Clinical trial NCT02437669
Conditions: Pain
Keywords: Intranasal Hydromorphone Pediatric Emergency department
Sponsor: Columbia University
Start date: 2015-05-01; Completion date: 2018-04-01
Enrollment: 35 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Intranasal hydromorphone has been shown to be effective in reducing acute pain in adults. It has not been previously studied in children, but may be a viable option for effectively and safely reducing pain in children by administering an analgesic by the intranasal route.

This study will be a prospective, open-label pilot study of intranasal hydromorphone in children with moderate to severe acute pain presenting to the pediatric emergency department. The investigators aim to describe the amount of pain reduction associated with intranasal hydromorphone, and to determine the optimal dose of intranasal hydromorphone associated with a clinically meaningful improvement in acute pain.

Detailed description:
Primary Aim: Determine the change in pain intensity in children with moderate to severe pain who receive intranasal hydromorphone one hour after administration.

Secondary Aim(s): Describe the incidence of minor and major adverse events associated with intranasal hydromorphone in children with acute pain.

The investigators will assess the patient's pain at baseline (prior to study drug administration), then after study drug administration: 5 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, and then every 30 minutes thereafter until 6 hours; administration of non-protocolized rescue medication administration (i.e. administered after first two rescue doses of IN hydromorphone); or discharge from emergency department (whichever comes first). The pain score at 60 minutes will be the primary outcome.

The investigators will evaluate qualitative improvement in pain intensity at 15- and 30-minutes after study drug administration. If there is no improvement, or worsening of pain intensity, at each assessment, an additional rescue dose rescue dose of intranasal hydromorphone will be administered. After 60 minutes, the treating physician may administer any additional rescue medications at their discretion to treat the child's pain.

The patient will be assessed for minor and major adverse events for the duration of the study.

Arms: arm 1: Hydromorphone, intranasal. 2 mg/mL concentration. Initial dose: 0.03 mg/kg, maximum single dose 4 mg. Rescue dose: 0.015 mg/kg, maximum single dose 2 mg.
Interventions: intervention 1: Hydromorphone
Intervention descriptions: intervention 1: To be administered by intranasal route using mucosal atomization device.

Protocol documents:
Prot_SAP_000.pdf: 
Intranasal Hydromorphone for the Treatment of Acute Pain in Children: A Pilot Study 
 
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Page 1 of 4 
Principal Investigator: Daniel S. Tsze, MD, MPH 
 
Study Purpose and Rationale: 
 
Hydromorphone is a commonly prescribed opioid analgesic that is used in both adults and children. It 
can be administered by the oral (PO) route, but is associated with poor bioavailability and slow time to 
onset of action. It can also be administered by the intramuscular (IM) or intravenous (IV) routes, but 
both require needle sticks, which children report to be their most feared medical procedure, and that 
which they find highly distressing. The intranasal (IN) route is a safe and effective way of 
administering opioid analgesics (e.g. fentanyl, sufentanil) in both adults and children. Although there 
have been studies evaluating the bioavailability, pharmacokinetics, clinical efficacy, and adverse 
events of IN hydromorphone in adults, IN hydromorphone has not been yet been studied in children. 
Given the safe and efficacious reports of IN hydromorphone in adults, and the potential benefits of 
administering hydromorphone by the IN route for children, we aim to conduct a pilot study to evaluate 
the efficacy of IN hydromorphone in reducing pain in children with acute pain who present to the 
pediatric emergency department. 
 
Study Design: 
 
This will be a pilot study, in which we will prospectively enroll a convenience sample of children who 
present with moderate to severe acute pain to the pediatric emergency department of a single 
institution. 
 
Study Procedures: 
 
The treating physician will determine if their patient fulfills inclusion criteria. If they do, the physician 
will approach the patient and family to see if they are willing to discuss the study with a member of the 
study team. If they agree, a member of the study team will determine if the patient is eligible for the 
study, and if they are, they will then approach the patient and family to discuss the study and obtain 
consent. The consent and assent process will be conducted in the patients primary language (English 
or Spanish only). Patients who are eligible for the study and have provided consent/assent will first 
have their pain intensity measured within 15 minutes prior to receiving the IN hydromorphone 
(baseline assessment). They will be monitored as per standard practice by the health care providers 
in the emergency department for patients receiving an opioid analgesic (i.e. pulse oximetry, interval 
vital signs including blood pressure). All pain assessments will be performed using the Faces Pain 
Scale – Revised (FPS-R) and verbal Numeric Rating Scale (vNRS) by a research assistant, 
coordinator or study team physician. A nurse will administer the IN hydromorphone using a mucosal 
atomization device: this is Time 0. Immediately after the medication is administered, the patient will be 
asked to report how much pain or discomfort they experienced with the administration (also using the 
FPS-R and vNRS). The patient will have their pain assessed at the following time points: 5 minutes, 
15 minutes, 30 minutes, 45 minutes, 60 minutes, and then every 30 minutes thereafter until 6 hours, 
the patient is discharged from the emergency department, or a non-IN hydromorphone rescue 
analgesic is administered (see following paragraph regarding first and second rescue medication 
assessments at 15- and 30-minutes). This non-IN hydromorphone rescue analgesic will be 
considered after 60 minutes, and its administration will be determined at the discretion of the primary 
attending physician. If a non-IN hydromorphone rescue analgesic is administered, the time when it 


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was given will be recorded. The attending physician may administer an analgesic of their choice as a 
rescue analgesic (e.g. IV hydromorphone, IV morphine) as per standard practice.  
 
At the 15- and 30-minute marks, the patient will undergo a first and second rescue IN hydromorphone 
assessment. They will be asked if their pain is, “much less, a little less, the same, or worse” 
compared to before they received the IN hydromorphone. If they reply, “the same”, or “worse”, they 
will receive an additional rescue dose of IN hydromorphone at 0.015 mg/kg, maximum single dose of 
2 mg. We will also ask the patient, " "Do you want more medicine to make your pain less?", as 
patients who report that their pain is "a little less" or "a lot less" may still not have achieved adequate 
pain relief, and this deficit will not be identified without asking this specific follow-up question to 
confirm adequacy of pain relief. Intranasal hydromorphone has been shown to reliably produce 
adequate analgesia by 10 minutes when an adequate dose has been administered. Therefore, 
determining whether additional analgesia is required at 15 minutes is a reasonable amount of time to 
wait after administering a dose of IN hydromorphone to see if a patient experienced any improvement 
in pain intensity. This methodology has been used in prior pilot studies of analgesics, to prevent 
patients from receiving inadequate analgesia if the initially selected dose was not sufficient, and so 
that an effective dose can be determined. In addition, administering additional reduced doses (i.e. half 
initial dose) after 15 minutes of receiving a dose of parenteral opioid analgesic, if there has been no 
improvement in pain intensity, is standard practice when administering IV opioid analgesics as part of 
typical clinical care when treating pain in children.  
 
Adverse events will be assessed and recorded by the research assistant or study investigator, in 
conjunction with the nursing staff and treating physician. These adverse events will include those 
considered minor and major. The specific adverse events being assessed are detailed on pages 8 
and 9 of the data collection form. All adverse events will be assessed every hour.  
 
Patients will receive IN hydromorphone (2 mg/mL concentration) at a dose of 0.03 mg/kg, maximum 
single dose 4 mg. This dose was obtained from prior studies demonstrating that the bioavailability of 
IN hydromorphone was 55%, and clinical studies showing that at least 4 mg was required to achieve 
clinically meaningful improvement in pain in adults, with no incidence of serious adverse events, and 
no significant difference in adverse events compared to lower doses. The usual pediatric dosing of IV 
hydromorphone is 0.015 mg/kg, so the use of 0.03 mg/kg is consistent with this demonstrated 
bioavailability of IN hydromorphone. In addition, other commonly-used IN analgesics and sedatives 
(e.g. fentanyl, midazolam, ketamine) are dosed in a similar fashion: that is, at least double (and for 
some medications, up to five times) the IV dose is used when administering the medication by the IN 
route. This dosing strategy and interpretation of the bioavailability and pharmacokinetic data for 
intranasal hydromorphone was discussed with Dr. Serge Cremers (Director of Biomarkers Core 
Laboratory of the Irving Institute for Clinical and Translational Research). 
 
Statistical Procedures: 
 
We will use descriptive statistics (mean/SD, median/IQR) to describe our patient population and their 
characteristics. Our primary outcome of median change in pain intensity will be measured using the 
Faces Pain Scale – Revised (FPS-R), a validated pain scale in children ages 4 to 17 years old, which 
allows a child to report their pain intensity on a scale from 0 (no pain) to 10 (most pain). Median 
change in pain intensity will also be measured using the verbal Numeric Rating Scale (vNRS), which 
assesses pain by asking how much pain they have on a scale from 0 to 10. We will report the median 


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change in pain intensity of our patients who receive intranasal hydromorphone. Our secondary 
outcome of adverse events will be reported using descriptive statistics, i.e. the proportion of patients 
who experienced each type of adverse events. We will also be recording the time at which rescue 
analgesics are administered, and report the results as a Kaplan-Meier curve.  For the purposes of this 
pilot study, we will enrol 40 patients, which has been previously demonstrated to be sufficient in 
similar pilot studies evaluating the analgesic efficacy of other medications. 
 
Potential Risks: 
 
The risks associated with receiving intranasal hydromorphone are the same as if administered by 
another route (e.g. intravenous). There is a chance that the patient may not experience the same 
degree of pain relief that they may have experienced if they had received intravenous 
hydromorphone. However, patients will have their pain assessed as per usual standard care, and can 
receive additional required analgesics at any point in time if their pain relief is inadequate. The 
procedures involved in this study do not increase the risk for adverse events normally associated with 
receiving hydromorphone. Potential Benefits: Provide information regarding any anticipated benefits 
of participating in this research. There should be a rational description of why such benefits are 
expected based on current knowledge. If there is unlikely to be direct benefit to participants/subjects, 
describe benefits to society. Please note that elements of participation such as compensation, access 
to medical care, receiving study results, etc. are not considered benefits of Risks, Benefits & 
Monitoring THe most common adverse events reported by patients who have received intranasal 
hydromorphone include bad taste in mouth (21%), dizziness (14%), somnolence (15%), nausea (6%), 
and vomiting (2%). Except for bad taste in mouth, the incidence of these adverse events associated 
with intranasal hydromorphone were all less than that experienced by patients who received the same 
dose of intravenous hydromorphone (Coda et al. 2003)  
 
Coda BA, Rudy AC, Archer SM, Wermeling DP. Pharmacokinetics and bioavailability of singledose 
intranasal hydromorphone hydrochloride in healthy volunteers. Anesth Analg 2003;97(1):117–23. 
 
Potential Benefits: 
 
If the treating physician was going to initiate an intravenous line for the sole purpose of 
administering a parenteral opioid analgesic to treat the child’s pain, one potential benefit is that 
receiving intranasal hydromorphone instead would spare the child a painful and distressing needle 
stick. Another benefit is that the patient may receive longer duration of analgesia than if they had 
received intranasal fentanyl, which is a commonly-administered parenteral opioid analgesic in the 
pediatric emergency department. 
 
Alternatives: 
 
An alternative to participation in this study is to choose not to participate, or to receive an opioid 
analgesic by an alternate route (e.g. oral, intramuscular, or intravenous). 
 
Data and Safety Monitoring: 
 
Data will be reviewed on an ongoing basis by the PI with each patient enrolled. On an ongoing basis, 
the investigators will monitor accrual of study subjects, assess adherence to study protocol, assess 


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data quality, and collect and review adverse events and other subject safety matters. We will submit 
to the IRB protocol deviations and any requested protocol modifications. A data safety monitoring 
board (DSMB) consisting of two physicians unrelated to the study will be formed to evaluate safety 
and adherence to the protocol (Drs. Colin Carter and Maria Kwok, Division of Pediatric Emergency 
Medicine). The first review will be conducted after the first 10 patients are enrolled, and then the 
DSMB will convene every 6 months until the study is completed. 
 
Adverse Event Reporting: An adverse event is any untoward medical occurrence by a subject. For 
each patient, the investigators will evaluate adverse events after completion of enrollment. All 
unanticipated problems (i.e. unexpected events, outcomes, or occurrences, at least possibly related 
to the research, and suggest an increase in risk of harm to subjects or others) will be reported to the 
IRB. This reporting will be done promptly, but no later than one week after the occurrence or after the 
PI acquiring knowledge of the unanticipated problem, and will also be reported at time of continuing 
review. All data will be maintained on password-protected computers and in locked file cabinets in a 
locked room to which only authorized study personnel will have access. Only approved research staff 
will view the clinical information of children enrolled in this study. We will retain study records and 
documentation for 3 years after the last enrolled patient has completed all study procedures.