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Principles of Effective Pain Management at the End of Life CME/CE
Author: Perry G. Fine, MDMedical Writer: Clarinda Mac Low
Complete author affiliations and disclosures are at the end of this activity.
Release Date: October 5, 2006; Reviewed and Renewed: October 11, 2007; Valid for credit through October 11, 2008
Target Audience
This activity is intended for physicians, advanced practice and registered nurses, pharmacists, physician assistants, social workers, and other healthcare professionals who care for patients with far-advanced illness.
GoalThe goal of this activity is to provide readers with a current and comprehensive overview of pain management at the end of life, offering guidance and detailed resources to practicing clinicians.
Learning ObjectivesUpon completion of this activity, participants will be able to:
Describe the prevalence and significance of pain at the end of life.
Identify techniques to assess pain in patients, including those unable to provide verbal reports;
List differential features of nociceptive and neuropathic pain states;
Describe effective nonpharmacological means to relieve pain;
Recognize the therapeutic benefits and potential adverse effects associated with opioid and nonopioid pharmacotherapy for acute and chronic pain states at end-of-life.
Credits AvailablePhysicians - maximum of 2.0 AMA PRA Category 1 Credit(s)™ for physicians;Nurses - 2.0 nursing contact hours (1.0 contact hours are in the area of pharmacology);Pharmacists - 2.0 ACPE continuing education credits for pharmacists (0.2 CEUs)
All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation.
Physicians should only claim credit commensurate with the extent of their participation in the activity.
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Contents of This CME/CE Activity-->
Principles of Effective Pain Management at the End of Life-->
Principles of Effective Pain Management at the End of Life
Introduction
The end stages of chronic, progressive, life-limiting diseases bring a host of difficult symptoms and causes of suffering. There are disease-mediated symptoms, such as pain, dyspnea, fatigue, and loss of mobility, and there are the accompanying emotional states, such as depression, anxiety, and a sense of uselessness.[1] These symptoms and states intertwine and interact in a complex manner, and each one deserves attention.
Of the many symptoms experienced by those at the end of life, pain is one of the most common and most feared.[2,3] Pain is often undertreated, even when prevalence rates and syndromes are well understood and the means of relief are within all practitioners' capabilities to provide, directly or through consultation. With careful assessment and a comprehensive plan of care that addresses the various aspects of the patient's needs, pain can be controlled in the vast majority of cases. Awareness and provision of basic and specialized interventions can ensure comfort for all patients through the final stages of a terminal illness. This is equally important in order to prevent prolonged and pathologic grief in surviving loved ones.
All the members of a palliative care team play important roles in comprehensive pain management. Both physicians' and nurses' roles begin with assessment and continue throughout the development of a plan of care and its implementation. Rehabilitation specialists, clinical pharmacists, psychologists, social workers, and spiritual counselors also provide important elements in helping patients optimize their quality of life, stay comfortable, heal relationships, complete unfinished business, and find peace as they approach death. To provide optimal pain control, all healthcare professionals must understand the prevalence of pain at the end of life, the treatments used to provide relief, and the barriers that prevent good management.
To illustrate some common scenarios, we present 3 different fictional, but typical, case studies.
Case 1: Eleanor is a frail, 78-year-old woman who lives on her own with assistance from a homecare nurse and from a daughter who lives nearby. She was admitted to the hospital with acute respiratory failure due to bronchitis. She has advanced chronic obstructive pulmonary disease (COPD), with general fatigue and a poor appetite, and reports severe, debilitating pain in the midthoracic region from postherpetic neuralgia (PHN). She also struggles with coronary artery disease and attendant angina pectoris that is usually relieved with nitrates. Eleanor says that she has been feeling "pretty low" lately and finds herself becoming irritated at small events. She characterizes her pain as "bad as it can be" (see Figure 1). After a 2- to 3-day intensive care unit (ICU) stay, she will soon be ready for discharge. However, her pain from PHN is still not controlled, and her life expectancy is most likely limited due to her ongoing comorbidities. She does not have a written advanced directive. The hospital staff discuss the next step.
Figure 1. Pain Thermometer. Originally published in: Herr KA, Garand L. Assessment and measurement of pain in older adults. Clin Geriatr Med. 2001;17:457-478, vi. Reprinted with permission.



1.
Survey - If you were the attending clinician, would you feel confident that you could address Eleanor's pain management needs successfully?
Yes
No
Prevalence of Pain at the End of Life
Assessing pain in patients approaching the end of life requires a multifactorial evaluation. It is important to acknowledge and address the prevalence, high incidence, and serious adverse consequences of pain in the end-stage conditions that affect patients with advanced medical illness, such as controlled and uncontrolled cancer; heart disease; HIV disease; neurodegenerative diseases (eg, ALS and multiple sclerosis); and end-stage renal and respiratory diseases (see Figures 2 and 3).[4,5] These conditions may also be accompanied by other pain-producing disorders that may require separate treatments, as in the case above.
Figure 2. Common causes of persistent pain in advanced medical illness.
Figure 3. Consequences of undertreatment of pain.
The prevalence of pain in the terminally ill varies by diagnosis and demographics. Approximately one third of the people who are actively receiving treatment for cancer and two thirds of those with advanced malignant disease experience pain.[6-9] Almost 75% of patients with advanced cancer who are admitted to the hospital report pain upon admission.[10] In a study of cancer patients who were very near the end of life, pain occurred in 54% and 34% at 4 weeks and 1 week prior to death, respectively.[11] In a recent study by Goudas and colleagues[12] that compiled the results of 28 epidemiologic surveys, the study authors found that, in one study of over 35,000 Japanese cancer patients, 68% to 72% of patients in the terminal stages reported pain. In another study of over 13,000 cancer patients in US nursing homes, an average of 30% of the patients reported daily pain. In those patients, pain varied according to age, sex, race, marital status, physical function, depression, and cognitive status.[12]
In other studies of patients admitted to palliative care units, pain often is the dominant symptom, along with fatigue and dyspnea.[2] Until recently, it was widely believed that patients dying from nonmalignant disease did not have high levels of pain. However, it is now known that patients dying from cardiac failure, COPD, end-stage renal disease, and other end-stage diseases suffer similar levels of pain to those found in patients with malignant disease.[13,14] People at particular risk for undertreatment include the elderly, minorities, and women.[15,16]
More recently, an attempt has been made to characterize the pain experience of those with HIV disease, a disorder frequently seen in palliative care settings. Over 56% of patients with HIV disease report pain, with the most common symptoms being headache, abdominal pain, chest pain, and neuropathies.[4,5,17,18] Lower CD4+ cell counts and HIV-1 RNA levels are associated with higher rates of neuropathy.[17,18] There have been many reports of undertreatment of patients with HIV disease, including those patients with a history of addictive disease.[19,20]
General Principles of Assessing and Managing Pain
Assessment of pain, including a thorough history and comprehensive physical exam, guides indications for diagnostic studies and the development of the pharmacologic and nonpharmacologic treatment plan. The primary source of information should be a patient's self-report. There are many different pain rating scales available, ranging from complex multidimensional tools to very simple numeric and picture scales, which can help patients identify pain and then document the efficacy of treatment (see Figures 1 and 4 and Table 1 for links to sample pain scales). When using pain scales, be sure to follow the directions for administration carefully.
Figure 4. Pain assessment scales. Reprinted with permission. FACES Pain Scale - Revised: Copyright 2001 International Association for the Study of Pain (IASP). Originally published in: Hicks CL, von Baeyer CL, Spafford P, van Korlaar I, Goodenough B. The Faces Pain Scale -- Revised: toward a common metric in pediatric pain measurement. Pain. 2001;93:173-183. Other scales: Originally published in: Herr KA, Garand L. Assessment and measurement of pain in older adults. Clin Geriatr Med. 2001;17:457-478, vi.
Table 1. Pain Scales Online
Description
Web Address
Wong-Baker FACES Pain Rating Scale
http://www3.us.elsevierhealth.com/WOW/faces.html
Sample of Wong-Baker FACES Pain Rating Scale, with instructions for administration available in many languages
http://www3.us.elsevierhealth.com/WOW/facesTranslations.html
Faces Pain Scale - Revised (FPS-R), with instructions for administration available in many languages
http://painsourcebook.ca/docs/pps92.html
Verbal pain scale
http://www.intelihealth.com/IH/ihtIH/WSIHW000/29721/32087.html#verbal
Numerical pain scales
http://www.intelihealth.com/IH/ihtIH/WSIHW000/29721/32087.html#numericalhttp://www.medtronic.com/neuro/paintherapies/pain_treatment_ladder/drug_infusion/patient_management/drug_pat_mgmt_strat.html
Pain map
http://www.medtronic.com/neuro/paintherapies/pain_treatment_ladder/pdf/prestim_pain_assess.pdf
McGill Pain Questionnaire
http://www.med.ualberta.ca/uofapain/documents/McGillPainQuestRevisited2005.pdf
Short-Form McGill Pain Questionnaire
http://www.med.umich.edu/obgyn/repro-endo/Lebovicresearch/PainSurvey.pdf
Brief Pain Inventory
http://www.ohsu.edu/ahec/pain/paininventory.pdf
List of pain scales with evaluations
http://www.chcr.brown.edu/pcoc/Physical.htm
Pain scales in 17 languages
http://www.britishpainsociety.org/members_pain_scales.htm
A pain scale that suits a given patient's ability to self-report should be part of each patient's medical record. Health professionals should teach patients and their families to use these scales themselves to help in longitudinal pain assessment and continuity of care. Patients with terminal illnesses should be encouraged to verbalize their experiences of pain in their own words. The use of the "pain thermometer" has been validated as a self-report instrument for pain intensity in patients with mild-to-moderate cognitive impairment.[5,21,22]
For example, Eleanor describes her PHN as a "burning, needling pain" near her spine, spreading out across her back on the right, beneath her axilla and around to her breast. Her pain subsides sometimes, but rarely goes away altogether. Knowing the character and location of her neuropathic pain allows her caregivers to pinpoint adjuvant pain relief. In contrast, Eleanor's angina pain is "a deep heavy ache" in her chest. She notes that it is intermittent and that it is stressful, because she never knows quite when to expect it. By asking her to keep track of when her angina occurs, her caregivers are able to predict more precisely when it may be triggered, and advise her accordingly, perhaps reducing both severity and frequency.
A comprehensive evaluation of pain should include an assessment of the pain intensity, character, frequency, onset, duration, and location as well as a detailed history of pain, a physical and neurologic examination, a psychosocial assessment, and a diagnostic evaluation that includes tests to determine the cause of pain. It is also important to take into account common comorbidities, such as sleep disturbances and depression, which can affect pain levels, suffering, and functioning.[21,22]
Patients sometimes complain of pain as a way of expressing other forms of suffering, anxiety, or depression. When this is the case, psychosocial evaluation and intervention will be more effective than analgesics. It is well established that attention and emotion influence pain processing and perception, and conversely, inadequately managed pain can lead to anxiety and depression.[7-9] Therefore, comprehensive assessment is required to determine the optimal plan of care, as specific to pain etiology as possible.
Pain Types
Pain can usually be defined as nociceptive or neuropathic. Patients in the terminal stage of an illness may often experience different mechanisms of pain operating simultaneously. It is important to differentiate among different types of pain because the type of treatment is largely dictated by the pain mechanism and its original source.[21] In some conditions, pain appears to be caused by a complex mix of nociceptive and neuropathic factors. In these cases, an initial nervous system dysfunction or injury may trigger the neural release of inflammatory mediators and subsequent neurogenic inflammation -- migraine headaches, for example, are most likely a mix of neuropathic and nociceptive pain.
Nociceptive Pain
Nociceptive pain is typically the result of a musculoskeletal or visceral injury or disease and includes somatic and visceral mechanisms. Primary afferent neurons receive nociceptive input from peripheral nociceptors. Nociceptors are activated in response to noxious stimuli, which can be thermal, chemical, or mechanical in character. Somatic pain is characterized by aching, throbbing, stabbing, and/or a sensation of pressure. Its source is skin, muscle, or bone. Visceral pain is characterized by gnawing, cramping, aching, sharp, and/or stabbing sensations, and its source is the internal organs. Nociceptive pain usually resolves when the initial tissue damage heals, and tends to respond well to treatment with anti-inflammatory agents and opioids.[22-24]
Neuropathic Pain
Neuropathic pain is caused by lesions or physiologic changes in the nervous system, and it is characterized by hypersensitivity either in the damaged area or in the surrounding normal tissue. The pain is often triggered by an injury or disease, but there may not be demonstrable damage to the nervous system other than the subjectively reported sensory disturbance of pain. The pain frequently has qualities of burning, numbness, tingling, touch sensitivity, sharp and shooting sensations (lancinating pain), or electric shocks (see Figure 5). Persistent allodynia, which is pain resulting from a nonpainful stimulus, such as a light touch, is a common characteristic of neuropathic pain. Neuropathic pain tends to persist long after the initiating event has resolved. Neural inflammation can change the actual structure of neural organization so that stimuli that were once interpreted as touch become perceived as painful. Typical examples include painful diabetic neuropathy, HIV/AIDS neuropathy, postherpetic neuralgia, and cancer-induced as well as post-treatment cancer pain syndromes, such as postmastectomy syndrome and radiation and chemotherapy neuropathies.[22,23,25]
Figure 5. Neuropathic Pain Questionnaire Short Form. Originally published in: Backonja MM, Krause SJ. Clin J Pain. 2003;19:315-316. Reprinted with permission.
Effects of Unrelieved Pain
There is significant evidence that inadequate pain relief hastens death by increasing physiologic stress, potentially diminishing immunocompetence, reducing mobility, increasing proclivities toward pneumonia and thromboembolism, and increasing the work of breathing and myocardial oxygen requirements.[26] Pain may lead to a spiritual despair and significant decrease in emotional well-being because the individual's quality of life is impaired.[4,5] It is the professional and ethical responsibility of clinicians to focus on and attend to adequate pain relief for their patients and to properly educate patients and their caregivers about analgesic therapies.[27]
Returning to Eleanor, who has COPD, coronary artery disease, and PHN, it is clear that discussions regarding care preferences (ie, advanced directives) are optimally done prior to a medical crisis and while there is cognitive capacity for decision making. However, under the current circumstances, a care planning meeting with the attending clinician, consultant clinicians (eg, palliative care/hospice team), and designated responsible family member is of paramount importance. Either pain must be adequately controlled prior to discharge with a follow-up plan in place, or transfer to a skilled facility, such as an inpatient palliative care/hospice unit (where pain management expertise and focus can rapidly take place). Alternatively, with a prognosis of 6 months or less, if Eleanor prefers to go home immediately, a hospice program with the ability to manage her pain condition should be consulted. Regardless of setting, nonpharmacologic approaches to pain control with titration of "first-line" agents for neuropathic pain (anticonvulsants, topical local anesthetic, and opioids) should proceed with close monitoring to balance therapeutic vs adverse effects.
Case 2: Sharon is a 70-year-old woman in the late stages of Alzheimer's disease with severe osteoarthritis in her knees and spine. She lives with her married daughter and 2 grandchildren. Her daughter and a son living nearby provide her essential care, and, until recently, she has remained active and ambulatory. She is beginning to experience severe pain from her arthritis, manifest by grimacing, crying, and moaning. The current caregivers are not always sure what she is expressing, but they understand that she is in some distress and are eager to help alleviate it. They meet with their family doctor to talk about options. Because Sharon is in the far-advanced stage of Alzheimer's disease, the physician refers her to hospice for comprehensive care and support of her family. During her initial evaluation, the family stresses that their primary goal is to make sure that "Mom" is comfortable. The hospice nurse evaluates Sharon and determines that she responds well to a variety of nonpharmacologic interventions. Her family members express a willingness to use a variety of hands-on and nonpharmacologic techniques to help Sharon live her last days relatively free of pain and suffering. Meanwhile, she is started on a regimen of around-the-clock acetaminophen (1000 mg 4 times daily) with the option for more potent pharmacologic therapies left open.



2.
Indicate from the examples below the nonpharmacologic modalities that you have personally recommended to patients for pain. (Check all that apply.)
Music therapy
Transcutaneous/percutaneous electrical nerve stimulation (TENS)
Massage
Acupuncture
Physical therapy
Cognitive interventions
Nonpharmacologic Approaches to Pain Management in Palliative Care
An important aspect of any management strategy is the use of nonpharmacologic treatments.[23,28] There are a variety of nonpharmacologic approaches to pain that have been shown to be effective in alleviating pain for patients with advanced illness. These include physical interventions, such as positioning and active or passive mobilization (therapeutic exercise); techniques, such as TENS, massage, and heat/cold; and complementary and alternative medicine techniques, music, and relaxation/imagery exercises. Table 2 offers a list of some of the most common nonpharmacologic interventions.
Table 2. Nonpharmacologic Approaches to Pain Management in Palliative Care
Intervention
Details
Rehabilitation/physical therapy
Physical, occupational, and speech therapy are potentially beneficial in managing pain
Mobility may be improved by strengthening, stretching, and the use of assisting devices
Home settings vary in their utility for a debilitated person, as does the degree of hands-on physical assistance that friends and family can provide
The decision to use these modalities is made on a case-by-case basis
Massage
Family members can be taught simple, safe techniques of massage
Hospice programs can often provide trained, certified massage therapists who are familiar with the clinical issues faced by cancer and noncancer patients with far-advanced disease
Transcutaneous/percutaneous electrical nerve stimulation
Evidence exists to support the use of percutaneous electrical nerve stimulation for persistent low back pain and knee pain
Acupuncture
Popular complementary therapy for patients with cancer and other end-stage pain
Many patients with cancer use acupuncture when symptoms persist with conventional treatments, or as a complement to their ongoing treatments
Several researchers have found acupuncture to be an effective antidepressant
Studies show that acupuncture has a significant positive effect on COPD, dyspnea associated with end-stage cancer, and asthma
Cognitive interventions
Some common cognitive interventions:
Psychological tools and strategies for the purposes of self-regulating emotions;
Distraction from noxious sensations and thoughts; and
Methods for reducing negative attitudes
Involving patients in cognitive self-care may improve mood and increase coping behaviors
Music therapy
Music effectively reduces anxiety and improves mood for:
Medical and surgical patients;
Patients in intensive care units;
Patients undergoing procedures; and
In children as well as adults
Low-cost intervention
Often reduces chronic pain
Improves the quality of life, enhancing a sense of comfort and relaxation
Music to caregivers may be a cost-effective and enjoyable strategy for improving empathy, compassion, and relationship-centered care without interfering with technical aspects of care
COPD = chronic obstructive pulmonary disease
The type of intervention, or combination of interventions, depends on the source and severity of pain as well as the physical condition and receptivity of the patient. In an investigation of the prevalence of complementary and alternative medicine use in an end-of-life population, Tilden and colleagues,[29] through a series of phone interviews with family caregivers of recently deceased, found that 53.7% of the deceased used some kind of complementary therapy, were more likely to be younger with college degrees and higher household incomes, and to have used 1 or more life-sustaining treatment. Symptom relief was the most frequent reason given for complementary and alternative medicine use.[29] Although a study by Weiner and Ernst[30] that reviewed common complementary and alternative treatment modalities for the treatment of persistent musculoskeletal pain found that the use of these modalities is increasing in older adults, the study authors concluded that rigorous clinical trials examining efficacy are still needed before definitive recommendations regarding the application of these modalities can be made.
Aside from their objective efficacy, a medical sociologic study by Garnett[31] on the use of complementary therapies by palliative care nurses sees these therapies as an "emotional inoculation" that builds resiliency and an important bond between patient and caregiver. Nonpharmacologic interventions often comfort the patient while involving and empowering family and other caregivers. The necessity of feeling effective for caregivers should not be overlooked -- it can have a direct effect on the experience of the patient as well as the emotional survival of the family caregiver in particular. A study by Keefe and colleagues[32] on the self-efficacy of family caregivers of cancer patients found that caregivers who rated their self-efficacy as high reported much lower levels of caregiver strain as well as lower negative mood and higher positive mood. Caregiver self-efficacy in managing the patient's pain was related to the patient's physical well-being. When the caregiver reported high self-efficacy, the patient reported having more energy, feeling less ill, and spending less time in bed.[32]
Rehabilitation and Physical Therapy
Functional rehabilitation and physical therapy techniques in appropriately selected patients add to quality of life even in the face of limited life expectancy. Sharon is a typical patient who responds well to nonpharmacologic pain intervention. A recent study by Montagnini and colleagues[33] assessing the use of physical therapy in a hospital-based palliative care setting found that a significant proportion demonstrated improvement in function after 2 weeks. The study authors found that patients with a diagnosis of dementia were most likely to show improvement in functional status and concluded that physical therapy assessment and use were uncommon in the studied group, but, when implemented, it benefited 56% of the patients.[33]
Massage
Research suggests that patients with cancer, particularly in the palliative care setting, are increasingly using aromatherapy and massage. There is good evidence that these therapies may be helpful for anxiety reduction for short periods. A study by Soden and colleagues[34] was designed to compare the effects of 4-week courses of aromatherapy with massage and massage alone on physical and psychological symptoms in patients with advanced cancer. The study authors were unable to demonstrate any significant long-term benefits of aromatherapy or massage in terms of improving pain control, anxiety, or quality of life, but sleep scores improved significantly in both groups, and there were statistically significant reductions in depression scores in the massage group -- suggesting that patients with high levels of psychological distress respond best to these therapies.[34]
Acupuncture and TENS
These modalities may be effective in selected patients based on meta-analyses of the literature and findings of National Institutes of Health (NIH) consensus panels.[35] For percutaneous procedures, appropriate cautions, skilled certified practitioners, and fastidious aseptic techniques are required to protect patients and staff from untoward adverse outcomes. Similarly, for therapies involving electrical stimulation, awareness of implanted devices (pumps, stimulators, implantable cardioverter defibrillators, or pacemakers) and precautions to prevent malfunction must be taken.
Cognitive Interventions
Simple psychological interventions can have a significant impact on pain. As an example, Paqueta and colleagues[36] explored the idea that everyday emotion regulation through a self-supporting maintenance or change in positive and negative emotions can help reduce pain intensity in the hospitalized elderly. Emotion regulation was found to be prospectively related to pain intensity for both overall emotion and anxiety-specific regulation. The study authors suggest that promoting emotion regulation as a self-management strategy could contribute to cost-effective pain management in general or targeted elderly populations.[36]
Music Therapy
There is growing interest in the therapeutic use of music. The difficulties inherent in the medical treatment of this population make the use of music, as a noninvasive therapeutic modality, attractive.[37] Music is often used to enhance well-being, reduce stress, and distract patients from unpleasant symptoms. Although there are wide variations in individual preferences, music appears to exert direct physiologic effects through the autonomic nervous system.[38]
Choosing the Best Approach
A combination of treatments is usually most effective when using nonpharmacologic approaches to pain management. Similar to pharmacotherapy, multimodal approaches offer the potential benefit of additive and synergistic effects. Because nonpharmacologic therapies need to be tailored to individual likes, dislikes, and effectiveness, knowledge of the various modalities, management of expectations, open-mindedness, and a "trial-and-error" approach should be embraced.
The hospice nurse was able to offer Sharon's family a variety of hands-on and alternative modalities that could be used in addition to pharmacologic interventions to successfully comfort the patient. The nurse found that simple stretches and strengthening and mobilization exercises were effective for reducing the stiffness that was associated with Sharon's musculoskeletal disease. This helped both to relax the patient and prevent the usual anxiety that is associated with getting her out of bed in the morning and daily personal care, such as bathing and toileting. A simple TENS unit appeared to ease the patient's knee pain. The nurse was also able to guide the family in some interventions that reduced Sharon's anxiety and increased the family's sense of involvement and effectiveness. They found that songs from her youth brought Sharon a great deal of pleasure, and her son, a fan of the music, enjoyed spending listening time with her. Physical contact often calmed Sharon, and the nurse trained Sharon's granddaughter in simple massage techniques.
Case 3: Jerry is an 82-year-old man with metastatic colon cancer who has just returned to his home in an assisted living facility postoperatively after a bowel resection. He sees a geriatric nurse practitioner, in collaboration with a family physician, for ongoing primary care. It has become clear that that there are widespread metastases, and his oncologist agrees that the current goal of care is comfort only. Jerry is still ambulatory and in the early stages of his terminal illness. No further chemotherapy or radiation therapies are indicated, but the patient reports progressive abdominal pain, and symptoms suggestive of intermittent bowel obstruction develop. Jerry refuses further hospitalization and surgery, and prefers noninterventional therapies -- if at all possible. A consulting pharmacist and medical director from the local hospice are asked to come in and help the nurse practitioner choose the best pharmacotherapy for pain and bowel-related signs and symptoms, including types of drugs, route of drug administration, and the best way to minimize possible side effects. The explicit goals of care are a comfortable, dignified death; crisis prevention; and self-determined life closure (no prolongation of dying by medical intervention).



3.
Survey - Which one of the following statements is true?
Pain treatment should be limited to single analgesic drug therapy to prevent drug-drug interactions(The answer you selected is incorrect. The correct answer is: "'Rational polypharmacy,' which combines drugs that have different mechanisms of action, may improve pain-related outcomes.")
"Rational polypharmacy," which combines drugs that have different mechanisms of action, may improve pain-related outcomes(The answer you selected is correct.)
Opioids should be avoided in older patients because they cause respiratory depression(The answer you selected is incorrect. The correct answer is: "'Rational polypharmacy,' which combines drugs that have different mechanisms of action, may improve pain-related outcomes.")
Drugs that are not explicitly US Food and Drug Administration (FDA)-approved for a pain-related indication are illegal to prescribe(The answer you selected is incorrect. The correct answer is: "'Rational polypharmacy,' which combines drugs that have different mechanisms of action, may improve pain-related outcomes.")
Explanation:It is often difficult to control severe pain with a single analgesic agent, especially neuropathic pain conditions which are common in many chronic progressive disease processes."Rational polypharmacy" involves combining 2 or more agents with different mechanisms of action, for synergistic or additive effects. This may allow improved analgesia at lower doses of any single agent, limiting toxicity that occurs with higher doses. However, drug-drug interactions must be carefully monitored.When opioids are titrated to effect (ie, pain control and functional improvement), respiratory depression is a rare occurrence.Clinicians may prescribe any available agent for which they have prescriptive privileges that their clinical judgment indicates. Needless to say, there should be a sufficient evidence base and appropriate context for whatever is prescribed.
Drugs for Pain Relief in Palliative Care
Pharmacologic therapies for pain include nonopioids, opioids, adjuvant analgesics, disease-modifying therapies, and (in some cases) interventional techniques. Intractable pain and symptoms that are not responsive to basic therapeutic techniques, although not common, must be treated appropriately and aggressively. In some highly selective cases, palliative sedation may be warranted. A sound understanding of pharmacotherapy for pain treatment allows the palliative care/hospice team to create a comprehensive plan of care as well as recognize and assess medication-related adverse effects, understand drug-drug and drug-disease interactions, and educate patients and caregivers regarding appropriate medication usage. Recognition of the limits of usual therapies and the ability to muster expert assistance are important skills. This will ensure a comfortable process of dying for the well-being of the patient and for the sake of those in attendance.
Genetic factors, pathologic processes, concurrent medication, and aging will all influence drug response and disposition. However, there are also a variety of nonmedical factors that influence responses to drug treatment in patients with far-advanced disease, including the social, environmental, and psychological milieu as well as the general vulnerability of this population. Understanding the clinical pharmacology of the drugs in question is essential for professional caregivers.[5] Commonly, there is a need to use drugs for non-FDA-approved indications or routes of administration, simply because randomized, controlled clinical trials have not been performed, due (usually) to financial constraints. Rational polypharmacy (combining drugs with different mechanisms of action to produce additive or synergistic effects and minimize adverse effects) is often necessary, but there is a high potential for drug interactions, so close monitoring is required.
The principles of effective symptom control are always paramount -- diagnose the underlying cause of each symptom and tailor the treatment to individual circumstances and clinical context. Keep in mind that normal pharmacokinetics and pharmacodynamics may be considerably altered by end-stage disease states. For example, in patients with chronic liver disease or hepatic metastases, drugs may bypass hepatic metabolism altogether, increasing bioavailability. Similarly, renal clearance is almost always diminished during the dying process, leading to the accumulation of drug metabolites, some of which (eg, those of morphine) may be toxic.[5,39,40]
Communicating With Patients, Families, and Other Healthcare Professionals
Communicating clearly about pharmacologic pain control with patients, families, and other members of the palliative care/hospice team is essential to providing effective pain management. It is important to be specific about the types of drugs that are available, how they are likely to affect the patient, how they are to be administered, and how they may interact with existing medications. Despite the importance of pain management at the end of life, there are often substantial roadblocks to overcome in getting patients the treatment that they need. Professional healthcare workers may have unsubstantiated but strong beliefs about analgesic use, especially opioid use, that lead to underprescribing.[41,42] There are several surveys that show that physicians, nurses, and pharmacists express concerns about addiction, tolerance, and side effects of morphine and related compounds.[43] These fears are pervasive among patients and family members as well. Studies have suggested that these fears lead to undermedication and increased pain intensity.[44] Concerns about being a "good" patient or belief in the inevitability of cancer pain lead patients to hesitate in reporting pain. In these studies, less educated and older patients were most likely to express these beliefs.[4]
Often, a physician or other providers may be reluctant to offer the patient direct and objective information on his or her health, especially toward the end of life, seeking to "soften the blow" by keeping the details vague. Most patients, however, prefer complete information about his or her condition.[45,46] However, patients may wish to defer decision making to the physician or family members.[45,47] Physicians have a professional duty to determine patients' medical wishes. Pragmatically, this responsibility may fall to the nurse or nurse practitioner, and there are tools, such as simple card sorting, that can be used to facilitate this exchange,[48] for example, the 5-card Control Preference Scale uses cards to portray different roles in treatment decision making with a statement and a picture.[49]
Dispelling Common Myths About Pain Management
Understanding the barriers that are faced when treating pain can lead professionals to better educate and counsel patients and their families.[32] Patients should be asked whether they are concerned about addiction and tolerance (often described as becoming "immune" to the drug).[50] At the end of life, patients may need to rely on family members or other support persons to dispense medications. Studies suggest that patients' pain experiences and family members' perceptions about them don't correlate well, leading to inadequate provision of analgesia.[51,52] The interdisciplinary palliative care/hospice team is essential in the communication effort, with nurses, social workers, chaplains, physicians, volunteers, and others providing support in exploring the meaning of pain and barriers to pain relief. Education, counseling, reframing, and spiritual support are imperative.
Overview of Nonopioid and Opioid Therapy
This section provides a brief overview of both commonly used and newer pharmaceutical agents available in the United States for the treatment of persistent pain associated with advanced disease. Pain-relieving drugs can be categorized as nonopioid analgesics, opioid analgesics, and the adjuvant analgesics. Detailed knowledge of these classes of agents is necessary to provide quality palliative care, and although a comprehensive review is beyond the scope of this article, links to more detailed lists of all drugs used for pain control throughout the world can be found in Table 3.
Table 3. Drugs for Pain Control at the End of Life
Web Address
Content
http://www.palliativedrugs.com
Palliative care formulary online
http://www.pallmed.net
Generic site, with drug-compatibility database
http://nccam.nih.gov
Information on complementary medicines
http://www.fda.gov/orphan/
Information on orphan drugs
Source: Doyle D, Hanks G, Cherny NI, Calman K, eds. Oxford Textbook of Palliative Medicine. 3rd ed. Oxford, United Kingdom: Oxford University Press; 2003.
There are several, possible methods of approaching pharmacologic pain management for patients with advanced diseases. Patients may require several different medications to deal with a variety of pain syndromes and disease- or treatment-related discomfort. For expedient and thorough treatment, it is often wise to adopt a stepwise approach to the use of pain medications. The World Health Organization (WHO) has developed a simple, 3-step model for managing cancer pain that can be applied to many different situations. It has been modified over time to adapt to the evolving fields of pain and palliative medicine (see Figure 6). This revised approach recommends that mild pain (1-3 on a numerical analogue scale) should be treated with nonopioid pain relievers, such as aspirin, acetaminophen, and nonsteroidal anti-inflammatory drugs (NSAIDs), with or without adjuvant therapy. Higher pain intensities indicate the use of nonopioid analgesics along with opiate derivatives, such as codeine, hydrocodone, or tramadol.[25] If pain is not relieved, then titration of opioids, such as morphine, hydromorphone, and fentanyl, in combination with nonopioid analgesics and adjuvants is indicated. Refractory pain syndromes will often require more invasive techniques, such as spinal opioids, nerve block, or neurostimulation.[1]
Figure 6. Modification of WHO 3-Step Ladder. Reprinted with permission from: Fine PG. Anesth Analg. 2005;100:183-188.
Nonopioid Analgesics
Acetaminophen. Acetaminophen has been determined to be one of the safest analgesics for long-term use in the management of mild pain or as a supplement in the management of more intense pain syndromes. It is especially useful in the management of nonspecific musculoskeletal pain or pain associated with osteoarthritis, but should be considered an adjunct to any chronic pain regimen. It is often forgotten or overlooked when severe pain is being treated, but it can be quite effective as a "coanalgesic." It is important to take into account acetaminophen's limited anti-inflammatory effect and its hepatic effects. Reduced doses or avoidance of acetaminophen is recommended for patients with renal insufficiency or liver failure, particularly in individuals with significant alcohol use.[53,54]
NSAIDs. NSAIDs reduce the biosynthesis of prostaglandins by inhibiting cyclooxygenase (COX) and the cascade of inflammatory events that cause, amplify, or maintain nociception. NSAIDs also appear to directly affect the peripheral and central nervous systems. COX has been identified in spinal cord neurons, and may play a role in the development of neuropathic pain, but these agents do not appear to be useful in the treatment of neuropathic pain.[25] The "classic" NSAIDs (eg, aspirin or ibuprofen) are relatively nonselective in their inhibitory effects on the enzymes that convert arachidonic acid to prostaglandins, so gastrointestinal ulceration, renal dysfunction, and impaired platelet aggregation are common.[4] The COX-2 selective NSAIDs rofecoxib (Vioxx) and valdecoxib (Bextra) are now off the market, and, due to potential problems and concerns with gastrointestinal bleeding and thrombosis, celecoxib (Celebrex) should be used with caution in high-risk palliative care patients.[55]
NSAIDs are useful in treating many pain conditions mediated by inflammation, including those caused by cancer.[58,59] These agents cause minimal nausea, constipation, sedation, or effects on mental function, although there is evidence that their use can impair short-term memory in older patients.[58] These agents may be very useful for moderate-to-severe pain control, either alone or as an adjunct to opioid analgesic therapy. Adding NSAIDs to an opioid regime may allow a reduced opioid dose when sedation, obtundation, confusion, dizziness, or other central nervous system effects of opioid analgesic therapy alone become problematic.[59] Extended-release formulations are likely to increase compliance and adherence.[25] As with acetaminophen, decreased renal function and liver failure are relative contraindications for NSAID use. Platelet dysfunction or other potential bleeding disorders also contraindicate use of the nonselective NSAIDs due to their inhibitory effects on platelet aggregation, a clear advantage of the coxib class of NSAIDs. If NSAIDs are effective, but there is need for prolonged use or there is a history of gastrointestinal complications, proton pump inhibitors can be given to lower the risk of gastrointestinal bleeding.[60]
Opioid Analgesics
Opioid analgesics are the most useful agents for the treatment of pain associated with advanced disease. They reduce pain-producing signals and perception throughout the nervous system, regardless of the pathophysiology of the pain.[61] Opioids exist in 3 classes -- pure agonists, mixed agonist-antagonist, and pure antagonists.[39] They are classified according to their interaction with the 3 major opioid receptor types. Pure agonists, which interact with (mu) receptors in the brain and spinal cord, are generally preferred for managing moderate-to-severe pain, and have been shown to reduce pain in a number of neuropathic pain syndromes, contrary to previous thinking.[62] Opioids can also be used to treat dyspnea and as an anesthetic adjunct. There are few, if any, indications for the mixed agonist-antagonist agents. The pure antagonists are used to treat acute overdose and, in selected cases, as a means of treating or preventing opioid-induced bowel dysfunction. The opioids used most commonly in palliative care are morphine, hydromorphone, fentanyl, oxycodone, and methadone. A sustained-release form of oxymorphone is in the approval stage and may add to this growing formulary.
The only absolute contraindication to the use of an opioid is a history of a hypersensitivity reaction (eg, rash, wheezing, and edema). Allergic reactions are almost exclusively limited to the morphine derivatives, and the prevalence of true allergic reactions to synthetic opioids is much lower. There is significant inter- and intraindividual variation in clinical responses to the various opioids, so dose titration is the best approach to initial management. Idiosyncratic responses may require trials of different agents in order to determine the most effective drug and route of delivery for any given patient. Table 4 lists more specific suggestions regarding optimal use of opioids.
Table 4. Choosing an Opioid: A Matrix of Factors Leading to a "First Best Choice"
General Pharmaco-Medical Considerations
Pharmaco-Clinical Considerations
Pharmacogenetic Considerations
Pharmacoeconomi Considerations
Allergies/sensitivities (e.g., morphine and its derivatives)
• Prior experience (subjective responses and preferences)• Adherence (compliance) issues• Social circumstances (cognitive capacity, reliable caregiver, etc.)
Cytochrome P-450 enzyme system genotypes (e.g., "slow metabolizers" at CYP 2D6 ineffectively convert the pro-drug codeine to the active drug morphine)
Insurance coverage and formulary restrictions
Drug-disease interactions (e.g., renal insufficiency; pulmonary disease)
Administration or absorption preferences and limitations (e.g., oral vs. transdermal formulation; once-a-day dosing vs. multiple dosings per day; G-tube "sprinkle" formulations)
Future possibilities of genotyping to match patient-specific opioid phenotypes to physiochemically different opioids
Indirect costs (e.g., care-giver time, utilization of clinical services, treatment of "side effects" such as constipation, etc.)
Drug-drug interactions (e.g., CNS depressants; MAOI's; SSRI's; shared metabolic pathways [i.e., inducers and inhibitors of at CYP2D6 and CYP3A4])
Monitor efficacy (e.g., activity, sleep, mood, pain intensity scores)


Monitor changes in clinical condition (e.g., resolution or progression of disease; new disease; change in medications)
Monitor adverse effects (e.g., sedation, nausea, bowel function, ataxia, cognitive effects, "tolerance"/hyperalgesia)


Originally published in: Fine PG. Opioid-induced hyperalgesia and opioid rotation. J Pain Palliat Care Pharmacother. 2004;18:75-79. Reprinted with permission from Haworth Press, Inc.
Opioid analgesics may accumulate toxic metabolites over time, especially when drug clearance and elimination decrease as disease progresses and organ function deteriorates.[63] Use of meperidine is specifically discouraged for chronic pain management due to its neurotoxic metabolite, normeperidine.[25] Use of propoxyphene (eg, Darvocet-N 100) is also discouraged due to the active metabolite norpropoxyphene, its weak analgesic efficacy, and the significant acetaminophen dose found in some formulations.[64] The mixed agonist-antagonist agents, typified by butorphanol, nalbuphine, and pentazocine, are not recommended for the treatment of chronic pain. They have limited efficacy, and their use may cause an acute abstinence syndrome in patients using pure agonist opioids.[39,65]
Morphine. Morphine, the prototype agonist, is considered the "gold standard" of opioid analgesics and is used as a measure for dose equivalence.[39,64] Although some patients cannot tolerate morphine due to pruritus, headache, dysphoria, or other adverse effects, common initial dosing effects, such as sedation and nausea, often resolve within a few days.[4] It is best to anticipate these adverse effects, especially constipation, nausea, and sedation, and prevent or treat appropriately (see below). Morphine-3-glucuronide, a metabolite of morphine, may contribute to myoclonus, seizures, and hyperalgesia, particularly when patients cannot clear the metabolite due to renal impairment.[63,66] Side effects and metabolite effects can be differentiated over time: Side effects generally occur soon after the drug is absorbed, whereas metabolite effects are generally delayed by several days. If adverse effects exceed the analgesic benefit of the drug, convert to an equianalgesic dose of a different opioid. Because cross-tolerance is incomplete, reduce the calculated dose by one third to one half and titrate upward based on the patient's pain intensity scores.[4]
Morphine's bitter taste may be prohibitive, especially if "immediate-release" tablets are left in the mouth to dissolve. In this case, several options are available. One available type of long-acting morphine comes in a capsule that can be opened, releasing small pellets that can be mixed in applesauce or other soft food.[67] Oral morphine solution can be swallowed, or small volumes (0.5-1 mL) of a concentrated solution (eg, 20 mg/mL) can be placed in the mouth of patients whose voluntary swallowing capabilities are significantly limited.[68]
Fentanyl. Fentanyl is a lipophilic opioid that can be administered parenterally, spinally, transdermally, transmucosally, and nebulized for the management of dyspnea.[4] Because of its potency, dosing is usually conducted in micrograms. It should be noted that on July 15, 2005, the FDA issued a public health advisory to alert healthcare professionals, patients, and their caregivers of reports of death and other serious side effects from overdoses of fentanyl in patients using transdermal fentanyl (Duragesic) for pain control.[69] Careful fentanyl dosing is particularly important in older patients; a recent study of transdermal fentanyl in postoperative patients found that absorption was significantly delayed in men 64-82 years of age compared with men 25-38 years of age.[70]
In consideration of the aforesaid cautions, transdermal fentanyl, often called the fentanyl patch, is particularly useful when patients cannot swallow, do not remember to take medications, or experience adverse effects from other opioids.[71] Opioid-naive patients should begin with titrated immediate-release opioids to establish the needed 24-hour dose of opioid before determining that the lowest available dose, currently a 12-mcg/hour patch, can be tolerated. Patients should be monitored by a responsible caregiver for the first 24-48 hours of therapy until steady-state blood levels are reached. Transdermal fentanyl may not be appropriate for patients with fever, diaphoresis, cachexia, morbid obesity, and ascites, all of which may have a significant impact on the absorption, blood levels, and clinical effects of the drug.[72,73]
Some patients experience reduced analgesic effects within 48 hours of applying a new patch. If so, determine whether a higher dose can be tolerated with increased duration of effect or whether a more frequent (every 48 h) patch change is the better alternative. Under most circumstances, breakthrough pain medications should be available to patients using continuous-release opioids, such as the fentanyl patch. There are several, novel transdermal fentanyl delivery systems under development, including ones that allow bolus dosing. There are insufficient data or experience to make recommendations about their relative safety or efficacy at this time.
Oral transmucosal fentanyl citrate (Actiq) is composed of fentanyl on an oral applicator ("lollipop") to provide rapid absorption of the drug. This formulation of fentanyl is particularly useful for breakthrough pain.
Oxycodone. Oxycodone is a synthetic opioid available in a long-acting formulation (OxyContin), as well as immediate-release tablets (alone or with acetaminophen) and liquid. It is approximately as lipid-soluble as morphine, but has better oral absorption.[74] Side effects appear to be similar to those experienced with morphine, but one study comparing the 2 formulations in patients with advanced cancer found that oxycodone was less likely to cause nausea and vomiting.[75] Despite significant media attention to oxycodone and its role in opioid abuse, there is no basis to infer that it is inherently "more addicting" than other opioids used in palliative care. Because of this attention, however, several states have restricted the numbers of tablets that can be distributed to an individual in a month.
Methadone. Methadone has several characteristics that make it useful in the management of severe, chronic pain.[39,76,77] Methadone has a half-life of 24-36 hours with a much longer terminal half-life, allowing for prolonged dosing intervals. Methadone is an N-methyl-D-aspartate (NMDA) receptor antagonist, which may be of particular benefit in neuropathic pain.[78,79] Methadone is much less costly than comparable doses of proprietary continuous-release formulations, making it potentially more available for patients without sufficient financial resources for more expensive drugs.
Despite these advantages, much is unknown about the appropriate dosing ratio between methadone and morphine, as well as the safest and most effective time course for conversion from another opioid to methadone.[4] Current data suggest that the dose ratio increases as the previous dose of oral opioid equivalents increases, and, although the long half-life is an advantage, it also increases the potential for drug accumulation prior to achieving steady-state blood levels.[80] There may be a risk of oversedation and respiratory depression after 2-5 days of treatment with methadone. Close monitoring of these potentially adverse or even life-threatening effects is required.[25,39] Myoclonus has been reported with methadone use, and recent studies suggest that high doses of methadone may lead to life-threatening QT interval prolongation (although it is not clear whether this is due to the methadone or preservatives in the parenteral formulation).[4]
Patients currently receiving methadone as part of a maintenance program for addictive disease often develop cross-tolerance to opioids and require higher doses than opioid-naive patients.[81] Prescribing methadone for addictive disease requires a special license in the United States, so prescriptions for methadone to manage pain in palliative care should specify "for pain."
Hydromorphone. Hydromorphone (Dilaudid) is a synthetic opioid that can be a useful alternative to morphine. It is available in oral tablets, liquids, suppositories, and parenteral formulations, but the only long-acting formulation was recently recalled by the FDA due to interactions with alcohol that could lead to excessively rapid drug release.[39,82] As a synthetic opioid, hydromorphone can be useful if there is inadequate pain control or when patients experience true allergic responses to morphine or intolerable side effects occur. The metabolite hydromorphone-3-glucuronide may lead to the same opioid neurotoxicity seen with morphine metabolites: myoclonus, hyperalgesia, and seizures.[83] This is particularly likely in patients with renal dysfunction.[84,85]
Other Opioids. Codeine, hydrocodone, levorphanol, oxymorphone, and tramadol are other opioids available in the United States for treatment of pain. See Table 5 for equianalgesic comparisons.
Table 5. Pure mu-Agonists Used for Pain in the United States*
Drug
Equianalgesic (mg) Doses†,‡
Half-life (hr)
Peak Effect (hr)
Duration (hr)
Toxicity
Comments
Morphine
10 IM/IV/SQ20-30 PO§
2-32-3
.5-11-2
3-43-6
Constipation, nausea, sedation most common; respiratory depression is rare when titrated to effect
Standard for comparison for opioids; multiple routes available
Controlled-release morphine
20-30 PO§
2-3
NA
8-12
Typical opioid effects
Brand name and generics available
Sustained-release morphine
20-30 PO§
2-3
4-6
12-24
Typical opioid effects
Once-a-day recently approved in the United States
Hydromorphone
1.5 IM/IV/SQ7.5 PO
2-32-3
.5-11-2
3-43-6
Typical opioid effects
Potency and high solubility may be beneficial for patients requiring high opioid doses and for SQ administration.
Oxycodone
20-30 PO
2-3
1-2
3-6
Typical opioid effects
Available as a single entity or combined with acetaminophen or NSAIDs
Controlled-release oxycodone
20-30 PO
NA
3-4
8-12
Typical opioid effects

Oxymorphone
1 IM/IV/SQ10 PR15 PO
NANA
.5-11.5-3
3-64-6
Typical opioid effects
Oral immediate releases and extended-release formulations under FDA review
Levorphanol
2 IM/IV/SQ4 PO
12-1512-15
.5-11-2
3-63-6
Typical opioid effects
With long half-life, accumulation possible after beginning or increasing dose
Methadone
Variable
12-150
1-2
6-8
Typical opioid effects
Highly variable half-life and potential for accumulation require greater vigilance for development of opioid toxicity; can prolong the QTc interval
Hydrocodone
30 PO
2-4
1-2
3-6
Typical opioid effects
Only available combined with acetaminophen or NSAIDs
Fentanyl
50-100 mcg IV/SQ
7-12
< 10 min
1-2
Typical opioid effects
Can be administered as a continuous IV or SQ infusion
Fentanyl transdermal system
NA
NA
12-24
48-72 per patch
Typical opioid effects
Refer to package for equianalgesic dosing guidelines for oral and parenteral medication. Not recommended for opioid-naive patients; not recommended for acute pain.
Oral transmucosal fentanyl citrate
NA
7-12
15-30 min
1-2
Typical opioid effects
Not recommended for opioid-naive patients. Recommended starting dose for breakthrough pain, 200-400 mcg, even with high "baseline" opioid doses
*Originally published in: Fine PG, Portenoy RK. A Clinical Guide to Opioid Analgesia. Minneapolis, Minn: McGraw-Hill Healthcare Information; 2004FDA = US Food and Drug Administration; IM = intramuscular; IV = intravenous; NA = not applicable or no data available; PO = by mouth; PR = per rectum; SQ = subcutaneous†Dose provides analgesia equivalent to 10 mg of morphine given by IM route. These ratios are useful guides when switching drugs or routes of administration. In clinical practice, the potency of the IM route is considered to be identical to the IV and SQ routes.‡When switching from one opioid to another, incomplete cross-tolerance requires a reduction in the dose of the new drug by 25% to 50% to prevent excessive opioid effects. Provision of "rescue" medication during the conversion period (a few days) prevents breakthrough pain that may result from relative underdosing. When switching to methadone from another drug, the reduction in the equianalgesic dose should be greater, usually 75% to 90%.§Extensive survey data suggest that the relative potency ratio of IM to PO morphine, which has been shown to be 1:6 in an acute dosing study, is 1:2 to 1:3 with chronic dosing.
Routes for Administering Opioids
The oral route is generally preferred when patients are capable and enteral absorption is not problematic. In the palliative care setting, alternative routes of administration must be available for patients who can no longer swallow or when other dynamics preclude the oral route. These include transdermal, transmucosal, rectal, vaginal, topical, epidural, and intrathecal. In a study of cancer patients at 4 weeks, 1 week, and 24 hours before death, over half of the patients required more than 1 route of opioid administration. As patients approached death and oral use diminished, the use of intermittent subcutaneous injections and intravenous or subcutaneous infusions increased.[11]
Enteral feeding tubes can be used to access the gut when patients can no longer swallow. The rectum, stoma, or vagina can be used to deliver medication, although fecal contents, mucosal dryness, thrombocytopenia, or painful lesions may preclude the use of these routes. For morphine, commercially prepared suppositories, compounded suppositories, or microenemas can be used to deliver the drug directly to the rectum or stoma.[86] Sustained-release morphine tablets have been used rectally, with resultant delayed time to peak plasma level and approximately 90% of the bioavailability achieved by oral administration. Because the vagina has no sphincter, a tampon covered with a condom or an inflated urinary catheter balloon may be used to prevent early discharge of the drug.[87] Although useful, the rectal or vaginal routes may be unacceptable to many patients and their caregivers, especially when the patient is obtunded or unable to assist.[5]
Parenteral administration in palliative care is usually limited to subcutaneous and intravenous delivery because repeated intramuscular opioid delivery is excessively noxious. The intravenous route provides rapid drug delivery but requires vascular access, which may not be easily obtained or maintained in a home or long-term care setting. In the absence of intravenous access, it must be remembered that subcutaneous boluses, although effective, have a slower onset and lower peak effect when compared with intravenous boluses.[4] Subcutaneous infusions as much as 10 mL/hour are usually absorbed, although most patients tolerate 2-3 mL/hour with least difficulty.[88,89]
Intraspinal routes, including epidural or intrathecal delivery, may allow administration of drugs, such as opioids, local anesthetics, and/or a-adrenergic agonists. A recent randomized, controlled trial demonstrated benefit for cancer patients experiencing pain.[90] However, the equipment used to deliver these medications is complex, requiring specialized knowledge for healthcare professionals and potentially greater caregiver burden. Risk of infection and other complications along with upfront and maintenance costs are significant concerns when contemplating high-technology procedures. Selection should be based on greater than 6 months life expectancy for implanted programmable pumps, and adequate organizational infrastructure to manage these devices should be in place.
Adjuvant Therapies
The term "adjuvant analgesics" is often used synonymously with "coanalgesics," "pain-modifying drugs," and similar descriptives. A wide variety of nonopioid medications from several pharmacologic classes have been demonstrated to reduce pain caused by various pathologic conditions (eg, tricyclic antidepressants) or to modify the ongoing disease process in a way that specifically reduces pain (eg, bisphosphonates). Under most circumstances, these drugs are indicated for the treatment of severe neuropathic pain or bone pain, and opioid analgesics are used concurrently to provide adequate pain relief. Typical adjuvants include tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants, anticonvulsants, corticosteroids, and other disease-modifying drugs, such as bisphosphonates for metastatic bone pain. See Table 6 for a listing of current adjuvant therapies for neuropathic pain.
Table 6. Adjuvant Therapies for Neuropathic Pain*
Category/Agents
Comments
Corticosteroids
DexamethasonePrednisonePrednisolone
Shown to reduce spontaneous discharge in injured nerves
Dexamethasone has the least mineralcorticoid effect (long duration of action for once-daily dosing)
May be dosed orally, intravenously, subcutaneously, or epidurally
May produce psychosis, proximal muscle wasting
Anticonvulsants
CarbamazepineGabapentinValproatePhenytoinClonazepamTiagabineLevetiracetamLamotrigineTopiramateZonisamideOxcarbazepinePregabalin
Older agents are used extensively, but potential for adverse events requires careful monitoring. Clinical experience is extensive for carbamazepine, but propensity for bone marrow suppression (ie, leukopenia) limits its use in patients with cancer
Lamotrigine has demonstrated efficacy in HIV sensory neuropathy, painful diabetic neuropathy, and poststroke pain, but requires slow titration. Also associated with Stevens-Johnson syndrome and severe rash
The role of newer agents (ie, levetiracetam, oxcarbazepine, tiagabine, etc) has not been established
Gabapentin approved for PHN
Pregabalin approved for painful diabetic neuropathy.
Tricyclic antidepressants
AmitriptylineNortriptylineDesipramineImipramineClomipramine
Use is associated with significant tolerability issues
Nortriptyline has lesser anticholinergic/anti-alpha-adrenergic effects, and therefore has better tolerability, especially in elderly persons
Should be administered at night to reduce daytime sedation and support good sleep hygiene
Local anesthetics
MexiletineLidocaine IV
Oral lidocaine analogs are effective in some patients, but long-term use may lead to clinically significant adverse events
Infusional lidocaine is gaining greater acceptance; may be particularly effective for visceral or central pain
A lidocaine challenge can assess whether a patient's pain is responsive; ie, 1-3 mg/kg IV or SC over 30-60 min. If challenge is effective or partially effective, continuous infusion consists of 1-2 mg/kg/hr
Perioral numbness suggests toxicity. Infusion should be halted and restarted at a slower rate upon resolution
Anticancer therapies
Radiation therapy
Local, half-body, or whole-body radiation therapy can enhance efficacy of analgesia by directly affecting tumor and other causes of pain
Surgery
Curative excision or palliative debulking of tumor may relieve pain directly, decrease symptoms of obstruction or compression, and improve prognosis
*Adapted and reprinted with permission from: Fine PG, Miaskowski C, Paice JA. Meeting the challenges in cancer pain. J Support Oncol. 2004;2(suppl4):5-22
Antidepressants. The analgesic effect of tricyclic antidepressants appears to be related to inhibition of norepinephrine and serotonin reuptake, making these neurotransmitters more available within central nervous system pain inhibitory pathways. There are many significant, controlled clinical trials for several pain conditions, and a recent consensus panel listed tricyclic antidepressants as 1 of 5 first-line therapies for neuropathic pain.[91,92] The significant side effects, especially in older patients, limit the use of these agents in palliative care, but their sleep-enhancing and mood-elevating effects may be beneficial enough to outweigh their disadvantages.[93] The newer mixed SNRIs-selective serotonin reuptake inhibitors (SSRIs), such as venlafaxine (Effexor) and duloxetine (Cymbalta), may offer some of the advantages of tricyclic antidepressants without the anticholinergic side effects.[39]
Anticonvulsants. The older anticonvulsants, such as carbamazepine and clonazepam, relieve pain by blocking sodium channels.[93] These compounds are very useful in the treatment of neuropathic pain, especially pain with episodic, lancinating qualities. Gabapentin seems to have several different mechanisms of action, although calcium ion channel blockade is thought to be its main pain-inhibiting mechanism.[94,95]
The analgesic doses of gabapentin reported to relieve pain in non-end-of-life pain conditions ranged from 900 mg/day to 3600 mg/day in divided doses.[4] A common reason for inadequate relief is failure to titrate upward after prescribing the usual starting dose of 100 mg by mouth 3 times daily. Additional evidence supports the use of gabapentin in neuropathic pain syndromes seen in palliative care, such as thalamic pain, pain due to spinal cord injury, cancer pain, and restless legs syndrome and HIV-associated sensory neuropathies.[23,95,96] Withdrawal from gabapentin should be gradual to prevent possible seizures.[97] Lamotrigine has been effective in HIV-associated neuropathy, diabetic neuropathy, and poststroke pain. It requires slow titration and may have prohibitive side effects, such as Steven-Johnson syndrome and severe rash.[23] Newer anticonvulsants that have been used successfully in treating neuropathies include levetiracetam, tiagabine, and oxcarbazepine, but no randomized, controlled clinical trials are available.[23]
Corticosteroids. Corticosteroids are particularly useful for neuropathic, visceral, and bone pain syndromes, including plexopathies and pain associated with stretching of the liver capsule due to metastases.[98,99] Dexamethasone produces the least amount of mineralocorticoid effect, making it the least toxic choice. Dexamethasone is available in oral, intravenous, subcutaneous, and epidural formulations. The standard dose is 16-24 mg/day and can be administered once daily due to the long half-life of this drug, but divided doses are usually used to mitigate high-dose toxic effects, such as psychosis and severe blood sugar abnormalities in diabetic patients. Doses as high as 100 mg may be given with severe pain crises, similar to the doses used in acute neurologic emergencies. Intravenous bolus doses should be administered over several minutes to reduce untoward reactions, such as burning sensations.
Local Anesthetics. Local anesthetics are useful for relieving neuropathic pain. They can be given orally, topically, intravenously, subcutaneously, or spinally.[23,100] Mexiletine has been reported to be useful when anticonvulsants and other adjuvant therapies have failed. Doses start at 150 mg/day and increase to levels as high as 900 mg/day in divided doses.[101,102] Pretreatment electrocardiogram evaluation is recommended to evaluate for conduction blocks that can be exacerbated by oral local anesthetics. Local anesthetic gels and patches have been used to prevent the pain that is associated with needlestick and other minor procedures. Both gel and patch (Lidoderm) versions of lidocaine have been shown to reduce the pain of postherpetic neuralgia.[103] Intravenous lidocaine at 1-5 mg/kg (maximum, 500 mg) administered over 1 hour, followed by a continuous infusion of 1-2 mg/kg/hour, has been reported to reduce intractable neuropathic pain in patients in inpatient palliative care and home hospice settings.[23] Epidural or intrathecal lidocaine or bupivacaine delivered with an opioid can reduce neuropathic pain.[104]
Bisphosphonates. Bisphosphonates inhibit osteoclast-mediated bone resorption and alleviate pain related to metastatic bone disease and multiple myeloma, reduce the incidence of pathologic fractures, and are used to treat tumor-related hypercalcemia.[105] In patients with breast cancer and multiple myeloma, zoledronic acid has demonstrated improved safety and efficacy compared with pamidronate.[106,107] Similarly, there appears to be more sustained pain relief with zoledronic acid compared with other bisphosphonates in patients with metastatic prostate cancer.[108] Clinical trials in patients with lung and renal cell carcinoma have also shown therapeutic benefit from regular infusions of zoledronic acid.[109]
Calcitonin. Subcutaneous calcitonin may be effective in the relief of neuropathic or bone pain, although studies are inconclusive.[110] The nasal form of this drug may be more acceptable in end-of-life care when other therapies are ineffective. Usual doses are 100-200 IU/day subcutaneously or nasally.
Chemotherapy and Radiation Therapy. Palliative chemotherapy is the use of antitumor therapy to relieve the symptoms that are associated with malignancy. Patient goals, performance status, sensitivity of the tumor, and potential toxicities must be considered.[4] Examples of symptoms that may improve with chemotherapy include relief of chest wall pain from reduced tumor ulceration through the use of hormonal therapy in breast cancer. Similarly, newer agents, such as docetaxel, reduce pain and improve quality of life in hormone-refractory prostate cancer, and topotecan and epidermal growth factor receptor inhibitors accomplish similar results for patients with lung cancers.[111-113]
Radiation therapy is also a highly useful adjunct to control pain from bone metastasis and pressure-inducing and ulcerative malignancies. Single-fraction and hypofractionated regimens are proving to be effective in very sick patients and those with limited life expectancy in whom the opportunity costs of multiple treatment sessions are untenable.[114,115] These therapies are often underutilized in hospice/palliative care, and they should be considered for any patient with a life expectancy of more than a few weeks.[116]
Other Adjunct Analgesics. Topical capsaicin has been shown to be useful in relieving the pain that is associated with postmastectomy syndrome, postherpetic neuralgia, and postsurgical neuropathic pain in cancer.[98] A burning sensation experienced by patients is a common reason for discontinuing therapy.
Baclofen, a skeletal muscle relaxant, is also useful for the relief of spasm-associated pain, and it may be helpful in the treatment of intractable hiccups, which can be painful and cause sleep disturbance.[117] Doses begin at 10 mg/day, increasing every few days. Feelings of weakness and confusion or hallucinations often occur with doses above 60 mg/day. Slow downward titration is necessary to prevent withdrawal-related seizures.
Calcium channel blockers are believed to provide pain relief in certain pain syndromes as well. For instance, nifedipine 10 mg orally may be useful to relieve ischemic or neuropathic pain syndromes.[118,119] There are few randomized, controlled clinical trials to support these mostly anecdotal findings.
Beginning Therapy, Adding or Changing Drugs, and Breakthrough Pain
Application of practical and mechanism-based approaches, coupled with context-appropriate follow-up, will optimize drug and other palliative therapies. The "best first choice" and subsequent timing of opioid rotation will depend on patient-specific medical, psychological, and social considerations and a sound knowledge of opioid pharmacotherapy. Titration and combining drugs that may provide additive or synergistic effects should proceed along rational lines, based on the pharmacokinetics and monitored pharmacodynamics of the drugs. Frail patients and those with pain crises may require observation in a monitored setting in order to provide safe and effective relief within an acceptable time frame.
Transitory flares of pain, or "breakthrough pain," can be expected both at rest and during movement. If breakthrough pain lasts longer than a few minutes, rescue doses of the patient's current analgesics may provide relief.[25] In patients without parenteral access, oral transmucosal fentanyl may be useful for rapid episodic pain relief or during a brief but painful dressing change. Adults should start with the 200-mcg dose and monitor efficacy, advancing to higher dose units as needed.[120] Clinicians must be aware that, unlike other breakthrough pain drugs, the around-the-clock dose of opioid does not predict the effective dose of oral transmucosal fentanyl. Pain relief can usually be expected in about 5-10 minutes after beginning use. Patients should use oral transmucosal fentanyl citrate over a period of 15 minutes because more active sucking will result in more swallowing and less transmucosal absorption.
Because misunderstandings lead to undertreatment, all clinicians involved in the care of patients with chronic pain must be able to differentiate the clinical conditions of tolerance, physical dependence, and addiction that come with the use of opioids. It is also critically important to be aware that titration of opioid analgesics to affect pain relief is rarely associated with induced respiratory depression and iatrogenic death. The most compelling evidence suggests that inadequate pain relief hastens death by increasing physiologic stress, decreasing immunocompetence, diminishing mobility, increasing the potential for thromboembolism, worsening respiratory effort and thus placing the patient at risk for pneumonia, and increasing myocardial oxygen requirements. In a recent survey of high-dose opioid use (> 299 mg of oral morphine equivalents) in a hospice setting, there was no relationship between opioid dose and survival.[121]
Minimizing and Managing Adverse Effects
There are a variety of adverse effects that drugs for pain can cause patients in palliative care. The normal side effects associated with pain relief medications are often exacerbated by changes in metabolism caused by end-stage disease, polypharmacy associated with old age, and other factors. Below are some of the more common adverse effects seen for these patients, and an overview of possible approaches to preventing or alleviating them.
Constipation. Patients in palliative care frequently experience constipation, in part due to opioid therapy.[44] Always begin a prophylactic bowel regimen when commencing opioid analgesic therapy. Avoid bulking agents, such as psyllium, because these tend to increase desiccation time in the large bowel, and debilitated patients can rarely take in sufficient fluid to facilitate the action of bulking agents. Instead use cost-effective and palatable products, such as senna tea and fruit.[39] If this is ineffective at creating regular laxation, then prescription therapies are indicated (eg, bisacodyl, senna derivatives, etc). Tables listing recommended regimens are readily available in clinical guidelines and texts.
Sedation. Excessive sedation may occur with the initial doses of opioids. If sedation persists after 24-48 hours and other correctable causes have been identified and treated, the use of psychostimulants may be beneficial. These include dextroamphetamine 2.5-5 mg by mouth every morning and midday or methylphenidate 5-10 mg by mouth every morning and 2.5-5 mg midday (although higher doses are frequently used, and use later in the day may be required for wakefulness throughout the evening hours, if desired).[4] Adjust both the dose and timing to prevent nocturnal insomnia, and monitor for undesirable psychotomimetic effects (such as agitation, hallucinations, and irritability). Once-daily dosing of modafinil, a newer agent approved to manage narcolepsy, has been reported to relieve opioid-induced sedation.[122]
Respiratory Depression. Respiratory depression is rarely a clinically significant problem for opioid-tolerant patients who are in pain.[39] When respiratory depression occurs in a patient with advanced disease, the cause is usually multifactorial.[123,124] When depressed consciousness occurs along with a respiratory rate less than 8/minute or hypoxemia (O2 saturation less than 90%) associated with opioid use, slow, cautious titration of naloxone should be instituted (0.4 mcg every 3-5 minutes while providing respiratory support and supplemental oxygen). Excessive administration may cause abrupt opioid reversal with pain and autonomic crisis.
Nausea and Vomiting. Nausea is common and vomiting is an occasional adverse effect associated with opioids due to activation of the chemoreceptor trigger zone in the medulla, vestibular sensitivity, and delayed gastric emptying, but habituation occurs in most cases within several days.[125] Assess for other treatable causes. In severe cases or when nausea and vomiting are not self-limited, pharmacotherapy is indicated. Usually, low doses of an H1 blocker (eg, diphenhydramine) are all that is required while the patient habituates to this unpleasant side effect. If there is no relief within a few days, a different opioid is recommended; also consider transdermal rather than enteral therapy.
Myoclonus. Myoclonic jerking can occur with high-dose opioid therapy.[39] If myoclonus develops, switch to an alternate opioid, especially if using morphine. Evidence suggests that this symptom is associated with metabolite accumulation, particularly in the face of renal dysfunction.[4] A lower relative dose of the substituted drug may be possible, due to incomplete cross-tolerance. Clonazepam 0.5-1 mg by mouth every 6-8 hours, to be increased as needed and tolerated, may be useful in treating myoclonus in patients who are still alert, able to communicate, and take oral preparations.[126] Lorazepam can be given sublingually if the patient is unable to swallow. Otherwise, parenteral administration of diazepam is indicated if symptoms are distressing. Grand mal seizures associated with high-dose parenteral opioid infusions have been reported and may be due to preservatives in the solution.[127] Preservative-free solutions should be used when administering high-dose infusions.
Pruritus. Pruritus can occur with most opioids, although it appears to be most common with morphine. Fentanyl and oxymorphone may be less likely to cause histamine release. Most antipruritus therapies cause sedation, so the patient must see this as an acceptable trade-off. Antihistamines (such as diphenhydramine) are the most common first-line approach to this opioid-induced symptom when treatment is indicated. Ondansetron and paroxetine have been reported to be effective in relieving opioid-induced pruritus, but no randomized, controlled studies exist.[128,129]
After examination and consultation, it is determined that Jerry can continue to live in the assisted living facility, attended to by home-based hospice staff. Treatment proceeded with subcutaneous administration of octreotide and hydromorphone to relieve bowel symptoms and provide analgesia on an as-needed basis. In this way, the unpleasantness of nasogastric suctioning, nausea, and vomiting was avoided, and the patient was able to die in a manner consistent with his preferences.
Summary
In summary, effective pain management in advanced medical illness and at the end of life is a critical component of quality medical care to ensure a dignified, safe, and comfortable dying. To quote Sir William Osler, the "father" of modern medicine, "The study of morbid anatomy combined with careful clinical observations has taught us to recognize our limitations and to accept the fact that a disease itself may be incurable and that the best we can do is to relieve symptoms and make the patient comfortable.[130]"
Principles to help improve this important domain of clinical care can be summarized with the following key points regarding pharmacotherapy for the relief of pain in far-advanced illness.
Principles of Effective Pain Management
Determine the etiology of pain and the social and prognostic circumstances that will affect the pain experience and pain therapy.
Focus on discernible clinical end points:
Pain reduction
Functional capacities
Mood
Sleep
Relationships
Pleasure in living
Match the mechanism of pain with the class of drug whenever possible; initiate therapy and adjust dose according to therapeutic response, side effects, and known pharmacokinetics of the drug.
Anticipate and monitor for adverse effects:
Prevent side effects
Actively treat side effects
Acetaminophen should be the first consideration in the treatment of mild-to-moderate pain of musculoskeletal origin.
Use adjunctive drug therapies, especially for neuropathic pain.
Opioid analgesic drugs are often necessary to relieve moderate-to-severe pain, and long-acting or sustained-release analgesic preparations should be used for continuous pain.
Breakthrough pain should be identified and treated by the use of fast-onset, short-acting preparations.
Lastly, and perhaps most importantly, know your limits. When a patient is not responding to therapy, be prepared to consult with someone who has more training, expertise, and experience.
Original content for this activity was supported by VistaCare and National Hospice and Palliative Care Organization.
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Author
Perry G. Fine, MD
Professor of Anesthesiology, University of Utah, Salt Lake City; Attending Physician, Pain Management Center, University of Utah, Salt Lake CityDisclosure: Perry G. Fine, MD, has disclosed that he owns stock in and is a board member and consultant for VistaCare.
Editor
Susan Yox, RN, EdD
Editorial Director, Medscape Nurses, New York, NYDisclosure: Susan Yox has disclosed no relevant financial relationships.
Writer
Clarinda Mac Low
Freelance Writer, Medscape and others, New York, NYDisclosure: Clarinda Mac Low has disclosed no relevant financial relationships.
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