What is the Action Mechanism of Gabapentin ? Is Gabapentin Addictive ?

signs someone is addicted to gabapentin

The chemical structure of gabapentin (Neurontin) is derived by addition of a cyclohexyl group to the backbone of gamma-aminobutyric acid (GABA). Gabapentin prevents seizures in a wide variety of models in animals, including generalized tonic-clonic and partial seizures.

Gabapentin has no activity at GABAA or GABAB receptors of GABA uptake carriers of brain. Gabapentin interacts with a high-affinity binding site in brain membranes, which has recently been 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.

Is Gabapentin Addictive ?

Asking about the signs someone is addicted to gabapentin first begs the question: What is gabapentin?

To answer that question requires putting gabapentin in perspective as a pharmaceutical drug that, while providing relief to thousands of people for nerve pain, also has the potential for abuse. It isn’t an opioid, but it has found a niche audience among those who take it recreationally, and for doctors who began to seek alternatives to narcotics as the opioid epidemic reached its apex, it seemed like a safer alternative.

In 2016, gabapentin was the 10th most prescribed drug in the United States, with 64 million prescriptions written that year . That was up from 39 million prescriptions written only four years earlier, in large part because “gabapentin, an anticonvulsant and analgesic for postherpetic neuralgia, has been thought to have no abuse potential despite numerous published reports to the contrary,” according to a 2018 article in the journal Psychology of Addictive Behaviors.

In that particular article, researchers analyzed data from a study of drug users in Kentucky who reported using gabapentin for non-medical purposes. Their findings? “Overall, the sample reported having initiated gabapentin more than 10 years earlier after having it prescribed for a legitimate, though generally off-label, medical indication (e.g., pain, anxiety, opioid detoxification). Participants reported use of gabapentin in combination with buprenorphine, other opioids, cocaine, and caffeine to produce sought-after central nervous system effects (e.g., muscle relaxation, pain reduction, sleep induction, feeling drunk, and feeling ‘high’).”

Gabapentin, such studies reveal, can be problematic. Whether used in conjunction with other drugs or on its own, it can be abused, which makes it a substance of concern. To understand the signs someone is addicted to gabapentin, however, requires some knowledge of what it is, where it comes from, how it works and how it can be addictive.

Comparative Studies

Gabapentin and lamotrigine have been compared in an open, parallel-group, add-on, randomized study in 109 patients with uncontrolled partial epilepsy and learning disabilities. The two drugs were similarly efficacious, with similar incidences of adverse events and serious adverse events. Neither lamotrigine nor gabapentin exacerbated any of the challenging behaviors observed in these patients.

The most common adverse reaction to gabapentin was somnolence, which was mostly reported during the initial titration phase.

In a double-blind comparison of gabapentin and lamotrigine in 309 patients with new-onset partial or generalized seizures, the target doses were gabapentin 1800 mg/day and lamotrigine 150 mg/day.

Severe adverse events were reported in 11% of patients taking gabapentin and 9.3% of patients taking lamotrigine. Two patients had serious adverse events thought to be related to the study drug; one took an overdose of gabapentin and the other had convulsions with lamotrigine. The most frequent treatment-related adverse events in both treatment groups were dizziness, weakness, and headache; 11% of patients taking gabapentin and 15% of those taking lamotrigine withdrew because of adverse events. There was an increase of over 7% in body weight from baseline in 14% of the patients taking gabapentin and 6.6% of those taking lamotrigine. There were benign rashes in 4.4% of those taking gabapentin and 11% of those taking lamotrigine.

The hypothesis that both amitriptyline and gabapentin are more effective in relieving neuropathic pain than diphenhydramine has been tested in a randomized, double-blind, triple crossover, 8-week trial in 38 adults with spinal cord injuries [18]. Maximum daily doses were 2600 mg for gabapentin and 150 mg for amitriptyline.

Amitriptyline was more efficacious in relieving neuropathic pain than diphenhydramine. Withdrawal because of possible adverse reactions occurred five times during gabapentin treatment:

(1) shortness of breath;

(2) dizziness, fatigue, and nausea;

(3) increased spasticity and pain;

(4) fatigue, drowsiness, constipation, and dry mouth; and

(5) severe itching.

The four most frequent adverse events were dry mouth, drowsiness, fatigue, and constipation, which were all more common with amitriptyline.

 

Gabapentin is used to treat Restless Legs Syndrome

Restless legs syndrome (RLS) is a disorder of the part of the nervous system that causes an urge to move the legs. Because it usually interferes with sleep, it also is considered a sleep disorder.

 

Causes of Restless Legs Syndrome

In most cases, doctors do not know the cause of restless legs syndrome; however, they suspect that genes play a role. Nearly half of people with RLS also have a family member with the condition.

Other factors associated with the development or worsening of restless legs syndrome include:

  • Chronic diseases. Certain chronic diseases and medical conditions, including iron deficiency, Parkinson’s disease, kidney failure,diabetes, and peripheral neuropathy often include symptoms of RLS. Treating these conditions often gives some relief from RLS symptoms.
  • Medications. Some types of medications, including antinausea drugs, antipsychotic drugs, some antidepressants, and cold and allergymedications containing sedating antihistamines, may worsen symptoms.
  • Pregnancy. Some women experience RLS during pregnancy, especially in the last trimester. Symptoms usually go away within a month after delivery.

Other factors, including alcohol use and sleep deprivation, may trigger symptoms or make them worse. Improving sleep or eliminating alcohol use in these cases may relieve symptoms.

Treatment for Restless Legs Syndrome

Treatment for RLS is targeted at easing symptoms. In people with mild to moderate restless legs syndrome, lifestyle changes, such as beginning a regular exercise program, establishing regular sleep patterns, and eliminating or decreasing the use of caffeine, alcohol, and tobacco, may be helpful. Treatment of an RLS-associated condition also may provide relief of symptoms.

Other non-drug RLS treatments may include:

Leg massages
Hot baths or heating pads or ice packs applied to the legs
Good sleep habits
A vibrating pad called Relaxis
Medications may be helpful as RLS treatments, but the same drugs are not helpful for everyone. In fact, a drug that relieves symptoms in one person may worsen them in another. In other cases, a drug that works for a while may lose its effectiveness over time.

Drugs used to treat RLS include:

  • Dopaminergic drugs, which act on the neurotransmitter dopamine in the brain.
  • Mirapex, Neupro, and Requip are FDA-approved for treatment of moderate to severe RLS. Others, such as levodopa, may also be prescribed.
  • Benzodiazepines, a class of sedative medications, may be used to help with sleep, but they can cause daytime drowsiness.
  • Narcotic pain relievers may be used for severe pain.
  • Anticonvulsants, or antiseizure drugs, such as Tegretol, Lyrica, Gabapentin ( Neurontin ), and Horizant.

Although there is no cure for restless legs syndrome, current treatments can help control the condition, decrease symptoms, and improve sleep.

Usual Adult Dose for Restless Legs Syndrome

Gabapentin enacarbil available under the trade name Horizant (R):
600 mg orally once daily with food at about 5 PM

Take Gabapentin as an Anticonvulsant

Anticonvulsants (also commonly known as antiepileptic drugs or as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder and borderline personality disorder, since many seem to act as mood stabilizers, and for the treatment of neuropathic pain.

Anticonvulsants suppress the rapid and excessive firing of neurons during seizures. Anticonvulsants also prevent the spread of the seizure within the brain. Some investigators have observed that anticonvulsants themselves may cause reduced IQ in children.   However these adverse effects must be balanced against the significant risk epileptic seizures pose to children and the distinct possibility of death and devastating neurological sequelaesecondary to seizures.

Anticonvulsants are more accurately called antiepileptic drugs (abbreviated “AEDs”), and are often referred to as antiseizure drugs because they provide symptomatic treatment only and have not been demonstrated to alter the course of epilepsy.

Gabapentin (Neurontin) has been approved as adjunctive therapy in adults with partial seizures with or without secondary generalization . Begin with 300 mg daily; increase to 900 to 1,800 mg daily given every 6 to 8 hours.  Side Effects maybe: Somnolence, fatigue, ataxia, dizziness, gastrointestinal upset, dyspnea.

A gamma-aminobutyric acid (GABA) analog, gabapentin does not interact with GABA receptors. Its mechanism of action is unknown.

Gabapentin is well absorbed orally, circulates mostly unbound in the plasma and is excreted unchanged in the kidneys without appreciable metabolism in the body. Oral bioavailability is approximately 60 percent and is not affected by food. The half-life is five to seven hours and is related to the creatinine clearance. Therefore, excretion is decreased in patients with renal impairment and decreased cardiac function, and in elderly patients. Gabapentin can be removed from the system through hemodialysis.

In clinical studies,  gabapentin was found to be effective in adults with refractory partial seizures and was also effective in preventing the progression of partial seizures to generalized tonic-clonic seizures.

Because gabapentin has no known pharmacokinetic interactions with any other antiepileptic drugs, it is useful in patients taking other antiepileptic medication.