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Medication-Assisted Treatment in Individuals with Co-Occurring Substance Use Disorders

Med-10
 
Category: Medication Use 
Published Date: February 2024
  1. INTRODUCTION
     
    1. The proper use of select medications to help treat specific substance use disorders are referred to as Medication Assisted Treatment (MAT).
       
    2. Individuals offered MAT should also be offered other appropriate psychosocial treatment interventions.
       
    3. Prescribers who treat individuals with co-occurring substance use disorders should be familiar with, and include, the use of selected medications recognized as potentially useful for the treatment of substance use disorders. Familiarity should include knowledge of the proper use of each medication, including proper elements of assessment and management.
       
    4. These parameters do not address the use of medications to ameliorate symptoms of substance intoxication or withdrawal.
       
    5. Use of MAT in individuals below 18 years of age should be associated with documentation in the medical record of the benefits outweighing the risks in these populations.
       
  2. PURPOSE
     
    1. To describe those situations in which MAT should be used to treat co-occurring substance use disorders and to discuss potential pharmacological treatment options in DMH programs.
       
  3. ALCOHOL USE DISORDER
     
    1. Individuals who have comorbid alcohol use disorder and do not have contraindications for MAT should be offered treatment trials of either oral naltrexone, Naltrexone Long-Acting Injectable (NLAI), acamprosate, disulfiram, gabapentin, topiramate, or a combination of any of these medications, if clinically appropriate. The sequence of the medication trials should be based upon clinical presentation, co-occurring conditions, medication-specific parameters, and individual preference.
       
    2. For individuals that have been unsuccessfully treated for more than one year by the Los Angeles County Department of Mental Health (DMH) for comorbid alcohol use disorder without the use of MAT, documentation must be provided to explain why the use of MAT is not indicated or has not been initiated.
       
    3. Pharmacotherapy
      1. Naltrexone (oral tablet, NLAI)
        1. Indication and usage
          1. An opioid antagonist that is FDA-indicated for treatment of alcohol use disorder. This medication is generally considered first-line for alcohol use disorder and has been shown to reduce overall alcohol consumption, alcohol cravings, and likelihood of return to heavy drinking1.
        2. Special considerations
          1. Must be abstinent from most opioids for 7-10 days and longer if taking methadone. Cannot be used in those who are currently dependent on opioid agonists or are actively withdrawing from opioids.
          2. Adherence is critical for optimal response - may consider NLAI to address poor adherence.
          3. Avoid oral naltrexone in those with acute liver failure, acute hepatitis, and/or decompensated cirrhosis. NLAI can be used with caution proceeding short trial of oral naltrexone to assess tolerability.
          4. For those with elevated liver enzymes (LFTs), LAI may be used, with oral naltrexone administered for the shortest period necessary to assess tolerability. Can still consider starting if AST/ALT < 5x the upper normal limit with closer monitoring.
        3. For additional information, such as dosages, warnings/precautions, administration, storage, disposal, and considerations in special populations please see package insert.
      2. Acamprosate
        1. Indication and usage
          1. FDA-indicated for treatment of alcohol use disorder.  This medication is best used for individuals who have already achieved some abstinence from alcohol. It has been shown to be effective in the maintenance of abstinence as it is associated with a decreased likelihood of return to drinking1. 
        2. Special considerations
          1. Dose adjustment recommended with renal impairment. Avoid in those with severe kidney dysfunction (CrCl < 30 mL/min).
          2. Adherence to three times daily dosing may limit utility.
          3. Improved outcomes and results in those who have already established abstinence2.
          4. For additional information, such as dosages, warnings/precautions, administration, storage, disposal, and considerations in special populations please see acamprosate package insert. 
      3. Disulfiram
        1. Indication and usage
          1. This is an aversive agent that causes an unpleasant reaction (e.g., flushing, shortness of breath, headache, nausea, tachycardia, and palpitations) when alcohol is consumed.  In the absence of contraindications, it is most effective when used for highly motivated individuals who want to remain in a state of enforced sobriety1.
        2. Special considerations
          1. Adherence is critical for success. Therefore, outcomes are enhanced when using directly observed therapy, which requires clinic staff or family member to observe the client taking each dose3
          2. Must be alcohol free for at least 12 hours or have a 0% Blood Alcohol Concentration before starting and for 14 days after stopping. 
          3. Avoid oral and topical alcohol-containing products including mouthwashes, over-the-counter medications, prescription medications and hand sanitizers.
          4. Use with caution in those who have chronic and acute nephritis.
          5. Avoid in hepatic cirrhosis or insufficiency.
        3. For additional information, such as dosages, warnings/precautions, administration, storage, disposal, and special populations please see disulfiram package insert.
           
          1. Gabapentin
            1. Indication and usage
              1. This is an off-label use for alcohol use disorder. Gabapentin has been found to improve drinking outcomes, insomnia and dysphoria4.  This medication is generally considered a second-line for treatment of alcohol use disorder, when acamprosate and naltrexone are ineffective or contraindicated, or in the presence of a co-morbid disorder where gabapentin may confer additional benefits1.
              2. Recommended starting dose is 300-600mg TID to QID, titrated as tolerated to minimum target dose of 1800mg total per day4.
            2. Special considerations
              1. Dose adjustment recommended with renal impairment.  
              2. Higher doses and those with three (3) or more days of abstinence have been associated with more robust impact on drinking outcomes4.
              3. Caution in use with concurrent opioid or Central Nervous System depressants given increased risk of respiratory depression5. 
              4. Caution in use with elderly or other individuals at increased risk for falls.
            3. For additional information, such as dosages, warnings/precautions, administration, storage, disposal, and considerations in special populations please see gabapentin package insert.
          2. Topiramate
            1. Indication and usage
              1. This is an off-label use for alcohol use disorder. Topiramate demonstrated largest effect in achieving abstinence and reducing alcohol consumption6. This is a second-line treatment of alcohol use disorder, when acamprosate and naltrexone are ineffective or contraindicated, or in the presence of a co-morbid disorder where topiramate may confer additional benefit1.
              2. Recommended starting dose is 25mg nightly with slow titration for better tolerability. 
            2. Special considerations
              1. Dose adjustment recommended with renal impairment. 
            3. For additional information, such as dosages, warnings/precautions, administration, storage, disposal, and considerations in special populations please see topiramate package insert. 
  4. OPIOID USE DISORDER
     
    1. Individuals who have comorbid opioid use disorder and do not have contraindications for MAT should be educated that MAT is considered a first-line therapy for opioid use disorder. FDA-approved treatments include methadone, SL buprenorphine, SL buprenorphine/naloxone, subcutaneous extended-release buprenorphine, and NLAI. Selection of medication shall be based upon an individual’s clinical characteristics and preferences. 
       
    2. For individuals with comorbid opioid use disorder who have not been initiated on or referred for MAT, documentation must be provided to explain why the use of MAT is not indicated or has not been initiated.
       
    3. Individuals receiving/maintaining MAT for opioid use disorder, who wish to discontinue treatment, should be made aware of the risks associated with opioid overdose, and especially the increased risk of overdose death if they return to illicit opioid use due to diminished tolerance.
       
    4. Pharmacotherapy
      1. Sublingual (SL) buprenorphine / naloxone
        1. Indication and usage
          1. This is a partial mu opioid agonist that is an effective treatment for opioid use disorder and is generally considered first-line treatment.
        2. Special considerations
          1. There is a risk of precipitated withdrawal during initiation of buprenorphine in individuals who are physically dependent on opioids. Buprenorphine is best initiated after an individual begins to show signs and symptoms of moderate opioid withdrawal (Clinical Opiate Withdrawal Scale [COWS] Score ≥13) at minimum to reduce risk of precipitating opioid withdrawal7. 
          2. For patients with previous issues of precipitated withdrawal from standard buprenorphine induction, may be reasonable to consider use of a microdose induction regimen8,9.
          3. For users of fentanyl, clients may require longer periods of time before induction, lower doses at initiation (such as 0.5 – 1 mg of buprenorphine), and higher levels on the COWS scale (≥ 17) before induction to avoid precipitated withdrawal10.
          4. For users of long-acting opioids, such as methadone, the time between last use and induction may require waiting 72 hours or longer, depending on the dose used.
          5. SL buprenorphine/naloxone has lower potential of misuse and diversion compared to the SL buprenorphine monoproduct.
          6. Duration of maintenance therapy is dependent on clinical judgment, patient presentation and other external factors (e.g. psychosocial stressors, engagement in programming, motivation, etc.). Evidence has shown that those on buprenorphine long-term (> 12 months) have improved outcomes7,11.
          7. There is a Risk Evaluation and Mitigation Strategy (REMS) program to educate on and mitigate risks of accidental overdose or misuse. Please see REMS elements for additional information.
          8. Buprenorphine/naloxone can safely be used in pregnancy, however, buprenorphine monoproduct has been recommended during pregnancy to prevent any potential prenatal exposure to naloxone, especially if injected7,12. Please see SL buprenorphine.
        3. For dose conversion to/from other buprenorphine products, please see Buprenorphine Bioequivalence Chart7.
        4. For additional information, such as dosages, warnings/precautions, administration, storage, disposal, and special populations please see SL buprenorphine-naloxone package insert. 
      2. Subcutaneous extended-release buprenorphine
        1. Indication and usage
          1. May be used for individuals who have already achieved stability with another buprenorphine formulation.  
          2. May be preferred over SL buprenorphine when concerns for misuse or poor adherence are present.
        2. Special considerations
          1. Not recommended in those with moderate to severe hepatic impairment. If patients begin to experience symptoms of hepatic impairment within two (2) weeks of injection, depot can be surgically excised under local anesthesia.
          2. For duration of maintenance therapy, please see SL buprenorphine. 
          3. Subcutaneous extended-release buprenorphine (Sublocade) is under a REMS program and can only be ordered/distributed from certified pharmacies in a restricted distribution program. As such, prescribers are to send prescriptions to a REMS certified pharmacy and coordinate medication delivery to the clinic for secure storage (controlled substance) until direct administration to the client. Medication should NEVER be dispensed directly to a patient. The program was created to ensure abdominal subcutaneous injection only by a healthcare provider because of the risk of serious harm or death that could result from intravenous self-administration. Please see REMS elements for additional information.
          4. For dose conversion to/from other buprenorphine products, please see Buprenorphine Bioequivalence Chart7.
        3. For additional information, such as dosages, warnings/precautions, administration, storage, disposal, and special populations please see subcutaneous extended-release buprenorphine package insert.
      3. SL buprenorphine
        1. Indication and usage
          1. Should be reserved for hospital-based detoxification. However, may be used in individuals who are pregnant or have validated contraindications to naloxone. 
        2. Special considerations
          1. See SL buprenorphine / naloxone 
          2. Induction with buprenorphine in pregnancy should be limited to providers with experience with Opioid Use Disorder (OUD) management in pregnancy or in co-management with provider with experience in obstetrical care. May consider referral to inpatient treatment for higher level of care and monitoring given pregnancy risk associated with precipitating opioid withdrawals, especially in mid-late term pregnancies. 
        3. For dose conversion to/from other buprenorphine products, please see Buprenorphine Bioequivalence Chart
        4. For additional information, such as dosages, warnings/precautions, administration, storage, disposal, and special populations please see SL buprenorphine package insert
      4. Naltrexone LAI
        1. Indication and usage
          1. Can be effective for highly motivated individuals who have achieved abstinence. 
        2. Special considerations
          1. Individuals must be abstinent from opioids for 7-10 days prior to initiating naltrexone to minimize risk of precipitated withdrawal. Individuals must be abstinent for a longer duration if transitioning from methadone to naltrexone. 
          2. May consider administering oral naltrexone prior to initiating NLAI if tolerability or the risk of precipitated withdrawal is uncertain.
          3. There is no recommended length of therapy with naltrexone LAI for OUD.  Duration is dependent on clinical judgment, patient presentation and other external factors (e.g. psychosocial stressors, engagement in programming, motivation, etc.). However, there is evidence that those on MAT for a longer duration have better outcomes7. 
          4. There is a REMS program to ensure clients are educated by their healthcare providers about severe injection site reactions associated with NLAI. 
        3. For additional information, such as dosages, warnings/precautions, administration, storage, disposal, and special populations please see NLAI package insert.
      5. Methadone
        1. Indication and usage
          1. This is a slow-acting, full opioid agonist that may be effective for individuals who have been unable to achieve stability with buprenorphine, who have previously been prescribed methadone, or who may need the structure of an Opioid Treatment Program (OTP). 
          2. Can only be administered through OTPs. 
          3. Individuals may be referred to a local OTP. Local OTPs can be identified using the OTP Directory: http://dpt2.samhsa.gov/treatment   
        2. Special Considerations
          1. Patients on methadone are typically treated for a minimum of 12 months. Long-term therapy is often needed given high relapse rate in those who drop out of treatment.  Evidence has shown that those on MAT for a longer duration have better outcomes7.
             
    5. Buprenorphine Bioequivalence Chart7
Suboxone
SL Film or Tablet
Zubsolv
SL Tablet
Bunavail
Buccal Film
Cassipa
SL Film
Subutex
SL Tablet
Sublocade
monthly SC injection
Brixadi
IM or deep 
SC injection
Dose reported as buprenorphine/naloxone
Dose reported as buprenoprhine
 
2 mg / 0.5 mg
1.4 mg / 0.36 mg
--
--
2 mg
--
--
4 mg / 1 mg
2.9 mg / 0.71 mg
2.1 mg / 0.3 mg
--
4 mg
--
--
8 / 2 mg
5.7 mg / 1.4 mg
4.2 mg / 0.7 mg
--
8 mg
100 mg
16 mg SC qweekly
or 64mg SC q monthly
12 mg / 3 mg
8.6 mg / 2.1 mg
6.3 mg / 1 mg
--
12 mg
--
--
16 mg / 4 mg
11.4 mg / 2.9 mg
(2) 4.2 mg / 0.7 mg
16 mg / 4 mg
16 mg
--
24 mg SC qweekly
or 96 mg SC q monthly
24 mg / 6 mg
(2) 8.6 mg / 2.1 mg
(2) 6.3 mg / 1 mg
--
24 mg
300 mg
32 mg SC qweekly
or 128 mg SC q monthly
*Patients should be inducted on Sublocade per manufacturer guidance. This reflects dose equivalency for monthly maintenance dose of Sublocade from other formulations of buprenorphine given once a day. 
 
  1. COCAINE USE DISORDER
     
    1. Pharmacotherapy

      Currently, there are no FDA-approved medications or published treatment guidelines for the treatment of cocaine use disorder. However, there are studies to support possible benefits with certain therapeutic drugs, though more robust trials are still needed13.
      1. Topiramate
        1. Indication and usage
          1. Evidence indicates that topiramate may be effective at sustaining abstinence but is not associated with retention in treatment14,15,16. Topiramate may be especially helpful for those with cocaine use and impulse control problems17.
        2. Special considerations
          1. Please see special considerations for topiramate.
        3. For additional information, such as dosages, warnings/precautions, administration, storage, disposal, and considerations in special populations please see topiramate package insert. 
      2. Bupropion
        1. Indication and usage
          1. If not contraindicated, may have some benefits in sustaining abstinence but is likely more effective for those with comorbid depression and/or ADHD12,18.
        2. Special considerations
          1. Although uncommon, there are anecdotal reports that bupropion may be misused19. 
          2. Bupropion may cause a false-positive amphetamine result on urine drug testing20,21.
        3. For additional information, such as dosages, warnings/precautions, administration, storage, disposal, and considerations in special populations please see bupropion package insert. 
      3. Antipsychotics
        1. Indication and usage
          1. Have shown mixed results historically for cocaine use disorder but may improve treatment retention. Consider these effects when treating comorbid mental disorder with antipsychotics12.
        2.  For additional information, such as dosages, warnings/precautions, administration, storage, disposal, and considerations in special populations please see package insert.
           
  2. METHAMPHETAMINE USE DISORDER
     
    1. Pharmacotherapy

      Currently, there are no FDA-approved medications or published treatment guidelines for the treatment of methamphetamine use disorder. However, there are studies to support possible benefits with certain therapeutic drugs, though more robust trials are still needed23.
      1. Bupropion + NLAI
        1. Indication and usage
          1. Has been shown to improve abstinence from methamphetamine in a randomized control trial (RCT); the combination of bupropion and extended-release naltrexone is preferred over bupropion alone24. 
        2. Suggested dosing24
          1. Naltrexone, extended release 380 mg IM (gluteal) every 3 weeks + Bupropion XL 450 mg PO daily
        3. Special considerations
          1. See special considerations for NLAI.
          2. See special considerations for bupropion.
        4. For additional information, such as dosages, warnings/precautions, administration, storage, disposal, and considerations in special populations please see package insert.
      2. Mirtazapine 
        1. Indication and usage
          1. Has shown modest reductions in methamphetamine use and may help with methamphetamine withdrawal symptoms25,26.
        2. Suggested dosing
          1. Mirtazapine 30mg PO given at bedtime. 
        3. Special considerations
          1. Lower doses should be considered in geriatric populations.
        4. For additional information, such as dosages, warnings/precautions, administration, storage, disposal, and considerations in special populations please see mirtazapine package insert.
      3. Stimulants
        1. Indication and usage
          1. There are limited mixed evidence that psychostimulants may reduce methamphetamine use. Because of limited evidence and potential risk, psychostimulants are not recommended as first-line treatment for methamphetamine use disorder and should only be started by an addiction specialist.
             
  3. CANNABIS USE DISORDER
     
    1. Medications 

      Currently, there are no FDA-approved medications or published treatment guidelines for the treatment of cannabis use disorder. However, there are studies to support possible benefits with certain therapeutic drugs, though more robust trials are still needed.
      1. Gabapentin
        1. Indication and usage
          1. One pilot study found that gabapentin was associated with decreased marijuana use, improved withdrawal symptoms including craving and disturbances in mood and sleep as well as improved executive functioning27. 
          2. Suggested dosing27
            1. Gabapentin 300mg PO QID (1200mg/day) but should be titrated based on clinical presentation.
          3. For additional information, such as dosages, warnings/precautions, administration, storage, disposal, and considerations in special populations please see gabapentin package insert.
      2. SSRI and selective norepinephrine reuptake inhibitors (SNRI)
        1. Indication and usage
          1. Limited evidence for maintenance treatment for cannabis use disorder but may be considered. While SSRIs and SNRIs have not shown efficacy in treating cannabis use disorders, they can be helpful for comorbid affective symptoms . 
        2. For additional information, such as dosages, warnings/precautions, administration, storage, disposal, and considerations in special populations please see package insert. 
           
  4. LABORATORY MONITORING
     
    1. General laboratory monitoring of individuals taking MAT medications should be determined by the clinical situation, including the type of medication, health risk factors, duration of treatment, and concurrent general medical and mental health condition. Please note that while there are recommendations for baseline labs for certain medications, it should not preclude MAT treatment if no aberrant concerns/contraindications are present. Suggested laboratory monitoring include:
      1. Acamprosate
        1. Renal function at baseline and as clinically indicated
      2. Buprenorphine, Buprenorphine / Naloxone 
        1. Urine drug screen prior to initiation and at random intervals thereafter
        2. Liver function tests (LFT) prior to initiation and periodically 
        3. HIV and hepatitis testing may be considered for those with risk factors
        4. Pregnancy test prior to initiation, if applicable
      3. Disulfiram 
        1. LFT at baseline and after 10-14 days of treatment 
        2. Complete Blood Count (CBC) at baseline
        3. Serum Chemistry at baseline
      4. Gabapentin
        1. Periodic renal function 
        2. Pregnancy test prior to initiation, if applicable
      5. Naltrexone
        1. Urine drug screen to rule out opioid use prior to therapy
        2. LFT at baseline and periodically
        3. HIV and hepatitis testing may be considered for those with risk factors
        4. Pregnancy test prior to initiation, if applicable
      6. Topiramate
        1. Periodic renal function
        2. Electrolytes, including sodium bicarbonate at baseline and periodically
        3. Ammonia levels, if altered mental status occurs
      7. For other MAT medications not listed here, please see package insert for recommendations. 
         
  5. PSYCHOSOCIAL TREATMENT AND SUPPORT
     
    1. Individuals who are receiving MAT should be offered all other relevant clinical services, including both psychotherapy and medication services, and comprehensive psychosocial sobriety / abstinence maintenance interventions. 
      1. Psychosocial treatment may include services such as contingency management, outpatient treatment, or residential treatment.
      2. Consider and recommend recovery support as appropriate, such as:
        1. 12-step meetings, such as Alcoholics Anonymous (AA), Narcotic Anonymous (NA), and others
        2. Smart Recovery
        3. Sober living environment
      3. Additional substance abuse services are available through Los Angeles County Substance Abuse Prevention and Control via Substance Abuse Service Helpline (SASH) helpline at 844-804-7500. 
         
  6.  APPENDIX
     
    1. Package Inserts
      3. Buprenorphine-Naloxone [package insert]. Parsippany, NJ: Teva Pharmaceuticals; 2022. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=6cccf229-9611-4b6f-8f1b-acc8ff1ed3f8&type=display 
      10. Topiramate [package insert]. Central Islip, NY. Ascent Pharmaceuticals; 2021. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=41a5a961-8756-464c-aef3-22f2c9047609&type=display 
      11. Vivitrol (naltrexone long-acting injection) [package insert]. Waltham, MA: Alkermes; 2022. https://www.vivitrol.com/content/pdfs/prescribing-information.pdf 
         
    2. REMS Programs
      2. Sublocade REMS Program. Indivior Inc.; 2022.  https://www.sublocaderems.com/#Main 
      3. Vivitrol (naltrexone for extended-re lease injectable suspension) REMS Program. Alkermes; 2016. https://www.accessdata.fda.gov/drugsatfda_docs/rems/Vivitrol_2016-05-17_REMS_full.pdf 
         
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