Clinical Update

Gabapentin (Neurontin, Gralise, Horizant) was first approved by the US Food and Drug Administration (FDA) in 1993 for the treatment of epilepsy, and in 2004 was approved for the treatment of post-herpetic neurological pain.¹ However, almost 95% of gabapentin prescriptions are for off-label use, including for some forms of anxiety disorders, management of pain-related conditions, alcohol use disorder (AUD), and others.^2-19 Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA), but has no effect on GABA binding, uptake, or degradation. Gabapentin has been shown to bind with high-affinity to voltage-activated calcium channels; however, the relationship of this binding to the therapeutic effects of gabapentin is unknown.²⁰ Although gabapentin is generally considered safe at low doses, when used with other central nervous system (CNS) depressants such as opioids, antidepressants, antihistamines, and benzodiazepines, there is risk for respiratory depression, potentially resulting in death.^16,20 In 2022, the U.S. Food and Drug Administration (FDA) administered a warning that patients using gabapentin who have respiratory risk factors may have serious breathing difficulties when used with opioids or other CNS depressants.²²

Although gabapentin is not considered a controlled substance by the federal government, it does have a potential for misuse or abuse. As of September 2022, gabapentin was classified as a controlled substance in Alabama, Kentucky, Michigan, North Dakota, Tennessee, Virginia, and West Virginia.²³ Gabapentin does not exhibit affinity for benzodiazepine, opiate (mu, delta, or kappa), or cannabinoid 1 receptors,¹ but varying desired effects have been reported with higher doses, including improved sociability, increased energy, marijuana-like relaxation, or dissociation. ^2,25,26 Gabapentin is primarily misused for recreational purposes, self-medication, or intentional self-harm.²⁴ There was an increase in the annual gabapentin diversion reports to the US Researched Abuse, Diversion, and Addiction Related Surveillance System from 2002 to 2015,²⁶ likely due to the availability of gabapentin from increased prescribing. Between 2009 and 2016, the prescription rate nearly doubled.²⁷ By 2019, gabapentin had become the seventh most prescribed drug in the US²⁸ and it still remains in the top 10 today.²⁹ According to the State Unintentional Drug Overdose Reporting System from 23 states and the District of Columbia, overdose deaths in which gabapentin was detected doubled from 449 in the first quarter of 2019 to 959 in the second quarter of 2020.³⁴ Whether this trend is stopped by increasing regulatory control or by focusing more on patient education is yet to be determined.^30,31 Either way, people who use gabapentin with CNS depressants like opioids, illicit opioids, antidepressants, antihistamines, and benzodiazepines should be educated about the increased risk for respiratory depression and death. Signs and symptoms of gabapentin misuse or abuse can include the development of tolerance, self-dose escalation, and drug-seeking behavior.^1,28,33,34 Because trends in gabapentin misuse and diversion are especially seen in those with a history of opioid abuse,^2,4,20,34 understanding risk factors of the patient before prescribing can reduce the rate of gabapentin abuse.^5,34

To better understand the frequency of the use of gabapentin when it has not been prescribed and the use of gabapentin with other substances, an analysis comparing Aegis gabapentin results in Q1 of both 2023 and 2024 was performed.

1. Included in the data were the number of samples with positive gabapentin findings that did not indicate gabapentin as prescribed. However, it is possible that gabapentin may not be indicated as prescribed with regularity when it is a prescription medication. Samples in which there were no medications at all indicated as prescribed were excluded in an attempt to eliminate potential bias. Overall positivity of gabapentin in samples in which it was not indicated as prescribed was similar in both time periods, right at 1 in 10 samples.
2. The overall positivity for gabapentin in both time periods, for all samples, regardless of whether or not it was indicated as prescribed, was nearly 25%, which is the highest positivity of any drug tested at Aegis currently.
3. The top five drug classes that were co-positive with gabapentin were similar for Q1 of 2023 and 2024 and are discussed below.

Number 1: Opioids

The opioid class was co-positive with gabapentin more often than any other drug or drug class. The co-administration of opioids with gabapentin may cause an increase in both the gabapentin and opioid concentrations resulting in CNS depression, with symptoms including somnolence, sedation, and respiratory depression.^1,2,20-22 Gabapentin has no direct ligand activity at opioid receptors, but it does potentiate the analgesic effect of most opioids.² The combination of opioids and gabapentin has been shown to increase the risk of respiratory depression and has been associated with increased opioid-related death compared to opioid use without gabapentin.²¹ And because the “high” can be accentuated with concurrent use of these two drugs, requests for high-dose gabapentin from patients may be a signal for potential opioid misuse.⁴ It has been shown that gabapentin is a highly abused drug worldwide and those who prescribe gabapentin should be aware of its abuse potential,³³ particularly in persons with a history of opioid misuse.^2,4,20,34 On the other hand, there are many studies that show the benefits of using gabapentin in a multimodal approach to pain management and in pre- and post-op for varying surgeries, but this use is in the absence of opioids.^6,7

Number 2: Buprenorphine + Opiate Antagonists

Buprenorphine and opioid antagonists tied as the second most prevalent drugs co-positive with gabapentin. This is not surprising as buprenorphine and naloxone (Suboxone) are often prescribed in the behavioral health community and are regularly co-positive. Because the co-administration of buprenorphine with gabapentin may result in CNS depression, with symptoms including somnolence, sedation, respiratory depression, it is recommended to use an alternative drug to gabapentin or to decrease the dose of one or both drugs. The use of opioid antagonists with gabapentin does not cause any known side effects.³² Literature is scant for the use of gabapentin in a substance use disorder (SUD) environment. One study found positive results for opioid use withdrawal using scheduled tizanidine, hydroxyzine, and gabapentin, instead of opioids or benzodiazepines, followed by an injectable extended-release naltrexone treatment.⁸

Number 3 and 4: Benzodiazepines and Antidepressants

Benzodiazepines were the third most co-positive drug class found with gabapentin and antidepressants were the fourth. Because some of the disease states overlap for these drugs, both will be discussed together.  The use of benzodiazepines with gabapentin may cause respiratory depression, or exacerbate the benzodiazepine side effects, such as dizziness, drowsiness, confusion, and difficulty concentrating. Anti-depressants are commonly prescribed alongside gabapentin for depression and anxiety, although when co-ingested there is an increased risk of hyponatremia and/or seizure.³² Gabapentin appears to be effective in some forms of anxiety disorders such as pre-operative anxiety, anxiety in breast cancer survivors, social phobia, social anxiety disorder, and severe panic disorder. No significant benefit of gabapentin has been conclusively observed in the treatment of obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), depression, major depressive disorder (MDD), posttraumatic stress disorder (PTSD), or stimulant use disorder.^9-12

Number 5: Amphetamines and Alcohol Biomarkers

Amphetamines and alcohol biomarkers tied for the fifth most detected drug class with gabapentin present. There is little literature available concerning amphetamine with gabapentin, except that gabapentin has not been shown to be effective in treating methamphetamine dependence or stimulant use disorder.⁹ Also, the use of amphetamine with gabapentin may exacerbate seizures in those who have seizure disorders.³²

Gabapentin is not FDA-approved for treating Alcohol Use Disorder (AUD) but has been shown to be safe and efficacious in treating alcohol withdrawal syndromes,^11,13,14 for treating AUD by reducing cravings, improving the rate of abstinence, delaying the return to heavy drinking, and reducing alcohol consumption.^9,15 Although it is unlikely that one single medication will be effective for all individuals with an AUD, much literature documents that gabapentin is best used in the withdrawal stages.^11,13,14here is still more research needed to develop new, more effective, and diverse pharmacological treatment options for AUD.¹⁶

Gabapentin can be efficacious when co-prescribed in the management of pain or pain-related conditions, AUD, and some forms of anxiety disorders, but gabapentin can be dangerous when used with CNS depressants or in high doses alone.^30,31 Prescribers may be able to minimize the increasing misuse of gabapentin and improve patient safety by vigilant monitoring and perhaps lowering doses for persons who may be at risk of gabapentin abuse, especially those who have a history of opioid abuse.^2,4,20,34 Additionally, decreases in prescribing of gabapentin would likely decrease the amount of gabapentin available in the general population and possibly minimize diversion.^27-29 The medical community overall especially must continue to educate patients about the risks of both ingesting large amounts of gabapentin and of administration of gabapentin with CNS depressants.^1,28,33,34