Clonidine premedication for postoperative analgesia in children: a meta-analysis Dr Paul Lambert Dr Nick Knight ANZCA-HKCA CSM, May 14th ANZCA-HKCA CSM, May 14th 2011

Rationale for review Clonidine premedication in children Postoperative pain A problem in search of a solution Premedication ? Analgesic efficacy postoperatively Has a number of other objectives May have adverse effects Clonidine may be useful for postoperative analgesia No systematic review, specifically of clonidine's analgesic efficacy, to date

Clonidine: Background α-adrenergic agonist Preferential α2 activity Useful/desirable characteristics Analgesic Sedative Anxiolytic Administered via a variety of routes Side-effects Hypotension Bradycardia Excessive sedation

Clonidine premedication review Study aims To determine the effects of clonidine premedication, in children, on postoperative pain

Clonidine premedication review Primary Outcomes Incidence of analgesia use in recovery unit postoperative period Incidence of sedation requiring intervention

Clonidine premedication Secondary outcomes Analgesia outcomes Pain-free in PACU Requiring opioid Pain scores Time to first analgesic dose Adverse effects Hypotension or bradycardia PONV Shivering Agitation or confusion HDU or ICU admission

Literature Search Electronic databases Medline, EMBASE, CENTRAL Bibliographies of retrieved studies Search strategy linical trials - clonidine - paediatric anaesthesia - pain and other postoperative complicationsFields - clinical trials - clonidine - paediatric anaesthesia - pain and other postoperative complications

Study (Number of patients) Comparison Georgiou 1999 (60) Hackmann 2003 (39) Mikawa 1996 (90) Nishina 2000 (125) Placebo or no treatment Reimer 1998 (36)Fentanyl Bergendahl 2004 (100) Cao 2009 (45) Fazi 2001 (134) Kuvaki 1999 (40) Schmidt 2007 (60) Midazolam Clonidine premedication: Included studies

Description of Studies HeterogeneityHeterogeneity Types of comparisonsTypes of comparisons Dose and route of clonidine Dose and route of clonidine Comparator Comparator Type of surgeryType of surgery Outcome measureOutcome measure Risk of biasRisk of bias Primary Outcome MeasurePrimary Outcome Measure Additional analgesia requirement:Additional analgesia requirement: Only one study (Riemer 1999) explicitly separates analgesia use in recovery unit from use on ward Only one study (Riemer 1999) explicitly separates analgesia use in recovery unit from use on ward

Supplementary analgesia Clonidine (any dose) vs placebo or no treatment

Supplementary analgesia Low or high dose clonidine vs placebo or no treatment

Clonidine can replace opioid Reimer 1998 (clonidine 4 µg/kg vs. fentanyl 3 µg/kg): No difference in opioid requirement postoperatively (RR 0.89 [ ]) Hackmann 2003 (clonidine 4µg/kg vs. placebo): No difference in additional analgesia requirements postoperatively, but more fentanyl given to placebo group intraoperatively

Supplementary analgesia Clonidine 4 µg/kg vs midazolam 0.5 mg/kg

Study Clonidine dose (µg/kg) Midazolam dose (mg/kg) Route Outcome measures Favours Bergendahl RectalOPSClonidine Cao 20092, 40.5Oral Analgesia use Clonidine Fazi Oral CHEOPS Time to first analgesia Midazolam Kuvaki Rectal Pain score parental rating Neither Schmidt Oral VAS or VNRS No. pain free Clonidine Clonidine vs midazolam

Adverse effects No study reported excessive (hazardous) sedationNo study reported excessive (hazardous) sedation Low incidence ofLow incidence of BradycardiaBradycardia HypotensionHypotension (Note: Bergendahl 2004, Georgiou 1999, Kuvaki 1998, Mikawa 1996, Nishina 2000 all gave atropine prophylaxis)

Study limitations Heterogeneity between studiesHeterogeneity between studies Inverse correlation of pain scores with sedation scores – are we looking at analgesia or sedation?Inverse correlation of pain scores with sedation scores – are we looking at analgesia or sedation?

Implications for practice Clonidine premedication at adequate dose does appear to lower analgesia requirements postoperatively in children Low incidence of serious side-effects

Future work Either small studies, each tailored to a particular type of surgery… …or a large trial with subgroup analysis Multiple outcome measures

Acknowledgements Formal project supervisorFormal project supervisor Allan M CynaAllan M Cyna Co-investigatorsCo-investigators Philippa MiddletonPhilippa Middleton Nicholas KnightNicholas Knight Other assistanceOther assistance T. HackmannT. Hackmann B. KuvakiB. Kuvaki E. ReimerE. Reimer A. SchmidtA. Schmidt Cochrane Collaboration Cochrane Collaboration

Thank you Any questions?