Symptoms and steroid dose adjustments following the Covid-19 vaccine in patients with adrenal insufficiency.

BACKGROUND: A proportion of patients with adrenal insufficiency (AI) require increases in their maintenance glucocorticoids following the Covid-19 vaccine as a result of vaccine-related symptoms or development of incipient or frank adrenal crisis. In a large cohort of AI patients, we aim to characterise symptoms, changes in glucocorticoid dosage, occurrence of adrenal crises and whether there are differences between the mRNA and adenovirus vector vaccines. PATIENTS AND METHODS: Patients with AI of any aetiology were invited to complete a short, structured questionnaire of their experience of the Covid-19 vaccination. RESULTS: 279 of the 290 patients enrolled to this study fully completed the questionnaires. 176, 100 and 3 received the Astra Zeneca (AZ), Pfizer-BioNTech (PB) and Moderna (MD) as initial vaccine respectively; and for the second vaccine, 170, 99 and 10 received AZ, PB and MD respectively. Moderate to severe symptoms occurred in 44.8 and 39.7% after the first and second vaccines respectively, were of early onset (6.0 h, IQR 2-12 &. 6.0 h, IQR 2-24 h) and short duration (24 h, IQR 12-72 h & 26 h, IQR 12-72 h). 34.4 and 29.7% increased their maintenance glucocorticoid dose. DISCUSSION: The Covid-19 vaccines appear well-tolerated in patients with AI, with similar frequency of symptoms to that reported in the background population. The AZ vaccine leads to slightly greater post-vaccination symptom burden and need to increase glucocorticoid dosage, but this does not translate to greater adverse outcomes.

Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.

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.

ChAdOx1 SARS-CoV-2 vaccination: A putative precipitant of adrenal crises.

BACKGROUND: Patients with adrenal insufficiency (AI) have excess mortality, in part due to the occurrence of life-threatening adrenal crises. Infective processes, including that of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are recognised as the major precipitant of adrenal crises. Adverse reactions to the ChAdOx1 SARS-CoV-2 vaccine occur in a significant proportion of individuals, however, are mild-moderate in the majority of cases. DESIGN: Case series. PATIENTS & RESULTS: We describe five cases where more severe adverse reactions to the ChAdOx1 SARS-CoV-2 vaccine led to actual or incipient adrenal crises requiring parenteral hydrocortisone within 24 h of receiving the first ChAdOx1 SARS-CoV-2 vaccination. CONCLUSION: In individuals with adrenal insufficiency, adverse reactions to the initial dose of the ChAdOx1 SARS-CoV-2 vaccination can precipitate adrenal crises. We recommend that patients with AI should immediately increase their maintenance glucocorticoid dosage 2-3 fold on experiencing any symptoms in the initial 24 h following vaccination.

Refractory paraneoplastic hypercalcaemia responding to cinacalcet.

A woman in her late 70s presented with an increased frequency of micturition, suprapubic pain and weight loss. She was found to be having advanced cancer of the urinary bladder, coupled with bilateral hydronephrosis.Whilst undergoing surgical intervention for the latter, she was incidentally found to be having hypercalcaemia. This was found to be paraneoplastic in nature, possibly due to elevated parathyroid hormone related peptide with no evidence of bone metastasis. The histology of the resected tumour revealed squamous and sarcomatoid differentiation. Her hypercalcaemia initially responded to intravenous fluids, and later on zolendronate,but the problem recurred again, with the response to a repeat dose of zolendronate and even denosumab being unsatisfactory. As a last resort cinacalcet was started, and although there was a good response to it, our patient sadly died a few weeks later.We believe our case to be the first case of hypercalcaemia associated with isolated bladder cancer which showed a successful response to cinacalcet.

Optimal pharmacotherapy pathway in adults with diabetic peripheral neuropathic pain: the OPTION-DM RCT.

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.

The number of people with diabetes is growing rapidly in the UK and is predicted to rise to over 5 million by 2025. Diabetes causes nerve damage that can lead to severe painful symptoms in the feet, legs and hands. One-quarter of all people with diabetes experience these symptoms, known as 'painful diabetic neuropathy'. Current individual medications provide only partial benefit, and in only around half of patients. The individual drugs, and their combinations, have not been compared directly against each other to see which is best. We conducted a study to see which treatment pathway would be best for patients with painful diabetic neuropathy. The study included three treatment pathways using combinations of amitriptyline, duloxetine and pregabalin. Patients received all three treatment pathways (i.e. amitriptyline treatment for 6 weeks and pregabalin added if needed for a further 10 weeks, duloxetine treatment for 6 weeks and pregabalin added if needed for a further 10 weeks and pregabalin treatment for 6 weeks and amitriptyline added if needed for a further 10 weeks); however, the order of the treatment pathways was decided at random. We compared the level of pain that participants experienced in each treatment pathway to see which worked best. On average, people said that their pain was similar after each of the three treatments and their combinations. However, two treatments in combination helped some patients with additional pain relief if they only partially responded to one. People also reported improved quality of life and sleep with the treatments, but these were similar for all the treatments. In the health economic analysis, the value for money and quality of life were similar for each pathway, and this resulted in uncertainty in the cost-effectiveness conclusions, with no one pathway being more cost-effective than the others. The treatments had different side effects, however; pregabalin appeared to make more people feel dizzy, duloxetine made more people nauseous and amitriptyline resulted in more people having a dry mouth. The pregabalin supplemented by amitriptyline pathway had the smallest number of treatment discontinuations due to side effects and may be the safest for patients.

Lesson of the month 2: An unusual presentation of hyperinsulinaemic hypoglycaemia with possible underlying diagnosis of glucose-sensitive insulinoma or islet cell hyperplasia.

Postprandial hypoglycaemia can occur in islet cell hyperplasia and in reactive hypoglycaemia. Less commonly, it can occur with insulinoma. A case is described where the differential diagnosis was glucose-sensitive insulinoma or islet cell hyperplasia. Typical provocation was prolonged exertion or fasting followed by ingestion of sugary snacks resulting in hypoglycaemic seizures and collapse. Biochemistry and computerised tomography imaging were consistent with an insulinoma in the pancreatic tail, but this was not confirmed on endoscopic ultrasound. Selective intra-arterial calcium stimulation with hepatic venous sampling results suggested a diagnosis of islet cell hyperplasia. Ten years later, repeat imaging was consistent with a neuroendocrine tumour. Surgical resection has resulted in remission of symptoms. The patient will be monitored long term to ensure no recurrence.

The effect of information and behavioural training on endoscopy patients' clinical outcomes.

This study was designed to examine the effects of preparatory information and behavioural training on patients about to undergo an endoscopy procedure. Forty-five first-time endoscopy patients (aged 20-70 years), were randomly assigned to one of three groups (cognitive, cognitive/behavioural and control group). The cognitive group received a 12 min preparation with sensory and procedural information relating to the sensations and sequence of events associated with the endoscopy procedure. The cognitive/behavioural group received, in addition, instruction in deep breathing exercises, tongue depressor task and swallowing technique. Results indicated that patients in the two experimental conditions experienced significantly fewer signs of behavioural distress during endoscopy. The cognitive group required a significantly shorter time to induce the scope. There were no statistical differences between the groups however, for mood, physiological and anxiety measures, although a positive trend was evident for the two intervention groups.