Gabapentin

• 1. Introduction

  ›

  Gabapentin, sold under the brand name Neurontin among others, was the ninth most commonly prescribed medication in the United States in 2023, with more than 45 million prescriptions. Its name points straight at GABA, the principal inhibitory chemical messenger in the mammalian brain. Yet the drug does not bind to GABA receptors at all. That mismatch is only the first oddity. A medicine first meant for epilepsy is now taken for nerve pain, insomnia, anxiety and even itching. Some of those uses rest on solid evidence, and others rest on very little. This documentary asks where gabapentin came from, how a drug named for GABA works without touching GABA's receptors, and which of its many jobs it actually does well. It also asks what happened when a company promoted it for jobs that regulators had never approved.

  1211871719

• 2. Freiburg Origins

  ›

  The idea took shape at Goedecke AG in Freiburg, Germany, a subsidiary of the pharmaceutical company Parke-Davis. Researchers there set out to build a structural analog of GABA that could cross the blood-brain barrier more easily than GABA itself. The science of the day gave them a map. By the early 1970s it was understood that GABA acts through two main classes of receptor, called GABA-A and GABA-B, and that the drug baclofen switches on the GABA-B type.

  The new molecule was first synthesized in 1974 or 1975. Satzinger and Hartenstein described it in 1975. The first pharmacology results showed that it was sedating and that it prevented seizures in mice. Those seizures had been provoked by thiosemicarbazide, a chemical that blocks GABA. Soon afterward, a test on slices of rat caudate nucleus showed that gabapentin reduced the release of dopamine. This suggested that, unlike baclofen, the drug was not working through the GABA-B receptor.

  The early human trials looked at spasticity and migraine. They involved small numbers of people, and neither had the statistical power to prove anything. The first positive result came in 1987. In that trial, patients who kept having seizures despite other medications received gabapentin as an add-on at three different dose levels. Their seizure frequency was compared with their own frequency before treatment, over 75 days.

  Regulators moved quickly after that. Britain approved Neurontin in May 1993 for refractory epilepsy. The US Food and Drug Administration followed in December 1993, approving it as an adjuvant for partial seizures in adults. Children were added to that indication in 2000. Approval for pain from postherpetic neuralgia came in 2002, and a generic version reached the American market in 2004. In January 2011 an extended-release form called Gralise won approval for postherpetic neuralgia, designed to be taken once a day.

  810858695

• 3. Inside The Body

  ›

  The protein that matters most to gabapentin is the α2δ subunit, which is coded by the CACNA2D1 gene in its α2δ-1 form. Scientists first described it as a helper attached to the main α1 subunit of high-voltage-activated calcium channels. Gabapentin is not a direct plug for those channels. Instead it disrupts the regulatory job of α2δ and the contacts α2δ makes with other proteins, including NMDA receptors, neurexins and thrombospondin. The result is that fewer calcium channels are delivered to the cell membrane. Signaling that triggers neurotransmitter release falls as well.

  The four known forms of α2δ are not equally affected. Gabapentin binds two of them, α2δ-1 and α2δ-2, with similar high affinity. Every pharmacological property tested so far traces back to just α2δ-1. The body may also supply its own rivals. The amino acids L-leucine and L-isoleucine resemble gabapentin and bind the same subunit, and they compete with the drug. That competition probably explains a puzzle. Gabapentin has nanomolar affinity in the lab, but its potency in living tissue sits in the low micromolar range.

  Other candidate targets have been checked. Gabapentin strongly activates the potassium channels KCNQ3 and KCNQ5 even at low nanomolar concentrations, though this is unlikely to be the main source of its benefit. It also competitively inhibits an enzyme called BCAT, but only the BCAT-1 form, and only at high concentration. At very high concentrations it can suppress the growth of cancer cells, and the precise mechanism remains unclear.

  Animal work fits this picture. Gabapentin prevented seizures in a dose-related way in mice and rats, including rats made seizure-prone by repeated electrical stimulation of the hippocampus. It did not stop pain behaviors in models of acute pain. It worked only once the animals had been sensitized by inflammation or by nerve damage.

  Getting the drug to those targets is its own challenge. Gabapentin crosses the gut wall by an active transport process that most likely relies on an amino acid transporter called LAT2. Because that route can saturate, absorption falls as the dose rises. With 100 mg taken every eight hours, oral bioavailability is about 80 percent. It drops to 60 percent at 300 mg, 47 percent at 400 mg, 34 percent at 800 mg, 33 percent at 1,200 mg and 27 percent at 1,600 mg. Taking oral morphine alongside a 600 mg dose raised bioavailability by 50 percent.

  Peak levels arrive about 1.7 hours after a 100 mg dose and 3 to 4 hours after higher doses. Food raises peak level and total exposure by roughly 10 percent. The brain is reached through another amino acid transporter, LAT1, because the molecule is not fat-soluble enough to slip through unaided. Cerebrospinal fluid holds only about 9 to 14 percent of the concentration found in blood plasma. Less than 1 percent of the drug binds to plasma proteins.

  The body barely changes gabapentin, and the kidneys remove it in urine. Its half-life averages 5 to 7 hours, so ordinary tablets are taken three or four times a day. People with kidney problems need lower doses, because the drug can build up to toxic levels. Whether it is safe in pregnancy or breastfeeding is unclear.

  8789909496

• 4. Established Uses

  ›

  In the United States, only two uses carry formal approval. One is postherpetic neuralgia, the nerve pain that can linger after shingles. The other is add-on treatment for partial-onset seizures. For seizures, the limits are clear: gabapentin helps in focal epilepsy but does not work for generalized epilepsy.

  Nerve pain is where its reputation is strongest. Various medical authorities recommend it as a first-line treatment for chronic neuropathic pain. The one exception is trigeminal neuralgia, where it is a second- or third-line choice. A systematic review found real relief for some people with postherpetic neuralgia and diabetic neuropathy. A guideline from the European Federation of Neurological Societies also notes benefit for central pain. Even so, only about 30 to 40 percent of people with diabetic neuropathy or postherpetic neuralgia get a meaningful benefit. Pairing it with an opioid or with nortriptyline may beat either drug alone.

  The failures are just as instructive. Evidence shows little or no benefit, and significant risk, for chronic low back pain and sciatica. It does not help HIV-associated sensory neuropathy or neuropathic pain caused by cancer. It also falls short for complex regional pain syndrome, post-surgical pain and tinnitus. Nor does it prevent episodic migraine in adults.

  A long list of smaller roles has accumulated. Gabapentin is a first-line choice for several forms of nystagmus, the involuntary eye movement, including acquired pendular, torsional and infantile types. It does not work for periodic alternating nystagmus. It reduces spasticity in multiple sclerosis and is an established treatment for restless legs syndrome. It eases itching in kidney failure and in some other conditions. It may help in essential or orthostatic tremor. It cuts the frequency of hot flashes in menopausal women and in people with breast cancer, although antidepressants work about as well and estrogen works better.

  Veterinarians have adopted it too. In cats it serves as a pain reliever, an anticonvulsant and a way to calm stress during travel or vet visits. In dogs it is used for epilepsy, several kinds of pain, storm phobia and fear-based aggression. Horses and dogs both receive it for nerve inflammation linked to chronic pain, and tiredness and poor coordination usually clear within 24 hours of starting.

  82592443

• 5. Off-Label Territory

  ›

  A trial in breast cancer survivors with anxiety found that gabapentin significantly lowered anxiety levels. So did a trial in social phobia. The drug works over the long term for social anxiety disorder and reduces anxiety before surgery. For panic disorder the results are mixed. Doctors also prescribe it for generalized anxiety disorder, but it is less effective there than pregabalin, a close relative.

  Sleep is another target. Gabapentin helps with insomnia that stems from an underlying illness. In people with primary insomnia it enhances slow-wave sleep, raises sleep efficiency and cuts spontaneous arousals. The catch is that prolonged use at higher doses carries some risk of withdrawal symptoms when the drug is stopped.

  In addiction medicine the picture is patchy. Gabapentin is moderately effective against alcohol withdrawal and craving. For treating alcoholism itself the evidence is weak: it does not help people reach abstinence and only reduces the share of days spent drinking heavily. It is ineffective for cocaine dependence and methamphetamine use, and it does not raise smoking cessation rates. Evidence for cannabis dependence is insufficient.

  Opioids are the most intriguing case. Some studies find no meaningful relief of opiate withdrawal symptoms. Other evidence suggests gabapentinoids control some symptoms during detoxification. A clinical study in Iran, where heroin dependence is a serious public health problem, found positive results in an inpatient program. Gabapentin reduced opioid-induced hyperalgesia and drug craving there.

  The broader worry is that off-label prescribing in the United States and Britain now covers non-neuropathic pain, anxiety, sleep problems and bipolar disorder. Use has grown in recent years, especially among older people. The evidence for many of these conditions is thin, the side effects are well established, and the potential for misuse and dependence is real. Some harms, including harms to the nervous system, have been underreported in published trials. That may have led guidelines to understate the risks.

  Bipolar disorder shows how the thin evidence took hold. In the 1990s some small studies without control groups, mostly sponsored by the manufacturer, hinted that gabapentin might be promising. The preponderance of later evidence says it is not effective.

  3136373359

• 6. Side Effects And Warnings

  ›

  Dizziness and sleepiness top the list of side effects. Fatigue, loss of coordination, swelling in the extremities and nystagmus are also common. A 2017 meta-analysis found that, compared with placebo, gabapentin raised the risk of difficulties in mentation and visual disturbances. Average weight gain was 2.2 kg after 1.5 months of use. Case studies link it to anorgasmia, erectile dysfunction and muscle jerks called myoclonus, which disappeared once the drug was stopped or replaced. Rare but serious effects include hallucinations, anaphylaxis, an inflamed pancreas, yellowing of the eyes or skin, and unusual bruising or bleeding.

  A systematic review pooled five cohort studies covering 1,085,488 patients. It tied gabapentinoids to a higher risk of blood clots in the veins and lungs, from as early as three months of use. Cardiovascular events rose with use beyond a year. Heart failure did not increase.

  Breathing is the most dangerous concern. Taken with opioids, benzodiazepines or other depressants, gabapentin can suppress breathing to a potentially fatal degree. Risk is also higher for people with lung disease such as COPD. Research shows the effect with opioids is additive. Giving gabapentin before joint replacement or laparoscopic surgery raised the risk of respiratory depression by 30 to 60 percent. A Canadian study linked gabapentinoid use to a 35-58 percent higher risk of severe flare-ups of existing COPD. In a large overdose, drowsiness, blurred vision, slurred speech and uncontrollable jerking can give way to coma and death, especially with alcohol or opioids.

  Mood and behavior can change too. Systematic reviews describe aggression, agitation, irritability and mood instability, with mania, hallucinations and psychosis in some cases. Children and people with existing psychiatric conditions seem most vulnerable. Large cohort studies and surveillance suggest neuropsychiatric symptoms may affect up to 29 percent of users. Most are mild to moderate and often depend on dose.

  Stopping suddenly brings its own trouble. Withdrawal typically starts one to two days after the last dose, resembling benzodiazepine withdrawal but milder. Agitation, confusion and disorientation are reported most often. Stomach complaints and sweating follow, and tremor, a racing heart, high blood pressure and insomnia are rarer. Some people on chronic use without breaks have had withdrawal seizures. All symptoms ease when the drug is restarted or tapered slowly.

  Suicide risk remains contested. On the 16th of December 2008 the FDA issued a class-wide warning on gabapentinoids, based on a meta-analysis of all approved antiepileptic drugs rather than on gabapentin alone. About two years later, a pharmacoepidemiologic study found no standout difference in suicide attempt rates before and after people began taking the drug. Later work points both ways. An analysis of insurance claims linked gabapentin to roughly 40 percent higher risk of suicide, attempts and violent death than the anticonvulsant topiramate. A study in bipolar disorder found about double the rate of attempts and self-harm compared with lithium. A large Swedish study tied gabapentinoids to suicidal behavior, accidental overdoses, injuries and road traffic offences. Yet a study in the Harvard Data Science Review found a significantly lower suicide rate. A 2010 study in Pharmacoepidemiology and Drug Safety saw no significant drop in non-psychiatric patients but significant reductions among psychiatric ones.

  797574712

• 7. Misuse And Law

  ›

  On its own, gabapentin does not seem strongly addictive. In human and animal experiments it shows little or no rewarding effect. The picture changes in people who already use opioids or sedatives, who make up the vast majority of those misusing it. For them it can amplify the opioid high and ease withdrawal symptoms such as anxiety.

  On the street it is known as "Gabbies". A 2017 report described growing abuse for its euphoria, a sense of calm and better sociability, and its ability to dull alcohol or cocaine cravings. About 1 percent of respondents to an internet poll reported a history of abuse. Among people attending addiction facilities, the figure was 22 percent. Misuse, toxicity and use in suicide attempts among American adults all rose from 2013 to 2017. Recreational users commonly combine it with opioids, benzodiazepines and alcohol.

  Kentucky offers a case study in how pressure on one drug can push people to another. The state tightened its opioid prescribing laws in 2012. From 2012 to 2015, cases involving gabapentin alone or with other drugs increased. Most were overdoses in suspected suicide attempts.

  The law has responded unevenly. Britain reclassified gabapentin as a class C controlled substance in April 2019. In the United States it is not controlled under the federal Controlled Substances Act. Kentucky made it a Schedule V controlled substance statewide in July 2017. West Virginia, Tennessee, Alabama, Utah and Virginia also treat it as Schedule V.

  77763785

• 8. The Marketing Reckoning

  ›

  In 2004, Warner-Lambert agreed to plead guilty over its Parke-Davis subsidiary's marketing of Neurontin for unapproved uses and to pay $430 million in fines. Warner-Lambert was later acquired by Pfizer. Doctors prescribing off-label is common, but a company promoting such uses is not. The settlement was one of the largest in US history up to that point. It was also the first off-label promotion case brought successfully under the False Claims Act. Pfizer had admitted violations of FDA guidelines in the Franklin v. Parke-Davis case.

  The lawsuits kept coming. Kaiser Foundation Hospitals and Kaiser Foundation Health Plan sued Pfizer, claiming it had misled them by promoting Neurontin for bipolar disorder, migraines and neuropathic pain. In 2010 a federal jury in Massachusetts found that Pfizer had violated the Racketeer Influenced and Corrupt Organizations Act. Damages of $47.36 million were automatically trebled to just under $142.1 million. Aetna and a group of employer health plans won similar claims. The First Circuit Court of Appeals upheld the verdict, and in 2013 the US Supreme Court declined to hear the case.

  A different scandal grew from gabapentin's use in addiction. Gabasync, marketed as PROMETA, combined gabapentin with flumazenil and hydroxyzine, plus therapy, and was promoted for methamphetamine addiction. It was also claimed to help with alcohol and cocaine dependence. The FDA had approved the individual drugs but never their off-label use for addiction. The company behind it, Hythiam, Inc., was owned by Terren Peizer, a former junk bond salesman who was later convicted of securities fraud over another company. Hythiam charged up to $15,000 per patient to license the treatment. Half went to the prescribing physician and half to Hythiam.

  The press was sharp. In November 2005 Barrons ran an article titled "Curb Your Cravings For This Stock". 60 Minutes, NBC News and The Dallas Morning News criticized Peizer for bringing PROMETA to market without clinical studies or government approval. CBS News journalist Scott Pelley told him in 2007: "Depending on who you talk to, you're either a revolutionary or a snake oil salesman." Journalist Adam Feuerstein judged most of what Peizer said to be dubious-sounding hype.

  In November 2011 the journal Addiction published a double-blind, placebo-controlled study carried out at UCLA and financed by Hythiam. It concluded: "The PROMETA protocol, consisting of flumazenil, gabapentin, and hydroxyzine, appears to be no more effective than placebo in reducing methamphetamine use, retaining patients in treatment, or reducing methamphetamine craving."

  The drug's commercial afterlife is sprawling. Since it went generic, gabapentin has been sold under more than 300 brand names worldwide. In the United States Neurontin is now sold by Viatris, after Upjohn was spun off from Pfizer. Parke-Davis developed pregabalin as a successor. Pfizer tried a similar drug, atagabalin, for insomnia without success. A prodrug form, gabapentin enacarbil, won FDA approval.

  The appetite for the whole family has not faded. A study published in 2023 analyzed healthcare data from 65 countries and regions. It found that consumption of gabapentinoids doubled between 2008 and 2018.

  1413201719