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# Cost effectiveness analysis of intravenous ketorolac and morphine for treating pain after limb injury: double blind randomised controlled trial

BMJ 2000; 321 (Published 18 November 2000) Cite this as: BMJ 2000;321:1247
1. Timothy H Rainer (rainer1091{at}cuhk.edu.hk), associate professora,
2. Philip Jacobs, professorb,
3. Y C Ng, associate professorc,
4. N K Cheung, associate professora,
5. Michael Tam, associate professora,
6. Peggo K W Lam, statisticiand,
8. Robert A Cocks, professor and directora
1. a Accident and Emergency Medicine Academic Unit, Chinese University of Hong Kong, Rooms G05/06, Cancer Center, Prince of Wales Hospital, Shatin, NT, Hong Kong
2. b Department of Public Health Sciences, Faculty of Medicine and Oral Health Sciences, University of Alberta, 13-103 Clinical Sciences Building, Edmonton, Alberta, Canada T6G 2G3,
3. c Department of Economics, Hong Kong Baptist University, 224 Waterloo Road, Kowloon Tong, Kowloon, Hong Kong,
4. d Centre for Clinical Trials and Epidemiological Research, Flat 7B, 7th floor, Block B, Staff Quarters, Prince of Wales Hospital, Shatin,
5. e Finance Department, Prince of Wales Hospital, Shatin
1. Correspondence to: T H Rainer
• Accepted 8 August 2000

## Abstract

Objectives: To investigate the cost effectiveness of intravenous ketorolac compared with intravenous morphine in relieving pain after blunt limb injury in an accident and emergency department.

Design: Double blind, randomised, controlled study and cost consequences analysis.

Setting: Emergency department of a university hospital in the New Territories of Hong Kong.

Participants: 148 adult patients with painful isolated limb injuries (limb injuries without other injuries).

Main outcome measures: Primary outcome measure was a cost consequences analysis comparing the use of ketorolac with morphine; secondary outcome measures were pain relief at rest and with limb movement, adverse events, patients' satisfaction, and time spent in the emergency department.

### Cost effectiveness

When we included admission costs we observed no significant differences in costs between the two groups. We found a significant reduction in pain with activity in the ketorolac group and significantly fewer common adverse events. Additionally, the participants in the ketorolac group showed a greater degree of satisfaction with that drug than the participants in the morphine group showed with their drug (table 8). Ketorolac administration therefore is the “dominant” strategy, with significantly better outcomes, lower costs when costs for the emergency department and pharmacy are combined, but not significantly higher overall costs.

Table 8

Participants' satisfaction with analgesia and with emergency department management

View this table:

## Discussion

This study shows that, although intravenous morphine costs less than intravenous ketorolac in Hong Kong, ketorolac is a cheaper option than morphine once all additional costs incurred by the accident and emergency department and the pharmacy are taken into account. When admission costs are included, however, the difference in cost is not significant. When both drugs are administered intravenously in titrated doses according to individual patients' needs, ketorolac is at least as efficacious as morphine and may afford a small advantage when the injured limb is moved. Ketorolac had fewer adverse effects than morphine, made fewer demands on doctors' and nurses' management time, resulted in earlier discharge or admission to a ward, and was associated with greater satisfaction among patients. Morphine may afford a small clinical advantage, however, with better odds of relieving pain at rest than with ketorolac.

### Originality of study

The study has the several original aspects. Firstly, it compares intravenous ketorolac and intravenous morphine in a nurse controlled, analgesic regimen with titrations according to the individual patients' needs. None of the many other studies that have compared parenteral ketorolac with parenteral opiates in a variety of settings 710 13 1520 3041 has compared one drug with the other as in this protocol. Secondly, the two drugs were studied within the context of an emergency department. Both morphine and ketorolac have been studied separately in emergency departments in both controlled and uncontrolled studies, 10 30 42 but no study has compared one with the other in this setting. Thirdly, a cost effectiveness analysis drew together the strands of efficacy, adverse effects, resource demands, and participants' satisfaction. Other studies have shown that ketorolac may be as efficacious as morphine and tolerated better, but none has examined the issue in a broader economic context.

### Study protocol versus routine practice

This study differs from normal emergency department practice in several respects. In normal practice no delay occurs as a result of patient information and consent procedures. The delay in this study was kept to an absolute minimum, and no complaints were received from patients or relatives. Secondly, in normal practice, analgesia is not given in a blinded regimen and patients are not observed and questioned closely by a research nurse. Some degree of artificiality has to be accepted if vital data are to be recorded. As the study was randomised and double blind, however, any deviations from normal should at least be the same for both groups, leaving the effect of the two analgesics as the only difference in outcome.

### Strengths and shortcomings

The strengths of the study lie in its randomised controlled design, delivery of analgesia according to individual needs, and its attempt to reflect the real world as far as reasonably possible. The economic evaluation follows recent guidelines published in the BMJ. 4345 Although every effort was made to blind both the research nurses and the participants to treatment, certain clinical clues—such as pinpoint pupils—might reveal the identity to discerning medical and paramedical staff. This is a shortcoming that is probably unavoidable and applies to all double blind studies comparing opiates with other drugs. In an ideal double blind regimen, treatment should not be prepared anywhere near the scene of research, so that contamination is completely impossible. In this study, nurses prepared the drugs within the department and used normal stock. This was important if we were to monitor the “real” time taken to prepare drugs for delivery and the different grades of nurses taking part in the process. The delay in starting to administer morphine compared with ketorolac was due to the extra checking procedures necessary for administering opiates.

Although more participants were admitted to hospital in the ketorolac group, the overall greater costs were not significant. No participant was admitted to an orthopaedic ward because of adverse drug effects (admission was principally for management of the injured limb). Only three of the six participants observed in an emergency observation ward were admitted specifically for adverse effects, and all were in the morphine group. Admission costs are much greater and more variable than for analgesia and associated drugs, which may explain why, when all additional costs are included, no difference was found between the two treatments. Others have noted that non-urgent visits to emergency departments cost relatively little when compared with the cost of admission.46

Baseline pain scores at rest were not high, and it may be argued that many of the participants did not need strong analgesia. With only minor degrees of movement, however, the average pain score rose to over 8 (out of a possible 10), showing that these participants did experience severe pain and that the administration of strong analgesia was appropriate. We could not study a placebo effect as it would have been both unethical and unjustified to deny some participants appropriate analgesia when they were in moderate to severe pain. Limb injuries are clearly painful, however, and most participants in this study had fractures confirmed by radiography. The reductions in pain score exceeded the minimum required for clinical significance. 47 48

The primary aim of this study was to investigate costs related to the input from the emergency department to pain management, but to follow any prolonged or delayed adverse events we had to extend data collection beyond the emergency department. No attempt was made to evaluate subsequent analgesia. Principal adverse events included drowsiness, sleeping, dizziness, nausea, vomiting, and phlebitis. These events occurred in a greater proportion of participants (and with greater severity and duration) in the morphine group than in the ketorolac group. Adverse events drain nursing resources, which during busy periods would be better used elsewhere. No cases of serious adverse effects, such as gastrointestinal haemorrhage, occurred in this study, which may be partly the result of the stringent exclusion criteria. One case of a serious adverse effect in either the morphine or the ketorolac group might dramatically alter the relative cost of each drug. It is difficult to assess the relative cost of rare drug reactions in any study, but provided that care is taken to exclude high risk subjects, then serious adverse effects should be few. In a post-marketing surveillance study the risk of gastrointestinal complications after intravenous ketorolac was low especially when treatment was limited to less than five days.49 Few patients were excluded from our study on the basis of an existing medical illness, showing that this study has relevance to most adults presenting to emergency departments with isolated painful limb injury.

Routinely administering an antiemetic with an opiate such as morphine might reduce adverse events with overall lower costs, and if lower doses of morphine were administered fewer adverse events might have occurred. However, the correlation between morphine dose and pain relief suggests that lower doses would have resulted in reduced analgesic effect. The poor correlation between morphine dose and vomiting also suggest that small reductions in the dose would not have influenced the duration of this adverse effect. It is surprising that there was no difference in age between the two groups. Any relation between perception of pain and age in this study was weak. Also, a relation between age and adverse events was not evident. The study protocol was designed such that reduced doses of analgesia would be given if adverse events arose, which may account for the poor correlation with age.

The time spent ordering, delivering, and controlling stock has not been taken into account as many other drugs are involved in those processes, and the contribution of ketorolac and morphine could not be evaluated separately. Average salaries of nurses and doctors have been used as a cost reference, but in real life more junior or senior staff may have a greater actual involvement.

Participants were studied between 9 am and 5 pm and only on weekdays. It is therefore unclear whether out of hours ratios of staff to patients, case mix, and demand would affect the results. Emergency departments function on a priority system, whereby the efficiency of processing an individual patient depends on the number of patients with higher priority in the department at a given time and the available resources. This study did not address the difficult and complex relations between the individual patient and the total demand on the rest of the department at the time that patient attended. If it is assumed that staff are always doing something useful while at work, then minutes of freedom from managing one patient means that other duties may be attended to, and this has an impact on cost effectiveness.

It is difficult to know how far these results may be applied to settings outside Hong Kong. If one assumes, however, that the difference in costs between ketorolac and morphine is 7.5-fold rather than 2.5-fold, that doctors and nurses salaries are a third of those in Hong Kong, and that all other variables are the same, then ketorolac and morphine are equally cost effective (data not shown).

### Implementing results

The management of pain remains one of the great challenges for emergency departments worldwide, and so policies on rapid, cost effective, and safe analgesia are essential for good patient care and patient satisfaction. High demand and prolonged waiting times also provide a drain on emergency departments' resources, and so any intervention that reduces the time that patients spend in the department is also important. This study showed that intravenous ketorolac is more cost effective than intravenous morphine in the management of acute pain after blunt limb injury in an emergency department. Doctors may be more confident about using an effective analgesic with no risk of dependence, fewer adverse effects, reduced arrival to discharge times in their departments, and reduced costs. These results are relevant to emergency departments in Hong Kong and are likely to be applicable to other systems that are organised along similar lines. Differences in staff salaries and other costs, however, may limit the application of our findings to some environments.

#### What is already known on this topic

Intravenous morphine sulphate is generally as effective as intravenous ketorolac tromethamine for surgical and cancer related pain

Morphine may cause more adverse events than ketorolac

No cost effectiveness analyses have compared the use of intravenous ketorolac and morphine titrated according to patient needs and none has evaluated such use in emergency departments

For limb injury in an emergency department ketorolac is as effective as morphine for pain at rest; for pain with movement, however, ketorolac may be marginally better than morphine

Ketorolac produced fewer, less severe, and shorter adverse events than morphine

Participants receiving ketorolac left the emergency department sooner than those receiving morphine

Ketorolac is a more cost effective analgesic than morphine in this setting and is associated with greater patient satisfaction

## Acknowledgments

Contributors: THR had the idea for the study, obtained approval, and has overseen the entire planning, execution, and analysis of the study, and the preparation of the manuscript. He is guarantor of the paper. PJ and YCN participated in planning a detailed economic analysis. NKC, MT, and RAC participated in the planning, execution, and analysis. PKWL and THR prepared the statistical analysis. RW was involved in planning and costing analysis. THR wrote the first draft of the paper, and all authors have contributed to the final version.

## Footnotes

• Funding This study was supported by the direct grants scheme of the Chinese University of Hong Kong (project code 2040668) and the Health Services Research Committee of Hong Kong (project code 921020).

• Competing interests None declared.

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