Chapter 38. Gabapentin and Pregabalin

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Mark A. Frye, Katherine Marshall Moore: Chapter 38. Gabapentin and Pregabalin, in The American Psychiatric Publishing

Textbook of Psychopharmacology, 4th Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009

American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623860.414338. Printed 5/10/2009 from

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Chapter 38. Gabapentin and Pregabalin

GABAPENTIN

Anticonvulsants have long been used in the treatment of certain psychiatric conditions. As

exemplified by the U.S. Food and Drug Administration (FDA) indications for divalproex sodium,

carbamazepine, and lamotrigine in the acute and maintenance phases of bipolar disorder (Yatham

et al. 2002), anticonvulsants are widely viewed as valid alternatives to, and in some cases

preferred over, the conventional first-line psychopharmacotherapy choices of lithium and

antipsychotics. Early observations of enhanced general well-being in epileptic patients treated with

anticonvulsants, as well as various early hypotheses of kindling and sensitization proposed as

models of affective illness progression (Weiss and Post 1998), have promoted controlled

investigations of anticonvulsant drugs as potential mood-stabilizing agents.

Gabapentin is FDA approved for the adjunctive treatment of complex partial epilepsy with and

without generalization and for the management of postherpetic neuralgia in adults. A retrospective

review of five placebo-controlled trials of gabapentin in more than 700 patients with refractory

partial seizure disorder additionally supported the concept of improvement in general well-being,

prompting controlled investigation of the drug in primary psychiatric conditions (Dimond et al.

1996).

Pharmacological Profile and Mechanism of Action

The mechanism of gabapentin’s anticonvulsant and psychotropic action is not fully understood.

Gabapentin was originally developed as a -aminobutyric (GABA) analog. As reviewed by Taylor et

1. (1998), GABA is the major inhibitory neurotransmitter in the cerebral cortex. Gabapentin does

not act as a GABA precursor, agonist, or antagonist. Preclinical studies have suggested that

gabapentin increases brain and intracellular GABA by an amino acid active transporter at the

blood–brain barrier and multiple enzymatic regulatory mechanisms, respectively. For example, in

vitro studies have shown that gabapentin increased the activity of glutamic acid decarboxylase,

which is the enzyme that converts glutamate to GABA (Taylor et al. 1992). Conversely, gabapentin

has been shown to inhibit GABA-transaminase (GABA-T), which is the enzyme primarily responsible

for GABA catabolism (Loscher et al. 1991). Glutamate metabolism is also modulated by gabapentin.

In vitro studies have demonstrated that gabapentin inhibits branched-chain amino acid

aminotransferase (BCAA-T), an enzyme responsible for glutamate synthesis (Hutson et al. 1998),

and activates glutamate dehydrogenase, an enzyme primarily involved in glutamate catabolism

(Goldlust et al. 1995).

These enzymatic regulatory mechanisms that suggest an increased synthesis and decreased

degradation of GABA are clinically relevant. Several, but not all, studies have reported decreased

levels of cerebrospinal fluid (Gerner et al. 1996; Gold et al. 1980; Roy et al. 1991), plasma (Petty et

1. 1990), and magnetic resonance (MR) spectroscopic GABA (Sanacora et al. 1999) in patients with

affective illness in comparison with healthy controls. Furthermore, increased MR spectroscopic

occipital GABA concentrations have been reported with serotonin reuptake inhibitor treatment in

depressed patients (Sanacora et al. 2002) and gabapentin treatment in patients with complex

partial epilepsy (Petroff et al. 1996).

Gabapentin has also been shown to bind to the 2 subunit receptor of brain voltage-dependent

calcium channels, which may relate to the subsequent inhibition of monoaminergic transmissionPrint: Chapter 38. Gabapentin and Pregabalin http://www.psychiatryonline.com/popup.aspx?aID=414342&print=yes…

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(Schlicker et al. 1985). There is no known direct activity at the dopamine, serotonin,

benzodiazepine, or histamine receptors. However, gabapentin has been reported to increase

whole-blood levels of serotonin in healthy controls (Rao et al. 1988). These potentially important

mechanisms of action have not been tested formally in psychiatric patient populations.

Pharmacokinetics and Disposition

All bioavailability, distribution, and elimination parameters are based on the gabapentin molecule

itself, as there is no active metabolite. Gabapentin exhibits nonlinear bioavailability most likely

related to an active saturable L-amino acid transport carrier present in gut and blood–brain barrier

(McLean 1999). There is no evidence of plasma protein binding, hepatic metabolism, or cytochrome

P450 (CYP) autoinduction. Elimination half-life is 6–8 hours, with a recommended

three-times-a-day dosing strategy. Gabapentin is eliminated from systemic circulation unchanged

by renal excretion. Patients with compromised renal function will show evidence of reduced

gabapentin clearance.

Indications and Efficacy

Epilepsy

Gabapentin currently is FDA approved as an adjunctive treatment for partial seizures with and

without secondary generalization in adults with epilepsy (“Neurontin” 2006). This indication was

based on controlled evaluations of gabapentin at daily doses of 600–1,800 mg. Additional research

has reported efficacy and tolerability for gabapentin monotherapy at daily dosages up to 4,800 mg

in patients with refractory epilepsy (Beydoun et al. 1998). There is no established therapeutic

plasma level for seizure control. Gabapentin has a highly desirable side-effect profile. Only mild

side effects (sedation, dizziness, and ataxia) have been commonly reported.

Nonepilepsy Neurological Conditions

Neuropathic pain

On the basis of two placebo-controlled studies (Rice et al. 2001; Rowbotham et al. 1998),

gabapentin has received FDA approval for use in the management of postherpetic neuralgia in

adults. Gabapentin has also been systemically evaluated in diabetic neuropathy (Backonja et al.

1998).

The initial postherpetic neuralgia (Rowbotham et al. 1998) and diabetic neuropathy (Backonja et al.

1998) studies were randomized, double-blind, placebo-controlled, parallel-group multicenter

investigations with three phases of evaluation. The first phase identified the subject population

(patients with diabetic neuropathy of 1–5 years’ duration [Backonja et al. 1998] or postherpetic

neuralgia of 3 months’ duration [Rowbotham et al. 1998]). The 8-week double-blind phases

consisted of a 4 week step titration (week 1, 900 mg; week 2, 1,800 mg; week 3, 2,400 mg; and

week 4, 3,600 mg) and a 4-week fixed-dose period wherein the dose that was effective and

tolerable from the titration phase was held constant. There were no differences in demographics or

rates of dropout because of inefficacy or adverse events between the gabapentin group and the

placebo group.

Among the 229 postherpetic neuralgia patients (Rowbotham et al. 1998), greater pain reduction

occurred with gabapentin, noted as early as week 2 and maintained throughout the entire study

period. Similarly, secondary measures of mood such as depression, anger–hostility, fatigue–inertia,

and physical functioning were more effectively treated with gabapentin than with placebo.

Eighty-three percent of the gabapentin group was maintained on the 2,400-mg daily dose, and 65%

were maintained on the 3,600-mg daily dose.

Among the 165 diabetic neuropathy patients (Backonja et al. 1998), greater pain reduction (as

measured with an 11-point Likert scale) occurred with gabapentin than with placebo; this

difference was statistically significant as early as week 2 of the blind titration phase and remainedPrint: Chapter 38. Gabapentin and Pregabalin http://www.psychiatryonline.com/popup.aspx?aID=414342&print=yes…

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significant for the duration of the 8-week study. The difference was also clinically relevant, as

demonstrated by significant reductions in sleep interference related to pain and improved quality of

life. Gabapentin appeared to be well tolerated, as 67% of the patient group maintained a maximum

dose of 3,600 mg. The most common side effects noted with greater frequency in the gabapentin

group were dizziness and somnolence.

Finally, a 7-week placebo-controlled study evaluated gabapentin (1,800 or 2,400 mg/day in three

divided doses) in 334 patients with postherpetic neuralgia (Rice et al. 2001). Pain was significantly

reduced with both gabapentin doses, with similar improvements in sleep. The improvement in pain

score was noted as early as week 1 and was maintained throughout the study.

Movement disorders

Controlled investigations of gabapentin have been conducted in several movement disorders. These

studies, albeit controlled, were much smaller than the neuropathic pain studies mentioned in the

prior section but included amyotrophic lateral sclerosis (ALS) (Miller et al. 1996), essential tremor

(Ondo et al. 2000; Pahwa et al. 1998), and parkinsonism (Olson et al. 1997).

In a study of 152 patients with ALS, patients were randomly assigned to a 2,400-mg daily dose of

gabapentin or placebo for 6 months. Decline in muscle strength, the primary outcome measure, was

slower in the gabapentin-treated patients than in the placebo-treated patients (Miller et al. 1996).

Controlled studies of gabapentin for essential tremor have reported mixed results. The first 2-week

controlled study showed no difference between gabapentin 1,800 mg/day and placebo for

treatment of essential tremor (Pahwa et al. 1998). A second 6-week controlled study evaluating

two gabapentin dosages—1,800 mg/day and 3,600 mg/day—in patients with essential tremor found

significant improvements in self-report scores, observed tremor scores, and activities of daily living

scores in patients randomly assigned to gabapentin compared with patients who received placebo

(Ondo et al. 2000).

In a 1-month double-blind, placebo-controlled evaluation of gabapentin in 19 patients with

advanced parkinsonism, gabapentin at a mean daily total dose of 1,200 mg was superior to placebo

in reducing rigidity, bradykinesia, and tremor, as measured by the United Parkinson’s Disease

Rating Scale (Olson et al. 1997). The authors pointed out that the rigidity and bradykinesia

improvements were independent of tremor improvement.

Migraine headache

The comorbidity of migraine headache disorder and bipolar disorder is highly prevalent and

clinically significant (Mahmood et al. 1999). Anticonvulsants, both for their anticonvulsant

mood-stabilizing effects and for their migraine prophylactic properties, appear to be ideal in this

patient population. A study by Mathew et al. (2001) suggested that gabapentin is an effective agent

for migraine prophylaxis. One hundred forty-three patients with migraine (with and without aura)

participated in this three-phase controlled evaluation of gabapentin. Phase 1 was a 4-week

single-blind placebo period during which baseline migraine headache frequency was established.

Phase 2 was a 4-week double-blind, placebo-controlled, flexible-dose titration period during which

patients received gabapentin dosages of up to 2,400 mg/day. Phase 3 was an 8-week double-blind,

placebo-controlled period during which the dosage of gabapentin was held constant. Patients

randomly assigned to 2,400 mg/day gabapentin had significant reductions in migraine attacks in

comparison with placebo-treated patients. Dropout rates were higher with gabapentin and were

primarily related to drowsiness and somnolence.

Anxiety Disorders

Gabapentin has been shown in a number of animal models to exhibit a dose-dependent anxiolytic

response (Singh et al. 1996). Open-trial investigations have reported positive results with add-on

gabapentin in the treatment of generalized anxiety disorder (Pollack et al. 1998), panic disorder

(Pollack et al. 1998), and refractory obsessive-compulsive disorder (Cora-Locatelli et al. 1998).

Two controlled investigations of gabapentin in social phobia (Pande et al. 1999) and panic disorderPrint: Chapter 38. Gabapentin and Pregabalin http://www.psychiatryonline.com/popup.aspx?aID=414342&print=yes…

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(Pande et al. 2000b) suggest anxiolytic activity.

Pande et al. (1999) investigated gabapentin in a 14-week randomized, double-blind,

placebo-controlled two-site study of 69 outpatients with DSM-IV (American Psychiatric Association

1994)–confirmed social phobia. All patients were required to have a score of 50 or higher on the

Liebowitz Social Anxiety Scale (LSAS) at baseline. Reduction in the LSAS score served as the

primary outcome measure. In the 69 patients randomly assigned to the intent-to-treat analysis,

gabapentin was more effective than placebo in reducing social anxiety symptoms. The dosage

range for gabapentin was 900–3,600 mg/day, with 56% of patients responding to and tolerating

the maximum daily dosage of 3,600 mg. Dizziness and dry mouth were significantly more common

in patients treated with gabapentin.

The second study was an 8-week randomized, placebo-controlled six-site monotherapy study of 103

patients with DSM-IV–confirmed panic disorder with or without agoraphobia (Pande et al. 2000b).

Subjects had been experiencing at least one panic attack per week for 3 weeks prior to study entry.

Gabapentin was dosed flexibly between 600 and 3,600 mg/day. The primary outcome measure was

a decrease in the Panic and Agoraphobia Scale (PAS) score. The two groups had no differences in

demographic profile or dropout rate. In the intent-to-treat analysis, no difference in PAS score

reduction was seen between patients randomly assigned to gabapentin and those given placebo. In

a post hoc stratification between high (20) and low (20) PAS symptom severity, patients with high

symptom severity randomly assigned to gabapentin had a greater baseline-to-endpoint decrease in

the PAS score than did those randomly assigned to placebo. Somnolence, headache, dizziness,

infection, asthenia, and ataxia were more common in gabapentin-treated patients.

Bipolar Disorder

Given the demonstrated role of the FDA-approved anticonvulsants in the treatment of bipolar

disorder, it was inevitable that there should be interest in evaluating gabapentin’s utility as a mood

stabilizer. Numerous case reports and open trials, encompassing more than 400 patients with a

pooled response rate between 65% and 70%, have been reviewed elsewhere (Frye et al. 2000;

Yatham et al. 2002).

One double-blind, placebo-controlled outpatient study evaluated add-on gabapentin for the

treatment of bipolar I disorder with manic, hypomanic, or mixed symptoms (Pande et al. 2000a).

The first phase of the study involved a 2-week single-blind, placebo lead-in wherein doses of the

subject’s primary mood stabilizer (lithium or valproate) could be adjusted to maximal clinical

benefit and minimum threshold of therapeutic level (i.e., lithium level of 0.5 mmol/L, valproate

level 50 g/mL). The second phase of the study was a 10-week double-blind phase in which

subjects were randomly assigned to either gabapentin, dosed flexibly between 600 and 3,600

mg/day (three-times-a-day dosing) or placebo. In the intent-to-treat population, 117 subjects were

randomized; no differences in demographic profile or dropout rate were found between the two

groups. The primary outcome measure—total decreased score on the Young Mania Rating

Scale—was significantly different between groups in favor of add-on placebo. In a post hoc

analysis, lithium adjustments in the single-blind, placebo lead-in phase were made more frequently

in the placebo group than in the gabapentin group; most of these adjustments (9 of 12; 75%)

consisted of a dosage increase. This fact suggests either a strong placebo response or the effect of

maximizing lithium blood levels to achieve a greater antimanic response. Of the gabapentin-treated

patients who had drug levels measured, nearly 20% had plasma gabapentin levels that were

undetectable.

The second controlled study was a 6-week double-blind, placebo-controlled crossover comparative

trial of gabapentin monotherapy, lamotrigine monotherapy, and placebo in 35 inpatients with

refractory mood disorder (Frye et al. 2000; Obrocea et al. 2002). The primary outcome measure

was a score of very much or much improved on the Clinical Global Impressions Scale; in the

preliminary analysis (Frye et al. 2000) and final analysis (Obrocea et al. 2002), gabapentin

demonstrated no better treatment response than placebo in a group of patients with highly

refractory bipolar (primarily rapid-cycling) disorder.Print: Chapter 38. Gabapentin and Pregabalin http://www.psychiatryonline.com/popup.aspx?aID=414342&print=yes…

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There appears to be a marked contrast between the pooled results of the uncontrolled observations

(generally positive) and the results of the controlled studies (generally negative). The important

limitations of the controlled investigations include placebo response versus maximizing lithium

response in the placebo group, lack of rigorous compliance assessment, and a monotherapy study

design in a cohort of patients with primarily rapid-cycling, treatment-refractory illness.

Substance Abuse and Withdrawal

Although benzodiazepines remain the gold standard for alcohol withdrawal, mood-stabilizing

anticonvulsants such as divalproex sodium and carbamazepine are clearly alternatives and possibly

preferred treatments for alcohol-abusing bipolar patients (Malcolm et al. 2001). Gabapentin has

been shown to decrease excitability and convulsions in animal models of alcohol withdrawal

(Watson et al. 1997). The lack of hepatic metabolism, CYP enzyme induction, protein binding, or

addictive potential makes gabapentin a potentially useful compound in this patient population.

The potential of gabapentin for treating alcohol withdrawal was considered after initial positive

reports emerged (Bozikas et al. 2002). One study demonstrated a similar efficacy to phenobarbital

in treating alcohol withdrawal (Mariani et al. 2006), although another controlled trial did not

substantiate gabapentin’s benefit over placebo (Bonnet et al. 2003). This latter study involved 61

inpatients admitted for a 1-week alcohol detoxification and randomly assigned to gabapentin (400

mg four times daily) or placebo. The primary outcome measure was the amount of rescue

medication (clomethiazole; 1 capsule = 192 mg) required during the first 24 hours (6.2 capsules for

gabapentin and 6.1 capsules for placebo). In a post hoc analysis (Bonnet et al. 2007), there was a

significant increase in the Profile of Mood States (POMS) vigor subscore in the gabapentin group

versus the placebo group; this was particularly robust in patients with comorbid mild depression.

Despite the conflicting results for gabapentin’s efficacy in alcohol withdrawal, there is increasing

recognition of its therapeutic benefit for the sleep disturbance component of alcohol withdrawal

syndrome. Low-dose gabapentin (mean dose = 900 mg) in the treatment of alcohol withdrawal, in

comparison with trazodone, was associated with greater improvement in sleep problems, as

assessed with the Sleep Problems Questionnaire (Karam-Hage and Brower 2003). As well, in

patients with a history of multiple previous alcohol withdrawals, gabapentin, in comparison with

lorazepam, was associated with significant reductions in self-report sleep disturbances and daytime

sleepiness (Malcolm et al. 2007).

One 4-week placebo-controlled, randomized, double-blind study evaluated gabapentin in alcohol

abuse relapse prevention (Furieri and Nakamura-Palacios 2007). After detoxification, 60

alcohol-dependent men who had been consuming, on average, 17 drinks per day for the preceding 3

months were randomly assigned to gabapentin (300 mg twice daily) or placebo. The gabapentin

group showed a significant reduction in both the number of drinks per day and the percentage of

heavy drinking days. In addition to an increase in the percentage of days abstinent, the gabapentin

group reported a significant reduction in craving for alcohol, specifically automaticity of drinking.

Side Effects and Toxicology

Gabapentin has a highly desirable side-effect profile that has been remarkably consistent among

the controlled studies of diverse disease states. Sedation, drowsiness, and dizziness always have

been reported, and ataxia, dry mouth, infection, and asthenia have been reported in at least one

placebo-controlled study.

Adverse events caused by gabapentin have been few but have important psychiatric implications.

Gabapentin-induced hypomania and mania have been reported (Leweke et al. 1999; Short and

Cooke 1995). The controlled mania study did not report data on percentage of the patients with

exacerbation of mania secondary to gabapentin treatment (Pande et al. 2000a). Gabapentin also

has been associated with aggression, both in pediatric epilepsy (Wolf et al. 1996) and in adult

mania (Pinninti and Mahajan 2001).

Gabapentin has a broad therapeutic index and appears to be safe in overdose. The broadness of thePrint: Chapter 38. Gabapentin and Pregabalin http://www.psychiatryonline.com/popup.aspx?aID=414342&print=yes…

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therapeutic index is most likely related to its nonlinear bioavailability secondary to a saturable

transport carrier (McLean 1999).

Drug–Drug Interactions

Given its lack of hepatic metabolism, CYP autoinduction, and minimal plasma protein binding,

gabapentin has been shown not to affect levels of anticonvulsant drugs; similarly, gabapentin

pharmacokinetics were unchanged with hepatically metabolized anticonvulsants (“Neurontin”

2006). Gabapentin’s renal excretion, however, does pose potential risk when the drug is used

concomitantly with lithium.

Although the therapeutic index with gabapentin is large, that is not the case with lithium. In a

single 600-mg lithium dose pharmacokinetic study, there was no difference in maximal lithium

concentration (Li Cmax), time to reach Cmax, or area under the curve in 13 patients receiving

steady-state gabapentin (mean dose = 3,645.15 ± 931.5 mg) compared with those receiving

steady-state placebo (Frye et al. 1998). It is important to emphasize that this study was in a

patient population with normal renal function; cases of reversible renal impairment associated with

gabapentin have been reported (Grunze et al. 1998).

Summary for Gabapentin

Controlled studies of gabapentin clearly have suggested its efficacy in several medical conditions,

including complex partial epilepsy, postherpetic neuropathy, diabetic neuropathy, and migraine

prophylaxis. Conclusions are less clear, either because of positive controlled studies of a small

sample size or because of negative studies in alcohol abuse/dependence relapse prevention, ALS,

essential tremor, parkinsonism, social phobia, and panic disorder. Gabapentin’s role as a mood

stabilizer is not clearly established. Gabapentin has a favorable pharmacokinetic profile, with

particular advantage in patients with compromised hepatic function. Its minimal drug–drug

interactions, low risk of toxicity, and favorable side-effect profile make it a useful addition to the

pharmacopoeia.

PREGABALIN

Pregabalin is an anticonvulsant drug approved by the FDA for the adjunctive treatment of

partial-onset seizures in adults. It is also approved for the treatment of neuropathic pain associated

with diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia. Like many of the

newer anticonvulsant agents, pregabalin has been evaluated in carefully controlled studies for

possible utility in neurological and psychiatric conditions other than primary epilepsy.

Pharmacological Profile and Mechanism of Action

Pregabalin, like gabapentin, is a structural analog of the inhibitory neurotransmitter GABA.

Pregabalin has shown greater potency than gabapentin in preclinical models of epilepsy, pain, and

anxiety (Hamandi and Sander 2006). Although pregabalin is a GABA structural analog, it has no

clinically significant effect at either the GABAA or GABAB receptor and is not converted

metabolically into GABA or a GABA agonist (Kavoussi 2006). Furthermore, pregabalin does not bind

to any serotonergic, dopaminergic, or glutamatergic receptors. It is known that pregabalin does

bind to the 2δ subunit of the presynaptic voltage-gated calcium channel and that this binding

results in a decrease in excitatory neurotransmitter release (Dooley et al. 2002; Kavoussi 2006). In

contrast to other GABA reuptake inhibitory anticonvulsants (e.g., tiagabine) or anticonvulsants that

modulate enzymatic activity related to GABA production (e.g., vigabatrin), pregabalin does not have

any direct GABA reuptake–inhibitory effects or GABA transaminase–inhibiting effects.

Pharmacokinetics and Disposition

Pregabalin exhibits linear pharmacokinetics. Pregabalin is not associated with any significant

protein binding or hepatic metabolism. Pregabalin oral bioavailability is greater than 90% and

independent of dose. Steady-state plasma levels are generally achieved within 24–48 hours.

Administration with food has no clinically significant effect on the extent of absorption or onPrint: Chapter 38. Gabapentin and Pregabalin http://www.psychiatryonline.com/popup.aspx?aID=414342&print=yes…

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elimination. The elimination half-life of the drug is approximately 6.5 hours (Montgomery 2006).

Pregabalin is highly lipophilic and does not bind to plasma protein and, therefore, readily crosses

the blood–brain barrier. Pregabalin is primarily renally excreted. There are no active metabolites.

Pregabalin does not induce or inhibit CYP enzymes, nor do CYP enzyme inhibitors alter its

pharmacokinetics as a consequence. Because of its renal elimination, dosage adjustment is required

in patients with renal impairment.

Indications and Efficacy

Epilepsy

Several placebo-controlled studies have evaluated pregabalin in the treatment of patients with

refractory partial epilepsy (Elger et al. 2005; Hamandi and Sander 2006). Response rates for

pregabalin dosed at 600 mg/day were similar to those reported in other trials of antiepileptic drugs

in refractory epilepsy. The study by Elger et al. (2005) showed that pregabalin administered in

either fixed or flexible doses was highly effective and generally well tolerated as add-on therapy for

partial seizures with or without secondary generalization.

Nonepilepsy Neurological Conditions

Postherpetic neuralgia

Four placebo-controlled studies have evaluated pregabalin for postherpetic neuropathic pain

(Dworkin et al. 2003; Freynhagen et al. 2005; Sabatowski et al. 2004; Van Seventer et al. 2006).

The first study (Dworkin et al. 2003) was an 8-week parallel-group, double-blind,

placebo-controlled, randomized multicenter trial of patients with postherpetic neuralgia, who

received either pregabalin 600 mg/day (300 mg/day if reduced creatinine clearance) or placebo.

The primary efficacy measure was mean pain ratings using an 11-point numerical pain rating scale

kept in a daily diary. At study endpoint, there was a significant decrease in mean pain scores for

patients treated with pregabalin compared with placebo. The superior pain relief with pregabalin

was identified as early as day 2 and was maintained throughout the 8 weeks of double-blind

treatment. In a second study (Freynhagen et al. 2005), patients with chronic postherpetic neuralgia

or diabetic peripheral neuropathy were randomly assigned to placebo, flexible-dose pregabalin

titrated upward to a maximum dosage of 600 mg/day, or fixed-dose pregabalin at 300 mg/day for

the first week followed by 600 mg/day for the remaining 11 weeks. Both flexible- and fixed-dose

pregabalin significantly reduced endpoint mean pain scores and were significantly superior to

placebo in improving pain-related sleep interference. In a third study, Van Seventer et al. (2006)

evaluated pregabalin (150, 300, or 600 mg/day in bid dosing) or placebo in 370 patients with

postherpetic neuralgia. Pregabalin provided significant dose-proportional pain relief at endpoint,

different from placebo. Sleep interference in all pregabalin groups was significantly improved at

endpoint. Similar results were obtained in the Sabatowski et al. (2004) study, which reported

improvement in sleep and mood disturbance in patients treated with pregabalin. In total, these four

studies showed benefit in pain reduction, sleep improvement, and mood associated with pregabalin

treatment. The most common side effects were dizziness, peripheral edema, weight gain, and

somnolence. The pain-reduction benefits, in comparison with placebo, were noted early in the

clinical trial and were sustained for the duration of the study.

Diabetic peripheral neuropathy

Freeman et al. (2008) conducted a pooled analysis of data from seven published randomized,

placebo-controlled trials encompassing 400 patients with diabetic peripheral neuropathy. The

primary outcome measure was change from baseline to endpoint in mean pain score from patients’

daily pain diaries. With three-times-daily administration, all pregabalin dosages (150, 300, and

600-mg/day) significantly reduced pain and pain-related sleep interference in comparison with

placebo. With twice-daily administration, only the 600-mg/day dosage showed efficacy.

Pregabalin’s pain-reducing and sleep-improving properties appeared to be positively correlated

with dose, with the greatest effect observed in patients treated with 600 mg/day.Print: Chapter 38. Gabapentin and Pregabalin http://www.psychiatryonline.com/popup.aspx?aID=414342&print=yes…

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Fibromyalgia

Pregabalin is the first medication to receive an FDA indication for the treatment of fibromyalgia.

Fibromyalgia is a common chronic pain disorder characterized by widespread diffuse

musculoskeletal pain and tenderness frequently accompanied by significant psychiatric

comorbidity, including fatigue, sleep disturbance, and mood and anxiety disorders. Classifications

of disease severity for fibromyalgia have been published by the American College of Rheumatology

(Wolfe et al. 1990). Prevalence estimates for fibromyalgia are 2% of the U.S. population, with rates

higher in adult women than in men (Arnold et al. 2007).

Two placebo-controlled acute-treatment studies (Crofford et al. 2005; Mease et al. 2008) and one

placebo-controlled relapse prevention study (Crofford et al. 2008) have evaluated pregabalin in the

treatment of patients with fibromyalgia. In the first, an 8-week double-blind, randomized,

placebo-controlled study of pregabalin (150, 300, and 450 mg/day) versus placebo, the 450-mg

daily dose significantly reduced the average severity of pain in comparison with placebo (Crofford

et al. 2005). Sleep improvement was noted at both the 300- and the 450-mg daily dosages.

Dizziness and somnolence were the most frequent adverse events. Arnold et al. (2007), in

recognition of the large overlap of psychiatric comorbidity in fibromyalgia, conducted a post hoc

analysis of the Crofford et al. (2005) study to assess symptoms of anxiety and depression and their

impact on pregabalin treatment. Of 529 patients who had enrolled in pregabalin treatment for

fibromyalgia, significantly more patients endorsed anxiety symptoms (71%) than endorsed

depressive symptoms (56%). Improvement in pain symptoms with pregabalin versus placebo did

not depend on baseline anxiety or depression; in fact, 75% of the pain reduction was not explained

by improvements in mood and/or anxiety.

The second 13-week double-blind, placebo-controlled multicenter study randomly assigned 748

patients with fibromyalgia to receive either placebo or pregabalin dosages of 300, 450, or 600

mg/day (twice-daily dosing) (Mease et al. 2008). The primary outcome measure was symptomatic

relief of pain associated with fibromyalgia, as measured by a mean pain score from an 11-point

numeric rating scale (0 = no pain; 10 = worst possible pain) from patients’ daily diaries. Patients in

all pregabalin groups showed statistically significant improvement in endpoint mean pain score.

Compared with the placebo group, all pregabalin treatment groups showed statistically significant

improvement in sleep.

Finally, the FREEDOM (Fibromyalgia Relapse Evaluation and Efficacy for Durability Of Meaningful

relief) study evaluated pregabalin in a 6-month double-blind, placebo-controlled design (Crofford et

1. 2008). This study included an initial 6-week open-label phase followed by a 26-week

double-blind treatment with ongoing pregabalin or blind substitution to placebo. The primary

outcome measure was time to loss of therapeutic response, defined as a less than 30% reduction in

pain or worsening of symptoms of fibromyalgia. More than 1,000 patients entered the open-label

phase, with 287 being randomly assigned to placebo and 279 to pregabalin. Time to loss of

therapeutic response was significantly greater for the pregabalin group than for the placebo group,

with Kaplan-Meier estimates of time to event showing that half of the placebo group had relapsed

by day 19, whereas half of the pregabalin group had still not lost response by trial end. At the end

of the double-blind phase, 61% of the placebo-treated patients had lost therapeutic response,

compared with only 32% of the pregabalin-treated patients.

These three placebo-controlled studies in the acute or relapse prevention phase in patients with

fibromyalgia mark a substantial advance in clinical trial design of novel uses of anticonvulsants and

represent a milestone in the first FDA-approved treatment for fibromyalgia.

Anxiety Disorders

Generalized anxiety disorder

Four placebo-controlled studies have evaluated pregabalin in generalized anxiety disorder

(Montgomery et al. 2006; Pande et al. 2003; Pohl et al. 2005; Rickels et al. 2005). In the first study Print: Chapter 38. Gabapentin and Pregabalin http://www.psychiatryonline.com/popup.aspx?aID=414342&print=yes…

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(Pande et al. 2003), 276 patients with generalized anxiety disorder were randomly assigned to

pregabalin 150 or 600 mg/day, lorazepam 6 mg/day, or placebo. The 6-week trial included a

1-week placebo lead-in, 4 weeks of blind treatment, and a 1-week taper. The primary efficacy

outcome measure was the endpoint Hamilton Anxiety Scale (Ham-A) score. The mean

baseline-to-endpoint decrease in Ham-A total score in all three active-treatment groups (pregabalin

150 mg/day, pregabalin 600 mg/day, and lorazepam 6 mg/day) was significantly greater than the

decrease in the placebo group. Percentages of subjects who met a secondary outcome measure, a

reduction of 50% or greater in the Ham-A score, were significantly higher in the pregabalin

600-mg/day group (46%) and the lorazepam group (61%) than in the placebo group (27%). There

were no significant differences in response rates by either definition between patients receiving

pregabalin 150 mg/day and patients receiving placebo.

In the second study by Pohl et al. (2005), twice-daily versus three-times-daily dosing of pregabalin

was evaluated in a 6-week double-blind, placebo-controlled study. In this study, 250 patients with

generalized anxiety disorder were randomly assigned to pregabalin 100 mg twice daily, 200 mg

twice daily, 150 mg three times daily, or placebo. Mean improvement in the Ham-A total score was

significantly greater with pregabalin at all doses than with placebo. Pairwise comparisons of

twice-daily versus three-times-daily dosing found no significant differences in outcome. All three

pregabalin groups showed significantly greater improvement in comparison with placebo at

endpoint.

In the third study by Rickels et al. (2005), 454 patients with generalized anxiety disorder were

randomly assigned in a 4-week design to pregabalin 300 mg/day, 450 mg/day, or 600 mg/day;

alprazolam 1.5 mg/day; or placebo. The primary outcome measure was change from baseline to

endpoint in the total Ham-A score. In comparison with the placebo group, all treatment groups

showed significantly greater reductions in mean Ham-A total score at

last-observation-carried-forward (LOCF) analysis. A significantly higher proportion of patients in

the pregabalin (all dosages) and alprazolam groups than in the placebo group met the endpoint

response criterion of 50% or greater reduction in Ham-A total score. The response rate for the

300-mg/day pregabalin group (61%) was significantly higher than that for the alprazolam group

(43%).

In the only pregabalin study with an active antidepressant comparator, Montgomery et al. (2006)

randomly assigned 421 patients with generalized anxiety disorder to 6 weeks of double-blind

treatment with pregabalin (400 or 600 mg/day), venlafaxine (75 mg/day), or placebo. The primary

outcome measure was change in the Ham-A total score from baseline to LOCF analysis. Pregabalin

(both dosages) and venlafaxine produced significantly greater improvement in the Ham-A total

score than did placebo. Patients receiving pregabalin 400 mg/day experienced significant

improvement in all primary and secondary outcome measures in comparison with those receiving

placebo. Rates of discontinuation associated with adverse events were highest in the venlafaxine

group (20.4%), followed by the pregabalin 600 mg/day (13.6%), pregabalin 400 mg/day (6.2%),

and placebo (9.9%) groups. These studies, taken together, contributed to the approval of

pregabalin in Europe for generalized anxiety disorder.

Social anxiety disorder

In the one study by Pande et al. (2004), 135 patients with social anxiety disorder were randomly

assigned to 10 weeks of double-blind treatment with either pregabalin (low dose: 150 mg/day;

high dose: 600 mg/day) or placebo. The primary outcome measure was change from baseline to

endpoint in the LSAS total score. Patients randomly assigned to pregabalin 600 mg/day showed

significant decreases in LSAS total score compared with those receiving placebo. Significant

differences between high-dose pregabalin and placebo were also noted on several secondary

measures, including the LSAS subscales total fear, avoidance, social fear, and social avoidance.

Low-dose pregabalin (150 mg/day) was not significantly better than placebo. Somnolence and

dizziness were the most frequently reported adverse events.

Substance Abuse and WithdrawalPrint: Chapter 38. Gabapentin and Pregabalin http://www.psychiatryonline.com/popup.aspx?aID=414342&print=yes…

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As previously noted, pregabalin has no hepatic metabolism and is excreted essentially unchanged in

the urine. This pharmacokinetic profile is ideal for patients with alcohol abuse or dependence who

have elevated transaminases but need safe, efficacious treatment for symptoms of alcohol

withdrawal. One preclinical study highlighted the potential use of pregabalin and its anticonvulsant,

analgesic, anxiolytic properties in a mouse model of alcohol dependence (Becker et al. 2006).

Controlled clinical studies of pregabalin in alcohol-dependent patients are encouraged.

Side Effects and Toxicology

In general, the side effects commonly occurring with pregabalin treatment have been mild and not

associated with a severity sufficient to warrant drug discontinuation. The most frequently reported

symptoms have been dizziness, sedation, dry mouth, edema, blurred vision, weight gain, and

concentration difficulty. In controlled clinical trials with pregabalin, significant weight gain (a gain

of 7% or more over baseline) was observed in 9% of patients treated with pregabalin, compared

with 2% of patients treated with placebo. Pregabalin treatment does not appear to be associated

with significant changes in heart rate, blood pressure, respirations, or electrocardiogram measures.

Peripheral edema has occurred in a small percentage of patients, but only in rare circumstances has

it been identified as severe.

Available preclinical and clinical data suggest that pregabalin has very low abuse liability and is

unlikely to produce significant physical dependence. There have been postmarketing reports of

angioedema and hypersensitivity in patients treated with pregabalin (Pfizer 2006).

Drug–Drug Interactions

Pregabalin does not induce or inhibit CYP enzymes, nor do CYP enzyme inhibitors alter its

pharmacokinetics as a consequence. Therefore, hepatic and CYP drug–drug interactions are not

relevant when pregabalin is part of a complex polypharmacotherapy regimen. Because of the drug’s

renal elimination, dosage adjustment is required for patients with renal impairment. To date, no

pharmacokinetic drug–drug interactions have been identified. There is some literature to suggest

that there can be an additive cognitive impairment when pregabalin is taken in conjunction with

oxycodone and that pregabalin may potentiate the effects of lorazepam and alcohol (Pfizer 2006).

Summary for Pregabalin

Controlled studies of pregabalin clearly have suggested its efficacy in complex partial epilepsy,

postherpetic neuropathy, diabetic neuropathy, fibromyalgia, generalized anxiety disorder, and

social anxiety disorder. Like gabapentin, pregabalin has a favorable pharmacokinetic profile, with

particular advantages in patients with compromised hepatic function. Its minimal drug–drug

interactions, low risk of toxicity, and favorable side-effect profile make it a useful addition to the

pharmacopoeia.

CONCLUSION

There is increasing interest in the use of anticonvulsant drugs in mood and anxiety disorders.

Controlled studies are needed to further assess specific patient populations and disease states that

can benefit from these agents.

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