Original article

Analgesia in Patients with Trauma in Emergency Medicine

A systematic review and meta-analysis

Dtsch Arztebl Int 2017; 114(46): 785-92; DOI: 10.3238/arztebl.2017.0785

Häske, D; Böttiger, B W; Bouillon, B; Fischer, M; Gaier, G; Gliwitzky, B; Helm, M; Hilbert-Carius, P; Hossfeld, B; Meisner, C; Schempf, B; Wafaisade, A; Bernhard, M

Background: Suitable analgesic drugs and techniques are needed for the acute care of the approximately 18 200—18 400 seriously injured patients in Germany each year.

Methods: This systematic review and meta-analysis of analgesia in trauma patients was carried out on the basis of randomized, controlled trials and observational studies. A systematic search of the literature over the 10-year period ending in February 2016 was carried out in the PubMed, Google Scholar, and Springer Link Library databases. Some of the considered trials and studies were included in a meta-analysis. Mean differences (MD) of pain reduction or pain outcome as measured on the Numeric Rating Scale were taken as a summarizing measure of treatment efficacy.

Results: Out of 685 studies, 41 studies were considered and 10 studies were included in the meta-analysis. Among the drugs and drug combinations studied, none was clearly superior to another with respect to pain relief. Neither fentanyl versus morphine (MD –0.10 with a 95% confidence interval of [−0.58; 0.39], p = 0.70) nor ketamine versus morphine (MD −1.27 [−3.71; 1.16], p = 0.31), or the combination of ketamine and morphine versus morphine alone (MD −1.23 [−2.29; −0.18], p = 0.02) showed clear superiority regarding analgesia.

Conclusion: Ketamine, fentanyl, and morphine are suitable for analgesia in spontaneously breathing trauma patients. Fentanyl and ketamine have a rapid onset of action and a strong analgesic effect. Our quantitative meta-analysis revealed no evidence for the superiority of any of the three substances over the others. Suitable monitoring equipment, and expertise in emergency procedures are prerequisites for safe and effective analgesia by healthcare professionals..

Each year 18 200–18 400 patients require treatment for severe injuries in Germany (1). In 2016, ca. 396 700 persons were injured in road traffic accidents (2). Adequate analgesia following trauma is a central aspect of emergency medical treatment before and after hospital admission (35). Although relief of pain is a fundamental human right (6), studies suggest that many trauma patients are undertreated in this respect (7). One of the tasks of the group convened to revise the German S3 guideline on treatment of multiple trauma and severe injuries in 2016 was to take steps towards the development of national recommendations on the treatment of pain in trauma patients (8).

The goals of this systematic analysis of the published literature were to compare the effects of various analgesics, alone and in combination, in (severely) injured but spontaneously breathing patients with no need for airway management; to review safety and adverse effects; and to formulate recommendations. To this end, we performed qualitative and quantitative analysis of the data from randomized controlled trials (RCTs) and observational studies.

Method

This study adhered to the principles of the PRISMA statement for systematic reviews and followed the PICO scheme (population, interventions, comparison, outcome). The protocol, search strategy, and search terms were entered in the PROSPERO registry of systematic reviews and have been published (www.crd.york.ac.uk/PROSPERO, ID: CRD42016046110). Details of the study’s methods can be found in eBox 1. The endpoints of the meta-analysis were pain reduction (difference in pain rating before and after administration of analgesics) and the post-treatment score on the numeric rating scale (NRS).

Results

Selection of studies

The initial literature survey turned up 665 relevant publications. A further 20 items were identified by an additional hand search. Of these 685 publications, 624 were excluded after perusal of titles and abstracts. Full-text inspection eliminated a further 20 publications, leaving 41 for analysis (Figure 1).

PRISMA flow chart of literature survey and study selection
Figure 1
PRISMA flow chart of literature survey and study selection

Study characteristics

Twenty-three of the 41 studies were of the emergency rescue services, covering a total of 67 269 patients (10, 16, 21, 22, 2732, 3740, e1e9), and the remaining 18 studies, comprising 1899 patients, were carried out in hospital emergency departments (9, 1115, 1720, 2326, 3336). Overall, the substances most commonly used for analgesia were the opiates fentanyl and morphine, the NMDA receptor antagonist ketamine, and combinations of ketamine with opiates, followed by methoxyflurane, nitrous oxide, paracetamol, pentazocine, and sufentanil or combinations thereof. An overview of the studies can be found in eTable 1. Ten studies were included in a meta-analysis of pain reduction but were highly heterogeneous.

Analgesics

Morphine

One RCT with 300 patients compared intravenous and inhaled morphine (10 or 20 mg). Inhalation of morphine was found to have efficacy comparable with that of intravenous administration, together with high safety (19). Observational studies showed that the intravenous administration of morphine can be safe and effective (30, 32).

Ketamine

Retrospective studies showed safe analgesia with ketamine (alone or in combination with midazolam) (33, e1, e2, e4, e9). Only in one of the included studies was S-ketamine used (e10). Administration of ketamine in a dosage <2 mg/kg was followed by a decrease in pulse-oximetric oxygen saturation (SpO2) in 0.7% of cases, but no ventilation was required (e9); assisted ventilation was needed, however, in 6% of cases after high-dose ketamine (2 mg/kg) (34). The adverse effects reported as being associated with ketamine included dysphoria (4%), hypersalivation (1%), and vomiting (5%) (e9). In one single case, laryngospasm lasting for 1 min was reported (34). Intranasal ketamine seems to be safe and effective in children (36).

Fentanyl

Intravenous administration of fentanyl by paramedics and emergency physicians was safe and effective with no significant adverse effects (31, 37, 38, e3, e5). Two observational studies showed that intranasal fentanyl in a dose of 50 to 100 μg or 2 μg/kg was safe, effective, and associated with no or only few adverse effects in adults and children (31, 35).

Fentanyl versus morphine

Data from four RCTs (9, 15, 16, 27) and one cohort study (28) permitted comparison of analgesia with fentanyl and with morphine in terms of post-treatment NRS score and pain reduction (RCTs: fentanyl pre-NRS 6.8 to 8.4/post-NRS 3.5 to 6.6, morphine pre-NRS 7.0 to 8.3/post-NRS 4.0 to 6.2; cohort study: fentanyl pre-NRS 8.0/post-NRS 5.5, morphine pre-NRS 8.0/post-NRS 5.8). The post-treatment NRS score showed no clear-cut advantage of fentanyl over morphine (mean difference: −0.10, 95% confidence interval [−0.58; 0.39], p = 0.70) (Figure 2), but all medications investigated brought about a marked reduction in pain.

Post-therapeutic pain status according to Numeric Rating Scale (NRS) score after analgesia with fentanyl or morphine
Figure 2
Post-therapeutic pain status according to Numeric Rating Scale (NRS) score after analgesia with fentanyl or morphine

One cohort study that was not included in the meta-analysis showed greater pain reduction with fentanyl i.v. than with morphine i.v. (fentanyl pre-NRS 8.5/post-NRS 4.4, morphine pre-NRS 8.2/post-NRS 5.9) (38). Both RCTs and retrospective studies compared intranasal/inhaled fentanyl with morphine i.v. The RCTs found that intranasal/inhaled fentanyl was equivalent to morphine i.v. for pain reduction (fentanyl pre-NRS 6.8 to 8.4/post-NRS 3.0 to 6.6, morphine pre-NRS 7.0 to 8.7/post-NRS 3.0 to 6.2) (9, 13, 15, 27, 40). Retrospective analysis also showed that morphine i.v. was comparable in efficacy with intranasal fentanyl (pre-NRS: fentanyl 8.4, morphine 8.3; pain difference: fentanyl −4.5, morphine −4.5) (e8).

Ketamine versus morphine

Analgesia with ketamine or ketamine/morphine and analgesia with morphine could be compared in terms of post-treatment NRS score and pain reduction using the data from four RCTs (ketamine: pre-NRS 7.1 to 8.6/post-NRS 3.2 to 3.4, pain reduction 4.9 to 5.6; morphine: pre-NRS 7.0 to 8.5/post-NRS 3.9 to 4.2, pain reduction 3.2 to 5.0) (17, 21, 24, 25) and one cohort study (39). Ketamine and ketamine combinations were more effective analgesics than morphine alone (post-NRS: mean difference −1.23 [−2.29; −0.18], p = 0.02 [Figure 3]; pain reduction: mean difference −1.27 [−3.71; 1.16], p = 0.31 [Figure 4]). Analgesia with morphine and ketamine took effect significantly more rapidly than morphine alone (17, 21, 39). However, two of the RCTs showed that pain reduction was comparable after 30 min (24, 25).

Post-therapeutic pain status after administration of ketamine or ketamine/morphine versus analgesia with morphine alone
Figure 3
Post-therapeutic pain status after administration of ketamine or ketamine/morphine versus analgesia with morphine alone
Pain reduction expressed as difference in scores on the Numeric Rating Scale (NRS) before and after analgesia with ketamine/morphine or ketamine alone and with morphine
Figure 4
Pain reduction expressed as difference in scores on the Numeric Rating Scale (NRS) before and after analgesia with ketamine/morphine or ketamine alone and with morphine

One cluster-randomized study that was not included in the meta-analysis showed comparable pain reduction with morphine i.v. (3.1) and with ketamine i.v. (3.5); however, airway problems and vomiting were reported more frequently in the morphine group (29).

Fentanyl versus ketamine

Two RCTs compared ketamine/midazolam i. v. with fentanyl/midazolam i. v. In one study the results were comparable (20), while the other found swifter pain reduction with a lower risk of hypoxia in the ketamine group (11) (fentanyl: pre-NRS 7 to 8/post-NRS 1 to 2; ketamine: pre-NRS 7 to 9/post-NRS 1 to 3). Owing to high heterogeneity, however, no meta-analysis could be performed. One RCT compared ketamine/propofol i.v. with fentanyl/midazolam i. v. for short anesthesia in the emergency department (post-NRS: median = 0, interquartile ratio [IQR] 0 to 1 versus median = 3, IQR 1 to 6; p <0.001). In the course of treatment, better pain reduction was described in the ketamine group and a higher incidence of SpO2 decrease in the fentanyl group (26). One RCT in children compared intranasal fentanyl with intranasal ketamine and found comparable pain reduction (fentanyl: pre-NRS 8, post-NRS 3; ketamine: pre-NRS 8, post-NRS 3) (18).

Sufentanil versus morphine

One RCT compared sufentanil i.v. with morphine i.v. in trauma-related pain (10). Sufentanil acted more rapidly than morphine, but was not superior with regard to pain reduction after 15 min (sufentanil: pre-NRS ≥ 6, post-NRS 3.0; morphine pre-NRS ≥ 6, post-NRS 4.0).

Onset and course of pain reduction by fentanyl, ketamine, and morphine

One cohort study reported that fentanyl and morphine were equally effective (28), but it seems that analgesia can usually be achieved more quickly with fentanyl than with morphine (16, 38). With regard to the onset of pain reduction, inhaled fentanyl and morphine i.v. were described as equivalent (9, 27, 40), but sometimes fentanyl was faster acting (13, 15). One RCT reported that morphine and ketamine were equally effective, while in other studies ketamine, alone or in combination with other substances, was more effective or quicker-acting than morphine alone (17, 21, 24, 25). Compared with fentanyl, ketamine was faster (11) or equally fast (18, 20) to take effect. The duration of effect that can be expected was given as 10 to 15 min for ketamine, 20 to 40 min for fentanyl, and up to 4 h for morphine (4, e11).

Other analgesics

Two RCTs compared the effect of N2O with that of ketamine or fentanyl (22, 23) and described equivalent analgesia. Similar results were reported for pentazocine (e6). A prehospital observational study in which paracetamol i.v. was administered to patients who predominantly had trauma of the extremities found pain reduction of NRS <5 in 50% of cases. The analgesia was described as mostly insufficient to manage severe pain (e7). One RCT compared paracetamol i.v. and morphine i.v.: the pain reduction was comparable, but morphine was quicker to take effect than paracetamol (12). Another RCT comparing paracetamol with ibuprofen described similar pain reduction in the two groups (14).

Adverse effects of the most commonly used analgesics

The documented adverse effects of fentanyl, ketamine, and morphine, the most commonly used analgesics, are summarized in eTable 2. Ketamine or combinations including ketamine led to (desired) reduced vigilance in 1.5 to 18% of cases (17, 18, 21, 36). Agitation may occur with ketamine. Decreases in SpO2 were found in all studies for fentanyl (mean 0.6%, maximum 16.1% [26]), ketamine (mean 0.4%, maximum 11.5% [33]), and morphine (mean 0.6%, maximum 4.8% [24]). Overall, assisted ventilation was necessary for 0.05% of patients with ketamine, 0.02% with fentanyl, and 0% with morphine (eTable 2). Hypersalivation was reported in 0.5 to 3% of cases, predominantly in children, but was clinically irrelevant and required no intervention (e9, 29, 33). Nausea and vomiting were the principal adverse effects of morphine (4.8%), fentanyl (1.5%), and ketamine (0.5%). Hypotension was described in 1.6% of cases for fentanyl and in 0.5% of cases for morphine (eTable 2).

eTable 2

Discussion

Analgesics

Despite the variously defined endpoints, all the analgesics used in the identified studies and the meta-analyses seem to be similar in efficacy; nevertheless, fentanyl, ketamine, and combinations of fentanyl or ketamine with other substances take effect more rapidly than morphine (1 to 3 min versus 5 to 15 min after i.v. administration). Morphine is the oldest of the analgesics investigated in this systematic review. It has a very wide field of application, and its adverse effects are nausea, vomiting, decreased SpO2, and reduced vigilance (e12). Fentanyl is described as very effective with a swift onset of action (e12) and a low risk of adverse effects (e.g., hypotension and hypoxemia) (e13). International guidelines recommend morphine, fentanyl, and ketamine, administered by trained personnel, for pre-hospital analgesia (e14, e15). There are no data on the pre-hospital use of piritramide.

Numerous studies in Germany and other countries have shown that ketamine, alone or in combination with an opioid, is safe and effective when used not just by physicians but also by appropriately trained paramedics and nurses (20, 21, 24, 25, 29, 33, 36, 39, e1, e2, e4, e9, e16, e17). Analgosedation with ketamine can lead to dysphoria and vivid hallucinations or even to agitation (e18). For this reason, accompanying administration of a low-dose benzodiazepine is recommended (e19). Ketamine has the advantage that the patient is sufficiently protected from pain and shielded from external stimuli during the rescue process or invasive procedures (e.g., repositioning or splinting). Moreover, ketamine is particularly well-suited for analgesia of hemodynamically unstable patients (e20e22). Several reviews have shown that ketamine does not differ from other substances in respect of intracranial pressure (ICP), cerebral perfusion pressure (CPP), neurological outcome, mortality, or length of stay in the intensive care unit (e23, e24); in fact, it is especially suitable for use in patients with head injuries (e25). In ventilated patients with elevated ICP, ketamine is effective in lowering the ICP and prevents undesired increases in ICP with stable blood pressure and CPP (e26). Steps must be taken to avoid hypercapnia. Nonpharmacological pain treatment and the embryotoxological aspects of the analgesics reviewed here are discussed in eBoxes 2 and 3.

Alternative routes of administration

Analgesics should be administered intravenously in the context of emergency medicine (5). All analgesics approved for i.v. administration can also be given by the intraosseous (i.o.) route (e27). Intranasal administration is an alternative in both children and adults. Most analgesics have not been approved for intranasal use, but clinical experience with ketamine and fentanyl has been reported (18, 31, e10, e28, e29).

Safety and monitoring

The prerequisites for safe analgesia are knowledge of the pharmacological characteristics of the substances involved, training in their administration, and presence of emergency equipment for treatment of any complications, independent of the user (e.g., nurse, paramedic, or emergency physician) or the situation (prehospital or in the hospital). The monitoring measures and the emergency equipment needed at hand depend on the expected complications and adverse effects. Monitoring of a spontaneously breathing patient under analgesia comprises ECG, blood pressure, breathing rate, heart rate, and SpO2, together with capnography if required (e30e32). Patients under analgesia should regularly receive oxygen. The equipment for mask ventilation and suction must be available, and every user must be in the position to keep the airway free and perform ventilation. An intravenous access is recommended for treatment of hypotension or administration of naloxone as an opioid antagonist (e22, e23). Titrated administration is advised to avoid respiratory depression.

Undertreatment

Pain has direct physiological effects (blood pressure, breathing rate, heart rate, oxygen consumption, inflammatory reaction) and is a risk factor for post-traumatic stress disorder (e34). From the patient’s point of view, adequate analgesia is an important goal of emergency medical care (5, e35). However, only half of trauma patients receive analgesics at all, and in most of those cases the analgesia achieved is insufficient (4, 7, e36e40); this is independent of the professional role of the person administering the analgesic (e41e44). The principal reasons for inadequate analgesia are concern about adverse effects and uncertainty regarding dosage. Proper training in analgesia is therefore essential and the corresponding steps must be taken (5).

Pain assessment

The perception of pain is subjective, and pain is rated differently by patients and professionals (e45). Not all patients want analgesia, so every patient should be asked (e46). The NRS cannot be used in all patients; an alternative is to ask patients whether they are suffering severe or unbearable pain (e47).

In most cases, however, the NRS is useful in assessing the success of analgesia. The aim is to achieve an NRS score ≤ 4 (e19, e48, e49). The vital signs (e.g., breathing rate) may also serve to indicate whether adults are in pain (e50), and for children one can use pain evaluation scales adapted to the pediatric age group (e51e53). Geriatric patients often have more and worse comorbidities, are frequently accustomed to pain, and are less liable to complain of pain; they must therefore be questioned in greater depth (e19).

Limitations

This review and meta-analysis focuses on the analgesics most commonly used in Germany. The selected study design, with several endpoints (e.g., safety, efficacy, and adverse effects), led to a wide-ranging survey of the literature. However, the high degree of heterogeneity among the studies with regard to endpoints, study quality, and study characteristics represents a crucial limitation. For example, not all controlled studies recorded the time of onset of pain reduction. Many of the studies included did not report adverse effects uniformly. These limitations have to be borne in mind when interpreting the results. Only a small number of studies assessed the trauma by means of the Injury Severity Score (ISS), and very few of them investigated analgesia in seriously injured patients (ISS >15).

Conclusion

Healthcare professionals must be in the position to carry out safe and effective analgesia. The basis is formed by physical measures for pain relief. The preferred means of administration of analgesic drugs is the intravenous route; however, other routes are possible. The recommended analgesics are fentanyl, ketamine, and morphine, with comparable efficacy. Our quantitative meta-analysis shows that there are very few comparable studies of acceptable quality. The current state of knowledge permits no evidence-based statement of superiority of any one of these substances over the others for analgesia in trauma patients in emergency medicine. Analgesia must be carried out only by properly trained persons, the patient must be monitored without interruption, and emergency equipment for treatment of complications must be at hand.

Acknowledgment

We extend heartfelt thanks to Stefanie Hultzsch (Pharmacovigilance and Information Center for Embryonal Toxicology, Charité University Medicine, Berlin) for her opinions and advice on embryonal toxicology.

Conflict of interest statement

Prof. Böttiger has received lecture fees and/or reimbursement of travel costs from medupdate, Baxalta Deutschland, Bayer Vital, Boehringer Ingelheim Pharma, ZOLL Medical Deutschland, C.R. Bard, and Forum für medizinische Fortbildung.

The remaining authors declare that no conflict of interest exists.

Manuscript submitted on 29 November 2016, revised version accepted on

3 July 2017

Translated from the original German by David Roseveare

Corresponding author
PD Dr. med. Michael Bernhard, MHBA
Zentrale Notaufnahme, Universitätsklinikum Leipzig
Liebigstr. 20, 04103 Leipzig, Germany
michael.bernhard@medizin.uni-leipzig.de

Supplementary material
eReferences:
www.aerzteblatt-international.de/ref4617

eTables, eFigure, eBoxes:
www.aerzteblatt-international.de/17m0785

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Faculty of Medicine, University of Tübingen: David Häske, MSc MBA
Department of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne: Prof. Böttiger
Department of Orthopedics, Trauma Surgery, and Sports Injuries, Cologne Hospitals, University of Witten/Herdecke: Prof. Bouillon, PD Dr. Wafaisade
Department of Anesthesiology, Surgical Intensive Care, Emergency Medicine, and Pain Therapy, Hospital am Eichert, ALB FILS Hospitals, Göppingen: Prof. Fischer
Department of Anesthesiology and Surgical Intensive Care, Hospital am Steinenberg, Reutlingen: Dr. Gaier
MegaMed GbR, Maikammer: Bernhard Gliwitzky
Department of Anaesthesiology and Intensive Care Medicine, Section Emergency Medicine, Federal Armed Forces Hospital, Ulm, Germany: Prof. Helm, Dr. Hossfeld
Department of Anesthesiology, Intensive Care, and Emergency Medicine, Bergmannstrost BG Hospital, Halle: Dr. Hilbert-Carius
Institute for Clinical Epidemiology and Applied Biometrics, University of Tübingen: Dr. Meisner, MA
Department of Medicine II – Cardiology, Angiology, Intensive Care, Hospital am Steinenberg, Reutlingen: Dr. Schempf
Central Emergency Department, Leipzig University Hospital: PD Dr. Bernhard, MHBA
PRISMA flow chart of literature survey and study selection
Figure 1
PRISMA flow chart of literature survey and study selection
Post-therapeutic pain status according to Numeric Rating Scale (NRS) score after analgesia with fentanyl or morphine
Figure 2
Post-therapeutic pain status according to Numeric Rating Scale (NRS) score after analgesia with fentanyl or morphine
Post-therapeutic pain status after administration of ketamine or ketamine/morphine versus analgesia with morphine alone
Figure 3
Post-therapeutic pain status after administration of ketamine or ketamine/morphine versus analgesia with morphine alone
Pain reduction expressed as difference in scores on the Numeric Rating Scale (NRS) before and after analgesia with ketamine/morphine or ketamine alone and with morphine
Figure 4
Pain reduction expressed as difference in scores on the Numeric Rating Scale (NRS) before and after analgesia with ketamine/morphine or ketamine alone and with morphine
Key messages
The clinical perspective
eFigure 1
eTable 2
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