Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Turan, 2016ᵃ

PS., study characteristics and results are extracted from the SR (unless stated otherwise)

SR and meta-analysis of  RCTs

Literature search up to June 2015.

A: Benhamou, 1994

B: Park, 1996

C: Owen, 1997

D: Dimou, 2003

E: Schlimp, 2011

F: Behdad, 2013

G: Turan, 2016

Study design: RCTs

Setting and Country:

USA

Source of funding and conflicts of interest:

Non-commercial funding, no conflicts of interest

Inclusion criteria SR:

“Full reports of RCTs testing the effect of systemic (IV, IM, subcutaneous, PO, TTS) alpha-2 agonists administered before, during, or after surgery, compared with placebo or no treatment in adults undergoing noncardiac surgery under general anesthesia”

Exclusion criteria SR:

- Surgery performed during sedation or locoregional anaesthesia

- N<10 per arm

7 studies included

Important patient characteristics at baseline:

No baseline characteristics presented

Describe intervention (n):

A: Clonidine PO 300 mcg 60’ PM + 300 mcg 12 h post-op (20)

B: Clonidine PO 5 mcg/kg 90’ PM + 12 h + 24 h after initial dose (20)

C: Clonidine PO 0.3/0.4 mg + Clonidine TTS 0.2 mg/24 h (14)

D: Clonidine TTS 0.3 mg/24 h + Clonidine IV 1 g/kg 10’ PM (18)

E: NR

F: NR

G: Clonidine 0.2 mg PO clonidine 2 to 4 hours before surgery, followed by 0.2 mg/d TTS clonidine 72 h post-op (303)

Describe  control (n):

A/D: Placebo (20)

B: Placebo (19)

C: Placebo (14)

E: NR

F: NR

G: Placebo (321)

End-point of follow-up:

A/B/C/D/E/F: NR

G: 72 h

For how many participants were no complete outcome data available?

(intervention/control)

A/B/C/D/E/F: NR

G: 0/0

Outcome measure-1

Defined as postoperative pain

At 24 hours, clonidine vs placebo

Effect measure: MD [95% CI]:

A: 0.10 (−1.05 to 1.25)

B: −1.40 (−2.19 to −0.61)

C: −0.20 (−1.54 to 1.14)

D: −0.10 (−1.44 to 1.24)

E: 1.10 (0.20 to 2.00)

F: −1.00 (−1.46 to −0.54)

G: 0.36 (−0.10 to 3.58)

Pooled effect (random effects model):

−0.19 (95% CI −0.86 to 0.48) favoring clonidine

Heterogeneity (I²): 80.7%

At 48 hours clonidine vs placebo

Effect measure: MD [95% CI]:

B: 0.30 (−0.39 to 0.99)

C: 0.00 (−1.41 to 1.14)

D: −0.40 (−1.61 to 0.81)

G: 0.15 (−0.66 to 0.36)

Pooled effect (random effects model):

−0.03 (95% CI −0.40 to 0.34) favoring clonidine

Heterogeneity (I²): 0%

Facultative:

An updated meta-analysis that includes all available data does not support clonidine, providing any important postoperative analgesia. Given that perioperative clonidine does not reduce the risk of myocardial infarction or death, does not provide useful analgesia, and promotes clinically significant hypotension and bradycardia, there appears to be little indication for using the

drug prophylactically in patients undergoing noncardiac surgery.

Updated meta-analysis with limited information provided. Information on the newly added RCTs (from 2011 onwards) is lacking. No information on the quality of the RCTs is provided.

Sanchez Munoz, 2017

PS., study characteristics and results are extracted from the SR (unless stated otherwise

SR and meta-analysis of  RCTs

Literature search up to November 2014

A: Arman Taheri, 2010

B: Doak, 1993

C: De Kock, 1992

D: Dimou, 2003

E: Inomata, 1999

F: Jeffs, 2002

G: Mohseni, 2011

H: Mujahid-ul-Islam, 2012

I: Oddby-Muhrbeck, 2002

J: Park, 1996

K: Samantaray, 2012

L: Singh, 2011

M: Taghipour, 2012

N: Watanabe, 1951

O: Yadav, 2013

P: Yu, 2003

Study design: RCTs

Setting and Country: Belgium

Source of funding and conflicts of interest:

 No external funding, no conflicts of interest

Inclusion criteria SR:

RCTs involving adults (>18 y) who received systemic (IV, IM, PO, TTS) clonidine pre, per or postoperative undergoing local, regional or general anesthesia.

Exclusion criteria:

None

16 studies included in quantitative analysis

Important patient characteristics at baseline:

No mean baseline characteristics reported, only ranges

Describe intervention (n):

A: Clonidine 4 μg/kg PO pre-op 60 min before induction (30)

B: Clonidine 5 μg/kg IV pre-op 90–120 min before surgery (14)

C: Clonidine 4 μg/kg + 2 μg/kg/h IV, pre-op 30 min and per-op (100)
D: Clonidine 1 μg/kg TTS + IV, pre-op night before and 10 min before induction (20)
E: Clonidine 4.5 μg/kg PO pre-op 90 min before induction (52)

F: Clonidine 4 μg/kg IV per-op (30)

G: Clonidine 200 μg PO, 90 min before induction (42)
H: Clonidine 200 μg IV pre-op 90 min before surgery (30)
I: Clonidine 2 μg/kg IV pre-op before induction (30)
J: Clonidine 5 μg/kg PO, pre-op – 90 min before induction + post-op 12 h + 24 h (22)
K: Clonidine 3 μg/kg IV, per-op 30 min (30)
L: Clonidine 150 μg PO, pre-op 90 min before induction (25)
M: Clonidine 200 μg PO, pre-op 60-90 min before induction (15)
N: Clonidine 150 μg vs 300 μg PO pre-op 90 min before induction (42)
O: Clonidine 150 μg PO, pre-op 60 min before induction (40)
P: Clonidine 150 μg PO, pre-op 60–90 min before induction (16)

Describe control (n):

A/F/H/I/K: Placebo (30)

B: Placebo (14)

C: Placebo (100)

D: Placebo (20)

E: Placebo (52)

G/N: Placebo (42)

J: Placebo (22)

L: Placebo (25)

M: Placebo (15)

O: Placebo (44)

P: Placebo (16)

End-point of follow-up:

Not reported

For how many participants were no complete outcome data available?

(intervention/control)

Not reported

Outcome measure-1

Defined as postoperative analgesia at 24 h, clonidine vs. placebo

Effect measure: MD [95% CI]

C: -0.22 [-0.31, -0.13]

D: -0.42 [-0.76, -0.08]
K: -0.20 [-1.02, 0.62]

P: -0.28 [-0.51, -0.05]

Outcome measure-2

Sedation and anxiolysis

No quantitative analysis was performed. The following is reported:

“Data of sedation and anxiolysis were reported in 10 trials including 858 patients (402 received clonidine, 257 placebo, 196 other drugs as sufentanil, diazepam, gabapentin, midazolam, pregabalin and 3 patients were excluded). Ramsay score for sedation, OAAS, VAS score for sedation and for anxiety or sedative and anxiety score were significantly decreased in 8 out of the 10 trials.”

Author’s conclusion:

Clonidine decreases analgesic consumption at least during the first 36 postoperative hours.

In spite of the heterogeneity of the assessment methods, clonidine may have advantages in term of anxiolysis and sedation quality than the other drugs commonly used.

Demiri, 2019

PS., study characteristics and results are extracted from the SR (unless stated otherwise

SR and meta-analysis of  RCTs

Literature search up to July 2018

A: Bernhard, 1991

B: Chattopadhyay,  2013

C: De Kock, 1992

D: El-Kerdawy, 2000

E: Fehr, 2001

F: Hazra, 2014

G: Horng, 2007

H: Marinangeli, 2002

I: Mohammadi,  2008

J: Reena 2017

K: Samantaray, 2012

L: Striebel, 1993

M: Vanderstappen, 1996

N: Yin Young-Chen, 2012

Study design: RCTs

Setting and Country:

France

Source of funding and conflicts of interest:

No conflict of interest

Inclusion criteria SR:

All RCTs, including adults undergoing major surgery except cardiovascular surgery under general anesthesia

Exclusion criteria:

RCTs that selected

patients at risk of cardiovascular event

16 studies included

reporting on clonidine

Important patient characteristics at baseline:

No mean baseline characteristics reported, except ASA physical status for clonidine and dexmedetomidine studies combined

Describe intervention (n):

A: Clonidine 3.5µ/kg bolus 0.3µ/kg/h IV per-op, post-op (16)

B: Clonidine 2µ/kg bolus IV per-op (30)

C: Clonidine 4µ/kg bolus 2µ/kg/h IV per-op, post-op (100)

D: Clonidine 2-4-6µ/kg bolus IV pre-op (20)

E: Clonidine 4µ/kg bolus IV per-op (25)

F: Clonidine 1µ/kg bolus IV pre-op (20)

G: Clonidine 2µ/kg bolus IV per-op (150)

H: Clonidine 2-3-5µ/kg bolus 0.3µ/kg/h IV per-op (40)

I: Clonidine 200µ bolus PO pre-op (40)

J: Clonidine 2.5µ/kg bolus 1µ/kg/h per-op (30)

K: Clonidine 3µ/kg bolus IV pre-op (30)

L:  Clonidine 150µ/90 min bolus IV postop (30)

M: Clonidine 2µ/kg bolus IV per-op (140)

N: Clonidine 3µ/kg bolus PO, pre-op

Describe control (n):

A: Placebo (16)

B/J/K/L/N: Placebo (30)

C: Placebo (100)

D/F: Placebo (20)

E: Placebo (25)

G: Placebo (150)

H: Placebo (40)

I: Placebo (40)

M: Placebo (140)

End-point of follow-up:

Not reported

For how many participants were no complete outcome data available?

(intervention/control)

Not reported

Outcome measure-1

Hypotension (requiring the administration of a drug to correct it)

Pooled effect of 12 studies

RR 1.85 [1; 2.65] in favor of placebo. “The analyses of subgroups defined in terms of dose and type of administration revealed no differences between subgroups”.

Outcome measure-2

Hypertension (requiring the administration of a drug to correct it)

Pooled effect of 4 studies

RR 0.17 [0.02; 1.33] in favor of clonidine

“No difference was found for both preoperative and postoperative hypertension.”

Outcome measure-3

Bradycardia (requiring the administration of a drug to correct it)

Pooled effect of 11 studies

RR 1.22 [0.89; 2.24] in favor of placebo. “No differences between subgroups were identified in the subgroup analyses by dose or type of administration.”

Author’s conclusions:

Review showed a high incidence of intraoperative hypotension for clonidine (and dexmedetomidine). Bradycardia was infrequently reported.

GRADE:

Hypotension: Low

Hypertension: Low

Bradycardia: Moderate

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Fernandes 2018

Type of study:

RCT

Setting and country:

Obstetrical Department of hospital in Sao Paulo, Brazil

Funding and conflicts of interest:

None

Inclusion criteria:

ASA physical status II, age 18 years

or older, term singleton pregnancy, undergoing elective

cesarean delivery, with a Pfannenstiel incision, under spinal anesthesia

Exclusion criteria:

in the presence of labor, contraindications for neuraxial anesthesia;

contraindications for any of the drugs involved in the

study; uncontrolled high blood pressure or diabetes mellitus

in need of insulin therapy; IV psychotropic drug use; previously known malformations of the fetus; and patients with a previous history of chronic pain

N total at baseline:

Intervention: 22

Control: 20

Important prognostic factors²:

age ± SD:

I: 30.32 ± 5.72

C: 31.55 ± 5.87

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

IV Ringer’s lactate 10

mL/kg bolus during spinal anesthesia with 0.5% hyperbaric bupivacaine (15 mg), 0.02% morphine (80 μg), 0.005% fentanyl (10 μg), and clonidine 0.015% (75 μg) and spinal placebo

Describe  control (treatment/procedure/test):

IV Ringer’s lactate 10

mL/kg bolus during spinal anesthesia with 0.5% hyperbaric bupivacaine (15 mg), 0.02% morphine (80 μg), 0.005% fentanyl (10 μg), and placebo (0.5 mL of 0.9% NaCl)

Length of follow-up:

3 months

Loss-to-follow-up:

Intervention:

N (%): 0

Control:

N (%): 0

Incomplete outcome data:

Intervention:

N (%): 2 (9.1)

Reasons: not able to make contact

Control:

N (%): 1 (5.0)

Reasons: not able to make contact

Outcome measures and effect size (include 95%CI and p-value if available):

NVS pain scores (0-10), mean (in figures; therefore means are estimated):

PACU:

I: 0.3

C: 0.15

6 hours post-surgery:

I: 0.4

C: 0.3

12 hours post-surgery:

I: 0.5

C: 0.8

24 hours post-surgery:

I: 0.4

C: 0.7

48 hours post-surgery

I: 0.3

C: 0.0

Chronic pain:

No quantitative data:

“The 3-month postoperative telephone interview showed

that 22% of the patients had chronic pain at that time, with

no differences among the groups.”

Minimum sedation scores (Richmond Agitation and Sedation Scale)

I: −0.73 ± 0.45

C: −0.30 ± 0.47

P<.001

Author’s conclusion

Clonidine IV had no effect on postoperative pain in caesarean delivery. In other route of administration (intrathecal) no evidence was found either.

Kumari 2015

Type of study:

RCT

Setting and country:

Academic hospital in India

Funding and conflicts of interest:

None

Inclusion criteria:

adult cooperative patients of ASA

physical status I-II, of both sexes, between 18 to

60 years of age, scheduled for elective ENT surgery under local anesthesia

Exclusion criteria:

patients having uncontrolled hypertension,

cardiovascular/ hepatic/ renal/ endocrine

diseases, coagulation disorder or taking drugs for systemic illness, any allergy to the study drug, on anticoagulation treatment, morbid obesity

N total at baseline:

Intervention: 30

Control: 30

Important prognostic factors²:

age ± SD:

I: 34.03 ± 13.61

C: 31.33 ± 11.02

Sex:

I: 36.7 % M

C: 86.7 % M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

Sedation regime of IV midazolam 0.03 mg/ kg and

fentanyl 2 μg/kg, which was followed by bolus

clonidine administration over 10 min. Immediately after, the infusion of

clonidine was started and the surgeon administered

local anesthesia using lidocaine 2% with 1:200000

adrenaline.

Describe  control (treatment/procedure/test):

Sedation regime of IV midazolam 0.03 mg/ kg and

fentanyl 2 μg/kg, which was followed by bolus

placebo administration over 10 min. Immediately after, the infusion of placebo was started and the surgeon administered local anesthesia using lidocaine 2% with 1:200000

adrenaline.

Length of follow-up:

Loss-to-follow-up:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Outcome measures and effect size (include 95%CI and p-value if available):

Hypotension (SBP < 90 mmHg)

I: 2/30 (6.7%)

C: 0/30

Bradycardia (HR < 60 /min)

I: 1/30 (3.3%)

C: 0/30

Observers Assessment of Alertness Sedation (OAAS) score (0-5), mean ± SD

I: 2.06 ± 0.61

C: 4.80 ± 0.40

Postoperative pain in PACU,  VAS (0-10) mean ± SD

I: 1.70 ± 1.29

C: 4.46 ± 1.35

Rescue fentanyl

I: 25 mcg required for 1 patient

C: 1550 mcg required for 26 patients

Author’s conclusion

clonidine 3 μg/kg IV bolus followed by infusion of 0.3 μg/kg/hr may be used as an adjunct to conventional MAC regime of midazolam and

fentanyl for variety of ENT procedures.

Mirhosseini 2017

Type of study:

RCT

Setting and country:

Funding and conflicts of interest:

Academic grant, no conflicts of interest

Inclusion criteria:

ASA grades I and II, male and female

gender, adult patients aged 18 to 65 years, BMI < 35 kg/m2, scheduled for elective laparoscopic cholecystectomy surgery

Exclusion criteria:

history of bronchial asthma, diabetes, hypertension

(essential or secondary), severe cardiovascular

abnormalities (ischemic heart disease, valvular heart disease, and AV conduction blocks), concomitant use of

monoamine oxidase inhibitors, tricyclic antidepressants

or opioids, and allergy to clonidine

N total at baseline:

Intervention: 30

Control: 30

Important prognostic factors²:

age ± SD:

I: 36.5 ± 11.1

C: 37.1 ± 10.8

Sex:

I: 30% M

C: 16.7% M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

0.2 mg oral

clonidine 90 minutes

before induction

Premedication was performed by metoclopramide 0.1

mg/kg, midazolam 0.05 mg/kg, and fentanyl 1 g/kg. General anaesthesia was induced by thiopentone 5 mg/kg and atracurium 0.5 mg/kg. Anesthesia was maintained with isoflurane and N2O (60%).

Describe  control (treatment/procedure/test):

100 mg of Vitamin C tablet at the same time

Premedication was performed by metoclopramide 0.1

mg/kg, midazolam 0.05 mg/kg, and fentanyl 1 g/kg. General anaesthesia was induced by thiopentone 5 mg/kg and atracurium 0.5 mg/kg. Anesthesia was maintained with isoflurane and N2O (60%).

Length of follow-up:

8 hours post-surgery

Loss-to-follow-up:

Intervention:

N (%): 0

Control:

N (%): 0

Incomplete outcome data:

Intervention:

N (%): 0

Control:

N (%): 0

Outcome measures and effect size (include 95%CI and p-value if available):

Hypotension (blood pressure less than 25% of baseline or SBP less than 90 mmHg)

I: 1/30 (3.3%)

C: 0/30

Post laparoscopic shoulder pain

After emergence from anesthesia:

I: 6.4 ± 1.9

C: 7.4 ± 0.6

4h

I: 5.1 ± 2.1

C: 6.6 ± 1.2

8h

I: 3.5 ± 2.2

C: 5.4 ± 2.1

Author’s conclusion:

Administration of premedication low dose oral clonidine is not effective in preventing post laparoscopic shoulder pain. However, it is safe and effective on post laparoscopic shoulder painintensity in the first postoperative hours.

Turan, 2016

Yes

Yes

Yes

No

Not described in this updated SR, but in original publication

NA

No

Not assessed in this updated SR, but in original publication

Yes

Yes

Yes

Sanchez Munoz, 2017

Yes

Unclear

EMBASE was not searched

Yes

Yes

NA

Yes

Yes

Yes

Yes

Demiri, 2019

Yes

Yes

Yes

Yes

Details are presented in a supplementary table

NA

Yes

Yes

Unclear

GRADE method is used, but no method of assessing publication bias was provided

Yes

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

Mirhosseini, 2017

Probably no;

Reason: simple random sampling method with blocks. No further information

Probably no;

Reason: no information provided

Probably yes

Reason: Patients and data collector blinded. Blinding of other personnel is not reported.

Probably yes

Reason: No loss to follow-up

Definitely yes

Reason: All relevant outcomes were reported;

Definitely yes;

Reason: No other problems noted

LOW

Fernandes, 2018

Definitely yes;

Reason: Randomization by computer-generated random numbers table

Probably not;

Reason: not described

Probably yes

Reason: Patient, healthcare provider and outcome assessor were blinded (blinding of data collectors and analysts not reported)

Probably yes

Reason: Loss to follow-up was infrequent in intervention and control group.

Definitely yes

Reason: All relevant outcomes were reported;

Definitely yes;

Reason: No other problems noted

LOW

Kumari 2015

Probably no;

Reason: no information is provided

Probably no;

Reason: no information is provided

Probably no

Reason: Article suggests RCT is double-blinded, but no information is provided

Probably yes

Reason: no loss to follow-up reported

Definitely yes

Reason: All relevant outcomes were reported;

Definitely yes;

Reason: No other problems noted

Some concerns