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Safety of benzodiazepines and opioids in very severe respiratory disease: national prospective study

BMJ 2014; 348 doi: (Published 30 January 2014) Cite this as: BMJ 2014;348:g445
  1. Magnus P Ekström, medical doctor, research fellow12,
  2. Anna Bornefalk-Hermansson, biostatistician3,
  3. Amy P Abernethy, associate professor45,
  4. David C Currow, professor5
  1. 1Department of Clinical Sciences, Division of Respiratory Medicine and Allergology, Lund University, SE-221 00 Lund, Sweden
  2. 2Department of Medicine, Blekinge Hospital, SE-37185 Karlskrona, Sweden
  3. 3Uppsala Clinical Research Center, Uppsala University Hospital, SE-752 37 Uppsala, Sweden
  4. 4Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, USA
  5. 5Discipline, Palliative and Supportive Services, Flinders University, SA-5041 Adelaide, Australia
  1. Correspondence to: M Ekström, Department of Medicine, Blekinge Hospital, SE-37185, Karlskrona, Sweden pmekstrom{at}
  • Accepted 17 January 2014


Objective To evaluate the safety of benzodiazepines and opioids in patients with very severe chronic obstructive pulmonary disease (COPD).

Design Population based longitudinal consecutive cohort study.

Setting Centres prescribing long term oxygen therapy in Sweden.

Patients 2249 patients starting long term oxygen therapy for COPD in Sweden between 2005 and 2009 in the national Swedevox Register.

Main outcome measures Effects of benzodiazepines and opioids on rates of admission to hospital and mortality, adjusted for age, sex, arterial blood gases, body mass index (BMI), performance status, previous admissions, comorbidities, and concurrent drugs.

Results 1681 (76%) patients were admitted to hospital, and 1129 (50%) died under observation. No patient was lost to follow-up. Benzodiazepines and opioids were not associated with increased admission: hazard ratio 0.98 (95% confidence interval, 0.87 to 1.10) and 0.98 (0.86 to 1.10), respectively. Benzodiazepines were associated with increased mortality (1.21, 1.05 to 1.39) with a dose response trend. Opioids also had a dose response relation with mortality: lower dose opioids (≤30 mg oral morphine equivalents a day) were not associated with increased mortality (1.03, 0.84 to 1.26) in contrast with higher dose opioids (1.21, 1.02 to 1.44). Concurrent benzodiazepines and opioids in lower doses were not associated with increased admissions (0.86, 0.53 to 1.42) or mortality (1.25, 0.78 to 1.99). Associations were not modified by being naive to the drugs or by hypercapnia.

Conclusions Lower dose opioids are not associated with increased admissions or deaths in patients with COPD and might be safe for symptom reduction in severe respiratory disease.


  • We thank Kerstin Ström, founder of the Swedevox register, and all the doctors and nurses who cared for the patients.

  • Contributors: MPE and AB-H acquired the data. MPE analysed and interpreted the data and is guarantor. All authors drafted the article, revised it for important intellectual content, and approved the final version.

  • Funding: This study was funded by the Research Council of Blekinge and the Swedish Heart-Lung Foundation.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work..

  • Ethical approval: The study was approved by the Lund University research ethics committee (157/2007 and 350/2008), the Swedish National Board of Health and Welfare, and the Data Inspection Board. All patients gave their informed consent to participate.

  • Transparency declaration: MPE affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

  • Data sharing: Group level data, statistical code, and full details of the exploratory secondary analyses are available from the corresponding author. Additional data are not available as patient consent for data sharing was not obtained.

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