Vaso-occlusive crises (VOC) is common and opioids are the treatment of choice.This study compared parenteral pethidine and morphine in the elimination/reduction of pain in acute VOC to tolerable levels. This open-label randomized study compared intravenous morphine 5mg 4 hourly to intramuscular pethidine 75mg 4 hourly. Eighty-two consenting adult sickle cell disease participants were recruited from the Korle-Bu Polyclinic. (Forty-one participants in each arm). There were 42 male and 40 female participants. Median age was 25 years. Pethidine participants totalling 31.7% (13/41) and 53.7% (22/41) in the morphine arm had a sustained response within 6h, p=0.027. In the pethidine and morphine arms 60.0% (24/40) and 62.5% (25/40) of participants respectively achieved adequate pain control within 72h of initiating therapy, p=0.296. Most participants, 96.3% (79/82) had no side effects to opioids. The commonest side effects were generalized pruritus, nausea and vomiting, and headaches. More pethidine than morphine participants experienced side effects 29.3% and 22.0% respectively; p=0.448. In conclusion, more morphine participants achieved a sustained pain response compared to the pethidine participants. There was no difference in the tolerability and side effect profile of the opioids. No participant experienced respiratory suppression.