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: http://addictionmedicineupdates.org/ for bringing this article to my attention. The tireless people at the GI support excellence in substance use treatment around the state.

  1. https://doi.org/10.1371.journal.pmed.1002396

 

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14 responses to this post.

  1. So thankful to have a post on this issue! We are seeing this more and more in the OTPs I work in.

    Reply

  2. Posted by Elizabeth on April 10, 2018 at 1:08 am

    Interesting analysis. I have been on Gabapentin for 3 years. I was addicted to alcohol and Valium to varying degrees for 10 years. Once I finally got sober the Gabapentin was the only drug that took away the horrible “jitters” I felt almost all day. I’m not thrilled to be taking it but it’s part of the mix that has kept me sober: Zoloft, Gaba, and Antabuse is my mixture. This is the only cocktail that has allowed me to get and stay sober. Prior to that I was in the constant relapse cycle. I don’t envy you. It must be so hard to know what to prescribe and often it’s life or death for the patient. I’m heartened, though, that you stay so current. I’ve been to doctors who seem to know nothing about the drugs beyond what the sales reps have told them.

    Reply

  3. Posted by jp on April 10, 2018 at 4:19 am

    Thank you for your articel.
    I am a Pain Mx doctor and GP.
    Gabapentin is used for neuropathic pain with a better NNH than Pregabalin. Both are sedatives. Many patients are inappropriately prescribed these medications as they do not have neuropathic pain and need to be weaned off these drugs.

    Reply

  4. Posted by Cindy on April 10, 2018 at 1:04 pm

    You have indicated in your article that gabapentin is not a controlled substance, however here in Virginia, you are required to have a written prescription and it shows up on the prescription monitoring program.

    Reply

  5. Posted by Gloria Yocum on April 11, 2018 at 11:00 am

    passed in the 2017 general assembly I will try to attach the VIRGINIA ACTS OF ASSEMBLY — 2017 SESSION
    CHAPTER 181
    An Act to amend and reenact § 54.1-3456.1 of the Code of Virginia, relating to drugs of concern;
    gabapentin.
    [H 2164]
    Approved February 23, 2017
    Be it enacted by the General Assembly of Virginia:
    1. That § 54.1-3456.1 of the Code of Virginia is amended and reenacted as follows:
    § 54.1-3456.1. Drugs of concern.
    A. The Board may promulgate regulations designating specific drugs and substances, including any
    controlled substance or other drug or substance where there has been or there is the actual or relative
    potential for abuse, as drugs of concern. Drugs or substances designated as drugs of concern shall be
    reported to the Department of Health Professions and shall be subject to reporting requirements for the
    Prescription Monitoring Program established pursuant to Chapter 25.2 (§ 54.1-2519 et seq.).
    B. Drugs and substances designated as drugs of concern shall include any material, compound,
    mixture, or preparation that contains any quantity of the substance Tramadol tramadol or gabapentin,
    including its salts. Drugs and substances designated as drugs of concern shall not include any
    non-narcotic nonnarcotic drug that may be lawfully sold over the counter or behind the counter without
    a prescription.
    2. That an emergency exists and this act is in force from its passage.

    Reply

  6. Posted by Obsteve on April 12, 2018 at 4:19 am

    Interesting but how did they determine who took gabapentin? Rx records or toxicology or both. If they only looked at pharmacy records they would have missed a vast swath of illicit abusers and their stats might have been skewed. We are seeing unprescribed GP show up in abt 25% of our random uds in OTP

    Reply

  7. I am an Addiction Psychiatrist in South Carolina, and I discovered your blog at the NC Addiction Medicine Conference. Overall, I find your blog to be highly beneficial and evidence-based. This post, however, is an outlier. In fact, it is dangerous as it is based on low-quality research and stigmatizes an effective and low-risk treatment, which will lead to patients to try ineffective and higher risk treatments instead. A “case-controlled” study is not appropriate to compare a treatment to lack of treatment. It is an inferior type of study only appropriate for looking at causes of rare diseases when a randomized controlled trial is impossible. For example, it’s appropriate to use a case-controlled study to compare the incidence of lung cancer in one town near a coal factor with another similar town that is not next to a coal factory. The investigators did attempt to control for a very limited number of confounding variables, but it is impossible to control for confounding and selection bias when studying a treatment. A physician evaluated and determined that each case patient (not a study subject) had a condition that warranted treatment with Gabapentin. In the controls, a physician made determination that Gabapentin was not appropriate. That’s a huge, huge, huge difference, and it makes this study worthless. A case-control study cannot substitute for a randomized controlled trial. I’m beginning to hear from lay people that they heard Gabapentin is dangerous (and patients on Gabapentin who find this laughable). I’ve treated several hundred patients with concurrent buprenorphine and gabapentin and well over 1000 patients otherwise with no significant negative outcomes (knock on wood). I can count on one hand where misuse was an issue (risk probably equivalent to Wellbutrin). In fact, Gabapentin is the standard alcohol detox protocol at the Medical University of South Carolina. I refer patients there and another major private hospital in Charleston that uses Librium for detox. In my patients, outcomes are consistently superior in patients placed on Gabapentin vs Librium (not directly relatable to opioids but shows Gabapentin has its role). You are a formdible and reputable voice on addictions treatment in the Carolinas. I hope you reconsider your statements on Gabapentin.

    Reply

    • Thanks for reading!
      I hope you attended Dr. Ashwin Patkar’s lecture this morning. He talked about gabapentin and gave some data that patients who misuse opioids are six times more likely to misuse gabapentin. The overall impression I got was that gabapentin is riskier when used with opioids.
      If you missed his lecture, I think slides of all the presentations will be available on one of these websites: http://www.sa4docs.org/
      or https://governorsinstitute.org/
      And yes, Dr. Patkar did mention that gabapentin helps with alcohol withdrawal, with doses ranging from 300-1200mg per day, for up to 16 weeks.

      Reply

      • Posted by Cassandra Lee on May 1, 2018 at 11:59 am

        I’ve also seen it commonly prescribed to methadone patients for withdrawals of benzodiazepines.
        Unrelated-I have wondered if Gabapentin had a similar chemical structure to the amino acid GABA because it does have similar effects.

  8. Posted by Lynn Walter on May 14, 2018 at 4:59 am

    Very interesting subject and glad to see. I had my own concerns. I know many people who abuse the gabipentin and sell it for a $1 A pill right in your parking lot.

    Reply

  9. Posted by Cindy Paplauskas on July 3, 2018 at 10:16 pm

    I’ve been on gabapentin for at least 15 yrs now. For the most part, I’ve abused it monthly. I’ve also been an opiate abuser on & off for 23 years. In March of this year I decided to give methadone a shot & it has been helping. The problem is, when I get my 270 400mg capsules I abuse the gabapentin to the point where they’re gone in 6 or 7 days.
    Monthly I’ve noticed that the methadone just stopped working by 4 that afternoon & by the next morning I felt like I was in full blown withdrawal. I FINALLY put it all together that the reason I felt so terrible was because of the gabapentin abuse. I go to see my Therapist on July 5th & I plan on getting honest. I don’t want to die. Thank you for writing this article.

    Reply

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