Tag: alcohol use disorder

Gabapentin/Neurontin The Most Common off-Label Prescription in Psychiatry 

Introduction 

Gabapentin is approved by the FDA for three specific indications to prevent and control partial seizures, relieve nerve pain following shingles (post herpetic neuralgia), and to treat moderate to severe restless leg syndrome. Unfortunately, less than 1% of the prescriptions written for gabapentin are for the above listed FDA approvals. In fact, much of the off-label prescribing of gabapentin is done for the treatment of psychiatric and substance use disorders. 

We were first alerted to the misleading marketing practices when Pfizer paid a $2.3 billion dollar fine for misleading clinicians through their marketing campaigns. Gabapentin is often thought of as a benign medication that can address symptoms in several common disorders including migraine, chronic pain, fibromyalgia, opioid use disorder, anxiety, and mood disorders. There is now mounting evidence that this medication is not as safe as people once assumed yet many of these prescribing practices continue despite a lack of quality data. Today we will review the safety and efficacy of gabapentin in psychiatric disorders. 

How Does Gabapentin Work?

Gabapentin functions by binding to the alpha-2-delta subunit of voltage gated calcium channels theoretically offering antipain, anticonvulsant, and anxiolytic properties. Although it’s structurally related to the GABA neurotransmitter, there is no direct interaction at GABA A or B receptors. 

Why is there such an increase in Gabapentin prescribing?

In the United States the opioid epidemic drove much of the 64% increase in gabapentin prescriptions 2012 to 2016 as policy makers searched for safer alternatives for pain management. Although lacking any data for the treatment of chronic pain, gabapentin was elevated into this role because of several factors cost, non-controlled status at the federal level, evidence in neuropathic pain, and benign side effect profile. 

However, the risk for gabapentin abuse became apparent as more prescriptions were written. The risk of adverse effects was prevalent when combined with other CNS depressants such as opioids, the exact thing gabapentin set out replace. Approximately 15%-22% of people with an existing substance use disorder abuse gabapentin. Those who overused gabapentin were found to be at increased risk of all-cause or drug-related hospital stay and emergency visits for altered mental status and respiratory depression. 

The off-label prescribing of gabapentin comes with risk. 

Evidence For Use in Anxiety Disorders

The evidence for gabapentin’s use in anxiety disorders comes from only two industry sponsored studies with a total of 172 participants. These are relatively small but well-designed studies that provide limited evidence for the use of gabapentin in anxiety disorders. The first study was in 1999 and looked at the use of gabapentin in social anxiety disorder. 69 participants were randomized to placebo or gabapentin 900-3600 mg/day for 14 weeks. A significant reduction in social anxiety was observed over the 14 weeks and the conclusion was more studies were needed to confirm the results. The other study looked at panic disorder with the same study design and doses of gabapentin, only this time the study lasted 8 weeks. The results indicated gabapentin was effective for severe panic disorder. One thing we notice is neither of these studies focused on generalized anxiety disorder. These results have not been replicated in other studies. 

There is far more evidence for the use of pregabalin in anxiety disorders. In Europe it does have regulatory approval for generalized anxiety disorder. 

Evidence For Use in Bipolar Disorder 

I’m going to burst this bubble and maybe a few other bubbles up front. While some believe all anticonvulsants are “mood stabilizers” they are wrong. Gabapentin has never proven in RCTs to treat mania or any other aspect of bipolar disorder. Likewise, Topiramate and oxcarbazepine have performed poorly in studies assessing their efficacy in bipolar disorder. Simply put, if you are on any of the three medications as primary mood stabilizers it’s best to consider other options such as lithium. 

Evidence For Use In Alcohol and Cannabis Use Disorder  

While addiction treatment is part of the reason we are in this mess with gabapentin, it does have a role in alcohol use disorder (AUD) and cannabis use disorder. The APA added gabapentin as a second line option for AUD because patients who take it for this indication report fewer heavy drinking days with an effect size in the moderate range. There is also some indication that sleep quality improves with gabapentin when patients are cutting back or stopping alcohol use. Alcohol is known to worsen sleep with more frequent nighttime awakenings. The dose range is 300-3600 mg/day in divided doses with many using an average of 900 mg/day. 

Gabapentin is sometimes used for alcohol withdrawal in place of benzodiazepines or phenobarbital. There were a few seizures in the gabapentin groups raising some questions about its use in severe alcohol withdrawal. It’s probably best left for those with less severe dependence. 

Typical Taper for Alcohol Withdrawal

-Start with 1200-2400 mg/day in three divided doses 

-Taper to 600 mg/day over the course or 4-7 days watching for objective signs of alcohol withdrawal and have Ativan available should a seizure develop. 

-Taper by 300 mg/day over the next 2-3 days until the medication is completely off. 

In cannabis use disorder there is limitted data. A single study showed improvement in withdrawal symptoms, reduced cannabis use, and improved executive function but this is not enough to recommend gabapentin on a regular basis in clinical practice. 

It’s important to note gabapentin failed in controlled trials for cocaine, methamphetamine, benzodiazepine, and opioid use disorder. It’s dangerous to combine gabapentin and opioids as discussed earlier in the video. 

A Quick Note on Gabapentin for Chronic back pain 

There are 8 total studies including a systematic review and meta-analysis to assess pain relief in patients with chronic lower back pain a reason many patients tell me they are taking gabapentin for. When you pool this data together, gabapentin demonstrated minimal improvement in pain compared to placebo and had an increase in adverse effects including dizziness, fatigue, and visual disturbances.

Adverse Effects 

The most common side effects include sedation, fatigue, dizziness, imbalance, tremor, and visual changes. 

Dosing

Gabapentin has a short half-life of 6 hours and will need to be dosed three times per day. The kinetics of gabapentin are not linear which means levels in the blood do not rise consistently. For a 900 mg dose, only 540 mg is absorbed. This has to do with the transporters responsible for gabapentin absorption becoming over saturated limiting the amount of medication absorbed. 

Conclusion

While there are very good reasons to consider the use of gabapentin many of the common reasons cited in clinical practice lack the appropriate evidence to support using the medication. It’s best to stick with FDA approved indications and if you are prescribing it off-label consider only using it for the disorders with the most evidence in my opinion that is alcohol use disorder when other treatments have failed. 

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Naltrexone For Opioid Use Disorder and Alcohol Use Disorder

MOA: mu opioid receptor antagonist which prevents exogenous opioids from binding blocking the pleasurable effects of opioid use. Reduces alcohol consumption through modulation of the opioid system, blocking the reinforcing effects of alcohol. 

FDA Indications: alcohol use disorder (oral or injectable), Prevention of relapse to opioid dependence (injection)

Oral Dose: 50 mg/day 

Injection Dose: 380 mg/month 

Caution: patient must be opioid free for 7-10 days prior to starting, conformed with a negative urine 

For alcohol use disorder start with 50 mg/day or 380 mg/month for IM formulation (injection may be preferred because it eliminates the daily decision to take the medication) 

Side effects: nausea, vomiting, decreased appetite, dizziness, injection site reaction, life-threatening side effect is hepatocellular injury in overdose 

Who is it good for?: Those ready to abstain completely from alcohol and for binge drinkers. Good evidence for reducing heavy drinking days. There is some risk of apathy or loss of pleasure with chronic use. The combination of naltrexone and bupropion has been used as a treatment for obesity. 

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Psychotropics: Acamprosate For Alcohol Use Disorder

I received a question asking me to discuss acamprosate as a medication and specifically to address any evidence to support its use to reduce urges to self-harm. I did the research, and this is what I found. 

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Ketamine for Alcohol Use Disorder

In a previous post we discussed the details of Esketamine and the important things patients need to know about the medication. In this post I will discuss the experimental treatment for problematic drinking that involves a single infusion of ketamine. Now I know what you might be thinking. Here we go again, psychiatrists using a medication with potential for addiction on patients already struggling with addiction. It seems like we are just substituting on drug for another drug. Before we get too excited let’s look at the evidence. 

The study looked at 90 heavy drinkers, which all had a score greater than 8 on the Alcohol Use Disorder Identification Test but did not have a formal diagnosis of alcohol use disorder. Bottom line, the people in the study were drinking a lot but were not diagnosed with a use disorder. 

The study participants received a single dose of intravenous (IV) ketamine along with cognitive behavioral therapy (CBT) that focused on “maladaptive reward memories” (MRMs). The idea behind the combination of ketamine and CBT is that it works to reboot the brains reward pathway which has been overrun by excessive drinking. The ketamine infusion sets the stage for the CBT and allows the patient to relearn new more adaptive associations in relation to alcohol. In the study the combination of ketamine and CBT resulted in a 50% reduction in weekly alcohol consumption at 9 months. 

We know the reward system in the brain in suspectable to alterations and disordered function in the presence of substance use. Environmental triggers become associated with drug use, and these associations can be difficult to change. It’s essential to interrupt these reward memories and learn new healthy associations to prevent relapse. This is where the single ketamine infusion comes in. A promising method to break these associations is by interrupting the process of memory reconsolidation. These memories rely on N-methyl D-aspartate receptors (NMDAR) and ketamine acts as an antagonist (blocker) of these receptors. Theoretically ketamine should weaken the memories and make it easier to form new associations. Once the brain is susceptible to forming new associations the patient would be forming new associations with the help of the CBT protocol. Thus, the two therapies work in combination with each other. The ketamine acts as a primer setting the stage for new learning and the CBT helps to form new health associations.

My Take

I actually have some experience with the use of a single ketamine infusion in opioid use disorder along with transcranial magnetic stimulation, and a mindfulness-based CBT protocol. The concept was essential the same, just applied to opioid use disorder. I think treatments like this have potential. Clearly more studies are required before this treatment is available to larger patient populations. Alcohol remains a major cause of morbidity and mortality worldwide. We are looking for treatments that work and are going to enhance the lives of our patients. Time and more research will tell what impact this treatment has on addiction medicine, but it remains an exciting new approach. 

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