Does gabapentin increase risk of opioid use disorder? Are the two correlated, causal, or something else entirely?

Gabapentin and Opioid Use Disorder: Correlation, Causation, or Callowness?

Gabapentin has a difficult time staying out of the spotlight these days. Whether for good or bad press, this poorly understood, but increasingly prescribed anticonvulsant continues to stand out among the rest of the medications used to treat pain. Namely, despite a growing list of concerns around its safety and efficacy, it seems to be the new go to analgesic often used to replace opioids altogether.

Though, even that makes very little sense.

According to a new “study” by EPIC, gabapentin is now apparently associated with increasing risk of opioid use disorder when combined with opioid prescriptions.


Let’s try to dive deeper into this seemingly correlated, but not causal relationship.


How does gabapentin work?

Gabapentin has been around for decades, first approved in 1993 under the brand name Neurontin to treat partial seizures. However, gabapentin was eventually approved for nerve pain from shingles years later. It is often used off-label to treat several other nerve pain related issues, including diabetic neuropathy, nerve pain from spinal cord injury, fibromyalgia, and others.

The anticonvulsant works by primarily binding to the alpha-2-delta subunit of voltage-gated calcium channels along neuronal membranes. A cascade of intracellular events follows this, leading to a reduction in neurotransmitter release into the synapse. Ultimately, this allows for membrane potential stabilization and thus the potential resolution neuropathic pain signals.

Remember, even though gabapentin looks like gamma-aminobutyric acid (GABA) and sounds like GABA, doesn’t mean it has GABA activity!

Due to the mechanism of gabapentin, the most common side effects include dizziness and somnolence, though can include edema, nausea, vomiting, word loss, and confusion, amongst others. A more concerning side effect are respiratory depressant effects, especially when used with opioids, alcohol, or other respiratory depressants. Finally, there does appear to be some increasing risk of misuse of gabapentin, potentially used to potentiate the ‘high’ effect from commonly abused substances.


Gabapentin increases risk of opioid use disorder?

According to a recent news release by EPIC, another side effect of gabapentin has been reportedly discovered. The group found that patients taking gabapentin in combination with opioids were 47% more likely to develop OUD or experience an opioid-related overdose than patients who are solely prescribed opioids. They also found this risk to be increased across all comorbid factors assessed. Finally, the authors noted that patients with gabapentin prescriptions both before and after their opioid prescription had the greatest risk of OUD or opioid overdose.

Now, little is actually stated in the news article detailing all of this data, and really, there is almost no information around how the data was collected, assessed, and statistically evaluated. There’s barely any detail of the trial at all. The only inkling of information that they noted was that they “matched 1.5 million patients with both gabapentin and opioid prescriptions to 2.1 million patients with only opioid prescriptions and evaluated their likelihood of being diagnosed with OUD or having an opioid-related overdose”. Matching occurred by prescribed opioid amount, age, at least one shared comorbidity, and length of time in the observation period.

Frankly, all of this sounds like performative dog doo-doo.

Let’s examine it.

The first and most egregious problem with this data is the lack of transparency, explanation of methods, statistical analysis, and, really, lack of almost anything about the trial itself. The patient selection process is completely unknown (was there actual randomization or did they cherry pick patients?). The entire “study” is retrospective in nature, as they appeared to have just looked at massive cohorts of generalized EPIC claims data (which itself has substantial flaws). There appears to have been no statistical analysis whatsoever (likely because statistical analysis was unable to be performed). We also have no information whether patients were prescribed either gabapentin or an opioid chronically or acutely, which could make an important difference.

Additionally, the specific endpoint was assessing risk of OUD OR overdose. Something just doesn’t seem right about that… Oh, that’s right! There has already been several well-documented and well-designed studies showing opioids combined with gabapentin increases risk of overdose and opioid-related respiratory depression. It is naïve, negligent, and just plain dumb to have used a combined endpoint (OUD or overdose) to assess risk of OUD by itself for an individual drug. It’s actually more of an impossibility to do that, given there is no way to weight how much the risk increase of opioid overdose when gabapentin and opioids were combined played in the combined outcome.

Of course, using diagnostic claims data to retrospectively evaluate OUD from any cause is exceedingly callow as well. OUD is one of the most misdiagnosed types of diseases that humans can be afflicted with (some studies showing misdiagnosis of OUD as high as 30%), and even the criteria for diagnosis has changed a multitude of times over the years. Providers often misinterpret ‘opioid dependence’ as solely OUD, and can be quick to label patients with OUD (or drug-seeking) when they do not actually qualify for the diagnosis itself. This makes the entire data set (that was already terribly flawed to begin with) invalid. The diagnosis of OUD was never verified in any of these millions of patients!


The bottom line on gabapentin increasing risk of OUD

The bottom line from this incredibly flawed, poorly designed, and terribly executed “study” is that, no, this has not shown any compelling data indicating gabapentin combined with opioids increases OUD risk. Certainly, that risk may be there, however this study hasn’t shown anything that indicates directly such. The entire thing wreaks of more gaslighting by anti-opioid zealots who appear to be shifting their focus to other medication classes besides opioids because of the dramatic plummeting in those receiving opioids over the past decade.

What makes matters worse? It would be entirely unsurprising if this “study” is used as evidence by certain government directed guidelines  that may dictate use of gabapentin in the future. I can see the narratives now… Gabapentin, it’s a gateway drug that leads to heroin! Or… Don’t let mom be treated by gabapentin, it will turn her into an opioid addict!

When it comes to those involved in evaluating seemingly any opioid related outcomes, as Forest Gump noted, “Stupid is as stupid does”. Ain’t that the god’s honest truth!

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