In a randomized, single-center, single-blinded, parallel group trial (1:1 allocation ratio), we compared the efficacy of morphine versus morphine plus IV calcium gluconate in reversal of abdominal pain due to lead poisoning in the patients who had referred with lead-contaminated opium induced lead poisoning. The study was performed in a single academic center in Kerman, Iran, between September 2017 and March 2018. The trial was submitted to and approved by Iranian Clinical Trial Registry (IRCT20171009036661N2). All patients provided informed consents before inclusion.
Trial Population
During a lead poisoning outbreak among opium users in Iran [4], all adult (older than 18 years of age) orally opium-dependent patients with blood lead levels (BLLs) higher than 25 µg/dL admitted to a single academic ER in Kerman who had acute abdominal pain were included into the trial. The referral center was in south of Iran with the highest percentage of opium abusers and dependents (17.1% and 5.3%, respectively) in the region [8]. Patients were randomly assigned into two groups (25 patients in each group) using random allocation sequence with SAS statistical software. We used sequentially numbered, sealed opaque envelopes for allocation concealment.
BLLs had been measured before ED presentation in medical clinics in an attempt to find the cause of anemia, weakness, constipation, neurological symptoms, or previous chronic abdominal discomfort. Thus, the initial impression was lead toxicity in ED, unless an acute abdomen was detected by emergency physician and general surgeons.
Patients had to be on regular opium or its natural derivatives consumption for at least three months. They were excluded from the trial if they had been suffering from mental retardation, neuropathic diseases (i.e. diabetes), chronic pain syndromes, hypertension and cardiac disorders, hypochondriasis, contraindications for calcium gluconate injection (i.e. hypersensitivity to this group of drugs), kidney stones, hypercalcemia, hypophosphatemia, pregnancy, asthma, obstructive bowel obstruction, acute abdominal symptoms and acute abdomen, any confirmed diagnosis other than lead poisoning, using psychoactive drugs, and chronic severe history of morphine sensitivity (CONSORT Diagram; Figure 1). Patients were characterized at baseline by age, sex, visual analogue scale (VAS) score, and BLL (Table 1).
Sample Size:
To provide 90% power at a 0.05 significance level (2-sided test) and to detect a VAS score difference in the primary endpoint of 10 mm (from mean of 65 to 55) on the 100-mm VAS with a standard deviation (SD) of 10 mm in a paired sample analysis, 22 patients were measured for each group. Considering 20% dropout, 25 patients were recruited in each arm.
Trial design
A flow diagram of the trial is shown in Figure 1. Our study adheres to CONSORT guidelines. The trial consisted of three time frames; an enrollment period, a blind treatment period, and 15-, 30-, and 60-minute follow-ups. During the enrollment period, patients' eligibility including high BLL, abdominal pain, and the VAS score was assessed.
Patients were randomized on admission to ED by first author using a block randomization list to two treatment arms: a slow IV morphine arm (0.1 mg/kg as the basic analgesic dose; group 1) and the same morphine dose plus 10 mL intravenous calcium gluconate 10% (intervention group; group 2). These doses were chosen based on data from previous studies [1,4]. VAS score was checked and recorded on admission and 15, 30, and 60 minutes after treatments were given in the two groups by co-authors. Changes in the VAS scores were then compared between the groups.
There was no changes to methods after trial commencement.
Measurement, efficacy and safety assessment
The VAS score was determined by each patient (0 to 100 mm) before treatment, and 15, 30 and 60 minutes after the administration of the trial medications. Safety assessment was done using cardiac monitoring, pulse oximetry, and evaluating vital signs during ED stay. There was no change to trial outcomes after the trial commenced.
Statistical Analysis
The data was analyzed using Statistical Package for Social Sciences (SPSS; IBM Corp., Armonk, N.Y., USA) software version 25 by application of Kolmogorov Smirnov, paired-samples t-test in different time intervals, One-way ANOVA, Mann Whitney U test, and chi square test. Considering significant reduction in VAS pairwise comparison in each time interval (Zero versus 15, 15 versus 30, and 30 versus 60 minutes post intervention) as the censored in event status, a log rank test (Kaplan-Meier) was run to determine if there were differences in the VAS score distribution by adding calcium to opioid prescriptions. A P value less than 0.05 was considered to be statistically significant.