Barriers and Best Practices on the Management of Opioid Use Disorder

Abstract

Opioids refer to chemicals that agonize opioid receptors in the body resulting in analgesia and sometimes, euphoria. Opiates include morphine and codeine; semi-synthetic opioids include heroin, hydrocodone, oxycodone, and buprenorphine; and fully synthetic opioids include tramadol, fentanyl and methadone. In 2021, an estimated 5.6 million individuals met criteria for opioid use disorder. This article provides an overview of the pharmacology of heroin and non-prescription fentanyl (NPF) and its synthetic analogues, and summarizes the literature related to the management of opioid use disorder, overdose, and withdrawal. This is followed by a description of barriers to treatment and best practices for management with a discussion on recent updates and their potential impact on this patient population. This is followed by a description of barriers to treatment and best practices for management with a discussion on recent updates and their potential impact on this patient population.

Keywords:

• Opioid use disorder
• barriers
• best practices
• harm reduction
• pregnancy
• adolescents

Introduction

Opioids are a broad term referring to chemicals that agonize opioid receptors in the body (1). They include endogenous neuropeptides (endorphins, enkephalins and dynorphins), opiates (morphine and codeine), semi-synthetic (heroin, hydrocodone, oxycodone, buprenorphine) and fully synthetic opioids (tramadol, fentanyl, methadone) (1, 2). Opioid receptors are located within the central nervous system, peripheral nerves, gastrointestinal tract, and immune cells; agonism provides analgesia and sometimes euphoria, but also sedation, constipation, impaired thinking, and respiratory depression (1, 2).

In 2021, ∼5.6 million individuals in the United States (U.S.) met criteria for opioid use disorder (OUD) (3). OUD is defined by the DSM-V as a problematic pattern of opioid use leading to clinically significant impairment or distress (1, 4). Having a history of substance misuse and psychological or mental health disorders are risk factors for both opioid misuse and opioid mortality (deaths due to overdose) (Table 1). Risk factors for opioid mortality are largely based on prescription and illicit polysubstance use, use of opioids by naïve individuals or after long-term opioid abstinence due to a decrease in opioid tolerance (5–7).

Table 1. Risk factors for opioid use disorder (5–7).

Opioid misuse or addiction	Opioid mortality
Male gender Young age Personal or family history of substance abuse Childhood adversity and/or preadolescent sexual abuse Psychological stress, trauma, or disease, especially if untreated psychiatric disorders Social or family environments that encourage misuse Poor social support Smoking Psychotropic substance use History of legal problems	13–19 years of age and 50–69 years of age Comorbid mental and medical disorders such as sleep apnea and/or heart or pulmonary complications (e.g., respiratory infections, asthma) History of substance abuse High opioid dose Methadone use Benzodiazepine or antidepressant co-prescribing Polysubstance abuse Opioid naivety Recent release from prison or abstinence-based addiction treatment Unemployment

From 2019 to 2020, synthetic opioid-involved death rates (excluding methadone) increased by 56% and appeared driven by illicitly manufactured fentanyl and fentanyl-like synthetics (8, 9). The 12-month ending provisional number of opioid-related drug overdose deaths as of January 2023 was 79,731. Deaths due to synthetic opioids (excluding methadone) was 72,158 (10). The purpose of this article is to briefly summarize heroin and non-prescription fentanyl (NPF) and its synthetic analogues, the management of opioid overdose and withdrawal, and describe barriers and best practices for patients with OUD.

Methods

A narrative literature review was conducted, using MEDLINE, PUBMED, and Google Scholar to search for articles in English (1995-current), with the keywords “opioid use disorder,” “heroin,” “fentanyl,” “opioid overdose,” “opioid withdrawal,” “treatment,” “buprenorphine,” “methadone,” “naltrexone,” “naloxone,” “pregnancy and opioid use disorder,” “adolescents and opioid use disorder” and “harm reduction.” Articles that describe pharmacology, pharmacokinetics, management strategies for opioid overdose and withdrawal, and harm reduction strategies were selected and reviewed by the authors for inclusion.

Commonly misused substances

Heroin

Heroin, or 3,6-diacetylmorphine, is a short acting opioid 2-4x more potent than morphine (11). It is rapidly absorbed and crosses the blood brain barrier quickly due to its lipophilicity (1). Onset of action is less than a minute with intravenous use (12, 13). With inhalation, onset of action is 3–5 min though drug exposure is reduced by ∼50% due to the heating process (12, 13). Once absorbed, heroin is rapidly hydrolyzed to 6-monoacetylmorphine (6-MAM), then further hydrolyzed via de-acetylation to morphine and other metabolites (12, 13). The half-lives of heroin and 6-MAM are ∼3–4 min and ∼25 min, respectively, providing a short window before heroin is indistinguishable from morphine on a urine drug screen (12). While overdose deaths secondary to heroin have decreased by >40% from their peak in June 2017, over 11% of overdose deaths in 2021 involved heroin and thus remains a concern as it is often mixed with illicit fentanyl or fentanyl analogues (14, 15).

Fentanyl

Fentanyl, a short-acting opioid, is 50x more potent than heroin and 50–100x more potent than morphine (16, 17). Onset of action is almost immediate with intravenous use with a half-life of 2–4 h in adults; however duration of analgesic action appears to be less than half-life (18, 19). Fentanyl is highly lipophilic and redistributes into muscle and fat (18). Examples of fentanyl analogues include sufentanil (5–7x more potent than fentanyl) and carfentanil (100x more potent than fentanyl) (2, 20, 21). While overall fentanyl prescribing has decreased, (22) most overdoses are linked to NPF (or analogues) (23). Often, heroin, cocaine, methamphetamine and counterfeit tablets made to look like prescription opioids or benzodiazepines are mixed with small amounts of NPF (or analogues), resulting in accidental overdoses (17, 23). Illicit substances are rarely pure and there was an 263% increase of illicit powders containing fentanyl and an 834% increase in pills containing fentanyl from 2018 through 2021 (24).

Xylaxine

Another emerging threat is the use of xylazine as an adulterant with fentanyl (25). Xylazine is a central alpha-2-adrenergic receptor agonist that is FDA-approved for veterinary use as a sedative and analgesic. Also known as “tranq,” xylazine lowers blood pressure, respiratory rate, and heart rate. When combined with fentanyl, it increases the opioid’s euphoric effects. The Centers for Disease Control (CDC) found that overdose deaths with xylazine and NPF increased 276% from 2019 to 2022 (26). Xylazine has been linked to increased skin/soft tissue infections (SSTIs) such as lesions, abscesses, or ulcerations on the extremities, as well as need for mechanical ventilation, thereby complicating and lengthening inpatient hospital stays (27). The mechanism for SSTIs is postulated to be reduced skin perfusion from vasoconstriction of blood vessels (28). At the time of this publication, xylazine does not have a specific reversal agent.

Opioid overdose & treatment

Signs of opioid overdose, a life-threatening emergency, are listed on Table 2 (1, 29). Miosis, or pinpoint pupils, is included, however, a normal pupillary finding does not exclude opioid toxicity, as, for example, use of cocaine and heroin together can result in any pupil size (1). Additionally, while patients may present with euphoria or dysphoria, delirium is an unusual presentation in opioid toxicity; therefore, if delirium is present, a differential should include advanced age, concurrent withdrawal from other substances such as alcohol, or presence of other drugs (e.g., anticholinergic agents, steroids, stimulants, benzodiazepines, or skeletal muscle relaxants) (29).

Table 2. Signs of opioid overdose (1, 29).

Decreased consciousness or unresponsiveness Decreased respiratory rate (usually less than 12 breaths per minute) and depth Pallor, blue or purple lips and/or nails Miosis Mild hypotension Bradycardia Hypothermia Euphoria or dysphoria

Inpatient management includes supporting the patient’s airway and breathing along with parenteral administration of an opioid antagonist such as naloxone 0.4–2 mg intravenously (IV), intramuscularly (IM) or subcutaneously every 2–3 min (30). Children < 5 years of age or weighing ≤ 20 kg should receive a weight-based dose (0.1 mg/kg/dose intravenously) (30).

Naloxone, a short-acting opioid antagonist, competes with and displaces opioids at receptor sites to reverse and block the action of opioids (30). With fentanyl or its analogues, intermittent naloxone may not reverse respiratory depression due to the drugs’ lipophilicity and prolonged clearance (31) and continuous infusions may be required. Duration of action of naloxone is 30–120 min which often necessitates re-dosing or continuous infusions (30). Providers should also search the patient and remove any long-acting opioid patches.

Outpatient management follows a similar course of action. An attempt at waking the patient should be made and breathing should be assessed. If patient is minimally responsive, a sternum rub can be used (rubbing knuckles of a fist against the sternum) (32). This maneuver produces a mildly painful sensation, which will arouse most people if not intoxicated. Emergency services should be activated, and CPR started if the person is trained (32). Currently, the two agents available for rapid overdose reversal are naloxone and nalmefene (Table 3). Naloxone can be administered intranasally, intramuscularly or subcutaneously and repeated every 2–3 min as needed (32–34). Nalmefene nasal spray (Opvee®) is an opioid antagonist that recently received FDA approval for the “emergency treatment of known or suspected overdose induced by natural or synthetic opioids” and is used in those ≥12 years of age (35). Nalmefene has a fivefold greater potency for mu-opioid receptors than naloxone (36). In a study of opioid-experienced, non-dependent patients experiencing respiratory depression induced by remifentanil, intranasal nalmefene demonstrated an onset of reversal of 2.5–5 min and full recovery of respiratory drive 5–15 min after administration (35). Table 4 describes candidates who should have quick access to these agents to reduce overdose deaths (35, 37).

Table 3. Administration of opioid reversal agents (32–35).

Intranasal Administration			IM/SQ Administration
Naloxone		Nalmefene	Naloxone
Narcan^® (4 mg/0.1 mL) Single Nostril	Kloxxado^™ (8 mg/0.1 mL) Single Nostril	Opvee^® (2.7 mg/0.1 mL) Single Nostril	Zimhi^™ (5 mg/0.5 mL) Single-dose prefilled syringe
A prescription is required for Kloxxado^™ and Opvee^® Each carton contains: 2 nasal sprays (Narcan and Kloxxado^™) 1 nasal spray (Opvee^®) Each nasal spray is one-time use only, no "priming" required Discard used nasal spray to avoid re-use			A prescription is required Intended to be administered by someone 12 years of age or older Place patient in supine position and then administer IM or SQ into anterolateral aspect of thigh (through clothing if necessary) If person is < 1 year of age, pinch the thigh muscle while administering the dose After administration Pull safety guard to cover needle and place used syringe in blue case Used syringes should be given to health care provider for inspection and proper disposal
After initial administration: Move person onto his/her side (recovery position) as they may vomit Always seek emergency medical care for continued support as some opioids will remain longer than the effect of naloxone or nalmefene If no response or responds, then relapses into respiratory depression, repeat administration every 2 to 3 minutes (naloxone) or 2 to 5 minutes (nalmefene) until emergency medical assistance arrives

Table 4. Individuals who should have ready access to naloxone/nalmefene (35, 37).

Those using heroin, illicit synthetic opioids, or misusing prescription opioids Those using other illicit drugs since these may be contaminated with illicit fentanyl Those receiving treatment for opioid use disorder, including medication-assisted treatment with methadone, buprenorphine, or naltrexone Those with a history of opioid misuse that were recently released from incarceration or other controlled settings where tolerance to opioids has been lost Those receiving ≥ 50 mg morphine milligram equivalents (MME) daily Those taking licit opioids (any dose) and medications that cause CNS depression (e.g., benzodiazepines, antihistamines, muscle relaxants, anticholinergic agents, gabapentin or pregabalin) Those receiving licit opioids (any dose) and have a non-opioid substance use disorder such as with methamphetamine or cocaine since these may be contaminated with illicit fentanyl Those receiving licit opioids (any dose) and have alcohol use disorder or a mental health disorder Those receiving licit opioids (any dose) and have respiratory conditions such as chronic obstructive pulmonary disease (COPD) or obstructive sleep apnea

Opioid withdrawal & treatment

Opioid withdrawal, while often severely physically and emotionally distressing, is generally not lethal unless there are concurrent life-threatening medical conditions. In extreme cases, discomfort and severity can lead to psychological distress and increased risk of suicide (38). In a pregnant individual, withdrawal can lead to miscarriage or premature delivery (23). Persistent vomiting and diarrhea can lead to dehydration and related complications, including cardiac arrhythmias (23).

Signs and symptoms of withdrawal can start within 8–24 h for short-acting opioids (morphine, oxycodone, and heroin), and up to 36 h for long-acting opioids, such as methadone (Table 5) (23, 29). Duration of withdrawal is 7–10 days for short-acting opioids and ≥14 days for long-acting opioids (23, 39). Physiologic and psychological effects of withdrawal (e.g., pain, anxiety, irritability, drug craving) can last weeks to months post-normalization of physiological manifestations (39). The Clinical Opiate Withdrawal Scale (COWS) is used to document and evaluate opioid withdrawal severity and to initiate certain medications for opioid use disorder (MOUD) (23, 39).

Table 5. Physiological manifestations of opioid withdrawal (23, 29).

Early withdrawal Short-acting opioids (morphine or heroin) 8–24 hours after last use Long-acting opioids (methadone) up to 36 hours after last use	Full withdrawal Short-acting opioids 1–3 days after last use Long-acting opioids 72–96 hours after last use
Lacrimation, rhinorrhea, or both Diaphoresis Yawning Restlessness Insomnia Dilated pupils Piloerection Muscle twitching Arthralgia Abdominal pain	Tachycardia Hypertension Tachypnea Fever Anorexia or nausea Extreme restlessness Diarrhea, vomiting, or both Dehydration Hyperglycemia Hypotension Curled-up position

Treatment for opioid withdrawal focuses on symptom management: analgesics for pain/fever; anti-diarrheal and anti-emetic therapies for diarrhea, nausea, and vomiting; alpha-2 adrenergic agonists clonidine or lofexidine for anxiety and agitation with or without a non-benzodiazepine anxiolytic such as buspirone or hydroxyzine; antipsychotics (at lowest effective dose) for refractory agitation (23, 29, 39).

MOUD is the use of methadone (a full opioid agonist), buprenorphine (a partial mu-opioid agonist) with or without naloxone (a mu-opioid receptor antagonist), or naltrexone (a mu-opioid antagonist) to treat OUD and prevent or reduce overdose in combination with counseling and behavioral therapies (23, 29, 40). Methadone, buprenorphine with or without naloxone, and long-acting naltrexone are FDA-indicated for the treatment of OUD (41–45). A 2014 Cochrane Review found that methadone and buprenorphine doses at ≥ 16 mg/day have better treatment retention and suppression of illicit opioid use compared to placebo (46). A 2020 real world study found that buprenorphine and methadone were associated with reduced overdose and opioid-related morbidity over 12 months as compared to naltrexone, inpatient treatment, or intensive outpatient treatment (47). Once a patient displays at least moderate signs of withdrawal, MOUD with methadone or buprenorphine can be initiated (40). A microdosing strategy may also be considered with buprenorphine to further mitigate the risk of precipitated withdrawal and can be initiated with no signs of withdrawal.

While patients on methadone or buprenorphine are physiologically dependent on these agents, there is a reduction in high-risk behaviors associated with addiction to illicit and prescription opioids (40). Methadone and buprenorphine decrease withdrawal severity and risk of overdose deaths, reduce cravings, and improve opioid abstinence, providing an opportunity for patients to identify and improve their biopsychosocial triggers and environments (23, 29). Patients should continue treatment as long as they benefit without the development of adverse events. Methadone and buprenorphine can be used in pregnant women with active OUD (23). Comprehensive OUD treatment includes MOUD and psychosocial therapy (e.g., cognitive behavioral therapy, peer support services, motivational interviewing) and are associated with improved treatment efficacy (i.e., engagement, retention in care) and patient outcomes (i.e., opioid use abstinence/reduction, disease remission) and mortality (23, 29, 47).

Methadone

Methadone is a full opioid agonist believed to dampen rewarding and euphoric effects of other opioids, while preventing withdrawal symptoms (Table 9) (29, 43). In addition to pain management, methadone is indicated for medically supervised withdrawal and maintenance treatment of opioid dependence from federally certified and accredited OTPs (methadone clinics). After providing informed consent, patients with OUD will typically visit the clinic daily to receive methadone (23, 29). Due to confidentiality regulations, methadone clinics are not required to report to a state’s prescription drug monitoring program (PDMP) thereby increasing risks for polypharmacy and adverse effects if a patient also receives a prescribed opioid (29). Methadone is associated with QT prolongation and a baseline ECG with routine monitoring is recommended (48). It may be inappropriate for patients with a history of QTc >450 milliseconds or prior ventricular arrhythmia (43). Methadone and buprenorphine are associated with respiratory depression, though the risk is significantly decreased when using buprenorphine (43, 49).

Table 9. Management of opioid use disorder: Methadone and naltrexone (23, 29, 42, 43).

	Methadone	Naltrexone
Mechanism of action	Full mu-opioid agonist	Mu-opioid receptor antagonist
Relevant PK / PD	Onset of action: 30–60 minutes Duration of action on cravings: 24–36 hours Elimination t ½: 8–59 hours	IM Duration of action: 4 weeks Elimination t½: 5–10 days
Dosage / Administration	Tablet or liquid Initial dose: 10–30 mg daily Maintenance dose: 60–120 mg daily Has no ceiling effect → induction should begin at a low dose with upward titration	Extended-release intramuscular injection (Vivitrol^®) Monthly administration of 380 mg to gluteal muscle by provider
Considerations	Avoid if QT interval is above 500 milliseconds Explain to patients that full effects will take several days (≥ 4 days) due to slow release from tissues Side effects Constipation Drowsiness Excess sweating Hypotension Syncope	No misuse potential or street value Do not develop tolerance to effects Low adherence rate Expensive Side effects Insomnia Injection site pain Hepatic enzyme abnormalities Nasopharyngitis

Buprenorphine

Although buprenorphine is a partial mu-opioid receptor agonist, its binding affinity for mu-opioid receptors is greater than full opioid agonists (e.g., heroin or oxycodone); thus, buprenorphine can effectively displace other opioids causing withdrawal (Table 6) (23, 29, 49–51). To avoid precipitating withdrawal, patients must show objective withdrawal symptoms prior to initiating buprenorphine. Buprenorphine will relieve cravings, with less euphoria than full agonists, possibly due to lower G-protein signaling and buprenorphine preferentially working more at spinal cord receptors than brain receptors (52).

Table 6. Buprenorphine kinetics (23, 29, 49–51).

Mechanism of action Buprenorphine: Partial mu-opioid receptor agonist & kappa-opioid receptor antagonist Buprenorphine-Naloxone: Partial mu-opioid receptor agonist plus mu-opioid receptor antagonist Onset of action: sublingual: 30–60 minutes Duration of action: Sublingual: 6–12 hours (doses < 4mg) and 24–72 hours (doses > 16mg) Elimination t½ Sublingual tablets: ∼37 hours Subcutaneous extended-release injection: Sublocade: 43–60 days Brixadi weekly: 3–5 days Brixadi monthly: 19–26 days Suboxone^® sublingual film: buprenorphine: 24–42 hours; naloxone: 2–12 hours Both buprenorphine and naloxone undergo extensive hepatic metabolism and moderate-to-severe impairment will result in reduced clearance and can lead to buprenorphine toxicity and precipitated withdrawal with naloxone; avoid combination product if severe hepatic impairment

Due to poor bioavailability, buprenorphine is available in several sublingual and parenteral preparations and dosage strengths for OUD (Table 7) (23, 29, 42, 49, 50). Sublingual buprenorphine is typically initiated 12–18 h after the last dose of a short-acting opioid (heroin or oxycodone), 24–48 h after the last dose of a long-acting opioid, or when the COWS score is 12 or greater (23, 29, 40, 49). Extended-release subcutaneous injections can be initiated after induction and stabilization with a transmucosal buprenorphine product after a minimum of 7 days (Sublocade) or after a test dose of 4 mg transmucosal buprenorphine does not precipitate withdrawal (Brixadi) (42, 50). However, with the introduction of NPF, patients have reported precipitated withdrawals at least 72 h after discontinuing NPF use (31). As buprenorphine is a substrate for cytochrome P450 3A4 isoenzyme, determine clinically significant drug interactions prior to therapy initiation (23, 49).

Table 7. Buprenorphine dosing and administration (23, 29, 42, 49, 50, 56).

Sublingual tablets (individuals ≥ 16 years of age) On day 1, starting dose is 2–4 mg; if no precipitated withdrawal after 1 hour, may give additional 2–4 mg every 2–4 hours if symptomatic based on COWS score; usual maximum dose on day 1 is 8 mg Continue day 1 dose if symptoms are relieved. If patient is symptomatic, increase dose by 2–4 mg Typical maintenance dose: 16 mg/day If sublingual buprenorphine is to be discontinued, taper down dose over several months to prevent withdrawal Provide patients with tips to prevent dental problems After buprenorphine is completely dissolved, take a large sip of water, swish it gently around teeth and gums, and swallow Wait at least 1 hour before brushing teeth Subcutaneous extended-release injection (Sublocade^®) Start Sublocade^® following induction/dose adjustment with transmucosal buprenorphine (buccal or sublingual) treatment for ≥ 7 days Health care worker injects 300 mg into patient’s abdominal area monthly for first 2 months Maintenance dose: 100 mg monthly; can titrate to 300 mg monthly if necessary Safety and effectiveness not established in pediatric patients Subcutaneous extended-release injection (Brixadi™) In buprenorphine-naïve patients, administer a test dose of 4 mg transmucosal buprenorphine and if tolerated without precipitated withdrawal, start weekly Brixadi™ formulation Health care worker slowly injects 16 mg into patient’s buttock, thigh, upper arm, or abdominal area. Then, administer 8 mg within 3 days of the first dose Maximum weekly dose is 32 mg Patients currently taking transmucosal buprenorphine can be switched to either weekly or monthly dosing with Brixadi™ based on the patient’s daily dose of buprenorphine and clinical judgment Only administered as part of a REMS program Subdermal implant (individuals ≥ 16 years of age) Indicated for maintenance treatment in clinically stable patients taking ≤ 8 mg/day of Suboxone^® Four implants are inserted on inner side of upper arm 12–24 hours after last dose of transmucosal buprenorphine; remove 6 months later; insert 4 new implants in alternate arm for another 6 months; then, convert back to sublingual tablets

Several buprenorphine formulations are combined with naloxone to deter buprenorphine misuse if used intravenously, however the pharmacokinetic properties of the drugs do not support this misuse assertion (Table 8) (23, 29, 44, 45, 53, 54). Combination product is not recommended for patients who are pregnant (buprenorphine monotherapy preferred) or have severe hepatic impairment as reduced naloxone clearance may precipitate withdrawal (23, 53, 55). Side effects of buprenorphine include headache, dizziness, vomiting, constipation, oral numbness, and QT prolongation (49, 53). Patients should be counseled to take a large sip of water, swish and swallow after transmucosal buprenorphine has completely dissolved to minimize dental problems (e.g., cavities, tooth decay) (56). Patients may require ≥ 16 mg of sublingual buprenorphine to reduce cravings and prevent relapse, and new research shows that blockade of reward effects may need to have doses as high as 32 mg per day (57, 58). Doses above 16 mg/day have the additional benefit of covering 80–90% of mu opioid receptors, so in the event that a patient has a recurrence of symptoms and uses an illicit opioid, buprenorphine’s long half-life, binding affinity and limited receptors work to decrease the risk of a fatal overdose (57). Subcutaneous buprenorphine extended-release formulation is administered weekly and monthly, thereby reducing the need for daily administration (42, 50).

Table 8. Buprenorphine-naloxone dosing & administration (23, 29, 44, 45, 53, 56).

Sublingual tablets (Zubsolv^® and generic) Day 1: administer up to 5.7 mg/1.4 mg in divided doses Day 2: administer up to a total dose of 11.4 mg/2.9 mg as a single dose Maintenance dose: 11.4 mg/2.9 mg as a single daily dose Sublingual Administration Place tablet under the tongue until dissolved (do not swallow tablet whole as it reduces bioavailability)

Sublingual film (Suboxone^® and generic) Day 1: administer up to 8 mg/2 mg in divided doses Day 2: administer up to 16 mg/4 mg as a single dose Maintenance dose: 16 mg/4 mg as a single daily dose Sublingual Administration Place one film under the tongue, close to the base on left or right side; allow to completely dissolve Buccal Administration Place one film on the inside of left or right cheek; allow to completely dissolve

- Due to wide variability in pharmacokinetics, after providing the first dose of transmucosal buprenorphine, wait at least 2 hours to determine if a second dose is necessary - Safety and effectiveness not established in pediatric patients - Provide patients with tips to prevent dental problems Do not eat or drink anything until buprenorphine is completely dissolved After buprenorphine is completely dissolved, take a large sip of water, swish it gently around teeth and gums, and swallow Wait at least 1 hour before brushing teeth

Buprenorphine is more accessible than methadone as, in the past, it could be prescribed by a provider with an X waiver via the Drug Addiction Treatment Act of 2000 (DATA 2000), or via an opioid treatment program (OTP) (23, 29). With the removal of the DATA 2000 waiver requirement as a result of the MAT act passed in 2022, it is hoped that access will further improve. As buprenorphine is a partial agonist with a ceiling effect on opioid activity, it is less likely than methadone to cause respiratory depression in an overdose, unless combined with other central nervous system depressants such as benzodiazepines or alcohol. Patients who are physiologically dependent on opioids can begin buprenorphine treatment with a prescription. In contrast, methadone can only be prescribed from a licensed OTP. Healthcare settings and pharmacies must be certified in the Sublocade^® REMS Program and Brixadi™ REMS and only dispense the agent directly to a provider for subcutaneous administration due to risk of serious harm or death from intravenous self-administration (42, 50).

Naltrexone

Naltrexone is an opioid antagonist with strong binding affinity for the mu-opioid receptor but will not activate the receptor (23, 29). Naltrexone will not reduce withdrawal symptoms. It is available as an oral tablet and as a long-acting injectable (Table 9) (23, 29, 41). Oral naltrexone has limited efficacy for OUD; however, the injectable is indicated for prevention of relapse due to opioid dependence following medically-supervised withdrawal (41). Although naltrexone is approved for OUD, if naltrexone (oral or injectable) is initiated, the patient must be opioid-free for ≥7–10 days (23, 41). The patient must no longer be in withdrawal or be physiologically-dependent on opioids (29). Injectable naltrexone is administered every 3–4 wk as some patients metabolize naltrexone more rapidly than others. Naltrexone is avoided in pregnancy due to unknown safety profile in this population (23, 29). Additionally, naltrexone should be used with caution in patients with hepatic impairment as acute hepatitis and hepatoxicity have been associated with the use of long-acting injectable naltrexone (41). A 24-week study of injectable naltrexone versus buprenorphine-naloxone showed similar efficacy, but increased cost of an additional $5,317 with injectable naltrexone versus buprenorphine-naloxone (59).

Barriers and best practices

Healthcare settings

In many patients with OUD, the emergency department (ED) is often their only access to a healthcare system and therefore becomes an excellent opportunity for intervention (40). In a randomized controlled trial of 216 opioid-dependent patients, 78% who received ED-initiated buprenorphine were engaged in treatment at 30 days versus only 37% who received screening and referral to treatment (60). Additional studies of ED-initiated buprenorphine with outpatient transitions-of-care demonstrated both cost-effectiveness and improved opioid misuse-related outcomes (40). Barriers to adoption of ED-initiated buprenorphine included lack of X-waivered providers in the ED, limited care resources for outpatient transition, and lack of knowledge about benefits and administration within the ED (40, 61).

Best practices include using a screening tool to identify substance use disorder (SUD), employing the gold standard of the DSM-5 criteria to diagnose OUD, dispensing naloxone to all high-risk patients and family members that request naloxone, and promoting/educating providers on ED-initiated buprenorphine protocols with transitions-of-care planning (23, 29). Guidelines recommend a standard induction; initiating buprenorphine for OUD at 2–4 mg with 2-h titrations up to 8 mg on day 1, and up to 16 mg on day 2 (29, 40). However, a reevaluation of the previous evidence in regard to MOUD initiation and pain management is necessary due to: (1) fentanyl’s unique pharmacologic and pharmacokinetic profile (high lipophilicity and potency) versus other opioids when misused; (2) prolonged clearance due to repeated fentanyl exposure; and, (3) increased frequency of patient-reported precipitated withdrawals when buprenorphine is initiated at 12–18 h in a patient with mild-to-moderate COWS score (19, 31, 62).

A new approach is the use of buprenorphine microdosing for sooner initiation versus traditional methods (where patients would be in moderate withdrawal prior to buprenorphine initiation) (63). For example, a patient presents to the emergency department either from an overdose or self-report that they want to stop the NPF. Instead of waiting for the patient to be in moderate withdrawal, a microdosing of buprenorphine is initiated at 0.25–2 mg/day of sublingual buprenorphine or 5–20 mcg/hour of transdermal buprenorphine (with titration to a minimum target dose of 16 mg/day) (63, 64). The patient is encouraged to stop the NPF. Several reviews provide additional guidance on buprenorphine microdosing for OUD and/or pain (39, 64). The American Society of Addiction Medicine (ASAM) guidelines recommend at least 12 months of treatment with methadone, and it is reasonable to apply the same standard to buprenorphine treatment (29). Lastly, while it is preferable to initiate buprenorphine in a monitored healthcare setting, the standard dose and microdose induction strategies for buprenorphine could be considered for home use with appropriate education and patient follow-up (65, 66).

Patients with OUD who require admission for co-occurring medically necessary care requiring pain management is another challenge. Similar to treating OUD due to NPF, providers may consider microdosing buprenorphine while using full opioid agonists for pain control (67). This allows for symptom control while reducing risks for patients who may use a patient directed discharge with a plan for cross tapering of buprenorphine and full opioid agonists during the discharge planning process (64).

An effective approach to incorporating naloxone dispensing and transitions-of-care is use of peer support programs in the ED (68, 69). This includes hiring trained personnel (minimum two years of recovery from SUD) to engage, support, educate, and provide resources and linkage to care. Peer support programs decrease the number of days to MOUD initiation, medical and behavioral health inpatient admissions and ED visits resulting in demonstrable cost-savings that can be used to justify the initiation of a program (68, 69). An adequate observation period post-naloxone administration is needed to ensure that overdose does not re-occur as naloxone is rapidly metabolized, but fentanyl is highly lipophilic and can leech out from its storage in fat tissues to cause overdose after naloxone administration. In patients with uncomplicated presumed fentanyl overdose, physicians at an ED in Vancouver, British Columbia, utilized a 2-h observation protocol post-final naloxone administration with an increase to 6 h if a naloxone infusion was required (70). While adequate monitoring is frequently mentioned, very few guidelines indicate a duration. The authors agree with the National Institutes of Health recommendation of a minimum of 2-h monitoring post last administration of naloxone (71). If 2 h is not possible, authors suggest providing patient education and take-home naloxone as a risk mitigation strategy.

While the passage of the MAT act decreases the barrier to prescribing buprenorphine for OUD, filling of those prescriptions remains a challenge (72). A 2021 study of over 900 community pharmacies found that nearly 20% would not dispense buprenorphine with the highest rates among independent pharmacies and pharmacies located in the Southern Unites States (73). Studies evaluating reasons for pharmacy access issues included belief that declining prescriptions would help with opioid diversion, fear of investigation by the DEA, declining prescriptions filled outside a limited geographical area, stigma regarding the patient population, concern regarding increased buprenorphine prescriptions from telehealth, and wholesaler thresholds for buprenorphine (73). Access to buprenorphine is not the only pharmacy barrier, but naloxone for harm reduction as well. Although pharmacists can dispense naloxone with or without a prescription in many states, a recent systematic review identified several barriers to pharmacist-driven naloxone distribution (74). These barriers include time constraints, inadequate reimbursement, possible inducement to increased opioid use, placing the pharmacist in an unsafe situation, inadequate training in detecting overdose risk or application of state laws or standing orders, and hesitation in dispensing a medication without a prescription (74–76).

While best practices for removing pharmacy barriers are not widely published, some facilitators for improved buprenorphine dispensing include “increased communication with prescribers, increased trust with prescribers, increased trust with patients, and increased education for pharmacists” (77). A 2023 paper recommends more specific, wide-spread approaches including lobbying the Drug Enforcement Agency (DEA) to de-schedule or re-schedule buprenorphine and encouraging the DEA to suspend enforcement actions against wholesalers and pharmacy in relation to buprenorphine (78). This would serve as a dual benefit; likely removing stigma around the use of the medication and reducing the wholesaler thresholds in place for controlled substances. Additional recommendations including improving communications between pharmacy staff and providers and wholesalers, a well as increased support by state pharmacy boards and associations (78). In regards to naloxone dispensing, as supported by the American Medical Association and the American Pharmacists Association, naloxone nasal spray should be re-classified as a behind-the-counter medication from prescription status (79, 80). While many states have protocols for standing orders for pharmacists to dispense naloxone, due to its legend drug status, it must have all the required federal and state labeling requirements including patient name. This greatly inhibits the ability to dispense this life-saving medication in a non-patient specific manner, especially to vulnerable patients such as those experiencing homelessness, or at large gatherings where drug use occurs such as festivals and spring break locales.

One benefit to the passage of the MAT act is the allowance for pharmacists to prescribe and manage MAT under collaborative practice with a physician. Pharmacists have a proven track record of improved health outcomes in patients when working under a collaborative practice with a variety of disease states including hypertension, diabetes, and reduction in ED visits and hospitalizations (81–85). However, pharmacists have been limited in their ability to demonstrate positive outcomes among patients with OUD as first, they were unable to acquire a DATA 2000 waiver under the previous law and second, only 10 states allowed pharmacists to obtain a DEA license necessary to prescribe a controlled substance such as buprenorphine (86). Several small studies have been published describing this collaboration in various practice settings: health department, rural Veterans Affairs hospital, three office-based buprenorphine treatment clinics and three community pharmacies, and six behavioral health pharmacies (87–90). The pharmacists’ patient care roles included obtaining detailed histories, performing comprehensive medication management, conducting appointments with patients already on buprenorphine or newly initiated buprenorphine, and checking the prescription drug monitoring program (PDMP) for signs of diversion (87–90). Benefits included increased communication, reduced physician burden, increased access to treatment and cost-savings (87, 88). While larger studies with a longer duration are needed to clarify best practices for this collaboration, with the removal of the DATA 2000 waiver requirement, it is recommended that pharmacists, providers and state governing boards advocate for changes to state laws to allow pharmacists to obtain DEA licenses and provide MAT under collaborative practice with a physician.

Harm reduction strategies

Best practices for the ED (use of screening tools for OUD and naloxone dispensing) remain the same in the outpatient setting. An additional harm reduction strategy is for individuals to use rapid fentanyl test strips (FTS) to detect illicitly-manufactured fentanyl or some of its analogues prior to use of street drugs (91). Patients should be counseled that FTS may not detect fentanyl analogues or even fentanyl if there is insufficient quantity in the tested batch, and to ensure that other harm reduction strategies are utilized if fentanyl is detected in their supply (e.g., not use their supply, have naloxone nearby and/or not using alone) (92). FTS were originally created to test for fentanyl in the urine, as standard urine drug screens are not designed to identify fully synthetic opioids (e.g., fentanyl, methadone, or tramadol). To detect fentanyl prior to use, a small amount of street drug is mixed with water followed by application of the single-use strip to sample (91, 92).

Needle exchange programs have been found to reduce the transmission of blood borne infections and show decreases in risky behaviors including sharing or re-using needles while providing cost savings (93). The Harm Reduction Coalition offers a guide to developing and managing syringe access programs (91).

In early 2023, the FDA approved naloxone nasal spray for over-the-counter use and prescription-only nalmefene nasal spray for rapid opioid reversal (35, 94). Previous federal and state labeling requirements greatly inhibited the ability to dispense naloxone in a non-patient specific manner especially to vulnerable individuals (e.g., those experiencing homelessness or those at large gatherings [e.g., festivals] where drug use occurs) (75, 95). Intranasal nalmefene has a terminal half-life of ∼11 h with a duration of action of 1–4 h, which may address the challenge posed by the long half-lives of NPF (and analogues), however, its utility in the community setting remains to be seen (35, 96, 97).

Special populations

Patients in the criminal justice system

It is estimated that 15% of incarcerated persons have OUD, but less than 14% of correction facilities offer treatment with MOUD (98). The ASAM guidelines recommend initiation and maintenance of MOUD for OUD in jails and prisons, with an offer of psychosocial treatment (29). Due to the high risk of relapse and subsequent overdose, it is also recommended that patients in the criminal justice system have appropriate transitions-of-care to ensure treatment is able to be immediately continued upon release (29).

Pregnancy

In the U.S., opioid use by pregnant women has increased in parallel to the epidemic noted in the general population. OUD during pregnancy can cause neonatal abstinence syndrome (NAS), which describes symptoms of withdrawal exhibited by neonates due to prenatal exposure (29). Nationally, from 2010 to 2017, rates of maternal OUD increased from 3.5 to 8.2 per 1,000 delivery hospitalizations and rates of NAS increased from 4 to 7.3 per 1,000 hospital births (99). This was associated with increased cost and length of stay during hospitalization for both mother and child (99). Complications of OUD during pregnancy include pre-eclampsia, premature delivery, and fetal growth restriction (29). As such, the American College of Obstetricians and Gynecologists (ACOG) recommends universal screening for OUD in pregnant women at the first prenatal visit (100). This emphasis on universal screening is crucial to decreasing missed diagnoses and stigma caused by a reliance on stereotypes and generic risk factors (e.g., poor adherence to prenatal care or a prior adverse pregnancy outcome) (100).

Standard of care for management of OUD in pregnancy should involve MOUD with access to counseling and community support, such as housing and employment, to stabilize the mother and reduce the risk of fetal morbidity and mortality from repeated withdrawal episodes (29, 100, 101). Withdrawal episodes are associated with high relapse rates and worse outcomes for mothers and children (100). Both methadone and buprenorphine are categorized as Pregnancy Category C by the FDA, and ACOG and ASAM recommend treatment with these medications for management of OUD in pregnancy (29, 43, 49, 100). Potential risk of birth defects and long-term developmental impacts are low in comparison to risks associated with continued opioid misuse during pregnancy (29, 100). There is a risk of NAS with methadone or buprenorphine treatment during pregnancy, but NAS can be managed with appropriate care and was not found to cause long-term consequences in these children (29). Therefore, ASAM guidelines recommend providing pharmacotherapeutic treatment with buprenorphine or methadone rather than treating withdrawal alone or providing only psychosocial support (29).

Pharmacokinetic changes that occur with pregnancy may further complicate OUD treatment with buprenorphine or methadone. Increased or rapid metabolism of methadone may occur, particularly during the third trimester, thus, a single daily dose may not be sufficient (can lead to withdrawal) and split-dosing may be necessary (100). Increased doses may also be needed throughout pregnancy and should be assessed by clinicians on a patient-specific basis. Dose adjustment with buprenorphine is not as common in pregnancy but split-dosing has been used in cases when discomfort is reported in the evenings (29). Buprenorphine has also been recommended as monotherapy in pregnancy to avoid prenatal exposure to naloxone (100, 102).

Access to medications and supervision is another key factor in selecting pharmacotherapy. Buprenorphine is prescribed in an office or outpatient setting, while methadone must be dispensed from a licensed OTP (100). It is not recommended to switch a pregnant woman who is stable on methadone treatment to buprenorphine as this carries a high risk of precipitating withdrawal (100). Further research is necessary to elaborate on the safety of combination buprenorphine/naloxone products and extended-release formulations, in addition to the efficacy of treatment of OUD in the inpatient versus outpatient settings (29).

Pregnant women with OUD may face legal consequences. Twenty-four states and the District of Columbia have passed statutes that categorize SUD during pregnancy as child abuse. Twenty-five states mandate reporting of suspected SUD during pregnancy by healthcare professionals (103). Since the 1970s, legal action has been sought by nearly 45 states against pregnant women for exposing their fetus to illicit substances (104). This may create a significant barrier to pregnant women seeking both care and OUD treatment during prenatal and postpartum periods, as well as generate reluctance in providers to provide care for fear of legal consequences (105). This also has implications for care during delivery, as hospitals may have protocols for urine and toxicology screenings in pregnant women and mandate reporting of positive screens (104). This patient population requires significant comprehensive medical care beyond screening and treatment of OUD, including sexually transmitted infections screening and treatment, behavioral health support, and social and economic support, all of which suffers when they are prevented from seeking care due to punitive state laws (29).

Adolescents

As a risk factor for OUD is young age, providers are encouraged to screen adolescents for OUD via the Screening, Brief Intervention, and Referral to Treatment (SBIRT) model to determine need for further interventions (106, 107). As with adults, they must receive harm reduction education as they are typically less knowledgeable about counterfeit pills, safe injection practices (e.g., needle exchanges, safe place to inject) and overdose risks and management (107). Treatment options are similar to those of adults but should be adjusted for adolescents at their developmental stage. Behavioral approaches include cognitive behavioral therapy (individual learns coping strategies), adolescent community reinforcement (exposure to healthier family/community relationships), contingency management (individual receives low-cost incentives for receiving treatment and avoiding substance use) and motivational enhancement therapy (therapist works with individual to motivate change) (106). Of note, all adolescents should be offered MOUD (even if they do not pursue behavioral interventions) (108). Regardless of age, multiple guidelines recommend treatment with MOUD to those who meet criteria for OUD (108). Buprenorphine sublingual tablet and subdermal implant are approved for use in individuals ≥16 years of age, however the package insert for extended-release injection states that its safety and effectiveness is not established in patients <18 years of age (49, 50). Similarly, naltrexone tablets and injectable formulations are only approved for use in individuals ≥ 18 years of age. Methadone can be used in those under 18 years of age, but only if the methadone clinic receives a special waiver to treat youths (107). Furthermore, these adolescents must have ≥ 2 documented, unsuccessful, medically supervised withdrawals or treatments without MOUD in a 12-month period as well as a written informed consent provided by a parent or legal guardian (23, 29).

Scarcity of clinical data on effectiveness, safety, and tolerability of MOUD in adolescents may be one reason this population is undertreated (108). It is unclear if medical insurance will cover the costs of pharmacotherapy used outside FDA-approved parameters such as age; high copays for medications and clinic visits are additional barriers (108). Of note, the stigma that MOUD is a substitute for substance use may result in family members unsupportive of adolescents receiving this treatment (109). Lastly, the significant shortage of addiction treatment centers is a barrier to treatment as adolescents with OUD are unable to receive MOUD in a timely manner (108, 110).

Legislative updates

At the time of this writing, the Mainstreaming Addiction Treatment (MAT) Act was passed at the end of 2022, removing the required registration process to prescribe buprenorphine (also known as the Data 2000 or X waiver) (111). This act introduced new training requirements for all prescribers, that go into effect after June 21, 2023 (111). One benefit to removal of this requirement is the allowance for pharmacists to prescribe and manage MOUD under collaborative practice with a physician. The financial and improved patient benefit outcomes have previously been discussed and provide a framework for the pharmacists’ patient care roles in the management of OUD. These included obtaining detailed histories, performing comprehensive medication management, conducting appointments with patients already on buprenorphine or newly initiated buprenorphine, and checking PDMP for diversion (87–90). With data demonstrating that a combination of pharmacotherapy and behavioral therapy show the best outcomes for recovery for patients with OUD, it is the authors’ hope that removal of the DATA 2000 waiver will increase access for patients struggling with this disorder.

Conclusion

OUD is a chronic disease state and should be treated and managed by the medical community as other chronic diseases, with evidence-based treatment to ensure positive health outcomes. This includes the use of methadone, buprenorphine with or without naloxone, or naltrexone. While there are important clinical distinctions between each medication, guidelines recommend initiation of MOUD in all patients with OUD, including special populations such as patients who are incarcerated, pregnant, or adolescents. The importance of MOUD lies in treating OUD, preventing or reducing overdose, and decreasing patient exposure to potentially harmful or high-risk behaviors. Despite the literature showing improvement in patient outcomes, OUD management remains a complex topic mired by challenges in access to treatment across different healthcare settings. Ultimately, the aim should be initiation of appropriate medical management in addition to counseling and addressing psychosocial challenges faced by patients with OUD. As a result, all healthcare professionals will need ongoing education on this disease state and associated legislative changes.

Declaration of interest

The author reports no conflict of interest. The author alone is responsible for the content and writing of the article.

Additional information

Funding

This publication was made possible by Grant Number FG-000068 from the Department of Health and Human Services Substance Abuse and Mental Health Services Administration (SAMHSA).10.13039/100000058 Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Department of Health and Human Services Substance Abuse and Mental Health Services Administration.