- Email: [email protected]
Gabapentin
Gabapentin
with
Background Epilepsy is a common clinical disorder characterised by hyperexcitability and paroxysmal discharge of cortical neurons. The prevalence is 0.5-1% of the population. While about 70% of people who get epilepsy have a short-lasting disorder that soon enters remission, others have a chronic, lifelong condition that is poorly responsive to antiepileptic drugs. Between 1 and 2 per 1000 of the population may have such "intractable" epilepsy.1 Existing antiepileptic drugs have various idiosyncratic, dose-related, chronic toxic and teratogenic effects. Thus, there is a need for new antiepileptic agents that might not only benefit patients with intractable seizures but also
voltage-dependent sodium channels or with benzodiazepine or excitatory neurotransmitter receptor sites, nor does it influence catecholamine, acetylcholine, or opioid receptors.
induce fewer adverse effects. Much is now known about the mechanism of action of antiepileptic drugs. Phenytoin, carbamazepine, and lamotrigine block repetitive firing of neurons by an action on voltage-sensitive sodium channels.2 Other agents exert their main effect via modulation of inhibitory or excitatory neurotransmission. Thus, vigabatrin blocks the inactivation of gamma aminobutyric acid (GABA) by acting as a suicidal inhibitor for GABA aminotransferase.3 Phenobarbitone and benzodiazepines facilitate the action of GABA at its receptor site by allosteric means.4 Lamotrigine, in addition to its phenytoin and carbamazepine like actions, may also reduce the release of excitatory neurotransmitters, glutamate and aspartate. Valproate may have actions on both GABA-ergic systems and excitatory neurotransmitters.
Mechanisms of action
Gabapentin (figure 1) (1-[aminomethyl] cyclohexaneacetic acid) was synthesised because of its structural similarity to GABA and its ability to cross the blood-brain barrier. Although gabapentin is effective in many animal seizure models (table 1), it cannot be shown to interact with GABAA or GABAB receptors and does not interfere with GABA metabolism, and so cannot be described as a GABA-mimetic drug. It has been shown to increase GABA content of some brain regions.s It does not interact
*All results are from unpublished studies ; tlowest effective dose; tat this dose, seizures were significantly delayed but not prevented. IP= intraperitoneal; IV= intravenous Table 1: Activity of gabapentin in animal models of seizures*
Gabapentin binds to a site that is found in brain but not elsewhere.6 This specific binding site seems to be a protein that is predominantly located on neurons and it does not bind any other antiepileptic drugs. It is found in its highest density in the neocortex of the rat and in those areas rich in glutaminergic synapses. The precise nature of this site has yet to be determined, but enantiomers of gabapentin show different potencies for binding at the gabapentin site and this potency is proportional to their efficacy in seizure models.7 Clinical
Figure
1: Structure of
gabapentin
Department of Neurological Science, Walton Hospital, Liverpool L9 1AE, UK (Prof D Chadwick FRCP)
Rice Lane,
pharmacokinetics
The pharmacokinetics of gabapentin is simple (table 2).8 There is no evidence that the drug interacts in any pharmacokinetic way with other antiepileptic agents, nor does it induce liver enzymes. Its only disadvantage is the half-life of 5-7 h which might necessitate thrice daily dosing. There is some evidence that twice daily dosing will suffice.
89
From ref 8, with permission. Table 2: Pharmacoklnetlc
properties of gabapentin
Efficacy Three double-blind, parallel group studies have been conducted in refractory patients with partial epilepsies.9-11 Two smaller supportive studies of similar design have likewise been conducted, and in total 792 patients were randomised to receive placebo or gabapentin doses of 600, 900, 1200, or 1800 mg per day. The similarity of designs of these trials lend themselves to meta-analysis, and the results of this are presented in figure 2, which shows the difference in mean response ratio with 95% CI. The response ratio is defined by: Treatment seizure Treatment seizure
frequency baseline seizure frequency frequency + baseline seizure frequency -
This transformation of seizure frequency leads to a more normal distribution with a range between - 1 (complete abolition of seizures) to +1 (an infinite worsening of seizures) and so allows the use of parametric statistics. A 50% reduction in seizure frequency is equivalent to a response ratio of -0-33. There is a clear dose-related antiepileptic effect. Figure 3 shows that maximum efficacy is in reducing tonic-clonic seizures and complex partial seizures. A similar dose-related effect on responder rates (proportion of patients showing a 50% or greater reduced reduction in seizure frequency during gabapentin treatment) is likewise seen, with 23% of patients receiving 1200 mg a day showing such a reduction vs 10% in the
placebo group. Longer-term open follow-up studies do not suggest any tolerance to gabapentin’s antiepileptic effect. 650 patients have received the drug for at least 1 year; 116 for more than 4 years.
There are no data on the drug’s antiepileptic properties in children or in patients with generalised epilepsies. Existing data do not indicate that gabapentin has any more efficacy than existing antiepileptic drugs and it will be important to
Figure 3: Mean response ratio in all placebo-controlled studies by seizure type GBP gabapentin; PLC placebo. *Mean response ratio for all patients = difference;—=95% Cl. =
=
receiving gabapentin.
prospective randomised comparisons of gabapentin as monotherapy with other first-line antiepileptic drugs for partial epilepsy. conduct
Adverse
experience
Gabapentin is well tolerated. 7-4% of 1748 patients who received the agent during any study withdrew due to an adverse event vs 3-3% of 485 patients who received placebo in addition to at least one concurrent antiepileptic drug. The incidence of the ten most common adverse events in patients receiving gabapentin is compared with placebo in table 3.12 The severity of these probably dose-related central nervous system effects is mild. No serious idiosyncratic reactions have been identified with gabapentin, and in particular there is no evidence of hypersensitivity reactions which are commonly seen with phenytoin, carbamazepine, and lamotrigine (3-10% of patients treated with these drugs). There are no data on potential chronic toxicity in man, but some concerns have been expressed about potential carcinogenicity. A significant increase in acinar-cell pancreatic tumours was seen in male rats treated for 2 years with gabapentin 2 gkg per day. Nevertheless, rats treated with this dose survived for longer than control animals and there was no evidence of local or metastatic spread of the tumours. Since rat pancreas accumulates gabapentin in much higher tissue concentrations than does human pancreas, the carcinogenic potential of gabapentin in man seems acceptably low. There are no teratogenicity data in man. Animal testing does not suggest any specific problems in this area.
Figure 2: Difference in mean response ratio and 95% CI at different gabapentin doses
Table 3: Ten adverse events occurring most
Combined data from three
patients receiving gabapentin
90
large trials.= difference;--=95%CL
From ref 12, with permission.
frequently in
Drug Interactions No clinically significant interactions have been detected, and theoretically none would be expected. Thus gabapentin should be easy to use as add-on therapy with existing
antiepileptic drugs. Clinical
use
in adult patients with refractory without secondarily generalised tonic-clonic seizures. On initiation of therapy, doses can be increased over a week to an initial total of 1200 mg per day in three divided doses. Thereafter, depending on response, dosage increments to 1 -8 g or 2 -4 g in three divided doses per day can be considered. The results of a large clinical trial in refractory generalised epilepsies should be available shortly, but the drug has no proven efficacy in these epilepsies, nor can it be recommended as monotherapy in newly diagnosed patients with generalised or partial epilepsies until adequate clinical trial data are available. The pharmacokinetic characteristics of gabapentin mean that there is no requirement to monitor drug concentrations during treatment; the dose should be adjusted on the basis of clinical symptoms and signs as well as seizure response. Monitoring of concurrently administered antiepileptic drug concentrations is not worthwhile since there are no interactions. Equally, there is no evidence that gabapentin affects haematological or biochemical variables to any degree and routine testing is unnecessary. Gabapentin is unlikely to prove more effective than existing antiepileptic drugs, but its ready application to add-on therapy may reduce the burden of adverse effects in
Gabapentin is indicated partial seizures with or
epileptic patients.
The author holds a consultancy agreement with manufacture gabapentin.
Parke-Davis, who
References Hauser WA, Hesdorffer DC. Epilepsy: frequency, causes and consequences. New York: Demos Publications, 1990. 2 Taylor CP. Mechanisms of action of new anti-epileptic drugs. In: Chadwick D, ed. New trends in epilepsy management: the role of gabapentin. London: Royal Society of Medicine, International Congress and Symposium Series, no 198: 13-40. 3 Lippert B, Metcalf BW, Jung MJ, Casara P. 4-amino-hex-5-enoic acid: a selective catalytic inhibitor of 4-aminobutyric acid aminotransferase in mammalian brain. Eur J Biochem 1977; 74: 441-45. 4 Twyman RE, McDonald RL. Antiepileptic drug regulation of GABAA receptor channels. In: Tunnicliff G, Raess BU, eds. GABA mechanisms in epilepsy. New York: Wiley-Liss, 1991: 89-104. 5 Loscher W, Honack D, Taylor CP. Gabapentin increases aminooxyacetic acid-induced GABA accumulation in several regions of rat brain. Neurosci Lett 1991; 128: 150-54. 6 Hill DR, Suman-Chauhan N, Woodruff GN. Localisation of [3H]-gabapentin to a novel site in rat brain: autoradiographic studies. Eur J Pharmacol 1993; 224: 303-09. 7 Taylor CP, Vartanian MG, Yuen P-W, Bigge C, Suman-Chauhan N, Hill DR. Potent and stereospecific anticonvulsant activity of 3-isobutyl GABA related to in vitro binding at a novel site labelled by tritiated gabapentin. Epilepsy Res 1992; 14: 11-15. 8 Richens A. Clinical pharmacokinetics of gabapentin. In: Chadwick D, ed. New trends in epilepsy management: the role of gabapentin. London: Royal Society of Medicine, International Congress and Symposium Series, no 198: 41-46. 9 UK Gabapentin Study Group. Gabapentin in partial epilepsy. Lancet 1990; 335: 1114-17. 10 The US Gabapentin Study Group. Gabapentin as add-on therapy 1
in 11
12
refractory epilepsy: a double-blind, placebo-controlled, parallel-group study. Neurology (in press). Anhut H, Ashman P, Feuerstein TJ, et al. Gabapentin as add-on therapy in patients with partial seizures: a double-blind, placebocontrolled study. Epilepsia (in press). Browne TR. Efficacy and safety of gabapentin. In: Chadwick D, ed. New trends in epilepsy management: the role of gabapentin. London: Royal Society of Medicine, International Congress and Symposium Series, no 198: 47-57.
Pathogenesis of non-insulin-dependent diabetes mellitus
mellitus (NIDDM) affects about 5-7% of the population and can be viewed as the tip of the iceberg of disordered glucose metabolism. Study of NIDDM patients is of limited help in understanding the pathogenesis, because once diabetes has developed, the many coexisting metabolic disturbances make it impossible to distinguish primary cause from secondary effects. Thus, characterisation of early metabolic alterations necessitates study of true prediabetics. Several studies have indicated that insulin resistance both precedes and predicts impaired glucose tolerance (IGT) and NIDDM.1 Whether insulin resistance reflects the strongest risk factor for NIDDM, a positive family history,1,2 or merely unmasks a primary &bgr;-cell defect3 is unknown.
Non-insulin-dependent
diabetes
Third Department of Medicine, University of Helsinki, Haartmaninkatu 4, SF-00290 Helsinki, Finland (Hannele Yki-Järvinen MD)
Although insulin resistance increases the risk of NIDDM/.4 impaired &bgr;-cell function is the hallmark of NIDDM (figure 1). Although several mechanisms could ultimately damage &bgr;-cell function and contribute to pathogenesis, subtypes of NIDDM may exist. There is need for a better definition of NIDDM than "a patient who survives without insulin".
Does insulin resistance precede NIDDM? Cross-sectional analyses Oral glucose tolerance tests (OGTTs) in a large sample give inverted U plots of insulin versus glucose in plasma (figure 1). This relation occurs in whites and in populations with exceptionally high prevalences ofNIDDM.1 Patients with NIDDM may have higher insulin concentrations than non-diabetic individuals (figure 1). However, despite hyperinsulinaemia, every patient with NIDDM is insulindeficient since insulin concentration is inappropriate when related to the prevailing glucose concentration. 91
with
Background Epilepsy is a common clinical disorder characterised by hyperexcitability and paroxysmal discharge of cortical neurons. The prevalence is 0.5-1% of the population. While about 70% of people who get epilepsy have a short-lasting disorder that soon enters remission, others have a chronic, lifelong condition that is poorly responsive to antiepileptic drugs. Between 1 and 2 per 1000 of the population may have such "intractable" epilepsy.1 Existing antiepileptic drugs have various idiosyncratic, dose-related, chronic toxic and teratogenic effects. Thus, there is a need for new antiepileptic agents that might not only benefit patients with intractable seizures but also
voltage-dependent sodium channels or with benzodiazepine or excitatory neurotransmitter receptor sites, nor does it influence catecholamine, acetylcholine, or opioid receptors.
induce fewer adverse effects. Much is now known about the mechanism of action of antiepileptic drugs. Phenytoin, carbamazepine, and lamotrigine block repetitive firing of neurons by an action on voltage-sensitive sodium channels.2 Other agents exert their main effect via modulation of inhibitory or excitatory neurotransmission. Thus, vigabatrin blocks the inactivation of gamma aminobutyric acid (GABA) by acting as a suicidal inhibitor for GABA aminotransferase.3 Phenobarbitone and benzodiazepines facilitate the action of GABA at its receptor site by allosteric means.4 Lamotrigine, in addition to its phenytoin and carbamazepine like actions, may also reduce the release of excitatory neurotransmitters, glutamate and aspartate. Valproate may have actions on both GABA-ergic systems and excitatory neurotransmitters.
Mechanisms of action
Gabapentin (figure 1) (1-[aminomethyl] cyclohexaneacetic acid) was synthesised because of its structural similarity to GABA and its ability to cross the blood-brain barrier. Although gabapentin is effective in many animal seizure models (table 1), it cannot be shown to interact with GABAA or GABAB receptors and does not interfere with GABA metabolism, and so cannot be described as a GABA-mimetic drug. It has been shown to increase GABA content of some brain regions.s It does not interact
*All results are from unpublished studies ; tlowest effective dose; tat this dose, seizures were significantly delayed but not prevented. IP= intraperitoneal; IV= intravenous Table 1: Activity of gabapentin in animal models of seizures*
Gabapentin binds to a site that is found in brain but not elsewhere.6 This specific binding site seems to be a protein that is predominantly located on neurons and it does not bind any other antiepileptic drugs. It is found in its highest density in the neocortex of the rat and in those areas rich in glutaminergic synapses. The precise nature of this site has yet to be determined, but enantiomers of gabapentin show different potencies for binding at the gabapentin site and this potency is proportional to their efficacy in seizure models.7 Clinical
Figure
1: Structure of
gabapentin
Department of Neurological Science, Walton Hospital, Liverpool L9 1AE, UK (Prof D Chadwick FRCP)
Rice Lane,
pharmacokinetics
The pharmacokinetics of gabapentin is simple (table 2).8 There is no evidence that the drug interacts in any pharmacokinetic way with other antiepileptic agents, nor does it induce liver enzymes. Its only disadvantage is the half-life of 5-7 h which might necessitate thrice daily dosing. There is some evidence that twice daily dosing will suffice.
89
From ref 8, with permission. Table 2: Pharmacoklnetlc
properties of gabapentin
Efficacy Three double-blind, parallel group studies have been conducted in refractory patients with partial epilepsies.9-11 Two smaller supportive studies of similar design have likewise been conducted, and in total 792 patients were randomised to receive placebo or gabapentin doses of 600, 900, 1200, or 1800 mg per day. The similarity of designs of these trials lend themselves to meta-analysis, and the results of this are presented in figure 2, which shows the difference in mean response ratio with 95% CI. The response ratio is defined by: Treatment seizure Treatment seizure
frequency baseline seizure frequency frequency + baseline seizure frequency -
This transformation of seizure frequency leads to a more normal distribution with a range between - 1 (complete abolition of seizures) to +1 (an infinite worsening of seizures) and so allows the use of parametric statistics. A 50% reduction in seizure frequency is equivalent to a response ratio of -0-33. There is a clear dose-related antiepileptic effect. Figure 3 shows that maximum efficacy is in reducing tonic-clonic seizures and complex partial seizures. A similar dose-related effect on responder rates (proportion of patients showing a 50% or greater reduced reduction in seizure frequency during gabapentin treatment) is likewise seen, with 23% of patients receiving 1200 mg a day showing such a reduction vs 10% in the
placebo group. Longer-term open follow-up studies do not suggest any tolerance to gabapentin’s antiepileptic effect. 650 patients have received the drug for at least 1 year; 116 for more than 4 years.
There are no data on the drug’s antiepileptic properties in children or in patients with generalised epilepsies. Existing data do not indicate that gabapentin has any more efficacy than existing antiepileptic drugs and it will be important to
Figure 3: Mean response ratio in all placebo-controlled studies by seizure type GBP gabapentin; PLC placebo. *Mean response ratio for all patients = difference;—=95% Cl. =
=
receiving gabapentin.
prospective randomised comparisons of gabapentin as monotherapy with other first-line antiepileptic drugs for partial epilepsy. conduct
Adverse
experience
Gabapentin is well tolerated. 7-4% of 1748 patients who received the agent during any study withdrew due to an adverse event vs 3-3% of 485 patients who received placebo in addition to at least one concurrent antiepileptic drug. The incidence of the ten most common adverse events in patients receiving gabapentin is compared with placebo in table 3.12 The severity of these probably dose-related central nervous system effects is mild. No serious idiosyncratic reactions have been identified with gabapentin, and in particular there is no evidence of hypersensitivity reactions which are commonly seen with phenytoin, carbamazepine, and lamotrigine (3-10% of patients treated with these drugs). There are no data on potential chronic toxicity in man, but some concerns have been expressed about potential carcinogenicity. A significant increase in acinar-cell pancreatic tumours was seen in male rats treated for 2 years with gabapentin 2 gkg per day. Nevertheless, rats treated with this dose survived for longer than control animals and there was no evidence of local or metastatic spread of the tumours. Since rat pancreas accumulates gabapentin in much higher tissue concentrations than does human pancreas, the carcinogenic potential of gabapentin in man seems acceptably low. There are no teratogenicity data in man. Animal testing does not suggest any specific problems in this area.
Figure 2: Difference in mean response ratio and 95% CI at different gabapentin doses
Table 3: Ten adverse events occurring most
Combined data from three
patients receiving gabapentin
90
large trials.= difference;--=95%CL
From ref 12, with permission.
frequently in
Drug Interactions No clinically significant interactions have been detected, and theoretically none would be expected. Thus gabapentin should be easy to use as add-on therapy with existing
antiepileptic drugs. Clinical
use
in adult patients with refractory without secondarily generalised tonic-clonic seizures. On initiation of therapy, doses can be increased over a week to an initial total of 1200 mg per day in three divided doses. Thereafter, depending on response, dosage increments to 1 -8 g or 2 -4 g in three divided doses per day can be considered. The results of a large clinical trial in refractory generalised epilepsies should be available shortly, but the drug has no proven efficacy in these epilepsies, nor can it be recommended as monotherapy in newly diagnosed patients with generalised or partial epilepsies until adequate clinical trial data are available. The pharmacokinetic characteristics of gabapentin mean that there is no requirement to monitor drug concentrations during treatment; the dose should be adjusted on the basis of clinical symptoms and signs as well as seizure response. Monitoring of concurrently administered antiepileptic drug concentrations is not worthwhile since there are no interactions. Equally, there is no evidence that gabapentin affects haematological or biochemical variables to any degree and routine testing is unnecessary. Gabapentin is unlikely to prove more effective than existing antiepileptic drugs, but its ready application to add-on therapy may reduce the burden of adverse effects in
Gabapentin is indicated partial seizures with or
epileptic patients.
The author holds a consultancy agreement with manufacture gabapentin.
Parke-Davis, who
References Hauser WA, Hesdorffer DC. Epilepsy: frequency, causes and consequences. New York: Demos Publications, 1990. 2 Taylor CP. Mechanisms of action of new anti-epileptic drugs. In: Chadwick D, ed. New trends in epilepsy management: the role of gabapentin. London: Royal Society of Medicine, International Congress and Symposium Series, no 198: 13-40. 3 Lippert B, Metcalf BW, Jung MJ, Casara P. 4-amino-hex-5-enoic acid: a selective catalytic inhibitor of 4-aminobutyric acid aminotransferase in mammalian brain. Eur J Biochem 1977; 74: 441-45. 4 Twyman RE, McDonald RL. Antiepileptic drug regulation of GABAA receptor channels. In: Tunnicliff G, Raess BU, eds. GABA mechanisms in epilepsy. New York: Wiley-Liss, 1991: 89-104. 5 Loscher W, Honack D, Taylor CP. Gabapentin increases aminooxyacetic acid-induced GABA accumulation in several regions of rat brain. Neurosci Lett 1991; 128: 150-54. 6 Hill DR, Suman-Chauhan N, Woodruff GN. Localisation of [3H]-gabapentin to a novel site in rat brain: autoradiographic studies. Eur J Pharmacol 1993; 224: 303-09. 7 Taylor CP, Vartanian MG, Yuen P-W, Bigge C, Suman-Chauhan N, Hill DR. Potent and stereospecific anticonvulsant activity of 3-isobutyl GABA related to in vitro binding at a novel site labelled by tritiated gabapentin. Epilepsy Res 1992; 14: 11-15. 8 Richens A. Clinical pharmacokinetics of gabapentin. In: Chadwick D, ed. New trends in epilepsy management: the role of gabapentin. London: Royal Society of Medicine, International Congress and Symposium Series, no 198: 41-46. 9 UK Gabapentin Study Group. Gabapentin in partial epilepsy. Lancet 1990; 335: 1114-17. 10 The US Gabapentin Study Group. Gabapentin as add-on therapy 1
in 11
12
refractory epilepsy: a double-blind, placebo-controlled, parallel-group study. Neurology (in press). Anhut H, Ashman P, Feuerstein TJ, et al. Gabapentin as add-on therapy in patients with partial seizures: a double-blind, placebocontrolled study. Epilepsia (in press). Browne TR. Efficacy and safety of gabapentin. In: Chadwick D, ed. New trends in epilepsy management: the role of gabapentin. London: Royal Society of Medicine, International Congress and Symposium Series, no 198: 47-57.
Pathogenesis of non-insulin-dependent diabetes mellitus
mellitus (NIDDM) affects about 5-7% of the population and can be viewed as the tip of the iceberg of disordered glucose metabolism. Study of NIDDM patients is of limited help in understanding the pathogenesis, because once diabetes has developed, the many coexisting metabolic disturbances make it impossible to distinguish primary cause from secondary effects. Thus, characterisation of early metabolic alterations necessitates study of true prediabetics. Several studies have indicated that insulin resistance both precedes and predicts impaired glucose tolerance (IGT) and NIDDM.1 Whether insulin resistance reflects the strongest risk factor for NIDDM, a positive family history,1,2 or merely unmasks a primary &bgr;-cell defect3 is unknown.
Non-insulin-dependent
diabetes
Third Department of Medicine, University of Helsinki, Haartmaninkatu 4, SF-00290 Helsinki, Finland (Hannele Yki-Järvinen MD)
Although insulin resistance increases the risk of NIDDM/.4 impaired &bgr;-cell function is the hallmark of NIDDM (figure 1). Although several mechanisms could ultimately damage &bgr;-cell function and contribute to pathogenesis, subtypes of NIDDM may exist. There is need for a better definition of NIDDM than "a patient who survives without insulin".
Does insulin resistance precede NIDDM? Cross-sectional analyses Oral glucose tolerance tests (OGTTs) in a large sample give inverted U plots of insulin versus glucose in plasma (figure 1). This relation occurs in whites and in populations with exceptionally high prevalences ofNIDDM.1 Patients with NIDDM may have higher insulin concentrations than non-diabetic individuals (figure 1). However, despite hyperinsulinaemia, every patient with NIDDM is insulindeficient since insulin concentration is inappropriate when related to the prevailing glucose concentration. 91