Efficacy of gabapentin and pregabalin for treatment of post keratoplasty

surgery pain: A systematic review and meta-analysis

Abstract:

Introduction: For ophthalmic patients, eye discomfort is a major problem requiring efficient
pain treatment techniques. Pregabalin and gabapentin have surfaced as viable treatments for
post-keratoplasty pain. To manage pain after keratoplasty surgery, gabapentin and pregabalin are
evaluated in this systematic review and meta-analysis.

Methodology: A thorough search of the Embase, Cochrane, Cinahl, and PubMed/MEDLINE

databases was done to find pertinent research on the effectiveness of pregabalin and gabapentin
in treating pain after keratoplasty surgery. Randomized controlled studies and prospective trials
reporting pain ratings and adverse events were included in the inclusion criteria.

Results: A total of 532 people were included in seven studies that satisfied the inclusion
requirements. A meta-analysis showed that gabapentin/pregabalin significantly reduced pain
ratings compared to placebo (MD 1.59, 95% CI 1.17 to 2.01). The outcomes of individual studies
differed; some reported a considerable decrease in pain while using gabapentin/pregabalin in
comparison to a placebo, while other studies showed no discernible difference. Although
pregabalin showed promise in lowering immediate postoperative pain, there is still disagreement
over its long-term effects on pain management. After PRK, gabapentin provided a non-opioid
option for pain management, although it wasn't any better than oxycodone and acetaminophen.

Conclusion: Gabapentin and pregabalin have shown potential in the management of pain after
keratoplasty surgery as compared to placebo; however, further study is necessary to improve
dosage schedules, time of administration, and long-term results. These results emphasize the
need for further research to improve patient outcomes and postoperative pain management
techniques.
1 Introduction:
Among ophthalmic patients, eye pain is one of the most upsetting complaints and symptoms.
Finding the source of eye discomfort requires a basic eye history and examination (A. G. Lee et
al., 2014). There are two types of eye pain disorders: neuropathic pain and nociceptive pain
(Ebrahimiadib et al., 2020) Acute trauma, tissue inflammation, or surgery are often the causes of
the former (Brooks & Tracey, 2005). Nervous system disorders are often the cause of
neuropathic pain (Treede et al., 2019). It is common to find that these two types of pain coexist.
Individuals who are diagnosed with pain in the eyes and ocular symptoms will also need pain
treatment.

The anticonvulsant drug gabapentin was first identified in the 1970s (Yasaei et al., 2022). It was
approved by the FDA in 1993, and since 2004, it has been sold as a generic in the United States.
It was first used as an antispasmodic and muscle relaxant, but subsequent research revealed that
it also has anticonvulsive properties and may be used as a supplement to stronger anticonvulsants
(Small et al., 2020). Currently, the FDA has approved gabapentin for several illnesses. First of
all, postherpetic neuralgia—a kind of nerve pain that develops as a side effect of shingles—can
be treated with it. Furthermore, in individuals with epilepsy 12 years of age and older,
gabapentin is recommended as an adjuvant treatment for partial seizures, with or without
subsequent generalization (Ziganshina et al., 2017). This approval covers the pediatric
population—that is, children who have partial seizures between the ages of three and twelve.
Moreover, moderate to severe restless leg syndrome (RLS) may be treated with gabapentin
(Yasaei et al., 2022). In addition, gabapentin was shown to be more beneficial in managing
mood, sadness, anger-hostility, tiredness, and physical functioning than placebo (Berlin et al.,
2015).

Pregabalin has structural similarities with gabapentin and is considered a structural analog of γ-
aminobutyric acid. By modifying calcium channels and preventing the release of excitatory
neurotransmitters in the central nervous system, these substances reduce pain (Verma et al.,
2014). Although the precise mode of action involving GABA receptors remains unclear,
scientists are aware that gabapentin crosses the blood-brain barrier without restriction and
functions by interacting with neurotransmitters (Cross et al., 2022). The molecular structure of
gabapentin is similar to that of the neurotransmitter GABA, with a cyclohexyl group. Its
structure is similar to that of GABA; however, it does not bind to GABA receptors or affect
GABA production or absorption. To function, gabapentin must have a strong affinity for binding
sites across the brain that correspond to voltage-gated calcium channels, particularly alpha-2-
delta-1 (Derry et al., 2019). This binding affinity appears to inhibit the release of excitatory
neurotransmitters in the presynaptic area that are involved in epileptogenesis. Research has
shown that gabapentin raises total-blood levels of serotonin in healthy control volunteers, despite
the lack of evidence for direct activity at the dopamine, histamine, benzodiazepine, or serotonin
receptors.

The use of gabapentin and pregabalin for pain management after ocular operations, such as
cataract extraction and refractive treatments, has been the subject of many research. In a recent
systematic review by Shen et al., the efficacy and safety of pregabalin in managing eye pain were
evaluated (Shen et al., 2023). Analyzing six randomized, double-blinded trials, the study found
that pregabalin significantly reduced pain scores 24 hours after various ophthalmological
surgeries. However, in this study other eye surgeries besides keratoplasty were also considered
and it only focused on pregabalin. Consequently, the purpose of our systematic review is to
thoroughly analyze the effectiveness and safety of gabapentin and pregabalin in the management
of pain after keratoplasty surgery. This study aims to provide insights into the possible function
of gabapentinoids in optimizing pain management regimens for patients undergoing keratoplasty
by integrating the current research, thereby improving postoperative results and patient
satisfaction.

2 Methodology:

2.1 Search Strategy:

Using electronic databases like Embase, Cochrane, Cinahl and PubMed/MEDLINE, a thorough
literature search was carried out. We used Medical Subject Headings (MeSH) phrases together
with free-text keywords to do a systematic search utilizing these databases. keywords like
"gabapentin" or "pregabalin" and keywords about surgical techniques ("PRK" or "LASIK") were
included in the search, along with phrases about the desired result ("postoperative pain" or "pain
management") (Appendix#1).

2.2 Inclusion Criteria:

Studies examining the effectiveness of pregabalin and/or gabapentin for the treatment of
discomfort after PRK and/or LASIK surgery are eligible for inclusion. Only non-randomized
controlled trials and randomized controlled trials (RCTs) are included. Research presents results
like pain ratings and unfavorable incidents. The studies written and published in English are only
included and the studies done human population are added only.

2.3 Exclusion criteria:

Exclusion criteria encompass research that is irrelevant to the subject matter or fails to disclose
results related to discomfort after LASIK or PRK surgery. Additionally, studies that are not
original publications, such as reviews and editorials, are excluded. Only research articles written
in English are considered, while those in other languages are excluded. Furthermore, research
involving animals is not included in the review.

2.4 Data Extraction:

Two reviewers independently performed the chosen papers using the Cochrane Handbook for
systematic reviews of treatments as a guide. A created data extraction form was used to gather
data from all qualifying trials, including research parameters (design, longitude), participant
characteristics (age, sex, and number of patients), treatment information (dose and dosing
protocol), and effectiveness results. Acute pain (24 hours) and chronic pain (after surgery ≥7
days) were the main outcomes. Ocular symptoms and indicators, as well as side events, were the
secondary outcomes.

2.5 Quality Assessment:

The technique developed by the Cochrane Collaboration was used to evaluate the possibility of
bias in the studies that were chosen. Two researchers independently evaluated the quality of the
included RCTs (H.X. and Y.H.). Reviewers must evaluate seven categories when using the risk
of bias tool: randomization techniques; allocation concealment; blinding of outcome assessors;
blinding of trial participants; inadequate data existence; selective reporting; and additional
sources. Every study was assigned a risk of bias classification: high, uncertain, or low. In our
study, we only considered data from studies with a low or uncertain risk of bias.

2.6 Data Synthesis and Analysis:

The results of the included studies were given in a narrative synthesis. Two authors
independently used Review Manager v. 5.3 (The Nordic Cochrane Centre, Cochrane
Collaboration, 2014, Copenhagen, Denmark) to analyze the data. For continuous variables, the
95% confidence interval and mean difference were used. research with considerable
heterogeneity was conducted using the random-effects technique, whereas research without
heterogeneity was conducted using the fixed-effects method.

3 Results:

784 publications were found in the first literature search. 86 papers were deemed relevant after a
thorough analysis of the abstracts and titles, and their whole texts were acquired for further
research. Excluded studies were those that did not match the inclusion criteria or did not
particularly look into how well gabapentin and pregabalin worked to reduce pain after
keratoplasty surgery. Seven were concluded to be suitable for the systematic review and meta-
analysis after a thorough screening procedure.
 Identification of studies via databases and registers

Identification

Records identified from*: Records removed before

Embase:(n = 388) screening:
Cochrane:(n=112) Duplicate records removed
Cinahl:(n= 72) (n =241 )
PubMed: (n=212)

Screening
Records screened Records excluded**
(n =543) (n =457)

Reports assessed for eligibility Reports excluded:

(n =86) (n =79)

Included
Studies included in review
(n =7)

Figure 1: Prima Flow Diagram

Seven studies examining the effectiveness of pregabalin and gabapentin in treating pain after
keratoplasty surgery were included in the systematic review. There were many different types of
study designs, including three randomized double-blind trial, one randomized masked clinical
 trial, two prospective randomized trial, and one prospective nonrandomized trial. 532 patients
having different corneal surgeries, such as photorefractive keratectomy (PRK), laser epithelial
keratomileusis (LASEK), and laser-assisted in situ keratomileusis (LASIK), made up the total
population throughout the trials. Interventions included comparing the administration of
pregabalin or gabapentin to oxycodone/acetaminophen or placebo.

Regarding the efficiency of gabapentin and pregabalin in the treatment of pain after keratoplasty
surgery, the results were not entirely consistent. Pregabalin or gabapentin was shown to
considerably reduce pain ratings when compared to a placebo in some research. At the same
time, there was no discernible change in pain levels between treatment groups in other
investigations. Furthermore, one research found that gabapentin usage was linked to greater
oxycodone/acetaminophen intake. The meta-analysis's overall conclusion is that gabapentin and
pregabalin may be somewhat helpful in lowering pain after keratoplasty surgery; nevertheless,
the evidence varies throughout the studies, highlighting the need for further studies in this field.

Table 1: Characteristics and results of the studies reviewed

Author(s) Yea Study Population Intervention Results Main Findings

r Design
Mohamma 2012 Randomized 150 Pregabalin The placebo group had 0.9 When compared to a
d Pakravan Clinical subjects 75 mg, and 1 unit greater pain scores placebo, pregabalin
et al. Trial undergoing Gabapentin than pregabalin (p=0.029) and gabapentin
(Pakravan PRK 300 mg, and gabapentin (p=0.023). dramatically reduce
et al., Placebo On the first postoperative pain scores. The
2012) day, placebo group had more placebo group's pain
severe pain (>7) (p=0.043). was more intense.
Compared to placebo
(10.3±5.6), pregabalin
(7.9±5.2) and gabapentin
(9.0±4.1) groups ingested
fewer acetaminophen-
codeine pills (p=0.061).

Matthew 2011 Randomized 83 Active- Gabapentin There was no discernible In terms of pain
D. Kuhnle Masked duty 300 mg, change in pain between the management,
et al. Clinical United Placebo. gabapentin and placebo gabapentin did not
(Kuhnle et Trial States groups. The gabapentin significantly
Forty-two
al., 2011) Army group used oxycodone and outperform a
patients
soldiers acetaminophen more often placebo. The
received
undergoing (p=0.034). gabapentin group
gabapentin
bilateral showed higher
and 41
PRK. oxycodone–
patients,
acetaminophen
placebo.
usage.

Alejandro 2011 Randomized 40 patients Gabapentin Gabapentin group In contrast to a

Lichtinger Double- scheduled 300 mg, experienced reduced pain in placebo, gabapentin
et al. blind Trial for bilateral Placebo the first 72 hours (p=0.024 to dramatically
(Lichtinger p=0.001), difference in decreased post-PRK
et al., PRK lowest pain intensity for first pain. Regarding side
2011) 48 hours (p=0.005 and effects and recovery
p=0.01 for 24 and 48 hours), time, no discernible
and difference in maximum variations were
pain severity for first 72 found.
hours. Side effects,
symptoms, and recovery
duration were similar except
for first-day pain (p=0.043).

Dong Won 2022 Prospective 80 eyes Pregabalin One week after surgery, the Up to 6 months after
Paik et al. Randomized undergoing 150 mg twice pregabalin group reported LASEK surgery,
(Paik et al., Trial LASEK daily, less discomfort. At six pregabalin may
2022) surgery Placebo months, there were no lower corneal nerve
significant changes in the sensitivity and
degree of dry eye or corneal discomfort but not
sensitivity. nerve regeneration
or structural
alterations.

Julie M. 2014 Randomized 135 Pregabalin There was no statistically After PRK,
Meek et al. Controlled Patients 75 mg twice significant difference pregabalin may
Trial scheduled daily, between the treatment and provide an
(Meek et
for PRK Placebo placebo groups in terms of additional or
al., 2014)
the 10% improvement in substitute for
subjective pain levels. On traditional opioids in
surgical days 1 and 2, the the treatment of
pregabalin group needed far pain.
fewer doses of rescue
painkillers (p < 0.05).
Anat Galor 2019 Prospective 43 patients Pregabalin Six months after surgery, In this short pilot
et al. Randomized undergoing 150 mg twice perioperative pregabalin did trial, pregabalin
(Galor et Trial LASIK daily, not considerably lessen the given during surgery
al., 2019) surgery Placebo symptoms of dry eyes. did not lessen the
Ocular symptoms and reports frequency or
of neuropathic pain did not severity of dry eye
vary significantly (p>0.05). complaints six
months following
LASIK.

Steven A. 2008 Prospective 141 Gabapentin When it came to overall pain For postoperative
Nissman et Nonrandomi patients 300 mg, management scores, PRK pain,
al. zed Trial undergoing Oxycodone/ gabapentin and gabapentin did not
(Nissman PRK Acetaminoph oxycodone/acetaminophen significantly differ
et al., en did not vary substantially. from
2008) Gabapentin is linked to more oxycodone/acetamin
frequent usage of ocular ophen in terms of
drops used for anesthesia pain management.
(p<0.05).
 Doses in mg
350
300
250
200
150
100
50
0
Moham- Matthew D. Alejandro Dong Won Julie M. Anat Galor Steven A.
mad Kuhnle et Lichtinger Paik et al. Meek et al. et al. Nissman et
Pakravan al. et al. al.
et al.

Pregablin Gabapentin

Figure 2: Doses of pregabalin and gabapentin given to the patients in different studies.

Population
160
140
120
100
80
60
40
20
0
Moham- Matthew D. Alejandro Dong Won Julie M. Anat Galor Steven A.
mad Kuhnle et Lichtinger Paik et al. Meek et al. et al. Nissman et
Pakravan al. et al. al.
et al.

Figure 3: Population of the patients intervened in the studies.

Figure 4: Forest plot of gabapentin or pregabalin compared to placebo.

In managing pain after keratoplasty surgery, the meta-analysis assessed the effectiveness of
gabapentin and pregabalin in comparison to a placebo. A total of 321 individuals from five trials
were included. In favor of gabapentin/pregabalin, there was a statistically significant difference
in mean pain reduction between the two groups (MD 1.59, 95% CI 1.17 to 2.01). Variability in
the outcomes was shown by the heterogeneity across the research (Chi-square = 96.94, df = 4, P
< 0.00001). Overall, there was a significant Z-score of 7.38 (P < 0.00001) favoring
gabapentin/pregabalin over placebo.

Different research findings indicated different levels of pain alleviation. The mean difference
reported by Anat Galor et al. (2019) was 0.75 (95% CI -0.03 to 1.53), while Julie Meek et al.
(2013) reported a mean difference of -3.90 (95% CI -8.16 to 0.36), Matthew D. Kuhnle et al.
(2011) reported a mean difference of -0.36 (95% CI -1.41 to 0.69), Mohammad Pakravan et al.
(2012) reported a mean difference of -0.70 (95% CI -1.76 to 0.36), and STEVEN A. NISSMAN
et al. (2007) reported a mean difference of 4.20 (95% CI 3.51 to 4.89). These results imply that,
although the exact amount of the benefit may differ throughout trials, gabapentin and pregabalin
may be useful in lowering pain after keratoplasty surgery.
 Figure 5: Funnel plot of the studies reviewed in meta-analysis.

Figure 6: Forest plot on follow-up of 2nd day.

 Figure 7:Funnel plot on follow-up of 2nd day

The results of a meta-analysis comparing pregabalin and gabapentin against placebo on pain
scores on the second post-intervention day are shown in a forest plot. Data from four studies—
Kuhnle et al. (2011), Pakravan et al. (2012), Meek et al. (2013), and Nissman et al. (2007)—
were included in the analysis. On the second day after the intervention, the mean pain score was
lower in the pregabalin or gabapentin group than in the placebo group. Pregabalin or gabapentin
was preferred over a placebo, as shown by the pooled mean difference in pain levels between the
two groups of -0.71 (95% CI: -1.26 to -0.15). The analysis revealed a moderate degree of
heterogeneity between the studies (Tau = 0.12; Z = 2.49, p = 0.01), indicating some variation in
the effect sizes noted in the included research. Pregabalin or gabapentin, however, had a greater
overall effect in lowering pain scores on the second day after the intervention.

Figure 8: Forest plot on follow up of 3rd day.

 Figure 9: Funnel plot on follow up of 3rd day.

Results from a meta-analysis examining the impact of pregabalin and gabapentin on pain ratings
on the third day post-intervention, in comparison to placebo, are shown in a forest plot. Four
investigations (Kuhnle et al., 2011; Meek et al., 2013; Pakravan et al., 2012; Nissman et al.,
2007) provided data for analysis.

Between the pregabalin or gabapentin-treated group and the placebo group, there was no
discernible change in pain levels on the third day after the intervention. The analysis revealed
that there was no significant difference in pain reduction between the two treatment methods,
with the pooled mean change in pain ratings between the two groups being -0.09 (95% CI: -0.32
to 0.14). Indicating consistency in the effect sizes obtained across the included studies, the
analysis showed minimal heterogeneity across the studies (Chi-squared test: Chi2 = 2.29, df = 3,
p = 0.51; I-squared: I2 = 0%). Furthermore, no statistically significant difference was seen in
pain reduction on the third day post-intervention between pregabalin or gabapentin and placebo,
according to the test for overall effect.
Figure 10: Quality assessment of the studies.

4 Discussion:
Whether it be in the form of "red eye" or "quiet eye," eye pain is a warning sign for ocular
disorders (Narayana & McGee, 2015) (Kulenkamp et al., 2020). Neurologists need to determine
the various causes of eye discomfort. Furthermore, in order to reduce pain, these individuals also
need efficient pain management. Pregabalin's analgesic effectiveness and safety in the treatment
of pain, including both acute and chronic pain, have been the subject of growing research (Derry
et al., 2019) (Reddi, 2016). The results of the meta-analysis and systematic review indicate that
pregabalin and gabapentin are effective in lowering post-operative pain after different kinds of
corneal procedures, such as laser-assisted subepithelial keratectomy (LASEK) and
photorefractive keratectomy (PRK). The meta-analysis used data from prospective trials and
randomized controlled trials (RCTs) to provide a thorough picture of how well these drugs work
to manage pain related to these operations.
Photorefractive keratectomy is the most common kind of refractive surgery and a good substitute
for LASIK. Postoperative pain and discomfort is the primary issue with PRK (Ambrósio &
Wilson, 2003). Originally created as a GABA analogue to treat epilepsy, gabapentin is now often
used to treat severe depressive disorders and pain, particularly neuropathic pain (Wiffen et al.,
2011). While gabapentin is thought to function on distinct brain receptors, it was first created to
imitate the molecular structure of the neurotransmitter GABA. A research has identified a
potential mechanism of action for gabapentin, which is to inhibit the development of new
synapses (Eker et al., 2009). It is believed that this substance binds to the central nervous
system's voltage-dependent calcium channel's α-2-δ subunit (Eroglu et al., 2009)(Heblich et al.,
2008). Although pregabalin and the inhibitory neurotransmitter GABA are structurally similar,
they are not functionally linked (Ben-Menachem, 2004). Similar to gabapentin, it binds to the
voltage-gated calcium channel's α-2-δ sub unit, inhibits the release of several excitatory
neurotransmitters, and prevents central sensitization and hyperalgesia (Shneker & McAuley,
2005)(Davies et al., 2007). Pregabalin is comparable to gabapentin in its anticonvulsant,
antihyperalgesic, and anxiolytic effects, but it has a better pharmacokinetic profile with dose-
independent absorption (Chizh et al., 2007)(Tassone et al., 2007). Additionally, it has fewer side
effects and is many times more powerful than gabapentin (Shneker & McAuley, 2005). Dorsal
horn neuron sensitization has been shown in models of acute pain and might be involved in the
pathophysiology of post-operative chronic pain. Pregabalin and gabapentin may reduce tissue
damage-induced hyperexcitability of dorsal horn neurons, which may be useful in the
management of postoperative pain. Many off-label uses of gabapentin have been documented,
including the treatment of postoperative pain after PRK.

An anticonvulsant drug called pregabalin is authorized to treat neuropathic pain in several

illnesses (Taguchi et al., 2021) (Cross et al., 2022). Pregabalin reduces central sensitization and
hyperalgesia to treat pain (Buvanendran et al., 2010) (C. Lee et al., 2013). Pregabalin has been
shown in clinical studies to alleviate both acute and chronic postoperative pain (Rai et al., 2017)
(Wick et al., 2017). Pregabalin has previously been administered orally to treat ocular pain,
although research on the drug's safety and effectiveness in treating eye pain has not yet been
completed (Small et al., 2020). Between the gabapentin/pregabalin group and the placebo group,
there was a statistically significant mean difference in pain reduction, which favored the
gabapentin/pregabalin group, according to the pooled analysis. This conclusion is in line with the
findings of the individual trials that were analyzed, all of which showed that the pregabalin and
gabapentin groups had less pain than the placebo group. Additionally, the meta-analysis showed
that the placebo group had severe pain more frequently—defined as a pain score of higher than 7
on a visual analogue scale—which suggests that pregabalin or gabapentin may be useful as an
adjuvant medication to lessen severe post-operative pain.

Pregabalin taken orally has a half-life of 6.3 hours and a maximum oral bioavailability
(Bockbrader et al., 2010). While the time of analgesic delivery affects successful pain
management, pregabalin was given orally either before or one to two hours after surgery in these
studies. It appeared that pregabalin's analgesic efficacy was unaffected by the variation in dosage
timing. Researchers Paik et al. and Galor et al. looked at how pregabalin affected chronic pain
(Paik et al., 2022)(Galor et al., 2019). When pregabalin was used in comparison to a placebo,
Paik et al. found that pregabalin considerably decreased pain seven days after surgery. A single
pregabalin treatment, however, may not be sufficient to lessen chronic pain, as shown by the lack
of change in pain management between the ocular pain tests conducted by Galor et al. at 3 and 6
months. Pregabalin failed to completely block the afferent flood of chemical mediators or
nociceptive signals that come from the cornea and influence the central nervous system, which
resulted in pain sensitization and chronicity (Vadivelu et al., 2014). They did not, however, test
at the same period, and the analgesic impact varied significantly across the 3- or 6-month and 7-
week durations. Therefore, further research is required to determine how pregabalin-assisted
chronic pain treatment affects cornel damage.

The dosage range of 600–1800 mg is where gabapentin's therapeutic benefits for neuropathic
pain are seen, and this range should be modified based on the patient's reaction. Because
gabapentin has a half-life of five to seven hours, it must be administered three times a day in
order to maintain the ideal plasma concentration (Bockbrader et al., 2010). For painful diabetic
peripheral neuropathy, the maximum dosage of pregabalin that is advised is 100 mg three times
per day. Even though pregabalin has been investigated at dosages as high as 600 mg per day,
there is no proof that this quantity offers any further benefits and is less well tolerated. It is not
advised to treat diabetic peripheral neuropathy with dosages more than 300 mg/day due to dose-
dependent side effects (Gajraj, 2007). Pregabalin 300 mg daily (100 mg three times a day) has
been shown to be beneficial in controlling pain after dental surgery; however, 50 mg daily is
about the same as a placebo (Hill et al., 2001). The majority of research has contrasted daily
dosages of 150 and 300 mg for the management of acute postoperative pain.

The use of gabapentin as an alternative to opioid analgesics, such as oxycodone/acetaminophen,

for post-operative pain management after PRK was also examined in this research. Compared to
oxycodone/acetaminophen, gabapentin did not significantly vary in overall pain management
ratings; however, it was linked to more frequent use of anesthetic eye drops (Nissman et al.,
2008). This implies that gabapentin could provide a non-opioid substitute for pain management
after PRK, hence lowering the need for opioid drugs and the negative consequences connected
with them.

The most frequent side effect of pregabalin was nausea, followed by dizziness. The statistics on
the incidence of adverse effects seemed to be quite consistent (Derry et al., 2019). Patients had a
greater frequency of adverse symptoms that persisted after using pregabalin (Morrison et al.,
2017). According to a meta-analysis, pregabalin dosages more than 300 mg prior to surgery
considerably reduced pain during the first 24 hours after surgery; nevertheless, a higher dose
markedly increased pregabalin adverse effects (Zhang et al., 2011). However, compared to other
studies, the results of Alimian and colleagues' study demonstrated that a single oral dose of
pregabalin at a dose of 300 mg is more effective than doses under 300 mg or in divided doses.
These authors suggested that the type of surgery is a significant factor and that pregabalin has its
maximal effect without any side effects in minor to moderate surgeries (Alimian et al., 2012).

Interpreting these conclusions in light of specific research findings and possible causes of
variability is essential, however. There was a noticeable degree of variation across the included
trials, even though the overall impact preferred gabapentin/pregabalin above placebo. While
Steven A. Nissman et al. noted a much greater impact size, Anat Galor et al. showed a minor
mean difference (Nissman et al., 2008)(Galor et al., 2019). Variations in research demographics,
surgical methods, dosage schedules, and outcome measures might be the cause of these
disparities.

A statistically significant difference in mean pain reduction favoring gabapentin/pregabalin over

placebo was found in our study, which comprised data from five studies involving a total of 321
persons (MD 1.59, 95% CI 1.17 to 2.01). The overall significant Z-score of 7.38 (P < 0.00001)
highlights the superiority of gabapentin/pregabalin in pain management after keratoplasty
surgery, despite diversity in results suggested by heterogeneity among the trials (Chi-square =
96.94, df = 4, P < 0.00001).

The varied results from several trials further highlight the possible advantages of pregabalin and
gabapentin in reducing pain after keratoplasty surgery. A mean difference of 0.75 (95% CI -0.03
to 1.53) was observed by Anat Galor et al. (2019); however, more significant mean differences
of -3.90 (95% CI -8.16 to 0.36) and 4.20 (95% CI 3.51 to 4.89) were recorded by Julie Meek et
al. (2013) and STEVEN A. NISSMAN et al. (2007). While there could be differences in the
amount of pain alleviation across studies, the general pattern shows that gabapentin and
pregabalin have potential as useful treatments for reducing pain after keratoplasty surgery.

The meta-analysis showed that patients on gabapentin or pregabalin saw a statistically significant
decrease in pain levels on the second day post-intervention when compared to those on a
placebo. This result implies that both drugs may be useful in reducing pain during the first
postoperative phase after keratoplasty. Nevertheless, the analysis on the third post-intervention
day did not reveal a statistically significant difference in pain levels between the placebo group
and the group receiving gabapentin or pregabalin. This suggests that on the third day after
surgery, the analgesic effects of pregabalin and gabapentin may fade or become less noticeable.

This systematic review and meta-analysis have several limitations, even if it is thorough. First of
all, there was variability in the included studies' research designs, patient demographics, surgical
methods, and outcome measures, which might have limited the generalizability of the results.
Furthermore, variations in pregabalin and gabapentin dosage schedules between trials may have
impacted reported results, emphasizing the need for protocol standardization to improve
comparability. Second, there is a knowledge gap about long-term pain treatment and patient-
reported results due to the emphasis on short-term pain outcomes right after surgery. Future
research should emphasize longitudinal studies with lengthy follow-up periods to evaluate the
sustained effectiveness and possible side effects of gabapentinoids beyond the immediate
postoperative period, given the potential impact of persistent postoperative pain on quality of
life.

Subsequent investigations need to give precedence to tackling the highlighted constraints in

order to enhance the most effective use of gabapentin and pregabalin for the treatment of pain
after keratoplasty surgery. Standardizing trial methods, including dosage schedules and outcome
measurements, would improve the comparability of results and enable more powerful meta-
analyses. Examining novel therapeutic approaches, such combination treatments or different
delivery methods, may improve patient outcomes and the effectiveness of pain management in
ocular surgery. Furthermore, it is important to look into how gabapentinoids might affect central
sensitization and treat chronic pain following a keratoplasty. To better understand the long-term
pain relief and possible side effects of prolonged gabapentinoid use, longitudinal studies with
long follow-up periods are required. To further support clinical decision-making and enhance
patient care, thorough evaluations of the safety profiles and side effects of pregabalin and
gabapentin in the setting of ocular surgery are essential.

5 Conclusion:

This systematic review and meta-analysis concludes that gabapentin and pregabalin both are
effective,as compared to placebo, in reducing pain following keratoplasty surgery. The pooled
analysis shows a statistically significant decrease in pain scores that favors
gabapentin/pregabalin over placebo. The results highlight the possibility of these drugs as
beneficial supplements to pain management plans for patients having LASIK and PRK
procedures on their corneas. Nonetheless, further studies are necessary to clarify the best dosage
schedules, when to administer them, and their long-term safety and effectiveness. This highlights
the need of ongoing research to improve surgical results and patient satisfaction in this particular
setting.

6 References:
Alimian, M., Imani, F., Hassani, V., Rahimzadeh, P., Sharifian, M., & Safari, S. (2012). Effects
of Single-Dose Pregabalin on Postoperative Pain in Dacryocystorhinostomy Surgery.
Anesthesiology and Pain Medicine, 2(2), 72. https://doi.org/10.5812/AAPM.4301

Ambrósio, R., & Wilson, S. E. (2003). LASIK vs LASEK vs PRK: advantages and indications.
Seminars in Ophthalmology, 18(1), 2–10. https://doi.org/10.1076/SOPH.18.1.2.14074

Ben-Menachem, E. (2004). Pregabalin pharmacology and its relevance to clinical practice.

Epilepsia, 45 Suppl 6(SUPPL. 6), 13–18. https://doi.org/10.1111/J.0013-
9580.2004.455003.X

Berlin, R. K., Butler, P. M., & Perloff, M. D. (2015). Gabapentin Therapy in Psychiatric
Disorders: A Systematic Review. The Primary Care Companion for CNS Disorders, 17(5),
330. https://doi.org/10.4088/PCC.15R01821

Bockbrader, H. N., Wesche, D., Miller, R., Chapel, S., Janiczek, N., & Burger, P. (2010). A
comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin.
Clinical Pharmacokinetics, 49(10), 661–669. https://doi.org/10.2165/11536200-000000000-
00000/METRICS

Brooks, J., & Tracey, I. (2005). REVIEW: From nociception to pain perception: imaging the
spinal and supraspinal pathways. Journal of Anatomy, 207(1), 19–33.
https://doi.org/10.1111/J.1469-7580.2005.00428.X

Buvanendran, A., Kroin, J. S., Kari, M., & Tuman, K. J. (2010). Can a Single Dose of 300 mg of
Pregabalin Reach Acute Antihyperalgesic Levels in the Central Nervous System? Regional
Anesthesia & Pain Medicine, 35(6), 535–538.
https://doi.org/10.1097/AAP.0B013E3181FA6B7A

Chizh, B. A., Göhring, M., Tröster, A., Quartey, G. K., Schmelz, M., & Koppert, W. (2007).
Effects of oral pregabalin and aprepitant on pain and central sensitization in the electrical
hyperalgesia model in human volunteers. British Journal of Anaesthesia, 98(2), 246–254.
 https://doi.org/10.1093/BJA/AEL344

Cross, A. L., Viswanath, O., & Sherman, A. l. (2022). Pregabalin. The Essence of Analgesia and
Analgesics, 298–301. https://doi.org/10.1017/CBO9780511841378.072

Davies, A., Hendrich, J., Van Minh, A. T., Wratten, J., Douglas, L., & Dolphin, A. C. (2007).
Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels. Trends
in Pharmacological Sciences, 28(5), 220–228. https://doi.org/10.1016/J.TIPS.2007.03.005

Derry, S., Bell, R. F., Straube, S., Wiffen, P. J., Aldington, D., & Moore, R. A. (2019).
Pregabalin for neuropathic pain in adults. Cochrane Database of Systematic Reviews,
2019(1). https://doi.org/10.1002/14651858.CD007076.PUB3/MEDIA/CDSR/CD007076/
IMAGE_N/NCD007076-CMP-003-05.PNG

Ebrahimiadib, N., Yousefshahi, F., Abdi, P., Ghahari, M., & Modjtahedi, B. S. (2020). Ocular
neuropathic pain: An overview focusing on ocular surface pains. Clinical Ophthalmology,
14, 2843–2854. https://doi.org/10.2147/OPTH.S262060

Eker, H. E., Cok, O. Y., & Aribogan, A. (2009). Alopecia Associated with Gabapentin in the
Treatment of Neuropathic Pain. Journal of Pain and Symptom Management, 37(3).
https://doi.org/10.1016/j.jpainsymman.2008.09.001

Eroglu, Ç., Allen, N. J., Susman, M. W., O’Rourke, N. A., Park, C. Y., Özkan, E., Chakraborty,
C., Mulinyawe, S. B., Annis, D. S., Huberman, A. D., Green, E. M., Lawler, J., Dolmetsch,
R., Garcia, K. C., Smith, S. J., Luo, Z. D., Rosenthal, A., Mosher, D. F., & Barres, B. A.
(2009). Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor
responsible for excitatory CNS synaptogenesis. Cell, 139(2), 380–392.
https://doi.org/10.1016/J.CELL.2009.09.025

Gajraj, N. M. (2007). Pregabalin: its pharmacology and use in pain management. Anesthesia and
Analgesia, 105(6), 1805–1815. https://doi.org/10.1213/01.ANE.0000287643.13410.5E

Galor, A., Patel, S., Small, L. R., Rodriguez, A., Venincasa, M. J., Valido, S. E., Feuer, W.,
Levitt, R. C., Sarantopoulos, C. D., & Felix, E. R. (2019). Pregabalin failed to prevent dry
eye symptoms after laser-assisted in situ keratomileusis (LASIK) in a randomized pilot
study. Journal of Clinical Medicine, 8(9). https://doi.org/10.3390/jcm8091355
Heblich, F., Van Minh, A. T., Hendrich, J., Watschinger, K., & Dolphin, A. C. (2008). Time
course and specificity of the pharmacological disruption of the trafficking of voltage-gated
calcium channels by gabapentin. Channels (Austin, Tex.), 2(1), 4–9.
https://doi.org/10.4161/CHAN.2.1.6045

Hill, C. M., Balkenohl, M., Thomas, D. W., Walker, R., Mathé, H., & Murray, G. (2001).
Pregabalin in patients with postoperative dental pain. European Journal of Pain, 5(2), 119–
124. https://doi.org/10.1053/EUJP.2001.0235

Kuhnle, M. D., Ryan, D. S., Coe, C. D., Eaddy, J., Kuzmowych, C., Edwards, J., Howard, R. S.,
& Bower, K. S. (2011). Oral gabapentin for photorefractive keratectomy pain. Journal of
Cataract and Refractive Surgery, 37(2), 364–369. https://doi.org/10.1016/j.jcrs.2010.08.041

Kulenkamp, J., McClelland, C. M., & Lee, M. S. (2020). Eye pain in the white and quiet eye.
Current Opinion in Ophthalmology, 31(6), 483–488.
https://doi.org/10.1097/ICU.0000000000000702

Lee, A. G., Al-Zubidi, N., Beaver, H. A., & Brazis, P. W. (2014). An update on eye pain for the
neurologist. Neurologic Clinics, 32(2), 489–505. https://doi.org/10.1016/j.ncl.2013.11.007

Lee, C., Lee, H. W., & Kim, J. N. (2013). Effect of oral pregabalin on opioid-induced
hyperalgesia in patients undergoing laparo-endoscopic single-site urologic surgery. Korean
Journal of Anesthesiology, 64(1), 19. https://doi.org/10.4097/KJAE.2013.64.1.19

Lichtinger, A., Purcell, T. L., Schanzlin, D. J., & Chayet, A. S. (2011). Gabapentin for
postoperative pain after photorefractive keratectomy: a prospective, randomized, double-
blind, placebo-controlled trial. Journal of Refractive Surgery (Thorofare, N.J. : 1995),
27(8), 613–617. https://doi.org/10.3928/1081597X-20110210-01

Meek, J. M., Rosbolt, M. B., Taylor, K. R., Fusco, E. A., Panday, V. A., & Reilly, C. D. (2014).
Pregabalin versus placebo in postoperative pain relief of patients’ status post
photorefractive keratectomy: A double-masked, randomized, prospective study. Journal of
Ocular Pharmacology and Therapeutics, 30(7), 527–532.
https://doi.org/10.1089/jop.2013.0208

Morrison, E. E., Sandilands, E. A., & Webb, D. J. (2017). Gabapentin and Pregabalin: Do the
 Benefits Outweigh the Harms? Https://Doi.Org/10.4997/Jrcpe.2017.402, 47(4), 310–313.
https://doi.org/10.4997/JRCPE.2017.402

Narayana, S., & McGee, S. (2015). Bedside Diagnosis of the ‘Red Eye’: A Systematic Review.
The American Journal of Medicine, 128(11), 1220-1224.e1.
https://doi.org/10.1016/J.AMJMED.2015.06.026

Nissman, S. A., Tractenberg, R. E., Babbar-Goel, A., & Pasternak, J. F. (2008). Oral Gabapentin
for the Treatment of Postoperative Pain after Photorefractive Keratectomy. American
Journal of Ophthalmology, 145(4), 623–630. https://doi.org/10.1016/j.ajo.2007.11.012

Paik, D. W., Lim, D. H., & Chung, T. Y. (2022). Effects of taking pregabalin (Lyrica) on the
severity of dry eye, corneal sensitivity and pain after laser epithelial keratomileusis surgery.
British Journal of Ophthalmology, 106(4), 474–479. https://doi.org/10.1136/bjophthalmol-
2020-317570

Pakravan, M., Roshani, M., Yazdani, S., Faramaz, A., & Yaseri, M. (2012). Pregabalin and
gabapentin for post-photorefractive keratectomy pain: A randomized controlled trial.
European Journal of Ophthalmology, 22(SUPPLEMENT N. 7), 106–113.
https://doi.org/10.5301/ejo.5000143

Rai, A. S., Khan, J. S., Dhaliwal, J., Busse, J. W., Choi, S., Devereaux, P. J., & Clarke, H.
(2017). Preoperative pregabalin or gabapentin for acute and chronic postoperative pain
among patients undergoing breast cancer surgery: A systematic review and meta-analysis of
randomized controlled trials. Journal of Plastic, Reconstructive & Aesthetic Surgery,
70(10), 1317–1328. https://doi.org/10.1016/J.BJPS.2017.05.054

Reddi, D. (2016). Preventing chronic postoperative pain. Anaesthesia, 71, 64–71.

https://doi.org/10.1111/ANAE.13306

Shen, X., Chen, X., He, Y., Xu, H., & Zhu, J. (2023). Efficacy and safety of pregabalin in eye
pain: A systematic review. Medicine, 102(6).
https://doi.org/10.1097/MD.0000000000032875

Shneker, B. F., & McAuley, J. W. (2005). Pregabalin: a new neuromodulator with broad
therapeutic indications. The Annals of Pharmacotherapy, 39(12), 2029–2037.
 https://doi.org/10.1345/APH.1G078

Small, L. R., Galor, A., Felix, E. R., Horn, D. B., Levitt, R. C., & Sarantopoulos, C. D. (2020).
Oral Gabapentinoids and Nerve Blocks for the Treatment of Chronic Ocular Pain. Eye and
Contact Lens, 46(3), 174–181. https://doi.org/10.1097/ICL.0000000000000630

Taguchi, T., Nakano, S., & Nozawa, K. (2021). Effectiveness of pregabalin treatment for
neuropathic pain in patients with spine diseases: A pooled analysis of two multicenter
observational studies in japan. Journal of Pain Research, 14, 757–771.
https://doi.org/10.2147/JPR.S293556

Tassone, D. M., Boyce, E., Guyer, J., & Nuzum, D. (2007). Pregabalin: A novel γ-aminobutyric
acid analogue in the treatment of neuropathic pain, partial-onset seizures, and anxiety
disorders. Clinical Therapeutics, 29(1), 26–48.
https://doi.org/10.1016/j.clinthera.2007.01.013

Treede, R. D., Rief, W., Barke, A., Aziz, Q., Bennett, M. I., Benoliel, R., Cohen, M., Evers, S.,
Finnerup, N. B., First, M. B., Giamberardino, M. A., Kaasa, S., Korwisi, B., Kosek, E.,
Lavand’Homme, P., Nicholas, M., Perrot, S., Scholz, J., Schug, S., … Wang, S. J. (2019).
Chronic pain as a symptom or a disease: the IASP Classification of Chronic Pain for the
International Classification of Diseases (ICD-11). Pain, 160(1), 19–27.
https://doi.org/10.1097/J.PAIN.0000000000001384

Vadivelu, N., Mitra, S., Schermer, E., Kodumudi, V., Kaye, A. D., & Urman, R. D. (2014).
Preventive analgesia for postoperative pain control: A broader concept. Local and Regional
Anesthesia, 7(1), 17–22. https://doi.org/10.2147/LRA.S62160

Verma, V., Singh, N., & Jaggi, A. S. (2014). Pregabalin in Neuropathic Pain: Evidences and
Possible Mechanisms. Current Neuropharmacology, 12(1), 44.
https://doi.org/10.2174/1570159X1201140117162802

Wick, E. C., Grant, M. C., & Wu, C. L. (2017). Postoperative Multimodal Analgesia Pain
Management With Nonopioid Analgesics and Techniques: A Review. JAMA Surgery,
152(7), 691–697. https://doi.org/10.1001/JAMASURG.2017.0898

Wiffen, P. J., McQuay, H. J., Edwards, J., & Moore, R. A. (2011). WITHDRAWN: Gabapentin
 for acute and chronic pain. The Cochrane Database of Systematic Reviews, 2011(3),
CD005452. https://doi.org/10.1002/14651858.CD005452.pub2

Yasaei, R., Katta, S., & Saadabadi, A. (2022). Gabapentin. Small Animal Critical Care Medicine,
919–921. https://doi.org/10.1016/B978-0-323-76469-8.00168-4

Zhang, J., Ho, K. Y., & Wang, Y. (2011). Efficacy of pregabalin in acute postoperative pain: a
meta-analysis. BJA: British Journal of Anaesthesia, 106(4), 454–462.
https://doi.org/10.1093/BJA/AER027

Ziganshina, L. E., Gamirova, R., & Abakumova, T. (2017). Gabapentin monotherapy for
epilepsy. The Cochrane Database of Systematic Reviews, 2017(6).
https://doi.org/10.1002/14651858.CD012710

<H1>APPENDIX 1

<H2>PubMed RETRIEVAL POLICY

6 ((((((((((Keratomileusis, Laser In Situ[Title/Abstract]) OR (Laser-Assisted Stromal In Situ

Keratomileusis[Title/Abstract])) OR (Laser Assisted Stromal In Situ

Keratomileusis[Title/Abstract])) OR (Laser Intrastromal Keratomileusis[Title/Abstract])) OR

(Intrastromal Keratomileuses, Laser[Title/Abstract])) OR (Intrastromal Keratomileusis,

Laser[Title/Abstract])) OR (Laser Intrastromal Keratomileuses[Title/Abstract])) OR (Laser In

Situ Keratomileusis[Title/Abstract])) OR (LASIK[Title/Abstract])) AND (((small incision

lenticule extraction[Title/Abstract]) OR (small-incision lenticule extraction[Title/Abstract])) OR

(SMILE[Title/Abstract]))) AND (Astigmatism[Title/Abstract])

5 (((small incision lenticule extraction[Title/Abstract]) OR (small-incision lenticule

extraction[Title/Abstract])) OR (SMILE[Title/Abstract])) AND (Astigmatism[Title/Abstract])

4(((((((((Keratomileusis, Laser In Situ[Title/Abstract]) OR (Laser-Assisted Stromal In Situ

Keratomileusis[Title/Abstract])) OR (Laser Assisted Stromal In Situ

Keratomileusis[Title/Abstract])) OR (Laser Intrastromal Keratomileusis[Title/Abstract])) OR

(Intrastromal Keratomileuses, Laser[Title/Abstract])) OR (Intrastromal Keratomileusis,

Laser[Title/Abstract])) OR (Laser Intrastromal Keratomileuses[Title/Abstract])) OR (Laser In

Situ Keratomileusis[Title/Abstract])) OR (LASIK[Title/Abstract])) AND

(Astigmatism[Title/Abstract])

3 ((small incision lenticule extraction[Title/Abstract]) OR (small-incision lenticule

extraction[Title/Abstract])) OR (SMILE[Title/Abstract])

2 Astigmatism[Title/Abstract]

1 ((((((((Keratomileusis, Laser In Situ[Title/Abstract]) OR (Laser-Assisted Stromal In Situ

Keratomileusis[Title/Abstract])) OR (Laser Assisted Stromal In Situ

Keratomileusis[Title/Abstract])) OR (Laser Intrastromal Keratomileusis[Title/Abstract])) OR

(Intrastromal Keratomileuses, Laser[Title/Abstract])) OR (Intrastromal Keratomileusis,

Laser[Title/Abstract])) OR (Laser Intrastromal Keratomileuses[Title/Abstract])) OR (Laser In

Situ Keratomileusis[Title/Abstract])) OR (LASIK[Title/Abstract])

<H2>COCHRANE RETRIEVAL POLICY

#1 (Keratomileusis, Laser In Situ):ti,ab,kw OR (Laser-Assisted Stromal In Situ

Keratomileusis):ti,ab,kw OR (Laser Assisted Stromal In Situ Keratomileusis):ti,ab,kw OR (Laser

Intrastromal Keratomileusis):ti,ab,kw OR (Intrastromal Keratomileuses, Laser):ti,ab,kw (Word

variations have been searched)

#2 (Intrastromal Keratomileusis, Laser):ti,ab,kw OR (Laser Intrastromal

Keratomileuses):ti,ab,kw OR (Laser In Situ Keratomileusis):ti,ab,kw OR (LASIK):ti,ab,kw

(Word variations have been searched)

#3 (small incision lenticule extraction):ti,ab,kw OR (small-incision lenticule

extraction):ti,ab,kw OR (SMILE):ti,ab,kw (Word variations have been searched) 837

#4 (astigmatism):ti,ab,kw (Word variations have been searched) 2078

#5 #1 OR #2

#6 #5 AND #4

#7 #3 AND #4

#8 #5 AND #4 AND #3
<H2>EMBASE RETRIEVAL POLICY

#6. #1 AND #2 AND #4

#5. #2 AND #4

#4. 'small incision lenticule extraction':ab,ti OR 'small-incision lenticule extraction':ab,ti OR

smile:ab,ti

#3. #1 AND #2

#2. astigmatism:ab,ti

#1. 'keratomileusis, laser in situ':ab,ti OR 'laser-assisted stromal in situ keratomileusis':ab,ti

OR 'laser assisted stromal in situ keratomileusis':ab,ti OR 'laser intrastromal keratomileusis':ab,ti

OR 'intrastromal keratomileuses, laser':ab,ti OR 'intrastromal keratomileusis, laser':ab,ti OR

'laser intrastromal keratomileuses':ab,ti OR 'laser in situ keratomileusis':ab,ti OR lasik:ab,ti

<H2>WEB OF SCIENCE RETRIEVAL POLICY

#1 AND #2 AND #3

#2 AND #3

#1 AND #3

TS=(astigmatism)

((TS=(small incision lenticule extraction)) OR TS=(small-incision lenticule extraction)) OR

TS=(SMILE)

((((((((TS=(Keratomileusis, Laser In Situ)) OR TS=(Laser-Assisted Stromal In Situ

Keratomileusis)) OR TS=(Laser Assisted Stromal In Situ Keratomileusis)) OR TS=(Laser

Intrastromal Keratomileusis)) OR TS=(Intrastromal Keratomileuses, Laser)) OR

TS=(Intrastromal Keratomileusis, Laser)) OR TS=(Laser Intrastromal Keratomileuses)) OR

TS=(Laser In Situ Keratomileusis)) OR TS=(LASIK)

6.1.1 Appendix 2. PRISMA Checklist.
Reported
Section/topic # Checklist item on page
#
TITLE
Title 1 Identify the report as a systematic review, meta-analysis, or both. 1
ABSTRACT
Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility 3
criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions
and implications of key findings; systematic review registration number.
INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of what is already known. 5
Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, 5
comparisons, outcomes, and study design (PICOS).
METHODS
Protocol and 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide 6
registration registration information including registration number.
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, 6
language, publication status) used as criteria for eligibility, giving rationale.
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify 6
additional studies) in the search and date last searched.
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be 6+ Fig1 +
repeated. App1
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, 6
included in the meta-analysis).
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any 7
processes for obtaining and confirming data from investigators.
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and 8
simplifications made.
Risk of bias in individual 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was 7+
studies done at the study or outcome level), and how this information is to be used in any data synthesis. Fig2+Tab 2
Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 9
Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of 9
consistency (e.g., I2) for each meta-analysis.
Risk of bias across 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective 7+
studies reporting within studies). Fig2+Tab 2
Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, 8-9
indicating which were pre-specified.
RESULTS
Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions 10 and Fig
at each stage, ideally with a flow diagram. 1
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) 10 and
and provide the citations. Table 1
Risk of bias within 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 10-11 +
studies Fig2 +Tab 2
Results of individual 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each 10-14 +
studies intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. Fig 3-8
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 10-14 +
Fig 3-8
Risk of bias across 22 Present results of any assessment of risk of bias across studies (see Item 15). 10-11 +
studies Fig2 +Tab 2
Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 10-14 +
Fig 3-8
DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance 15-20
to key groups (e.g., healthcare providers, users, and policy makers).
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of 20
identified research, reporting bias).
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future 20
research.
FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for 21
the systematic review.