Oxycodone, Overdoses, and Pharmacogenetics

Everywhere we look, news about the epidemic of opiate abuse, both prescription and illicit, abounds. We hear about frightening statistics, celebrities and neighbors alike overdosing; even the availability of overdose reversal agents has become a talking point among presidential candidates.  Recently, the Centers for Disease Control and Prevention (CDC) reported here that 78 Americans die every day from an opioid overdose and that the rate of overdose from prescription opioids such as oxycodone, hydrocodone, and methadone has nearly quadrupled since 1999. Disturbingly, it has come to light that the pharmaceutical manufacturer of one of the most prominent agents of abuse, oxycodone, or Oxycontin, may have had prior knowledge that its product did not last as long as it claimed in some patients, which may have contributed to its potential for abuse.

The FDA has recently released an initiative on mandated changes the healthcare system needs to adopt to prevent heroin and prescription opioid dependence, prevent overdoses, and ultimately save lives.  The Health and Human Services (HHS) initiative to address this healthcare problem includes three parts:

• to better inform the practitioners that are prescribing opioids
• to increase the use of naloxone, the agent that may emergently reverse overdose
• to expand access to MAT or medication-assisted therapy. MAT is the use of agents such as methadone or buprenorphine that blocks the pleasurable feelings associated opioid use, while minimizing the withdrawal effects and cravings in opioid addictions. These medications are combined with behavioral support and counseling and supervised by a physician.

The first component of the new initiative, to improve the practice of prescribing opioids and better inform, includes new labelling requirements with clearer directions for starting and adjusting the dose of immediate release opioids.  Other label changes include more detail about the long-term use of both short-acting and long-acting opioids such as increased risk of drug interactions with antidepressants and migraine medications, increased risk of hormonal changes that may lead to decreases in cortisol, and possibly the ability to respond to stress, as well as decreases in sex hormone levels which may lead to reduced interest in sex, as well as impotence or infertility.  More information can be found here .

While the majority of prescribers have long been aware of the risk of dependence associated with opioids, they may not always be aware of which patients have been obtaining multiple prescriptions of opiates from other prescribers.  Adoption of prescription drug monitoring programs, or PDMPs may allow doctors access to this information, and provide easier identification of patients that are potentially misusing prescriptions.  PDMPs also allow pharmacists to check data to ensure the patient has not already recently picked up an opioid prescription at a different pharmacy.  Currently, 49 states make have such programs available, but their use is not mandatory. Those in favor of the programs cite them as deterrents to abuse, but current practitioners maintain that the tools are slow, vary from state to state, and may further decrease patient time with doctors.

The second component involves increasing access to the opioid reversal agent, naloxone, by implementing grants for states to purchase the product, as well as to increase training for proper administration of the product.  The third component of the HHS initiative provides for broadening access to medications such as buprenorphine and methadone, both of which can be used to decrease relapse with heroin or recreational use of prescription opioids. A 2011 NIDA (National Institute on Drug Abuse) report demonstrates the woeful underuse of such programs and highlights varied opinions and biases even among healthcare professionals, legal authorities, and the general public about replacement of one opioid with supervised use and treatment with another, despite evidence that it is effective.

Earlier this year, the CDC released recommendations for prescribing opioids for chronic pain.  One of these recommendations is for prescribers to evaluate the risks and benefits of acute opioid therapy after one to four weeks before transitioning a patient to chronic therapy with opioids.  At this juncture, most prescribers will transition a patient from short-acting opioid therapy to long-acting opioid therapy.  Ideally, this allows for a patient to take a medication less frequently during the day and experience fewer ups and downs in the levels of drug.  This is important in that more consistent levels of the drug may provide consistent relief from pain, but also avoid sharp increases in drug levels that may increase risk of euphoria and accelerate the potential for abuse.

But, what about the pharmacogenetics of opioids?

The new CDC guidelines, HHS initiatives, and the manufacturers of oxycodone have not directly weighed in with more detail about genetic variants that may change the levels of drug and individual patient experiences.  Oxycodone is metabolized by CYP2D6 and by CYP3A4. Variants in either gene may impact the levels of drug a patient is exposed to, but CYP2D6 variants and their impact upon pain have more documentation.   CYP2D6 is responsible for converting oxycodone to oxymorphone, a more potent pain reliever. Patients can be CYP2D6 poor, intermediate, normal or ultrarapid metabolizers. Patients who are CYP2D6 ultrarapid metabolizers have higher than normal CYP2D6 enzyme activity and therefore higher levels of active metabolites. Generally, CYP2D6 ultrarapid metabolizers are at higher risk of experiencing side effects and opioid toxicity. Conversely, patients who are CYP2D6 intermediate or poor metabolizers with less than normal CYP2D6 enzyme activity may not receive the full benefits of opioid analgesics due to lower active metabolite drug levels. These fluctuating levels of drug may also subtly influence risk for euphoria and withdrawal symptoms, and indirectly, addiction.

Regarding the use of oxycodone in patients with CYP2D6 variants, The Dutch Pharmacogenetic Working Group, or DPWG has developed recommendations for both CYP2D6 poor metabolizer patients and CYP2D6 ultrarapid metabolizer patients.  DPWG states an alternative to oxycodone (other than codeine or tramadol) be chosen for pain relief, if possible, although there is insufficient data from current studies to allow for specific dose adjustments of oxycodone in CYP2D6 poor metabolizer patients. For CYP2D6 ultra rapid metabolizer patients, DPWG also recommends choosing an alternative to oxycodone (other than codeine or tramadol) if possible, monitoring for increased risk of side effects such as nausea, vomiting, extreme sedation, confusion and decreased respiratory rates, and cautions that a dose decrease may be necessary.

Clearly, numerous strategies are needed to decrease the epidemic of opioid misadventures.  Pharmacogenetic testing may be another tool in a provider’s armamentarium to improve and fine tune the prescribing of opioids, by finding the right medication for the right patient.