Medications: Opioid

Opioid Medications: Dosages, Adverse Events, and Patient Education APhA Pain Institute Opioid Medications: Dosages, Adverse Events, and Patient Education Opioid Mechanisms Learning Objectives Mu, delta, and kappa are the three receptors involved in the effects At the completion of this knowledge-based activity, of opioids, including both their analgesic activity and their adverse participants will be able to: effects. The mu-opioid receptor is most commonly responsible for analgesia, respiratory depression, and euphoria. The kappa-opioid 1. Identify the relative efficacy of various opioids for pain receptor can be responsible for dysphoria or analgesia depending management. on which receptor subtype is activated. Opioids also exhibit varying 2. Describe common adverse events associated with available activity at these receptor sites as agonists, antagonists, and partial opioids for pain management. agonists or mixed agonist/antagonist properties. 3. Discuss patient counseling and education strategies that support As the dose of a pure opioid agonist increases, analgesic effects appropriate use of opioids. increase but so does the risk of respiratory depression due to carbon dioxide accumulation. Partial agonists/antagonists, such as Background buprenorphine, are unique in that as the dose increases, carbon dioxide accumulation and the associated risk of respiratory The release of the Centers for Disease Control and Prevention depression plateaus.2 This could represent a potentially safer option (CDC) guidelines for prescribing opioids has brought national for patients with comorbid respiratory conditions. Buprenorphine attention to opioid prescribing in the primary care setting. These is also associated with decreased euphoria due to these mixed guidelines include specific qualifying parameters for initiating partial agonist/antagonist properties, which could offer a safe and and continuing opioids intended for long-term use in patients with effective treatment in patients with a history of “dose creeping” and 1 chronic noncancer pain. Although highlights include tapering opioid abuse/misuse when nonopioids present a larger risk due to high-dose opioids and using only the lowest effective dosage, the medical comorbidities. An example of this circumstance would be recommendations fail to provide guidance on how to taper and a patient with a history of opioid misuse that has severe low back do not provide quality evidence that delineates when a taper is pain with supportive pathology and a history of diabetes, coronary warranted. Nevertheless, pharmacists have been placed in the artery disease, and uncontrolled hypertension. The opioid antagonist crossfire of a somewhat political issue and are often called upon by naloxone binds to the mu receptor site with greater affinity than primary care providers for guidance on continuing opioids, reducing pure opioid agonists without activating the receptor; due to this the dose, or discontinuing these agents altogether. competitive inhibition activity, naloxone is used to reverse opioid- induced respiratory depression (OIRD). When health care providers are considering the initiation of long-term opioid therapy, pharmacists can provide unique insight Certain formulations of naloxone are now available and approved owing to their understanding of opioid chemistry, pharmacokinetics, by the U.S. Food and Drug Administration (FDA) for in-home use. pharmacodynamics, and perhaps less often, pharmacogenetics. Buprenorphine transdermal patches (Butrans) and buccal films Patient assessment is the first step when determining whether (Belbuca) have a specific FDA approval for chronic pain requiring opioid therapy is appropriate. Physical examination and imaging around-the-clock opioid dosing, and an injectable buprenorphine should be employed to support pathology with respect to a (Buprenex) has an indication for acute pain. These products are patient’s subjective pain report. In the absence of contraindications, specifically mentioned here because none require prescribers to nonpharmacological and nonopioid therapy should be initiated and have a special Drug Enforcement Administration (DEA) number maximized prior to considering long-term opioid therapy. Patients beginning with “X”—known as a narcotics DEA number or who are not appropriate candidates for opioid therapy include those NADEAN—from the DEA for prescribing. In contrast, physicians who have not received optimal trials of nonopioid therapies, most who prescribe buprenorphine products that are otherwise indicated patients with a history of substance abuse or aberrant behavior, and for the treatment of opioid abuse disorder are required to have a patients for whom the risk of adverse effects outweighs potential special narcotics DEA number. This difference is often misinterpreted benefits. Finally, providers may encounter patients who responded by prescribers and pharmacists. poorly to an initial opioid trial but determine that the benefits outweigh associated risks of other options, and thus a retrial of a different opioid may be warranted. Regardless of the reason for Opioid Classes opioid initiation or change, it is important to have a plan that allows Pharmacists’ extensive background in therapeutics and medicinal for the safe and controlled discontinuation of a selected opioid if, at chemistry affords a unique opportunity to collaborate with any point, risks to the patient outweigh potential benefits. prescribers on recommendations for a safe and workable opioid taper and/or transition to another opioid. Organizing opioids by © 2017 by the American Pharmacists Association. All rights reserved. Opioid Medications: Dosages, Adverse Events, and Patient Education chemical class is useful for understanding the various attributes in Figure 1 by an asterisk) are associated with increased and drawbacks of these agents (Figure 1).3,4 Several options have tolerability; in particular, they are associated with reduced different pharmacodynamic and pharmacokinetic characteristics gastrointestinal (GI) side effects and less pruritus.5 Patients who that should be considered when selecting appropriate therapy for cannot tolerate a hydroxylated phenanthrene may tolerate a individual patient needs. dehydroxylated phenanthrene. However, patients unable to tolerate a dehydroxylated phenanthrene generally have difficulty Phenanthrenes tolerating a hydroxylated phenanthrene. Patients who tolerate one dehydroxylated phenanthrene will generally tolerate another Phenanthrenes are the prototypical class of opioids and include dehydroxylated phenanthrene because of their chemical similarity more agents than the other classes of opioids. This chemical (e.g., a patient who previously tolerated hydrocodone will likely class also comprises the most commonly prescribed opioids (e.g., tolerate buprenorphine).3 When reading Figure 1 from left to right, morphine, codeine, hydrocodone, oxycodone, dextromethorphan) it is important to note the cross-sensitivity risk decreases. If a patient as well as the antagonist, naloxone.4 Within this class are two has a true allergic reaction (i.e., anaphylaxis) to codeine, then that subcategories, hydroxylated phenanthrenes and dehydroxylated individual will have a true allergy to hydromorphone. (There is a phenanthrenes. Dehydroxylated phenanthrenes (designated similar scenario when comparing penicillin to ampicillin.) However, Figure 1. Chemical Classes of Opioids PHENANTHRENES BENZOMORPHANS PHENYLPIPERIDINES DIPHENYLHEPTANES PHENYLPROPYL AMINES HO HO O O N NH O O N O HO H N H N HO MORPHINE PENTAZOCINE MEPERIDINE METHADONE TRAMADOL Buprenorphine* Diphenoxylate Alfentanil Methadone Tapentadol Butorphanol* Loperamide Fentanyl Propoxyphene Tramadol Codeine Pentazocine Meperidine Dextromethorphan* Remifentanil Heroin (diacetyl-morphine) Sufentanil Morphine Hydrocodone* Hydromorphone* Levorphanol* Methylnaltrexone** Morphine (Opium, conc) Nalbuphine* Naloxone* Naloxegol* Naltrexone** Oxycodone* Oxymorphone* CROSS-SENSITIVITY RISK PROBABLE POSSIBLE LOW RISK LOW RISK LOW RISK * Agents lacking the 6-OH group of morphine, possibly decreases cross-tolerability within the phenanthrene group. ** 6-position is substituted with a ketone group and tolerability is similar to hydroxylation. Source: Reference 4. Reprinted with permission from paindr.com. APhA PAIN INSTITUTE 3 Opioid Medications: Dosages, Adverse Events, and Patient Education cross-sensitivity within each opioid class decreases so that if a barrier), and risk of QTc prolongation requiring electrocardiogram patient has an intolerance, or even allergy to morphine, there is a (ECG) monitoring. Methadone titration should be slow with dose reduced risk of intolerance to tramadol and its phenylpropyl amine increases no more frequent than every 7 days.8,9 Methadone is chemical cousin, tapentadol. Nevertheless, tramadol and tapentadol commonly used for opioid detoxification and maintenance therapy. differ in pharmacology and they have very different metabolism and Antagonism at N-methyl-D-aspartate (NMDA) is associated with side effect profiles. decreased euphoria and cravings. Additionally, the long half-life of methadone allows for once-daily dosing for opioid dependence. Phenylpiperidines However, when used for chronic pain management, methadone generally requires dosing three- to four-times daily because the Due to significant risk profiles, use of sufentanil and remifentanil analgesic efficacy is approximately 6 to 8 hours. should be limited to experienced clinicians. Fentanyl is

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