Posts Tagged ‘ovderdose death risk with gabapentin’

Opioids and Gabapentin: A Potentially Dangerous Mixture


A Canadian study, published late last year, showed co-prescribing of gabapentin and opioids was associated with significantly increased risk of opioid-related death.

I’ve had a few of my patients on methadone or buprenorphine misuse gabapentin, and even had one patient end up in the emergency room with an overdose from a mixture of buprenorphine and gabapentin, but I thought it was because the patient took way too many of the gabapentin. In the past I’ve thought of gabapentin as a “junior” substance of abuse. I thought most people with opioid use disorder wouldn’t deign to be interested in such a low-powered drug. I thought it might fall in the category with trazadone, Seroquel, or Benadryl…something young people might experiment with, but not what people with established opioid use would want to mess with.

After reading this study, I’ve changed my mind. Gabapentin with opioids is associated with increased risk of death. This is serious.

The Canadian study by Gomes et al., says gabapentin is often prescribed for pain, and obviously opioids are as well, resulting in many patients who are prescribed both. The purpose of the study was to discover if co-prescribing gabapentin and opioids resulted in higher risk of death from accidental opioid-related reasons.

Before describing the study, let’s talk more about this medication, gabapentin, sometimes marketed and sold under the brand name Neurontin.

Gabapentin is a medication that is structurally similar to the neurotransmitter GABA, but gabapentin has no activity at the GABA receptor. Gabapentin appears to attach to calcium channels, but we don’t know the exact mechanism of action of its anti-seizure and anti-analgesic effects.

This medication isn’t changed into other compounds, meaning gabapentin is the active drug. It’s metabolized by the kidneys, and so the dose must be adjusted in patients with kidney failure.

This drug is odd because its bioavailability goes down as the dose goes up, which means that as the dose goes up, the amount available in the blood stream goes up too, but not by as much as one would expect, due to the decrease in bioavailability.

Its half-life is around 6 hours, and so it is dosed three times per day. It can be removed by hemodialysis.

Gabapentin can cause sedation and suppression of respiratory rate, both by itself and when combined with prescription opioids. In fact, the product’s monograph was changed in 2014 to emphasize the risk of suppression of respiratory rate when combined with opioids. This may be more important in patients with COPD, renal insufficiency, and older age.

Gabapentin can also cause dizziness, fatigue, and swelling of the lower legs. It is not categorized as a controlled substance because studies didn’t show it to be prone to misuse or addiction. In fact, it has been studied for use in alcohol and marijuana use disorders, with some evidence of benefit.

Gabapentin is prescribed for an assortment of reasons, and not all are FDA approved. Gabapentin is approved for the adjuvant treatment of partial seizures in kids and adults, which means it can be used as an add-on to main seizure treatment medications. It is also indicated for the treatment of pain after a bout of shingles, called post-herpetic neuralgia.

That’s it. There’s no FDA approval for the many other conditions for which it’s commonly prescribed, like fibromyalgia, anxiety, hot flashes of menopause, pain of diabetic neuropathy, or alcohol withdrawal symptoms, though there are studies that support its use for some of these conditions. There’s evidence gabapentin may help with restless legs syndrome and itching from kidney failure.

Use of gabapentin for other than FDA approved uses isn’t unusual and it isn’t necessarily bad medical practice. Many medications are used “off-label” which means they are used for purposes for which they don’t have FDA approval.

A newer version of gabapentin, called pregabalin, is marketed under the brand name Lyrica, and it is classified as a controlled substance because of its potential for addiction and misuse. It has FDA indication for treatment of neuropathic pain, post-herpetic neuralgia (pain from previous shingles outbreak), epilepsy, fibromyalgia, and diabetic peripheral neuropathy pain.

The article I’m describing today did not look at any data relating to pregabalin.

The study was a nested case-control study, which means each opioid user who died of opioid-related causes was matched with four control subjects, with age, sex, start date of opioids, and presence or absence of chronic kidney disease being similar for each index case and the controls.

This was a big study, with 1256 index cases and 4619 controls.

An analysis was conducted to see how many of the index cases, patients who died of opioid-related reasons, were also prescribed gabapentin within 120 days of the index date. The dose of gabapentin was further categorized as high, medium, or low dose.

The results showed that 12.3% of the people who died of opioid-related causes were prescribed gabapentin within 120days preceding death. Of the age and sex matched control patients who did not die, only 6.8% were prescribed gabapentin within 120 days.

This means that patients on opioids who were co-prescribed gabapentin had odds of an opioid-related death 49% higher than patients on opioids who were not prescribed gabapentin.

The authors also found a significantly increased risk with higher dose gabapentin than low or moderate dose.

The authors of the study used the same method looking at anti-inflammatory medication prescriptions, to see if those medications increased risk of opioid-related death, and found no difference in use of anti-inflammatories in patients who died compared to controls who did not die.

It’s important to note that patients with opioid use disorder who were being prescribed methadone were not included in this study. Patients with cancer diagnoses and who were in palliative care were also not included. The authors didn’t explicitly say why these patients were excluded, but patients in these groups may not represent general patient populations. Patients with cancer, getting end-of-life care, are likely to be prescribed much higher doses of opioids, due to a shifting of the focus of their care. At the end of life, comfort is of more importance that functioning.

As for patients on methadone, perhaps the authors thought patients with substance use disorders would be more likely to misuse their prescribed gabapentin. Maybe the authors thought including such patients would skew the data, and gabapentin would appear to be more dangerous than it is. This study was not done on people with substance use disorders; it was done on the general population.

This is a powerful study because it was so large, and it spanned sixteen years. Canada has a population similar to that of the U.S., so I think it’s safe to assume their data should be valid for patients in the U.S.

What does this mean for me and my patients? I don’t treat pain, I only treat opioid use disorders. But are my patients, for whom I prescribe buprenorphine and methadone, at increased danger if they are co-prescribed gabapentin by another doctor? Yes, by my interpretation of this data, they are at increased risk. For sure, if they take more gabapentin than prescribed, they are increased risk for death, but this study shows that even when taken as prescribed, this medication is associated with increased risk of death.

Association doesn’t always mean causation, but given what we know about how these medications who, a causal relationship is strongly suggested.

In the past, I had more of a “pick your battles” attitude. I was happy if my patients stopped drinking alcohol or using benzodiazepines. For the latter, we have good studies (for example, Park et al., 2015, BMJ, “Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics”) that have shown a four-fold increase in the risk of overdose death when benzodiazepines are co-prescribed with opioids. Now I will add gabapentin and pregabalin to my list of medications that can harm my patients.

It’s tempting to issue a blanket policy against gabapentin. Blanket policies make life easier for the opioid treatment program, but such policies treat every patient the same.

For this issue, I think the best course is to talk to each patient, evaluate each patient, and ask them how much benefit they receive from gabapentin. I will advise them of the increased risks of this medication, and we will decide whether it’s best to stop or continue the gabapentin. Some patients may decide the benefit it worth the risk. Other patients may decide it’s better to stop taking gabapentin. Either way, I’ll document this in their charts, and re-visit the issue regularly.

I am grateful, as always, to the website sponsored by the North Carolina Governor’s Institute: for bringing this article to my attention. The tireless people at the GI support excellence in substance use treatment around the state.