Sedative medications: an avoidable cause of asthma and COPD exacerbations?

We are concerned about the number of patients we have seen with asthma or chronic obstructive pulmonary disease (COPD) exacerbations who have been prescribed sedative medications. Asthma and COPD are obstructive lung diseases that, especially in the case of asthma, can be difficult to diagnose accurately. The main complications of obstructive lung disease are exacerbations—ie, episodes of worsening symptoms and lung function caused by infective or inflammatory insults.1Chan R Lipworth BJ Determinants of asthma control and exacerbations in moderate to severe asthma.J Allergy Clin Immunol Pract. 2022; 10: 2758-2760Summary Full Text Full Text PDF PubMed Scopus (4) Google Scholar One potentially overlooked cause of acute exacerbations is episodes of sedation or hypoventilation provoked by medication, leading to subclinical aspiration, chest infection, and even death,2Joseph KS Asthma mortality and antipsychotic or sedative use. What is the link?.Drug Saf. 1997; 16: 351-354Crossref PubMed Scopus (12) Google Scholar, 3Vozoris NT Wang X Fischer HD et al.Incident opioid drug use and adverse respiratory outcomes among older adults with COPD.Eur Respir J. 2016; 48: 683-693Crossref PubMed Scopus (91) Google Scholar especially in people who are obese or who have comorbidities, both of which are common in asthma and COPD.4Soriano JB Visick GT Muellerova H Payvandi N Hansell AL Patterns of comorbidities in newly diagnosed COPD and asthma in primary care.Chest. 2005; 128: 2099-2107Summary Full Text Full Text PDF PubMed Scopus (463) Google Scholar Sedative medications, such as opioids, depress respiratory drive, reduce muscle tone, and are associated with an increased risk of pneumonia, probably due to an increased risk of aspiration.3Vozoris NT Wang X Fischer HD et al.Incident opioid drug use and adverse respiratory outcomes among older adults with COPD.Eur Respir J. 2016; 48: 683-693Crossref PubMed Scopus (91) Google Scholar We hypothesise that there is also likely to be an increased risk of sedative-induced aspiration or hypoventilation events in patients taking other medications, such as pregabalin, gabapentin, and amitriptyline, which are mainly prescribed for neuropathic pain and depression. Concomitant treatment with gabapentin and opioids is associated with a substantially increased risk of opioid-related death5Gomes T Juurlink DN Antoniou T Mamdani MM Paterson JM van den Brink W Gabapentin, opioids, and the risk of opioid-related death: a population-based nested case-control study.PLoS Med. 2017; 14e1002396Crossref PubMed Scopus (320) Google Scholar and, collectively, these sedative drugs are listed online as potential respiratory depressants and as increasing the risk of chest infection or aspiration. Other mechanisms might be involved; sedative medications can suppress cough leading to airway mucous impaction and potentially infection, and various classes of psychoactive drugs could have immunosuppressive effects.6Roy S Ninkovic J Banerjee S et al.Opioid drug abuse and modulation of immune function: consequences in the susceptibility to opportunistic infections.J Neuroimmune Pharmacol. 2011; 6: 442-465Crossref PubMed Scopus (211) Google Scholar, 7Vallejo R de Leon-Casasola O Benyamin R Opioid therapy and immunosuppression: a review.Am J Ther. 2004; 11: 354-365Crossref PubMed Scopus (340) Google Scholar Most research on exacerbation prevention has focused on pharmaceutical therapies, reducing exposure to smoking and other forms of air pollution, and developing personalised asthma action plans for lung health. However, the possible role of sedative medications taken for reasons other than obstructive lung disease has received little interest from the research community. Although the risk of sedation and hypoventilation events are known to be increased by opioids and antipsychotic drugs,2Joseph KS Asthma mortality and antipsychotic or sedative use. What is the link?.Drug Saf. 1997; 16: 351-354Crossref PubMed Scopus (12) Google Scholar, 3Vozoris NT Wang X Fischer HD et al.Incident opioid drug use and adverse respiratory outcomes among older adults with COPD.Eur Respir J. 2016; 48: 683-693Crossref PubMed Scopus (91) Google Scholar, 8Wang MT Tsai CL Lin CW et al.Association between antipsychotic agents and risk of acute respiratory failure in patients with chronic obstructive pulmonary disease.JAMA Psychiatry. 2017; 74: 252-260Crossref PubMed Scopus (43) Google Scholar there has not been a systematic assessment of commonly prescribed medications with potential respiratory side-effects, including gabapentin, amitriptyline, and pregabalin. Moreover, the US Food and Drug Administration issued a safety alert about gabapentin and pregabalin, and both the Medicines and Healthcare products Regulatory Agency and Commission on Human Medicines legislative committee published advice on sedative medication after reports of severe respiratory depression with or without concomitant opioid treatment. Polypharmacy is increasing, and drugs with sedative effects have seen a surge in prescription over the past 10 years in England—although opioid use has now plateaued (figure). We used national prescribing data from National Health Service Digital, capturing all the prescriptions filled in England from Jan 1, 1998, to Dec 31, 2018. Over the past two decades, prescriptions of opioids have increased by almost 400% per 1000 population and gabapentin and pregabalin by well over 1000% per 1000 population in accordance with a UK study (figure).9Montastruc F Loo SY Renoux C Trends in first gabapentin and pregabalin prescriptions in primary care in the United Kingdom, 1993–2017.JAMA. 2018; 320: 2149-2151Crossref PubMed Scopus (72) Google Scholar Patients with asthma also have a higher prevalence of opioid use (10·4%) than those without asthma (6·1%).10Chalitsios CV McKeever TM Shaw DE Incidence of osteoporosis and fragility fractures in asthma: a UK population-based matched cohort study.Eur Respir J. 2021; 572001251Crossref PubMed Scopus (11) Google Scholar On our hospital wards, we regularly see patients with acute exacerbations of either asthma or COPD admitted while on a combination of gabapentin, pregabalin, amitriptyline, and opioids; however, there is little data or disease-specific guidance on how best to manage this problem, which often starts with a prescription in primary care. More research in this area is needed to provide robust evidence for any potential association between the prescription of sedative medications and exacerbations of obstructive airways disease, especially as a study in Taiwan in 2022 concluded that the use of typical antipsychotics is associated with a dose-dependent increased risk of severe asthma exacerbation.11Kuo CW Yang SC Shih YF Liao XM Lin SH Typical antipsychotics is associated with increased risk of severe exacerbation in asthma patients: a nationwide population-based cohort study.BMC Pulm Med. 2022; 22: 85Crossref PubMed Scopus (1) Google Scholar Although some secondary care respiratory physicians recognise the potential respiratory side-effects of polypharmacy, many other doctors and health-care professionals do not. The size of the problem urgently needs to be established, as well as any potential risk communicated to key stakeholders. In our experience, if a clinical problem can be observed during routine respiratory admissions, the size of the effect and, hence, the importance from a public health and societal perspective, is potentially large. Analysis of primary care databases using well established epidemiological methodologies should provide clarification of the presence and scale of any concerns regarding these medication categories and exacerbations of obstructive lung diseases. If correlation and causation are shown, other substances that have sedative effects, such as opioids in cough syrup, first-generation antihistamines, and excessive consumption of alcohol, should also be considered as potentially reversible risk factors for exacerbations of obstructive lung disease. Cessation of sedative medications can be problematic, as some are addictive, and the underlying indication or reason for the initial prescription is unlikely to have resolved. Occasionally these drugs are prescribed for neurological conditions, such as epilepsy, and the dose should not be altered. However, most are prescribed for chronic pain, fibromyalgia, or general anxiety disorder. Balancing the benefits of these drugs versus the potential risk of future respiratory exacerbations can be difficult and should be discussed with each patient. However, in our experience, once the rationale has been explained, cautious dose reduction is often possible. On discharge from hospital, a request should be made to the primary care doctor to reassess the indication and dose for sedative drugs. The potential risk of these sedative drugs can be explained in the request, and alternative analgesic and supportive strategies could be suggested. These supportive strategies could include physiotherapy, rehabilitation, or referral to a pain clinic,12Macfarlane GJ Kronisch C Dean LE et al.EULAR revised recommendations for the management of fibromyalgia.Ann Rheum Dis. 2017; 76: 318-328Crossref PubMed Scopus (718) Google Scholar many of which might be helpful once the patient is stable. Highlighting the risk of respiratory depression and polypharmacy in patients with chronic respiratory disease will enable general practitioners and family doctors to suggest these alternative treatments (with less risk for the individual patient), potentially reducing the number of exacerbations of obstructive lung disease. We declare no competing interests. CVC had full access to all the study data and takes full responsibility for the integrity of the data and the accuracy of the data analysis. CVC and DES had final responsibility for the decision to submit for publication.