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10 Articles in Volume 16, Issue #4
Achilles Tendon Injuries
Brain Trauma in Sports
Genetic Testing: Adjunct in the Medical Management of Chronic Pain
Letters to the Editor: Sleep Apnea, SPG Blocks for Migraines, Pancreatic Pain, CDC Guidelines
Pain and Weather—A Cloudy Issue
Phulchand Prithvi Raj, MD, Pioneer in Pain Management, Dies at 84
Physical Medicine & Rehabilitation
Preventing Chronic Overuse Sports Injuries
Sports-Related Pain: Topical Treatments
The “Missing Link” in the Physiology of Pain: Glial Cells

Genetic Testing: Adjunct in the Medical Management of Chronic Pain

A case report of a 47-year-old man with severe chronic pain who underwent pharmacogenetic testing and experienced a significant reduction in pain scores and adverse drug effects as a result of appropriate medication changes to reflect his cytochrome P450 (CYP) profile.

Pharmacogenetic testing in medical management has developed renewed interest in recent years. Its use was discussed in the literature more than a decade ago as a means to reduce adverse side effects, improve drug effectiveness, and provide cost-effective health care.1 At the time, most authors concluded that the high cost of pharmacogenetics limited its general use, and the majority of tests were indeed used for rare single-gene disorders in a limited number of people.2,3

Today, the price of genetic testing has decreased considerably from a decade ago, with a subsequent increase in the use of pharmacogenetic testing for pharmaceutical care. We present the case of a chronic pain patient who underwent pharmacogenetic testing and experienced a significant reduction in pain scores and adverse drug effects as a result of appropriate medication changes to reflect his cytochrome P450 (CYP) profile.

Case Description

A 47-year-old man presented to the chronic pain clinic with severe pain primarily located in his right leg and right foot. He had been suffering from pain since being involved in a motor vehicle accident—during which his right leg was shattered—9 years earlier. He underwent multiple appropriate orthopedic interventions after his injury, including rod placement, screws, and reconstruction.

The patient described his current pain level as 10/10 on a visual analogue scale (VAS). This persistent pain was exacerbated with weight-bearing activities and relieved with rest and right lower extremity elevation. For pain relief, the patient had been prescribed oxycodone (OxyContin) 100 mg twice daily, but he admitted taking up to 3 pills daily for several years. In the past, he was told that he was not a candidate for dorsal column stimulator placement, but he was unsure of the reason.

At the time of his evaluation, the patient reported no drug allergies. His medical history included hypertension, anxiety disorder, Factor V Leiden mutation, and lupus coagulant disorder, with a history of pulmonary embolism, deep vein thrombosis, and idiopathic spontaneous subarachnoid intracranial hemorrhage. In addition to OxyContin, his medications included nebivolol 5 mg per day (Bystolic), alprazolam 1 mg 3 times daily (Xanax), aspirin 325 mg per day, and minocycline 50 mg per day (Minocin). His surgical history, in addition to his multiple orthopedic repairs, included incisional herniorrhaphy, cholecystectomy, and exploratory laparotomy. His social status was not contributory.

On physical examination, his vital signs were stable. He was alert and oriented. He used a brace on the right side for ambulation. At the right lower extremity, multiple healed scars were noted, as was a concave area at the lateral aspect of the right knee joint. His right ankle had mild edema and a healing open wound at the posterior aspect. His right foot rotated externally without difficulty. Review of the New Jersey Prescription Monitoring Program database demonstrated that his prescriptions were consistent with what he reported.

Initial Treatment Plan

Because the patient was on exceedingly high-dose opioids at the time of initial consultation (OxyContin, 300 mg/d) and was still experiencing chronic neuropathic pain, the goal was to prescribe the best opioid at the lowest possible dose and to introduce non-opioid adjuvant medications in order to provide multimodal management. Before decreasing the patient’s opioid, a long-acting gabapentin was started (Gralise, 600 mg/d) to evaluate its effect on his neuropathic pain. In addition to having the patient sign a medication contract and provide urine for drug testing, information on dorsal column stimulation was provided on his initial visit.

At the second visit 2 weeks later, the patient still described his pain level as 10/10. He noticed no difference in his pain level with his Gralise prescription. In addition, he said he reviewed the dorsal column stimulation information but he felt he was not active enough to benefit from that intervention. Because of his very high dose of opioids and lack of pain relief, pharmacogenetic testing was performed with a buccal swab sample. In addition, his Gralise dose was increased to 900 mg per day.

Genetic Profile, Best Treatment

Within 3 days of receiving the DNA sample, a cytochrome P450 test report was sent to the clinic by the pharmacogenetic testing company. The report stated that the patient was a CYP2D6 ultra-rapid metabolizer, a CYP2C19 rapid metabolizer, and a CYP2C9 intermediate metabolizer. As a CYP2D6 ultra-rapid metabolizer, he had elevated levels of enzyme activity due to duplication of active CYP2D6 alleles; he had three or more active CYP2D6 alleles, requiring more than standard dosages to prevent treatment failure with drugs inactivated by CYP2D6.

Due to the fact that he was a CYP2C19 rapid metabolizer, he had elevated levels of enzyme activity, with one increased activity and one normal CYP2C19 allele, which would also require more than standard dosage to prevent treatment failure with drugs inactivated by CYP2C19. Given that the patient was a CYP2C9 intermediate metabolizer, he had approximately one-half the normal enzyme activity; he would require less than standard dosages to prevent overdose toxicities and drug interactions, as well as to provide optimal therapeutic response to CYP2C9-inactivated medications. In addition, the report described the patient as being highly sensitive to warfarin according to his VKORC1 enzyme profile.

Comparison of the patient’s prescribed medications and his pharmacogenetic test report revealed that OxyContin was affected, since the drug is metabolized by both CYP3A4 and CYP2D6. The patient’s pharmacogenetic testing profile was explained to the patient when the report was available, and changes were made to his pain medications: oxycodone was discontinued, and methadone 5 mg twice daily started. Methadone is metabolized by CYP3A4, and the patient’s altered CYP alleles would not affect its metabolism.

The next week, the patient described an improvement in pain, a VAS average of 6-8/10, and a reduction in cluster headaches, which he experienced intermittently with OxyContin use. His pain regimen was titrated up to methadone 10 mg three times a day over the following 4 weeks until a pain score of 3-4/10 was achieved. The patient’s pain scores were maintained at 3-4/10 on the same methadone dose for more than 1 year, and he was extremely satisfied with his pain management.

Discussion

Pharmacogenetics, a term often used interchangeably with pharmacogenomics, has been defined as the study of variability in drug response because of heredity.4 The first use of pharmacogenetics occurred in the 1950s, involving succinylcholine and patients with an abnormal pseudocholinesterase gene. Patients with 1 or 2 copies of the abnormal pseudocholinesterase gene would experience longer durations of muscle blockade with succinylcholine. Pharmacogenetics remained a relatively reactive science until the advent of the Human Genome Project, which made the widespread utilization of pharmacogenetic testing a reality.

By the time the Human Genome Project was officially completed in 2003, a number of articles in the literature expressed enthusiasm for the role of pharmacogenetics to improve outcomes by decreasing adverse side effects and increasing drug effectiveness. A number of factors limited its initial widespread use, including ethical, legal, social, economic, and regulatory issues.5

The cost of DNA screening has dropped dramatically over the past 15 years. In 2001, the cost of generating a DNA sequence was approximately $10,000; by contrast, in 2015, the cost was less than 10 cents.6 As the practice of medicine advances, there is increasing recognition that pharmacogenetic testing can reduce serious adverse reactions to medications (including over- and under-dosing) and benefit patients who are non-responders.7

The Genetic Information Nondiscrimination Act of 2008 and the Patient Protection and Affordable Care Act passed in 2010 have allayed concerns regarding patient privacy and confidentiality with pharmacogenetic testing.8 One aspect that has not changed since the turn of the 20th century is the assertion that pharmacogenetics is best applied to life-threatening or chronic diseases, especially chronic diseases for which treatment response is difficult to evaluate.9

Chronic pain is a chronic disease. Evaluating the patient’s response to treatment is difficult because of the subjective nature of pain. Especially difficult is the medical management of chronic pain, which often involves prescribing medications on a trial-and-error basis. This method, if successful, often takes time to achieve an appropriate level of satisfaction from the patient. During that time, the patient may have increased pain levels, adverse side effects, and dissatisfaction with care. This is very similar to incompletely effective pharmacotherapies for psychiatric disorders, where between 10% and 20% of patients experience adverse side effects, and between 25% and 35% of patients do not respond to medication.10 This is significant because some of the first articles in the literature that discussed implementing pharmacogenetics described its use with psychotropic drugs to improve treatment outcomes.11

Today, the utility of pharmacogenetics in pain medicine is more meaningfully recognized as a value in the care of patients with pain. Some of this contemporary literature was introduced as a result of evidence of deleterious effects of opioid administration in patients with altered CYP metabolism. For example, there were several fatalities involving the use of codeine for postoperative pain control in children undergoing tonsillectomy.12 Genetic studies of those children demonstrated they were CYP2D6 ultra-rapid metabolizers. Because codeine is converted from its inactive form to morphine via CYP2D6, ultra-rapid metabolizers experience considerably higher levels of conversion resulting in significant morphine-induced central nervous system depression and apnea.

Perhaps in part due to the morbidity and mortality that occurred with altered codeine metabolism secondary to increased CYP2D6 activity, guidelines were published discussing the use of morphine and non-opioid analgesics in that patient population, and conversely, abstinence from tramadol, hydrocodone, and oxycodone, because their metabolism is also affected by the same altered CYP allele.13

Conclusion

The current case demonstrates that the use of pharmacogenetics in the management of chronic pain patients can improve treatment outcomes. While not all patients may experience the same results, the benefits of decreased pain scores and adverse side effects for patients will, on average, outweigh the risks implicated in a buccal swab pharmacogenetic test. The patient presented is part of a larger cohort of patients at the same chronic pain center who underwent pharmacogenetic testing. Preliminary outcome results from that cohort reveal, on average, a decrease of 3 points on a 10-point VAS pain scale after implementation of pharmacogenetic testing, with subsequent changes to medications to reflect any altered CYP activity. As the complexity and quantity of patients’ medications increase, the use of pharmacogenetic testing as an adjunct to decrease pain scores and adverse side effects is a reasonable and efficacious decision.

Last updated on: May 17, 2016
Continue Reading:
The “Missing Link” in the Physiology of Pain: Glial Cells

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