TABLE 1.

Systematic reviews of pharmacological interventions

Reference, number of studies	Quality score	Focus	Main results
Bellù et al (31), 2005, n=13	7	Opioids for mechanical ventilation	Opioids resulted in reduced PIPP scores compared with the control group (WMD = −1.71, 95% CI −3.18 to −0.24) but the reduction was not deemed to be clinically significant; morphine in very preterm infants delayed time to reach full enteral feedings compared with control group (WMD = 2.10 days, 95% CI 0.35 to 3.85); opioid group showed no statistically significant differences in mortality, duration of mechanical ventilation, and long-and short-term neurodevelopmental outcomes compared with control groups
Brady-Fryer et al (32), 2004, n=35	7	Dorsal penile nerve block (DPNB), EMLA* and sucrose for reducing pain in neonatal circumcision	DPNB resulted in significantly lower HR (WMD = 35 beats/min; 95% CI −41 to −30), decreased crying time (WMD = 54%; 95% CI −64 to −44) and increased SpO2 (WMD = 3.7%; 95% CI 2.7 to 3.7) compared with placebo; DPNB resulted in significantly lower HR (WMD = −17 beats/min, 95% CI −23 to −11) and lower pain scores compared with EMLA*; DPNB resulted in a significantly decreased crying time (MD = −166 s, 95% CI −211 to −121) and lower HR (WMD = −27 beats/min, 95% CI −33 to −20) compared with sucrose; EMLA* resulted in lower facial action scores (WMD = −46.5, 95% CI −80.4 to −12.6), decreased time crying (WMD = −15.2%, 95% CI −21 to −9.3) and a lower HR (WMD = −15 beats/min; 95% CI −19 to −10) compared with placebo; minor bleeding, swelling and hematoma with DPNB; erythema and mild skin pallor with EMLA*; reported methemoglobin levels were within normal limits for the EMLA* group
Shah and Ohlsson (38), 2002, n=9	6	Premedication for endotracheal intubation	4/9 studies had evidence that premedication reduced physiological indicators of pain/distress; 4/9 studies reported significant adverse effects associated with premedication; 2/9 studies reported that premedication reduced the duration of the intubation; adverse event of chest wall rigidity was associated with fentanyl
Stevens et al (22), 2004, n=21	7	Sucrose for pain from heel lance	Sucrose significantly reduced PIPP scores compared with control group at 30 s (WMD = −1.64, 95% CI −2.47 to −0.81) and 60 s (WMD = −2.05, CI −3.08 to −1.02) after heel lance; 6 studies reported adverse events. One of these studies reported that both the placebo and sucrose; groups had decreased SpO2 compared with the control group; saturation levels recovered spontaneously
Taddio et al (30), 1998, n=11 (procedural pain, including 3 circumcision papers below)	6	Lidocaine-prilocaine cream (EMLA*) for acute procedural pain	EMLA* group had reduced crying times, reduced facial grimacing and a lower HR (WMD = −12 to −27 beats/min) for circumcision compared with placebo; inconclusive evidence for EMLA* for venipuncture, arterial puncture and percutaneous venous catheter placement
Taddio et al (29), 2000, n=3 (circumcision)			EMLA* (single dose) ineffective for heel lance pain and lumbar puncture (no significant difference between control and EMLA* groups); methemoglobin levels not different between EMLA* and placebo-treated infants (WMD = −0.11%; 95% CI −0.31 to 0.10)

^*AstraZeneca Canada, Inc. HR Heart rate; MD Mean difference; PIPP Premature Infant pain Profile; SpO₂ Oxygen saturation; WMD Weighted mean difference