Full mu-agonists bind selectively to the mu- opioid receptor. When an antagonist occupies the receptor, it displaces the agonist and causes opioid withdrawal. Partial agonists, such as buprenorphine, have high receptor occupancy, some antagonistic effects, and low intrinsic activity at the site. Kappa opioid receptor agonists (including levorphanol, pentazocine, and butorphanol) have been used clinically but are associated with such side effects as dysphoria and hallucinations. Buprenorphine has a reduced potential for respiratory depression and is considered safer than full agonists such as morphine, hydrocodone, and oxycodone. 1 Buprenorphine also acts as an antagonist at the kappa receptor, which is shown to reduce anxiety, depression, and the unpleasantness of opioid withdrawal. 1 Tapentadol and tramadol have dual modes of action as agonists at the mu receptor and SNRIs. 1 Considerations with dual- mechanism opioids include lowering of seizure threshold in susceptible patients and the risk of serotonin syndrome due to concomitant serotonin activity. 20 Opioid delivery systems include oral, buccal, sublingual, spray, intravenous, intramuscular, intrathecal, suppository, and transdermal routes. 1 Administration includes ER/LA and IR/SA formulations. IR/SA opioids typically have a rapid onset from 10 to 60 minutes and a duration of action of 2 to 4 hours. In contrast, ER/LA opioids have a relatively slow onset of action of 30 to 90 minutes and longer duration of action from 4 to 72 hours. ER/LA opioids are indicated for the management of pain severe enough to require daily, around-the- clock, long-term opioid treatment and for which alternative treatment options are inadequate for patients with existing opioid tolerance. The class of ER/LA opioids are not for use “as needed,” not for mild pain, and not for acute pain or pain that not expected to persist for an extended duration: 67,68 Opioid risks, warnings, and side effects include an FDA boxed warning about the serious risks for misuse, abuse, addiction, overdose and death that apply to all IR/SA and ER/LA prescription opioids. 69 These risks are present whenever opioids are misused but apply even at prescribed doses. The labels for opioid combination products containing ACET also warn of the potential for severe liver damage. 60 An FDA boxed warning details the risks of prescribing opioids and benzodiazepines together, a combination of medications that has increased in recent years but which is associated with extreme sleepiness, respiratory depression, coma, and death. 70 In addition, patients may suffer serious harm, including serious withdrawal symptoms, uncontrolled pain, and suicide, if opioids are suddenly discontinued or tapered too rapidly. 71,72 Concomitant drugs that act as inhibitors or inducers of various cytochrome P450 enzymes can result in higher or lower than expected blood levels of some opioids. Dosages should be reduced in the presence of hepatic or renal impairment. 68
Certain cautions apply to specific opioid types, formulations, and delivery systems. Some opioids (e.g., methadone, buprenorphine) can prolong the QTc interval. Relative potency to oral morphine is intended as a general guide with additional conversion instructions included in each product’s PI. 68 ER/LA opioid tablets should be swallowed whole, never crushed, chewed, broken, cut, or dissolved. Altering them in such ways may result in rapid release and absorption of a potentially fatal dose. 67,68 When necessary, some products may be sprinkled as pellets on applesauce and swallowed without chewing. Transdermal systems and buccal films should not be cut, torn, or damaged before use. Transdermal dosage forms should not be chewed or swallowed, and exposing patches to heat may lead to fatal overdose. Possible opioid side effects include but are not limited to: 1,61 • Lightheadedness
syndrome with certain opioids. Opioids induce the release of antidiuretic hormone, reducing the efficacy of diuretics. Initiating CYP 3A4 inhibitors or discontinuing CYP 3A4 inducers can result in higher than expected opioid blood levels leading to overdose. Opioid contraindications. There are some absolute contraindications for initiating a trial of long-term opioid therapy that include: 20 • Known hypersensitivity to active ingredients or other components of opioid analgesics. • Significant respiratory depression or compromise. • Acute or severe bronchial asthma. • Known or suspected paralytic ileus and gastrointestinal obstruction. • Evidence for or history of diversion of controlled substances (e.g., forged prescriptions, pharmacy robberies, selling own prescription drugs, theft of others’ drugs). Although the combination is sometimes used, the Department of Veterans Affairs/Department of Defense (VA/DoD) practice guideline lists concomitant use of benzodiazepines as a contraindication to initiating a trial of long-term opioid therapy. 20 The Centers for Disease Control and Prevention (CDC) recommends avoiding prescribing opioids and benzodiazepines concurrently whenever possible but allows for rare instances when the combination may be indicated (e.g., severe acute pain in the presence of long- term, stable, low-dose benzodiazepine therapy). 61 Medication errors may result from miscommunication, packaging design, confusion caused by similar drug names, and other sources. Patient counseling and education can help guard against medication errors. Methadone for pain presents special clinical challenges due to a long and variable half-life, risk for toxicity due to accumulation in plasma concentrations during the several days necessary to achieve steady-state, and risk for cardiac toxicities due to prolongation of the QTc interval. 76-78 Methadone-related deaths have occurred in disproportionate numbers relative to the frequency with which it is prescribed for pain. 61 Methadone is only for patients whose severe pain is unrelieved by other opioids. Close monitoring is critical when initiating methadone and during dose changes, and caution is needed in patients with heart disease or taking medications with concurrent QTc interval effects. Patients should be assessed for cardiac health ahead of being prescribed methadone, and an initial ECG may be advisable, particularly if the patient has cardiac disease or risk factors. If methadone is initiated, it should be started at a very low dose (e.g., 2.5mg tid) and slowly titrated (e.g., by no more than 25%-50%, no more frequently than weekly. 76,77 In adults on relatively low previous opioid doses (e.g., <40–60 mg per day of morphine or equivalent), experts suggest a starting dose of 2.5 mg tid with initial dose increases of no more than 5 mg daily every 5 to 7 days. 79
• Dizziness • Sedation • Nausea and vomiting • Drowsiness • Mental clouding • Constipation • Hormonal deficiencies • Pruritis • Myoclonus • Irritability • Respiratory depression
Opioid pharmacokinetics influence the bioavailability of the drug, the production and elimination of metabolites, and the activity of metabolic enzymes. 73 Most opioids are metabolized through the liver microsomal cytochrome P-450 (CYP) system with CYP2D6 or CYP3A4 being responsible for much metabolism of opioids and many other drugs. Certain clinical applications are relevant. Slow metabolizers of CYP2D6 may gain little benefit from codeine, for example. Opioids metabolized through the CYP450 system, including codeine, oxycodone, hydrocodone, fentanyl, tramadol, and methadone, may have heightened or reduced CYP450-associated effects with drug combinations, while morphine, oxymorphone, and hydromorphone are not as prone to such interactions. 74 Codeine and tramadol should be avoided in breastfeeding women due to risks to the infant from ultra-rapid CYP2D6 metabolism in some people. 61,75 All opioids have similar pharmacodynamics, which describe effects in the body such as binding action and location to receptors, although individual patient responses may vary. 73 Drug-Drug interactions are possible with opioids. 68 Co-ingesting CNS-depressants that include alcohol, benzodiazepines, sedatives, hypnotics, tranquilizers, and tricyclic antidepressants can potentiate the sedation and respiratory depression caused by opioids. Alcohol can cause rapid release of ER/LA opioid formulations leading to an increased drug level. Combining opioids with monoamine oxidase inhibitors (MAOIs) can increase respiratory depression and cause serotonin
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