Barriers and Best Practices on the Management of Opioid Use Disorder

Figures & data

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

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

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

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

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

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

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

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

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