Opioid Agonists Opioid agonists are drugs that bind tightly to opioid receptors to illicit a response. Opioid agonists can be classified further as naturally occurring, semi-synthetic, or synthetic. Commonly prescribed opioid agonists are discussed below. 143 Morphine Morphine is the prototype naturally-occurring opioid by which all other opioids are compared. It is available in immediate-release oral formulations, extended-release oral tablets, as well as parenteral formulations. The effects of morphine are primarily due to the parent drug, but its hepatic metabolism creates two metabolites that contribute to its efficacy as well as toxicity. Patients with significant hepatic disease should use morphine cautiously due to the increased risk of adverse effects, such as CNS irritability, development of tolerance, and seizure. Intravenous and rectal routes of administration bypass hepatic metabolism, resulting in lower concentrations of metabolites compared to the oral route. Morphine’s metabolites are excreted through the kidneys, so patients with renal disease may require dosage adjustments. Morphine is known to release histamine, which can lead to allergic-type reactions such as itching. 145 Codeine Another naturally-occurring opioid, codeine is commonly used for the treatment of pain and cough. It is available in oral formulations, as a single drug product or in combination with acetaminophen or cough medications. It is readily absorbed from the GI tract, and is metabolized in the liver by the cytochrome P450 enzymes 2D6 and 3A4; prescribers should use caution when prescribing codeine to patients with hepatic disease or in combination with medications that utilize the 2D6 and 3A4 enzymes. Codeine is primarily eliminated through the kidney, so dosage adjustments should be made in patients with significant renal disease. Similar to morphine, codeine can cause histamine release, leading to allergic-type reactions such as itching. 111,145 Oxycodone Oxycodone is a semi-synthetic opioid that has been used as a pain reliever for over 80 years. It is available in immediate-release and extended- release formulations, as a single drug product or in combination with acetaminophen. Oxycodone has a number of characteristics that one would want in an ideal opioid: it has few side effects, is easy to titrate, has a relatively quick onset of action and a short half-life, and its pharmacokinetics are predictable. It is metabolized by the cytochrome P450 2D6 enzyme, which converts it to oxymorphone, and the 3A4 enzyme, which converts it to an inactive metabolite. Approximately 10% of the population has lower levels of the 2D6 enzyme; these patients may require higher than average doses to achieve analgesia. Patients taking medications that are strong inhibitors of the cytochrome P450 system should be titrated on to oxycodone with caution.
Oxycodone and its metabolites are excreted through the kidneys, so dose adjustment is needed in patients with renal disease. 145 Oxymorphone Oxymorphone is a semi-synthetic opioid that has been available since 1959 as an intravenous preparation, but was not developed into an oral product until 2006. When given intravenously, it is 10 times more potent than morphine. Oxymorphone experiences extensive first-pass metabolism, resulting in only 10% bioavailability when taken orally. However, it is more lipophilic than morphine and oxycodone, which allows it to cross the blood-brain barrier more quickly, resulting in a more rapid onset of action. After hepatic metabolism, oxymorphone is excreted through the kidney. Renal impairment can significantly increase bioavailability, so dosing adjustments are critical in patients with kidney disease. Oxymorphone is contraindicated in patients with moderate to severe hepatic impairment. Taking oxymorphone with food can significantly increase plasma concentrations, so patients should be counseled to take it on an empty stomach. Avoiding alcohol is also important, since it can increase plasma concentrations by nearly 300%. 145 Hydromorphone Hydromorphone is a semi-synthetic opioid that is five to six times more potent than morphine when given parenterally. It is commonly given orally and intravenously, and can also be administered by the epidural or intrathecal routes. Oral tablets are available in immediate-release and extended- release forms. Short-acting oral forms are effective within 30 minutes of administration and last for 3 to 4 hours. Intravenous hydromorphone is effective within 5 minutes. Hydromorphone is preferred over morphine in patients with renal impairment because its metabolites are produced in small quantities that have minimal accumulation. 145 Fentanyl Fentanyl is a synthetic opioid that is 50 to 100 times more potent than morphine. It has a relatively short half-life of 3 to 7 hours, requiring frequent or continuous administration. It is safe for use in patients with kidney disease, but is contraindicated in patients with liver failure. 111,146 The most common formulation used in the out- patient setting is the transdermal fentanyl patch. Patients initiated on this formulation must be toler- ant to opioids; it is recommended for patients tak- ing more than 60 morphine milligram equivalents (MME) per day if they are cognitively able to ap- ply, remove, and dispose of the patches in a safe manner. Fentanyl patches contain residual medica- tion even after they are used for the recommended amount of time and can pose a significant safety risk to children, pets, and other family members. They should be disposed of by folding them in half with the sticky side inward and either flushed down the toilet or mixed with an unsavory substance such as used coffee grounds and sealed in a container that has a child-resistant closing mechanism.
Fentanyl is also available in sublingual and intravenous formulations, which have utility in inpatient and palliative care settings. 140,146 Methadone Methadone is a synthetic opioid that is used for pain and as a maintenance drug for use in the treatment of opioid addiction. Although specialized training and DEA registration is required for the treatment of addiction, any provider authorized to prescribe Schedule II controlled substances can prescribe methadone to treat pain. Over the past few decades, methadone sales have risen sharply, largely for use outside of the narcotic treatment arena. Coupled with the increase in the use of methadone for pain, questions of its safety have also been on the rise. Although methadone accounts for fewer than 5% of opioid prescriptions, it has been linked to one-third of opioid-related deaths. 147,148 There is a disconnect between the half-life of methadone in the blood and the duration of analgesia that it provides. The plasma half- life ranges from 8 to 60 hours; the duration of methadone analgesia is 6 to 12 hours. In practice, pain relief may end long before the drug is eliminated from the body, leading to redosing and potentially dangerous systemic accumulations. Furthermore, methadone is metabolized by several different enzyme systems, subjecting it to multiple potential drug-drug interactions. The use of methadone is also complicated by its interaction with cigarette smoking, which increases the rate of its metabolism, and alcohol, which can augment its toxicity in addition to increasing the rate of its metabolism. Because of these liabilities, prescribers must exercise great caution when prescribing methadone. 111,148 Although methadone is not commonly employed as a first-line opioid, it could be beneficial in opioid- naïve patients. Because of its slow onset and long duration of effect, it may help avoid some of the reward behaviors common to fast-acting opioids. The American Pain Society and American Academy of Pain Medicine (APS/AAPM) guidelines recommend a starting dose in most opioid-naïve patients of 2.5 mg every 8 hours, with dose increases occurring no more frequently than weekly. 111,148 It is nearly impossible to determine an equivalent dose of methadone based on morphine dosing because the required methadone dose will decrease over time. Therefore, the lowest possible dose titration should be followed in opioid-tolerant patients. Most available narcotic equivalence tables are based on single doses. Because of its potential accumulation, relying on these charts for chronic methadone dosing can result in a substantial overdose that may not become apparent for several days. 111,148 In 2006, the FDA issued an alert warning that methadone can cause serious cardiac conduction disturbances, including QT-interval prolongation and torsades de pointes, a potentially fatal ventricular arrhythmia.
22
Powered by FlippingBook