Comparative analysis of opioid use in sickle cell crisis in an urban facility in Ghana

Abstract 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 5 mg 4 hourly to intramuscular pethidine 75 mg 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 6 h, 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 72 h 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.

Unfortunately, certain barriers limit the effective use of these opioids. First, there are concerns from healthcare workers, family members and even the patients related to the possible side effects, the development of tolerance associated with chronic use, and the risk of dependence/addiction. In the USA, pethidine and morphine are categorized as schedule II for controlled substances. This classification indicates their level of addiction potential [8].
The acute pain of SCD is sometimes difficult to treat [9]. There are different views on the treatment of the pain, which have to do with the suitability of opioids, and which is preferred, the efficacy of parenteral administration, and the risk of dependence on opioids.
This study compared parenteral pethidine and morphine in the elimination/reduction of the acute pain of vaso-occlusive crises (VOC) in adult SCD patients. We tested the hypothesis 'There is no difference between morphine and pethidine in time to achieving sustained pain relief and their safety profiles in adult SCD patients with an acute pain crisis' .

METHODS
The study was an open randomized comparative study of parenteral Morphine and Pethidine in adult (18 years and above) Sickle Cell Disease patients presenting to the Korle Bu Polyclinic. Previous studies suggest that morphine is more effective in relieving pain crises than pethidine [9,10].
All consenting adult sickle cell patients in acute pain crisis, with a minimum pain score of 7 on the McCaffery et al Pain Scale [13] during the period of the study were included. is, the proportion of participants whose admission pain reduced from a rating of at least seven to a level three or below (and remained so continuously for 24 h) within 72 h following the commencement of the analgesia. Secondary outcome measures were, the time taken for the initial pain to reduce by a margin of at least 2 within a 6-h period (even if the pain went up thereafter), as well as the incidence of adverse events in the two treatment groups. The time interval for the complete resolution of crisis between the two arms was measured.
Operative definitions derived for the purposes of this study. They  (Table 1).

RESULTS
There were a total of 82 participants, aged 18 to 47 years. The median age 25.0 years (SD-6.3years) and 42 (51.2%) were males. Sixty-seven (81.7%) of the participants were SS phenotype; the remainder were SC.
The proportions of haemoglobin phenotype in the age categories did not differ significantly from each other at the 0.05 level (  A total of 23 side effects were experienced in 21 participants. More pethidine participants experienced side effects 12 (29.3%) compared to those in the morphine arm 9 (22.0%) ( Table 3). However, the difference was not statistically significant, p = 0.448.
The commonest side effects were generalized pruritus, nausea and vomiting and headaches (Table 4).  to the treatment when the patient was pain-free (Table 5). It is interesting to note that the dose of analgesia had to be increased in more participants in the morphine arm, nine of 13 participants between patients and the dose of morphine needed to treat pain [15].
In this study, side effects were experienced 23 times affecting 21 participants (25.6%), 14 (60.9%) in the pethidine arm and 9 (39.1%) in the morphine arm. The side effects manifested were pruritus, nausea/vomiting, headaches, dizziness/drowsiness and seizures. There were no significant differences between the two analgesics in terms of whether a side effect was observed or not, p = 0.448. Neither was there any difference in what the specific type of side effect experienced was; Benyamin et al. found constipation and nausea to be the most common adverse effects, and this led to dropouts in controlled trials [16]. This observation partially conformed to the current study, but there were no dropouts. Another study whose findings somewhat conformed to the current study was the Huse et al. study, which found out that the most common adverse events were nausea (33% opioid versus 9% control) and constipation (33% opioid versus 10% control), followed by drowsiness (29% opioid versus 6% control) and vomiting (15% opioid versus 3% control) [17]. However, the findings of the current study were in disparity to that of Dellemijn et al. in which the researchers reported a high incidence of sweating, anorexia, and clouded vision [18]. This finding of the current study is supported by Smith who suggested that when these side effects occur, they are largely manageable [19].
In the Trinidad and Tobago study also, one of 82 admissions had an episode of seizure, but the authors could not exactly attribute it to the pethidine given [14].
For the other three participants in the current study, their analgesia had to be discontinued while in the study because the side effects were not tolerable. Two were in the morphine arm and the third in the pethidine arm. It is reassuring to observe that the two analgesics have comparable side effect profiles managed with similar interventions. Even more, these side effect profiles are generally safe and largely fleeting.
The advantage of combining paracetamol with opioids is the dual analgesic effect it provides. However, the combination is potentially hepatic toxicity [22]. In this study, a maximum dose of 3-g paracetamol daily was used.

CONCLUSION
More morphine participants achieved a sustained pain response during compared to the pethidine participants. This difference was statistically significant. There was no significant difference in the effectiveness of pethidine and morphine in the reduction of acute pain in SCD patients within the first 72 h of initiating analgesia. Finally, there was no difference in the tolerability and side effect profile of pethidine in comparison to morphine in SCD patients presenting in VOC.