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Is it time to change? The use of intranasal fentanyl for severe pain in the pre-hospital setting

02 November 2014
Volume 6 · Issue 11


The treatment of pain is a commonplace issue for today's paramedics, where the need for new analgesics to overcome cannulation barriers is gathering momentum. Intranasal fentanyl has proven itself to be a very safe and effective form of analgesia that overcomes those barriers and can help paramedics provide a higher standard of care. Although research into its use in the pre-hospital environment is still limited, evidence of its effectiveness in the accident and emergency department has highlighted its potential for helping paramedics treat severe pain where venous access is compromised. Studies have shown that intranasal fentanyl compares with the analgesic standard set by intravenous morphine and is rapidly becoming the drug of choice in the paediatric accident and emergency department.

Second to illness, pain is the most common symptom that paramedics working in the pre-hospital environment assess and treat on a daily basis (Cordell et al, 2002; Alonso-Serra and Wesley, 2003; Weber et al, 2012). A review of patient report forms have shown that approximately 20% of patients reported moderate to severe pain upon arrival of the paramedics (McLean et al, 2002), of which 1 in 5 expressed a need for more or better pain relief (Siriwardena et al, 2010). When mild to moderate pain is factored into the equation, it is clear that good pre-hospital pain management is a large component in the role of the modern day paramedic (Weber et al, 2012). For paediatric hospital emergency attendances, 60% are attributed to injuries that require analgesic intervention (College of Emergency Medicine Clinical Effectiveness Committee, 2013).

The issues surrounding the current analgesic are that: oral administration display an inconsistent absorption and bioavailability rate (Maurice et al, 2002), inhaled analgesics can sometimes be difficult to administer (especially in young children) and possess a quick offset time (Babl et al, 2008), and intravenous analgesics cannot always be achieved due to barriers surrounding cannulation. Therefore, the need for a quick acting and reliable opioid analgesic is required.

The use of intravenous morphine is now common-place and considered the gold standard analgesic within the pre-hospital environment. However, it is not always possible to gain venous access with every patient and a certain demographic of patients (e.g. children, dementia, shocked patients, and needle phobic patients) will not allow for venipuncture, thus providing the clinician with a barrier to providing adequate pain relief. Oligoanalgesia (poor pain management) is well recognised in both the emergency department (ED) as well as the pre-hospital environment and so the need for another form of administration is required to treat those unable to receive canula-fed analgesia (Rupp and Delaney, 2004; Zempsky and Cravero, 2004; Arendts and Fry, 2006; Jadav et al, 2009). To this end, the intranasal route of administration offers a quick, safe and effective method of providing opioid analgesia, and is gaining popularity for acute pain management (Pasero and Montgomery, 2002).

To date there is no Cochrane literature review looking at the use of intranasal fentanyl (INF) either in the ED or the pre-hospital setting (although a protocol has been submitted looking at INF for paediatrics in the ED). There is, however, randomised controlled trials (RCTs) comparing INF to other modes of analgesia to test for effectiveness and safety of use (Borland et al, 2007; Mahar et al, 2007; Furyk et al, 2009; Borland et al, 2011). The context of these studies can be analysed and, where appropriate, be translated to the out-of-hospital setting, to determine the effectiveness and safety of INF for use by paramedics.

Patients at particular risk

Pain management in children

Oligoanalgesia in children with moderate to severe pain is a well-documented and commonplace problem (Cole et al, 2009; Furyk et al, 2009; Finn and Harris, 2010; Borland et al, 2011) within both the pre-hospital environment and the emergency department. And with injuries responsible for over 60% of child emergency attendances (College of Emergency Medicine Clinical Effectiveness Committee, 2013), it is clear that this is a problem that all paramedics will encounter on a regular basis. Easily accessible opioid analgesia is an important progression for pre-hospital management of pain (Shelley and Paech, 2008) and the intranasal route is rapidly becoming the preferred choice (Cole et al, 2009). Cole et al showed that therapeutic levels can be achieved within two minutes of administration and the adverse effects of respiratory depression is no different than seen with adults with similar plasma fentanyl concentrations (Cole et al, 2009). The safety and efficacy of INF in children is well documented and has shown to be very effective in all groups although its use in the pre-hospital setting is still limited. Studies have shown that its effectiveness is comparable to intravenous morphine (IVM) (Boorland et al, 2007).

Pain management in patients with dementia

Pain management in the cognitively impaired (dementia) presents a particular challenge due to poor communication of the patient, educational and organisational shortcomings, and a perceived lack of knowledge by the clinician (Achterberg et al, 2013). There are currently approximately 835 000 people living with dementia in the UK at present, and this number will rise to over a million by 2025 (Alzheimer's Society, 2014). Recent figures have shown that 5% of people over 65 years of age will have a diagnosis of dementia rising to 50% of 90-year-olds (Alzheimer's Society, 2014). As attending falls and injuries by the elderly is a major component of pre-hospital care, it is clear that more research into pain assessment and treatment needs to be done. As with all other patients, the need for good early analgesic intervention is required which, when dealing with patients with dementia, can pose a considerable challenge.

Description of the administration

Cannulation is the main barrier to the administration of opioid analgesia, and this has been shown to be a problem in the young, the elderly, the shocked patient and the cognitively impaired. Studies looking at the pain management in children have shown that the intranasal route offers a kinder and less intrusive mechanism for drug delivery and offers the same level of analgesia as IVM (Cole et al, 2009; Borland et al, 2007; Borland et al, 2008; Borland et al, 2011). When accompanied by the time taken to canulate, this offers a quicker time to analgesia than can be achieved by IVM (Cole et al, 2009; Borland et al, 2011; Mahar, 2007). In addition, the duration of action of 30 minutes offers greater control for the physician and can reduce hospital stay if not required in the emergency department. Also, due to the lack of histamine release with fentanyl, the risk of hypotension is diminished for the patient; this is especially useful in trauma situations (Mahar et al, 2007; Cole et al, 2009; Borland et al, 2011). The combined surface area of around 90 m2 for the lungs offers a large capillary-rich environment for absorption (Grape et al, 2010), although the small area of the nasal mucosa restricts the dosage given at any one time to <200 µL to prevent a run-off into the pharynx (Grape et al, 2010).

Pharmacology of fentanyl

Fentanyl is a highly selective µ-opioid receptor agonist with the potency of approximately 100–300 times that of morphine (Maguire et al, 1992). It displays all the opioid-related adverse effects of vomiting, pruritis, and urinary retention, although research of its adverse effects in the acute pre-hospital setting is limited (Peng and Sandler, 1999). Due to its high potency and lipophilicity, fentanyl will produce rapid and effective analgesia within five minutes of administration (Striebel et al, 1993). The intranasal route will avoid first-pass metabolism and be absorbed rapidly into the systemic circulatory system via the highly vascularised nasal mucosa (Grape et al, 2010; Murphy et al, 2013). Elimination half-life is achieved within 3–12 hours dependent upon the quantity of fatty tissue (Hanks and Reid, 2005). The primary metabolite, norfentanyl, is pharmacologically inactive and eliminated through the renal system (Dean, 2004).

‘Intranasal fentanyl offers a safe and effective alternative to intravenous morphine to patients with cannulation barriers, and is a valuable tool to treat acute severe pain’

Comparison to intravenous morphine

An RCT carried out by Borland et al (2007) looked at comparing INF to IVM with a view to using INF as an alternative for children where rapid, effective and painless analgesia is required without the barriers of cannulation. The trial was double-blinded and placebo controlled, thus reducing the risk of bias on the side of the patients and doctors, as well as eliminating the placebo effect which may favour any aspect of the trial. The treatment effect of the two groups showed that the IVM group had a lower pain score throughout the 30-minute time span of the experiment; although the author claims that the differences are not clinically significant. At five minutes into the study the IVM group had a 13-points difference over the INF group; however, this gap narrowed to five points at the 10-minute interval. This implied that IVM had a quicker time to onset than INF, although the known pharmacokinetics of INF, and previous studies, has shown that this is not the case and in fact INF has the same, or quicker, time to onset than IVM (Hermannn et al, 1999; Renstsch et al, 2001). At 30 minutes the pain scores were below the 40/100 mark (equivalent to 4/10 on the Numeric Rating Scale), which had reduced the pain to below the mark generally regarded as ‘severe pain’, and the mark by which some services have set a maximum limit for the pre-hospital clinician.

Ideal concentration of fentanyl

A second study compared the differing concentrations of fentanyl for acute pain (Borland et, 2011). The RCT looked at the effectiveness of using a high concentration solution (HINF) of 300 mcg/ml to a standard concentration solution (SINF) of 50 mcg/ml. The outcomes of this study were to compare the pain reduction over intermediate periods of pre-analgesia to 10 minutes, 10–20 minutes, 20–30 minutes, and pre-analgesia to 30 minutes. There was no statistical significance between each group regarding the pain scores either, but surprisingly the HINF seemed to work better in the first 20 minutes, with the SINF working better thereafter. However, the only analysis for each group was age and weight, and this was for groups only and not the individuals involved. The size of the groups were equal at the start of the trial and the size of groups (HINF, n=97; SINF, n=102) were large enough to allow for the results to show integrity. The application of these results can of course be carried into the pre-hospital setting when given to children; however, in the elderly, the resulting analgesic effect may differ, and so more research needs to be done in this area.

Effectiveness in children

A prospective intervention study by Cole et al (2009) looked to determine the effectiveness of intranasal fentanyl in children aged 1–3 years of age as this is a demographic that often receives inadequate pain relief (especially those who are unable to verbalise their pain) (Brislin and Rose, 2005; Cole et al, 2009). Cole et al commented that the child's inability to self-report pain combined with limited communication and the reluctance of clinicians to gain intravenous access often results in reduced opioid analgesia. The study concluded that INF provided effective rapid analgesia, which sustained analgesic integrity for at least 30 minutes. Of the 57 participants, 2 children required a second dose of INF and only 1 needed the rescue analgesia of IVM. The value of the 30 minutes effective analgesia allowed for a more thorough assessment of the children and gave time for the topical anaesthesia to work prior to intravenous access for the administration of morphine should it be required. Cole et al commented on the lack of published data available and advised for more research in this area to be carried out. Finn and Harris’ 2010 prospective observational study looked at 81 children between 1–16 years of age who were admitted to an accident and emergency department with moderate to severe pain (Finn and Harris, 2010). The result of the study showed a significant reduction in pain score at 5 minutes of 48/100 (using the 100mm visual analogue scale and a margin of error of 40–75) and again at 30 minutes of 84/100 (with a margin of error of 8–42). Only one patient required further opioid analgesia. The author concluded that the time to discharge was reduced to less than four hours for those not admitted onto a ward.

Conclusions and implications for practice

As pain is a very common condition seen by paramedics, an integration of new analgesics into practice should be sought as and when appropriate. Intranasal fentanyl offers a safe and effective alternative to intravenous morphine to patients with cannulation barriers, and is a valuable tool to treat acute severe pain. The drug, and its mode of delivery, has proven itself to be quick acting and reliable (essential in the pre-hospital environment), and because of its use becoming more common in the emergency department, a recognised form of analgesia.

Oligoanalgesia in children is a well documented and commonplace problem. With over 60% of paediatric accident and emergency attendances being attributed to trauma, the intranasal route is rapidly becoming a preferred choice of administration. Severe pain in the cognitively impaired and elderly is also under-treated, mainly due to educational and organisational shortcomings, and with an ever increasing ageing population and the number of dementia patients forecasted to be over a million by 2025, the need to effectively treat these patients should be addressed.

Research has shown no clinical significance between intranasal fentanyl and intravenous morphine when used in the emergency department, and is accompanied with the added bonus of reducing the time to discharge.

To date, no research has been conducted into the cost of implementation for intranasal fentanyl into practice and whether this change is practically possible.