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Clonidine premedication for postoperative analgesia in children

  1. Paul Lambert1,
  2. Allan M Cyna1,*,
  3. Nicholas Knight2,
  4. Philippa Middleton3

Editorial Group: Cochrane Anaesthesia, Critical and Emergency Care Group

Published Online: 28 JAN 2014

Assessed as up-to-date: 21 DEC 2012

DOI: 10.1002/14651858.CD009633.pub2


How to Cite

Lambert P, Cyna AM, Knight N, Middleton P. Clonidine premedication for postoperative analgesia in children. Cochrane Database of Systematic Reviews 2014, Issue 1. Art. No.: CD009633. DOI: 10.1002/14651858.CD009633.pub2.

Author Information

  1. 1

    Women's and Children's Hospital, Department of Women's Anaesthesia, Adelaide, South Australia, Australia

  2. 2

    Royal Adelaide Hospital, Department of Anaesthesia, Adelaide, SA, Australia

  3. 3

    The University of Adelaide, ARCH: Australian Research Centre for Health of Women and Babies, The Robinson Institute, Discipline of Obstetrics and Gynaecology, Adelaide, South Australia, Australia

*Allan M Cyna, Department of Women's Anaesthesia, Women's and Children's Hospital, 72 King William Road, Adelaide, South Australia, 5006, Australia. allan.cyna@health.sa.gov.au.

Publication History

  1. Publication Status: New
  2. Published Online: 28 JAN 2014

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Characteristics of included studies [ordered by study ID]
Bergendahl 2004

MethodsRandomized, double-blinded, controlled clinical trial


ParticipantsASA I patients, age 1-11 years, for adeno-tonsillectomy
One hundred and four (104) children enrolled; 100 participated (48 in clonidine group, 52 in midazolam group)
Four patients excluded (refusal to accept rectal premedication, unexpected severe haemorrhage (>15% of calculated blood volume, requiring blood transfusion), surgery cancelled due to severe post-intubation bronchospasm, refusal to accept mask induction)


InterventionsGroup C: clonidine 5 ug/kg/atropine 40 ug/kg rectally, 30-60 min pre-induction
Group M: midazolam 300 ug/kg/atropine 40 ug/kg rectally, 30-60 min pre-induction


OutcomesPain by Objective Pain Scale (Hannallah 1992) at 0, 30, 60, 90, 120 min; then during first 24 hours by parents (pain and paracetamol requirements); sedation at same time points
Shivering and vomiting reported in text as present or absent

Confusion score at same time points, but summed and presented as one number


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomized by computer-generated list

Allocation concealment (selection bias)Low riskText states: "Both patients and investigators were blinded with respect to the randomized treatment and the study code was opened once the entire study was concluded."

Blinding (performance bias and detection bias)
All outcomes
Low riskPerson responsible for participants care, participant and outcome assessor all blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskOnly 4 patients were excluded, each for a different reason

Selective reporting (reporting bias)Unclear riskNone evident

Other biasLow riskNo other obvious source of bias; control and experimental patient characteristics appear similar

Cao 2009

MethodsRandomized, double-blinded, controlled trial


ParticipantsASA I-II patients, aged 2-8 years, undergoing ventriculoperitoneal shunt insertion
Forty-five (45) children: 15 in each of two clonidine groups; 15 in midazolam group
Excluded any children who refused or spat out the medication
Other exclusion criteria: abnormal liver function, renal and mental disease


InterventionsGroup C2: clonidine 2 μg/kg, orally
Group C4: clonidine 4 μg/kg, orally
Group M: midazolam 0.5 mg/kg, orally
All medications given in 5 ml of syrup, 60 min pre-induction


OutcomesMain outcomes of study were: preoperative sedation, mask acceptance, separation from parents; also included postoperative analgesia, haemodynamic status and adverse effects (hypotension, bradycardia, respiratory depression, nausea/vomiting, shivering)
Pain is reported as whether or not rescue analgesia was required postoperatively


NotesRescue analgesia was given in the cases of child complaints of pain, frequent crying, or dysphoria after operation; analgesia was via a rectal loading dose of paracetamol of 30-40 mg/kg


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskTrial is described as "Randomized" but no description of this given

Allocation concealment (selection bias)Unclear riskNo details given

Blinding (performance bias and detection bias)
All outcomes
Unclear riskUnclear as to whether the person responsible for the patient's care, or the patient, were blinded. Outcome assessor appears to have been blinded

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskChildren who spat out drug were excluded but no details on frequency of this

Selective reporting (reporting bias)Unclear riskNone evident

Other biasLow riskNo other obvious source of bias; control and experimental patient characteristics appear similar

Fazi 2001

MethodsRandomized, double-blinded, controlled clinical trial


ParticipantsASA I-II children, 4-12 years old, scheduled for tonsillectomy with or without adenoidectomy. One hundred and thirty-four (134) children enrolled (64 in clonidine group; 70 in midazolam group)
Trial excluded patients with: hypertension, CNS disorders, obesity (weight > 95th percentile for age), GI disorders affecting drug absorption, those with previous reactions to clonidine or benzodiazepines


InterventionsClonidine 4 ug/kg to 300 ug max, 60-90 min pre-induction
Midazolam 0.5 mg/kg to 15 mg max, 30 min pre-induction


OutcomesPain assessed using Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS) (Beyer 1990; Tyler 1993) on admission to the PACU and then each 15 minutes for the first hour (maximum score recorded)
Morphine dose in PACU (given if CHEOPS score ≥ 8)
Emesis
Supplemental oxygen given in PACU
Actual discharge time (PACU and hospital)

Excitement score in PACU
Discharge readiness time (PACU and hospital)
Unanticipated hospital admission
Return to baseline preoperative activity
Number of parents not completely satisfied


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated random number table

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
Low riskDescribed as "Double blind"; design of experiment, with drugs formulated to identical volumes by pharmacist, strongly implies that the anaesthetist and patient were also blinded. Outcome assessor blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo patients appear to have been excluded

Selective reporting (reporting bias)Unclear riskNone evident

Other biasLow riskNone apparent; group demographics appear similar

Georgiou 1999

MethodsControlled trial


ParticipantsSixty (60) children, aged 6-12 years, undergoing minor surgical procedures. No information in abstract as to how these were divided


InterventionsExperimental group: clonidine 4 μg/kg orally, plus atropine
Control group: atropine only


OutcomesPain by Visual Analogue Scale at 1, 3 and 6 hours postoperatively

Need for analgesia


NotesAbstract does not report pain scores; only reports numbers of children needing analgesia at 1, 3 and 6 hours


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information available

Allocation concealment (selection bias)Unclear riskNo information available

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information available

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo information available

Selective reporting (reporting bias)Unclear riskNo information available

Other biasUnclear riskNo information available

Hackmann 2003

MethodsRandomized, double-blind, controlled trial


ParticipantsHealthy adolescent patients scheduled for orthognathic surgery. Forty-six (46) consecutive patients considered eligible; excluded 7 as below, leaving 19 for the clonidine group and 20 for the placebo group
Exclusion criteria: significant heart disease that contraindicated the use of controlled hypotension, medically important liver or kidney dysfunction, allergy to clonidine, allergy or contraindication to the use of labetalol or β-blocking drugs, weight heavier than 80 kg, and inability to comply with the protocol, i.e., a language barrier
Excluded 6 patients (patient refusal, language barrier, or weight heavier than 80 kg). One patient who had initially consented to participate refused to take the study drug, and his data were not included in the analysis


InterventionsExperimental group: clonidine 5 μg/kg orally at bedtime the night before surgery and 90 min prior to induction (rounded to nearest 50 μg)
Control group: identical-looking placebo at the same times


OutcomesMorphine or codeine given in PACU
PACU length of stay
Haemodynamic values before surgery and at induction

Preoperative sedation
Temperature
Time to arrival in PACU
Time to eye opening
Time to movement to command
Extubation


NotesPrimary outcome of this study was controlled hypotension perioperatively, but also reported on analgesic requirements postoperatively; note that fentanyl was given intraoperatively to control BP (different amounts to each group)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomization by hospital pharmacy using a table of random numbers

Allocation concealment (selection bias)Low riskCommunication with Dr. Hackmann: "Only the pharmacists knew to which study group the patients were assigned." "The randomization code did not have to be broken for any of the study participants." "Only after all patients had completed the study were the assignments revealed to the authors so that statistical analysis could be performed."

Blinding (performance bias and detection bias)
All outcomes
Low riskExplicitly states that "the patients, investigators, surgeons, and nurses involved in the patients’ care were blinded to the nature of the assignment ".

Incomplete outcome data (attrition bias)
All outcomes
Low riskAppears to be satisfactory; 7 out of 46 patients excluded for various reasons (distribution between groups not stated)

Selective reporting (reporting bias)Unclear riskNone evident

Other biasLow riskNone considered to be significant. Height in control group slightly less than that in clonidine group (159 ± 6.9 versus 166 ± 10.4, P=0.02) but no difference in weight or other demographical and surgical characteristics

Kuvaki 1998

MethodsRandomized controlled trial


ParticipantsASA I-II children from 2-10 years old, undergoing inguinal hernia repair. Forty children divided into two groups of 20
No exclusion criteria given


InterventionsExperimental group: clonidine 2.5 μg/kg
Control group: midazolam 0.5 mg/kg
Premedications given rectally 30 min before the procedure


OutcomesPain as judged by a parental pain rating scale from 0-3
Level of sedation

Mask acceptance


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskSealed envelopes drawn at random from a box

Allocation concealment (selection bias)Low riskContents of the envelope read by an independent doctor, who administered the treatment as read and had no other involvement in the study

Blinding (performance bias and detection bias)
All outcomes
Low riskInvestigators, patients and parents all blinded (information from original publication and from correspondence with Dr. Kuvaki)

Incomplete outcome data (attrition bias)
All outcomes
Low riskOnly one patient excluded

Selective reporting (reporting bias)Unclear riskNone evident

Other biasLow riskNone evident; group demographics appear similar

Mikawa 1996

MethodsRandomized, placebo-controlled trial; anaesthetists, patients and observers blinded to treatment


ParticipantsASA I children from 5-12 years old, undergoing minor surgery (ophthalmic, otological or urological). Ninety (90) children divided into 3 groups of 30: one group for placebo, the others for two different doses of clonidine
No exclusion criteria given


InterventionsClonidine 2 μg/kg or
Clonidine 4 μg/kg or
Control: placebo
All premedications given in apple juice, 105 min before estimated time of induction of anaesthesia. Atropine 0.03 mg/kg in apple juice given to all children 60 min before estimated time of induction


OutcomesPain by Objective Pain Scale; presented as overall highest OPS score
Number of children requiring rescue analgesia (diclofenac suppository) in the first 12 hours after surgery
Number of children pain-free in the first 12 hours after surgery
Sedation score

Perioperative vital signs also recorded at various points throughout course of anaesthesia, surgery and recovery
Time to extubation
Time to eye opening
Time to obeying commands
Postoperative recovery score (Aldrete) on return to ward


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStates "randomized" but method not given

Allocation concealment (selection bias)Unclear riskNot given

Blinding (performance bias and detection bias)
All outcomes
Low riskAnaesthetist and observers blinded to group assignment; premedication or placebo given to patient in apple juice so patient appears also to have been blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients appear to have been included

Selective reporting (reporting bias)Unclear riskNone evident

Other biasLow riskNone evident; patient demographics and types of surgery are evenly distributed among between groups

Nishina 2000

MethodsRandomized, placebo-controlled trial; anaesthetists, patients and observers blinded to treatment. Rectal or intravenous medications for different study arms were prepared and administered by an anaesthetist who had no other involvement in either in anaesthesia or data collection


ParticipantsASA I children from 2-12 years old, undergoing ophthalmological surgery. One hundred and twenty five children were allocated to 5 groups of 25
No exclusion criteria given


InterventionsOral placebo followed by rectal diclofenac 2 mg/kg
Oral placebo followed by intravenous flurbiprofen 1 mg/kg
Oral clonidine 4 μg/kg alone
Oral clonidine 4 μg/kg followed by rectal diclofenac 2 mg/kg
Oral clonidine 4 μg/kg followed by intravenous flurbiprofen 1 mg/kg

Clonidine given 105 min before estimated time of induction; diclofenac and flurbiprofen given immediately post-induction


OutcomesPain by modified Objective Pain Scale (OPS) (blood pressure component removed to avoid confounding by clonidine's antihypertensive effect; presented as overall highest OPS score
Number of children requiring rescue analgesia (diclofenac suppository) in the first 12 hours after surgery
Number of children pain-free in the first 12 hours after surgery
Postoperative nausea and vomiting

Time to extubation
Time to eye opening
Time to obeying commands
Postoperative recovery score (Aldrete) on return to ward


NotesFor the purposes of comparison, we have pooled the diclofenac/placebo and flurbiprofen/placebo groups together, and compared these to the pooled diclofenac/clonidine and flurbiprofen/clonidine groups


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStates only "were randomly allocated".

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
Low riskReport states that "the individual anaesthetist ... was blinded to the group assignment ". Pain was rated by an "independent observer" and other postoperative variables were recorded by nurses and anaesthetists blinded to group assignment

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo exclusions given: all patients appear to have been included

Selective reporting (reporting bias)Unclear riskNone evident

Other biasLow riskNo evident other bias; demographic characteristics appear evenly distributed across groups

Qteshat 2011

MethodsMainly unclear: states only "double blind randomized study" without giving further details of design


Participants54 children, age 6-14, presenting for tonsillectomy; no data relating to age or gender, but states that there were no statistically significant differences between study arms. Divided into equal groups; no exclusion criteria given


InterventionsClonidine 4 μg/kg versus midazolam 0.5 mg/kg


OutcomesTime to first analgesia postoperatively, in minutes


NotesAlso states that there was no difference in morphine use between groups and no clinically significant episodes of hypotension or bradycardia, but that the mean intraoperative blood pressure was lower in the clonidine group; however, no data were presented for any of these outcomes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskStates only "double-blind randomized study" without giving methods for achieving this

Allocation concealment (selection bias)Unclear riskNot stated

Blinding (performance bias and detection bias)
All outcomes
Unclear riskSee "Random sequence generation".

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo data on excluded/lost data

Selective reporting (reporting bias)High riskTime to first analgesia is not explicitly stated as an outcome in the Methods section; however, the Methods section does not refer to any intended outcomes relevant to this meta-analysis

Other biasUnclear riskStates no statistically significant difference in age and gender between groups, but no details of this or other baseline characteristics given

Reimer 1998

MethodsRandomized, controlled, double-blinded study


ParticipantsASA I-II children from 7-12 years old, undergoing adenotonsillectomy. 41 enrolled but only 36 in final analysis. Removals due to breach of protocol (3); inability to cooperate with VAS due to ADD (1) and bronchospasm on extubation requiring adrenaline nebuliser (1)
Exclusions: inability to understand English, contraindications to any of the medications in the study, obesity (weight > 90th percentile by nomogram), inability to use a visual analogue scale, use of any preoperative sedative, hypnotic or analgesic medications


InterventionsClonidine group: clonidine 4 μg/kg orally to maximum 200 μg, 60-90 min preoperatively; then intravenous placebo immediately post-induction
Fentanyl group: placebo orally, 60-90 min preoperatively; then intravenous fentanyl 3 μg/kg immediately post-induction


OutcomesPatients receiving morphine (0.05 mg/kg) in PACU
Total morphine given
Number of morphine doses given
Number receiving codeine and/or paracetamol (acetaminophen) in day care unit
Vomiting within 24 hours
Use of analgesia post-discharge

Excessive sedation

Also measured preoperative anxiety and sedation scores, satisfaction scores, and vital signs


NotesLocal anaesthetic infiltration of tonsillar bed by surgeon prior to incision


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated random numbers, done by pharmacy

Allocation concealment (selection bias)Low riskSealed envelopes. Randomization code kept by pharmacy; also held in sealed envelopes by one investigator in case the information was needed after hours

Blinding (performance bias and detection bias)
All outcomes
Low riskAll parties, including anaesthetist, patient, and observer blinded

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients included in the analysis

Selective reporting (reporting bias)Unclear riskNone evident

Other biasLow riskNone apparent; patient demographics and surgery type distributed evenly between groups

Schmidt 2007

MethodsRandomized open-label trial


ParticipantsASA I-II children, 7-12 years old, undergoing general or combined general/regional anaesthesia for various surgeries. Sixty (60) children enrolled (clonidine 18; dexmedetomidine 20; midazolam 22)
Exclusions: chronic pain, cerebral palsy, autism, difficulty understanding verbal commands, preoperative use of analgesics or anticonvulsants, pre-anaesthesia medications prior to evaluation


InterventionsExperimental group (1): clonidine 4 μg/kg orally, 90 min before surgery
Experimental group (2): dexmedetomidine 1 μg/kg transmucosally, 45 min before surgery
Comparison group: midazolam 0.5 mg/kg orally, 30 min before surgery


OutcomesPain by verbal pain scale (reported as categorical data: numbers with none, mild, moderate or severe pain)
Pain by visual analogue scale (categorically as none-mild and moderate-severe, and as continuous data for average score)
Sedation
Anxiety
Time to discharge from PACU

Recovery time
Mean arterial pressure and heart rate


NotesChildren received regional blocks pre-incision according to routine: individual numbers not specified but overall rates of blockade for each treatment group given as a percentage

The data from the dexmedetomidine group have not been included in this review


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated random list

Allocation concealment (selection bias)Low riskDescribed as concealed by communication with principal author

Blinding (performance bias and detection bias)
All outcomes
High riskOpen-label study

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants' data analysed

Selective reporting (reporting bias)Unclear riskAnalgesic use was reportedly recorded, but this does not appear in Results section

Other biasUnclear riskNone evident; patient demographics, type of surgery, and use of regional anaesthesia evenly distributed between groups

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Akin 2010Compares caudal bupivacaine, caudal bupivacaine plus caudal clonidine, and caudal bupivacaine plus intravenous clonidine in children 2-8 years old having orchidopexy or inguinal hernia surgery. However, clonidine is given post-induction, not as a premedication (premedication was with midazolam in all children)

Almenrader 2007aCompares oral and nasal clonidine only; no clonidine-free control. Does not measure pain or related variables

Almenrader 2007bMeasures several outcomes including agitation and parental satisfaction, comparing clonidine to midazolam, but does not measure pain or analgesic use

Cao 2011Compares intrathecal bupivacaine, intrathecal bupivacaine plus intrathecal clonidine, and intrathecal bupivacaine plus intravenous clonidine in children 6-8 years old having orthopaedic surgery. However, intravenous clonidine is given post-induction, at the time of subarachnoid block placement

Constant 2004Compares midazolam and clonidine as premedication, measures only agitation, BIS and EEG parameters, not pain or its associated outcomes

De Kort 2007Measures emergence agitation, not pain. Also, clonidine is given intravenously, post-induction

Freeman 2002Measures pain and analgesic use after tonsillectomy/adenoidectomy, but clonidine is given intramuscularly following induction, not as a premedication

Fujii 2000Compares clonidine to diazepam in children having surgery for inguinal hernia or phimosis, but measures only haemodynamic response to extubation, not pain or related outcomes

Ghai 2010Measures effect of intravenous clonidine on emergence agitation after cataract surgery. Although it uses the Pain Discomfort Score this is modified (items 3-5 only) to assess agitation, and patients without an effective regional block are excluded from the analysis

Gulhas 2001Compares clonidine with placebo as premedication but measures only postoperative nausea and vomiting

Gulhas 2003Measures postoperative nausea and vomiting with clonidine versus placebo, but not pain

Handa 2001Measures postoperative nausea and vomiting with clonidine versus diazepam, but not pain

Jatti 1998Compares clonidine with diazepam premedication but measures only psychomotor function, which does not include pain or its surrogates

Kihara 2000Compares clonidine premedication with placebo, but measures MAC-awake, not pain or its surrogates

Lankinen 2006Clonidine, tropisetron or placebo given intravenously post-induction, not as a premedication. Modified pain scale used to assess specifically agitation (although time to first dose of oxycodone is reported - no difference between groups)

Mikawa 1993Clonidine versus diazepam; reports preoperative anxiolysis, mask acceptance, separation from parents, haemodynamic responses to tracheal intubation; no report of pain or analgesic use

Mikawa 1995Clonidine versus placebo or diazepam; assesses nausea and vomiting, not pain

Nishina 1994Compares clonidine premedication versus placebo for its effect on induction dose of thiamylal, but does not measure pain or associated events

Nishina 1995Clonidine premedication versus placebo but only measures effect on cardiovascular response to atropine; does not measure pain

Ramesh 1997Clonidine versus diazepam; assesses sedation, haemodynamic response to tracheal intubation and recovery score, not pain

Sfyra 2005Clonidine versus control given post-induction, not as a premedication

Shiga 2000Clonidine versus placebo, but looks at effect on response to intravenous adrenaline or isoproterenol; no measurement of pain or its associated events

Sumiya 2003Kinetic study looking at plasma clonidine concentrations after oral dosing

Tazeroualti 2007Modified objective pain scale used; this excludes the arterial pressure and verbal/bodily expression components of the original and is used to assess postoperative agitation, not pain

Tesoro 2005Assessed clonidine's effects on postoperative agitation following sevoflurane anaesthesia, using a modified Pain Discomfort Score. Measures were taken specifically to exclude pain as a contributor to agitation

Trevor 2012Compares clonidine and midazolam premedication, but looks only at anxiety and sedation, not pain or related variables

Yun 2003Examines the effect of clonidine given intravenously 10 minutes pre-induction, but only on sedation, separation anxiety and haemodynamic variables, not pain or its surrogates

 
Comparison 1. Clonidine versus placebo or no treatment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number requiring additional analgesia at any time postoperatively3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Any dose clonidine
3250Risk Ratio (M-H, Random, 95% CI)0.28 [0.05, 1.45]

    1.2 Low dose clonidine
145Risk Ratio (M-H, Random, 95% CI)1.0 [0.78, 1.28]

    1.3 High dose clonidine
3205Risk Ratio (M-H, Random, 95% CI)0.24 [0.11, 0.51]

    1.4 High dose clonidine, studies with lower risk of bias
2160Risk Ratio (M-H, Random, 95% CI)0.24 [0.09, 0.69]

 2 Number pain-free in PACU2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Any dose clonidine
2190Risk Ratio (M-H, Random, 95% CI)11.50 [1.55, 85.29]

    2.2 Low dose clonidine
145Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.3 High dose clonidine
2145Risk Ratio (M-H, Random, 95% CI)11.50 [1.57, 84.38]

 3 Postoperative pain score2Std. Mean Difference (IV, Random, 95% CI)Subtotals only

    3.1 Low dose clonidine
145Std. Mean Difference (IV, Random, 95% CI)0.23 [-0.40, 0.85]

    3.2 High dose clonidine
2145Std. Mean Difference (IV, Random, 95% CI)-1.11 [-1.46, -0.75]

 
Comparison 2. Clonidine versus midazolam

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number pain-free in PACU280Risk Ratio (M-H, Random, 95% CI)1.21 [0.61, 2.38]

    1.1 Low dose clonidine
140Risk Ratio (M-H, Random, 95% CI)0.92 [0.54, 1.56]

    1.2 High dose clonidine
140Risk Ratio (M-H, Random, 95% CI)1.83 [0.80, 4.18]

 2 Nausea and vomiting3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Low dose clonidine
123Risk Ratio (M-H, Random, 95% CI)0.27 [0.03, 2.51]

    2.2 High dose clonidine
3257Risk Ratio (M-H, Random, 95% CI)0.67 [0.32, 1.40]

 3 Postoperative shivering2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Low dose clonidine
123Risk Ratio (M-H, Fixed, 95% CI)0.18 [0.02, 1.44]

    3.2 High dose clonidine
2123Risk Ratio (M-H, Fixed, 95% CI)0.09 [0.01, 0.69]

 4 Time to discharge from PACU2174Mean Difference (IV, Random, 95% CI)-9.85 [-19.61, -0.09]

 
Comparison 3. High dose versus low dose clonidine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number requiring additional analgesia required postoperatively290Risk Ratio (M-H, Random, 95% CI)0.49 [0.22, 1.11]

 
Summary of findings for the main comparison. Clonidine compared to placebo or no treatment for postoperative analgesia in children

Clonidine compared to placebo or no treatment for postoperative analgesia in children

Patient or population: patients with postoperative pain
Settings: paediatric surgery
Intervention: clonidine
Comparison: placebo or no treatment

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Placebo/no treatmentClonidine

Number requiring additional analgesia at any time postoperatively - low dose clonidine867 per 1000867 per 1000
(676 to 1000)
RR 1
(0.78 to 1.28)
45
(1 study)
⊕⊕⊝⊝
low1,2

Number requiring additional analgesia at any time postoperatively - high dose clonidine558 per 1000134 per 1000
(61 to 285)
RR 0.24
(0.11 to 0.51)
205
(3 studies)
⊕⊕⊕⊝
moderate3,4

Number requiring additional analgesia at any time postoperatively - high dose clonidine, studies with lower risk of bias700 per 1000168 per 1000
(63 to 483)
RR 0.24
(0.09 to 0.69)
160
(2 studies)
⊕⊕⊕⊝
moderate1

Postoperative pain score - low dose clonidineThe mean postoperative pain score - low dose clonidine in the intervention groups was
0.23 standard deviations higher
(0.4 lower to 0.85 higher)
45
(1 study)
⊕⊕⊝⊝
low1,2
SMD 0.23 (-0.4 to 0.85)

Postoperative pain score - high dose clonidineThe mean postoperative pain score - high dose clonidine in the intervention groups was
1.11 standard deviations lower
(1.46 to 0.75 lower)
145
(2 studies)
⊕⊕⊕⊝
moderate1
SMD -1.11 (-1.46 to -0.75)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Missing information on methods of randomization and allocation concealment.
2 Single, small study.
3 Missing information on methods of randomization and allocation concealment; no information at all for Georgiou 1999 study.
4 GRADE Quality of evidence is weighted towards 'Moderate' by the two studies judged to be at lower risk of bias.
 
Summary of findings 2. Clonidine compared to midazolam for postoperative analgesia in children

Clonidine compared to midazolam for postoperative analgesia in children

Patient or population: patients with postoperative pain
Settings: paediatric surgery
Intervention: clonidine
Comparison: midazolam

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

MidazolamClonidine

Number requiring additional analgesia at any time postoperatively - low dose clonidine800 per 1000200 per 1000
(72 to 568)
RR 0.25
(0.09 to 0.71)
30
(1 study)
⊕⊕⊝⊝
low1,2

Number requiring additional analgesia at any time postoperatively - high dose clonidine800 per 1000200 per 1000
(72 to 568)
RR 0.25
(0.09 to 0.71)
30
(1 study)
⊕⊕⊝⊝
low1,2

Haemodynamic or respiratory changes requiring intervention371 per 1000204 per 1000
(115 to 360)
RR 0.55
(0.31 to 0.97)
134
(1 study)
⊕⊕⊕⊝
moderate3

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Minimal or no information on methods of randomization, allocation concealment or blinding.
2 Very low patient and event numbers.
3 Missing information on concealment of randomizations.
 
Summary of findings 3. Clonidine compared to fentanyl for postoperative analgesia in children

Clonidine compared to fentanyl for postoperative analgesia in children

Patient or population: patients with postoperative pain
Settings: paediatric surgery
Intervention: clonidine
Comparison: fentanyl

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

FentanylClonidine

Number requiring additional analgesia at any time postoperatively706 per 1000628 per 1000
(395 to 1000)
RR 0.89
(0.56 to 1.42)
36
(1 study)
⊕⊕⊕⊝
moderate1

Number requiring opioids postoperatively706 per 1000628 per 1000
(395 to 1000)
RR 0.89
(0.56 to 1.42)
36
(1 study)
⊕⊕⊕⊝
moderate1

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Single, small study.
 
Summary of findings 4. High dose clonidine compared to low dose clonidine for postoperative analgesia in children

High dose clonidine compared to low dose clonidine for postoperative analgesia in children

Patient or population: patients with postoperative pain
Settings: paediatric surgery
Intervention: high dose clonidine
Comparison: low dose clonidine

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Low dose clonidineHigh dose clonidine

Number requiring additional analgesia required postoperatively - all studies644 per 1000316 per 1000
(142 to 715)
RR 0.49
(0.22 to 1.11)
90
(2 studies)
⊕⊕⊝⊝
low1,2

Number requiring additional analgesia required postoperatively - moderate quality studies867 per 1000329 per 1000
(199 to 563)
RR 0.38
(0.23 to 0.65)
60
(1 study)
⊕⊕⊝⊝
low3,4

Postoperative pain scoreThe mean postoperative pain score in the intervention groups was
1.25 standard deviations lower
(1.8 to 0.69 lower)
60
(1 study)
⊕⊕⊝⊝
low3,4
SMD -1.25 (-1.8 to -0.69)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Missing data on methods for randomization and concealment for both studies, and on blinding and reporting rates for Cao 2009.
2 Low total numbers, especially in Cao 2009 study.
3 Missing information on randomization and allocation concealment methods.
4 Single, small study