Search

Rapid improvement in glycaemic control induced by GLP-1 agonist therapy could be yet another illustration of transient or permanent progression of diabetic retinopathy, similar to documented examples such as pregnancy and continuous subcutaneous insulin infusion. Specific guidelines would be needed to monitor this paradoxical phenomenon during treatment with GLP-1 agonists. [ABSTRACT FROM AUTHOR]

Background: The mainstay of treatment for diabetic peripheral neuropathic pain is pharmacotherapy, but the current National Institute for Health and Care Excellence guideline is not based on robust evidence, as the treatments and their combinations have not been directly compared., Objectives: To determine the most clinically beneficial, cost-effective and tolerated treatment pathway for diabetic peripheral neuropathic pain., Design: A randomised crossover trial with health economic analysis., Setting: Twenty-one secondary care centres in the UK., Participants: Adults with diabetic peripheral neuropathic pain with a 7-day average self-rated pain score of ≥ 4 points (Numeric Rating Scale 0-10)., Interventions: Participants were randomised to three commonly used treatment pathways: (1) amitriptyline supplemented with pregabalin, (2) duloxetine supplemented with pregabalin and (3) pregabalin supplemented with amitriptyline. Participants and research teams were blinded to treatment allocation, using over-encapsulated capsules and matching placebos. Site pharmacists were unblinded., Outcomes: The primary outcome was the difference in 7-day average 24-hour Numeric Rating Scale score between pathways, measured during the final week of each pathway. Secondary end points included 7-day average daily Numeric Rating Scale pain score at week 6 between monotherapies, quality of life (Short Form questionnaire-36 items), Hospital Anxiety and Depression Scale score, the proportion of patients achieving 30% and 50% pain reduction, Brief Pain Inventory - Modified Short Form items scores, Insomnia Severity Index score, Neuropathic Pain Symptom Inventory score, tolerability (scale 0-10), Patient Global Impression of Change score at week 16 and patients' preferred treatment pathway at week 50. Adverse events and serious adverse events were recorded. A within-trial cost-utility analysis was carried out to compare treatment pathways using incremental costs per quality-adjusted life-years from an NHS and social care perspective., Results: A total of 140 participants were randomised from 13 UK centres, 130 of whom were included in the analyses. Pain score at week 16 was similar between the arms, with a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for duloxetine supplemented with pregabalin compared with amitriptyline supplemented with pregabalin, a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for pregabalin supplemented with amitriptyline compared with amitriptyline supplemented with pregabalin and a mean difference of 0.0 points (98.3% confidence interval -0.4 to 0.4 points) for pregabalin supplemented with amitriptyline compared with duloxetine supplemented with pregabalin. Results for tolerability, discontinuation and quality of life were similar. The adverse events were predictable for each drug. Combination therapy (weeks 6-16) was associated with a further reduction in Numeric Rating Scale pain score (mean 1.0 points, 98.3% confidence interval 0.6 to 1.3 points) compared with those who remained on monotherapy (mean 0.2 points, 98.3% confidence interval -0.1 to 0.5 points). The pregabalin supplemented with amitriptyline pathway had the fewest monotherapy discontinuations due to treatment-emergent adverse events and was most commonly preferred (most commonly preferred by participants: amitriptyline supplemented with pregabalin, 24%; duloxetine supplemented with pregabalin, 33%; pregabalin supplemented with amitriptyline, 43%; p  = 0.26). No single pathway was superior in cost-effectiveness. The incremental gains in quality-adjusted life-years were small for each pathway comparison [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -0.002 (95% confidence interval -0.011 to 0.007) quality-adjusted life-years, amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline -0.006 (95% confidence interval -0.002 to 0.014) quality-adjusted life-years and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline 0.007 (95% confidence interval 0.0002 to 0.015) quality-adjusted life-years] and incremental costs over 16 weeks were similar [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -£113 (95% confidence interval -£381 to £90), amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £155 (95% confidence interval -£37 to £625) and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £141 (95% confidence interval -£13 to £398)]., Limitations: Although there was no placebo arm, there is strong evidence for the use of each study medication from randomised placebo-controlled trials. The addition of a placebo arm would have increased the duration of this already long and demanding trial and it was not felt to be ethically justifiable., Future Work: Future research should explore (1) variations in diabetic peripheral neuropathic pain management at the practice level, (2) how OPTION-DM (Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus) trial findings can be best implemented, (3) why some patients respond to a particular drug and others do not and (4) what options there are for further treatments for those patients on combination treatment with inadequate pain relief., Conclusions: The three treatment pathways appear to give comparable patient outcomes at similar costs, suggesting that the optimal treatment may depend on patients' preference in terms of side effects., Trial Registration: The trial is registered as ISRCTN17545443 and EudraCT 2016-003146-89., Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme, and will be published in full in Health Technology Assessment ; Vol. 26, No. 39. See the NIHR Journals Library website for further project information.

Background: Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP., Methods: OPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0-10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443., Findings: Between Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was -0·1 (98·3% CI -0·5 to 0·3) for D-P versus A-P, -0·1 (-0·5 to 0·3) for P-A versus A-P, and 0·0 (-0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway., Interpretation: To our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy., Funding: National Institute for Health Research (NIHR) Health Technology Assessment programme., Competing Interests: Declaration of interests ST reports honoraria for educational meetings from Pfizer, Viatris, Wörwag Pharma, Novo Nordisk, Merck & Co, Eva Pharma, Hikma Pharmaceuticals, Abbott Laboratories, AstraZeneca, Nevro, Procter & Gamble Health, Astellas Pharma, and Berlin-Chemi; consulting fees from Bayer, NeuroPn Therapeutics, Wörwag Pharma, Angelini, Grünenthal, TRIGOcare International, Nevro Mitsubishi Tanabe Pharma Corporation, and Confo Therapeutics; and a research grant from Procter and Gamble Health paid to Sheffield Teaching Hospitals. UA reports honoraria for educational meetings from Eli Lilly, Napp Pharmaceuticals, Sanofi, and Boehringer Ingelheim. EBJ reports honoraria and research support from Novo Nordisk and Sanofi. SHA reports honoraria for educational meetings from Novo Nordisk, Eli Lilly, and Sanofi. PV reports honoraria from Merck and Sanofi. MJ reports honoraria for advisory boards and speaker fees from Grünenthal (2015 to present) and being a co-chairperson, since 2014, of the Chronic Pain Policy Coalition and a council (2012 to present) and ordinary member of the British Pain Society. DB reports grants and contracts from Novartis, Grunenthal, Bayer, and Air Liquide; and consulting fees from Bayer and Air Liquide. DLB has acted as a consultant on behalf of Oxford University Innovation for AditumBio, Amgen, Bristows, Latigo Biotherapeutics, GlaxoSmithKline, Ionis Pharmaceuticals, Eli Lilly, OliPass, Regeneron Pharmaceuticals, and Theranexus, over the past 2 years; has received research funding from Eli Lilly and AstraZeneca; has received an industrial partnership grant from the Biotechnology and Biological Sciences Research Council and AstraZeneca; and reports grants and contracts for several studies from the UK Research and Innovation, Medical Research Council (MRC), Action Medical Research for Children, MRC Research Grant, Wellcome Trust Senior Clinical Scientist Fellowship, Novo Nordisk Foundation, EU Horizon 2020, MRC Clinical Research Training Fellowship, and Wellcome Trust Strategic Award. DS reports membership of the advisory boards of Impeto Medical, PelliTec, and FeetMe. CC is a member of the NIHR Clinical Trial Unit (CTU) Support Funding Committee, NIHR CTU Standing Advisory Committee, NIHR Programme Grants for Applied Research Subcommittee, and Trial Steering Committees for other NIHR-funded trials. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Diagnosis of Cushing's syndrome (CS) and identification of the aetiology of hypercortisolism can be challenging. The Endocrine Society clinical practice guidelines recommends one of the four tests for initial screening of CS, namely, urinary-free cortisol, late night salivary cortisol, overnight dexamethasone suppression test or a longer low-dose dexamethasone suppression test, for 48 hours. Confirmation and localisation of CS requires additional biochemical and radiological tests. Radiological evaluation involves different imaging modalities including MRI with or without different radio-nuclear imaging techniques. Invasive testing such as bilateral inferior petrosal sinus sampling may be necessary in some patients for accurate localisation of the cause for hypercortisolism. This best practice review discusses a practical approach for the diagnostic evaluation of CS with a brief discussion on differential diagnoses, and cyclical CS, to enhance the skills of clinicians and laboratory personnel., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)