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The Potential of Pregabalin in Neurology,

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Current Pharmaceutical Design, 2014, 20, 000-000 1

The Potential of Pregabalin in Neurology, Psychiatry and Addiction: A Qualitative

Overview

Giovanni Martinotti1, Matteo Lupi1, Fabiola Sarchione1, Rita Santacroce1, Anatolia Salone1, Domenico De
Berardis1-2*, Nicola Serroni1, Marilde Cavuto3, Maria Signorelli4, Eugenio Aguglia4, Alessandro Valchera5,
Felice Iasevoli6 and Massimo Di Giannantonio1

1
Department of Neuroscience and Imaging, University “G.d’Annunzio”, Chieti; 2NHS, Department of Mental Health, Psychiatric
Service of Diagnosis and Treatment, Hospital “G. Mazzini”, ASL 4, Teramo, Italy; 3IASM, L’Aquila, Italy; 4Department of Molecular
Pharmacology and Biomedicine, University of Catania; 5Villa S. Giuseppe Hospital, FoRiPsi, Hermanas Hospitalarias, Ascoli Pi-
ceno, Italy; 6Laboratory of Molecular Psychiatry and Psychopharmacotherapeutics, Section of Psychiatry, Department of Neurosci-
ence, University School of Medicine “Federico II”, Naples, Italy

Abstract: Pregabalin is an anticonvulsant drug that binds to the
2 (alpha2delta) subunit of the voltage-dependent calcium channel in
central nervous system (CNS). Pregabalin decreases the release of neurotransmitters, including glutamate, norepinephrine, substance P
and calcitonin gene-related peptide. Purpose of this paper is to offer a qualitative overview of the studies currently available in literature
about this drug, examining the effectiveness of pregabalin in its various fields of application. Our analysis, conducted on a final selection
of 349 scientific papers, shows that pregabalin may help to reduce pain in diabetic neuropathy, in post-herpetic neuralgia and in some pa-
tients affected by fibromyalgia. It is also effective for the treatment of diverse types of seizures and has similar efficacy to benzodiazepi-
nes and venlafaxine in anxiety disorder. Moreover, pregabalin may be a therapeutic agent for the treatment of alcohol abuse, in both
withdrawal phase and relapse prevention. Possible implications in the treatment of benzodiazepines dependence are emerging, but a po-
tential abuse or misuse of the drug has also been reported. Range of dosage may fluctuate considerably, from 75 mg to 600 mg per day.
Further studies are needed to completely understand pregabalin mechanism of action in the different diseases.
Keywords: Abuse, alcohol, anxiety, benzodiazepines, epilepsy, fibromyalgia, neuropathic pain, pregabalin.

INTRODUCTION
Pregabalin is an antiepileptic drug approved in the US and
Europe for adjunctive therapy of partial seizures in adults, for the
treatment of pain from diabetic neuropathy or post-herpetic neural-
gia in adults and for the treatment of anxiety disorders. Recent stud-
ies have highlighted possible implications for the treatment of to-
bacco, alcohol and benzodiazepine addiction.
Pregabalin (3-isobutyl GABA) is a structural analogue of the
GABA neurotransmitter, with a pharmacological profile similar, but
not identical, to that of gabapentin; it is an S-enantiomer of 3-
aminomethyl-5-methylhexanoic acid (Fig 1. [1]).
Not directly interacting with GABA A and GABA B receptors
nor influencing the reuptake of the neurotransmitter, its mechanism
of action is likely to depend on its high affinity link with the al-
pha2-delta protein, an auxiliary subunit of voltage-dependent cal-
cium channels. The link of the drug with the aforementioned pro-
tein reduces the Ca and K-dependent release of norepinephrine and
the K-dependent release of glutamate in cortical tissue. These modi-
fications represent a precondition for the molecule analgesic activ-
ity, according to the possibility that pregabalin acts through inhibi-
tory modulation of neuronal excitability [2,3].
Pregabalin takes approximately 24-48 hours to reach steady
state, with no significant differences among healthy volunteers,
epileptic patients treated with anticonvulsants and individuals with
chronic pain [4].
As described by preclinical studies in animals (rats, monkeys),
pregabalin is able to cross blood-brain barrier and placenta; no
plasma proteins binding has also been demonstrated [4].
*Address corrspondence to this author at the National Health Service, De-
partment of Mental Health, Psychiatric Service of Diagnosis and Treatment,
“G. Mazzini” Hospital, p.zza Italia 1, 64100 Teramo (Italy); Tel: +39
0861429708; Fax: +39 0861429709; E-mail: dodebera@aliceposta.it
The drug has a rapid oral absorption both with and without
meals; an oral bioavailability > or = 90%, dose-independent; a neg-
ligible hepatic metabolism; it is eliminated from systemic circula-
tion primarily by renal excretion as unchanged drug, proportionally
to creatinine clearance [5].
H3C CH3
H
OH
O
H2N
[1] http://commons.wikimedia.org/wiki/File:Pregabalin_Structural_Formulae.png
Fig. (1).
Recommended starting dose for pregabalin is 150 mg/day (di-
vided into two or three daily administrations); it may be increased
to 300 mg/day after three to seven days [6].
The dose may be augmented up to doubling until the most
effective dosage has been reached, with a maximum daily dose of
600 mg/day. Treatment suspension should be done gradually, over
at least a week [6].
The most common side effects reported for pregabalin (ob-
served in more than one out of ten patients) are dizziness and
drowsiness. Moreover, because of the drug’s potential weight gain
side effect, patients should be emboldened to routine physical exer-
cise and their weight should be closely monitored [7,8].

1381-6128/14 $58.00+.00 © 2014 Bentham Science Publishers

2 Current Pharmaceutical Design, 2014, Vol. 20, No. 00
METHODS
We searched Pubmed (http://www.ncbi.nlm.nih.gov/pubmed) to
identify published metanalysis, reviews, randomized double-blind
trials, open-label trials, and case reports written in English, report-
ing the use of pregabalin in different clinical situations. The follow-
ing key words were used: Pregabalin AND Neuropathic pain, Pre-
gabalin AND Fibromyalgia, Pregabalin AND Epilepsy, Pregabalin
AND Anxiety, Pregabalin AND Alcohol, Pregabalin AND Benzo-
diazepines, Pregabalin AND Abuse. The search was conducted on
November 5th, 2012 and yielded a total number of 1389 results. By
reading titles and abstracts we excluded 1040 articles from total
records, removing papers that discussed the drug marginally or
repeated the same information. We focused instead on articles in
which pregabalin was considered a central topic, with more case
studies and most relevant results.
By reading the full text of the 349 remaining articles, we made
a qualitative synthesis, reporting in this overview the most repre-
sentative papers. We therefore searched Scopus, Google Scholar
and PsychInfo to identify any other study missed by the previous
analysis. No further study has been evidenced using the same key-
words.
PREGABALIN IN NEUROPATHIC PAIN
Pregabalin has showed a good efficacy against hyperalgesia and
allodynia in several animal models of neuropathic pain. Hyperalge-
sia is the perception of a very severe pain in response to mild pain-
ful stimuli; allodynia is a pain perception in response to stimuli that
are not normally painful.
The drug demonstrated analgesic activity in both allodynia,
which may be caused by nerve damage or by vincristine or strepto-
zocin, and hyperalgesia, which may be determined by a thermal
damage or by formalin, carrageenans, P substance or NMDA (N-
methyl-D-aspartate). Pregabalin efficacy on hyperalgesia and allo-
dynia was observed with doses 2 to 4 times lower than gabapentin
[9].
Moreover, pregabalin has been evaluated for the treatment of
pain associated with neuropathy of diabetic origin, diagnosed from
at least 6 months or from 1-5 years in controlled clinical trials (Ta-
ble 1). The drug has shown efficacy in reducing pain associated
with diabetic neuropathy at doses of 300 and 600 mg / day, divided
into 3 daily administrations, but not at doses of 75 and 150 mg /
day. The average initial pain score, measured on a weekly basis and
calculated by the method of least squares (LS), was approximately
7.6 in all patients: the reduction of this value was equal to 3.80 and
3.60 vs 5.06 for pregabalin 300 and 600 mg / day vs placebo [10]
and equal to 3.99 vs 5.46 for pregabalin 300 mg / day vs placebo
[11]. In addition, patients treated with pregabalin 3 times per day
showed better sleep quality than patients in placebo group: the
score related to sleep disturbances (calculated by the method of
least squares) was equal to 2.78 vs 4.32 for pregabalin 300 mg / day
vs placebo [11]; the initial sleep disturbances score for all patients
was comprised between 4.5 and 6.
Similar results have been observed by Toelle et al (2004) for
pregabalin administration in two daily doses, with reduction of both
pain associated with herpetic neuralgia and diabetic neuropathy,
and improvement of sleep quality. Statistically significant results
vs. placebo were obtained as early as the first week of therapy
(fixed dose of drug equal to 600 mg / day) and were maintained for
all the 12 weeks of the study. The percentage of patients responding
to treatment was significantly higher with the drug in respect to
placbo (46 vs 30%) [12].
In an open-label, randomized study, the clinical efficacy of
amitriptyline 25 mg / day and pregabalin 75 mg / day was com-
pared, showing that treatment with pregabalin may achieve better
results than amitriptyline in patients with post-herpetic neuralgia
Martinotti et al.
[13]. Two other studies, very similar in terms of methodology
evaluated the efficacy of pregabalin in postherpetic neuralgia over
an 8 weeks follow-up. The results highlighted that the group treated
with pregabalin showed a maximum pain reduction of 1.7 points in
comparison to placebo group, using a 0 to 10-value scale [14,15].
With particular regard to sleep, pregabalin appears to be effec-
tive on resistant insomnia associated with subsyndromal RLS (Rest-
less Legs Syndrome), even when the latter does not fully satisfy all
diagnostic criteria [16].
In a comparative study with amitriptyline, patients with neuro-
pathic pain caused by diabetes were treated with amitriptyline (10,
25 and 50 mg / day in the evening) and pregabalin (75, 150 and 300
mg 2 times / day); either treatment lasted 5 weeks and between a
treatment and the other was elapsed a 3 weeks period of placebo
administration. The various measurement indexes revealed no dif-
ferences between the two treatments. The incidence of adverse
events was higher with amitriptylin; the most frequent side effect
was somnolence for both drugs [17]. Boyle (2012) underlined that
there was no significant difference in analgesic efficacy between
amitriptyline, duloxetine, and pregabalin [18].
In another study, while amitriptyline (75 mg / day) was more
effective than placebo (p = 0.01) in reducing the painful symptoms
in patients with diabetic neuropathy, pregabalin (600 mg / day) was
not equally effective (p = 0.08) [19].
Two out of three patients experience a chronic pain condition
after a spinal cord injury, whereas a third of the cases is classified
as severe pain entity; a study conducted by Cardenas et al has con-
firmed the effectiveness of pregabalin (at doses of 150 and 600 mg /
day) in the reduction of duration-adjusted average change in pain
compared with baseline after 16 weeks of treatment [20].
PREGABALIN AND FIBROMYALGIA
Fibromyalgia is a clinical condition whose cause has not yet
been defined. Its symptoms are unspecific and include pain, fatigue,
and unrefreshing sleep. Headache, intestinal disorders, dysmenor-
rhea, anxiety and/or depression may also be associated. It is more
common in women than in men (USA: 3.4% vs 0.5%) [21].
Pregabalin administration in patients suffering from fibromyal-
gia was more effective than placebo in reducing pain at the dose of
450 mg/day, but not at the doses of 300 mg/day and 150 mg/day
[22].
In another study, pregabalin was administered at doses of 300,
450 and 600 mg / day in patients with fibromyalgia (94% female),
while comparison group was treated with placebo. All three tested
doses were more effective than placebo in reducing pain. There
were no differences between pregabalin and placebo in terms of
impact on fatigue and FIQ (Fibromyalgia Impact Questionnaire)
overall score [23].
When data related to sleep are analyzed (Medical Outcomes
Study (MOS) Sleep Scale and assessment of sleep quality by daily
diary), it appears that 40-80% of pregabalin benefits on sleep may
be due to a direct effect, while the remaining percentage to an indi-
rect effect depending on the analgesic action of the drug [24]. The
study by Roth et al. (2012) also confirmed statistically significant
improvements in sleep in patients with fibromyalgia treated with
pregabalin 300 / 450 mg / day [25].
The evaluation of pregabalin analgesic effects in fibromyalgia
was performed by a clinical study that enrolled patients already
treated with the drug, which had had a pain reduction of at least
50%. These patients were randomized to receive pregabalin or pla-
cebo for 26 weeks. At the end of this period, approximately 50% of
patients in the placebo group went to meet a loss of therapeutic
response, while the group treated with pregabalin kept showing a
therapeutic response at the end of the study [26].
The Potential of Pregabalin in Neurology Current Pharmaceutical Design, 2014, Vol. 20, No. 00 3

Table 1. Pregabalin in Neuropathic Pain and Fibromyalgia.

Study Subjects Functions tested Dosage used Findings

PREGABALIN IN NEUROPATHIC PAIN AND FIBROMYALGIA

Lesser H et al. Patients (n=338) were random-
2004 [10] ized to receive one of three
doses of pregabalin or placebo.
Evaluate efficacy and toler-
ability of pregabalin (75, 300,
600 mg/day) vs placebo in
patients with diabetic periph-
eral neuropathy (DPN).
Pregabalin 75, 300, 600 Pregabalin demonstrated early and
mg/day sustained improvement in pain and
vs. beneficial effect on sleep.
Placebo

Rosenstock J Patients (n=146) were random-
et al. 2004 [11] ized to receive placebo (n=70)
or pregabalin 300 mg/day
(n=76).
Assess efficacy of pregabalin
in alleviating pain associated
with diabetic peripheral neu-
ropathy.
Pregabalin 300 mg Pregabalin was safe and effective in
vs. decreasing pain associated with
DPN, and also improved mood,
Placebo
sleep disturbance, and quality of life.

Achar A The study included 50 patients
et al. 2012 [13] randomized to receive either
amitriptyline or pregabalin
(n=25 each).
Demonstrate clinical efficacy
of amitriptyline and pre-
gabalin.
Amitriptyline 25 mg/day Therapy with pregabalin showed
vs. better results compared to amitrip-
tyline in postherpetic neuralgia
pregabalin 75 mg/day
patients.

Bansal D Patients (n=51) were random-
et al. 2009 [17] ized to receive amitriptyline
orally, at doses of 10, 25 and 50
mg at night-time, and pre-
gabalin orally, at doses of 75,
150 and 300 mg twice daily.
Compare the efficacy and
safety of pregabalin and
amitriptyline in alleviating
pain associated with diabetic
peripheral neuropathy.
Amitriptyline 10, 25, 50 Pregabalin 150 mg twice daily might
mg at night time be the alternative choice as it is
vs. associated with fewer adverse ef-
fects in study population.
Pregabalin 75,100, 300
mg twice daily

Dworkin RH Patients (n=173) were random-
et al. 2003 [14] ized to receive treatment with
pregabalin or placebo.
Evaluate the efficacy and
safety of pregabalin in the
treatment of postherpetic neu-
ralgia (PHN).
Pregabalin 300, 600 Treatment of PHN with pregabalin
mg/day is safe, efficacious in relieving pain
vs. and sleep interference.
Placebo

Mease PJ This multicenter, double-blind,
et al. 2008 [23] placebo-controlled trial ran-
domly assigned patients
(n=748) with FM to receive
placebo or pregabalin.
Evaluate the efficacy and
safety of pregabalin for symp-
tomatic relief of pain associ-
ated with fibromyalgia (FM)
and for management of FM.
Pregabalin 300, 450, 600 Pregabalin at 300, 450, and 600
mg/day mg/day was efficacious and safe for
vs. the treatment of pain associated with
fibromyalgia (FM).
Placebo

Roth T Patients (n=119) were random- Assess the effect of pregabalin Pregabalin 300, 450 Patients with fibromyalgia treated
et al. 2012 [25] ized in double-blind and pla- on polysomnographic (PSG) mg/day with pregabalin had statistically
cebo-controlled. measures of sleep and patient- vs. significant and meaningful im-
rated sleep, tiredness, and pain provements in sleep, as assessed by
Placebo
in fibromyalgia patients. PSG. Patients with fibromyalgia also
reported decreased daily pain.

Cardenas DD et Patients with chronic neuro-
al. 2013 [20] pathic pain due to SCI were
randomized to receive 150 to
600 mg/day pregabalin (n =
108) or matching placebo (n =
112) for 17 weeks.
To assess the efficacy and Pregabalin 150, 600 This study demonstrates that pre-
tolerability of pregabalin for mg/day gabalin is effective and well toler-
the treatment of central neuro- vs. ated in patients with neuropathic
pathic pain after spinal cord pain due to SCI.
Placebo
injury (SCI).

PREGABALIN AND EPILEPSY
Epilepsy is a chronic neurological disease characterized by
recurrent unprovoked epileptic seizures; its frequency in population
is estimated to range from 0.5% to 1% [27].
No therapy may be considered curative for epilepsy, and the
main therapeutic goal is to prevent seizures through antiepileptic
drugs (AEDs); it has been demonstrated that two-thirds of the pa-
tients with an adequate AED therapy become seizure-free [28],
while one third are constricted to be treated with AEDs for the rest
of their life.
Pregabalin is the latest antiepileptic medication approved in the
United States as an add-on therapy for refractory partial epilepsy, at
doses comprised between 150 and 600 mg/day (the lowest effective
dose is 150 mg/day) [29,30] (Table 2); its efficacy in generalized
epilepsy is not yet established.
The prescribing information recommend a starting dose of 50
mg three times a day or 75 mg twice a day in adult patients, while
escalation doses range from 100 to 150 mg per week, until a maxi-
4 Current Pharmaceutical Design, 2014, Vol. 20, No. 00 Martinotti et al.

Table 2. Pregabalin and Epilepsy.

Study Subjects Function tested Dosage tested Findings

PREGABALIN AND EPILEPSY

Ryvlin P Four double-blind placebo-
et al. 2008 controlled trials (n = 1396)
[30] and 4 long-term open-label
studies (n = 1480).
Evaluate the efficacy and safety
of pregabalin as adjunctive
therapy in refractory partial
epilepsy.
Pregabalin 150-600 mg/day Pregabalin appears to be a useful
vs. addition to the therapeutic armamen-
tariun for the management of refrac-
Placebo
tory partial epilepsy.

De Haas S Patients on adjunctive pre- Evaluate the effects of adjunc-
et al. 2007 [33] gabalin 300 mg/day (n=8) tive pregabalin 300 mg/day
were compared with pa- versus placebo on polysomno-
tients on placebo (n=7). graphic (PSG) variables in
patients with well controlled
partial seizures and subjectively
reported sleep disturbances.
Pregabalin 300 mg/day This exploratory pilot study suggests
vs. that pregabalin may improve sleep
continuity in patients with clinically
Placebo
relevant sleep disturbance. The
effect on disturbed sleep appears
independent of seizure control.

Romigi A Twelve patients affected by
et al. 2009 [34] partial epilepsy underwent a
24 h ambulatory polysom-
nography and a subjective
evaluation of daytime
somnolence.
To evaluate the effects of pre-
gabalin (PGB) adjunctive ther-
apy on sleep-wake cycle and
daytime somnolence in adult
patients affected by partial
epilepsy.
Pregabalin 300 mg/day Pregabalin seems to be effective and
safe in partial epilepsy. The increase
of REM sleep may be indicative of
an improvement of nocturnal sleep
quality.

mum of 300 mg twice a day. These recommendations are derived
by pivotal trials; clinical experience and post-marketing evidences
suggest instead a lower starting dose of 50 mg twice a day or 75 mg
at bedtime, because of the excessive sedation that pregabalin may
cause, with an escalation to 75 mg twice a day after 1 week, if start-
ing dose has been well tolerated. It is important to remember that in
patients with an high risk for behavioral-psychiatric adverse effects,
starting dose must be lowered to 50 mg at bedtime. Moreover, in
patients who well tolerate pregabalin but whose seizures are still
uncontrolled, the dose can be increased to 300 mg twice a day or
200 mg three times a day for a better efficacy.
Sleep problems are common in epileptic patients and lack of
sleep may worsen seizures [31]. Unfortunately, the relationships
between epilepsy and sleep disturbance are still complex and poorly
understood. Main sleep alterations detected through polysomno-
graphic studies in this class of patients are sleep fragmentation,
decreased sleep efficiency and high number of awakenings and
arousals [32,33]. In studies on rats, pregabalin 300 mg / day has
showed to enhance REM sleep and to reduce NREM sleep [34]; in
humans pregabalin improves sleep quality.
PREGABALIN AND ANXIETY
The specific mechanism of direct blocking of calcium channels
through binding to subunit
2 reduces neuronal excitability in all
the structures of the CNS. This lowering in neuronal hyperactivity
may explain pregabalin action on both epilepsy and generalized
anxiety.
Pregabalin showed anxiolytic activity in cases of generalized
anxiety disorder (GAD), social phobia and panic disorder [9] (Table
3). Comparative studies between pregabalin and benzodiazepines
(BDZ) are of particular interest. A wide range of secondary effects
is associated with protracted use of BDZ in anxiety therapy. Among
these we can number interferences with cognitive functions, possi-
bility to frequently reach sedation threshold, risk of dependence and
rebound effect at suspension. These phenomena are mainly linked
to the symptomatic action of this group of molecules [35].
Pregabalin, at all doses (200, 300, 400 and 600 mg / day), has
shown efficacy in improving both psychic and somatic symptoms
linked to generalized anxiety disorder. The therapeutic efficacy of
pregabalin on the control of somatic symptoms has been considered
comparable to that of benzodiazepines [36]. Systematic observa-
tions in GAD were carried out in 2003 by Feltner et al. In this
study, pregabalin effectiveness on the disorder has resulted higher
at doses of 600 mg / day compared to 150 mg / day and placebo; in
addition, clinical evidences similar with the ones achieved with
lorazepam at daily doses of 6 mg have been highlighted [37].
According to the safety profile and the data collected in studies
with healthy volunteers, pregabalin seems to bring additional bene-
fits in terms of tolerability, compared to both benzodiazepines and
venlafaxine. The existing clinical trial database indicates that pre-
gabalin is better tolerated than venlafaxine, alprazolam, and loraze-
pam; moreover, data suggest that the risk of development of toler-
ance or dependence is likely to be lower with pregabalin than with
benzodiazepines [38].
As pointed out by Montgomery, pregabalin demonstrated a
quick efficacy, as early as the first week of therapy, in improving
psychic and somatic symptoms of GAD; it seems capable to reduce
subsyndromal depressive symptoms too, evidencing a potential
thymoleptic effect and the ability to prevent the risk of a long term
exacerbation of the pathology or its evolution to other psychiatric
disorders [39].
As for administration, the splitting of pregabalin 200-400-450
mg / day in 2 or 3 daily deliveries did not show any difference in
efficacy or tolerability compared to single daily delivery [40].
In a clinical study on the use of pregabalin in social phobia
treatment emerged that the score on Liebowitz Social Anxiety Scale
(LSAS) after 11 weeks of therapy was significantly reduced by the
maximum recommended dose of pregabalin (600 mg/day) com-
pared with placebo; the administration of pregabalin 150 mg/die,
instead, did not achieve better clinical results than placebo in any
measure [41].
PREGABALIN AND ALCOHOL
Recent studies demonstrated that pregabalin may be a new op-
tion for the treatment of alcohol consumption relapse in detoxified
The Potential of Pregabalin in Neurology Current Pharmaceutical Design, 2014, Vol. 20, No. 00 5

Table 3. Anxiolytic Activity of Pregabalin.

Study Subjects Function tested Dosage used Findings

ANXIOLYTIC ACTIVITY OF PREGABALIN

Pande AC A total of 276 patients were
et al. 2003 [36] randomly assigned to a treat-
ment group and received at
least one dose of their as-
signed medication.
Evaluation for treatment of
patients with generalized anxi-
ety disorder.
Pregabalin 150-600 mg/day Pregabalin is an effective, rap-
vs. idly acting, and safe treatment
for generalized anxiety disorder.
Lorazepam 6 mg/day
vs.
Placebo

Feltner DE This study has compared 271
et al. 2003 [37] patients randomized to re-
ceive pregabalin 50 mg tid (N
= 70), pregabalin 200 mg tid
(N = 66), placebo (N = 67), or
lorazepam 2 mg tid (N = 68).
Obtain an evaluation of the
efficacy and safety of pre-
gabalin in the treatment of
generalized anxiety disorder
(GAD).
Pregabalin 50 mg/day tid. This study supports the hypothe-
vs. sis that pregabalin is effective
and safe in short-term therapy
Pregabalin 200 mg/day tid
for GAD.
vs.
Lorazepam 2 mg/day tid
vs.
Placebo

Pohl RB Patients were randomized to 6
et al. 2005 [40] weeks of double-blind treat-
ment with pregabalin 200
mg/d (BID; N = 78), 400
mg/d (BID; N = 89), or 450
mg/d (TID; N = 88) or pla-
cebo (N = 86).
Evaluation of anxiolytic effi- Pregabalin 200-400-450 This study demonstrates that
cacy of pregabalin. mg/day pregabalin is an effective treat-
vs. ment for generalized anxiety
disorder.
Placebo

Pande AC 135 patients were randomized
et al. 2004 [41] to 10 weeks of double-blind
treatment with either pre-
gabalin 150 mg/d, pregabalin
600 mg/d, or placebo.
Evaluate safety and efficacy of
pregabalin for the treatment of
social anxiety disorder.
Pregabalin 150-600 mg/day Pregabalin 600 mg/die was an
vs. effective and well-tolerated
treatment for social anxiety
Placebo
disorder.

patients, in addition to its use in alcohol withdrawal syndrome
[42,43] (Table 4).
The mechanism through which pregabalin modulates neuro-
transmitters like glutamate and norepinephrine is not completely
clear. A chronic alcohol abuse causes adaptive changes on gamma-
aminobutyric acid (GABA) receptors, glutamate receptors and cen-
tral noradrenaline and dopamine activity. In particular, it has been
evidenced an important inhibition of GABA neurotransmission
[44], that plays a decisive role in the development of intoxication,
tolerance and withdrawal [45,46] and an increase of excitatory glu-
tamatergic neurotransmission determining the CNS to result hyper-
excitable [47].
Martinotti et al. (2008) demonstrated that pregabalin at 50-150-
450 mg / day may be effective in relapse prevention and well toler-
ated for long-term management of moderate-to-severe alcoholics
[46,48,49]; moreover, patients treated with pregabalin 150-450 mg /
day remained abstinent from alcohol for a longer time if compared
to patients treated with naltrexone, an approved drug for the treat-
ment of alcohol dependence [49].
It is noteworthy that using pregabalin improves the comorbid
condition of generalized anxiety disorders, which is frequently as-
sociated with alcohol dependence [45].
Alcohol withdrawal syndrome (AWS) is a dangerous clinical
situation that may be developed by alcohol-dependent patients who
discontinue or decrease alcohol consumption too suddenly [50,51].
In this kind of patients the nervous system results hyper-activated
and dysfunctional [52], due to neuroadaptative changes induced by
alcohol assumption, that restore a new neurochemical equilibrium
[53]. AWS can last for months after suspension of alcohol ingestion
[54]. Recent studies suggested that GABA agonists may decrease
CNS hyper-excitability and ethanol withdrawal-induced convul-
sions [46].
AWS symptoms typically develop within 6-24 hours after the
last drink. Is it possible to identify different forms, ranging from the
mildest in which increased blood pressure and pulse rate, tremors,
hyperreflexia, irritability, anxiety and depression are the most fre-
quent signs [52,53], to the most severe forms characterized by delir-
ium tremens [55], seizures [56] and coma [57], in which cardiac
arrest represents the most feared death cause (5-10% of patients)
[57,58].
The main clinical purpose is to decrease symptoms severity, to
prevent fatalities and to incite patients to enter a treatment program,
maintaining long-term abstinence from alcohol [59,60].
Ideally, treatment should be based on the use of a drug with
rapid onset, long duration of action, few side effects, a wide margin
of safety, a metabolism not centered on liver function and absence
of abuse potential [61]. Until now, BDZ have been the first choice
for AWS treatment [62, 63], thanks to their efficacy in ameliorating
symptoms and decreasing seizure and delirium tremens risk [64].
On the other hand though, BDZ can determine abuse and depend-
ence [65,66], excessive sedation, memory deficits and respiratory
depression in patients with liver disfunction, often present in alco-
holics, which constitute a limitation to their use [65,67].
6 Current Pharmaceutical Design, 2014, Vol. 20, No. 00 Martinotti et al.

Table 4. Pregabalin and Alcohol.

Study Subjects Function tested Dosage used Findings

PREGABALIN AND ALCOHOL

Martinotti G. 111 patients were enrolled Compare lorazepam with Pregabalin 450 mg/day Pregabalin may be considered as a
et al. and divided into three into non-benzodiazepine medica- vs. potentially useful new drug for
groups of 37 subjects each. tions such as pregabalin and AWS treatment, deserving further
2010 (1) [46] Tiapride 800 mg/day
tiapride in the treatment of investigation.
vs.
alcohol withdrawal syndrome
(AWS). Lorazepam 10 mg/day

Martinitti G. Thirty-one alcohol-
et al. dependent patients were
consecutively recruited and
2008 [48]
screened for the study.
Investigate the efficacy of Pregabalin 50-150-450 Pregabalin shows promises as a
pregabalin on alcoholism indi- mg/day treatment for alcohol dependence.
ces in detoxified alcohol-
dependent subjects.

Martinotti G. Seventy-one alcohol- Investigate the efficacy of Pregabalin 150-450 mg/day Results from this study globally
et al. dependent subjects were pregabalin on alcohol drinking vs. place pregabalin within the same
detoxified and subse- indices. range of efficacy as naltrexone.
2010 (2) [49] Naltrexone
quently randomized into
two groups, receiving 50
mg of naltrexone or 150-
450 mg of pregabalin.

Martinotti et al. (2010) compared lorazepam with non-
benzodiazepine drugs, such as pregabalin, as treatment for AWS.
Their results suggest that pregabalin has a better efficacy than
lorazepam, normally considered the “gold standard” drug, in treat-
ing uncomplicated forms of AWS. This result was later confirmed
by Di Nicola et al. (2011) [68].
The use of pregabalin in dependence from other substances and
in multiple substance abuse [69] is still in need to be investigated.
PREGABALIN AND BENZODIAZEPINE DEPENDENCE
Recently, pregabalin therapeutic use has been broadened; in
fact, different studies justify its use in cases of benzodiazepine de-
pendence, a chronic condition characterized by important physical
and psychic effects [70] as tolerance, dependence and changes in
cognitive functions. This condition is mostly consequent to a long-
term and high-dose benzodiazepine dependence [71]. Available
evidences suggest pregabalin used in monotherapy within the dos-
age range of 150 - 600 mg/day as a new and efficacious therapy for
this medical condition [9].
Oulis et al. (2008) have conducted various studies on BDZ
dependence. In the first, the sample was composed by 15 patients
with long-term, high-dose dependence from BDZ, treated with
pregabalin at doses 225–900 mg in an open-label study; anxiety and
depressive symptoms were evaluated by Hamilton Anxiety and
Depressive Scales (HARS, HDRS), while cognitive functions were
evaluated by Mini-Mental State Examination (MMSE). All patients
discontinued successfully BDZ in 3–14 weeks. Moreover, they
presented improvements in anxiety levels as demonstrated by re-
duction of HARS scores of more than 50%, improvements in mood
depression as demonstrated by reduction of HDRS scores, and their
cognitive functions presented immediate ameliorating as demon-
strated by increase of MMSE scores [72].
The study stated that no serious pregabalin side-effects have
been noticed and that the linear pharmacokinetic profile of the
molecule, that includes complete absorption without subsequent
binding to plasma proteins, lack of metabolites and interaction with
other drugs and renal elimination, makes pregabalin an effective
and safe drug for BDZ dependence treatment [9,72]. The only limi-
tations of this study is the lack of randomization and control group.
In the same year (2008), Oulis et al. presented a case-series of four
women with long-term, high-dose BDZ dependence treated with
pregabalin at doses of 225-600 mg. All patients discontinued BDZ
in 3-7 weeks, reduced their anxiety levels and improved their cogni-
tive functions. Pregabalin side effects, present only during the first
2 week of treatment, were mild and transient [72]. All these results
can be interpreted as preliminary findings, as pregabalin efficacy in
BDZ dependence needs to be investigated and detailed in future
studies.
PREGABALIN: MISUSE POTENTIAL
The use of pregabalin is spreading in the psychiatric scenario.
The abuse and misuse potential, however, are problems that must
be taken into account, especially in subjects with high risk of de-
veloping substance/alcohol abuse conducts [73]. Although the pos-
sibility of pregabalin abuse is reportedly low, data on this event
have been recently identified. Web sites, case reports and epidemi-
ological study suggest that the drug can be misused, especially by
substance-dependent individuals [74,75].
It has been observed that pregabalin is commonly offered for
sale by illegal websites, often without a prescription and sometimes
at discounted prices. Usually, reported dosages were significantly
higher than those recommended in clinical practice and idiosyn-
cratic methods of intake of the drug (es. rectal, intranasal) are de-
scribed [76]. Relevant is a case report in which a man was accused
and then acquitted due to paradoxical agitation, anxiety attacks and
abnormal thinking due to abuse of the drug; the concentration of 25
pg pregabalin/mL serum determined in the present case is the sec-
ond highest value published so far after misuse of the substance
[77].
In clinical studies, some patients ingested as much as 2400
mg/day. The types of adverse events experienced by patients ex-
posed to higher doses (
900 mg) were not clinically different from
those of patients receiving recommended doses of pregabalin. Cur-
rently, there seems to be no specific antidotes for pregabalin over-
dose [78]. Furthermore, following abrupt or rapid discontinuation
of pregabalin, some patients may report insomnia, nausea, head-
The Potential of Pregabalin in Neurology
ache, or diarrhoea, which may be suggestive of physical depend-
ence [79,80].
The spread of this new trend can be attributed to pregabalin
online availability and to psychoactive effects of the substance.
Physicians should carefully evaluate patients for history of drug
abuse and be prepared to observe any sign of pregabalin abuse.
CONCLUSIONS
Pregabalin is an example of drug primarily approved only for a
limited group of diseases, for example neurological diseases like
partial epilepsy. Nowadays, thanks to scientific researches and
clinical trials, pregabalin efficacy has been demonstrated also in
other diseases such as pain from diabetic neuropathy or post-
herpetic neuralgia and anxiety disorders, mostly justified by its easy
use, linear pharmacokinetics and lack of drug-drug interaction.
Pregabalin use is becoming widespread in the psychiatric scenario.
Data are encouraging, with some good evidence for efficacy in
alcohol and benzodiazepine abuse/dependence. The abuse potential,
however, is an issue that should be taken into account, especially in
subjects with higher risk of developing substances or alcohol mis-
use.
Obviously, further studies are needed to completely understand
pregabalin mechanism of action in the diverse diseases and most
appropriate doses for different treatment indications.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflicts of
interest.
ACKNOWLEDGEMENTS
Declared none.
DISCLOSURE
This manuscript was entirely funded by the authors, and no
pharmaceutical companies were informed of or were involved in
the review. All authors contributed to this review with equal efforts.
The authors have no potential conflict of interest directly relevant to
the contents of the manuscript.
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