Methods

Design: RCT, cross‐over, placebo‐controlled

Blinding: double

Methodological quality: 10/22 (Edwards Method Score)

Participants

Disease: COPD

Number (randomised): N = 5

Setting: hospital

Age (years, mean): not stated (only range: 51 to 68)

Sex (male/female): 4/1

Participant pool: 56

Randomised: 5; study completed: 5

Withdrawals/dropouts: 0 (intervention 2 (clorazepate 22.5 mg) with 3 dropouts; whole intervention excluded from analysis)

Reason for drop‐out (intervention 2): intolerable AEs (which AEs not mentioned)

Baseline parameters: FEV1 less than 50%

SpO₂ (mmHg): 65.36; SpCO₂ (mmHg): 41.58

Interventions

Drug (dose): 1. clorazepate (7.5 mg) at bedtime; 2. clorazepate (22.5) mg at bedtime; 3. placebo

Delivery: oral

Duration of treatment: 2 weeks

Outcomes

Breathlessness grade (1 to 6)

Results: no significant difference between clorazepate and placebo regarding dyspnoea and walking test (no numbers given; dyspnoea change only in graphs)

Adverse effects: none within the 5 participants in intervention 1 and placebo

SpO₂ and SpCO₂: no significant change

Notes

Author conclusion: this study failed to demonstrate that placebo or clorazepate consistently relieved breathlessness in non‐anxious people with severe COPD

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method not mentioned

(“Patients were assigned in a randomised double‐blind manner”)

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Double‐blinding stated in the abstract, but not mentioned further

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Not mentioned

Selective reporting (reporting bias)

High risk

Anxiety, depression, etc. were assessed but data not reported

Other bias

High risk

• Inclusion criterion “severe COPD” not explained (although the results of COPD functions did meet our inclusion criteria)

• No literature/validity regarding dyspnoea grading

• Lack of participant demographics (only gender and age range)

• Imbalance in male/female (4/1)

• No reasons for exclusion after screening

• Not clearly mentioned that “treatment” means “7.5 mg clorazepate” (conclusion made only after a statement that 22.5 mg group was excluded due to attrition)

• Results, especially for dyspnoea, poorly presented and difficult to read

• Data have been presented only in a graph describing “improvement” or “worse” compared to baseline after first and second week of intervention or placebo

• Numbers are only approximate, because it is difficult to read them in the graph

Methods

Design: RCT, cross‐over, placebo‐controlled

Blinding: double‐blind

Methodological quality: 18/22 (Edwards Method Score)

Participants

Disease: advanced cancer (12/17 lung cancer)

Number (randomised): N = 26

Setting: outpatient and inpatient

Age (years, SD): 67.2 (8.3)

Sex (male/female): 16/1

Participant pool: 54

Randomised: 26; study completed: 17

Withdrawals/dropouts: 9 (4 drowsiness, 1 deterioration, 1 dysphagia, 2 death, 1 unclear) (excluded from analysis)

Interventions

Drug (dose): lorazepam (0.5 mg twice daily = 1 mg per day)

Delivery: oral

Duration of treatment: 5 days (2 days wash‐out)

Outcomes

Dyspnoea VAS 0 to 100 ("How much trouble has your breathing caused you over the last 24 hours?")

Results (mean): baseline to 5 days after intervention: 1. lorazepam 49.18 to 44.49; 2. placebo 48.06 to 45.94

Adverse effects (number of AEs/number with withdrawals): 1. lorazepam: 5/3; 2 placebo: 4/1

No change or differences in anxiety and depression (HADS)

Notes

Author conclusion: there were no differences between lorazepam and placebo in relieving breathlessness

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"...was randomly determined by computer prior to the study commencement"

Allocation concealment (selection bias)

Low risk

"A randomisation list was kept by the pharmacy"

Blinding (performance bias and detection bias)
All outcomes

Low risk

Study was blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All data were presented

The study author sent the raw data in addition

Selective reporting (reporting bias)

Low risk

Study protocol is available

Other bias

Low risk

Study appeared to be free of other bias

Methods

Design: RCT, cross‐over, placebo‐controlled

Blinding: double

Methodological quality: 16/22 (Edwards Method Score)

Participants

Disease: COPD

Number (randomised): N = 29

Setting: outpatient

Age (years, mean): 65.4

Sex (male/female): 16/8 (complete)

Participant pool: not stated

Randomised: 29; study completed: 24

Withdrawals/dropouts: 5 (excluded from analysis)

Reason for drop‐out: 1 AE (placebo), 4 missed appointments

Baseline parameters: FEV1/FVC: 54%

SpO₂ (mmHg): 73.4; SpCO₂ (mmHg): 32.8

Interventions

Drug (dose): alprazolam 1.0 mg/day (0.5 mg twice daily)

Control: placebo

Delivery: oral

Duration of treatment: 1 week

Outcomes

Dyspnoea grade at rest (1 to 5); dyspnoea scoring at rest and exercise (VAS 0 to 10)

Results (mean, baseline to after intervention): alprazolam: 3.0 to 3.0; placebo: 3.2 to 3.0

No significant change in dyspnoea scoring during rest and exercise

Adverse effects: 11 reported (7/11 drowsiness), 9/11 on alprazolam

Functional test (12‐minute walking test in metres; baseline to after intervention): alprazolam: 896.5 to 880.88; placebo: 902.17 to 931.29

The resting SpO₂ was significantly higher with placebo and exercising SpCO₂ was significantly lower with placebo

Notes

Author conclusion: the subjective perception of dyspnoea was the same before and after alprazolam, at rest and during exercise

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

“...designed as a randomized...”

Not mentioned how this was done

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding (performance bias and detection bias)
All outcomes

Low risk

“double‐blind...using alprazolam and matching placebo”

Labelled bottles with tablets (alprazolam‐placebo‐wash‐out) described in detail

Probably done

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Total screened patients not mentioned

No intention‐to‐treat analysis (5/29 lost were excluded from analysis), however only one with AE (placebo)

Selective reporting (reporting bias)

Low risk

Broad information available, good summaries, good presentation

Other bias

Low risk

Pharmaceutical funding (company with alprazolam), although negative results

Methods

Design: RCT, parallel, multi‐arm (3), control: morphine and morphine + midazolam

Blinding: single‐blind (only participant blinded)

Methodological quality: 17/22 (Edwards Method Score)

Participants

Disease: terminal cancer (life expectancy less than a week)

Number (randomised): N = 101

Setting: hospital inpatient

Age (years, mean): 57.3

Sex (male/female): 47/54

Participant pool: n = 146

Randomised: 101; study completed: 70

Withdrawals/dropouts: 31 (all deaths) (excluded from analysis)

Interventions

Drug (dose): 1. morphine (Mo ‐ 10 mg/day); 2. midazolam (Mi ‐ 20 mg/day); 3. morphine + midazolam (MM ‐ Mo 10 mg/day + Mi 20 mg/day)

Rescue dose: 1. Mi 5 mg; 2. Mo 2.5 mg; 3. Mo 2.5 mg (this means that all 3 treatment arms could include a combination of morphine and midazolam)

Delivery: subcutaneous

Duration of treatment: 48 hours

Outcomes

Dyspnoea intensity: modified Borg scale 0 to 10

Results presented in the paper: baseline (mean) to after intervention (24/48 hours = median and P‐values): 1. (Mo) 7.1 to 3/2 (P=0.002/P=0.0001); 2. (Mi) 6.9 to 4/2 (P=0.018/P=0.004); 3. (MM) 6.8 to 3/2 (P=0.003/P<0.0001)

(Mean and CI (95%) for 24‐ and 48‐hour measures received from the authors (data skewed): 1. (Mo) 24 hours: 3.9 (2.8 to 5.0), 48 hours: 2.8 (1.6 to 4.0); 2. (Mi) 24 hours: 4.1 (2.8 to 5.4), 48 hours: 3.1 (1.7 to 4.5); 3. (MM) 24 hours: 3.4 (2.4 to 4.4), 48 hours: 3.0 (2.0 to 4.0))

Percentages of participants with breakthrough dyspnoea (24/48 hours): 1. (Mo) 34.3%/38%; 2. (Mi) 36.4%/38.5%; 3. (MM) 21.2%/24%

Numbers of breakthrough episodes of dyspnoea per participant (24/48 hours): 1. (Mo) 2/2; 2. (Mi) 1/1; 3. (MM) 1/1

Percentages of participants with dyspnoea relief after 24 hours: 1. (Mo) 69% (P=0.03); 2. (Mi) 46% (P=0.004); 3. (MM) 92% (P‐values compare to MM)

Percentages of participants with persistent, uncontrolled dyspnoea after 48 hours: 1. (Mo) 12.6%; 2. (Mi) 26% (P=0.04 compare to MM); 3. (MM) 4%

Adverse effects: the most frequently recorded AE was somnolence (Mo > MM > Mi)

Oxygen saturation (mean; baseline to after intervention; 24/48 hours): 1. (Mo) 72% to 72%/70%; 2. (Mi) 73% to 70%/70%; 3. (MM) 73% to 73%/71.5%

Anxiety: significant correlation between dyspnoea and anxiety at all times

Notes

Author conclusion: the data demonstrate that the beneficial effects of morphine in controlling baseline levels of dyspnoea could be improved with the addition of midazolam to the treatment

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

“...using a random number generator in 1:1:1 ratio in blocks of nine”

Allocation concealment (selection bias)

Unclear risk

Not mentioned how it was done

Blinding (performance bias and detection bias)
All outcomes

Low risk

“Drug administrations were performed in a single‐blind fashion.”

“One potential limitation of our study is the single‐blinded nature of the design. The treating physicians’ knowledge of which schedule of drugs the patient received could influence their need for administering rescue medications. A double‐blind design can avoid this, but was considered not appropriate for our study population by the Ethics Committee at our institution. Nevertheless, the risk for underestimation of rescue needs was minimized by a double assessment of breakthrough episodes carried out by caregivers and research physicians.”

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

45/146 excluded with statement of reasons

Attrition (deaths) clearly mentioned

Missing data not stated

Unclear if participants who experienced relief of dyspnoea was assessed on the whole number of participants or only on participants alive at the end of the study (30% died)

Selective reporting (reporting bias)

High risk

Unclear which other symptoms were measured (only anxiety‐dyspnoea is reported). Results of ECOG and MMSE not reported.

Dyspnoea relief (only after 24 hours) and uncontrolled dyspnoea (only after 48 hours)

Other bias

High risk

Using cross‐over rescue medication (midazolam for the morphine group and vice versa) could produce confusion for separate analysis

Methods

Design: RCT, parallel, control: morphine

Blinding: single‐blind (only participant and caregiver blinded)

Methodological quality: 21/22 (Edwards Method Score)

Participants

Disease: advanced cancer

Number (randomised): N = 63

Setting: outpatient clinic

Age (years, median, intervention group 1/2): 59/55

Sex (male/female): not mentioned

Participant pool: not mentioned

Randomised: 63; study completed: 61*

Withdrawals/dropouts: 2* (unable or unwilling to comply with the programmed follow‐up visits) (excluded from analysis)

*Data at day 5 for the morphine group were only available for 29 participants, therefore all calculations at day 5 were done with 29 participants

Interventions

Drug (starting dose within fast titration phase): 2 mg for oral midazolam or 3 mg for oral morphine with incremental steps of 25% of the preceding dose every 30 min until dyspnoea was alleviated 50% or more ("effective dose" used in follow‐up assessment)

Delivery: oral

Duration of follow‐up treatment: 5 days using the "effective dose" every 4 hours (except the sleep hours)

Outcomes

Dyspnoea relief (fast titration phase): 5‐category scale (0% none, 25% slight, 50% moderate, 75% a lot, 100% complete)

Dyspnoea intensity for the chronic component of dyspnoea (baseline and follow‐up assessment): NRS 0 to 10

Proportion of participants with BTD episodes

Number of BTD episodes per day

Results presented in the published paper:

In the fast titration phase dyspnoea relief of at least 50% was achieved in all participants in both arms (after starting dose: midazolam 21/32 vs morphine 11/31 (P = 0.023), after dosing step 1: 9/32 vs 11/31 (P = 0.59), and after dosing step 2: 2/32 vs 9/31 (P = 0.022)); in the follow‐up phase, mean (95% CI) baseline dyspnoea intensity is presented in a table: midazolam 8.8 (±0.3) vs morphine 8.7 (±0.3) (P = 0.62), but follow‐up results on dyspnoea intensity are only presented in figure with box plots (participants receiving midazolam maintained a significantly lower dyspnoea intensity level in comparison with the morphine group, during the 4 days of follow‐up) and as median at the second day in text: midazolam 6 vs morphine 4.5 (P = 0.003);

number of participants with 1 or more BTD episodes at baseline was 25 in both arms, and the proportion of participants with BTD episodes was significantly different at days 3 to 5, favouring the midazolam arm (data only presented by a figure);

therapeutic failure (i.e. NRS 8 to 10 by day 5) midazolam 0/31 vs morphine 6/30;

AE (n during fast titration phase): mild somnolence midazolam 18/32 vs morphine 15/31, mild agitation 2/32 vs 2/31, mild and moderate nausea only morphine 2/31 and 1/31;

AE (n during follow‐up): somnolence (time spent sleeping during daytime) 3 h to 5 h midazolam 4/31 vs morphine 5/30, 6.11 h only morphine 1/30; agitation grade 1/2 only in morphine arm 2/1/30; nausea grade 1 only morphine 1/30; constipation grade 2 only morphine 2/30; others midazolam 1/31 (cognitive disturbance) vs morphine 2/31 (cough g1, pruritus g2, xerostomia g1, flushing g1);

dose reduction (because of excessive somnolence): midazolam 1 vs morphine 2;

Oxygen saturation: no change in either group

Additional results received from the authors:

Mean (95% CI) dyspnoea intensity for baseline and day 5 measures (data skewed): 1. (midazolam) baseline: 8.84 (8.50 to 9.19), day 5: 3.23 (2.51 to 3.94); 2. (morphine) baseline: 8.74 (8.44 to 9.04), day 5: 6.00 (5.31 to 6.69)

Notes

Author conclusion: the data demonstrate the beneficial effect of midazolam versus morphine in the relief of chronic dyspnoea intensity and the number of episodes of breathlessness (breakthrough dyspnoea), while adverse events occurred and were comparable between both arms

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"random number generator in 1:1 ratio in blocks of six"

Allocation concealment (selection bias)

Low risk

"Numbered envelopes that were used to implement the randomization were concealed until interventions were assigned. The researchers had final responsibility for patient enrollment"

Blinding (performance bias and detection bias)
All outcomes

High risk

Only single‐blind

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No information on dealing with missing data or presence of it

Selective reporting (reporting bias)

Low risk

No indication of selective reporting

Other bias

Unclear risk

None

Methods

Design: RCT, cross‐over, placebo‐controlled

Blinding: double

Methodological quality: 15/22 (Edwards Method Score)

Participants

Disease: COPD

Number (randomised): N = 12

Setting: unclear

Age (years, mean): 64.9

Sex (male/female): 8/0

Participant pool: not stated

Randomised: 12; study completed: 8

Withdrawals/dropouts: 4 (excluded from analysis)

Reason for drop‐out: all on placebo (3/4 increasing dyspnoea and drowsiness, 1/4 acute exacerbation)

Baseline parameters: FEV1/FVC: all less than 65%

SpO₂ (mmHg): 76.0; SpCO₂ (mmHg): 38.0

Interventions

Drug (dose): alprazolam 0.75 mg/day (0.25 mg 3 times a day)

Control: placebo

Delivery: oral

Duration of treatment: 2 weeks

Outcomes

Dyspnoea (modified Borg scale 0 to 10)

Results* (baseline to after intervention): alprazolam: 3.6 to 3.6; placebo: 3.6 to 3.0 (*not explicitly stated if mean or median, but must be mean because of decimal numbers)

Adverse effects: none within the 8 participants

SpO₂ and SpCO₂: no significant change

Notes

Author conclusion: alprazolam did not alter the sensation of breathlessness

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

“Patients were started on a double‐blind, randomized crossover regimen”

“The patients then received either placebo or alprazolam 0.25 mg in a double‐blind fashion”

Not mentioned how this was done

Allocation concealment (selection bias)

Unclear risk

Not mentioned how it was done

Blinding (performance bias and detection bias)
All outcomes

Low risk

“The medication code was known only to the hospital pharmacist.”

“Patients were started on a double‐blind, randomized crossover regimen”

“The patients then received either placebo or alprazolam 0.25 mg in a double‐blind fashion”

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Described the attrition and reasons for it

Excluded from analysis, but stated that they did not differ with regard to spirometric measures

Demographics only from included participants (8/12)

No predicted FEV1 and FVC mentioned

Selective reporting (reporting bias)

Low risk

No indication for selective reporting

Other bias

High risk

Only men (Veterans Affairs Medical Center)

Methods

Design: RCT, placebo‐controlled, cross‐over design

Blinding: double

Methodological quality: 16/22 (Edwards Method Score)

Participants

Disease: COPD (stages III to IV)

Number (randomised/analysed): n = 17/14

Setting: outpatient center of a respiratory medicine department

Age (years, mean, SD): 61.6 ∓ 8.0

Sex (male/female): 10/4

Participant pool: 199

Randomised: 17; study completed: 14

Withdrawals/dropouts: 3 (excluded from analysis)

Reason for drop‐out: 1/3 on intervention: (exacerbation of COPD), 2/3 on placebo (1 obstructive sleep apnoea‐hypopnoea syndrome, 1 withdrew due to burden of the measurements)

Baseline parameters: FEV1/FVC (mean, SD) 32.7 ∓ 13, PaCO₂, kPa 5.4 ∓ 0.4, PaO₂, kPa 9.6 ∓ 0.7

Baseline sleep‐related complaints: difficulty maintaining sleep (experienced by 8 participants), a prolonged sleep‐onset latency (experienced by 7 participants), extensive daytime sleepiness (experienced by 6 participants), and nocturnal dyspnoea (experienced by 2 participants)

Baseline medication: inhaled corticosteroids 14/14, anticholinergics 13/14, β2‐antagonists 9/14, oral steroids 4/14, proton pump inhibitors 4/14, anticoagulants 4/14, other antihypertensives 4/14, theophylline 3/14, diuretics 3/14, acetylcysteine 1/14

Interventions

Drug (dose): temazepam 10 mg/day (30 min before bedtime)

Control: placebo

Delivery: oral

Duration of treatment: 1 week each, with 1‐week wash‐out time

Outcomes

Subjective dyspnoea (10‐point VAS)

Results (mean (SD)): subjective dyspnoea: baseline 3.8 (2.6), temazepam 4.2 (2.9), placebo 4.1 (2.5), P = 0.90;

transcutaneous carbon dioxide (PtcCO₂) during sleep: baseline 6.2 (0.6), temazepam 5.9 (1.0), placebo 6.3 (1.4), P = 0.27; oxygen saturation (SpO₂) during sleep: baseline 92 (2), temazepam 92 (3), placebo 92 (2), P = 0.31;

total sleep time, h (mean (SD)): baseline 5.7 (1.2), temazepam 6.3 (1.0), placebo 5.4 (1.1), P = 0.03;

sleep latency (10‐point VAS): baseline 4.4 (3.2), temazepam 3.3 (2.8), placebo 4.6 (3.2), P = 0.03;

amount of stage 2 sleep, minutes (non‐rapid eye movement sleep): baseline 130.8 (54.5), temazepam 168.8 (34.4), placebo 140.0 (44.6), P = 0.03;

no statistically significant changes for the other secondary outcomes;

Adverse effects: none reported

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Subjects were randomized after the baseline measurements to use 10 mg temazepam or placebo once a day orally, both during one week, separated by a washout‐period of one week. (...) Randomization was done by the hospital pharmacy."

Not mentioned of how this was done

Allocation concealment (selection bias)

Unclear risk

"Subjects were randomized after the baseline measurements to use 10 mg temazepam or placebo once a day orally, both during one week, separated by a washout‐period of one week. Randomization was done by the hospital pharmacy."

Blinding (performance bias and detection bias)
All outcomes

Low risk

"Subjects were randomized after the baseline measurements to use 10 mg temazepam or placebo once a day orally, both during one week, separated by a washout‐period of one week. Randomization was done by the hospital pharmacy. Subjects were instructed to take the study medication 30 min before they went to bed. (…) Sleep was manually staged according to standard methods by two qualified sleep technicians blinded to the subject’s treatment status."

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Described the attrition (3/17) and the reasons for it, but did not describe participant characteristics of dropouts. No intention‐to‐treat analysis (14 of 17 enrolled participants analysed)

Selective reporting (reporting bias)

Unclear risk

The article addresses only respiratory adverse events; it is unclear if other than respiratory events had occurred

Other bias

Unclear risk

• Lack of participant characteristics (e.g. no information on comorbidity, functional status)

• More male than female participants

• No control for specific participant characteristics or medication, no sensitivity analysis

• The stability of the COPD was not objectively confirmed with spirometry at the second week, but only assessed on clinical grounds

• Small sample size limits interpretation of secondary endpoints (including breathlessness intensity)

Methods

Design: RCT, cross‐over, placebo‐controlled, multi‐arm (3)

Blinding: double

Methodological quality: 15/22 (Edwards Method Score)

Participants

Disease: COPD

Number (randomised): N = 18

Setting: outpatient

Age (years, mean): 60.5

Sex (male/female): 15/3

Participant pool: not stated

Randomised: 18; study completed: 15

Withdrawals/dropouts: 3 (excluded from analysis)

Reason for drop‐out: 1 death (diazepam), 1 intolerable drowsiness (diazepam), 1 hypercapnia (placebo)

Baseline parameters: FEV1: 25.3%; FEV1/FVC: 0.38

SpO₂ (kPa): 9.5 (= 71.25 mmHg); SpCO₂ (kPa): 4.6 (= 34.5 mmHg)

Interventions

Drug (dose): 1. diazepam 25 mg/day (5 mg 3 times a day plus 10 mg at bedtime); 2. promethazine 125 mg/day (25 mg 3 times a day plus 50 mg at bedtime); 3. placebo

Delivery: oral

Duration of treatment: 2 weeks

Outcomes

Dyspnoea grade (1 to 5) after each intervention and daily dyspnoea by VAS (0 to 10) at rest and after exercise (only by graph)

Results (mean): dyspnoea grade: 1. 3.46 (diazepam); 2. 3.29 (P < 0.05) (promethazine); 3. 4.00 (placebo)

Adverse effects (6 ‐ reduce dosage): all drowsiness: 5/6 diazepam; 1/6 promethazine; 5/5 drowsiness incidents (like falling down stairs) with diazepam

Functional test (12‐minute walking test in metres): 1. 642 (P < 0.05) (diazepam); 2. 707 (P < 0.05) (promethazine); 3. 675 (placebo)

SpO₂ and SpCO₂: no significant change

No significant change in anxiety and depression

Notes

Author conclusion: diazepam had no significant effect on breathlessness and noticeably reduced exercise tolerance. Promethazine reduced breathlessness and improved exercise tolerance without altering lung function.

Review author: however, there is a beneficial effect of diazepam, although not significant

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

“The treatments were given in a randomized order.”

Not mentioned how this was done

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding (performance bias and detection bias)
All outcomes

Low risk

“Double‐blind” procedure was described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Although 3/18 participants were lost and excluded from the analysis, they would underline the presented results rather than bias them

Selective reporting (reporting bias)

Unclear risk

All main outcomes are presented in detail

The effect of diazepam in the relief of breathlessness is nearly statistically significant, but was discussed as "diazepam had no effect on breathlessness"

Other bias

Unclear risk

It is not explicitly stated if a wash‐out phase was used (on contacting the author, there was no wash‐out)

Results of compliance test are not mentioned

Screening method and numbers are not mentioned