US Pharm. 2015;40(3):23-26.
ABSTRACT: A majority of medications are metabolized by the liver’s CYP450 system. Metabolism of specific pain medications differs among individuals due to pharmacogenetic variation. CYP450 genotyping displays the type of metabolizer a patient is, in order to determine drug appropriateness, dosage, and dosing interval. Results of pharmacogenetic tests allow patients to be dosed appropriately and avoid experiencing dose-dependent side effects or lack of drug efficacy. Pharmacists can play a role in providing information to patients on selecting opioids where genetic testing may be useful.
Patients with CYP450 pharmacogenetic variations may respond differently to opioids, ranging from drug unresponsiveness to toxicity with elevated serum levels. The administration of opioids may be associated with adverse drug reactions including sedation, dizziness, nausea, vomiting, constipation, physical dependence, tolerance, and respiratory depression.1 By performing pharmacogenetic testing, patients can be dosed appropriately to avoid experiencing dose-dependent side effects or lack of drug efficacy.
Pharmacogenetics is the influence of genes on pharmacodynamics and pharmacokinetics.2 Pharmacodynamics describes an individual’s response to a medication with regard to the duration of action or the incidence of side effects. Pharmacokinetics describes the drug’s absorption, distribution, metabolism, and excretion. Pharmacogenetic testing (PGT) is the application of pharmacogenetics in clinical practice, also known as personalized medicine. The one-time collection of an individual’s genetic information through a blood or saliva test provides genetic data pertaining to drug metabolism. With these data, clinicians are able to predict drug responsiveness before a patient receives a single dose. Results from PGT provide information to aid in determining a target drug regimen, avoiding adverse effects, and achieving the desired response. For example, a pain medication may alleviate pain for one patient while proving no relief for another. Personalized medicine allows for the right drug to be administered for adequate pain control.
More specifically, PGT displays an individual’s genotype for genes that encode for drug-metabolizing enzymes.3 One gene is inherited from each parent, and these alleles can be altered by polymorphisms. Genes provide instructions for making enzymes. Many drugs require enzymes for activation, metabolism, or both. A patient’s genotype determines what type of metabolizer he or she is for that particular enzyme.
CYP450 Metabolizer Profile
Drug-metabolizing enzymes are commonly influenced by genetic variations. The CYP450 enzymes, CYP3A4 (fentanyl) and CYP2D6 (codeine, hydrocodone, oxycodone, tramadol) are involved in the metabolism of opioids.4 There are four basic types of metabolizers. Ultra-rapid metabolizers (UM) carry multiple copies of functional alleles leading to excess activity. UMs of CYP2D6 carry more than two copies of functional alleles. Extensive metabolizers (EM) have two normal or “wild-type” alleles and are considered to have normal metabolism. Intermediate metabolizers (IM) carry one normal and one nonfunctional or two reduced-functional alleles. Poor metabolizers (PM) have two mutated alleles with very limited or completely lost enzymatic activity.2 See TABLE 1 for examples of allele combinations associated with metabolizer status.4
It is important to note that CYP2D6 genotyping does not in all instances accurately describe one’s metabolizer status. In some cases, such as with ethnicity, a patient’s metabolizer status may be misclassified. Approximately 3% of African Americans, 1% to 10% of Caucasians, and 16% to 28% of North Africans and Ethiopians are CYP2D6 UMs.5 Approximately 10% of Caucasians and 1% of Asians are CYP2D6 PMs.6,7 There is an exception to the rule with prodrugs (codeine, morphine, oxycodone, tramadol). Prodrugs have to be metabolized to an active agent, meaning UMs may experience drug toxicity and PMs may have subtherapeutic effects.8
Evidence-based guidelines are available to assist pharmacists on how to interpret genetic information and make clinical recommendations. One organization, the Clinical Pharmacogenetics Implementation Consortium (CPIC), has an Internet-based research tool, the Pharmacogenomics Knowledge Base (PharmGKB). The PharmGKB was developed by Stanford University with funding from the National Institutes of Health (NIH) and a partnership with the NIH Pharmacogenomics Research Network. The PharmGKB is publicly available (www.pharmgkb.org) and aims to help clinicians understand the impact of genetic variation on drug response by providing information on genomic variations, examples of variants, and clinical information such as dosages using patient-specific alleles.4 Using PharmGKB guidelines, one study investigated the use of a gene-based prescribing program at the point of care in a children’s hospital. Using electronic health records, the authors demonstrated a change in drug prescribing (of codeine, tramadol, and others) in over 90% of patients.9
Drug labeling may also contain information regarding genetic biomarkers to alert healthcare providers about patients who may be fast or slow metabolizers. The FDA requires certain drugs (codeine and others) to include genomic biomarkers in the drug labeling.4,10
In 2013, 127.86 million prescriptions for opioid drugs were dispensed, and opioid drug sales reached $1.05 billion in the United States.11 One hospital-based study showed opiate agonists to be among the top-three types of drugs producing preventable adverse-drug reactions.12
The first step in the treatment of nonmalignant pain is to decide whether it is acute or chronic. Acute pain does not persist longer than 6 months and resolves with treatment of the underlying cause. Unrelieved acute pain may lead to chronic pain.12 Chronic pain persists even after an injury has healed or been treated, resulting in physical and emotional distress. Chronic pain can last for weeks, months, and even years. There may be no cure for the causative disease, or the origin of the pain may not be well understood.13
The sensation of pain is subjective and may vary between individuals, making the selection of treatment difficult. To aid in assessing severity of pain and pain management efficacy, pain scales have been created. Three commonly used pain rating scales are the Visual Analogue Scale, the Verbal Rating Scale, and the Numerical Rating Scale.14 While enlightening, data produced from these scales can be easily misunderstood by both patients and clinicians.14 With information from a patient’s PGT and data collected from pain scales, clinicians can more closely and accurately assess a patient’s response to pain medications.
Acute pain treatment guidelines for low back pain recommend the use of opioids in patients with persistent moderate-to-severe pain or after failed treatment with acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), muscle relaxants, and tramadol.15,16 Opioid use in chronic pain patients is reserved for those unresponsive to the following nonopioid treatment options: self-care, cognitive therapy, acetaminophen, tricyclic antidepressants, NSAIDs, pregabalin, gabapentin, and physical therapy.15,17
Codeine is an opioid analgesic that is related to morphine, with less potent analgesic properties. Codeine is selective for the mu receptor but with much weaker affinity than morphine. Once administered, codeine is metabolized to codeine-6-glucuronide (C6G), morphine, and norcodeine through different pathways. CYP2D6 is the major enzyme responsible for the conversion of codeine to morphine.18
Normally, a patient converts approximately 10% of codeine to morphine for analgesia. There are many combinations of alleles, which determine metabolizer status that can be detected from PGT. Approximately 1% to 2% of patients are UMs (e.g., CYP2D6*1/*1XN ) and make up to 75% more morphine than non-UMs, substantially increasing their risk of toxicity.19 Alternative analgesics are recommended for CYP2D6 UMs. EMs and IMs produce normal morphine formation (e.g., CYP2D6*1/*1 and CYP2D6*4/*10, respectively). Age- or weight-specific codeine dosing is recommended in these types of metabolizers.4 Patients who are PMs (~5%-10% of the population) have greatly reduced morphine formation, leading to insufficient pain relief (e.g., CYP2D6*3/*6 ). Codeine should be avoided in these patients due to insufficient pain relief.4 Other opioid analgesics, which are not metabolized by the CYP2D6 enzyme system to active metabolites, include morphine, hydromorphone, oxymorphone, buprenorphine, and fentanyl.20 These alternatives are potentially safer than codeine in UM patients. Please refer to CASE 1 regarding the dosing of codeine.21
Case 1. Codeine
JM, a 4-year-old (27.6 kg) male, was discharged from the hospital after an overnight stay post adenotonsillectomy for treatment of recurrent tonsillitis and pediatric obstructive sleep apnea syndrome. Patient was receiving liquid codeine at age-appropriate dose (8 mg up to 5 doses a day as needed) inpatient, which was continued after discharge. Two days post discharge, after four doses, the child was brought to the hospital without vital signs. Postmortem morphine serum concentration was 17.6 ng/mL (therapeutic range 4.5 +/- 2.1 ng/mL). Blood codeine range was within the expected range with no other medications detected. Postmortem genotyping results revealed a CYP2D6 genotype (CYP2D6*1/*2XN ). CYP2D6 status resulted in supratherapeutic morphine levels leading to respiratory arrest. Cause of death was determined to be bilateral acute bronchopneumonia; a consequence of codeine and morphine toxicity post adenotonsillectomy.21
Fentanyl is a potent opioid agonist, available in several different formulations including buccal tablets, transdermal patches, and solution for injection. Fentanyl’s hepatic metabolism is extensive and rapid. Norfentanyl, product of CYP3A4 fentanyl metabolism, is the most abundant metabolite found. Like all fentanyl metabolites, norfentanyl possesses no significant pharmacologic activity.22 Patients who are ultrarapid or slow CYP3A4 metabolizers may produce subtherapeutic or supratherapeutic fentanyl levels (respectively), leading to minimal pain relief or toxicity (respectively), and proving the need for fentanyl dosing guidelines to benefit those who are abnormal metabolizers. Please refer to CASE 2 regarding the dosing of fentanyl.
Case 2. Fentanyl
BC, a 50-year-old male, presents to his physician with the complaint of inadequate pain control while taking a total daily dose of oxycodone 70 mg. After consulting the dose conversion guidelines, the physician gave BC a prescription for fentanyl patch 50 mcg/h to apply one patch every 72 hours. BC’s wife contacted his physician’s office 24 hours after the first patch application stating that her husband was heavily sedated and having difficulty breathing. After pharmacogenetic testing (PGT), BC learned that he is a slow CYP3A4 metabolizer, which caused decreased metabolism of fentanyl to its inactive metabolites. Based on clinical evaluation in this case, a 50% dose reduction to 25 mcg/h provided BC with adequate pain control and minimal adverse drug effects.
Oxycodone is a morphine-like, pure agonist opioid that is metabolized to noroxycodone and oxymorphone. The formation of oxymorphone, which also provides analgesic activity, is mediated by CYP2D6.23 The PharmGKB recommends the use of alternative drug therapy other than oxycodone for CYP2D6 PMs (e.g., CYP2D6*3/*6 ) and IMs (e.g., CYP2D6*9/*10 ) due to lack of pain relief. For CYP2D6 UMs, such as CYP2D6*1/*1, alternative drug therapy is also recommended to avoid toxicity. Signs of toxicity include drowsiness progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, and death.23 Please refer to CASE 3 regarding the dosing of oxycodone.
Case 3. Oxycodone
After elective outpatient surgery, AN, a 26-year-old female, was given a prescription for oxycodone 5-mg tablets to be used every 4 hours as needed for pain. The next day, after six doses within a 24-hour period, AN called her surgeon stating that she was receiving minimal pain relief from her medications, causing her to get very little or no sleep. Her husband stated that she has complained about minimal pain relief since her operative pain medications wore off. If PGT had been performed prior to surgery, it would have revealed that AN is a poor CYP2D6 metabolizer (CYP2D6*19/*38 ). AN’s CYP2D6 status resulted in subtherapeutic oxymorphone levels, leaving the patient without pain relief. Alternative therapy, such as morphine or hydromorphone, might have provided the patient with adequate pain control.
Tramadol is an alternative to stronger opioids in selected patients for the treatment of moderate-to-moderately-severe pain. Tramadol is metabolized primarily by CYP2D6 and to some extent CYP3A4. The main metabolite with analgesic activity is O-desmethyltramadol.24 The bioavailability of 100 mg of the immediate-release tablet is 75% with an onset of action within 60 minutes. Steady-state concentrations are reached within 2 days when the agent is taken four times daily.25 For CYP2D6 UMs, a dose decrease of 30% is recommended.4 For IMs and PMs, an increase in tramadol dose up to 30% is recommended to provide pain relief, or an alternative drug for pain control should be considered.4 Drugs that should not be considered include oxycodone and codeine.
Hydrocodone is a semisynthetic narcotic analgesic and antitussive prodrug. Hydrocodone bitartrate and acetaminophen tablets (Vicodin) are indicated for the relief of moderate-to-moderately-severe pain.26 Hydrocodone is demethylated by CYP2D6 to its active metabolite hydromorphone. Approximately <30% of the absorbed drug is metabolized to hydromorphone.27 UMs have been shown to possibly produce higher concentrations of hydromorphone. Therefore, UMs achieve a greater degree of pain relief or may experience dose-related toxicities.27 A personalized hydrocodone dosing algorithm using target therapeutic concentrations has been postulated when linked to a patient’s CYP2D6 genotype.28 Steps have been taken to decrease the abuse potential of hydrocodone, such as combination use with acetaminophen and, most recently, drug class rescheduling.
Access to Genetic Information
Genetic information is obtained by a blood sample or buccal swab and usually ordered by a health professional and sent to a laboratory. The Roche AmpliChip CYP450 Test identifies drugs metabolized through the CYP2D6 and CYP2C19 enzyme systems.29 Direct-to-consumer genetic tests remain controversial. The FDA classifies genetic tests as medical devices, and they are subject to FDA regulation. Until the end of 2013, at least one direct-to-consumer genetic test (23andMe) that provided personalized health reports was available for <$100 (currently marketed for ancestry-related genetic reports only).30
The results of PGT can provide patients with better pain control and increased quality of life while taking opioids. The role of the pharmacist includes patient education and interpretation of the results. The PharmGKB (www.pharmgkb.org) tool is available to help pharmacists understand patient genetic variation on drug response and provide assistance for drug dosing.
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19. Kirchheiner J, Schmidt H, Tzvetkov M, et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J. 2007;7(4):257-265.
20. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol. 2014;95(4):376-382.
21. Kelly L, Rieder M, Van Den Anker J, et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics. 2012;129(5):e1343-e1347.
22. Labroo RB, Paine MF, Thummel KE, et al. Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for interindividual variability in disposition, efficacy, and drug interactions. Drug Metab Dispos. 1997;25(9):1072-1080.
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24. Leppert W. CYP2D6 in the metabolism of opioids for mild to moderate pain. Pharmacology. 2011;87(5-6):274-285.
25. Tramadol hydrochloride tablet. Drug label information. www.accessdata.fda.gov/drugsatfda_docs/label/2009/ 020281s032s033lbl.pdf. Accessed February 15, 2015.
26. Norco—hydrocodone bitartrate and acetaminophen tablet. Drug label information. DailyMed. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cb805564-d418-4339-aaf2-646800dd4161. Accessed October 11, 2014.
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29. Roche AmpliChip Cytochrome P450 Genotyping Test and Affymetrix GeneChip Microarray Instrumentation System—K042259. FDA. www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm078879.htm. Accessed October 23,2014.
30. Loftus P. Genetic test service 23andMe ordered to halt marketing by FDA. Wall Street J. November 25, 2013. http://online.wsj.com/news/articles/SB10001424052702304281004579219893863966448. Accessed October 23, 2014.
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