, Julie Burkin1, Catherine Moffat1 and Anna Spathis1
(1)
Department of Palliative Care, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
Abstract
There are many similarities in the central neurophysiology of pain and breathlessness but the treatment strategies are different. The pharmacological treatment of breathlessness lags behind that of pain in both the number of drugs available and the effectiveness of current drug regimens. There is reason for hope as increasing research is being carried out in this area. In general drug treatment is most effective in those with the most severe breathlessness or at the end of life. Oral morphine is the drug with the greatest evidence base and is most widely used. Second line treatment is open to question as there is no high quality evidence currently to support the use of benzodiazepines which are certainly useful at the end of life when sedation is needed but can promote hazardous dependency in those with months or years to live. Mirtazapine may have a more substantial rationale for its use although it has not been researched rigorously yet. In mobile patients with a lengthy prognosis non-pharmacological, procentral approaches are likely to be best approach.
It is clear that breathlessness has many neurophysiological similarities to pain – both are
integrated in the central nervous system
comprise qualitatively distinct sensations
modulated by signals from the ‘higher’ areas of the CNS, cortical regions where thinking, feeling and previous experience can exacerbate or palliate the sensation
influenced by outputs from the limbic system: anxiety and other unpleasant affective states can increase the severity of these symptoms.
There are, however, major differences in the pharmacological management of pain and breathlessness. Drug treatment for malignant pain has progressed enormously in the last 20 years. There is an expectation that patients with uncomplicated pain from cancer will have excellent control on oral drug therapy alone, often a combination of drugs working in different ways. Only 5–10 % of patients with intractable or complex pain will require anaesthetic, radiological or very rarely surgical interventions (as attempts to get the best relief possible) and still continue to have significant pain. Although improvement is possible with current drug therapy, sadly clinicians cannot reassure patients that any medicines taken specifically to improve breathlessness will achieve excellent relief, returning the patient to a state in which they are free of the symptom and as active as before. The evidence base, although improving is also thinner.
Another difference from pain, is that the same management strategies are presented as appropriate for both malignant and non-malignant breathlessness. It is not confirmed that there is a final common pathway for breathlessness of all aetiologies, though it seems likely, so we currently consider pharmacological treatment for both sorts of breathlessness as the same, with prognosis and severity the guides to when and what sort of drug therapy should be initiated. In contrast, there are marked differences in the management of malignant and non-malignant pain which are considered almost as separate entities. Palliative care physicians are rarely involved in the management of stable, chronic non-malignant pain in those with years to live; anaesthetists usually lead the multiprofessional teams which care for these patients. Drugs, anaesthetic, surgical and radiological interventions are seen to be of limited in value in chronic non-malignant pain in if not used in conjunction with behavioural and psychosocial approaches.
Slowly Progressive or Rapidly Progressive Breathlessness
The division into malignant and non-malignant breathlessness does not correlate with the patient’s lived experience, patients with some non-malignant diseases can have very rapid, frightening deteriorations in their breathlessness. It is more accurate to consider breathlessness as slowly or rapidly progressive.
Patients with chronic non-malignant breathlessness from COPD and those with lung cancer have different disease trajectories (outlined in Chap. 1) but there are more indolent cancers where patients live with breathlessness for many years. Some patients with fibrosing lung disease experience rapidly progressive ‘malignant’ breathlessness with a concomitant physical and social decline.
The individual patient’s prognosis is central to the decision about which drugs are used, by which route, and when they are initiated to palliate breathlessness.
For many patients, especially these with chronic intractable breathlessness who are mobile and who may live with it for years, rather than months or weeks, drug treatment is a second choice, and non-pharmacological, (also known within CBIS as pro-central) interventions remain the most appropriate management strategy.
In this chapter, those drugs routinely used in breathless patients are considered individually and their use in patients discussed in those (1) breathless on exertion (2) breathless on minimal exertion, such as talking, hair brushing, washing or dressing (3) breathless at rest, i.e. continuously even without exertion (4) breathless and entering the end of life phase.
Drugs are discussed in order of the depth of the evidence base available for each one, and those which are used rarely or experimentally are only briefly reviewed.
It is sometimes justifiable to use a drug for which there is little evidence, to try to help a patient in desperate suffering, at the end of their life, provided you have a rationale. Using a drug with a poor evidence base should be done after discussion with a specialist with experience in this area, most commonly a palliative care physician.
Individual Drugs
Opioids e.g. Morphine, Fentanyl, Hydromorphone, Buprenorphine, Diamorphine
Opioids have the best evidence base of all the drugs used in the management of breathlessness. Most of the (small number) of trials carried out have been done using morphine sulphate immediate release solution and morphine sulphate modified release tablets such as MST. The earliest evidence was a systematic review carried out by Jennings et al. (2002), which has never been repeated. Then a fully powered RCT was carried out in medical in-patients (most of whom had COPD) by Abernethy et al. (2003), and there have been other studies since looking at dosing regimens and safety. To date most trials have used opioids for days to weeks or at most 3 months, longer is needed to establish safety and acceptability when prescribing a drug that may be used for years in moderately breathless patients with COPD. There is a relatively high attrition rate in those using opioids for breathlessness, mostly attributed by participants to adverse effects of the drugs.
Possible Mechanisms of Action
The areas of the brain concerned with the genesis of breathlessness are particularly rich in mu receptors which are found throughout the CNS and the respiratory system. Morphine and other opioids form a family of drugs which primarily stimulate the mu receptor. This underlies the rationale for using them in breathlessness, though their use originally followed from clinical observation and physiological evidence – it had been shown that opioids reduced the rate and increased the tidal volume of respiration.
Opioids
1.
reduce the drive to breath and the discomfort of air hunger, rather than reducing the sensation of called ‘the work of breathing.’ The reduction in respiratory drive reduces corollary discharge (see page 19)
2.
modulate cortical activity reducing the sensation of breathlessness
3.
reduce the anxiety associated with breathlessness
4.
may act through causing sedation, even if not overt
5.
there is a postulated effect on the production of endogenous opioids (β endorphins) which bind to opioid receptors
6.
have an effect on peripheral opioid receptors in the lung
There is a growing evidence base demonstrating that opioids are helpful in the palliation of the intractable breathlessness associated with advanced disease.
Indications
Whilst most clinicians have little hesitation in using opioids in breathless patients with cancer who have months to live there is still sometimes a reluctance to use them in patients with COPD. However important international guidelines for the management of this symptom (e.g. GOLD) in COPD have begun to recommend opioids for these patients.
Patients with interstitial lung disease (ILD) are often tachypnoeic with an increased work of breathing: opioids may be particularly helpful in this situation.
Using Opioids to Palliate Breathlessness
Patients Breathless on Exertion
In these patients most clinicians would prefer to use a physically rehabilitative approach first backed up by non-pharmacological, procentral approaches to aid motivation and concordance. This is the approach that CBIS uses. Of course there are grades of severity of ‘breathless on exertion:’ some patients who describe themselves as very troubled by breathlessness can walk substantial distances (e.g. a mile or more) others who use the same sort of description can only one flight of stairs or walk 100 yards before they have to stop. In those who border on ‘breathlessness on slightest exertion’ an approach that combines a reversal of deconditioning, other procentral approaches and then possibly opioids may be most helpful. These patients, intuitively, may also be particularly helped by walking aids or neuro-muscular electrical stimulation to help ‘kickstart’ their rehabilitation.
If these approaches have been tried, with appropriate support, and not been helpful or been unacceptable then treatment with an opioid may be helpful (using the regimen discussed below) but it is in this group that the adverse effects of opioids are most likely to lead to the rejection of this treatment.
Patients Breathless on Minimal Exertion
This group of individuals may live for years with breathlessness suffering greatly and opioids can play an important part in providing relief for these patients – pro-central and rehabilitative non-pharmacological approaches should also be used.
At CBIS we use a regimen of slow titration of opioid and we always discuss the prescription with the respiratory clinician (or other specialist) caring for that patient as well as the family doctor. Some patients with COPD go into Type II respiratory failure during exacerbations and it is essential that this group stop opioid use during these times, unless monitored in hospital. Sometimes other clinicians, unfamiliar with the use of opioids in breathlessness may take the initiation of opioids as a sign that the patient is entering the end of life phase, such misunderstandings or worse, the stopping and starting of opoids with conflicting messages from different caring teams is very detrimental to a patient’s morale and trust in those teams. This is best avoided by excellent communication. The respiratory specialists and others involved in that patient’s care need to support the prescription. A co-ordinated approach to opioid prescription is essential.
The starting dose of opoids on this regimen is low enough that those patients may not notice any change in their breathlessness initially. We use this regimen:
1.
To avoid sedation or other adverse side effects, like nausea, which may discourage the patient from using opioids and which are less likely with a “start low and increase slow” regimen.
2.
To avoid respiratory depression in patients, particularly those with CO2 retention, where it is difficult to monitor a patient in the community.
3.
In order to reassure other clinicians not used to giving opioids to patients with non-malignant disease.
4.
Many patients with advanced non-malignant disease and breathlessness have lived with the symptom for months, even years. Opioids are going to make possibly a 20 % impact on the patients’ breathlessness at best. Rapid titration is more likely to lead to adverse effects and the patient may lose the willingness to use the drugs at all. Other clinicians unused to using opioids in non-malignant disease may be deterred from using them if they get unfavourable feedback. A slow titration, that may take some weeks to get maximum benefit, may be better both strategically and clinically. Opioids are a precious evidence-based drug, it is important not to alienate patients by adverse effects. Slow titration is used for drugs used in other conditions to minimise adverse effects e.g. antidepressants for neuropathic pain.
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