Gabapentin:

Pharmacology

and its use in pain management

BY B. SHIVA KUMAR

PHARMACOLOGY

Gabapentin (1-(aminomethyl )cyclohexane acetic acid ) is a novel anti-epileptic agent developed as a GABA mimitic compound initially approved for use in partial seizures , soon it is used in treatment of chronic pain syndromes , especially neuropathic pain

Chemistry
Gabapentin is water soluble, bittertasting,white

crystalline substance with a structure resembling gaba with a cyclohexane ring incorporated M.wt = 171.34 At physiological pH it is highly charged &exist as zwitter ion with 2 pKa values of 3.68 &10.70 Assayed in plasma and in urine using gas chromatography & HPLC

CH2 NH2

CH2CO2H

Structure of gabapentin

Pharmacokinetics
Available as oral preparations , is absorbed in the

small intestine by a diffusion & facilitated transport the bioavailability of gabapentin varies inversely with the dose Peak plasma levels (cmax) of gabapentin of2.72.99 mg/L are achieved 3-h after ingestion of single 300mg capsule

 Its extensively distribution is reflected in a volume of

0.6 -0.8 l/kg In rats , the pancreatic & renal tissue concentration found to be 8-4 times higher than serum concentrations. Pancreatic accmulation of the drug does in humans as it exist in highly ionised state at physiological pH Gabapentin is not metabolised in humans , eliminated unchanged in urine , under goes first order kinetic elimination The elimination half life of gabapentin is between 4.8-8.7h removed by haemodialysis so patients in renal failure should receive their maintainance dose after

Interactions
Gabapentin has no pharmcokinetic interaction

with other anticonvulsant drugs . Cimetidine ,decrease clearance of gabapentin by 12% cimetidine decrease glomerular filtration rate Busch et al reported that antacids reduce the bioavailability of gabapentin by 20 % when given concomitently

Mechanism of action
Gabapentin blocks the tonic phase of nociception

induced by formalin &carrageenan, and exerts a potent inhibitory effect in neuropathic pain models of hyperalgesia & allodynia Gabapentin binds preferentially to neurons in the outer layer of cortex at sites distinct from that other anticonvulsants Gabapentin acts at an intracellular site as max anticonvulsant is achieved 2h after iv injection of gabapentin in rats

 Mech of anti allodynic effects of gabapentin include

CNS effects due to either enhanced inhibitory input of gaba mediated pathways antagonism of NMDA receptors ;antagonism of ca channels in CNS & inhibition of peripheral nerves Fink et.al showed that in the rat neo cortex, gabapentin inhibits neuronal ca influx in a concentration dependent manner by inhibiting p/q type ca channel .the decreased ca influx reduces excitatory aminoacid (e.g glutamate) release leading to decreased AMPA receptor activation

Adverse effects
McLean et. al in a large label multicentre study

involving 2216patients to examine safety & tolerability of gabapentin in seizure control shows that Common adverse effects include Somnolence(15.2%) Dizziness(10.9%) Asthenia(6.0%) Serious adverse effect was convulsions(0.9%)

 Relatively safety of gabapentin is supported by

case reports of massive over doses of drug in which serious toxicity was absent Fisher et al reported a patient who injested 48.9 g of gabapentin from which a full recovery was achieved after symptoms of lethargy & dizziness Recent trails conducted to determine safety & efficacy in paediatric population . Open label trail reported that gabapentin was safe at doses of 2678 mg/kg in 52 children .

Dosage and administration

Oral doses of gabapentin are administered 3 times

a day because of its short half life Dosages up to 2400 mg/day are recommended for epilepsy in adults in children aged up t o 3-12yrs ,25-35 mg/day in 3 divided doses are recommended the recommended starting dose in treatment of neuropathic pain is 300mg three times a day

Use in pain management

Neuropathic pain

involve several mechanisms including primary and secondary hyperalgesia , windup phenamena.
the use of anticonvulsant drugs for the treatment of neuropathic pain is based on similarities in the pathophysiological events observed in epilepsy

Other types of neuropathic pain

Neuropathic pain in malignancy

Trigeminal neuralgia
Multiple sclorosis Complex regional pain syndrome

Head ache syndromes

Spinal injury Erythromelalgia

post poliomyelitis pain

Non pain related uses

Gabapentin may be beneficial in treatment of

alcohol withdrawl use in psychiatric conditions such as bipolar disorder , schizoaffective disorder

Animal studies
Numerous studies in rats shows efficacy of

gabapentin on allodynia and hyperalgesia Intraperitoneal gabapentin attenuated mechanical hyperalgesia indused by thermal injury in rats Gabapentin was efective against abnormal sensory processing in diabetic rats using formalin test ,it was suggested that it may be effective in diabetic neuropathy in humans Gabapentin was superior to morphine and amitriptyline in blocking both static and dynamic components of allodynia in rats when administered orally or intrathecally but not locally at the site of allodynia

Human studies
Case reports and pilot studies

In a study of 122 chronic pain patients with 97 with neuropathic pain treated with gabapentin treated for 30 days , rosenberg et.al showed decrease in pain scores on a median dose of 1200mg/day Attal et.al in a pilot study on effect of gabapentin in 18 patients with pain from central or peripheral nerve lesion ,shows relief of pain especially paroxysmal pain

Randomised controlled studies these are conducted to determine the efficacy of gabapentin in treatment of diabetic neuropathy & postherhapetic neuralgia Diabetic neuropathy:a double blind ,placebo controlleed ,165 diabetic patients with a 1-5yrs history of painful diabetic neuropathy reports beneficial effects with gabapentin 84 allocated to gabapentin ,81 to placebo group. A significant reduction in pain scores in gabapentin group compare to placebo group The NNT for analgesic effect of gabapentin in neuropathic pain was 3.8 for carbamazepine 2.3 ,phenytoin 2.1 in other

 Postherapetic neuralgia:gabapentin is efficacious

in the treatment of neuropathic pain associatefd with Postherapetic neuralgia. A study involving 229 subjects with post therapeutic neuralgia demonstrated by ROWBOTHAM showed that the efficacy of gabapentin in the treatment of the above condition has been proved beneficial at a dose of 3600mg/day. This study showed a significant decrese in pain scores from 6.3-4.2 for gabapentin group compared with 6.5-6.0 of placebo group.

Role of gabapentin in pain management

Opoids ,NSAIDS ,antidepressants , and

anticonvulsants, are pharmacological agents to treat pain .no single class was found to be effective in all types of pain Treatment of neuropathic pain involved the anticonvulsants : carbamazepine , phenytoin,valproic acid tricyclic antideprassants : amitryptyline , nortryptline ,doxepine anticonvulsants disadvantage: potential to drug interactions resulting from inhibition of hepatic enzymes by other drugs minor side effects : carbamazepine , phenytoin include

 Tricyclic antideprassants : sedation , hypotension ,

tachycardia , atrio-ventricular conduction disturbances the NNH (number needed to harm ) for minor adverse effect was 2.7 for antidepressants & anti convulsants . collins et al .used two trails to provide data on minor adverse effects for gabapentin & two trails for phenytion NNH was 2.6 for gabapentin &3.2 for phenytoin . with increasing evidence of efficacy of gabapentin in a wide variety of pain syndromes ,especially neuropathic pain ,it may be potentially useful because of its relative freedom from serious adverse

 The evidences suggests that gabapentin is as

efficacious at treating neuropathic painwith no significant difference in minor adverse effects and low propensity for serious adverse effects compared with anticonvulsant and antidepressants.Therefore gabapentin is a useful agent in the multimodal approach in the management of neuropathic pain.

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