Gabapentin
Encyclopedia
Gabapentin is a pharmaceutical drug, specifically a GABA
analogue. It was originally developed for the treatment of epilepsy
, and currently is also used to relieve neuropathic pain
. There are, however, concerns regarding the quality of the trials conducted.
, and hot flashes. There are, however, concerns regarding the quality of the research on its use to treat migraines, bipolar disorders, and pain.
or chronic neuropathic pain
. It is also effective in reducing narcotic
usage post operatively and is helpful in neuropathic pain due to cancer
. It has not been shown to be useful for HIV
associated sensory neuropathy. When used for neuropathic pain it does not appear superior to carbamazepine
. Further evidence is needed to determine if it is effective for migraine
prevention. It appears to be equally effective as pregabalin
and is of lower cost. It does not appear to be of benefit in treating complex regional pain syndrome
.
in a number of countries and evidence supports it use for treating partial and mixed seizure disorders however there is insufficient evidence for it use in generalized epilepsy. There is little data to support its initial use over older anticonvulsant
medication for any type of seizure disorder.
Gabapentin may help with menopausal symptoms. It may be effective in reducing pain and spasticity in multiple sclerosis
. Gabapentin has been used to treat some symptoms of opiate withdrawal, but tests for smoking cessation
treatment have had mixed results.
treatment for bipolar disorder
and so has no therapeutic advantage in having fewer side-effects over better established bipolar drugs such as lithium
and valproic acid
. Gabapentin has limited usefulness in the treatment of anxiety
disorders such as social anxiety disorder
and obsessive-compulsive disorder
, in treatment-resistant depression
, and for insomnia
. Gabapentin can also cause weight gain.
A double blind, randomized controlled
trial
found gabapentin ineffective for the treatment of idiopathic subjective tinnitus
.
(swelling of extremities); these mainly occur at higher doses in the elderly. Also, children 3–12 years of age were observed to be susceptible to mild-to-moderate mood swings, hostility, concentration problems, and hyperactivity. Although rare, there are several cases of hepatotoxicity
reported in the literature. Gabapentin should be used carefully in patients with renal impairment
due to possible accumulation and toxicity.
An increase in formation of adenocarcinoma
s was observed in rats during preclinical trials; however, the clinical significance of these results remains undetermined. Gabapentin is also known to induce pancreatic acinar cell carcinomas in rats through an unknown mechanism, perhaps by stimulation of DNA synthesis; these tumors did not affect the lifespan of the rats and did not metastasize.
to reflect this. In July 2009, the manufacturer of gabapentin (Pfizer
) went to trial regarding the association between gabapentin and the increased risk of suicide.
or benzodiazepine withdrawal. Gradual reduction over a period of weeks or months helps minimize or prevents the withdrawal syndrome.
Side effects upon discontinuation of gabapentin that have been reported in medical literature include insomnia
, restlessness, agitation
, anxiety
, disorientation, confusion
, light sensitivity
, diaphoresis
, headache
s, palpitation
s, hypertension
, chest pain
, and flu-like symptoms
. In at least one case, abrupt cessation of a high dose of gabapentin triggered a seizure
in an individual with no history of epilepsy
.
or coma. Serum gabapentin concentrations may be measured to confirm diagnosis.
of the neurotransmitter
gamma-aminobutyric acid (GABA), but is not believed to act on the same brain receptors.
One possible mechanism of action
, reported by Ben Barres of Stanford University and colleagues in Cell
in 2009, was that gabapentin halts the formation of new synapses. Gabapentin binds to the α2δ subunit (1
and 2
) and has been found to reduce calcium currents after chronic but not acute application via an effect on trafficking of voltage-dependent calcium channels in the central nervous system
. This effect on calcium channel trafficking is another possible mechanism of action of gabapentin, but the exact mechanism remains in dispute.
developed a drug called pregabalin
to be a successor of gabapentin. Pregabalin was brought to market by Pfizer as Lyrica after the company acquired Warner-Lambert. Pregabalin is related in structure to gabapentin and is approved for treatment of epilepsy, neuropathic pain associated with diabetes, fibromyalgia
, post-herpetic neuralgia, and generalized anxiety disorder.
Compared to gabapentin, pregabalin is more potent, absorbs faster and has greater bioavailability. Higher potency means that less of the medication is required for the same effect. This does not necessarily result in fewer side effects. Another new drug atagabalin
has been trialled by Pfizer as a treatment for insomnia
. One must remain skeptical of industry run trials as, despite significant monetary damages awarded in trials discussed below, there is no certainty the company is not still suppressing negative or equivocal data and news reports indicate this may be the case with pregabalin
as well.
subsidiary Parke-Davis
. A Pfizer subsidiary named Greenstone markets generic gabapentin.
In December 2004, the FDA granted final approval to a generic equivalent to Neurontin made by the Israeli firm Teva
.
Neurontin is one of Pfizer's best-selling drugs, and was one of the 50 most-prescribed drugs
in the United States
in 2003. However, Pfizer has come under heavy criticism and serious litigation for its marketing of Neurontin, facing allegations that, behind the scenes, Parke-Davis
marketed the drug for at least a dozen supposed uses for which the drug had not been FDA approved. Today it is a mainstay drug for migraines, even though it was not approved for such use in 2004.
was added for treating postherpetic neuralgia
(neuropathic pain following shingles).
painful diabetic peripheral neuropathy (DPN) and postherpetic
neuralgia (PHN)."
While it is often prescribed off-label
(that is, at the discretion of a physician) for various conditions, this use is probably frequently due to the widespread illicit marketing Pfizer was convicted of, which was communicated via promotional messages through advisory boards, consultants’ meetings, and accredited continuing medical education events posing as independent third-party organizations, co-opting opinion leaders, educational enterprises and academia in their marketing campaign.
admitted that there had been violations of FDA guidelines regarding the promotion of unproven off-label uses for gabapentin in the Franklin v. Pfizer case. In addition, the FDA black box warning states: "Antiepileptic drugs (AEDs), including Neurontin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication."
Despite this controversy, many psychiatrists continue to prescribe it for a variety of off-label purposes. Oftentimes, it is tried as an alternative treatment when patients are unable to tolerate the side effects of more proven mood stabilizers such as lithium. More frequently, it is prescribed on a speculative basis as an auxiliary treatment, when single-drug therapy has consistently failed to yield sufficient positive results.
Reuters
reported on March 25, 2010 that "Pfizer Inc... violated federal racketeering law by improperly promoting the epilepsy drug Neurontin... Under federal RICO
law... the penalty is automatically tripled, so the finding will cost Pfizer $141 million." The case stems from a claim from Kaiser Foundation Health Plan Inc. that "it was misled into believing Neurontin was effective for off-label treatment of migraines, bipolar disorder and other conditions. Pfizer argued that Kaiser physicians still recommend the drug for those uses."
Bloomberg News (3/26/10, Voris, Lawrence) added that "during the trial, Pfizer argued that Kaiser doctors continued to prescribe the drug even after the health insurer sued Pfizer in 2005. The insurer's website also still lists Neurontin as a drug for neuropathic pain, Pfizer lawyers said in closing argument."
The Wall Street Journal (3/26/10, Kamp) noted that Pfizer spokesman Christopher Loder said, "We are disappointed with the verdict and will pursue post-trial motions and an appeal." "The verdict and the judge's rulings are not consistent with the facts and the law," he added, according to Reuters (3/26/10, Berkrot).
prescriptions account for roughly 90% of Neurontin sales.
While off-label prescriptions are common for a number of drugs and are perfectly legal (if not always appropriate), marketing of off-label uses of a drug is strictly illegal. In 2004, Warner-Lambert agreed to plead guilty and pay $430 million in fines to settle civil and criminal charges regarding the illegal marketing of Neurontin for off-label purposes, and further legal action is pending. The courts of New York State, for example, have refused to certify a class of injured parties who took Neurontin for off-label use, finding that they had failed to state that they had any injury.
The University of California, San Francisco
(UCSF) has archived and studied the documents made public by this case, which opens a unique window into the illegal promotion and marketing of pharmaceuticals. However, Pfizer maintains that the illegal activity originated in 1996, well before it acquired Parke-Davis
(through its acquisition of Warner-Lambert) in 2000. Several lawsuits are underway after people who had been prescribed gabapentin for off-label treatment of bipolar disorder later attempted or committed suicide
.
, a subsequent Pfizer spin-off, is a controlled substance under Schedule V of the United States' Controlled Substances Act
.
Staggering
Because of perceived low bioavaliablity, a commonly reported method of Gabapentin usage is staggering, as reported on drug-experience sharing websites such as Bluelight and Erowid1. Staggering involves taking more than the prescribed daily amount of drug, often over an interval of half hours or longer. The method sometimes include food with the repeated dosings. Users have reported mixed feelings; ranging from euphoria to nausea and chest tension.. Gastrointestinal side effects of very high doses of gabapentin are extremely common. Profuse diarrea is common with doses of gabapentin exceeding 4800mg at a time, or perhaps more over the course of a day. It is likely that the large quantities of binders and fillers in gabapentin tablets cause diarrea, although the sheer volume of the alkaloid itself needed to produce recreational effects may irritate the GI tract causing the diarreah. The effects of staggering are intended to maximize the saturation along it's main transporter. Because Gabapentin's mechanism for action remains relatively unknown, especially because additional research is needed into it's effects on bipolar and psychological disorders, the tendency of users to experiment and self-regulate the acceptable levels of gabapentin in them should be considered when examining it's adverse effects. It is actively absorbed via the L amino acid transporter system. Because it is a non-plasma-bound renally excreted drug, it is entirely eliminated by the kidneys.
Other methods of recreational Gabapentin abuse are chewing the time-released pills into a powder that can be absorbed through swallowing or absorption into the lining of the mouth. Snorting a powdery residue of chopped-up Gabapentin is reported as well, although highly ill-advised. Such abuse led to the removal of gabapentin in certain California correctional facilities ,.
Neurocognitive Effects with Other Interactions
Alcohol Dependence
While symptoms of abrupt gabapentin withdrawal are many-fold, a study has combined gabapentin and flumazenil, a benzodiapazine antagonist, in order to measure cognitive performance on individual's in the beginning stages of alcohol withdrawal. The research impetus came from the GABA and glutamate signaling that occurs during alcohol withdrawal. The study observed for improvement of response inhibitions between subjects that had received treatment versus a group receiving a placebo; over 60 alcohol-dependent participants were evaluated.
The results were moderate; the gabapentin and flumazenil treatment slightly improved response inhibition task during the early phases of abstinence, and this corresponds to many self-testimonials. However the quality of the overall impact was mixed and the medication cannot be said to improve alcoholic relapse; however it has the potential to subdue early withdrawal discomforts when combined with the benzodiapazine receptor antagonist.
Cocaine
Frequently mentioned online in drug-experience sharing websites, Gabapentin has been considered for reducing cocaine use or assisting in cocaine withdrawal because of it's GABAergic feedback properties. One study chose nine individuals with cocaine withdrawal symptoms from a clincial setting. Gabapentin presence was tested over a 24-week trial; the study concluded that Gabapentin may be a useful medicine for reducing cocaine usage in addicted patients, especially during the early weeks of any attempt to come clean.
which is toxic to dogs, so care must be taken if the human version is used for veterinary purposes.
Gamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
analogue. It was originally developed for the treatment of epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
, and currently is also used to relieve neuropathic pain
Neuropathic pain
Neuropathic pain results from lesions or diseases affecting the somatosensory system. It may be associated with abnormal sensations called dysesthesia, which occur spontaneously and allodynia that occurs in response to external stimuli. Neuropathic pain may have continuous and/or episodic ...
. There are, however, concerns regarding the quality of the trials conducted.
Medical uses
Gabapentin is used primarily for the treatment of seizures, neuropathic painNeuropathic pain
Neuropathic pain results from lesions or diseases affecting the somatosensory system. It may be associated with abnormal sensations called dysesthesia, which occur spontaneously and allodynia that occurs in response to external stimuli. Neuropathic pain may have continuous and/or episodic ...
, and hot flashes. There are, however, concerns regarding the quality of the research on its use to treat migraines, bipolar disorders, and pain.
Pain
Gabapentin provides significant pain relief in about a third of people who take it for fibromyalgiaFibromyalgia
Fibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...
or chronic neuropathic pain
Neuropathic pain
Neuropathic pain results from lesions or diseases affecting the somatosensory system. It may be associated with abnormal sensations called dysesthesia, which occur spontaneously and allodynia that occurs in response to external stimuli. Neuropathic pain may have continuous and/or episodic ...
. It is also effective in reducing narcotic
Narcotic
The term narcotic originally referred medically to any psychoactive compound with any sleep-inducing properties. In the United States of America it has since become associated with opioids, commonly morphine and heroin and their derivatives, such as hydrocodone. The term is, today, imprecisely...
usage post operatively and is helpful in neuropathic pain due to cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. It has not been shown to be useful for HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
associated sensory neuropathy. When used for neuropathic pain it does not appear superior to carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
. Further evidence is needed to determine if it is effective for migraine
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
prevention. It appears to be equally effective as pregabalin
Pregabalin
Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. It has also been found effective for generalized anxiety disorder and is approved for this use in the European Union. It was designed...
and is of lower cost. It does not appear to be of benefit in treating complex regional pain syndrome
Complex regional pain syndrome
Complex regional pain syndrome is a chronic progressive disease characterized by severe pain, swelling and changes in the skin. It often affects an arm or a leg and may spread to another part of the body.Though treatment is often unsatisfactory, early multimodal therapy can cause dramatic...
.
Seizures
Gabapentin is approved for treatment of focal seizuresFocal seizures
Partial seizures are seizures which affect only a part of the brain at onset. The brain is divided into two hemispheres, each consisting of four lobes - the frontal, temporal, parietal and occipital lobes...
in a number of countries and evidence supports it use for treating partial and mixed seizure disorders however there is insufficient evidence for it use in generalized epilepsy. There is little data to support its initial use over older anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
medication for any type of seizure disorder.
Other
There is some evidence of benefit in acquired pendular nystagmus and infantile nystagmus but not in periodic alternating nystagmus.Gabapentin may help with menopausal symptoms. It may be effective in reducing pain and spasticity in multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
. Gabapentin has been used to treat some symptoms of opiate withdrawal, but tests for smoking cessation
Smoking cessation
Smoking cessation is the process of discontinuing the practice of inhaling a smoked substance. This article focuses exclusively on cessation of tobacco smoking; however, the methods described may apply to cessation of smoking other substances that can be difficult to stop using due to the...
treatment have had mixed results.
Negative
Gabapentin has been prescribed in the mental health context. Numerous trials show that it is not effective as a mood-stabilizingMood stabilizer
A mood stabilizer is a psychiatric medication used to treat mood disorders characterized by intense and sustained mood shifts, typically bipolar disorder.-Uses:...
treatment for bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
and so has no therapeutic advantage in having fewer side-effects over better established bipolar drugs such as lithium
Lithium pharmacology
Lithium pharmacology refers to use of the lithium ion, Li+, as a drug. A number of chemical salts of lithium are used medically as a mood stabilizing drug, primarily in the treatment of bipolar disorder, where they have a role in the treatment of depression and particularly of mania, both acutely...
and valproic acid
Valproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
. Gabapentin has limited usefulness in the treatment of anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
disorders such as social anxiety disorder
Social anxiety disorder
Social anxiety disorder , also known as social phobia, is an anxiety disorder characterized by intense fear in social situations causing considerable distress and impaired ability to function in at least some parts of daily life...
and obsessive-compulsive disorder
Obsessive-compulsive disorder
Obsessive–compulsive disorder is an anxiety disorder characterized by intrusive thoughts that produce uneasiness, apprehension, fear, or worry, by repetitive behaviors aimed at reducing the associated anxiety, or by a combination of such obsessions and compulsions...
, in treatment-resistant depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
, and for insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
. Gabapentin can also cause weight gain.
A double blind, randomized controlled
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
found gabapentin ineffective for the treatment of idiopathic subjective tinnitus
Tinnitus
Tinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...
.
Adverse effects
Gabapentin's most common side effects in adult patients include dizziness, drowsiness, and peripheral edemaPeripheral edema
Peripheral edema is the swelling of tissues, usually in the lower limbs, due to the accumulation of fluids.The condition is commonly associated with aging, but can be caused by many other conditions, including congestive heart failure, trauma, alcoholism, altitude sickness, pregnancy,...
(swelling of extremities); these mainly occur at higher doses in the elderly. Also, children 3–12 years of age were observed to be susceptible to mild-to-moderate mood swings, hostility, concentration problems, and hyperactivity. Although rare, there are several cases of hepatotoxicity
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
reported in the literature. Gabapentin should be used carefully in patients with renal impairment
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
due to possible accumulation and toxicity.
An increase in formation of adenocarcinoma
Adenocarcinoma
Adenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body. Epithelium can be derived embryologically from...
s was observed in rats during preclinical trials; however, the clinical significance of these results remains undetermined. Gabapentin is also known to induce pancreatic acinar cell carcinomas in rats through an unknown mechanism, perhaps by stimulation of DNA synthesis; these tumors did not affect the lifespan of the rats and did not metastasize.
Suicide
Gabapentin has been associated with an increased risk of suicidal acts or violent deaths. In 2009, the FDA issued a warning of an increased risk of depression and suicidal thoughts and behaviors in patients taking gabapentin, along with other anticonvulsant drugs modifying the packaging insertBlack box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
to reflect this. In July 2009, the manufacturer of gabapentin (Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
) went to trial regarding the association between gabapentin and the increased risk of suicide.
Withdrawal
Gabapentin should not be discontinued abruptly after long term use. Abrupt or over rapid withdrawal may provoke a withdrawal syndrome reminiscent to alcoholAlcohol withdrawal syndrome
-Protracted withdrawal:A protracted alcohol withdrawal syndrome occurs in many alcoholics where withdrawal symptoms continue beyond the acute withdrawal stage but usually at a subacute level of intensity and gradually decreasing with severity over time. This syndrome is also sometimes referred to...
or benzodiazepine withdrawal. Gradual reduction over a period of weeks or months helps minimize or prevents the withdrawal syndrome.
Side effects upon discontinuation of gabapentin that have been reported in medical literature include insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, restlessness, agitation
Agitation
Agitation may refer to:* Agitation , putting into motion by shaking or stirring* Emotional state of excitement or restlessness** Psychomotor agitation, an extreme form of the above, which can be a side effect of antipsychotic medication...
, anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, disorientation, confusion
ConFusion
ConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...
, light sensitivity
Light sensitivity
Light sensitivity or photosensitivity is an increase in the reactivity of the skin to sunlight. Apart from vision, human beings have many physiological and psychological responses to light. In rare individuals an atypical response may result in serious discomfort, disease, or injury. Some drugs...
, diaphoresis
Diaphoresis
Diaphoresis is excessive sweating commonly associated with shock and other medical emergency conditions.Diaphoretic is the state of perspiring profusely, or something that has the power to cause increased perspiration....
, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
s, palpitation
Palpitation
A palpitation is an abnormality of heartbeat that causes a conscious awareness of its beating, whether it is too slow, too fast, irregular, or at its normal frequency. The word may also refer to this sensation itself...
s, hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, chest pain
Chest pain
Chest pain may be a symptom of a number of serious conditions and is generally considered a medical emergency. Even though it may be determined that the pain is non-cardiac in origin, this is often a diagnosis of exclusion made after ruling out more serious causes of the pain.-Differential...
, and flu-like symptoms
Influenza-like illness
Influenza-like illness , also known as acute respiratory infection and flu-like syndrome, is a medical diagnosis of possible influenza or other illness causing a set of common symptoms, with SARI referring to Severe Acute Respiratory Infection.Symptoms commonly include fever, shivering, chills,...
. In at least one case, abrupt cessation of a high dose of gabapentin triggered a seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
in an individual with no history of epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
.
Overdosage
Persons who accidentally or intentionally ingested overdoses have manifested drowsiness, blurred vision, slurred speech and somnolenceSomnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
or coma. Serum gabapentin concentrations may be measured to confirm diagnosis.
Pharmacology
Gabapentin was initially synthesized to mimic the chemical structureChemical structure
A chemical structure includes molecular geometry, electronic structure and crystal structure of molecules. Molecular geometry refers to the spatial arrangement of atoms in a molecule and the chemical bonds that hold the atoms together. Molecular geometry can range from the very simple, such as...
of the neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
gamma-aminobutyric acid (GABA), but is not believed to act on the same brain receptors.
One possible mechanism of action
Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
, reported by Ben Barres of Stanford University and colleagues in Cell
Cell (journal)
Cell is a peer-reviewed scientific journal publishing research papers across a broad range of disciplines within the life sciences. Areas covered include molecular biology, cell biology, systems biology, stem cells, developmental biology, genetics and genomics, proteomics, cancer research,...
in 2009, was that gabapentin halts the formation of new synapses. Gabapentin binds to the α2δ subunit (1
CACNA2D1
Voltage-dependent calcium channel subunit alpha-2/delta-1 is a protein that in humans is encoded by the CACNA2D1 gene.- External links :...
and 2
CACNA2D2
Voltage-dependent calcium channel subunit alpha2delta-2 is a protein that in humans is encoded by the CACNA2D2 gene....
) and has been found to reduce calcium currents after chronic but not acute application via an effect on trafficking of voltage-dependent calcium channels in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. This effect on calcium channel trafficking is another possible mechanism of action of gabapentin, but the exact mechanism remains in dispute.
Related drugs
Parke-DavisParke-Davis
Parke-Davis is a subsidiary of the pharmaceutical company Pfizer. Although no longer an independent corporation, it was once America's oldest and largest drug maker, and played an important role in medical history.- History :...
developed a drug called pregabalin
Pregabalin
Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. It has also been found effective for generalized anxiety disorder and is approved for this use in the European Union. It was designed...
to be a successor of gabapentin. Pregabalin was brought to market by Pfizer as Lyrica after the company acquired Warner-Lambert. Pregabalin is related in structure to gabapentin and is approved for treatment of epilepsy, neuropathic pain associated with diabetes, fibromyalgia
Fibromyalgia
Fibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...
, post-herpetic neuralgia, and generalized anxiety disorder.
Compared to gabapentin, pregabalin is more potent, absorbs faster and has greater bioavailability. Higher potency means that less of the medication is required for the same effect. This does not necessarily result in fewer side effects. Another new drug atagabalin
Atagabalin
Atagabalin is a drug developed by Pfizer and related to gabapentin, which similarly binds to the α2δ calcium channels . It is under development as a treatment for insomnia....
has been trialled by Pfizer as a treatment for insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
. One must remain skeptical of industry run trials as, despite significant monetary damages awarded in trials discussed below, there is no certainty the company is not still suppressing negative or equivocal data and news reports indicate this may be the case with pregabalin
Pregabalin
Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. It has also been found effective for generalized anxiety disorder and is approved for this use in the European Union. It was designed...
as well.
Sales
Gabapentin is best known under the brand name Neurontin manufactured by PfizerPfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
subsidiary Parke-Davis
Parke-Davis
Parke-Davis is a subsidiary of the pharmaceutical company Pfizer. Although no longer an independent corporation, it was once America's oldest and largest drug maker, and played an important role in medical history.- History :...
. A Pfizer subsidiary named Greenstone markets generic gabapentin.
In December 2004, the FDA granted final approval to a generic equivalent to Neurontin made by the Israeli firm Teva
Teva Pharmaceutical Industries
Teva Pharmaceutical Industries Ltd. , is an international pharmaceutical company headquartered in Petah Tikva, Israel. It specializes in generic and proprietary pharmaceuticals and active pharmaceutical ingredients...
.
Neurontin is one of Pfizer's best-selling drugs, and was one of the 50 most-prescribed drugs
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
in 2003. However, Pfizer has come under heavy criticism and serious litigation for its marketing of Neurontin, facing allegations that, behind the scenes, Parke-Davis
Parke-Davis
Parke-Davis is a subsidiary of the pharmaceutical company Pfizer. Although no longer an independent corporation, it was once America's oldest and largest drug maker, and played an important role in medical history.- History :...
marketed the drug for at least a dozen supposed uses for which the drug had not been FDA approved. Today it is a mainstay drug for migraines, even though it was not approved for such use in 2004.
FDA approval
Gabapentin was originally approved by the U.S. Food and Drug Administration (FDA) in 1994 for use as an adjunctive medication to control partial seizures (effective when added to other antiseizure drugs). In 2002, an indicationIndication (medicine)
In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. The opposite of indication is contraindication.-Drugs:...
was added for treating postherpetic neuralgia
Postherpetic neuralgia
Postherpetic neuralgia is a neuralgia caused by the varicella zoster virus. Typically, the neuralgia is confined to a dermatomic area of the skin and follows an outbreak of herpes zoster in that same dermatomic area...
(neuropathic pain following shingles).
Legal action
Numerous cases have been brought against the makers of Neurontin, with convictions arising not only for the illegal promotion of off-label uses. Much of the popular use of Neurontin among physicians stems from the widespread illicit marketing that Pfizer was convicted of, which was communicated via promotional messages through advisory boards, consultants’ meetings, and accredited continuing medical education events posing as independent third-party organizations, co-opting opinion leaders, educational enterprises and academia in their marketing campaign. The convictions for fraud set a new standard that goes beyond “scientific misconduct” and elevates the seriousness of the suppression of negative or unsupportive evidence as a form of fraud. As part of a case (CIVIL ACTION NO. 04-cv-10739-PBS) brought by Kaiser Foundation Health Plan against Pfizer, it was noted that "The general neuropathic pain indication cannot be granted for Neurontin based on the clinical trials inpainful diabetic peripheral neuropathy (DPN) and postherpetic
neuralgia (PHN)."
While it is often prescribed off-label
Off-label use
Off-label use is the practice of prescribing pharmaceuticals for an unapproved indication or in an unapproved age group, unapproved dose or unapproved form of administration...
(that is, at the discretion of a physician) for various conditions, this use is probably frequently due to the widespread illicit marketing Pfizer was convicted of, which was communicated via promotional messages through advisory boards, consultants’ meetings, and accredited continuing medical education events posing as independent third-party organizations, co-opting opinion leaders, educational enterprises and academia in their marketing campaign.
Off label promotion
Off-label use of gabapentin for psychiatric off-label use also resulted in convictions. Although some small, non-controlled studies in the 1990s — mostly sponsored by gabapentin's manufacturer — suggested that gabapentin treatment for bipolar disorder may be promising, other more recent and better controlled studies have found it to be no more effective (and in one study, slightly less effective) than placebo. Subsequent to the corporate acquisition of the original patent holder, the pharmaceutical company PfizerPfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
admitted that there had been violations of FDA guidelines regarding the promotion of unproven off-label uses for gabapentin in the Franklin v. Pfizer case. In addition, the FDA black box warning states: "Antiepileptic drugs (AEDs), including Neurontin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication."
Despite this controversy, many psychiatrists continue to prescribe it for a variety of off-label purposes. Oftentimes, it is tried as an alternative treatment when patients are unable to tolerate the side effects of more proven mood stabilizers such as lithium. More frequently, it is prescribed on a speculative basis as an auxiliary treatment, when single-drug therapy has consistently failed to yield sufficient positive results.
Reuters
Reuters
Reuters is a news agency headquartered in New York City. Until 2008 the Reuters news agency formed part of a British independent company, Reuters Group plc, which was also a provider of financial market data...
reported on March 25, 2010 that "Pfizer Inc... violated federal racketeering law by improperly promoting the epilepsy drug Neurontin... Under federal RICO
RICO
-Music:*Rico , a 2000 album by Matt Bianco*"Rico" , a 1998 song the Matthew Good Band from the album Underdogs*Rico International, a manufacturer of reeds, mouthpieces, and woodwind accessories...
law... the penalty is automatically tripled, so the finding will cost Pfizer $141 million." The case stems from a claim from Kaiser Foundation Health Plan Inc. that "it was misled into believing Neurontin was effective for off-label treatment of migraines, bipolar disorder and other conditions. Pfizer argued that Kaiser physicians still recommend the drug for those uses."
Bloomberg News (3/26/10, Voris, Lawrence) added that "during the trial, Pfizer argued that Kaiser doctors continued to prescribe the drug even after the health insurer sued Pfizer in 2005. The insurer's website also still lists Neurontin as a drug for neuropathic pain, Pfizer lawyers said in closing argument."
The Wall Street Journal (3/26/10, Kamp) noted that Pfizer spokesman Christopher Loder said, "We are disappointed with the verdict and will pursue post-trial motions and an appeal." "The verdict and the judge's rulings are not consistent with the facts and the law," he added, according to Reuters (3/26/10, Berkrot).
Franklin v. Pfizer case
By some estimates, off-labelOff-label use
Off-label use is the practice of prescribing pharmaceuticals for an unapproved indication or in an unapproved age group, unapproved dose or unapproved form of administration...
prescriptions account for roughly 90% of Neurontin sales.
While off-label prescriptions are common for a number of drugs and are perfectly legal (if not always appropriate), marketing of off-label uses of a drug is strictly illegal. In 2004, Warner-Lambert agreed to plead guilty and pay $430 million in fines to settle civil and criminal charges regarding the illegal marketing of Neurontin for off-label purposes, and further legal action is pending. The courts of New York State, for example, have refused to certify a class of injured parties who took Neurontin for off-label use, finding that they had failed to state that they had any injury.
The University of California, San Francisco
University of California, San Francisco
The University of California, San Francisco is one of the world's leading centers of health sciences research, patient care, and education. UCSF's medical, pharmacy, dentistry, nursing, and graduate schools are among the top health science professional schools in the world...
(UCSF) has archived and studied the documents made public by this case, which opens a unique window into the illegal promotion and marketing of pharmaceuticals. However, Pfizer maintains that the illegal activity originated in 1996, well before it acquired Parke-Davis
Parke-Davis
Parke-Davis is a subsidiary of the pharmaceutical company Pfizer. Although no longer an independent corporation, it was once America's oldest and largest drug maker, and played an important role in medical history.- History :...
(through its acquisition of Warner-Lambert) in 2000. Several lawsuits are underway after people who had been prescribed gabapentin for off-label treatment of bipolar disorder later attempted or committed suicide
Suicide
Suicide is the act of intentionally causing one's own death. Suicide is often committed out of despair or attributed to some underlying mental disorder, such as depression, bipolar disorder, schizophrenia, alcoholism, or drug abuse...
.
Recreational use
Although gabapentin is not a controlled substance, it does produce psychoactive effects that cause it to have potential for recreational use. Even in low doses, gabapentin causes sensations of reduced acute pain, reduced anxiety and even a tendency to become overly social and talkative. Larger doses can cause the user to become numb and even fully insensate. Tolerance to gabapentin occurs extremely rapidly with recreational use, with the user often needing to double the dosage within a day or two of misuse. Although it is widely regarded as having little or no potential for misuse, it is often a misused drug in Canadian Northern communities and among inmates in California State prisons. However, PregabalinPregabalin
Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. It has also been found effective for generalized anxiety disorder and is approved for this use in the European Union. It was designed...
, a subsequent Pfizer spin-off, is a controlled substance under Schedule V of the United States' Controlled Substances Act
Controlled Substances Act
The Controlled Substances Act was enacted into law by the Congress of the United States as Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970. The CSA is the federal U.S. drug policy under which the manufacture, importation, possession, use and distribution of certain...
.
Staggering
Because of perceived low bioavaliablity, a commonly reported method of Gabapentin usage is staggering, as reported on drug-experience sharing websites such as Bluelight and Erowid1. Staggering involves taking more than the prescribed daily amount of drug, often over an interval of half hours or longer. The method sometimes include food with the repeated dosings. Users have reported mixed feelings; ranging from euphoria to nausea and chest tension.. Gastrointestinal side effects of very high doses of gabapentin are extremely common. Profuse diarrea is common with doses of gabapentin exceeding 4800mg at a time, or perhaps more over the course of a day. It is likely that the large quantities of binders and fillers in gabapentin tablets cause diarrea, although the sheer volume of the alkaloid itself needed to produce recreational effects may irritate the GI tract causing the diarreah. The effects of staggering are intended to maximize the saturation along it's main transporter. Because Gabapentin's mechanism for action remains relatively unknown, especially because additional research is needed into it's effects on bipolar and psychological disorders, the tendency of users to experiment and self-regulate the acceptable levels of gabapentin in them should be considered when examining it's adverse effects. It is actively absorbed via the L amino acid transporter system. Because it is a non-plasma-bound renally excreted drug, it is entirely eliminated by the kidneys.
Other methods of recreational Gabapentin abuse are chewing the time-released pills into a powder that can be absorbed through swallowing or absorption into the lining of the mouth. Snorting a powdery residue of chopped-up Gabapentin is reported as well, although highly ill-advised. Such abuse led to the removal of gabapentin in certain California correctional facilities ,.
Neurocognitive Effects with Other Interactions
Alcohol Dependence
While symptoms of abrupt gabapentin withdrawal are many-fold, a study has combined gabapentin and flumazenil, a benzodiapazine antagonist, in order to measure cognitive performance on individual's in the beginning stages of alcohol withdrawal. The research impetus came from the GABA and glutamate signaling that occurs during alcohol withdrawal. The study observed for improvement of response inhibitions between subjects that had received treatment versus a group receiving a placebo; over 60 alcohol-dependent participants were evaluated.
The results were moderate; the gabapentin and flumazenil treatment slightly improved response inhibition task during the early phases of abstinence, and this corresponds to many self-testimonials. However the quality of the overall impact was mixed and the medication cannot be said to improve alcoholic relapse; however it has the potential to subdue early withdrawal discomforts when combined with the benzodiapazine receptor antagonist.
Cocaine
Frequently mentioned online in drug-experience sharing websites, Gabapentin has been considered for reducing cocaine use or assisting in cocaine withdrawal because of it's GABAergic feedback properties. One study chose nine individuals with cocaine withdrawal symptoms from a clincial setting. Gabapentin presence was tested over a 24-week trial; the study concluded that Gabapentin may be a useful medicine for reducing cocaine usage in addicted patients, especially during the early weeks of any attempt to come clean.
Veterinary use
Gabapentin is also used for some animal treatments, but formulations (especially liquid forms) for human use may contain the sweetener XylitolXylitol
Xylitol is a sugar alcohol sweetener used as a naturally occurring sugar substitute. It is found in the fibers of many fruits and vegetables, and can be extracted from various berries, oats, and mushrooms, as well as fibrous material such as corn husks and sugar cane bagasse, and birch...
which is toxic to dogs, so care must be taken if the human version is used for veterinary purposes.
External links
- Gabapentin information from MedlinePlus
- Gabapentin PubMed Health. National Center for Biotechnology Information (NCBI)
- News Article regarding Neurontin settlement and off-label marketing/use
- Website for the pending Class Action Lawsuit against Pfizer
- U.S. FDA information on safety of antiepileptics
- Bloomberg News on Neurontin lawsuit
- U.S. National Library of Medicine: Drug Information Portal - Gabapentin
- ErowidErowidErowid, also called The Vaults of Erowid, is an online library of information about psychoactive plants and chemicals and other topics on altered states of consciousness such as meditation and lucid dreaming. It provides information about legal and illegal substances, including their desired and...
Gabapentin Vault