Psychological interventions for symptomatic management of non-specific chest pain in patients with normal coronary anatomy.

BACKGROUND: Recurrent chest pain in the absence of coronary artery disease is a common problem which sometimes leads to excess use of medical care. Although many studies have examined the causes of pain in these patients, few clinical trials have evaluated treatment. This is an update of a Cochrane review originally published in 2005 and last updated in 2010. The studies reviewed in this paper provide an insight into the effectiveness of psychological interventions for this group of patients. OBJECTIVES: To assess the effects of psychological interventions for chest pain, quality of life and psychological parameters in people with non-specific chest pain. SEARCH METHODS: We searched the Cochrane Library (CENTRAL, Issue 4 of 12, 2014 and DARE Issue 2 of 4, 2014), MEDLINE (OVID, 1966 to April week 4 2014), EMBASE (OVID, 1980 to week 18 2014), CINAHL (EBSCO, 1982 to April 2014), PsycINFO (OVID, 1887 to April week 5 2014) and BIOSIS Previews (Web of Knowledge, 1969 to 2 May 2014). We also searched citation lists and contacted study authors. SELECTION CRITERIA: Randomised controlled trials (RCTs) with standardised outcome methodology that tested any form of psychotherapy for chest pain with normal anatomy. Diagnoses included non-specific chest pain (NSCP), atypical chest pain, syndrome X or chest pain with normal coronary anatomy (as either inpatients or outpatients). DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, extracted data and assessed quality of studies. We contacted trial authors for further information about the included RCTs. MAIN RESULTS: We included two new papers, one of which was an update of a previously included study. Therefore, a total of 17 RCTs with 1006 randomised participants met the inclusion criteria, with the one new study contributing an additional 113 participants. There was a significant reduction in reports of chest pain in the first three months following the intervention: random-effects relative risk = 0.70 (95% CI 0.53 to 0.92). This was maintained from three to nine months afterwards: relative risk 0.59 (95% CI 0.45 to 0.76). There was also a significant increase in the number of chest pain-free days up to three months following the intervention: mean difference (MD) 3.00 (95% CI 0.23 to 5.77). This was associated with reduced chest pain frequency (random-effects MD -2.26, 95% CI -4.41 to -0.12) but there was no evidence of effect of treatment on chest pain frequency from three to twelve months (random-effects MD -0.81, 95% CI -2.35 to 0.74). There was no effect on severity (random-effects MD -4.64 (95% CI -12.18 to 2.89) up to three months after the intervention. Due to the nature of the main interventions of interest, it was impossible to blind the therapists as to whether the participant was in the intervention or control arm. In addition, in three studies the blinding of participants was expressly forbidden by the local ethics committee because of issues in obtaining fully informed consent . For this reason, all studies had a high risk of performance bias. In addition, three studies were thought to have a high risk of outcome bias. In general, there was a low risk of bias in the other domains. However, there was high heterogeneity and caution is required in interpreting these results. The wide variability in secondary outcome measures made it difficult to integrate findings from studies. AUTHORS' CONCLUSIONS: This Cochrane review suggests a modest to moderate benefit for psychological interventions, particularly those using a cognitive-behavioural framework, which was largely restricted to the first three months after the intervention. Hypnotherapy is also a possible alternative. However, these conclusions are limited by high heterogeneity in many of the results and low numbers of participants in individual studies. The evidence for other brief interventions was less clear. Further RCTs of psychological interventions for NSCP with follow-up periods of at least 12 months are needed.

Using aggregated single patient (N-of-1) trials to determine the effectiveness of psychostimulants to reduce fatigue in advanced cancer patients: a rationale and protocol.

BACKGROUND: It is estimated that 29% of deaths in Australia are caused by malignant disease each year and can be expected to increase with population ageing. In advanced cancer, the prevalence of fatigue is high at 70-90%, and can be related to the disease and/or the treatment. The negative impact of fatigue on function (physical, mental, social and spiritual) and quality of life is substantial for many palliative patients as well as their families/carers. METHOD/DESIGN: This paper describes the design of single patient trials (n-of-1 s or SPTs) of a psychostimulant, methylphenidate hydrochloride (MPH) (5 mg bd), compared to placebo as a treatment for fatigue, with a population estimate of the benefit by the aggregation of multiple SPTs. Forty patients who have advanced cancer will be enrolled through specialist palliative care services in Australia. Patients will complete up to 3 cycles of treatment. Each cycle is 6 days long and has 3 days treatment and 3 days placebo. The order of treatment and placebo is randomly allocated for each cycle. The primary outcome is a reduction in fatigue severity as measured by the Functional Assessment of Cancer Therapy-fatigue subscale (FACIT-F). Secondary outcomes include adverse events, quality of life, additional fatigue assessments, depression and Australian Karnovsky Performance Scale. DISCUSSION: This study will provide high-level evidence using a novel methodological approach about the effectiveness of psychostimulants for cancer-related fatigue. If effective, the findings will guide clinical practice in reducing this prevalent condition to improve function and quality of life. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12609000794202.

Psychological interventions for symptomatic management of non-specific chest pain in patients with normal coronary anatomy.

BACKGROUND: Recurrent chest pain in the absence of coronary artery disease is a common problem that sometimes leads to excess use of medical care. Although many studies examine the causes of pain in these patients, few clinical trials have evaluated treatment. The studies reviewed in this paper provide an insight into the effectiveness of psychological interventions for this group of patients. OBJECTIVES: To update the previously published systematic review. SEARCH METHODS: We searched the Cochrane LIbrary (CENTRAL and DARE) (Issue 3 of 4 2011), MEDLINE (1966 to August Week 5, 2011), CINAHL (1982 to Sept 2011) EMBASE (1980 to Week 35 2011), PsycINFO (1887 to Sept Week 1, 2011), and Biological Abstracts (January 1980 to Sept 2011). We also searched citation lists and approached authors. SELECTION CRITERIA: Randomised controlled trials (RCTs) with standardised outcome methodology that tested any form of psychotherapy for chest pain with normal anatomy. Diagnoses included non-specific chest pain (NSCP), atypical chest pain, syndrome X, or chest pain with normal coronary anatomy (as either inpatients or outpatients). DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion, extracted data and assessed quality of studies. The authors contacted trial authors for further information about the RCTs included. MAIN RESULTS: Six new RCTs were located and added to the existing trials, therefore, a total of 15 RCTs (803 participants) were included. There was a significant reduction in reports of chest pain in the first three months following the intervention; fixed-effect relative risk = 0.68 (95% CI 0.57 to 0.81). This was maintained from three to nine months afterwards; relative risk = 0.59 (95% CI 0.45 to 0.76). There was also a significant increase in the number of chest pain free days up to three months following the intervention; mean difference = 2.81 (95% CI 1.28 to 4.34). This was associated with reduced chest pain frequency (random-effects mean difference = -2.26 95% CI -4.41 to -0.12) but there was no evidence of effect of treatment on chest pain frequency from three to twelve months (random-effects mean difference -0.81 95% CI -2.35, 0.74). There was no effect on severity (random-effects mean difference = -4.64 (95% CI -12.18 to 2.89) up to three months after the intervention. Overall there was generally a low risk of bias, however, there was high heterogeneity and caution is required in interpreting these results. Wide variability in outcome measures made integration of studies for secondary outcome measures difficult to report on. AUTHORS' CONCLUSIONS: This review suggests a modest to moderate benefit for psychological interventions, particularly those using a cognitive-behavioural framework, which was largely restricted to the first three months after the intervention. Hypnotherapy is also a possible alternative. The evidence for brief interventions was less clear. Further RCTs of psychological interventions for NSCP with follow-up periods of at least 12 months are needed.

Patient preferences for treatment of achilles tendon pain: results from a discrete-choice experiment.

BACKGROUND: Discrete-choice experiments are based on the premise that any good or service can be described by its characteristics (or attributes), and the extent to which an individual values a good or service depends on the levels of these characteristics. Little is known about patient preferences for treatment of chronic musculoskeletal pain such as Achilles tendinopathy. METHODS: A discrete-choice experiment was conducted in 58 adults with a history of Achilles tendon pain at the conclusion of a three-arm randomized clinical trial. Participants were asked to complete a questionnaire consisting of ten hypothetical treatment scenarios and some sociodemographic questions. For each scenario, participants were asked to choose which option they would prefer if seeking treatment for their painful Achilles tendon. A mixed logit model was estimated to quantify subject preferences and marginal willingness to pay for the treatment attributes. RESULTS: A response rate of 62% was achieved. A significant positive impact on utility was observed for chance of treatment success. A significant negative impact on utility was observed for cost, weeks before exercise can be completed free of pain, chance of side effects (p = 0.06), and injections as a stand-alone treatment. Respondents were willing to pay Australian dollars ($A)238 (95% CI -312, 788) for a 10% increase in the chance of treatment success. CONCLUSIONS: Study participants with Achilles tendon pain who had either participated or expressed an interest in participating in a randomized trial prefer a treatment that costs less, has a greater chance of success, has a shorter duration before being able to exercise free of pain, and has less likelihood of side effects. On average, participants preferred exercises over injections as a stand-alone treatment. Further research is required to confirm the findings in patients outside of the trial setting. Nevertheless, this study contributes to an area that is deficient in research by identifying priorities and marginal willingness to pay for attributes related to Achilles tendinopathy.

Prolotherapy injections and eccentric loading exercises for painful Achilles tendinosis: a randomised trial.

OBJECTIVE: To compare the effectiveness and cost-effectiveness of eccentric loading exercises (ELE) with prolotherapy injections used singly and in combination for painful Achilles tendinosis. DESIGN: A single-blinded randomised clinical trial. The primary outcome measure was the VISA-A questionnaire with a minimum clinically important change (MCIC) of 20 points. SETTING: Five Australian primary care centres. PARTICIPANTS: 43 patients with painful mid-portion Achilles tendinosis commenced and 40 completed treatment protocols. INTERVENTIONS: Participants were randomised to a 12-week program of ELE (n=15), or prolotherapy injections of hypertonic glucose with lignocaine alongside the affected tendon (n=14) or combined treatment (n=14). MAIN OUTCOME MEASUREMENTS: VISA-A, pain, stiffness and limitation of activity scores; treatment costs. RESULTS: At 12 months, proportions achieving the MCIC for VISA-A were 73% for ELE, 79% for prolotherapy and 86% for combined treatment. Mean (95% CI) increases in VISA-A scores at 12 months were 23.7 (15.6 to 31.9) for ELE, 27.5 (12.8 to 42.2) for prolotherapy and 41.1 (29.3 to 52.9) for combined treatment. At 6 weeks and 12 months, these increases were significantly less for ELE than for combined treatment. Compared with ELE, reductions in stiffness and limitation of activity occurred earlier with prolotherapy and reductions in pain, stiffness and limitation of activity occurred earlier with combined treatment. Combined treatment had the lowest incremental cost per additional responder ($A1539) compared with ELE. CONCLUSIONS: For Achilles tendinosis, prolotherapy and particularly ELE combined with prolotherapy give more rapid improvements in symptoms than ELE alone but long-term VISA-A scores are similar. TRIAL REGISTRATION NUMBER: ACTRN: 12606000179538.

Using N-of-1 trials to improve patient management and save costs.

BACKGROUND: N-of-1 trials test treatment effectiveness within an individual patient. OBJECTIVE: To assess (i) the impact of three different N-of-1 trials on both clinical and economic outcomes over 12 months and (ii) whether the use of N-of-1 trials to target patients' access to high-cost drugs might be cost-effective in Australia. DESIGN: Descriptive study of management change, persistence, and costs summarizing three N-of-1 trials. PARTICIPANTS: Volunteer patients with osteoarthritis, chronic neuropathic pain or ADHD whose optimal choice of treatment was uncertain. INTERVENTIONS: Double-blind cyclical alternative medications for the three conditions. MEASURES: Detailed resource use, treatment and health outcomes (response) data collected by postal and telephone surveys immediately before and after the trial and at 3, 6 and 12 months. Estimated costs to the Australian healthcare system for the pre-trial vs. 12 months post-trial. RESULTS: Participants persisting with the joint patient-doctor decision 12 months after trial completion were 32% for osteoarthritis, 45% for chronic neuropathic pain and 70% for the ADHD trials. Cost-offsets were obtained from reduced usage of non-optimal drugs, and reduced medical consultations. Drug costs increased for the chronic neuropathic pain and ADHD trials due to many patients being on either low-cost or no pharmaceuticals before the trial. CONCLUSIONS: N-of-1 trials are an effective method to identify optimal treatment in patients in whom disease management is uncertain. Using this evidence-based approach, patients and doctors tend to persist with optimal treatment resulting in cost-savings. N-of-1 trials are clinically acceptable and may be an effective way of rationally prescribing some expensive long-term medicines.

Stakeholders' views on the routine use of n-of-1 trials to improve clinical care and to make resource allocation decisions for drug use.

N-of-1 trials are empirical formal tests using a within-patient randomised, double-blind, cross-over comparison of drug and placebo (or another drug), which we adapted to study individual patients' responses as a clinical tool to guide clinical management. We administered semi-structured interviews to gauge stakeholder perspectives on the possibility of using routine n-of-1 trials for this purpose. Stakeholders included government and non-government health care sector, and patient, clinician and consumer, organisations. Stakeholders supported more widespread implementation of n-of-1 trials, in a targeted fashion, with some caveats. Barriers to their widespread implementation included constraints on doctors' time, doctors' acceptance, drug company acceptance, patient willingness, and cost. Strategies for overcoming barriers included conditional Pharmaceutical Benefits Scheme listing if cost-effective. There was little consensus on which model of n-of-1 trial implementation would be most effective. We discuss different approaches to addressing the several concerns raised to enable widespread introduction of n-of-1 trials into routine clinical practice as a decision tool.

Psychological interventions for symptomatic management of non-specific chest pain in patients with normal coronary anatomy.

BACKGROUND: Recurrent chest pain in the absence of coronary artery disease is a common problem that sometimes leads to excess use of medical care. Although many studies examine the causes of pain in these patients, few clinical trials have evaluated treatment. The studies reviewed in this paper provide an insight into the effectiveness of psychological interventions for this group of patients. OBJECTIVES: To investigate psychological treatments for non-specific chest pain (NSCP) with normal coronary anatomy. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2008, Issue 4), MEDLINE (1966 to December 2008), CINAHL (1982 to December 2008) EMBASE (1980 to December 2008), PsycINFO (1887 to December 2008), the Database of Abstracts of Reviews of Effectiveness (DARE) and Biological Abstracts (January 1980 to December 2008). We also searched citation lists and approached authors. SELECTION CRITERIA: Randomised controlled trials (RCTs) with standardised outcome methodology that tested any form of psychotherapy for chest pain with normal anatomy. Diagnoses included non-specific chest pain, atypical chest pain, syndrome X, or chest pain with normal coronary anatomy (as either inpatients or outpatients). DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion, extracted data and assessed quality of studies. The authors contacted trial authors for further information about the RCTs included. MAIN RESULTS: Ten RCTs (484 participants) were included. There was a significant reduction in reports of chest pain in the first three months following the intervention; fixed effects relative risk = 0.68 (95% CI 0.57 to 0.81). This was maintained from 3 to 9 months afterwards; relative risk = 0.59 (95% CI 0.45 to 0.76). There was also a significant increase in the number of chest pain free days up to three months following the intervention; mean difference = 2.81 (95% CI 1.28 to 4.34). This was associated with reduced chest pain frequency (mean difference = -1.73 (95% CI -2.21 to -1.26)) and severity (mean difference = -6.86 (95% CI -10.74 to -2.97)). However, there was high heterogeneity and caution is required in interpreting these results. Wide variability in outcome measures made integration of studies for secondary outcome measures difficult to report on. AUTHORS' CONCLUSIONS: This review suggests a modest to moderate benefit for psychological interventions, particularly those using a cognitive-behavioural framework, which was largely restricted to the first three months after the intervention. Hypnotherapy is also a possible alternative. The evidence for brief interventions was less clear. Further RCTs of psychological interventions for NSCP with follow-up periods of at least 12 months are needed.

N-of-1 randomized trials to assess the efficacy of gabapentin for chronic neuropathic pain.

OBJECTIVE: The objective of this study was to compare the efficacy of gabapentin with placebo for neuropathic pain at the individual and population levels. DESIGN: This study used an n-of-1 trial methodology with three double-blind, randomized, crossover comparisons of gabapentin with placebo. SETTING: This study was carried out at specialist outpatient clinics at two Australian hospitals. Patients. The patients are adults with chronic neuropathic pain. INTERVENTIONS: Following a dose-finding period, participants underwent three comparisons of 2-week periods on gabapentin (600-1,800 mg per day) and placebo. The dose-finding period was commenced by 112 patients, of whom 39 had no response so they did not enroll, leaving 73 trial participants. Of these, 48 completed and 7 partially completed their trials, and 18 withdrew. OUTCOME MEASURES: The five outcome measures were the visual analog scale (0-10) of pain, sleep interference and functional limitation; frequency of adverse events and medication preference. The aggregate response was determined by weighting the response to each measure equally. RESULTS: Of the 55 participants who completed at least one cycle, the aggregate response to gabapentin was better than placebo in 16 (29%), of whom 15 continued gabapentin posttrial. No difference was shown in 38 (69%), and 1 (2%) showed a better response to placebo. Fifteen of these 39 continued gabapentin posttrial. Meta-analysis of the mean scores showed lower mean (standard deviation) scores for gabapentin by 0.8 (0.2) for pain, 0.6 (0.2) for sleep interference, and 0.6 (0.2) for functional limitation. CONCLUSIONS: The response rate and mean reduction in symptoms with gabapentin were small. Gabapentin prescribing posttrial was significantly influenced by the trial results.

Are N-of-1 trials an economically viable option to improve access to selected high cost medications? The Australian experience.

OBJECTIVE: To explore the economic viability of N-of-1 trials for improving access to selected high cost medications in Australia. METHODS: Cost and effectiveness estimates were derived from two N-of-1 trials conducted by The University of Queensland from 2003 to 2005-celecoxib versus sustained-release paracetamol for osteoarthritis in a general practice setting and gabapentin versus placebo for chronic neuropathic pain in a hospital setting. Effectiveness was determined by the proportion of responders to each medication. The costs of trials were offset against the savings generated by subsequent changes in prescribing. Decision analysis models with semi-Markov processes were used to compare different scenarios of N-of-1 trials versus usual care. RESULTS: The fixed cost of performing N-of-1 trials was approximately AUS$23,000 for each trial and the variable cost was approximately AUS$1300 per participant. Clinical outcomes favored celecoxib over paracetamol in 17% of participants and gabapentin over placebo in 24% of participants. Modeling these results showed that the cost-offsets from efficient use of medications were less than the cost of running a trial; however, the incremental costs per quality-adjusted life-year gained were AUS$6,896 and AUS$29,550 for the gabapentin/placebo and celecoxib/paracetamol trials, respectively, over a 5-year horizon. Key factors affecting the viability were the time horizon modeled, the variable cost per participant, the probability of response to the intervention medication, and rates of use in nonresponders and the usual care alternative. CONCLUSIONS: The N-of-1 strategy offers a realistic and viable option for increasing access to selected high cost medications where the medications are used for the symptomatic treatment of chronic disease, have rapid onset of action, and clinical response is unpredictable without a trial.