Gabapentinoids: A Deeper Look

Psychiatric TimesVol 40, Issue 11

"During the past 5 years has gabapentin retained its position as one of the top 10 drugs prescribed in the United States."




To keep up-to-date with the voluminous psychiatric literature, I scan many psychiatric and neuroscience publications in search of articles that pull me in for a deeper look. Recently, I skimmed the titles of a weekly email newsletter I receive and was immediately drawn to the first article: “Before You Prescribe Gabapentin, Consider These Risks.”1

The first sentence of the third paragraph got my attention. The author erroneously stated: “Gabapentin (Neurontin) and pregabalin (Lyrica) are both gabapentinoids—psychotropic medications that cross the blood-brain barrier and mimic the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).”1

The next step was to read all of this article’s references.2-6 Surprisingly, all 5 references focused on the relationship of gabapentin with the use of opioids or in the treatment of pain, with no mention of the common off-label use of gabapentin in various psychiatric disorders such as anxiety and insomnia. Hence, I embarked on a literature search for recent comprehensive review articles to explore gabapentin in these disease states.

Finally, I downloaded the most recently updated US Food and Drug Administration (FDA)-approved product insert for gabapentin, which gained FDA approval in 1993, and its more potent successor, pregabalin, which was approved by the FDA in 2004.7,8 Both drugs are available in generic formulations, and a 90-day supply of an average dose of either drug costs approximately $20 through GoodRx.

Gabapentin’s History

Researchers at Parke-Davis pharmaceuticals developed gabapentin as an analogue of the ubiquitous inhibitory neurotransmitter GABA, initially expecting it to interface with the GABA system. GABA receptors are ion channels that are activated by GABA, alcohol, benzodiazepines, Z-drug sleep hypnotics, barbiturates, and allopregnanolone.

However, to everyone’s surprise, gabapentin has no activity in any part of the GABA system and no affinity to the GABA receptors, and it is not involved in any aspect of GABA transport or metabolism. Rather, it binds to the α2δ subunit of a voltage-dependent calcium channel. Its activity at this channel is quite complex, but it is believed that the final physiological effect is decreased neuronal release of excitatory neurotransmitters glutamate and norepinephrine on ascending neurons in the central nervous system (CNS).9

Gabapentin gained FDA approval in 1993 under the brand name Neurontin as an adjunctive therapy in the treatment of partial onset seizures, and subsequently for the treatment of postherpetic neuralgia in adults in 2002. It became available as a generic in 2004. Given its unique mechanism of action and clinicians’ experience with gabapentin, its use in off-label indications grew steadily and rapidly starting in the late 1990s.

Just in the year 2019, 69 million gabapentin prescriptions were dispensed in the United States, making it the seventh most prescribed drug nationally.6 Table 1 lists the current FDA approvals of pregabalin.

Table 1. FDA-Approved Indications for Pregabalin

Table 1. FDA-Approved Indications for Pregabalin


Gabapentin and pregabalin are metabolically clean molecules. They are excreted in the urine unchanged. They are not metabolized by, nor do they have any impact on, the body’s cytochrome P450 isoenzyme system. Their serum levels are affected by renal disease; hence, dosage adjustments are required in patients with decreased renal functioning. In a healthy adult, gabapentin’s elimination half-life is 5 to 7 hours and pregabalin’s half-life is 6 hours.

Gabapentin is absorbed from the intestines through active transport by an amino acid transporter which becomes increasingly saturated with increasing dose (Table 2).

 Table 2. Decreasing Bioavailability of Gabapentin With Increased Dosing

Table 2. Decreasing Bioavailability of Gabapentin With Increased Dosing

As such, gabapentin’s serum level is minimally elevated once a dose of 900 mg orally 3 times per day is surpassed. These nonlinear pharmacokinetics provide a protective effect against high serum levels if large doses are taken by mistake or intentionally. Pregabalin does not share this property, demonstrating linear pharmacokinetics, which can result in much higher serum levels with increased dosing.

The only contraindication for both gabapentin and pregabalin is in patients who have demonstrated hypersensitivity to either drug/ingredients.

Gabapentin has 2 drug-drug interactions listed in its most recent product insert, with the mechanisms not known:

  1. Coadministration of gabapentin with hydrocodone decreases hydrocodone exposure.
  2. Coadministration of a 60-mg controlled release morphine capsule was administered 2 hours prior to a 600-mg gabapentin capsule (N = 12), with the resulting mean gabapentin area under the curve increased by 44% compared with gabapentin administered without morphine.

Gabapentinoid Risks

The most common adverse effects are sedation/somnolence, dizziness, edema, weight gain, dry mouth, blurred vision, and decreased attention. All patients should be educated with a detailed risk/benefit overview of both gabapentinoids and told that they should not engage in any behaviors requiring alertness and attention until they know how each specific dose affects them.

It is common to titrate up on both gabapentinoids. The clinician must review all prescription medications, OTC medications/supplements, and recreational drugs being used by each patient to review possible pharmacodynamic drug-drug interactions before prescribing. If the patient has a seizure disorder or is at risk for seizures, they need to be instructed not to discontinue the gabapentinoids abruptly, but rather consult the prescriber regarding a safe taper to reduce the risk of a withdrawal seizure.

Patients currently taking CNS depressants, including opioids, benzodiazepines, barbiturates, z-sleep hypnotics, or alcohol, need to be assessed carefully given the likely synergy of sedating effects.

In 2019, the FDA added a warning and precaution about the possibility of respiratory depression that states: “There is evidence from case reports, human studies, and animal studies associating gabapentin with serious, life-threatening, or fatal respiratory depression when coadministered with CNS depressants, including opioids, or in the setting of underlying respiratory impairment.”

One of the reasons for this warning was the increasing presence of gabapentin in toxicology reports of patients who died from an accidental overdose of an opioid, especially fentanyl.

Off-Label Use of Gabapentinoids

Any competent clinician routinely prescribes medications off-label if there is clinical justification and it is a practice that a colleague would agree is reasonable. This is especially the case in psychiatry, where most diagnoses have no on-label approved medication. A review in 2009 documented that 88.5% of all DSM-IV-TR diagnoses lacked an FDA-approved medication for their treatment.10

Additionally, during the past 15 years the medical prescribing of opioids for pain management has steadily decreased, which created a large population of patients dependent on opioids who lost access through the traditional health care system.

Goodman et al hypothesized that “clinicians who are desperate for alternatives to opioids have lowered their threshold for prescribing gabapentinoids to patients with various types of acute, subacute, and chronic noncancer pain.”5

As gabapentinoids began being prescribed more for various types of pain, it is likely they found their way into the illicit drug markets to fill a void for opioid-dependent individuals, providing a bridge drug for many patients to lessen their opioid withdrawal until they could obtain illicit opioids. Tragically, this coincided with the surge of inexpensive illicit fentanyl, which has fueled the opioid epidemic and dramatically increased accidental opioid overdose deaths.

Mattson et al concluded that “illicit opioid-involved deaths accounted for 56.8% of overdose deaths with gabapentin detected in the first quarter of 2019 and 69.2% in the last quarter of 2020; this increase was largely driven by illicitly manufactured fentanyl and fentanyl analogs.”6

GABAergic medications, including benzodiazepines and the Z-drug sleep hypnotics, constitute a great number of on-label medications for sleep disorders and various anxiety disorders. When used for brief periods or as needed, they are quite effective and well tolerated. However, their use often precedes a slippery slope to daily use. This creates tolerance and dependence, as well as the possibility of a dangerous physiological withdrawal if they are stopped rapidly.

Additionally, these GABAergic medications cause respiratory depression in overdose, and will synergistically significantly increase the risk of accidental death when used in combination with opioids. This is well established and pharmacodynamically and pharmacokinetically well understood.

Not surprisingly, gabapentinoids have become a common and safer alternative for subsets of patients, albeit off-label in the United States, in the treatment of sleep disorders and anxiety disorders. In fact, pregabalin is approved for the treatment of generalized anxiety disorder (GAD) in the European Medicines Agency, and has been since 2004.11,12

Gabapentinoid Addiction

Gabapentinoids alone do not have significant addictive potential. A recent review failed to find evidence of a strong addictive property of gabapentinoids.9 The authors concluded that there are limited rewarding properties, a low incidence of relapse phenomenon, and rare behavioral dependence symptoms, as well as no literature describing patients seeking treatment for the use of gabapentinoids.

The authors said pregabalin demonstrated a greater propensity toward addiction-like behaviors than gabapentin, which could be related to its greater potency and linear pharmacokinetics.

However, there was clear evidence that individuals with former or active substance use disorders, especially abusers of opioids or sedatives, seem to be at increased risk of abusing gabapentinoids, pregabalin more than gabapentin. Hence, they conclude that in patients with a significant history of a substance use disorder, gabapentinoids should be avoided, or if indicated should be administered through a prescription monitoring program.

In patients with no current or past substance use disorder, they conclude, the risk of developing a dependence on gabapentinoids is very low. It is recommended that pregabalin and gabapentin be tapered over 1 week to minimize any potential withdrawal symptoms.

Anxiety/Depressive Disorders

Soon after its FDA approval in 1993, different medical specialties began prescribing gabapentin off-label looking for efficacy in a range of disorders. In psychiatry, there was initially a signal that it was effective in treating bipolar I disorder mania. Subsequently, however, it was determined to be no more effective than placebo in mania. Both gabapentinoids have demonstrated no efficacy for depressive disorders in both unipolar and bipolar depression.13

Pregabalin has been extensively studied for the treatment of GAD, with consistent positive outcomes.11,12 One study of patients with GAD treated with pregabalin for 12 to 24 weeks demonstrated a low risk of withdrawal symptoms and rebound anxiety after discontinuation.14 A small number of studies have demonstrated efficacy for gabapentin in the treatment of social anxiety disorder and severe panic disorder.13-15

Gabapentin and Sleep

Insomnia and sleep disorders continue to be among the most challenging disorders to treat adequately in the United States. Given the favorable pharmacokinetic profile of gabapentin, it is surprising that more clinical studies have not occurred. Significantly, most sleep hypnotics negatively affect sleep architecture, and many have a propensity toward tolerance with nightly use.

Some early reports from gabapentin studies observed an increase in slow-wave sleep in both healthy volunteers and patients. Lo et al utilized polysomnography, prolactin levels, and neuropsychological testing in 18 patients with primary insomnia who were treated with gabapentin for at least 4 weeks, comparing measurements before and after the treatment period.

Polysomnography demonstrated “increased sleep efficiency and slow-wave sleep, decreased wake after sleep onset, and spontaneous arousal index after gabapentin treatment.”

Additionally, prolactin levels were decreased in the morning after treatment and neuropsychological testing showed an elevation of visual motor processing speed after the gabapentin treatment period.16 Two recent reviews on restless legs syndrome both concluded that gabapentin and pregabalin should be used as first-line treatments.17,18

Concluding Thoughts

Gabapentin is frequently prescribed off-label for a wide range of disorders, and during the past 5 or so years has retained its position as one of the top 10 drugs prescribed in the United States. This suggests efficacy in a broader array of disorders across different specialties.

However, due to the loss of patent protection for both gabapentin and pregabalin, there is little motivation for industry to fund more studies. Perhaps the National Institute of Mental Health could fund future studies to clarify additional evidence-based indications for this unique drug class.

The literature consistently reports that both gabapentinoids have a low risk of addiction, dependence, and withdrawal. The population at risk for gabapentinoid abuse includes patients with a past or present history of significant substance use disorders, and the prescribing and monitoring in this patient subset should be more conservative.

Gabapentinoids have no negative pharmacokinetic effect with alcohol; a growing literature supports the use of gabapentin in the treatment of some alcohol use disorders.13,15 The increasing presence of gabapentin in toxicology reports alongside opioids in postmortem examinations of accidental overdose deaths is concerning, although it is not clear whether the gabapentin contributes to the respiratory depression or is rather the canary in the coal mine.

The gabapentinoids have no role in treating opioid withdrawal, but individuals withdrawing from opioids may obtain some relief from their withdrawal symptoms by using gabapentinoids.

Using gabapentinoids to subjectively decrease some of the opioid withdrawal symptoms until illicit opioids can be obtained may explain the increasing presence of gabapentinoids in toxicology reports of individuals who have died from accidental opioid overdoses.

Dr Miller is Medical Director, Brain Health, Exeter, New Hampshire; Editor in Chief, Psychiatric Times®; Staff Psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Exeter Hospital, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.


1. Egan D. Before you prescribe gabapentin, consider these risks. Psychiatric News. 2023;58(10).

2. Smith RV, Havens JR, Walsh SL. Gabapentin misuse, abuse and diversion: a systemic review. Addiction. 2016;111(7):1160-1174.

3. Pauly NJ, Delcher C, Slavova S, et al. Trends in gabapentin prescribing in a commercially insured U.S. adult population, 2009-2016. J Manag Care Spec Pharm. 2020;26(3):246-252.

4. Peet ED, Dana B, Sheng FY, et al. Trends in the concurrent prescription of opioids and gabapentin in the US, 2006 to 2018. JAMA Intern Med. 2023;183(2):162-164.

5. Goodman CW, Brett AS. Gabapentin and pregabalin for pain — is increased prescribing a cause for concern? N Engl J Med. 2017;377(5):411-414.

6. Mattson CL, Chowdhury F, Gilson TP. Notes from the field: trends in gabapentin detection and involvement in drug overdose deaths – 23 states and the District of Columbia, 2019-2020. MMWR Morb Mortal Wkly Rep. 2022;71(19):664-666.

7. Neurontin. Prescribing information. Pfizer; updated 2022. Accessed October 16, 2023.

8. Lyrica. Prescribing information. Pfizer; April 2020. Accessed October 16, 2023.

9. Bonnet U, Scherbaum N. How addictive are gabapentin and pregabalin? A systematic review. Eur Neuropsychopharmacol. 2017;27(12):1185-1215.

10. Devulapalli KK, Nasrallah HA. An analysis of the high psychotropic off-label use in psychiatric disorders: the majority of psychiatric diagnoses have no approved drug. Asian J Psychiatr. 2009;2(1):29-36.

11. Montgomery SA. Pregabalin for the treatment of generalised anxiety disorder. Expert Opin Pharmacother. 2006;7(15):2139-2154.

12. Frampton JE. Pregabalin: a review of its use in adults with generalized anxiety disorder. CNS Drugs. 2014;28(9):835-854.

13. Martin JC, Gainer D. Psychiatric uses of gabapentin. Innov Clin Neurosci. 2022;19(7-9):55-60.

14. Greenblatt HK, Greenblatt DJ. Gabapentin and pregabalin for the treatment of anxiety disorders. Clin Pharmacol Drug Dev. 2018;7(3):228-232.

15. Ahmed S, Bachu R, Kotapati P, et al. Use of gabapentin in the treatment of substance use and psychiatric disorders: a systematic review. Front Psychiatry. 2019;10:228.

16. Lo HS, Yang CM, Lo HG, et al. Treatment effects of gabapentin for primary insomnia. Clin Neuropharmacol. 2010;33(2):84-90.

17. Zhou X, Du J, Liang Y, et al. The efficacy and safety of pharmacological treatments for restless legs syndrome: systemic review and network meta-analysis. Front Neurosci. 2021;15:751643.

18. Gonzalez-Latapi P, Malkani R. Update on restless legs syndrome: from mechanisms to treatment. Curr Neurol Neurosci Rep. 2019;19(8):54.

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