METHODS

Study design

This randomised controlled trial compared two dosing regimens of paramedic administered nalbuphine hydrochloride (Du Pont Pharmaceuticals Limited, Letchworth Garden City, UK). Subjects in the rapid regimen group received 10 mg nalbuphine over 30 seconds, repeated once after three minutes if their pain score remained above three. Those treated with the cautious regimen received 5 mg nalbuphine over two minutes, repeated at three minute intervals if their pain score remained above three to a maximum dose of 20 mg.

Patients were asked to score their pain using a numerical rating scale (NRS) graded from 0–10, with four or higher indicating moderate to severe pain. The NRS has been recommended for use in a variety of settings,⁷ avoids under-estimation or over-estimation of pain by independent observers,⁸ and correlates well with the validated visual analogue scale.^9–12 Paramedics gave a standardised explanation of the NRS:

“On a scale of 0 to 10, with zero representing no pain and 10 being the worst pain you can imagine, what score would you give to the pain you are experiencing now?”

Patients aged 18 or over with pain scores of more than three associated with long bone injury, burns, or ischaemic heart disease were recruited. Patients not meeting the criteria for nalbuphine administration or who had previously received analgesia (other than Entonox) were excluded.

Six hundred forms identifying the regimen to be used were randomised using statistical software (SPSS, version 9.0.0, SPSS Inc, Chicago), assigned a unique number, and placed in opaque envelopes. These were distributed in consecutively numbered groups of 10 to each participating ambulance. Paramedics opened the envelope with the lowest remaining number after recruitment of each patient.

If the attending paramedic judged the patient was not too distressed, verbal informed consent was obtained. An information sheet, including a form to indicate their wish to withdraw their data from the study, was given to all patients after hospital admission. Ethics approval was obtained from the Bro Taf and North Wales Health Authority (Central and East) committees.

Sample sizes for a range of outcome variables were calculated and the largest selected for adoption. Based on a 1.74% incidence of nausea in a previous study,⁶ 152 subjects were required in total to detect a between groups difference of 10% with an α of 5% and a power of 90% (χ² test).

Outcome measures and statistical analysis

Between groups comparisons were made for homogeneity, analgesic efficacy, changes in vital signs, side effects, and for evidence of antagonism of hospital administered opioids.

Data were analysed using SPSS (version 9.0.0, SPSS Inc, Chicago, USA). The Mann-Whitney U test was used for between groups comparisons of non-parametric data. Student’s unpaired t test was used for between groups comparisons of changes in pain score and pulse rate. Fisher’s exact test was used for analysis of contingency tables. StatsDirect (version 1.9.8, CamCode, Ashwell, UK) was used to calculate p values and 95% confidence intervals for differences in proportions.

RESULTS

Recruitment

Recruitment is described in the Consort flowchart (fig 1).¹³

Heterogeneity of groups

Before nalbuphine administration there were no significant between groups differences in age, ratio of male to female subjects, on-scene time, journey time to hospital, ratio of chest pain to trauma patients, vital signs or pain scores (data available on request).

Analgesic efficacy and side effects

The rapid dosing regimen resulted in a significantly greater reduction in pain score. There were no significant between groups differences for changes in vital signs after nalbuphine. However, significantly more side effects occurred in the rapid regimen group, largely explained by a greater incidence of patient reported drowsiness (table 1).

Hospital staff reported signs of antagonism to hospital administered opioids in two patients in each group.

DISCUSSION

Rapid dosing resulted in a greater decrease in pain score. Although the difference of 0.79 is small, it represents a benefit that patients can perceive.⁸ However, over half the patients in both groups continued to suffer from significant pain before arrival at hospital.

Rapid regimen patients suffered significantly more patient reported side effects, largely accounted for by an increased incidence of patient reported drowsiness. This was not associated with significant changes in Glasgow coma scores, however, and it is suggested that drowsiness may be a beneficial effect for distressed patients.

No antiemetic agent was administered to patients during this study. The incidence of nausea or vomiting was higher in this trial (21% v 16% for rapid and cautious regimen respectively) than in a previous low dose study,⁶ suggesting a dose related effect.

Paramedics did not give the maximum dose of nalbuphine to patients continuing to report significant pain. In both groups, the total dose administered was identical for patients who achieved adequate analgesia and those that did not. This was not accounted for by differences in on-scene time, journey time to hospital, or initial pain score, and would appear to imply poor compliance to both regimens. We were unable to determine why this was the case.

Although missing hospital data prevented identification of the true incidence of nalbuphine related opioid antagonism, the limited evidence available suggested that it did occur. This has been reported in a previous study,¹⁴ although others have not observed this effect.^15,16

In conclusion, a rapid dosing regimen of nalbuphine is more effective than and equally as safe as a cautious regimen. The incidence of nausea or vomiting is significant for both regimens, and research is required to determine an optimum antiemetic drug. Although pain scores fell in both groups, over half of all patients continued to suffer from significant pain before arrival at hospital. Despite this, paramedics often failed to administer the maximum permitted dose. Further research is required to determine why this was the case, and whether the availability of a higher maximum dose of nalbuphine (or the use of morphine) would result in a reduction in the proportion of patients continuing to suffer pain despite paramedic administered analgesia.