Managing COVID-19 symptoms (including at the end of life) in the community: summary of NICE guidelinesBMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1461 (Published 20 April 2020) Cite this as: BMJ 2020;369:m1461
All rapid responses
Managing COVID-19 symptoms in the community (including at the end of life): NICE NG163 is a welcome step, but needs review
We read with great interest the summary of NICE guideline NG163: COVID-19 rapid guideline: managing symptoms (including at the end of life) in the community. NICE is to be congratulated on producing a series of guidelines for the COVID-19 crisis in such a short time. The letter from Dr (Lieutenant Colonel) Rajesh Chauhan et al, detailing their concerns around the recommendations for codeine, and the response by Dr Paul Chrisp, Director of the Centre for Guidelines at NICE, illustrate the inherent problems associated with producing UK national guidelines for a global problem.
We fully understand why shortcuts to the normal NICE guideline procedure were necessary, in order to produce COVID-19 guidance rapidly. But we are concerned that uncritical use of NG163 may create unintended risks for people with suspected or actual COVID-19 infection.
Under ‘General advice for managing COVID-19 symptoms’, NG163 recommends: “3.2 When managing key symptoms of COVID 19 in the last hours and days of life, follow the relevant parts of NICE guideline [NG31] on care of dying adults in the last days of life. This includes pharmacological interventions and anticipatory prescribing.” The earlier NICE guideline NG31 (2015) for symptom management at the end of life was based on studies carried out in people who were mostly in the advanced stages of cancer. However, in NG31 the evidence base was so poor that it did not publish detailed recommendations for drugs and doses. We are unaware of more recent high-quality research evidence that NICE could have used to produce such specific drug and dosing recommendations now for COVID-19 patients.
NG31 was aimed at care of people who were likely to die in the coming hours and days - usually from advanced diseases, from which recovery was deemed most improbable. Many people in the UK who are suspected of having COVID-19 will not have advanced cancer or be dying from another existing terminal condition. The accumulating global evidence shows that the case fatality rate reaches >50% in those needing mechanical ventilation, over 80 years and with serious underlying health conditions including congestive heart failure, chronic kidney disease and lung cancer. So it is worrying that while NG163 states “Note that symptoms can change, and patients can deteriorate rapidly in a few hours or less”, there is no counterpoint that most patients without the preconditions above will eventually recover. In contrast, NICE guideline NG31 emphasised the importance of how to recognise whether someone was dying, but also to keep open the possibility for recovery by ‘monitoring for further changes at least every 24 hours’.(5)
Compared with advanced cancer, COVID-19 is a condition that very few practitioners will have sufficient confidence to prognosticate on. For no doubt good intention to provide ease from distress, patients may be started by inexperienced practitioners on potent medications with detailed advice on how to escalate doses, but not on monitoring daily or more frequently, and how to wean off medication if the patient stabilises and recovery becomes possible.
We have further specific concerns. NG163 recommends codeine and morphine for the management of cough and breathlessness. (Codeine, is of course, a pro-drug converted to morphine by a process dependent on common pharmacogenetic variations which can lead to little or no effect in some patients, or severe opioid toxicity in others.) Although morphine is recommended in several places, only once is there mention of switching to oxycodone “if estimated glomerular filtration rate (eGFR) is less than 30 ml per minute”. We doubt if most practitioners in the community will have access to daily renal function results to know when to make that switch.
Given the propensity for COVID-19 to lead to acute kidney injury in 4 – 31% of cases, we would suggest that oxycodone could be considered as an alternative first-line drug for symptoms of COVID-19 (including pain), especially for those at risk of renal impairment or in the older population. Although small compared to the literature on morphine for breathlessness, the evidence for oxycodone is growing.
Moreover, the effect of renal impairment on morphine pharmacokinetics leading to adverse neurotoxic effects including acute delirium is well established. Thus focusing on morphine in NG163 might lead to increased use of lorazepam, midazolam, haloperidol or levomepromazine for sedation. Such a situation could potentially be avoided if oxycodone were used instead.
With respect to drugs used for sedation, the neuroleptics haloperidol and levomepromazine are recommended if midazolam alone does not work. There is no mention of the potential pharmacokinetic or pharmacodynamic drug interactions between the antibiotics that could be used for bacterial pneumonia in the community (e.g. clarithromycin/erythromycin, ciprofloxacin/levofloxacin) [10,11] and opioids or neuroleptics. For people who are not on antibiotics this will be of no consequence; but for those who are, it could lead to opioid toxicity including prolonged QTC interval.[12,13,14]
The combination of opioid, benzodiazepine and/or neuroleptic is used in specialist palliative care settings for symptom control and for ‘palliative sedation’ to reduce agitation at the end of life. It takes great skill and experience to use palliative sedation proportionately so that extreme physical and existential distress are palliated, but death is not primarily accelerated. NG163 states: “Sedation and opioid use should not be withheld because of a fear of causing respiratory depression.” If COVID-19 infection were uniformly fatal, this would be an acceptable statement. But for people not previously known to be at the end of life, there is potential risk of unintended serious harm, if these medications are used incorrectly and without the benefit of specialist palliative care advice.
Another concern is that the recommended doses for morphine and midazolam are sometimes higher than current guidelines state for non-specialist use; and moreover there are inconsistencies between the maximum doses recommended by the oral or subcutaneous routes.
In summary, we welcome NICE’s rapid production of practical guidelines to help community practitioners prescribe medication to ease the distress of people with serious COVID-19 infection. However, as current or retired consultants in palliative medicine, we respectfully suggest that some recommendations in NG163 should be revised to prevent inadvertently adding to that suffering.
Professor Emeritus Sam H Ahmedzai, The University of Sheffield
Dr Andrew Dickman, Liverpool University Hospitals NHS Foundation Trust
Dr Amara Callistus Nwosu, Lancaster University
Dr Barry J A Laird, The University of Edinburgh and St Columba’s Hospice, Edinburgh
Dr Catriona R Mayland, The University of Sheffield
Dr Ashique Ahamed, Manchester University Hospitals NHS Foundation Trust
Dr Sophie Harrison, Manchester University Hospitals NHS Foundation Trust
Dr Donna Wakefield, Consultant in Palliative Medicine, Newcastle-Upon-Tyne
Professor Mari Lloyd-Williams, University of Liverpool and LCCG / Liverpool Health Partners
Dr Jason Boland, Hull York Medical School, University of Hull
Dr Sam Fingas, Sheffield Teaching Hospitals NHS Foundation Trust
1. National Institute for Health and Care Excellence (NICE) in collaboration with NHS England and NHS Improvement. Managing COVID-19 symptoms (including at the end of life) in the community: summary of NICE guidelines. BMJ 2020;369:m1461
2. Chauhan R, Titus VTK, Singh AK, Chauhan S. Rapid Response: Perhaps a small change in NICE guidelines could help reduce mortality COVID-19 mortality. https://doi.org/10.1136/bmj.m1461
3. Chrisp P. Rapid Response: Re: Managing COVID-19 symptoms (including at the end of life) in the community: summary of NICE guidelines. https://doi.org/10.1136/bmj.m1461
4. BMJ Best Practice Coronavirus Disease 2019. (2020) https://bestpractice.bmj.com/topics/en-gb/3000168/prognosis (Accessed 13th May 2020)
5. NICE NG31 (2015). Care of dying adults in the last days of life.
6. Gasche Y, Daali Y, Fathi M, et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med. 2004;351:2827–2831.
7. NICE NG175 (2020). COVID-19 rapid guideline: acute kidney injury in hospital.
8. Yamamoto Y, Watanabe H, Sakurai A, et al. Effect of continuous intravenous oxycodone infusion in opioid-naïve cancer patients with dyspnea. Jpn J Clin Oncol. 2018;48(8):748‐752. doi:10.1093/jjco/hyy079
9. Lee KA, Ganta N, Horton JR, Chai E. Evidence for Neurotoxicity Due to Morphine or Hydromorphone Use in Renal Impairment: A Systematic Review. J Palliat Med. 2016 Nov;19(11):1179-1187
10. NICE NG165 (2020). Managing suspected or confirmed pneumonia in adults in the community.
11. NICE NG138 (2019). Pneumonia (community-acquired): antimicrobial prescribing.
12. Baxter K, Preston CL (eds), Stockley's Drug Interactions. [online] London: Pharmaceutical Press
13. Liukas A, Hagelberg NM, Kuusniemi K, Neuvonen PJ, Olkkola KT. Inhibition of cytochrome P450 3A by clarithromycin uniformly affects the pharmacokinetics and pharmacodynamics of oxycodone in young and elderly volunteers. J Clin Psychopharmacol. 2011;31(3):302–8.
14. Cronnolly B, Pegrum H. Fentanyl-clarithromycin interaction. BMJ Case Rep [published online]. 2012. doi:10.1136/bcr.02.2012.5936. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3417012/. (Accessed 10th May 2020)
15. Beller EM, van Driel ML, McGregor L, Truong S, Mitchell G. Palliative pharmacological sedation for terminally ill adults. Cochrane Database of Systematic Reviews 2015, Issue 1. Art. No.: CD010206. DOI: 10.1002/14651858.CD010206.pub2.
Competing interests: SHA has received financial payments from the pharmaceutical industry for research, education and consultancy on matters relating to drugs used for pain management in supportive and palliative care. SHA has previously worked with NICE on guideline and quality standards committees on end of life care - clinical management and service delivery. AD has received financial payments from the pharmaceutical industry for research, education and consultancy on matters relating to supportive and palliative care. ACN has no declarations. BJAL has received financial payments and grants from the pharmaceutical industry for research, education and consultancy on matters relating to drugs used in supportive and palliative care. CRM has no declarations. AA has no declarations. SH has no declarations. DW has no declarations. ML-W has no declarations. JB has no declarations. SF has no declarations of interest.
Re: Managing COVID-19 symptoms (including at the end of life) in the community: summary of NICE guidelines
Our new COVID-19 guidelines have been developed in direct response to the rapidly evolving situation. As with all our guidance, our recommendations are developed and reviewed using the best available evidence. We recognise that that this is a fast-moving situation and are reviewing and updating our rapid COVID-19 guidance as new evidence, policy and practice emerges.
In our rapid guideline on COVID-19 symptom management, we recommend simple measures such as honey for managing cough in the first instance. We recommend that short-term use of codeine linctus, codeine phosphate tablets or morphine sulfate oral solution is considered if a cough is distressing.
Codeine is indicated for dry or painful cough, and respiratory depression is a well-known side effect. As with all medication, clinicians should be aware of the risks and benefits before prescribing. As no suitable new evidence of safety issues has emerged regarding the use of codeine for patients with a distressing cough, the current recommendations remain valid and supported by the best available evidence. We will of course respond to any new safety advice as it emerges.
Our guidance also emphasises that it is important to be aware that older patients or those with comorbidities, frailty, impaired immunity, or a reduced ability to cough and clear secretions are more likely to develop severe pneumonia. In these situations, healthcare professionals should weigh the risks and benefits when deciding whether to prescribe codeine. As is reflected in current practice, these decisions are made every day and the new guidelines are there to support staff in their decision making.
As COVID-19 is a new disease, the global scientific community is generating significant volume of additional evidence every day. We are reviewing this evidence daily for the safety and efficacy of treatments for COVID-19. Our recommendations across all COVID-19 rapid guidelines will be updated as new evidence becomes available.
Competing interests: Director of the Centre for Guidelines, National Institute for Health and Care Excellence
Whole world has been wondering about this unusually high fatality rate in the UK, USA, and in some other European countries. It has commonly been the elderly octogenarians and above, who have fallen to COVID-19. Obviously their age and ill health due to previous medical conditions are at play. But is that all ?
Guidelines for managing COVID-19 symptoms have been given out by NICE and NHS, that have been recently published in the BMJ . It seems that herein lies the major problem, which needs to be rectified at the earliest before we lose out many more patients like the falling pins, one after another. Since these recommendations are more or less obligatory, perhaps that might be the reason for increased mortality that is being witnessed wherever these recommendations are implemented and being copied.
But for the sudden onset of respiratory depression and viral pneumonia in a few percent of cases of COVID-19 cases, this disease has been by and large been an irritating but a harmless disease [2-3]. Perhaps the recommendation to use Codeine is for the dry hacking cough, and maybe at the heart of this problem of high mortality .
MedlinePlus (Trusted Health Information for You) of the U.S. National Library of Medicine, gives out that, "Codeine may cause serious or life-threatening breathing problems, especially during the first 24 to 72 hours of your treatment and any time your dose is increased" . For the children, It says, " When codeine was used in children, serious and life-threatening breathing problems such as slow or difficulty breathing and deaths were reported. Codeine should never be used to treat pain or a cough in children younger than 18 years of age. If your child is currently prescribed a cough and cold medicine containing codeine, talk to your child's doctor about other treatments" . Notwithstanding, NICE and NHS still recommends, "For patients with COVID-19, consider short term use of codeine linctus, codeine phosphate tablets, or morphine sulfate oral solution to suppress coughing if it is distressing" .
We cannot speak sweepingly about all elderly, as many have been maintaining a good health and are far better than many of the youth around . That said, some do seem to be disproportionately affected as is given out in one of the recent news in the BMJ . One also needs to factor the management of pain through opioids and their combinations, plus the problem of polypharmacy in geriatrics . This should further limit the use of codeine because of adverse reactions to the medicines that are already being taken by a large percentage of elderly population for other associated medical problems. Simply put, unbridled use of Codeine may be fraught with danger, not only in the elderly who have other co-morbidities as well, but in the youth as well.
As such, not all but some elderly individuals also have decreased respiratory muscle strength and with codeine suppressing the cough reflex, build up of viral pneumonia and respiratory depression may be inadvertently hastened. Waning immunity in some of the elderly population as such would impair viral clearance, allowing easy spread of COVID-19 to the lower respiratory tract, resulting in increased inflammation. Slowed breathing, long pauses between breaths, or shortness of breath, are known to occur as adverse effects of codeine. In addition, there are chances of causing overdose of opioids, as many of the pain relievers may contain opioids, and codeine is from the opioid family. Addiction of these drugs could also be playing up in some cases.
Clearly, there are contraindications for codeine use [4-5]. We don't presume that all deaths can be averted by taking back the recommendation of using codeine. But if some lives can be saved, why not? Perhaps for the same reason the U.S. Food and Drug Administration had restricted the use of prescription codeine cough-and-cold medicines in children. A viral pneumonia can vary from a mild, self-limited illness to a life-threatening disease, and usually exhibits an overexuberant inflammation from the immune response, which is the mainstay of the pathogenic process. Respiratory viruses are known to damage the respiratory tract and multiple humoral factors are released as a host response. There already is a reduced mucociliary clearance, and stopping the cough reflex through codeine or other opioids may just be that tipping point, especially in such cases when antecedent factors have been unfavorable. Codeine is a bronchoconstrictor, and should be as such avoided in cases of a lung problem, breathing difficulty or short shallow breathing [8-10].
Amongst some of the youth, entertainment drugs, vaping, use of e-cigarettes, hookah bar/ vaping bars, tobacco smoking, and its effect on the children and family members of smokers, vapers. must not be forgotten. Codeine, if given as per the recommendations for the dry hacking cough that is co common with COVID-19, may suddenly tip the balance and cause poor outcomes because of its use. There could also be an element of possible euphoria, until it is too late. Impaired type 1 response may be the reason why immuno-compromised patients have more severe viral pneumonia.
So, there you see. Over a period of time, we have been conveying our best inputs about so many medical and health issues, which we think have been of considerable help. Of late, we have shared our advice and recommendations about COVID -19 as well [12-18]. Even for just an iota of difference, we might have to consider switch of opioids for pain and withhold recommending codeine during this COVID-19 pandemic for relief of dry hacking cough. World seems to be getting more and more impatient by the day . Too many deaths are causing panic and forcing lockdowns all around, with serious downturn of economy, productivity, jobs, shortage of essentials and of food as well. Maybe we can provide some hope, and prevent some of the deaths by reconsidering the official recommendations which are possibly being followed to the last word.
Dr (Lieutenant Colonel) Rajesh Chauhan
MBBS (AFMC), Master in Medicine (CMC Vellore), PGDGM (Geriatric Medicine), PGDDM (Disaster Management), AFIH (Industrial Health), DFM (Family Medicine), FISCD, ADHA (Hospital Administration) & LLB
Dr. V.T.K. Titus.
MS (Ortho), Diploma National Board (Ortho), Diploma Orthopedics
Professor & Head, Department of Orthopedics,
CMC Vellore, Tamil Nadu. INDIA.
Dr. Ajay Kumar Singh, MD (Medicine)
Asst Professor, Department of Medicine,
Index Medical College, Indore. India.
Dr. Shruti Chauhan, MDS
Reader, Index Dental College, Indore. India.
1. Managing COVID-19 symptoms (including at the end of life) in the community: summary of NICE guidelines BMJ 2020; 369 :m1461
2. Onder G, Rezza G, Brusaferro S. Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy. JAMA. Published online March 23, 2020. doi:10.1001/jama.2020.4683
3. Day Michael. Covid-19: four fifths of cases are asymptomatic, China figures indicate BMJ 2020; 369 :m1375
4. Codeine. Medline Plus. Available at : https://medlineplus.gov/druginfo/meds/a682065.html Accessed on 22 April 2020
5. Oliver David. David Oliver: What the pandemic measures reveal about ageism BMJ 2020; 369 :m1545
6. Iacobucci Gareth. Covid-19: Care home deaths in England and Wales double in four weeks BMJ 2020; 369 :m1612
7. Chauhan R, Chauhan S, Singh AK (2017) Polypharmacy in Geriatrics. J Gerontol Geriatr Res 6: e147. doi:10.4172/2167-7182.1000e147
8. Saggesse NP. Think twice before prescribing certain drugs to children. Br J Oral Maxillofac Surg. 2019 Jan;57(1):88-89. doi: 10.1016/j.bjoms.2018.11.013. Epub 2018 Dec 19.
9. Ono S, Ono Y, Koide D, Yasunaga H. Relationship Between Severe Respiratory Depression and Codeine-Containing Antitussives in Children: A Nested Case-Control Study. J Epidemiol. 2020;30(3):116–120. doi:10.2188/jea.JE20180224
10. Falsey AR; Walsh EE. Viral pneumonia in older adults. Clin Infect Dis. 2006; 42(4):518-24 (ISSN: 1537-6591)
11. Levy MM, Baylor MS, Bernard GR, Fowler R, Franks TJ, et al. Clinical issues and research in respiratory failure from severe acute respiratory syndrome. Am J Respir Crit Care Med. 2005; 171(5):518-26 (ISSN: 1073-449X)
12. Chauhan R, Titus VTK, Singh AK, Chauhan S. COVID 19 : Certain salient points. BMJ 17 April 2020. Available at :
https://www.bmj.com/content/369/bmj.m1447/rr Accessed on 23 April 2020
13. Chauhan Rajesh. COVID 19 : Fresh approach, initiative, and opportunity. BMJ 24 March 2020. Available at : https://www.bmj.com/content/368/bmj.m1141/rr-4 Accessed on 23 April 2020
14. Chauhan R, Singh AK, Chauhan S.. Covid-19 : Catch the tiger by its tail.
BMJ 28 March 2020. Available at : https://www.bmj.com/content/368/bmj.m1190/rr-1 Accessed on 23 April 2020
15. Chauhan R, Titus VTK. COVID 19 : Alcatraz type maximum security for only those who really need it. BMJ 03 April 2020. Available at : https://www.bmj.com/content/369/bmj.m1375/rr-3 Accessed on 23 April 2020
16. Chauhan R, Titus VKT. It shall be prudent to start testing seniors first for new corona virus infection (COVID-19). BMJ 04 April 2010. Available at : https://www.bmj.com/content/369/bmj.m1392/rr-0 Accessed on 23 April 2020
17. Chauhan R, Singh AK, Chauhan S. COVID 19: The last straw that broke a weak camel's back. BMJ 01 April 2020. Available at : https://www.bmj.com/content/368/bmj.m1199/rr-11 Accessed on 23 April 2020
18. Chauhan R, Titus VTK. COVID-19 : Stop this panic and be more reasonable fellas, huh? BMJ 08 April 2020. Available at : https://www.bmj.com/content/369/bmj.m1373/rr Accessed on : 23 April 2020.
19. Dyer Owen. Covid-19: Trump stokes protests against social distancing measures BMJ 2020; 369 :m1596
Competing interests: No competing interests