Clinical Oral Investigations

https://doi.org/10.1007/s00784-020-03352-y

REVIEW

Preoperative oral pregabalin for anxiety control: a systematic review

María Isabel Torres-González 1 & Francisco Javier Manzano-Moreno 1,2,3,4 &
Manuel Francisco Vallecillo-Capilla 1,2 & Maria Victoria Olmedo-Gaya 1,2

Received: 1 April 2020 / Accepted: 19 May 2020

# Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
Objective The objective of this systematic review was to determine the effectiveness of preoperative oral pregabalin for anxiety
control, the most effective dosage regimen, its impact on postoperative pain, and its adverse effects.
Materials and methods A search was conducted of PubMed/Medline and clinicaltrials.gov (National Library of Medicine,
Washington, DC), Scopus, Web of Science, and Cochrane databases for studies published between January 2009 and
November 2018, with no language restriction. Based on PRISMA guidelines, the specific question was: is preoperative oral
pregabalin effective and safe for anxiety control in patients undergoing surgery? The critical reading of retrieved studies followed
questions prepared by the CASPe Network, and their methodological quality was evaluated using the Jadad Scale.
Results Twelve randomized controlled trials were selected for review. All twelve studies were trials of high quality. A dose of
75 mg preoperative oral pregabalin has been found to reduce anxiety and stabilize intraoperative hemodynamics, although a more
significant improvement appears to be achieved with a single dose of 150 mg pregabalin at least 1 h before the surgery. It is not
associated with any severe adverse effects.
Conclusion Preoperative administration of oral pregabalin in a single dose of 150 mg appears to be effective to significantly
reduce the anxiety of patients, intraoperative hemodynamic changes, and postoperative pain.
Clinical relevance These findings suggest that pregabalin is useful and safe for preoperative and intraoperative anxiety control in
patients undergoing surgery.

Keywords Pregabalin . Systematic review . Anxiety . Preoperative . Side effects

Introduction somatic symptoms, including perspiration, palpitations, precor-

dial oppression, fatigue, frequent urination, headaches, myal-
Preoperative anxiety has been reported to affect up to one out of gias, insomnia, and digestive discomfort [2]. The intensity of
six adults due to undergo surgery, and it has been widely se- preoperative anxiety is influenced by multiple factors, includ-
lected as model to test the acute anxiolytic effect of various ing the expected magnitude of the intervention, the amount of
drugs [1]. Components of anxiety include the following: in- time patients have to adapt to the upcoming event, and personal
tense feelings of apprehension, fear, or anguish when and family histories of experiences with surgery, besides the
confronting a perceived threat; a state of irritability that can propensity of individuals for anxiety [3]. Health care profes-
lead to a loss of concentration capacity; and a set of variable sionals should be aware that routine interventions that appear to
be of little importance can pose a major challenge to emotion-
ally vulnerable patients and may affect their recovery.
* Francisco Javier Manzano-Moreno Benzodiazepines have classically been prescribed for preop-
[email protected]
erative anxiolysis but are associated with adverse effects (e.g.,
dizziness, somnolence, respiratory depression), and there is con-
1
Master of Oral Surgery and Implant Dentistry, School of Dentistry, siderable research interest in the development of alternative drugs
University of Granada, Granada, Spain
to treat anxiety, including gabapentinoids [4]. One member of
2
Department of Stomatology, School of Dentistry, University of this class of drugs, pregabalin (CASRN: 148553-50-8), is a struc-
Granada, Colegio Máximo s/n, 18071 Granada, Spain
tural analog of the inhibitory neurotransmitter gamma-
3
Biomedical Group (BIO277), University of Granada, Granada, Spain aminobutyric acid (GABA), to which it is not functionally relat-
4
Instituto Investigación Biosanitaria, ibs.Granada, Granada, Spain ed. It possesses anticonvulsive, anxiolytic, and antihyperalgesic
 Clin Oral Invest

properties [5]. Pregabalin acts by binding to auxiliary subunit medication for the same purpose; and (d) study of patients
α2-δ of voltage-gated calcium channels in the central nervous receiving surgery under general or local anesthesia and admin-
system, potentially displacing [3H]-gabapentin and thereby in- istered with preoperative oral pregabalin for anxiety control
creasing its affinity for this subunit. Activation of these receptors and/or intraoperative hemodynamic stability. Exclusion
has been implicated in the onset of partial epilepsy seizures, pain, criteria were letters to the editor, reviews, systematic reviews,
and hypersensitization phenomena [6, 7]. Pregabalin can there- meta-analyses, and case reports.
fore reduce excitatory neurotransmitters and block hyperalgesia
and the sensitization center [6–8]. Oral pregabalin is rapidly Search strategy and study selection
absorbed, demonstrating linear pharmacokinetics and 90% bio-
availability, and it does not bind to plasmatic proteins; it reaches A search was conducted of PubMed/Medline and clinicaltrials.
its maximum blood concentration at 1 h and has an elimination gov (National Library of Medicine, Washington, DC), Scopus,
half-life of 6 h [9]. Web of Science, and Cochrane databases for studies published
Pregabalin is used for pain relief in diabetic neuropathy, between January 2009 and November 2018, with no language
postherpetic neuralgia, and focal epileptic seizures. Reports restriction. The search strategy was:
of its effectiveness for acute postoperative pain in minor gy- (“mouth”[MeSH Terms] OR “mouth”[All Fields] OR
necological surgery, laparoscopic cholecystectomy, “oral”[All Fields]) AND (“pregabalin”[Supplementary
amygdalectomy, and third molar surgery [10] have prompted Concept] OR “pregabalin”[All Fields]) AND
research into its effectiveness against fibromyalgia and gener- (“anxiety”[MeSH Terms] OR “anxiety”[All Fields]) AND
alized anxiety and as co-adjuvant in the multimodal treatment (preoperative[All Fields] OR “preoperative period”[MeSH
of postoperative analgesia. There have been numerous reports Terms] OR “preoperative period”[All Fields]) AND
on the use of pregabalin to control preoperative anxiety and (“surgery”[Subheading] OR “surgery”[All Fields] OR “surgi-
reduce postoperative pain and opioid consumption. However, cal procedures, operative”[MeSH Terms]) OR (“surgical”[All
no consensual guidelines have been established on the appro- Fields]) AND “procedures”[All Fields] AND (“operative”[All
priate dosage regimen. Fields] OR “operative surgical procedures”[All Fields] OR
With this background, we performed a systematic review “surgery”[All Fields] OR “general surgery”[MeSH Terms]
on the utilization of preoperative oral pregabalin for anxiety OR “general”[All Fields]) AND (“surgery”[All Fields] OR
control, given the frequency of preoperative anxiety in oral “general surgery”[All Fields]).
surgery and its relationship with postoperative pain. Our ob- The titles and abstracts of retrieved items were indepen-
jective was to determine its effectiveness, the optimal dosage dently examined by two researchers (MITG, FJMM) to select
regimen, its role in intraoperative hemodynamic changes, and those meeting eligibility criteria. If the abstract included inad-
its adverse effects. equate information for this purpose, the whole article was
reviewed before making the final decision. Discrepancies be-
tween evaluators were solved by consensus or, when this not
Material and methods possible, by consulting a third examiner (MVOG). A Kappa
value of 0.92 was obtained for agreement between the evalu-
Scope of the question ators on the inclusion/exclusion of studies. Search results were
cross-verified to eliminate duplicates. The initial search re-
We constructed the following PICO question based on trieved 84 studies from PubMed, 132 from Scopus, 78 from
PRISMA (Preferred Reporting Items for Systematic Review WOS, and 53 from Cochrane. Out of the ten items selected for
and Meta-analysis) guidelines: is preoperative oral pregabalin meeting eligibility criteria, nine were finally included in the
effective and safe in anxiety control for patients undergoing review (see below). Figure 1 depicts the article selection
surgery intervention? P and I (patients and intervention) = process.
patients subjected to surgery under general or local anesthesia
receiving a single dose of preoperative pregabalin for anxiety Evaluation of the methodological quality of the study
control; C (comparison) = control group of patients not treated
with pregabalin; O (outcome) = hemodynamic changes, anxi- The critical reading of the retrieved articles addressed the
olytic effect, level of sedation, and drug-related adverse eleven questions proposed by the Spanish Critical Appraisal
events. Skills Program (CASPe) Network [11]. The first three ques-
tions rule out articles for which the response is negative, while
Eligibility criteria the remaining eight concern their methodological quality (re-
search design) (Table 1)
Review inclusion criteria: (a) clinical trial; (b) randomized The widely used Jadad scale [24] was applied to evaluate
study; (c) presence of control group and/or group with other the methodological quality of the thirteen retrieved studies,
Clin Oral Invest

Fig. 1 Flow diagram of the article

selection for the systematic

Identification
review, in agreement with
PRISMA guidelines
350 studies were idenfied in the electronic
search

-162 duplicate studies

Screening
337 studies were excluded
-175 studies did not respond to
our PICO queson

Eligibility
The eligibility of 13 arcles was
evaluated
Included

12 studies were included in our

systemac review

which were all randomized controlled trials (RCTs). This All reviewed RCTs reported the absence of any bias attrib-
scale evaluates randomization, blinding, and withdrawals utable to the characteristics of participants. All except for one
and dropouts of patients who fail to complete the course of study [13] contained a table displaying these variables, includ-
the trial by answering a 3-point questionnaire. Each question ing age, sex, ethnicity, ASA classification, weight, and body
was to be answered with either a yes or a no. Each yes would mass index. The type of surgery was specified in seven studies
score a single point, each no zero points, and deduct 1 point in [12, 14, 15, 20–23] and its duration in nine [12–14, 17,
case the method of randomization or blinding is inappropriate. 19–23]. Preoperative variables gathered by three RCTs [17,
This system allocates trials a score of between zero (very poor) 21, 22] included the consumption of beta-blockers or calcium-
and five (rigorous). Twelve RCTs obtained a score ≥ 3, consid- inhibitors and anesthetic risk factors such as the presence of
ered evidence level Ib (evidence from at least one RCT), and hypertension or diabetes mellitus or a history of myocardial
were included in the final sample, whereas one obtained a score infarction. In addition, Nutt et al. [18] applied a test to evaluate
< 3 and was therefore excluded (Table 2). Consequently, twelve the preoperative anxiety and apprehension of patients. Study
RCTs were finally included in the review. populations were divided into two groups in seven trials [13,
14, 16, 17, 19, 21, 23], into three groups in four [12, 15, 18,
22], and into four groups in one [20].

Results Sample size selection

Characteristics of reviewed studies The sample size was selected to achieve 80% reliability to
detect clinically significant results in seven studies [12, 14,
The search found twelve relevant study articles [12–23]. All 15, 18–20, 22] and 90% reliability in three [19, 21, 23], and
twelve studies were RCTs of high quality. The surgery was all seven assumed a type I error α = 0.05 and type II error β =
conducted under general anesthesia in nine of them [12, 13, 0.5. The other two studies did not specify the estimation of
15–17, 20–23], under local anesthesia in two [14, 19], and their sample size.
without anesthesia in one [18]. Four RCTs had 40–80 partic-
ipants [13, 14, 17, 19, 23] and the other five had 81–120 [12, Dosage and administration guidelines
15, 16, 18, 20–22], with a total age range of 18–65 years.
Control groups received a placebo in nine RCTs, including Pregabalin was administered in a single dose in all reviewed
one with an additional control group receiving 0.5 mg alpraz- RCTs, at 1 h pre-surgery in eleven studies and at 4 h pre-
olam [18], being administered with 0.3 mg clonidine in the surgery in one [18]. A dose of 150 mg was selected by Par
other RCT [13]. Two RCTs include a control group who re- Veen et al. [13], Rahat et al. [16], Sundar et al. [17], Spreng
ceived i.v dexmedetomidine [21, 22] and a combination of et al. [19], Nutt et al. [18], Jain et al. [21], and Singh et al. [23]
pregabalin and i.v dexmedetomidine [22] (Table 3). and a dose of 300 mg by Gonano et al. [14]. Finally, Chen
 Clin Oral Invest

Table 1 Evaluation of the quality of studies according to the CASPe Critical Reading Program

Study Are results valid? What are the results? Can these results be helpful?

1 2 3 4 5 6 7 8a 8b 8c 9 10 11

Chen et al.[12] Yes Yes Yes No Yes Yes No P < 0.05 - P < 0.05 Yes Yes Yes
Par Venn et al.[13] Yes Yes Yes Yes Yes Yes No P > 0.05 - P < 0.05 Yes Yes Yes
Gonano et al.[14] Yes Yes Yes Yes Yes Yes No - P < 0.05 - Yes Yes Yes
Rastogi et al.[15] Yes Yes Yes No Yes Yes No P < 0.05 - P > 0.05 Yes Yes Yes
Rahat et al.[16] Yes Yes Yes Yes Yes Yes No P < 0.05 P > 0.05 - Yes Yes Yes
Sundar et al.[17] Yes Yes Yes Yes Yes Yes No P < 0.05 - P > 0.05 Yes Yes Yes
Nutt et al.[18] Yes Yes Yes Yes Yes Yes No - P < 0.05 P < 0.05 Yes Yes Yes
Spreng et al.[19] Yes Yes Yes Yes Yes Yes No - P < 0.05 - Yes Yes Yes
White et al.[20] Yes Yes Yes Yes Yes Yes No - P > 0.05 P < 0.05 Yes Yes Yes
Jain et al. [21] Yes Yes Yes Yes Yes Yes No P < 0.05 - - Yes Yes Yes
Vijayan et al. [22] Yes Yes Yes Yes Yes Yes No P < 0.05 - P < 0.05 Yes Yes Yes
Singh et al. [23] Yes Yes Yes Yes Yes Yes No P < 0.05 P > 0.05 - Yes Yes Yes

1, Was the trial aimed at a clearly defined question?

2, Was patient assignment to treatments randomized?
3, Were all patients who entered the trial properly accounted for at its conclusion?
4, Was binding maintained for patients, health workers, and study personnel?
5, Were groups similar at the beginning of the trial?
6, Besides the intervention under study, did all patients receive the same treatment?
7, Was the effect of treatment very large?
8, What was the precision of this effect?
8a, hemodynamic changes (HR / MAP)
8b, anxiety control (VAS-anxiety)
8c, sedation level (VAS-sedation / Ramsay sedation score)
9, Can these results be applied to a study in your setting or local population?
10, Were all clinically relevant results considered?
11, Do the benefits to be obtained justify the risks and costs?

et al. [12] used two pregabalin dose groups (150 and 300 mg), Chen et al. [12] observed a significant decrease in HR ver-
Rastogi et al. [15] two pregabalin dose groups (75 and 150 sus the placebo group at 1-h post-medication in groups receiv-
mg); and White et al. [20] three (75, 150, and 300 mg). ing preoperative pregabalin at a dose of 150 mg (P = 0.045) or
Vijayan et al. [22] also include a combination of 75 mg 300 mg (P < 0.001), with no significant difference between
pregabalin and dexmedetomidine. pregabalin groups (P = 0.153), and significantly lower MAP
values versus the placebo group in groups treated with 150 mg
Study outcomes (P = 0.025) or 300 mg (P = 0.044) pregabalin. At the same
time point, the RSS score was higher in the pregabalin groups
The main study outcome was the level of preoperative and than in the control group, although statistical significance was
perioperative anxiety, evaluated using a visual analog scale not reached, with no significant difference between them.
(VAS) (Table 4). Additional outcomes were perioperative Par Veen et al. [13] observed a significantly greater decrease
changes in heart rate (HR) and mean arterial pressure (MAP) (P < 0.01) in HR at 1-h post-medication in patients preoperative-
and in the level of sedation, measured using a VAS or the ly treated with 0.3 mg clonidine versus 150 mg pregabalin, al-
Ramsay Sedation Score (RSS) [15, 17]. This scale measures though there was no difference between them in interoperative
sedation on a numerical score of 1–6: 1, anxious, agitated, or HR. MAP values were significantly lower (P < 0.01) in the
restless; 2, co-operative, oriented, and tranquil; 3, responds to clonidine group at 1-h post-medication, immediately before and
command; 4, asleep with brisk response to stimulus; 5, asleep induction, but not after intubation. RSS scale scores were also
with sluggish response to stimulus; and 6, asleep with no significantly lower in the clonidine versus pregabalin group (P <
response. 0.01) at 1-h post- medication and 1-h post-surgery.
Clin Oral Invest

Table 2 Independent evaluation of the methodological quality of the pregabalin, 300 mg pregabalin, or placebo. However, VAS-
studies according to the Jadad scale [24]
sedation scores were significantly higher (P = 0.01) in the
ECA I II III IV V VI VII Jadad 300-mg pregabalin group than in the control group during
score the pre-induction period and at 90- and 120-min post-surgery.
Gonano et al. [14] reported a significantly lower (P =
Chen et al. [12] Yes Yes Yes No Yes Yes Yes 4
0.003) VAS-anxiety score immediately before anesthesia in-
Par Venn et al. Yes Yes Yes Yes Yes Yes No 4
[13]
duction in patients receiving 300-mg pregabalin than in con-
Gonano et al. [14] Yes Yes Yes Yes Yes Yes Yes 5 trols, although no significant between-group difference was
Rastogi et al. [15] Yes Yes Yes Yes Yes Yes No 4 observed during the first 24-h post-surgery.
Rahat et al. [16] Yes Yes Yes Yes Yes Yes No 4 Spreng et al. [19] described a significant decrease in anxi-
Sundar et al. [17] Yes Yes Yes Yes Yes Yes No 4 ety at 1-h pre-surgery in the 150-mg pregabalin group versus
Nutt et al. [18] Yes Yes Yes Yes Yes Yes Yes 5 controls (P = 0.001) and a positive correlation between pre-
Spreng et al. [19] Yes Yes Yes Yes Yes Yes No 4
operative anxiety and postoperative pain at 120 min after its
White et al. [20] Yes Yes Yes Yes Yes Yes No 4
administration.
Nutt et al. [18] observed a significant reduction in VAS-
Jain et al. [21] Yes Yes Yes Yes Yes Yes Yes 5
anxiety score at 2.5-h post-medication in patients receiving
Vijayan et al. [22] Yes Yes Yes Yes Yes Yes Yes 5
150-mg pregabalin (P = 0.014) or 0.5-mg alprazolam (P =
Singh et al. [23] Yes Yes Yes Yes Yes Yes Yes 5
0.018) than in those administered with a placebo. The statis-
I, Was the study described as randomized?1/0 tical significance of this anxiolytic effect was higher between
II, Was the randomization scheme described?1/0 2.5- and 4-h post-medication in the alprazolam group (P =
III, Was the randomization scheme appropriate?0/− 1 0.01) but not in the pregabalin group. They also found a sig-
IV, Is the study described as double-blinded?1/0 nificantly higher (P < 0.01) VAS-sedation score versus the
V, Was the blinding method described?1/0 placebo group in the pregabalin group between 2.5- and 4-h
VI, Was the blinding method appropriate? 0/− 1 post-medication and in the alprazolam group at 2-h post-med-
VII, Were losses to follow-up and withdrawals described?1/0 ication (P < 0.01).
Jain et al. [21] reported that mean intraoperative HR was
significantly higher (P = 0.036) in 150-mg premedicated
pregabalin group compared with dexmedetomidine group.
Rastogi et al. [15] reported significantly higher (P = 0.03) They also found MAP values were significantly lower (P =
preoperative RSS scale scores in patients pretreated with 0.025) in dexmedetomidine group intraoperatively. However,
pregabalin (75 mg or 150 mg) than in patients receiving pla- these changes in HR and MAP were not significant statistical-
cebo, with no significant differences between the pregabalin ly intragroup when comparing with baseline (immediately be-
groups, and significantly higher HR (P = 0.03) and MAP (P = fore induction of general anesthesia).
0.001) values in the control group and 75 mg pregabalin group Vijayan et al. [22] describe a significant reduction in mean
than in the 150 mg pregabalin group. No group showed a HR in all three groups intraoperatively compared with preop-
significantly greater decrease in intra-operative HR values. erative period. Comparison intergroups showed a significant
Sundar et al. [17] observed a significantly higher HR at 1- decreased HR in group D (i.v. dexmedetomidine 1 μg.kg−1)
min post-intubation in controls than in patients receiving compared with Group P (oral pregabalin 150 mg) (P = 0.001-
150 mg pregabalin (P = 0.041), but there was no significant 0.045) and compared with group C (combination
difference at 1-, 3-, or 5-min post-intubation. MAP values dexmedetomidine (0.5 μg.kg−1)/ pregabalin 75 mg) (P =
were significantly lower in the pregabalin group at all time 0.009–0.047) during intraoperative period. They also ob-
points before anesthesia induction (P = 0.021), reaching a served mean MAP was to be significantly lower in Group D
significance of P = 0.001 at 5-min post-intubation. There compared with Groups P and C at all intraoperative time in-
was no significant difference (P = 0.053) between groups in tervals (Group D vs. Group P: P = 0.000–0.037 and Group D
VAS anxiety score at 6-, 12-, or 24-h post-surgery. vs. Group C: P = 0.000–0.024). There was no difference in
Rahat et al. [16] reported that MAP values were significant- mean MAP between Groups P and C in the intraoperative
ly (P = 0.01) lower and HR values even more significantly period. Postoperative Ramsay sedation score value was sig-
lower (P = 0.001) at 1 h post-medication in the 150 mg nificantly higher (P < 0.05) in Group D comparing with
pregabalin versus placebo group. VAS-anxiety scores were Group P and Group C. VAS sedation score in Group D was
also significantly lower (P = 0.03) in the patients receiving significantly higher than in Groups P and C at 60 min after
150 mg pregabalin than in those administered with placebo. extubation (postoperative) (P = 0.0001).
White et al. [20] found no significant difference in post- Singh et al. [23] observed a significant decrease (P < 0.01)
operative VAS-anxiety score among groups receiving 150 mg in HR in the 150-mg pregabalin group compared with placebo
 Clin Oral Invest

Table 3 General characteristics of the reviewed studies

Author and year N Age range (years) Sex (M/F) Intervention Measurements

Chen et al. (2018) [12] 90 18–60 43/47 Laryngoscopy and endotracheal intubation HR/MAP
RSS
Par Venn et al. (2016) [13] 80 20–60 NS Laparoscopic colostomy HR/MAP
VAS-sedation
RSS
Gonano et al. (2011) [14] 40 18–65 26/14 Arthroscopic knee surgery VAS-anxiety
Rastogi et al. (2012) [15] 90 24/56 30/60 Laryngoscopy and tracheal intubation HR/MAP
RSS
Rahat et al. (2016) [16] 120 20–70 63/57 Orthopedic surgery for tibial fracture HR/MAP
VAS-anxiety
Sundar et al. (2011) [17] 60 NS 42/18 Tracheal intubation for arterial bypass HR/MAP
VAS-sedation
RSS
Nutt et al. (2009) [18] 89 > 18 34/55 Any dental procedure VAS-anxiety
VAS-sedation
Spreng et al. (2011) [19] 50 > 18 24/22 Lumbar microdiscectomy VAS-anxiety
White et al. (2009) [20] 108 18–70 52/53 Any outpatient surgery < 24 h VRS-sedation
VRS-sedation
Jain et al (2019) [21] 130 18–65 68/62 Laparoscopic cholecystectomy HR/MAP
Vijayan et al. (2019) [22] 90 18–65 - Laparoscopic cholecystectomy HR/MAP
RSS
VAS-sedation
Singh et al.(2019) [23] 60 18/65 - Laparoscopic cholecystectomy HR/MAP
VAS-anxiety

HR, beats/min. MAP mean arterial pressure, RSS Ramsay sedation score, VAS visual analog scale, PACU postoperative anesthesia care unit

group from 2 min after laryngoscopy and at all intraoperative (P = 0.010). Veen et al. [13] found no difference in the fre-
times after. However, changes in HR were not statistically quency of adverse effects between pregabalin and clonidine
significant neither in pregabalin group nor placebo group groups. Sundar et al. [17] observed no significant differences
when comparing with preoperative time (just before induction in the frequency of nausea between premedicated and control
of anesthesia). They also found a significant increase of MAP groups and reported no cases of dizziness or vomiting. Rahat
among the groups when comparing preoperative and intraop- et al. [16] found a higher prevalence of dizziness in the
erative (P < 0.05) values, and intergroup comparison showed pregabalin group versus controls (P = 0.01) but no significant
a highly significant lower MAP value in 150-mg pregabalin between-group differences in the frequency of nausea and
group at all intraoperative times (P < 0.001). Finally, they vomiting. In comparison with controls, White et al. [20] ob-
reported a lower score in VAS anxiety scale in pregabalin served a similar frequency of adverse effects in the 150-mg
group comparing with placebo group 60 min after pregabalin group but a significantly higher frequency of diz-
premedication, but it was not statistically significant. ziness and difficulty to awaken in the 300-mg pregabalin
group (P < 0.05). Spreng et al. [19] found no significant dif-
Adverse effects ferences between premedicated and control groups in the fre-
quency of adverse effects, which were most commonly dizzi-
All except for two of the reviewed RCTs gathered data on ness, nausea, and vomiting. In the study by Nutt et al. [18], the
drug-related adverse effects, which were never severe in any most frequent adverse events in the pregabalin and alprazolam
study group. The most frequent adverse events were dizziness, groups were fatigue and dizziness, with no significant
somnolence, vomiting, and nausea. None of the articles in- between-group differences. Jain et al. [21] reported a signifi-
cluded in this systematic review reported respiratory depres- cant higher incidence of nausea in pregabalin group during
sion associated with pregabalin as a side effect. postoperative period. Neither vomiting nor dizziness was re-
Chen et al. [12] reported that dizziness at 1-h post-medica- ported in any group. Vijayan et al. [22] found no significant
tion was more frequent in the control group than in the 150- difference in the incidence of side effects among the three
mg pregabalin group (P = 0.038) or 300-mg pregabalin group groups except for three patients in dexmedetomidine group
Table 4 Pregabalin guideline: results in the pregabalin group and adverse effects

Author and year Study groups Drug administration Additional Results Adverse effects Conclusions
pharmacotherapy
Clin Oral Invest

Chen et al. (2018) [12] Group 1(n = 30): placebo Preoperative administration Intravenous medication for Significantly reduced HR and More frequent hemodynamic Both pregabalin doses can effectively
Group 2(n = 30): 150 mg (1 h before) general anesthesia and MAP (P < 0.05) in groups 2 complications in the placebo group attenuate cardiovascular responses
pregabalin opioid administration in and 3 versus group 1 No differences among groups in in patients subjected to tracheal
Group 3 (n = 30): 300 mg PACU Significantly higher RSS score dizziness, nausea, or vomiting intubation under general anesthesia
pregabalin (P < 0.05) in groups 2 and 3
Par Veen et al. (2016) [13] Group 1(n = 40): 0.3 mg Preoperative pregabalin/ 0.25 mg alprazolam the HR did not significantly differ More frequent bradycardia in clonidine Pregabalin provides superior
clonidine clonidine (1 h before) previous night. between groups MAP group postoperative analgesia and
Group 2(n = 40): 150 mg Intravenous medication for significantly lower in group 1 sedation and lower bradycardia risk
pregabalin general anesthesia and (P = 0.01) versus clonidine
75 mg i.m. diclofenac on VAS- and RSS- measured seda-
request in PACU tion significantly higher (P =
0.001) in group 2
Gonano et al. (2011) [14] Group 1(n = 20): placebo Preoperative administration Intravenous medication for VAS-anxiety score significantly NS A single 300 mg dose of pregabalin
Group 2(n = 20): 300 mg (1 h before) general anesthesia and lower (P = 0.03) in group 2 provides effective preoperative
pregabalin fenamin administration in anxiolysis in patients undergoing
PACU minor orthopedic surgery
Rastogi et al. (2012) [15] Group 1 (n = 30): placebo Preoperative administration Intravenous medication for Significant increase in HR (P = NS Pregabalin is effective and safe,
Group 2(n = 30): 75 mg (1 h before) general anesthesia 0.03) and MAP (P = 0.001) in producing sedation and analgesia
pregabalin groups 1 and 2 and stabilizing hemodynamics
Group 3 (n = 30): 150 mg Significantly higher RSS score
pregabalin (P = 0.03) in group 3
Rahat et al. (2016) [16] Group 1(n = 60): placebo Preoperative administration Intravenous medication for Significant reductions in MAP (P Similar frequency of nausea and A single dose of preoperative oral
Group 2(n = 60): 150 mg (1 h before) general anesthesia and = 0.01) and HR (P = 0.001) in vomiting between groups pregabalin reduces pain and leads to
pregabalin analgesic administration in group 2 Higher dizziness P < 0.05 in the hemodynamic stabilization of
PACU VAS-anxiety score significantly pregabalin group patients
lower (P = 0.03) in group 2
Sundar et al. (2011) [17] Group 1 (n = 30): placebo Preoperative administration 10 mg oral diazepam the Significantly higher HR (P = No vomiting or dizziness in either A single pregabalin dose reduces
Group 2 (n = 30): 150 mg (1 h before) previous night 0.04) and MAP (P = 0.02) in group. The frequency of nausea was intubation-related tachycardia and
pregabalin Intravenous medication for group 1 similar between groups hypertension, producing no dizzi-
general anesthesia No significant differences in ness or visual involvement
0.5 mg/kg fentanyl when VAS or RSS sedation scores
VAS-pain score was > 4 in between groups
PACU
Nutt et al. (2009) [18] Group 1 (n = 27): placebo Preoperative administration NS VAS-anxiety score significantly No significant differences among A clinically relevant anxiolytic effect
Group 2(n = 31): 0.5 mg (4 h before) lower (P = 0.014) in group 3 groups in fatigue and dizziness manifests during the first 3–4 h after
alprazolam VAS-sedation score significantly a single oral dose of pregabalin
Group 3 (n = 31): higher (P < 0.01) in group 3
150 mg pregabalin
Spreng et al. (2011) [19] Group 1 (n = 24): placebo \Preoperative Intravenous medication for VAS-anxiety score significantly No differences between groups in A single dose of oral pregabalin
Group 2 (n = 22): 150 mg administration (1 h general anesthesia. lower (P = 0.001) in group 2 nausea, dizziness, or vomiting administered 1 h before lumbar
pregabalin before) 1 g paracetamol in patients < discectomy reduces preoperative
60 kg and 1.5 g in patients > anxiety with no increase in
60 kg as rescue medication frequency of adverse effects
White et al. (2009) [20] Group 1 (n = 27): placebo Preoperative administration Intravenous medication for No significant difference in More frequent dizziness and difficulty Administration of pregabalin (75-300
Group 2 (n = 27): 75 mg (60–90 min before) general anesthesia VAS-anxiety score among to awaken in group 4 (P < 0.05). No mg) did not achieve a significant
pregabalin Intravenous fentanyl in PACU groups significant differences among anxiolytic effect; but a dose of
Group 3 (n = 50): 150 mg and analgesic rescue Significantly higher groups 1, 2, and 3 300 mg significantly increased pre-
pregabalin medication on request VAS-sedation score (P = operative sedation but was more
Group 4 (n = 27): 300 mg 0.01) in group 4 frequently associated with adverse
pregabalin effects
Table 4 (continued)

Author and year Study groups Drug administration Additional Results Adverse effects Conclusions
pharmacotherapy

Jain et al. (2019) [21] Group A (n = 58): Preoperative Intravenous medication for Significantly lower (P < 0.05) No differences between groups in Intravenous dexmedetomidine 1
oral placebo + i.v administration: oral general anesthesia intraoperative HR in group A nausea, dizziness, or vomiting μg.kg-1 is more effective than oral
dexmedetomidine 1 placebo/pregabalin Intravenous fentanyl in PACU Significantly lower (P < 0.05) pregabalin 150 mg in attenuating
μg.kg-1 (60 min before) intraoperative MAP in group perioperative stress response,
Group B (n = 59): Induction A including hemodynamic response
150 mg oral pregabalin + dexmedetomidine/saline
100 ml i.v saline (20 min before)
Vijayan et al. (2019) [22] Group D (n = 30): Preoperative Intravenous medication for Significantly lower (P < 0.05) No differences between groups in Dexmedetomidine was more effective
oral placebo + i.v administration: general anesthesia intraoperative HR in group D nausea, dizziness, or vomiting than pregabalin and the
dexmedetomidine 1 placebo/pregabalin Intravenous fentanyl in PACU Significantly lower (P < 0.05) Significantly more incidence of combination of pregabalin and
μg.kg-1 (60 min before) and diclofenac if required intraoperative MAP in group bradycardia in group D P = 0.01 dexmedetomidine in attenuating
Group P (n = 30): Induction D hemodynamic response
150 mg oral pregabalin dexmedetomidine/saline Significantly higher score (P < Dexmedetomidine also provides better
+100 ml i.v saline (20 min before) 0.05) in postoperative RSS sedation in the postoperative period
Group C (n = 30): Significantly higher score P < compared with pregabalin and
75 mg oral pregabalin + i.v 0.05 in postoperative combination of pregabalin and
dexmedetomidine 0.5 VAS-sedation dexmedetomidine.
μg.kg-1
Singh et al. (2019) [23] Group A (n = 30) oral placebo Preoperative administration Intravenous medication for Significantly lower No differences between groups in Pregabalin 150 mg seems to be an
Group B (n = 30) 150 mg oral (60 min before) general anesthesia intraoperative HR (P < 0.01) nausea, dizziness, or vomiting effective and safe drug for
pregabalin in group B anxiolysis, analgesia, and
Significantly lower hemodynamic stability.
intraoperative MAP (P <
0.01) in group B
Lower preoperative
VAS-anxiety score in group
B but not significant P > 0.05
Clin Oral Invest
Clin Oral Invest

who had bradycardia associated with hypotension in compar- associated with somnolence and dizziness in comparison
ison with none in the other groups. Finally, Singh et al. [23] with 150 mg pregabalin. In another study [25], no differ-
reported no significant difference in incidence of side effects ence in anxiolytic effect was found between 75 or 150 mg
among groups. oral pregabalin and 5 mg diazepam, but adverse events
Concerning the time when side effects caused by were more frequent in the diazepam group. Clonidine is
pregabalin such as nausea or vomiting are reported, all the an antihypertensive drug that acts on the central nervous
articles included make this summary at the end of surgery. system and is used in combination with other drugs to
Therefore, this might be considered a bias since general anes- treat attention-deficit hyperactivity disorder, and an
thetics might also cause this side effect by itself. 0.3 mg dose was reported [13] to have a superior effect
on anxiety and hemodynamic changes in comparison with
150 mg pregabalin; however, clonidine has more contra-
Discussion indications and drug interactions and exerts no analgesic
effects.
In this review of data on the effectiveness and safety of oral Dexmedetomidine is a newer α2-agonist which causes a
pregabalin to control preoperative anxiety, all studies found a decrease in mean MAP and HR when used preoperatively
positive correlation between its pre-operative administration comparing with pregabalin [21, 22]. It seems to improve he-
at a dose of ≥ 150 mg and a lower VAS anxiety score in modynamic stability during the intraoperative period and raise
comparison with controls. Likewise, the sedation level (VAS sedation level because of its hypnotic effects. In contrast,
or RSS score) was higher in patients pre-medicated with dexmedetomidine premedicated groups reported more inci-
pregabalin at a dose of ≥ 150 mg, and the difference with dence of bradycardia as side effect.
controls was statistically significant in all except one RCT. Five studies studied the association with postoperative pain
Results confirmed that the minimum effective pregabalin reg- [13, 14, 17, 19, 20]. No significant between-group difference
imen for anxiety control and sedation is 150 mg administered in opioid and/or analgesic consumption or VAS-pain score
in a single oral dose. Mild side effects (e.g., dizziness or nau- was observed during the recovery period with the exception
sea) were more frequent at higher pregabalin doses. of one of these studies [19], which also found a statistically
The studies that analyzed MAP and HR values [12, 15–18, significant correlation between preoperative anxiety and post-
21–23] found an improvement in patients receiving preoper- operative pain. In a systemic review and meta-analysis [2],
ative pregabalin, which was statistically significant in those greater anxiety about a dental visit was found to be closely
receiving a dose ≥ 150 mg. Rastogi et al. [15] and Sundar et al. associated with a worse experience of pain during the proce-
[17] observed that these stabilizing hemodynamic effects were dure, suggesting that special efforts are needed to improve the
more marked at 1 h after pregabalin administration and grad- comfort of patients especially prone to anxiety during their
ually decreased over the next 3 h. On the other hand, Jain et al treatment.
[21] and Vijayan et al. [23] reported a longer maintenance of The limitations of the present systematic review include
hemodynamic effects even until postoperative time for differences among the trials in the type of surgery, the dose
dexmedetomidine groups. of pregabalin, and the anesthetic technique used for the
MAP and HR values were always recorded before the surgery.
drug/placebo administration and again immediately before
surgery, except for one study [12] that measured them only
before the intervention. All of these studies excluded patients
under antihypertensive medication or whose MAP and HR Conclusion
values were abnormal before the drug/placebo administration.
Other RCTs [17, 21, 22] also excluded patients with diabetes Preoperative oral pregabalin can be effective to signifi-
mellitus or previous myocardial infarction that could affect the cantly reduce the anxiety of surgery patients and control
hemodynamic data. hemodynamic changes, with no severe adverse effects.
In accordance with the pharmacokinetics of pregabalin A dose of 75 mg oral pregabalin has been found to
and alprazolam, they were always administered at 1-h pre- reduce anxiety and stabilize intraoperative hemodynam-
surgery except for one study [18], in which 150 mg ics, although a more significant improvement appears to
pregabalin or 0.5 mg alprazolam was administered at 4 h be achieved with a single dose of 150 mg pregabalin at
before surgery to estimate the duration of their analgesic least 1 h before the surgery.
and anxiolytic effects and to determine the maximum ef-
fectiveness peak. This study [18] obtained greater anxio- Funding information The work was supported by the Master of Oral
Surgery and Implant Dentistry, School of Dentistry, University of
lytic effects and longer duration of sedation levels with
Granada, Spain.
0.5 mg alprazolam, although it was more frequently
 Clin Oral Invest

Compliance with ethical standards direct laryngoscopy in patients undergoing laparoscopic cholecyste.
J Clin Diagn Res 10:UC21–UC25
Conflict of Interest The authors declare that they have no conflict of 14. Gonano C, Latzke D, Sabeti-Aschraf M, Kettner SC, Chiari A,
interest. Gustorff B (2011) The anxiolytic effect of pregabalin in outpatients
undergoing minor orthopaedic surgery. J Psychopharmacol 25:
249–253
Ethical approval This article does not contain any studies with human
15. Rastogi B, Gupta K, Gupta PK, Agarwal S, Jain M, Chauhan H
participants or animals carried out by any of the authors.
(2012) Oral pregabalin premedication for attenuation of haemody-
namic pressor response of airway instrumentation during general
Informed consent For this type of study, formal consent is not required. anaesthesia: a dose response study. Indian J Anaesth 56:49–54
16. Rahat Dahmardeh A, Moosavi A, Nasir-Al-Din Tabatabaei SM,
Ordoni Avval J, Sistanizad M (2018) The effect of a single dose
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