An Intranasal Diamorphine Spray for Acute Pain in Children
An Intranasal Diamorphine Spray for Acute Pain in Children
Two hundred and twenty-six patients were recruited into DIASAFE between April 2010 and September 2011, all of whom received IND. One child was withdrawn from the study due to rapid transfer to theatre for surgery, making further observations impossible. Two hundred and twenty-five (191 aged 2–11 years, and 34 aged 12–<16 years) completed the study. Table 1 shows the characteristics of children included. For a number of children (56) study staff failed to follow study protocol (the majority (36) of which were due to insufficient safety observations); this was anticipated in the emergency setting and was reflected in the study sample size (226), with over 150 children completed without major protocol deviation.
The majority of children attended with fractures (80%), most of which were upper limb fractures. Burn injury was less frequent (7%). Other presentations included amputation/partial amputation, laceration and dislocation. A small number of children had a history of previous medical problems, but none were considered to be clinically relevant to the study.
Table 2 and Table 3 show concomitant medication administered before and during the DIASAFE study data collection period, respectively.
Adverse Events. There were 87 TEAEs reported by 60 patients with 26.5% (95% CI 20.9% to 32.8%) of patients reporting one or more events, 25.1% of the younger children (2–11 years), and 34.3% of the older children (12–<16) (Table 4). No events were severe or serious. Most AEs were mild (93%) except five moderate AEs in three patients (all resolved by discharge) and one event not given a severity rating (resolved by discharge).
The most common events involved the respiratory system (53 events in 45 children) including nasal discomfort (24 children) and sneezing (22 children). Nervous system disorders were reported by 11 children, the most common being an unpleasant taste (five children). Nine children reported gastrointestinal-related events (11 events, including vomiting in seven children).
The majority (88.5%) of AEs (77 events in 54 children) were considered to be causally related to treatment, and were anticipated due to the drug itself or route of administration, with the exception of three events in two children: moderate itchy eyes in one child and mild pallor and 'feeling hot' in another.
The percentage of patients experiencing an AE was higher in the older age group than in the younger (34.3% vs 25.1%).
Ten children experienced an AE after discharge from the ED, reporting 13 AEs, most of which (12) were mild. One child experienced moderate vomiting.
Any vital signs measure or reduction in GCS score that the investigator considered clinically relevant for the study was to be reported as an AE. No vital sign measures were reported as AEs.
Three children had AEs recorded that were associated with a decrease in GCS, all mild, and considered to be causally related to IND. All but one resolved within the study period, in this case the GCS value returned to normal at 50 min after dosing.
Nasal Tolerability. There were 20.4% (95% CI 15.3% to 26.2%) of patients who reported at least one nasal AE, 19.9% of the younger children (2–11 years), and 22.9% of the older children (12–<16 years) (Table 5). There were 52 mild, one moderate and one unclassified AEs related to nasal irritation reported by 46 children. The most common was itching reported by 22 patients, all considered to be mild except one (moderate). Persistent and troublesome sneezing (mild) was reported by nine patients. There were single reports of mild redness, and mild nasal discharge. The remainder of the events were classified as 'Other' (19 patients) which included instances of a single sneeze following administration. No patient reported local tenderness or swelling. No further nasal AEs were seen after discharge.
Most (45 out of 54 (83.3%)) nasal AEs occurred within 30 min of dosing, seven between 30 min and 1 h, and two started beyond 1 h of dosing. Most events (76%) resolved within 1 h (37% within 5 min), with 11% resolving later than 1 h. The remaining 13% had an unknown resolution time. The onset and resolution of AEs is consistent with the short half-life of diamorphine and its active metabolites.
The majority of patients reporting nasal events were treated with higher strength (1600 μg/actuation) spray (32 (70%)). However, there was not an increased reporting rate in patients administered two sprays per nostril versus one spray per nostril.
Results
Study Population
Two hundred and twenty-six patients were recruited into DIASAFE between April 2010 and September 2011, all of whom received IND. One child was withdrawn from the study due to rapid transfer to theatre for surgery, making further observations impossible. Two hundred and twenty-five (191 aged 2–11 years, and 34 aged 12–<16 years) completed the study. Table 1 shows the characteristics of children included. For a number of children (56) study staff failed to follow study protocol (the majority (36) of which were due to insufficient safety observations); this was anticipated in the emergency setting and was reflected in the study sample size (226), with over 150 children completed without major protocol deviation.
The majority of children attended with fractures (80%), most of which were upper limb fractures. Burn injury was less frequent (7%). Other presentations included amputation/partial amputation, laceration and dislocation. A small number of children had a history of previous medical problems, but none were considered to be clinically relevant to the study.
Table 2 and Table 3 show concomitant medication administered before and during the DIASAFE study data collection period, respectively.
Safety
Adverse Events. There were 87 TEAEs reported by 60 patients with 26.5% (95% CI 20.9% to 32.8%) of patients reporting one or more events, 25.1% of the younger children (2–11 years), and 34.3% of the older children (12–<16) (Table 4). No events were severe or serious. Most AEs were mild (93%) except five moderate AEs in three patients (all resolved by discharge) and one event not given a severity rating (resolved by discharge).
The most common events involved the respiratory system (53 events in 45 children) including nasal discomfort (24 children) and sneezing (22 children). Nervous system disorders were reported by 11 children, the most common being an unpleasant taste (five children). Nine children reported gastrointestinal-related events (11 events, including vomiting in seven children).
The majority (88.5%) of AEs (77 events in 54 children) were considered to be causally related to treatment, and were anticipated due to the drug itself or route of administration, with the exception of three events in two children: moderate itchy eyes in one child and mild pallor and 'feeling hot' in another.
The percentage of patients experiencing an AE was higher in the older age group than in the younger (34.3% vs 25.1%).
Ten children experienced an AE after discharge from the ED, reporting 13 AEs, most of which (12) were mild. One child experienced moderate vomiting.
Any vital signs measure or reduction in GCS score that the investigator considered clinically relevant for the study was to be reported as an AE. No vital sign measures were reported as AEs.
Three children had AEs recorded that were associated with a decrease in GCS, all mild, and considered to be causally related to IND. All but one resolved within the study period, in this case the GCS value returned to normal at 50 min after dosing.
Nasal Tolerability. There were 20.4% (95% CI 15.3% to 26.2%) of patients who reported at least one nasal AE, 19.9% of the younger children (2–11 years), and 22.9% of the older children (12–<16 years) (Table 5). There were 52 mild, one moderate and one unclassified AEs related to nasal irritation reported by 46 children. The most common was itching reported by 22 patients, all considered to be mild except one (moderate). Persistent and troublesome sneezing (mild) was reported by nine patients. There were single reports of mild redness, and mild nasal discharge. The remainder of the events were classified as 'Other' (19 patients) which included instances of a single sneeze following administration. No patient reported local tenderness or swelling. No further nasal AEs were seen after discharge.
Most (45 out of 54 (83.3%)) nasal AEs occurred within 30 min of dosing, seven between 30 min and 1 h, and two started beyond 1 h of dosing. Most events (76%) resolved within 1 h (37% within 5 min), with 11% resolving later than 1 h. The remaining 13% had an unknown resolution time. The onset and resolution of AEs is consistent with the short half-life of diamorphine and its active metabolites.
The majority of patients reporting nasal events were treated with higher strength (1600 μg/actuation) spray (32 (70%)). However, there was not an increased reporting rate in patients administered two sprays per nostril versus one spray per nostril.
