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Orodispersible and transmucosal alternative medications for symptom control in adults
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  1. Anna Elizabeth Sutherland1,
  2. Melinda Presland1,
  3. Emily Harrop2,3,
  4. Matthew Carey1,
  5. Mary Miller3,4 and
  6. Ian Chi Kei CK Wong5,6
  1. 1Palliative Medicine, Sir Michael Sobell House Hospice, Oxford, UK
  2. 2Paediatric Palliative Medicine, Helen and Douglas House, Oxford, UK
  3. 3Palliative Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  4. 4Palliative Care, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  5. 5Research Department of Practice and Policy, University College London School of Pharmacy, London, UK
  6. 6Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong, China
  1. Correspondence to Dr Anna Elizabeth Sutherland, Palliative Medicine, Sir Michael Sobell House Hospice, Oxford OX3 7LE, UK; annasutherland{at}doctors.org.uk

Abstract

Background Paediatric palliative care makes frequent use of orodispersible and transmucosal drug delivery routes. The limited published experience of this practice suggests that it enables the delivery of needle-free symptom relief, with the potential to train family carers to administer anticipatory medications without reliance on trained health professionals.

Aims To identify orodispersible and potential transmucosal alternatives that may be used in adults in the event of a patient having no oral or intravenous route and no access to subcutaneous injections.

Methods The author panel identified medications through review of multiple drug formularies, review of the published evidence and their experience. Where possible, licensed alternatives were identified and any ‘off label’ or unlicensed medications clearly highlighted.

Results A list of 27 medications is provided, which could be used either via the orodispersible or transmucosal alternative route for healthcare professionals delivering end of life care to consider when the licensed alternative routes are unavailable. All users of this guide are encouraged to use their professional judgement whenever selecting a medication for a patient, recognising that this review is neither a guideline nor a systematic review, and taking account of licensing considerations, adverse effects, potential unpredictability of time to effect and contraindications.

Conclusion Should it be necessary to use these orodispersible or transmucosal alternatives then any experience gained should be reported in the literature. Combined with further research, this experience offers the possibility of reducing injection frequency and inherent delays in medication administration, particularly in the community setting during the COVID-19 pandemic.

  • drug administration
  • home care
  • pharmacology
  • terminal care

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Aim

Our aim in writing this guide is to provide a resource from which healthcare professionals can select medications to control symptoms when patients do not have an oral route and when injectable medications are not available. This will enable high-quality needle-free palliative care, particularly in the community. We aim to summarise the evidence available regarding the transmucosal route, how transmucosal medications are administered, why they are effective and how transmucosal medications might be integrated into clinical practice.

Background

Transmucosal drug administration uses the mucous membranes to deliver medication and is particularly beneficial when a patient cannot swallow tablets or liquids but does not have access to injectable medications or where the patient prefers to avoid injections. The mucosal membranes absorb lipophilic drugs rapidly, minimising first pass metabolism and therefore frequently leading to a rapid onset of effect. For these reasons, transmucosal drug administration lends itself to use for rapid management of breakthrough symptoms.1 The utilisation of transmucosal routes of administration is widely established in paediatrics.2

Prior to consideration of the transmucosal route, it is important that every effort is made to use other available routes. In particular, it is important to consider alternative formulations, such as liquids in order to optimise the oral route before switching to a transmucosal alternative.

Examples of medications licenced and commonly used in the adult palliative population, which use the transmucosal route include nasal administration of fentanyl for pain; buccal administration of prochlorperazine for nausea and vomiting and rectal paracetamol for fever.

We defined methods of transmucosal drug administration as including buccal, sublingual, orodispersible, nasal and rectal routes. A prerequisite to the use of transmucosal medications is that the mucosal membrane must be moist. There are several important general principles for transmucosal drug administration, which include:

  1. Only soluble drug molecules can be readily absorbed via mucosal membranes. Therefore, liquid preparations are preferable such as injection, concentrated solution or spray.

  2. If chewable or orodispersible tablets are used, it is critical to ensure sufficient saliva is available to dissolve the tablets or alternatively tablets may be dissolved prior to administration. Buccal hydration may be improved by 2 hourly ice chips, Biotene oral gel or AS Orthna (contains porcine mucin).

  3. To promote buccal or sublingual absorption keep the liquid in the mouth as long as possible without swallowing. Where the patient is not able to hold liquid in the mouth, the prescriber may choose to use a buccal tablet and gently massage the outside of the cheek following administration.

  4. The bioavailability of drugs is likely to be higher via transmucosal route compared with oral route but lower than via parenteral routes. The effect of the drug will depend on how long it can be retained next to the mucosa and any gastrointestinal absorption if the drug is swallowed.

  5. The need to supply the patient or caregiver with clear instructions on what each drug is being used for, how frequently it may be administered and how to administer each drug to avoid any administration errors, as well as any adverse effects to be aware of.

  6. Patients need to be monitored and assessed when switched to a transmucosal route and the dose adjusted as necessary.

  7. It is best practice that injections prepared for sublingual or buccal administration are drawn up through a filter needle to reduce the risk of any glass injury to oral mucosa.

Furthermore, care needs to be taken to identify whether patients are swallowing or spitting out a large proportion of orally administered medications as this may further affect its efficacy. Taste is a particularly important factor as an unpleasant taste may make patients less likely to retain the medication on the buccal mucosa long enough for it to be effective. Anderson observed that:

‘Buccal and sublingual administration, where there is considerable drug swallowed, results in lower plasma concentrations if that drug has a high first-pass effect because bioavailability is reduced’.3

In general, however, there is very limited pharmacokinetic and pharmacodynamic data available such as time to maximum concentration, time to maximum effect and half-life when using the mucosal route for off licensed drug administration. The lack of data regarding ‘concentration–response relationship for either the beneficial or adverse effects’3 of drugs means that adjustment of dose and frequency of administration to maximise efficacy and yet minimise adverse effects is very challenging.

Furthermore, many orodispersible products must be swallowed in order to be fully absorbed as they are designed to ease oral administration, rather than to be directly absorbed across the mucosal membrane. It is therefore not clear whether they would be clinically effective if a patient was unable to swallow the tablet residue. The extent of transmucosal absorption will depend on the physiochemical properties of the drug molecules, specifically molecular size and lipophilicity. In general, drugs that can penetrate blood brain barrier to act on the central nervous system are likely to have reasonable transmucosal absorption.

Despite these caveats and considerations, transmucosal medications present the possibility of delivering needle-free symptom control, something which is routinely employed in paediatric palliative care because ‘by and large, children hate needles’.3

Spathis and colleagues identified that this was an area of paediatric palliative care that had the potential to augment and enhance practice in adult palliative care:

‘Family members can respond immediately to symptoms, without having to wait for the arrival of nursing staff. This approach could be of considerable value in adult community palliative care practice’.4

The COVID-19 pandemic raised concerns that availability of district nurses in the community to administer medications via the traditional subcutaneous route for adults approaching the end of their lives may be outstripped by the steep increase in demand for their services. Additionally, there is a need to ensure that alternative medications are identified early so that this information is available to inform practice in the event of drug shortages.

Caution

All users of this guide are encouraged to use their professional judgement whenever selecting a transmucosal medication for a patient. The reader should note that this is neither a guideline nor a systematic review. Users must therefore consider their local and national guidelines as well as considering the evidence base for the drug they elect to use, its licencing, contraindications to its use and adverse events. Any statements regarding a drug’s licencing are related to its use in the UK only and users are advised to check the relevant licencing requirements if they are practising in other countries around the world.

Methods

During the initial phase of the COVID-19 pandemic, local, regional and national symptom management guidelines were created.5–15 These were hand searched to identify potential transmucosal alternatives that might be of use in the event of a patient having no oral or intravenous route and no access to subcutaneous injections.

Transmucosal alternatives are used in paediatric palliative care practice, both in the UK and internationally were explored. The experiences of expert colleagues working in a range of settings were sought, through both personal communication and published work.

Having identified potential therapeutic options, a list of alternative orodisperisible and transmucosal medications was reported and cross referenced with the British National Formulary (BNF), the Palliative Care Formulary (PCF) and the Association of Paediatric Palliative Care (APPM) Formulary and the Enteral Drug Handbook as appropriate.16–19

The potential list of transmucosal medications was discussed and reviewed by the author panel until consensus was achieved.

Results

We identified 27 potential transmucosal alternative medications, listed below, and present the potential risks and benefits of each, their licensing status and costings, as listed in the BNF. We present an example table, see (tables 1–28).

Table 1

Alfentanil buccal, sublingual or nasal

Table 2

Atropine sublingual

Table 3

Buprenorphine sublingual

Table 4

Carbamazepine rectal

Table 5

Cyclizine sublingual or rectal

Table 6

Diazepam rectal

Table 7

Diamorphine intranasal or sublingual

Table 8

Diclofenac rectal

Table 9

Docusate rectal

Table 10

Domperidone orodispersible

Table 11

Fentanyl nasal, buccal or sublingual

Table 12

Glycopyrronium sublingual

Table 13

Haloperidol buccal or sublingual

Table 14

Hyoscine hydrobromide chewable

Table 15

Ibuprofen orodispersible or chewable capsule

Table 16

Ipratropium nasal

Table 17

Levomepromazine buccal or sublingual

Table 18

Loperamide orodispersible

Table 19

Lorazepam sublingual

Table 20

Miconazole buccal

Table 21

Morphine rectal

Table 22

Morphine sublingual

Table 23

Olanzapine orodispersible

Table 24

Ondansetron orodispersible or rectal

Table 25

Oxycodone sublingual

Table 26

Paracetamol orodispersible or rectal

Table 27

Prochlorperazine buccal

Table 28

Risperidone orodispersible

Discussion

Paediatric palliative has historically made greater use of oral transmucosal drug delivery for symptom relief in the community than adult palliative care. This practice offers an opportunity for rapid administration of needle-free symptom management in adults for whom transfer to hospital or hospice is not their preference or may be inappropriate, without delay inherent in subcutaneous medication administration by healthcare professionals in the community.

Use of licenced orodispersible medication in novel ways in adult palliative care via the transmucosal route minimised the necessity to include other forms of ‘off licence’ or ‘unlicensed’ products in the list above. Healthcare professionals should use licensed medications by licensed routes in preference to ‘off licence’ or ‘unlicensed’ products wherever possible. However, situations may arise where, due to the nature of a patients’ condition, symptom(s) or the complexity of the clinical situation (including drug and staff shortages), there are no licensed alternatives available. In these circumstances, it is necessary to ‘give patients (or their carers) sufficient information about the medicines you propose to prescribe to allow them to make an informed decision’, answering any ‘questions from patients (or their carers) about medicines fully and honestly’.20

Therefore ‘off licence’ or ‘unlicenced’ alternatives have been included above where the author panel agreed that there is sufficient evidence, clinical experience or expertise of their use.

Reporting of learning from the experience in using transmucosal drugs in adult palliative care in the literature is encouraged to inform future practice. If combined with further research, this learning could lead to long-term changes in clinical practice, perhaps reducing the need for subcutaneous medication administration in the community in future.

Limitations

Due to the COVID-19 pandemic and the urgent need to generate a list of transmucosal medications, there was insufficient time to undertake a rapid literature review of every medication listed above in order to establish an up to date evidence base for each.

It is outside the scope of this document to be able to offer guidance on the order of transmucosal drug selection to achieve symptom management, that is, which drug would be first, second or third line for any given symptom.

Unlicensed alternatives that have been reported in the literature but are not listed in the BNF, PCF or APPM are not included. Consequently, the list of transmucosal drugs in this article may not include all those which some specialists may elect to use.

Conclusion

Transmucosal medications offer the possibility of enabling rapidly delivered needle-free symptom relief in the community without the need to wait for a healthcare practitioner to visit. However, the evidence base for their use via these routes is, largely, yet to be established.

A practical list of 27 medications has been identified and collated for healthcare professionals delivering care at the end of life to consider using in their practice. The list draws on existing knowledge of transmucosal delivery, in large part gained from clinical experience by colleagues in paediatric palliative care.

Should it be necessary to use this list of transmucosal drugs to deliver symptom management, then any experience gained should be combined and reported either on www.palliativedrugs.com or in the format of published articles. Combined with further research, this experience offers the possibility of reducing injection frequency and inherent delays in medication administration, particularly in the community setting.

References

Footnotes

  • Twitter @dr_mary_miller

  • Contributors AES drafted the manuscript, undertaking the literature search and constructing the tables for each drug listed assisted by MP and EH. AES, MP, EH, MC, MM and ICKW jointly agree the drugs to include in the manuscript. MP, EH, MC, MM and ICKW had supervising input throughout the drafting the final manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests ICKW is the founder of Therakind Ltd (UCL spin-off company) which developed Buccolam (buccal midazolam) and Ayendi (intranasal diamorphine).

    ICKW and EH received funding from the NIHR in England to investigate transmucosal use of diamorphine in paediatric palliative care.

  • Patient consent for publication Not required.

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

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