Show Summary Details
Page of

Non-respiratory symptoms 

Non-respiratory symptoms
Chapter:
Non-respiratory symptoms
Author(s):

Anna Spathis

, Helen E. Davies

, Sara Booth

, and Max Watson

DOI:
10.1093/med/9780199564033.003.006
Page of

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford University Press, 2016. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy and Legal Notice).

Subscriber: null; date: 23 October 2019

Introduction

Breathlessness is the most prevalent symptom experienced by patients with advanced respiratory disease. It is an expected consequence of chest pathology, and clinicians understandably tend to focus on controlling this symptom above all others.

It is imperative, however, that attention is also given to non-respiratory symptoms. Fatigue, insomnia, pain, anorexia, anxiety, and depression are each experienced by the majority of patients in the last year of life. Such symptoms contribute significantly to patients’ poor quality of life.

The greatest priority of patients approaching the end of life and their carers is to avoid dying in distress with uncontrolled symptoms.

Symptom burden

The symptom burden experienced by those with advanced respiratory disease is considerable. Whereas it is well established that patients with advanced lung cancer tend to experience a range of non-respiratory symptoms, clinicians fail to appreciate that those with benign disease suffer a remarkably similar symptom burden.1

  • In both chronic respiratory disease (CRD) and lung cancer (LC), the mean number of symptoms per patient is seven.

  • The mean number of ‘very distressing’ symptoms is two in both groups.

Table 3.1 (see Non-respiratory symptoms [link]) documents the prevalence of symptoms in both patients with benign and patients with malignant advanced respiratory disease.

  • Those with CRD suffer more breathlessness, anxiety, and depression.

  • Patients with LC develop more pain, anorexia, and constipation.

Principles of symptom control

These principles apply to the management of all symptoms.

  • Aim to find the underlying cause and treat any reversible causes.

  • Be proactive, ask direct questions, and do not wait for the patient to complain.

  • Treat promptly, as neglected symptoms deteriorate and become harder to manage.

  • Reassess repeatedly until symptom free.

  • Make one change at a time if possible, so that it is easier to establish which change has been useful.

The principles that underpin palliative care are also of value.

  • Consider the contribution of psychosocial and spiritual factors. For example, addressing a mistaken belief that the symptom reflects progressive disease may help more than pharmacological intervention.

  • Remember the contribution of open and sensitive communication to successful symptom control, eliciting patients’ concerns and involving patients in decision-making.

  • Attend to detail at every stage of assessment and management.

  • Consider seeking help from the multidisciplinary team, including physiotherapists, psychologists, and chaplains.

  • Never ‘give up’; there are invariably further strategies that can be tried.

Barriers to symptom control

There is mounting evidence that the symptom control needs of patients with advanced respiratory disease are not being met.2 , 3 This is particularly true for those with benign CRD who, compared to patients with LC:

  • are more likely to suffer from uncontrolled symptoms

  • experience morbidity over a longer period of time

  • receive fewer medications to control symptoms.

A number of factors contribute to inadequate symptom control in non-malignant disease:

  • Clinicians erroneously perceive that providing symptom control is inconsistent with disease-modifying treatment and tantamount to ‘giving up’.

  • Staff lack experience in providing symptom control in benign CRD—palliative care specialists mostly care for those with cancer and respiratory specialists are more familiar with disease-modifying treatment.

  • Prescribers are concerned about the potential adverse effects of medication, such as respiratory depression from opioids or anxiolytics.

  • Professionals and patients experience therapeutic nihilism, believing that there is no treatment for a number of symptoms, such as fatigue.

  • There is a failure to appreciate the importance of a focus on quality of life in benign disease, due to under-recognition of the poor prognosis and unpredictable trajectory.

  • Professionals and patients may perceive that smoking-induced CRD is self-inflicted, rendering such patients less eligible for or deserving of measures to improve quality of life.

  • The evidence base is inadequate, most research on symptom control being carried out in those with cancer, and often focusing on the physical rather than psychological dimension.

The key to overcoming these barriers lies in the education of all healthcare professionals involved in the care of patients with advanced respiratory disease. Such education must focus on:

  • mixed management models of care, combining disease-modifying treatment with symptom control interventions

  • sharing of evidence-based best practice and knowledge between disciplines, in particular between respiratory and palliative care specialists.

References

1. Edmonds P, Karlsen S, Khan S, et al. (2001) A comparison of the palliative care needs of patients dying from chronic respiratory diseases and lung cancer. Palliat Med; 15: 287–295.Find this resource:

2. Au D, Udris E, Fihn S et al. (2006) Differences in health utilization at the end of life among patients with chronic obstructive pulmonary disease and patients with lung cancer. Arch Intern Med; 166: 326–331.Find this resource:

3. Habraken J, Riet G, Gore J et al. (2009) Health-related quality of life in end-stage COPD and lung cancer patients. J Pain Sy Manage; 37 (6): 973–981.Find this resource:

Pain in respiratory disease

Definitions

  • ‘Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.’1

  • ‘Nociception’ is the perception of a painful stimulus by the nervous system. Pain is the personal experience of this.

  • ‘Total pain’ is a term that encompasses the multidimensional nature of pain. Physical, psychological, social, and spiritual elements all contribute to patients’ suffering.

Pain is a psychosomatic phenomenon affected by mood, morale, and the meaning the pain has for the patient.

Prevalence

Pain is a common symptom experienced by the majority of patients with advanced respiratory disease. Prevalence data vary widely due to heterogeneity of study populations and outcomes. It is, however, apparent that:

  • lung cancer is one of the most likely primary neoplasms to cause pain, and approximately three-quarters of those with incurable disease suffer from this symptom

  • non-malignant CRD is also associated with pain in one- to two-thirds of patients, and the pain in such patients is particularly under-assessed and inadequately managed.

Causes

Pain in LC is usually due to the disease itself. Pain in CRD is more likely to be due to complications of the disease or concurrent morbidity.

Primary respiratory disease

  • Local malignant invasion of primary lung cancer such as:

    • apical Pancoast's tumour infiltrating brachial plexus

    • peripheral disease infiltrating pleura, ribs, and chest wall

    • central disease invading mediastinum

  • Metastatic spread of malignancy to bone, brain, liver etc.

  • Paraneoplastic syndromes such as myositis and peripheral neuropathy.

Complications of respiratory disease

  • Chest infection causing pleuritis or tracheobronchitis.

  • Rib fracture, costochondritis, and muscle sprain secondary to cough.

  • Diaphragmatic and intercostal muscle fatigue.

  • Pulmonary embolism.

  • Pneumothorax.

  • Pleural effusion.

  • Hypertrophic pulmonary osteoarthropathy.

Treatment of respiratory disease

  • Steroid-induced osteoporosis causing vertebral crush fractures.

  • Post-thoracotomy pain.

  • Peripheral neuropathy caused by chemotherapy such as cisplatin.

Concurrent morbidity

  • Osteoarthritis.

  • Cardiovascular disease.

  • Oesophagitis.

  • Constipation.

  • Intercostal radiculopathy.

  • Herpes zoster infection.

Most pain in advanced respiratory disease is predominantly felt in the chest. This is particularly true for pain that is caused by the primary respiratory disease or a complication of that disease.

Consequences

The consequences of living with uncontrolled pain can be significant. Restriction of chest wall movement and reduction in overall mobility can cause a number of physical sequelae that contribute to morbidity and indeed mortality. The psychosocial consequences of pain are also considerable and can have a profoundly negative impact on carers and family, as well as on the patient.

Table 6.1 Potential consequences of uncontrolled pain

Physical

Psychosocial

Difficulty coughing

Hypoventilation

Lung atelectasis

Chest infection

Pressure sores

Deconditioning

Venous thromboembolism

Anxiety and depression

Reduced social performance

Inability to work

Social isolation

Financial difficulties

Strained relationships

Reference

1. IASP Task Force on Taxonomy, edited by Merskey H, Bogduk, N (1994) Classification of Chronic Pain, 2nd edition, IASP Press, Seattle.Find this resource:

    Assessment of pain

    The purpose of assessing a patient's pain is to determine the most likely cause of the symptom. Knowledge of the cause of pain facilitates effective pain management because it allows:
    • treatment of any reversible underlying cause of the symptom

    • selection of the most appropriate analgesic regimen.

    Accurate assessment of a patient's pain is a vital skill that is underpinned by a number of important principles:

    • Always believe the patient's complaint of pain. ‘Pain is what a patient says it is.’

    • Most patients have more than one pain; each pain must be assessed individually and prioritized.

    • Evaluation of psychosocial and spiritual factors is as important as assessment of the physical symptom.

    • Assessment of pain is rarely a one-off event and often requires multiple consultations over a period of time.

    History

    Pain is a subjective and complex experience and a detailed history of the symptom is the key to its assessment. It is important to gain the patient's confidence and establish a trusting relationship. Good communication skills also improve the quality of the pain history and include active listening, open questioning, and summarizing of information received.

    Details of the pain itself must be established, particularly its site, severity, character, temporal pattern, and associated symptoms. The mnemonic SOCRATES is widely used as a tool to aid recall of these factors (see Figure 6.1). Other important information includes:

    • Management of pain so far:

      • current and past medication including dose, route, response, side effects, and reason for discontinuation

      • previous medical consultations

      • non-pharmacological treatments.

    • Consequences of the pain:

      • psychological state

      • impact on ADLs and social functioning.

    • Patient's understanding of the meaning of the pain:

      • likely cause of the symptom

      • implications for the patient.

    Fig. 6.1 SOCRATES pain assessment tool.

    Fig. 6.1
    SOCRATES pain assessment tool.

    This latter factor can be one of the most revealing areas of enquiry:

    • Patients can be remarkably accurate in appraising the cause of pain; they have first-hand knowledge of the characteristics of the symptom and a vested interest in determining its cause.

    • Mistaken beliefs as to the cause and implications of the symptom can hinder control of pain and can be relatively easily corrected.

    DS was a 61-year-old lady with stage 3b NSCLC who had been treated with chemotherapy and radiotherapy 6 months ago. She was admitted to hospital in a state of distress, complaining of severe epigastric pain. It was considered that the pain was likely to be due to gastritis secondary to the use of a non-steroidal anti-inflammatory drug. However, the pain did not resolve after commencing the proton pump inhibitor, omeprazole. She subsequently underwent a gastroscopy that confirmed the presence of gastritis. The pain persisted. Two days later she was asked ‘What do you think might be causing this pain?’ She responded, ‘I know that you think there is an irritation in my stomach, but I'm afraid that this pain means that the cancer has spread.’ She was reassured strongly that there was no evidence of disease progression on a recent chest X-ray. The epigastric pain resolved that day.

    Examination

    • Pay particular attention to the exact site of pain (facilitated by the patient pointing with one finger to the site of worst pain on exposed body part).

    • Palpate at the site of pain to elicit tenderness or palpate abnormal swellings, areas of muscle spasm etc.

    • Undertake a full neurological examination of the affected area, particularly in the presence of neck or back pain.

    • Observe for the degree of functional impairment while moving in and out of a chair, undressing etc.

    • Remember general observation of mood, wincing, grimacing etc.

    Abnormal sensory signs include:

    • paraesthesia—any abnormal sensation, whether spontaneous or evoked

    • analgesia—an absence of pain in response to a stimulus that would normally be painful

    • hyperalgesia—an increased painful response to a stimulus that would normally be painful

    • allodynia—pain caused by a stimulus, such as a light touch, that should not normally provoke pain.

    Investigations

    These do not form an important part of the clinical evaluation of pain and serve mainly to confirm or refute the clinical diagnosis of the cause of pain. Computerized tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and radio-isotope scanning can be used to assess the site and extent of malignant disease. MRI is of value in appraising skeletal or soft tissue pathology and evaluating potential neurological involvement e.g. brachial plexus disease. Thoracic ultrasound (USS) and contrast-enhanced CT scanning can accurately demonstrate pleural pathology.

    Outcomes of assessment

    Cause of pain

    By the end of the pain assessment the intention is to have determined the most likely cause of the pain(s) or a short differential diagnosis. This greatly facilitates pain management by allowing the treatment of reversible causes of pain and aiding analgesic selection.

    Type of pain

    In addition, the assessment can allow the type of pain to be characterized (see Table 6.2). Knowledge of the likely pain type can help determine the most likely cause of pain and can aid selection of the most appropriate analgesic. The type of pain can be described according to:

    • Pathophysiology:

      • nociceptive pain—following somatic or visceral tissue damage and conducted by a normal nervous system

      • neuropathic pain—either following nerve injury or compression.

    • Temporal pattern:

      • acute pain—following an event that would be expected to cause pain such as a pathological fracture

      • chronic pain—a persistent pain that requires continual analgesia

      • breakthrough pain—intermittent exacerbations of pain otherwise well controlled with appropriate doses of analgesia

      • incident pain—absent at rest and brought on by a particular movement such as walking or coughing.

    • Response to opioids:

      • opioid-responsive—a good response to opioids, without significant or uncontrollable adverse effects

      • partially opioid-responsive—some response, but pain incompletely controlled and increase in opioid dose limited by adverse effects

      • poorly opioid-responsive—little/no response to opioid treatment.

    Table 6.2 Characteristics of different pain types

    Pain type

    Examples

    Typical clinical features

    Nociceptive somatic

    Osteoporotic vertebral fracture

    Rib fracture

    Muscle injury

    Sometimes described as ‘aching’ ‘stabbing’ or ‘throbbing’ in nature and may be worse on movement.

    Nociceptive visceral

    Liver capsule pain secondary to hepatic metastases from lung cancer

    Bowel colic secondary to consipation

    ‘Gnawing’ or ‘cramping’ character, sometimes ‘sharp’ or ‘throbbing’ when solid organ or capsule involved

    Neuropathic

    Spinal nerve root compression

    Post thoracotomy pain

    ‘Burning’ ‘tingling’ or ‘deep aching’ quality. Occasionally lancinating ‘like an electric shock’. Can be associated with abnormal sensations such as allodynia. Often partially or poorly responsive to strong opioids

    Mr WS was a 63-year-old gentleman with severe COPD. He presented in some distress with a 48-hour history of increasing breathlessness and a new chest pain that was worse on inspiration, and he was immediately admitted to hospital for evaluation and treatment of a suspected pulmonary embolus. A detailed pain history established that the pain had started after he had stumbled at home and fallen against a door. The pain was ‘stabbing’ in nature and was worse when he moved or took a deep breath, and it radiated between his back and a point near his left nipple. He had noticed that even his shirt rubbing on the skin there was uncomfortable. On examination, there was focal, mid-thoracic spinal tenderness and a band of allodynia across his left chest.
    The pain was classified as an acute, incident, thoracic bone pain with associated acute neuropathic pain in the T6 dermatome. A steroid-induced osteoporotic vertebral collapse with nerve root compression was considered to be the most likely cause of the pain and the diagnosis was confirmed by an MRI scan. He could not tolerate non-steroidal anti-inflammatory drugs or strong opioids, and a trial of gabapentin was ineffective. A vertebroplasty was performed under local anaesthetic. He made an uneventful recovery, mild residual pain being fully controlled by regular paracetamol.
    This case demonstrates the importance of a detailed pain assessment. This can help determine the type of pain, which in turn facilitates diagnosis of the underlying cause of pain. Once the cause is known, its reversal can lead to highly effective pain relief.

    Overview of pain management

    Treatment of reversible causes

    The most effective method of treating any symptom is to reverse the underlying cause. Pain is no exception to this principle and examples include:

    • treatment of infection-induced pleuritic pain with antibiotics

    • relief of dyspepsia secondary to gastritis with a proton pump inhibitor

    • surgical fixation of a malignant pathological bone fracture

    • use of appropriate diet and laxatives to treat bowel colic secondary to constipation.

    Oral analgesia

    The World Health Organization guidelines for the use of analgesic drugs are recommended and used worldwide. Although developed initially for use in cancer pain, they provide a useful framework for all chronic pain irrespective of cause. The use of oral analgesics is described in detail on Non-respiratory symptoms [link][link].

    The principles of analgesic use are as follows:

    • Use a three-step ladder (Figure 6.2). Start with step 1, reassess after 24 hours, and move up the ladder if pain remains inadequately controlled.

    • Prescribe regular analgesia. This is more effective than ‘as needed’ analgesia, taken only when the pain is present.

    • In addition, prescribe ‘as needed’ medication for breakthrough pain i.e. pain that breaks through despite the regular analgesic.

    • Use the oral route. If inadequate analgesia is achieved, consider a higher dose or an alternative analgesic rather than altering the route. Other than a faster onset of action, an equianalgesic parenteral dose is usually no more effective in patients with unimpaired absorption of oral drugs.

    • Monitor frequently to assess for efficacy or adverse effects. Adjust drug dose or type as needed and actively treat adverse effects.

    Fig. 6.2 World Health Organization three-step analgesic ladder.(Adapted from WHO (1996) Cancer pain relief: with a guide to opioid availability, 2nd edn. Geneva: WHO).

    Fig. 6.2
    World Health Organization three-step analgesic ladder.(Adapted from WHO (1996) Cancer pain relief: with a guide to opioid availability, 2nd edn. Geneva: WHO).

    Non-pharmacological approaches

    Oral analgesics are the primary method of pain control. Non-drug approaches can be combined with oral analgesia as an adjunct, particularly if suboptimal analgesia has been achieved. The multidimensional nature of pain is reflected in the use of the following holistic and patient-centred approaches:

    • Psychological interventions. Useful techniques include:

      • cognitive behavioural therapy—aiming to change maladaptive thoughts and behaviours

      • relaxation—such as passive relaxation (focusing attention on sensations of warmth and decreased tension around the body) and progressive muscular relaxation (active tensing and relaxing of muscles)

      • imagery/distraction techniques—the patient can, for example, imagine a place or activity where he/she felt most safe and secure and then can focus on this, utilizing all the senses.

    • Radiotherapy can be considered in pain caused by malignant disease.

    A narrative for progressive muscle relaxation could go as follows:1
    ‘I wonder if you could tense up every muscle in your body… that's it, squeeze in the muscles… hold it, and then just let it go… once more, tense up your muscles… make them very tight and tense, hold it, hold it… and then breathe out, and let your muscles relax, just let them go… Now, as your body begins to feel more and more relaxed, clench your jaw, squeeze it tight, clench it, then let it go… now open your mouth wide, as wide as it will go, stick out your tongue, stick it way out, hold it, then let it go. Feel your head becoming more and more relaxed, as it sinks down into the pillow, allowing all the tension and tightness to drift out of it. Now I wonder if you can lift up your shoulders, lift them up, up to your ears, hold them there squeezing them tightly, squeeze and then let them drop down, just let them go… and then once more, lift them up… hold it… then let them go… as you feel all the tightness and tension in your shoulders begin to drain away… Now I wonder if you can clench your hands into fists, make a tight fist as your whole arm tightens, tense your arms as you squeeze your fingers tighter and tighter… and now just let them go, once more make a fist, a tight fist, hold it, and then let it go…’

    There is little evidence to support the efficacy of the following techniques, but they can be highly effective for some individuals and, at worst, do not appear to cause significant harm:

    • Transcutaneous electrical nerve stimulation (TENS)—indications for the treatment of chest pain could include:

      • post-thoracotomy pain (electrodes on either side of scar)

      • rib fracture or metastasis (electrodes on either side of affected rib)

      • neuropathic pain from intercostal radiculopathy or post-herpetic neuralgia (electrodes above or across affected dermatome)

    • Acupuncture—this appears to be most useful for pain due to muscle spasm, such as injury following prolonged coughing, and for post-thoracotomy pain.

    • Complementary therapies—these include massage, reflexology, aromatherapy, and creative therapies such as art and music therapy.

    Anaesthetic techniques

    These techniques are used when a patient fails to gain adequate pain control with systemic analgesia. They can be considered as the fourth and highest step on the analgesic ladder.

    • Spinal analgesia is the most frequently used anaesthetic technique:

      • Drugs are injected through either an epidural or, preferably, subarachnoid (intrathecal) catheter.

      • Morphine is the most widely used spinal analgesic, being the least lipid soluble, and it is often combined with a local anaesthetic (e.g. bupivicaine) and α‎2-adrenergic agonist (e.g. clonidine).

      • In advanced respiratory disease, the main roles for spinal analgesia are to treat uncontrolled pain from vertebral compression fractures or rib fractures, or to control intractable cancer pain.

    • Local anaesthetic or neurolytic nerve blocks tend to be reserved for patients in whom spinal analgesia is contraindicated:

      • Neurolytic intercostal nerve blocks or paravertebral blocks can be used in intractable chest wall pain, such as that caused by malignant chest wall invasion.

      • Before proceeding with neurolysis, a prognostic local anaesthetic block should be used to determine whether neurolysis is likely to be effective.

      • Cingulotomy and cervical cordotomy are occasionally used in specialist centres, particularly for uncontrolled chest pain related to mesothelioma.

    Reference

    1. Breitbart W, Payne D, Passik S (2005) Psychological and psychiatric interventions in pain control. In: Doyle D, Hanks G, Cherny N, Calman K (eds.), Oxford Textbook of Palliative Medicine, 3rd edition. Oxford University Press, Oxford, pp424–438.Find this resource:

      Non-opioid analgesia

      Paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) are the principal non-opioid analgesics. They can be used alone in step 1 of the WHO ladder (Figure 6.2) and can also be effective in combination with opioids in steps 2 and 3.

      Paracetamol

      • Paracetamol is a synthetic non-opioid analgesic that acts centrally, inhibiting brain cyclo-oxygenase and nitric oxide synthetase.

      • It has a high oral bioavailability (90% after 1g paracetamol); onset of analgesia occurs in 15–30 minutes and analgesia lasts 4–6 hours.

      • The usual route of administration is oral, although it can be given intravenously and rectally if the oral route is not available. Intravenous paracetamol has an earlier onset and longer duration of action than oral paracetamol.

      • Adverse effects are very rare and occur in less than 0.1% of patients. However, patients who are elderly and poorly nourished have lower glutathione stores and are more susceptible to hepatic toxicity.

      • Concurrent use of 5HT3 receptor antagonists with paracetamol may completely block the analgesic effect of the drug.

      • Dispersible paracetamol tablets have a high sodium content and should be avoided in patients with hypertension or renal impairment.

      • A small proportion of patients who experience bronchospasm with NSAIDs or aspirin (probably less than 2%) may also develop bronchospasm following paracetamol. The reaction to paracetamol is less severe than to NSAIDs.

      Recommendations in advanced respiratory disease:
      • Prescribe regular oral paracetamol 1g qds as the first step in the management of chronic pain.

      • If there has been no definite benefit within 48 hours, stop the drug.

      • When a strong opioid is added to paracetamol (WHO ladder step 3) and pain control is good, review the need for paracetamol by stopping it, only reinstating it if the pain returns.

      • Patients with a history of NSAID- or aspirin-induced bronchospasm should take a test dose of 250mg paracetamol and be observed for a few hours before commencing regular full-dose paracetamol.

      Formulations:
      • Tablets, 500mg.

      • Dispersible tablets, 500mg.

      • Capsules, 500mg.

      • Oral suspension, 120mg/5mL, 250mg/5mL.

      • Suppositories, 60mg, 125mg, 250mg, 500mg.

      • Intravenous infusion, 10mg/mL.

      NSAIDs

      NSAIDs inhibit the enzyme cyclo-oxgenase, thereby reducing the production of pro-inflammatory prostaglandins. They can be categorized according to their selectivity for COX-1 and COX-2 isoforms:

      • preferential COX-1 inhibition—indometacin, ketorolac

      • non-selective—ibuprofen, naproxen, flurbiprofen

      • preferential COX-2 inhibition—diclofenac, celecoxib, meloxicam

      • selective COX-2 inhibitors—parecoxib, valdecoxib, etoricoxib.

      Adverse effects

      NSAIDs are highly effective analgesics, particularly for musculoskeletal pain. However, their use is hindered by their adverse effect profile as detailed in Table 6.3. Potentially serious complications include:

      • gastroduodenal toxicity such as ulceration

      • acute bronchospasm

      • thrombotic events such as MI or CVA

      • anti-platelet action with resultant risk of bleeding

      • renal impairment.

      Table 6.3 Adverse effects of NSAIDs

      Adverse effect

      Comments

      Gastroduodenal toxicity

      Lowest risk with coxibs (risk is less than 50% non-selective drugs), ibuprofen and diclofenac.

      Risk factors particularly prevalent in advanced respiratory disease include age >65 years, serious co-morbidity, concurrent use of corticosteroid, aspirin, anticoagulant or SSRI.

      Acute bronchospasm

      Prevalence is ∼20% in adult population and 5% in children.

      Typically occurs 0.5-3hrs after ingestion of tablet.

      Cross-sensitivity between NSAIDs is high (>90%).

      No evidence that COPD increases the risk of sensitivity to NSAIDs, but pragmatic approach is to use NSAIDs with caution in patients with bronchospasm element to disease.

      Celecoxib least likely to cause bronchospasm, but avoid because of risk of thrombotic events.

      Interestingly, in population terms, NSAID use is associated with improved FEV1, possibly due to anti-inflammatory effect.

      Thrombotic cardiovascular events

      Coxibs confer the greatest risk of events such as MI or CVA; most NSAIDs increase risk slightly.

      Low dose ibuprofen <1200mg/day and naproxen appear to be safest.

      Advanced respiratory disease is a risk factor for thrombotic events, so avoid use of coxibs.

      Antiplatelet action

      Aspirin causes irreversible platelet dysfunction, most NSAIDs cause reversible dysfunction, diclofenac and coxibs do not alter function.

      Risk of bleeding increased in advanced respiratory disease as patients may require anticoagulation (increased VTE prevalence) or may be taking gastric irritant drugs such as corticosteroids, SSRIs.

      Renal impairment

      Cause salt/water retention and can impair renal function, contributing to overall morbidity (eg worsening of cor pulmonale).

      Risk factors include chronic renal disease, hypovolaemia and concurrent use of loop diuretics.

      Renal risks of NSAIDs are similar, therefore not a factor in determining choice of drug.

      Route of administration

      Oral administration, if available, is preferred. There is no evidence for therapeutic advantage from rectal or parenteral preparations.

      There is increasing evidence for the efficacy of topical NSAIDs in chronic musculoskeletal pain. In the UK, the National Institute for Health and Clinical Excellence (NICE) has recommended that because of their favourable safety profile, topical NSAIDs should be used in preference to oral NSAIDs for pain related to osteoarthritis. Topical NSAIDs offer:

      • enhanced local delivery of the drug to affected tissues

      • significantly fewer adverse effects than oral NSAIDs due to low systemic absorption (of 3–5%)

      • benefit from rubbing the painful area, possibly contributing to the significant placebo effect.

      Recommendations in advanced respiratory disease:
      • First-line: for musculoskeletal pain or for other pains associated with inflammation, such as pleurisy, prescribe ibuprofen 400mg tds po.

      • Second-line: consider using naproxen 250–500mg bd po.

      • Prescribe a proton pump inhibitor concurrently, such as omeprazole 20mg od po.

      • Avoid long-term prescription of oral NSAIDs and use for the shortest period of time necessary to control symptoms.

      • Prescribe topical NSAIDs for patients with localized superficial muscular pain, costochondritis, or osteoarthritis.

      • Use NSAIDs with caution in patients with asthma and COPD patients with significant bronchospasm, and give a test dose under medical supervision.

      Formulations of ibuprofen:
      • Tablets, 200mg, 400mg, 600mg.

      • Oral suspension or syrup, 100mg/5mL.

      • Topical forte gel, ibuprofen 10% (Ibugel® Forte).

      Formulations of naproxen:
      • Tablets, 250mg, 500mg.

      • Tablets e/c, 250mg, 375mg, 500mg.

      Opioid analgesia

      Opiates are naturally-occurring opium alkaloids, such as morphine and codeine, and their semi-synthetic derivatives, such as oxycodone and hydromorphone. Opioids are fully synthetic drugs with a morphine-like action on the body, such as tramadol, fentanyl, and methadone.

      Codeine

      • Codeine (methylmorphine) is a naturally-occurring weak opiate that acts mostly through demethylation to morphine by cytochrome P450 CYP2D6. Approximately 7% of Caucasians lack CYP2D6 activity, and in these individuals codeine has a much reduced analgesic effect. Fluoxetine and paroxetine inhibit CYP2D6 and reduce the efficacy of codeine.

      • Codeine has approximately one-tenth of the potency of morphine. The usual oral dose is 30–60mg qds and the duration of action of each dose is 4–6 hours.

      • There is good evidence that compound preparations containing codeine and paracetamol are more effective than paracetamol alone. Co-codamol 8/500 and 30/500 contain paracetamol 500mg with codeine 8mg and 30mg respectively.

      • Codeine causes significant constipation that is greater than an equivalent dose of morphine, and laxatives should be prescribed when the drug is used regularly.

      Dihydrocodeine

      • Dihydrocodeine is a semi-synthetic analogue of codeine that, unlike codeine, is an active drug rather than a pro-drug. Poor CYP2D6 activity does not appear to impact on the efficacy of dihydrocodeine.

      • It is equipotent to oral codeine, but appears to have a narrower therapeutic index leading to more adverse effects at higher doses.

      Tramadol

      • Tramadol is a moderately strong synthetic analgesic that has both opioid and non-opioid properties. It has a high affinity for µ, δ‎, and κ‎ opioid receptors, stimulates 5HT release, and inhibits pre-synaptic uptake of 5HT and NA.

      • By mouth, it has one-fifth of the potency of morphine and can therefore be considered as double-strength codeine. The usual oral dose is 50–100mg qds and the duration of action of each dose is 4–9 hours.

      • It causes less respiratory depression and constipation than equi-analgesic doses of morphine.

      • The analgesic effect of tramadol is reduced by ondansetron and possibly other 5HT3 antagonists. Potentially lethal serotonin toxicity can occur when used in combination with other drugs that increase central 5HT levels, such as SSRIs.

      Morphine

      • Morphine is the strong opiate of choice for the management of moderate to severe chronic pain in advanced respiratory disease. It is used in step 3 of the WHO analgesic ladder, often in combination with non-opioid and adjuvant drugs.

      • It is a µ-opioid receptor agonist and is metabolized to M3G and M6G, which are renally excreted. M6G is an active metabolite that can accumulate in renal failure and lead to opioid toxicity.

      Starting a patient on oral morphine

      • Consider using morphine when a patient is still in pain despite use of a weak opioid and a non-opioid.

      • Commence a regular 4-hourly dose of morphine, with the same dose available for prn use:

        • Commence morphine immediate release (IR) 5mg 4-hourly if previously taking 240mg codeine/24 hours (total 30mg morphine/24 hours, 240mg codeine being equivalent to ∼24mg morphine).

        • Commence morphine IR 10mg 4-hourly if previously taking 400mg tramadol/24 hours (total 60mg morphine/24 hours, 400mg tramadol being equivalent to ∼80mg morphine).

      • After 1–2 days recalculate the dose of morphine IR based on total morphine requirement in last 24 hours (both regular and prn).

      • When the morphine IR dose is stable, replace it with morphine modified release (MR), prescribed 12-hourly (or daily if a 24-hour formulation). Calculate the 12-hourly morphine MR dose by adding all the morphine IR doses in the previous 24 hours, and divide by 2.

      • Continue to prescribe morphine IR for prn use, at a dose of one-sixth of the total morphine dose over 24 hours. The prn dose should be increased when the 24-hour dose increases.

      • Warn patients about constipation and prescribe a laxative routinely.

      • Explain the possibility of initial drowsiness and nausea. Prescribe an anti-emetic for prn or regular use in the first week, such as haloperidol 1.5mg bd po prn.

      • Reassess regularly to evaluate pain control and adverse effects.

      Mrs G was a 63-year-old lady with COPD and NSCLC. She developed severe right-sided chest pain that only responded partially to co-codamol 30/500 8 tablets/day. She was converted to paracetamol and morphine IR 5mg 4-hourly and prn. After 24 hours she had used a total of 65mg regular and prn morphine. She was converted to morphine IR 10mg 4-hourly with the same dose for prn use. During the next 24 hours she only required one prn dose, and was then converted to morphine MR 30mg bd with morphine IR 10mg prn for breakthrough pain.
      Examples of formulations of morphine IR for 4-hourly use:
      • Oral solution, 10mg/5mL (Oramorph®).

      • Concentrated oral solution, 100mg/5mL (Oramorph®).

      • Tablets, 10mg, 20mg, 50mg (Sevredol®).

      Examples of formulations of morphine MR for 12-hourly use (MST Continus®):

      • Tablets, 5mg, 10mg, 15mg, 30mg, 60mg, 100mg, 200mg.

      • Oral suspension, 20mg, 30mg, 60mg, 100mg, 200mg/sachet.

      • Subcutaneous morphine can be used when the oral route is not available. It is twice as potent as oral morphine.

      • Adverse effects of morphine are detailed in Table 6.4. Nausea and vomiting, mild drowsiness, and unsteadiness are relatively common initial effects that tend to resolve within the first week of morphine administration. Tolerance to the constipating effect of morphine does not develop, however, and long-term laxatives are usually necessary.

      Table 6.4 Adverse effects of morphine

      Effect

      Comments

      Management

      Nausea

      Opioid effect on chemoreceptor trigger zone, tolerance develops

      Haloperidol 1.5mg bd Consider opioid switch if persists

      Constipation

      Persistent symptom, laxative invariably needed

      See [link][link] for laxative details

      Gastric stasis

      Early satiety, hiccup, anorexia, vomiting

      Metoclopramide 10mg qds

      Dry mouth

      Tends to persist

      Frequent sips of waterSaliva substitutes

      Sedation

      Drowsiness, tolerance usually develops

      Reduce opioid doseLook for other causes if persists

      Vestibular stimulation

      Vertigo, ‘unsteadiness’, movement induced nausea and vomiting

      Cyclizine 25-50mg tdsConsider opioid switch

      Neurotoxicity

      Agitated delirium, hallucinations, myoclonus, hyperalgesia

      Reduce opioid doseConsider opioid switch

      Pruritis

      Whole body itch, does not respond to antihistamines

      Ondansetron 8mg po bd

      Pain is a physiological antagonist to the respiratory depressant effect of strong opioids.
      • When started at a low dose and carefully titrated upwards, morphine does not cause clinically important respiratory depression in patients with pain.

      • Significant respiratory depression can occur in patients who are opioid-naıïve and are without pain (or with short-lived pain that then subsides, such as post-operatively), particularly if the medication is given parenterally with faster absorption and higher peak concentration. This, in combination with high profile court cases in which doctors have been tried for murder (and the doctrine of double-effect has been used as a successful defence), has led to an entrenched societal misconception that morphine can kill even when used for symptom control.

      • Large safety studies have been carried out in cancer patients. Numerous studies involving opioid use for pain and dyspnoea in patients with COPD have never revealed clinically significant respiratory depression but they have, to date, been inadequately powered to detect rare but serious adverse effects.

      • In the absence of definitive safety data, care is needed when using morphine in advanced respiratory disease associated with respiratory failure.

      Diamorphine

      • Diamorphine (di-acetylmorphine, heroin) is considered to be a pro-drug for morphine. Subcutaneous diamorphine is three times more potent than oral morphine.

      • It has no clinical advantage over morphine, other than being much more water-soluble. Therefore, in countries where it is available, it is the strong opioid of choice for parenteral use when high doses are needed, as it can be given in a smaller volume.

      Alternative strong opioids

      • Although morphine is the strong opioid of choice, alternative opioids may be used in the following situations:

        • poor response to morphine plus adjuvant drugs

        • unacceptable adverse effects from morphine

        • transdermal route preferable

        • moderate to severe renal impairment.

      • Before switching to an alternative opioid, consider the following:

        • The pain may be poorly opioid responsive, such as neuropathic pain, and may require alternative interventions rather than opioid switching (see Non-respiratory symptoms [link][link]).

        • Adverse effects could be controlled by reducing the morphine dose and prescribing medication to treat the adverse effects, such as haloperidol for nausea or hallucinations.

      • The characteristics of alternative strong opioids are detailed in Table 6.5. Seek specialist advice if unfamiliar with a drug. Take particular care with fentanyl and methadone in respiratory disease (see [link]).

      • Dose conversions between strong opioids (Table 6.5) are approximate. Always err on the side of caution and, if in doubt, convert to a dose under the calculated equivalent. Conversions are particularly likely to be inaccurate when higher doses are involved; it is then safest to give 50% or less of the calculated dose.

      Table 6.5 Comparison of opioids with oral morphine

      Drug

      Advantages

      Disadvantages

      Dose conversion example

      Codeine (po)

      Familiar, avoids ‘stigma’ of morphine

      More constipating, ‘ceiling’ effect, no analgesic effect in ∼1 in 10 Caucasians

      Codeine 240mg po  morphine 24mg po

      Tramadol (po)

      Less constipation and respiratory depression, a potent ‘weak’ opioid

      Risk of seizures or serotonin toxicity

      Tramadol 400mg po  morphine 60–80mg po

      Diamorphine (sc)

      Highly soluble, suitable for high dose parenteral use

      Limited availability, only within UK and Belgium

      Diamorphine 10mg sc morphine 30mg po

      Oxycodone (po, sc)

      Vomiting, hallucinations, pruritis less common, slightly safer in renal impairment

      More expensive

      Oxycodone 10mg po morphine 15–20mg Oxycodone 10mg sc  morphine 10mg sc  morphine 20mg po

      Fentanyl (TD)

      Useful when oral route unavailable, safe in renal failure, less constipating

      Cannot be titrated rapidly

      Fentanyl patch 25mcg/hr  morphine 60–90mg/24hrs po

      Fentanyl (SL/TM)

      Rapid onset and short half-life, role in breakthrough pain, safe in renal failure

      Expensive, administration requires co-operation

      Always start with lowest dose and titrate up (eg Actiq®200mcg lozenge, eg Abstral®100mcg tablet)

      Alfentanil (sc)

      Short half-life, can be used in syringe driver, safe in renal failure, small volume

      Unfamiliar

      Alfentanil 1mg sc  diamorphine 10mg sc  morphine 30mg po

      Methadone (po)

      Role in neuropathic pain, safe in renal failure

      Long half-life, danger of accumulation, only commence in specialist unit

      Give 3 hourly prn doses 1/30 of previous 24 hr oral morphine dose

      Buprenorphine (TD)

      Useful when oral route not available, safe in renal failure, less constipating

      Skin reactions common, cannot be reversed with naloxone, unfamiliar

      Buprenorphine patch 10mcg/hr  morphine 30mg/24hrs po

      Dose conversions are only a guide. Always convert cautiously particularly at higher doses. Erroneous conversions can be fatal. Seek specialist advice if unfamiliar with drug.

      Key po: oral, sc: subcutaneous, TD: transdermal, SL: sublingual, TM, transmucosal

      Recommendations in advanced respiratory disease:
      • Use codeine as the first-line weak opiate for mild to moderate pain.

      • Tramadol has a role in patients with severe constipation or type II respiratory failure.

      • Morphine is the first-line strong opioid for use in moderate to severe pain. Start with a low dose, titrate carefully, and assess repeatedly.

      • Prescribe laxatives. Warn about initial adverse effects, such as nausea, that should settle in the first week, and consider prescribing an anti-emetic for use if needed.

      • In patients with type II respiratory failure, commence morphine under medical supervision and if appropriate (not in terminal phase) consider checking arterial blood gases after 24–48 hours.

      • Consider opioid switching to oxycodone in patients who cannot tolerate morphine.

      • Avoid using the lipophilic and highly protein-bound opioids, fentanyl and methadone, without specialist advice and support.

      Warning: lipophilic and highly protein-bound opioids are associated with a risk of respiratory depression occurring with little warning. Cachexia leads to a fall in the volume of distribution and more drug entering the plasma compartment. In addition, increasing pCO2 causes:
      • vasodilatation and increased mobilization of drug from fat to plasma

      • reduced plasma protein binding due to acidosis, releasing free drug.

      The resulting ‘vicious cycle’ can occasionally lead to rapid development of opioid toxicity and potentially lethal respiratory depression.

      Difficult pain problems

      Opioid poorly responsive pain

      Most pain can be controlled with oral analgesics and adjuvant drugs, used in accordance with the WHO ladder (Figure 6.2). Some pain does not, however, respond easily to these approaches and can be complex to manage. Upward titration of the opioid dose may lead to intolerable and/or uncontrollable adverse effects without achieving adequate pain control. There are a number of potential causes of opioid poorly responsive pain that can occur in advanced respiratory disease:

      • neuropathic pain

      • bone pain and other incident pain

      • ‘total’ pain.

      Neuropathic pain

      This is pain that is precipitated by either peripheral or central nervous system injury. Possible causes in this patient group include:

      • Post-thoracotomy pain caused by surgical damage of peripheral nerves.

      • Radicular pain from spinal nerve root damage, such as secondary to osteoarthritis or vertebral/paraspinal malignant disease.

      • Herpes zoster infection, triggered, for example, by immunosuppression secondary to corticosteroid use.

      • Brachial plexus infiltration by apical lung cancer (Pancoast tumour).

      • Chest wall infiltration by mesothelioma causing intercostal nerve injury.

      Neuropathic pain typically has a ‘burning’, ‘tingling’, or ‘deep aching’ quality. It can be lancinating ‘like an electric shock’ and can be associated with abnormal sensations such as allodynia. It is often poorly or only partially responsive to strong opioids.

      This type of pain can be responsive to NSAIDs. Consider conversion to an alternative NSAID and maximize opioid dose, whilst actively treating opioid adverse effects. If this fails to achieve adequate pain control, consider the following options in a step-wise approach.

      • Anticonvulsant or tricyclic antidepressant (TCA):

        • Gabapentin 100mg od, titrated up to tds over 3–6 days, then 300mg od, titrated up to tds over a further week; or amitriptyline 10mg nocte, titrated up to maximum of 50mg nocte.

        • Choose gabapentin if you wish to avoid anti-muscarinic adverse effects.

        • Choose amitripyline if night sedation would be useful, a daily dose preferable, or antidepressant action is required.

      • Anticonvulsant and TCA:

        • If there is no benefit from first drug, stop and try an alternative drug.

        • If there is incomplete benefit from first drug, add in an alterative drug.

      • Corticosteroids:

        • Consider dexamethasone 4–8mg od, particularly if nerve compression is more likely than infiltration.

      • Topical lidocaine patch:

        • Lidocaine 5% patch can be effective for superficial, localized pain.

        • Cut matrix patch to size of painful area; up to three patches can be used at a time if area is large.

        • Change patch daily, keeping on for 12 hours out of every 24 hours.

      • Opioid switch to methadone:

        • Methadone has NMDA receptor antagonist activity that can reduce the central sensitization that occurs with chronic neuropathic pain.

        • Only commence in a specialist unit (see Table 6.5).

      • Spinal or peripheral anaesthetic procedures:

      • Ketamine:

        • This dissociative anaesthetic is a potent NMDA receptor antagonist.

        • It can be effective for neuropathic pain but its use is hindered by a high prevalence of psychotomimetic phenomena including euphoria.

        • Commence on 10–25mg po tds and prn and titrate up to 50mg qds if necessary. Alternatively, administer ‘short-burst therapy’ by continuous subcutaneous infusion (CSCI), 100mg/24hrs, increased after 24 hours to 300mg/24hrs if not effective, and then to 500mg/24hrs after a further 24 hours if still not effective. Stop 3 days after last dose increment.

        • Unless familiar with the drug, prescribe only with specialist support.

      Bone pain and other incident pain

      Incident pain is pain that is evoked by specific activities such as moving in bed, walking, coughing, sneezing etc. Its episodic nature means that it is a type of breakthrough pain; in other words a flare of pain occurring on a background of otherwise well-controlled pain.

      This type of intermittent pain is difficult to control because, if sufficient analgesia is given to control the pain when it occurs, during the time when the triggering activity is not being performed and the patient is pain free a relative excess of analgesia may lead to adverse effects.

      Causes of incident pain in respiratory disease include:

      • rib fracture

      • rib or vertebral bone metastasis

      • muscle sprain

      • costochondritis

      • pleurisy.

      Consider the following management options:

      • NSAIDs with gastroprotection, often the most effective approach. Consider switching to an alternative NSAID if pain control is inadequate.

      • Single fraction palliative radiotherapy for malignant bone pain.

      • Bisphosphonates for malignant bone pain (may also prevent pathological fractures).

      • Oral transmucosal fentanyl citrate lozenges or sublingual fentanyl tablets (see Table 6.5) for rapid onset and brief analgesia during time of triggering activity.

      ‘Total pain’

      This concept encompasses the physical, psychological, social, and spiritual factors that contribute to this complex, multidimensional, and subjective symptom. When the complaint of pain is more a reflection of the psychological or spiritual turmoil being experienced by a patient, such pain will not respond to morphine. Such pain is sometimes termed ‘opioid irrelevant pain’.

      Careful communication and exploration of underlying mood, concerns, and expectations will be more effective than a pharmacological approach. Specialist psychological interventions may be needed.

      Pain control in renal failure

      Management of pain in patients with advanced respiratory disease and concurrent renal impairment can be challenging. A number of commonly used analgesics become unsafe to use. Morphine is converted to active metabolites that are excreted through the renal system. Accumulation of such metabolites in renal impairment can lead to significant opioid toxicity and potential respiratory depression. Furthermore, NSAIDs are contra-indicated. The safest drugs to use at each step of the WHO ladder are as follows:

      • Step 1:

        • Paracetamol: 1g qds, reducing to 1g tds when GFR <10mL/min.

      • Step 2:

        • Tramadol: 50–100mg qds reducing to 50mg bd when GFR <50mL/min.

      • Step 3:

        • Alfentanil subcutaneous infusion: dose unaltered by renal failure.

        • Fentanyl (transdermal, subcutaneous, or transmucosal): titrate to pain

        • Morphine: small doses on prn basis only, when GFR <50mL/min.

        • Methadone oral or subcutaneous infusion: only in specialist unit.

      See Table 6.5 for further details.

      • Adjuvant drugs:

        • Amitriptyline: use normal dose.

        • Gabapentin: maximum of 300mg/24hrs when GFR <50mL/min.

      Fatigue

      After breathlessness, fatigue is the most common symptom experienced by patients with advanced respiratory disease. It occurs in more than 50% of patients with advanced lung cancer, and up to 80% of those with COPD. The symptom is multidimensional with physical, affective, and cognitive components.

      • Physical:

        • Generalized weakness or limb heaviness.

        • Extreme tiredness.

        • Inability to perform tasks.

      • Affective:

        • Low mood.

        • Decreased motivation.

        • Lack of energy.

      • Cognitive:

        • Lack of concentration or attention.

        • Difficulty thinking clearly.

        • Poor short-term memory.

      Fatigue has a particularly negative impact on quality of life. It can hinder social functioning and ability to self-care, and can lead to a deteriorating cycle of dependence, social isolation, low self-esteem, and depression.

      Despite being one of the most prevalent and distressing symptoms, fatigue tends to be neglected by both medical staff and patients. It has traditionally been viewed as an inevitable and unavoidable consequence of advanced disease. However, with diagnosis and active management, fatigue can be ameliorated. It is vital that this important symptom is not ignored.

      Causes

      The underlying mechanism for fatigue in advanced respiratory disease is unknown, but may involve excess production of pro-inflammatory cytokines (IL6, IL1, and TNF-α‎) and abnormalities in ATP synthesis. A large number of clinical factors are known to contribute to fatigue as detailed in Table 6.6.

      Table 6.6 Factors contributing to fatigue

      Clinical correlates

      Treatments

      Comorbidities

      Depression

      β‎-blockers

      Anaemia

      Breathlessness

      Opioids

      Infection

      Deconditioning

      Hypnotics

      Cardiac dysfunction

      Sleep disturbance

      Sedative antihistamines

      Adrenal insufficiency

      Cachexia

      Chemotherapy

      Hypothyroidism

      Pain

      Radiotherapy

      Neuromuscular disease

      Diagnosis

      • Patient reports that tiredness interferes with ability to function and is not relieved by rest.

      • Fatigue severity score of ≥5 using an 11-point numerical rating scale ranging from 0 (no fatigue) to 10 (worst fatigue imaginable).

      Management

      Reverse underlying causes

      The key to fatigue management is to search for and correct reversible underlying factors.

      Common, treatable contributing causes include:

      • depression

      • breathlessness

      • pain

      • sleep disturbance

      • drugs e.g. Non-respiratory symptoms-blockers

      • anaemia

      • co-existing infection.

      Non-pharmacological approaches

      Fatigue causes inactivity, which leads to deconditioning. This, in turn, worsens fatigue. There is high quality evidence that exercise, ranging from gentle exercise at home to formal pulmonary rehabilitation, interrupts this vicious cycle and can significantly improve fatigue.1 However, in advanced disease, exercise may no longer be appropriate. Patients who still function independently can benefit from a simple explanation as to why keeping reasonably active can be helpful.

      As performance status deteriorates, energy conservation techniques become more useful:

      • Encourage patients to prioritize and avoid unnecessary activities.

      • Discuss adapting tasks so that they require less effort.

      • Practise relaxation techniques.

      Counselling and support can be helpful too, openly acknowledging the presence and negative impact of the symptom.

      Pharmacological approaches

      Erythropoetin is the only evidence-based pharmacological treatment for anaemia-related fatigue. However, recent evidence of excess mortality in cancer patients treated with erythropoetin means that use of erythropoetin cannot be recommended for cancer-related fatigue.2

      Corticosteroids can improve well-being and energy, and there is some evidence from patients with advanced cancer that they can relieve fatigue. However, steroids have considerable adverse effects; proximal myopathy and gastritis-related GI bleeding may increase fatigue. If there has been no improvement in fatigue in 4 weeks, corticosteroids should be stopped.

      Central nervous stimulants, such as methylphenidate or modafinil, may have a role, but further research evidence is required before adoption into mainstream practice.

      Mrs C is a 72-year-old widow with advanced COPD, who asked for a home visit from her respiratory nurse specialist. She was complaining that, although her breathlessness was in control when she moved slowly, she was getting so tired that she was struggling to make meals and was losing weight. In addition, her daughter had stopped bringing her young grandchildren, as they were making her even more exhausted. She was increasingly spending the whole of her waking day in one chair, overlooking the garden. Recently she had begun to sleep in the chair at night, as she could not gather the energy to go to bed. During the conversation, it became clear that she was afraid that the extreme tiredness was a sign that she was dying.
      It was sensitively explained to her that a number of factors were contributing to her fatigue, including deconditioning from inactivity, sleep disturbance from sleeping in a chair, poor nutrition, and low mood due to increasing social isolation and undiscussed fears. Over a number of home visits, she was encouraged to set herself reasonable goals to increase her activity, including walking to the kitchen regularly to make simple, nutritious meals. Her daughter met her specialist nurse, and she began to visit more often and provide support. After one month, Mrs C felt confident enough to take small walks in the garden, and was amazed that her quality of life had improved so much.

      References

      1. Lacasse Y, Goldstein R, Lasserson TJ, et al. (2006) Pulmonary rehabilitation for chronic obstructive pulmonary disease. Cochrane Database Syst Rev, CD003793.Find this resource:

      2. National Institute for Health and Clinical Evidence Epoetin alfa, epoetin beta darbepoetin alfa for cancer treatment-induced anaemia. NICE technology appraisal guidance 142 May 2008.Find this resource:

        Anxiety

        Causes

        A degree of anxiety is a common consequence of any illness. Advanced respiratory disease is, however, particularly likely to lead to significant anxiety for a number of reasons:

        • Breathlessness is both a cause and a consequence of anxiety. This results in a deteriorating vicious circle that can lead to panic (see Figure 6.3).

        • The disease trajectory is often associated with sudden and unexpected deteriorations in condition, and this unpredictability can lead to intense fear and uncertainty about the future.

        • Patients with advanced respiratory disease are at risk of becoming socially isolated; unexpressed concerns fester and grow.

        • Many patients have a poor functional status, a significant proportion becoming housebound, and this can lead to fear of losing independence.

        • A number of treatments for respiratory diseases can cause or exacerbate anxiety, such as β‎2-agonists and corticosteroids.

        Consequences

        Patients with respiratory disease who are suffering from anxiety:

        • have a significantly worse quality of life

        • suffer from more severe dyspnoea

        • are more likely to be admitted to hospital

        • have poorer outcomes from hospital treatment.

        Despite its high prevalence and negative impact, anxiety in patients with respiratory disease is often neglected. There is an expectation that it will be present, which leads to it being ignored. Furthermore, health professionals tend towards therapeutic nihilism, believing that, other than by using potentially harmful drugs such as benzodiazepines, it is not possible to treat. This is not true. A number of interventions have been proven to be effective in the management of anxiety in respiratory disease.

        Active screening, diagnosis, and treatment of anxiety has the potential to be one of the most effective approaches to improving the quality of life of patients with advanced respiratory disease.

        Diagnosis

        Anxiety is a problem that should be actively managed if its severity or duration exceed normal expectations and if it interferes with a patient's ability to function. Screen all patients with advanced respiratory disease for the presence of anxiety, particularly if they are complaining of:

        • inability to relax, indecisiveness, irritability, or insomnia

        • sweating, tremor, nausea, or panic.

        Use a single-item screening question, such as:

        • ‘Are you feeling very anxious?’

        • ‘Many people with… (e.g. COPD) find it makes them feel quite worried/frightened/anxious at times. Are you experiencing this too?’

        • Patients that are anxious tend to be preoccupied with what may happen in the future.

        • Patients that are depressed tend to be preoccupied with what has happened in the past.

        Management

        The mainstay of anxiety management is non-pharmacological. There can be no substitute to giving patients encouragement and time to express their concerns, fears, and expectations. Even in advanced disease it is common for the imagined future to be worse than the likely reality. Listen well and respond with honesty and clarity.

        Management of contributing factors

        • Dyspnoea—this symptom is inextricably linked with anxiety; the management of one inevitably helps the other.

        • Depression—it may be that anxiety symptoms are part of a depressive illness.

        • Carer/family anxiety—giving appropriate support to carers can ease the suffering of patients.

        • Staff anxiety—this should not be forgotten; anxiety is ‘catching’ and can impact on the mood and objectivity of healthcare professionals.

        Non-pharmacological approaches

        Non-drug measures tend to be more effective and better tolerated than pharmacological management of both anxiety and depression.

        Pulmonary rehabilitation

        There is consistent high-quality evidence that pulmonary rehabilitation can improve both anxiety and depression in patients with COPD, as well as improving breathlessness, fatigue, and quality of life (see Non-respiratory symptoms chapter 5 [link] for further details).1 , 2

        Cognitive behavioural therapy

        CBT has been shown to improve anxiety and depression in advanced COPD (see box)2.

        Other measures

        Progressive muscular relaxation, imagery/distraction techniques, and self-hypnosis may all contribute to alleviating anxiety. These approaches require time and cooperation to learn. All techniques need to be practised, and patients derive most benefit if they are taught as early as possible (see Non-respiratory symptoms Chapter 5 [link]) for further details).

        Pharmacological approaches

        Despite their ‘bad press’, benzodiazepines can be useful in the short-term to break the anxiety/dyspnoea cycle and restore sleep. Non-drug approaches should always be used concurrently, and benzodiazepines (BDZ) have a role in helping regain control while waiting for psychological approaches to become effective. The addictive potential is less of a concern when prognosis is short. Consider using the following:

        • Diazepam 1–5mg od nocte and prn, long half-life (24–120hrs) giving ‘background’ symptom control.

        • Lorazepam 0.5mg sublingually, rapid onset (5 min onset, time to peak concentration 1hr) useful for prn use at times of acute anxiety.

        • Midazolam 2.5mg sc prn or 10–30mg (or more) continuous sc infusion over 24hrs, when oral route not available.

        As well as reducing anxiety, BDZ may have a direct effect on reducing dyspnoea (see Non-respiratory symptoms Chapter 5 [link]), can relax muscle spasm, and raise the seizure threshold, and there is some evidence that clonazepam (250mcg–2mg po od) can be effective in neuropathic pain.

        BDZ may cause a paradoxical agitation, or even delirium, in some patients; avoid the classic error of increasing the BDZ dose to control anxiety/agitation in such instances. BDZ have a central respiratory depressant effect and care must therefore be taken in respiratory failure.

        A number of non-BDZ drugs have anxiolytic properties:

        • Antidepressants with anxiolytic properties include amitriptyline, mirtazapine, paroxetine, and citalopram (see Non-respiratory symptoms [link][link]).

        • There is limited evidence that buspirone, a non-benzodiazepine anxiolytic, can reduce anxiety in COPD. It takes 2–4 weeks to be effective but may have a role in respiratory failure as it has no respiratory depressant effect. Start at 5mg bd and titrate up the dose every 2–3 days.

        Cognitive behavioural therapy for anxiety and panic4

        The cognitive behavioural approach involves recognizing the way feelings, thoughts, behaviour, and physical sensations can influence each other. A vicious circle can develop (see Figure 6.3) with a spiralling descent into anxiety and panic. A number of helpful and simple cognitive techniques and behavioural experiments can help breathlessness-related anxiety and panic. Consider accessing the services of a trained CBT therapist for specialist help.

        1. 1. Psychoeducation: Understand the causes and consequences of hyperventilation; understand that panic does not lead to death; ask the patient to deliberately hyperventilate to demonstrate the associated symptoms and then show the effectiveness of rebreathing with a paper bag.

        2. 2. Unhelpful thoughts: Challenge the thoughts that catastrophe and death will occur with more realistic alternatives volunteered by the patient, based on his/her own experience of panic attacks.

        3. 3. Breathing control: Encourage learning to relax the abdomen, breathing gently from the diaphragm; practise with two or three diaphragmatic breaths every hour until it becomes easy and natural.

        References

        1. Withers N, Rudkin S, White R (1999) Anxiety and depression in severe chronic obstructive pulmonary disease: the effects of pulmonary rehabilitation. J Cardiopul Rehab; 19 (6): 362–365.Find this resource:

        2. Coventry PA (2009) Does pulmonary rehabilitation reduce anxiety and depression in chronic obstructive pulmonary disease? Curr Opin Pulm Medicine; 15: 143–149.Find this resource:

        3. Kunik M, Veazey C, Culley J et al. (2008) COPD education and cognitive behavioural therapy group treatment for clinically significant symptoms of depression and anxiety in COPD patients: a randomised controlled trial. Psychol Med; 38 (3): 385–396.Find this resource:

        4. Sage N, Sowden M, Chorlton E, Edeleanu A (2008) CBT for Chronic Illness and Palliative Care: A workbook and toolkit. John Wiley and Sons Ltd, England.Find this resource:

          Depression

          Untreated depression, like anxiety, can lead to poor quality of life, worse symptom control, increased admission to hospital, and worse outcomes. Diagnosis and proactive management is of great importance.

          Although a significant proportion of patients with advanced respiratory disease become depressed, it is often under-recognized and only one-third of patients with depression receive treatment.

          • Medical staff may ignore low mood, considering it to be an ‘understandable reaction’ to a difficult situation.

          • Symptoms such as sleep disturbance, weight loss, and anorexia may be attributed to the underlying disease rather than to depression.

          • Patients withhold symptoms of depression as they are embarrassed and fear being stigmatized.

          • The focus of medical visits tends to be on disease and physical symptom management.

          Diagnosis

          An assessment for depression must be undertaken in all patients. A single-item screening tool can be helpful, such as, ‘Do you think you have become depressed?’

          A number of clinical features can help distinguish a depressive illness from appropriate sadness in patients with advanced disease:

          • Anhedonia: lack of interest or pleasure in anything, including things that would normally be enjoyed, such as seeing grandchildren.

          • Hopelessness: this may be associated with persistent thoughts of death or suicide.

          • Loss of emotion: patients may have a flat affect and be unable to express sad emotions as well as happy ones.

          • Low self-esteem: guilty ruminations, loss of confidence, and a sense of worthlessness are particularly relevant when they occur with regard to family and friends.

          • Diurnal variation: symptoms are typically worse in the morning rather than later in the day.

          Management

          Management of contributing factors

          Breathlessness, uncontrolled pain, and social isolation are all examples of factors that can contribute to depression.

          Non-drug measures

          As in the management of anxiety, there is more evidence to support the use of non-drug measures than there is for pharmacological intervention. Both pulmonary rehabilitation and cognitive behavioral therapy can improve depression in patients with chronic lung disease.

          The National Institute for Health and Clinical Excellence recommends the use of cognitive behavioural therapy as a first-line intervention for the treatment of mild to moderate depression in patients with a chronic physical health problem1.

          Antidepressants

          Antidepressants are recommended for use in patients with moderate to severe depression.

          SSRIs (sertraline, citalopram, paroxetine)

          • SSRIs are as effective as tricyclic antidepressants, better tolerated, and safer in overdose.

          • Avoid fluoxetine in respiratory disease as it may worsen anxiety and there is a greater risk of drug interactions.

          Amitriptyline

          • Amitriptyline is of particular use when depression is associated with anxiety and insomnia, and/or if the patient is experiencing concurrent neuropathic pain.

          Mirtazapine

          • Mirtazapine (a noradrenergic and specific serotonergic antidepressant, NaSSA) is a potentially useful antidepressant in patients with respiratory disease.

          • It has significant anxiolytic activity (mirtazapine 15mg is equivalent to diazepam 15mg in terms of reducing anxiety), increases appetite, and appears to improve sleep as well as neuropathic pain.

          • Start with 15mg at night, and if necessary increase the dose by 15mg every 2 weeks.

          Psychostimulants

          Antidepressants usually take 2–4 weeks to work. When the prognosis is short, psychostimulants may be considered, as a response can be gained in a small number of days2.

          • Methylphenidate is the best tolerated of the traditional psychostimulants. 10–30% of patients experience anxiety or insomnia, particularly at the start of treatment. Start at 2.5mg bd (on wakening and at lunchtime) and titrate up by increments of 2.5mg bd.

          • Modafinil is a novel stimulant that is better tolerated than methylphenidate. There is as yet insufficient evidence to support its use for depression, other than in the context of a clinical trial.

          References

          1. NICE Depression in adults with a chronic physical health problem. NICE clinical guideline 91, Oct 2009.Find this resource:

            2. Candy B, Jones L, Williams R, Tookman A, King M (2008). Psychostimulants for depression. Cochrane Database Syst Rev, Issue 2, CD006722.Find this resource:

            Insomnia

            Sleep disturbance is a common and neglected problem in patients with advanced respiratory disease. Insomnia is a heterogeneous complaint that may involve:

            • difficulty initiating sleep

            • difficulty maintaining sleep

            • early morning wakening

            • poor quality or non-restorative sleep.

            Prevalence

            • Rates vary according to the definition of insomnia.

            • Up to 50–60% of patients with chronic lung disease and a similar proportion of those with cancer experience sleep disturbance.

            • Using a more strict definition, in the region of 20% of these patients suffer from an insomnia syndrome (see box on Non-respiratory symptoms [link]).

            • Overall, these prevalence rates are more than twice those experienced by healthy individuals.

            Causes

            • Direct effect of respiratory disease:

              • cough (can be worse when supine)

              • excess sputum

              • dyspnoea (can be worse when supine)

              • nocturnal oxygen desaturation

              • chest pain.

            • Drug treatment:

              • corticosteroids

              • Non-respiratory symptoms-adrenoreceptor agonists

              • theophylline.

            • Psychological morbidity:

              • anxiety

              • depression.

            • Hospitalization:

              • noise or disturbances

              • warm room

              • hospital routines

              • poor sleep hygiene.

            Consequences

            Insomnia has a highly negative impact on quality of life and results in a number of adverse psychological and physical consequences (Table 6.7).

            Table 6.7 Consequences of insomnia

            Psychological

            Physical

            Loss of concentration

            Fatigue, exhaustion

            Poor short term memory

            Muscle aches

            Irritability

            Reduced ability to perform activities

            Depression

            Immune down-regulation

            Anxiety

            There is evidence from large epidemiological surveys that insomnia can reduce longevity. Individuals who report sleeping less than 4–6 hours per night have an all-cause mortality that is up to three times greater than those that sleep 7–8 hours per night.

            Diagnostic criteria of the insomnia syndrome (ICSD, DSM-IV)

            A. Difficulty sleeping characterized by either or both of the following:

            • difficulty initiating sleep (30 minutes or more until fall asleep)

            • difficulty maintaining sleep (more than 30 minutes of nocturnal awakenings).

            B. Sleep disturbance occurs at least three nights per week.

            C. Sleep disturbance causes:

            • significant impairment of daytime functioning, or

            • marked distress.

            Management

            Despite being one of the most common symptoms experienced by patients with advanced respiratory disease and having an adverse effect on quality of life, insomnia is a neglected symptom:

            • Healthcare professionals tend to view it as an inevitable consequence of advanced disease.

            • Patients under-report sleep disturbance.

            • Clinicians are understandably reluctant to use drugs such as benzodiazepines, and lack knowledge about effective non-drug approaches.

            Do not rely on patients complaining of insomnia. Clinicians must proactively assess patients for the presence of sleep disturbances.

            Treat or remove underlying cause

            • Treat infective exacerbations to reduce cough, sputum, dyspnoea etc.

            • Avoid use of Non-respiratory symptoms-adrenoreceptor agonists before sleep. There is evidence that anti-muscarinic agents can improve sleep.

            • Ensure that steroids are never taken after 14:00, as they interfere with normal sleep after this time.

            Optimize ‘sleep hygiene’

            • These simple measures are easily understood by patients and can be a highly effective and entirely safe way of improving sleep (Table 6.8).

            Table 6.8 Sleep hygiene methods

            Strategy

            Techniques

            Improve sleep-wake pattern

            • Go to bed only when sleepy

            • Get up at the same time every morning

            • Regular exercise in morning/afternoon but not evening

            • Avoid daytime naps

            • Regular, relaxing pre-sleep routine eg warm bath

            • Light snack or milky drink before sleep

            • Avoid going to bed hungry or too full

            • Avoid excessive liquid intake during evening

            • Optimise bowel or bladder function

            Improve sleep environment

            • Aim for dark and quiet bedroom, not too warm or cool

            • Avoid using bedroom for work, television etc

            • Only use bed for sleep or sex

            • Remove clocks and other time cues

            Change drug intake

            • Avoid caffeine-containing drinks or alcohol

            • Change diuretic timing for daytime diuresis

            Non-pharmacological approaches

            • Stimulus control therapy:

              • Aim to re-associate bed/bedroom with rapid sleep onset.

              • Develop good sleep hygiene techniques, including going to bed only when sleepy. If unable to fall asleep or go back to sleep within 15–30 minutes, get out of bed and leave the bedroom, carry out a non-stimulating activity, and return to bed only when sleepy.

            • Sleep restriction procedures:

              • Aim to curtail the time in bed awake by creating mild sleep deprivation, which results in more efficient sleep and re-association of bed/bedroom with good sleep.

              • Keep a sleep-wake diary. Time allowed in bed is restricted to the average time asleep or felt to be asleep. Time allowed in bed is increased in small increments of 15–30 minutes every few days. Adhere to a constant wakening time and no daytime naps are allowed.

            • Relaxation techniques:

              • Progressive muscular relaxation and visual imagery (see chapter 5 [link]) can reduce the arousal that interferes with sleep.

            • Cognitive therapy:

              • This aims to challenge unhelpful attitudes and misconceptions about sleep. It is important to reduce both the expectation of and the belief in the need for ‘a good night's sleep’.

              • Challenge catastrophizing. Broken sleep is not a catastrophe; a restful night with short periods of sleep will be enough for the body's needs. The need for sleep reduces with age, particularly when activity levels are low. Recall past experiences of successfully managing without much sleep.

              • Don't ‘try’ to sleep. Passive acceptance should be encouraged.

              • Use mental distraction, particularly if the mind is in ‘worry’ or ‘planning’ mode. Reading and story tapes may be helpful.

            Pharmacological approaches

            • Hypnotics:

              • Benzodiazepine (BDZ) use is limited by the risk of tolerance, dependence, daytime sedation, and nocturnal respiratory depression. Rebound insomnia can occur on stopping the drug. The main role of BDZ lies in short-term use at a crisis point, in order to ‘regain control’.

            • Other sedating drugs:

              • Tricyclic antidepressants, mirtazapine, and anti-psychotics all have the useful ‘side effect’ of improving sleep, while avoiding many of the risks of BDZ.

            • Drugs that improve sleep-wake patterns:

              • Case reports suggest a role for psychostimulants such as methylphenidate and modafinil. Alternatively melatonin may be prescribed, usually in consultation with a sleep specialist.

            Recommendations in advanced respiratory disease:
            • Correction of reversible underlying causes, education in sleep hygiene, and cognitive behavioural non-pharmacological approaches form the mainstay of insomnia management.

            • Drug treatments should be avoided if at all possible:

              • First-line: tricyclic anti-depressant e.g. amitripytline 25–75mg po nocte.

              • Second-line: short-term use of short-acting BDZ e.g. lorazepam 0.5mg sublingually if difficulty initiating sleep and anxious.

            Confusion

            Definitions

            • Confusion is a symptom of an organic brain syndrome.

            • Chronic organic brain syndrome, or dementia, is a consequence of damage to cells within the brain and is irreversible.

            • Acute organic brain syndrome, or delirium, is a consequence of physical illness. It can be reversible and involves global impairment of cognitive function:

              • Consciousness: less awake and alert.

              • Attention: poor concentration.

              • Perception: misinterpretation of sensory input.

              • Thinking: internal and external worlds confused.

              • Memory: new information cannot be stored.

              • Behaviour: agitated or withdrawn.

            It is important to distinguish delirium from dementia (see Table 6.9). Patients with advanced respiratory disease are at risk of developing delirium. However, they are often elderly, and dementia may also be present.

            Table 6.9 Features of delirium and dementia

            Delirium

            Dementia

            • Acute

            • Often reversible

            • Fluctuating

            • Clouding of consciousness

            • Information not taken in

            • Often aware and anxious

            • Sleep disturbances

            • Hallucinations

            • Speech rambling and incoherent

            • Global cognitive impairment

            • Chronic

            • Irreversible

            • Slowly progressive

            • Clear consciousness

            • Information not retained

            • Unaware and unconcerned

            • Normal sleep amount

            • Hallucinations rare

            • Speech stereotyped and limited

            • Memory changes apparent first

            Prevalence

            • 5–40% of patients with advanced disease.

            • 25–85% of patients in terminal phase (referred to as ‘terminal agitation’).

            Consequences

            • Highly negative impact on quality of life.

            • Fear and distress (partial insight).

            • Falls, fractures, and catheter/cannula withdrawal.

            • Interference with control of other symptoms.

            • Barrier to patient and family communication.

            • Adverse effect on family grief.

            Causes

            Patients with advanced respiratory disease are at risk of developing delirium and consequent confusion for a number of reasons. Delirium is usually multi-factorial and many patients have a number of co-existing contributory factors:

            • Drugs e.g. anticholinergic agents, steroids, benzodiazepines, opioids.

            • Infection e.g. chest infection, urinary tract infection.

            • Cerebral hypoxia e.g. respiratory failure, pulmonary embolism.

            • Biochemical e.g. dehydration, hypercalcaemia, hyponatraemia.

            • Others e.g. pain, severe anxiety, constipation.

            Management

            Assessment

            • Undertake a detailed bedside clinical evaluation to determine whether confusion is a feature of delirium or dementia. Involve family/carers.

            • Check that communication difficulties are not causing misdiagnosis, for example deafness or dysphasia.

            • Limit investigations to those causes that are easily identified and effectively treated.

            • Quantify severity of confusion using a mental test score (see Table 6.10 for an example).

            Table 6.10 Simplified mental test score

            Question

            Score

            What is the date today? (day, month, year)

            3

            What is the address here? (three parts)

            3

            Can you take 7 away from 100? (93, 86, 79, 72, 65)

            5

            What is this called? (eg watch, pen, glass)

            3

            Remember and recall three imagined objects (after next task)

            3

            Three stage command (eg pick up paper in right hand, fold it, place it on table)

            3

            Total score

            20

            Correct potentially reversible causes

            • Drugs

            • Dehydration

            • Infection

            • Biochemical abnormalities

            • Hypoxia

            Non-pharmacological approaches

            • Reduce fear and anxiety:

              • exploration and explanation

              • rationalization and reassurance

              • calm surroundings and familiar people.

            • Orientate to reality:

              • well-lit environment

              • time cues e.g. clock, newspaper

              • regular daily schedule

              • use spectacles, hearing aids etc. as needed.

            ‘Above all, the confused person needs constant reassurance by calm, sympathetic and familiar people, that he or she is safe, sane and understood.’

            Kath Mannix

            Pharmacological approaches

            • Anti-psychotic medication:

              • Can lead to cognitive improvement, particularly of hallucinations, delusions, and paranoia.

              • Vary in sedative properties; haloperidol and risperidone are less sedating, levomepromazine and olanzapine are more sedating.

              • If drug treatment is required, haloperidol is recommended first-line (minimal anticholinergic and sedating effects and available through oral and parenteral routes).

            • Benzodiazepines:

              • Can reduce anxiety and cause sedation.

            • Use of sedating drugs will not reverse confusion and can often worsen it. A degree of sedation can further reduce a dwindling sense of reality and orientation. Avoid using sedative medications in confused patients other than in emergency situations, such as uncontrollable and dangerous behaviour.

            • The key to control of confusion lies in correction of the underlying cause(s) and non-pharmacological approaches.

            Anorexia and weight loss

            Weight loss is common in advanced respiratory disease and involves loss of both fat and muscle. It is associated with:

            • muscle weakness

            • diaphragmatic dysfunction

            • respiratory failure

            • poor quality of life

            • increased mortality.

            Weight loss in both malignant and benign disease is caused by two main mechanisms:

            • Reduced food intake (anorexia) due to a number of factors that can reduce appetite and cause difficulty eating, such as:

              • breathlessness

              • fatigue

              • social isolation.

            • Increased production of pro-inflammatory cytokines such as TNF-α‎ and IL1 that lead to a wide range of effects, including:

              • anorexia, because of production of anorectic agents such as corticotrophin-releasing factor

              • early satiety, because of delayed gastric emptying

              • wasting of muscle, because of impaired protein synthesis and proteolysis

              • fat loss, because of lipolysis and energy wasting.

            Inadequate calorie intake (first mechanism) leads predominantly to fat loss. A hypercatabolic, chronic inflammatory state (second mechanism) leads to loss of muscle as well as fat, which has a particularly adverse effect on respiratory function.

            Cachexia is diagnosed when the following criteria are present:1

            • unintentional weight loss (5%)

            • BMI:

              • less than 22 in those aged 65 years

              • less than 20 in those aged 65 years

            • albumin 35g/L

            • low fat

            • evidence of cytokine excess e.g. elevated C-reactive protein.

            Management

            Non-pharmacological approaches

            • Provide small, well-presented meals of patient's favourite food.

            • Encourage ‘little and often’, particularly when experiencing fatigue or early satiety.

            • Make sure that food can be prepared for and accessed by socially isolated patients if they are too breathless or fatigued to do it themselves.

            • Encourage patients to get dressed, eat at a table, and ideally eat with others; eating is a social habit.

            • Give general dietary advice including full-fat food and substitution of water-based drinks with milk-based drinks.

            • Consider using nutritional supplements. Compliance can be increased by serving chilled with ice, adding extra full-fat milk or fruit juice (according to whether juice- or milk-based), making into a smoothie by adding fresh fruit and ice cream, making into a jelly, or freezing to make an ice lolly or ice cubes.

            • Use appropriate non-drug measures to reduce contributing symptoms such as breathlessness and fatigue (see Non-respiratory symptoms Chapter 5 [link][link] and Chapter 6 [link][link] respectively).

            • In far advanced disease, avoid contributing to the pressure felt by patients to eat and the guilt/helplessness felt by families when patients do not eat. Explain that a full, balanced diet is unnecessary at this stage. Paradoxically, reducing the pressure on patients to eat can increase the pleasure gained from eating and even enhance intake.

            Pharmacological approaches

            Increasing oral intake alone is generally ineffective, because of the underlying catabolic, chronic inflammatory state. A number of drugs appear to reduce weight loss through an anti-inflammatory effect, decreasing pro-inflammatory cytokines:

            • Progestogens:

              • Megesterol acetate 80–160mg daily, up to maximum of 800mg daily.

            • Corticosteroids:

              • Dexamethasone 4mg daily.

              • Prednisolone 10–20mg daily.

            • Omega-3 fatty acids:

              • Eicosapentanoic acid (EPA) 1.5–2g daily.

            These drugs should only be used in the short term and when non-pharmacological approaches have been exhausted, because:

            • The evidence to support their use is, as yet, limited and conflicting.

            • Progestogens and corticosteroids can cause muscle catabolism. Much of the morbidity of cachexia comes from the muscle loss and the resulting negative impact on respiratory muscle strength. This may therefore be exacerbated by these drugs.

            • Progestogens and corticosteroids have significant adverse effect profiles, including increased risk of venous thrombosis, hyperglycaemia, osteoporosis, and psychological disturbances.

            Reference

            1. Morley JE, Thomas DR, Wilson M-MG (2006) Cachexia: pathophysiology and clinical relevance. Am J Clinical Nutrition; 83: 735–743.

            Constipation

            Constipation is a common and neglected symptom in patients with advanced respiratory disease. It is experienced by 30–70% of patients, particularly those with malignant disease, and by 80–90% of those on opioids. It occurs in this patient group for a number of reasons:

            • diminished food, fibre, and fluid intake

            • drugs, such as opioids, anticholinergic agents, and diuretics

            • poor mobility due to breathlessness and fatigue.

            Immobility is a particularly important cause in this patient group. It results in slower intestinal transit and also hinders patients from getting to a toilet. The longer stool stays in the large bowel, the greater the resorption of fluid from it, and the firmer and less easy to expel it becomes.

            Management

            General measures

            • Stop or reduce the dose of constipating drugs; tramadol and fentanyl are less constipating than morphine.

            • Increase intake of fluid, particularly fruit juice, and fibre.

            • Encourage mobility and manage symptoms that are hindering it.

            • Improve access to a toilet or commode with good privacy.

            • Avoid using a bedpan if at all possible.

            • Raise the toilet seat.

            • Install arm rails to facilitate independence and use of accessory respiratory muscles.

            • Support feet on a footstool to help brace abdominal muscles.

            Oral laxatives

            • Surface-wetting agents have a stool-softening action by lowering stool surface tension, allowing water to percolate into its substance:

              • Docusate sodium 100mg bd, increasing to maximum of 500mg daily.

            • Osmotic laxatives retain water in the intestinal tract and have a stool-softening effect by hydrating hardened faeces. The increased faecal volume, in turn, stimulates peristalsis, so these drugs have a stimulating as well as stool-softening action:

              • Lactulose syrup 15ml bd.

              • Macrogol e.g. Movicol 1 sachet bd to tds, up to 8 in 24 hours.

            • Stimulant laxatives act mainly on the submucosal and myenteric plexus of the large intestine to stimulate peristalsis. They tend to be most effective when combined with a stool-softening agent:

              • Bisacodyl 10–20mg po nocte, increasing up to tds.

              • Senna 15mg nocte, increasing to bd or tds.

              • Sodium picosulfate 5–10mg nocte, up to maximum of 30mg daily.

            • Bulk-forming agents increase faecal mass and therefore stimulate peristalsis. These drugs are not recommended in this patient group because of the risk of worsening constipation in patients with inadequate fluid intake. They are particularly ineffective for opioid-induced constipation:

              • Ispaghula husk e.g. Fybogel 1 sachet bd.

            Rectal measures

            • Suppositories take 30 minutes to dissolve after insertion:

              • Glycerin suppositories soften and lubricate faeces.

              • Bisacodyl suppositories have a stimulant action and must be in contact with the rectal mucosa to be effective.

            • Enemas:

              • Osmotic standard enemas (118–128mL) contain phosphates.

              • Osmotic micro-enemas (5mL) contain sodium citrate, sodium lauryl sulphoacetate, glycerin, and sorbitol.

              • Arachis oil enema (130mL) is a lubricant (note: check for peanut allergy). It is instilled and left overnight before giving a further stimulant suppository or osmotic enema.

            Recommendations in advanced respiratory disease:
            • Always undertake general, non-drug measures to reduce constipation.

            • A combination of a stool softener (e.g. docusate) and bowel stimulant (e.g. senna) is usually most effective.

            • Avoid lactulose as it tends to cause flatulence and abdominal cramps and needs to be taken with a large fluid volume.

            • For faecal impaction try either arachis oil enema followed by bisacodyl suppository, or high-dose Movicol for 3 days.

            • All patients commenced on strong opioids should also be started on oral laxatives (including a bowel stimulant).

            Nausea and vomiting

            • Nausea is more unpleasant than vomiting and is comparable to pain in terms of the distress it causes.

            • Significant adverse consequences of nausea and vomiting include dehydration, anorexia, weight loss, anxiety, depression, and inability to prepare food and function socially.

            Causes

            • Respiratory disease:

              • benign CRD: cough, anxiety, pain, constipation

              • lung cancer: all the above and hypercalcaemia, hyponatraemia, hepatomegaly, raised intracranial pressure (ICP).

            • Treatment:

              • drugs: opioids, antibiotics, TCA, SSRI, digoxin, ferrous sulphate, NSAIDs

              • chemotherapy, radiotherapy.

            • Concurrent morbidity:

              • chest infection, UTI

              • peptic ulcer disease, dyspepsia

              • candidiasis

              • motion sickness.

            Management

            The most important step is to determine the underlying cause of the symptom through detailed symptom evaluation. This will then allow:
            • reversible causes to be found and treated

            • the mechanism of the symptom to be established and the most appropriate anti-emetic to be chosen.

            Assessment

            Take a detailed history of the nausea and vomiting, not unlike a detailed ‘pain history’. This should include:

            • separate evaluation of nausea (feeling of needing to vomit) and vomiting

            • severity and timing of each symptom, including relief/persistence of nausea after vomiting

            • frequency of vomiting, symptom triggers, and diurnal variation

            • associated symptoms such as headache and abdominal distension

            • volume and content of vomitus.

            Two common clinical pictures are given in Table 6.11. The clinical features of the symptoms can help guide towards the likely cause of the symptom.

            Table 6.11 Typical clinical pictures of nausea and vomiting

            Chemical causes

            Bowel related causes

            Severe persistent nausea

            Early satiety

            Vomiting may not relieve nausea for long

            Relatively little nausea and fully relieved by vomit

            Smaller volume vomitus or retching

            Larger volume vomitus

            Undigested food or faeculent vomitus

            Associated symptoms eg abdominal colic

            As always, a full history and examination must be conducted, including a review of the drug regimen. The clinical picture can be used to guide this; if, for example, a chemical cause is anticipated, then it becomes even more appropriate to check serum biochemistry and recent drug changes.

            Reversible causes

            • Causes that may be reversible include emetogenic drugs, cough, anxiety, constipation, and severe pain.

            • It is particularly important to try to control anxiety. Nausea and vomiting both cause and are caused by anxiety. The resulting ‘vicious cycle’ can be broken if anxiety is reduced.

            Non-pharmacological management

            • Avoid exposure to foods that may trigger nausea.

            • Try small, frequent snacks rather than large meals.

            • Measures to curb anxiety are vital, including a calm, reassuring environment and relaxation techniques.

            Pharmacological management

            See Table 6.12 for details of dose, mechanisms of action, and indications.

            • First-line anti-emetics:

              • Metoclopramide—gastric stasis and functional bowel obstruction.

              • Cyclizine—raised intracranial pressure or motion induced.

              • Haloperidol—chemical causes such as drugs.

            • Second-line anti-emetics:

              • Levomepromazine—multi-factorial aetiology, requiring sedation.

              • Dexamethasone—chemical causes, raised ICP due to brain metastases.

              • 5HT3 receptor antagonists such as granisetron—chemical causes.

            • Principles of anti-emetic prescribing:

              • Start with a first-line drug selected according to the most likely cause of symptoms.

              • Re-evaluate regularly.

              • If the first selected drug is ineffective, either substitute another first-line anti-emetic or try a combination of first-line drugs such as cyclizine and haloperidol.

              • Never combine metoclopramide and cyclizine, as the latter blocks the prokinetic action of the former.

              • Always use the subcutaneous route even for nausea without vomiting, as nausea causes delayed gastric emptying.

              • If symptoms persist, consider substituting a second-line anti-emetic (or adding, in the case of dexamethasone).

            Table 6.12 Anti-emetic drugs used in advanced disease

            Drug

            Indications

            Mechanism of action

            Dose

            Comments

            Metoclopramide

            Functional bowel obstruction

            Gastric stasis

            Gastritis

            Prokinetic: D2 antagonist + 5HT4 agonist

            Prokinetic cholinergic nerves from myenteric plexus inhibited by dopamine and stimulated by 5HT

            10mg tds po

            30mg/24hrs CSCI

            Effect blocked by anti-muscarinic drugs e.g. cyclizine

            Cyclizine

            Raised intracranial pressure

            Movement related N+V Mechanical bowel obstruction

            Antihistaminic and anti-muscarinic

            Acts on vomiting centre

            50mg tds po

            100–150mg/24hrs CSCI

            Can cause irritation at injection site

            Can be sedating

            Haloperidol

            Chemical causes of N+V including renal failure, drugs

            Butyrophenone anti-psychotic

            D2 antagonist

            Acts on chemoreceptor trigger zone

            1.5mg on/bd po

            3–5mg/24hrs CSCI

            Combines well with cyclizine

            Useful in patients with anxiety, hallucinations, hiccups etc.

            Levomepromazine

            Multi-factorial N+V

            Phenothiazine anti-psychotic

            Very broad spectrum: D2, H1, AChM, and 5HT2 antagonist

            6–6.25mg od/bd po/sc

            6.25–12.5mg/24hrs CSCI

            Acts for 12–24hrs (CSCI not necessarily needed)

            Usually substituted rather than added

            Sedating

            Can be used to replace drug combinations

            May lower seizure threshold

            Dexamethasone

            Multiple causes

            May reduce permeability of BBB to emetogenic substances

            4–8mg od, po, or sc

            Usually added to existing anti-emetic regimen

            Give in morning to avoid sleep disturbance

            Granisetron

            Chemical causes of N+V

            Situations of serotonin release

            5HT3 antagonist

            1mg od or bd po or sc

            Dose (sc) lasts 24hrs and therefore CSCI not needed

            Advantages over ondansetron: only once daily, and as effective po as sc

            Constipating

            CSCI: continuous subcutaneous infusion; po: oral; sc: subcutaneously; od: once daily; bd: twice daily; tds: three times daily; on: once at night; BBB: blood-brain barrier