We have illustrated the study selection process for the update of this review in Figure 1.
Results of the search
For the update, we included eight studies in total (Eimer 1985, Harrison (unpublished), Man 1986, Navigante 2006, Navigante 2010 (updated data which was an unpublished study in the earlier review), Shivaram 1989, Stege 2010 (this study was awaiting assessment in the earlier review), Woodcock 1981). In addition in this update, we included two study for awaiting classification (Hart 2012, Hardy 2016).
For the earlier review, we identified a total of 1309 references through the search of 14 databases. We excluded 207 duplicates. We studied the titles and abstracts of each of the 1102 articles and selected relevant articles if they met the inclusion criteria. In the earlier review, we sorted the 1071 excluded articles into the following exclusion groups: different disease (241 articles), different drug (223), reviews (242), anaesthesia-related study (111), psychology-related study (61), pharmacokinetic study (45), different design (38), palliative/terminal sedation (37), non-pharmacological interventions (14), and other (for example children) (59). We retrieved 31 articles for more detailed evaluation in the original review. In the earlier review, we identified 48 additional references from the reference lists of the original 31 articles by handsearching and the auxiliary function ‘Related Articles’ in Science Direct (www.sciencedirect.com). The search of 59 reviews, 16 textbooks, and seven websites did not yield any new articles. For the earlier review, we studied a total of 79 articles in more detail after obtaining the full text. Of these 79 articles, seven studies met our inclusion criteria and were included in the earlier review, and one study was awaiting classification (Stege 2010). We excluded a total of 74 articles for the earlier review. In addition, after sending a letter to all members of the Association of Palliative Medicine (UK) and after personal contact with several investigators (see above) at time of the original review, we were able to identify three new and unpublished studies (Harrison (unpublished), Navigante 2010, Stege 2010). We received data from two out of the three unpublished studies which we could include in the earlier review (Harrison (unpublished), Navigante 2010). The author of the third study could not send the data before submission and was set for "awaiting classification" of the earlier review (Stege 2010).
For the update of the review, we identified 1884 records: 32 articles in CENTRAL, 92 in MEDLINE, and 1760 in EMBASE. We also identified one potentially relevant clinical study report in trial registries. After de-duplication, there were 1769 articles for assessment. After screening titles and abstracts and exclusion of 1749 studies (see Figure 1 for reasons of exclusion) we obtained full copies of 19 published studies and one study from trial registries. Of these 20 records, we excluded 17 studies and the record from trial registries (this was a pilot study which failed to recruit any participants and was therefore excluded (NCT01687751, personal communication with Neil Hilliard, June 2015)). One of the excluded records was a study protocol only, and the study was cancelled early before any participants were included (Daubert 2014; personal communication with Eliza Daubert and Scott Bolesta in June 2015). Two additional studies were considered for awaiting classification. One out of these two studies was published only as a conference abstract and we received no data until the time of submission of the review (see Characteristics of studies awaiting classification) (Hart 2012). The second study was published just before the submission of this review and the data will be considered at the next update (conclusion of this study supports the conclusion of the review) (see Characteristics of studies awaiting classification) (Hardy 2016). Finally for the update, we added one new study to the seven studies of the original review (Stege 2010 - this study was unpublished and awaited assessment in the earlier review). In addition, we updated data of one previously unpublished but previously included study (Navigante 2010).
See Characteristics of included studies.
Eimer 1985: a double-blind, placebo-controlled, cross-over RCT tested clorazepate in five non-anxious participants with severe COPD in a hospital setting to determine whether relieving breathlessness could be achieved. The study started with three arms (7.5 mg/day and 22.5 mg/day oral clorazepate compared to placebo), but the high-dose arm (22.5 mg) was excluded from analysis after 3 out of 5 participants dropped out due to intolerable adverse effects. The duration of treatment was two weeks with a one-week wash-out period. Breathlessness was assessed weekly with a Breathlessness Grade from 1 (little breathlessness) to 6 (extreme breathlessness). Secondary outcomes were anxiety, depression, adverse effects, a 12-minute walking test, and attrition.
Harrison (unpublished): the effectiveness of lorazepam in the relief of breathlessness was tested in a randomised, double-blind, placebo-controlled, cross-over study of 26 participants with advanced cancer in an in- and outpatient setting (single-centre). Seventeen participants completed the study and were included in the analysis. The study tested lorazepam 0.5 mg twice daily orally over five days with a two-day wash-out period. A visual analogue scale (VAS) (0 to 100) was used to measure breathlessness as primary outcome (responding to three questions: 1. breathlessness in general over the last 24 hours (summary); 2. breathlessness at its best over the last 24 hours; and 3. breathlessness at its worst over the last 24 hours). Secondary outcomes were anxiety and depression (measured on the Hospital Anxiety and Depression Scale (HADS)) and adverse effects after the treatment.
Man 1986: a double-blind, placebo-controlled, cross-over RCT of 29 participants with advanced but clinically stable COPD in an outpatient setting assessed the efficacy and safety of alprazolam in relieving breathlessness. The analysis included 24 participants, and five participants dropped out. The study compared the effect of alprazolam 1.0 mg/day orally to placebo before and after one week of treatment (with a one-week wash-out period after cross-over). Breathlessness was measured either by Grade of Dyspnoea with 5 (breathlessness at rest) to 2 (able to keep up with people of similar age on level, but not on hills and stairs) to 1 (other than 2 to 5), as well as with a Dyspnoea Scoring (VAS 0 to 10) at rest and during exercise (bicycle ergometer). The study measured adverse effects, attrition, and a 12-minute walking test as additional outcomes.
Navigante 2006: a single-blind RCT with a parallel design assessed the role of midazolam in the alleviation of severe breathlessness during the last week of life of 101 participants with advanced cancer. The investigators conducted a three-arm trial in a hospital setting comparing morphine only (10 mg/day), midazolam only (20 mg/day), and the combination of morphine plus midazolam (10 plus 20 mg/day), with a treatment duration of 48 hours and subcutaneous administration. The dose was adjusted if the participant was not morphine naive (+25% on top of daily subcutaneous equivalent dose of morphine). Rescue medication was provided with 5 mg midazolam in the morphine group and 2.5 mg morphine in the midazolam and midazolam plus morphine group. Breathlessness was the primary outcome, assessed in four different ways:
Breathlessness intensity with the modified Borg scale (0 to 10) before the intervention and 24 and 48 hours after intervention;
Percentage of participants with breathlessness relief (yes/no) after 24 and 48 hours and no breathlessness relief after 48 hours;
Numbers of episodes of breathlessness ('breakthrough dyspnoea' = numbers of rescue medication) per participant after 24 and 48 hours; and
Percentage of participants with episodic breathlessness after 24 and 48 hours.
Other outcomes were adverse effects (total of clinical relevance and different adverse effects in grading 1 to 3), anxiety, and attrition.
Navigante 2010: a single-blind RCT with a parallel design was undertaken with 63 participants with advanced cancer and breathlessness in a single-centre outpatient clinic (two participants dropped out after randomisation). The aim was to assess the efficacy of oral midazolam for the relief of breathlessness in comparison to oral morphine. A fast titration phase (FTP) was used to determine the effective dose (effect of at least 50% reduction of breathlessness) for the follow-up phase (FUP) starting with midazolam 2 mg every four hours (excluding sleeping time) and morphine 3 mg every four hours (excluding sleeping time) with incremental steps of 25% of the preceding dose every 30 minutes. The duration of treatment in the FUP was five days with daily assessment of the primary endpoint breathlessness intensity (numeric rating scale (NRS), 0 to 10) and the secondary outcomes number of episodes of breathlessness per day, descriptors the participant used for breathlessness, and the number of adverse effects. The study reported dose reduction, therapeutic failure, and additional procedures (for example antibiotics).
Shivaram 1989: a double-blind, randomised, placebo-controlled, cross-over study of 12 participants with advanced COPD with anxiety (non-psychiatric stage) in an unknown setting (probably hospital) assessed the effect of alprazolam to relieve breathlessness. Four participants dropped out and were excluded, leaving eight participants for analysis. The study compared the effect of oral alprazolam 0.75 mg/day to placebo at baseline and after two weeks of treatment (with two days wash-out). Breathlessness was measured on a modified Borg scale (0 to 10). No other outcomes except adverse effects were assessed.
Stege 2010: a double-blind, randomised, placebo-controlled, cross-over study of 17 participants with COPD (Global Initiative for Obstructive Lung Disease (GOLD) stages 3 or 4) with insomnia in an outpatient centre of a respiratory medicine hospital department. The aim of the study was to assess whether temazepam (10 mg daily over one week) influences indices of breathing and gas exchanges during sleep; the effect on dyspnoea sensation (assessed with 10-point VAS) and other outcomes were secondary objectives. Three participants dropped out, leaving 14 participants for analysis.
Woodcock 1981: a double-blind, placebo-controlled, cross-over RCT of 18 participants with severe COPD compared the effect of oral diazepam (25 mg/day) and promethazine (125 mg/day) on breathlessness. Three participants dropped out, leaving 15 participants for analysis. Breathlessness was the main outcome, assessed as 'daily dyspnoea' by VAS (0 to 10) and 'dyspnoea grade' 5 (breathlessness at rest) to 2 (able to keep up with people of similar age on level, but not on hills and stairs) to 1 (other than 2 to 5), after each intervention in an outpatient setting with a two-week treatment duration (no wash-out period). The study assessed adverse effects, dose modification, anxiety, depression, a 12-minute walking test, treadmill, and ergometer measurement.
All studies were RCTs (Eimer 1985; Harrison (unpublished); Man 1986; Navigante 2006; Navigante 2010; Shivaram 1989; Woodcock 1981). Besides Navigante 2006 and Navigante 2010, who used a single-blind, parallel, and morphine-controlled design, all other studies were double-blind, cross-over, and placebo-controlled (Eimer 1985; Harrison (unpublished); Man 1986; Shivaram 1989; Stege 2010; Woodcock 1981).
In general, the sample size was small (between five and 29 participants), except for two studies of Navigante and colleagues (Navigante 2006 with 101 participants and Navigante 2010 with 63 participants). One study finished data collection without dropouts (Eimer 1985). Five studies had between three and nine dropouts (dropout/N: 9/26, 5/29, 4/12, 3/17, 3/18) (Harrison (unpublished); Man 1986; Shivaram 1989; Stege 2010; Woodcock 1981); one study lost two of 63 participants (Navigante 2010); and one study lost 31 participants due to death during the study (Navigante 2006), which were always excluded from the analysis. Four studies provided a power calculation (Harrison (unpublished); Navigante 2010; Shivaram 1989; Stege 2010), and three of them reached an appropriate number of participants (Navigante 2010; Shivaram 1989; Stege 2010). None of the studies presented an intention-to-treat analysis. A total of 214 participants were analysed, including 33 participants of the third intervention arm of the parallel-designed study from Navigante 2006.
Three studies included participants with cancer (Harrison (unpublished); Navigante 2006; Navigante 2010), and five studies included participants with advanced COPD (Eimer 1985; Man 1986; Shivaram 1989; Stege 2010; Woodcock 1981).
Breathlessness intensity was measured mainly on a VAS/NRS (Harrison (unpublished); Man 1986; Navigante 2010; Stege 2010; Woodcock 1981), a modified Borg scale (Navigante 2006; Shivaram 1989), and a Dyspnoea Grade 1 to 6 scale or 1 to 5 scale (Eimer 1985; Man 1986; Woodcock 1981). The majority of studies measured breathlessness at rest (Eimer 1985; Harrison (unpublished); Navigante 2006; Navigante 2010; Shivaram 1989); only three studies also assessed breathlessness on exercise (Eimer 1985; Man 1986; Woodcock 1981). Two studies assessed episodic breathlessness (Navigante 2006; Navigante 2010), and one study did not further specify breathlessness (Stege 2010). Other outcomes were anxiety (Harrison (unpublished); Navigante 2006; Woodcock 1981), depression (Harrison (unpublished); Woodcock 1981), adverse effects (all), walking tests (Eimer 1985; Man 1986; Woodcock 1981), and attrition (all).
Two studies tested alprazolam, one with 1.0 mg/day (Man 1986), and one with 0.75 mg/day (Shivaram 1989). One study tested 25 mg/day diazepam within a three-arm design with 125 mg/day promethazine compared to placebo (Woodcock 1981). Navigante 2006 applied midazolam 20 mg/day only and in combination with morphine 10 mg/day compared to morphine 10 mg/day only within a three-arm design. Navigante 2010 studied oral midazolam 8 mg/day versus morphine 12 mg/day (both starting doses). Harrison (unpublished) examined lorazepam 1 mg/day. Eimer 1985 tested two different doses of clorazepate, 7.5 and 22.5 mg/day, compared to placebo; however, due to intolerable adverse effects, the 22.5 mg arm was excluded from analysis. Stege 2010 examined the effect of temazepam 10 mg/day orally. The treatment durations ranged between 48 hours, in Navigante 2006, and two weeks, in Eimer 1985, Shivaram 1989, and Woodcock 1981.
See Characteristics of excluded studies.
We excluded 90 out of 97 full-text publications because they did not meet the inclusion criteria (30 'no subjective measurement of breathlessness'; 24 'reviews'; 15 'different drugs'; six 'different disease/healthy participant'; three 'combination of drugs'; six 'different study design', two 'guidelines', two 'editorials', and two studies 'failed in recruiting any participants'. We excluded a substantial number of studies because of a lack of subjective measurement of breathlessness, mainly older studies from the 1970s and 1980s that studied benzodiazepines in relation to spirometry, functional tests, or blood tests. Among them is the most cited paper in this area (Mitchell-Heggs 1980a), which we had to exclude because of a lack of subjective measurement of breathlessness. Although the authors mentioned breathlessness as an outcome, we could determine no subjective measure, either in the text, tables, or graphs. Other reasons for excluding this study were the lack of systematic or standardised design and absence of control group. Four excluded studies used benzodiazepines only in combination with other drugs (Clemens 2011; Lichterfeld 1967; Navigante 1997; Navigante 2003), thus a separate assessment of the drug effect was not possible. Three excluded studies assessed breathlessness in healthy people (comparing diazepam, promethazine, and placebo) (Jones 1985; Stark 1981a; Stark 1981b). One study compared diazepam versus flupenthixol in people with psychosomatic disorders (breathlessness was only one of 12 associated symptoms and was not the primary outcome) (Jokinen 1984). Although we expected to find a substantial number of observational studies, there were only a few thematically relevant non-controlled or retrospective studies, which we had to exclude. Among them was the case report from Greene 1989, a non-controlled phase II study (Allcroft 2013), the above-mentioned non-controlled study on the combined use of opioids and benzodiazepines (Clemens 2011), a retrospective study on the management of dyspnoea in hospitalised palliative-care patients (Gomutbutra 2013), and a prospective observational study on the patterns of benzodiazepine use among older adults with COPD in Canada (Vozoris 2013). We excluded the study Hosaka 1996 because four of the 22 participants did not meet our inclusion criteria regarding the underlying disease (asthma, tuberculosis), and the level of airways obstruction was above our inclusion criteria (mean FEV1 63% and FEV1/FVC 1.06), indicating that the disease stage was not as advanced as required for this review. This non-randomised, placebo-controlled, double-blind, cross-over trial studied the use of diazepam 10 to 12 mg/day over four weeks in 22 people with chronic respiratory insufficiency (mainly COPD and fibrosis) who received home oxygen therapy. The study, which was published in Japanese (abstract in English), showed a statistically significant improvement in breathlessness at rest in the diazepam group and a statistically non-significant worsening in the placebo group, but the levels of breathlessness at baseline were different between the groups.
In the search for the update, we excluded the potentially relevant studies of Daubert 2014 and NCT01687751 (identified through register search), because no participants could be recruited in these trials and no future results are expected (personal communication with Neil Hilliard, Eliza Daubert and Scott Bolesta in June 2015).
Studies awaiting classification
In the update, we identified one potentially relevant study with the database search (Hart 2012), and one potentially relevant study in the clinical trial registries (Hardy 2016) (see Characteristics of studies awaiting classification).
Hardy 2016 is a randomised, placebo-controlled, cross-over trial testing the hypothesis that intranasal midazolam is superior to placebo for the palliation of dyspnoea in people with optimally treated life-limiting disease. A sample size of 200 participants was planned but the study was terminated after interim analysis of 75 participants showing no difference between intervention arms. The primary outcome was breathlessness intensity at 15 min compared to baseline. There was no difference at any time points in breathlessness scores between arms. This study concludes that intranasal midazolam had no clinical benefit over intranasal placebo for the control of breathlessness.
The aim of the randomised, double-blind, double-dummy, placebo-controlled pilot study of Hart 2012 was to compare the efficacy of intranasal midazolam with that of oral lorazepam tablets in relieving dyspnoea in people with severe respiratory disease. The study included 30 participants, and the findings showed a "worthwhile improvement in symptom control of dyspnoea and quality of life" (Hart 2012). Unfortunately, this study was only published as a conference abstract, and we did not receive data from the authors at time of the submission (personal contact with Dr. Hart in August 2016).