Gabapentin (Neurontin)

Based on "Essential Pain Pharmacology"
written by Howard S. Smith, MD; Marco Pappagallo, MD

History

Gabapentin was originally discovered over 40 years ago by the Japanese, who initially were looking for an antispasmodic or muscle relaxant. It was later sold to Parke-Davis (Warner-Lambert, which merged with Pfizer in 2000), who discovered effectiveness of gabapentin for treating epileptics. During Parke-Davis' initial clinical studies, Gabapentin was given in low doses and therefore efficacy was established as an add-on. In other words, the patient was first given another anti-convulsant, and then Gabapentin was added. Another study, being done at this time, but as yet incomplete, will establish Neurontin as a mono therapy. Currently, gabapentin is used by some doctors in doses up to 6,000 mg per day.

FDA approved indications

• Postherpetic neuralgia
• Epilepsy:
  Adjunctive therapy in the treatment of partial seizures with and without secondary generalization in patients over 12 years of age with epilepsy.
  Adjunctive therapy in the treatment of partial seizures in pediatric patients age 3–12 years.
• Moderate-to-severe restless legs syndrome (RLS) (Horizant® only)

Off-label & Investigational uses

• fibromyalgia 5
• bipolar disorder 8, 30
• postoperative analgesic 9
• migraine prophylaxis 10
• headache 31
• postmenopausal hot flashes 12
• interstitial cystitis (IC) 13
• painful diabetic neuropathy 14, 15
• social phobia 16
• depression 18
• panic disorder 19
• essential tremor 20
• generalized tonic-clonic seizures
• restless legs syndrome (RLS) 21, 22
• insomnia 23
• posttraumatic stress disorder (PTSD) 17
• irritable bowel syndrome (IBS) 24
• trigeminal neuralgia 25
• alcohol dependence 36
• refractory chronic cough 11
• postoperative nausea and vomiting 1
• itching (pruritus) 37

Gabapentin for Fibromyalgia
Gabapentin (1200-2400 mg per day) is safe and effective for the treatment of pain and other symptoms associated with fibromyalgia. In a 12-week, randomized, double-blind study a significantly greater proportion of gabapentin-treated patients achieved response than placebo-treated patients (51% versus 31%). Gabapentin compared with placebo also significantly improved the BPI average pain interference score, the Fibromyalgia Impact Questionnaire total score, the Clinical Global Impression of Severity, the Patient Global Impression of Improvement, the Medical Outcomes Study Sleep Problems Index , but not the mean tender point pain threshold or the Montgomery Asberg Depression Rating Scale 5.

Gabapentin for Bipolar disorder
Evidence suggests that it may have mood-stabilizing and possibly antidepressant properties in bipolar depression. However, gabapentin off-label use for bipolar disorder is increasingly controversial.

Gabapentin may have a role as adjunctive agent in the treatment of patients with bipolar disorders when complicated by co-morbid anxiety or substance abuse 29.

Small, randomized clinical trial comparing the prophylactic efficacy of adjunctive gabapentin to placebo has shown that, despite lack of acute efficacy, treatment with gabapentin may provide some benefitial long-term effects in bipolar disorder 3.

In small, uncontrolled, heterogeneous study gabapentin, either alone or as an adjunct, appeared moderately effective for depressive and manic symptoms 28.

The findings of placebo-controlled study did not demonstrate that gabapentin is an effective adjunctive treatment for patients with bipolar disorder 4.

Dosage for Bipolar disorder: The dosage in clinical trials examining gabapentin for mood stabilization ranged from 900 mg to 2400 mg per day in 3 divided doses.

Gabapentin for restless leg syndrome (RLS)
Restless legs syndrome is a disorder characterized by sensory and motor symptoms in the legs that is best treated with dopaminergic drugs and opiates. RLS is often difficult to treat. Gabapentin provides a well-tolerated and effective treatment of RLS. It improves sensory and motor symptoms in RLS and also improves sleep.

In clinical study gabapentin was associated with reduced symptoms on RLS Rating Scale, Clinical Global Impression, pain analogue scale, and Pittsburgh Sleep Quality Index. Also, studies showed significantly reduced periodic leg movements during sleep and improved sleep architecture (increased total sleep time, sleep efficiency, and slow wave sleep, and decreased stage 1 sleep). Patients whose symptoms included pain benefited most from gabapentin 22.

Gabapentin "pros" and "cons"

Advantages:

• Lack of cardiovascular or respiratory side effects
• Very good tolerability
• Benign side effect profile
• Lack of hepatic metabolism
• Lack of liver and enzyme-inducing or -inhibiting effects
• Absence of drug interactions with other AEDs
• Available in liquid formulation
• Gabapentin may be effective in treatment-resistant depression 18 and refractory bipolar disorder 30
• Can be rapidly titrated 32
• Broad therapeutic index -- gabapentin can be prescribed in a wide range of doses, based on individual patient needs, without increased risk of dose-dependent side effects.

Disadvantages:

• Delay in response due to need for dosage titration
• Dosage adjustment is required in patients with renal impairment
• Frequent dosing regimen due to the short half-life
• Low antiepileptic potency, not effective for all types of seizures 34, 35
• High rate of somnolence and dizziness 33
• Gabapentin may cause weight gain 7
• Possible withdrawal syndrome after discontinuation 8
• Decreased bioavailability at the high doses.
• Non-predictable dose-response relationship due to nonlinear pharmacokinetics requires careful titration.

Mechanism of action

The chemical structure of gabapentin is derived by addition of a cyclohexyl group to the backbone of neurotransmitter GABA (gamma-aminobutyric acid).

Gabapentin is structurally related to GABA. However, it does not bind to GABAA or GABAB receptors, and it does not appear to influence synthesis or uptake of GABA. High affinity gabapentin binding sites have been located throughout the brain; these sites correspond to the presence of voltage-gated calcium channels specifically possessing the alpha-2-delta-1 subunit. This channel appears to be located presynaptically, and may modulate the release of excitatory neurotransmitters which participate in epileptogenesis and nociception.

Analgesic action
Gabapentin works by changing the way in which nerves send messages to the brain.

The mechanism by which Gabapentin exerts its analgesic action is unknown, but in animal models of analgesia, Gabapentin prevents allodynia (pain-related behavior in response to a normally innocuous stimulus) and hyperalgesia (exaggerated response to painful stimuli). In particular, Gabapentin prevents pain-related responses in several models of neuropathic pain in rats or mice (e.g. spinal nerve ligation models, streptozocin-induced diabetes model, spinal cord injury model, acute herpes zoster model). It also decreases pain-related responses after peripheral inflammation (carrageenan footpad test, late phase of formalin test). Gabapentin did not alter immediate pain-related behaviors (rat tail flick test, formalin footpad acute phase, acetic acid abdominal constriction test, footpad heat irradiation test). The relevance of these models to human pain is not known.

Anticonvulsant action
The mechanism by which Gabapentin exerts its anticonvulsant action is unknown, but in animal test systems designed to detect anticonvulsant activity, Gabapentin prevents seizures as do other marketed anticonvulsants. Gabapentin exhibits antiseizure activity in mice and rats in both the maximal electroshock and pentylenetetrazole seizure models and other preclinical models (e.g., strains with genetic epilepsy, etc.). The relevance of these models to human epilepsy is not known.

Gabapentin has no activity at GABAA or GABAB receptors of GABA uptake carriers of brain. It interacts with a high-affinity binding site in brain membranes. 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. It 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 6.

Half-life & Time to clear out of the system

The elimination half-life is 5-7 hours and is unaltered by dose or following multiple dosing. It usually takes 2 days for gabapentin to leave the system.

How long does it take for Gabapentin to work?

While some people notice the antimanic and antidepressant effects within a week or two of starting treatment, others have to take a therapeutic amount of gabapentin for up to a month before feeling a significant improvement.

You should notice that your pain starts to alleviate over 1-2 weeks after starting gabapentin, but it may take a little longer in some people. On the other hand, some people feel the benefit straight away.

Gabapentin and Alcohol interaction

There are no known interactions between gabapentin and alcohol. Gabapentin does not alter the effects of alcohol2.

Gabapentin withdrawal

Gabapentin should be tapered off gradually. Abrupt discontinuation of gabapentin is associated with development of a syndrome resembling alcohol or benzodiazepine withdrawal, perhaps due to a similar mechanism of action at GABA levels8.

Withdrawal symptoms can present after 1-2 days upon abrupt discontinuation of gabapentin.

Gabapentin abuse

Though gabapentin is not a controlled substance, it does produce psychoactive effects. It is regarded as having little or no abuse potential.

Currently, case reports indicate that gabapentin misuse is possible in certain populations26.

Further reading

• Gabapentin (Neurontin) versus other anticonvulsants
• Gabapentin for treating migraines

References

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Published: October 6, 2008
Last updated: January 30, 2017