Pain Management at the End of Life

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1		Michele Domenico Spampinato	--	3681	2023-07-12 08:30:45	\|
2	format correction	Dean Liu	Meta information modification	3681	2023-07-14 02:15:37	\|

This entry is adapted from the peer-reviewed paper 10.3390/jcm12134357

Access to pain management is a fundamental human right for all people, including those who are at the end of life (EOL). In end-stage patients, severe and uncontrolled pain is a common cause of admission to the emergency department (ED), and its treatment is challenging due to its complex, often multifactorial genesis.

pain management emergency department end of life care palliative care

1. Introduction

Pain is a common symptom at the end of life and can manifest itself in both acute and chronic forms. In particular, severe pain at the end of life is common, with a high prevalence two years before death and a marked increase in the last four months ^[1]. Hagarty et al. found that 17% of the more than 20,000 participants in their study reported severe pain daily. No association was found between the cause of impending death or the medical setting and the occurrence of pain at the end of life. ^[2]. Seventy-five to ninety percent of patients with an advanced disease require opioid therapy for severe chronic pain ^[3], but cancer patients are not the only ones who experience end-of-life pain. In a systematic review, 66% of patients with moderate to severe COPD and 21% to 77% of patients with end-stage lung disease reported pain ^[4]. The prevalence of moderate to severe pain ranges from 37% to 50% in patients with end-stage renal disease ^[5], while the prevalence in patients with end-stage liver disease ranges from 30% to 79% ^[6]. In any stage of heart failure ^[7], AIDS ^[8] or neurological degenerative diseases ^[9]^[10], the prevalence of pain is high, showing that it is a significant issue.

Regardless of the clinical setting or cause, the management of severe pain is a highly complex problem. According to the revised 2020 definition of the International Association for the Study of Pain, pain is “an unpleasant sensory and emotional experience associated with or resembling that associated with actual or potential tissue damage” ^[11]. Chronic pain, on the other hand, should be considered a health condition in its own right ^[12], and its treatment should be based on a comprehensive biopsychosocial model that recognises the complex, multidimensional nature of the condition and examines the pathophysiology of pain in relation to a variety of cognitive, affective, behavioural, and social characteristics ^[13]. Years of suffering and fear of death can profoundly alter the perception and meaning of pain ^[14]^[15]^[16]^[17], leading to “total pain” in terminally ill patients ^[18]. This term was coined by Dame Cicely Saunders, founder of the hospice movement, who proposed that pain should be understood as having physical, psychological, social, emotional, and spiritual components. The ICD-11 ^[19] classifies chronic pain (defined as pain lasting at least three months) into seven categories: chronic primary pain, chronic cancer pain, chronic post-traumatic pain, chronic neuropathic pain, head and facial pain, visceral pain, and musculoskeletal pain. Moreover, pain can be classified as somatic, visceral, or neuropathic, depending on its origin and the type of fibres involved in transmitting pain signals to the brain (A-beta, A-delta, and C fibres). In addition, some types of interventions such as transfers, suctioning of secretions, and dressings for skin ulcers, can cause acute end-of-life pain. All types of pain can occur at the end of life in both acute and chronic forms. Careful pain assessment is essential to identify the specific pain characteristics and guide treatment.

End-stage patients are often admitted to the emergency department because of severe, uncontrolled pain. Admission to the ED often occurs when symptoms are unbearable and cannot be adequately treated at home to intensify palliative care ^[20]^[21]. Nevertheless, pain is often multifactorial, and only one of many symptoms’ patients may present with at the end of life, making management decisions difficult ^[17]^[18]^[22]^[23].

2. Management of Pain at EOL in the ED in Clinical Practice

2.1. Identify Patient Worthy of End-of Life Care

Palliative or end-of-life care may be necessary for ED patients in two circumstances: (i) following a likely fatal event (major stroke, cardiac event, or surgical emergency) and (ii) in advanced chronic illness with progressive symptom burden and an unmet need for palliative care. In both cases, patients and their families may not be aware that they are dying. Several screening tools have been developed to identify patients in the emergency department who are eligible for palliative care consultation ^[24], which is based on (i) functional status, such as the Karnofsky Performance Status Scale ^[25]^[26]^[27], the Knau classification ^[28] and the Katz Activities of Daily Living ^[29]^[30], the Timed Up and Go test (risk of falling) ^[29], the Functional Assessment Staging Tool ^[26], the Outcome and Assessment Information Set ^[31] or the Palliative Performance Scale ^[31]), (ii) comorbidities, such as the Charlson Comorbidities Index ^[28]^[30], Charlson–Manitoba Comorbidity ^[32], (iii) short-term mortality, such as the Modified CriSTAL ^[33]^[34], identification of at-risk seniors ^[29]^[30]^[32], and the “Surprise Question” ^[35], or (iv) a combination of them, such as the NECessidades PALiativas Centro Colaborador da Organização Mundial da Saúde-Institut Català d’Oncologia (NECPAL CCOMS-ICO tool) ^[36] or George et al.’s simple checklist to evaluate the terminal illness and severe uncontrolled symptoms ^[37]. However, no screening tool has been shown to be better than another ^[38]. Despite several screening tools, a clear conversation with patients may be the better approach to reveal the presence of hidden palliative care needs. Reuter et al. in 2019 proposed the 5-SPEED survey to identify patients in the ED with unmet palliative care needs ^[39]: (i) How much discomfort do you feel? (ii) How challenging is it for you to receive the care you require at home? (iii) What challenges do you encounter when taking medication? (iv) How much do you feel overwhelmed? (v) How challenging do you find it to receive medical care that meets your needs? Moreover, to tailor the extent of medical intervention to a patient’s goals, it is essential to discuss the patient’s current condition and treatment objectives ^[40]. In his 2015 book “Being Mortal”, Atul Gawande proposed five questions that can serve as a framework for such clear conversations: “What do you know about your illness and condition? What are your future-related fears and concerns? What are your priorities and objectives? What outcomes did you deem acceptable? What are you willing and unwilling to sacrifice? What would a good day look like in the future?” ^[41].

Due to poorly controlled symptoms or conflicts between the patient (who may refuse life-prolonging measures) and carers (who insist on life-prolonging measures), terminal patients are occasionally referred to the emergency department. In addition, referral to ED may indicate that the patient or family is anxious and unable to cope with the distressing symptoms of impending death. According to Reeves ^[42], when a patient is mistakenly admitted to the emergency department (ED), it is imperative to determine resuscitation status and treat distressing signs by providing supportive care and avoiding unnecessary tests and invasive procedures, providing privacy, and discussing hospitalisation with the patient, family, and palliative care service.

2.2. Pain Assessment in EOL Patients in ED

Pain assessment is critical to pain management and should include information about the location, quality, intensity, onset, duration, and frequency of pain as well as factors that relieve or exacerbate pain. Cancer-related pain should be classified according to the ICD-11 taxonomy and the intensity and impact of pain on quality of life determined ^[43]. The distinction between peripherally generated pain and centrally maintained pain may be more accurate in assessing pain and selecting the appropriate drug treatment for the patient ^[44]. Pain rating scales adapted to the patient’s age and cognitive status help standardise treatment and provide objective assessment tools. Acute pain can be measured with the Numerical Rating Scale (NRS), the Visual Analogue Scale (VAS) ^[45] and the Faces Pain Scale Revised ^[46].

However, chronic pain often affects patients at the end of life, so a multidimensional assessment may be more appropriate. The Brief Pain Inventory (BPI) ^[47] measures actual and the past 24 h pain intensity, multiple sources of pain and the impact of pain on daily activities. The Short-Form McGill Pain Questionnaire (SF-MPQ) ^[48] measures sensory, affective, and general pain in patients with chronic pain. The presence of neuropathic pain should be thoroughly assessed using appropriate scales such as the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) ^[49] or the Neuropathic Pain Scale (NPS) ^[50], which assesses the presence of stabbing, burning, numb, electric, tingling, pressing, freezing and simple touch pain. Scales that assess facial expression, body movements, crying and well-being, such as the Face Leg Activity Cry Consolability (FLACC) for infants and children ^[51], the Pain Assessment in Advanced Dementia (PAINAD) for non-verbal patients ^[52] and the Critical Care Pain Observation Tool for non-verbal patients ^[53], should be used to identify and manage pain in these patients.

2.3. Non-Pharmacological Management of Pain in EOL Patients

The non-pharmaceutical treatment of end-stage pain remains under-researched and under-utilised. Consistent with the biopsychosocial model of pain, non-pharmacological techniques are essential to a comprehensive pain management strategy, often require minimal resources, and they can be implemented in the emergency department, although it is busy and often chaotic ^[54]^[55]. Managing the psychological and social aspects of pain (including an appraisal of thoughts and emotions, perceptions of pain, beliefs and attitudes, unhelpful thinking patterns, previous pain experiences, fear, depression, anxiety, psychological distress, and sharing information at caring level) can have a significant impact on patient suffering ^[56]. Sharing information about stressful medical procedures, pain and postoperative pain has been shown to be beneficial ^[57]^[58]. Despite limited evidence of benefit in the emergency department ^[54], the “difficult conversation” (i.e., the communication of bad news and prognosis) is an essential part of patient care. Detailed conversations can still be held with people with dementia to communicate their wishes, preferences, and choices, even though dying people are often cognitively or emotionally unable to have such a conversation, which should ideally take place before death. However, a culture change is needed in the health professions so that such conversations may be seen as “essential” rather than “difficult”. This conversation is a professional duty and a right for those individuals and families who want it ^[59]. Baile et al. ^[60] created the SPIKES model in 2020, which is a useful mnemonic model consisting of six components for communicating bad medical news:

−: Setting: creating time, space, and resources for appropriate, uninterrupted communication with patients and their families.
−: Perception: asking first about illness awareness and severity.
−: Invitation: ensuring that the patient or family members are ready to discuss palliative or end-of-life care.
−: Knowledge: ensure that the patient or family members are aware of the disease context in which the pathology manifests.
−: Emotion: address emotions empathically; use the mnemonic NURSE ^[61] (Name the patient’s emotion, Understand the emotion through empathy, Respect the patient’s response, Support the patient, Explore the patient’s response, and inquire about the emotion).
−: Strategy: develop a plan for shared care.

Non-pharmacological interventions (such as massage, aromatherapy, and music therapy) to promote well-being or other aspects related to well-being such as stress, fatigue, anxiety, and depression can be beneficial in palliative care ^[62] and even in the management of breakthrough pain in cancer ^[63]. Other techniques such as transcutaneous electrical nerve stimulation (TENS), acupuncture, cold and heat, traction and patient positioning all play a role in acute pain, especially traumatic pain; however, there is no evidence to support their use in the emergency setting in EOL patients ^[56]. The environment is critical to non-pharmaceutical treatment and care. When patients arrive at the emergency department and death is imminent, they and their families should be moved to a private, quiet room. The number of monitors should be reduced as much as possible, and the presence of family members and caregivers should be allowed. Some emergency departments have established single-bed rooms for end-of-life care to ensure respect and dignity for the patient and to allow family members to stay with their loved ones around the clock in a quiet environment ^[64]^[65].

2.4. Pharmacological Management of Pain in EOL Patients

The three-step WHO pain ladder is a benchmark for the selection of pharmacological agents for pain treatment ^[66]. This strategy was proposed in 1986 to provide adequate analgesia to cancer patients. However, in the years that followed, this technique was used to treat pain of any origin. In accordance with the WHO pain ladder, patients have prescribed medication according to the severity of their pain: (i) non-steroidal anti-inflammatory drugs (NSAIDs) or paracetamol with or without additives for level I, mild pain; (ii) weak opioids such as hydrocodone, codeine and tramadol with or without non-opioid analgesics and with or without adjuvants for level II, moderate pain; (iii) strong opioids such as morphine, methadone, fentanyl, oxycodone, buprenorphine, tapentadol, hydromorphone or oxymorphone, with or without non-opioid analgesics and with or without adjuvants, for level III, severe pain. Antidepressants (such as tricyclic antidepressants (TCAs) or serotonin-norepinephrine reuptake inhibitors (SNRIs)), anticonvulsants (such as gabapentin and pregabalin), topical anaesthetics (such as lidocaine patches), topical therapies (such as capsaicin), and corticosteroids are examples of adjuvants. The WHO pain ladder is considered one of the most successful global health interventions ^[67]^[68] and one of the most significant advances in the treatment of pain patients, as it is effective in 69 to 100% of patients ^[69]^[70]. However, numerous authors have criticised this approach for the following reasons: (i) Some adjuvants are first-line therapies for certain types of pain, such as neuropathic pain ^[71]; (ii) Weak opioids have been shown to be of little use in the treatment of pain ^[72]; (iii) The presence of NSAIDs proposed for tier I gives the false impression that these drugs are safe in the treatment of pain, while they have been shown to be associated with numerous adverse effects ^[73]. In addition, NSAIDs may have a role in the treatment of bone pain due to their effect on prostaglandin production. However, recent systematic reviews have found little evidence to support or refute the use of NSAIDs in this area ^[74]^[75]; (iv) Specific types of pain such as neuropathic pain, bone pain or fibromyalgia, for which opioids are of limited benefit, have not been considered; (v) The benefits of interventional and minimally invasive procedures ^[76], as well as the use of complementary and alternative medicine, relaxation techniques, psychological support and physiotherapy ^[77], have not been considered. Morphine is the first-line treatment for severe pain, but it is poorly available orally, the dose required varies widely, active metabolites can accumulate and lead to neurotoxicity, and morphine-induced histamine release can lead to poorly tolerated side effects, whereas oxycodone, hydromorphone, and fentanyl have the same efficacy with fewer side effects and better tolerability ^[78]. Neuropathic pain must be appropriately identified and treated, and opioids should only be considered as a third-line treatment due to their poor efficacy. Although tramadol is a second-line agent and gabapentin, duloxetine and antidepressants are recommended as first-line agents for neuropathic pain; these drugs take several days to work and there is limited evidence of their efficacy and safety, especially in the ED ^[79]. In addition, antiepileptic drugs such as phenytoin, lamotrigine, valproic acid and levetiracetam have not shown efficacy despite increased side effects ^[80]^[81]^[82]. Ketamine inhibits glutamatergic neurons primarily through its antagonistic action on NMDA receptors. However, its action on dopaminergic, adrenergic, serotoninergic, opioid, and cholinergic receptors, as well as on spinal GABA interneurons, appears to be responsible for the analgesic effect of this drug, which is effective in chronic, neuropathic and cancer pain ^[83]. In addition, corticosteroids, and magnesium sulphate ^[84]^[85]^[86] have been shown to be useful adjuvants, especially in neuropathic pain and bone pain ^[87]^[88]^[89]. Therefore, the most effective drug for neuropathic pain needs to be identified ^[78], especially for acute pain management in the emergency department, so a multidisciplinary approach is strongly recommended.

Interventional pain management may be an option for patients with severe, persistent pain who do not respond to other pharmacological treatments. However, it should be integrated into a multidisciplinary approach to pain management and not just considered as a last resort ^[90]. Interventional pain management includes injection therapies, including soft tissue and joint injections, as well as spinal-related injections (i.e., epidural steroid injections, facet joint injections, facet denervation approaches and sacroiliac injections), non-neurolytic (including sympathetic blockade of the stellate ganglion, lumbar sympathetic truncus, celiac plexus, superior hypogastric plexus and impar ganglion or somatic nerve blocks, including paravertebral and intercostal nerve blocks, brachial plexus block and epidural or intrathecal blocks), neurolytic blocks (neurolysis of the celiac plexus, neurolysis of the superior hypogastric plexus and dorsal punctate midline myelotomy, especially for visceral intractable pain) or newer advanced neuraxial techniques, including spinal cord stimulation. Interventional pain procedures provide effective pain relief, reduce symptom burden, decrease opioid use, and have a favourable safety profile ^[91]^[92]^[93]. Although some peripheral and fascial nerve blocks have been shown to be safe and feasible in the emergency department ^[94]^[95]^[96], they are still underused, and other invasive treatments should be discussed on a case-by-case basis in a multidisciplinary team.

2.5. Special Situations: Rapid Pain Worsening in Chronic Pain

Opioids are increasingly used to treat chronic pain in terminally ill patients. Patients currently receiving opioids should be assessed for the amount of opioids they were taking daily before the onset of the new pain, and appropriate doses of opioids should be prescribed to treat the baseline pain in combination with short-acting opioids to treat the new severe pain. Equianalgesia refers to the amount of different opioid formulations and/or different routes of administration that achieve the same analgesic effect (the morphine milligram equivalents, MME), while opioid titration refers to the individual adjustment of the drug dose ^[97]. There are numerous equianalgesic dosing charts or web/application resources available to help clinicians manage severe pain in opioid-tolerant patients or switch formulations and routes of administration. A dose equivalent to 1/6 of the daily dose of the first opioid should be administered when a second opioid is added to ongoing treatment ^[97].

Breakthrough Pain

Davies et al. ^[63] define breakthrough pain as a transient exacerbation of pain that occurs spontaneously or in response to a specific predictable or unpredictable trigger, although the background pain is relatively stable and well-controlled. It is common in patients with cancer pain (40–80%), but there is currently no evidence of its prevalence in chronic non-cancer pain ^[98]. Transmucosal fentanyl preparations are reserved for situations requiring a faster onset and shorter duration of action ^[99]. In patients who are not opioid-naïve, the right opioid dose should be calculated as follows ^[97]: (i) determine the last 24 h effective MME; (ii) determine the breakthrough dose, which is usually 10–15% of the calculated MME daily dose; (iii) titrate the dose upwards if the pain is not under control or if more than 3 breakthrough doses per day are administered; and (iv) start with one opioid (via continuous infusion, oral or transdermal patch) and reduce the calculated conversion dose of a new opioid by 25% to 50% when switching from one opioid to another, as tolerance to one opioid is not the same as tolerance to another. Long et al. ^[100] suggested a rapid fentanyl titration protocol in which intravenous fentanyl boluses are administered 5 min apart until the pain is controlled, with the initial dose equal to 1/10 of the total MME of the previous 24 h if the reported pain is at least 4/10 on the NRS (or equivalent according to the pain scale used), and the fentanyl dose is increased by 50–100% from the third administration.

Opioid-Induced Hyperalgesia

Opioid-induced hyperalgesia is characterised by increased pain sensitivity despite a higher opioid dose, which is often accompanied by a diffuse extension of the pain site and allodynia. It can occur at any dose but is more pronounced at higher parenteral doses of morphine and hydromorphone. The initial treatment consists of reducing or eliminating the current opioid dose or switching to an opioid with less neurotoxic effects, such as fentanyl, and maximising non-opioid adjuvants when indicated. The use of low-dose ketamine for pain relief may have a role in the management of this issue in the ED ^[83].

2.6. Palliative Sedation

Although pain symptoms in EOL patients often respond to pharmacological and/or non-pharmacological interventions, there may be cases where treatment is extremely difficult, impossible, or ineffective. This is the case with so-called refractory symptoms because (i) the treatment does not respond, (ii) the analgesic effect is too long in coming, or (iii) the patient cannot tolerate the side effects ^[101]^[102]^[103]^[104]. Palliative sedation is defined as an intervention aimed at relieving intolerable suffering caused by one or more refractory symptoms ^[105] and is limited to terminally ill patients. Sedation in palliative care is fundamentally different from euthanasia. Unlike euthanasia, which aims to bring about the patient’s death through standard protocols, palliative sedation aims to relieve intolerable suffering through appropriate sedation. Furthermore, palliative sedation does not hasten death, which may be an important factor for physicians and families to consider when prescribing this treatment ^[106]^[107]^[108], so the term “terminal sedation” is no longer appropriate ^[102]. Sedation in palliative care can be light, deep, continuous, or intermittent ^[109]. Short-term sedation and intermittent sedation can be used at an earlier stage to provide temporary relief while another therapeutic approach takes effect. When light sedation is ineffective, when the condition is severe and unresponsive to treatment, when death is expected within hours or days and the patient specifically requests it, or in the case of a catastrophic end-of-life event, deeper sedation should be used ^[105]. Palliative sedation is based on the use of sedatives selected on a case-by-case basis and titrated to the minimally effective dose by continuous reassessment using validated scales such as the Richmond Agitation–Sedation Scale ^[101]^[109]^[110]^[111]. Because of its short half-life, midazolam is recognised in all guidelines as the drug of choice for palliative sedation. Alternatives to midazolam include diazepam, lorazepam, and clonazepam ^[101]^[105]. Sedation can be achieved with midazolam (1–5 mg bolus, 1–5 mg/h via continuous infusion), lorazepam (1–5 mg bolus, 0.025–0.05 mg/kg/h via continuous infusion) or propofol (20 mg to 1 mg/kg bolus, 5–10 mg/h to 0.5–3 mg/kg/h via continuous infusion) ^[105]^[111]^[112]^[113]. However, there is no approved maximum dose, and the dosage must be adjusted according to the degree of sedation and pain control. In addition, isolated case reports have been published on the successful use of dexmedetomidine in palliative care for cancer pain and opioid-induced hyperalgesia ^[114]. The administration of a neuroleptic (preferably levomepromazine, but also chlorpromazine, clotiapine and promethazine) may be considered ^[101]^[105], especially in the presence of concurrent agitation due to suspected delirium. Opioids should be administered as pain and dyspnea medications but not as sedatives. Morphine is the opioid of choice, but other opioids have been reported in the literature ^[115]. The dissociative anaesthetic ketamine maintains a clear airway and stabilises the cardiovascular system. However, further research is needed to determine which terminally ill patients may benefit from ketamine therapy ^[116].

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Sossio Serra

Michele Domenico Spampinato

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