sign in sign up
<<
Home , Hydromorphone

Medications: Dosages, Adverse Events, and Patient Education

APhA 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 , including both their activity and their adverse participants will be able to: effects. The mu- is most commonly responsible for analgesia, respiratory depression, and . The kappa-opioid 1. Identify the relative efficacy of various opioids for pain receptor can be responsible for 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 , antagonists, and partial opioids for . agonists or mixed /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 , 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 /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 crossfire of a somewhat political issue and are often called upon by 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, , by the U.S. Food and Administration (FDA) for in-home use. , 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 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 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 will likely class also comprises the most commonly prescribed opioids (e.g., tolerate buprenorphine).3 When reading Figure 1 from left to right, , , hydrocodone, , ) 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 PEATREE BEOMORPA PELPIPERIDIE DIPELEPTAE PELPROPL AMIE

HO HO O O N NH O O N O HO H N H N HO

MORPIE PETAOCIE MEPERIDIE METADOE

Buprenorphine* * Propoxyphene Tramadol Codeine Meperidine Dextromethorphan* (diacetyl-morphine) Morphine Hydrocodone* Hydromorphone* * ** Morphine (, conc) * Naloxone* * ** Oxycodone* *

CRO-EITIIT RI

PROBABLE POIBLE LO RI LO RI LO RI

* 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 available in a transdermal patch for chronic use, which is indicated for Methadone acts as an agonist at the mu-opioid receptor and opioid-tolerant patients requiring around-the-clock analgesia. an NMDA antagonist, and it is both a norepinephrine (NE) and Fentanyl is also available in various transmucosal immediate-release serotonin (5-hydroxytryptamine [5-HT]) reuptake inhibitor. NMDA formulations, which are reserved for patients with and blockade and NE reuptake are the two activities that may provide are highly restricted by the federal risk evaluation and mitigation additional benefit to treat pain associated with a neuropathic strategy (REMS) program. Some patients may state that they cannot component. The 5-HT reuptake inhibition offers no therapeutic tolerate any opioids except meperidine. In this situation, keep in benefit to enhance analgesic activity other than a potential to mind that since meperidine is a phenylpiperidine, fentanyl is a reduce associated depression.10,11 Levorphanol has similar activity to viable option. Previous opioid dose should be used to determine methadone, but has more potent NMDA antagonism and additional an appropriate starting dose of fentanyl. (Note: Dosing conversion delta and kappa receptor affinity. Unlike methadone, levorphanol will be discussed later in this article.) Standard dosing interval has a much more predictable half-life (11 to 16 hours) and does for the transdermal patch is every 72 hours; however, in patients not prolong QTc. It also undergoes phase II metabolism only, which with inadequate analgesia or who experience end-of-dose failure, decreases the risk for drug-drug interactions. Recent price increases frequency may be increased to every 48 hours. Decreasing have made levorphanol a cost-prohibitive option for many patients. application frequency allows for maintenance of lower therapeutic serum levels while minimizing toxicity, whereas increased doses while maintaining an every 72-hour interval will cause an increased Phenylpropyl Amines maximum serum concentration (Cmax). Notably, fentanyl and the This opioid class includes tramadol and tapentadol. Owing to fentanyl family (i.e., sufentanil, remifentanil, alfentanil, etc.) have the structural similarities of these two agents, patients who exhibit a true least histamine reactivity compared with other opioids and thus there allergy to one will have a reaction to the other. Therefore, if a patient is less likelihood of pruritus.6,7 cannot tolerate tramadol, the pharmacist should carefully ascertain whether a similar reaction was had with a serotonin-enhancing antidepressant; in that case, tapentadol may be a viable option, because the reaction could have been pharmacological rather than Patients’ opioid therapy should be chemical. Tramadol is a partial and very weak mu-opioid agonist with NE continually monitored and assessed for and 5-HT reuptake inhibition. NE activity benefits neuropathic efficacy, tolerability, and safety. pain; however, the increased serotonin activity can decrease the threshold and elevate risk of when combined with specific serotonin reuptake inhibitors and/or other 5-HT enhancing . Tapentadol has significant pure mu-opioid agonist properties far exceeding that of tramadol and it inhibits Diphenylheptanes NE reuptake. Tapentadol does not have serotonin activity, as Because propoxyphene is no longer on the market, methadone does tramadol; however, the package insert warns against is the only diphenylheptane currently available. Methadone is possible serotonin syndrome. It is also associated with decreased characterized by a long and variable half-life (15 to 60 hours, and euphoria that is associated with many opioids. While chronic up to 150 hours depending on phenotype and polymorphism), opioid use can have a significant effect on the hypogonadal many drug-drug interactions via cytochrome P450 enzymes and axis and can cause low testosterone levels, inadequate P-glycoprotein (oral absorption and passage through the blood brain serum testosterone levels can greatly inhibit adequate pain

APhA PAIN INSTITUTE 4 Opioid Medications: Dosages, Adverse Events, and Patient Education

management.12-14 In a patient treated with chronic opioids and Table 1. Most Common Opioid-Induced Adverse Effects having persistently low testosterone, consideration may be given to switching therapy to tapentadol due to decreased activity on Category the hypogonadal axis. Common • • Benzomorphans • Dry mouth The use of benzomorphans for pain management is limited. • Fatigue Pentazocine is a partial opioid agonist with short duration of • Impaired cognition action. This agent is associated with neurotoxicity and its analgesic • and activity will eventually plateau. As such, pentazocine is typically • Pruritus considered a last-line agent only for those patients unable to • Postural tolerate other opioids. Diphenoxylate and loperamide are also • Sexual dysfunction categorized as benzomorphans; however, neither is generally • useful for pain management. Loperamide has gained popularity • Testosterone abnormalities in supra-therapeutic doses as a drug of abuse and an agent for the self-management of .15 The side effects of Severe • Opioid-induced respiratory depression high-dose loperamide can be fatal and this agent is associated with • Addiction/dependence arrhythmias and respiratory depression when combined with other • Death central nervous system (i.e., ). Other Risks • Falls • Hyperalgesia • Neonatal abstinence syndrome There are currently no (potentially life-threatening)

universally accepted be avoided because they can create a larger stool and cause impaction.16 Recently, several new products known as peripherally opioid conversion or acting mu-opioid receptor antagonists (PAMORAs) have been developed; PAMORAs provide a welcomed option for patients with tapering guidelines. refractory OIC. Examples of these agents include naloxegol and methylnaltrexone, both of which are in the phenanthrene class. Opioid-Induced Adverse Effects Opioids are associated with a variety of adverse effects (Table 1). Respiratory Depression Many of these effects, particularly fatigue, diminish over time as OIRD is a potentially fatal adverse effect of opioid therapy. patients develop tolerance. The severity of some of these adverse Increased activation of mu-opioid receptors progressively increases effects can vary among opioids; for example, tramadol is associated respiratory depression as accumulation of carbon dioxide with the most opioid-induced constipation (OIC). ensues. The risk of OIRD is greater in patients with comorbid respiratory diseases. OIRD and overdose is also much greater when opioid use is combined with other central nervous system Constipation depressants such as , benzodiazepines, or other Unfortunately, OIC persists regardless of duration of therapy. The (e.g., ) and sedating agents such as the analgesic effect of opioids is due to the binding of opioid receptors tricyclic anti-depressants, which include commonly co-prescribed in the central and peripheral nervous systems, but these are not and . The triad of opioids and the only locations of opioid receptors. It is the activation of opioid benzodiazepines, combined with carisoprodol is well-recognized receptors lining the GI tract that decreases GI motility resulting in as “the holy trinity” among substance abusers and regulatory OIC. Often, a stool softener combined with a laxative is agencies; their combination has been attributed to thousands of used as first-line therapy for management of OIC. Stool softeners opioid deaths.17 Naloxone, previously mentioned in the section alone are inadequate to treat OIC because diminished motility is on opioid mechanisms, is an opioid receptor antagonist that can in part the cause. Other resultant effects from mu-agonism include be used to reverse OIRD and overdose. Many states have passed decreased fluid influx to gut, increased efflux, and reduced muscle legislation designed to increase layperson access to life-saving tone to the anal sphincter. Considering the decreased motility and naloxone. Currently, there are two FDA-approved naloxone diminished bowel hydration, bulk laxatives such a psyllium should

APhA PAIN INSTITUTE 5 Opioid Medications: Dosages, Adverse Events, and Patient Education

products designated for in-home use and available for layperson treatment of chronic pain result in frequent serum peaks and troughs administration: Evzio auto-injector and Narcan nasal spray. with a higher Cmax compared with ER/LA opioids. Over time, this frequent fluctuation in serum levels, particularly with higher Table 2 highlights clinical pearls, monitoring requirements, side doses, increases the risk of tolerance and toxicity, but may minimize effects, and patient counseling points for various opioids. Of adverse activity at the hypothalamic-pituitary-adrenal axis.12,13 The important note is that although abrupt abstinence from opioids may use of ER/LA opioids decreases serum peaks and troughs allowing cause uncomfortable withdrawal syndrome, this is generally not for more consistent analgesia and can provide a safer option with life threatening in adults; however, neonates exposed to opioids diminished peaks compared with high-dose IR opioids and may regularly in utero can die from these symptoms soon after birth if improve uninterrupted nighttime sleep. they are not provided with an opioid taper utilizing methadone or buprenorphine. Abuse deterrent technology (ADT) has become available for many opioid formulations. ADT creates barriers in an attempt to hinder Despite having largely similar adverse effect profiles, many opioids abuse and misuse. Strategies include developing formulas that utilize have unique characteristics that must be considered when selecting polyethylene oxide, gums, and carbomers that gel when crushed an appropriate agent or while monitoring therapy. Table 3 discusses or mixed with solvents, thereby altering viscosity. Combination key clinical pearls specific to certain opioid therapies. products, such as those with an opioid antagonist, emetics, or mucous membrane irritants, also make abuse unpleasant.19

Opioid Formulations The CDC guidelines for prescribing opioids includes a Morphine-Equivalent Daily Dose recommendation against using extended-release (ER) or long-acting Morphine-equivalent daily dose (MEDD)—also known as morphine (LA) opioids in patients who are not already prescribed a short- equivalent dose (MED), morphine milligram equivalent (MME), acting immediate-release (IR) opioid, with a suggestion favoring or morphine equivalent (MEQ)—is a term coined in an effort to IR opioids over ER/LA opioids. Long-term use of IR opioids in the compare opioids with disregard for differing pharmacokinetic

Table 2. General Opioid Considerations for Health Care Professionals and Patients Clinical Pearls, Monitoring Requirements, Side Effects Patient Counseling Points • Opioids have a risk of addiction, physical dependence, and • Take this medicine exactly as prescribed. Talk to tolerance. While addiction is a risk, it is not the same as physical your health care provider if you feel your pain is not adequately dependence or tolerance. (See definitions of opioid terminology in the controlled. sidebar.) • These drugs cause dizziness and drowsiness. Avoid operating • Physiological dependence may result in withdrawal machinery when using these drugs or at least do not operate a motor syndrome upon discontinuation. Health care providers should monitor vehicle soon after starting the medicine, adjusting the dose, or adding for abuse, misuse, and diversion. another medicine that causes dizziness or drowsiness. • Abruptly stopping tramadol does not cause opioid withdrawal; instead • Don’t chew or crush long-acting formulations. Breaking the tablet or 5-HT withdrawal is a common side effect that can be avoided with capsule may result in too much drug in your blood because it is all slow taper or introduction of a selective serotonin reuptake inhibitor. released at once instead of over several hours. • Consider starting at a lower dosage in elderly patients and patients • Avoid using alcohol, sleeping pills and/or while using this with renal or liver impairment. Careful titration and monitoring are medicine. required to avoid potentially toxic serum drug levels. • Avoid using antihistamines with this medication because it can • Patients typically develop tolerance to all side effects except increase your risk of constipation. constipation. • These medicines can be constipating. Please increase the amount • Combining an opioid medication with alcohol, other opioids, and of fiber in your diet and drink more fluids. There are many products other central nervous system depressants increases risk of adverse to help relieve your constipation while on this medicine. Talk to your events, opioid-induced respiratory depression, and death. pharmacist or health care provider for their recommendation. • The absorption of transdermal opioid preparations can increase • Don’t share this medication with anyone. rapidly with application of heat and result in dangerous toxicity. • For patients using the medicated skin patch, apply the patch to a • With transdermal opioid preparations, absorption via the dermal clean, dry, hairless area. If applying to a hairy area, clip the hair layer is slow and can take many hours to reach steady state serum with scissors—do not shave or use shaving cream or similar products concentrations (up to 3 days). because using these products can affect the medicine in the patch and shaving can irritate the skin. Do not apply heating pads over the patch.

APhA PAIN INSTITUTE 6 Opioid Medications: Dosages, Adverse Events, and Patient Education

Opioid Terminology

Abuse: Physical Dependence: Inappropriate use of a prescription or illegal substance for a Abrupt cessation or reduction resulting in physical symptomatic nonmedical purpose. withdrawal symptoms. Addiction: Tolerance: A disease in which one or more of the following is exhibited: Decreased response to the same dose over time, requiring higher compulsive and/or continued use despite harm, craving, and doses for a similar previous effect. inability to control drug use. Source: Reference 18. Misuse: A willful or unintentional use of a prescribed medication for a purpose other than how it is prescribed.

Table 3. Opioid-Specific Clinical Pearls Opioid by Class Clinical Pearls Phenanthrenes Oxycodone Approximately 30% of patients will experience wakefulness instead of drowsiness typically associated with oxycodone. This effect could be beneficial for patients who experience drowsiness on other opioids. CYP3A4 converts oxycodone to the major metabolite . Avoid concomitant use with CYP3A4 inhibitors (including grapefruit juice), which can lead to increased serum drug concentrations. High-dose oxycodone immediate-release formulations such as 15 mg (or higher-strength tablets) have a high street value and are sought out for crushing and snorting. Codeine Black Box Warning: Contraindicated in pediatric patients following tonsillectomy. Unknown presence of ultra-rapid CYP2D6 metabolizers have resulted in pediatric overdose. Codeine is readily found in breast milk and should not be given to nursing mothers. Hydromorphone, Metabolized via phase II. No CYP drug-drug interactions. Oxymorphone, Generic oxymorphone extended-release formulation is not an abuse deterrent and is highly abused by crushing Morphine, and snorting. Levorphanol, Mechanism as partial agonist/antagonist is associated with unique traits: Buprenorphine • Accumulation of carbon dioxide plateaus decreasing the risk of opioid-induced respiratory depression. • Concomitant use of central nervous system depressants mollifies this benefit. • Decreased constipation. • Three buprenorphine product formulations are specifically approved by the U.S. Food and Drug Administration for pain management (i.e., injectable, transdermal patch, and buccal film). The branded buccal films need to be applied to a wet cheek; lick or drink water, place film on fingertip (yellow or “sunny side up”), and hold in place for 5 seconds. • NADEAN is not required to prescribe any of the above buprenorphine products for pain. Naloxone Naloxone is used for . Repeated doses may be required because opioid activity may last longer than the antagonist. Naloxone can cause withdrawal symptoms in patients with opioid dependence. Buprenorphine has a higher binding affinity to mu-receptors than naloxone; therefore, this can cause opioid withdrawal symptoms in persons previously prescribed pure opioids. (Continued on next page.)

APhA PAIN INSTITUTE 7 Opioid Medications: Dosages, Adverse Events, and Patient Education

Table 3. Opioid-Specific Clinical Pearls (continued) Opioid by Class Clinical Pearls Phenylpiperidines Fentanyl In patients who report decreased effect on day 3, patch change interval could be every 48 hours instead of every 72 hours. This can decrease end-of-dose failures and provide safer maintenance serum fentanyl levels. An occlusive dressing can be applied over the patch in patients who complain of difficulty adhering patch to the skin. Triamcinolone spray can help alleviate itching or prevent rash when administered prior to application. Steroids otherwise intended for oral inhalation are off-label and less desirable. Creams, lotions, and other topical products are not practical prior to patch placement. Registration with the REMS program is required for transmucosal immediate-release fentanyl. These products are not interchangeable by dose with exception of a specific generic equivalent to a branded product. Meperidine Do not use within 11 days of a monoamine oxidase inhibitor.

Diphenylheptanes Methadone When converting to methadone, the higher the morphine equivalent dose, the more potent methadone becomes. Careful and slow titration must occur when transitioning. Likewise, because methadone has a long and variable half-life, dose increases should be limited to no more frequently than every 7 days. When converting from methadone, consider that the long half-life and high volume of distribution means it will linger for several days after discontinuation; therefore, when transitioning to the new opioid, patients still have significant methadone in their blood. Pharmacokinetics is complex and variable with very high likelihood of CYP interactions. Phenylpropyl Amines Tramadol Abrupt discontinuation can cause serotonin withdrawal, but not opioid withdrawal, because the mu binding affinity is 6,000 times less than that of morphine (similar to dextromethorphan). If the patient becomes agitated, reduce the dose and escalate more slowly to alleviate 5-HT side effects. There is increased risk of agitation and nervousness if combined with other drugs that increase serotonin. Tramadol is a prodrug that requires three CYP enzymes for metabolism lending itself to high risk for drug interactions. Do not use within 14 days of a monoamine oxidase inhibitor. Tapentadol Tapentadol is chemically similar to tramadol, but it is not a “glorified” tramadol. Despite being listed in the package insert, essentially no serotonin activity is associated with tapentadol. Metabolized via phase II. No CYP drug-drug interactions. Do not use within 14 days of a monoamine oxidase inhibitor. 5-HT = 5-hydroxytryptamine; CYP = cytochrome P450; NADEAN= addiction Drug Enforcement Administration number; REMS=risk evaluation and mitigation strategy. and pharmacodynamic properties, potency, and receptor-binding surface area and body mass index, or variable patient response, affinity. Recently, with the release of the CDC guidelines for all of which present significant shortcomings with a presumptive prescribing opioids, MEDD has received increased attention with equivalency. Even more problematic is whether certain opioids recommended thresholds and dose reductions to minimize adverse such as those with noradrenergic activity, NMDA blockade, partial effects. As a result of these recommendations, some professional agonist/antagonists, and inhibitors can fairly be organizations, various states, and third-party insurance carriers have likened to any predictable morphine equivalent without an even begun initiatives aimed at tapering and dose-reducing therapy. higher significant risk for error. It is also noteworthy that despite all Unfortunately, MEDD is unable to account for individualized therapy, this attention to limiting MEDD, there are currently no universally including but not limited to patient genetic polymorphism, body accepted opioid conversion or tapering guidelines. Although

APhA PAIN INSTITUTE 8 Opioid Medications: Dosages, Adverse Events, and Patient Education

accurate conversion from one opioid to another requires artful skill • Which opioids have minimal risk of withdrawal as rated by and careful titration, a commonly used schematic for conversion is the Clinical Withdrawal Scale? provided in Table 4.20–22 Nevertheless, from state to state, various • How quickly should the taper be accomplished? legislative bodies have developed their own equivalencies, which • Is there a medical risk to quick taper (i.e., unstable angina or often differ significantly from one another. arrhythmia)? • Is there a mental health risk to quick taper (i.e., suicidality)? • Is a moderate or slow taper in order and if so, is it specific to Table 4. Opioid Dosing uniquely prescribed opioids?

Drug Parental Oral To convert from one opioid to another, consider the steps in Table 5.

Codeine 100 mg 200 mg Table 5. Guidance for Changing Opioid Therapy Fentanyl 0.1 mg N/A Step Description Hydrocodone N/A 30 mg 1 Determine the total 24-hour dose of the currently prescribed analgesic. Hydromorphone 1.5 mg 7. 5 m g 2 Convert the currently prescribed opioid to an equivalent Methadone * N/A* morphine dose of the same route (oral vs. parenteral). Morphine 10 mg 30 mg 3 If the route is to remain the same, use the conversion table to convert the morphine dose to the equivalent new opioid Oxycodone 10 mg 20 mg use. If the route is to change, first convert the morphine dose to the desired route before converting from morphine to the Oxymorphone 1 mg 10 mg new opioid. * Methadone dosing is variable. Conversion between methadone and other opioids • Consider decreasing dose by 50% in elderly & in patients is not a linear relationship. Multiple strategies exist for the conversion of methadone, with renal failure. however the authors of this continuing education activity recommend the following: 4 If pain is controlled, start at 50% to 75% of the equivalent Fudin J, Marcoux MD, Fudin JA. Mathematical model for methadone conversion dose. If pain is uncontrolled, then start at 100% of the dose. examined. Pract Pain Manag. 2012;12(8):46–51. Conversions to or from methadone may be used for approximating a target dose, but in all cases the transition should be 5 Determine the strength per dose by dividing the dose made slowly and carefully. When converting to methadone, even in opioid-tolerant calculated in Step 4 by the dosing interval. patients, the initial dose should not exceed 10 mg per day in divided doses. • Choose a dosing interval consistent with the medication N/A = not applicable. duration of action. Source: Reference 22. 6 Provide an appropriate “rescue” dose for breakthrough pain. • Ten percent of the total opioid dose given every one to Considering an Opioid Taper? two hours as needed. • Elderly: Rescue dose= 5% of the total opioid dose Patients’ opioid therapy should be continually monitored and assessed administered every 4 hours as needed. for efficacy, tolerability, and safety. If at any point during treatment, 7 Titrate baseline and as needed dose to provide effective opioids are determined to no longer provide benefit or are too risky, pain relief. alternative opioid therapy with intent for improved efficacy could be 8 Use cathartic and stool-softening medications as considered and, when necessary, a taper may be in order. In certain constipation prophylaxis. cases, where pure opioid agonists are inherently less dangerous than alternative therapies, a safer opioid option such as a partial opioid Source: Reference 23 agonist or partial opioid agonist/antagonist may be considered. At times, providers may inherit patients already established on opioids and become tasked with discontinuing therapy. The first steps in initiating a taper are to ask the following questions:

• Is an opioid taper clinically indicated for the patient’s best interest or is the decrease being made for political or policy reasons? • Can therapy be abruptly discontinued?

APhA PAIN INSTITUTE 9 Opioid Medications: Dosages, Adverse Events, and Patient Education

Quick Knowledge Check

Case 1

LB is a 61-year-old white male patient with a past medical history significant for bipolar disorder and type 2 diabetes with neuropathy to the feet and hands. He is currently prescribed quetiapine 200 mg PO BID, 300 mg PO BID, and duloxetine 60 mg PO QAM. Because the patient’s diabetic neuropathy is not responding, his health care provider wants to start opioid therapy. LB has a history of angioedema from hydrocodone and morphine. Which of the following is definitely not an option for LB specifically due to cross-allergenicity? a. Tapentadol b. Methadone c. Pentazocine d. Buprenorphine

LB’s health care provider decides to initiate tramadol. After multiple titrations, there has been little benefit and increasing serotonin side effects. The physician looks to you, the pharmacist, for additional recommendations. After reviewing the patient’s chart and active medications, you decide to recommend an ECG, which reveals QTc = 491 msec (normal is ≤450 msec). Which of the following medications may provide additional pharmacological benefit for neuropathy, minimize serotonin side effects, and not elevate QTc? a. Hydromorphone b. Methadone c. Oxycodone d. Tapentadol

The physician thanks you for your recommendation, tells LB to stop taking tramadol, and plans to begin tapentadol. One day after discontinuing tramadol, LB calls complaining of agitation and a persistent , which are consistent with serotonin withdrawal. Will initiating tapentadol alleviate LB’s symptoms? a. Yes b. No

Case 2

KT is a 58-year-old woman whose chronic low back pain has been managed with oxycodone ER 20 mg PO every 12 hours. She recently changed employers and her new third-party health insurance plan will not cover the branded product without a documented failed trial of morphine ER. KT is currently taking sertraline and prescribed by a different health care provider. You note that carbamazepine is a potent CYP3A4 inducer. Which of the following statements is true? a. Morphine ER 20 mg PO every 12 hours is an equivalent dose to previous oxycodone regimen b. Morphine ER 30 mg PO every 12 hours is an equivalent dose to previous oxycodone regimen c. Morphine does not undergo phase I CYP metabolism but oxycodone does d. It is not appropriate to switch patients from oxycodone ER to morphine

The physician decides to do a pharmacogenetic test on KT before making adjustments to her medications. Test results reveal that KT is an ultra-rapid CYP2D6 metabolizer. Which of the following agents should be avoided for KT in the future? a. Tapentadol b. Codeine c. Oxymorphone d. Hydromorphone

Case 3

JF is a 67-year-old man with severe back pain. He has been taking oxycodone SR 80 mg every 12 hours for the past 6 months. His physician would like to switch him to morphine ER; his insurance covers morphine ER. How much morphine ER should the patient receive?

(See page 11 for answers to the Quick Knowledge Check).

APhA PAIN INSTITUTE 10 Opioid Medications: Dosages, Adverse Events, and Patient Education

References 12. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men 1. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing with androgen deficiency syndromes: an Endocrine Society clinical opioids for chronic pain—United States, 2016. JAMA. practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536–59. 2016;315(15):1624–45. 13. Tennant F. The physiologic effects of pain on the endocrine system. Pain 2. Dahan A. Opioid-induced respiratory effects: new data on Ther. 2013;2(2):75–86. buprenorphine. Palliat Med. 2006;20:(suppl 1):S3–S8. 14. Cepeda MS, Fife D, Ma Q, Ryan PB. Comparison of the risks of opioid 3. Brooks A, Kominek C, Pham TC, Fudin J. Exploring the use of chronic abuse or dependence between tapentadol and oxycodone: results from opioid therapy for chronic pain: when, how, and for whom? Med Clin a cohort study. J Pain. 2013;14(10):1227–41. North Am. 2016;100(1):81–102. 15. Cooney RE. The highs and lows of loperamide abuse. Medscape. 4. Fudin J. Chemical classes of opioids. 2011. Revised November 2016. May 23, 2016. Available at: http://www.medscape.com/ Available at: http://paindr.com/wp-content/uploads/2016/11/Opioid- viewarticle/863538. Accessed October 30, 2016. Structural-Classes_edited-November-2016.pdf. 16. Kumar L, Barker C, Emmanuel A. Opioid-induced constipation: 5. Wirz S, Wartenberg HC, Nadstawek J. Less nausea, emesis, and pathophysiology, clinical consequences, and management. constipation comparing hydromorphone and morphine? A prospective Gastroenterol Res Pract. 2014 (141737)1–6. open-labeled investigation on cancer pain. Support Care Cancer. 17. Fudin J. The perfect storm: opioid risks and ‘the holy trinity.’ Pharmacy 20 08;16(9):999–10 09. Times. September 24, 2014. Available at: http://www.pharmacytimes. 6. Hermens JM, Ebertz JM, Hanifin JM, Hirshman CA. Comparison of com/contributor/jeffrey-fudin/2014/09/the-perfect-storm-opioid-risks- histamine release in human skin mast cells induced by morphine, and-the-holy-trinity/. Accessed November12, 2016. fentanyl, and oxymorphone. Anesthesiology. 1985;62(2):124 –9. 18. Chou R, Fanciullo GJ, Fine PG, et al.; American Pain Society–American 7. Gutstein HB, Akil H. Opioid . In: Hardman JG, Limbird LE, Academy of Pain Medicine Opioids Guidelines Panel. Clinical Gilman AG, eds. Goodman & Gilman’s The Pharmacological Basis of guidelines for the use of chronic opioid therapy in chronic noncancer Therapeutics. 10th ed. Columbus, OH: McGraw-Hill; 2001. pain. J Pain. 2009;10(2):113–30. 8. Pham TC, Fudin J, Raffa RB. Is levorphanol a better option than 19. Mastropietro DJ, Omidian H. Abuse-deterrent formulations: part 1— methadone? Pain Med. 2015;16(9):1673–9. development of a formulation-based classification system.Expert Opin Drug Metab Toxicol. 2015;11(2):193–204. 9. Janicki PK. Pharmacogenomics of pain management. In: Deer TR, Leong MS, eds. Comprehensive Treatment of Chronic Pain by Medical, 20. Rennick A, Atkinson T, Cimino NM, et al. Variability in opioid Interventional, and Integrative Approaches: The American Academy equivalence calculations. Pain Med. September 9, 2015 [epub ahead of Pain Medicine Textbook on Pain Management. New York, NY: of print]. Springer; 2013. 21. Fudin J, Marcoux MD, Fudin JA. Mathematical model for methadone 10. Fudin J, Atkinson TJ, Raouf M, Schatman ME. Can we not work together conversion examined. Pract Pain Manag. 2012;12(8):46 –51. to help family practitioners become more effective pain managers? J 22. McPherson ML. Demystifying Opioid Conversion Calculations: A Guide Pain Res. 2016;9:803– 6. for Effective Dosing. Bethesda, MD: American Society of Health-System 11. Raffa RB, Buschmann H, Christoph T, et al. Mechanistic and functional Pharmacists; 2010. differentiation of tapentadol and tramadol. Expert Opin Pharmacother. 23. Abrons JP. Peripheral Brain for the Pharmacist 2016 -17. Washington,

2012;13(10):1437– 49. DC: American Pharmacists Association; 2016.

incomplete cross tolerance.) cross incomplete

mg total daily dose of morphine. (The 50% reduction helps account for for account helps reduction 50% (The morphine. of dose daily total mg

3. Reduce the total daily dose of the new drug by 50%: 240 mg x 0.5 = 120 120 = 0.5 x mg 240 50%: by drug new the of dose daily total the Reduce 3.

X = 240 mg morphine morphine mg 240 = X

mg 160 oxycodone mg 20 oxycodone

Table 2. 2. Table mg X morphine = mg 30 morphine

6. Monitor the patient and provide the patient with counseling points listed in in listed points counseling with patient the provide and patient the Monitor 6. ER: morphine

Use Opioid Equianalgesic Dosing Chart (Table 4) to convert oxycodone to to oxycodone convert to 4) (Table Chart Dosing Equianalgesic Opioid Use 2.

because it is approximately the same as the morphine dose. morphine the as same the approximately is it because

may not be available. Hydrocodone/acetaminophen could be used instead instead used be could Hydrocodone/acetaminophen available. be not may daily. daily.

equals approximately 10 mg of morphine IR. In clinical practice, morphine IR IR morphine practice, clinical In IR. morphine of mg 10 approximately equals Calculate total daily oxycodone the patient is on: 80 mg x 2 = 160 mg mg 160 = 2 x mg 80 on: is patient the oxycodone daily total Calculate 1.

pain, which range from 5% to 17% of the total baseline opioid dose, which which dose, opioid baseline total the of 17% to 5% from range which pain,

To convert: convert: To

Don’t forget to provide the patient with medications for his breakthrough breakthrough his for medications with patient the provide to forget Don’t 5.

Case 3: Case

c, b c, Case 2: Case opioid drug: 60 mg every 12 hours. hours. 12 every mg 60 drug: opioid

d, d, b d, d, Case 1: Case Divide the new daily dose to get appropriate interval and dose for new new for dose and interval appropriate get to dose daily new the Divide 4. Answers to Quick Knowledge Check Knowledge Quick to Answers 16380

APhA PAIN INSTITUTE 11