End-of-Life Evaluation and Management of Pain

Etiology

Pain associated with noxious stimuli at the end of life is related to the patient's illnesses. Pain can be acute or chronic. Acute pain is often associated with an intervention like a surgical procedure or repositioning. Chronic pain is usually a complex interplay between several organ systems. Examples of chronic pain include headaches, joint pain from arthritis, and pain from skin breakdown. Pain can be classified as somatic, visceral, or neuropathic based on anatomic location. Each of these classifications is associated with a specific pain character, which helps guide therapy.

Somatic pain originates from pain receptors in the skin and musculoskeletal tissues and is usually deep and aching. Common sources include joints, bones, and wounds. Visceral pain involves pain receptors in visceral organs and is generally described as a squeezing or cramping pain. Palpation of the involved viscera can increase the intensity of pain. Neuropathic pain is usually described as sharp, burning, or like an electric shock.

Anxiety and depression frequently accompany pain, and addressing these emotions is important for alleviating total pain. Anxiety can be described as a feeling of impending doom, especially in patients with respiratory disease and dyspnea. Additional psychological sources of total pain include emotional discomfort, interpersonal conflicts, and the nonacceptance of one's death. Emotional discomfort and interpersonal conflicts contribute to suffering at the end of life. Financial instability, marital discord, conflicts with family members, and an inability to get one's affairs in order before death are common causes of psychological distress. Nonacceptance of the end of one's life can result from shock and anger at the prospect of impending death. Counseling and spiritual care can help address these issues and aid in pain management at the end of life.

Epidemiology

Results from studies showed that more than 17% of patients experience severe daily pain at the end of life. The involvement of pain does not appear to vary based on treatment setting or terminal diagnosis.[3][4] Pain is seen in patients at home, in the community, and in long-term care facilities, and is often inadequately managed.[5][6][7][8] Including palliative medicine professionals in the care of the dying patient can improve pain relief.[9] Racial and ethnic disparities were noted in hospice and palliative care use among racial and ethnic minority groups. However, no difference in pain incidence was observed across individuals of all racial and ethnic groups.[10][11] This healthcare disparity deserves further research and evaluation.[12][13]

Pathophysiology

The pathophysiology of pain rests in the nociceptive pathway, leading to the perception of noxious stimuli in the body. At the end of life, the activation of this nociceptive pathway leads to pain, distress, and suffering in patients. Most interventions aim to block the nociceptive pathway at various levels.  

History and Physical

Pain management at the end of life starts with a thorough evaluation of both the physical and psychological sources of pain in line with the concept of total pain. Clinicians should gain a thorough understanding of the primary diagnosis and course of the illness, as well as other comorbidities that compound the experience of pain. Developing rapport among the patient, caregiver, and clinician is essential, and open communication helps all parties work toward the common goal of treating the patient.

In addition to medical and psychological history, clinicians should understand the patient's values and treatment goals. Treatments should be tailored to support these individualized priorities. For example, attending an important family event could be significant for one patient, who may be willing to tolerate pain to attend, whereas for others, the priority could be avoiding shortness of breath at all costs. Some patients may tolerate more sedating adverse effects of medications to meet that goal. Care goals should be outlined early, and every effort should be made to ensure adherence to the patient's wishes. This often involves helping the patient and caregiver communicate to reach a common understanding of the treatment goals.

Physical examination includes a detailed head-to-toe assessment for factors contributing to pain. Physical signs of pain include facial grimacing, restlessness, tachypnea, and tachycardia. Prolonged time in bed can lead to skin breakdown or pressure ulcers. Dry eyes can lead to painful keratitis and infections. Long-term oxygen therapy can lead to skin irritation around the nares, dryness, and episodes of epistaxis. Noninvasive ventilation modes may lead to pressure ulcers at the nasal bridge and cheeks. Patients who are intubated and mechanically ventilated can have pooling secretions and oral ulcers or dental decay. Head positioning and lack of proper support can lead to painful spasms of the neck muscles.

Signs of malnutrition include temporal wasting, periclavicular wasting, scaphoid abdomen, and skin dryness. Dehydration leads to dryness of mucous membranes, loss of skin turgor, and dry skin. Abdominal fullness points towards constipation or urinary retention. Examination of the genitalia, especially in patients with chronic Foley catheters, can reveal infections or skin breakdown. All intravenous access sites require frequent evaluation for thrombophlebitis, and infiltrating medications or fluids into the subcutaneous tissue can be painful. Lastly, a general assessment of hygiene and well-being, with a focus on maintaining the patient's dignity at the end of life, is essential.

Evaluation

Evaluation starts with a pain assessment focused on the location, timing of onset, character, radiation, and exacerbating and relieving factors. A verbal description of the quality of the pain is helpful in determining the source. Somatic pain can be described as aching, whereas visceral pain may be described as cramping. Similarly, neuropathic pain may be burning or shooting in character. An evaluation of the intensity and duration of pain in the last 24 hours helps the caregiver quantify and manage pain. The cornerstone of efficient pain management includes round-the-clock assessment and repeated evaluations, especially following intervention.[14]

Pain scales can help standardize care and provide objective assessment tools that are not clinician-dependent. Several pain grading scales have been validated, although none has been proven superior to the others. The Likert-type pain scale ranges from 0 to 10, with 10 indicating the worst pain imaginable and 0 indicating no pain. The Wong-Baker FACES® Pain Rating Scale comprises a series of faces depicting increasing levels of distress. This scale provides superior assessment in children and is also helpful in adults who may be unable to communicate verbally. Intensive care and inpatient hospital units have started incorporating a board facing the patient with information to keep the patient informed and oriented. This includes the date, short-term and long-term care aims, caregivers' contact details, and a visual pain scale. For patients with cognitive impairment and dementia, some scales incorporate signs observed at the bedside to indicate the presence of pain. The Pain Assessment in Advanced Dementia Scale can help quantify the response to pain treatment in patients with dementia.

Treatment / Management

Pain management at the end of life includes nonpharmacological, pharmacological, and psychosocial interventions.

Pharmacologic Management of Pain

The World Health Organization devised a cancer pain ladder to guide caregivers in selecting medications to manage pain.[15] The initial agents are nonopioids, with escalation to incremental doses of opioids and adjuvant agents, ultimately leading to the abolishment of pain. Please see StatPearls' companion reference, "WHO Analgesic Ladder," for further information. While this is a good guide in managing pain, individual assessment of each patient should be performed to gauge the initial intensity of pain to avoid delay in therapy.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used initial pharmacological agents for pain. The mechanism of action of these drugs is to inhibit prostaglandin synthesis, which plays a key role in pain generated by inflammatory cells. NSAIDs also interfere with G-protein–mediated signal transduction, aiding in analgesia. Increasing evidence suggests that NSAIDs also have a central effect in the CNS mediated by endogenous opioid peptides or blockade of the release of serotonin.[16] NSAIDs are useful for decreasing inflammation and associated pain; however, they can produce adverse effects such as gastrointestinal tract bleeding, renal impairment, rashes, hypertension, and an increased risk of cardiovascular thrombotic events and strokes. Please see StatPearls' companion reference, "Ibuprofen," for further information. Selective cyclooxygenase-2 inhibitors like celecoxib can help manage pain associated with the musculoskeletal system and theoretically have a more favorable adverse effect profile compared to other NSAIDs. Celecoxib contains the sulfonamide group and can cause severe allergic reactions in patients with sulfa drug allergies. If any of these medications are used for more than a week, a proton pump inhibitor should be added as gastric prophylaxis. Adequate hydration should be maintained to protect the kidneys during their use. (B3)

For patients who cannot take NSAIDs, acetaminophen is often recommended in divided doses, equaling a maximal dose of 4000 mg every 24 hours. Many clinicians limit acetaminophen to lower doses, such as 2000 mg to 3000 mg in 24 hours, depending on the patient's comorbidities. Acetaminophen is frequently associated with hepatotoxicity, and lower dosages may be needed in patients with hepatic disease or in the pediatric or geriatric population.

Opioid analgesics are considered the gold standard of pain management at the end of life, providing the greatest analgesic relief. Opioids act by interacting with the μ, δ, or κ opioid receptors. Mu (μ) receptors mediate analgesia, euphoria, sedation, gastrointestinal tract dysmotility, and respiratory depression. These receptors can cause respiratory depression by a decreased response to hypoxia and hypercarbia, resulting in decreased stimulus to breathe. However, respiratory depression is preceded by sedation, and clinicians should perform a frequent assessment of mentation to avoid respiratory depression.

The different pharmacokinetics of opiates can be used for appropriate pain management at the end of life. The time to peak analgesic effect is important in choosing the right medication. Several routes of administration are available for opioids, including oral, intravenous, subcutaneous, intramuscular, transmucosal, nasal, transdermal, and rectal. In general, the peak analgesic effect of oral opioids is close to 1 hour, whereas intravenous doses of opiates cause a peak effect around 10 minutes from the administration. Certain newer opiates using the transmucosal or intranasal mode of administration can have a faster onset of action and peak effect.

The doses of opiates need individualization and should be titrated per the analgesic effect. Patients who need repeated doses of short-acting opiates may need longer-acting opiates scheduled around the clock. The daily short-acting doses should be added up, and 50% to 75% of the dose should be converted to long-acting opiates.[17] As needed, opiates should be prescribed to address breakthrough pain caused by interventions like turning, suctioning, and changing dressings.(B3)

Morphine sulfate is approved for acute or chronic pain with moderate to severe intensity. Morphine is metabolized in the liver and excreted by the kidneys. In patients with renal dysfunction, the active metabolites, namely 3-glucuronide and morphine-6-glucuronide, can accumulate, causing myoclonus and seizures. Oxycodone is another potent opiate approved for use in moderate to severe pain, available in immediate-release as well as extended-release formulations, with metabolism similar to morphine. Hydromorphone is another potent opiate analgesic available in oral, subcutaneous, or sublingual preparations. Fentanyl has gained popularity due to its several routes of administration and predictable analgesic effects. Apart from being used as an infusion for sedation and analgesia in mechanically ventilated patients, fentanyl can be used as a transdermal patch in patients who cannot take medications orally. Care is necessary when removing the used patch before placing a new patch to avoid an overdose. Fentanyl is stored in the adipose tissue and takes 12 to 24 hours to wash out of the system once the patch is removed.

Methadone is a long-acting pure μ-opioid receptor agonist with the advantages of a long half-life and an inexpensive, orally available formulation. Unfortunately, methadone has a curvilinear pharmacokinetic curve, leading to exponential effects in higher doses, exposing patients to potentially life-threatening overdoses. Methadone can also lead to QT interval prolongation and should be used cautiously in patients with underlying cardiac conditions. Tramadol has a dual action at the μ-opioid receptor as well as a weak action as a serotonin-norepinephrine reuptake inhibitor. Tramadol use has been approved for moderate to moderately severe pain.

The selection of an opiate agent should take into account the individual needs of the patient. Patients who are mechanically ventilated can receive fentanyl or hydromorphone due to their fast action and easy titration. Patients with renal and hepatic insufficiency should receive intravenous fentanyl with doses adjusted. Remifentanil can also be used because its metabolism does not depend on hepatic or renal function; it is metabolized by nonspecific plasma esterases located primarily within erythrocytes. Patients who require frequent neurological examinations can also benefit from remifentanil due to its ultrashort duration of action. Patients with hemodynamic instability or bronchospasm should not receive morphine sulfate because it causes histamine release. Meperidine should be avoided in patients with renal and hepatic failure because of severe neurotoxicity from the accumulation of an active metabolite. Codeine is another medication with limited use at the end of life, with a high incidence of constipation. Approximately 10% of the population lacks the enzyme necessary to convert codeine, a prodrug, to morphine, leading to insufficient analgesia.[18]

Patient-controlled analgesia (PCA) via an infusion pump is a modality that can be used when the required daily doses are high or the patient is unable to tolerate oral analgesia. PCA pumps have a button that allows a breakthrough dose when the patient presses it. The pumps can be programmed to separate doses by a safety interval. The dose delivered when the button is pressed is typically 50% of the hourly dose. Monitoring for sedation in patients on a PCA pump is important to avoid respiratory depression. In patients with inability, debility, or cognitive decline, the PCA can be replaced with a nurse-controlled analgesia pump, where the nurse administers breakthrough doses before interventions or on observing objective signs of pain in the patient.

Nonopioid medications can be used as an adjunct to opiates or NSAIDs for pain management. Antiepileptic medications like gabapentin and pregabalin can be used for pain from neuropathy and bony metastasis. Both these medications require dose adjustments for renal impairment. Corticosteroids can be used as an adjunct to treat late-stage disease, especially when edema or inflammation is present, and can improve appetite and mood. However, severe interactions and adverse effect profiles warrant a risk-benefit discussion with the patient.[19]

The role of the anesthesiologist is expanding into palliative care with selective treatment options for pain relief. While this use is still fairly rare, there are opportunities for additional modalities to address pain, such as the use of tunneled epidurals to treat severe, refractory cancer-related pain at the end of life.[20][21] Additionally, neurosurgical procedures such as neurostimulators or nerve ablative procedures can provide targeted pain relief at the end of life and are likely underused in current practice, although additional research is needed to clarify their role.[22] (A1)

Nonpharmacological Management of Pain

The nonpharmacological measures for the management of pain include measures aimed at avoiding pain triggers and psychosocial assistance in managing the end of life. Proper head positioning and neck support can help prevent neck spasms. Artificial tears and lubricants can help avoid painful keratitis. Using gel foam pads on the skin-appliance interface can help avoid ulceration, such as nasal bridge gel pads for noninvasive ventilation. Oral care and proper hydration can avoid painful ulcerations and dental decay. Frequent repositioning and offloading of the body's dependent areas can help prevent decubitus ulcers. In cases of skin breaks, nonbulky, nonstinging chemical dressings can be used to reduce pain.

Counseling to get affairs in order and to devise robust goals of care while the patient can still make decisions can help alleviate anxiety and improve interpersonal relationships. Daily sponging and grooming, as tolerated, improves hygiene and preserves the patient's dignity and sense of self-worth. Spiritual counseling and pastoral visits can help counter the nonacceptance of impending death and alleviate suffering. Alternative medicinal therapies like acupuncture and Reiki can be offered to support pharmacological measures in managing pain.

Differential Diagnosis

Certain conditions can mimic pain at the end of life and need evaluation to provide appropriate therapy. Severe dehydration can lead to an alteration of mental status, lethargy, and discomfort. This discomfort can be misdiagnosed as pain, and pain medications can worsen the change in mental status. As illness progresses, multiorgan failure can set in, and renal and hepatic impairments can lead to a buildup of toxic metabolites. Long-term use of opiates can lead to dependence, and with a drop in dose, signs of withdrawal can ensue, mimicking pain. Long-term use of opiates can also lead to opioid hyperalgesia, causing a vicious cycle of pain.

Prognosis

By definition, terminal illness has a poor prognosis; the goal of care often shifts from prolonging life to managing symptoms and minimizing suffering in the last days to weeks of life. Patients with impending death and good social support may benefit from discharge to familiar surroundings with family and specialized end-of-life medical care at home. In the absence of social support, inpatient hospice should be considered. Patients with intractable pain and impending demise should be offered palliative sedation.

Complications

NSAIDs are commonly used in the management of pain and are frequently associated with adverse effects. Acetaminophen is associated with hepatic injury, and its use should be limited in patients with underlying hepatic impairment. Other NSAIDs like ibuprofen and ketorolac can lead to severe gastrointestinal tract adverse effects, including hemorrhage, ulceration, and perforation. Proton pump inhibitors for prophylaxis should be used with prolonged use. NSAIDs increase the risk of stroke, myocardial infarction, and renal failure. Please see StatPearls' companion reference, "Ketorolac," for further information.

Opiates can be associated with overdoses, with grave consequences. Lethargy and a depressed level of consciousness are the most common symptoms of overdose. Respiratory depression can ensue if the overdose is not countered in time. Respiratory distress, hypoxia, and cardiovascular compromise from hypotension are other signs of opiate overdose. In the case of a suspected overdose, naloxone, a pure competitive antagonist of opiate receptors, should be used. Naloxone can be administered subcutaneously or via intravenous, intramuscular, intranasal, or endotracheal routes. The dosage is 0.4 mg to 1 mg in adults. If the patient continues to show signs of toxicity, a dose may be repeated after 3 to 8 minutes, corresponding to the time to peak effect. Please see StatPearls' companion reference, "Opioid Toxicity," for further information. Opiates can cause physical and psychological dependence, and the potential for abuse should be kept in mind while treating pain.

Opioid-induced hyperalgesia involves increased pain sensitivity, with the diffuse extension of pain despite an escalation of opiate dose. Opioid-induced hyperalgesia is thought to result from neuroplastic changes to the peripheral and central nervous system, leading to sensitization of pain pathways. N-methyl-D-aspartate (NMDA) receptor activation has been thought to be a predominant mechanism for opioid-induced hyperalgesia, which is more often seen in association with morphine and hydromorphone. Treatment is focused primarily on reducing the dose of opioids and switching the opioid class. The addition of NMDA receptor modulators like ketamine, methadone, and buprenorphine has also been suggested.[23] Severe constipation can be associated with opiate use due to delayed gastric emptying and peristalsis in the gastrointestinal tract. Increased dietary fiber and fluid intake can help counter constipation. Methylnaltrexone bromide, a peripherally acting opiate antagonist that does not cross the blood-brain barrier, can be used to treat opiate-induced constipation.