Pain

Pain is defined by the International Association for the Study of Pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Although pain is a sensation in the body, it is always unpleasant and therefore can be considered an emotional experience. Based on this definition, activity induced in the nociceptor per se is clearly not pain, because the nociceptive signal must be processed in the brain and consciously appreciated before it can be called pain. This fact must be taken into account when translating basic pain research findings into clinical applications. For example, a discrepancy exists between basic and clinical research in that most basic research studies use evoked pain or reflex behaviors as their primary outcome measures, although usually the spontaneous pain is the primary problem in the clinical situation.

The rates of persistent pain in people who have multiple sclerosis range from 43% to 79%. Among people who have spinal cord injuries, the reported prevalence of pain is similar and ranges between 26% to 96% ; however, many large-scale studies report frequencies around two thirds. Similarly, pain and fatigue have been reported by most people experiencing post-polio syndrome.

Pain can be divided into two general categories regardless of the underlying medical condition: nociceptive, which is pain caused by activation of specific pain receptors (ie, nociceptors), and neuropathic, which is pain initiated or caused by a primary lesion or dysfunction in the nervous system. Nociceptive pain is usually experienced as being located in a region of sensory preservation and may be described as dull, aching, and cramping. In contrast, neuropathic pain is usually located in a region of sensory dysfunction and may be described as sharp, shooting, electric, or burning. Neuropathic pain is often associated with sensory deficits and abnormal sensory phenomena, such as allodynia or hyperalgesia. Allodynia is pain that is evoked by a normally innocuous (nonpainful) stimulus, such as touch, cooling, or warmth. Hyperalgesia is pain that is felt as abnormally intense when evoked by a mild to moderately intense nociceptive stimulus. Both hyperalgesia and allodynia can be evoked by thermal or mechanical stimuli.

The classification of pain into specific pain types is based on a combination of pain characteristics (eg, pain locations and various pain descriptors) and injury characteristics, if applicable (eg, level of injury). Recently, Treede and colleagues suggested revising the definition of neuropathic pain to “pain, arising as a direct consequence of a lesion or disease affecting the somatosensory system.” Because the diagnosis of neuropathic pain is not always straightforward, they also suggested including a grading system of “definite,” “probable,” and “possible” neuropathic pain with specific criteria, including the presence of symptoms such as hyperalgesia and allodynia.

Fatigue

For healthy people, the experience of fatigue can be a positive one, reflecting a normal response to a busy day or period of exercise. This type of fatigue can be remediated with rest. However, for people who are aging with a physical impairment or have a chronic health condition, fatigue is often a multidimensional, disabling, and negative symptom that significantly disrupts everyday life. Fatigue is a common problem among several groups of people who may experience aging and physical disability concurrently, such as people who have multiple sclerosis, late-effects polio, spinal cord injury, muscular dystrophy, and stroke.

Fatigue has many definitions, ranging from broad, subjective ones (eg, overwhelming sense of tiredness, subjective lack of physical or mental energy) to others that are narrow, objective, and physiologically based (eg, exercise-induced reduction in maximal voluntary muscle force). Fatigue has also been described as a common, protective response to reduce the likelihood of individuals engaging in an activity beyond their functional reserve, either physically or mentally. Ultimately, fatigue “may be best characterized as the absence of energy and the mind-body response to that absence.”

Among some populations, fatigue may be one of the major presenting symptoms of the disease process. When fatigue can be directly attributed to the disease state, it is labeled primary fatigue. In multiple sclerosis, primary fatigue may be related to lesion load, immune activation, neuroendocrine involvement, and/or peripheral abnormalities. Among people who have late-effects polio, primary fatigue is believed to be a function of the extra demands and resulting overload placed on surviving motor neuron units. The extent of injury (ie, full or partial) may be a factor in the primary fatigue of people who have spinal cord injury, with partial injury contributing to greater fatigue.

Many other factors, not directly related to the disease process itself, may also contribute to fatigue. This secondary fatigue is associated with inefficient movement patterns or cardiorespiratory functions, deconditioning, sleep problems, medication side effects, depression, pain, nutritional deficiencies, or chronic infections. Because many secondary factors can contribute to fatigue, health care providers must conduct comprehensive assessments to identify and remediate as many of them as possible.

The distinction between primary and secondary fatigue is only one way to conceptualize fatigue. Other conceptualizations include acute versus chronic, experienced versus physiologic, and physical versus cognitive. Acute fatigue has a recent onset and a short duration, and is usually produced by physical activity. It can typically be remediated through appropriate rest.

Generally, acute fatigue is not considered disabling, whereas chronic fatigue is disabling. It is often unrelated to physical activity, is not fully resolved with rest, and tends to be more generalized (physical, cognitive, and emotional components). The point at which fatigue is considered chronic varies according to diagnosis. Among people who have multiple sclerosis, fatigue lasting more than 6 weeks is considered chronic. However, in people who have many other potentially disabling diagnoses, such as congestive heart failure, diabetes, sleep apnea, rheumatoid arthritis, depression, and late-effects polio, fatigue lasting more than 6 months is considered chronic.

Experienced fatigue reflects the subjective experience, such as severity and impact on daily life. Prevalence of severe fatigue as measured by an average score of 4 or greater on the Fatigue Severity Scale was reported in 74% of people who had multiple sclerosis (N = 9205). In much smaller studies of people who had spinal cord injury (N = 76), muscular dystrophy (N = 200), and stroke (N = 40), rates of severe fatigue using this same scale were reported as 57%, 62%, and 30%, respectively.

In comparison to the subjective nature of experienced fatigue, physiologic fatigue captures exercise-induced muscle weakness or fatigability, and reflects reduction in maximal voluntary muscle force. It has both central and peripheral components, and is common in people who have neuromuscular disorders. Central fatigue is also linked to subjective feelings of exhaustion, and difficulties with alertness and arousal.

Pain

Aging is associated with several common comorbidities that in combination may decrease physical function and increase disability. For example, a large-scale study in persons aged 85 to 105 years showed that the presence of persistent pain was predictive of functional limitations, fatigue, sleeping problems, depressed mood, and a decreased quality of life. Similarly, lower scores on the physical subscale of the Medical Outcomes Study 36-item Short Form Survey were significantly associated with increased frequencies of common diseases, such as congestive heart failure, chronic lung disease, and arthritis, however, the associations were more pronounced between the physical function scores and common symptoms such as muscle weakness, pain, and shortness of breath in older adults.

Another large-scale study in older individuals showed that approximately 50% experience pain that interferes with physical and psychological functioning, and that the severity and chronicity of pain are the primary determinants for this interference. Similarly, a study in women showed that sleep problems, pain, and visual and hearing impairments increased significantly with age. Studies also suggest that the effects of pain on distress and disability may be less pronounced in older adults than in younger cohorts, possibly because older adults either underreport pain or see it as part of the aging process, or because they have acquired better pain coping skills.

Emotional distress, such as depression, anxiety and anger, is intimately linked to the experience of chronic pain in various heterogeneous populations. Thus, in people with physical impairments, persistent pain is yet another significant burden that contributes to increased psychological distress and disability. Although it may be difficult to interpret the influence of pain on emotional functioning in a person who has a physical impairment, this domain must be evaluated because it is central to individuals’ assessment of their well-being and satisfaction with life.

The term pain interference refers to the extent that pain hinders or interferes with common activities of daily life. Persistent pain naturally increases disability through limiting a person’s ability to perform and participate in daily activities. For example, pain interfering with the performance of daily activities can result in decreased independence, ultimately leading to affective distress. In fact, high levels of pain interference assessed by the spinal cord injury (SCI) version of the Multidimensional Pain Inventory, rather than the severity of pain, were predictive of decreased life satisfaction in 161 persons who had SCI and chronic pain. The extent to which chronic pain specifically (distinct from physical impairments) hinders or interferes with activities of daily life may be more important than general physical function in populations experiencing physical impairment. Furthermore, when an individual is aging, the capacity to deal with added physical and emotional stress imposed by persistent pain and an underlying disease is reduced and may result in additional disability.

Up to 60% of people who have multiple sclerosis, SCI, and post-polio syndrome experience fatigue severe enough to interfere with daily activities. Research shows that pain and fatigue are common comorbidities in diseases affecting the nervous and muscular systems, such as post-polio syndrome, muscular dystrophy, and cancer, and in older people. The combination of pain and fatigue was associated with an increased degree of disability in older individuals who had experienced a stroke.

The relationship between sleep problems and disability in persons who have persistent pain is not straightforward. Although poor quality of sleep has been shown to be significantly related to pain-related disability and depression, these relationships may be primarily mediated by the severity of pain and by depression. Additionally, although sleep problems are often considered a consequence of chronic pain, some studies suggest that the relationship between pain and sleep may be bidirectional.

Fatigue

Although acute fatigue can typically be remedied by a short rest or a good night’s sleep, chronic fatigue typically does not resolve with these strategies alone. For this reason, individuals who have chronic fatigue often stop performing important and valued activities in their everyday lives, including instrumental activities of daily living (eg, shopping, home management responsibilities), employment, socializing, and other leisure interests, which often contributes to reductions in quality of life and overall life satisfaction. Among people who have multiple sclerosis and muscular dystrophy, fatigue has been identified as a major factor in the inability to maintain employment.

In a mixed sample of 961 adults with a mean age of 43.6 years (SD = 10.2), 25 different adjectives were used to describe fatigue. Using principal components analysis, the authors identified four factors: frustrating, exhausting, pleasant, and frightening, which explained 24%, 9%, 6%, and 5% of the variance, respectively. Healthy controls and individuals who did not report fatigue were significantly more likely to report fatigue as pleasant than those who reported fatigue caused by chronic fatigue syndrome, neuromuscular disorders, pancreatitis, or cancer. People who had unexplained fatigue were more likely to report fatigue as frightening than those who had chronic disease.

These descriptions are consistent with findings from qualitative research involving people who had multiple sclerosis, muscular dystrophy, and SCI. Among people who had multiple sclerosis, fatigue has been described as frustrating, overwhelming, and disabling. People who had SCI used similar descriptors for their fatigue and also identified it as stressful. People who had muscular dystrophy linked fatigue to feebleness and lack of initiative.

For people who have multiple sclerosis, fatigue contributes to redefinitions of work and the need to prioritize everyday tasks, find and use resources, plan in advance, and develop and evaluate strategies to change how tasks get completed. However, making change is not easy, because it requires disclosure to others who often do not understand the fatigue experience, or requires simply deciding that some tasks will not get done. Similarly, people who have SCI have described how fatigue leads to prioritization of tasks and the need to reduce or eliminate recreational, leisure, and other pleasant activities from their daily life because of lack of energy. Curtailing pleasant activities contributes to stress, depression, and increased fatigue, creating a vicious cycle.

The findings of two recent longitudinal studies of fatigue among patients who had multiple sclerosis indicate the complexity and variability of this symptom over time, and raise questions about how its impact may also vary over time. Both studies used the Fatigue Severity Scale for assessment; one used it every 6 months for 2 years and the other every year for 3 years. Across the two studies, one fifth to one quarter of participants were nonfatigued throughout the study period, but 25% to 38% experienced persistent fatigue. Factors associated with increased fatigue over time included depressive symptoms, weak/moderate sense of coherence, living with a partner, and not working. Factors associated with persistent or sporadic fatigue over time included depression, heat sensitivity, and physical impairment. Together with literature about how fatigue influences everyday life, these longitudinal studies indicate the need for more nuanced investigations of fatigue and its impact on health and functioning.

Pain

Aging is associated with several common comorbidities that in combination may decrease physical function and increase disability. For example, a large-scale study in persons aged 85 to 105 years showed that the presence of persistent pain was predictive of functional limitations, fatigue, sleeping problems, depressed mood, and a decreased quality of life. Similarly, lower scores on the physical subscale of the Medical Outcomes Study 36-item Short Form Survey were significantly associated with increased frequencies of common diseases, such as congestive heart failure, chronic lung disease, and arthritis, however, the associations were more pronounced between the physical function scores and common symptoms such as muscle weakness, pain, and shortness of breath in older adults.

Another large-scale study in older individuals showed that approximately 50% experience pain that interferes with physical and psychological functioning, and that the severity and chronicity of pain are the primary determinants for this interference. Similarly, a study in women showed that sleep problems, pain, and visual and hearing impairments increased significantly with age. Studies also suggest that the effects of pain on distress and disability may be less pronounced in older adults than in younger cohorts, possibly because older adults either underreport pain or see it as part of the aging process, or because they have acquired better pain coping skills.

Emotional distress, such as depression, anxiety and anger, is intimately linked to the experience of chronic pain in various heterogeneous populations. Thus, in people with physical impairments, persistent pain is yet another significant burden that contributes to increased psychological distress and disability. Although it may be difficult to interpret the influence of pain on emotional functioning in a person who has a physical impairment, this domain must be evaluated because it is central to individuals’ assessment of their well-being and satisfaction with life.

The term pain interference refers to the extent that pain hinders or interferes with common activities of daily life. Persistent pain naturally increases disability through limiting a person’s ability to perform and participate in daily activities. For example, pain interfering with the performance of daily activities can result in decreased independence, ultimately leading to affective distress. In fact, high levels of pain interference assessed by the spinal cord injury (SCI) version of the Multidimensional Pain Inventory, rather than the severity of pain, were predictive of decreased life satisfaction in 161 persons who had SCI and chronic pain. The extent to which chronic pain specifically (distinct from physical impairments) hinders or interferes with activities of daily life may be more important than general physical function in populations experiencing physical impairment. Furthermore, when an individual is aging, the capacity to deal with added physical and emotional stress imposed by persistent pain and an underlying disease is reduced and may result in additional disability.

Up to 60% of people who have multiple sclerosis, SCI, and post-polio syndrome experience fatigue severe enough to interfere with daily activities. Research shows that pain and fatigue are common comorbidities in diseases affecting the nervous and muscular systems, such as post-polio syndrome, muscular dystrophy, and cancer, and in older people. The combination of pain and fatigue was associated with an increased degree of disability in older individuals who had experienced a stroke.

The relationship between sleep problems and disability in persons who have persistent pain is not straightforward. Although poor quality of sleep has been shown to be significantly related to pain-related disability and depression, these relationships may be primarily mediated by the severity of pain and by depression. Additionally, although sleep problems are often considered a consequence of chronic pain, some studies suggest that the relationship between pain and sleep may be bidirectional.

Fatigue

Although acute fatigue can typically be remedied by a short rest or a good night’s sleep, chronic fatigue typically does not resolve with these strategies alone. For this reason, individuals who have chronic fatigue often stop performing important and valued activities in their everyday lives, including instrumental activities of daily living (eg, shopping, home management responsibilities), employment, socializing, and other leisure interests, which often contributes to reductions in quality of life and overall life satisfaction. Among people who have multiple sclerosis and muscular dystrophy, fatigue has been identified as a major factor in the inability to maintain employment.

In a mixed sample of 961 adults with a mean age of 43.6 years (SD = 10.2), 25 different adjectives were used to describe fatigue. Using principal components analysis, the authors identified four factors: frustrating, exhausting, pleasant, and frightening, which explained 24%, 9%, 6%, and 5% of the variance, respectively. Healthy controls and individuals who did not report fatigue were significantly more likely to report fatigue as pleasant than those who reported fatigue caused by chronic fatigue syndrome, neuromuscular disorders, pancreatitis, or cancer. People who had unexplained fatigue were more likely to report fatigue as frightening than those who had chronic disease.

These descriptions are consistent with findings from qualitative research involving people who had multiple sclerosis, muscular dystrophy, and SCI. Among people who had multiple sclerosis, fatigue has been described as frustrating, overwhelming, and disabling. People who had SCI used similar descriptors for their fatigue and also identified it as stressful. People who had muscular dystrophy linked fatigue to feebleness and lack of initiative.

For people who have multiple sclerosis, fatigue contributes to redefinitions of work and the need to prioritize everyday tasks, find and use resources, plan in advance, and develop and evaluate strategies to change how tasks get completed. However, making change is not easy, because it requires disclosure to others who often do not understand the fatigue experience, or requires simply deciding that some tasks will not get done. Similarly, people who have SCI have described how fatigue leads to prioritization of tasks and the need to reduce or eliminate recreational, leisure, and other pleasant activities from their daily life because of lack of energy. Curtailing pleasant activities contributes to stress, depression, and increased fatigue, creating a vicious cycle.

The findings of two recent longitudinal studies of fatigue among patients who had multiple sclerosis indicate the complexity and variability of this symptom over time, and raise questions about how its impact may also vary over time. Both studies used the Fatigue Severity Scale for assessment; one used it every 6 months for 2 years and the other every year for 3 years. Across the two studies, one fifth to one quarter of participants were nonfatigued throughout the study period, but 25% to 38% experienced persistent fatigue. Factors associated with increased fatigue over time included depressive symptoms, weak/moderate sense of coherence, living with a partner, and not working. Factors associated with persistent or sporadic fatigue over time included depression, heat sensitivity, and physical impairment. Together with literature about how fatigue influences everyday life, these longitudinal studies indicate the need for more nuanced investigations of fatigue and its impact on health and functioning.

Pain

Because pain is a subjective and conscious experience, the individual experience of pain and its perceived impact on daily life are integral parts of the pain evaluation. This concept was recognized by The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) group, which recommends that investigators consider including a standard core set of outcome domains in clinical pain trials regardless of pain population. Complete relief of pain problems that have persisted over a long time is unlikely, either spontaneously or as a result of treatment, especially in persons who have experienced neurologic injury or disease and who have developed neuropathic pain. Therefore, domains such as pain severity and physical and emotional function that reflect Health-Related Quality of Life are of particular interest for the multidimensional evaluation of pain.

However, in populations of individuals who have physical impairments, a decrease in physical function may be more dependent on physical impairments than on pain. Therefore, a decrease in function specifically because of pain (ie, pain interference) should be assessed.

Standardized pain assessments in physically impaired populations are needed, and recent efforts have been made to this end. For instance, in the SCI pain field, the International Spinal Cord Injury Pain Data Set (ISCIPDS) committee developed a basic pain dataset (ISCIBPDS) that contains a basic amount of clinically relevant information concerning pain. The ISCIBPDS is consistent with the recommendations made by the IMMPACT group and includes questions about pain severity and physical and emotional function. Several other international workgroups in this field also have made important contributions toward the standardization of SCI pain measures.

Ratings of pain intensity or severity using Numerical Rating or Visual Analog Scales are common primary outcome measures in most clinical pain trials. However, additional information regarding location, quality, and temporal pattern of pain is usually evaluated in the pain history, and this information provides information important for diagnosing pain. The pain evaluation in individuals who have experienced neurologic trauma or disease is particularly complicated, because these individuals frequently experience different types of pain that may have different underlying origins. Thus, different pain types are important to evaluate separately to determine treatment effect.

In neuropathic pain conditions, an evaluation of neurologic dysfunction is often performed to quantify and determine sensory, motor, or autonomic function. Bedside clinical examination of sensory function and the more time-consuming quantitative sensory testing (QST) assess decreased function of specific spinal pathways, such as the dorsal column and the spinothalamocortical tract, and stimulus-evoked pain. Although QST may potentially be a useful diagnostic and outcome measure in clinical settings and trials, further research is needed to establish validity and reliability in physically impaired populations.

In summary, the assessment domains recommended by the IMMPACT group are appropriate for diverse chronic pain populations, including persons who have nervous system trauma (eg, spinal cord injury, traumatic brain injury, stroke), diseases of the nervous system (eg, multiple sclerosis, post-polio syndrome, Parkinson’s disease), and degenerative muscle diseases (eg, muscular dystrophy). When people experiencing chronic pain also have varying degrees of physical impairments, specific assessment of pain-related interference with physical and emotional functioning is more useful than general measures of physical and emotional function. A set of core outcome measures in combination with more disease-specific measures would be useful for comparing clinical outcomes and trials in these populations. When selecting specific instruments to be used as core outcome measures, not only validity and reliability but also whether the instrument can be used in pain populations associated with underlying disease or trauma must be considered.

Fatigue

Although fatigue can be experienced and physiologic, its measurement among people who have chronic illness is largely based on self-report. Many instruments are available, but no gold standard currently exists. Several review papers have been published recently that identify methods of fatigue assessment among people who have chronic illness or critically examine specific self-report fatigue assessment scales. In one study, 252 different ways to measure fatigue were identified across 2285 papers published between 1975 and 2004. Only 152 of these methods were used more than once. Overall, the authors found that single-item questions, retrospective chart review, and ad hoc scales were the most frequently used methods for assessing fatigue. Among fatigue specific scales, 71 multidimensional ones were identified, primarily for assessing cancer-related fatigue.

Across the reviews by Dittner and colleagues, Kos and colleagues, Mota and Pimenta, and Taylor and colleageus, a total of 34 fatigue-specific instruments are described and critiqued. Individuals interested in fatigue assessment are strongly encouraged to read these papers because the instruments described include both unidimensional (eg, Brief Fatigue Inventory, Fatigue Severity Scale [FSS]) and multidimensional measures (eg, Fatigue Impact Scale, Fatigue Assessment Instrument), identify the populations for which the tool was developed and have been validated, and offer a detailed critique of psychometric properties and overall usefulness.

According to Hjollund and colleagues, the most frequently used fatigue-specific assessment instruments include the FSS, the Fatigue Questionnaire (FQ; also called the Fatigue Rating Scale or the Chalder Fatigue Scale ), and the Multidimensional Fatigue Inventory (MFI). Although the instruments are used widely, they were originally developed for chronic medical patients (FSS), individuals who have chronic fatigue syndrome (FQ), and general medical patients (MFI). Each instrument uses Likert-scale response options for its items (9, 11, and 20, respectively), has good internal consistency documented across several studies, and has some documentation of different aspects of validity and reliability. Despite the strong psychometric properties reported on the FSS, a recent evaluation of this instrument using Rasch analysis has raised some questions about the 9-item structure of the tool, which will require further examination given its common use.

Because of the wide range of fatigue assessment instruments that are available, clinicians and researchers must be focused and deliberate in choosing a tool for use in their setting. Considerations must include availability, ease of administration, level of measurement, applicability to the specific patient population, and psychometric properties (reliability, validity, and sensitivity to change as a result of intervention). In addition, consideration must be given to the definition of fatigue used in the setting and the extent to which an instrument provides a suitable match. In clinical settings, a comprehensive history will also be needed to identify potential sources of secondary fatigue so that they can be addressed through appropriate referrals and intervention.

In the future, self-reported assessment of fatigue may become more consistent because of the Patient-Reported Outcomes Measurement System (PROMIS) initiative, established in 2004 by the National Institutes of Health. The focus of PROMIS is on developing “efficient, consistent, well-validated” ways to measure patient-reported symptoms that are known to be difficult to measure (eg, fatigue). The preliminary item bank on fatigue contains 95 items, with 55 addressing the fatigue experience and 40 addressing fatigue impact. Testing and calibration continues, and eventually these instruments will be possible to access publicly through computerized adaptive tests ( http://www.nihpromis.org/default.aspx ).