Intravenous ondansetron reduced nausea but not pruritus following intrathecal morphine in children: Interim results of a randomized, double-blinded, placebo-control trial.

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Study Design

• Prospective, double-blinded, randomized, placebo-controlled trial. Single centre in USA where intrathecal morphine (ITM) is commonly utilised.
• Ondansetron 0.1mg/kg (max 16mg) or placebo given IV just prior and q6hrly for 24 hours after ITM (4-5mcg/kg) for urological or orthopaedic surgery.
• Inclusion criteria: age 3-17 years; ≤100kg weight; able to use pain assessment tool.
• Exclusion criteria: posterior spinal fusion operations; hypersensitivity or contraindications to any anti-pruritic and anti-emetic in the study protocol; regular 5-HT₃ antagonist or SSRI use.
• Routine anti-emetics given: dexamethasone 0.15mg/kg (max 4mg) and diphenhydramine 0.3mg/kg (max 12.5mg).
• Postoperatively:
  • Treatment of pruritus: 1^st nalbuphine, 2^nd diphenhydramine
  • Treatment of PONV: 1^st prochlorperazine, 2^nd promethazine
• Power calculation suggested 56 patients in each group (total N=112) would be adequate to detect reduction in pruritus from 40% to 20%.

 

Findings

• Study was discontinued after interim analysis, by which time 45 patients had been recruited.
• Groups similar in age, weight, ASA, gender, surgery type. However, size of groups differed (active N=18 vs. control N=27) due to randomisation error.
• Primary outcome: efficacy of ondansetron as an anti-pruritic
  • Overall, 84% incidence of pruritus, with 87% of these requiring treatment.
  • No difference between groups for incidence (active 78% vs. control 89%) or treatment requirement (active 93% vs. control 83%)
• Secondary outcome: incidence of nausea
  • Significant difference (p=0.008) in incidence of nausea in active group (44%) vs. control group (85%)
• Secondary outcome: adequacy of pain relief
  • Similarly low mean pain scores in PACU (active 1.78 vs. control 1.96) and at 24h (2.30 vs. 2.25) with a high overall satisfaction of pain control (44/45).

 

Discussion

This was a well-designed study, having been a prospective, double-blinded RCT that conformed to CONSORT guidelines.

It is commendable that the authors discontinued the study after their pre-planned interim analysis, citing these two reasons:

• High overall pruritus rates with only a small difference between groups, meaning the study was very underpowered for its primary outcome.
• The large difference in PONV rates between those receiving ondansetron and those not meant withholding ondansetron from the control group was considered unacceptable.

 

The incidence of pruritus (84%) is considerably higher in this study than in previously published data (30-60%). It is important to consider nocebo and Hawthorne effects when monitoring for drug side effects. Additionally, these data reinforce that extrapolating drug effects and side effects from adult literature to paediatrics, although common and often necessary, has limitations.

 

Take Home Messages

Pruritus and nausea are common side effects of ITM use.  Treatment for these side effects is rarely unsuccessful. Administering a 5-HT₃ antagonist to patients having ITM lowers PONV rates dramatically.

 

Reviewed by Dr Falk Reinholz