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Gabapentin (Neurontin)

Gabapentin in Brief
  • Generic name : Gabapentin
  • Brand names: Neurontin®
    Gralise® (gabapentin extended release)
    Horizant® (gabapentin enacarbil)
  • Therapeutic class: Anti-epileptic, Anticonvulsant
  • Pharmacologic class: 1-amino-methyl cyclohexoneacetic acid, Gamma-aminobutyric acid (GABA) analogue
  • FDA Approved: December 30, 1993
  • Chemical Formula: C9H17NO2
  • Pregnancy Category: C
  • Habit forming? No
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 312 years.

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

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, its 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 disorder or substance abuse 29.

Small, randomized clinical trial comparing the prophylactic efficacy of adjunctive gabapentin to placebo suggests that, despite lack of acute efficacy, treatment with gabapentin might provide some benefit on the long-term outcome of 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 when administered to outpatients with bipolar disorder 4.

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.

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 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

References
  • 3. Vieta E, Manuel Goikolea J, Martinez-Aran A, Comes M, Verger K, Masramon X, Sanchez-Moreno J, Colom F. A double-blind, randomized, placebo-controlled, prophylaxis study of adjunctive gabapentin for bipolar disorder. J Clin Psychiatry. 2006 Mar;67(3):473-7. PubMed
  • 4. Pande AC, Crockatt JG, Janney CA, Werth JL, Tsaroucha G. Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Bipolar Disord. 2000 Sep;2(3 Pt 2):249-55. PubMed
  • 5. Arnold LM, Goldenberg DL, Stanford SB, Lalonde JK, Sandhu HS, Keck PE Jr, Welge JA, Bishop F, Stanford KE, Hess EV, Hudson JI. Gabapentin in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled, multicenter trial. Arthritis Rheum. 2007 Apr;56(4):1336-44. PubMed
  • 6. Taylor CP. Mechanisms of action of gabapentin. Rev Neurol (Paris). 1997;153 Suppl 1:S39-45. PubMed
  • 7. DeToledo JC, Toledo C, DeCerce J, Ramsay RE. Changes in body weight with chronic, high-dose gabapentin therapy. Ther Drug Monit. 1997 Aug;19(4):394-6.
  • 8. Norton JW. Gabapentin withdrawal syndrome. Clin Neuropharmacol. 2001 Jul-Aug;24(4):245-6.
  • 9. Mathiesen O, Moiniche S, Dahl JB. Gabapentin and postoperative pain: a qualitative and quantitative systematic review, with focus on procedure. BMC Anesthesiol. 2007 Jul 7;7:6. PubMed
  • 10. Di Trapani G, Mei D, Marra C, Mazza S, Capuano A. Clin Ter. 2000 May-Jun;151(3):145-8. PubMed
  • 11. Ryan NM, Birring SS, Gibson PG. Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet. 2012 Nov 3;380(9853). PubMed
  • 12. Saadati N, Mohammadjafari R, Natanj S, Abedi P. The effect of gabapentin on intensity and duration of hot flashes in postmenopausal women: a randomized controlled trial. Glob J Health Sci. 2013 Sep 10;5(6):126-30. PubMed
  • 13. Hansen HC. Interstitial cystitis and the potential role of gabapentin. South Med J. 2000 Feb;93(2):238-42.
  • 14.Hemstreet B, Lapointe M. Evidence for the use of gabapentin in the treatment of diabetic peripheral neuropathy. Clin Ther. 2001 Apr;23(4):520-31. PubMed
  • 15. Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, Hes M, LaMoreaux L, Garofalo E. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA. 1998 Dec 2;280(21):1831-6. PubMed
  • 16. Pande AC, Davidson JR, Jefferson JW, Janney CA, Katzelnick DJ, Weisler RH, Greist JH, Sutherland SM. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol. 1999 Aug;19(4):341-8. PubMed
  • 17. Hamner MB, Brodrick PS, Labbate LA. Gabapentin in PTSD: a retrospective, clinical series of adjunctive therapy. Ann Clin Psychiatry. 2001 Sep;13(3):141-6.
  • 18. Yasmin S, Carpenter LL, Leon Z, Siniscalchi JM. Adjunctive gabapentin in treatment-resistant depression: a retrospective chart review. J Affect Disord. 2001 Mar;63(1-3):243-7. PubMed
  • 19. Pande AC, Pollack MH, Crockatt J, Greiner M, Chouinard G, Lydiard RB, Taylor CB, Dager SR, Shiovitz T. Placebo-controlled study of gabapentin treatment of panic disorder. J Clin Psychopharmacol. 2000 Aug;20(4):467-71. PubMed
  • 20. Ondo W, Hunter C, Vuong KD, Schwartz K, Jankovic J. Gabapentin for essential tremor: a multiple-dose, double-blind, placebo-controlled trial. Mov Disord. 2000 Jul;15(4):678-82. PubMed
  • 21. Inoue Y, Hirata K, Uchimura N, Kuroda K, Hattori N, Takeuchi M. Gabapentin enacarbil in Japanese patients with restless legs syndrome: a 12-week, randomized, double-blind, placebo-controlled, parallel-group study. Curr Med Res Opin. 2013 Jan;29(1):13-21. PubMed
  • 22. Garcia-Borreguero D, Larrosa O, de la Llave Y, Verger K, Masramon X, Hernandez G. Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study. Neurology. 2002 Nov 26;59(10):1573-9.
  • 23. Karam-Hage M, Brower KJ. Psychiatry Clin Neurosci. 2003 Oct;57(5):542-4. PubMed
  • 24. Lee KJ, Kim JH, Cho SW. Gabapentin reduces rectal mechanosensitivity and increases rectal compliance in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2005 Nov 15;22(10):981-8. PubMed
  • 25. Cheshire WP Jr. Defining the role for gabapentin in the treatment of trigeminal neuralgia: a retrospective study. J Pain. 2002 Apr;3(2):137-42.
  • 26. Kruszewski SP, Paczynski RP, Kahn DA. Gabapentin-induced delirium and dependence. J Psychiatr Pract. 2009 Jul;15(4):314-9.
  • 27. Huge penalty in drug fraud Pfizer settles felony case in Neurontin off-label promotion. Bernadette Tansey, Chronicle Staff Writer May 14, 2004. SFGate
  • 28. Ghaemi SN, Goodwin FK. Gabapentin treatment of the non-refractory bipolar spectrum: an open case series. J Affect Disord. 2001 Jul;65(2):167-71. PubMed
  • 29. Perugi G, Toni C, Frare F, Ruffolo G, Moretti L, Torti C, Akiskal HS. Effectiveness of adjunctive gabapentin in resistant bipolar disorder: is it due to anxious-alcohol abuse comorbidity? J Clin Psychopharmacol. 2002 Dec;22(6):584-91. PubMed
  • 30. Altshuler LL, Keck PE Jr, McElroy SL, Suppes T, Brown ES, Denicoff K, Frye M, Gitlin M, Hwang S, Goodman R, Leverich G, Nolen W, Kupka R, Post R. Gabapentin in the acute treatment of refractory bipolar disorder. Bipolar Disord. 1999 Sep;1(1):61-5. PubMed
  • 31. Spira PJ, Beran RG. Neurology. 2003 Dec 23;61(12):1753-9.
  • 32. McLean MJ, Gidal BE. Gabapentin dosing in the treatment of epilepsy. Clin Ther. 2003 May;25(5):1382-406. PubMed
  • 33. Yamauchi T, Kaneko S, Yagi K, Sase S. Treatment of partial seizures with gabapentin: double-blind, placebo-controlled, parallel-group study. Psychiatry Clin Neurosci. 2006 Aug;60(4):507-15. PubMed
  • 34. Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA. et al. Lancet. 2007 Mar 24;369(9566):1000-15. PubMed
  • 35. Sethi A, Chandra D, Puri V, Mallika V. Gabapentin and lamotrigine in Indian patients of partial epilepsy refractory to carbamazepine. Neurol India. 2002 Sep;50(3):359-63. PubMed
  • 36. Mason BJ, Quello S, Goodell V, Shadan F, Kyle M, Begovic A. Gabapentin treatment for alcohol dependence: a randomized clinical trial. JAMA Intern Med. 2014 Jan;174(1):70-7. PubMed

Published: October 6, 2008
Last updated: July 15, 2014

Interesting facts

Gabapentin facts
  • Gabapentin has advantages over other anticonvulsants because of its safety profile and lack of drug interactions.
  • By some estimates, off-label prescriptions account for roughly 90% of Neurontin sales.27
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