What are the risks and guidelines for using lorazepam (Ativan) in a patient with a history of substance abuse who is taking naltrexone (opioid antagonist) for opioid or alcohol dependence?

Lorazepam and Naltrexone: Safety and Clinical Considerations

Lorazepam can be safely used alongside naltrexone in patients with substance use disorder, and in fact, benzodiazepines may improve treatment outcomes by reducing the hyperexcitability and insomnia that can occur with naltrexone therapy.

No Direct Drug Interaction Between Lorazepam and Naltrexone

• There is no pharmacological contraindication to combining lorazepam (a benzodiazepine) with naltrexone (an opioid antagonist), as they act on completely different receptor systems—GABA-A receptors versus mu-opioid receptors 1.
• The FDA label for naltrexone does not list benzodiazepines as contraindicated or requiring special caution, though it notes that studies evaluating interactions between naltrexone and drugs other than opiates have not been systematically performed 1.
• Research evidence actually supports combining naltrexone with benzodiazepines: a controlled study demonstrated that naltrexone plus the benzodiazepine prazepam was significantly more effective than naltrexone alone in maintaining opioid abstinence over 6 months (12 of 14 patients remained opioid-free versus 6 of 14 with naltrexone alone) 2.

Benzodiazepines May Enhance Naltrexone Treatment Adherence

• Naltrexone is associated with insomnia and "hyperexcitability" that can result in treatment withdrawal, and benzodiazepines can mitigate these adverse effects 2.
• In the study combining naltrexone with prazepam, patients also showed significantly higher rates of remaining free from cannabis use compared to naltrexone alone, suggesting improved overall substance use outcomes 2.
• The combination addresses a common pitfall: naltrexone's side effect profile can lead to poor medication compliance, which is the primary limitation of oral naltrexone therapy 3.

Critical Safety Considerations in Substance Use Disorder Patients

Opioid-Free Status is Mandatory Before Naltrexone Initiation

• Patients must be completely opioid-free (including tramadol) for a minimum of 7-10 days before starting naltrexone to prevent precipitated withdrawal, which can be severe enough to require ICU admission 1.
• For patients transitioning from buprenorphine or methadone, they may be vulnerable to precipitated withdrawal for as long as 2 weeks, and a 3-5 week transition protocol is recommended 4, 1.
• Precipitated withdrawal symptoms include confusion, somnolence, visual hallucinations, significant fluid losses from vomiting and diarrhea requiring IV fluids, and can occur within 5 minutes of naltrexone ingestion 1, 5.

Benzodiazepine Use Requires Caution in Substance Use Disorder

• While lorazepam can be used with naltrexone, clinicians must exercise caution when prescribing benzodiazepines to patients with a history of substance abuse, as benzodiazepines themselves carry abuse potential 6.
• The CDC guidelines emphasize that clinicians should screen for drug and alcohol use disorders and carefully consider whether benefits outweigh risks when prescribing controlled substances to patients with substance use history 6.
• Short-term, time-limited use of lorazepam is preferable to minimize dependence risk, particularly during the initial naltrexone stabilization period when insomnia and anxiety may be most pronounced 2.

Clinical Algorithm for Combined Use

Step 1: Verify Opioid-Free Status

• Confirm patient has been opioid-free for minimum 7-10 days (short-acting opioids) or 14 days (buprenorphine/methadone) 1.
• Consider naloxone challenge test if any question of occult opioid dependence, though this is not completely reliable 1.
• Review urine drug screen, noting that naltrexone metabolites can cause false-positive oxycodone results requiring confirmatory testing 7.

Step 2: Assess for Contraindications to Naltrexone

• Obtain baseline liver function tests, as naltrexone carries hepatotoxicity risk, particularly in patients with alcoholic liver disease 1.
• Screen for depression and suicidality, as these have been reported with naltrexone use 1.
• Ensure patient is not taking opioid-containing medications (analgesics, antidiarrheals, antitussives) 1.

Step 3: Initiate Naltrexone with Monitoring Protocol

• Start with 25 mg naltrexone on day 1, advancing to 50 mg daily if no withdrawal signs occur 1.
• Monitor closely for precipitated withdrawal symptoms in the first 48 hours 1.
• Provide patient with naltrexone identification card and counsel on increased overdose risk if opioids are used after treatment 1.

Step 4: Consider Adjunctive Lorazepam for Specific Indications

• If patient develops insomnia, anxiety, or hyperexcitability on naltrexone, consider lorazepam 0.5-2 mg as needed or scheduled for 2-4 weeks 2.
• Use lowest effective dose for shortest duration necessary to minimize dependence risk 6.
• Taper benzodiazepine once naltrexone side effects stabilize (typically within first month) 2.

Step 5: Ensure Comprehensive Treatment Program

• Naltrexone is effective only when combined with counseling and psychosocial support—medication alone is insufficient 1, 8.
• Implement compliance-enhancing techniques, as poor adherence is the primary limitation of oral naltrexone 8, 3.
• Consider extended-release injectable naltrexone (Vivitrol) if oral compliance is problematic 3.

Special Warnings and Common Pitfalls

Do Not Use Naltrexone If:

• Patient shows any clinical signs of opioid withdrawal 1.
• Patient has decompensated cirrhosis or acute hepatitis 1.
• Patient requires opioid analgesics for pain management, as naltrexone blocks their effectiveness 1.
• Patient is pregnant (offer buprenorphine or methadone instead) 9.

Avoid These Errors:

• Never assume a negative urine screen or naloxone challenge guarantees safety—precipitated withdrawal can still occur, particularly when transitioning from buprenorphine 1.
• Do not prescribe naltrexone to alcohol-dependent patients without first assessing for underlying opioid use, as precipitated withdrawal has occurred when prescribers were unaware of concurrent opioid use 1.
• Do not fail to warn patients about increased overdose risk if they discontinue naltrexone and return to opioid use, as tolerance will be reduced 1.
• Avoid combining naltrexone with other potentially hepatotoxic medications (like disulfiram) unless benefits clearly outweigh risks 1.

Monitor for These Complications:

• Hepatotoxicity: obtain liver function tests every 3-6 months and discontinue if signs of acute hepatitis develop 1.
• Depression and suicidality: monitor closely and educate family members to watch for these symptoms 1.
• Precipitated withdrawal: be prepared to manage symptomatically with non-opioid medications including alpha-2 agonists like clonidine 4.

Evidence Quality and Practical Considerations

The recommendation to combine benzodiazepines with naltrexone is supported by a small but well-designed randomized controlled trial showing improved outcomes 2. However, this must be balanced against CDC guidelines emphasizing caution with controlled substances in substance use disorder populations 6. The FDA label provides clear safety parameters for naltrexone use but does not specifically address benzodiazepine combinations 1.

In clinical practice, short-term lorazepam use during naltrexone initiation represents a reasonable risk-benefit balance for patients experiencing significant insomnia or anxiety that threatens treatment adherence, provided close monitoring and time-limited prescribing are implemented 2, 6.