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Safety of benzodiazepines and opioids in interstitial lung disease: a national prospective study

Sabrina Bajwah, Joanna M. Davies, Hanan Tanash, David C. Currow, Adejoke O. Oluyase, Magnus Ekström
European Respiratory Journal 2018 52: 1801278; DOI: 10.1183/13993003.01278-2018
Sabrina Bajwah
1Dept of Palliative Care Policy and Rehabilitation, Cicely Saunders Institute, King's College London, London, UK
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Joanna M. Davies
1Dept of Palliative Care Policy and Rehabilitation, Cicely Saunders Institute, King's College London, London, UK
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Hanan Tanash
2Dept of Respiratory Medicine and Allergology, Institution for Clinical Sciences, Lund University, Lund, Sweden
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David C. Currow
3ImPACCT, Faculty of Health, University of Technology Sydney, Sydney, Australia
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Adejoke O. Oluyase
1Dept of Palliative Care Policy and Rehabilitation, Cicely Saunders Institute, King's College London, London, UK
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Magnus Ekström
2Dept of Respiratory Medicine and Allergology, Institution for Clinical Sciences, Lund University, Lund, Sweden
3ImPACCT, Faculty of Health, University of Technology Sydney, Sydney, Australia
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  • FIGURE 1
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    FIGURE 1

    Forest plot of benzodiazepine (BDZ)/opioid treatment and hospital admissions.

  • FIGURE 2
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    FIGURE 2

    Forest plot of benzodiazepine (BDZ)/opioid treatment and mortality.

  • FIGURE 3
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    FIGURE 3

    Cumulative incidence function (CIF) plot of benzodiazepine treatment on mortality.

Tables

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  • TABLE 1

    Baseline characteristics according to treatment status of 1603 patients with oxygen-dependent fibrotic interstitial lung disease

    BDZsOpioidsUnexposedp-value
    Subjects1962521214
    Age at starting LTOT years77.5±8.276.1±8.976.3±8.80.156
    Female89 (45.4)123 (48.8)415 (34.2)<0.001
    FEV1 % pred#66.3±37.367.0±39.771.6±40.30.106
    VC % pred#54.7±34.256.2±35.660.4±34.70.052
    FEV1/VC#0.9±0.30.9±0.30.8±0.40.427
    PaO2 breathing air# kPa6.5±1.06.6±1.06.6±1.00.441
    PaCO2 breathing air# kPa5.3±1.05.3±1.05.1±0.9<0.001
    PaO2 breathing oxygen# kPa5.7±0.95.7±1.05.4±1.00.001
    Smoking status
     Never-smoker61 (31.1)66 (26.2)338 (27.8)0.797
     Ex-smoker1 (1.0)3 (1.2)9 (0.7)
     Ex-/current smoker105 (53.6)149 (59.1)698 (57.5)
     Missing30 (15.31)37 (14.7)178 (14.7)
    BMI¶ kg·m−2
     <18.510 (5.1)12 (4.8)35 (2.9)0.579
     18.5–24.9107 (54.6)143 (56.8)707 (58.2)
     25–29.953 (27.0)67 (26.6)314 (25.9)
     ≥3026 (13.3)30 (11.9)158 (13.0)
    WHO Performance Status
     0–176 (38.8)93 (36.9)566 (46.6)<0.001
     254 (27.6)70 (27.8)350 (28.8)
     3–449 (25.0)60 (23.8)161 (13.3)
     Missing17 (8.7)29 (11.5)137 (11.3)
    Hospitalisations within 4 years before baseline4 (2–6)4 (2–6)2 (1–4)<0.001
    Hospitalised days out of the 91 days before baseline14 (5.5–24)15 (8–27)11.5 (4–21)<0.001
    Follow-up time hospitalised (follow-up time/hospitalised days) %7.6 (2.3–20.3)8.4 (2.6–19.8)6.2 (2.1–16.8)0.175
    Cardiovascular diseases n
     045 (23.0)59 (23.4)416 (34.3)<0.001
     13 (1.5)3 (1.2)58 (4.8)
     265 (33.2)68 (27.0)300 (24.7)
     ≥383 (42.4)122 (48.4)440 (36.2)
    Comorbidity
     COPD50 (25.5)67 (26.4)234 (19.3)0.010
     Cancer81 (41.3)107 (42.5)417 (34.4)0.016
     Depression/anxiety43 (21.9)33 (13.1)37 (3.1)<0.001
     Diabetes mellitus44 (22.5)73 (29.0)219 (18.0)<0.001
     Injury33 (16.8)54 (21.4)154 (12.7)<0.001
     Osteoporosis11 (5.6)35 (13.9)47 (3.9)<0.001
     Renal failure18 (9.2)25 (9.9)65 (5.4)0.007
     Pulmonary hypertension12 (6.1)24 (9.5)86 (7.1)0.315
     GORD12 (6.1)18 (7.1)37 (3.1)0.003
    BDZs
     High (>15 mg·day−1 oral oxazepam equivalent)65 (33.2)27 (10.7)
     Low (≤15 mg·day−1 oral oxazepam equivalent)131 (66.8)32 (12.7)
    Opioids
     High (>30 mg·day−1 oral morphine equivalent)33 (16.8)122 (48.4)
     Low (≤30 mg·day−1 oral morphine equivalent)27 (13.8)130 (51.6)
    Oral corticosteroids107 (54.6)135 (53.6)603 (49.7)0.284
    Azathioprine8 (4.1)13 (5.2)89 (7.3)0.142
    N-acetylcysteine81 (41.3)76 (30.2)372 (30.6)0.010

    Data presented as n, mean±sd, n (%) or median (interquartile range), unless otherwise stated. LTOT: long-term oxygen therapy; FEV1: forced expiratory volume in 1 s; VC: vital capacity; PaO2: arterial oxygen tension; PaCO2: arterial carbon dioxide tension; BMI: body mass index; WHO: World Health Organization; COPD: chronic obstructive pulmonary disease; GORD: gastro-oesophageal reflux disease; BDZ: benzodiazepine. Immunosuppressive drugs (including mycophenolate) used by five patients at baseline. #: summary statistics for imputed data applying Rubin's combination rules: FEV1 % pred (42.4% missing), VC % pred (42.7% missing), FEV1 (38.9% missing), VC (39.2% missing), PaO2 breathing air (22.4% missing), PaCO2 breathing air (22.8% missing) and PaO2 breathing oxygen (15.5% missing); ¶: missing BMI (31.1%) imputed into category 18.5–24.9 kg·m−2. p-value calculated using ANOVA, Kruskal–Wallis or Chi-squared test.

    • TABLE 2

      Exposure to benzodiazepines (BDZs) and opioids in 1603 patients with fibrotic interstitial lung disease

      BDZsOpioids
      Exposed at baseline
       Total196252
       Low dose131 (66.8)130 (51.6)
       High dose65 (33.2)122 (48.4)
       Dose at baseline DDD·day−10.2 (0.1–0.4)0.3 (0.1–0.5)
       Exposed at baseline but unexposed during follow-up51 (26.0)77 (30.6)
       Exposure during follow-up % of time83 (0–100)63 (0–100)
       Medication-naive (unexposed) in preceding 12 months#55 (29.3)59 (25.0)
      Not exposed at baseline
       Total14071351
       Unexposed at baseline but exposed during follow-up429 (30.5)401 (29.7)
       Dose during follow-up DDD·day−10.0 (0.0–0.0)0.0 (0.0–0.0)
       Exposure during follow-up % of time0 (0–16)0 (0–10)
       Medication-naive (unexposed) in preceding 12 months#1199 (92.7)1034 (83.1)

      Data are presented as n, n (%) or median (interquartile range). DDD: defined daily dose. #: among patients with at least 12 months of medication exposure data (n=1481).

      • TABLE 3

        Benzodiazepines (BDZs) and opioids and adjusted hazard ratio of admission to hospital and mortality in 1603 patients with oxygen-dependent fibrotic interstitial lung disease

        Adjusted HR (95% CI)#
        AdmissionMortality
        BDZs
         Untreated11
         Low dose1.19 (0.95–1.49)1.13 (0.92–1.38)
         High dose1.27 (0.92–1.73)1.46 (1.08–1.97)
        Opioids
         Untreated11
         Low dose1.21 (0.96–1.52)1.22 (0.99–1.50)
         High dose1.08 (0.86–1.35)1.11 (0.89–1.39)
        Covariates
         Age years0.98 (0.98–0.99)1.02 (1.01–1.03)
         Male1.05 (0.93–1.19)1.41 (1.24–1.60)
         VC % pred1.00 (1.00–1.00)1.00 (1.00–1.00)
         FEV1/VC1.07 (0.94–1.22)0.99 (0.89–1.11)
         PaO2 breathing air1.00 (0.93–1.07)1.00 (0.94–1.07)
         PaCO2 breathing air0.95 (0.84–1.07)0.89 (0.79–1.00)
         PaO2 breathing oxygen0.99 (0.88–1.10)0.99 (0.89–1.11)
         BMI kg·m−2
          <18.511
          18.5–24.91.26 (0.86–1.85)0.72 (0.52–0.99)
          25–29.91.30 (0.87–1.92)0.70 (0.50–0.97)
          ≥301.28 (0.85–1.93)0.54 (0.38–0.77)
         WHO Performance Status
          0–111
          21.09 (0.95–1.25)1.48 (1.29–1.70)
          3–40.78 (0.63–0.96)2.00 (1.67–2.38)
          Missing1.04 (0.86–1.26)1.49 (1.22–1.81)
         Cardiovascular diseases n
          011
          11.11 (0.85–1.47)1.03 (0.76–1.41)
          21.05 (0.90–1.22)0.99 (0.85–1.16)
          ≥31.04 (0.89–1.21)1.05 (0.90–1.23)
         Comorbidity
          Cancer1.15 (1.02–1.30)0.85 (0.75–0.96)
          Depression/anxiety0.79 (0.60–1.05)1.08 (0.82–1.41)
          Diabetes mellitus0.95 (0.82–1.10)1.04 (0.90–1.20)
          Injury1.05 (0.90–1.24)1.10 (0.93–1.29)
          Osteoporosis1.03 (0.80–1.33)0.83 (0.64–1.09)
          Renal failure0.83 (0.61–1.13)1.50 (1.19–1.90)
          Pulmonary hypertension0.88 (0.68–1.14)1.10 (0.86–1.41)
          GORD1.15 (0.85–1.56)0.85 (0.62–1.17)
         Hospitalisations within 4 years before baseline1.05 (1.02–1.07)0.99 (0.97–1.01)
         Hospitalised days within the 91 days before baseline1.00 (1.00–1.01)1.00 (1.00–1.01)

        VC: vital capacity; FEV1: forced expiratory volume in 1 s; PaO2: arterial oxygen tension; PaCO2: arterial carbon dioxide tension; BMI: body mass index; WHO: World Health Organization; GORD: gastro-oesophageal reflux disease. #: model adjusted for all variables in the table as well as smoking status, and use of corticosteroids, azathioprine and N-acetylcysteine.

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          Supplementary tables: sensitivity analyses ERJ-01278-2018_Supplement

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        Safety of benzodiazepines and opioids in interstitial lung disease: a national prospective study
        Sabrina Bajwah, Joanna M. Davies, Hanan Tanash, David C. Currow, Adejoke O. Oluyase, Magnus Ekström
        European Respiratory Journal Dec 2018, 52 (6) 1801278; DOI: 10.1183/13993003.01278-2018

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        Safety of benzodiazepines and opioids in interstitial lung disease: a national prospective study
        Sabrina Bajwah, Joanna M. Davies, Hanan Tanash, David C. Currow, Adejoke O. Oluyase, Magnus Ekström
        European Respiratory Journal Dec 2018, 52 (6) 1801278; DOI: 10.1183/13993003.01278-2018
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