Pharmacogenomics and Therapeutic Drug Monitoring for Opioid Pain Management

Abstract and Introduction

Abstract

Aims: The use of medication in pain management currently involves empirical adjustment based on observed clinical outcome and the presence of adverse drug reactions. In this study, pharmacogenomics and therapeutic drug monitoring were used to evaluate the clinical effectiveness of genotyping chronic pain patients on analgesic therapy. It was hypothesized that patients who have inherited polymorphisms in CYP2D6 that make them poor or intermediate metabolizers of opioid medications would have higher steady-state concentrations of those opioids and may be more likely to experience adverse drug reactions.
Materials & Methods: In an attempt to investigate the relationship between the polymorphic enzymes, steady-state drug concentrations, therapeutic effects and side effects, 61 patients were clinically evaluated and genotyped, and drug concentrations were measured and outcomes analyzed. Samples were collected and DNA extracted from whole blood using a Puregene^® DNA isolation kit. CYP2D6 genotyping (*3, *4, *5, *6, *7, *8 and gene duplication) were carried out using Pyrosequencing^®. Steady-state plasma concentrations of methadone, oxycodone, hydrocodone and tramadol were determined by HPLC tandem mass spectrometry.
Results: The results demonstrated the prevalence of CYP2D6 polymorphisms in the population undergoing pain management was not statistically different from the general population. The majority of the pain patients (54%) were extensive metabolizers; 41% were intermediate metabolizers and 5% poor metabolizers. Poor metabolizers in general tended to have the highest steady-state drug concentrations compared with extensive metabolizers (poor metabolizers > intermediate metabolizers > extensive metabolizers) although this wasn't statistically significant. Also, a relationship between oxycodone steady-state drug concentrations and pain relief was found. A total of 80% of patients reporting adverse drug reactions also had impaired CYP2D6 metabolism. The remaining 20% with adverse drug reactions had other cofactors (i.e., drug-drug interactions) that could explain the toxicity.
Conclusion: These results suggest that patient care may be improved by genotyping and following therapeutic drug concentrations. Benefits include increased efficiency in proper drug selection, dose optimization and minimization of adverse drug reactions to improve patient outcome and safety. In addition, this study clearly demonstrated a relationship between oxycodone steady-state drug concentrations and pain relief. Future large-scale prospective studies are needed to confirm the clinical value of using genetic information to guide pain management therapy.

Introduction

Pain is a complex and subjective experience with multiple dimensions. It is also one of the most common reasons people seek medical care.^[1] It is estimated that nine out of ten individuals regularly suffer from pain.^[2,101] However, pain is often undertreated leading to immense costs for society including lost productivity and unnecessary suffering. For example, inadequately managed acute pain can impair recovery from an injury or procedure, lead to medical complications and may progress to chronic pain.^[3] Poorly treated chronic pain can lead to work absenteeism, unemployment and a diminished quality of life.^[102] Many consensus opinions and guidelines have been developed for the management of acute and chronic pain^[3] and cancer pain,^[4] including those developed by the US Department of Health and Human Services. In addition, pain management is a focus of regulatory bodies such as the Joint Commission on Accreditation of Healthcare Organizations (JCAHO; IL, USA).^[103] Overall, there is a high priority mandated in the USA to provide appropriate and adequate pain management in patient care.

Treatment of Pain

Many strategies and modalities for the treatment of pain exist, but can be broadly categorized as pharmacologic and nonpharmacologic. Although there are several approaches to treating pain, pharmacotherapy using medications alone or in combination is the strategy most often used. In fact, one in five Americans use over-the-counter or prescription analgesics on a daily basis.^[2]

Current basic analgesic strategies for chronic pain and cancer pain can be summarized by the WHO analgesic ladder (1990) in which NSAIDs or other non-opioid analgesics are used first, followed by a stepwise progression to stronger centrally acting analgesics.^[5] Analgesics can be broadly categorized as: non-opioid, opioid and adjuvant analgesics. Non-opioids may be used in combination with opioids for their opioid-sparing effect, permitting the use of lower doses of opioids.^[6] Opioids are primarily used to treat moderate to severe pain that has not responded to non-opioids alone. Although opioids have a higher analgesic potency and wider range of indications than any of the other medications for pain control, they remain underutilized.^[7] There are many factors that are barriers to opioid prescribing and medication compliance with these medications, including: concerns and lack of understanding of addiction, pseudoaddiction, tolerance, the risks of abuse and diversion and other potential side effects. Despite these concerns, opioids still play an essential key role in the treatment of pain.^[104]

Pharmacogenomics

Pharmacogenomics is the study of how genes influence the way a patient responds to drug therapy. Pharmacogenomics can be clinically useful in several important therapeutic settings including:

Use of medication cleared primarily by a polymorphic enzyme (e.g., antidepressants);
Use of medications with a narrow therapeutic index (e.g., aminoglycosides, immunosuppressants);
Use of prodrugs whose activity is dependent upon the metabolite formed by a polymorphic enzyme (e.g., codeine);
In situations when a patient demonstrates a suboptimal or unexpected response to therapy.^[8]

The Mayo Clinic (MN, USA) is routinely offering pharmacogenetic testing of cytochrome P450s to help pinpoint genetic factors that influence a patient's response to certain antidepressants. The test does not predict which antidepressant will work best, but is being used to help suggest which ones may not work and which ones may have the greatest side effects. Pharmacogenomic testing is clearly not standard at all medical centers, but this may be slowly changing. The rationale behind genotyping is that it will lead to increased therapeutic effectiveness, safety and improved patient outcomes, while minimizing adverse reactions.

In general, the majority of therapeutic drugs used in pain management (i.e., codeine, dihydrocodeine, fentanyl, hydrocodone, methadone, morphine, oxycodone, tramadol and tricyclic antidepressants) are metabolized by polymorphic CYP450 enzymes such as CYP2D6, CYP3A4 and/or uridine diphosphate glucuronosyltransferase 2B7 (UGT2B7).^[9,10] The wide range of genetic polymorphisms of CYP2D6 can be categorized into four groups: ultrarapid metabolizers (UMs) containing multiple copies of the CYP2D6 gene; extensive metabolizers (EMs) with a single wild-type copy of the CYP2D6 gene; intermediate metabolizers (IMs) exhibiting decreased enzymatic activity; and poor metabolizers (PMs) with no detectable activity. Differences in drug metabolism can lead to severe toxicity or therapeutic failure by altering the relationship between the dose and steady-state blood concentration of the pharmacologically active drug. In fact, inherited differences in the metabolism and disposition of drugs and genetic polymorphisms in drug targets can have a greater influence on the efficacy and toxicity of medications than other clinical variables.^[11] Although the majority of the population are EMs of CYP2D6, 5-10% of Caucasians and 1-4% of most other ethnic groups have decreased CYP2D6 activity (PMs) and risk toxic effects if they receive the routine clinical dose of a drug inactivated by this enzyme.^[8,12] As a result, pharmacogenomics may serve as a tool for optimizing the action of medications in the treatment of various diseases and disorders, including pain management.

Therapeutic Drug Monitoring

Despite the fact that analgesics comprise the largest category of pharmaceutical agents used in the USA, therapeutic drug monitoring (TDM) is not routinely used when prescribing analgesics as its role in the titration and monitoring of these medications is not well defined, and analgesics are generally considered to have a low therapeutic index. However, the reduction in analgesic toxicity is important considering that the Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System shows that analgesics are the primary substance in 24% of all reported fatalities in this system.^[13] Previously, TDM for analgesics had only been proposed for the following situations:

To confirm or identify suspected drug toxicity;
To aid in the identification of an unknown drug ingested in unknown quantities;
To monitor select patient groups at greater risk for analgesic drug toxicity or drug-drug interaction;
To confirm complete drug absorption and adequate drug elimination as an adjunct in drug overdose management.^[14]

The goal of this study was to characterize the relationship between TDM and effectiveness of analgesics metabolized by CYP2D6 (i.e., tramadol, hydrocodone, oxycodone and methadone), including the pharmacogenomic CYP2D6 genotype as an independent variable. The relationship between steady-state drug concentrations (Css) and clinical effectiveness (degree of pain relief) or adverse drug reactions (ADRs), along with the patient's CYP2D6 genotype, was examined. It was hypothesized that PMs taking analgesics metabolized by CYP2D6 would have higher plasma concentrations of the parent drug (whether active or inactive), and be more likely to experience ADRs and therapeutic failure for agents requiring CYP2D6 metabolism to convert a prodrug to the active metabolite.

Table 1. Summary of pain management patient demographics, diagnosis, therapy and *CYP2D6* genotype.
Patient information	Pain cohort (n = 61)	CYP2D6 genotype
Wt/Wt (n = 33)	Wt/Vt (n = 25)	Vt/Vt (n = 3)
Average age (years)	51	49	53	43
Sex	Male	31	14	15	2
	Female	30	19	10	1
Race	Caucasian	54	27	24	3
	African-American	5	4	1	0
	Hispanic	1	1	0	0
	American-Indian	1	1	0	0
Diagnosis	Chronic lower back pain	23	12	11	0
	Migraine/headache	5	4	1	0
	Neuropathic pain	4	4	0	0
	Post-laminectomy syndrome	3	0	2	1
	Myofascial pain	3	2	1	0
	Other (e.g., fibromyalgia)	23	11	10	2
Opioid medications	Oxycodone only	23	10	11	2
	Tramadol only	11	9	2	0
	Methadone only	8	4	3	1
	Hydrocodone only	4	3	1	0
	Oxycodone and methadone	6	3	3	0
	Oxycodone and tramadol	3	2	1	0
	Methadone and tramadol	3	1	2	0
	Hydrocodone and tramadol	2	1	1	0
	Hydrocodone and oxycodone	1	0	1	0

Table 2. Summary of opioid Css according to *CYP2D6* genotype.
Opioid	Css units	Extensive metabolizers	Intermediate metabolizers	Poor metabolizers	p-value
Hydrocodone	Css (ng/ml)	16 ± 16	19 ± 24	0	0.83
	Css (ng/ml per mg)	0.6 ± 0.5	0.7 ± 1.0	0
	Css (ng/ml per mg/kg)	39 ± 27	55 ± 77	0
	n	4	3	0
Methadone	Css (ng/ml)	114 ± 153	138 ± 163	342 ± 0	0.56
	Css (ng/ml per mg)	2.7 ± 3.1	3.1 ± 1.9	3.8 ± 0
	Css (ng/ml per mg/kg)	240 ± 242	269 ± 165	296 ± 0
	n	8	8	1
Tramadol	Css (ng/ml)	31 ± 38	51 ± 70	0	0.89
	Css (ng/ml per mg)	0.2 ± 0.4	0.4 ± 0.5	0
	Css (ng/ml per mg/kg)	10 ± 19	28 ± 44	0
	n	12	5	0
Oxycodone	Css (ng/ml)	22 ± 21	28 ± 22	10 ± 0.4	0.91
	Css (ng/ml per mg)	0.5 ± 0.6	0.6 ± 0.5	0.2 ± 0.2
	Css (ng/ml per mg/kg)	39 ± 36	60 ± 72	20 ± 18
	n	13	14	2

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