End-of-Life Evaluation and Management of Pain

Etiology

Pain at the end of life is most commonly associated with the pathology causing the disease and ultimately leading to death. Based on acuity, pain can be acute or chronic. Acute pain is usually associated with an intervention like surgical interventions, repositioning, or suctioning that may be performed as a palliative measure. Chronic pain is usually a complex interplay between several organ systems. Examples of chronic pain include headaches, joint pain due to arthritis, pain due to skin breaks, decubitus ulcers, etc. The pain can be classified as somatic, visceral, or neuropathic based on the pain fibers' location. Each of these classifications leads to a specific character of pain, 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, infections like abscesses, and skin breaks. As the name suggests, Visceral pain involves the stimulation of pain receptors of the visceral organs and is generally described as a “squeezing” or “cramping” kind of pain. Palpation of the involved viscera can lead to an aggravation of the intensity of the pain. On the other hand, neuropathic pain is usually described as a sharp pain that is “burning” or like an "electric shock."

Anxiety and depression frequently accompany pain, and addressing this is pivotal to alleviating “total pain.” The anxiety caused by organic causes includes a feeling of impending doom in patients with respiratory diseases causing hypoxia and dyspnea, cardiac diseases, electrolyte imbalances, dehydration, and infection leading to sepsis. Medications like nebulization treatments, corticosteroids (Dosage and rapid tapering), and anti-emetics like metoclopramide can cause a feeling of anxiety. Failure to address pre-existing anxiety can lead to significant distress at the end of life.   

Apart from physical noxious stimuli, other factors that can affect individuals at the end of life, as elucidated by the concept of total pain, include emotional discomfort, interpersonal conflicts, and the nonacceptance of one’s death. Emotional discomfort and interpersonal conflicts go hand in hand in causing 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 total pain. 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

The pain of varying intensities is a common accompanying factor at the end of life, as evidenced by a recent population-based observational study.[2] In this study, the researchers found severe daily pain in over 17% of the over 20,000 participants studied. The cause of impending death or the health care setting does not appear to change the involvement of pain at the end of life. Pain is an accompanying factor seen in patients with the commonest causes of death worldwide, namely cancer, heart failure, chronic obstructive pulmonary disease, and lung cancer.[3]

Pain is seen in patients at home, in the community, and long-term care facilities.[4][5][6] Unfortunately, pain and its management at the end of life are often inadequate.[7] The involvement of supportive care/palliative medicine in the care of the dying patient can improve pain relief.[8] Ethnic and racial disparities were noted in hospice and palliative care utilization amongst minorities. However, there was no difference in the incidence of pain symptoms among individuals of all races and ethnicities.[9][10] This healthcare disparity deserves further research and evaluation.[11][12][11]

Pathophysiology

The pathophysiology of pain rests in the nociceptive pathway, leading to the perception of noxious stimuli in the body. This pathway acts as a protective mechanism in healthy individuals, pointing towards pathologies causing pain and aiding in removing the noxious stimuli or seeking treatment. 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.  

Pain perception begins at the level of nerve endings, which are unsheathed portions of the nerve. There are 2 major types of nociceptive nerve fibers: A-delta and C. The A-delta fibers are myelinated and allow for fast transmission of signals, leading to pain's initial perception. The C Fibers are unmyelinated and relay pain intensity. The A-delta fibers release glutamate onto the second-order neurons, while C fibers release neuropeptide neurotransmitters. Both of these fibers end in the dorsal root ganglion. They are associated with the first-order neurons of the nucleus posterior marginalis of the relaxed layer I and substantia gelatinosa of the Rexed layer II. These first-order neurons form the 3 major ascending pain pathways: the neospinothalamic, paleospinothalamic, and archispinothalamic tracts. The body has an innate defense mechanism from pain generated by these pathways in the form of the descending pain suppression pathway.

History and Physical

Approaching a patient at the end of life to manage pain involves a thorough evaluation of the primary diagnosis and the extent of involvement of organ systems. A comprehensive patient interview should be performed to outline the course of the disease—this aids in establishing a rapport between the caregiver and the patient and leads to better communication. The care goals should be outlined early, and every effort should be made to ensure strict adherence to the patient’s wishes. After an initial evaluation, open-ended questions should help ascertain the patient’s expectations of care. The concept of total pain should guide the discussion, and the history should also focus on physical and mental well-being.

Physical examination includes a head-to-toe assessment for factors that may contribute to pain. Physical signs of pain include facial grimacing, restlessness, tachypnea, and tachycardia. Patients who have been in bed for prolonged periods can have skin breaks or pressure ulcers in the dependent portions of the body, including the back of the head, shoulder blades, back, sacrum, hips, ankles, and heels. Dryness of the eyes can lead to painful keratitis as well as infections. Patients on long-term oxygen therapy may have skin breaks around the nares, dryness, and episodes of epistaxis, which can be distressing. Patients using noninvasive ventilation modes may have pressure ulcers at the nasal bridge and cheeks. In patients who are intubated and mechanically ventilated, pooling secretions and improper oral care can lead to oral ulcers and dental decay. Head positioning and lack of proper support can lead to painful spasms of the neck muscles.

Signs of malnutrition include temporal wasting, supra, infra-clavicular wasting, scaphoid abdomen, and skin dryness. Dehydration signs follow a similar pattern, including dryness of mucosal surfaces, loss of skin turgor, and dryness of the skin. Abdominal fullness points towards constipation or urinary retention, causing significant distress to the patient. Examination of the genitalia, especially in patients with chronic Foley catheters, can shed light on ulcers and signs of infection. All intravenous access sites require frequent evaluation for thrombophlebitis; infiltrating medications or fluids into the subcutaneous tissue can lead to pain, swelling, and infection. Lastly, a general assessment of hygiene and well-being focused on maintaining the patient's dignity at the end of life is essential.

Evaluation

The Evaluation of pain at the end of life follows the general pattern of pain assessment aimed at the site of pain, the onset of pain, character, radiation of pain, exacerbating, and relieving factors. A verbal description of the quality of pain is an important marker of the origin of pain. 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.[13]

Pain scales can help standardize care and provide objective assessment tools that are not provider-dependent. Several pain grading scales have been developed with validation. However, none of these scales is proven to be superior to others. The Likert-type scale for pain grades pain on a scale of 0-10, with “10” being the worst pain imaginable and “0” no pain. The Wong-Baker Faces pain scale comprises a series of faces with expressions of increasing distress. This scale provides superior assessment in children with reliability and validation, and its implementation in adults allows for the evaluation of pain in patients 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.

The patient is educated on admission to point at the pain scale to indicate pain and choose a face that best represents their pain. Using the same scale consistently between providers can help maintain the accuracy and effectiveness of care. In patients with cognitive impairment and dementia, some scales incorporate several factors that caregivers can observe at the bedside and evaluate the presence of pain. The Pain Assessment in Advanced Dementia scale is 1 such measure that can quantify pain and the response to intervention in patients with dementia.

Treatment / Management

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

Pharmacological Management of Pain

The World Health Organization devised a cancer pain ladder to guide caregivers in selecting pharmacological agents to manage pain.[14] This is a stepwise process in which the initial agents are nonopioids, with escalation to incremental doses of opioids and adjuvant agents, ultimately leading to the abolishment of pain.[15] 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 based on inhibiting the synthesis of prostaglandins. The cyclo-oxygenase enzymes COX-1 and COX-2 are inhibited by NSAIDs, with the COX-2 enzyme playing a key role in pain generated by inflammatory cells. Some NSAIDs can also inhibit the lipoxygenase pathway, which is responsible for producing some algogenic (pain-producing) metabolites. 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] (B3)

Acetaminophen is used frequently in divided doses, equaling a maximal dose of 4000mg every 24 hours. However, it is frequently associated with hepatotoxicity and lower dosages may be needed in patients with hepatic disease. Ibuprofen is another NSAID that the FDA has approved for mild to moderate pain; however, it is associated with gastrointestinal bleeding, renal impairment rashes, and hypertension.[17] Ketorolac is another NSAID that has a higher demonstrated potency than most other NSAIDs.[18] However, in addition to gastrointestinal and renal side effects, it can cause an increased risk of cardiovascular thrombotic events and strokes. Selective COX-2 inhibitors like celecoxib can help manage pain associated with the musculoskeletal system and theoretically have a favorable side 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.

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 mu, delta, or kappa opioid receptors by mimicking endogenous opioid peptides. These receptors are coupled to G1 proteins and act in an inhibitory capacity. They cause the closure of N-type voltage-gated calcium channels and open calcium-dependent inwardly-rectifying potassium channels. This causes a reduction in neuronal hyperexcitability due to hyperpolarization. They also decrease the intracellular cAMP, thereby decreasing the release of nociceptive neurotransmitters like substance P. The Mu receptors mediate analgesia, euphoria, sedation, gastrointestinal dysmotility, and respiratory depression. Mu 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 constant assessment of mentation to avoid respiratory depression.

The pharmacokinetics of different opiates can be utilized in 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 trans-mucosal 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 round 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.[19] As needed, opiates should be prescribed to address breakthrough pain caused by interventions like turning, suctioning, changing of dressing, etc.(B3)

The FDA approves morphine sulfate 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 similarly is another potent opiate that is approved for use in moderate to severe pain. It is available in immediate-release as well as extended-release formulations. Its metabolism is similar to morphine. Hydromorphone is another potent opiate analgesic available in oral, subcutaneous, or sublingual preparation. 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, it 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 mu-agonist with the advantages of having a long half-life and an inexpensive preparation available orally. Unfortunately, methadone has a curvilinear pharmacokinetic curve, leading to exponential effects in higher doses, exposing to potentially life-threatening overdoses. It 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 mu-opioid receptor as well as a weak action as a serotonin-norepinephrine reuptake inhibitor. Its use has been approved for moderate pain to moderately severe pain.

The selection of an opiate agent should take into account the individual needs of the patient. The mechanically ventilated patient can get fentanyl or hydromorphone due to the fast action and easy titration. Patients with renal and hepatic insufficiency should get IV Fentanyl with doses adjusted. Remifentanil can also be used because its metabolism is not dependent on hepatic or renal function. It is metabolized by nonspecific plasma esterases located primarily within erythrocytes. Patients who require frequent neurological checks can also benefit from remifentanil due to its ultra-short duration of action. Patients with hemodynamic instability or bronchospasm should not receive morphine sulfate as 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.[20]

Patient-controlled analgesia (PCA) via an infusion pump is a modality that can be utilized when the daily dosages required are high or the patient is unable to tolerate oral analgesia. PCA pumps have a button that allows for a breakthrough dose when pressed by the patient. The pumps can be programmed to separate doses by a safety interval. The dose delivered when pressing the button 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.

Nonopiate 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 disease and can aid in improving appetite and mood. However, severe interactions and adverse side effect profiles warrant a risk vs. benefit discussion with the patient.

Non-Pharmacological 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 avoid spasms of the neck. 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 dependent areas of the body can help avoid decubitus ulcers. In case of skin breaks, non-bulky, non-stinging chemical dressings can be used to avoid pain.

Counseling for getting affairs in order and devising robust goals of care while the patient can still make decisions can help alleviate anxiety and improve interpersonal relations. Daily sponging and grooming, as tolerated, leads to better hygiene and preserves the patient’s dignity and sense of self-worth. Spiritual counseling and pastoral visits can help counter non–acceptance 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 an 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 proceeds, multi-organ failure can set in, and renal and hepatic impairments can lead to a build-up 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, leading to a vicious cycle of pain.

Prognosis

With an inherently poor prognosis associated with the end of life, each circumstance's potential life expectancy should be used to guide placement. Patients with an impending demise and good social support may benefit from discharge back to familiar surroundings with family. In case of a lack of social support, inpatient hospice should be considered. Patients suffering from 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 side 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 side effects, including hemorrhage, ulceration, and perforation. Proton pump inhibitors for prophylaxis should accompany their prolonged use. NSAIDs increase the risk of stroke, myocardial infarction, and renal failure.[21]

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 case of a suspected overdose, Naloxone, a pure competitive antagonist of opiate receptors, should be used. It can be dosed subcutaneously or from the intravenous, intramuscular, intranasal, or endotracheal route. The dosage is 0.4 mg to 1 mg in adults. If the patient continues showing signs of toxicity, a dose may be repeated after 3 to 8 minutes, corresponding to the time-to-peak effect.[22] 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. It is thought to result from neuroplastic changes to the peripheral and central nervous system, leading to sensitization of pain pathways. NMDA receptor activation has been thought to be a predominant mechanism for opioid-induced hyperalgesia. It 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 GI tract. Increased fiber in the diet 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.