Oxycodone

Oxycodone is found in the following branded combination products: Percocet, Roxicet Solution, Xartemis XR, Combunox, and Percodan. Oxycodone is a semisynthetic opioid processed from thebaine, an organic chemical found in opium. Oxycodone is available as an immediate-release tablet combined with acetaminophen, aspirin, or ibuprofen. It is also available as an immediate release (IR) solution and controlled-release tablet combined with acetaminophen. With so many formulations available, it is one of the most popular opioids in the United States. The popularity of oxycodone is, in some part, due to its suitability for oral administration due to high bioavailability (60%); oral oxycodone is 1.5 times more potent than oral morphine. Unfortunately, this property may also contribute to its abuse. Even though oxycodone in combination products has been placed in the more restricted Schedule II controlled substance category in the United States, its abuse has been a recurrent problem with law enforcement authorities. Clinicians also need to be aware that oxycodone is converted by P450 CYP2D6 hepatic enzymes to oxymorphone and P450 CYP3A4 to noroxycodone. Patients that are poor metabolizers at CYP2D6 are at risk for accumulation of oxycodone if they take a drug such as fluconazole, a moderate CYP3A4 inhibitor. Similarly, patients taking a strong CYP2D6 inhibitor (paroxetine) and strong CYP3A4 inhibitor (itraconazole) are at risk for the accumulation of oxycodone. It is less clear whether CYP2D6 phenotypes correlate with analgesia or risk of toxicity because physiologic effects correlate best with exposure to the parent compound, oxycodone.

Hydrocodone

Hydrocodone, an opium derivative, found in both combination products and single entity extended-release (ER) formulations was rescheduled from Schedule III to Schedule II on October 6, 2014 by the Drug Enforcement Administration. Hydrocodone is slightly less potent than oxycodone and is found in the following combination products: Norco, Hycet oral solution (hydrocodone and acetaminophen), and Vicoprofen (hydrocodone and ibuprofen). Clinicians need to be aware that hydrocodone is converted by P450 hepatic enzymes CYP2D6 to hydromorphone and CYP3A4 to norhydrocodone. Patients who are poor metabolizers at CYP2D6 are at risk for the accumulation of hydrocodone when given a potent CYP 3A4 inhibitor. A case report describing a fatal hydrocodone overdose provides evidence for the seriousness of drug interactions in patients that are poor metabolizers at CYP2D6. In this case, a young girl was given hydrocodone 3 times per day for cold symptoms, and clarithromycin for an ear infection. The patient used approximately 30 mg of hydrocodone over 24 hours along with clarithromycin, a potent CYP3A4 inhibitor. Postmortem hydrocodone blood concentration was 0.14 μg/mL, a concentration associated with fatality while the hydromorphone concentration was below the limit of detection 0.008 μg/mL (a finding expected in a poor metabolizer at CYP2D6). Postmortem analysis showed the patient had a CYP2D6 ∗ 2A/∗41 genotype, which is associated with poor metabolizer status. As pharmacogenetic testing becomes more widely available, pharmacists with access to this patient data will be able to anticipate significant pharmacogenetic–drug interactions and help clinicians manage them.

Codeine

Codeine has a very similar chemical structure to morphine, but has approximately 200 times less affinity for the mu-opioid receptor than morphine. Approximately 5% to 10% of codeine is metabolized via the hepatic microsomal enzyme cytochrome P450 2D6 to morphine. In patients with poor metabolizer phenotype at CYP 2D6 (∼5% to 10% of patients), there is greatly reduced morphine formation after codeine administration, leading to insufficient pain relief. In patients with ultrarapid metabolizer phenotype (∼1% to 2% of patients), there is greatly increased morphine formation after codeine administration, leading to a higher risk of toxicity. The FDA issued a Boxed Warning that codeine is contraindicated in children undergoing tonsillectomy and/or adenoidectomy because deaths have occurred postoperatively in children with obstructive sleep apnea who received codeine for pain relief following a tonsillectomy and/or adenoidectomy. These children had evidence of being ultrarapid metabolizers of codeine. When codeine (≤90 mg per dosage unit) is administered in combination with acetaminophen as an analgesic, it is placed in the Schedule III controlled substance category. This allows clinicians to prescribe codeine combination products with less regulatory restrictions than combination products containing oxycodone or hydrocodone. Many physicians view codeine as a safer analgesic than morphine as evidenced by the 13.2 million patients in the United States that received codeine-containing products in 2014. On December 10, 2015, an FDA advisory committee recommended codeine be contraindicated for pain and cough management in children and adolescents younger than 18 years of age due to concerns about respiratory depression and death.

Tramadol

Tramadol (Ultram) is a Schedule IV controlled substance and has a dual mechanism of action. Tramadol is a weak mu agonist and inhibits norepinephrine and serotonin reuptake. Tramadol is metabolized via CYP2D6 to the active metabolite O -desmethyl tramadol (M1). The parent compound is primarily responsible for norepinephrine and serotonin reuptake inhibition, whereas M1 is primarily responsible for mu agonistic properties. Tramadol has approximately 6000 times less affinity for mu receptors than morphine. M1 has approximately 300 times greater affinity for mu receptors than the parent drug. In contrast to tramadol and M1, tapentandol, which is discussed below, is a relatively strong opioid agonist and norepinephrine reuptake inhibitor. Patients who are poor CYP2D6 metabolizers form less M1 after tramadol administration, leading to inadequate pain relief. Patients who are ultrarapid CYP2D6 metabolizers produce an increased amount of M1 after tramadol administration, leading to higher risk of toxicities, such as respiratory depression and over-sedation. On September 21, 2015, the FDA issued a safety alert stating that the use of tramadol is under investigation when used in children 17 years and younger, due to increased risk for respiratory depression. This alert was in response to the case report of a 5-year-old who experienced difficulty breathing after one dose of tramadol. It was later discovered the child was an ultrarapid metabolizer of CYP2D6 and had high levels of M1. This risk may be increased in children following a tonsillectomy and/or adenoidectomy, or potentially after any other use in children. The risk of inadequate pain relief and toxicities can be reduced with preemptive genetic testing. Tramadol is mostly renally excreted (30% as unchanged drug and 60% as metabolites). In normal renal function, the maximum total daily dose is 400 mg. In severe renal dysfunction (CrCl less than 30 mL/min), the IR formulation should not exceed 200 mg/day, and the dosing interval should be increased to 12 hours. The ER formulation of tramadol should be avoided in patients with severe renal dysfunction.

Tapentadol

Tapentadol (Nucynta), a Schedule II controlled substance, is an opioid agonist and a norepinephrine reuptake inhibitor that works at both the ascending (excitatory) and descending (inhibitory) pathways. Tapentadol appears to be 2 to 3 times less potent than morphine, even though its binding affinity for opioid receptors is 50 times lower. Data suggest that 3.3 mg of oral tapentandol is equivalent to 1 mg of oral morphine equivalence in both opioid naïve and tolerant patients.

Currently tapentadol is available in both IR (50, 75, and 100 mg) and ER (50, 100, 150, 200, and 250 mg) formulations. It is more expensive compared to other generically available opioids. Tapentadol has been shown equal to and noninferior to equianalgesic doses of oxycodone and morphine with a lower incidence of gastrointestinal side effects, including vomiting and constipation. Tapentadol is generally well tolerated, but it may cause nausea, vomiting, dizziness, and drowsiness. Although tapentadol does not directly increase serotonin levels, data suggest norepinephrine reuptake inhibition may indirectly elevate serotonin. This is demonstrated by case reports of serotonin syndrome, implying that additional serotonergic drugs should be avoided when prescribing tapentadol. The IR formulation of tapentadol is FDA approved for moderate to severe acute pain, and has further shown efficacy for acute lower back pain and associated radicular leg pain, osteoarthritis pain, and postoperative pain secondary to dental and orthopedic surgeries. The ER formulation is FDA approved for diabetic peripheral neuropathy severe enough to require daily, long-term, around-the-clock opioid use, and when alternative treatments are inadequate. The ER formulation has shown efficacy for chronic lower back pain, osteoarthritis knee pain, and moderate to severe chronic malignant tumor pain. For acute moderate to severe pain, the IR formulation dose is 50 mg to 100 mg by mouth every 4 to 6 hours as needed. On the first day of therapy, a second dose may be administered one or more hours after the initial dose (maximum total daily dose is equal to 700 mg). Subsequential maximum total daily doses are 600 mg daily.

Clinicians should be aware of how to transition a patient from a long-acting opioid to ER tapentadol. A general approach is to discontinue all other long-acting opioids, and then initiate ER tapentadol at 50% of the patient’s current 24-hour oral morphine equivalence. Titration should be limited to 50 mg twice daily every 3 days until the most effective dose is achieved. During the titration process, an IR opioid may be used for breakthrough pain.

Renal dose adjustments are not required for creatinine clearances greater than or equal to 30 mL/min; however, tapentadol should be avoided if creatinine clearance is less than 30 mL/min.

Tapentadol is mostly metabolized to tapentadol- O -glucuronide via glucuronidation and, to a lesser degree, through oxidation via CYP2C9, CYP2C19, and CYP2D6 pathways. All metabolites are inactive. Hepatic dose adjustments are not required for mild dysfunction (Child–Pugh score 5 to 6). For moderate dysfunction (Child-Pugh score 7 to 9), the initial IR tapentadol dose should not exceed 50 mg by mouth every 8 hours, and the initial ER tapentadol dose should be limited to 50 mg by mouth once daily with a maximum ER dose of 100 mg daily. Tapentadol is not recommended for severe hepatic dysfunction (Child–Pugh score 10 to 15).