The Frontier Psychiatrists is a newsletter. It’s also now a podcast. It is also now a live event production workshop, also! We have our first live event on the Sunday night before JPM Healthcare 2024. It’s called Rapid Acting Mental Health Treatment 2024, and you should get your ticket now!
But today, we bring you another installment in our exploration of the small molecule oral medicines of yesterday….
As a brief plug, I work at Fermata, and I don’t do small molecule pharmacology first line any more. I still see patients, who live in states in which I’m licensed and for research by the way!
Gabapentin is a misleading name for a drug—it has no activity at GABA receptors. The brand name is Neurontin, now a part of the Pfizer family of pharmaceuticals.
“It is of paramount importance that the Department use every legal tool at its disposal…to pursue companies and individuals…that inflict suffering on patients and families”
—US Attorney Michael Sullivan, Regarding Marketing of Gabapentin, 2004, for US DOJ.
It was conceptualized as a GABA (the primary inhibitory neurotransmitter in the brain) mimic1. It doesn’t do that, though:
Gabapentin was designed to mimic the neurotransmitter GABA. It does not, however, bind to GABA receptors. Its mechanism of action as an antiepileptic agent likely involves its inhibition of the alpha 2-delta subunit of voltage-gated calcium channels.2
Gabapentin is an anticonvulsive medication for reasons so endlessly complex that I will banish them to a footnote3. It was first discovered in the 1970s.4 It received FDA approval in 1994 and has been available generically in the USA since 2004. Its original use was as a muscle relaxer and anti-spasmodic medication, but later, its potential as anticonvulsive medication and as an adjunct to more potent anticonvulsants came to light. Gabapentin has FDA approval for:
Postherpetic neuralgia (FDA, 2002).
Adjunctive therapy in the treatment of partial seizures with or without secondary generalization in patients over the age of 12 years old with epilepsy and the pediatric population, 3 to 12-year-olds with a partial seizure.
Moderate to severe restless leg syndrome (RLS) moderate to severe.
I am not going to write about those on-label indications that, as far as I can tell, work. It is a safe an effective medicine in the above conditions. Today’s journey is through the world of off-label prescribing of gabapentin.
Although off-label prescribing of a drug is permissible, the off-label marketing of that drug is not, and it is within the purview of the FDA to regulate such marketing.
It never had an FDA approval for a psychiatric illness. This didn’t stop its manufacturer from aggressively marketing it in the treatment of bipolar disorder—on the theory that since Depakote and Lamictal were anticonvulsants, and so was this, hey, why not? It is not like this would lead to the largest fines for off-label marketing or….wait. That is foreshadowing!5
Pharmacology We Can Understand
One way it’s awesome from a pharmacology standpoint is that it is cleared via the kidneys—you pee it out. There is no “metabolism” to worry about. The liver gives it a pass…on first and second-pass metabolism! This is what happens when human dad jokes write pharmacology-the-themed newsletter articles. This means limited drug-drug interactions to worry about, and doctors love less to worry about.
It is simple in other ways, pharmacology wise, in other ways too— which are endlessly appealing to physicians:
Gabapentin is highly lipophilic but not bound to plasma proteins — this means it gets into the brain fast—remember Xanax?— but doesn’t hang out in the blood unpredictably.
It has linear pharmacokinetics and does not demonstrate any significant protein binding or liver metabolization— again, it doesn’t act “weird” thanks to genetic variability like Effexor or Risperdal, for example.
It has an oral bioavailability of greater than 90%, independent of dose. Take gabapentin orally, absorb gabapentin. It’s predictable!
Generally, patients achieve steady-state plasma levels within 24 to 48 hours. This means the dose your doctor prescribes will be in your system soon, which isn’t true with Prozac, for example, which can take up to 10 weeks at any given dose!
There is no clinically significant effect in administration with food nor on the extent of absorption or elimination. The elimination half-life of the drug is approximately 6.5 hours—it’s out of your system quick. Gabapentin readily crosses the blood-brain barrier. It is primarily excreted renally, with no active metabolites. Dosage adjustment is necessary for patients with renal impairment. Pregabalin does not induce or inhibit CYP enzymes. Also, none of the CYP enzyme inhibitors alter its pharmacokinetics.
When it comes to the use of gabapentin in psychiatric disorders, there are a few definitive things to be said.
Gabapentin DOES NOT WORK in Bipolar Disorder:
The randomized controlled trials investigating gabapentin for treating bipolar disorder indicate it is likely to be ineffective.678
Open-label (non-blinded and non-randomized trials) demonstrated that, similarly, gabapentin it maybe, sort of, kind of, might be an effective treatment for bipolar disorder. Still, people squinted enough at the data to justify the above RCTs —which proved that it was not.910
Meta-analysis of the bipolar disorder studies found:
gabapentin [is no more effective] than placebo.11
Gabapentin is commonly used in substance use disorders…”but.”
It may be helpful in Alcohol Use Disorder, but scant evidence for its use in other substance use disorders.
In alcohol use disorder, the data is mixed, with enough studies indicating that it could be helpful in mood, insomnia, and craving to keep it commonly prescribed.12.
It seems like it can help get people through alcohol withdrawal, which is a life-threatening condition for many.13. As an approved antiepileptic, this makes endless mechanistic sense to me.
There are more comprehensive reviews than this one on the gabapentin by reliable academics, so I will briefly add:
We have no data that it helps methamphetamine withdrawal in randomized trials.14
Similarly:
Several placebo-controlled trials show that gabapentin is an inappropriate therapy in preventing cocaine relapse.15
In opiate use disorder and its withdrawal syndrome, gabapentin is broadly ineffective:
Although initial case reports and uncontrolled studies16 suggested a role for gabapentin in treating opioid dependence, cravings, and withdrawal symptoms, a randomized controlled trial contradicts such claims.17
Gabapentin has evidence in some anxiety disorders…but not much.
It has RCT data supporting its efficacy over placebo in social phobia.18
It’s not better in panic disorder unless you were REALLY freaking out (the subgroup of very panic-y patients got more benefit from gabapentin than placebo).19
It’s a touch better than a placebo in various perisurgical anxiety trials.20
It does little in PTSD21, but might help with sleep or nightmares22.
One study in OCD—which was negative at four weeks— demonstrated it maybe helped versus Prozac alone at two weeks but not at four weeks… it feels like it might do something, but doesn't.23
Maybe it is Never Taken as Prescribed?
Gabapentin has a really broad dosing range…much like water?
For oral dosage forms (capsules, liquid, and tablets):
For epilepsy and post herpetic neuralgia:
Adults and children 12 years of age and older—At first, 300 milligrams (mg) 3 times per day. Your doctor may adjust your dose as needed and tolerated. However, the dose is usually not more than 1800 mg per day (600 mg 3 times per day).
You can feel like you are doing things as a doctor by dosing it thrice daily. You can explain that it didn’t work—to yourself— because your patient was non-adherent with your quixotic dosing regimen! Patient adherence to a dosing regimen greater than once daily is as follows (in chronic disease cohorts):
In multivariate meta-regression analyses, the adjusted weighted mean percentage adherence rates for all regimens dosed more frequently than once per day were significantly lower compared with once-daily regimens (for 2-times, 3-times, and 4-times daily regimens, respectively: differences for taking adherence: –6.7%, –13.5%, and –19.2%; regimen adherence: –13.1%, –24.9%, and –23.1%; and timing adherence: –26.7%, –39.0%, and –54.2%).24
Using the strictest definition of “taking the meds when you are supposed to when you are supposed to?” One is 39% less likely to take the drug at the right time with three times a day dosing, which is what we pretend will happen with gabapentin. As someone who works in adherence tech, I can attest this is a more complex problem than people assume, and many of the above trials might be negative simply due to predictably poor adherence in the trials.
And now, to the Warnings and Lawsuits!
Everyone who reads this newsletter can see this part coming…the following warning about gabapentin have been offered by FDA:
You might stop breathing and die (2019):
The U.S. Food and Drug Administration (FDA) is warning that serious breathing difficulties may occur in patients using gabapentin (Neurontin, Gralise, Horizant) or pregabalin (Lyrica, Lyrica CR) who have respiratory risk factors. These include the use of opioid pain medicines and other drugs that depress the central nervous system, and conditions such as chronic obstructive pulmonary disease (COPD) that reduce lung function. The elderly are also at higher risk.
So we can add this drug to Xanax as an accelerant of death in the opioid crisis.
The first settlement with FDA was In 2004; the company shelled out $430 million in a settlement with the U.S. Justice Department for off-label marketing through 2004. This was for claims related to bipolar disorder and other off label marketing.
“This illegal and fraudulent promotion scheme corrupted the information process relied upon by doctors in their medical decision-making, thereby putting patients at risk,” stated U.S. Attorney Michael Sullivan.
Although Pfizer admitted no wrongdoing, they did agree to pay another $325,000,000 as a settlement to the FDA for off-label marketing of gabapentin in 2014, which is how we all, on our best days, handle personal and corporate accountability—denial and millions to make it all go away! Oh, wait.
They also settled on an antitrust lawsuit about delaying generic versions into the market for $190,000,000 in a class action in 2014.
All told total payouts across lawsuits for gabapentin amounted to $945,000,000 at the end of 2014.
I will quote the Department of Justice at some length to close us out:
Warner-Lambert’s strategic marketing plans, as well as other evidence, show that Neurontin was aggressively marketed to treat a wide array of ailments for which the drug was not approved. The company promoted Neurontin for the treatment of bipolar mental disorder, various pain disorders, Amyotrophic Lateral Sclerosis (ALS, a degenerative nerve disease commonly referred to as Lou Gehrig's Disease), attention deficit disorder, migraine, drug and alcohol withdrawal seizures, restless leg syndrome, and as a first-line monotherapy treatment for epilepsy (using Neurontin alone, rather than in addition to another drug).
“The Department of Justice is committed to rooting out and prosecuting health care fraud,” said Associate Attorney General Robert McCallum. “It is of paramount importance that the Department use every legal tool at its disposal to assure the health and safety of the consumers of America’s health care system, and to pursue companies and individuals that steal from the taxpayers and inflict suffering on patients and families. The Department's commitment to effective health care fraud enforcement is driven by a mandate that wrongdoers be brought to justice, to deter conduct which threatens the safety and welfare of all Americans, and the need to protect the resources of the Medicare Trust Fund, state Medicaid programs, and other government health programs.”
Warner-Lambert promoted Neurontin even when scientific studies had shown it was not effective. For example, the company promoted Neurontin as effective for use as the sole drug (monotherapy) for epileptic seizures, even after solo use had been specifically rejected by the FDA. Similarly, the pharmaceutical company falsely promoted Neurontin as effective for treating bipolar disease, even when a scientific study demonstrated that a placebo worked as well or better than the drug.
This sort of thing is not okay…except, even with the fines, it makes perfect sense. These predatory marketing strategies— which I will push to a footnote25—made the drug maker a bajillion dollars, which is more than the fines by a lot. The cost of doing business! When fines are less than the profits, expect the behavior to continue.
The sales of gabapentin were on the order of between $1b and $2.7b annually while on patent.26
The fines and lawsuits? Less than one bad year’s revenue. Even when scientific studies have shown it was ineffective, this strategy is profitable.
Taylor CP. Mechanisms of action of gabapentin. Rev Neurol (Paris). 1997;153 Suppl 1:S39-45. PMID: 9686247.
Alison M. Pack, in Osteoporosis (Fourth Edition), 2013
Gabapentin has no activity at GABAA or GABAB receptors of GABA uptake carriers of the brain. Gabapentin interacts with a high-affinity binding site in brain membranes, recently identified as an auxiliary subunit of voltage-sensitive Ca2+ channels. However, the functional correlate of gabapentin binding is unclear and remains under study. Gabapentin crosses several lipid membrane barriers via system L amino acid transporters. In vitro, gabapentin modulates the action of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD) and the glutamate synthesizing enzyme, branched-chain amino acid transaminase. Results with human and rat brain NMR spectroscopy indicate that gabapentin increases GABA synthesis. Gabapentin increases non-synaptic GABA responses from neuronal tissues in vitro. In vitro, gabapentin reduces the release of several mono-amine neurotransmitters. Gabapentin prevents pain responses in several animal models of hyperalgesia and prevents neuronal death in vitro and in vivo with models of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Gabapentin is also active in models that detect anxiolytic activity. Although gabapentin may have several different pharmacological actions, it appears that modulation of GABA synthesis and glutamate synthesis may be important.
Lumsden DE, Crowe B, Basu A, Amin S, Devlin A, DeAlwis Y, Kumar R, Lodh R, Lundy CT, Mordekar SR, Smith M, Cadwgan J. Pharmacological management of abnormal tone and movement in cerebral palsy. Arch Dis Child. 2019 Aug;104(8):775-780
Lenzer J. Pfizer pleads guilty, but drug sales continue to soar. BMJ. 2004 May 22;328(7450):1217. doi: 10.1136/bmj.328.7450.1217. PMID: 15155480; PMCID: PMC416587.
Pande AC, Crockatt JG, Janney CA, et al. Gabapentin Bipolar Disorder Study Group. Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Bipolar Disord. 2000;2(3 pt 2):249–255
Berlin, R. K., Butler, P. M., & Perloff, M. D. (2015). Gabapentin Therapy in Psychiatric Disorders: A Systematic Review. The Primary Care Companion for CNS Disorders, 17(5). https://doi.org/10.4088/PCC.15r01821
Frye MA, Ketter TA, Kimbrell TA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol. 2000;20(6):607–614.
Sethi MA, Mehta R, Devanand DP. Gabapentin in geriatric mania. J Geriatr Psychiatry Neurol. 2003;16(2):117–120.
Astaneh AN, Rezaei O. Adjunctive treatment with gabapentin in bipolar patients during acute mania. Int J Psychiatry Med. 2012;43(3):261–271.
Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011;378(9799):1306–1315
Mason BJ, Quello S, Goodell V, et al. Gabapentin treatment for alcohol dependence: a randomized clinical trial. JAMA Intern Med. 2014;174(1):70–77.
Bonnet U, Banger M, Leweke FM, et al. Treatment of alcohol withdrawal syndrome with gabapentin. Pharmacopsychiatry. 1999;32(3):107–109.
Heinzerling KG, Shoptaw S, Peck JA, et al. Randomized, placebo-controlled trial of baclofen and gabapentin for the treatment of methamphetamine dependence. Drug Alcohol Depend. 2006;85(3):177–184.
Bisaga A, Aharonovich E, Garawi F, et al. A randomized placebo-controlled trial of gabapentin for cocaine dependence. Drug Alcohol Depend. 2006;81(3):267–274.
and
González G, Desai R, Sofuoglu M, et al. Clinical efficacy of gabapentin versus tiagabine for reducing cocaine use among cocaine dependent methadone-treated patients. Drug Alcohol Depend. 2007;87(1):1–9.
and
Mancino MJ, McGaugh J, Chopra MP, et al. Clinical efficacy of sertraline alone and augmented with gabapentin in recently abstinent cocaine-dependent patients with depressive symptoms. J Clin Psychopharmacol. 2014;34(2):234–239.
Martínez-Raga J, Sabater A, Perez-Galvez B, et al. Add-on gabapentin in the treatment of opiate withdrawal. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(3):599–601.
Salehi M, Kheirabadi GR, Maracy MR, et al. Importance of gabapentin dose in treatment of opioid withdrawal. J Clin Psychopharmacol. 2011;31(5):593–596.
and
Salehi M, Kheirabadi GR, Maracy MR, et al. Importance of gabapentin dose in treatment of opioid withdrawal. J Clin Psychopharmacol. 2011;31(5):593–596.
and
Moghadam MS, Alavinia M. The effects of gabapentin on methadone based addiction treatment: a randomized controlled trial. Pak J Pharm Sci. 2013;26(5):985–989.
Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol. 1999;19(4):341–348.
Pande AC, Pollack MH, Crockatt J, et al. Placebo-controlled study of gabapentin treatment of panic disorder. J Clin Psychopharmacol. 2000;20(4):467–471.
Khezri MB, Oladi MR, Atlasbaf A. Effect of melatonin and gabapentin on anxiety and pain associated with retrobulbar eye block for cataract surgery: a randomized double-blind study. Indian J Pharmacol. 2013;45(6):581–586.
Fowler M, Garza TH, Slater TM, et al. The relationship between gabapentin and pregabalin and posttraumatic stress disorder in burned servicemembers. J Burn Care Res. 2012;33(5):612–618.
Hamner MB, Brodrick PS, Labbate LA. Gabapentin in PTSD: a retrospective, clinical series of adjunctive therapy. Ann Clin Psychiatry. 2001;13(3):141–146.
Onder E, Tural U, Gökbakan M. Does gabapentin lead to early symptom improvement in obsessive-compulsive disorder? Eur Arch Psychiatry Clin Neurosci. 2008;258(6):319–323.
Coleman, C. I., Limone, B., Sobieraj, D. M., Lee, S., Roberts, M. S., Kaur, R., & Alam, T. (2012). Dosing frequency and medication adherence in chronic disease. Journal of Managed Care Pharmacy, 18(7), 527-539.
(From the DOJ): Warner-Lambert used a number of tactics to achieve its marketing goals, including
encouraging sales representatives to provide one-on-one sales pitches to physicians about off-label uses of Neurontin without prior inquiry by doctors. The company’s agents also made false or misleading statements to health care professionals regarding Neurontin’s efficacy and whether it had been approved by the FDA for the off-label uses. Warner-Lambert also utilized "Medical Liaisons," who represented themselves (often falsely) as scientific experts in a particular disease, to promote off-label uses for Neurontin.
Warner-Lambert paid doctors to attend so-called "consultants meetings" in which physicians received a fee for attending expensive dinners or conferences during which presentations about off-label uses of Neurontin were made. These events included lavish weekends and trips to Florida, the 1996 Atlanta Olympics and Hawaii. There was little or no significant consulting provided by the physicians.
The pharmaceutical company implemented numerous teleconferences in which physicians were recruited by sales representatives to call into a pre-arranged number where they would listen to a doctor or a Warner-Lambert employee speak about an off-label use of Neurontin.
The company also sponsored purportedly "independent medical education" events on off-label Neurontin uses with extensive input from Warner-Lambert regarding topics, speakers, content, and participants.
Warner-Lambert misled the medical community beforehand about the content, as well as the lack of independence from the company’s influence, of many of these educational events. In at least one instance, when unfavorable remarks were proposed by a speaker, Warner-Lambert offset the negative impact by "planting" people in the audience to ask questions highlighting the benefits of the drug.
Warner-Lambert paid physicians to allow a sales representative to accompany the physician while he or she saw patients, with the representative offering advice regarding the patient’s treatment which was biased towards the use of Neurontin.
These tactics were part of a widespread, coordinated national effort to implement an off-label marketing plan. At the same time, Warner-Lambert decided not to seek FDA approval for any of the new uses because it was concerned that approval for any of the non-epilepsy uses would allow generic competitors of Neurontin, which was expected to go off-patent soon, to compete with a "son of Neurontin" drug that Warner-Lambert hoped to have approved by the FDA for both epilepsy and non-epilepsy uses.
Neurontin was launched into the marketplace in February of 1994; from mid-1995 to at least 2001, the growth of off-label sales was tremendous. While not all of these sales were the consequence of Warner-Lambert’s illegal marketing, the marketing scheme was very successful in increasing Neurontin prescriptions for unapproved uses.
The state Medicaid programs were harmed by Warner-Lambert’s aggressive promotion for off-label uses in numerous ways. The conduct caused doctors to write prescriptions for Medicaid patients when those medications were not eligible for Medicaid reimbursement in that the prescriptions were fraudulently obtained through false statements to doctors and by payment of illegal kickbacks, including so-called "consulting fees" and trips for physicians.
The investigation was commenced in the District of Massachusetts when a former medical liaison for Warner-Lambert, Dr. David Franklin, filed a suit on behalf of the U.S. government. Private individuals like Dr. Franklin are allowed to file whistleblower suits under the federal False Claims Act to bring the United States information about wrongdoing. If the United States successfully resolves or litigating the whistleblower’s claims, the whistleblower may share in part of the recovery. As a part of today’s resolution, Dr. Franklin will receive approximately $24.64 million of the civil recovery.
Lenzer J. Pfizer pleads guilty, but drug sales continue to soar. BMJ. 2004 May 22;328(7450):1217. doi: 10.1136/bmj.328.7450.1217. PMID: 15155480; PMCID: PMC416587.
I am today years old when I learned that humans can take this medicine too.... My vet gives us gabapentin fish oil for our cats to give them before their appointments so she can take blood. I thought this med was only for animals lol
Okay but it is a godsend for my cat when it’s time to go to the vet or trim nails!! Gabapentin is my favorite drug because it saves us so much stress and scratches!