Introduction

Chronic obstructive pulmonary disease (COPD) is a major cause of disability, morbidity and mortality in old age. The World Health Organization estimates that over 200 million are living with COPD worldwide [1, 2, 3]. Studies [2, 4] report that over two-thirds of people with COPD patients are two or more comorbidities that interfere with their activities of daily living (ADL). The most common symptoms in moderate-to-severe COPD patients include breathlessness with minimal exertion and excessive fatigue which are associated with a reduction in the ability to undertake activities of daily living (ADLs). Some of the most common comorbidities are depression and anxiety disorders which represent an increasingly greater burden as the person with COPD ages and respiratory symptoms become worse. Elkington and co-workers [5] found that at the end-stage COPD (i.e. the last phase in the course of the progressive disease) 98% of patients exhibited breathlessness ‘all the time’, which persisted at rest or minimal exertion despite receiving optimal treatment. In addition, the other symptoms at this stage included excessive tiredness, low mood and pain (‘some or all the time’) reported by 96, 77 and 70% of respondents, respectively. Other studies have reported that people with advanced-stage COPD are more breathlessness than those with advanced lung cancer [5, 6]. Furthermore, health-related quality of life has been reported as comparable to or worse than in advanced non-small-cell lung cancer patients [6].

A recent systematic review [7] reported the prevalence of depression to range from (8–80% and 6–74% of anxiety) symptoms in COPD patients compared with chronic heart failure (CHF) (10–60% depression; 11–45% anxiety), respectively. Furthermore, the psychological burden of clinical depression may be as high as 90% in advanced COPD patients compared to 52% with non-resectable non-small-cell lung cancer patients [6]. Those with COPD and comorbid depression are less likely to engage in many social activities and are frequently isolated and housebound because of increased physical disability and fear of breathlessness. In addition, in this group, depression can interfere with self-management and adherence to medical treatment.

For these reasons, diagnosing and treating comorbid depression is crucial. Antidepressants and anxiolytics are widely used in older adults [8, 9]; however, the efficacy of these drugs in people with advanced-stage COPD to treat moderate-to-severe depression, breathlessness and pain has not been adequately examined [10, 11]. The aim of the review is twofold: (1) To examine the efficacy of antidepressants drug therapy in patients with COPD and major depression and (2) to examine the safety of benzodiazepines and opioids (anxiolytics) in patients with severe respiratory disease with advanced-stage of COPD. It will also provide clinical tips to improve the management of depression, breathlessness and pain in patients with COPD.

Antidepressants Drug Therapy in Patients with COPD

Untreated and undiagnosed major depression in patients with COPD may lead to a greater burden of an increase in physical disability, poorer adherence to medical treatment, lower self-esteem and social interaction, more impaired quality of life and greater healthcare utilisation compared to COPD patients without major depression [12, 13]. Therefore, the optimisation of medical treatment for COPD in conjunction with the selection of appropriate antidepressants while minimising drug interactions is important.

The National Institute for Clinical Excellence (NICE) recommends the use of antidepressants in the treatment of major depression for patients with chronic diseases in both primary and secondary care settings [13]. Furthermore, NICE guidelines recommend selective serotonin reuptake inhibitors [SSRIs] as a first line of treatment choice in the acute phase of treatment for patients with major depression. SSRIs have better safety records and fewer side effects compared to older antidepressants such as tricyclic antidepressants. This review focuses primarily on antidepressant drug trials that have been conducted in patients with COPD and major depression.

Selective Serotonin Reuptake Inhibitors (SSRIs)

There are only seven studies that have been conducted using the SSRIs in the treatment of major depression in patients with COPD [14], and all are having relatively small sample sizes and some methodological limitations. The summary of the main findings will be reported here. For a detailed review, the reader is referred to Yohannes and Alexopoulos paper [14].

Sertraline

Smoller et al. [15] conducted a non-randomised, open-label pilot study (n = 6) which examined the efficacy of sertraline over a 6-week period, with initial dose of 12.5 mg daily increasing to 100 mg within the first two weeks. There was no significant improvement in depressive symptoms and signs, or physiological measures of COPD such as lung function test. However, 5 out of the 6 COPD patients showed some improvement in their daily activities. A retrospective study [16] by Papp and co-workers explored the effectiveness of sertraline at a daily dose ranging from 25 to 100 mg in seven patients with chronic obstructive pulmonary disease for the treatment of comorbid depression. They observed significant improvement in dyspnoea scores in all seven COPD patients. A few patients had shown some improvement in exercise capacity, depression and anxiety. In addition, the authors have investigated the potential antidepressants effect on physiological parameters or not. However, no improvement was observed in forced expiratory volume in one second (FEV1). A recent study by He and co-workers [17] examined the efficacy of Sertraline hydrochloride 50 mg/day for 6 weeks [n = 60] compared to the placebo group [ n = 60] receiving dummy pills. Depression was diagnosed using the 17-item Hamilton Depression Rating Scale. They showed statistically significant improvement in quality of life, reduced depressive symptoms and increased in exercise capacity in the intervention group compared to the placebo. The findings are encouraging, but 6 weeks of Sertraline treatment was insufficient to assess the long-term effect to full remission. Thus, a longer term treatment and follow-up is required.

Fluoxetine

Evans and co-workers conduced an 8-week randomised, double-blind trail comparing the efficacy of fluoxetine 20 mg daily to that of placebo in 42 elderly inpatients with depression and respiratory diseases including COPD diseases [18]. Sixty-seven per cent of patients in the fluoxetine group, compared to 37% of those in the placebo group, had an improvement in depression rating scores (defined as a 50% reduction in the 17-item Hamilton Depression Rating Scale (HDRS) and/or a final score of 10 or less [18]. However, this difference in response rates between the two groups did not meet statistical significance and there was no difference between groups in lung function scores. This might be due to small sample size, which led to type 1 error.

In a single blind study, Yohannes et al. [19] examined the efficacy of fluoxetine 20 mg daily over six months. Major depression was diagnosed using the Geriatric Mental State Scale [20]. Fourteen depressed COPD patients commenced the fluoxetine therapy, and (n = 7) completed the study. Five patients withdrew because of adverse side effects (intolerable tremor, feeling lethargic, agitation and nightmares), 1 withdrew due to family problems, and 1 died due to unrelated cause. Of those who completed the study, 4 responded to fluoxetine (50% reduction in the Geriatric Mental State scale score). There was no significant improvement in forced expiratory volume in one second (FEV1), quality of life (measured by the Breathing Problems Questionnaire) and physical activity scores after 6 months of fluoxetine therapy.

Paroxetine

A relatively small, double-blind, randomised controlled trial [21] examined the efficacy of paroxetine 20 mg daily over 12 weeks in advanced stage of COPD patients with comorbid depression. Twenty-three participants were randomised. Of these, 15 participants (8 paroxetine and 7 placebos) completed the study. A clinically significant difference favouring paroxetine was observed in quality of life, measured on the chronic disease respiratory questionnaire, especially in ‘mastery’ and ‘emotional function’. There was some improvement in dyspnoea and fatigue scores in the paroxetine group, but this did not reach statistical significance. Notably, as was seen with the fluoxetine studies mentioned above, almost one-third of the participants discontinued treatment due to adverse side effects. Eiser and colleagues compared the efficacy of paroxetine (20 mg daily) against placebo over 6 weeks in 28 patients with COPD [22]. There was no statistically significant difference between the two groups in exercise capacity, lung function and quality of life. Paroxetine was un-blinded after 6 weeks, and both groups continued on open-label paroxetine 20 mg daily. A statistically significant improvement in depression scores, walking distance and quality of life was observed three months later.

Tricyclic Antidepressants (TCA)

To date, only four randomised double-blind studies have investigated the efficacy of TCAs in people with COPD [23–26]. Again, because of the low sample sizes of the trials and high dropouts of participants from these studies, briefly the summary of main findings for each of several TCAs will be reported here [14].

Desipramine

An 8-week, placebo-controlled study [23] examined the efficacy of desipramine in 13 people with stable COPD as defined as no hospital admission in the previous 6 weeks due to acute exacerbation of COPD) and depression. Desipramine was started at a dose of 25 mg daily and increased weekly to a target dose of 100 mg. Six participants completed the trial. Both groups had similarly improved depression scores using the Beck Depression Inventory (BDI), and no significant difference in physiological outcomes was noted.

Doxepin

Light and co-workers examined the efficacy of doxepin in 12 outpatients with COPD and depression in a randomised placebo-controlled trial [24]. In this 6-week study, doxepin was started at a dose of 25 mg daily and increased as tolerated with a maximum dose of 105 mg daily. Three patients withdrew from the study because of adverse side effects (diarrhoea, tremor and somnolence). There was no significant improvement in depression scores measured by Beck Depression Inventory, anxiety tested by the State-Trait Anxiety Inventory, exercise capacity examined by twelve-minute walk test, and physiological parameters were examined using spirometer for lung function tests.

Nortriptyline

Borson and colleagues, in a double-blind, placebo-controlled trial, examined [25] the efficacy of 12 weeks nortriptyline of in patients with COPD patients with major depression, confirmed by psychiatrists using the Structured Clinical Interview for DSM-III. Nortriptyline was started at 0.25 mg/kg of body weight and increased weekly up to 1 mg/kg. Thirty participants with COPD completed the study. The nortriptyline group showed greater improvements in depression, anxiety, respiratory symptoms and daily activities compared to the placebo group. However, there was no improvement in physiological outcomes in either group.

Protriptyline

Strom et al. [26] examined the efficacy of protriptyline, 10 mg/d for 12 weeks, in a double-blind randomised trial. Twenty-six participants with COPD and chronic hypoxaemia and depression, defined by the Hospital Anxiety Depression Scale, started the trial but only five completed it. Twelve participants in the protriptyline and six participants in the placebo group discontinued treatment due to adverse events, the most commonly reported of which were anticholinergic side effects, i.e. dryness in the mouth. There was no improvement in arterial blood gas tensions, spirometry values, and dyspnoea and quality of life scores in either group.

In summary, the efficacy of antidepressant drugs using both SSRIs and TCAs for treatment of depression in patients with COPD was inconclusive. Findings from the current literature are greatly limited by methodological weaknesses including low sample size, sample heterogeneity and variation in the screening and diagnostic tools used to measure and to monitor the treatment of depression [14]. In addition, which specific SSRIs or TCAs may be appropriate to treat depression in patients with COPD requires further investigation in larger randomised controlled trials since to date there have been no head-to-head studies of different antidepressants.

Barriers to Treatment of Depression in COPD

Treatment of depression in people with COPD can be a challenge. A recent national survey of general practitioners (GPs) in England reported that convincing COPD patients with comorbid depression to receive appropriate treatment was an arduous task [27]. Reasons for this include patient misapprehension of antidepressants, fear of the side effects of antidepressants, misconceptions that antidepressants are addictive and difficult to ‘come-off’, and stigma attached to depression and mental illness [27]. Furthermore, the lack of adequate provision of psychological services and long waiting times for psychological treatment represents another barrier to adequate management of depression in COPD [27, 28].

In contrast to conventional therapeutic approaches, the collaborative care model (CCM) has been shown to improve treatment adherence [29] and improve quality of life and reduce healthcare utilisation in patients with chronic diseases with major depression. The CCM is a behavioural management approach; which is administered by trained case managers, who work collaboratively with each patient to implement their individual treatment plan. Care managers will identify barriers to adherence specific to each patient and, through education and support, help promote adherence to antidepressants drug therapy. They will engage with the patient on a regular basis either face-to-face or by phone. In addition, the care manager will monitor the patient’s condition regularly and if adverse events arise, will communicate with the patient’s primary care physician or psychiatrist. To date, the efficacy of CCM for managing depression in COPD is unknown.

A recent systematic review [30] investigated complex interventions including education, exercise therapy life style interventions and cognitive behavioural therapy on the efficacy of treatment of depressive symptoms. Thirty independent comparisons from 29 randomised controlled trials (n = 2063) were included in the meta-analysis. Overall, psychological and/or lifestyle interventions were associated with small reductions in symptoms of depression (standardised mean difference −0.28, 95% confidence interval −0.41 to −0.14) and anxiety (standardised mean difference −0.23, 95% confidence interval −0.38 to −0.09). Multi-component exercise training was the only intervention subgroup associated with significant treatment effects for depression (standardised mean difference −0.47, 95% confidence interval −0.66 to −0.28) and for anxiety (standardised mean difference −0.45, 95% confidence interval −0.71 to −0.18) [30]. However, the efficacy of these interventions on depression severe enough to meet criteria for major depression is unclear. This is partly due to some of the reviewed studies being uncontrolled and underpowered to show the magnitude and the efficacy of the intervention to ameliorate depression. Another systematic review and meta-regression analysis [31] that examined the efficacy of antidepressants for older adults with chronic diseases, including COPD, advocated that future research should focus more on the benefits of combining psychotherapy and antidepressant drug therapy to maximise efficacy in the treatment of major depression, rather than investigating single modality therapies by themselves.

Managing Depression in Patients with COPD

A number of studies have reported that both SSRIs and TCAs are associated with considerable side effects in patients with COPD and major depression. Hatcher and Arroll [32] provide helpful management plan of treating patients who experienced side effects commencing antidepressants such as diziness, sedation, dry mouth, sexual dysfunction, insomnia, suicidal thoughts, anxiety, hyponatraemia, serotonin syndrome, and discontinuation syndrome. This management approach will be helpful to treat COPD patients who experience side effects with antidepressants.

The Effect of Opioids and Benzodiazepine on Health Outcomes in Advanced Stage of COPD

The NICE recommends that opioids and benzodiazepine and major tranquilisers are appropriate in palliating symptoms in patients with advanced-stage COPD [33]. These agents should be used when patients with advanced stage of COPD with intolerable dyspnoea are unresponsive to other medical therapy. However, American Thoracic Society/European Respiratory Society guidelines warn against the use of benzodiazepines and recommend avoiding hypnotics, if possible, in patients with severe COPD [34]. Despite these warnings, benzodiazepines are widely used in older adults in patients with COPD [35]. Benzodiazepines are prescribed including treatment for insomnia, agitation, depression and anxiety, and refractory dyspnoea, which are common in advanced stage of COPD [11].

Dyspnoea

Excessive dyspnoea on exertion is a hallmark of advanced stage of COPD, and it is disabling and challenging to treat. Dyspnoea impairs quality of life, increases dependency on others for daily activities and decreases social interaction. The prevalence of breathlessness with minimal exertion or at rest is as high as 90% in patients with advanced COPD compared with 60% in patients with chronic heart disease [36]. There are a number of options of treatment that are available to relief the distressing symptoms of breathlessness in patients with severe COPD including bronchodilators, long-term oxygen therapy (LTOT), pulmonary rehabilitation and use of opioids [33, 37]. Other forms of therapy to reduce the sensation of dyspnoea include the use of a fan direct cooler to the face, which showed some benefits in normal subjects [38], LTOT for hypoxemic patients [39], pursed-lip breathing, relaxation techniques and smoking cessation could be effective strategies for relief of dyspnoea. The judicious use of bronchodilator therapy in dyspnoeic patients is recommended. However, apart from optimising (active) medical treatment for patients with advanced COPD, opioids remain the most effective dyspnoea relieving medications and cough in end-of-life care [40, 41] as recommended by the Canadian Thoracic Society [41]. The American College of Chest Physicians consensus statement [42] affirms the use of opioids, but the dose should be titrated for individual patient with consideration of multiple factors (e.g. renal, hepatic, pulmonary function and past opioids use) for relief of dyspnoea. It is important to monitor patient’s condition regularly for benefits and side effects and adjust accordingly any of the medication on an individual basis.

As there are fewer than handful studies, that investigated the benefits of Benzodiazepines and/or opioids in patients with advanced COPD, and largely in small sample size and uncontrolled, and short-term duration of intervention. Therefore, this review provides summary of these study findings including population-based studies as follows.

Benzodiazepine

A recent national prospective study in Sweden [43] examined the safety and effects of benzodiazepines and opioids in patients with severe respiratory diseases on rates of admission to hospital and mortality. All patients were using LTOT during the four-year follow-up. Over three quarter of the patients were admitted to hospital because of acute exacerbations. Fifty per cent of the patients died during the observation period. Benzodiazepine and opioids were not related to hospital admission. The use of benzodiazepines was associated with 21% increased mortality with a higher level of dose response trend. Opioids had a dose response rate with mortality: lower doses of opioids (≤30 mg oral morphine equivalents a day) were not associated with elevated mortality. In contrast, higher dose of opioids was associated with increased mortality by 21%. Their findings indicate that concurrent use of benzodiazepines and opioids in lower doses to treat severe dyspnoea in patients with COPD is not associated with increased hospital admissions or mortality. In this study, the most commonly used benzodiazepines were oxazepam (74%), diazepam (17%) and alprazolam (8%). In the study the weak opioids were tramadol (31%), codeine (19%), and dextropropoxyphene (15%) and strong opioids were oxycodone (15%), morphine (11%) and fentanyl (5%). Benzodiazepines and higher dose opioids were associated with increased mortality. Lower dose of opioids are not associated with elevated mortality or hospital admissions in patients with COPD and might be safe to relieve symptom of dyspnoea in patients with respiratory diseases [43].

Vozoris et al. [44] investigated the use of benzodiazepine and the potential risk of adverse respiratory outcomes in patients with COPD. This seven-year retrospective population-based Canadian study comprised of 177,355 community-dwelling individuals with COPD who were aged 66 years and older. Of these, 50,358 (28.4%) were new benzodiazepine users. Their findings indicated that benzodiazepine users were at significantly higher risk for outpatient respiratory exacerbations (relative risk, 1.45, 95% Confidence interval 1.36–1.54) and emergency room visits for COPD or pneumonia (relative risk 1.92, 95% Confidence interval 1.69–2.18) compared to non-users [44]. Likewise, no significant differences between new users and non-users of benzodiazepines were observed in regard to intensive care admissions during hospitalisations for COPD or pneumonia. Thus, caution should be exercised when prescribing benzodiazepine in older patients with COPD and plan appropriate strategies, e.g. regular monitoring to reduce adverse respiratory outcomes.

A recent Cochrane review examined the efficacy of benzodiazepine [45] to relieve the symptoms of breathlessness including advanced stages of cancer, COPD, CHF, motor neuron disease (MND) and idiopathic pulmonary fibrosis (IPF). The review identified seven studies that included 200 subjects with advanced cancer and COPD. Analyses of these seven studies did not identify the beneficial effect of benzodiazepines for the relief of breathlessness in patients with advanced cancer or COPD. The authors performed sensitivity analyses to show differences in relation to type of benzodiazepine, dose, route and frequency of delivery, duration of treatment or type of control [45]. There were no significant differences in any of the physiological parameters. Benzodiazepines caused more drowsiness as an adverse effect compared to placebo, but less compared to morphine. The authors suggest benzodiazepines should be considered as the last resort [45], if there was no improvement using opioids and other non-pharmacological treatments to control breathlessness.

Temazepam

A double-blind, placebo-controlled trial, cross-over study [46] examined the efficacy of 10 mg temazepam or placebo once daily for one week in [n = 14 stable COPD patients] with chronic insomnia. The washout period was one week. Findings indicate that one-week usage of temazepam does not influence circadian respiratory function, dyspnoea and sleepiness in patients with severe normocapnic COPD with insomnia. However, it improves total sleep time and subjective sleep latency. This study was a preliminary explorative study. Therefore, further studies are required to examine the clinical efficacy of temazepam in larger sample size and with longer duration time.

Opioids

Morphine with Clonazepam

In a single site, open-label phase II study, Allcroft and colleagues [47] examined the additional benefits of regular clonazepam 0.5 mg nocte orally to Kapanol (R) 10 mg (sustained-release morphine sulphate) orally mane together with docusate/sennosides in people with modified Medical Research Council Scale ≥2 over 4 days. The primary outcome was the intensity of breathlessness on day four. Patients were allowed to extend for another 10 days if they achieved >15% reduction over their own baseline breathlessness intensity. Eleven COPD patients (8 = male) were recruited, and (n = 10) completed day four duration of intervention. The median age was 76 years. One person withdrew because of unsteadiness on day four. Five participants reached the 15% reduction in the level of breathlessness, but only three went on to the extension study, and all patients completed the study without toxicity [46]. The findings indicate it was safe and feasible and there appears to be as a whole group who derive benefits comparable to titrated opioids. However, further studies are required to examine the efficacy of clonazepam in larger randomised controlled trial.

Morphine

Abernety et al. [48] examined the efficacy of oral morphine in relieving the sensation of breathlessness measured by patients with COPD with optimum medical treatment was randomised to four days of 20 mg oral morphine with sustained release followed by four days of identically formulated placebo, or vice versa. Forty-eight participants who had not previously been treated with opioids (mean age 76, SD 5) years started the trial. Out of these, 38 participants completed the trial, three withdrew because of definite and two because of possible side effects of morphine (nausea, vomiting and sedation). Their findings indicate that when patients were receiving morphine their dyspnoea scores were significantly reduced and had better sleep compared when they were not. However, participants reported distressing constipation while they were receiving morphine. Thus, sustained release, oral morphine at low dosage provides significant symptomatic improvement in refractory dyspnoea in patients with COPD in the community setting. However, the long-term benefit of morphine requires further testing.

Currow and co-workers [49] examined the minimum effective once-daily dose of sustained-release morphine, and whether net clinical benefits are sustained safely in patients with respiratory diseases with refractory dyspnoea (breathlessness that cannot be relieved with regular medication) including COPD patients with the 3-month follow-up. This dose increment study started with 10 mg daily of sustained-release morphine and increased in non-responders by 10 mg daily each week to a maximum of 30 mg daily. Patients were withdrawn from the study when they experience intolerable side effects or no response to the maximum dose to reduce breathlessness. Eighty-three patients (53 males, mean age 75 years, 54% with chronic obstructive pulmonary disease) were recruited to the study. Over three-fifths of the patients derived ≥10% benefit (on average 35% improvement over baseline), with the dose of 10 mg/24 h in reducing dyspnoea. These benefits were sustained at three months by 28 (33%) of the patients. In addition, statistical significant improvement was observed in the level of dyspnoea at p < 0.0001. However, a significant proportion of patients developed constipation during the study period, despite receiving laxatives. It demonstrates ten milligrams of sustained-release oral morphine once daily is safe and effective for those patients who respond.

Challenges in the Use of Opioids

A small pilot study [50] investigated the views of the healthcare professionals [n = 18] including respiratory therapists and family physicians in the primary care settings in the use of opioids for the treatment of refractory dyspnoea in patients with advanced COPD. They have reported the value of opioids to relieve the symptoms of dyspnoea in advanced stage of the disease. However, family physicians have reported their discomfort (uneasiness) of prescribing opioids routinely for the treatment of dyspnoea. Furthermore, they have identified insufficient knowledge of the participants, lack of education and guidelines when to prescribe opioids and fear of censure. This underscores the importance of training and developing appropriate educational materials for healthcare professionals including family physicians in the use of opioids and the value of palliation for patients with advanced stage of COPD to treat distressing dyspnoea-related symptoms.

A recent retrospective review of four international studies of 213 individuals of pooled analysis data [51] examined factors that predict better opioids response in the treatment of refractory dyspnoea in patients with severe chronic respiratory diseases. Their findings indicate that higher baseline breathlessness intensity scores were strongly predicted by absolute and relative response (p < 0.001). In addition, younger age patients with worse breathlessness are more likely to derive greater benefit in the treatment of opioids. Although opioids have a role in the treatment of refractory dyspnoea, it requires careful monitoring of individual patient to maximise benefits. This is crucial, as the therapeutic index may be narrower for older patients with less to gain. ‘Likewise, older people are at particular risk of excessive fatigue and decrease in ADL, drug–drug interaction and drug–host-related adverse events’ [50]. This review highlights the paucity of evidence, the therapeutic dosage and duration of treatment of opioids to treat patients with respiratory diseases with refractory dyspnoea and pain. Thus, well-controlled prospective studies are needed.

A retrospective study from the administrative data [52] from the Veterans Affairs (VA) patients with posttraumatic disorder (PTSD) examined the safety of combinations of benzodiazepine and opioids and selective serotonin reuptake inhibitors (SSRIs) or serotonin/norepinephrine reuptake inhibitors (SNRIs). The study compared the 2-year incidence of adverse events among VA patients with PTSD [n = 5236] exposed to combination groups. They have reported that either SSRIs or SNRIs in combination with benzodiazepine and opioids were associated with increased hospitalisations for mental health-related problems and increased for medicine/surgery hospitalizations and emergency department visits and harmful events (e.g. injuries and death) compared to those prescribed SSRIs/SNRIs only. Therefore, regular monitoring and close follow-up of patients are required especially to those patients prescribed combined medications in order to reduce the adverse events. Furthermore, the efficacy and applicability of concurrently prescribing of these combined drugs has not been examined to treat intolerable dyspnoea or pain in patients with advanced stage of COPD. Therefore, well-controlled trials are needed.

Conclusion

The available evidence suggests that the efficacy of antidepressants drug therapy in people with COPD and major depression is inconclusive. Therefore, appropriately powered prospective randomised controlled trials are needed. General guidance and specific medical points are provided in how to use antidepressants and anxiolytics in patients with COPD as outlined in Table 11.1.

Table 11.1 Clinical tips for the use of antidepressants and anxiolytics therapy for patients with respiratory diseases
Full size table

Lower doses of opioids are beneficial in ameliorating dyspnoea in patients with COPD without series adverse events. However, only a few studies have been conducted to address this question and they are all small in sample size. Thus, again, prospective randomised controlled trials with larger sample sizes are required. Additionally, the safety of benzodiazepines for use in patients with severe COPD requires further investigation.