Clinical perspective on the Clinical Pharmacogenetics Implementation Consortium Updated 2014 guidelines for CYP2D6 and codeine.

As pharmacogenomics makes further advances into clinical practice, the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provide considerable assistance in clinical decision making. The new 2014 CPIC guidelines on CYP2D6 and codeine (1 ) have an update on considerations for clinicians and healthcare providers. The previous CPIC guidelines provided recommendations primarily on codeine and tramadol. The new guidelines maintain the dosing recommendations for codeine—specifically, to avoid codeine in both CYP2D6 poor and ultrarapid metabolizers; however, the guidelines take another step forward by noting that, not only may tramadol be problematic, but hydrocodone and oxycodone are also not considered good analgesic alternatives when metabolic concerns exist with CYP2D6. Additionally, this update recommends alternatives with the following statement: “To avoid treatment complications, opioids that are not metabolized by CYP2D6, including morphine, oxymorphone, buprenorphine, fentanyl, methadone, and hydromorphone, along with nonopioid analgesics, may be considered as alternatives for use in CYP2D6 poor metabolizers and in ultrarapid metabolizers. . . .” Although appropriate from a CYP2D6 metabolic standpoint, these recommendations may present some challenges to healthcare providers when applied to some clinical settings. Pain is one of the leading reasons a patient presents to healthcare providers, which includes physicians, dentists, physician assistants, and nurse practitioners in both inpatient hospital and outpatient clinic community settings. Many healthcare providers follow a WHO ladder “type” approach for the treatment of pain (2 ). In this paradigm, depending on the severity of the pain, a nonopioid drug is considered as a first step in pain management (e.g., acetaminophen, nonsteroidal anti-inflammatory drugs). The second step employs an opioid commonly used for moderate pain (e.g., tramadol, codeine, hydrocodone, and possibly oxycodone), often in combination with acetaminophen or nonsteroidal antiinflammatory drugs. The third step includes the use of an opioid usually reserved for severe pain presentation (e.g., morphine, oxymorphone, fentanyl, methadone, and hydromorphone). Of concern, the new CPIC considerations advise increased restrictions for the second step in pain management for CYP2D6 poor and ultrarapid metabolizers. Several problems are presented to healthcare providers when avoiding all of the common analgesic agents in the second step of pain management. First, analgesics including morphine, oxymorphone, fentanyl, methadone, and hydromorphone are usually reserved for opioid-tolerant patients currently receiving opioid therapy. These agents are readily used in nontolerant patients not currently receiving opioid therapy, within an inpatient hospital setting under the direct supervision of a healthcare provider for severe, acute pain (e.g., surgery, postoperative pain). In contrast, within the outpatient clinic setting, these analgesic agents would not be usually used except in cases of more severe chronic pain (e.g., oncological pain). Second, many outpatient clinic healthcare providers are unfamiliar with the use of these drugs, and their inappropriate use greatly increases the risk of medication toxicity. Evidence demonstrating toxicity is abundant in the literature, including inadvertent drug overdoses when opioids for severe pain, such as morphine, oxymorphone, fentanyl, hydromorphone, and methadone, are used inappropriately. Because of its complex pharmacokinetic profile, methadone alone is responsible for one third of the drug deaths from opioids (3 ). A third consideration is the availability of proper analgesic dosage forms. These drugs usually require alternative formulations such as intravenous administration, extended release/duration, or transdermal dosage forms. These drug formulations are inappropriate for the treatment of acute, moderate pain. One should note that the CPIC guidelines state that a healthcare provider’s clinical judgment should be used and that the recommended alternatives should be used in the appropriate manner based on type, severity, and chronicity of the pain that requires treatment. However, when consideration is given to the many outpatient clinic uses for moderate pain where an opioid might be required (e.g., musculoskeletal pain, toothache), it is unlikely that the provided alternatives would be an appropriate opioid choice for routine use. Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN. * Address correspondence to this author at: Mayo Clinic College of Medicine, 200 First St, Rochester, MN 55905. Fax 507-255-7300; e-mail [email protected]. Received June 30, 2014; accepted August 14, 2014. Previously published online at DOI: 10.1373/clinchem.2014.226795 © 2014 American Association for Clinical Chemistry Clinical Chemistry 61:2 319–321 (2015) Perspective