The Gabapentinoid Cure-All

Gabapentinoids – gabapentin and pregabalin – were traditionally prescribed for their approved indications: the treatment of seizures and various manifestations of neuropathic pain. Of course, there are many newer agents for epilepsy, and the the market for neuropathic pain ought to remain fairly stable. Therefore, why has gabapentinoid use effectively tripled over the past decade, as generally described by this research letter?

Most notably, in this letter, gapapentin use increased most in those with multiple comorbidities, as well as those with concurrent opioid and benzodiazepine prescriptions. Considering the lack of proven efficacy and the potential for misuse or adverse effects, there’s frankly no excuse for such rampant overuse. Nearly all this expansion represents waste and harm in our health system, with mixed and scattershot evaluation of its various applications almost certain to mislead rather than inform true treatment effects.

It seems it really ought to be time to reduce prescribing of gabapentinoids – particularly off-label – but the reverse seems true!

“Gabapentinoid Use in the United States 2002 Through 2015”
https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2666788

Would You Use A Syncope SDM Instrument?

Much has been made, off and on, about the chest pain shared decision-making tool rolled out over the past couple years. It turns out, when properly informed of their low risk for subsequent cardiac events, most patients look at you sideways and wonder why anyone was offering them admission in the first place.  Whether that was its intended purpose, or a happy little accident, is a subject of controversy.

Their next target: syncope.

The content of this article is not very profound, other than to show the first step in the process of developing such an SDM instrument. These authors detail their involvement of emergency physicians, cardiologists, and patient stakeholders to inform their iterative design process. In the end, their tool looks a lot like the their chest pain instrument:

Generally speaking, because the approach to low-risk syncope has some of the same issues as low-risk chest pain, I have essentially the same fundamental problems. Much like for chest pain, inpatient evaluations for syncope are generally unrevealing. We probably ought not be admitting most of these patients. Therefore, this SDM instrument is again addressing the problem of low-value resource utilization by shifting the burden of the decision onto the patient, and trying to convince them to make what we already know to be the correct one (go home). That’s not how the Force works.

Then, just like the chest pain tool, this fails to convey the benefit of hospitalization for comparison. In their pictogram, two out of 100 patients suffer an adverse event after fainting. Is admission to the hospital protective against those adverse events – even if a diagnosis is made? The patient needs to receive some simplified visualization of their expected benefit from staying in the hospital, not just simply the base rate for deterioration.

I love shared decision-making. I use it constantly in my practice in situations where the next step in evaluation or treatment has no clearly superior path. Again, I don’t think this reflects the same uncertainty.

“Development of a Patient Decision Aid for Syncope in the Emergency Department: the SynDA tool”

https://www.ncbi.nlm.nih.gov/pubmed/29288554

The HSV Meningitis Question

This is one of those questions that always crops up when evaluating an infant for sepsis and meningitis – should we test and/or empirically cover for herpes simplex virus infection? Just how frequently is this diagnosis made?

The answers, as described in this retrospective, multi-center study, are complex. First, the basics: 26,533 total encounters analyzed, with 112 children ultimately diagnosed with HSV meningitis. Then, it’s basically chaos. The percent of patients whose CSF was tested for HSV ranged from 12.5% to 70.9% across hospitals included, along with empiric coverage with acyclovir ranging from 4.2% to 53.0%. Rates of positive HSV results were unrelated to overall institutional testing or empiric acyclovir coverage rates, excepting in the sense that HSV infection was more frequent in younger infants – and younger infants were more likely to be tested and empirically treated, in general.  A handful of patients with ultimate diagnoses of HSV meningitis were not treated or tested initially, and were found on a subsequent visit.

The authors go into some detail regarding the questionable value of empiric treatment, citing a number needed to treat of 152 for infants 0-28 days and an NNT of 583 for infants from 29-60 days. Generally speaking, these authors agree with a prior cost-effectiveness analysis recommending waiting for the initial CSF cell count, and empirically treating those with a CSF pleocytosis. Consequently, these authors would therefore recommend testing only those ultimately treated empirically – but this is naturally a pragmatic consideration, rather than a statistically modeled balance between sensitivity and specificity.

There are a few more nuances within the paper with regard to their gold standard for diagnosis of HSV meningitis, limitations with regard to selection of patients undergoing testing, and generalizability from these tertiary referral settings, but it is still generally an interesting snapshot of data. Unfortunately, their ultimate conclusion is still back at square one – reiterating a call for specific clinical and laboratory data to help guide clinicians in selecting patients for HSV testing and empiric treatment. In the meantime, we’ll just keep doing our best to differentiate the ill child at the bedside based on gestalt and the culture of our practice setting.

“Herpes Simplex Virus Infection in Infants Undergoing Meningitis Evaluation”
http://pediatrics.aappublications.org/content/early/2017/12/29/peds.2017-1688

Influenza, Sideways

Hello, everyone! Influenza, influenza, influenza. Influenza? Influenza. Influenza influenza, influenza – influenza – influenza, influenza!

It’s that time of year in the Northern Hemisphere, following up last year’s busy season, and a terrible one in the Southern Hemisphere in the interim. At this point, for your general ambulatory patient, I hope you’ve stopped sending swabs. If you think they have it, they probably do – although, there is some respiratory syncytial virus out there, too.

But, I’ve also been surprised by a couple of people who didn’t look like typical influenza, and this little expert commentary is a nice reminder of the less-common manifestations of influenza infection. The respiratory compromise is well-documented, but patients can not uncommonly become seriously ill with myocarditis, myositis, and viral encephalitis, as well as causing less serious serious hepatic injury and acute tubular necrosis. There have also been case reports implicating influenza less frequently in a scattershot of clinically interesting entities.

Just in case you weren’t getting enough influenza in your life.

“The hidden burden of influenza: A review of the extra- pulmonary complications of influenza infection”
http://onlinelibrary.wiley.com/doi/10.1111/irv.12470/abstract [open access]

Are We Getting Better at Controlling Epilepsy?

Many things in medicine have changed for the better in medicine over the last 30 years. Some “innovations” have resulted in unintended consequences and costs, and, unfortunately, a few have ultimately proven harmful.

And then some just haven’t changed.

This rather depressing look at anti-epileptic therapy comes from an observational cohort in Scotland, monitoring the various outcomes and seizure frequencies in epilepsy over the last thirty years. There has been an explosion of new options for control of epilepsy – at no small cost – and, one would hope newer would be better.

After following changes in therapy and outcomes in 1,795 patients across 30 years, starting in 1982, the unfortunate conclusion is: little improvement. Starting from an era of primarily carbamazepine, phenytoin and valproic acid, despite the addition of a wide variety of modern options, the proportion of patients with 1-year seizure freedom has not changed. The primary driver of this observation appears to be little change in successful control of refractory epilepsy, in which patients failing to be controlled on their initial agent – about half – remain difficult to control, regardless of changes or additions to therapy.

I would not go so far as to say no benefit is derived from newer agents, as this study does not delve into safety profiles, adverse effects, and other reasons for discontinuation. I suspect, unfortunately however, this generally mirrors results from across the practice of medicine – where expectations and perceptions of efficacy do not match reality.

“Treatment Outcomes in Patients with Newly Diagnosed Epilepsy Treated With Established and New Antiepileptic Drugs A 30-Year Longitudinal Cohort Study”
https://jamanetwork.com/journals/jamaneurology/article-abstract/2666189

Treatment Failure, or is Treatment the Failure?

Acute respiratory tract infections – otitis media, streptococcal pharyngitis, and sinusitis – comprise virtually a laundry list for antibiotic overuse in self-limited conditions. Certainly, a subset of each of these conditions are true bacterial infections and, again, a subset of these have their resolution hastened by antibiotics – and, finally, a subset of those would have clinically important worsening if antibiotics were not used. Conversely, the harms of antibiotics are generally well-recognized,though not necessarily routinely appreciated in clinical practice.

This patient-centered outcomes study, with both retrospective and prospective portions, enrolled children diagnosed with the aforementioned “acute respiratory tract infections” and evaluated outcomes differences between those receiving “narrow-spectrum” antibiotics and those receiving “broad-spectrum antibiotics”. Before even delving into their results, let’s go straight to this quote from the limitations:

Because children were identified based on clinician diagnosis plus an antibiotic prescription to identify bacterial acute respiratory tract infections, some children likely had viral infections.

“Some children likely had viral infections” is a strong contender for understatement of the year.

So, with untold numbers of viral infections included, it should be no surprise these authors found no difference in “treatment failure” between narrow-spectrum and broad-spectrum antibiotics. Nor, in their prospective portion, did they identify any statistically difference in surrogates for wellness, such as missed school, symptom resolution, or pediatric quality of life. However, adverse events were higher (35.6% vs. 25.1%, p < 0.001) in the broad-spectrum antibiotic cohort, and this accompanied smaller, but consistent, differences favoring narrow-spectrum antibiotics on those wellness measures.

So, the takeaway: broad-spectrum antibiotics conferred no advantage, only harms. If you’re using antibiotics (unnecessarily), use the cheapest, most benign ones possible.

“Association of Broad- vs Narrow-Spectrum Antibiotics With Treatment Failure, Adverse Events, and Quality of Life in Children With Acute Respiratory Tract Infections”

https://jamanetwork.com/journals/jama/article-abstract/2666503

Intravenous or Oral Analgesia?

Or, better translated, is the new, fancier option really superior?

In many cases, the intravenous option is superior than the oral alternative. Cephalexin, for example, reaches higher serum levels via intravenous administration. The oral versions of morphine and hydromorphone are not equivalent intravenously. So, what about acetaminophen/paracetamol?

It is already well-established (by the manufacturer) the intravenous version of acetaminophen reaches higher peak serum levels, and does so more quickly, than oral versions. This study, however, asks the question from a patient-oriented standpoint – does this actually provide superior pain relief?

The short answer is no. This small study analyzing 87 patients receiving intravenous or oral acetaminophen in a double-blind, double-dummy fashion found no difference in mean change in pain levels at 30 minutes.  This is consistent with the limited previous evidence, and reasonably suggests there is no justification for IV use when patients are capable of taking the oral alternative.

Interestingly, this same group recently presented these data in abstract form with 108 patients rather than 87, and using median pain score reduction rather than means. Their abstract results are consistent with these, but the discordant number of analyzed patients is odd.

“Intravenous versus oral paracetamol for acute pain in adults in the emergency department setting: a prospective, double-blind, double-dummy, randomised controlled trial.”
https://www.ncbi.nlm.nih.gov/pubmed/29247042

Prescribing Opiates to the Entire House

Opiate prescribing has blossomed into an appropriately huge issue in the current medical landscape. A fair bit of thought now goes into evaluating individuals for their potential for use and misuse – including even state-mandated prescription database review.

But, this interesting analysis suggests it should not only be the individual recipient considered when prescribing – but the impact on the health of the entire household. These authors compared administrative health care claims from 12,695,280 patients with a family member prescribed opiates against 6,359,639 patients whose family members were prescribed a non-opiate analgesic. Within one year, 11.68% of family members of those prescribed an opiate subsequently received their own, compared with 10.60% in the non-opiate cohort. After statistical adjustment, the absolute difference narrowed somewhat, and the authors also report their sensitivity analysis cannot rule out invalidation of their findings by an unmeasured confounder.

Regardless, this fits with my anecdotal experience – where many patients coming in for musculoskeletal pain have used a family member’s leftover opiate medication for breakthrough pain control. Despite the underlying limitations from this statistical analysis, it certainly seems to have face validity. It is reasonable to consider not just the individual patient being prescribed opiates, but also the risk to the household as being a gateway to subsequent opiate prescribing for family members.

“Association of Household Opioid Availability and Prescription Opioid Initiation Among Household Members”
https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2664515

Atraumatic Spinal Needles are Less Traumatic

It’s a tautology!

In a solid “not news, but newsworthy” systematic review and meta-analysis published in The Lancet, these authors pooled data from 110 trials comparing conventional (“cutting”) spinal needles with “atraumatic” ones. The atraumatic ones, after all, are thought to result in less tissue damage and corresponding complications. The perceived downside to the atraumatic needles, however, is related to potentially decreased procedural success.

In short, none of the results favor the conventional needles.  The sample sizes for each measure ranged from 24,000 patients to 1,000, with most right in the middle of the range.  These authors evaluated incidence of such complications as post-procedural headaches, need for analgesia, need for epidural blood patch, nerve root irritation, or hearing disturbances. With regard to procedural success, these authors evaluated the traumatic taps, first attempt success, and overall procedural failure rate.

The magnitude of reduction in various complications was wide, but consistent. In an absolute sense, any post-procedural headache associated with use of atraumatic needles was from 12% to 7%, and the need for epidural blood patch decreased from 2% to 1%.  With regard to any reduction in procedural success, no signal of difference was observed.

The authors accurately report there is low awareness of the advantages of the atraumatic needles among clinicians. These data, even if not novel, at least are published on an adequate platform to improve awareness of the superior alternative.

“Atraumatic versus conventional lumbar puncture needles: a systematic review and meta-analysis”
https://www.ncbi.nlm.nih.gov/pubmed/29223694

What Does the ACC Say About OAC Reversal?

Just in case you were curious ….

Conventional tests useful for ruling out clinically relevant levels contributing to bleeding risk:

  • Dabigatran – a normal Thrombin Time or sensitive activated partial thromboplastin time (aPTT).
  • Factor Xa-inhibitors – None.

If you have access to Anti-Xa specialized assays, they can be used to measure the level of activity for the Factor Xa-inhibitors.

Managing OAC-associated bleeding:

  • Warfarin – 4-factor prothrombin concentrate complexes (PCCs) at weight-based dosing between 25 units/kg and 50 units/kg based on INR.
  • Dabigatran – Idarucizumab.
  • Factor Xa-inhibitors – 4-factor PCCs at 50 units/kg.

The authors also suggest use of PCCs as second line for idarucizumab, but this is likely to be fruitless and the evidence is very weak. Hemodialysis is also an option for removal of circulating dabigatran in a narrow set of clinical scenarios.

The authors also mention andexanet alfa and ciraparantag as potentially useful adjuncts at some point in the future, but no specific clinical role has yet been defined.

“2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants”
http://www.onlinejacc.org/content/early/2017/11/10/j.jacc.2017.09.1085