Title: Intravenous Morphine compared with Intravenous Paracetamol for Pain Relief in Patients Presenting with Acute Fractured Neck of Femur to the Emergency Department: A randomised, Double-Blind Non-inferiority Trial. (MiPAIN).
Funder: Department of Health and Social Care

Abstract: Background Annually in the UK 70,000 patients, the majority of which are elderly, are treated in hospital Accident & Emergency (A&E) Departments for fractured neck of femur (NOF). With an increasingly ageing population, the estimated number of NOF fractures is expected to rise to 130,000 by 2046 [7]. The National Institute for Health and Care Excellence (NICE) recommend intravenous paracetamol, with intravenous morphine for breakthrough pain. However, little evidence exists to support this recommendation. Treatment of fractured NOF has been identified by the Department of Health as a clinical area with significant unexplained variation in quality of clinical practice and lacking evidence of what constitutes best practice. There is further inconsistency in dosage guidance, especially for morphine, with no guidance on dose reduction being provided. Since the majority of fractured NOF patients are elderly, correct morphine dosage is essential to avoid harmful side effects. Aims: This trial aims to investigate whether IV paracetamol is no worse (within a margin) at providing pain relief for NOF fractures than IV morphine. If non-inferiority of IV paracetamol compared to IV morphine is demonstrated, superiority of IV paracetamol will be assessed. A secondary objective will be to assess whether patients treated with IV paracetamol have fewer adverse events than those treated with IV morphine. Plan of investigation: MiPAIN is a two centre double-blind randomised non-inferiority trial, with two parallel treatment arms, in which patients with fractured NOF will be allocated to receive either IV paracetamol (patient weight >50 kg, 1000 mg over 15 minutes; patient weight 10 or &le;50 kg, 15 mg/kg over 15 minutes) or IV morphine (0.1 mg/kg slow injection) It is likely that a large proportion of eligible patients will have co-morbidities such as dementia. In previous research, this has excluded their participation. This study hopes to achieve a representative sample of the wider population by including as many eligible patients as possible, utilising the Helsinki principle. Patients who present to A&E with suspected fractured NOF will be identified via triage staff and a MiPAIN dedicated Research Nurse. Consenting patients will complete baseline characteristics, including demographics, medical history, injury, and pain score via a visual analogue scale (VAS). Following random allocation of treatments, to ensure double-blinding, treatment packs will contain both an ampoule and a bottle prepared to administer either paracetamol or morphine. Both containers will look as if they contained an active drug and will be administered sequentially. However, only one of them will have the allocated drug, the other will contain a sodium chloride placebo. Information on the drug pack and dosage received by the patient will be secured to enable unblinding in an emergency situation. Pain score will be recorded via a 100mm anchored VAS at baseline, i.e. when the patient presents to A&E, then 15 mins, 30mins, 60 mins and 120 mins after administering pain relief. Patients who require, or request, rescue analgesia will be given IV morphine 50mcg/kg over 5 minutes (current standard treatment). Additionally, blood pressure, pulse rate, respiratory rate, oxygen saturation and Glasgow Coma Scale will be recorded by the Research Nurse on the Case Report Form (CRF). Any adverse events will be recorded on the CRF, and followed up to resolution. Potential benefits to patients and NHS: Health economics analysis will determine the resource costs of IV paracetamol vs. IV morphine in fractured NOF patients. Resource costs will be confined to an NHS perspective, considering drug cost as well as the associated resources, treatment complications and drug side effects. Patient benefit will be measured using the difference in 100mm pain score between patients receiving IV morphine and IV paracetamol.

Lay abstract: Fractured neck of femur, also known as fractured hip, is an extremely painful condition requiring rapid pain relief. In the UK, 70,000 patients, predominantly elderly, are treated in hospital emergency departments annually for fractured hips, often following falls. Pain relief treatments for a fractured hip currently include morphine or paracetamol delivered into the bloodstream. Whilst morphine offers pain relief, it can cause side-effects including nausea, vomiting, breathing difficulties and low blood pressure. These side-effects are more common among elderly patients. Morphine is also a controlled drug and may cost more to administer as it requires presence of 2 staff members when authorising its use. Furthermore, morphine may require additional costly resources and medications to manage its side-effects. When paracetamol is delivered into the bloodstream it is thought to have similar pain relief and fewer side-effects than morphine in treatment for several conditions. Therefore, current guidelines instruct use of paracetamol delivered into the bloodstream for pain relief for patients with a fractured hip. However, most emergency departments use morphine because there is no high-quality evidence to support the guidelines. We aim to provide this evidence by performing a trial to assess whether use of paracetamol is not inferior to morphine for pain relief and causes fewer side-effects in patients with a fractured hip. Patients will be given either paracetamol or morphine and within the 2 hours following treatment, the team will assess patient-reported pain relief, side-effects, requirement for additional pain relief, blood pressure, pulse rate, respiratory rate and blood oxygen levels. The cost-effectiveness of each treatment will also be assessed by looking at costs of giving the drugs and resources and medications needed to manage the side-effects of each drug. This study will provide high-quality evidence to support the most effective management of pain for a fractured hip.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INJURIES AND ACCIDENTS