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On The Pulse - January 2019

On The Pulse

Tertius Lydgate

Friday, 25 January 2019

The true extent of the opioid prescribing rise in the UK
A retrospective database study, published in The Lancet, which used open data sources on prescribing for all general practices in England, revealed that between 1998 and 2016, opioid prescriptions increased by 34% in England (from 568 to 761 per 1,000). But, after correcting for total oral morphine equivalency, the increase was 127% (from 190,000 mg to 431,000 mg per 1,000 population). There was however a decline in prescriptions from 2016 to 2017. If every practice prescribed high-dose opioids at the lowest decile rate, 543,000 fewer high-dose prescriptions could have been issued over a period of six months. Larger practice list size, ruralness, and deprivation were associated with greater high-dose prescribing rates. The clinical commissioning group to which a practice belongs accounted for 11·7% of the variation in high-dose prescribing. The authors point out that failing to account for opioid strength would substantially underestimate the true increase in opioid prescribing in the NHS in England and they call for greater action to promote best practice in chronic pain prescribing and to reduce geographical variation. The authors developed a publicly available interactive online tool, OpenPrescribing.net, which displays all primary care opioid prescribing data in England down to the individual practice level, and provide a model for routine monitoring of opioid prescribing to aid targeting of interventions to reduce high-dose prescribing.

CAR T-cell therapy for lymphoma
In December, NICE recommended CAR T-cell therapy tisagenlecleucel, within the Cancer Drug Fund, as an option for treating relapsed or refractory B‑cell acute lymphoblastic leukaemia in people aged up to 25 years. An international study, funded by Novartis and published in the NEJM, now shows that tisagenlecleucel produced high rates of durable responses in relapsed or refractory diffuse large B-cell lymphoma in adults. For this phase 2 study, 93 eligible patients received an infusion (median time from infusion to data cut-off: 14 months). The best overall response rate, as judged by an independent review committee, was 52% (95% CI, 41 to 62); 40% of the patients had complete responses, and 12% had partial responses. Response rates were consistent across prognostic subgroups. At 12 months after the initial response, the rate of relapse-free survival was estimated to be 65% (79% among patients with a complete response). The most common grade 3 or 4 adverse events of special interest included cytokine release syndrome (22%), neurologic events (12%), cytopenias lasting more than 28 days (32%), infections (20%), and febrile neutropenia (14%).

No VTE risk from transdermal oestrogen for HRT
Despite past negative publicity on HRT, based on concerns about the risk of venous thromboembolism (VTE), it is now acknowledged that the risk is rare, and that HRT is beneficial in managing menopausal symptoms in women counselled appropriately. However, NICE guidance suggests VTE risk is higher for oral preparations over the transdermal route, highlighting the need for more detailed studies on the long-term risks with different HRT regimens. Two nested case-controlled studies in The BMJ sought to assess this risk by looking at 80,396 women aged 40-79 with a primary diagnosis of VTE between 1998 and 2017, matched by age, general practice, and index date to 391,494 female controls. Overall, 7.2% of women who had VTE and 5.5% of controls had been exposed to HRT within 90 days before the index date. Of these two groups, 85% and 78% women used oral therapy, respectively, which was associated with a significantly increased risk of VTE compared with no exposure (adjusted OR 1.58, 95% CI 1.52 to 1.64), for both oestrogen only preparations and combined preparations. Compared with no exposure, conjugated equine oestrogen with medroxyprogesterone acetate had the highest risk (2.10, 1.92 to 2.31), and oestradiol with dydrogesterone had the lowest risk (1.18, 0.98 to 1.42). Transdermal treatment was not associated with VTE risk, prompting the authors to conclude it was the safest option.

Operative repair of Achilles tendon rupture
Achilles rupture is a significant debilitating injury that usually affects the young to middle aged population. However, there is much debate as to whether an operative fixation or conservative treatment is the better course of action. A meta-analysis published in The BMJ looked at 10 RCTs and 19 observational studies to try and answer this question. They found a significant reduction in re-ruptures after operative treatment (2.3%) compared with non-operative treatment (3.9%) (risk difference 1.6%; risk ratio 0.43, 95% CI 0.31 to 0.60; I2 = 22%). But there was a higher complication rate, mainly infection, following an operation (4.9% v 1.6%; risk difference 3.3%; risk ratio 2.76, 1.84 to 4.13; I2 = 45%). A similar reduction in re-rupture rate in favour of operative treatment was seen after both early and late full weight bearing. The authors conclude that an operation to repair reduces the risk of re-rupture but point out that re-rupture rates are low and differences between groups are small. They suggest patient factors and shared decision making should form the basis of the management plan.

Increasing fibre intake linked to a reduction in disease
It is well known that few people in the UK consume as much dietary fibre as recommended. However, previous research explaining the relationship between carbohydrate quality and health have usually examined a single marker and a limited number of clinical outcomes. A series of systematic reviews and meta-analyses in The Lancet of 185 prospective studies and 58 clinical trials including 4,635 adult participants (135 million person-years of data) looked at indicators of carbohydrate quality and non-communicable disease incidence, mortality, and risk factors. Observational data suggest a 15–30% decrease in all-cause and cardiovascular related mortality, and incidence of coronary heart disease, stroke incidence and mortality, type 2 diabetes, and colorectal cancer when comparing the highest with the lowest dietary fibre consumers. In addition, trials showed significantly lower bodyweight, systolic blood pressure, and total cholesterol when comparing higher with lower intakes of dietary fibre. Risk reduction associated with a range of critical outcomes was greatest when daily intake of dietary fibre was between 25 g and 29 g. The authors add that striking dose-response evidence indicates that the relationships to several non-communicable diseases could be causal, and they suggest recommendations to increase dietary fibre intake would confer health improvements.

Postoperative pain reduced by using intravenous ketamine
Pain following an operation is commonplace and inadequate pain management can increase the risks of complications from the procedure or even chronic pain. A Cochrane Systematic Review evaluated the efficacy and safety of perioperative intravenous ketamine in adult patients by looking at 130 double‐blind, controlled trials with 8,341 participants: 4,588 who received ketamine and 3,753 controls. Perioperative intravenous ketamine reduced postoperative opioid consumption over 24 and 48 hours by 8 mg and 13 mg morphine equivalents respectively. In addition, it reduced pain at rest at 24 and 48 hours both by 5/100mm on a visual analogue scale. Pain on movement was also seen to be lower. Ketamine increased the time for the first postoperative analgesic request by 54 minutes (95% CI 37 to 71 minutes), from a mean of 39 minutes with placebo and reduced the area of postoperative hyperalgesia by 7 cm² (95% CI −11.9 to −2.2). Overall, 187/3614 (5%) participants receiving ketamine and 122/2924 (4%) receiving control treatment experienced an adverse event. The authors conclude that using ketamine during an operation probably reduces postoperative analgesic consumption and pain intensity across a multitude of operation types with little difference in side effect profile.

No serious adverse effects with naltrexone use
Naltrexone, a pure opioid antagonist, is licenced to prevent relapse in alcohol use disorders (AUDs), in opioid addiction after withdrawal and used with bupropion for obesity. However, this medication is under-utilised across most countries, particularly for AUDs, mainly due to concerns about liver toxicity (reported in older studies with high dose regimens) and the reluctance to prescribe/take a drug to overcome addiction. A systematic review and meta-analysis in BMC Medicine sought to evaluate the safety of oral naltrexone by examining the risk of serious adverse events and adverse events in randomised controlled trials (n= 89; 11,194 participants) of naltrexone compared to placebo, which included any condition or age group but excluded use of opioids or ex-opioid users. The majority of trials (n=38) looked at AUDs with others looking at various psychiatric disorders (n= 13), impulse control disorders (n= 9), other addictions including smoking (n= 18), obesity or eating disorders (n= 6), Crohn’s disease (n= 2), fibromyalgia (n= 1) and cancers (n= 2). Twenty-six studies (4,960 participants) recorded serious adverse events occurring by arm of study. There was no evidence of increased risk of serious adverse events for naltrexone compared to placebo (risk ratio 0.84, 95% CI 0.66–1.06). The authors suggest fears by clinicians over prescribing naltrexone for AUDs may be unfounded and it should be used more frequently.

Nurse-led advance care planning session in patients with COPD
Advance care planning (ACP) is uncommon in patients with chronic obstructive pulmonary disease (COPD), however a cluster-randomised trial in Thorax sought to identify the possible benefits of a nurse-led ACP-intervention in patients with advanced COPD. The intervention group received a 1.5 hours structured nurse-led ACP-session. The improvement of quality of patient-physician end-of-life care communication was significantly higher in the intervention group (n= 89) compared with the control group (n= 76). The ACP-intervention was significantly associated with the occurrence of an ACP-discussion with physicians within six months. At follow-up, symptoms of anxiety were significantly lower in loved ones in the intervention group compared with the control group. Symptoms of anxiety in patients and symptoms of depression in both patients and loved ones were comparable at follow-up. The quality of death and dying was comparable between both groups. The results suggest one nurse-led ACP-intervention session improves patient-physician end-of-life care communication without causing psychosocial distress in both patients and loved ones.

Suspecting cancer in patients who rarely present
It has been shown that patients who rarely consult a GP in the 19-36 months before a cancer diagnosis tend to have cancer at a more advanced stage along with a worse prognosis. A Danish cross-sectional study in the BJGP, looking at 3,985 patients diagnosed with cancer, attempted to determine the relationship between the GP’s suspicion of cancer and how the patient consulted the practice. It was found that frequent attenders caused a reduction in the GP’s clinical suspicion of cancer. This was the same over usual consultation categories and for both sexes. Interestingly, age was a factor with a lower cancer suspicion for patients aged <55 in both rare and frequent attenders compared with average attenders. The authors conclude that opportunities to diagnose cancer at an early stage can be increased in the younger age group.

Author's Image

Tertius Lydgate

Originally from Northumberland, Tertius Lydgate studied medicine in Edinburgh, London and Paris. There he developed a special interest in communicable diseases and hoped to make great advances in treating and preventing them. But, after a promising start in a provincial centre of excellence in middle England, he was forced by circumstances (please, don't inquire) to abandon his high ideals. He now scrapes a living by pouring cold water on the over-enthusiastic at his private cryohydrotherapy clinic. Dreaming of the contributions he once hoped to make himself, he finds consolation in the latest medical journals and is happy to share his discoveries with his readers. He thinks that his creator, George Eliot, would have approved.
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