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

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.

The exact mechanism of action with the GABA receptors is unknown; however, researchers know that gabapentin freely passes the blood-brain barrier and acts on neurotransmitters.

Gabapentin has a cyclohexyl group to the structure of neurotransmitter GABA as a chemical structure. Even though it has a similar structure to GABA, it does not bind to GABA receptors and does not influence the synthesis or uptake of GABA.

Gabapentin works by showing a high affinity for binding sites throughout the brain correspondent to the presence of the voltage-gated calcium channels, especially alpha-2-delta-1, which seems to inhibit the release of excitatory neurotransmitters in the presynaptic area which participate in epileptogenesis.

Even though there is no evidence for direct action at the serotonin, dopamine, benzodiazepine, or histamine receptors, research has shown gabapentin to increase total-blood levels of serotonin in healthy control subjects.

The elimination half-life of gabapentin is 5 to 7 hours, and it takes two days for the body to eliminate gabapentin from its system.

One benefit of gabapentin use is its mild side-effect profile. The most common side effects are fatigue, dizziness, and headache.

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

There are several non-pharmacological approaches that may help alleviate the symptoms of restless legs syndrome (RLS), including:

  1. Regular exercise: Engaging in moderate exercise, such as walking or yoga, on a regular basis may help reduce symptoms of RLS.
  2. Hot or cold compresses: Applying a hot or cold compress to the legs may help alleviate discomfort and reduce the urge to move the legs.
  3. Massage: Gentle massage or self-massage of the legs may help relax muscles and improve circulation.
  4. Compression stockings: Wearing compression stockings or socks may help improve blood flow and reduce symptoms of RLS.
  5. Relaxation techniques: Practicing relaxation techniques, such as deep breathing, meditation, or progressive muscle relaxation, may help reduce stress and tension in the body, which can exacerbate symptoms of RLS.
  6. Maintaining a regular sleep schedule: Establishing a regular sleep schedule, including a consistent bedtime and wake-up time, may help improve sleep quality and reduce symptoms of RLS.
  7. Avoiding triggers: Avoiding triggers such as caffeine, alcohol, and nicotine, as well as certain medications, may help reduce symptoms of RLS.

It is important to note that these approaches may not work for everyone with RLS, and individuals should talk to their healthcare provider before starting any new treatment regimen.

There are several medications that may be prescribed to alleviate the symptoms of restless legs syndrome (RLS), including:

  1. Dopamine agonists: These medications increase the levels of dopamine, a neurotransmitter that helps regulate movement and sensation, in the brain. Examples include pramipexole (Mirapex), ropinirole (Requip), and rotigotine (Neupro).
  2. Iron supplements: Iron deficiency can contribute to RLS symptoms, so taking iron supplements may help alleviate symptoms in some individuals.
  3. Anticonvulsants: Certain anticonvulsant medications, such as gabapentin (Neurontin) and pregabalin (Lyrica), may help alleviate symptoms of RLS by modulating the levels of certain neurotransmitters in the brain.
  4. Opioids: In some cases, opioids such as oxycodone or hydrocodone may be prescribed to alleviate severe symptoms of RLS, although their use is generally reserved for individuals with severe symptoms who have not responded to other treatments.

It is important to note that all medications carry some risks, and individuals should talk to their healthcare provider about the potential benefits and risks of any medication before starting treatment. In addition, treatment for RLS may need to be adjusted over time, as the effectiveness of certain medications may diminish or side effects may become problematic.

Can I Drive or Ride a Bike After I Take Gabapentin ?

Gabapentin is used with other medications to prevent and control seizures. It is also used to relieve nerve pain following shingles (a painful rash due to herpes zoster infection) in adults.

Gabapentin is known as an anticonvulsant or antiepileptic drug.

You may feel sleepy, tired or dizzy when you first start taking gabapentin. This may also happen if your dose has increased.

If this happens to you, do not drive or ride a bike until you feel better.

It’s an offence to drive a car if your ability to drive safely is affected. It’s your responsibility to decide if it’s safe to drive. If you’re in any doubt, do not drive.

If you have epilepsy, you are generally not allowed to drive until:

    • you have not had any seizures (while awake) for 1 year
    • you have only had seizures while you’re asleep

If you change your epilepsy medicine, your doctor will tell you whether you need to stop driving and for how long.