Gabapentin is an anticonvulsant medication indicated in the treatment of epilepsy and neuropathic pain. Gabapentin is known for having a relatively mild side-effect profile, and passes through the body unmetabolized. 

The US FDA approved Gabapentin in May 2002.

2.GABAPENTIN FACTS

Gabapentin is similar in structure to the neurotransmitter GABA but is not believed to act on the same brain receptors. Its exact mechanism of action is unknown, but its therapeutic action on neuropathic pain is thought to involve voltage-gated calcium ion channels.

Gabapentin has also been used in the treatment of bipolar disorder. However, its off-label use for this purpose is increasingly controversial. Some claim Gabapentin acts as a mood stabilizer and has the advantage of having fewer side effects than more conventional bipolar drugs such as lithium and valproic acid. Some small, non-controlled studies in the 1990s, most sponsored by Gabapentin's manufacturer, suggested that Gabapentin treatment for bipolar disorder may be promising. However, more recently, several larger, controlled, and double-blind studies have found that Gabapentin was no more effective than (and in one study, slightly less effective than) placebo, and the manufacturer has even halted its own studies regarding Gabapentin and bipolar disorder. Despite this scientific evidence against the efficacy of Gabapentin in the treatment of bipolar disorder, many psychiatrists continue to prescribe it for this purpose.

Gabapentin has also been used off label in the treatment of anxiety disorders such as social anxiety disorder and obsessive-compulsive disorder, in treatment-resistant depression, and for insomnia. Gabapentin may be effective in reducing pain and spasticity in multiple sclerosis.

3.ABOUT GABAPENTIN MEDICATION

What is Epilepsy?

Epilepsy is a brain disorder in which clusters of nerve cells, or neurons, in the brain sometimes signal abnormally. In epilepsy, the normal pattern of neuronal activity becomes disturbed, causing strange sensations, emotions, and behavior or sometimes convulsions, muscle spasms, and loss of consciousness. Epilepsy is a disorder with many possible causes. Anything that disturbs the normal pattern of neuron activity - from illness to brain damage to abnormal brain development - can lead to seizures. Epilepsy may develop because of an abnormality in brain wiring, an imbalance of nerve signaling chemicals called neurotransmitters, or some combination of these factors. Having a seizure does not necessarily mean that a person has epilepsy. Only when a person has had two or more seizures is he or she considered having epilepsy. EEGs and brain scans are common diagnostic test for epilepsy.

Is there any treatment?

Once epilepsy is diagnosed, it is important to begin treatment as soon as possible. For about 80 percent of those diagnosed with epilepsy, seizures can be controlled with modern medicines and surgical techniques. Some antiepileptic drugs can interfere with the effectiveness of oral contraceptives. In 1997, the FDA approved the vagus nerve stimulator for use in people with seizures that are not well controlled by medication.

What is the prognosis?

Most people with epilepsy lead outwardly normal lives. While epilepsy cannot currently be cured, for some people it does eventually go away. Most seizures do not cause brain damage. It is not uncommon for people with epilepsy, especially children, to develop behavioral and emotional problems, sometimes the consequence of embarrassment and frustration or bullying, teasing, or avoidance in school and other social setting. For many people with epilepsy, the risk of seizures restricts their independence (some states refuse drivers licenses to people with epilepsy) and recreational activities. People with epilepsy are at special risk for two life-threatening conditions: status epilepticus and sudden unexplained death. Most women with epilepsy can become pregnant, but they should discuss their epilepsy and the medications they are taking with their doctors. Women with epilepsy have a 90 percent or better chance of having a normal, healthy baby.

Antiepileptics or Anticonvulsants can be divided into older medications (called first-generation anticonvulsants) and more recently developed medications (second-generation anticonvulsants). 

First-Generation anticonvulsants

Phenytoin: This is one of the more commonly used agents and often is considered the first-line drug to treat partial and generalized tonic-clonic (grand mal) seizures and status epilepticus.

Phenytoin is thought to work by suppressing electrical activity in brain nerve cells. It can be given orally or intravenously (IV), and a newer form of the drug, fosphenytoin, can be injected into muscle. The oral form has the benefit of once-a-day dosing.

Carbamazepine : This drug is commonly prescribed for the treatment of partial and generalized tonic-clonic (grand mal) seizures. The mechanism by which it works is not well understood. In oral form, it can be taken 2 to 3 times a day; a recent development of the drug in sustained-release form allows for twice-a-day dosing.

Phenobarbital : This drug is used to treat both partial and generalized seizures. It also is used as part of the protocol after phenytoin use in status epilepticus as well as in neonatal epilepsy. It is available in oral and intravenous forms.

Valproate : This is prescribed for partial seizures, generalized tonic-clonic (grand mal) seizures, absence (petit mal) seizures, and myoclonic epilepsy. Its mechanism of action is thought to be related to the effect of a brain substance known as GABA (gamma-aminobutyric acid). It is available in oral form and must be taken 2 to 3 times per day for adequate dosing. 

Second-Generation anticonvulsants

Topiramate : This drug is used with other anticonvulsant drugs in the treatment of partial seizures and generalized tonic-clonic seizures in adults and children aged 2 to 16. Its precise mechanism of action is unknown, but its anticonvulsant activity may be due in part to increasing GABA (gamma-aminobutyric acid), a neurotransmitter that inhibits excitation of nerve cells in the brain. It is available in oral form, including sprinkles for children, and is taken twice daily. There are few drug interactions between topiramate and other medications or other anticonvulsants.

Gabapentin : This drug is indicated for the adjunct treatment of partial seizures, with or without secondary generalization. Although it is structurally related to the substance GABA (gamma-aminobutyric acid), it does not interact with GABA receptors in the brain, and its mechanism of action is unknown. It is available in oral form and is taken 3 times daily.

Lamotrigine: This drug is used for the adjunct treatment of partial seizures. Its precise mechanism of action is unknown. It is presently available in oral form and is taken twice daily. No laboratory monitoring of drug levels are necessary.

Tiagabine: This drug is indicated for adjunct therapy in adults with partial seizures. Its mechanism of action may be related to its effect on the brain substance GABA (gamma-aminobutyric acid). It is available in oral form and should be given in divided doses 2 to 4 times daily. Its metabolism may be altered when taken with other anticonvulsants.

Levetiracetam : This drug is approved for use in adults as adjunct therapy for the treatment of partial seizure disorders. It is available in tablet form and as an oral solution for patients who prefer a liquid or cannot swallow tablets. Side effects can include fatigue, imbalance, and behavioral changes, which often dissipate after the first month of treatment.

Oxcarbazepine : This drug is indicated for monotherapy (used alone) and adjunct therapy (in addition to other medications) in adults who have partial seizures and as adjunct therapy in children aged 4 and older who have partial seizures. When used as monotherapy, Trileptal causes very few of the side effects associated with other AEDs.

Zonisamide : This drug is approved for use in adults as adjunct therapy for partial seizures. It has however, been used fairly extensively in other countries for use in other seizure types including generalized seizures, myoclonic seizures, and absence seizures. Patients who are allergic to sulfonamide drugs should not use zonisamide because it is a derivative of this class of drug.

Ethosuximide: This agent is used to treat absence (petit mal) seizures. It is thought to work by suppressing brain cell activity that is associated with lapses of consciousness. It is given orally and is available as a tablet or flavored syrup.

Primidone : This drug is a barbiturate that contains phenobarbitol. It is used to control generalized tonic-clonic (grand mal) seizures and partial seizures and is used in adults and children over 8 years old. Primidone is not known to interact with other drugs. It is present in breast milk and is associated with neonatal hemorrhage and coagulation defects similar to vitamin K deficiency. Patients hypersensitive to phenobarbital should not take primidone. 

4.GABAPENTIN EFFECTIVENESS
(When is Gabapentin best taken?)

All pharmacological actions following Gabapentin administration are due to the activity of the parent compound; Gabapentin is not appreciably metabolized in humans.

Oral Bioavailability : Gabapentin bioavailability is not dose proportional; i.e., as dose is increased, bioavailability decreases. Bioavailability of Gabapentin is approximately 60%, 47%, 34%, 33%, and 27% following 900, 1200, 2400, 3600, and 4800 mg/day given in 3 divided doses, respectively. Food has only a slight effect on the rate and extent of absorption of Gabapentin (14% increase in AUC and Cmax).

Distribution : Less than 3% of Gabapentin circulates bound to plasma protein. The apparent volume of distribution of Gabapentin after 150 mg intravenous administration is 58±6 L (Mean ±SD). In patients with epilepsy, steady-state predose (Cmin) concentrations of Gabapentin in cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations.

Elimination : Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug. Gabapentin is not appreciably metabolized in humans.

Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple dosing. Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance. In elderly patients, and in patients with impaired renal function, Gabapentin plasma clearance is reduced. Gabapentin can be removed from plasma by hemodialysis.

Dosage adjustment in patients with compromised renal function or undergoing hemodialysis is recommended.

5.GABAPENTIN EFFECTS ON SPECIAL POPULATION
(How do different people react to Gabapentin?)

Age : The effect of age was studied in subjects 20-80 years of age. Apparent oral clearance (CL/F) of Gabapentin decreased as age increased, from about 225 mL/min in those under 30 years of age to about 125 mL/min in those over 70 years of age. Renal clearance (CLr) and CLr adjusted for body surface area also declined with age; however, the decline in the renal clearance of Gabapentin with age can largely be explained by the decline in renal function.

Reduction of Gabapentin dose may be required in patients who have age related compromised renal function.

Pediatric : Gabapentin pharmacokinetics were determined in 48 pediatric subjects between the ages of 1 month and 12 years following a Gabapentin dose of approximately 10 mg/kg. Peak plasma concentrations were similar across the entire age group and occurred 2 to 3 hours post Gabapentin dose. In general, pediatric subjects between 1 month and <5 years of age achieved approximately 30% lower exposure (AUC) than that observed in those 5 years of age and older. Accordingly, oral clearance normalized per body weight was higher in the younger children. Apparent oral clearance of Gabapentin was directly proportional to creatinine clearance. Gabapentin elimination half-life averaged 4.7 hours and was similar across the age groups studied.

A population pharmacokinetic analysis was performed in 253 pediatric subjects between 1 month and 13 years of age. Patients received 10 to 65 mg/kg/day given TID. Apparent oral clearance (CL/F) was directly proportional to creatinine clearance and this relationship was similar following a single Gabapentin dose and at steady state. Higher oral clearance values were observed in children <5 years of age compared to those observed in children 5 years of age and older, when normalized per body weight. The clearance was highly variable in infants <1 year of age. The normalized CL/F values observed in pediatric patients 5 years of age and older were consistent with values observed in adults after a single dose. The oral volume of distribution normalized per body weight was constant across the age range.

These pharmacokinetic data indicate that the effective daily Gabapentin dose in pediatric patients with epilepsy ages 3 and 4 years should be 40 mg/kg/day to achieve average plasma concentrations similar to those achieved in patients 5 years of age and older receiving Gabapentin at 30 mg/kg/day.

Gender : Although no formal study has been conducted to compare the pharmacokinetics of Gabapentin in men and women, it appears that the pharmacokinetic parameters for males and females are similar and there are no significant gender differences.

Race : Pharmacokinetic differences due to race have not been studied. Because Gabapentin is primarily renally excreted and there are no important racial differences in creatinine clearance, pharmacokinetic differences due to race are not expected.

6.GABAPENTIN EFFECTS ON MEDICAL CONDITIONS
(How does Gabapentin affect your existing condition/ailment?)

Renal Insufficiency:
Dosage adjustment in adult patients with compromised renal function is necessary. Pediatric patients with renal insufficiency have not been studied.

Hemodialysis:
In a study in anuric adult subjects (N=11), the apparent elimination half-life of Gabapentin on nondialysis days was about 132 hours; during dialysis the apparent half-life of Gabapentin was reduced to 3.8 hours. Hemodialysis thus has a significant effect on Gabapentin elimination in anuric subjects.

Dosage adjustment in patients undergoing hemodialysis is necessary.

Hepatic Disease:

Because Gabapentin is not metabolized, no study was performed in patients with hepatic impairment. 

7.OTHER/ALTERNATE USES OF GABAPENTIN
(What else does Gabapentin treat?)

In addition to its use in mood disorders, Gabapentin has been approved by the FDA for treating postherpetic neuralgia (neuropathic pain following shingles).

8.ADVERSE/SIDE EFFECTS of GABAPENTIN
(What are the side effects of Gabapentin?)

Body As A Whole: Frequent: asthenia, malaise, face edema; Infrequent: allergy, generalized edema, weight decrease, chill; Rare: strange feelings, lassitude, alcohol intolerance, hangover effect.

Cardiovascular System: Frequent: hypertension; Infrequent: hypotension, angina pectoris, peripheral vascular disorder, palpitation, tachycardia, migraine, murmur; Rare: atrial fibrillation, heart failure, thrombophlebitis, deep thrombophlebitis, myocardial infarction, cerebrovascular accident, pulmonary thrombosis, ventricular extrasystoles, bradycardia, premature atrial contraction, pericardial rub, heart block, pulmonary embolus, hyperlipidemia, hypercholesterolemia, pericardial effusion, pericarditis. 

Digestive System : Frequent: anorexia, flatulence, gingivitis; Infrequent: glossitis, gum hemorrhage, thirst, stomatitis, increased salivation, gastroenteritis, hemorrhoids, bloody stools, fecal incontinence, hepatomegaly; Rare: dysphagia, eructation, pancreatitis, peptic ulcer, colitis, blisters in mouth, tooth discolor, perlèche, salivary gland enlarged, lip hemorrhage, esophagitis, hiatal hernia, hematemesis, proctitis, irritable bowel syndrome, rectal hemorrhage, esophageal spasm.

Endocrine System : Rare: hyperthyroid, hypothyroid, goiter, hypoestrogen, ovarian failure, epididymitis, swollen testicle, cushingoid appearance.  

Hematologic and Lymphatic System : Frequent: purpura most often described as bruises resulting from physical trauma; Infrequent: anemia, thrombocytopenia, lymphadenopathy; Rare: WBC count increased, lymphocytosis, non-Hodgkin's lymphoma, bleeding time increased.

Musculoskeletal System : Frequent: arthralgia; Infrequent: tendinitis, arthritis, joint stiffness, joint swelling, positive Romberg test; Rare: costochondritis, osteoporosis, bursitis, contracture.

Nervous System : Frequent: vertigo, hyperkinesia, paresthesia, decreased or absent reflexes, increased reflexes, anxiety, hostility; Infrequent: CNS tumors, syncope, dreaming abnormal, aphasia, hypesthesia, intracranial hemorrhage, hypotonia, dysesthesia, paresis, dystonia, hemiplegia, facial paralysis, stupor, cerebellar dysfunction, positive Babinski sign, decreased position sense, subdural hematoma, apathy, hallucination, decrease or loss of libido, agitation, paranoia, depersonalization, euphoria, feeling high, doped-up sensation, suicidal, psychosis; Rare: choreoathetosis, orofacial dyskinesia, encephalopathy, nerve palsy, personality disorder, increased libido, subdued temperament, apraxia, fine motor control disorder, meningismus, local myoclonus, hyperesthesia, hypokinesia, mania, neurosis, hysteria, antisocial reaction, suicide gesture.

Respiratory System : Frequent: pneumonia; Infrequent: epistaxis, dyspnea, apnea; Rare: mucositis, aspiration pneumonia, hyperventilation, hiccup, laryngitis, nasal obstruction, snoring, bronchospasm, hypoventilation, lung edema.

Dermatological : Infrequent: alopecia, eczema, dry skin, increased sweating, urticaria, hirsutism, seborrhea, cyst, herpes simplex; Rare: herpes zoster, skin discolor, skin papules, photosensitive reaction, leg ulcer, scalp seborrhea, psoriasis, desquamation, maceration, skin nodules, subcutaneous nodule, melanosis, skin necrosis, local swelling.

Urogenital System : Infrequent: hematuria, dysuria, urination frequency, cystitis, urinary retention, urinary incontinence, vaginal hemorrhage, amenorrhea, dysmenorrhea, menorrhagia, breast cancer, unable to climax, ejaculation abnormal; Rare: kidney pain, leukorrhea, pruritus genital, renal stone, acute renal failure, anuria, glycosuria, nephrosis, nocturia, pyuria, urination urgency, vaginal pain, breast pain, testicle pain.

Special Senses : Frequent: abnormal vision; Infrequent: cataract, conjunctivitis, eyes dry, eye pain, visual field defect, photophobia, bilateral or unilateral ptosis, eye hemorrhage, hordeolum, hearing loss, earache, tinnitus, inner ear infection, otitis, taste loss, unusual taste, eye twitching, ear fullness; Rare: eye itching, abnormal accommodation, perforated ear drum, sensitivity to noise, eye focusing problem, watery eyes, retinopathy, glaucoma, iritis, corneal disorders, lacrimal dysfunction, degenerative eye changes, blindness, retinal degeneration, miosis, chorioretinitis, strabismus, eustachian tube dysfunction, labyrinthitis, otitis externa, odd smell.