Methotrexate, Obesity, and Ectopic Pregnancy

Obstetric emergencies can be challenging to many pharmacists given the critical nature of these diseases and the need for immediate recall of medication information ranging from teratogenicity to second/third line agents in light of drug shortages.(1-4) Ectopic pregnancy is one of those scenarios where advanced knowledge and comprehension of the medical management is essential for pharmacists working in emergency departments. This, in large part, is as a result of the frequent use of methotrexate for this indication and the instilled fear of methotrexate from pharmacy school. Despite all of the safety measures deployed to reduce the likelihood of selecting the incorrect dosing (since there are many variations) confusion can still occur. However, given the worsening obesity epidemic in the United States, whether or not to adjust the dosing of methotrexate (often based on body surface area {BSA}) can further complicate the use of this drug.

Early application of methotrexate to management of ectopic pregnancy used moderate doses of 1mg/kg IM on days 0, 1, 3, 5, 7 with leucovorin rescue.(5,6)  While this regimen was clinically successful in reducing hCG level by 15% over two days in 92.7% of patients, several simpler single or two-dose regimens have found to be similarly effective and have replaced this multidose option.(6)  At many institutions, methotrexate is now dosed at 50 mg per meter squared on day 0 and hCG level is assessed on day 4, with the option for a one-time repeat dose of methotrexate if hCG level have not declined by 15% between days 4 and 7.

Contraindications and relative contraindications in ectopic pregnancy

Contraindication to methotrexate
High risk of treatment failure or relative contraindications
Allergy to methotrexate
Hemodynamically unstable/Ruptured ectopic pregnancy
Intrauterine pregnancy
Breastfeeding
Active pulmonary disease
Renal/Liver disease
Preexisting blood dyscrasia
Immunocompromised
Peptic ulcer disease
Unable to follow up
hGG > 5000 nIU/,L
Large mass > 3.5 cm
Embryonic cardiac activity present
IUP has not been ruled out

However, in obese and morbidly obese patients, dosing based on BSA may lead to underdosing (not to mention inadvertent subcutaneous administration and altered absorption characteristics), treatment failure and potential complications or surgery.(7) On the flip side, methotrexate can cause dose-dependent toxicities including stomatitis, esophagitis, kidney failure, myelosuppression, hepatitis, and central nervous system dysfunction.(8) Therefore, it is necessary to limit the exposure of patients to this drug to the minimum necessary to achieve the desired clinical outcome.

Unfortunately, there is no recommendation from ACOG on how to approach methotrexate dosing in obese patients, and until recently there was no evidence of whether dose adjustments or capping in safety or efficacy.

In this recent study from Detroit, Hoyos et al. conducted a retrospective cohort study of patients diagnosed with tubal ectopic pregnancy who underwent medical management with methotrexate dosed at 50 mg per meter squared, but with a maximum dose of 100 mg, over a 3 year period.(9)

Patients were included if the ectopic pregnancy was located in the fallopian tube, had a BMI recorded, were hemodynamically stable, consented to methotrexate therapy, and had at least one beta-hCG follow up level drawn. They excluded patients whose initial beta-hCG was less than 1000 mIU/mL, did not have beta-hCG follow up or were not treated with single-dose methotrexate.

Patients who met the study inclusion criteria were divided into two groups based on their BMI; > 40 kg per meter squared or < 40 kg per meter squared. Analyses were also planned for patients divided into the following groups: presence of embryonic heart tones, maximum diameter of ectopic size (<35 mm="" vs=""> 35 mm) and beta-hCG levels before methotrexate (< 5000 mIU/mL vs > 5000 mIU/mL).

The main outcome measures were as follows: a decrease in serum beta-hCG of at least 80% following methotrexate, need for > 2 doses of methotrexate, surgery despite medical management, a combined variable of either surgery or the need for additional methotrexate as defined as a decrease in serum beta-hCG of at least 80% following methotrexate. 

During the study period, 290 patients were identified, but 137 (47.2%) were excluded due to hCG levels less than 1000 mIU/mL. Of the remaining 151 patients, 89.4%(135/151) were non-morbidly obese (BMI < 40kg/m2), leaving only 10.6% (16/151) in the morbidly obese arm.

With regards to the study outcomes, morbidly obese patients (BMI > 40 kg/m2) were significantly more likely (31.3%, 5/16) to require at least 2 doses of methotrexate compared to non-morbidly obese patients (8.2%, 11/134, OR 5.1 95% CI 1.5-17.3, p =0.015). However, there were no statistically significant differences in the proportion of patients requiring surgery despite medical management, achieving a decrease in serum beta-hCG of at least 80% following methotrexate or a combined variable of either surgery or the need for additional methotrexate.

The authors concluded that this method of dose capping led to more patients requiring additional methotrexate doses, but concede that there is insufficient data to make any recommendations and adequately powered randomized studies are needed.

Given the nature of the design of this study, its inherent limitations, lack of safety data for both higher doses of methotrexate or clinical sequelae of repeated doses vs underexposure, this study does little more than add confusion. As is seems currently, there is another medication safety paradox emerging: methotrexate dosing can continue to increase with increasing BMI, with unknown consequences - or - methotrexate dosing can be empirically/arbitrarily capped with unknown consequences.

Given the awareness of methotrexate from a toxicologic perspective can shed some light on this paradox. Consider a patient with a BSA of 2.25 m2 - (roughly 62” and 130kg). Based on a 50 mg/m2 dose, this patient would receive 112.5 mg IM x 1.

  • Absorption: while the absorption from IM tissue is desired, there is no guarantee that there will be sufficient needle penetration beyond subcutaneous tissue. The clinical ramifications of this are unknown. 
  • Distribution/elimination: Methotrexate distribution (0.6-0.9% L/kg) does not appear to be affected by obesity based on pharmacokinetic data from a single case report(10). But, the third phase of methotrexate elimination (redistribution from tissues), patients could be exposed to methotrexate for longer periods of time, possibly mimicking the common error of daily vs weekly oral methotrexate. 
  • Risk reduction: So you give a little more methotrexate, then avoid other drugs that will increase risk of nephrotoxicity from methotrexate (ex., NSAIDs, aminoglycosides, salicylates and piperacillin).(8) 
  • Consider the dose: Capping the dose at 100 mg or giving 112.5 mg comes nowhere close to higher doses use for cancer (upwards of 1-10g per m2). So perhaps this concern is really not a concern at all.  

References:

1 - Gynceologists ACoG. ACOG Practice Bulletin No. 94: Medical management of ectopic pregnancy. Obstet Gynecol 2008; 111(6):1479-85.
2 - Barnhart KT, et al. Clinical practice. Ectopic pregnancy. N Engl J Med 2009;361(4):379-87.
3 - Seeber BE, Barnhart KT. Suspected ectopic pregnancy [published correction appears in Obstet Gynecol. 2006;107(4):955]. Obstet Gynecol 2006;107(2 pt 1):399-413.
4 - Lipscomb GH, et al. Medical management of ectopic pregnancy. Clin Obstet Gynecol 2012;55(2):424-32.
5 - Barnhart KT, et al. The medical management of ectopic pregnancy: a meta-analysis comparing single dose and multidose regimens. Obstet Gynecol 2003;101(4):778-784.
6 - Bachman EA, et al. Medical Management of Ectopic Pregnancy: A Comparison of Regimens. Clin Obstet Gynecol 2012 Jun; 55(2): 440-447.
7 - Pai MP, et al. Drug dosing based on weight and body surface area: mathematical assumptions and limitations in obese adults. Pharmacotherapy 2012;32(9):856-68.
8 - Wang RY. Wang R.Y. Wang, Richard Y. Chemotherapeutics: Methotrexate. In: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. Hoffman R.S., Howland M, Lewin N.A., Nelson L.S., Goldfrank L.R. Eds. Robert S. Hoffman, et al.eds. Goldfrank's Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1163&sectionid=65095222. Accessed April 15, 2017.
9 - Hoyos LR, et al. Morbid obesity and outcome of ectopic pregnancy following capped single dose regimen methotrexate. Arch Gynecol Obstet 2017; 295:375-81.
10 - Flemming R, et al. Disposition of high-dose methotrexate in obese cancer patient. Cancer 1991;68:1247-50.

I’ve Felt the Burn, and Live to Tell About It

After 6 years of experience since completion of my residency training, I have felt a tremendous amount of growth. As I have said earlier, the more experience I gain, the more I respect those who have it, and realize how little I truly have. There is no hidden meaning or cryptic message. Rather than resisting advice or guidance, I now listen to someone who's been through it all and come out wiser. It's such an obvious epiphany but it took burnout and reflection for me to figure it out.

Yes, I felt burnt out. My early (still early, but who’s counting) career was spent relearning what I should have learned in pharmacy school, discovering what a pharmacist actually does (not the fairy tale described in school) and learning from mistakes. The final straw was actually FOAMed. But let me be clear: I do NOT blame FOAMed. My participation and consumption of blogs and podcasts has created a broader understanding of a plethora of topics that I would have otherwise not been exposed to. But, it also led me down a path of becoming frustrated with the philosophy of evidence-based medicine. At first, it was invigorating to learn the truth behind a dogma or clarify a prescribed doctrine. But an unintended consequence emerged and it began to seem that everything I thought I knew was probably wrong, what I was instructed as fact turned out to be opinion or misrepresentation of evidence, there was no point reading new literature since it's probably crap or biased and even if it was solid, nobody I work with is reading it. This lead to an endless cycle of defending my point of view to dogma or experience. Most of what I wrote or read became cynical, pointing out flaws without solid solutions and ultimately becoming regressive. This bled into my day-to-day work. After 6 years of practice, I did not expect to feel so defeated and to continue to have the same discussions, the same replies, and the same outcomes. I was close to giving up.

I certainly do not feel I am out of the hole yet, although I do feel I’ve seen the light at the end. It may seem simple, but how I got there was further reflection on what I love about my job. The two strongest elements of which are: the scientific method, and learning how things work. There are however, forces intended to help which actually hinder development and led to my burnout. My perception of FOAMed was one, but changing my perspective and attitude addressed my issues. But without addressing the remainder, I feel as though others may follow my path, or I may find myself back where I started. Those forces are pharmacy education and professional societies.

Scientific Method 

Similar to many children of the 80’s I grew up with amazing popular culture science figures. For me, Bill Nye was my man. I could point to all the usual things about how inspiring he was to me, or the exposure to science in general as reasons to fall in love with the field. But thinking back on it now, as an adult, I feel strongly drawn to the idea of observing - forming a question - designing an experiment to try to answer the question - observing a result - deriving a new question from this result - designing a new experiment, and so on. It’s a never-ending process. But in some perverted way, pharmacy school imprinted an attitude that some results of this process are good or bad - right and wrong - and (most importantly) that the cycle is finite. Personal biases and attitudes poisoned the process and halted any further exploration of a study conclusion. For example: learning rate versus rhythm control for atrial fibrillation. Rate control = good; rhythm control = bad, and so sayeth the guidelines. However, looking further into the research and guidelines themselves - additional questions arose, and the research cycle seemed to stop rather than ask foster lines of question flowing into investigations with the same rigor.

My perception of literature as either being good or bad led me to form emotional connections with a given therapy, or strategy. So when the idea was challenged, I recoiled and felt insulted or attacked rather than embracing a new idea and challenging my hypothesis. This attitude permeates through the profession. In essence, I lost what I loved about the process of scientific investigation. Piling on top, a number of FOAMed contributions, including my own, furthered my nihilistic, or at the very least, cynical attitude.

Although I cannot fully describe how it happened, I knew why I needed to change and snap out of this dark place. It was like looking down two paths: one that was an easy slide down into this self deprecating, sarcastic pit - or - a sheer cliff, straight up, towards embracing the scientific method. Approaching each question now, not with fear of finding out something else I thought I knew turns out to be totally wrong, but embracing the idea that I may have a new exciting question to further investigate through research of my own or reading other supporting or refuting evidence. However, the most crucial component is that this cycle is infinite. Embracing that, has provided me with some inner peace and invigoration to keep learning.

Also, I stopped pretending I knew everything. I shook off the shame of hearing a voice echoing from preceptors and faculty, “You don’t know this?! You have to know this!”

How Things Work 

The second piece fits directly into this scientific view: I love to learn about how things work. This was a leading factor pushing me towards engineering when I was a kid in high school. Although I’m glad to end up in pharmacy, there are just as many mechanisms of drugs, disease and the body to understand and feed my interest. But I had no idea to the degree with which a deep and thorough knowledge of fundamental mechanisms plays into understanding everything else to come in medicine and pharmacy. I mean, of course I should have known, but I was a naive cocky little shit.

If the scientific method is my door through pharmacy/medicine, physiology and pharmacology are the keys. They must go hand in hand. When one holds onto a therapeutic dogma like loop diuretics in acute pulmonary edema, pharmacology (with physiology) is the prevailing logic. Yet, I find it challenging to have discussions with residents or other professionals who forget these fundamentals, and end up relying on what is dictated in the guidelines or what they remember from a teacher or preceptor. What’s worse is that we are now teaching the guidelines in school rather than teaching fundamentals. For any students, or residents out there- you will have a very difficult time with me (or anyone else) if you can’t talk to me about what beta-blockers have to do with calcium. Sure, you’ll get by in professional life, but there will come a stopping point. I could care less what CHEST says. If you know the pharmacology and pathophysiology, and can challenge your ideas with primary literature, I guarantee you can predict what the guidelines will say. Furthermore, you’d be able to predict how they would change in the future.

Embracing this method, admitting that I don’t know everything, and continually building and maintaining a foundation in fundamental concepts is where I find myself now. However, it isn’t easy (nor should it be), but it feels as though professional CE or BCPS CE hinders, rather than helps, in my view. But I’ll get to that in a moment.

Education and Organizations 

Burnout is no joke. I had no idea it was happening, but I’m glad to have recognized it and had the luxury of working through it. I fully appreciate how burnout can be different to different individuals, but for pharmacy - particularly young pharmacists within 5 years of finishing residency - we, as a profession, are at tremendous risk of losing great minds. After finishing residency, the professional societies have little to offer (at least for me) in real professional development and guidance. The furious pace of 2 years of residency is not sustainable through the length of a career. Yet, nobody stops to tell anyone that. Nor do we help those new to practice how to develop healthy learning habits. And I’m not talking CE. CE is useless and everyone knows it. That includes BCPS CE. For example, since completing residency, I have attended numerous national professional pharmacy conferences, but the content at each remains the same. Someone (including myself who has presented nationally) read a few papers that they did not write, and is now telling you about them. It’s a glorified book report and offers little room for debate and opinion outside of the norm. While I’ve been frustrated by the lack of innovation and controversy, I know feel even more concerned. Largely by asking this question: Where are the pharmacists doing innovative, controversial, thought provoking or practice challenging research? And why aren’t the presenting here? The hopeful answer is that they’re presenting at “better” medical conferences, but I fear they actually don’t exists at all.

It is challenging to bring up concerns or alternative views for fear of repercussion, because I feel as though having an alternative view will be labeled “unprofessional.” But this model makes sense in a way when considering the figures of our profession and thus the target audience. According to data from the Bureau of Labor Statistics, there were approximately 297,000 pharmacists in 2014 in the USA. Of which 105,000 belonged to one of our two major professional organizations: APhA and ASHP (almost a 60/40 split, respectively). While it is next to impossible to find membership data, I would wager that for ASHP, more than 50% of their 43,000 members are either in school or within 5 years of finishing school (i.e. residents or new pharmacists) with the remainder being members of boards, and advanced leadership positions, and faculty/preceptors who get their memberships paid for. So directing education at 0-5 year level experience is logical, easy to do and requires very little intellectual currency. Contracting young speakers, throwing a little cash at them and a nice feather on their CV makes a recipe for professional development (again, I did this, and benefited from it). But keeping those interested and continuing their development from 5-10 years, then 10-20 years, and engaging those with 20+ years experience to give lectures, present arguments and facilitate debate is hard to do. A similar pattern is playing out in academia as well - turning it into an entry-level position (again, myself included - I had no business being in the classroom with less than 5 years experience). This lonely island of too experienced to benefit from novice lectures, having questions, or seeking discussion that is ‘controversial’ but not experienced enough to have wisdom, is a threat to the profession. And it’s worse than I think it may be.

Yes, burnout is being ignored, but what’s worse, in my opinion, is that the reality of what an actual pharmacist does is starkly in contrast to what professional organizations think we do. This constant pushing of furthering practice, by those who do not practice or have insufficient practice, is a measuring stick to which we assess our careers. The ever-moving goal posts to which we measure professional success adds onto the brutality of professional life as a pharmacist. After long, expensive education, entering into thankless employment with poor external gratification for a job well done makes deriving fulfillment difficult to do. This assessment will always land me falling short of misguided expectations, and thus feeding into burnout.

The expectation becomes: Doing A, B and C is nice and all, but you should be A, B and C, plus X, Y, and Z since that is what our profession needs. The push du jour is pharmacists' prescribing of medications. Even if I could prescribe, I wouldn't because I do not fully comprehend every aspect that entails diagnosis. Furthermore, our education is insufficient to do so in safe and productive manner. I’d rather be the expert in everything to do with medication, and provide that experience to the team who is making those diagnoses, and ultimately prescribing. Personally, I like that method better. But what I’m being told by professional organizations is that that attitude is wrong. To me, we have no business prescribing while drug errors occur in the capacities that they do on a regular basis in medicine. Once medication errors are 0 (or near zero) then we can make sure that each and every person taking a medication is on the correct drug, correct dose, correct route, frequency, fully understands why they take it, and ensure the risks are accounted for, no unnecessary medications, and on and on - then we can talk about prescribing. It’s not a sexy view of pharmacy. But I'm not here for the sexiness.

But there I go again, being cynical and not offering solutions. After seeing burnout, and living to tell about it, I know I must offer at least something to start the discussion. I cannot continue to pretend that I agree with the direction of the profession. To change course, stop political contributions and PAC spending by our organizations used to lobby for provider/prescriber status and redistribute the money and effort to facilitate professional education and fund post-graduate education for those qualified to seek it. Why I believe this is several-fold:
  1. There is a clear disaster in demand for residency-trained pharmacists, and demand for residencies - but insufficient residency positions. The obvious consequence is that good candidates are losing out just because of the sheer odds (nearly a 2:1 ratio of candidates to positions) of landing a position. What’s more concerning, is that eventually, these smart students will look to pharmacy and ask themselves: six figure debt, and (at least) 8 years of training, for this? Or choose medicine/law/PA/anything else. Pharmacy schools are in fact losing applicants year by year, and we will feel it soon. 
  2. Any political spending should be directed towards revising CMS pass-through funding to include PGY-2 residencies, not just PGY-1. The ball was fumbled at the 1-yard line here and needs to be picked up. 
  3. To push our profession forward, I believe in demonstrating capability, rather than mandating a function. Thus, education (including post-graduate residencies) and continuing professional development is fundamental. I cannot prescribe, however, I feel as though through hard work, building of trust and a professional relationship, I can still achieve the same outcome for patients. Furthermore, there has been more than one circumstance where a physician has brought up additional questions I did not consider which ultimately led to a different treatment path. 
  4. Board certification must be meaningful. The certificate looks great on my wall (it's actually not, it's in a bag, in a closet). But with or without it, I still make the same amount of money, can have the same job, perform the same activities - but I have to pay a "maintenance fee," and recertification credit. It (BCPS) either becomes the standard for practice (bye-bye NAPLEX), or the two are merged to create a new standard. This is an easy task if more are able to go through a residency program. 
  5. We forget about those who have > 10 years experience, and how the proposed change in practice would isolate, rather than engage them. With poor quality, and really no incentive to seek challenging CE, many pharmacists feel intimidated by the changing professional landscape. We should feel ashamed by that, not sweep it under the rug.
I may be wrong. However, I remembered I have the desire to develop questions/hypothesis, design solutions/investigations and observe outcomes. Most importantly, not fear the potential that my opinion may change based on new discussion or new facts.

Revisiting Esmolol for Refractory Ventricular Fibrillation in Cardiac Arrest

A 63-year-old male arrives to the resuscitation bay in cardiac arrest with ongoing cardiopulmonary resuscitation (CPR). Per EMS, the patient was found in ventricular fibrillation (Vfib) and has received defibrillation 6 times with four rounds of epinephrine and 2 doses of amiodarone (300 mg, 150 mg) prior to arrival. In the emergency department (ED), the patient is noted to still be in Vfib and a dose of 1 mg/kg of lidocaine is administered without termination of the arrhythmia. Are there any additional agents that can be utilized in hopes of achieving return of spontaneous circulation (ROSC)?

Refractory Vfib (RVF) is defined as ventricular fibrillation resistant to at least 3 defibrillation attempts, 3 mg of epinephrine, and 300 mg of amiodarone without ROSC after at least 10 minutes of CPR (1). RVF has also been described as a severe form of electrical storm in which rapidly clustering episodes of Vfib recur or persist after multiple defibrillation attempts (2). Although epinephrine is known to increase ROSC, high levels of endogenous or exogenous catecholamines may have potentially harmful effects on the myocardium via β-1 receptor agonism (3). Notable deleterious effects include increased myocardial oxygen requirements, worsening ischemic injury, lowering of Vfib threshold, and a worsening of post-resuscitation myocardial function (2). It has been theorized that antagonism of β-receptors in the myocardial tissue during cardiac arrest may mitigate the potentially harmful effects of epinephrine, while preserving the beneficial alpha-receptor mediated actions (3).

Animal models experimenting with beta-antagonists during cardiac arrest is not novel. Propranolol was studied in several animal models in 1994 followed by esmolol in 1995. Overall, the animal literature has shown beta-antagonists to reduce myocardial oxygen requirements, decrease the number of defibrillation attempts, improve post-resuscitation myocardial function, diminish arrhythmia recurrence, and prolong survival (4). Esmolol is preferred over propranolol given its faster onset of action and very short half-life should therapy need to be discontinued if the patient exhibits cardiogenic shock (2).


Two case series have been published examining the effects of esmolol on human subjects with RVF. The first, published in 2014, reviewed 6 cases of patients receiving esmolol in the ED compared to 19 control patients also in RVF (see table below for individual patient details) (2). Overall, 4 of 6 patients achieved sustained ROSC after a 500 mcg/kg intravenous bolus of esmolol was administered followed by a continuous intravenous infusion of at most 100 mcg/kg/min. The other 2 patients achieved temporary ROSC after esmolol, but eventually re-arrested and expired. Comparing esmolol versus standard-of-care, patients who received esmolol were more likely to have temporary ROSC (67% versus 42%), sustained ROSC (67% versus 32%), survive to hospital discharge (50% versus 16%), and survive to discharge with a favorable neurologic outcome (50% versus 11%). The authors concluded that beta-blockers “should be considered in patients with RVF in the ED prior to cessation of resuscitative efforts” (2).

In late 2016, a group of investigators from Korea published a pre- and post-cohort study following implementation of esmolol for RVF in out-of-hospital cardiac arrest. Adult patients received an intravenous bolus dose of 500 mcg/kg of esmolol followed by a continuous intravenous infusion of up to 100 mcg/kg/min in patients without ROSC following 3 or more defibrillation attempts, 3 mg of epinephrine, and 300 mg of amiodarone. Patients in the esmolol (n= 16) and non-esmolol (n= 25) groups were well-matched at baseline; however, the details regarding the timing of administration of esmolol were not provided. The esmolol group demonstrated a higher rate of temporary ROSC, sustained ROSC, and survival to the intensive care unit.

In conclusion, esmolol is a β-1 selective antagonist that may mitigate potential negative effects of high levels of epinephrine such as increased myocardial oxygen requirements, lowering of the Vfib threshold, and worsening of post-resuscitation myocardial function. In several animal models, and now human subjects, esmolol has been shown to increase ROSC, improve post-resuscitation myocardial function, diminish arrhythmia recurrence, and most importantly increase the chance of survival to discharge with good neurological function. After failure of standard ACLS measures among patients with refractory Vfib (and potentially pulseless ventricular tachycardia), an intravenous bolus dose of 500 mcg/kg of esmolol can be considered, with or without a continuous infusion, to increase the likelihood of sustained ROSC and survival.

References:

  1. Lee YH, et al. Refractory ventricular fibrillation treated with esmolol. Resuscitation. 2016;107:150-155. 
  2. Driver BE, Debaty G, Plummer DW, Smith SW. Use of esmolol after failure of standard cardiopulmonary resuscitation to treat patients with refractory ventricular fibrillation. Resuscitation. 2014;85:1337-1341.
  3. BET 2: Usefulness of epinephrine in out-of-hospital cardiac arrest. Emergency Medicine Journal. 2016;33(5):367-368.
  4. Oliveira FC, Feitsoa-Filho GS, Ritt LEF. Use of beta-blockers for the treatment of cardiac arrest due to ventricular fibrillation/pulseless ventricular tachycardia: a systematic review. Resuscitation. 2012;83:674-683.
  5. McNally B et al. Out-of-hospital cardiac arrest surveillance --- Cardiac Arrest Registry to Enhance Survival (CARES), United States, October 1, 2005--December 31, 2010. MMWR Surveill Summ. 2011;60(8):1-19.
  6. Kudenchuk PJ et al. Amiodarone, lidocaine, or placebo in out-of-hospital cardiac arrest. New England J Med. 2016;374(18):1711-1722.
Scott Dietrich, PharmD (@PCC_PharmD)
Emergency Medicine Clinical Pharmacist
University of Colorado Health - North

Peer reviewed by Craig Cocchio, PharmD, BCPS (@iEMPharmD) and Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)

Antihistamines for Analgesia: Down to the Bone (Pain)

Clinicians in emergency departments across the country have increasingly become more savvy in their approach to the management of common pain conditions that patients may present with in this setting. In the effort to overcome the effects and consequences of the opioid abuse epidemic, great emphasis is now being placed in leveraging opioid-free alternatives in new ways for the management of these frequently encountered common pain conditions. This may involve utilizing target-specific agents in the mitigation of pain based on the known or hypothesized mechanism of pathophysiology, down to the very level of the receptor.

There is one niche patient population where managing pain may present somewhat of a challenge to the clinician - the cancer patient with bone pain following the administration of granulocyte-colony stimulating factors (G-CSFs), which are commonly used in conjunction with chemotherapy for the prevention of febrile neutropenia. G-CSFs have a notorious adverse effect of inducing bone pain, which can occur in upwards of 60% of patients who receive these agents (1-2).

The multimodal mechanism for induction of bone pain by G-CSFs has been theorized to involve increased sensitivity to peripheral nociception; propagation of the inflammatory pathway, with modulation and release of inflammatory cytokines; and remodeling and metabolism of the bone through activation of osteoblasts and osteoclasts and expansion of the cells of the bone marrow, which may result in an increased release of histamine (3).


Treatment options for G-CSF-induced bone pain have traditionally involved the use of acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and opioid analgesics (3). These agents are not without their risks and any benefit that may be provided by these agents may be suboptimal, as they may not necessarily target the area of focus that drives the propagation of pain associated with this condition in the first place.

In the case of G-CSF-induced bone pain, one means of providing analgesia may very well mean utilizing H1-receptor antagonists (antihistamines). As early as the mid-1990s (4), H1-receptor antagonists have been evaluated for its utility as analgesics for the management of bone pain secondary to the administration of G-CSFs. Relatively recently, within this class of agents, loratadine has emerged as a treatment option for treatment of G-CSF-induced bone pain. Because it is a second-generation antihistamine, it is less likely to induce less sedation and other anticholinergic adverse effects relative to the first-generation antihistamines due to its reduced ability to cross the blood-brain barrier, which makes it relatively tolerable for most patients. In addition, as it was one of the first agents within this subclass to exist as a generic medication that is widely available over-the-counter, it has gained traction with this off-label use for treating G-CSF-induced bone pain (although that is not to say that other second-generation antihistamines are any more or less effective than loratadine in managing this condition).

There have been a number of case reports (5-6) published related to the successful use of loratadine in the treatment of G-CSF-induced bone pain, one which notably documented its use as abortive therapy for treating this condition in the emergency department (6). The results of a recently published pilot study consisting of 213 patients who randomized to receive a one-week regimen of either loratadine or placebo as a prophylactic agent in the treatment of bone pain following the use of G-CSFs demonstrated no significant differences in pain scores in patients with severe bone pain nor any significant improvement in quality of life for those patients with risk factors for developing bone pain (7). However, a number of factors may have contributed to these observed results, such as the use of other adjunct analgesic agents, the mixed patient population with multiple types of cancer, and the investigators' reliance on questionnaires distributed to patients as a means to assess pain status over the course of the study.

In contrast, the results of one open-label investigation (not surprisingly) demonstrate that loratadine is better tolerated than naproxen in managing pain associated this condition in those patients with a history of stages I through III breast cancer (8). In addition, one investigation is currently ongoing in recruiting participants to evaluate the effects of loratadine in mitigation of bone pain associated with administration of G-CSF in those patients with hematologic malignancies (9). Investigators of a rather unique but small observational, retrospective study of cancer patients evaluated the utility of using both H1 and H2-receptor antagonists (loratadine in combination with famotidine) as prophylactic agents for G-CSF-induced bone pain, and improvement in pain scores was noted (10). 

As important as it is to recognize the cause of pain associated with this phenomenon, it may be worth considering the use of loratadine as a treatment option for bone pain associated with G-CSFs. The typical adult daily dose of loratadine is 10 mg, which may be prescribed in the emergency department. With coordination from the oncologist, recommendations may be made for future use of loratadine in managing G-CSF-induced bone pain should the patient require subsequent administration of G-CSF.

Done and done.

References:
  1. Pinto L, Liu Z, Doan Q, et al. Comparison of pegfilgrastim with filgrastim on febrile neutropenia, grade IV neutropenia and bone pain: a meta-analysis of randomized controlled trials. Curr Med Res Opin 2007; 23:2283-95.
  2. Gregory SA, Schwartzberg LS, Mo M, et al. Evaluation of reported bone pain in cancer patients receiving chemotherapy in pegfilgrastim clinical trials: a restrospective analysis. Community Oncol 2010; 7:297-308.
  3. Lambertini M, Del Mastro L, Bellodi A, et al. The five "Ws" for bone pain due to the administration of granulocyte-colony stimulating factors (G-CSFs). Crit Rev Oncol Hematol  2014; 89:112-28. 
  4. Gudi R, Krishnamurthy M, Pachter BR. Astemizole in the treatment of granulocyte colony-stimulating factor-induced bone pain. Ann Intern Med 1995;123:236-7.
  5. Romeo C, Quan L, Copeland L. Severe pegfilgrastim-induced bone pain completely alleviated with loratadine: a case report. J Oncol Pharm Pract 2015; 21:301-4.
  6. Moore K, Haroz R. When Hydromorphone Is Not Working, Try Loratadine: An Emergency Department Case of Loratadine as Abortive Therapy for Severe Pegfilgrastim-Induced Bone Pain. J Emerg Med 2017; 52:e29-e31.
  7. Moukharskaya J, Abrams DM, Ashikaga T, et al. Randomized phase II study of loratadine for the prevention of bone pain caused by pegfilgrastim. Support Care Cancer 2016; 24:3085-93.
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Trick of the Trade: Quick & Painless Ampule and Filter Needle Technique

Standard technique for transferring a medication from a glass ampule involves swabbing the ampule with isopropyl alcohol and breaking the neck of the ampule with the alcohol pad or gauze. The problem that many can attest to is the glass breaking in a way that punctures through the pad or gauze and cuts into one’s digits.
Not only is this a painful issue, but there are other considerations when a member of the team cuts themselves: leaving the bedside, hemostasis, glove replacement, potential need for a new ampule, infection, and a focus change from the patient's needs to yours.
Ampule assortment of commonly used medications in emergency medicine

TRICK OF THE TRADE

Avoiding glass in your finger(s) when using a filter needle

Detailed step-by-step instructions:
1. Pull a syringe, alcohol pad, and filter needle. Quickly swab the neck of the ampule.
Keep the syringe and needle aseptic and not on a counter

2. Attach the filter needle to the syringe and place the bottom cap of filter needle on to the top of the ampule. Break neck with hands away and out from you. Withdraw the solution from ampule.
Note: Never inject medication back through the filter needle after withdrawing from a glass ampule.

This trick of the trade works for almost every ampule size and may take a few attempts to optimize the aseptic components of the technique (see video above). 

Mark Culver, PharmD, BCPS (@EMdruggist)
Emergency Medicine Pharmacist
Banner - University Medical Center Phoenix
Phoenix, Arizona

Peer reviewed by Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)