The Florida Pediatrician Journal

Will the Birthday Cake Be Gluten Free?A brief review of gluten related disorders for the primary care physician.

Florida Chapter

Journal | Volume 34, Issue 1 | Spring 2015

Contents

Editor’s Note 3

Will the Birthday Cake Be Gluten Free? 4

Save the Date—The Future of Pediatric Practice 2015 7

Cardiac safety of stimulants 8

Medicinal Marijuana 12

UF College of Medicine Department of Pediatrics Rising 16

▼ University of Florida Pediatrics Rising, page 16

▼ Will the Birthday Cake Be Gluten Free, page 4

▼ FCAAP Annual Meeting September 4-6, page 7

Spring 2015 The Florida Pediatrician 3

Editor’s Note

Dear Colleagues,

Welcome to the new Florida Pediatrician. We are coming to

you after a hiatus of more than two years. First, I want to

thank Dr. Nancy Silva, who served as Editor of the journal

for several years and did an excellent job. We hope to keep

up the tradition of publishing an excellent journal on a

quarterly basis.

I am delighted to inform you that I have the honor of

serving as the new Editor of your journal, and I am very

ably assisted by an editorial board that includes Drs. Varun

Aggarwal, Lisa Gwynn, Gregory Hale, Nizar Maraqa and

John Waidner. We would love to have at least two more

members of the editorial board, one from central Florida

and the second from the panhandle area.

We hope to provide you with high-quality, peer-reviewed

articles and would encourage you to submit original man-

uscripts, review papers and case reports. This is also a great

opportunity for our trainees to submit their work.

We will provide you with timely legislative reports and

updates from the various departments of pediatrics at the

medical schools and children’s hospitals in Florida.

We look forward to hearing from you on how we can im-

prove the journal.

Mobeen H. Rathore, M.D.

Editor


A brief review of gluten related disorders for the primary care physician.

At a recent well visit, a mother spoke of planning a birth-day party for her 5-year-old daughter. Another parent had called to reply to the invitation and asked the following question: “Will the birthday cake be gluten free?” The mom asked me for help regarding this. In this brief review, we will analyze current issues related to gluten, with the aim of helping providers who care for children address such questions in their practice.

It is difficult to ignore the explosion of gluten free products in the last 5-10 years. The Girl Scouts recently introduced a gluten free cookie to their product line, and it is hard to vis-it a grocery store or restaurant without being overwhelmed by the gluten free choices. According to a recent New York Times article, the annual sales for gluten free products in the United States are at 10 billion dollars and rising. It is estimated that as much as 11% of U.S. households have pur-chased a gluten free product in their lifetime.1

However, the increasing consumption of gluten free products in the United States does not correlate with the

true prevalence of Celiac Disease. According to the most recent information published in the American Journal of Gastroenterology in 2012, the prevalence of Celiac Disease is approximately 0.71% (1 in 141). This is clearly less than the 11% of U.S. households that are currently purchasing gluten free products. 2

Disorders related to gluten fall into three main categories: 1) true Celiac Disease, 2) allergy to wheat, 3) non-Celiac Dis-ease gluten sensitivity. The latter, albeit the most nebulous, is where the majority of confusion resides. Each of these will be reviewed below. 3,6

Celiac DiseaseIt is estimated that only 1% of current gluten free con-sumers fall into the category of true Celiac Disease. Celiac Disease is the most common genetically-induced food intolerance. It is an autoimmune (not allergic) reaction that is triggered by ingestion of gluten. Gluten is found in wheat, barley and rye, and can also cross-contaminate many oat

John W. Waidner M.D. and Mariana Lacerda, D.O. St. Vincent’s Family Medicine Residency Program, Jacksonville, FL

Will the Birthday Cake Be Gluten Free?


products. It tends to give foods elasticity and is an additive to many unexpected items, such as processed foods. 3

Celiac Disease is triggered by the ingestion of gluten in ge-netically predisposed individuals. The subsequent reaction causes an inflammatory response and mucosal damage in the small intestines, which leads to clinical symptoms. HLA DQ2 and HLA DQ8 are generally thought to be required for the development of Celiac Disease. They are required but not sufficient, meaning many HLA DQ2 and HLA DQ8-positive individuals don’t have Celiac, but virtually all Celiac Disease patients are positive for one of these mark-ers. It is estimated that 30-35% of the U.S. population are HLA DQ2 and DQ8 positive, but less than 1% have Celiac Disease. 3,4,6

The most classic presentation of Celiac Disease would be severe abdominal distention, as well as a thin chest, arms and legs. A more common presentation today would include non-specific GI complaints such as diarrhea, vomiting and abdominal pain. In addition, extra-intestinal manifesta-tions have also been described. These include rashes (der-matitis herpetiformis), poor growth, short stature, pubertal delay, neurologic symptoms (headache, “gluten ataxia”), fatigue and behavioral changes, amongst others. 3,6,7

While there are several major organizations, each with independent guidelines related to gluten, the traditional nomenclature for true Celiac Disease has been classified in the following 5 categories: 1) Typical: These patients have typical GI-related symptoms, abnormal screening serology, and abnormal duodenal biopsy. 2) Atypical: These patients have non-GI related symptoms but abnormal serology and abnormal biopsies. 3) Silent: These patients have abnormal serology and abnormal biopsies, but no clinical symptoms. These are discovered when screening patients with in-

creased risk, such as relatives of Celiac Disease or patients with other associated diagnoses. 4) Potential: These are patients with mild or no symptoms, abnormal serology but normal biopsies. 5) Latent: These are patients with prior diagnosis of Celiac Disease, who now have no symptoms and normal duodenal biopsies. 3,6,7

Most experts recommend screening tests for symptomat-ic patients with both typical GI complaints and the de-scribed extra-intestinal symptoms. Also recommended for screening are patients at higher risk, such as those with the following associated conditions: Down Syndrome, Turner Syndrome and Williams Syndrome. While screening symp-tomatic patients is agreed upon by most, screening asymp-tomatic high-risk individuals is more controversial. 3,4,6

Initial work-up for suspected Celiac Disease involves serology with one of the four available tests: 1) anti-gliadin IgA and IgG. There is wide consensus amongst the existing guidelines that anti-gliadin IgA and IgG should no longer be used for Celiac Disease diagnosis, due to lack of sensi-tivity and specificity and wide test-to-test variability; 2) En-domysial IgA and IgG; 3) Tissue Transglutaminase (TTG) IgA and IgG; 4) Deamidated Gliadin Peptides IgA and IgG. Of these, TTG IgA is felt to be the best screening test by most authorities, as it has 95% sensitivity, 97% specificity, and it is widely available. It is important to note that up to 2-3% of Celiac Disease patients can also have selective IgA deficiency, and a total IgA level should be simultaneously performed with TTG IgA. Identified IgA deficient patients must be screened with IgG testing. Some experts recom-mend more than one screening test for patients less than 2 years of age, as TTG IgA alone may not be a sufficient screening test at this age. There is currently a lack of univer-sal agreement on this subject, and hopefully with further

research the answer to this question will become clearer. As mentioned earlier, virtually all Celiac Disease patients are HLA DQ2 and DQ8 positive. Secondary to the fact that as much as 35% of the general population is positive for one of these markers, it is not rec-ommended to use them during the screening process. 3,4,6,7

Patients with abnormal screening serology and clinical symptoms for both GI and extra-intestinal complaints consistent with Celiac Disease should be referred to a gastro-enterologist for confirmatory duodenal biopsy. Considering that no currently available


screening serology is 100% sensitive and specific, providers should also consider referring patients with a very high clinical suspicion for Celiac Disease, even in the absence of positive serology. Providers should avoid the institution of a gluten free diet prior to biopsy as this could result in falsely normal biopsy results. 3,4,6

A comprehensive discussion of the treatment of Celiac Disease exceeds the scope of this article. The central core of treatment is the lifelong institution of a gluten free diet, with the absence of wheat, barley, rye and oat products (due to cross-contamination) during daily meals. Attention must also be focused on less obvious products that may contain gluten, such as processed foods which contain gluten as an additive agent for taste and texture. Referral to an expert in pediatric nutrition is critical for education in this matter. 3

Wheat AllergyThe second category of gluten related disorders is true Wheat Allergy. It is estimated that approximately 0.1%

of gluten free consumers fall into this category. Wheat is a common food allergen, and affected patients develop allergic symptoms shortly after ingesting wheat-containing products. These can be classic allergic reactions symptoms such as urticaria, conjunctivitis or wheezing, but can also be obscure and non-specific, such as general GI complaints. Some more chronic conditions such as eosinophilic esoph-agitis and Baker’s asthma (a chronic cough and asthma picture in patients with a workplace exposure to wheat) can also occur. An interesting but rare variant of Wheat Allergy is Exercise Induced Anaphylaxis. These patients develop an anaphylaxis-like picture during exercise when wheat con-taining foods were consumed shortly prior to the activity, usually within 2 hours of ingestion. 3,4,6

The diagnosis of Wheat Allergy involves confirmatory aller-gy testing either via skin-prick testing, or allergen specific IgE serum tests. The gold standard would be an oral food challenge with consumption of wheat. 3,4,6

Non Celiac Gluten SensitivityThe final category of gluten related disorders is Non-Celiac Gluten Sensitivity. It is estimated that more than 98% of current gluten free consumers fall into this category. As mentioned earlier, this is the most nebulous and contro-

versial category. Patients with this condition report many non-specific symptoms, such as abdominal pain, rashes, headaches, foggy mind, fatigue and depression. Many other symptoms are described as well, and symptoms often overlap with those of true Celiac Disease. Non-Celiac gluten sensitivity is a diagnosis of exclusion and requires negative allergy testing to wheat and negative celiac serol-ogy (endomysial or TTG IgA). If patients have undergone duodenal biopsy, the results of that biopsy should also be negative. There is controversy around the meaning of elevated anti-gliadin antibodies in this population. After the institution of gluten free diet, this population of patients will frequently report improvement in symptoms. Since the symptoms are non-specific and the details of any particular patient’s attempt at gluten free can vary, the gold standard for this diagnosis remains a double blind, placebo con-trolled, food challenge (DBPCFC). In reality, a true DBP-CFC is done in very few of these patients. 3,4,5

Summary Pediatricians are increasingly faced with questions and clinical situations involving gluten related disorders. It is imperative to be aware of the three main categories of gluten related disorders, their presentation, appropriate screening laboratory testing, and gastroenterology referral criteria. Non-Celiac Gluten Sensitivity remains the most ill-defined of these disorders, and is responsible for the vast majority of parental concerns as well as consumers’ use of gluten free products. In regards to the gluten free birthday cake that began this article, I would certainly inquire about signs and symptoms of true Celiac Disease as well as Wheat Allergy. I would also note that the routine provision of glu-ten free products at social events seems highly unwarranted at the present time. Hopefully, ongoing research in this area will provide additional information for the practicing pediatrician in the near future.

1) A Big Bet on Gluten Free, Stephanie Strom, The New York Times, February 17th, 2014.

2) Rubio-Tapia A, et al. The Prevelance of Celiac Disease in the United States. Am J Gastroenterol. 2012 Oct; 107(10):1538-44

3) Fassano A, et al. NASPGHAN Webinar: Gluten Related Disorders: Facts and Fallacies June 5th 2013

4) Baic JC, et al. World Gastroenterology Organisation global guidelines on celiac disease. J Clin Gastroenterol. 2013 Feb;47(2):121-6 PMID 23314668

5) Lundin KE, Alaedini A. Non-Celiac Gluten Sensitivity. Gastrointest Endosc Clin N Am. 2012 Oct; 22(4):723-34 Review. PMID 23083989

6) Tonutti E, Bazzaro n. Diagnosis and classification of celiac disease and gluten sensitivity. Autoimmun Rev. 2014 Apr-May; 13(4-5):472-6 PMID 24440147

7) Husby S, et al. European Society for Pediatric Gastroenterology, Hepatolo-gy and Nutrition Guidelines for the Diagnosis of Coeliac Disease. J Pediatr Gastroenterol Nutr 2012 Jan; 54(1): 136-60 PMID 221197856

The second category of gluten related disorders is true Wheat Allergy. It is estimated that approximately 0.1% of gluten free consumers fall into this category.


Special conference rate of $199.00 single/double per night. Learn more at www.fcaap.org or call 850.224.3939

Sept. 4: Welcome Event—Family Fun Night

Sept. 5: Medical Student Research Forum Workshop: The Pursuit of a Healthy Adolescent Member Luncheon & Annual Business Meeting

Sept. 6: Workshop: The Pursuit of a Healthy Adolescent (Part 2) The Pediatric Practice Brain Bowl for Residents: Pediatric Jeopardy

FCAAP Annual Meeting September 4-6at Disney’s Grand Floridian Resort & Spa

Save the Date

L A B O R D A Y W E E K E N D !


ECG prior to starting stimulant medications: to order or not?

Case: D is an eight-year-old boy brought to his pediatri-cian for evaluation. His mom says that his teacher has been frequently complaining that he is very restless, and often disturbs the rest of the class by getting up on some pretext or the other. He is unable to concentrate on his work and gets distracted easily. He makes many careless mistakes and can hardly finish his tasks on time. He is frequently reprimanded for talking during class. He often answers out of turn, or before the question has been completed. How-ever so far he has been managing to get passing grades. At home, he is constantly on the go, while he is awake. If he is forced to sit, like at mealtimes he fidgets a lot. He also needs to be constantly nagged to do everything, even his daily activities (like brushing his teeth), or he forgets to do them or leaves them incomplete. He takes ages to finish his food. It’s a major job to get him to do his homework. His mother says that at home he has been like that since the last 2–3 years but now she is concerned because of the difficulties he is experiencing at school as well. After history, examina-tion and getting response from parents and teachers (using Vanderbuilt Assessment Scales), the pediatrician diagnoses

him to have ADHD. Besides behavioral interventions, he considers medications for his management. The pediatri-cian is debating the merits of doing an electrocardiogram (ECG) and/or referring to a cardiologist prior to starting stimulant medications. If you were caring for this patient, how would you proceed?

ADHD is not uncommon and needs treatmentAttention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood with a reported prevalence of 5% to 20% among school-aged children.1 Untreated, it can lead to significant impairment in the functioning of the child and potentially have long-term influence on the child’s performance, self-esteem and productivity. Management involves various psychological interventions and medications.

Principles of pharmacotherapy in ADHDThe basic premise of ADHD pharmacotherapy is that a relative deficiency of dopamine is seen in the frontal cortex

Anjali Aggarwal, M.D., Varun Aggarwal, M.D., Danyal Khan, M.D.: Department of Pediatrics and Pediatric Cardiology, Miami Children’s Hospital, Miami, FL

Cardiac safety of stimulants


in children with ADHD2, and this results in an increased background rate of neuronal discharges. By using medica-tions which can increase the dopamine levels, it is postu-lated that the frequency of random neuronal discharges is reduced and thereby improvement in higher neurological performance. The medications used to treat ADHD are broadly classified as stimulants and non-stimulants. The most commonly used stimulants are methylphenidate and amphetamine. The mechanisms underlying the pharmaco-logic effects of the amphetamines are due to direct release of dopamine and norepinephrine from the presynaptic neurons.2 Conversely, the methylphenidate class of action is based primarily on re-uptake inhibition of dopamine and norepinephrine.2 Atomoxetine works by a similar mech-anism, although norepinephrine uptake blockade is the primary mode of effect.2 The non-stimulant group compris-es the guanfacine compounds, marketed as Tenex and the long-acting version, Intuiv. Their mechanism of action is due to direct stimulation of alpha 1A receptors in the fron-tal cortex. Guanfacine is structurally and pharmacological-ly similar to clonidine and thus may result in mild sedation and an overall decrease in peripheral vascular resistance.

Controversy regarding cardiac monitoringAs the term implies, “stimulant” medications can be associated with secondary sympathomimetic effects on the cardiovascular system resulting in hypertension and tachycardia. These effects have caused considerable debate regarding the need/benefits/risks and cost for a detailed cardiac evaluation prior to prescribing these stimulant medications.

AHA scientific statement 19993

The primary concern stemmed from the use of tricyclic antidepressants but no specific cardiovascular monitor-ing was recommended.

Health Canada 20054

February 2005: Based on U.S. post marketing reports of sudden death in pediatric patients, sale of Adderall XR in Canadian market was suspended.

August 2005: Sale of Adderall was reinstated but with a statement advising health care professionals to be aware of cardiac risk factors before initiating therapy and to avoid stimulant use for all patients with ‘‘symptomatic cardiac disease’’ or ‘‘known structural cardiac abnormal-ities.’’

FDA advisory panel 20066

February 2006: A warning to Adderall label was added, which stated, ‘‘Sudden death has been reported in asso-ciation with amphetamine treatment at usual doses in children with structural cardiac abnormalities. Adderall XR generally should not be used in children or adults with structural cardiac abnormalities.’’

February 2006: FDA advisory panel, by 8-to-7 vote, rec-ommended a ‘‘black-box’’ warning on the risk of sudden death for individuals receiving any stimulant medications.

February 2007: FDA issued a press release titled “FDA Directs ADHD Drug Manufacturers to Notify Patients About Cardiovascular Adverse Events and Psychiatric Adverse Events.”

AHA Scientific statement 20086

April 2008: Routine ECG was advised in the assessment of children with ADHD prior to treatment with medications. The level of evidence was categorized as class 2A (‘‘weight of evidence/opinion is in favor of usefulness/efficacy’’) and assigned it a level of evidence C label (‘‘only consensus opinion of experts, case studies, or standard of care’’).

AAP Scientific Statement (2008)7

May 2008: Noted the lack of any evidence that the rou-tine use of ECG screening before the start of medication for ADHD treatment would prevent sudden death. AAP completely disagreed with AHA recommendations for doing ECG prior to initiating stimulant medications. Using AHA criteria, the AAP classified this recommen-dation as 2B (‘‘the level of evidence is less well established by evidence/opinion, additional studies with broad objec-tives needed’’). In addition, using the AAP classification of recommendations, the AAP assigned the recommen-dation a category D level of evidence (‘‘on the basis of expert opinion without even observational studies’’). For children with CHD, evaluation by a pediatric cardiologist was recommended.

Canadian Position Statement (2009)8

Routine ECG prior to initiation of medications in chil-dren with ADHD was not supported or recommended.

Current evidenceControversies raised by the publications noted above have


created much uncertainty among primary caregivers as to how to best monitor patients for whom stimulant medi-cations are being considered. Current evidence does show small increases in mean heart rate and blood pressure with use of stimulant medications like methylphenidate, amphetamines and atomoxetine for treatment periods of less than 2 years.9 The changes are small and have been described as being clinically insignificant9. There is no compelling clinical evidence to demonstrate that the likelihood of sudden death is higher in children receiving medications for ADHD than that in the general population. It has not been shown that screening ECGs before starting stimulants has an appropriate balance of benefit, risk, and cost-effectiveness for general use in identifying risk factors for sudden death.

Before prescribing stimulantsComplete in-depth history and physical examination should be done prior to initiating stimulant medications for children or adolescents with ADHD.

The patient history should include questions to elicit but not limited to the following:

• History of fainting, dizziness, syncopal events or sei-zures (especially during or after exercise)

• Prior history of palpitations, increased heart rate, extra or skipped beats, chest pain or shortness of breath especially during or after exercise or any noticeable change in exercise tolerance

• History of high blood pressure

• History of heart murmur other than innocent or functional murmur or history of other heart problems (congenital heart disease or rheumatic fever)

• History of chest pains and/or palpitations with inter-current viral illness

• Current medications (prescribed and over the counter, especially supplements and drugs in case of adoles-cents)

The family history should include:• Sudden or unexplained death at a young age (espe-

cially during exercise), sudden cardiac death or “heart attack” in members before 35 years of age

• History of cardiac arrhythmias and any family member with a cardiac pacemaker

• History of any cardiac disease in family members like cardiomyopathy, pre-excitation syndromes, long QT syndrome or abnormal rhythm conditions

• Any family member requiring cardio-pulmonary resuscitation, especially during young age

A thorough physical examination should be done, espe-cially looking for any abnormal murmur, hypertension, irregular rhythm, or physical stigmata of other diseases like Marfan syndrome. The aim of the above evaluation is to identify conditions that increase the likelihood of sudden cardiac death like hypertrophic cardiomyopathy (HCM), long QT interval syndrome (LQTS), and Wolff-Parkin-son-White syndrome (WPW).

Opposition to routine ECG screening prior to use of stimulantsThomas et al10 has reported the results of screening ECG prior to stimulant medications in 372 patients. 24 (6.4%) had abnormal findings and 18 were referred for further evaluation, but none were found to have cardiac disease. ADHD therapy was delayed in 6 patients because of the ECG. The mean cost to do the ECG screening including the cost of further testing for patients with abnormal results has been described by Mahle et al11 to be $58 per child. However, the mean cost to identify a true positive result was $17,163.18. Also it has been reported that ordering the ECG screen for three common cardiac conditions linked to sudden cardiac death (HCM, WPW, LQTS) would add less than two days to a patient’s projected life expectancy.12

Case: After performing a thorough history (including family


history) and physical examination as described above, the pediatrician could not find any condition that can potentially increase the likelihood of sudden cardiac death in D. So based on the current evidence he decided not to do ECG and started him on amphetamines. Mom was instructed to report immediately if he complained of any chest pain or tachy-cardia. His progress was monitored and he improved in his performance at both school and home. Follow-up visit in 4 weeks showed marginal increase in baseline heart rate (by 2 beats) and without any other side effects.

Summary of recommendations:• Current evidence shows that stimulant medications do

cause a slight increase in heart rate and blood pressure.

• There is no increased incidence of sudden cardiac death with use of stimulant medications.

• A detailed family history and examination is mandato-ry prior to initiation of stimulants.

• Routine ECG prior to initiation of stimulant medica-tions has not been shown to add any benefit in pre-venting sudden cardiac events and may be associated with unnecessary anxiety in the family and delay in the initiation of treatment.

• Monitor all children on stimulant medications for tachycardia, hypertension, chest pain and palpitations.

• Any known cardiac condition or suspicion of it based on family history or physical examination necessitates evaluation by a pediatric cardiologist and further evaluation.

References:

1) Franke B, Farone SV, Asherson P, et al. International Multicentre persistent ADHD CollaboraTion. Mol Psychiatry 2012;17(10):960–87.

2) Wigal SB, Chae S, Patel A et al. Advances in the treatment of atten-tion-deficit/hyperactivity disorder: a guide for pediatric neurologists. Semin Pediatr Neurol 2010;17:230–236

3) Gutgesell H, Atkins D, Barst R et al. AHA scientific statement: cardiovascu-lar monitoring of children and adolescents receiving psychotropic drugs. Circulation. 1999;99:979–982.

4) Health Canada (2006) Search page. www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2006/adhd-tdah_medic_hpc-cps-eng.php. Accessed Sep 2014.

5) U.S. Food and Drug Administration (2005) Detailed view: safety labeling changes approved by FDA Center for drug Evaluation and Research (CDER). http://www.fda.gov/medwatch/safety/2005/aug05.htm. Accessed Sep 2014.

6) Vetter VL, Elia J, Erickson C, et al. Cardiovascular monitoring of children and adolescents with heart disease receiving medications for attention deficit/hyperactivity disorder. Circulation 2008;117:2407–23.

7) Perrin JM, Friedman RA, Knilans TK, Black Box Working Group, Section on Cardiology and Cardaic Surgery. Cardiovascular monitoring and stimulant drugs for attention deficit / hyperactivity disorder. Pediatrics 2008;122:451–3.

8) Warren AE, Hamilton RM, Be´langer SA et al. Cardiac risk assessment before the use of stimulant medications in children and youth: a joint position statement by the Canadian paediatric society, the Canadian cardiovascular society, and the Canadian academy of child and adolescent psychiatry. Can J Cardiol 2009;25:625–630.

9) Awudu GA, Besag FM. Cardiovascular Effects of Methylphenidate, Amphetamines and Atomoxetine in the Treatment of Attention-Deficit Hyperactivity Disorder: An Update. Drug Saf. 2014 Sep;37(9):661-76.

10) Thomas PE, Carlo WF, Decker JA, et al. Impact of the American Heart Association scientific statement on screening electrocardiograms and stimulant medications. Arch Pediatr Adolesc Med. 2011;165:166-170.

11) Mahle WT, Hebson C, Strieper MJ. Electrocardiographic screening in children with attention-deficit hyperactivity disorder. Am J Cardiol. 2009;104:1296-1299.

12) Leslie LK, Cohen JT, Newburger JW, et al. Costs and benefits of targeted screening for causes of sudden cardiac death in children and adolescents. Circulation. 2012;125:2621-2629.


Americans remained sharply divided over the legal use of marijuana, whether it is for recreational or med-ical purposes.1 Advocates argue for the legalization of marijuana, citing the importance of the rights of individuals, that legalizing marijuana use will elimi-nate the black market, and will enhance tax revenue. Contrariwise, others argue that marijuana use may in-crease the use of other illicit drugs, that marijuana has significant adverse physical and mental effects, that costs to society will increase and that little is definitely known about the medical efficacy of marijuana. This disagreement overlies significant medical concerns that highlight the lack of efficacy of medical marijuana for many conditions for which it is being prescribed, particularly for pediatric patients.

Legal aspectsMarijuana use is becoming increasingly accepted throughout the United States.2 There is a strong push for the elimination of federal mandatory minimum sentencing requirements for marijuana use. Since Cal-ifornia became the first state to legalize medical mar-ijuana in 1996, 20 additional states and the District of Columbia have legalized its use for medical purposes for adults who are under the care of a physician. Two states, Washington and Colorado, have legalized the non-medical, recreational use of marijuana as well. To date, no state has legalized recreational use for minors. Complicating the legal view of marijuana in many states is that marijuana remains illegal under federal law. Marijuana has been illegal in the United States since the 1937 Marijuana Tax Act. The United States Food and Drug Administration categorizes marijuana as a schedule 1 drug, indicating that it has a high poten-tial for abuse, has no accepted medical use in the United States, and lacks accepted safety for use under supervi-sion by a physician. Presently marijuana accounts for 75% of illegal drug usage in the United States.

BiochemistryCannabis chemicals are isolated from the hemp plan, Cannabis sativa. Marijuana is a complex mixture of more than 60 cannabinoids and over 400 other chem-icals, so formulations may vary significantly in their chemical composition.1 Benzopyrene, a carcinogen,

Gregory Hale, M.D.

Medicinal Marijuana

Americans remained sharply divided over the legal use of marijuana, whether it is for recreational or medical purposes.


is found in cannabis. The primary psychoactive agent is delta-9-tetrahydrocannabinol (THC), whose content varies. There are other components of cannabis that are not psycho-active, which include cannabidiol, cannabigerol, and cannab-inol. The leaves of the plant are most commonly smoked but can also be consumed orally. When inhaled, by combustion or vaporization, the onset is within minutes; when ingested orally the onset is within 30 minutes.

The endocannabinoid system consists of cannabinoid receptors and their ligands throughout the body, including the CNS.3 The cannabinoid 1 receptor (CB1R) is primarily found in the central nervous system and the CB2 receptor is located on immune effector cells throughout the body. CB1R can be activated by lipid molecules which function as endogenous ligands. Cannabinoid receptors are found throughout the body in the heart, lungs, endocrine cells, ar-teries, immune system, sympathetic neurons, gastrointesti-nal tract, and reproductive tract. Effects of cannabis and its metabolites may be enhanced or lead to long-term changes in the developing brain.

Medical formulations Three pharmaceutical-grade cannabinoid formulations exist for medical use: dronabinol, nabilone and sativex.4 Only dronabinol and nabilone are approved by the FDA for use in the United States; sativex is available for use in the United Kingdom. Dronabinol, which contains THC, is a schedule III oral medication approved for the treatment of AIDS-related cachexia and chemotherapy-induced nausea and emesis. It has also been used to treat glaucoma. Nabi-lone, which contains THC, is a schedule II oral medica-tion approved to treat spasticity due to spinal cord injury; nabilone has a higher abuse potential compared to dronab-inol. Sativex, which contains THC and cannabidiol, is a

fast-acting oral mucosal spray for neuropathic pain due to multiple sclerosis or as an adjunct to cancer pain treatment. In contrast, medical marijuana is not currently regulated by the FDA and the purity and tetrahydrocannabinoid content of each formulation are inconsistent and not uniformly verified. No pharmaceutical products are approved for use by inhalation.

Medical indicationsMedical marijuana is said to be necessary to treat spe-cific conditions such as anorexia and cachexia in cancer and HIV patients, nausea and emesis in cancer patients, chronic pain syndromes, and spasticity in disorders such as multiple sclerosis.1,5 Specifically, researchers are exploring cannabinoids in the treatment of neuropathic pain, neuro-protection, multiple sclerosis, seizure disorders, hyperten-sion, dystonia, inflammatory bowel disease, rheumatoid

arthritis, glaucoma, Huntington’s disease, post-traumatic stress disorder, and atherosclerosis. Users of cannabis re-port less anxiety and depression, yet no proven use of these compounds as medical treatment of these disorders exists.

Yet, no published clinical trials have been reported in the pediatric population and no clinical trials for med-ical marijuana or cannabinoids to treat pediatric health conditions are registered on the clinicaltrials.gov website. In addition, some pediatric patients are being treated with medical marijuana for attention deficit hyperactivity disorder and bipolar disorder with no scientific evidence of efficacy. Complicating matters are the observations that pediatricians may legally prescribe medical marijuana in some states and minors may obtain medical marijuana with written parental permission in other states. In 2004, the American Academy of Pediatrics issued a policy statement opposing the legalization of marijuana and supporting rig-orous scientific research regarding the use of cannabinoids for relief of symptoms not currently treated by existing legal medications. 6

Adverse consequencesMarijuana is associated with adverse health consequences associated with both acute and long-term use, but to a lesser extent than tobacco use, which is currently legal in all

Yet, no published clinical trials have been reported in the pediatric population and no clinical trials for medical marijuana or cannabinoids to treat pediatric health conditions are registered on clinicaltrials.gov website.


states.9 Side effects can occur in a dose-dependent or idio-pathic manner. Controlled studies have demonstrated that marijuana users do have a higher mortality risk compared to non-users, largely due to motor vehicle accidents from driving while intoxicated, suicide and respiratory tract and brain cancers. However, the non-fatal adverse effects of marijuana are much more common, including cardiovas-cular disease, respiratory illnesses, impaired pulmonary function, and mental illness along with impaired cognitive abilities. These studies are largely done in the adult popu-lation and do not take into account the developing brain of the child and adolescent, where the cognitive consequences could be greater. Marijuana is also addictive, but remains less addictive than tobacco; 9% of cannabis users are addicts compared with 32% of tobacco users are addicts. 7-8

Marijuana is known to have negative neuropsychiatric effects on short-term memory, concentration, attention span, motivation and problem-solving capabilities.10-12 It has been shown to interfere with learning and to negatively affect coordination, judgment, reaction time and tracking ability. Marijuana use is associated with significant social consequences as well. The earlier an individual begins to use illicit drugs, there is an increased risk of dependence and addiction as an adult. Arrests for the use of these illegal drugs have led to incarceration of youth, with a predomi-nance of minorities, resulting in criminal records that can have life-long adverse consequences. Cannabis use can lead to a variety of medical disorders including dependence, abuse, intoxication, delirium, psychotic disorder and anxi-ety disorder. 13

Marijuana smoke contains toxic chemicals in amounts similar to or higher than those found in tobacco. Similarly, marijuana is linked as a potential respiratory tract carcin-ogen although specific links to lung cancer are not proven. In cannabis users, precancerous airway changes have been identified in a dose-dependent relationship as well as an increase in airway cancers. Individuals who only smoke cannabis are at a lower risk of lung cancer than those who smoke tobacco only. While epidemiologic data dose suggest

that cannabis smoking plays a role in the development of lung cancer, no specific link of cannabis to lung cancer has been proven. Cannabis users frequently also consume alcohol and tobacco, which increase the exposure to carcin-ogens, which increase the risk of squamous cell carcinoma of the oral cavity.14

Finally ,cannabis is known to cause hyperemesis, which is characterized by the sudden onset of sever and cyclic emesis.15 A diagnosis of exclusion, this syndrome typically resolved in 48 hours with improvement noted with bathing. The emesis may recur with resumption of cannabis use. This effect is in stark contrast to the medical use of certain cannabinoids to treat cancer-related emesis. Dental effects include caries oral infections and periodontal disease. Cardiovascular adverse events have been reported with can-nabis use including acute coronary syndrome, arrhythmias and congestive heart failure; myocardial infarction may be triggered by cannabis use and patients at high risk for coronary disease should avoid cannabis use.16

Cannabis is a banned drug by the World Anti-Doping Agency and has been on the list of prohibited drugs of the International Olympic Committee since 1989. Cannabis use reduces exercise test duration during maximal exercise, increases heart rate, increases blood pressure, and reduces psychomotor activity, all of which may decrease athletic performance.

Neurodevelopmental issuesPediatricians care for a vulnerable population that is under-going rapid physical growth and psychological development. Both animal and human studies clearly demonstrate that the developing brain is vulnerable to exogenous cannabinoids. These effects are particularly notable in the perinatal and pre-natal period and during adolescence. 17-18 The early use of can-nabis in adolescence increases the rates of cognive dysfunc-tion, low striatal dopamine release, neuropsychiatric diseases, cannabis dependence and additional abuse of other illegal drugs.19 Ongoing use leads to impaired function in daily life,


including at school and work, including higher rates of drop-out behavior.20 Marijuana use in early adolescence is thought to alter signaling through the endocannabinoid system with impaired axonal fiber connectivity resulting in detrimental effects on the white matter. Several studies have reported approximately 35% of adolescents receiving treatment for marijuana–related problems have ADHD, supporting the theory that ADHD and adolescent substance abuse may have similar mechanisms. 21

Medical marijuana will likely remain controversial as it becomes increasingly visible in the media in the future. There is currently a paucity of published, peer-reviewed scientific data supporting the use of medical marijuana in adult patients, but this paucity is particularly evident in pediatric and adolescent patients. As many states move to legalizing marijuana for medical purposes, it is imperative to realize that the safety and efficacy of a drug cannot be decided by a popular vote. Future efforts in both the adult and pediatric populations will require well-designed clin-ical trials to identify the clinical efficacy and the acute and long-term toxicities associated with the use of these agents. All research should be performed with FDA oversight so that all regulatory guidelines are observed and as a patient safety oversight mechanism so that the risk-benefit ratio can be better described for medical marijuana. Long-term follow-up will be extremely important in the younger age population as the side effects on a growing and developing brain may be quite different than observed in adults. Clear distinctions should be made between marijuana and the use of pharmaceutical grade cannabinoid medications. Finally, any product that requires smoking cannot currently be recommended for health purposes, and potential dangerous effects from marijuana use are well described and should be clearly taught to the public.

References

1) Greydanus DE, Hawver EK, Greydanus MM et al. Marijuana: current concepts. Frontiers in Public Health 2013: 42(1): 1-17.

2) Clark PA, Capuzzi K, Fick C. Medical marijuana: medical necessity versus political agenda. Med Sci Monit 2011: 17(12); RA 249-261.

3) Mechoulam R, Parker LA. The endocannabinoid system and the brain. Annu rev Psychol 2012: 64: 21-27.

4) Aggarwal SK, Carter Gt, Sullivan MD et al. Medicinal use of cannabis in the United States: historical perspectives, current trends, and future directions. J Opoid Manag. 2009: 5(3): 153-168.

5) Cotter J. Efficacy of crude marijuana and synthetic delta-9-tetrahydrocan-nabinol as treatment for chemotherapy-induced nausea and vomiting: a systematic literature review. Oncology Nursing Forum 2009:36(3); 345-352.

6) American Academy of Pediatrics Policy Statement. Committee on Sub-stance Abuse and Committee on Adolescence. Legalization of marijuana: potential impact on youth. Pediatrics 2004: 113 (6); 1825-1826.

7) Wang GS, Roosevelt G, Heard K. Pediatric marijuana exposures in a medi-cal marijuana state. JAMA Pediatrics 2013: 167 (7); 630-633.

8) Wall MM, Poh E, Cerda M, et al. Adolescent marijuana use from 2002 to 2008: higher in states with medical marijuana laws, cause still unclear. Annals of epidemiology 2009: 21(9); 714-716.

9) Kalant H. Adverse effects of cannabis on health: an update of the litera-ture since 1996. Prog Neuropsychopharmacol Biol Psychiatry 2004: 28(5); 849-863.

10) Schweinsburg AD, Brown SA, Tapert SF. The influence of marijuana use on neurocognitive functioning in adolescents. Current Drug Abuse Reviews 2008: 1: 99-111.

11) Evans EA, Green EI, Kane JM et al. The effect of marijuana use on the risk for schizophrenia. Journal of Clinical Psychiatry 2012: 73(11); 1463-1468.

12) Schepis TS, Adinoff B, Roa U. Neurobiological processes in adolescent addictive disorders. Am J Addict. 2008: 17(1); 6-23.

13) Jaffe SL, Klein M. Medical marijuana and adolescent treatment. American Journal on Addictions. 2010: 19: 460-461.

14) Van Hoozen BE, Cross CE. Marijuana. Respiratory tract effects. Clin Rev Allergy Immunol 1997: 15(3): 243-269.

15) Galli JA, Sawaya RA, Friedenberg FK. Cannabinoid hyperemesis syndrome. Curr Drug Abuse Rev 2011: 4(4); 479-481.

16) Sidney S. Cardiovascular consequences of marijuana use. J Clin Pharmacol 2002: 42(11 Suppl); 64S-70S.

17) Trezza V, Cuomo VO, Vanderschuren LJ. Cannabis and the developing brain: insights from behavious. Eur J Pharmacol 2008: 585 (2-3); 441-452.

18) Sundram S. Cannabis and neurodevelopment: implication for psychiatric disorders. Hum Psychopharmacol 2006: 21(4); 245-254.

19) Schneider M. Puberty as a highly vulnerable developmental period for the consequences of cannabis exposure. Addict Biol 2008: 13(2); 253-263.

20) Leach LS, Butterworth P. The effect of early onset common mental disor-ders on educational attainment in Australia. Psychiatry Res 2012.

21) Ivanov I, Pearson A, Kaplan K et al. Attention deficit disorder and comor-bid substance abuse. In: Greydanus DE, Calles JL Jr, Patel DR, et al editors. Clinicial Aspects of Psychopharmacology in Childhood and Adolescence. New York: Nova Science (2011): 33-49.


University of Florida College of Medicine’s Department of Pediatrics Rising

2014 marked a year of growth, innovation, discovery and celebration for the University of Florida Department of Pediatrics in Gainesville. Our faculty members received national acclaim and our educational programs were heralded, and at a time of one of the most austere funding climates, UF’s Department of Pediatrics doubled NIH-funded research. Our substantial programmatic growth was also accompanied by major children’s hospital renovations.

Faculty growthIn 2014, we welcomed 28 new faculty members to the Department of Pediatrics, strengthening our clinical and research programs. New faculty members joined us from Harvard, Tufts, Yale, the University of Chicago, the University of California, Colorado University, and Florida, to name a few programs.

We were delighted to have Peter Kang, M.D., an interna-tionally renowned expert in neuromuscular diseases at Harvard, join us as chief of pediatric neurology. Bill Pietra, M.D., a national figure in cardiac transplantation, also joined us as the new chief of pediatric cardiology from the University of Colorado.

Clinical growthIn 2014, the University of Florida Department of Pediatrics cared for more than 100,000 children. Recognizing the broad geography of our state, subspecialty care was provid-ed at sites around the state including Pensacola, Tallahas-see, Lake City, Ocala and Daytona. Specialized “Centers of

Excellence” were created to care for children with asthma, Turner syndrome, diabetes, neuromuscular disorders, gly-cogen storage diseases and Prader Willi syndrome.

Our pediatric surgical program expanded to complement the clinical gains. Laura Blakemore, M.D., chief of pediatric orthopaedics at National Children’s Hospital, was recruited. Romero DeMarco, M.D., joined us as the new chief of pediatric urology and Swati Agarwal, M.D., and Casey Beal, M.D., were also welcomed to pediatric ophthalmology.

The University of Florida Department of Pediatrics became the leading pediatric transplantation center in the state. In 2014, it performed more than 20 bone marrow transplants, 14 pediatric kidney transplants and 24 pediatric heart transplants. Over the past 18 months, we have performed 14 pediatric liver transplants and three pediatric lung trans-plants. This past year, we were also the first center in the southern United States to implant an artificial heart.

Our department has had long-standing interests in the care of children with medically complex conditions, via the University of Florida Ped-I-Care program that is nationally recognized. In 2014, we were delighted to have the opportunity to expand these Title XIX and XXI programs to care for 40,000 children with medically complex conditions in north Florida.

Importantly, we continue to make great strides in pediatric and hospital-wide patient quality and safety programs. This past year, UF Health was recognized by three different groups for excellence in this area: the Joint Commission, Leapfrog and University Health System Consortium (UHC).


EducationAbout two years ago, we undertook comprehensive reform of our educational program. Reflecting these efforts, more graduating University of Florida medical students are enter-ing pediatrics this year and next than any other specialty.

Bringing recognition to the state of Florida for interest in pediatric medical student education, we hosted the first Pediatric Medical Student Research Forum, in conjunction with the Florida Chapter of the American Academy of Pediatrics in August 2014 in Orlando, Florida. This event brought together medical students from across the United States to share their discoveries and interests in pediatrics, and will become an annual event.

We also launched an inventive residency training program that allows house officers to focus on long-term career goals. We developed specialized track systems with spe-cialized programs for the medical home/primary care, research, global health, public health and education. This program was recently highlighted by the Association for Medical School Departments of Pediatrics (AMSPDC) in the Journal of Pediatrics.

To address shortages in several pediatric specialties, we have initiated new fellowship training programs in pe-diatric neurology, child protection and rheumatology. These programs join pediatric fellowship programs in neonatology, critical care, cardiology, hematology/oncolo-gy, endocrinology, pulmonary medicine, nephrology and gastroenterology.

The University of Florida also became the sponsoring insti-tution for pediatric graduate medical education for Orlando Health, which has 48 pediatric residents and fellows. This spe-cial opportunity is leading to the development of new teaching models, including teleconference and exchange training.

ResearchOver the past two years, the National Institutes of Health research support to our department has nearly doubled. This places us in the top 15 of NIH-funded departments of

pediatrics. Our faculty published more than 500 reports and chapters in 2014. Our collective grant and research contracts now exceed $75,000,000.

Notable research highlights include the University of Flori-da Diabetes Institute, which was recognized as being among the top programs in the world. The University of Florida Powell Gene Therapy Center continues to attract children from across the United States. Most recently, we launched a cutting-edge immunotherapy program for children with refractory brain tumors, the UF Brain Tumor Immunother-apy Program. This program is led by Duane Mitchell, M.D., who joined us from Duke University.

FacilitiesOver the past year, we moved further along in our $130-mil-lion-plus modernization plan that already has had dramatic at UF Health Shands Children’s Hospital. The new Sebastian Ferrero Atrium opened in the fall. We previously renovated the hospital unit in which children with cancer and complex immune conditions are treated. We completed a state-of-the-art pediatric emergency room, where more than 25,000 children are seen annually and an additional 8,000 children are seen in the UF Health Pediatrics After Hours program. We added another 23 rooms to the children’s hospital with the opening of a new Pediatric Cardiovascular Intensive Care Unit and modernized the Pediatric Intensive Care Unit. This summer, we begin renovation of our Neonatal Intensive Care Unit into a state-of-the-art facility.

Although these facility projects, faculty recruitments and patient care programs have been funded largely by UF Health, we would not have achieved these important milestones without the support of the community and other organizations, including the Sebastian Ferrero Foundation, the Children’s Miracle Network including Dance Marathon, Stop Children’s Cancer, the Climb for Cancer Foundation, the V Foundation and the NASCAR Foundation, along with many private donors and our employees.


National recognitionThe University of Florida Department of Pediatrics con-tinues to rise in its national recognition. In the U.S. News & World Report rankings, seven of our subspecialties were ranked among the best in the country.

Members of our faculty have continued to distinguish themselves. Desmond Schatz, M.D., a pediatric endocrinol-ogist, has been elected president of the American Diabetes Association. Barry Byrne, M.D., Ph.D., director of the Pow-ell Gene therapy Center, was named to the FDA Advisory Panel. Scott Rivkees, M.D., was named chair of the AMSP-DC Public Policy committee. Nicole Black, M.D., M.Ed., program director for the pediatric residency program, received a national award for her role in medical education form the Association of Pediatric Program Directors.

Overall, we are delighted to continue to thrive and serve the children and families of Florida through care, discovery and training the next generation of pediatric providers. We ex-press our gratitude to our community partners and the mul-titude of practitioners and pediatricians in the community who stand behind UF Health Shands Children’s Hospital to make our continued growth in facilities, people and programs possible, and a true gateway to exceptional pediatric care.

Scott A. Rivkees, M.D.

Professor and ChairUniversity of Florida Department of Pediatrics

Physician-in-ChiefShands Children’s Hospital

Documents

The Florida Pediatrician Journal