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”

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”

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.”

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”

The Acetaminophen/Ibuprofen Ascendancy

The new hotness of the day is the piece out of JAMA comparing our various oral analgesic treatment options for acute pain the Emergency Department. This relatively mundane line of research has been relatively fertile over the last few years, so, what do we have in store here?

This was a double-blind, placebo-controlled trial of four different analgesic combinations for acute extremity pain. To enter the trial, one of the criteria was receipt of an imaging study, which served twofold: an assumed proxy for more serious injuries and pain, and because it increased ED length-of-stay enough to reduce patients lost to follow-up for their primary outcome. The primary outcome, then, was reduction in pain on a 0 to 10 numerical rating scale at the 2-hour mark, with an interim 1-hour mark recorded as well.

The study drugs were as follows: 400 mg of ibuprofen and 1000 mg of acetaminophen; 5 mg of oxycodone and 325 mg of acetaminophen; 5 mg of hydrocodone and 300 mg of acetaminophen; or 30 mg of codeine and 300 mg of acetaminophen. Approximately 100 patients per arm were targeted from their sample size calculations, and they ultimately randomized 416 into generally similar groups with respect to final diagnoses.

The outcomes are essentially a wash – raising a question of whether there is any advantage to opiate therapy for this indication.  In our beautiful public health tapestry of increasing opiate misuse and addiction, any opportunity to reduce opiate prescribing is important.  There are some reasonable takeaways with respect to the relative efficacy of ibuprofen/acetaminophen, oxycodone/acetaminophen,  hydrocodone/acetaminophen and codeine/acetaminophen combinations, but their clinical relevance is highly questionable considering the doses tested in this study.  This is, unfortunately, essentially a straw-man comparison between an adequate dose of non-opiate analgesia compared with the least-adequate preparation of each of the commonly used combination opiate products.  A proper comparison in patients with severe pain ought to use a more typical maximal dose, which would probably be twice as much of each of the combination opiate products.

There are a few other small oddities relating to this study, of course. As an unavoidable consequence of the study setting, 60% of their study cohort identified as Latino and another 31% identified as black. There are potential genetic differences in pharmacokinetics relating to ethnicity, as well as cultural factors relating to the cohort enrolled at the study site, so the generalization of these data requires some caution. The study protocol states patients were to be asked whether they were satisfied with their pain control and side effects were to be recorded (nausea, vomiting, itchiness, etc.), but these are not reported in the final manuscript or supplement. Finally, these data are also limited, essentially, to sprains, fractures, and contusions. This represents an important slice of outpatients seeking analgesia, but may not be applicable to other types of pain.

Overall, however, this is reasonable evidence to support strategies of combination non-opiate therapy in patients without contraindications to both acetaminophen and ibuprofen.  It should not, however, be offered as evidence of the disutility of commonly used combination opiate preparations.

“Effect of a Single Dose of Oral Opioid and Nonopioid Analgesics on Acute Extremity Pain in the Emergency Department”

And, The Safest Pediatric Sedation Drug Is …


This ought not surprise virtually anyone, considering the vast body of experience physicians have performing safe, effective procedural sedation with ketamine. However, medicine is prone to its dogmatic confirmation bias, so I applaud these authors for this important report.

This is a prospective, observational, multi-center cohort specifically evaluating all episodes of procedural sedation for serious adverse events and important interventions. These authors recorded medication cocktails used for sedation, any adjunctive use of medication, the procedure performed, fasting status, and underlying health risks, and then tracked the outcomes of each procedure performed.

Ultimately, they included 6,295 children and sedation events in this study. The most commonly used sedation medications were ketamine, propofol, and combinations of ketamine, propofol, and fentanyl. Serious events were rare, occurring in about 1% of sedations – and, likewise, so were important interventions. Furthermore, the vast majority of events and interventions were simply temporary use of positive pressure ventilation in response to periods of apnea. Importantly, no patients required intubation or unplanned hospital admission. Oxygen desaturation was tracked separately from serious events and, along with vomiting, occurred in approximately 5% of sedation procedures.

With regard to other contributing factors to serious events or interventions, any deviation from ketamine monotherapy increased such risks. Whether it be combining ketamine with another opiate or benzodiazepine, or whether propofol were used alone or in combination, all increased the risk of serious events a small absolute amount over the baseline. Several figures included in the manuscript describe the various risk factors associated with serious outcomes with generally predictable associations, including increased risks with periprocedural opiate use, and decreased vomiting when ketamine were excluded.

Overall, even though the short answer to the question posed in the title is “ketamine”, the slightly longer answer is “any choice is probably fine”. Even though the relative risks are increased, the absolute risks are small – and the severity of interventions required, despite their labeling, were essentially benign.

“Risk Factors for Adverse Events in Emergency Department Procedural Sedation for Children”

Morphine Not a Good Adjunct For Pediatric Pain

Treating acute musculoskeletal pain in the Emergency Department is a common occurrence – and even on the docket as a time-to-analgesia quality measure. Where we frequently see failures and delays, however, are in children, with much written regarding oligoanalgesia and the dragging of feet before any sort of pain management. Furthermore, adults are frequently managed with opiate therapy, which, despite its various pitfalls, may be considered to stand above the commonly used ibuprofen and acetaminophen monotherapy in children.

So, does it work better to combine an oral non-steroidal analgesic with opiate therapy in children? Or, perhaps, is even an opiate alone better with regard to adverse effects? That is the question asked by this three-arm, double-blinded, placebo-controlled, randomized trial. Children with painful musculoskeletal injuries were randomized either ti 10mg/kg oral ibuprofen, 0.2mg/kg oral morphine, or the combination of both.

The winner is: not children. With 91 analyzed in the ibuprofen-only arm, 188 in the morphine-only arm, and 177 in the combination arm, there were no reliable differences between analgesia between groups. More disappointingly, the average pain score on the visual analogue scale was ~60mm across all groups, and no group improved more than 20mm within an hour. The authors considered a VAS score of <30mm at 60 minutes to represent adequate pain control, and less than a third from each group achieved this. There were no serious adverse events in any group, but 20% of those receiving morphine complained of mild adverse events, mostly nausea and abdominal pain, compared with 7% of the ibuprofen-only arm.

So, still at square one for oral analgesia – but, at least, this negative trial helps inform our avoidance of the intervention tested here.

“Oral Analgesics Utilization for Children With Musculoskeletal Injury (OUCH Trial): An RCT”

Azithromycin Ruins Everything

For some reason – and by “some reason”, I mean extensive evaluation of immunomodulatory properties – there is an obsession with azithromycin use for more than simply its anti-bacterial indications. It has been hypothesized to diminish inflammation and have antiviral properties, and, of course, functions as a floor wax and dessert topping.

This is a randomized, controlled trial of azithromycin versus placebo in pre-school children with acute wheezing as a primary diagnosis. The primary outcome was time to resolution of respiratory symptoms, and secondary outcomes included any use of short-acting beta-agonists, adverse events, and time to any repeat exacerbation of wheezing.  These authors enrolled 300 before funding ran out, and were able to follow-up 222 with completed symptom diaries. Patients were generally similar between the two groups, and over 80% of each cohort had prior episodes of wheezing, and a similar percentage used or was prescribed a beta-agonist at discharge from the Emergency Department.

The winner: nothing and no one. Azithromycin did not improve any outcomes versus placebo, and should not be used for suspected viral wheezing in the hopes of anti-inflammatory symptom improvement until better evidence of benefit emerges.

“Treatment of preschool children presenting to the emergency department with wheeze with azithromycin: A placebo-controlled randomized trial”

The Futility of NSAIDs for Back Pain?

This article filled with reproach for non-steroidal anti-inflammatories was highlighted in a New England Journal of Medicine Journal Watch and on Twitter – a wistful treatise remarking on the general ineffectiveness of pharmacologic analgesics. “Nothing works!” accompanied by a general gnashing of teeth and writhing on invisible flames.

But – does this meta-analysis actually reach such a conclusion? Examine the first few words in their conclusion:

NSAIDs are effective for spinal pain …

Off to a good start! But, the catch:

… but the magnitude of the difference in outcomes between the intervention and placebo groups is not clinically important.

These authors pool the results of 35 randomized, placebo-controlled trials for “spinal pain”, which is to say undifferentiated pain relating anatomically to any part of the spine. These trials comprised 6,065 participants – or, if you do the math, an average of 173 patients per trial, nearly all of them performed over a decade ago. The pooled effects of these trials all favored NSAIDs – but, as the authors mention, the absolute magnitude of effect on pain scales was a the edge of their threshold for clinical significance. The authors defined a difference of 10 points on a 100-point scale as clinically important, but most of their pooled results landed between -7 and -16, favoring NSAIDs over placebo. With these small samples, generally moderate GRADE quality, and moderate to high heterogeneity between the pooled results, there is a lot of fuzziness around their ultimate conclusion.

These authors do many, other, exploratory analyses, and it is reasonable to suggest the limitations inherent to each render any conclusions unreliable. Adverse events, as reported, were similar between groups – excepting for increased gastrointestinal adverse events, most of which were non-serious. The authors report this difference as a relative risk of 2.5 for GI side effects in their comparison, but the absolute differences are on the order of an excess of 1 in 100.

This is probably much ado about nothing. Their perspective is not inaccurate, per se, but these trials do find a consistent benefit to NSAIDs. The value judgment here on clinical effectiveness probably misses the mark, particularly considering these are inexpensive, readily available, with few adverse effects in short-term use. I would probably argue it is easier to defend a position they still have utility in multi-modal pain control regimens, rather than to conclude they be consigned to the rubbish bin.

“Non-steroidal anti-inflammatory drugs for spinal pain: a systematic review and meta-analysis”


Idarucizumab, the Sequel

There’s nothing hotter than idarucizumab, the reversal agent for dabigatran. It’s so hot, the New England Journal of Medicine once published a farcical 91 patient interim analysis of a planned 500 patient enrollment.  Now, two years later, we have the full cohort and it’s, well, more of the same, with all the flaws previewed in the previous iteration.

To recap, there are no viable reversal options for dabigatran besides this antibody fragment. And, in full sucker-born-every-minute fashion, Boehringer Ingelheim is both good cop and bad cop, selling us both the poison and the antidote.

There are 503 patients enrolled in this open-label study with two arms: Group A, with uncontrolled bleeding, or Group B, anticoagulated and requiring an urgent procedure. The primary outcome is, essentially, utterly unrelated to any of the context of enrollment – “maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab”, which is frankly already well-documented in the healthy-volunteer pharmacokinetic studies.

Theoretically, the interesting portion here is supposed to be the clinical relevance of the reversal effect – which is measured by secondary outcomes of subjective assessment of median time to cessation of bleeding in Group A or by periprocedural hemostasis in Group B. The most striking result in the interim result was a median time to cessation of bleeding of 11.4 hours – a concerningly high number calling into question the entire purpose of reversal. In this new publication, the median time to reversal is now reported as 2.5 hours. This also, oddly, differs from nearly identical cohort results presented to the American Heart Association – explicitly broken down as shown below:

Then, compare with this slide passed along by @bloodman from #ISTH2017 in Berlin:

Considering this was an easily critiqued result – and essentially the most clinically relevant – it’s not surprising the sponsor and their funded- and fee-supported collaborators solved the issue in the most expeditious fashion possible: exclude >55% of Group A from time-to-bleeding assessment.  Just toss out the patients who didn’t have cessation of bleeding within 24 hours, or – despite inclusion criteria of “signs and symptoms of (overt) uncontrolled bleeding” – the “bleeding location could not be identified”.

Most (93.4%) of patients in Group B were assessed as having normal hemostasis during their procedures, which occurred a median of 1.6 hours after completion of idarucizumab infusion. That said, many of the procedures were minimally invasive (catheter placement for dialysis, lumbar puncture, cutaneous abscess drainage) and likely favorably influenced both the fraction reported having normal hemostasis, as well as driving down the time to the intended procedure.

About 10% of the cohort had normal hemostasis at baseline as judged by the central laboratory, meaning they were likely not taking the dabigatran as reported or suspected – a smaller percentage than the interim analysis, where almost 25% were not. Whether this reflects better enrollment screening, or simply moving the goalposts again, cannot be reliably discerned from the results provided. Adverse events relating to the study drug, likewise, are difficult to parse without a true unexposed comparator.  Most of the cohort was elderly, with multiple comorbid conditions, in addition to their serious bleeding event or need for urgent procedural intervention. A handful of early thrombotic events and hypersensitivity-type reactions occurred, demonstrating there may yet be some consequential, but poorly quantified, risk to idarucizumab administration.

But, hand-wringing aside, we’re in the same place we were yesterday. Idarucizumab clearly and effectively removes dabigatran from circulation, unlike andexanet alfa and Factor-Xa inhibitors, and this ought to be occasionally clinically useful. I would certainly exhaust all potential supportive and expectant management options first, as well as try to definitively confirm dabigatran as the culprit for abnormal hemostasis. Ultimately, the best way to avoid idarucizumab? Don’t use dabigtran in the first place.

“Idarucizumab for Dabigatran Reversal — Full Cohort Analysis”