Received Date : 04-May-2016

Revised Date : 06-Oct-2016

Accepted Date : 14-Nov-2016
Article type : Review
Accepted Article
Postoperative Pain Control Following Craniotomy: A Systematic Review of Recent Clinical Literature

Georgia G. Tsaousi, MD, MSc, PhD1,*; Simon W. Logan, MD2; and Federico Bilotta, MD,

PhD3

1
Department of Anesthesiology and Intensive Care Unit, Aristotle University of Thessaloniki,

Thessaloniki, Greece
2
Department of Anesthesiology, University Hospital of Wales, Cardiff, Wales, Great Britain
3
Department of Anesthesiology, University of Rome “La Sapienza,” Rome, Italy

*
Address correspondence and reprint requests to Georgia G. Tsaousi, MD, MSc, PhD,

Maiandrou 32, GR 56224, Thessaloniki, Greece. E-mail: tsaousig@otenet.gr

Article Type: REVIEW

Key Words: craniotomy pain, analgesia, analgesic, local anesthetic, opioid, dexmedetomidine,

scalp block

Running Head: Postcraniotomy Pain Control

Submitted: May 4, 2016; Revision accepted: November 14, 2016

Trial Registration

PROSPERO CRD42015029537

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/papr.12548
This article is protected by copyright. All rights reserved.
 Abstract

Background
Accepted Article
Pain intensity after craniotomy is considered to be moderate to severe during the first 2

postoperative days. The ideal pain treatment to facilitate a rapid postoperative recovery and

optimize outcome is unknown.

Objectives

This systematic review aims to report current clinical evidence related to pharmacological

and adjuvant analgesic modalities for postcraniotomy pain control.

Design

Systematic review of randomized controlled trials (RCTs).

Data Sources

PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (January 2011 to

April 2016).

Eligibility Criteria

Use of any analgesic drug, analgesic method, or nonpharmacological intervention for

postcraniotomy pain relief. Also reported data on pain scores up to 48 hours postoperatively,

supplemental analgesic requirements, or adverse events.

Results

Nineteen RCTs enrolling a total of 1,805 patients were included. Most of the retrieved studies

were of moderate to good methodological quality. Systemic pharmacological intervention

was assessed in 14 RCTs. Opioids (5 RCTs) provided superior pain relief to other analgesics

with no significant side-effects, but the quality of studies was low. Diclofenac (3 RCTs)

presented adequate craniotomy pain control without any adverse effects, while the use of

parecoxib is not supported. Dexmedetomidine (3 RCTs) provided adequate transitional

analgesia, but further research is needed. Data on the analgesic efficacy of gabapentin,

This article is protected by copyright. All rights reserved.

 pregabalin, and intravenous lidocaine is very limited (1 RCT for each). Scalp

infiltration/block (3 RCTs) provided adequate analgesia in the early postoperative period,

Accepted Article
while more studies are needed to verify the analgesic benefit obtained from

nonpharmacological interventions, such as multipoint electro-acupuncture, in craniotomy

surgery (2 RCTs).

Conclusions

No definite recommendations can be made based on this systematic review of

pharamacological interventions following craniotomy due to significant divergence in the

methodology of available studies. Limited evidence on scalp infiltration/block suggests an

adequate analgesic effect in the early postoperative period. Analgesic efficacy of

dexmedetomidine and multipoint electro-acupuncture needs further evaluation.

INTRODUCTION

Pain following craniotomy has been neglected in the past, mostly because of the common

belief that craniotomy pain is mild to moderate in intensity, and it has been the subject of

limited and inconsistent research.1,2 Currently, this aspect is debatable as a body of

accumulating evidence shows that approximately 60% of postcraniotomy patients experience

moderate or severe pain in the early postoperative period, or present with persistent pain with

neuropathic elements several months postsurgery.3–6 This task should balance between proper

analgesia establishment, while having an awake and cooperative patient in order to

accomplish neurological evaluation and suboptimal pain treatment that might induce an

implicated postoperative course, resulting into increased healthcare expenditures.7 However,

persistent forms of pain might have significant repercussions on patients’ quality of life.8

The evolving awareness on this issue has led to a growing number of published

articles in the past years assessing the safety and efficacy of traditional and novel analgesic

This article is protected by copyright. All rights reserved.

 modalities for postcraniotomy pain management.2,4,7,8 Although, several analgesic regimens

have been tested aiming to reduce the need for opioids, the optimal form of analgesic therapy
Accepted Article
remains unidentified.

A previous attempt to identify a solid evidence-based practice on analgesic therapy

following craniotomy, by reviewing all double-blinded randomized controlled trials (RCTs)

published up to December 2010, failed to highlight any firm recommendations on this issue

because the number of the included studies was limited and the study populations were very

small.9 However, new trials have been conducted since 2010 and thus a systematic update of

the existing evidence on this topic with thorough methodology is needed, with a view to

outline the best possible practice.

Considering that a multimodal analgesic approach with an emphasis on nonopiate

elements has been proposed as an appealing option for pain control in this subset of

patients,2,8,9 it would be of clinical interest to undertake a literature review including not only

RCTs among various pharmacologic analgesic regimens, but also alternative analgesic

modalities.

This systematic review aims to report current clinical evidence, published between

2011 and 2016, related to pharmacological and adjuvant analgesic modalities for the control

of pain following craniotomy.

METHODS

Search Strategy and Study Selection

This systematic review was performed in accordance with the Preferred Reporting Items for

Systematic Reviews and Meta-analyses (PRISMA) statement recommendations.10 The study

protocol was registered with PROSPERO under the number CRD42015029537.

All RCTs relevant to postoperative pain relief after craniotomy indexed in PubMed,

EMBASE, and Cochrane Central Register of Controlled Trials databases from January 2011

This article is protected by copyright. All rights reserved.

 up to March 2016 were sought using a combination of medical subject headings (MeSH)

terms (“craniotomy” and “pain”) and free text words (“analgesia,” “scalp block,” “scalp
Accepted Article
infiltration,” “opioid,” “non-steroidal anti-inflammatory drug (NSAID)” “a2-adrenergic

agonists” or “dexmedetomidine”). No differentiation between postcraniotomy pain and

headache was attempted. The final check of all databases was performed April 20, 2016.

Two investigators (F.B. and G.G.T.) independently screened and assessed titles and

abstracts before retrieval of the full manuscripts. The selected full papers were reviewed for

eligibility according to the inclusion criteria. References in the selected papers were

scrutinized for additional articles in a further effort to ensure that relevant publications were

not missed. All controversies concerning study selection or data extraction were resolved by

consensus with a third reviewer (S.W.L.).

Inclusion and Exclusion Criteria

To be eligible for this systematic review, publications had to meet the following inclusion

criteria: (1) adult patients (age 18 years); (2) original research involving the use of any

analgesic drug or analgesic method (scalp block or infiltration) or nonpharmacological

intervention for postoperative pain relief compared with placebo or active comparator in both

pediatric and adult populations undergoing elective intracranial procedures; (3) provision of

at least 1 of the following outcome measures: craniotomy pain assessment up to 48 hours

postoperatively, analgesic requirements, adverse events such as hemodynamic alterations

(bradycardia, arrhythmias or hypotension), nausea, vomiting, somnolence, sedation, urinary

retention, or other rare side effects; and (4) availability of full text publication in the English

language. All other studies not fulfilling 1 of the above-mentioned criteria were excluded.

The primary outcome measures were the analgesic efficacy of each method assessed

by pain evaluation scores and supplemental postoperative analgesic consumption between

study groups, while the occurrence of adverse events constituted the secondary endpoint.

This article is protected by copyright. All rights reserved.

 Data Extraction and Quality Assessment

All relevant details were recorded using a dedicated data extraction form. The extracted data
Accepted Article
were as follows: publication details (author and year of publication), details of the study

population (number of patients and type of surgical procedure), interventions (perioperative

anesthetic protocol, postcraniotomy pain treatment modality, and drug dosage), findings

related to primary and secondary outcomes of interest, and quality score assessment of each

trial.

Quality assessment of RCTs was performed using the Jadad scale,11 which considered

the reporting and adequacy of randomization (maximum 2 points) and blinding (maximum 2

points), while an additional point is given if withdrawals or dropouts are described. The risk

of bias in each study was assessed using the Cochrane Collaboration Risk of Bias Tool.12 The

following risks of bias domains were assessed: generation of the allocation sequence,

allocation concealment, blinding of investigators and participants, blinding of outcome

assessors, and incomplete outcome data. Each item was classified as low, unclear, or at high

risk of bias.

RESULTS

Description of Studies

A total of 3,746 records of postoperative analgesic therapy after craniotomy were retrieved

from the database search. Among them, 114 studies were screened and identified as eligible

for inclusion after filtering and application of inclusion criteria. After excluding 88 studies as

“double hits” (identical publications tracked in different databases), 27 RCTs were

considered as candidates for full-text assessment. Only 19 RCTs met the criteria to be

included in the final analysis, as 4 articles were excluded due to lack of predefined endpoints

This article is protected by copyright. All rights reserved.

 assessment and 4 for not involving RCTs. The literature review selection process is

summarized in Figure 1.
Accepted Article
Description of Included Studies

The studies included in this systematic review were of reasonable quality, with a Jadad

quality score ranging from 3 to 5 in 15 of them. Characteristics of the reviewed studies are

summarized in Table 1. Methodological quality assessment demonstrated an acceptable risk

of bias (Table 2). Postoperative pain constituted the primary outcome in 15 studies,13–15,17,19–
23,25–30
while in the remaining studies the main point of interest was intraoperative

performance,24,31 postoperative nausea and vomiting (PONV),18 or cost analysis of the tested

analgesics.16

On the basis of analgesic regimen used for postcraniotomy pain management, the

selected articles were divided into 3 subcategories: systemic pharmacological intervention,13–

26
scalp infiltration/block,27–29 and nonpharmacological intervention mainly involving

acupuncture,30–31 enrolling a total of 1,805 patients of both sexes.

The visual analog scale (VAS) was the most common tool for postcraniotomy pain

assessment,13,15–17,20–22,29,30 followed by the verbal rating scale (VRS)18,23,24 and numeric

rating scale (NRS).14,19,25-28,31 Most of the studies provided a 24-hour postcraniotomy pain

follow-up,13–15,17,18,20,23,25,27,29 2 reported a 48-hour follow-up,21,31 3 extended the study period

to 319,28,30 or 5 days22 postoperatively, while 2 studies had a very short-term follow-up limited

to the postanesthesia care unit (PACU) period.24,26. In one study, the duration of

postcraniotomy assessment was not reported.16

Systemic Pharmacological Intervention

Fourteen RCTs of systemic pharmacological intervention vs. placebo or active control were

identified, and included a total of 1,491 patients.13–26 The analgesic effect of opioids was

evaluated in 5 RCTs13–17 and of dexmedetomidine in 3 RCTs,23–25 while 6 RCTs assessed

This article is protected by copyright. All rights reserved.

 non-opioid drugs such as gabapentin,18 pregabalin,19 cyclo-oxygenase-2 inhibitors

(COXIBs),20 NSAIDs,21,22 or intraoperative infusion of lidocaine.26

Accepted Article
Four different analgesic protocols tested the postoperative use of opioids vs. active

comparator. Administration of fentanyl plus ketorolac13 (or alone)14 using the patient-

controlled analgesia (PCA) technique was more effective in pain management up to 24 hours

postcraniotomy compared to their administration upon request. Although, the total opioid

consumption was higher in PCA technique than intermittent administration, this did not

promote the presence of adverse effects.13,14 Postcraniotomy pain control obtained by

infusion of sufentanil was superior to intermittent administration of morphine or paracetamol,

which was further related to lower rescue morphine dose.15 Although use of paracetamol

presented the lowest incidence of PONV, this was at the expense of pain relief quality.15 The

analgesic efficacy of tramadol in combination with other analgesic agents was tested in 2

RCTs.16,17 The supplementation of a predefined analgesic regimen involving tablets of

oxycodone/paracetamol plus morphine with tramadol was associated with lower VAS scores

and less morphine consumption, while no effect on PONV was identified.16 Interestingly, the

authors of this study recorded a notable reduction of duration and overall cost of

hospitalization in the analgesic mixture including tramadol. In an RCT involving the co-

administration of tramadol with either diclofenac sodium or paracetamol, tramadol-diclofenac

was shown to be more effective in terms of postcraniotomy analgesia at 4 and 24 hours and

need for rescue analgesia with meperidine.17 However, no difference in PONV was noted

between groups.

Although premedication with 600 mg of gabapentin was more effective than placebo

in decreasing the 24-hour incidence of PONV, it failed to reduce either postoperative pain

scores or fentanyl consumption when it was applied as rescue analgesia.18 Interestingly,

administration of pregabalin 150 mg on the evening before surgery, as premedication 2 hours

This article is protected by copyright. All rights reserved.

 before surgery, and twice per day for 72 hours after craniotomy improved pain scores and

reduced analgesic consumption during hospitalization, an effect extended to 3 months after

Accepted Article
surgery. Furthermore, administration of pregabalin was related to fewer side effects, such as

PONV, anxiety, and sleep disorders up to hospital discharge.19

The analgesic efficacy of COXIBs or NSAIDs for postcraniotomy pain control was

assessed in 3 RCTs.20–22 Administration of parecoxib at dural closure demonstrated no

clinical benefit regarding the primary and secondary endpoints of this systematic review.20

Oral use of diclofenac or flupirtine were equally effective for pain relief at 6 hours

postdosing, while both gave superior analgesia to placebo for up to 48 hours.21 Furthermore,

the need for rescue analgesia was less in the diclofenac and flupirtine group as compared to

placebo, while no difference in adverse effects was recorded.21 Similarly, premedication with

100 mg of diclofenac reduced the severity of postcraniotomy headache, predominantly on

postoperative day 1 (POD1), whereas on POD5 it was no longer superior to placebo.

Interestingly, in the subgroup of patients who underwent infratentorial interventions, the

benefit of pain relief with the use of diclofenac was maintained up to the late postoperative

period (POD5). Analgesic requirements as assessed with equivalent doses of morphine were

lower in the diclofenac group, without any adverse effects.22

Intraoperative administration of dexmedetomidine compared to placebo23,25 or active

comparator24 provided better analgesic effect during PACU stay,23,24 and up to the first 12

hours in the ward.25 This was associated with reduced consumption of either tramadol22 or

cumulative morphine compared to placebo or control group up to 24 hours

postoperatively.24,25 Additionally, the mean time to first request for analgesia was prolonged

in the dexmedetomidine group compared to placebo. However, there was inconsistency about

PONV management, as only 1 RCT identified a significant reduction of PONV in the

This article is protected by copyright. All rights reserved.

 dexmedetomidine group during PACU stay and up to 4 hours in the ward,23 while 2 others

failed to demonstrate any favorable effect on PONV.24,25

Accepted Article
In supratentorial craniotomies, the intraoperative infusion of lidocaine significantly

reduced the incidence of acute postoperative pain in the PACU compared to placebo, while

the need for supplemental analgesia was marginally reduced.26 No difference in the presence

of PONV was identified between the groups.

Scalp Infiltration or Scalp Nerve Block

Three RCTs of scalp infiltration27 or scalp nerve blocks28,29 vs. active control or placebo were

identified, and included a total of 138 patients. The analgesic efficacy of scalp infiltration

using a mixture of ropivacaine 0.5% and lidocaine 1% applied either before skin incision or

closure was evaluated by 1 RCT.27 Significant pain relief within the first 6 hours

postoperatively was induced by application of scalp infiltration prior to surgery compared to

skin closure, further associated with more prolonged time to first request for morphine and

less morphine consumption 24 hours after craniotomy.27 The incidence of PONV was similar

between groups.

Application of scalp block with bupivacaine 0.75% before awakening vs. placebo

significantly improved pain scores, attenuated rescue analgesic needs, prolonged time to first

analgesic rescue, and reduced the incidence of PONV during the 72-hour period of

assessment.28 However, the overall consumption of fentanyl provided as a basic analgesic

agent with a PCA device was similar between groups. When bilateral maxillary block was

tested against scalp block applied after induction to anesthesia, it provided a better analgesic

effect (became apparent at 12 hours postoperatively) and less need for rescue analgesia with

diclofenac.29

This article is protected by copyright. All rights reserved.

 Nonpharmacological Intervention

Two RCTs reporting the application of multipoint transcutaneous electric acupuncture

Accepted Article
stimulation (TEAS) before induction to anesthesia for postcraniotomy pain relief vs. placebo

were identified, and included a total of 176 patients.30,31 In both studies, use of multipoint

electro-acupuncture induced better pain control, lower incidence of moderate to severe

dizziness and feeling of full-head, and less need for fentanyl administration during the first 6

hours postoperatively compared to placebo. Nevertheless, no difference in total PCA fentanyl

requirements was recorded. Although the incidence of PONV was lower in the acupuncture

group on both POD1 and POD2, the difference was not statistically significant.31

DISCUSSION

This systematic review of clinical literature published from 2011 to 2016 reports current

evidence related to pharmacological and adjuvant analgesic modalities for the control of pain

following craniotomy, updating the knowledge provided on this topic by a systematic review

published in 2011.9

The first attempt to provide evidence on postcraniotomy management was performed

in 2007 by Nemergut et al.32 Since then, a constantly growing body of evidence has tried to

further enlighten this issue. Although the number of trials identified from 2007 to 2010 was

substantially higher than those previously reported, still no firm recommendation on

analgesic therapy following craniotomy could be provided, as well-performed RCTs were

quite limited.9 Our systematic review identified a notable number of RCTs examining the

efficacy of systemic pharmacological intervention on postcraniotomy pain management,

while up to 2010 only 2 RCTs related to this issue were encountered.33,34 Another interesting

finding was that the interest on scalp blocks or infiltration seems to be declining, while

alternative analgesic modalities such as acupuncture emerge as attractive alternatives.

This article is protected by copyright. All rights reserved.

 Systemic Pharmacological Interventions

Most of the included RCTs examined the analgesic efficacy of systemic pharmacological
Accepted Article
intervention vs. control or placebo groups.13–26 These studies varied significantly in terms of

methodology, craniotomy location, basic analgesia protocol, tested analgesic regimens and

length of follow-up period, but they were of reasonable quality.

Although the use of opioids in the neurosurgical setting is a debatable issue,

parenteral opioids remain the cornerstone for managing moderate-to-severe pain. In line with

previous studies, Hassani et al.15 confirmed the superiority of a potent opioid such as

sufentanil over a less potent one such as morphine. As expected, both opioids provided better

pain relief than a weaker analgesic such as paracetamol, but this benefit was at the expense of

an enhanced incidence of PONV, this adverse effect being more pronounced with morphine

use.15

As a rule of thumb, to minimize opioid-related adverse effects, non-opioid analgesics

such as paracetamol, COXIBs, or NSAIDs should be included in the analgesic regimen. A

great variability of analgesic combinations was encountered in our review, including fentanyl

plus ketorolac,13 morphine plus oxycodone/acetaminophen plus tramadol,16 and tramadol plus

diclophenac sodium or paracetamol,17 all of which enhanced the postoperative analgesic

efficacy of opioids.

In many institutions, opioids are given upon patient request only. However, this

strategy may result in alternate periods of oversedation and inadequate analgesia. Na et al.13

and Morad et al.14 showed that the use of PCA with fentanyl was more effective in pain

management after craniotomy compared to their intermittent use; no difference in the

incidence of adverse effects was recorded. It could be argued that the higher consumption of

opioids in the PCA group, which was common in both studies, might have amplified this

favorable analgesic effect.13,14 Nevertheless, these findings related to opioid-based analgesic

This article is protected by copyright. All rights reserved.

 protocols should be interpreted with scepticism as the RCTs were of rather low scientific

quality.
Accepted Article
The administration of gabapentinoids, which constitute a new generation of

antiepileptic drugs with antinociceptive and antihyperalgesic properties, has emerged as a

promising analgesic alternative for postoperative pain relief in the neurosurgical field, but

their use in this area still remains unclear.37 Presumably, the failure to identify any clear

positive effect of premedication with 600 mg of gabapentin on postcraniotomy pain relief and

opioid consumption during the 18-hour follow-up period was due to inadequate dosing,18 as it

has been shown that a dose of 1,200 mg per day might be needed for successful analgesic

effect following craniotomy.37,38 However, preemptive administration of 150 mg pregabalin

and twice-daily dosing for 3 days following craniotomy optimally affected antinociception

and the occurrence of adverse effects during the first 48 hours after craniotomy.19

Considering that the clinical effects of gabapentinoids are not solely pharmacologically

modulated but may also depend upon the activities of unidentified neurological pathways,

such as pain neuroadaptation, more studies are warranted to elucidate their potential role in

the neurosurgical setting, both on a short-term and long-term basis.39

Preoperative administration of NSAIDs may enhance analgesia through local

inflammation attenuation and consequent sensitization and pain windup during craniotomy,

but their use in neurosurgery is still a contentious issue, mainly due to augmentation of the

risk of intracranial bleeding.40 Premedication with diclofenac22 or its administration at regular

time intervals21 provided satisfactory pain relief postoperatively, persisting over a 5-day

period, which far exceeds its duration of analgesic efficacy.22 No difference in adverse

effects, including bleeding, was recorded in both studies. Diclofenac seems to be the most

popular NSAID for craniotomy pain control, as 2 out of 3 studies applying NSAIDs or

COXIBs in this clinical setting included diclofenac sodium in their analgesic regimen.21,22 Of

This article is protected by copyright. All rights reserved.

 interest, in both studies diclofenac sodium was administered either as a single dose22 or at the

lowest effective dose for a limited time frame,21 possibly with a view to provide an analgesic
Accepted Article
benefit without significant toxicity.40

COXIBs were initially proposed as ideal alternatives to traditional NSAIDs for

postcraniotomy analgesia, as they have no antiplatelet action and do not incur increased

bleeding risk.35,36 Despite the concern about their potential dose-dependent cardiovascular

adverse effects and thromboembolic events, their relevance to “single-shot” administration is

debatable, while parecoxib has been shown to be safe in the perioperative period in

noncardiac surgery.36 Nevertheless, existing evidence on the use of parecoxib in

postcraniotomy pain setting is not supportive of its analgesic superiority.20,35,36 Failure to

attribute a clear analgesic benefit to the use of parecoxib could possibly be explained in the

light of study design and analgesic protocol applied in the most recent RCTs conducted on

this topic.20,35 Based on the limited available evidence, this drug class cannot still be

considered as welcome analgesics in the setting of postcraniotomy pain management, and

further investigation may reveal subgroups of patients in whom a stronger benefit may be

seen.35,36

A new intervention compared to the systematic review of 20119 was the retrieval of 3

RCTs assessing the use of dexmedetomidine for postcraniotomy pain management.23–25

Investigations involving dexmedetomidine use in intra-abdominal and orthopedic procedures

claim an opioid-sparing effect by as much as 60%,41 a finding further confirmed by our

systematic review. Importantly, the short-term analgesic efficacy (in the PACU) of

intraoperative infusion of dexmedetomidine was superior to that of remifentanil.24

Considering that the administration of dexmedetomidine perioperatively might be implicated

with delayed recovery and longer discharge times from the PACU, ideally this agent can be

used as transitional analgesia from the surgical plane of anesthesia to the PACU.42

This article is protected by copyright. All rights reserved.

 Undoubtedly, further research is needed to assess the adequacy of dexmedetomidine for pain

control vs. side-effects following craniotomy.

Accepted Article
Based on previous knowledge supporting the analgesic efficacy of lidocaine in a

number of clinical settings,43,44 Peng et al.23 reported that intraoperative administration of

lidocaine reduces the incidence of postcraniotomy pain in the PACU. However, the extremely

short duration of this effect raises concerns about the efficacy of this intervention for

postcraniotomy pain control.

Scalp Infiltration or Scalp Nerve Block

Of interest, the number of studies examining the analgesic efficacy of scalp infiltration or

scalp nerve block has notably declined since the systematic report published in 2011.9 A

previous meta-analysis published in 2013 identified a positive impact of regional scalp block

for postcraniotomy analgesia, but the RCTs included were small and of limited

methodological quality.45 Up to now, only the 3 RCTs included in our study were performed,

which seem not to provide strong evidence on scalp block analgesic efficacy.27–29 During the

first 6 postoperative hours, the analgesic efficacy of scalp infiltration applied prior to surgery

was superior to that performed upon skin closure,27 while the results from scalp block applied

before awakening28 vs. placebo presented conflicting results, as the positive results in terms

of pain and PONV control can be questioned by the equivalent overall consumption of

fentanyl between groups. Any favorable analgesic effect reported28 could possibly rely on the

relatively high concentration of bupivacaine used for scalp block (0.75%), lasting up to 72

hours postoperatively. This prolonged analgesic effect of scalp block constitutes an

interesting finding compared to the systematic review of 2011.9 No clear analgesic

superiority was identified when bilateral maxillary block was tested against scalp block.29

Several factors could affect the potential efficacy of regional techniques for postcraniotomy

pain control, such as the mismatch of the territory covered by the block, the site of the

This article is protected by copyright. All rights reserved.

 craniotomy, and the level of expertise in this technique. An additional point of consideration

is that scalp block could be applied just once, and its repeatability constitutes an issue.
Accepted Article
Nonpharmacological Intervention

Application of acupuncture and its related methods to postcraniotomy pain management

constitutes an intriguing aspect of nonpharmacological analgesic therapy. Existing evidence

indicates that multipoint TEAS can shorten the anesthesia recovery time, improve the quality

of recovery, and decrease the incidence of anesthesia-related side-effects for patients

undergoing surgery.31,46 From the 2 RCTs included in our systematic review applying

multipoint TEAS before induction to anesthesia for supratentorial craniotomy surgery as an

adjunct to postoperative use of opioids, a notable reduction of pain scores occurred.30,31 The

duration of this adjuvant beneficial effect ranged from 6 hours postoperatively to POD1, a

finding contradictory to similar studies, which have demonstrated a constant pain

improvement up to POD3.46 Nevertheless, no definitive evidence regarding the duration of

analgesia effect of TEAS after the discontinuation of stimulation exists. Furthermore,

contrary to previous findings,46 no clear positive effect on opioid consumption or incidence of

PONV occurred. Differences in the surgical site and in the acupuncture points along with the

intensity, frequency, and duration of electro-acupuncture application may help explain these

divergent findings. These promising preliminary findings should be further documented by

established acupuncture protocols. However, there are issues concerning the applicability and

generalizability of the procedure in current neurosurgical practice, as a major drawback of

this technique is that it necessitates properly trained personnel.

Language restriction of the included RCTs can be considered as a possible limitation

of our study. Furthermore, the time span of the literature search was limited to the past 6

years. Nevertheless, as there was a relevant publication in 2011, we considered that an update

This article is protected by copyright. All rights reserved.

 of the previous knowledge regarding all the available postoperative craniotomy pain

modalities would be of clinical importance.

Accepted Article
In conclusion, critical appraisal of recent studies related to postcraniotomy pain relief

could not provide any definite recommendations regarding systemic pharmacological

interventions due to significant divergence in terms of study methodology and thus highlights

the need for further, more rigorously designed trials. Dexmetedetomidine and newer

anticonvulsants emerge as promising alternatives for short-term and long-term

postcraniotomy pain control, respectively. Evidence on scalp infiltration/block suggests an

adequate analgesic effect in the early postoperative period, but the scientific interest in this

field has notably declined. The promising early findings from multipoint electro-acupuncture

need further evaluation.

Implications for Research

There is an urgent need to conduct research on practice gaps regarding use of evidence-based

interventions for management of postcraniotomy pain. Future RCTs need to be carefully

powered to address (1) the exact components of effective multimodal analgesic regimens

from a more “individualized” approach based on patients’ clinical characteristics and setting

or location of craniotomy; (2) optimal methods of pain assessment and monitoring; and (3)

safety and efficacy of newer promising opioid-sparing multimodal regimens with a focus on

short- and long-term outcomes.

This article is protected by copyright. All rights reserved.

 REFERENCES

1. Rocha-Filho PA. Post-craniotomy headache: a clinical view with a focus on the persistent
Accepted Article
form. Headache. 2015;55:733-738.

2. Haldar R, Kaushal A, Gupta D, Srivastava S, Singh PK. Pain following craniotomy:

Reassessment of the available options. Biomed Res Int. 2015;2015:509164.

3. Mordhorst C, Latz B, Kerz T, et al. Prospective assessment of postoperative pain after

craniotomy. J Neurosurg Anesthesiol. 2010;22:202–206.

4. Flexman AM, Ng JL, Gelb AW. Acute and chronic pain following craniotomy. Curr

Opin Anaesthesiol. 2010;23:551–557.

5. Headache Classification Committee of the International Headache Society. The

International Classification of Headache Disorders, 3rd edition (beta version).

Cephalalgia. 2013;33:629-808.

6. Gottschalk A, Berkow LC, Stevens RD, et al. Prospective evaluation of pain and

analgesic use following major elective intracranial surgery. J Neurosurg. 2007;106:210–

216.

7. Rahimi SY, Vender JR, Macomson SD, French A, Smith JR, Alleyne CH Jr.

Postoperative pain management after craniotomy: evaluation and cost analysis.

Neurosurgery. 2006;59:852–857.

8. Roberts GC. Postcraniotomy analgesia: current practices in British neurosurgical

centres—a survey of postcraniotomy analgesic practices. Eur J Anaesthesiol.

2005;22:328–332.

9. Hansen MS, Brennum J, Moltke FB, Dahl JB. Pain treatment after craniotomy: where is

the (procedure-specific) evidence? A qualitative systematic review. Eur J Anaesthesiol.

2011;28:821-829.

This article is protected by copyright. All rights reserved.

 10. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic

reviews and meta-analyses of studies that evaluate healthcare interventions: explanation

Accepted Article
and elaboration. BMJ. 2009;339:b2700

11. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized

clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12.

12. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration's tool for

assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.

13. Na HS, An SB, Park HP, et al. Intravenous patient-controlled analgesia to manage the

postoperative pain in patients undergoing craniotomy. Korean J Anesthesiol. 2011;60:30-

35.

14. Morad A, Winters B, Stevens R, et al. The efficacy of intravenous patient-controlled

analgesia after intracranial surgery of the posterior fossa: a prospective, randomized

controlled trial. Anesth Analg. 2012;114:416-423.

15. Hassani E, Mahoori A, Sane S, Tolumehr A. Comparison the effects of paracetamol with

sufentanil infusion on postoperative pain control after craniotomy in patients with brain

tumor. Adv Biomed Res. 2015;4:64.

16. Rahimi SY, Alleyne CH, Vernier E, Witcher MR, Vender JR. Postoperative pain

management with tramadol after craniotomy: evaluation and cost analysis. J Neurosurg.

2010;112:268-272.

17. Gunes Y, Unlugenc H, Yilmaz DM, Ozcengiz D. Management of acute craniotomy pain:

the analgesic effect of diclofenac sodium-tramadol or paracetamol-tramadol. Neurosurg

Q. 2011;21:236-239.

18. Misra S, Parthasarathi G, Vilanilam GC. The effect of gabapentin premedication on

postoperative nausea, vomiting, and pain in patients on preoperative dexamethasone

This article is protected by copyright. All rights reserved.

 undergoing craniotomy for intracranial tumors. J Neurosurg Anesthesiol. 2013;25:386-

391.
Accepted Article
19. Shimony N, Amit U, Minz B, et al. Perioperative pregabalin for reducing pain, analgesic

consumption, and anxiety and enhancing sleep quality in elective neurosurgical patients: a

prospective, randomized, double-blind, and controlled clinical study. J Neurosurg.

2016;12:1-10.

20. Williams DL, Pemberton E, Leslie K. Effect of intravenous parecoxib on post-craniotomy

pain. Br J Anaesth. 2011;107:398-403.

21. Yadav G, Choupoo S, Das SK, et al. Evaluating the role of flupirtine for postcraniotomy

pain and compare it with diclofenac sodium: a prospective, randomized, double blind,

placebo-controlled study. J Neurosurg Anesthesiol. 2014;26:32-36.

22. Molnár C, Simon É, Kazup Á, et al. A single preoperative dose of diclofenac reduces the

intensity of acute postcraniotomy headache and decreases analgesic requirements over

five postoperative days in adults: a single center, randomized, blinded trial. J Neurol Sci.

2015;353:70-73.

23. Peng K, Jin XH, Liu SL, Ji FH. Effect of intraoperative dexmedetomidine on post-

craniotomy pain. Clin Ther. 2015;37:1114-1121.

24. Rajan S, Hutcherson MT, Sessler DI, et al. The effects of dexmedetomidine and

remifentanil on hemodynamic stability and analgesic requirement after craniotomy: a

randomized controlled trial. J Neurosurg Anesthesiol. 2015;28 [Epub ahead of print].

25. Song J, Ji Q, Sun Q, Gao T, Liu K, Li L. The opioid-sparing effect of intraoperative

dexmedetomidine infusion after craniotomy. J Neurosurg Anesthesiol. 2016;28:14-20.

26. Peng Y, Zhang W, Kass IS, Han R. Lidocaine reduces acute postoperative pain after

supratentorial tumor surgery in the PACU: a secondary finding from a randomized,

controlled trial. J Neurosurg Anesthesiol. 2015;20 [Epub ahead of print].

This article is protected by copyright. All rights reserved.

 27. Song J, Li L, Yu P, Gao T, Liu K. Preemptive scalp infiltration with 0.5% ropivacaine

and 1% lidocaine reduces postoperative pain after craniotomy. Acta Neurochir (Wien).
Accepted Article
2015;157:993-998.

28. Hwang JY, Bang JS, Oh CW, et al. Effect of scalp blocks with levobupivacaine on

recovery profiles after craniotomy for aneurysm clipping: a randomized, double-blind,

and controlled study. World Neurosurg. 2015;83:108-113.

29. Jayaram K, Srilata M, Kulkarni D, Ramachandran G. Regional anesthesia to scalp for

craniotomy: innovation with innervation. J Neurosurg Anesthesiol. 2016;28:32-37.

30. Liu X, Li S, Wang B, An L, Ren X, Wu H. Intraoperative and postoperative anaesthetic

and analgesic effect of multipoint transcutaneous electrical acupuncture stimulation

combined with sufentanil anaesthesia in patients undergoing supratentorial craniotomy.

Acupunct Med. 2015;33:270-276.

31. An LX, Chen X, Ren XJ, Wu HF. Electro-acupuncture decreases postoperative pain and

improves recovery in patients undergoing a supratentorial craniotomy. Am J Chin Med.

2014;42:1099-1109.

32. Nemergut EC, Durieux ME, Missaghi NB, Himmelseher S. Pain management after

craniotomy. Best Pract Res Clin Anaesthesiol. 2007;21:557–573.

33. Jones SJ, Cormack J, Murphy MA, Scott DA. Parecoxib for analgesia after craniotomy.

Br J Anaesth. 2009;102:76–79.

34. Jellish WS, Leonetti JP, Sawicki K, Anderson D, Origitano TC. Morphine/ondansetron

PCA for postoperative pain, nausea, and vomiting after skull base surgery. Otolaryngol

Head Neck Surg. 2006;135:175–181.

35. Jones SJ, Cormack J, Murphy MA, Scott DA. Parecoxib for analgesia after craniotomy.

Br J Anaesth. 2008;102:76–79.

This article is protected by copyright. All rights reserved.

 36. Schug S, Camu F, Joshi G, Pan S, Cheung R. Cardiovascular safety of the

cyclooxygenase-2 selective inhibitor parecoxib sodium: review of pooled data from

Accepted Article
surgical studies. Eur J Anaesthesiol. 2006;23:219–220.

37. Tiippana EM, Hamunen K, Kontinen VK, Kalso E. Do surgical patients benefit from

perioperative gabapentin/pregabalin? A systematic review of efficacy and safety. Anesth

Analg. 2007;104:1545–1556.

38. Türe H, Sayin M, Karlikaya G, Bingol CA, Aykac B, Türe U. The analgesic effect of

gabapentin as a prophylactic anticonvulsant drug on postcraniotomy pain: a prospective

randomized study. Anesth Analg. 2009;109:1625-1631.

39. Weinbroum AA. Non-opioid IV adjuvants in the perioperative period: pharmacological

and clinical aspects of ketamine and gabapentinoids. Pharmacol Res. 2012;65:411–429.

40. Kotak D, Cheserem B, Sloth A. A survey of post-craniotomy analgesia in British

neurosurgical centres: time for perceptions and prescribing to change. Br J Neurosurg.

2009;23:538–542.

41. Arain SR, Ruehlow RM, Uhrich TD, Ebert TJ. The efficacy of dexmedetomidine versus

morphine for postoperative analgesia after major inpatient surgery. Anesth Analg.

2004;98:153–158.

42. Iirola T, Ihmsen H, Laitio R, et al. Population pharmacokinetics of dexmedetomidine

during long-term sedation in intensive care patients. Br J Anaesth. 2012;108:460–468.

43. Boas RA, Covino BG, Shahnarian A. Analgesic responses to i.v. lignocaine. Br J

Anaesth. 1982;54:501–505.

44. Atkinson RL. Intravenous lidocaine for the treatment of intractable pain of adiposis

dolorosa. Int J Obes. 1982;6:351–357.

This article is protected by copyright. All rights reserved.

 45. Guilfoyle MR, Helmy A, Duane D, Hutchinson PJ. Regional scalp block for

postcraniotomy analgesia: a systematic review and meta-analysis. Anesth Analg.

Accepted Article
2013;116:1093-1102.

46. Wang XQ, Yu JL, Du ZY, Xu R, Jiang CC, Cao X. Electroacupoint stimulation for

postoperative nausea and vomiting in patients undergoing supratentorial craniotomy. J

Neurosurg Anesthesiol. 2010;22:128–131.

Figure 1. Flow diagram showing the results of the search and reasons for exclusion of studies.

This article is protected by copyright. All rights reserved.

ccepted Articl
Table 1. Characteristics of the included studies.
Study
ID
No
activ
Surgical
procedu
Perioperat
ive
Basic
analgesi
Dose active/ control Pain
assessme
Primary Outcomes Secondary
outcome
Other
findings
Quality
score
e/con re anesthetic a active nt Effect on pain Analgesic Adverse
trol and requirements effects
control
Randomized control studies involving systemic pharmacological intervention
Na et 53/53 Supra- Propofol/ NR Fentanyl 20μg/kg plus VAS at 1, VAS at postop 1 Analgesics reduced Nausea, GCS, 2
13
al /infratent remifentani ketorolac 3mg/kg in 4, 24h h: NS, in PCA at 1h and respiratory hemodynami
orial l TCI PCA device vs postop VAS reduced at even more at 24hrs depression, cs: NS.
cranioto fentanyl or ketorolac 4, 24h (PCA) At 4h: NS miosis: NS
my upon demand
Morad 31/34 Infratento Propofol/fe Paraceta Fentanyl 0.5μg/kg (4 NRS NRS reduced in Fentanyl use higher PONV: NS GCS, 3
14
et al rial ntanyl mol doses/hr) in PCA hourly up PCA group in PCA vs upon sedation,
cranioto 650mg/4 device vs fentanyl 25- to 10hrs (p=0.003) demand group (54.8 hemodynami
my hr 50μg/30min upon and every μg/hr vs 29.9 μg/hr; cs,
(rectally) demand 2hrs up to p=0.002) oxygenation:
or 16hrs NS.
1gr/6hr postop
(iv)
Hassa 15/15 Cranioto Propofol/ Morphine Sufentanil VAS at 0, VAS increased Rescue morphine PONV HR and MAP 1
ni et /15 my remifentani 0.14 0.0015μg/kg/min (civ) 2, 4, 12, 24 from 1.7 increased from 4% increased increased
15
al (location l mg/kg Morphine 5mg/4hr h postop (sufentanil) to (sufentanil) to 32% from 15.6% from
NR) (iv) (sc) 2.3 (morphine) (morphine) to 64% (paracetamol sufentanil to
intraop Paracetamol to 3.2 (paracetamol) ) morphine to
Rescue 15mg/kg/6h (paracetamol) to 24% paracetamol
analgesic (sufentanil) GCS, SatO2:
:morphin to 60.3% NS
e 3mg (morphine)
(iv) for
VAS4
Rahimi 25/25 Supraten NR NR Oxycodone/acetamin VAS (time VAS reduced in Morphine use PONV: NS Hospital 1
16
et al torial ophen 5/325 mg-1-2 of tramadol reduced in tramadol LOS
cranioto tb/4 hr plus morphine assessmen Oxycodone/acetami increased
my 1–2 mg (iv)/2h t NR) nophen use: NS from 3.1d
(Narcotics gr) vs (tramadol) to
Previous analgesics 4.1d
plus Tramadol (narcotics)
100mg/12h
(Tramadol gr)
Gunes 25/25 Supraten Sevofluran Rescue Tramadol 1.5mg/kg/ VAS at 15 VAS reduced at Rescue analgesia PONV: NS Hemodynam 2
17
et al torial e/ nitrous analgesic 6h civ plus diclofenac and 30 min 4, 24 h in during 24h ics, SpO2:

This article is protected by copyright. All rights reserved.

ccepted Articl cranioto
my
tumor
for
oxide
/remifentan
il
:
meperidi
ne 25mg
75mg im or
paracetamol 15mg/kg
iv
and at 1, 4,
8, 12, 16,
24 h
diclofenac/trmad
ol
increased from 16%
in diclofenac-
tramadol to 40% in
NS

surgery (iv) postop paracetamol-

tramadol (p=0.002)
Misra 36/37 Supra- Isoflurane/ Paraceta Gabapentin 600mg VRS hourly VRS: NS Rescue analgesia: Nausea N/A 5
18
et al /infratent fentanyl mol peros 2h before up to 6 h 8.3% in GD vs 18% (11.1% vs
orial 1gr/6hr anesthesia induction and every in D group; NS) 35.1%;
cranioto (iv) (GD group) or 2h for the Mean (SD) fentanyl p=0.02),
my for Rescue placebo (D group) next 18hr consumption: 75 PONV
tumor analgesic Plus dexamethasone (25) μg in GD group (13.9% vs
surgery : fentanyl 4 mg (iv) on the vs.120.8 (81.5) μg 37.8%;
1μg/kg morning of surgery - in D group; NS) P=0.02) and
(iv) for up to 48h rescue
VRS3 antiemetics
(13.9% vs
35.1%;
p=0.03)
reduced at
24hrs in GD
vs D group
Shimo 43/45 Supra- Propofol/fe Wound Pregabalin (PGL) 150 NRS NRS reduced Rescue analgesia PONV 40% Anxiety and 5
ny et al /infratent ntanyl infiltration mg night before and hourly in 30-40% in PGL reduced in PGL less in PGL quality of
19
orial remifentani with 20 1.5 h before and 2 h PACU and on POD0 and from POD 0 to 2 (p=0.034) sleep better
cranioto l ml after surgery and every 8h POD1 (p<0.01) (p<0.05) and rescue in PGL
my for lidocaine twice/day for the next for 0-3 and 10% on On POD3 and antiemetics (p=0.04;
tumor/ma 1.5% 72 h vs placebo 500 days POD2 and discharge no PGL 74% p<0.01)
ss plus mg starch POD3 (NS) difference vs and placebo Out-of-
surgery bupivacai placebo 94% (p = hospital (up
ne 0.25% 0.0092) to 3months)
Paraceta NRS
mol/dipyr reduced by
one 1gr 16% and
Rescue analgesic
analgesic use by 43%
s:diclofen vs placebo
ac 75 (NS)
mg/
tramadol
100 mg
or
morphine
1mg for

This article is protected by copyright. All rights reserved.

ccepted Articl
William
s
20
et
47/49 Supraten
torial
Propofol/
remifentani
NRS5
Paraceta
mol
Parecoxib 40mg (iv)
vs placebo at dural
VAS 1, 2,
4, 8, 24 h
VAS: NS Rescue analgesia:
NS
PONV: NS Hemodynam
ics, sedation
5

al cranioto l TCI 1gr/6h closure postop score: NS

my (peros)
Rescue
analgesic
: PCA-
morphine
for
VAS>4
Yadav 125/1 Supra- NR Paraceta Diclofenac 50mg/8h VAS on VAS reduced Rescue analgesia PONY: NS NS 5
21
et al 22/12 /infratent mol (peros) vs POD2 (diclofenac and reduced in
4 orial 1gr/6h Flupirtine 100mg/8h every 6hr flupirtine) at 6 diclofenac and
cranioto (iv) on (peros) vs placebo on for 48hrs hrs to 48h flupirtine (p<0.0001)
my POD1 POD2 for 48hrs (p<0.0001)
Rescue Pain relief
analgesia higher in
: diclofenac
tramadol (90.2%) and
50mg (iv) flupirtine
on POD2 (90.5%) groups
for 48hrs vs placebo
for (69.8%)
VAS>3
Molnar 100/1 Supra- Sevofluran IS Diclofenac VAS VAS reduced on Morphine NR N/A 5
22
et al 00 /infratent e/fentanyl lidocaine 100mgplus preop, on evening postop, equivalents for VAS
orial 2% midazolam 7.5mg evening POD1, POD5 scores ≤3 cm
cranioto before peros postop, (diclofenac) increased from
my for surgery vs midazolam 7.5mg POD1, Analgesic 3.3mg (diclofenac)
tumor plus peros as POD5 efficacy superior to 4.3 (control);
surgery Paraceta premedication in infratentorial p=0.044
mol 1-2gr craniotomies
(iv) plus
Tramadol
100mg
(orally)
Rescue
analgesia
: fentanyl
1μg/kg
(iv) for
VAS>3

This article is protected by copyright. All rights reserved.

ccepted Articl
Peng
et al
23
38/38 Supraten
torial
cranioto
Sevofluran
e/fentanyl
Tramadol
0.5mg/kg
(iv)
DEX 0.5μg/kg/h
placebo
vs VRS at 10,
20, 30, 40,
60, 90 min
VRS reduced at
30 min, 2h
(DEX)
Tramadol
consumption
reduced at 0-2, 0-6,
DEX
reduced
PONV
Hypotensive
events,
excessive
5

my Rescue (PACU) 0-12, 0-24 h (DEX) reduced at sedation

analgesia and at 20, 60, 90 respiratory
: 2,4,8,12,18 min in PACU depression:
flurbiprof ,24hrs and at 2,4h NS
en axetil (ward) in ward
50 mg postop (DEX)
(iv) DEX group
had
PONV
events
needed
treatment
less in DEX.
Rajan 68/71 Supra- Sevofluran Rescue DEX 0.5-1μg/kg VRS at 15, VRS increased Morphine PONV: NS HR and MAP 3
24
et al /infratent e/fentanyl analgesia (bolus) plus 0.2- 30, 45, 60, from 2.9 (DEX) equivalents lower in DEX
orial : fentanyl 0.7μg/kg/h vs 90 min to 5.1 increased from 5mg Shivering:
cranioto 50μg/kg remifentanil 0.08- (PACU) (remifentanil) (DEX to 10mg NS
my or (iv) for 0.15μg/kg/min intraop (remifentanil)
Transsph VRS>4
enoidal
approach
Song 25/27 Supra- Propofol/ Tramadol DEX 0.5 mg/kg/h NRS at 1, NRS within 12 h Rescue analgesia PONV Agitation 5
25
et al /infratent remifentani 100mg (bolus) plus 2, 4, 6, 8, reduced (DEX) at 4, 12, 24h increased higher in
orial l TCI (iv) plus 0.2-0.5mg/kg/h vs 12, 24h reduced (DEX) from 4% placebo
cranioto Paraceta placebo postop Patients used (DEX) to Respiratory
my mol 54.4%, 43.3%, and 22.2% depression,
1gr/6h 31.4% less PCA (placebo) hypotension,
(peros) morphine at 4, 12, (NS) bradycardia:
Rescue 24 h NR
analgesia Time to first
: PCA- analgesic request
morphine increased from
for 171.2 (DEX) to
NRS>4 69.6(placebo)
Peng 40/40 Supraten Sevofluran PCA - Lidocaine 1.5mg/kg NRS upon NRS=0 higher; Rescue analgesia PONY: NS Hemodynam 5
26
et al torial e/remifenta sufentanil (bolus) plus 2mg/kg/h admission, NRS=1-3 lower increased from ics: NS
cranioto nil plus Rescue intraop vs placebo at (lidocaine) at 12.5% (lidocaine) to No lidocaine
my rescue analgesia 30,60min,P PACU discharge 30% (placebo): NS toxicity
sufentanil : ACU
tramadol discharge

This article is protected by copyright. All rights reserved.

ccepted Articl
Randomized control studies involving scalp infiltration or scalp block
Song
et al
27
25/27 Supraten Propofol/
torial/
Tramadol Scalp infiltration
remifentani 100mg iv ropivacaine 0.5% plus
NRS at 1,
2, 4, 6, 8,
NRS within 6h
reduced in
Time to
analgesic request
first PONV: NS Respiratory
depression:
3

infratento l Rescue lidocaine 1% before 12, 24 h infiltration before reduced from NR

rial analgesia skin incision vs before postop skin incision 300min (before
cranioto : PCA- skin closure incision) to 150min
my morphine (after closure)
for NRS Morphine
>4 consumption at 24h
increased from 10.5
mg (before incision)
to 28 mg (after
closure)
Hwang 23/23 Supraten Propofol/ PCA- Scalp block NRS at NRS reduced in Rescue analgesia PONV Use of 5
28
et al torial remifentani fentanyl levobupivacaine (L) 1,2,4,8,12, levobupivacaine increased from 30% increased antihyperten
cranioto l 15μg/kg 0.75% plus 16, 24, 48, in each time- (L) to 65% from 30% (L) sive drugs
my for Rescue epinephrine vs 72 h point (placebo) to 65% and sleeping
aneurys analgesia placebo before postop Time to first (placebo) tendency
mal : awakening analgesic request higher in
clipping Ketorolac reduced from 16h placebo
30mg (iv) (L) to 6h (placebo) Fever,
for PCA-fentanyl dizziness,
NRS30 consumption up to delirium: NS
4h reduced in L
Overall PCA-
fentanyl
consumption: NS
Jayara 20/20 Supra- Isoflurane/ Rescue
Maxillary block vs VAS at 0, VAS at 1,2,4h: Rescue analgesia NR Sedation at 3
m et tentorial/i fentanyl analgesia
scalp block with 15 ml 1,2,4, 12h NS increased from 4 h lower in
29
al nfratentor : bupivacaine 0.5% postop VAS at 12 h 11.1% (maxillary maxillary
ial/retrom Diclofena
plus 15 ml lidocaine reduced in block) to 44.4% block
astoid c 75mg
2% after anesthesia maxillary block (scalp block)
cranioto (im)induction
my In both groups
greater plus lesser
occipital nerves block
Randomized control studies involving no pharmacological intervention
Liu et 44/44 Supraten Propofol/ Rescue TEAS multipoint 30 VAS on Pain lower in NA PONY, Total 5
30
al torial sufentanil analgesia min before POD 1, 2,3 TEAS group on respiratory sufentanil
cranioto : anesthesia induction POD1 but it was depression consumption
my Sulfentan up to surgery higher on : NS intra and
il completion vs POD2& 3 postoperativ
100μg/50 placebo ely lower in

This article is protected by copyright. All rights reserved.

ccepted Articl ml
(1ml/h)
TEAS group
Intraoperativ
e
hemodynami
cs and BIS:
NS
An et 45/43 Supraten Sevofluran PCA EA stimulation via a VAS at VAS up to 6h Total and effective PONV: NS Better 4
31
al torial e/ fentanyl LH202H HANS 1,2,3,4,6, lower in EA PCA bolus up to 6h Dizziness, appetite up
cranioto sufentanil 10μg/kg acupuncture point 24, 48 hrs group reduced (EA) feeling of to 24 hrs
my nerve stimulator postop Total fentanyl use: full head (EA)
before anesthesia NS up to 24 h
induction vs placebo reduced
(EA)
PCA, patient control analgesia; EA, electroacupuncture; VAS, visual analogue scale; VRS, verbal rating scale; NRS, numerical rating scale; sc, subcutaneous; iv,
intravenous; 95%CI, 95% confidence interval; preop, preoperatively; postop, postoperatively; SCPB, Superficial cervical plexus block; civ, continuous intravenous infusion;
im, intramuscularly; SE, standard error; bpm, beats per minute; GCS, Glasgow Coma Scale; SatO 2, arterial oxygen saturation; OR, odds ratio; N/A, not assessed; TEAS,
electrical acupuncture stimulation; NR, not reported; IS, infiltration of incision site; SpO2, pulse oximetry; BIS, Bispectral Index; OR, operating room

This article is protected by copyright. All rights reserved.

 Table 2. Critical appraisal of risk bias of the included studies
Study ID Allocation Blinding of Blinding of Incomplete Selective Other Random
Accepted Article
concealmen investigator outcome outcome reporting bias sequence

t (selection s and assessment data (reportin generation

bias) participants (detection (attrition g bias) (selection

(performanc bias) bias) bias)

e bias)

Randomized control studies involving systemic pharmacological intervention

Na et al low high high low unclear high high

Morad et al low low high unclear low high low

Hassani et al high high high low high unclear high

Rahimi et al high high high low low unclear high

Gunes et al high high high low unclear unclear high

Misra et al low low low low low low low

Shimony et al low unclear low low low unclear low

Williams et al low low low low low low low

Yadav et al low low low low low unclear low

Molnar et al low low low low low unclear low

Peng et al low low low low low low low

Rajan et al low low high low unclear unclear low

Song et al low unclear high low low unclear low

Peng et al low low low low low low low

Randomized control studies involving scalp infiltration or scalp block

Song et al low low low low low low low

Hwang et al low low low low low low low

Jayaram et al low high high low low unclear low

Randomized control studies involving no pharmacological intervention

Liu et al low low low low unclear unclear low

An et al high low low low low unclear high

This article is protected by copyright. All rights reserved.

Accepted Article

This article is protected by copyright. All rights reserved.