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The fentanyl ‘lozenge’ story: from books to battlefield
  1. Dominic Aldington1 and
  2. S Jagdish2
  1. 1Department of Pain Medicine, Royal Hampshire County Hospital, Winchester, UK
  2. 2Department of Anaesthesia, Queen Alexandra Hospital, Portsmouth, Hants, UK
  1. Correspondence to Lt Col Dominic Aldington, Department of Pain Medicine, Royal Hampshire County Hospital, Winchester SO22 5DG, UK; daldington{at}me.com

Abstract

This article outlines the process that led to the introduction of the fentanyl lozenge for acute pain management. It starts with the historical context before discussing the recognition of an ongoing problem and then identifies the options that were considered. There follows a description of the pharmacology of fentanyl before describing the trial of concept that was conducted. This leads into an outline of the meetings and committees that had to be engaged with before the final acceptance and subsequent ushering in. The final section describes an option that was unsuccessful.

  • Accident & Emergency Medicine
  • Pain Management
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Introduction

Much has changed in 100 years of medicine but the use of opioids in combat casualty care continues. The first report in this journal of the use of opioids for combat casualty care is found in an article describing the management of a casualty from the battle for Spion Kop in 1900.1 In it, two-thirds of a grain (c. 40 mg) of morphia was given ‘hypodermically’ to a man who had been struck by an unexploded shell ‘carrying away most of the lower ribs and practically the entire liver’. Despite the injuries, the man was ‘quite conscious and rational’ with ‘little or no hæmorrhage’ and ‘little shock but intense pain’. It is stated the morphia ‘relieved the pain and permitted the patient to die in peace’.

Recently, the fentanyl ‘lozenge’ has been introduced into the Role 1 analgesic armamentarium and this article describes the steps taken for its introduction in the hope it will act as a template for further advances; it also describes the constraints that need to be dealt with.

Problem recognition

‘Analgesic failure’ is defined as greater than mild pain or a score of more than about a third of the maximum.2 A survey of 65 casualties undergoing rehabilitation at the Defence Medical Rehabilitation Centre suggested 85% of casualties would class their initial analgesic management as a failure and thus in need of further intervention.3 The deficiencies of the morphine autoject from the view of the healthcare provider have also been described previously.4 Thus, it was apparent that an improvement in battlefield analgesic provision was necessary.

Options to consider

Possible improvements to battlefield analgesia have been suggested previously and included the individual issue of oral transmucosal fentanyl citrate (the fentanyl lozenge), as part of a multimodal analgesic regime.5 To support the further development of options for a battlefield analgesic, a systematic review of pre-hospital analgesics was undertaken;6 its conclusion was that there was little high quality evidence available but one possible option was the use of the fentanyl lozenge.

It was understood that any solution would have to be found ‘off the shelf’ as the Defence Medical Services were unable to develop their own agent, delivery system or packaging. It was also important that there was an easy way of accounting for the use of any prescription-only agent. It needed to have an appropriate existing evidence base for its use and a widely understood pharmacology. The retention of a parenteral analgesic route was deemed essential to allow for use in chemical, biological, radiological and nuclear contaminated environments. Thus, any option would have to either replace the autojects in this environment or not preclude their use. The fentanyl lozenge met all of these conditions.

Pharmacology

Fentanyl is an opioid first introduced into clinical practice in the 1960s and like pethidine and alfentanil is a phenylpyperidine derivative.7 The lozenge is available in a number of different doses from 200 to 1600 µg and is described as a solid drug matrix on a stick.8 In the UK, it has a license for use in breakthrough cancer pain in patients already receiving maintenance opioid therapy for chronic cancer pain.; 400 µg was chosen initially as it is the only dose with any evidence in the opioid-naive population.9 It has an analgesic potency of 4–8 mg intravenous morphine, and thus is similar to the 10 mg intramuscular morphine autoject,9 and can be safely used to augment the latter. The United States Special Operations Command forces tend to use the 800 µg lozenge but use it de novo, without prior (intramuscular) morphine administration.10

Pharmacokinetics

Fentanyl is approximately 500 times more lipid soluble than morphine but with a volume of distribution, µ-receptor dissociation constant and elimination half-life approximately the same. Thus, the difference in lipid solubility is the primary reason for differences in clinical actions, with fentanyl having a faster onset of action and, after a small dose, a faster off-set, since the high lipid solubility will facilitate trans-membrane transport.11 ,12 Fentanyl is metabolised in the liver to norfentanyl, which is inactive.

When administered correctly (rubbing against the buccal mucosa), 25% of the fentanyl lozenge is absorbed directly while 75% will be swallowed. Two-thirds of the swallowed dose will undergo extensive first-pass hepatic metabolism being almost completely deactivated; thus, 50% of the lozenge dose is destroyed before it provides analgesia. The swallowed proportion that escapes this metabolism provides a slower onset of analgesia. The importance of the correct application technique is clear to appreciate as it will optimise the fast onset of analgesia. With appropriate application, the entire lozenge will dissolve in about 15 min and have maximum efficacy in 15–30 min.9

Pharmacodynamics

In common with other opioids, fentanyl is a µ-receptor agonist. It provides analgesia, together with sedation and anxiolysis, although it may lead to hallucinations, dysphoria and meiosis. It causes both respiratory and cough suppression, although dyspnoea is uncommon. It has relatively little action on the cardiovascular system although vasodilation can occur. Nausea and constipation are very common while puritis and sweating are said to be common and urinary retention is uncommon.13

The trial of concept

Extensive discussions were held with clinical end-users in Defence Anæsthesia, Emergency Medicine and Primary Care that confirmed the usefulness of a trial of concept. The analgesic efficacy was not in doubt, while the usefulness, side effects and logistic considerations were. Safety and logistic advice was sought from senior and relevant personnel in Clinical Pharmacy, Defence Equipment Capability & Sustainment and the Medical & General Supplies (Pharmaceuticals) (M&GS) division of Defence Equipment & Supplies. Experience from coalition allies was sought through both personal contacts and The Technical Cooperation Panel (TTCP) via the Defence Scientific and Technical Laboratories; TTCP is an international organisation that collaborates in Defence scientific and technical information exchange principally among the USA, the UK, Canada, Australia and New Zealand.14 The evaluation was discussed with the Ministry of Defence Research Ethics Committee who confirmed in February 2010 in an Out Of Committee statement that a full ethics application was not necessary. Finally, the project was presented to the Surgeon General's Research Strategy Group (SGRSG) in March 2010 who supported the proposal. The Director of Research at Royal Centre for Defence Medicine supplied funding; it was considered too small for Science and Technology Rapid Assistance To Operations. SGRSG had suggested the Medicines and Healthcare products Regulatory Agency (MHRA) may be concerned it would be classed as a phase IV trial and so a copy of the research protocol was sent to their clinical trial helpline (ctdhelpline@mhra.gsi.gov.uk) in March 2010. MHRA confirmed this was not a Clinical Trial of an Investigational Medicinal Product as defined by the EU Directive 2001/20/EC and no further permission was required from them.

The research lead in Afghanistan was the Deployed Medical Director for HERRICK 12 (April 2010–October 2010) and through him Commander Medical was informed.

M&GS arranged for the 400 µg dose to be codified and receive its own NATO Stock Number before 300 units of 400 µg fentanyl lozenge were sent to theatre. An initial 21 units were used within the field hospital at Camp Bastion before the remainder were sent forward to Role 1. Clinicians were asked to keep note of their impressions of the agent although in many cases this proved difficult contemporaneously and so a retrospective trawl for information was undertaken at the end of their deployment.

The report of this evaluation was sent to SGRSG, the Advisory Group on Military Medicine (AGoMM) and the Medical Director, with a number of key points identified. First, it proved very difficult to undertake the project and get responses back; only about 70–100 units were accounted for in the results although eventually unused units were accounted for and disposed of. Despite the planning, a research project was understandably significantly less important than the clinical activity. Second, the side effects were those commonly associated with opioids, particularly nausea, vomiting and variable efficacy. However, none of the clinically significant side effects such as respiratory depression were noted at this dose. Finally, a clear deficit in the understanding of the pharmacology of the agent was apparent, with surprise at the delay in onset of analgesia being commented on frequently.

Ushering in the fentanyl lozenge

Under the guidance of the Medical Director, Joint Medical Command, a Defence Medical Services (DMS) Pain Symposium was convened in April 2011 for interested parties and the proposed use of the fentanyl lozenge was one of the points discussed and agreed upon. Prior to much of this work, the existence of the fentanyl lozenges and their use had been discussed on the Post-Graduate Medical Officer's Course ‘Pain Day’.15 The information has subsequently been introduced into the 2012 Clinical Guidance for Operations, into the Pain Management SOIs and with support from the Officer Commanding Department of Distributed Training into the latest Battlefield Advanced Trauma Life Support training package (2013).

The initial permission was given for its use by AGoMM for medical officers alone on 15 February 2012 but has since been broadened in their Record of Out of Committee Action of 26 March 2013 to include Nursing Officers and Combat Medical Technicians together with their equivalents in other Services.

Analgesic flops

While the introduction of the fentanyl lollipop has taken longer than one may have hoped, it has occurred; this is not the same for all recent analgesic proposals. As part of the Battlefield Review,5 it was suggested individuals be issued with simple analgesia in the form of 1 g paracetamol and 400 mg ibuprofen as part of a multimodal analgesic provision. In the DMS Clinical Committee meeting of June 2011, this individual issue of simple analgesia was again proposed, albeit with the tentative suggestion of 1 week's supply of paracetamol and ibuprofen. However, there were three main concerns expressed: some clinicians were worried that if soldiers had their own simple analgesia they may not present to the medical chain, and thus injuries that should be reported would not be. An antithetical concern was presented with many clinicians believing personnel should provide their own simple analgesia and not rely on a supply being issued to them. The final concern focused upon the fear of a deliberate overdose being taken with issued medication and worries about who would be held responsible for this. It is likely this concept will be revisited in the future.

Future

While it is tempting to hope there will one day be the perfect analgesic (robust packaging, multiple delivery options, stable over a wide range of environmental conditions, immediate onset, complete analgesia, long duration, no side effects to any physiological system, etc), we know this is unlikely. Instead, the DMS must continue to look for evidence of problems, with pain management, seek possible solutions and introduce such solutions through clinical trials. This must be underpinned by an understanding of evidence-based medicine, physiology, pharmacology and the principles of military medicine.

We must also continue to educate the DMS providers. While responses to drugs can be reasonably predicted in the well state, we deal with physiological states in casualties where drug behaviour is still unclear. Thus, in the mix of a perfectly understood compound (molecular weight, chemical structure, boiling point, melting point) and an imperfectly understood casualty, the only magic in the real world lies with the educated provider.

Acknowledgments

In addition to those already mentioned, the authors would like to thank the Defence Professors and Consultant Advisors, Professor Henry McQuay (the Honorary Consultant Advisor in Pain) and Dr Andrew Moore for their ideas and support, Major (now Lt Col) Bartels RAMC for his help in writing the evaluation report, and the individual clinicians who were able to provide feedback of their experiences using the fentanyl ‘lozenge’ on HERRICK12.

References

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Footnotes

  • Contributors The article was planned, written and rewritten by both authors.

  • Competing interests None.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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