What treatments are available for patients with opioid use disorder (OUD)?

Opioid use disorder (OUD), as defined by the American Society of Addiction Medicine (ASAM), is “a primary, chronic disease of brain reward, motivation, memory, and related circuitry, with a dysfunction in these circuits being reflected in an individual pathologically pursuing reward and/or relief by substance use and other behaviors.”¹ In 2017, approximately 2.1 million people aged 12 years or older in the United States had an OUD.² Opioid use disorder is a chronic disease that is treatable.³ Despite the availability of effective OUD treatment programs, a gap remains between the number of people needing treatment and the capacity of opioid treatment programs (OTPs).

The treatment for OUD includes medication and other interventions to address behavioral and cognitive complications, living environment, and recovery support.¹ Opioid treatment programs are federally mandated to provide medical, vocational, educational, and other services in addition to medication-assisted treatment (MAT).⁴ The use of Food and Drug Administration (FDA)-approved MAT for OUD, in combination with counseling and behavioral approaches, benefits the patient as a whole through potential improvement in quality of life. Medication-assisted treatment in combination with psychosocial treatment is superior to withdrawal management alone or withdrawal management in combination with psychosocial treatment.¹

There are three FDA-approved medications available to treat OUD: methadone, buprenorphine, and naltrexone.⁵ Prescribers should use shared decision making when determining which medication is most appropriate for each patient.¹ Patient preferences, past OUD treatment, and treatment setting should be considered. Duration of treatment is patient-specific and should last as long as patients receive benefit from treatment.³ Longer treatment periods are associated with better outcomes.

Methadone, a schedule II controlled medication, is a synthetic, long-acting, full mu-agonist indicated for induction and maintenance treatment of OUD.⁶ Methadone binds to the same receptors as heroin, morphine, and other opioids, but at a slower rate.⁷ Euphoria associated with the activation of opioid receptors is mitigated with treatment doses of methadone due to its prolonged activity. Methadone reduces cravings and helps minimize withdrawal symptoms. Methadone is available as a liquid concentrate, powder, and dispersible tablet for outpatient treatment of OUD.³ It is administered orally once daily under supervision at approved OTPs.¹ Eventually, if a patient demonstrates positive progress and is considered at low risk for diversion, a patient may be allowed to take some doses at home between OTP visits. Initial dosing of 10 to 30 mg daily is recommended, with typical maintenance doses ranging from 60 to 120 mg daily. Side effects include edema, drowsiness, sweating, constipation, and nausea.³ Methadone is recommended for the treatment of OUD in pregnancy.¹ Methadone should be used with caution in patients with respiratory disease, like chronic obstructive pulmonary disease (COPD) or preexisting respiratory depression.³ Methadone may increase the risk of prolonged QT interval and torsades de pointes.¹ If a patient has a history of cardiac conduction abnormalities, is taking doses of methadone over 120 mg per day, or is at increased risk due to QT interval prolonging drug therapy, an electrocardiogram should be considered. Due to an FDA black box warning associated with QT prolongation, alternate therapies may be warranted in high-risk patients. Methadone has many significant potential drug-drug interactions. More specifically, it interacts with drugs that cause QT interval prolongation, CYP450 34A inducers or inhibitors, other respiratory depressants, and naltrexone. Depending on the drug-drug interaction, careful monitoring or an alternate therapy should be used.

Buprenorphine, a schedule III-controlled medication, is a partial mu-agonist and kappa antagonist indicated for the treatment of OUD.⁸ Buprenorphine binds to the same opioid receptors as heroin, morphine, and other opioids, with less activation than a full agonist. Buprenorphine reduces cravings and helps minimize withdrawal symptoms without euphoria. To prescribe or dispense buprenorphine for OUD or withdrawal management in an office-based opioid treatment (OBOT) setting, prescribers must qualify for a practioner waiver under the Drug Addiction Treatment Act of 2000 (DATA 2000).¹ Buprenorphine is commercially available as a single ingredient agent or in combination with the opioid antagonist, naloxone. The combination product discourages intravenous misuse of buprenorphine.¹ Buprenorphine is available as a sublingual tablet, implant, and depot injection and buprenorphine/naloxone is available as a buccal film, sublingual film, and sublingual tablet.⁹ Monotherapy buprenorphine or buprenorphine/naloxone may be used for induction. If a patient is transitioning from methadone or another long-acting opioid or has hepatic impairment, the use of buprenorphine monotherapy is recommended due to an increased risk of precipitated withdrawal with the combination product.¹ Buprenorphine induction should begin when the patient is exhibiting signs of mild to moderate withdrawal. Induction doses of buprenorphine should begin with a dose of 2 to 4 mg. This dose may be titrated up to 8 mg on day one at two-hour intervals in 2 to 4 mg increments based on symptoms. On day two, administration of a single daily dose up to 16 mg is recommended. For maintenance dosing (day 3 and onward), dosing should be adjusted in increments or decrements of 2 to 4 mg to a dose that suppresses opioid withdrawal signs and symptoms. The recommended maintenance dose ranges from 4 to 16 mg/day. Doses greater than 24 mg/day have not demonstrated greater clinical efficacy.^8,10 In general, buprenorphine is well tolerated.⁷ Some common side effects include insomnia, constipation, excessive sweating, oral hypoesthesia, oral mucosal erythema, intoxication, blurred vision, palpitations, and opioid withdrawal syndrome.³ Buprenorphine is recommended for the treatment of OUD in pregnancy. There is limited data indicating that buprenorphine/naloxone is as safe and efficacious as buprenorphine alone, but currently it is recommended to use monotherapy buprenorphine in pregnancy.¹ Buprenorphine should be used with caution in patients with respiratory disease, like COPD or preexisting respiratory depression. Buprenorphine/naloxone combination products should be used with caution for maintenance therapy in patients with moderate hepatic impairment and are contraindicated in patients with severe hepatic impairment. Buprenorphine has less clinically significant drug interactions than methadone. However, since buprenorphine is metabolized by CYP450 3A4 liver enzymes, monitoring is needed for patients stopping or starting medications that are CYP450 3A4 inhibitors or inducers.³

Naltrexone, an opioid antagonist is a non-controlled federal legend medication.^11,12 It competitively blocks the activation of mu-opioid receptors and the euphoric effects of opioids.³ Naltrexone does not alleviate withdrawal symptoms unlike methadone and buprenorphine. It can precipitate withdrawal after recent use of opioids. Patients must wait 10 to 14 days after their last use of long-acting opioids and 7 to 10 days after their last use of short acting opioids before starting naltrexone. Oral naltrexone comes as a 50 mg tablet. The usual recommended dosing is 50 mg daily or 3 times weekly (with two 100 mg doses followed by a 150 mg dose). There is a high risk for non-adherence with oral naltrexone; therefore, this agent should be considered only in patients whose adherence can be supervised. In a Cochrane Review, oral naltrexone was not shown to be superior to placebo in reduction of illicit opioid use or treatment retention.³ Extended-release injectable naltrexone (Vivitrol) is given as 380 mg every 4 weeks and may be more suitable in patients with adherence issues. In contrast to oral naltrexone, intramuscular naltrexone has been demonstrated to be more effective than no medication or placebo in reducing the risk of relapse. Naltrexone is well tolerated. Some common side effects are insomnia, muscle aches, nausea, lack of energy, anxiety, injection site reactions (with IM formulation), and headache.¹ Caution should be used in patients with moderate to severe renal impairment.³ Hepatitis has been associated with naltrexone and liver function tests should be assessed periodically during treatment. Naltrexone has been associated with dysphoria and it is recommended to monitor patients for depression and suicidal ideation. Naltrexone is not recommended in pregnant patients with OUD.¹ It is very important to educate patients maintained on naltrexone to avoid abrupt discontinuation of therapy. Naltrexone maintenance therapy lowers opioid tolerance. Abrupt discontinuation of naltrexone and reuse of opioids at the same doses used before starting naltrexone treatment may result in an increased risk for opioid overdose.

Another important consideration for choice of agent is availability of MAT and adherence issues. Methadone is only available through OTPs. Buprenorphine is available for administration at OTPs as well as for home and practitioner-waivered office settings. Naltrexone can be prescribed in any setting, without prescriber limitations. The table below provides an overview of the currently available MATs.

References

1. The American Society of Addiction Medicine (ASAM). The ASAM national practice guideline for the use of medications in the treatment of addiction involving opioid use. https://www.asam.org/docs/default-source/practice-support/guidelines-and-consensus-docs/asam-national-practice-guideline-supplement.pdf. Published June 1, 2015. Accessed November 18, 2019.
2. Substance Abuse and Mental Health Services Administration (SAMHSA). Key substance use and mental health indicators in the United States: Results from the 2017 national survey on drug use and health (HHS Publication No. SMA 18-5068, NSDUH Series H-53). Rockville, MD: https://www.samhsa.gov/data/. Published September 2018. Accessed December 12, 2019.
3. Substance Abuse and Mental Health Services Administration (SAMSHA). Medications for opioid use disorder. Treatment Improvement Protocol (TIP) Series 63, Full Document. HHS Publication No. (SMA) 19- 5063FULLDOC. Rockville, MD: https://store.samhsa.gov/system/files/tip63_fulldoc_052919_508.pdf. Published 2018. Revised 2019. Accessed December 12, 2019.
4. U.S. Department of Health & Human Services Substance Abuse and Mental Health Services Administration (SAMHSA). Medication and counseling treatment. https://www.samhsa.gov/medication-assisted-treatment/treatment . Updated May 7, 2019. Accessed November 18, 2019.
5. National Institute of Health-National Institute on Drug Abuse. Medications to treat opioid use disorder: Overview. https://www.drugabuse.gov/publications/research-reports/medications-to-treat-opioid-addiction/overview. Updated June 2018. Accessed November 18, 2019.
6. Methadone [package insert]. Columbus, OH. Boehringer Ingelheim Roxane, Inc.; 2008.
7. National Institute of Health-National Institute on Drug Abuse. Medications to treat opioid use disorder—how do medications to treat opioid use disorder work? https://www.drugabuse.gov/publications/research-reports/medications-to-treat-opioid-addiction/how-do-medications-to-treat-opioid-addiction-work. Update June 2018. Accessed November 24, 2019.
8. Buprenorphine hydrochloride sublingual tablet [package insert]. Eatontown, NJ. Hikma Pharmaceuticals USA Inc.; April 2019.
9. Management of opioid dependence. Pharmacist’s Letter. 2018. Clinical Resource No.: 340106 [Electronic version]. Available at: http://www.pharmacistsletter.com. Accessed December 11, 2019.
10. Suboxone [package insert]. North Chesterfield, VA. Indivior Inc.; October 2019.
11. Vivitrol [package insert]. Waltham, MA. Alkermes, Inc.; July 2019.
12. Naltrexone hydrochloride tablet, film coated [package insert]. Durham, NC. Accord Healthcare, Inc.; February 2017.
13. Methadone hydrochloride powder [package insert]. St. Louis, Missouri. Mallinckrodt; December 2016.

Prepared by:
Lori Uildriks, PharmD, BCPS
Wendy Ko, PharmD
Clinical Instructors
University of Illinois at Chicago College of Pharmacy

The information presented is current as of December 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.