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Abstract
Rationale: Patients with chronic obstructive pulmonary disease (COPD) commonly suffer from breathlessness, deconditioning, and reduced health-related quality of life (HRQL) despite best medical management. Opioids may relieve breathlessness at rest and on exertion in COPD.
Objectives: We aimed to estimate the efficacy and safety of opioids on refractory breathlessness, exercise capacity, and HRQL in COPD.
Methods: This was a systematic review and metaanalysis using Cochrane methodology. We searched Cochrane Central Register of Controlled Trials, MEDLINE, and Embase up to 8 September, 2014 for randomized, double-blind, placebo-controlled trials of any opioid for breathlessness, exercise capacity, or HRQL that included at least one participant with COPD. Effects were analyzed as standardized mean differences (SMDs) with 95% confidence intervals (CIs) using random effect models.
Measurements and Main Results: A total of 16 studies (15 crossover trials and 1 parallel-group study, 271 participants, 95% with severe COPD) were included. There were no serious adverse effects. Breathlessness was reduced by opioids overall: SMD, −0.35 (95% CI, −0.53 to −0.17; I2, 48.9%), by systemic opioids (eight studies, 118 participants): SMD, −0.34 (95% CI, −0.58 to −0.10; I2, 0%), and less consistently by nebulized opioids (four studies, 82 participants): SMD, −0.39 (95% CI, −0.71 to −0.07; I2, 78.9%). The quality of evidence was moderate for systemic opioids and low for nebulized opioids on breathlessness. Opioids did not affect exercise capacity (13 studies, 149 participants): SMD, 0.06 (95% CI, −0.15 to 0.28; I2, 70.7%). HRQL could not be analyzed. Findings were robust in sensitivity analyses. Risk of study bias was low or unclear.
Conclusions: Opioids improved breathlessness but not exercise capacity in severe COPD.
COPD affects 330 million people worldwide and is a major cause of suffering and earlier death (1). COPD is strongly associated with breathlessness, reduced physical capacity and activity, and impaired health-related quality of life (HRQL), often in a self-perpetuating cycle (2, 3). No intervention besides smoking cessation and long-term oxygen therapy in chronic hypoxemia has been consistently shown to slow the long-term progression of the disease and to improve prognosis in COPD (3). Given the scarcity of disease-modifying interventions and the presence of symptoms that often limit activity for many years, the backbone of current COPD management is symptomatic treatment (3).
Breathlessness is defined as the subjective experience of breathing discomfort and is the cardinal symptom of COPD (2, 3). In severe and end-stage COPD, as many as 95% of patients may suffer from breathlessness at rest or on minimal exertion (4). Patients may enter a vicious circle of limited physical activity to reduce distress from breathlessness, which leads to deconditioning and worsening breathlessness (2). Breathlessness is a harmful symptom, associated with increased anxiety and depression, impaired HRQL, loss of the will to live near death, increased risk of hospitalization, and increased mortality (2).
Evidence-based treatment of breathlessness in COPD includes pulmonary rehabilitation, optimal bronchodilation, and treatment of concurrent disease(s) (2, 3, 5). However, patients often have significant breathlessness despite optimal medical management of the underlying disease(s), termed refractory breathlessness (2). There is currently no registered treatment for the symptomatic relief of refractory breathlessness in COPD (3).
Regular, low-dose opioids have shown promising results for the relief of breathlessness in severe disease. Widely used in the treatment of refractory pain, systemic (but not nebulized) opioids were suggested to relieve refractory breathlessness in a metaanalysis of 18 small trials published by Jennings and colleagues in 2002 (6). No clear effect on exercise capacity was found (6). Jennings and colleagues evaluated effects in COPD in a subanalysis only and did not assess the quality of the evidence useful for clinical practice (6). Since then, several studies have been published on the effects of opioids on breathlessness and exercise capacity (7–9), including an adequately powered randomized trial (7). Physicians have reported concerns and reluctance to prescribe opioids in patients with severe COPD for fear of adverse effects, including respiratory depression (10). Systematic data on adverse effects across opioid trials in COPD are limited (11, 12). International guidelines on palliative care (13) and recent guidelines of the management of COPD state that systemic opioids can relieve breathlessness in severe disease (14–17) but highlight the need for data on net clinical benefit and safety of opioids in this population. A large national registry–based study recently reported that low-dose opioids were associated with neither increased rates of hospitalization nor death in patients with oxygen-dependent COPD (18). In light of the high burden and impact of breathlessness on HRQL and physical function, a comprehensive analysis of the safety and efficacy of opioids in COPD is needed.
We therefore conducted a systematic review and metaanalysis to estimate the efficacy and safety of opioid treatment on refractory breathlessness, exercise capacity, and HRQL in COPD.
This was a systematic review and metaanalysis using Cochrane methodology (19), reported in accordance with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements (20, 21). The review protocol is registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42014013918).
We included studies meeting all the inclusion criteria: (1) randomized; (2) double blind; (3) any opioid as intervention; (4) placebo controlled; (5) outcomes included breathlessness, exercise capacity, or HRQL; and (6) included at least one patient with COPD.
Exclusion criteria were lack of an intention-to-treat analysis and any systematic difference in given treatment between the study groups other than the intervention studied.
Searches were performed without any language restriction using the Cochrane Central Register of Controlled Trials (from inception to 8 September, 2014), MEDLINE including unindexed articles (1996 to 8 September, 2014), Embase (1996 to 8 September, 2014), Cochrane metaanalysis by Jennings and colleagues (6) published in 2001 (last search May 1999), and through hand searches of reference lists, personal reference libraries, contact with researchers in the field, and textbooks in respiratory and palliative medicine. Complete search history is found in the online supplement.
Articles were screened for eligibility based on title and abstract using Endnote X6 (Thomson Reuters, Philadelphia, PA). Articles judged as unlikely to be eligible and duplicates were removed. Articles with likely or unclear eligibility were obtained in full text and assessed independently by two authors (M.E. and F.N.) against the inclusion and exclusion criteria. Conflicting assessments were resolved through discussion with the other review authors (A.A.A. and D.C.C.).
Data were extracted on study characteristics, study population, interventions, and outcomes independently by two authors (F.N. and M.E.).
COPD diagnoses were categorized as whether verified by spirometry using the Global Initiative for Chronic Obstructive Pulmonary Disease criteria (3). High-dose opioid treatment was predefined as a daily dose above 30 mg oral morphine equivalents or a bolus equivalent to more than 10 mg intravenous morphine. Measurement at steady state was defined as outcome measurement after at least four biological half-lives of steady-dose treatment.
Risk of bias was assessed on the study level regarding the random sequence generation, allocation concealment, blinding, incomplete outcome data, and selective outcome reporting, using the Cochrane risk of bias tool (19).
The systematic review includes studies with ethical approval involving informed consent of participants to participate, wherefore additional ethical approval of this analysis was not needed.
Effects of opioid compared with placebo were analyzed on (1) level of breathlessness, (2) exercise capacity, (3) HRQL, and (4) risk of adverse effects.
The primary analysis was the effect on breathlessness of systemic (nonnebulized) opioids at steady state in the nonlaboratory (outpatient) setting.
Subgroup analyses were predefined according to route of treatment (nebulized or systemic), setting (laboratory or outpatient), measurement at steady state or not, measurement at rest or during exercise, and according to opioid dose in studies of systemic treatment (low or high using the abovementioned definition; nebulized doses could not be reliably categorized).
Sensitivity analyses were predefined as the exclusion of: studies involving any subjects without COPD, studies in which the COPD diagnoses were not verified by spirometry, trials of overlapping study populations, outliers (defined as a study Z below −1.96 or above 1.96), and studies analyzed using imputed correlations between crossover measurements, respectively. An ad hoc analysis including only the 25% largest trials was performed to explore the robustness of the findings.
For breathlessness, only submaximal measures at a defined time point (isotime) or work rate were included in the analyses, as people may exercise up to the maximal tolerable level of breathlessness irrespective of treatment. The 6-minute-walk test was regarded as a submaximal measure in line with international guidelines (22). For exercise capacity, distance on 6-minute-walk test and duration on cycle test were used if available, as these measures are likely to be most responsive (22). Changes from baseline were used in preference to postintervention scores in all analyses.
When a study reported several measurements on the same scale, a combined mean of the scores with the longest follow-up was included in the analysis (19). Correlations between crossover measurements were calculated for each study using source data whenever possible (23) or imputed using a conservative estimate from another study for breathlessness (7) and exercise capacity (24), respectively.
Effect sizes measured on different scales were compared as standardized mean differences (SMDs), calculated by dividing each study mean difference with its pooled SD (19).
Summary effects were estimated using random effects models and expressed as SMDs with 95% confidence intervals (CIs). The variance of SMD in crossover studies was calculated (19, 23). Heterogeneity was expressed as the I2 (19). Publication bias was explored using funnel plots (19).
Analyses were performed using Stata version 12.1 (StataCorp LP, College Station, TX) and Comprehensive Meta-Analysis version 2.2 (Biostat, Englewood, NJ).
Of an initial 3,896 articles, 16 studies with a total 271 participants (95% with COPD) were included in the review (Figure 1) (7–9, 24–35). All included studies were randomized and double-blind, and characteristics are shown in Tables 1 and 2. One study was a parallel-group trial (9), and 15 were crossover trials (7, 8, 24–35).
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 study flow diagram. COPD = chronic obstructive pulmonary disease.
[More] [Minimize]| Study | N (% Women) | Population | Mean Age (SD) (yr) | COPD Severity, Mean (SD) | Design | Setting | Comparison | Duration | Included Outcomes |
|---|---|---|---|---|---|---|---|---|---|
| Abernethy, 2003 | 48 (27) | COPD (n = 42), cancer (n = 3), motor neuron disease (n = 1) | 76 (5) | No data | Crossover | Outpatient | Oral morphine 20 mg vs. placebo | 4 d | VAS for dyspnea (at rest) |
| Restrictive lung disease (n = 2) | |||||||||
| Poole, 1998 | 16 (31) | COPD (n = 16) | 70.7 (6.4) | FEV1/VC 0.32 | Crossover | Outpatient | Sustained-released morphine, target dose 40 mg (mean 25 mg) vs. placebo | 6 wk | Likert scale for dyspnea (at rest) |
| FEV1 0.6 (0.16) L | 6MWT for exercise capacity | ||||||||
| Light, 1996 | 7 (0) | COPD (n = 7) | 66.4 (3.3) | FEV1/FVC 0.35 (0.07) | Crossover | Laboratory | Oral morphine 30 mg vs. placebo | Single dose | Borg score for dyspnea (exercise) |
| FEV1 0.99 (0.30) L | Cycle ergometer for exercise capacity | ||||||||
| Eiser: 1, 1991 | 14 (43) | COPD (n = 14) | 65 (range, 49–79) | FEV1/VC 0.43 (0.12) | Crossover | Outpatient | Oral diamorphine 2.5 mg × 4 and 5 mg × 4 vs. placebo | 2 wk | VAS for dyspnea (exercise) |
| FEV1 0.32 (range, 0.21–0.52) of predicted | 6MWT for exercise capacity | ||||||||
| Eiser: 2, 1991 | 10 (40) | COPD (n = 10) | 65 (range, 49–79) | FEV1/VC 0.44 (0.14) | Crossover | Laboratory | Oral diamorphine | 1 d | VAS for dyspnea (exercise) |
| FEV1 0.34 (range, 0.21–0.52) of predicted | 7.5 mg × 2 vs. placebo | 6MWT for exercise capacity | |||||||
| Johnson, 1983 | 19 (17) | COPD (n = 19) | 64.9 (9.1) | FEV1 0.83 (0.26) L | Crossover | Outpatient | Oral dihydrocodeine 15 mg vs. placebo | 1 wk | VAS for dyspnea (exercise) |
| Treadmill for exercise capacity | |||||||||
| Woodcock, 1982 | 16 (no data) | COPD (n = 16) | No data | FEV1 0.75 (0.27) L | Crossover | Outpatient | Oral dihydrocodeine 30 mg × 3 and 60 mg × 3 vs. placebo | 2 wk | Oxygen cost diagram for dyspnea (exercise) |
| 6MWT for exercise capacity | |||||||||
| Woodcock, 1981 | 12 (17) | COPD (n = 12) | 62 | FEV1 26% (range, 14–44) of predicted | Crossover | Laboratory | Oral dihydrocodeine 1 mg/kg | Single dose | VAS for dyspnea (exercise) |
| Treadmill for exercise capacity |
| Study | N (% Women) | Population | Mean Age (SD) (yr) | COPD Severity, Mean (SD) | Design | Setting | Comparison | Duration | Included Outcomes |
|---|---|---|---|---|---|---|---|---|---|
| Shohrati, 2012 | 40 (0) | COPD (n = 40) | No data | No data | Parallel groups (20 in each arm) | Outpatient | Nebulized morphine 1 mg vs. placebo | 5 d | VAS for dyspnea (at rest) |
| Jensen, 2012 | 16 (42) | COPD (n = 16) | 70.5 (2.3) | FEV1/FVC 0.49 (0.12) | Crossover | Laboratory | Nebulized fentanyl | 1 d | Borg score for dyspnea (exercise) |
| FEV1 69 (16) percent of predicted | Citrate 50 μg vs. placebo | Cycle ergometer for exercise capacity | |||||||
| Jankelson, 1997 | 16 (31) | COPD (n = 16) | 69 (range, 61–85) | FEV1/FVC 0.42 (0.10) | Crossover | Laboratory | Nebulized morphine | Single dose | Borg score for dyspnea (exercise) |
| FEV1 0.93 (0.33) L | 20 mg and 40 mg vs. placebo | 6MWT for exercise capacity | |||||||
| Noseda, 1997 | 17 (24) | COPD (n = 12), ILD (n = 1), heart failure (n = 1), cancer (n = 3) | 69 (11) | FEV1/FVC 0.43 (0.11) | Crossover | Inpatient | Nebulized morphine | Single dose | VAS for dyspnea (at rest) |
| FEV1 0.92 (0.29) L | 10 mg and 20 mg vs. placebo | ||||||||
| Leung, 1996 | 10 (40) | COPD (n = 9), ILD (n = 1) | 62 (range, 51–71) | FEV1/VC 0.51 (0.14) | Crossover | Laboratory | Nebulized morphine | Single dose | Cycle ergometer for exercise capacity |
| FEV1 43 (11) percent of predicted | 5 mg vs. placebo | ||||||||
| Masood, 1995 | 12 (0) | COPD (n = 12) | 66 (range, 58–79) | FEV1/FVC 0.41 (0.08) | Crossover | Laboratory | Nebulized morphine | Single dose | Cycle ergometer for exercise capacity |
| FEV1 0.88 (0.29) L | 10 mg and 25 mg and intravenous morphine 1 mg and 2.5 mg vs. placebo | ||||||||
| Beauford, 1993 | 8 (13) | COPD (n = 8) | 60.8 (9.1) | FEV1 0.90 (0.26) L | Crossover | Laboratory | Nebulized morphine | Single dose | Cycle ergometer for exercise capacity |
| 1 mg, 4 mg, and 10 mg vs. placebo | |||||||||
| Young, 1989 | 11 (no data) | COPD (n = 9), ILD (n = 2) | 58 (range, 39–74) | FEV1/FVC 0.31 (0.11) | Crossover | Laboratory | Nebulized morphine | Single dose | Cycle ergometer for exercise capacity |
| FEV1 0.82 (0.36) L | 5 mg vs. placebo |
As shown in Table 3, the risk of bias was estimated as unclear for the majority of study bias categories (Table3): random sequence allocation (69%), allocation concealment (69%), blinding of patients and personnel (69%), blinding of outcome assessment (94%), incomplete outcome data (38%), and selective outcome reporting (50%). The risk of bias was, however, not judged as high for any category (Table 3).
| Study | Random Sequence Generation (Selection Bias) | Allocation Concealment (Selection Bias) | Blinding of Participants and Personnel (Performance Bias) | Blinding of Outcome Assessment (Detection Bias) | Incomplete Outcome Data (Attrition Bias) | Selective Outcome Reporting (Reporting Bias) |
|---|---|---|---|---|---|---|
| Jensen, 2012 | Low | Low | Low | Unclear | Unclear | Unclear |
| Shohrati, 2012 | Unclear | Unclear | Unclear | Unclear | Unclear | Unclear |
| Abernethy, 2003 | Low | Low | Low | Low | Low | Low |
| Poole, 1998 | Low | Low | Unclear | Unclear | Unclear | Unclear |
| Jankelson, 1997 | Low | Low | Low | Unclear | Low | Low |
| Noseda, 1997 | Unclear | Unclear | Low | Unclear | Low | Unclear |
| Leung, 1996 | Unclear | Unclear | Unclear | Unclear | Low | Unclear |
| Light, 1996 | Unclear | Unclear | Unclear | Unclear | Low | Low |
| Masood, 1995 | Unclear | Unclear | Low | Unclear | Low | Unclear |
| Beauford, 1993 | Unclear | Unclear | Unclear | Unclear | Unclear | Low |
| Eiser: 1, 1991 | Unclear | Unclear | Unclear | Unclear | Low | Unclear |
| Eiser: 2, 1991 | Unclear | Unclear | Unclear | Unclear | Low | Unclear |
| Young, 1989 | Low | Low | Unclear | Unclear | Unclear | Low |
| Johnson, 1983 | Unclear | Unclear | Unclear | Unclear | Low | Low |
| Woodcock, 1982 | Unclear | Unclear | Unclear | Unclear | Unclear | Low |
| Woodcock, 1981 | Unclear | Unclear | Unclear | Unclear | Low | Low |
The analysis of breathlessness (12 studies [7, 8, 24–31], 8 of systemic and 4 of nebulized opioids; 200 participants) is shown in Tables 4 and 5.
| Study | Breathlessness | Exercise Capacity | HRQL | ||||
|---|---|---|---|---|---|---|---|
| Measure | Mean Change (Pooled SD) | Correlation between Measurements (from Data/Imputed) | Measure | Mean Change (Pooled SD) | Correlation between Measurements (from Data/Imputed) | Measure | |
| Abernethy, 2003 | VAS at rest; post scores | −9.5 (23.5) | 0.67 (Data) | No | — | — | Categorical 4-point scale of overall wellbeing |
| Poole, 1998 | CRQ dyspnea subscale (7-point Likert scale; high is good); change from baseline | −2.06 (4.38) | 0.38 (Data) | Distance on 6MWT; change from baseline | −56.7 (66.6) | 0.02 (Data) | CRQ total score; mean change from baseline |
| Light, 1996 | Borg scale at highest equivalent workload; change from baseline | −0.28 (0.49) | 0 (Imputed) | Time on incremental cycle test; change from baseline | 0.13 (0.65) | 0 (Imputed) | No |
| Masood, 1995 | Excluded (max only) | — | — | Time on incremental cycle test; mean of 2 doses; % change from placebo; post scores | −5.0 (19.6) | 0.82 (Imputed) | No |
| Eiser: 1, 1991 | VAS at end of 6MWT; mean of 2 doses; post scores | 0.5 (2.3) | 0.67 (Imputed) | Distance on 6MWT; mean of 2 doses; post scores | 7.5 (118.1) | 0.82 (Imputed) | Insufficient data |
| Eiser: 2, 1991 | VAS at end of 6MWT; mean of 2 measurements; post scores | 1.92 (1.90) | 0.49 (Data) | Distance on 6MWT; mean of 2 measurements; post scores | 15.0 (140.3) | 0.96 (Data) | No |
| Johnson, 1983 | VAS at treadmill at 75% of placebo distance; post scores | −0.9 (2.11) | 0.91 (Data) | Distance on incremental treadmill test; post scores | 36.0 (133.1) | 0.88 (Data) | No |
| Woodcock, 1982 | OCD (high score is good); mean of 2 doses; post scores | −2.6 (9.25) | 0.67 (Imputed) | Distance on 6MWT; mean of 2 doses; post scores | 19.0 (103.2) | 0.82 (Imputed) | No |
| Woodcock, 1981 | VAS on treadmill at 75% of placebo max distance; change from baseline | −1.23 (1.61) | 0 (Imputed) | Distance on incremental treadmill; change from baseline | 49.0 (39.2) | 0 (Imputed) | No |
| Study | Breathlessness | Exercise Capacity | HRQL | ||||
|---|---|---|---|---|---|---|---|
| Measure | Mean Change (Pooled SD) | Correlation between Measurements (from Data/Imputed) | Measure | Mean Change (Pooled SD) | Correlation between Measurements (from Data/Imputed) | Measure | |
| Jensen, 2012 | Borg scale at 75% of max on incremental cycle test; post scores | −0.6 (1.73) | 0.67 (Imputed) | Time on isotime incremental cycle test; post scores | 1.3 (2.31) | 0.82 (Imputed) | No |
| Shohrati, 2012 | VAS at rest; change from baseline | −1.9 (0.57) | Parallel study | No | — | — | VAS (high = better status); change from baseline |
| Jankelson, 1997 | Borg scale; highest value during 6MWT; mean of 4 measurements: directly and 1 h after each of 2 doses; post scores | −0.33 (2.04) | 0.67 (Imputed) | Distance on 6MWT; mean of 4 measurements (as for breathlessness); post scores | −9.45 (77.7) | 0.82 (Imputed) | No |
| Noseda, 1997 | VAS at rest; mean of 4 measurements (directly and 10 min after inhalation for each of 2 doses); change from baseline | −3.1 (27.1) | 0.84 (Data) | No | — | — | No |
| Leung, 1996 | Excluded (max only) | — | — | Max watts of incremental cycle test; post scores | −5 (11) | −0.13 (Data) | No |
| Masood, 1995 | Excluded (max only) | — | — | Time of incremental cycle test; mean of 2 doses; % change from placebo; post scores | −16.0 (25.5) | 0.82 (Imputed) | No |
| Beauford, 1993 | Excluded (max only) | — | — | Time on incremental cycle test; mean of 3 doses; change from baseline | 0.1 (0.58) | 0 (Imputed) | No |
| Young, 1989 | No | — | — | Time on cycle test at 80% of Wmax; change from baseline | 55.7 (90.1) | 0 (Imputed) | No |
In pooled analysis of all studies, opioids reduced breathlessness (SMD, −0.35; 95% CI, −0.55 to −0.17) (Figure 2). There was significant heterogeneity between studies of nebulized opioids (I2, 78.9%; P = 0.003) but not between studies of systemic opioids (I2, 0%; P = 0.438).
Figure 2. Effects of opioids on breathlessness in severe chronic obstructive pulmonary disease. Pooled estimates for nebulized and nonnebulized (systemic) opioids, respectively, and for opioids overall with 95% confidence intervals (CIs) using random effects metaanalysis.
[More] [Minimize]In the primary analysis, systemic opioids improved breathlessness in outpatients measured at steady state (five studies, 91 participants): SMD −0.33 (−0.52 to −0.14; I2, 30.4%).
Breathlessness was reduced by both systemic opioids (eight studies, 118 participants): SMD, −0.34 (95% CI, −0.58 to −0.10; I2, 0%) and nebulized opioids (four studies, 82 participants): SMD, −0.39 (95% CI, −0.71 to −0.07; I2, 78.9%), as shown in Figure 2. Excluding the outlier of Shohrati and colleagues (9), the heterogeneity was removed, but the effect of nebulized opioids became smaller and statistically nonsignificant (SMD, −0.17; 95% CI, −0.39 to 0.04; I2, 0%).
The effect of opioids seemed to be slightly lower in laboratory settings (SMD, −0.28; 95% CI, −0.56 to 0.00) than in outpatient studies (SMD, −0.42; 95% CI, −0.66 to −0.17). Measurement at steady state of the opioid showed slightly larger reductions in breathlessness: SMD, −0.42 (95% CI, −0.66 to −0.17) versus −0.28 (95% CI, −0.56 to 0.00) at nonsteady state.
The opioid effect was similar between studies measuring at rest/daily life (SMD, −0.30; 95% CI, −0.50 to −0.09) and at exercise (SMD, −0.31; 95% CI, −0.47 to −0.15), excluding Shohrati and colleagues (9). As only the study by Poole and colleagues (25) was categorized as high dose, analysis according to dose level could not be performed.
The findings remained unchanged in all sensitivity analyses: excluding (1) non-COPD studies (n = 2), (2) studies without spirometry-verified COPD, (3) the studies by Eiser and colleagues, which had overlapping study populations (27), (4) studies with imputed correlations between crossover measurements, (5) the 75% smallest trials (7, 28, 30), and (6) when setting the correlation between crossover measurements to zero for studies with imputed correlations.
Effects of opioids on exercise capacity were assessed by 13 studies (149 participants) (Tables 4 and 5) (8, 24–30, 32–35). All were crossover trials; 11 of 13 studies included patients with COPD only (8, 24–30, 33, 34), and all studies defined COPD using spirometry (Tables 1 and 2).
In a pooled analysis, there was no clear effect of opioids on exercise capacity: SMD, 0.06 (95% CI, −0.15 to 0.28; I2, 70.7%), as shown in Figure 3.
Figure 3. Effects of opioids on exercise capacity in severe chronic obstructive pulmonary disease. Pooled estimates for nebulized and nonnebulized (systemic) opioids, respectively, and for opioids overall with 95% confidence intervals (CIs) using random effects metaanalysis.
[More] [Minimize]There was no sign of effect on exercise capacity for systemic opioids (eight studies, 92 participants): SMD, 0.11 (95% CI, −0.17 to 0.39; I2, 63.3%) or for nebulized opioids (six studies, 69 participants): SMD, −0.01 (95% CI, −0.36 to 0.34; I2, 78.5%) (Figure 3). Findings were similar when only including the 11 studies of patients with COPD only and for measurements at steady state (four studies, 53 patients; after a mean 2.7 wk).
The estimates were similar when excluding the studies by Eiser and colleagues (27) and Masood and colleagues (33), which reported multiple exercise outcomes of overlapping study populations; when analyzing only the 25% largest trials (25, 28, 30); and when setting imputed study correlations between crossover measurements to zero.
Owing to study heterogeneity and insufficient data, metaanalysis of HRQL could not be performed. Data on quality of life were reported in three studies (7, 9, 25).
Poole and colleagues reported that quality of life, measured as the total Chronic Respiratory Questionnaire score, decreased slightly from baseline, −0.86 (pooled SD, 15.1), after 6 weeks’ opioid treatment compared with placebo (25). Abernethy and colleagues found no significant difference in overall wellbeing (categorical scale: poor, fair, good, or very good) after 4 days of morphine as compared with placebo (Wilcoxon signed rank test, P = 0.452) (7).
In the study by Shohrati and colleagues, global quality of life on a 100-mm visual analog scale (VAS) increased after 5 days’ opioid treatment by a mean 4.0 mm (pooled SD, 6.2) over baseline compared with placebo (9).
Owing to the heterogeneity of reported data, metaanalysis of adverse effects could not be performed. The mode of toxicity assessment, reported withdrawals, and adverse effects for each study are presented in Table 6. There were no reports in any study of major or serious adverse effects, no events of hypoventilation or respiratory depression, no opioid-related hospitalizations, and no deaths.
| Study | Assessment | Reported on Possible Adverse Effects |
|---|---|---|
| Shohrati, 2012 | Checked by physician 7 times daily | No considerable adverse effects. |
| Jensen, 2012 | Unclear | Four subjects were withdrawn from the study: 2 experienced lightheadedness, dizziness, and mild nausea during and immediately after nebulization of placebo and fentanyl citrate at visit 2, respectively. |
| Abernethy, 2003 | Prospectively using daily diary cards | Ten withdrawals: 5 on morphine (nausea, vomiting, sedation, chest pain, and atrial fibrillation) and 5 on placebo (chest infection, constipation, fall, pain, and increased dyspnea) |
| Among patients completing the study, morphine caused more distressing constipation than placebo (9 vs. 1, P = 0.021). Neither treatment caused significantly more distressing vomiting, confusion, sedation, or suppression of appetite. No irreversible events, hospitalizations, or deaths. | ||
| Poole, 1998 | Used no formal measurement tools. Three interviews per treatment period. | Two withdrawals: 1 due to constipation and shakiness and 1 exacerbation, both on morphine. More patients reported constipation, nausea/anorexia, and drowsiness on morphine than on placebo (36 vs. 15; P = 0.004). Four patients developed potential opiate withdrawal symptoms (sympathetic overactivity, insomnia, diarrhea, generalized lassitude, increased breathlessness and sputum production). Other adverse effects did not differ significantly. |
| Jankelson, 1997 | Unclear | One patient experienced lightheadedness on morphine. No other side effects. |
| Noseda, 1997 | Unclear | Three deaths, all unrelated to the experiment. None of the treatments caused any important adverse effects. |
| Leung, 1996 | Unclear | No adverse effects |
| Light, 1996 | Self-reported mental acuity (VAS scales) | No adverse effects |
| Masood, 1995 | Unclear | No major adverse effects. Three events of minor lightheadedness: 2 on low-dose nebulized morphine and 1 on placebo. A bitter taste was noted by 1 subject after low-dose and 2 subjects after high-dose nebulized morphine. |
| Beauford, 1993 | Self-reported mental acuity (VAS scales), test of motor speed | No adverse effects |
| Eiser: 1, 1991 | Prospectively using daily diary cards | Four withdrawals: 1 chest infection, 1 itching on diamorphine, 1 constipation on diamorphine, and 1 headache (cerebral metastases). Two patients had nausea and vomiting on diamorphine but completed the study. |
| Eiser: 2, 1991 | Unclear | Two withdrawals: 1 chest pain and 1 deteriorating blood gases (treatment unclear) |
| Young, 1989 | Unclear | No adverse effects |
| Johnson, 1983 | Prospectively of constipation, drowsiness, nausea, and anxiety using VAS scales | One withdrawal because of chest infection and right heart failure on dihydrocodeine. No significant difference in drowsiness, nausea, constipation, or anxiety between the treatment and placebo periods. |
| Woodcock, 1982 | Unclear | Five withdrawals: nausea and vomiting on dihydrocodeine. |
| Woodcock, 1981 | Unclear | Two were nauseated and dizzy after dihydrocodeine, but all subjects completed the trial. |
Reported side effects were transient and mainly mild to moderate constipation, nausea, and lightheadedness (Table 6).
Of studies measuring arterial blood gases (24, 27, 34), only one study reported an increase in PaCO2 on opioids, but in no patient did PaCO2 reach above 5.3 kPa after the intervention (24). There were no reports of significant opioid-related decreases in oxygen partial pressure (24, 27, 34) or oxygen saturation (7–9, 24–27, 29–34) or reduced ventilation during exercise (8, 29, 33, 35).
Funnel plots exploring possible publication bias for breathlessness and exercise capacity are shown in Figure 4. The funnel plot indicated that smaller studies (with less precision) may have been more likely to show a beneficial than nonbeneficial effect on breathlessness, suggesting possible publication bias among initial smaller trials. There were no indications of publication bias among larger trials, which had the largest weight in the random effects analyses.
Figure 4. (A and B) Funnel plots of studies of opioids on breathlessness and exercise capacity in chronic obstructive pulmonary disease.
[More] [Minimize]The main outcome measures for breathlessness and exercise capacity, along with ratings of the quality of the evidence according to GRADE, are shown in Table 7. The quality of evidence was rated as moderate for systemic opioids and low for nebulized opioids for the treatment of breathlessness and as low overall regarding exercise capacity.
| Outcomes | Pooled Standardized Mean Difference (95% CI) Compared with Placebo | Pooled Mean Difference* | No. of Participants (Studies) | Quality of the Evidence (GRADE) (21) | Comments |
|---|---|---|---|---|---|
| Breathlessness | On a 100-mm VAS* | ||||
| Systemic opioids | −0.34 (−0.58 to −0.10) | −8.0 (−13.6 to −2.4) | 118 (8) | +++ Moderate† | Studies of long-term, net clinical benefit in clinical settings might improve the quality of the evidence. |
| Nebulized opioids | −0.39 (−0.71 to −0.07) | −9.2 (−16.7 to −1.6) | 82 (4) | ++ Low‡ | Significant heterogeneity with the effect largely driven by a single outlier, in addition to the comments for systemic opioids. |
| Exercise capacity | Distance on a 6MWT (95% CI)* | ||||
| Systemic opioids | 0.11 (−0.17 to 0.39) | 11.4 (−17.5 to 40.2) | 92 (8) | ++ Low§ | Studies of long-term outcomes in clinical settings might improve the quality of the evidence. |
| Nebulized opioids | −0.01 (−0.36 to 0.34) | −1.0 (−37.2 to 35.1) | 69 (6) | ++ Low§ | Studies of drug delivery needed, in addition to the comments for systemic opioids. |
The main findings are that opioids reduced breathlessness in COPD with the strongest evidence for systemic therapy, whereas there were no effects on exercise capacity. No serious adverse effects related to opioids were reported in any study, including no reports of hospitalizations, respiratory depression, or carbon dioxide retention.
The opioid effect of SMD −0.35 (−0.53 to −0.17) corresponds to a mean difference in breathlessness of −8.2 mm (95% CI, −12.5 to −4.0) on a 100-mm VAS compared with placebo, or a 19% improvement from baseline, using data from Abernethy and colleagues (7) The minimally clinically important difference for chronic breathlessness has been estimated to be approximately 9 mm, although in the chronic setting patients may notice a difference with a reduction as small as 5.5 mm on a 100-mm VAS (36). Thus, the present analysis supports that low-dose opioids decrease breathlessness in a clinically important way in a substantial proportion of patients. The quality of evidence was graded as moderate for systemic opioids and low for nebulized opioids.
This analysis incorporates data from recent studies (7–9), including an adequately powered randomized trial (7); explores the validity of the findings through subanalyses; and assesses the quality of the current evidence. The effect overall and for systemic opioids, SMD −0.34 (−0.58 to −0.10), is consistent with the pooled effect reported by Jennings and colleagues, SMD −0.31 (−0.50 to −0.13) (6). The effect size of nebulized opioids was similar to that of systemic opioids in the current analysis and indicated a more beneficial effect than the effect in Jennings and colleagues (not only COPD): SMD, −0.39 (−0.71 to −0.07) versus −0.11 (−0.32 to 0.10) (37). The analysis of nebulized opioids, however, only included four heterogeneous studies and was largely driven by an outlier (9). When the outlier was removed, the effect of nebulized opioids became statistically and clinically nonsignificant. The quality of the evidence for nebulized opioids according to GRADE was rated as low. The net clinical benefit of nebulized opioids for breathlessness needs to be further validated in pharmacological and clinical studies.
The present study shows that in a pooled analysis of published trials, there is no evidence that opioids affect the submaximal exercise capacity in severe COPD. Any effect of opioids on quality of life remains unclear.
The review was conducted according to Cochrane methodology, using the PRISMA and GRADE statements (19–21). Analyzes included outcomes from all identified relevant double-blind, randomized trials and were performed including predefined subgroup and sensitivity analyses using random effects models. Findings were robust to the sensitivity analyses, supporting their validity.
Most included studies were small, which might carry the risk of residual confounding despite randomization. However, 15 of 16 studies were crossover trials, in which participants act as their own control subjects. The findings for systemic opioids were robust in sensitivity analyses, supporting their validity. The pooled effect of nebulized opioids was driven by the outlier finding from the study by Shohrati and colleagues (9), which studied a selected patient group with COPD secondary to mustard gas exposure. The clinical efficacy of nebulized opioids for breathlessness remains uncertain. The risk of bias was often difficult to estimate from available data but was not assessed as high for any category of any included study. Overall, most studies were of short duration, and data are limited on long-term effects of opioids and how the effect differs depending on the doses used (dose–response) and between different types of opioids. For exercise capacity, there are limited data on opioid effect in the longer term during training or daily life in a nonlaboratory setting. Assessments of adverse effects were often nonstandardized, insufficiently reported, short term, and likely underpowered to detect less common adverse effects even in this review across all published placebo-controlled trials in COPD. Data are lacking on whether reduced breathlessness from opioids translates into a net clinical benefit and improved HRQL.
The quality of evidence for regular, low-dose opioids for breathlessness in severe COPD would be improved by studies of longer-term treatment, including titration to desired effect, in clinical settings including rehabilitation training and daily life, with longitudinal systematic monitoring of adverse effects (including observational follow-up and pharmacovigilance studies adequately powered to detect clinically important adverse effects).
Registered or ongoing placebo-controlled studies include a crossover phase III trial of oral morphine on breathlessness and exercise tolerance in COPD (ClinicalTrials.gov: NCT01718496), a phase III study of oral morphine during pulmonary rehabilitation in COPD (Australian New Zealand Clinical Trial Registry: ACTRN12615000121561), and a phase III parallel group trial of oral morphine for refractory breathlessness in life limiting disease (Australian New Zealand Clinical Trial Registry: ACTRN12609000806268).
For the clinician, this systematic review supports that regular, low-dose opioids can improve breathlessness in a clinically meaningful way in patients with severe COPD (36), with the strongest and most consistent evidence for systemic therapy.
There were no reported serious adverse effects when starting opioids in 16 studies of 271 opioid-naive people (95% with severe COPD). The safety of regular, low-dose opioids in the present study is consistent with: the absence of any published case reports of serious adverse effects including respiratory depression, hospitalization, and death; an acceptable safety profile during a titration study of opioids in life-limiting disease with more than 30 person-years of follow-up (38); and the recent report that low-dose opioid treatment (up to 30 mg oral morphine equivalents per day) were not associated with increased hospitalization or death in 2,249 patients with oxygen-dependent COPD (18).
Based on the evidence to date (5–7, 18, 38, 39), regular, low-dose, oral morphine should be considered as a first-line treatment for breathlessness in severe COPD that persists despite best medical management. This recommendation is consistent with guidelines on palliative care (13) and on the management of severe and end-stage COPD by the National Institute for Health and Care Excellence NICE (17), the Canadian Thoracic Society (16), and the latest update from the Global Initiative for Chronic Obstructive Pulmonary Disease (15). We suggest that opioids should be initiated at a low dose regularly and titrated upward over days and weeks, balancing beneficial and adverse effects (11). Treatment assumes adequate follow-up of the patient’s clinical condition and reassessment of breathlessness using a validated tool as a numerical rating scale (5, 40). All patients should receive proper prophylaxis and treatment for common side effects such as opioid-related nausea and constipation (5, 7, 11). In this, the approach for chronic breathlessness is not different from that of opioid treatment for pain (5, 11).
In severe COPD, low-dose opioids reduced breathlessness, with the strongest evidence for systemic therapy, whereas exercise capacity was not affected. There were no serious adverse effects.
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Supported by the Swedish Society of Medicine, the Swedish Respiratory Society, the Swedish Heart-Lung Foundation, the Scientific Committee of Blekinge County Council, and the Wera and Emil Cornell Foundation.
No funding organization had a role in the design and conduct of the study, in the analysis and interpretation of data, or in the preparation or approval of the manuscript to be submitted.
Author Contributions: M.E. was the guarantor of the study and all authors had full access to all of the data in the study and take full responsibility for the integrity of the data and the accuracy of the data analysis. Conception and design: M.E., A.A.A., and D.C.C.; acquisition of data: M.E. and F.N.; analysis and interpretation of data: M.E., A.A.A., and D.C.C.; drafting the article: M.E. and F.N.; revision for important intellectual content and approval of the version to be published: M.E., F.N., A.A.A., and D.C.C.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org
Author disclosures are available with the text of this article at www.atsjournals.org.
