Zackary Berger’s weekly research reviews—19 November

Zackary Berger reviews the latest research from the top medical journals


Standing orders for naloxone in California

The number of opiate deaths in the US is increasing. States have adopted regulations regarding standing orders for naloxone, a medication to reverse opiate overdose. Under the standing order model, a doctor can prescribe naloxone to be distributed by trained health workers (such as pharmacists) to anyone who meets prescribed criteria for the drug. In practice, any individual should be able to enter a pharmacy in California and request naloxone without a prescription. This study assesses how commonly naloxone is currently found in pharmacies in the state.

The study sent researchers with identical scripts to a representative sample of retail pharmacies asking whether they could receive naloxone without a doctor’s prescription. Only 24% of pharmacies responded that they provided naloxone this way. Chain and urban pharmacies were more likely to furnish naloxone without a prescription. Only 50% of these pharmacies had nasal naloxone in stock.

Naloxone at community pharmacy chains in Texas

Texas has no statewide regulation regarding standing orders, but several chain pharmacies there offer naloxone without prescription. In a study, 2317 chain pharmacies (all pharmacies of four major chains) in Texas were contacted by telephone asking about naloxone availability. Perhaps because only chain pharmacies were contacted, or because telephone rather than in-person data were collected, the availability was higher than in California: 84% indicated they would dispense naloxone without prescription, and 69% said they had it immediately available.

Barriers clearly remain. Further work might examine whether stigma or fear on the part of individuals or pharmacists might affect when, to whom, and how quickly naloxone is provided.

The Lancet

Mortality due to low-quality health systems in the universal health coverage era

The Global Burden of Disease study has given rise to a great number of publications. One quails from being too critical, but large claims require strong evidence.

The claim here: in low and middle income countries, universal health coverage can only improve health if there is good quality healthcare. The authors use three different categories in attributions of morbidity and mortality: those which can be prevented by public health; those due to non-utilisation of healthcare; and those due to poor-quality healthcare.

A cursory glance at the conditions listed illuminates the assumptions such a study rests on. For example, one of the 61 conditions “for which personal health care plays an important role in reducing mortality” is “drug use disorders.” It is an issue of some difficulty to decide whether drug use disorders are to be laid at the feet of public health, the health care system, or the individual.

Such questions could be asked for many of the conditions: is ischaemic heart disease a public health issue or a poor healthcare issue? And does such a method of dividing attributions help health care systems, or individuals, achieve better health? I am not sure a single study like this can be accepted or denied at face value: it needs to be dissected and debated with philosophical rigour.


Minimally invasive versus abdominal radical hysterectomy for cervical cancer

It has apparently been believed for a few years that minimally invasive surgery in women with early stage cervical cancer, ie, laparoscopic or robot assisted radical hysterectomy, is just as good as open surgery with an abdominal incision. However, this belief was based on retrospective trials and meta-analyses combining the findings of multiple such trials. This trial is prospective, designed to show the non-inferiority of minimally invasive surgery to open surgery.

It showed the opposite. Minimally invasive surgery was associated with lower overall survival and disease-free survival; the trial was stopped early after the difference in survival exceeded predefined limits for non-inferiority.

What next? While the authors’ conclusions are appropriately couched in tactful language, and this is, after all, just one study, with the mechanisms of the difference as yet unknown, I wouldn’t refer any patient of mine with early stage cervical cancer to minimally invasive surgery.


Prevalence of potentially inappropriate prescribing in older people in primary care and its association with hospital admission

A quiz. Has the incidence of inappropriate prescribing among elderly people increased in the past five years?

Is incidence of inappropriate prescribing associated with hospital admission?

After admission to the hospital, are elderly patients more prescribed inappropriate medications?

If you answered yes to all of the above, you are correct. We can thus summarize the results of this important study done in Ireland.

The researchers found that inappropriate prescribing increased from 45% of patients in 2010 to 51% in 201. The most commonly over prescribed drugs were proton pump inhibitors, benzodiazepines, and Z-class hypnotics like zolpidem. For patients admitted to the hospital, the probability of at least one inappropriate prescription increased by 49%. Finally, the risk of an inappropriate prescription increased by 72% after admission to the hospital.

Skeptics raise the possibility that strict criteria for inappropriateness might not apply in older people ill enough to be admitted, but covariate controls and sensitivity analyses (as well as propensity score matching) render this unlikely. A more likely take-away is that too many medications are bad, and we need strategies to reduce them in older people. Coordination of care among doctors, nurses, pharmacists, and families is the obvious answer. But that doesn’t make it easy, or cheap.


Increased adverse outcomes with SGLT2 inhibitors

Sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors), also called gliflozins, were first approved by the US Food and Drug Administration in 2013. As is usually the case, the randomized controlled trials establishing effectiveness in diabetes were not large enough, and did not last long enough, to detect rare adverse effects. Of course, they were not designed to do so. Reports of adverse effects arrived as early as 2015, including cases of lower limb amputations. 

Sweden and Denmark have a reliable national patient registry which researchers used for this retrospective cohort study comparing the incidence of adverse effects in patients taking SGLT2 inhibitors to those taking glucagon-like-peptide 1 (GLP1) receptor agonists.

The adverse events most strongly associated with SGLT2 inhibitors were lower limb amputations and diabetic ketoacidosis. These are rare events: the rate of amputations in SGLT2 inhibitor group was 2.7 per 1,000 person years. But they are very disquieting and will hover menacingly in the background of any visit at which these medications are discussed.

JAMA Internal Medicine

Efficacy of low-dose amitriptyline for chronic low back pain

Trials of treatments in chronic lower back pain so rarely impress that my heart sank when I read the title of this study. The greatest impression on my clinical practice regarding low back pain (something nearly everybody has at some point in their life) was made by an American College of Physicians clinical guideline in 2017. The guideline said that nonpharmacological treatment should be tried first, for example: heat, massage, acupuncture, or spinal manipulation, and acknowledged that most medications for back pain aren’t very good.

I read this study with hope, and admired the authors optimistic conclusion (“This trial suggests that amitriptyline may be an effective treatment for chronic low back pain”) considering their actual findings, which showed decreased disability at three months, but none at six months, and no other statistically significant benefits. Grasping at straws should be done safely without straining the back.

But their final point was excellent: if opiates are the next stop on the train, jump off, for goodness’ sakes, and try a tricyclic. Perhaps I should discuss this with my next patient wincing from lumbago.

A multicomponent exercise programme prevented functional decline in hospitalised older people

Hospitalisation can be disastrous for older, sick people. A significant part of the problem is older people’s lack of mobility and the tendency to let them “rest” in bed. Thus I was cheered to read this randomized control trial, conducted in Spain, of a multicomponent exercise intervention among very ill older people in a geriatrics inpatient unit.

Read the study for a detailed report of the intervention, which involved different kinds of exercises using various devices and surfaces. There are accompanying videos. Whereas usual care involved normal visits from physical therapists, the intervention was provided twice daily. Was it the added time or the components of the intervention? Hard to know, but after five days, there was a significant difference in function at discharge, as well as improvement in secondary outcomes like mood and mental status (though not delirium).

Questions come fast: does improvement on the measures used on discharge translate into less decline at home? Are these patients like mine—in their 80s, with an average of nine conditions?

You might not be surprised at my real-life question: would your local hospital, on the basis of a promising trial, actually hire an additional physiotherapist?

Zackary Berger, is an associate professor at Johns Hopkins School of Medicine in the division of general internal medicine, and core faculty in the Johns Hopkins Berman Institute of Bioethics, both in Baltimore, Maryland. Zackary’s research focuses on shared decision making, patient-centered care, and health justice. He is also a practising physician at a free health clinic for undocumented, predominantly Spanish-speaking, immigrants.

Competing interests: None declared