Prehospital trauma care patient management and effective analgesia are at the forefront of treatment (Porter, 2004; Lord and Nicholls, 2014; Michelet et al, 2023), and are among the primary roles of the prehospital clinician. Effective analgesia assists with patient assessment and treatment at the scene. This is an important humanitarian issue, which improves patient experience, reduces long-term adverse outcomes (Lord and Nicholls, 2014; Michelet et al, 2023), and is integral to ethical medicine (European Society for Emergency Medicine (EUSEM), 2020). In the UK, all NHS paramedics are licensed to carry and administer morphine sulphate as analgesia.
According to Schedule 17 of the Human Medications Regulations 2012, morphine sulphate can be administered by paramedics independently.
Ketamine however is not listed within Schedule 17 and is therefore only available for administration by UK clinicians who have undergone additional training and governance, such as Advanced Practitioners in Critical Care under a patient group direction (PGD).
Ketamine overview
Ketamine was first synthesised in 1962 as a derivative of phencyclidine, which was deemed unsuitable for human use owing to its side effects, including extended emergence delirium (Domino and Luby, 2012). Pharmacodynamically, ketamine uniquely affects the central nervous system (CNS) because of its rapid uptake by the brain. Ketamine acts as an N-methyl-D-aspartate (NMDA) antagonist, binding to phencyclidine receptors and inhibiting glutamate activation (Aroni et al, 2009). This process depresses the limbic system, which integrates sensory information and plays a crucial role in memory. By depressing the limbic system, ketamine prevents the CNS from processing sensory information. Ketamine has been widely used for several years in the prehospital environment, predominantly by physicians, to facilitate safe extrication and provide effective analgesia and sedation during painful interventions. The dissociative state induced by ketamine allows these procedures to be undertaken more comfortably for the patient (Moy and Le Clerc, 2011). However, in recent times, ketamine has been increasingly administered by non-physician responders in a safe and effective manner. This is highlighted in the literature from other countries, showcasing the successful use of ketamine by ambulance personnel in various clinical settings, including analgesia, sedation and prehospital emergency anaesthesia (PHEA) (Fouche et al, 2017).
Routes of administration
The method of drug administration is pivotal to the care provided within the ambulance service, as routes differ significantly in mechanisms, speed of onset, bioavailability, and overall efficacy. Each method presents distinct advantages and disadvantages. Invasive methods, such as intravenous (IV), intraosseous (IO), and intramuscular (IM) administration, offer the advantage of rapid drug delivery. However, the invasiveness of these methods can increase psychological stress, pain, and complications for patients – particularly in the paediatric population (Orenius et al, 2018) – along with an inherent risk of sharps injury and additional training for the clinician. IV administration provides rapid onset and boasts 100% bioavailability, making it ideal in emergency situations. However, IV cannulation necessitates skilled and trained personnel and carries inherent risks for both patient and clinician (Morgaonkar et al, 2017; Ravik and Bjørk, 2023). Additionally, obtaining IV access is not always feasible, as patients may experience peripheral vascular failure or suffer from trypanophobia, the fear of needles. In cases of peripheral vascular failure, IM administration may serve as a viable alternative for certain medications. Unlike IV administration, IM does not guarantee 100% bioavailability, as it can vary depending on factors such as injection site, blood flow, and medication properties. The issue of trypanophobia persists with IM administration, along with the inherent risk of injury to both patient and clinician.
Conversely, non-invasive methods such as oral, buccal, and intranasal (IN) administration do not necessitate tissue penetration. They offer several advantages over invasive methods, including a reduced risk of infection or injury, minimal patient discomfort, and improved patient compliance (Nicholas and Husbands, 2022). However, non-invasive methods may result in inferior bioavailability as a result of first-pass metabolism, potentially delayed onset, and limitations in administering certain medications (Bajracharya et al, 2019). Oral medication administration is common and offers numerous advantages, yet the drug must traverse the gastrointestinal tract before absorption in the intestines, leading to significantly lower bioavailability compared with other routes. Like IM administration, oral medications can vary in onset time and potency. Advanced analgesics, such as ketamine, are currently unavailable for oral administration within the ambulance service.
Intranasal administration
IN administration is becoming an increasingly popular method of therapeutic drug administration, both within in-hospital and prehospital environments, offering direct drug transport into the central nervous system circulation (Rech et al, 2017). The effectiveness of its delivery can be accredited to the unique structure of the nasal cavity, which is comprised of three regions: the respiratory, olfactory, and vestibules. These regions provide a total surface area of approximately 150 cm2 (Costantino et al, 2007). IN delivery can be accomplished by different methods, including instillation into the nasal cavity with syringes or droppers by applying a few drops at a time or via atomisation. Atomisation has been shown to be a preferred route owing to the reduced possibility of ‘run-off’ and optimised larger surface area compared with droplets (Corrigan et al, 2015; Rech et al, 2017). Furthermore, atomisation does not require patient cooperation in head positioning, which could potentially lead to swallowing the medication rather than IN administration (Rech et al, 2017). The use of a specified mucosal atomisation device (MAD) has been highlighted as an effective and safe route for IN administration, with a potential to increase acceptability and increase bioavailability, and should therefore be the first choice for this method of drug administration – particularly with paediatrics (Fantacci et al, 2018; Pansini et al, 2021). Despite the nasal cavity having a capacity of approximately 15–20 mls, the IN dose should not exceed 1 ml per nostril to avoid run-off or swallowing (Costantino et al, 2007; Rech et al, 2017).
IN administration is favoured because of the high vascularity of the nasal mucosa and the direct conduit provided by the olfactory tissues to the central nervous system, thereby bypassing first-pass metabolism and achieving an onset of action resembling IV administration. This route of administration has also been shown to reduce delays in drug delivery, significantly impacting various emergency scenarios, including trauma management (Bailey et al, 2017). The IN route also bypasses the risk of needle-stick injuries and reduces potential emotional trauma. IN drug delivery can be used across a variety of patient populations, regardless of age, body habitus, clinical condition, or level of patient cooperation. Moreover, IN administration has been shown to decrease the time to drug administration compared with IV administration, which can profoundly impact overall treatment time and reduce the time on scene to gain definitive care (Del Pizzo and Callahan, 2014; Corrigan et al, 2015; Erdő et al, 2018).
The use of IN ketamine for analgesia has been well-researched, particularly within the paediatric population, in the hospital setting. In a double-blind randomised controlled trial comparing IN fentanyl and IN ketamine in paediatric patients with traumatic limb injuries, 73 participants were enrolled over a period of 12 months, with the primary objective being pain reduction after 30 minutes (Graudins et al, 2015). The study was conducted across two separate sites; however, one site withdrew owing to a low enrolment rate (though reasons for this low enrolment were not specified). The study concluded that both IN fentanyl and IN ketamine were effective in reducing pain associated with paediatric limb trauma. However, the study did not mention additional factors that may contribute to pain relief, such as splinting or staff reassurance.
These results were echoed in a systematic review and meta-analysis of four studies presenting a comprehensive evaluation of the efficacy and safety of IN ketamine as a treatment for acute pain in paediatric patients (Oliveira JE Silva et al, 2020). Notably, the review considered the risk of non-serious and serious adverse reactions, highlighting a higher incidence of non-serious adverse reactions compared with other IN options, including IN fentanyl. Interestingly, there were no serious adverse reactions associated with IN ketamine, while one serious adverse reaction was associated with IN fentanyl. Across the four articles, a total of 256 patients were recruited for the trials; however, patient age ranges and sex were not specified. A main strength of this systematic review and meta-analysis is its clinical relevance. By focusing on a non-invasive, rapidacting analgesic, the study addresses a significant gap in paediatric pain management, which has also been noted in the prehospital setting (Abebe et al, 2021). The authors suggest that IN ketamine is a promising option for acute pain relief in children. However, the article would benefit from a more detailed discussion of the practical implications of the study's findings. For instance, considerations regarding optimal dosing, with doses ranging from 1–1.5 mg/kg, potential side effects, and guidelines for clinical implementation could be elaborated upon to provide more actionable insights for practitioners. Again, all of these studies were conducted in the in-hospital setting. Some evidence highlights that IN ketamine is not superior over standardised analgesia options in paediatric limb pain; however, this does not consider any issues that arise from invasive administration (Rocchio and Ward, 2021).
While these studies highlight the effectiveness of both medications (Graudins et al, 2015), it is worth noting that paramedics in the UK are not currently licensed to carry, administer or prescribe fentanyl, even with a PGD, despite several exemptions listed for Schedule-2 drugs noted within the Specialist Pharmacy Service (SPS) (2024), including morphine sulphate and ketamine.
Several issues of relevance to paediatric patients are also apparent within the adult population, such as trypanophobia, difficulty gaining IV access, and the prevalence of other invasive medication administration routes. A previous systematic review and meta-analysis aimed to evaluate the use of IN ketamine as an alternative analgesic in emergency settings. The authors examined various studies and consolidated data on the effectiveness and safety of this method of pain relief (Seak et al, 2021).
Not isolated to the paediatric population alone, the topic of prehospital analgesia within the general population remains a highly relevant topic, as the need for alternative pain management strategies increase. The use of IN ketamine could provide a non-opioid solution for acute pain, reducing the risk of addiction and other opioidrelated complications. The review highlighted quantitative data supporting the efficacy and safety of IN ketamine (Seak et al, 2021).
However, there is room for improvement in discussing the heterogeneity among the included studies. Addressing variability in study design, population, and dosages of IN ketamine could provide a more nuanced interpretation of the results, similar to the findings within the paediatric studies. However, several studies have stated a range of IN ketamine dosages from 0.5 mg/kg for analgesia up to 9 mg/kg, where sedation was required (Del Pizzo and Callahan, 2014). Overall, the authors of both studies highlight the potential benefits of IN ketamine, such as rapid onset of action and minimal invasiveness. Nonetheless, the discussion could be strengthened by providing more concrete suggestions for future research, particularly in terms of standardising dosing protocols and exploring the long-term feasibility of IN ketamine (Oliveira JE Silva et al, 2020; Seak et al, 2021).
It is worth noting that a review of case studies highlighted that the median dose of 0.94 mg/kg IN ketamine was used to good effect to reduce an average pain score from 10/10 to 3/10 in the wprehospital setting; the doses were delivered in w0.5–1 ml boluses to avoid ‘run off’ (Johansson et wl, 2013).
Intranasal bioavailability
IN ketamine bioavailability has been shown to reach 45%, which is significantly lower than that achieved by IV administration. However, to optimise the bioavailability of IN-administered drugs, providers must minimise the barriers to absorption, reduce the volume by maximising the concentration, increase the absorptive surface of the nasal mucosa, and use a delivery system that maximises drug dispersion and minimises drug run-off. Medications can be instilled into the nasal cavity with syringes via atomisation (Corrigan et al, 2015). This lowered bioavailability can be counteracted by adjusting the dosing regimen. IV ketamine has analgesic properties at doses of 0.1–0.3 mg/kg (Morgan et al, 2021), whereas IN analgesic ketamine dosages range from 1–1.5 mg/kg (Farnia et al, 2017; Oliveira JE Silva et al, 2020). Advanced practitioners in critical care (APCCs) within the Scottish Ambulance Service currently carry two separate concentrations of ketamine: 20mg/ml, which is primarily used for IV or IO administration, and 50 mg/ml, which is used for IM administration. The 50 mg/ml concentration would mitigate the reduced bioavailability of IN administration and offer an option for lower volume administration.
Complications, cautions and contraindications
The prehospital administration of IN ketamine for analgesia requires careful consideration owing to its potential cautions and contraindications. Ketamine, while effective for pain management, has a unique pharmacological profile that necessitates specific precautions to ensure patient safety (Royal College of Emergency Medicine, 2020). One major caution involves patients with a history of, or with current, psychiatric conditions, such as schizophrenia or severe anxiety. Because of its psychoactive effects, ketamine can exacerbate symptoms of these disorders. Previously, an important consideration was the potential for increased intracranial pressure, which can be detrimental in patients with head injuries or intracranial pathologies. However, recent publications indicate that this is becoming less of a concern (Laws et al, 2023). Nonetheless, ketamine should be used with caution in these scenarios. Cardiovascular considerations are also crucial, as ketamine can cause hypertension and tachycardia (Porter, 2004). Patients with preexisting hypertension, tachyarrhythmias, or ischaemic heart disease might experience exacerbated symptoms, necessitating close monitoring, and potentially requiring the avoidance of ketamine use altogether. Moreover, ketamine's impact on the respiratory system should be acknowledged. While it typically preserves airway reflexes and respiratory drive, there is a risk of respiratory depression, particularly with higher doses or in combination with other sedatives (Sinner and Graf, 2008). Therefore, careful dose titration and monitoring are essential to mitigate this risk (Sinner and Graf, 2008). Other contraindications include patients with known hypersensitivity to ketamine, where administration could trigger severe allergic reactions. Additionally, those with conditions involving a compromised airway or significant nasal pathology, such as nasal fractures or blockages, or any recent IN vasoconstriction (cocaine, phenylephrine), may not be suitable candidates for IN administration because of the potential for reduced drug absorption and effectiveness (Bailey et al, 2017).
However, despite adverse reactions being evident, the majority of these are not directly related to the administration route. Rather, these are generalised adverse reactions to ketamine, as noted by a triple-blind study comparing IV ketamine against IN ketamine for orthopaedic trauma (Parvizrad et al, 2017). It was shown that a higher percentage of patients receiving IV ketamine experienced greater adverse reactions compared to IN administration, with the main reaction being euphoria within the IV group and drowsiness in the IN group (Parvizrad et al, 2017).
While IN ketamine offers a valuable option for prehospital analgesia for competently trained clinicians, its administration must be approached with caution, particularly in patients with psychiatric disorders, cardiovascular issues, potential for increased intracranial pressure, or respiratory concerns (Aroni et al, 2009). Additionally, ensuring that patients do not have contraindications such as hypersensitivity to ketamine or significant nasal pathology is essential to safe and effective use.
Summary
Ultimately, ketamine has been successfully utilised within the medical profession, both in hospital and prehospital settings, for many years. Its unique properties allow to provide a variety of effects on the body by simply varying the dosing regimens. As an analgesic, ketamine has been shown to be a safe and reliable option when additional analgesia is required. The route of administration for ketamine also provides several options during an emergency. IV, IO, and IM routes all provide effective means for rapid administration. However, each of these options poses some level of difficulty and potential psychological stress owing to their invasiveness, which could be particularly problematic for the paediatric population. IN administration bypasses the necessity for an invasive procedure to administer effective analgesia, minimising the potential emotional trauma, yet offers a safe alternative with rapid onset. The effectiveness of this route can be attributed to the unique structure of the nasal cavity and its large surface area for absorption. However, as with all medications, ketamine is not without its cautions and contraindications, which clinicians must be aware of. These cautions and contraindications apply to ketamine in general, rather than being specific to IN ketamine administration. The IN route, however, highlights certain contraindications and considerations.
Despite current literature suggesting that IN ketamine is a practical and effective alternative for analgesia in the prehospital setting, this alternative would require additional training and governance to ensure that all clinicians are competent. Clinicians need to remain aware of any possible complications, cautions, or contraindications that IN ketamine administration may present. Finally, based on the published literature, IN administration of ketamine may be a safe, effective, and well-tolerated alternative to IM or IV administration (Corrigan et al, 2015). Use of IN as a method of drug administration is becoming more commonplace in prehospital settings, providing effective analgesia when required (Bailey et al, 2017).