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The National Institute for Health and Clinical Excellence (NICE) issued guideline CG140 in May 2012, for professionals commencing strong opioids in adult palliative care patients.1 Although this guideline is for non-specialist professionals who initiate opioid treatment (eg, general practitioners and generalist hospital doctors), the implications for those working in specialist palliative care settings will be significant. It is important that NICE guidelines should facilitate and consolidate the ongoing dialogue between generalists and specialists in palliative care. Here, we summarise the recommendations to highlight areas that are of particular importance to specialist palliative care providers.
Development of this guideline followed the NICE process for short clinical guideline development.2 Recommendations within the guideline were made after systematic reviews had been conducted to consider the best available evidence. Where minimal evidence was available, the Guideline Development Group's experience and opinion of what constitutes good practice was debated, considered and summarised. The guideline takes effect at the point in time when a palliative care patient has moderate to severe pain, which necessitates commencing strong opioid analgesia. The guideline does not cover the last days of life, nor does it go further into recommendations for second-line approaches for pain control.
A number of key areas are addressed: communication, starting strong opioids (first-line treatment options, titrating the dose, maintenance phase and what to do when oral opioids are not suitable), management of breakthrough pain, and management of side effects (constipation, nausea and drowsiness). These are summarised in table 1.
The Guideline Development Group (GDG) highlighted that communication with patients starting opioids is often inadequate and should incorporate the salient aspects of what opioid therapy entails. GDG members working in both community and hospital settings were aware that communication gaps exist when this intervention (initiation of opioids) is made. Exploring patients' concerns when discussing an opioid for the first time has a significant impact on whether or not a patient actually takes their medication as prescribed. The GDG recommended a minimum level of information that should be covered to constitute a good standard baseline of care (table 1). While the prescriber is responsible for ensuring that this patient–professional dialogue occurs, it may be the case that other healthcare professionals (nurses, pharmacists) will engage and/or expand on these conversations. Given the limited research to date in this area, a research recommendation was agreed upon to explore this further:
What are the most clinically effective and cost-effective methods of addressing patient and carer concerns about strong opioids, including anticipating and managing adverse effects and engaging patients in prescribing decisions? (Research Recommendation B13).
Starting strong opioids
Titrating the dose: the guideline is focused on the decision to commence strong opioids. This decision might be made by a general practitioner reviewing a community palliative care patient or a hospital doctor seeing an inpatient on a ward. The GDG agreed that offering patients a choice of immediate- or sustained-release formulations would be likely to improve adherence because patients would be able to choose the formulation that was most acceptable to them. Based on their clinical experience, the GDG recommended that all patients are given rescue doses of an immediate-release opioid to be taken as required, in order to minimise pain in the initial titration phase.
Wide ranges of doses are used in the initiation of opioids by hospital and community practitioners, and the guideline literature varies considerably.4 While NICE guidelines would not usually recommend doses, feedback from the consultation process and the GDG was that this was an important safety consideration. It was therefore decided that a safe starting dose of morphine should be suggested, to give inexperienced practitioners faced with a prescribing decision clearer guidance. The GDG recommended a starting dose of regular oral daily opioid (which can be prescribed as a regular immediate-release or sustained-release preparation) of 20–30 mg of morphine over 24 h, plus additional rescue doses of immediate-release oral morphine at a dose of 5 mg. It was also agreed that in both inpatient and community settings, regular and frequent review was necessary in the titration phase to allow appropriate dose escalation to achieve analgesia and to monitor side effects. For those patients with renal or hepatic impairment, specialist advice from a palliative care team should be sought, due to the challenges these particular clinical situations can pose when prescribing opioids.
First-line maintenance treatment
A literature search and a health economic modelling exercise5 were conducted to establish the most effective first-line maintenance treatment for patients with advanced and progressive disease who are able to take oral opioids. The GDG noted that uncertainty exists over the choice of a strong opioid for the maintenance treatment of background pain. The prescription of transdermal fentanyl and buprenorphine preparations has increased in both hospital and community settings, and the GDG decided that this warranted further consideration.
Based on the available evidence, the GDG noted that morphine is an effective and inexpensive opioid analgesic. Although its use may result in a small increase in gastrointestinal side effects compared with transdermal patches, the GDG agreed that this could be managed by using adjunctive treatment. More costly preparations would need to be justified by evidence of superior efficacy or a much lower side-effect burden. Studies comparing the effectiveness of fentanyl, buprenorphine and oxycodone with morphine were of poor quality and did not demonstrate superiority over morphine.
Health economic modelling showed that the benefit potentially conferred by fentanyl in reducing gastrointestinal side effects was not shown to be cost effective (ICER £107 532 per quality adjusted life year (QALY) gained at 1 month, see table 2 for explanation of abbreviations. The threshold that NICE sets for QALYs is £20 000 per QALY).
It was agreed that oral sustained-release morphine should be recommended as first-line maintenance treatment for patients with advanced disease, and that transdermal patch formulations should not be used routinely as first-line treatment. If pain control remains inadequate despite titrating and optimising oral sustained-release morphine, then generalist prescribers should consider seeking specialist palliative care advice.
First-line treatment if oral opioids are not suitable – transdermal patches and subcutaneous delivery
The GDG addressed the question of what happens to patients who cannot swallow oral medication, or have impaired absorption from the gastrointestinal tract (eg, due to nausea and vomiting). Recommendations were made on the use of transdermal and subcutaneous routes of administration in this setting. The evidence for effectiveness of transdermal patches was low quality, and definitive recommendations on which transdermal patch to offer patients could not be made. The GDG recognised that most patients in this category would have complex medical needs requiring specialist advice, however, there needed to be flexibility for experienced generalist prescribers and practitioners to offer transdermal preparations if and when analgesic requirements are stable. It was felt important to highlight approximate opioid equivalences for transdermal patches, so that generalist prescribers can make decisions on whether a patch would be at an adequate dose, compared with oral morphine.
For the subcutaneous delivery method, the review question focused on effectiveness of subcutaneous morphine compared with subcutaneous diamorphine or subcutaneous oxycodone in these patients. No evidence was found. The GDG recommended that subcutaneous opioids should be considered for patients in whom oral opioids are not suitable and whose analgesic requirements are unstable. The subcutaneous opioid with the lowest acquisition cost should be used, depending on a patient's potential previous adverse effect profile.
First-line treatment for breakthrough pain in patients who can take oral opioids
The aim of this topic was to determine the most effective strong opioid treatment for breakthrough pain. No randomised controlled trial (RCT) evidence was found comparing immediate-release morphine with immediate-release oxycodone. Based on clinical experience, the GDG agreed that oxycodone and morphine have very similar efficacies and side-effect profiles when used to manage breakthrough pain. However, morphine is less expensive than oxycodone and, therefore, the GDG recommended morphine for the first-line management of breakthrough pain.
For the comparison of immediate-release morphine with fast-acting fentanyls, evidence was reported for intranasal fentanyl compared with immediate-release morphine, and for transmucosal fentanyl compared with immediate-release morphine. This evidence related to breakthrough cancer pain. The GDG was aware that the available literature on non-cancer-related breakthrough pain is consistent with results from the cancer population and, therefore, the GDG agreed it was appropriate to extrapolate this evidence to the wider population. No evidence was found comparing sublingual and buccal fentanyl with immediate-release morphine.
The overall quality of the evidence across each of these interventions ranged from low to moderate as assessed by Grading of Recommendations Assessment Development and Evaluation Working Group (GRADE). Pain was the only outcome reported from the available evidence. No evidence was found for opioid side effects, adverse events, health-related quality of life or the percentage of patients switching to a different opioid. Because the patients included in these trials were already on other opioids, it was difficult to attribute side effects to the opioids given for breakthrough pain.
Evidence reported in both systematic reviews and one RCT suggested that intranasal fentanyl was associated with superior pain relief at particular time points compared with immediate-release morphine. Although this difference was statistically significant, differences were reported at only two out of six time points. At 10 min, 52.4% of patients taking fentanyl had responded, compared with 45% of patients taking morphine. At 15 min, 75.5% of patients taking fentanyl had responded, compared with 69.3% of patients taking morphine. Given the high numbers of patients responding to morphine in these trials, the GDG did not think that these differences in pain relief from this single, moderate quality trial were clinically relevant. The GDG was also aware of the relatively small population size in each of the included studies.
No formal cost-effectiveness analysis was conducted for this question, and a systematic review of the economic literature yielded no relevant data. The cost of treating an average breakthrough event was calculated, as shown in table 3. For the purpose of the costing exercise, it is assumed that the dose of the immediate-release preparations is equal to one-sixth of the regular daily dose. The GDG noted that fast-acting fentanyls (especially those which also require a spray canister) are considerably more expensive than immediate-release morphine, and there is no direct dose correlation with background opioid; median doses vary between trials.
The GDG was satisfied that there was limited evidence to suggest that fentanyl is more clinically effective than immediate-release morphine (and immediate-release oxycodone) for the management of breakthrough pain. However, it felt the cost impact of recommending fentanyl over immediate-release morphine or oxycodone would be considerable and, therefore, could not be justified. Therefore, the GDG agreed to recommend that fast-acting fentanyls are not offered to patients commencing first-line opioids, who are able to take oral opioid.
Management of side effects
The GDG considered constipation to be a side effect that affects nearly all patients receiving strong opioids. It therefore agreed that the best treatment strategy should be to offer regular laxatives at the same time as starting opioids. Laxatives should then be titrated and optimised before an opioid switch for constipation is considered. The GDG felt it important that patients be informed that treatment for constipation can take time to work, and that adherence is key to avoiding difficulties.
The GDG noted that nausea, as a side effect of opioid treatment, tends to occur at the start or when a dose is increased, but is usually transient. However, there was insufficient evidence to recommend that a regular antiemetic be prescribed in all patients when opioids are initiated. If nausea persists, antiemetic treatment should be considered, and there was some discussion as to delays that can occur for patients in the community setting who need to access adjuvant medications. For those patients where antiemetic regimens had been tried unsuccessfully, an opioid switch can be considered.
A research recommendation was agreed to explore this further:
‘Is prophylactic prescription of antiemetic treatment or the availability of antiemetic treatment at the patient’s home more effective in reducing nausea than the availability of prescription on request for patients starting opioids?’
The GDG noted that despite a lack of available evidence, recommendations were required on managing drowsiness in patients who are started on opioids for advanced and progressive disease. The GDG agreed that patients should be forewarned of this side effect, and while this may be transient, persistent symptoms require opioid switching. Dose reduction if pain is responding, or opioid switching, were both seen as appropriate management strategies when and where central side effects were persistent, and/or severe and specialist palliative care advice should be sought.
The GDG agreed that on starting opioids, and when doses are increased, patients may have impaired concentration which could affect their ability to undertake manual tasks such as driving. The GDG recommended that this should be discussed with the individual patient.
This guideline is the first opioid guideline to include a formal cost-effectiveness analysis. As such, the emphasis is different from the recent guideline from the European Association for Palliative Care.6 The clear recommendation is that oral morphine, rather than oral oxycodone or transdermal fentanyl/buprenorphine, be used first-line in palliative care patients requiring strong opioids for pain control. Improving dialogue with patients and carers to discuss their concerns, and advising them regarding dose titration and side effects is also paramount, and will be a challenge to take forward. A NICE electronic audit tool has been developed in parallel with this guideline, as a suggested way to help with implementing the recommendations in various settings.7 Specialist palliative care providers need to support their generalist colleagues in taking these steps, and must be available to give additional advice for more complex patients, or for those who fail to respond to a first-line opioid strategy.
This work was undertaken by The National Collaborating Centre for Cancer which received funding from the National Institute for Health and Clinical Excellence. The views expressed in this publication are those of the authors and not necessarily those of the Institute. The members of the NICE Guideline Development Group were Damien Longson (chair), Michael Bennett, Margaret Gibbs, Natalie Laine, Catherine Piggin, Joy Ross, Lindsay Smith, Catherine Stannard, Anna-Marie Stevens and Mark Taubert.
Competing interests MT, MB and JR were members of the NICE Guideline Development Group (GDG) tasked with writing NICE Guideline CG140. The National Collaborating Centre for Cancer was commissioned and funded by the National Institute for Health and Clinical Excellence to write this summary; MB has received honorariums for lectures from Cephalon and Grünenthal in the past three years but not during the period when the guideline was being developed; there were no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review Not commissioned; internally peer reviewed.
Correction notice This article has been corrected since it was published Online First. The following sections have been updated for grammatical purposes: 'The National Institute for Health and Clinical Excellence (NICE) issued guideline in May 2012,' now reads 'The National Institute for Health and Clinical Excellence (NICE) issued guideline CG140 in May 2012,'; 'While NICE guideline would not usually recommend doses,' now reads 'While NICE guidelines would not usually recommend doses,'; and the phrase 'to give inexperienced practitioners faced with a prescribing decision clearer guideline.' now reads 'to give inexperienced practitioners faced with a prescribing decision clearer guidance.'
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