New Year's Resolutions for the Pharmacist

Most of the time, the New Year ushers in thoughts of dropping 15-20 lbs and signing up for a few road races.  No, not to race, but just to finish.  This year, I have been much more introspective thinking about life and career and all the above.  Maybe some of these pharmacy related resolutions will be similar to yours.

1. Begin studying for another certification.  I am heavily learning toward the BCNSP.  I am in no hurry because quite honestly, there is no reason professionally to obtain.  I would just accomplish something that has interested me in the past.  I used to work for a home infusion company and there was a pharmacist (JB) who was quite fabulous.  I am sure he still is today, but I noticed he has this designation and is probably running circles around most in the area when it comes to nutrition.  It is quite an in-depth topic from enteral to parenteral nutrition, and I am predicting another 1-2 year study.  I have purchased the material and have started though not nearly as much gusto as the BCPS so far.  If you are not certified, consider it.  IT MATTERS.
2. Stop worrying about what other pharmacists think about you.  You cannot live your professional life trying to beat out or outsmart the guy/gal next to you.  Yes, you may be in fact more qualified and more experienced, but you cannot control how a company decides to utilize your experience or knowledge.  Perhaps a position in a different area will open up and any type of learning on the side you have pursued will open doors!?  Sometimes it is just timing and sometimes just sheer luck.  In the meantime, focus on being a better pharmacist.  Focus on remaining competitive and the go-to person for all things current.  If you keep up with the current practice and move forward, the people who win are your patients.
3. Look to the future.  Prepare for the future so that when it happens, you will be ready to step right into the role without any problems.

Those are my resolutions for pharmacy this year.  I hope 2014 holds many wonderful things for you in your career whether it is pursuing a board certification or attending an update to begin the process to do more for your patients than last year.

Cheers!

Should you be recommending a proton pump inhibitor (PPI) or H2-receptor antagonist (H2RA) for stress ulcer prophylaxis in critically ill patients?

We know that PPIs are better than H2RAs at raising intragastric pH, but we don’t know whether this higher pH value translates to superior clinical outcomes.  In fact, there is some debate whether a higher pH could actually cause problems, like nosocomial pneumonia or Clostridium difficile infection.  Given that clinically important GI bleeding has been associated with a high mortality rate (48.5% vs. 9.1% in non-bleeders), it seems that selecting the best agent for stress ulcer prophylaxis is an important decision. This hotly-debated topic, reinvigorated by the 2012 Surviving Sepsis Campaign Guidelines’ grade 2D recommendation in favor of PPIs, has again been examined with a recent meta-analysis by Alhazzani et al published in the March 2013 issue of Critical Care Medicine.

Actual .pdf of meta-analysis.

Of course, this is not the first meta-analysis to examine the topic.  In fact, three other meta-analyses have been published since 2009.  Here, here, and here. Naturally, the authors of this most recent meta-analysis claim that their statistical analysis was superior, they included more relevant trials, and they excluded more inappropriate trials to make this analysis a more pure, scientifically-valid view of the data.

This meta-analysis combined 14 randomized controlled trials with 1,720 total patients.  The analysis concluded that PPIs were associated with a reduction in clinically important upper GI bleeding (1.2% vs. 6.4%, NNT 19, RR 0.36, p=0.002) and overt upper GI bleeding (3.8% vs. 15.7%, NNT 9, RR 0.35, p<0.0001).  There was no difference in nosocomial pneumonia, ICU mortality, or ICU length of stay.

Is it time for famotidine and ranitidine to hang up their hat in the ICU?  The evidence from this meta-analysis appears compelling at first glance, but diving deep into the manuscript reveals some troubling issues.

First, the included trials were not comparing similar treatments of H2RAs.  Some trials used continuous infusions, some used once daily dosing, and one did not report dose at all.  It is scientifically questionable to pool a variety of different H2RAs with different dosing strategies together into a single group and categorize the treatments as being the same.

Second, the included trials did not have consistent definitions for “clinically important bleeding” and “overt bleeding”.  Some trials used very strict definitions where bleeding had to be confirmed with EGD, others has very loose criteria (eg, hemodynamic instability not explained by other causes), and some did not even provide definitions.  Indicative of the questionable criteria, 5 of the 12 included trials had an event rate of 0% in both arms, whereas one trial had an event rate as high as 31%.

Third, one must question whether the endpoint of “clinically important bleeding” is a surrogate or a clinically relevant outcome.  Given the questionable definitions and criteria used, a firm endpoint like ICU mortality would be a definitive approach to concluding a victor.  Unfortunately, there was no difference in ICU mortality demonstrated in this meta-analysis (17.5% PPI vs. 21.2% H2RA, p=0.91).

Given the paucity of high-quality data examining PPIs versus H2RAs for stress ulcer prophylaxis, it can be extremely temping to favor meta-analyses to find an answer to this compelling question.  The fallacy in this approach, however, is that you cannot take a multitude of poor-quality trials (many with fewer than 50 patients in the H2RA arm) and somehow combine the data into a valid, reliable, unbiased manuscript on which you base your clinical practice.

So how should we interpret this meta-analysis?  In my view, until better quality evidence comes out, there is no proven difference in the prevention of stress ulcer prophylaxis between PPIs and H2RAs.  The decision should be made based on formulary considerations (cost and availability), formulation considerations (ability to be crushed), the patient’s history of using a particular agent prior to admission, and potentially drug interactions (although I believe the PPI/omeprazole debate has not been concluded).

Sean P. Kane is a critical care clinical pharmacist and the author of ClinCalc.com -- an evidence-based website with clinical tools and calculators for medical professionals.

Nexium photo:  Photo credit: License Some rights reserved by Rennett Stowe

BCPS 2013: ADHD Pediatrics (Stimulants: Methylphenidates)

The DSM-5 will not be out until later this year (hopefully).  So, the criteria for ADHD in the DSM-IV-TR:

DSM-IV Criteria for ADHD

I. Either A or B:

Six or more of the following symptoms of inattention have been present for at least 6 months to a point that is inappropriate for developmental level: Inattention

1. • Often does not give close attention to details or makes careless mistakes in schoolwork, work, or other activities.
   • Often has trouble keeping attention on tasks or play activities.
   • Often does not seem to listen when spoken to directly.
   • Often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions).
   • Often has trouble organizing activities.
   • Often avoids, dislikes, or doesn't want to do things that take a lot of mental effort for a long period of time (such as schoolwork or homework).
   • Often loses things needed for tasks and activities (e.g. toys, school assignments, pencils, books, or tools).
   • Is often easily distracted.
   • Is often forgetful in daily activities.

   Six or more of the following symptoms of hyperactivity-impulsivity have been present for at least 6 months to an extent that is disruptive and inappropriate for developmental level: Hyperactivity

• Often fidgets with hands or feet or squirms in seat when sitting still is expected
• Impulsivity
• Often blurts out answers before questions have been finished.
• Often has trouble waiting one's turn.
• Often interrupts or intrudes on others (e.g., butts into conversations or games)
• Often gets up from seat when remaining in seat is expected
• Often excessively runs about or climbs when and where it is not appropriate (adolescents/adults feel restless)
• Often has trouble playing or doing leisure activities quietly
• Is often on the go or often acts as if driven by a motor
• Often talks excessively

II. Some symptoms that cause impairment were present before age 7 years.

III. Some impairment from the symptoms is present in two or more settings (e.g. at school/work and at home).

IV. There must be clear evidence of clinically significant impairment in social, school, or work functioning.

V. The symptoms do not happen only during the course of a Pervasive Developmental Disorder, Schizophrenia, or other Psychotic Disorder. The symptoms are not better accounted for by another mental disorder (e.g. Mood Disorder, Anxiety Disorder, Dissociative Disorder, or a Personality Disorder).

Based on these criteria, three types of ADHD are identified:

IA. ADHD, Combined Type: if both criteria IA and IB are met for the past 6 months

IB. ADHD, Predominantly Inattentive Type: if criterion IA is met but criterion IB is not met for the past six months

IC. ADHD, Predominantly Hyperactive-Impulsive Type: if Criterion IB is met but Criterion IA is not met for the past six months.

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000.

In late October 2011, the American Academy of Pediatrics (AAP) released new guidelines for the diagnosis and treatment of ADHD, updating guidelines that dated back to 2000 and 2001. The biggest change is that the guidelines were expanded to include recommendations for children and adolescents ages 4 to 18. The previous guidelines included children ages 6 to 12.

There are two recommended forms of treatment for ADHD, medication and behavior therapy. The new guidelines recommend starting with a course of behavior therapy in preschool age children (ages 4-5) and adding medication if necessary. For older children, they recommend a combination of medication and behavior therapy.

Treatment Options: Combination of pharmacotherapy and behavioral therapy is more beneficial compared

with either intervention alone.

Stimulant medications: Some children with ADHD respond better to one stimulant type than another; therefore, both methylphenidate- and amphetamine-containing products should be tried before stimulant treatment is deemed a failure.

a. Methylphenidate-containing products: “Ramp effect” = behavioral effects are proportional to the

rate of methylphenidate absorption into the central nervous system

Treatment

**Combination therapy with behavioral therapy and medication is better than either alone.

Stimulant Medications (amphetamine or methylphenidate try both before deeming stimulants a failure)

Adverse Effects of this category:  (a) Headache, stomachache, loss of appetite, and insomnia  (b) Use with caution in patients with glaucoma, tics, psychosis, and concomitant monoamine oxidase inhibitors (c) Insomnia

Methylphenidate immediate release (Ritalin)

• A 50:50 racemic mixture of l-threo and d-threo isomers of methylphenidate
• The short duration of action requires two or three doses daily.

Dexmethylphenidate (Focalin)

• Only d-threo isomer, thought to be the active enantiomer of methylphenidate
• l-Threo isomer hasn't been shown to hinder the effectiveness or increase the adverse effects of methylphenidate
• Recommended doses are half those of racemic methylphenidate immediate release
• Short duration of effect requires two or three doses daily
• Offers no proven pharmacoeconomic benefit over other methylphenidate immediate release products (i.e., Ritalin and generics)

Methylphenidate sustained/extended release (Metadate ER, Ritalin SR)

• Duration of action may be up to 8 hours, but must use two doses daily for afternoon control
• May be used in place of methylphenidate immediate-release BID dosing regimen after dose titration with IR product

Methylphenidate (OROS) (Concerta)

• Indicated for the treatment of ADHD in children 6 years and older
• Tablet contains osmotic agents and a rate-controlling membrane with a laser-drilled hole for release
• Outer capsule contains 22% of drug (immediate release) and tablet core contains the remainder released over 10 hours
• Do not crush or divide
• Duration of effects is 10-12 hours (behavioral)
• Once daily dose with/without food

Dexmethylphenidate ER (Focalin XR)

• Uses spheroidal oral drug absorption system polymer-coated beads
• Bimodal drug release
• Faster onset than methylphenidate (OROS), but shorter duration of action.  Afternoon symptom control isn't as good as with methylphenidate (OROS) Concerta.

Methylphenidate modified release (Metadate CD)

• Treatment for children 6 and older
• Capsule contains 30% immediate-release beads and 70% extended-release beads (slowly released about 4 hours after ingestion)
• Duration of behavioral effects is 6–8 hours probably need afternoon coverate
• Once-daily dosing; capsule may be opened and sprinkled on applesauce

Methylphenidate extended release (Ritalin LA)

• Indicated for the treatment of ADHD in children 6 years and older
• Uses spheroidal oral drug absorption system polymer-coated beads
• Contains 50/50 immediate/extended release to mimic BID methylphenidate immediate release
• Efficacy can wane later in the day requiring methylphenidate IR coverage for late-day symptoms
• Once daily dosing can sprinkle on applesauce

Methylphenidate transdermal system (Daytrana)

• Apply to hip 2 hours before effect is needed; recommended to remove 9 hours after but can wear up to 16 hrs
• Duration of effect is about 3 hours after removing the patch
• Dose may be titrated weekly to desired effect
• Can swim or exercise while wearing

Amphetamine containing continued tomorrow...

Physical Punishment and Mental Disorders

I do not care for statistics.  It's not in my DNA to ENJOY them but this is the perfect example why all pharmacists (and the lay public, for that matter) should understand and interpret study results.  Just the other night, I was watching the news and the anchor states, "Parents should think twice about spanking their children."  Most people would look at the anchor, hear the words, and then turn right around and pass it on as though it was spoken by God Himself. A study was cited:

BACKGROUND: The use of physical punishment is controversial. Few studies have examined the relationship between physical punishment and a wide range of mental disorders in a nationally representative sample. The current research investigated the possible link between harsh physical punishment (ie, pushing, grabbing, shoving, slapping, hitting) in the absence of more severe child maltreatment (ie, physical abuse, sexual abuse, emotional abuse, physical neglect, emotional neglect, exposure to intimate partner violence) and Axis I and II mental disorders.

METHODS: Data were from the National Epidemiologic Survey on Alcohol and Related Conditions collected between 2004 and 2005 (N = 34 653). The survey was conducted with a representative US adult population sample (aged ≥20 years). Statistical methods included logistic regression models and population-attributable fractions.

This is a retrospective study which automatically introduces bias.  Correlation does not imply causation.  That's the biggest issue I see with this study.  For example, the media will pick up a press release about this type of study and report that spankings make children grow into adults with mental disorders, but correlation does not imply causation.  For example, children who were spanked may end up with a mental disorder, but there is no proof that it was the spanking itself that caused the mental illness but perhaps several other factors or combinations of factors.  Even schizophrenia and depression have had genetic components.  What happened to pure genetics?

The next big issue with this study is they looked at many types of mental illnesses since it is not very efficient to run a large study, gather data, and analyze it to look at only one type of mental illness.  Scientific studies, however, rely on statistical analysis to determine whether something is true.  Even if your estimated error is less than one percent, in a study examining thousands of items some will appear to have an effect even though they are just statistical aberrations.  These false positives are then reported, and when a new study fails to confirm them as true, the press reports a scientific “change of mind”.

Finally, when a cohort study is retrospective, the problem is compounded since retrospective studies often rely on memory.  If you developed a mental illness, you may have a different memory recall of punishment and its effect and your perception vs if you did not have a mental disorder.

Be careful with retrospective studies!   As in this case, there are many flaws and biased automatically introduced.

I definitely understand the rationale for wanting to run this study as many parents are probably over the top with physical punishment; however, I don't believe those parents that reserve a spanking for a type of punishment as abusive or that their child will end up with a mental illness due to that one decision.  Too bad the media doesn't know how to interpret studies!

Another critique:

While the new study rules out the most severe cases of physically lashing out at children, "it does nothing to move beyond correlations to figure out what is actually causing the mental health problems," says psychologist Robert Larzelere of Oklahoma State University,. He criticized the study's reliance on memories of events from years earlier, and says it's not clear when punishment occurred.

Afifi acknowledges that it's difficult to change people's mind on this topic, but says "we're confident of the reliability of our data, and the data strongly indicate that physical punishment should not be used on children — at any age. And it's important for parents to be aware of that."

Night Shift Pharmacists

Looks like working the night shift is carcinogenic.  Can't you hear it now?  The lawyers on TV asking, "Have you been working the graveyard shift for such-and-such years?  It's not called graveyard for nothing!  Call 555-5555 and file your claim today against your company!" Article here and here.