Is Naltrexone-Topiramate Combination Therapy Better For Alcohol Use Treatment?

Naltrexone-topiramate combination therapy is used off-label to hopefully expand the benefits, but clinical research on the effectiveness is mixed.

What You’ll Learn:

• What naltrexone and topiramate are used for individually.
• Why people use combination naltrexone-topiramate therapy.
• Clinical data on whether or not naltrexone-topiramate combinations are effective.
  
  • Evidence on the effects of combination therapy.
  • Data on how combination therapy compares to monotherapies.
• How safe it is to take naltrexone and topiramate together.
  
  • Individual side effects and safety considerations for each medication.
  • Overlapping side effects for naltrexone and topiramate.

There are two primary reward pathways in the brain that are related to alcohol consumption and behaviors: the opioid-dopamine and the GABA-glutamate pathways. Most medications that reduce alcohol use act on one of the pathways. The idea behind combining certain medications is that both reward pathways will be influenced at once improving the outcomes.

One of the medication combinations that is being used today is a naltrexone-topiramate combo. The combination therapy acts on both reward pathways and each medication is proven effective on its own, but it’s still unclear if using naltrexone and topiramate together provides an added benefit.  

How the Medications Work Individually as Monotherapies

Naltrexone and topiramate have some key similarities and differences. To understand how and why naltrexone is combined with topiramate it helps to first know the mechanisms for each medication individually. 

Naltrexone

As one of the few FDA-approved medications for alcohol use disorder (AUD), Naltrexone is considered a first-line monotherapy. It’s an opioid receptor antagonist that blocks μ-opioid receptors and reduces dopamine release in the reward regions of the brain when alcohol is consumed. The reduction in dopamine blunts the buzzed feeling, which helps to reduce alcohol cravings, heavy drinking and relapse.

Topiramate

Topiramate is not an FDA-approved medication for AUD. It is, however, an approved anticonvulsant medication for migraines and epilepsy. The medication increases GABA-mediated inhibitory transmission and suppresses AMPA/kainate glutamate receptors. 

By inhibiting the excitatory glutamate signaling and improving GABA’s inhibition response the theory is that alcohol cue reactivity and cravings will be reduced. There have been research studies that have found topiramate could help in reducing alcohol cravings and heavy drinking.

Why Naltrexone and Topiramate Are Sometimes Combined

The goal with naltrexone-topiramate combination therapy is to simultaneously alter different neural pathways that are associated with alcohol use. In theory, doing so could have potential benefits:

More symptoms are treated at once: While naltrexone and topiramate provide similar benefits, by using both together there’s the possibility for a broader range of effects that work synergistically. It’s also believed that combination therapy may be superior in individuals who only have a partial response to naltrexone or topiramate. 

Strong effectiveness with moderate doses of each medication to avoid side effects: Typically, the doses for naltrexone and topiramate are lower when the medications are combined compared to when they are used separately while still reducing alcohol cravings and heavy drinking. The lower doses help reduce the likelihood of side effects that could impede treatment. 

Clinical Data on the Use of Naltrexone-Topiramate Combination Therapy

If you consider how the two medications work, there are mechanistic reasons to believe that combining them would be beneficial. There are also a few animal studies that suggest this could be true. But when it comes to robust clinical studies involving humans and studies that directly compare this combination therapy to the monotherapies, the data is scarce. 

One study involving alcohol-preferring rats found that a low-dose combination of topiramate (10 mg/kg) and naltrexone (1 mg/kg) significantly reduced ethanol consumption. When examining each drug alone at those doses there wasn’t a significant effect. The same study also noted that combination therapy reduced ethanol reinforcement more selectively than naltrexone alone.

However, if the same is true for humans is largely unknown. There’s a lack of clinical research making it impossible to draw a clear conclusion. 

Current high-level reviews support the use of oral naltrexone 50 mg/day and acamprosate as first-line pharmacotherapies for AUD. At the moment, topiramate is often considered a promising second-line option, but the combination of naltrexone and topiramate isn’t yet a part of standard guidelines for AUD treatment.

Safety Considerations When Combining Naltrexone and Topiramate

One of the reasons that naltrexone and topiramate are used in combination is to hopefully get the benefits without the side effects. While it may not reduce drinking any more than taking naltrexone on its own, it also shouldn’t increase the risk. 

There is no known pharmacokinetic interaction between naltrexone and topiramate. That means the side effects are basically the same for each individual medication and there isn’t an increased risk in experiencing them. Of course, overall there are more potential side effects when you are taking both medications at the same time. 

Naltrexone side effects: 

• Are considered rare, with nausea being the most common side effect. 
• Tend to be mild to moderate in severity.
• Typically happens at the start of treatment and resolve within 1-2 weeks.
• Are dose dependent - the higher the naltrexone dose the more likely you are to experience side effects.

Topiramate side effects:

• Are most notable for their cognitive impact in decreasing attention and slowed processing.
• Appear to be dose dependent with higher doses increasing the likelihood of side effects.
• Sedation increases for those who drink alcohol while taking topiramate. 

Patients taking both medications need to be aware of the overlapping side effects that could be more pronounced with combination therapy. 

• Fatigue
• Dizziness
• Cognitive impairment
• Mood changes

The biggest concern is with patients that have a history of depression or bipolar disorder. It’s very rare, but both naltrexone and topiramate can have a negative impact on mood. Close monitoring by a health professional is needed to identify mood changes and ensure patient safety. 

If you’re considering the use of medications for alcohol treatment it’s important to discuss your options with a qualified clinician. Choose Your Horizon makes it easy for anyone to get a free alcohol use assessment, meet virtually with a clinician and get a naltrexone online prescription that can be used on its own or as a part of a treatment plan. 

Today, you don’t have to struggle on your own. You can find the support you need to take control of your drinking.