Randomized open-label phase II study comparing oxycodone-naloxone with oxycodone in early return of gastrointestinal function after laparoscopic colorectal surgery.

BACKGROUND: Combined oral modified-release oxycodone-naloxone may reduce opioid-induced postoperative gut dysfunction. This study examined the feasibility of a randomized trial of oxycodone-naloxone within the context of enhanced recovery for laparoscopic colorectal resection. METHODS: In a single-centre open-label phase II feasibility study, patients received analgesia based on either oxycodone-naloxone or oxycodone. Primary endpoints were recruitment, retention and protocol compliance. Secondary endpoints included a composite endpoint of gut function (tolerance of solid food, low nausea/vomiting score, passage of flatus or faeces). RESULTS: Eighty-two patients were screened and 62 randomized (76 per cent); the attrition rate was 19 per cent (12 of 62), leaving 50 patients who received the allocated intervention with 100 per cent follow-up and retention (modified intention-to-treat cohort). Protocol compliance was more than 90 per cent. Return of gut function by day 3 was similar in the two groups: 13 (48 per cent) of 27 in the oxycodone-naloxone group and 15 (65 per cent) of 23 in the control group (95 per cent c.i. for difference -10·0 to 40·7 per cent; P = 0·264). However, patients in the oxycodone-naloxone group had a shorter time to first bowel movement (mean(s.d.) 87(38) h versus 111(37) h in the control group; 95 per cent c.i. for difference 2·3 to 45·4 h, P = 0·031) and reduced total (oral plus parenteral) opioid consumption (mean(s.d.) 78(36) versus 94(56) mg respectively; 95 per cent c.i. for difference -10·2 to 42·8 mg, P = 0·222). CONCLUSION: High participation, retention and protocol compliance confirmed feasibility. Potential benefits of oxycodone-naloxone in reducing time to bowel movement and total opioid consumption could be tested in a randomized trial. Registration number: NCT02109640 (https://www.clinicaltrials.gov/).

Patterns of treatment response in newly diagnosed epilepsy.

OBJECTIVE: To delineate the temporal patterns of outcome and to determine the probability of seizure freedom with successive antiepileptic drug regimens in newly diagnosed epilepsy. METHODS: Patients in whom epilepsy was diagnosed and the first antiepileptic drug prescribed between July 1, 1982, and April 1, 2006, were followed up until March 31, 2008. Outcomes were categorized into 4 patterns: (A) early and sustained seizure freedom; (B) delayed but sustained seizure freedom; (C) fluctuation between periods of seizure freedom and relapse; and (D) seizure freedom never attained. Probability of seizure freedom with successive drug regimens was compared. Seizure freedom was defined as no seizures for ≥1 year. RESULTS: A total of 1,098 patients were included (median age 32 years, range 9-93). At the last clinic visit, 749 (68%) patients were seizure-free, 678 (62%) on monotherapy. Outcome pattern A was observed in 408 (37%), pattern B in 246 (22%), pattern C in 172 (16%), and pattern D in 272 (25%) patients. There was a higher probability of seizure freedom in patients receiving 1 compared to 2 drug regimens, and 2 compared to 3 regimens (p < 0.001). The difference was greater among patients with symptomatic or cryptogenic than with idiopathic epilepsy. Less than 2% of patients became seizure-free on subsequent regimens but a few did so on their sixth or seventh regimen. CONCLUSIONS: Most patients with newly diagnosed epilepsy had a constant course which could usually be predicted early. The chance of seizure freedom declined with successive drug regimens, most markedly from the first to the third and among patients with localization-related epilepsies.

Developing a placebo-controlled trial in surgery: issues of design, acceptability and feasibility.

BACKGROUND: Surgical placebos are controversial. This in-depth study explored the design, acceptability, and feasibility issues relevant to designing a surgical placebo-controlled trial for the evaluation of the clinical and cost effectiveness of arthroscopic lavage for the management of people with osteoarthritis of the knee in the UK. METHODS: Two surgeon focus groups at a UK national meeting for orthopaedic surgeons and one regional surgeon focus group (41 surgeons); plenary discussion at a UK national meeting for orthopaedic anaesthetists (130 anaesthetists); three focus groups with anaesthetists (one national, two regional; 58 anaesthetists); two focus groups with members of the patient organisation Arthritis Care (7 participants); telephone interviews with people on consultant waiting lists from two UK regional centres (15 participants); interviews with Chairs of UK ethics committees (6 individuals); postal surveys of members of the British Association of Surgeons of the Knee (382 surgeons) and members of the British Society of Orthopaedic Anaesthetists (398 anaesthetists); two centre pilot (49 patients assessed). RESULTS: There was widespread acceptance that evaluation of arthroscopic lavage had to be conducted with a placebo control if scientific rigour was not to be compromised. The choice of placebo surgical procedure (three small incisions) proved easier than the method of anaesthesia (general anaesthesia). General anaesthesia, while an excellent mimic, was more intrusive and raised concerns among some stakeholders and caused extensive discussion with local decision-makers when seeking formal approval for the pilot.Patients were willing to participate in a pilot with a placebo arm; although some patients when allocated to surgery became apprehensive about the possibility of receiving placebo, and withdrew. Placebo surgery was undertaken successfully. CONCLUSIONS: Our study illustrated the opposing and often strongly held opinions about surgical placebos, the ethical issues underpinning this controversy, and the challenges that exist even when ethics committee approval has been granted. It showed that a placebo-controlled trial could be conducted in principle, albeit with difficulty. It also highlighted that not only does a placebo-controlled trial in surgery have to be ethically and scientifically acceptable but that it also must be a feasible course of action. The place of placebo-controlled surgical trials more generally is likely to be limited and require specific circumstances to be met. Suggested criteria are presented. TRIAL REGISTRATION NUMBER: The trial was assigned ISRCTN02328576 through http://controlled-trials.com/ in June 2006. The first patient was randomised to the pilot in July 2007.

Effectiveness and cost-effectiveness of arthroscopic lavage in the treatment of osteoarthritis of the knee: a mixed methods study of the feasibility of conducting a surgical placebo-controlled trial (the KORAL study).

OBJECTIVES: To ascertain the acceptability of a randomised controlled trial comparing arthroscopic lavage with a placebo-surgical procedure for the management of osteoarthritis of the knee; and to assess the practical feasibility of mounting such a multicentre placebo-controlled trial. DESIGN: Mixed methods study including: focus groups with surgeons and anaesthetists; focus groups and interviews with potential participants; interviews with chairpersons of UK Multicentre Research Ethics Committees (MRECs); surveys of surgeons and anaesthetists; and a two-centre, three-arm pilot. SETTING: UK secondary care. PARTICIPANTS: Members of the British Association of Surgeons of the Knee and members of the British Society of Orthopaedic Anaesthetists took part in the focus groups and surveys. Surgeons and anaesthetists from two regional centres in the UK also contributed to focus groups, as did patients from consultant lists in two UK regional centres, and members of Arthritis Care. Chairpersons of six UK MRECs were interviewed. Participants were eligible for the pilot if they were adults (18 years or older) with radiological evidence of osteoarthritis of the knee who might be considered for arthroscopic lavage, and were fit for general anaesthetic (defined by the American Society of Anaesthesiologists grades 1 and 2), and able to give informed consent. INTERVENTIONS: Participants in the pilot study were randomised to arthrosocopic lavage (with or without debridement at the clinical discretion of the surgeon); placebo surgery; or non-operative management with specialist reassessment. MAIN OUTCOME MEASURES: The acceptability and feasibility of mounting a placebo-controlled trial for the evaluation of knee arthroscopic lavage. RESULTS: There was broad acceptance across all stakeholder groups of the need to find out more about the effectiveness of arthroscopic lavage. Despite this there was variation in opinion within all the groups about how researchers should approach this and whether or not it would be acceptable to investigate using placebo surgery. Within the health professional groups, there tended to be a split between those who were strongly opposed to the inclusion of a placebo surgery arm and those who were more in favour. For prospective trial participants who had osteoarthritis of the knee, the acceptability of the trial was discussed from a more individual perspective - reflecting on their personal reasons for or against participating. The majority of this group said they would consider taking part. The pilot study showed that, in principle, a placebo-controlled trial could be conducted. It showed that patients were willing to participate in a trial which would involve a placebo-surgical arm and that it was possible to undertake placebo surgery successfully and to blind patients to their allocation - although once patients knew their allocation, some patients allocated to surgery became more concerned about the possibility of undergoing placebo surgery, and withdrew. The experience of the pilot, however, showed that, despite full MREC approval, the study required major discussion and negotiation before local clinical approvals could be obtained. The fact that ethics approval had been granted did not mean that clinicians would automatically accept that the process was ethical. CONCLUSIONS: The study showed that, in principle, a placebo-controlled trial of arthroscopic lavage could be conducted in the UK, albeit with difficulty. Against the background of falling use of arthroscopic lavage the decision was, therefore, taken not to proceed to full-scale trial for this procedure. The study showed that for some health professionals the use of placebo surgery can never be justified. It highlighted the importance of the surgeon-anaesthetist relationship in this context and how acceptance of the trial design by both parties is essential to successful participation. It also highlighted the importance of informed consent for trial participants and the strength and influence of individuals' ethical perspectives in addition to collective ethics provided by MRECs. TRIAL REGISTRATION: Current Controlled Trials ISRCTN02328576.

Randomised placebo-controlled trial of outpatient (at home) cervical ripening with isosorbide mononitrate (IMN) prior to induction of labour--clinical trial with analyses of efficacy and acceptability. The IMOP study.

OBJECTIVE: To determine whether isosorbide mononitrate (IMN), self-administered vaginally by women at home, improves the process of induction of labour. DESIGN: Randomised double blind placebo-controlled trial. SETTING: Large UK maternity hospital. POPULATION OR SAMPLE: Nulliparous women with a singleton pregnancy, cephalic presentation > or = 37 weeks gestation, requiring cervical ripening prior to induction of labour. METHODS: IMN (n = 177) or placebo (n = 173) self-administered vaginally at home at 48, 32 and 16 hours prior to the scheduled time of admission for induction. MAIN OUTCOME MEASURES: Admission to delivery interval and women's experience of induction of labour. RESULTS: IMN did not shorten the admission to delivery interval as compared with placebo [mean difference of -1.6 hours (95% CI -5.1,1.9, P = 0.37)], despite being more effective than placebo in inducing a change in Bishop score [mean difference of 0.65 (95% CI 0.14,1.17, P = 0.013)]. While both groups found the overall experience of home treatment to be positive, (mean score of 3.8/10 +/- 2.3/10 for the IMN group, where 1 = extremely good and 10 = not at all good) women in the placebo group found it marginally more positive than those in the IMN group (just over half a unit on a 10-point scale, P = 0.043). There were no differences between the groups in the pain or anxiety experienced or willingness to take the treatment in a subsequent pregnancy. CONCLUSIONS: IMN self-administered vaginally at home does not shorten admission to delivery interval despite a significant effect on cervical ripeness assessed using the Bishop score. However, women report positive views on cervical ripening at home, and the setting deserves further investigation.

Review of new regulations for the conduct of clinical trials of investigational medicinal products.

The EU Clinical Trials Directive came into force on 1 May 2004 and has changed the face of Clinical Trials of investigational medicinal products in the UK. An enthusiastic registrar or consultant who comes up with an idea for a therapeutic intervention now needs to comply with a complex and demanding set of legal, ethical and regulatory requirements, contravention of which may lead to criminal proceedings. The aim of this review was to detail the relevant procedures and regulations and to provide a 'user-friendly' guide to obstetricians and gynaecologists wishing to conduct a clinical trial of an investigational medicinal product. Sources of further information are listed.

Assessment of the performance of five intensive care scoring models within a large Scottish database.

OBJECTIVE: To assess and compare the performance of five severity of illness scoring systems used commonly for intensive care unit (ICU) patients in the United Kingdom. The five models analyzed were versions II and III of the Acute Physiology and Chronic Health Evaluation (APACHE) system, a version of APACHE II using United Kingdom (UK)-derived coefficients (UK APACHE II), version II of the Simplified Acute Physiology Score (SAPS), and version II of the Mortality Probability Model, computed at admission (MPM0) and after 24 hrs in the ICU (MPM24). DESIGN: A 2-yr prospective cohort study of consecutive admissions to intensive care units. SETTING: A total of 22 general ICUs in Scotland PATIENTS: A total of 13,291 admissions to the study, which after prospectively agreed exclusions left a total of 10,393 patients for the analysis. OUTCOME MEASURES: Death or survival at hospital discharge. MEASUREMENTS AND MAIN RESULTS: All the models showed reasonable discrimination using the area under the receiver operating characteristic curve (APACHE III, 0.845; APACHE II, 0.805; UKAPACHE II, 0.809; SAPS II, 0.843; MPM0, 0.785; MPM24, 0.799). The levels of observed mortality were significantly different than that predicted by all models, using the Hosmer-Lemeshow goodness-of-fit C test (p < .001), with the results of the test being confirmed by calibration curves. When excluding patients discharged in the first 24 hrs to allow for comparisons using the same patient group, APACHE III, MPM24, and SAPS II (APACHE III, 0.795; MPM24, 0.791; SAPS II, 0.784) showed significantly better discrimination than APACHE II, UK APACHE II, and MPM0 (APACHE II, 0.763; UK APACHE II, 0.756; MPM0, 0.741). However, calibration changed little for all models with observed mortality still significantly different from that predicted by the scoring systems (p < .001). For equivalent data sets, APACHE II demonstrated superior calibration to all the models using the chi-squared value from the Hosmer-Lemeshow test for both populations (APACHE III, 366; APACHE II, 67; UKAPACHE II, 237; SAPS II, 142; MPM0, 452; MPM24, 101). CONCLUSIONS: SAPS II demonstrated the best overall performance, but the superior calibration of APACHE II makes it the most appropriate model for comparisons of mortality rates in different ICUs. The significance of the Hosmer-Lemeshow C test in all the models suggest that new logistic regression coefficients should be generated and the systems retested before they could be used with confidence in Scottish ICUs.

Inhibition of nitric oxide synthesis: effects on cerebral blood flow and glucose utilisation in the rat.

The consequences of inhibition of nitric oxide synthesis on local CBF and glucose utilisation have been studied in the conscious rat using the specific nitric oxide synthase inhibitor Ng-nitro-L-arginine methyl ester (L-NAME; 30 mg kg-1 i.v.). Local CBF and glucose utilisation were assessed with the [14C]iodoantipyrine and the 2-deoxy-D-[14C]glucose autoradiographic techniques, respectively. L-NAME induced prolonged (> 3 h) reductions in local CBF throughout the CNS with concomitant increases in arterial blood pressure. For example, 1 h post L-NAME, CBF dropped from 79 +/- 4 to 45 +/- 1 ml 100 g-1 min-1 in cerebellum, from 76 +/- 4 to 47 +/- 2 ml 100 g-1 min-1 in medulla oblongata, and from 117 +/- 6 to 72 +/- 2 ml 100 g-1 min-1 in cortex. L-NAME produced sustained elevations (e.g., 46 +/- 2 mm Hg at 1 h after bolus administration) in mean arterial blood pressure throughout the period evaluated. Despite evidence implicating nitric oxide in neuronal signalling, L-NAME did not significantly influence CNS functional activity, as measured by local rates of glucose utilisation, in any neuroanatomical region examined. Consequently, the normal ratio of blood flow to glucose use throughout the brain was significantly reduced in the presence of L-NAME, although the hierarchy of blood flow levels in different neuroanatomical regions was preserved. These results are consistent with the involvement of nitric oxide in the tonic control of cerebral tissue perfusion.