US Pharm. 2022;47(3):HS2-HS6.
ABSTRACT: Opioid use disorder (OUD) may be medically managed with opioid agonist therapy (OAT), including buprenorphine and methadone. Shared decision making between provider and patient is imperative. Clinicians should discourage unplanned cessation or tapering of medication without a compelling cause. Frequently, patients receiving OAT experience episodes of acute pain during inpatient hospitalization or in the postoperative setting. This situation frequently leads to encounters with providers who may not be well-versed in OAT pharmacology or in the use of these agents. Additionally, concerns for possible manipulative behavior by patients may deter clinicians from treating acute pain appropriately. Pharmacists can play a key role in the management of OAT in acute pain and ensuring appropriate home OAT administration routes, doses, and frequencies.
From 1999 to 2019, an estimated 500,000 people died from overdoses of prescription or illicit opioids in the United States.1 The literature classifies the increase in deaths from opioid overdose into three different waves. An increase in the prescribing of opioids in the 1990s constituted the first wave; the second wave, which began in 2010, was defined by rapid increases in overdose deaths involving heroin; and 2013 saw the beginning of the third wave, characterized by substantial increases in overdose deaths related to synthetic opioids (especially fentanyl that was illicitly manufactured).2-4 Globally, the burden of disease from opioids approaches 11 million life-years lost to health problems, disabilities, and early death.5
Data suggest that opioid use disorder (OUD) is a chronic disease that should be managed medically. Several medications have been approved by the FDA for OUD. With medication management, patients are more likely to enter full recovery, contribute to their family and community, and reach their full potential.6 Medication management should involve shared decision making between the patient and the medical provider. Additionally, patient preference, adverse effects, availability, cost, access, and tolerability should also play a role. Long-term pharmacotherapy for OUD doubles the likelihood of opioid abstinence compared with behavior therapy alone.7 Additionally, a meta-analysis found that patients receiving opioid agonist therapy (OAT) had significantly lower rates of mortality compared with patients not receiving OAT.8 However, access to OAT and insurance coverage for OAT remain low, presenting challenges for patients.
The abrupt cessation or tapering of OAT without a compelling cause should be discouraged. Too often, however, patients with OUD experience abrupt cessation or inappropriate management of acute pain when admitted to the hospital or in the postoperative period. Many clinicians are unfamiliar with OAT and the treatment of acute pain in patients with OUD. Additionally, many providers are concerned with manipulative or drug-seeking behavior, and this may deter the use of opioid agents to treat acute pain. This review aims to describe the pharmacology of OAT agents and discuss current considerations for the treatment of acute pain in patients receiving OAT.
Treatment of OUD
Buprenorphine and methadone are commonly used for the treatment of OUD. The pharmacologic properties of these agents differ substantially, as highlighted below.
Buprenorphine: This agent is a semisynthetic partial opioid analgesic that binds to mu-, kappa-, and delta-opioid receptors. Its analgesic effect is via high-affinity binding to the opiate receptors in the central nervous system. Buprenorphine displays partial mu-agonist and weak kappa-antagonist activity, but its agonist activity at the delta receptor is not well understood. The half-life of buprenorphine is variable, ranging from 3 hours for IV administration to 24 to 60 hours for sublingual administration.9 The dissociation from binding sites is slow, leading to a longer duration of action than that of other opioids. This slow dissociation allows for prolonged therapeutic effects in treating opioid dependence and chronic pain.10 Buprenorphine’s high binding affinity and slow mu-opioid receptor dissociation make the use of mu-opioid receptor antagonists, such as naloxone, difficult.
Multiple buprenorphine formulations are FDA approved for the treatment of OUD, including sublingual tablet, sublingual film, buccal film, implant, and extended-release injection. The buprenorphine concentration of these formulations has euphoric effects when administered IV; accordingly, naloxone is added because its effect is significantly increased when injected IV, antagonizing buprenorphine’s euphoric effects and precipitating immediate withdrawal, thus discouraging misuse.9 Patients should show signs of opioid withdrawal prior to starting buprenorphine, as buprenorphine’s high affinity causes it to rapidly displace opioid agonist–bound mu receptors, thereby hastening withdrawal.9
Buprenorphine provides analgesia at low-to-moderate doses and is approximately 25 to 100 times more potent than morphine.10 Furthermore, buprenorphine exhibits a ceiling effect, so doses exceeding 32 mg do not produce a greater analgesic effect.11 Providers typically are more inclined to use buprenorphine for OUD because of its decreased potential for abuse and because, in contrast to methadone, it enables the provision of office-based treatment. Additionally, buprenorphine has a lower risk of respiratory depression than methadone, and it has the ability to treat opioid-induced hyperalgesia through kappa-receptor antagonism.11 Because buprenorphine antagonizes the action of mu agonists, the practice of withholding buprenorphine before surgery has become widespread. Preclinical and clinical studies have shown that the administration of buprenorphine and mu agonists produces an additive analgesic response at analgesic doses of buprenorphine. However, little is known about the interaction between buprenorphine and opioid agonists when buprenorphine is used to treat OUD.9 The difficulties of managing pain in patients taking buprenorphine, combined with the pharmacologic properties noted above, have led to conflicting views on how to optimally treat acute pain in these patients.
Methadone: Methadone, a synthetic full mu-receptor agonist, is structurally unrelated to other opioids; it exhibits N-methyl-d-aspartate (NMDA) receptor antagonist activity. Available formulations are racemic mixtures of two isomers. The R-isomer is an NMDA receptor antagonist that inhibits the uptake of norepinephrine and serotonin, and the S-isomer is a mu- and delta-opioid receptor agonist.12 Historically, an influx of heroin into U.S. metropolitan areas following World War II resulted in increased rates of illicit drug use, leading to the establishment of narcotic-maintenance programs that used methadone as the primary opioid-replacement agent based on its slow onset of action (3-5 days) and long elimination half-life (8-59 hours).11 In higher doses, methadone may have serious side effects including respiratory depression, arrhythmias due to prolonged QT interval, and drug-drug interactions from CYP450 metabolism. A study of maintenance methadone found that patients were cross-tolerant to the analgesic effects of morphine and that pain relief, when achieved, did not last as long as expected.13 Cross-tolerance between opioids may explain why patients receiving OAT require higher and more frequent doses of opioid analgesics for adequate pain control. These are all important considerations in the management of acute pain in the setting of methadone OAT.
Managing Acute Pain in OUD
The approach to managing acute pain—including perioperative pain—in patients receiving OAT is a common clinical conundrum. As aforementioned, clinicians may be less familiar with OAT, potentially leading to the undertreatment of acute pain. Undertreatment is often perpetuated by some providers’ fear of adverse effects, including respiratory and cognitive suppression, and by the misinterpretation of patient-reported pain as drug-seeking behavior. Furthermore, the misconception that patients derive sustained analgesia from OAT may play a role in the undermanagement of acute pain. Chronic opioid exposure results in opioid- and NMDA-receptor trafficking, which contributes to tolerance and hyperalgesia and minimizes the analgesic properties of chronic OAT.14 Therefore, it is important for clinicians to familiarize themselves with the management of acute pain in patients receiving OAT.
Methadone Management: Adequate analgesia may be more challenging to achieve in patients on methadone maintenance therapy (MMT), as there is often a degree of opioid cross-tolerance.13,15,16 Retrospective studies have demonstrated that patients on MMT frequently have higher opioid requirements in the setting of acute perioperative pain.17,18 Furthermore, methadone has an analgesic duration of action of 4 to 8 hours, which is substantially shorter than the suppression of opioid withdrawal. It is recommended to continue the patient’s home MMT and employ short-acting opioids to manage acute breakthrough pain.14 Given methadone’s unique pharmacologic profile, dose conversion to an alternative opioid often is inaccurate, limiting the practicality of alternative regimens. In addition, nonopioid analgesics—including nonsteroidal anti-inflammatory agents and acetaminophen—should be used when appropriate. If a patient is unable to take oral medications, the methadone dose may be administered IV or subcutaneously as one-half to two-thirds of the maintenance dose divided into two to four equal doses.14 Importantly, the patient’s methadone clinic should always be contacted in order to confirm the patient’s MMT regimen as well as to inform the staff of the patient’s hospitalization, as these clinics routinely perform urine drug screens.
Buprenorphine Management: Guidelines published in 2004 by the Department of Health and Human Services’ Center for Substance Abuse Treatment recommended the discontinuation of home buprenorphine OAT.19 In conjunction with limited evidence, this recommendation was largely based on the considerations that buprenorphine is a partial opioid receptor agonist and that it impairs the effectiveness of other opioids. However, clinical studies in the perioperative setting have since shown that the use of additional opioids for acute pain plus maintenance of the patient’s home buprenorphine OAT is an effective strategy.20,21 Furthermore, clinical studies have demonstrated that patients whose home buprenorphine OAT was held perioperatively had increased opioid requirements as well as increased pain scores relative to patients whose home buprenorphine OAT was continued.22,23
As with methadone, patients who are on buprenorphine prior to admission may still have higher opioid requirements relative to patients not on chronic opioids. This has led some institutions to implement perioperative protocols that either hold or wean buprenorphine products; however, this likely adds unnecessary complexity including reintroduction and may increase the risk of withdrawal.11,18,19 Discontinuation of buprenorphine has also been associated with higher rates of illicit opioid use.24 Accordingly, many experts now recommend continuing home buprenorphine OAT perioperatively and in other acute-pain settings.14,19,25,26
Short-acting opioid agonists are recommended for management of acute pain, keeping in mind that these patients will have some degree of cross-tolerance. The total daily buprenorphine dose may be divided into three or four doses, with each dose taken every 6 to 8 hours.19 Most patients likely can tolerate transmucosal or sublingual administration, but for those who cannot, buprenorphine may be administered IV. Dose equivalence between transmucosal or sublingual and IV administration is not well established; however, the oral bioavailability of the buccal film is 46% to 65% and that of the sublingual tablet is 29%, so this may be taken into consideration in establishing an IV dose.27
Many patients with OUD are receiving OAT with methadone or buprenorphine. Therefore, clinicians may encounter patients receiving OAT who have acute pain during hospitalization or in the postoperative setting. Providers should familiarize themselves with OAT pharmacology and determine the appropriate regimen for acute pain by continuing OAT with short-acting agents as needed. As the opioid epidemic continues, it is of paramount importance to ensure appropriate acute pain treatment while managing OUD. Pharmacists can play a key role in managing OAT in the setting of acute pain and in determining the appropriate administration route, dose, and frequency of home OAT.
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