American Association for Clinical Chemistry
Better health through laboratory medicine
November 2009 Clinical Laboratory News: Pain Management

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November 2009: Volume 35, Number 11


Pain Management
What Role Can Pharmacogenetics Testing Play?
By Saeed A. Jortani, PhD, Gary E. Loyd, MD, and Elaine Stauble, MD

Pain management refers to a broad range of services designed to diagnose the source of acute or chronic pain and remove or control it without surgery. As a specialty, pain management has experienced tremendous growth in the past decade and has become an important aspect of patient care. In the course of treatment, physicians frequently prescribe analgesics to maintain patients’ mobility and functionality and to limit impairment. However, administration of analgesics is plagued with toxic and often fatal side effects, such as respiratory depression for opioids and gastrointestinal and cardiovascular adverse effects for non-steroidal anti-inflammatory drugs (NSAIDs).

These well-recognized side effects have prompted caregivers and patients to look for more effective ways to manage pain. Using pharmacogenetic (PGx) tests to select the most appropriate medication and the optimal dose holds promise for facilitating personalized pain management. Although clinical labs have been slow to implement PGx tests in general, now several important developments are making the utilization of PGx testing in clinical practice timely. Here we briefly describe the genetic variants that are involved in metabolism of pain management drugs and discuss recent developments that may impact the field of PGx testing. Two case studies of PGx testing are provided to demonstrate the value of this emerging field.

The Case for Integrating PGx in Pain Management

Pain medications, especially opioids, are notorious for their variable and frequently unpredictable toxicity and efficacy. Due to the unpleasant effects of analgesics, patients often forgo taking them for pain. In other patients, however, analgesics lack efficacy and offer little to no pain relief. This variability is now better understood in relation to an individual’s genetic makeup.

The body’s handling of drugs is primarily carried out by proteins serving as metabolizing enzymes or transporters, and the effects caused by drugs involve protein receptors. Therefore, proteins play a central role in both the pharmacokinetics and pharmacodynamics of a given drug. Since the genes encoding these proteins are polymorphic, genetic differences in how an individual metabolizes or responds to a drug are rational targets for assessing variability in drug response.

CYP2D6 is one of the major groups of enzymes taking part in the metabolism of many drugs including the opioids such as codeine, hydrocodone, and oxycodone. Other enzymes such as the CYP3A4 and CYP3A5 are responsible for the metabolism of the synthetic opiates, buprenorphine and fentanyl (1,2). It is also important to note that not only can the same enzymes metabolize other classes of drugs that may be co-administered with opioids, but a given opioid can also be metabolized by multiple polymorphic enzymes.

Drug receptors can be a source of variability as well. For example, patients with a single nucleotide polymorphism at position 118 (A to G) in the gene encoding for the µ-opioid receptor (OPRM1) require larger morphine doses for analgesia (3). Interestingly, polymorphisms in this gene have also been associated with a tendency for addiction to opioids (4). Researchers are currently investigating OPRM1 genotyping for assessing sensitivity to the analgesic effects of opioids.

Analgesics and Pain Management

In current pain management practice, much focus is centered on the use of opioid analgesics that are narcotics. Either alone or in combination with milder analgesics such as acetaminophen or NSAIDs, these drugs are used to treat a wide spectrum of pain intensities. However, caution is needed because of the potential for abuse and addiction.

Table 1 (below) lists analgesics and adjuvants often co-administered in pain management. Many of these drugs and their counterparts are metabolized by enzymes that are polymorphic in various patient populations. In Table 2 (below), enzymes relevant to the metabolism of pain management analgesics are provided.

Table 1
Selected Analgesics and Adjuvants Used in Pain Management

Type of Drug

Example

Site and Mechanism of Action

Analgesic (mild)

aspirin, acetaminophen

Peripheral action, blocking synthesis of prostaglandins in damaged tissue

Analgesic (narcotic)

morphine, fentanyl

Central action on opiate receptors in the CNS

Local anesthetic

lidocaine, bupivicaine

Prevents propagation of action potentials by blocking axonal sodium channels

Tranquilizer

benzodiazepines, phenothiazines

Alteration of CNS transmitter function

Antidepressant

tricyclines (desipramine), SSRIs (citalopram,
sertaline)

Alteration of CNS transmitter function

Anticonvulsant

phenytoin,
carbamazephine

Alteration of CNS transmitter function

NMDA antagonists

ketamine and some opiods (methadone)

Altering CNS sensitization

Abbreviations: central nervous system (CNS);
selective serotonin reuptake inhibitors (SSRI)


Table 2
Analgesics and Polymorphic Enzymes

Drug

Enzyme

Comment

Opiods

Codeine

CYP2D6, CYP3A4

10% converted to morphine by CYP2D6

Hydrocodone

CYP2D6, CYP3A4

Hydromorphone is active metabolite

Oxycodone

CYP2D6, CYP3A4/5

Oxymorphone is active metabolite

Morphine

CYP3A4, UGT2B7

 

Buprenorphine

CYP3A4

Norbuprenorphine more toxic than parent

Fentanyl

CYP3A4/5

Norfentanyl generated by CYP3A4

Tramadol

CYP2D6, CYP2B6, CYP3A4

(-)O-desmethyltramadol is active metabolite

Tramadol inhibits CYP2D6

Meperidine

CYP2B6, CYP3A4, CYP2C19

Normeperidine is a potent CNS stimulant

Methadone

CYP3A4, CYP2B6, CYP2C19

Others (e.g., CYP2D6) also have minor role

Non-Opioids

Acetaminophen

CYP2E1, CYP3A4/5

Toxic metabolites generated by CYP2E1

Naproxen

CYP2C9

Several other NSAIDs (Diclofenac, Celecoxib and Ibuprofen) also metabolized by CYP2C9

Abbreviations: non-steroidal anti-inflammatory drugs (NSAID); central nervous system (CNS)

Avoiding Toxicity

Physician demand for PGx testing for management of pain patients so far has been limited; however, highly publicized patient deaths have brought more attention to the discipline. For example, a report involving an infant who was breast fed by his mother and died after the mother had taken codeine for several days was widely reported (5). The mother had multiple copies of CYP2D6 gene, a rapid metabolizer, and therefore converted codeine to morphine at a higher level than normal. As a result, her milk contained toxic amounts of morphine that caused her infant’s death. This case prompted both Canadian and U.S. regulators to issue warning labels on codeine regarding its administration to breastfeeding mothers.

There is also a growing body of information on the use of PGx assays in monitoring patients receiving hydrocodone, fentanyl, and oxycodone. Several articles and book chapters have described use of these tests for assessing toxicity, as well as interpreting postmortem opioid results (6).

Recent developments are now poised to contribute to the translation of PGx testing into clinical practice. First, the National Academy of Clinical Biochemistry (NACB) has developed the first set of laboratory medicine practice guidelines for PGx. Laboratorians can currently access a draft of the guidelines on the NACB website (www.nacb.org). Second, the College of American Pathologists and other proficiency testing organizations have made testing material available for several enzymes that are involved in the uptake and breakdown of pain medications, including: CYP2D6, CYP2C9, CYP2C19, and others.

Labs can also now purchase FDA-cleared tests for PGx testing from several manufacturers. These tests detect CYP2C9, CYP2C19 and CYP2D6, some of which are available in a multiplexed format and use whole blood collected in an EDTA tube. The sample must be centrifuged to obtain the buffy coat layer that is used to isolate the DNA. Alternative samples such as buccal swabs or saliva have also been shown to be useful for DNA isolation. The typical turnaround time for PGx testing is 5 to 7 days, and a growing number of reference labs offer this service.

Not surprisingly, challenges must be overcome before PGx testing can become more widespread. Obtaining adequate reimbursement for PGx tests is often difficult. While some labs have had sporadic success in getting reimbursement from third-party payers, in other cases patients are willing to pay out of their own pockets. Furthermore, more outcome studies are needed to encourage physician adoption of this new paradigm of pain management.

In spite of these challenges, labels for more than 20 different medications have statements about PGx testing for drug selection and dosing. Examples include warfarin dosing and CYP2C9/VKORC1 genetic variants and irinotecan therapy and testing for UGT1A1 polymorphisms.

PGx in Post-operative Pain Management

PGx testing in management of post-operative acute pain is also emerging as a valuable tool to improve patient safety. At our institution we have investigated the use of PGx testing for expectant mothers about to deliver their infants. These women are good candidates for individualized pain management for several reasons. PGx tests that identify the mother-to-be’s genetic variants of genes involved in drug metabolism can help clinicians look for alternative means of post-operative pain control if necessary. Not only can the clinician avoid putting the patient and her newborn at risk, but he or she can also make better informed decisions about effective post-surgical pain management.

Opioid analgesics are the most commonly used medications for post-operative pain relief, but their side effects can pose significant risks for women who undergo Cesarean section. These mothers need to recover quickly and be relatively pain-free so that they are competent to care for their newborns. Pain relief is of vital importance in allowing new mothers to move about, eat normally, and have normal bowel and bladder function.

The side effects of opioid analgesia include nausea and vomiting, constipation, sedation or drowsiness, pruritus, urinary retention, and respiratory depression. Immobility due to over-sedation can be especially problematic in pregnant mothers. Pregnancy doubles the risk of thrombo-embolic disease, which is compounded by Cesarean section surgery and immobility due to pain medications. Thromboembolic phenomena are also increased in the postpartum time frame compared to the antenatal period. Other common factors such as obesity, diabetes, and preeclampsia increase the risk of deep venous thrombosis or pulmonary embolism. A newly delivered mother’s inability to ambulate due to pain, anxiety, or over-sedation may significantly worsen the risk of post-operative morbidity.

Potential side effects with concomitant medicines that affect metabolism and efficacy of opioids may also greatly increase the risk of respiratory depression. An example is the anti-nausea medication promethazine. New mothers who have been taking excessive amounts of pain medication in the post-operative time period may also be less successful at breast feeding and have difficulty bonding with their infant in the first few days after surgery. These early interactions between mother and baby are crucial in establishing secure bonding; therefore, physicians must take extra precautions when prescribing analgesics.

All these factors make post-operative analgesia of newly delivered mothers a balancing act between pain relief and the ability to return to the activities of daily living and caring for the newborn. Within a few hours of Cesarean delivery, the patient can tolerate oral medications and clinicians frequently prescribe codeine, oxycodone, or hydrocodone along with NSAIDs.

With all of these drugs, CYP2D6 polymorphisms have been shown to result in variable toxicity and response among patients with normal activity (extensive metabolizers) versus those with reduced activity (poor or intermediate metabolizers) or enhanced activity (ultra-rapid metabolizers). Reduced activity in the case of codeine dosing can mean inadequate pain relief since the morphine generated by the body is less than optimal for analgesia. The ultra-rapid genotype can result in a situation similar to the case previously mentioned with too much morphine generated leading to toxicity. For hydrocodone, patients with more than two copies of CYP2D6 gene (ultrarapid metabolizers) generate more hydromorphone than normal. Since hydromorphone is several-fold more potent than hydrocodone, serious toxicity and side effects are likely.

PGx and Forensic Applications

Today, pain management drugs are frequently implicated in forensic settings, including urine drug screening and interpretation of postmortem drug concentrations. Compared to clinical applications, PGx is gaining considerable popularity in forensics because turnaround time and reimbursement do not hinder adoption of the technology.

It is now well understood that the ability of an individual to metabolize an opioid can affect drug screening results. For example, extensive metabolizers (CYP2D6) clear more of the administered doses of hydrocodone as hydromorphone. One study reported the difference between extensive and poor metabolizers to be significant: 28.1 ± 10.3 mL/hr/kg versus 3.4 ± 2.4 mL/hr/kg hydromorphone, respectively (7), a result that could be predicted from an individual’s genetic makeup.

In postmortem forensic applications, PGx has been very useful in describing unusual death situations that result from drug toxicity. In one published report, a set of monozygotic, 3-year-old male twins had been prescribed 10 mg of codeine to treat their cough following the diagnosis of upper respiratory infection (8, 9). After 6 days of therapy with this opioid, one of the twins was found dead in his bed. The second twin was discovered to be apneic and had vomited 5 hours after taking the last dose of codeine. The parents began resuscitation and took the child to the emergency room. He was treated in the intensive care unit and eventually recovered. The serum concentrations of both codeine and morphine in this child, as well as in his dead brother’s blood collected at autopsy, were in the toxic range.

Genotyping for CYP2D6 was used to confirm that the children had adequate metabolic capacity since they both were extensive metabolizers; therefore, investigation focused on the dosing amount. Further insight into the case revealed a problem with parental understanding of the “drop” sizes prescribed for dosing the children, leading to greater amounts of codeine given to each child than prescribed.

Standing at the Threshold

Pain management covers almost all disciplines of medicine and is widely recognized as a growing segment of healthcare. While the analgesics used to provide pain relief have many beneficial effects, knowledge of each drug’s pharmacokinetic and pharmacodynamic characteristics would help physicians assess toxicity and efficacy in a given patient.

Currently, utilization of PGx testing in the field of pain management is rather limited. Many complex clinical and technical issues must be tackled before individualized pain management takes off. Equally daunting, however, are the concerns related to administration of opioids for treatment of long-term pain.

Many case reports and studies on the utility of genotyping for enzymes with a role in metabolism of opioids, as well as the availability of commercial tests, have set the stage for adoption of PGx in pain management. Clinical laboratories now have access to several FDA-cleared genotyping tests and platforms for the three most common enzymes—CYP2D6, CYP2C19, and CYP2C9—that are involved in metabolism of the majority of drugs used in pain management.

Despite the fact that progress has been slow, the promise of optimal dosing and selection of the right medications on an individualized basis continues to fuel further interest in this area. Until research provides better answers, labs can play a role in optimal opioid selection and therapy for acute pain, especially in post-operative settings.

REFERENCES

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  2. Zanger UM, Turpeinen M, Klein K, Schwab M. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem 2008;392(6):1093–108.
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  8. Ferreiros N, Dresen S, Hermanns-Clausen M, Auwaerter V, et al. Fatal and severe codeine intoxication in 3-year-old twins-interpretation of drug and metabolite concentrations. Int J Legal Med 2009;. DOI 10.1007/s00414-009-0340-0.
  9. Hermanns-Clausen M, Weinmann W, Auwarter V, Ferreiros N, et al. Drug dosing error with drops: severe clinical course of codeine intoxication in twins. Eur J Pediatr 2009;168(7):819–24.

Saeed A. Jortani, PhD, DABCC, FACB, is associate professor of pathology and laboratory medicine at the University of Louisville School of Medicine, and associate director of the University of Louisville's clinical chemistry and toxicology laboratory. Dr. Jortani is chair of the AACC Clinical Proteomics Division.

 

Gary E. Loyd, MD, is professor and interim chair of the department of anesthesiology and perioperative medicine, and medical director of the Outpatient Surgery Center at the University of Louisville.

 

 

Elaine Stauble, MD, is assistant professor of obstetrics and gynecology at the University of Louisville School of Medicine, and medical director of the University Gynecology Obstetric Foundation at the University of Louisville.