Chronic pain affects about one-third of children in our current medical system.¹ In fact, patients with chronic pain make up a growing percentage of pediatric hospital admissions, with a significant number related to adverse medication events.² Poor treatment modalities can have profound effects that persist into adulthood, including permanent functional disability and increased pain sensitivity.³

As the specialty of pediatric pain continues to evolve, understanding the role pharmacogenetics plays is essential to providing appropriate, effective care. Pharmacogenetic testing (PGT) has a proven ability to identify individual genetic allele polymorphisms related to drug metabolism in adults.⁴ Such information has facilitated the prescribing of more targeted drug therapies. Thus, by steering physicians toward more individualized and effective pain medication regimens, PGT could be the key to treating chronic pain in children.

Role of Pharmacogenetic Testing
When an adult patient with chronic pain fails multiple pharmacological therapies, genetic testing is used to diagnose genetic polymorphisms.⁵ This testing can provide physicians with molecular information that indicates which therapies are most likely to be safe and produce an effective outcome. PGT is used to identify a patient’s unique metabolizing system. Because a vast majority of drugs are metabolized via the cytochrome P450 system (see FIGURE 1), identifying patients with poorly functioning variants in P450 alleles can spare them side effects and delays in pain relief associated with prescribing medications they cannot optimally metabolize, thus steering patients and their physicians to the right drug the first time. When a patient’s physician is capable of individualizing long-term treatment with minimal adverse events and optimal efficacy, patient compliance and outcomes improve significantly.⁶

Use of PGT in Pediatric Patients
PGT is not novel to the pediatric community. Pediatric subspecialties, such as oncology, hematology, rheumatology, endocrinology, neurology, gastroenterology, and transplant, have long embraced the science of PGT. In the field of pediatric neurology, for example, PGT can be beneficial in finding effective antiepileptic medication and optimal treatment without undesirable side effects for attention deficit hyperactivity disorder. In pediatric oncology, PGT can be life saving. The treatment for acute lymphoblastic leukemia, for example, requires the enzyme thiopurine S-methyltransferase (TPMT) for effective metabolism of 6-mercaptopurine (6-MP) drug therapy. Using PGT prior to therapy can help patients avoid the life-threatening effects of TPMT-mediated myelo- or hepatotoxicity related to poor enzyme function.⁷ In addition, PGT offers a non-invasive testing method; testing can be performed on saliva or urine specimens, making it conducive to the pediatric population.

When considering PGT in relation to chronic pain treatment in children, it is important to note that chronic pain treatments for pediatric patients differ from those used in adults. Physicians try to minimize the use of opioid therapies for long-term pain management in favor of cognitive behavioral therapy, physical therapy, occupational therapy, and alternative medicine (ie, acupuncture) options, which frequently are effective at ameliorating chronic pain in children. Despite the utility of these interventions, the use of pharmacological agents, such as antidepressants and narcoleptics, often play adjunctive roles. Although studies support the effectiveness of PGT as a tool in caring for adult patients, research in children with chronic pain is lacking.

One of the key differences in the application of PGT in pediatric patients compared with the adult population is that children are still developing and growing. Opponents to the application of PGT in children posit that identification of the expression of gene variations may change with age and developmental stages, thus making PGT results invalid at a later date; however, the limited data available in this population have failed to validate these concerns.

The Financial Factor
Yearly losses of $300 billion dollars are attributed to ineffective drug therapies.⁸ Personalized medicine and PGT may potentially decrease health care costs by making medical care more effective and minimizing health care utilization. Detecting populations who have genetic variation in enzymes and transport systems can decrease health costs by facilitating safer, more effective prescribing plans and can minimize hospital admissions associated with adverse drug events. For example, an increasing number of pediatric pain patients are using antidepressants; knowing which agents a patient can metabolize will avert the wasted time and dollars spent on therapies that are suboptimal.

An example of a cost-effective outcome of PGT testing was noted in psychiatric patients who were deficient in cytochrome P450 enzyme 2D6 (CYP2D6). Researchers found that adult patients with this single polymorphism cost $4000 to $6000 more per year to treat compared with patients who had CYP2D6 and were prescribed drugs that are metabolized by CYP2D6.⁹ With the cost of PGT typically under $1000 per test, and partial reimbursement by Medicare and private insurance companies increasing, implementing PGT is feasible and cost-effective.¹⁰

The Role of the Pharmacist
Pharmacists may be on the forefront of addressing the need for PGT when a patient or family member notes changes in how a medication is working and/or increasing adverse events. Pharmacists often are the first to discuss medication safety and, therefore, must recognize how these tests may be beneficial in the overall management of a patient’s medical care.

As the number of pediatric pain patients continues to increase, laboratory assessment of patients’ capacities to metabolize chronic therapies is paramount to optimal care. PGT testing has a proven role in maximizing drug benefits and minimizing adverse events for chronic conditions; this approach is critical to achieving remission and control of pain symptoms. As such, it is crucial to conduct further studies that address the use of PGT for pediatric pain. Increased access to PGT could be an important factor in providing cost-effective, efficacious, and safe relief of chronic pain in children.

References

1. Huguet A, Miro J. The severity of chronic pediatric pain: an epidemiological study. J Pain. 2008;9(3):226-236.
2. Coffelt TA, Bauer BD, Carroll AE. Inpatient characteristics of the child admitted with chronic pain. Pediatrics. 2013;132(2):e422-e429.
3. Walco GA, Goldschneider JR (eds). Pain in Children: A Practical Guide for Primary Care. Totowa, NJ: Humana Press; 2008:3-9.
4. Shenfield GM. Genetic polymorphisms, drug metabolism and drug concentrations. Clin Biochem Rev. 2004;25(4):203-206.
5. Gupta A. Pharmacogenetic Testing in Pain Medicine: Experts Weigh In. CLADD.org. 2015.http://claad.org/pharmacogenetic-testing-in-pain-medicine-experts-weigh-in/. Accessed March 15, 2015.
6. Sadhasivam S, Chidambaran V. Pharmacogenomics of opioids and perioperative pain management. Pharmacogenomics. 2012;13(15):1719-1740.
7. Stevens A, De Leonibus C, Hanson D, et al. Pediatric perspective on pharmacogenomics. Pharmacogenomics. 2013;14(15):1889-1905.
8. Biospace. Millennium Laboratories Changes Name To Millennium Health, Reflecting Evolution To Broader Health Solutions Company. September 3, 2014. http://www.biospace.com/News/millennium-laboratories-changes-name-to-millennium/345201. Accessed October 8, 2015.
9. Wedlund PJ, de Leon J. Pharmacogenomic testing: the cost factor. Pharmacogenomics J. 2001;1(3):171-174. http://www.nature.com/tpj/journal/v1/n3/full/6500033a.html. Accessed October 8, 2015.
10. Gupta A. Can Genetic Testing Be The Answer For Pain Relief? PGX Medical. 2013. http://pgxmed.com/can-genetic-testing-be-the-answer-for-pain-relief/. Accessed March 14, 2015.

Leigh A. Stevens, MD, MBA, is Chief Anesthesiology Resident at Hahnemann University Hospital, Drexel University School of Medicine, Philadelphia, Pennsylvania. She is a graduate of Saba University School of Medicine and will be an interventional pain fellow at Baystate Medical Center/Tufts University School of Medicine 2016-2017. As a former certified registered nurse anesthetist, Leigh has over 15 years of clinical anesthesia experience.   
 
 
Anita Gupta, DO, PharmD, is Vice Chair of the Division of Pain Medicine and Regional Anesthesiology, and Associate Professor in the Department of Anesthesiology and Perioperative Medicine at Drexel University School of Medicine, Philadelphia, Pennsylvania. Currently, she serves as a special government employee to the FDA as an advisor. Anita has completed the Wharton Total Leadership program and is a Founding Fellow of the Harvard Medical School, Institute of Coaching Professional Association.

Resources

Pediatric Pharmacy Association (PPAG)
www.ppag.org

Society for Pediatric Pain Medicine
www.pedspainmedicine.org

American Pain Society
www.americanpainsociety.org

International Association for the Study of Pain
www.iasp-pain.org