports, after 5 tDCS treatment periods, mean pain intensity and unpleasantness rating were not significantly different from initial assessment. That is, in this trial tDCS did not provide any pain relief in subjects with neuropathic SCI pain (n = 10). A similar lack of effect was also seen after sham treatment. Because the injury duration in this study was significantly greater than that of previous investigations, it is possible that tDCS is an effective analgesic only in individuals with relatively recent injuries and pain. Future investigations comparing a range of injury durations are required if we are to determine whether this is indeed the case. © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.


Garland E.M.,Vanderbilt University | Hooper W.B.,Greenwich Hospital | Robertson D.,Vanderbilt University
Handbook of Clinical Neurology | Year: 2013

A 1925 report by Bradbury and Eggleston first described patients with extreme orthostatic hypotension and a low, steady heart rate. Evidence accumulated over the next two decades that patients with orthostatic hypotension include those with pure autonomic failure (PAF), characterized by isolated peripheral autonomic dysfunction and decreased norepinephrine synthesis; multiple system atrophy (MSA) with symptoms of a central Parkinson-like syndrome and normal resting plasma norepinephrine; and Parkinson's disease (PD), with lesions in postganglionic noradrenergic neurons and signs of autonomic dysfunction. All three disorders are classified as α-synucleinopathies. Insoluble deposits of α-synuclein are found in glia in MSA, whereas they take the form of neuronal cytoplasmic inclusions called Lewy bodies in PAF and PD. The exact relationship between α-synuclein deposits and the pathology remains undetermined.PAF occurs sporadically, and progresses slowly with a relatively good prognosis. However, it has been proposed that some cases of PAF may develop a central neurodegenerative disorder. Differentiation between PAF, MSA, and PD with autonomic failure can be facilitated by a number of biochemical and functional tests and by imaging studies. Cardiac sympathetic innervation is generally intact in MSA but decreased or absent in Parkinson's disease with autonomic failure and PAF.Treatment of PAF is directed at relieving symptoms with nonpharmacological interventions and with medications producing volume expansion and vasoconstriction. Future studies should focus on determining the factors that lead to central rather than solely peripheral neurodegeneration. © 2013 Elsevier B.V.


Sabetta J.R.,Yale University | Sabetta J.R.,Greenwich Hospital | Depetrillo P.,Wake forest University | Cipriani R.J.,Greenwich Hospital | And 3 more authors.
PLoS ONE | Year: 2010

Background: Declining serum concentrations of 25-hydroxyvitamin D seen in the fall and winter as distance increases from the equator may be a factor in the seasonal increased prevalence of influenza and other viral infections. This study was done to determine if serum 25-hydroxyvitamin D concentrations correlated with the incidence of acute viral respiratory tract infections. Methodology/Findings: In this prospective cohort study serial monthly concentrations of 25-hydroxyvitamin D were measured over the fall and winter 2009-2010 in 198 healthy adults, blinded to the nature of the substance being measured. The participants were evaluated for the development of any acute respiratory tract infections by investigators blinded to the 25-hydroxyvitamin D concentrations. The incidence of infection in participants with different concentrations of vitamin D was determined. One hundred ninety-five (98.5%) of the enrolled participants completed the study. Light skin pigmentation, lean body mass, and supplementation with vitamin D were found to correlate with higher concentrations of 25-hydroxyvitamin D. Concentrations of 38 ng/ml or more were associated with a significant (p<0.0001) two-fold reduction in the risk of developing acute respiratory tract infections and with a marked reduction in the percentages of days ill. Conclusions/Significance: Maintenance of a 25-hydroxyvitamin D serum concentration of 38 ng/ml or higher should significantly reduce the incidence of acute viral respiratory tract infections and the burden of illness caused thereby, at least during the fall and winter in temperate zones. The findings of the present study provide direction for and call for future interventional studies examining the efficacy of vitamin D supplementation in reducing the incidence and severity of specific viral infections, including influenza, in the general population and in subpopulations with lower 25-hydroxyvitamin D concentrations, such as pregnant women, dark skinned individuals, and the obese. © 2010 Sabetta et al.


Keall R.,University of Sydney | Clayton J.M.,Greenwich Hospital | Butow P.,University of Sydney
Journal of Clinical Nursing | Year: 2014

Aims and objectives: To investigate the facilitators, barriers and strategies that Australian palliative care nurses identify in providing existential and spiritual care for patients with life-limiting illnesses. Background: Palliative care aims to be holistic, incorporating all domains of personhood, but spiritual/existential domain issues are often undertreated. Lack of time and skills and concerns for what you may uncover hamper care provision. Design: A qualitative study through semistructured interviews. Methods: We interviewed 20 palliative care nurses from a cross section of area of work, place of work, years of experience, spiritual beliefs and importance of those beliefs within their lives. Questions focused on their current practices of existential and spiritual care, identification of facilitators of, barriers to and strategies for provision of that care. Their responses were transcribed and subjected to thematic analysis. Results: The nurses' interviews yielded several themes including development of the nurse-patient relationship (14/20 nurses), good communication skills and examples of questions they use to 'create openings' to facilitate care. Barriers were identified as follows: lack of time (11/20 nurses), skills, privacy and fear of what you may uncover, unresolved symptoms and differences in culture or belief. Novel to our study, the nurses offered strategies that included the following: undertaking further education in this area, being self-aware and ensuring the setting is conducive to in-depth conversations and interactions and documentation and/or interdisciplinary sharing for continuity of care. Conclusion: Palliative care nurses are well placed to provide existential and spiritual care to patients with the primary facilitator being the nurse-patient relationship, the primary barrier being lack of time and the primary strategy being undertaking further education in this area. Relevance to clinical practice: These findings could be used for nurse-support programmes, undergraduate or graduate studies or communication workshop for nurses. © 2014 John Wiley & Sons Ltd.


Best M.,University of Sydney | Best M.,Greenwich Hospital | Butow P.,University of Sydney | Olver I.,Cancer Council Australia
Supportive Care in Cancer | Year: 2014

Purpose: Spiritual care is reported as important for cancer patients, but the role of the doctor in its provision is unclear. We undertook to understand the nature of spiritual support for Australian cancer patients and their preferences regarding spiritual care from doctors. Methods: Using grounded theory, semistructured interviews were conducted with 15 cancer patients with advanced disease in a variety of care settings. Patients were asked about the source of their spiritual support and how they would like their doctors to engage with them on spiritual issues. Results: Three themes were identified as follows: (1) sources of spiritual support which helped patients cope with illness and meet spiritual needs, (2) facilitators of spiritual support, and (3) role of the doctor in spiritual support. Regardless of religious background, the majority of patients wanted their doctor to ask about their source of spiritual support and facilitate access to it. Patients did not want spiritual guidance from their doctors, but wanted to be treated holistically and to have a good relationship, which allowed them to discuss their fears. Doctors' understanding of the spiritual dimension of the patient was part of this. Conclusions: Spirituality is a universal phenomenon. Patients in a secular society want their doctor to take an interest in their spiritual support and facilitate access to it during illness. © 2013 Springer-Verlag.


Walczak A.,University of Sydney | Butow P.N.,University of Sydney | Bu S.,University of Sydney | Clayton J.M.,University of Sydney | Clayton J.M.,Greenwich Hospital
Patient Education and Counseling | Year: 2016

Objective: To identify and synthesise evidence for interventions targeting end-of-life communication. Methods: Database, reference list and author searches were conducted to identify evaluations of end-of-life communication-focussed interventions. Data were extracted, synthesised and QUALSYST quality analyses were performed. Results: Forty-five studies met inclusion criteria. Interventions targeted patients (n = 6), caregivers (n = 3), healthcare professionals (HCPs n = 24) and multiple stakeholders (n = 12). Interventions took various forms including communication skills training, education, advance care planning and structured practice changes. Substantial heterogeneity in study designs, outcomes, settings and measures was apparent and study quality was variable. Conclusion: A substantial number of end-of-life communication interventions have been evaluated. Interventions have particularly targeted HCPs in cancer settings, though patient, caregiver and multi-focal interventions have also been evaluated. While some interventions were efficacious in well-designed RCTs, most evidence was from less robust studies. While additional interventions targeting patients and caregivers are needed, multi-focal interventions may more effectively remove barriers to end-of-life communication. Practice Implications: Despite the limitations evident in the existing literature, healthcare professionals may still derive useful insights into effective approaches to end-of-life communication if appropriate caution is exercised. However, additional RCTs, implementation studies and cost-benefit analyses are required to bolster arguments for implementing and resourcing communication interventions. © 2015 Elsevier Ireland Ltd.


DeLong A.K.,Brown University | Blossom B.,Colorado State University | Maloney E.L.,Partnership for Healing and Health Ltd. | Phillips S.E.,Greenwich Hospital
Contemporary Clinical Trials | Year: 2012

Introduction: Lyme disease (Lyme borreliosis) is caused by the tick-borne spirochete Borrelia burgdorferi. Long-term persistent illness following antibiotic treatment is not uncommon, particularly when treatment is delayed. Current treatment guidelines for persistent disease primarily rely on findings from four randomized, controlled trials (RCTs), strongly advising against retreatment. Methods: We performed a biostatistical review of all published RCTs evaluating antibiotic retreatment, focusing on trial design, analysis and conclusions. Results: Four RCTs met the inclusion criteria; all examined the efficacy of intravenous ceftriaxone versus placebo at approximately 3 or 6. months. Design assumptions for the primary outcomes in the two Klempner trials and two outcomes in the Krupp trial were unrealistic and the trials were likely underpowered to detect clinically meaningful treatment effects. The Klempner trials were analyzed using inefficient statistical methods. The Krupp RCT was well-designed and analyzed for fatigue, finding statistically significant and clinically meaningful improvement. Fallon corroborated this finding. Fallon also found improvement in cognitive functioning, a primary outcome, at 12. weeks which was not sustained at 24. weeks; improvements in physical functioning and pain were demonstrated at week 24 as an interaction effect between treatment and baseline symptom severity with the drug effect increasing with higher baseline impairment. Discussion: This biostatistical review reveals that retreatment can be beneficial. Primary outcomes originally reported as statistically insignificant were likely underpowered. The positive treatment effects of ceftriaxone are encouraging and consistent with continued infection, a hypothesis deserving additional study. Additional studies of persistent infection and antibiotic treatment are warranted. © 2012 Elsevier Inc.


Best M.,Greenwich Hospital | Best M.,University of Sydney | Butow P.,University of Sydney | Olver I.,Cancer Council Australia
Palliative Medicine | Year: 2014

Results: Patients were observed to be along a spectrum between having peace and not having peace. Features of the two extreme positions are described. Doctors could facilitate peace by developing a good relationship with cancer patients and supplying clear and honest information about what patients could expect as they approached their death.Conclusion: Spiritual well-being in cancer patients can be promoted by communication from doctors regarding prognosis, which allows them time to prepare for death, and recognition of their fears. However, acceptance of death does not always lead to the patient experiencing peace.Background: Being at peace is important for the quality of life of dying cancer patients, but its features, and the role of the doctor in facilitating peace, are unclear.Aim: We sought to understand the features of a peaceful patient, and patients' preferences regarding the role of the doctor in facilitating a sense of peace.Design: A grounded theory approach was used with semi-structured interviews. Patients were asked about the things that gave their life meaning and a sense of peace and how the doctor could support their spiritual well-being. Patients were also questioned about their concerns for their future.Setting/participants: In total, 15 cancer patients with advanced disease were interviewed in a variety of care settings. © The Author(s) 2014.


Katz L.D.,Yale University | Lindskog D.,Yale University | Eisen R.,Yale University | Eisen R.,Greenwich Hospital
Journal of Bone and Joint Surgery - Series B | Year: 2011

We describe a 23-year-old woman with neuritis ossificans involving the tibial, common peroneal and lateral sural nerves. She presented with chronic debilitating posterior knee pain. An MRI scan showed masses in these nerves, biopsy of which revealed a histological diagnosis of neuritis ossificans. Treatment with OxyContin and Neurotin for two years resulted in resolution of symptoms. Follow-up MRI demonstrated a resolution of two of the three masses. There was a persistent area of ossification without associated oedema in the common peroneal nerve. Neuritis ossificans has the histological appearance of myositis ossificans and follows a similar clinical course. The success of conservative treatment in this case suggests that the potential complications of surgical excision can be avoided. ©2011 British Editorial Society of Bone and Joint Surgery.

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