Introduction
Since the 1990s, the increasing incidence of opioid use disorder (OUD) and overdose deaths involving opioids have reached epidemic proportions. Rising use has been associated with both medical and nonmedical opioid use. While opioids are an effective form of analgesia for acute and postoperative pain, the overprescribing of opioids, in part, has contributed to the escalation of opioid overdoses in the United States.
In 1996, the American Pain Society advocated for progressive evaluation of pain control with “the fifth vital sign” assessment. Although well intentioned and supported by physicians, patients, and professional societies, it promoted the aggressive treatment of both acute and chronic pain, often with opioids to improve subjective numeric pain scores at the point of care. During a similar time frame, opioid prescriptions rose dramatically, as did nonmedical opioid use. Individuals in the United States consumed more opioid medication than all other nations worldwide combined.
In 2013, the economic cost of prescription opioid-related overdose and OUD exceeded $78.5 billion with a large portion spent on healthcare, substance use disorder treatment, and loss of work productivity.
By 2017, opioid-related deaths continued to increase, and the United States government declared a public health emergency related to opioid use.
According to the 2019 National Survey on Drug Use and Health, 9.7 million people reported nonmedical use of prescription pain medicine. In an evidence-based consensus report published in 2019, an estimated 2.1 million people suffered from OUD, including 1.8 million with primary prescription opioid use and over 600,000 with primary heroin use.
In 2019, more than 70,000 Americans died from a drug-involved overdose, including illicit drugs and prescription opioids. Synthetic opioids, primarily fentanyl, were the main driver of these drug overdose deaths with a nearly 14-fold increase from 2012 to 2019 resulting in more than 36,359 casualties.
The Centers for Disease Control and Prevention (CDC) summarizes the rise in opioid overdose deaths in three distinct waves in its publication, “Understanding the Epidemic” ( Fig. 9.1 ).
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The first wave began with increased prescribing of opioids in the 1990s, with overdose deaths involving prescription opioids increasing since at least 1999.
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The second wave began in 2010, with rapid increases in overdose deaths involving heroin.
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The third wave began in 2013, with significant increases in overdose deaths involving synthetic opioids, particularly those involving illicitly manufactured fentanyl and its many analogs. Illicit fentanyl can be found in combination with heroin, counterfeit pills, and cocaine.
Many opioid-involved overdose deaths are associated with the use of multiple substances, including benzodiazepines, alcohol, cocaine, and methamphetamine.
There has been an ongoing public health crisis of infectious diseases driven by the opioid epidemic, including the transmission of the human immunodeficiency virus (HIV), hepatitis C, endocarditis, and infections of the skin, bones, and joints related to the rise of injection drug use. In addition to trauma and suicide risks, people with OUD have a 20-fold greater chance of early death.
What is opioid use disorder ?
OUD describes patients who have lost control and have a compulsion to use opioids. Physical dependence is the physical adaption to opioids characterized by symptoms of withdrawal when the drug is stopped and need to take more to get the desired effect. Physical dependence alone does not mean OUD. In fact, individuals who take opioids over a long enough period of time will develop physiologic dependence manifested by withdrawal and tolerance. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for OUD includes physical dependency, but differs as this is also characterized by the presence of cravings, compulsive use, and eventually loss of control, with continued use despite negative consequences from opioid use. Additionally, for patients prescribed opioids, physiologic dependence criteria should not be used in the diagnosis of OUD. The diagnostic criteria are summarized in Table 9.1 .
| Use of an opioid in increased amounts or longer than intended Persistent wish or unsuccessful effort to cut down or control opioid use Excessive time spent in obtaining, using, or recovering from opioid use Strong desire or urge to use an opioid Interference of opioid use with important obligations Continued opioid use despite resulting interpersonal problems, social problems (e.g., interference with work), or both Elimination or reduction of important activities because of opioid use Use of an opioid in physically hazardous situations (e.g., while driving) Continued opioid use despite resulting physical problems, psychological problems, or both Need for increased doses of an opioid for effects, diminished effect per dose, or both b Withdrawal when dose of an opioid is decreased, use of drug to relieve withdrawal, or both b |
a If two or three items cluster together in the same 12 months, the disorder is mild; if four or five items cluster, the disorder is moderate; and if six or more items cluster, the disorder is severe. Criteria are from the Diagnostic and Statistical Manual of Mental Disorders, fifth edition.
b If the opioid is taken only as prescribed, this item does not count toward a diagnosis of an opioid-use disorder.
Risk of developing opioid use disorder
OUD is considered a bio-psycho-social illness. Genetic factors, psychological factors, and social environments can place an individual at a higher risk of developing OUD. See Table 9.2 . However, repeated opioid use alone can result in changes in neural structure and function and can change the brain’s pleasure and reward pathways, leading to the development of OUD.
Several reviews have identified the most common risk factors for nonmedical opioid use:
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The likelihood of chronic opioid use after an opioid-naïve individual is prescribed an opioid medication has been shown to increase after as little as 3–5 days of opioid use.
In a survey of individuals who use heroin, approximately 75% reported nonmedical use of a prescription opioid in the prior year, often obtained from a family members’ prescription or from opioid diversion from another individual’s prescription.
A challenge that remains is the safe use of prescription opioids among surgical patients. More than 50 million Americans undergo inpatient surgery annually, and opioids remain a primary modality for postoperative acute pain management.
Surgical patients routinely receive the most commonly prescribed opioids—oxycodone and hydrocodone—which are also the most commonly implicated in nonmedical use and drug overdose deaths. , Consequently, it is of the utmost importance that all medical providers who prescribe opioid medications adopt screening and safe prescribing practices.
The American Academy of Otolaryngology-Head and Neck Surgery Foundation’s Clinical Practice Guideline on Opioid Prescribing for Analgesia After Common Otolaryngology Operations offers specialty-specific, evidence-based recommendations on the preoperative identification of OUD risk factors, and the postoperative management of pain, emphasizing prudent prescribing, storage, and disposal of opioids.
Screening for opioid use disorder
Every clinical encounter is an opportunity to screen for substance use disorder, and this is especially important when considering prescribing opioid medication for acute or postoperative pain.
The screening, brief intervention, and referral to treatment (SBIRT) model is a useful technique to identify patients at risk of substance use disorders. SBIRT is a comprehensive, integrated, public health approach to the delivery of early intervention for individuals with risky alcohol and drug use, as well as timely referral for treatment in those with substance use disorders. Primary care centers, hospital emergency rooms, trauma centers, and community health settings provide opportunities for early intervention before more consequences occur.
Screening
Ask every patient if they have any history of opioid use—prescribed or nonprescribed. A single question related to drug use (i.e., “How many times in the past year have you used an illegal drug or used a prescription medication for nonmedical reasons?”) was found to be effective in detecting drug use among primary care patients. One or more times was considered a positive screen requiring further questioning.
Brief Intervention
The goal of brief treatment is to raise awareness of the risky behavior, delegate responsibility to the patient for successful improvement, and advise on strategies for change. It is important to approach each individual with empathy and support and to encourage optimistic empowerment.
Referral to treatment
If there is a concern for OUD, then consider referring to an addiction medicine specialist or coordinating care with the patient’s primary care provider.
A newer screening, treatment initiation, and referral (STIR) model (STIR for substance use treatment) also offers a clinically effective approach to the treatment of substance use in clinical care settings with initiation using medications.
Training opportunities, resources, and treatment programs in addiction are available from the Substance Abuse and Mental Health Services Administration (SAMSHA).
Safe prescribing practices
Pain following otolaryngological procedures can range from minimal to severe. Opioid prescriptions should be offered judiciously, with a high awareness for a preexisting OUD, and considerations for safe prescribing habits should be discussed to limit the potential for risk.
Patients who undergo otolaryngological procedures should be kept on limited opioids for postoperative pain control, or be treated with a nonopioid pain management modality if at all possible. Pain control and medication adherence should be assessed at appropriate postoperative follow-up.
Patients should be counseled on safe storage and disposal of opioid medications, as unused opioids can subsequently be diverted to nonmedical purposes by the patient, his or her family, or others who may have access to improperly stored medications. Studies have shown that the majority of patients kept their leftover pills in an unsecured location in their homes. Most patients were not given information on how to properly dispose of unused opioid medication. , CDC guidelines recommend disposing of unused opioids by dropping off medication at the community drug take-back program or your pharmacy mail-back program. Check with your local and state guidelines for any other options. ,
Coprescribing naloxone with opioid medication is recommended to reduce the risk of opioid overdose. Naloxone comes in the following United States Food and Drug Administration (FDA)-approved forms: injectable, auto-injectable (Evzio), and prepackaged nasal spray. Instructions for administration should be reviewed with the patient and a household member, who may be assisting during the postoperative period.
Overview of opioid use disorder treatment
As with many chronic illnesses, treatment of OUD requires ongoing management and reduction of risks, rather than the attainment of a cure. Medication treatment of OUD is effective and enables people to counteract the disruptive effects on their brain and behavior and regain control of their lives. Table 9.3 describes the goals of medication management.
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An understanding of opioid clinical pharmacology, especially the affinity for specific receptors and anticipated analgesic effects, is necessary for the selection of the appropriate opioid and nonopioid medication for pain management. , Different opioid classes have different pharmacologic effects on intrinsic opioid receptor activity with increasing doses. These classes are as follows: full opioid agonists, partial opioid agonists, and opioid antagonists ( Fig. 9.2 ).
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Full opioid agonists are substances that bind tightly to the opioid receptor and undergo a significant conformational change to produce a maximal effect. Examples of full opioid agonists include codeine, hydrocodone, oxycodone, morphine, methadone, fentanyl, and heroin.
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Partial opioid agonists are substances that cause less conformational change and receptor activation than full agonists. Examples of partial agonists include buprenorphine and pentazocine.
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Opioid antagonists are substances that block the effects of opioids by competitive binding to the opioid receptor. Examples of opioid antagonists include naloxone and naltrexone.
In 2018, the National Institute on Drug Abuse and the SAMSHA commissioned the National Academies of Sciences, Engineering, and Medicine (the National Academies) with developing a Consensus Study Report to update the current knowledge on medication-based treatment for OUD and to highlight gaps for future research, policy, and service provision.
A recent consensus report showed that medications are undeniably the most effective way to treat OUD, reducing the likelihood of overdose death by up to threefold. Combining opioid agonist medications with behavioral health counseling may offer the best treatment outcomes of OUD. , Effective agonist medication used for an indefinite period of time is the safest option for treating OUD.
Opioid detoxification programs without continued pharmacotherapy have not been shown to have long-term efficacy for treating OUD due to low rates of retention in treatment, high rates of relapse posttreatment, and increased rates of overdose due to decreased tolerance after a period of abstinence.
Medications for opioid use disorder
Methadone, buprenorphine, and extended-release naltrexone are the three medications currently approved by the FDA for treating OUD. All three medications reduce opioid cravings and help to sever the ties between opioid use and established situational and emotional triggers. They all target the μ-receptor, though with distinct mechanisms of action and safety and efficacy profiles. , , See Fig. 9.2 .
Methadone
Methadone is a synthetic, long-acting, full μ-opioid receptor agonist, and as such, provides a sustained effect to reduce opioid cravings and withdrawal symptoms for more than 24 h. Methadone is 70%–80% bioavailable and metabolized by the CYP450 enzyme system. Methadone is a schedule II-controlled medication, and by law in the United States, outpatient methadone treatment can only be offered through state- or federally approved treatment centers. At initiating doses (20–30 mg orally), it alleviates all aspects of opioid withdrawal. The therapeutic dose may be achieved in 2 weeks or more, and at that dose (over 60 mg), it attenuates the euphoric “highs” of shorter-acting opioids, such as heroin and oxycodone. Patients enrolled in opioid treatment programs (OTPs) are required to have daily visits for supervised medication dispensing and regular counseling sessions with close monitoring. Eventually, stable patients may receive take-home doses if they meet certain criteria, such as stable periods without any illicit drug use.
Like all agonists, patients treated with methadone will have opioid tolerance and physical dependence, thus missing doses can cause opioid withdrawal. Methadone, even at a low dose, can be fatal to opioid-naïve individuals. Overdose risk is highest during the first 2 weeks of methadone induction, after which the risk of overdose death is significantly lower than for those with OUD and not in treatment. At the stabilization dose, the main effect of blocking or blunting the euphoria from other self-administrated opioids usually deters from continued illicit opioid use. Recent high-potency fentanyl analogs have increased the risk of overdose in those with OUD, including patients taking methadone. Use of other sedatives, including benzodiazepines, will increase the risks of an overdose in individuals taking methadone. The other potential side effects include sedation, which is worst at its peak serum concentration (2–4 h), though its effects are gradually blunted with tolerance; hypogonadism with low testosterone; and prolongation of the corrected QT (QTc) interval, which may potentially lead to Torsades de pointes. Risk of QTc prolongation increases by dose, combination with other medications that prolong the QTc interval, and acute medical conditions, such as hypokalemia. Drug interactions, especially those metabolized by the P450 system, have to be considered.
Despite the strong evidence supporting methadone treatment, patients taking methadone remain highly stigmatized.
Buprenorphine
Buprenorphine is a high-affinity partial μ-opioid receptor agonist and weak κ-opioid receptor antagonist. As a partial μ-opioid agonist, buprenorphine does not fully substitute for full opioid agonists, such as heroin, on the μ-receptors, and thus has limited euphoric effect. It is effective in alleviating opioid withdrawal symptoms and reducing cravings. As a partial agonist, it also acts as a competitive antagonist for full opioid agonists, thus blocking the effects of other opioids. Additionally, buprenorphine has a ceiling effect, thus limiting the respiratory depression effects and the risk of overdose. It is a schedule III-controlled medication.
Buprenorphine has poor oral bioavailability and has no oral formulation. Coadministration of other medications that use the CY450 pathway can affect the rate of buprenorphine metabolism, though it has fewer relevant drug interactions than methadone.
Formulations of buprenorphine are typically combined with the short-acting opioid antagonist, naloxone, in a 4:1 ratio, which serves to discourage nonmedical use of the medication. When this combination medication is taken properly in its sublingual (Suboxone, Zubsolv) or buccal (Bunavail) formulation, the naloxone component of the medication does not absorb to reach bioavailable levels in the body. If this combination medication were injected intravenously, then the user would experience the opioid antagonist properties of naloxone, counteracting the effects of buprenorphine. The dose range of the buprenorphine component in the sublingual product is between 8 and 16 mg. The maximum daily dose of buprenorphine is 24 mg, as dosages above this amount have shown no clinical advantage.
Buprenorphine is also available in extended-release monthly subcutaneous formulation (Sublocade) and biannual subdermal implants (Probuphine), both necessitating administration by a medical provider, which makes them more difficult to divert and theoretically increases treatment adherence. A clinical trial of CAM2038, a weekly buprenorphine injection, is underway.
In the United States, buprenorphine can be provided at an OTP but is commonly prescribed in an office-based setting, such as a primary care clinic or community health center. Patients are seen and evaluated by trained providers, frequently at first, and then with reduced frequency as the treatment progresses. The prescription can be dispensed at regular pharmacies, and patients self-administer the buprenorphine, similar to other medications of chronic diseases. Since FDA approval of buprenorphine in 2002, physicians, nurse practitioners, and physician assistants were required to undergo training and obtain a waiver from the Drug Enforcement Administration (DEA) to prescribe. As of 2021, medical providers treating 30 or fewer patients with buprenorphine-based treatment do not require a special DEA waiver.
Similar to methadone, patients are physically dependent on this medication, and discontinuation can lead to withdrawal, though buprenorphine’s withdrawal syndrome may be less severe than that of methadone or other opioids. The most prominent risk of administering buprenorphine to a patient with OUD is the precipitation of nonlife-threatening opioid withdrawal at the first dose (induction). In general, induction of buprenorphine will require the patient to be in a mild-to-moderate withdrawal after opioid abstinence for 8–24 h, to minimize precipitated symptoms. Newer protocols such as buprenorphine-naloxone “microdosing” (Bernese method) , offer an alternative induction approach for the treatment of OUD in the wake of increasingly potent illicit drug marketing and sales. Patients have consistently reported that the induction process is well tolerated, with a reduction or elimination of cravings and avoidance of precipitated withdrawal.
With the initiation of buprenorphine treatment, the risks of opioid overdose-related death immediately decline. Hypogonadotropic effects are less with buprenorphine than with methadone. Buprenorphine is not associated with QTc prolongation or cardiac arrhythmia.
Extended-release naltrexone
Naltrexone is not an opioid, but rather a μ-opioid receptor full antagonist that blocks the euphoric and analgesic effects of opioids and helps maintain abstinence from opioids in highly motivated patients.
Naltrexone can be administered as an intramuscular injection for OUD (XR Naltrexone) or as an oral pill (FDA approved for alcohol use disorder). The intramuscular injection causes a transient peak blood concentration 2 h after injection and then another at 2–3 days after injection. After sustained use of extended-release (XR) Naltrexone, the patient’s drug cravings decline. Treatment initiation of XR Naltrexone requires medically supervised withdrawal followed by at least 4–7 days without any opioids, including methadone or buprenorphine. This remains a key barrier to its popular use. The risk of overdose for patients being treated with the XR formulation may be reduced compared to treatment with a placebo, nonmedication-based treatment , and treatment with oral naltrexone. It is not uncommon for patients to try to use opioids while on extended-release naltrexone, but it is exceedingly rare that using any opioid can override the effect of naltrexone to yield any rewarding effects. Patients can experience an increased risk of overdose when they approach the end of the 28-day period of the XR formulation. The once-a-day 50 mg oral tablet was found to be no better than a placebo in retaining patients in treatment or eliminating opioid use, with a possible increased risk of opioid overdose compared to methadone if a user attempted an opioid challenge. This observation requires further validation. Thus, the FDA only approved the injectable XR formulation (380 mg) for OUD treatment given on a monthly basis. No special training is required for medical providers to prescribe naltrexone. XR Naltrexone treatment is most effective when administered in combination with cognitive-behavioral therapy ( Table 9.4 ).
