Management of the Patient with Chronic Pain

Excitatory Mechanisms

Pain may be roughly divided into two broad categories: physiologic and pathologic pain. Physiologic (acute, nociceptive) pain is an essential early warning sign that usually elicits reflex withdrawal and thereby promotes survival by protecting the organism from further injury. In contrast, pathologic (e.g., neuropathic) pain is an expression of the maladaptive operation of the nervous system; it is pain as a disease. Physiologic pain is mediated by a sensory system consisting of primary afferent neurons, spinal interneurons and ascending tracts, and several supraspinal areas. Trigeminal and dorsal root ganglia (DRG) give rise to high-threshold Aδ− and C-fibers innervating peripheral tissues (skin, muscles, joints, viscera). These specialized primary afferent neurons, also called nociceptors, transduce noxious stimuli into action potentials and conduct them to the dorsal horn of the spinal cord ( Fig. 51.1 ). When peripheral tissue is damaged, primary afferent neurons are sensitized or directly activated (or both) by a variety of thermal, mechanical, and/or chemical stimuli. Examples are protons, sympathetic amines, adenosine triphosphate (ATP), glutamate, neuropeptides (calcitonin gene-related peptide, substance P), nerve growth factor, prostanoids, bradykinin, proinflammatory cytokines, and chemokines. Many of these agents lead to opening (gating) of cation channels in the neuronal membrane. Such channels include the capsaicin-, proton-, and heat-sensitive transient receptor potential vanilloid 1 (TRPV1), or the ATP-gated purinergic P2X ₃ receptor. Gating produces an inward current of Na ⁺ and Ca ⁺⁺ ions into the peripheral nociceptor terminal. If this depolarizing current is sufficient to activate voltage-gated Na ⁺ channels (e.g., Na _v 1.8), they too will open, further depolarizing the membrane and initiating a burst of action potentials that are then conducted along the sensory axon to the dorsal horn of the spinal cord.

Transmission of input from nociceptors to spinal neurons that project to the brain is mediated by direct monosynaptic contact or through multiple excitatory or inhibitory interneurons. The central terminals of nociceptors contain excitatory transmitters such as glutamate, substance P, and neurotrophic factors that activate postsynaptic N-methyl-D-aspartate (NMDA), neurokinin (NK ₁ ), and tyrosine kinase receptors, respectively. Repeated nociceptor stimulation can sensitize both peripheral and central neurons (activity-dependent plasticity). In spinal neurons such a progressive increase of output in response to persistent nociceptor excitation has been termed “wind-up.” Later, sensitization can be sustained by transcriptional changes in the expression of genes coding for various neuropeptides, transmitters, ion channels, receptors, and signaling molecules (transcription-dependent plasticity) in both nociceptors and spinal neurons. Important examples include the NMDA receptor, cyclooxygenase-2 (COX-2), Ca ⁺⁺ and Na ⁺ channels, cytokines and chemokines expressed by neurons and/or glial cells. In addition, physical rearrangement of neuronal circuits by apoptosis, nerve growth, and sprouting occurs in the peripheral and central nervous system. Both induction and maintenance of central sensitization are critically dependent on the peripheral drive by nociceptors, indicating that therapeutic interventions targeting such neurons may be particularly effective, even in chronic pain syndromes.

Inhibitory Mechanisms

Concurrent with the events just described, powerful endogenous mechanisms counteracting pain unfold. This was initially proposed in the “gate control theory of pain” in 1965 and has since been corroborated and expanded by experimental data. In 1990, a “peripheral gate” was discovered at the source of pain generation by demonstrating that immune cell-derived opioid peptides can block the excitation of nociceptors carrying opioid receptors within injured tissue ( Fig. 51.2 ). This represented the first example of many subsequently described neuro-immune interactions relevant to pain. Inflammation of peripheral tissue leads to increased expression, axonal transport, and enhanced G-protein coupling of opioid receptors in DRG neurons as well as enhanced permeability of the perineurium. These phenomena are dependent on sensory neuron electrical activity, production of proinflammatory cytokines, and the presence of nerve growth factor within the inflamed tissue. In parallel, opioid peptide-containing immune cells extravasate and accumulate in the inflamed tissue. These cells upregulate the gene expression of opioid precursors and the enzymatic machinery for their processing into functionally active peptides. In response to stress, catecholamines, corticotropin-releasing factor, cytokines, chemokines, or bacteria, leukocytes secrete opioids, which then activate peripheral opioid receptors and produce analgesia by inhibiting the excitability of nociceptors, the release of excitatory neuropeptides, or both (see Fig. 51.2 ). The clinical relevance of these mechanisms has been shown in studies demonstrating that patients with knee joint inflammation express opioid peptides in immune cells and opioid receptors on sensory nerve terminals within synovial tissue. After knee surgery, pain and analgesic consumption was enhanced by blocking the interaction between the endogenous opioids and their receptors with intraarticular naloxone, and was diminished by stimulating opioid secretion.

In the spinal cord, inhibition is mediated by the release of opioids, γ-aminobutyric acid (GABA), or glycine from interneurons, which activate presynaptic opioid- or GABA-receptors (or both) on central nociceptor terminals to reduce excitatory transmitter release. In addition, the opening of postsynaptic K ⁺ or Cl ⁻ channels by opioids or GABA, respectively, evokes hyperpolarizing inhibitory potentials in dorsal horn neurons. During ongoing nociceptive stimulation spinal interneurons upregulate gene expression and the production of opioid peptides. Powerful descending inhibitory pathways from the brainstem also become active by operating mostly through noradrenergic, serotonergic, and opioid systems. Key regions are the periaqueductal grey and the rostral ventromedial medulla, which then projects along the dorsolateral funiculus to the dorsal horn. The integration of signals from excitatory and inhibitory neurotransmitters with cognitive, emotional, and environmental factors (see later) eventually results in the central perception of pain. When the intricate balance between biologic, psychological, and social factors becomes disturbed, chronic pain can develop.

Translation of Basic Research

Basic research on pain continues at a rapid pace but translation into clinical applications has been difficult. Many obstacles have been discussed, including overinterpretation of data, reporting bias toward neglecting negative results, inadequate animal models, flawed study design, genetic and species differences. Notwithstanding, animal studies are indispensable, continue to be improved, and have successfully predicted adverse side effects of drug candidates. For ethical reasons, many models are restricted to days or weeks, while human chronic pain can last for months or years. Therefore, animal models may be more cautiously termed as reflecting “persistent” pain. Brain imaging is an area of intense research and numerous studies have investigated changes in patients with various pain syndromes. However, such studies have not yet provided reproducible findings specific for a disease or a pathophysiologic basis for individual syndromes. Neuroimaging can only detect alterations associated with nociceptive processes whereas clinical pain encompasses a much more complex subjective experience that critically relies on self-evaluation. Thus, although recent data have provided valuable information on pain neurophysiology, current imaging techniques cannot provide an objective proxy, biomarker, or predictor for clinical pain. Genetics is another budding scientific field. However, with the possible exception of the metabolic enzyme CYP2D6, pharmacogenetics is not expected to serve as a guide to individualized (“personalized”) clinical pain therapy any time soon.

Definitions

The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” This classification further states that pain is always subjective and that it is a sensation in parts of the body. At the same time, it is unpleasant and therefore also has emotional/psychological components. Aside from malignant disease, many people report chronic pain in the absence of tissue damage or any likely pathophysiologic cause. There is usually no way to distinguish their experience from that due to tissue damage. If patients regard their experience as pain or if they report it in the same ways as pain caused by tissue damage, it should be accepted as pain. Nociception is neurophysiological activity in peripheral sensory neurons (nociceptors) and higher nociceptive pathways and is defined by the IASP as the “neural process of encoding noxious stimuli.” Nociception is not synonymous to pain. Chronic pain is defined as “extending in duration beyond the expected temporal boundary of tissue injury and normal healing, and adversely affecting the function or well-being of the individual” by the American Society of Anesthesiologists. The IASP subcommittee on taxonomy defined it in 1986 as “pain without apparent biological value that has persisted beyond the normal tissue healing time usually taken to be three months.”

Prevalence

Beyond these general definitions there exists no common understanding about the characteristics of the chronic pain patient. This may be one reason why estimates of prevalence differ greatly from one publication to another. Heterogeneous populations, the occurrence of undetected comorbidity, different definitions of chronic pain, and different approaches to data collection have resulted in estimates from 20% to 60%. Some surveys indicate a more frequent prevalence among women and the elderly. Chronic pain has enormous socioeconomic costs due to the need for healthcare services, disability compensation, lost workdays, and related expenses.

Classification

There is a tradition to distinguish between malignant (related to cancer and its treatment) and nonmalignant (e.g., neuropathic, musculoskeletal, inflammatory) chronic pain. Nonmalignant chronic pain is frequently classified into inflammatory (e.g., arthritic), musculoskeletal (e.g., low back pain), headaches, and neuropathic pain (e.g., postherpetic neuralgia, phantom pain, complex regional pain syndrome, diabetic neuropathy, human immunodeficiency virus-associated neuropathy). Frequent symptoms of neuropathic pain include spontaneous lancinating, shooting, or burning pain; hyperalgesia; and allodynia. Cancer pain can originate from invasion of the tumor into tissues innervated by primary afferent neurons (e.g., pleura, peritoneum) or directly into a peripheral nerve plexus. In the latter, neuropathic symptoms may be predominant. Pain may be underestimated by medical staff and family members, resulting in poor pain control. Many treatments for cancer are associated with severe pain. For example, cytoreductive radiotherapy or chemotherapy frequently causes painful oral mucositis, especially in patients with bone marrow transplantation.

Biopsychosocial Concept of Chronic Pain

Chronic pain is characterized by the complex interaction of biologic (tissue damage), psychological (cognition, memory, conditioning), and environmental/social factors (attention, reinforcement). Studies have shown that multimodal pain management programs rooted in this concept can lead to reduced pain, increased activity, and improved daily functioning. Therefore, it is of utmost importance to screen patients with ongoing pain for risk factors. Special attention should be paid to patients presenting with limited mobility, lack of motivation, depression, anger, anxiety, and fear of reinjury, which hamper the return to normal work or recreational activities. Such patients may become preoccupied with pain and somatic processes, which may disrupt sleep and cause irritability and social withdrawal. Other cognitive factors such as patients’ expectations or beliefs (e.g., perceived inability to control the pain) influence psychosocial and physical functioning. Pain behavior such as limping, medication intake, or avoidance of activity is subject to operant conditioning; that is, it responds to reward and punishment. For example, pain behavior may be positively reinforced by attention from a spouse or healthcare provider (e.g., by inadequate use of nerve blocks or medications). Conversely, such behavior can be extinguished when it is disregarded and incremental activity is reinforced by social attention and praise. Respondent learning mechanisms (i.e., classical conditioning) may also contribute to chronicity. Other issues often coexist, such as substance abuse problems, family dysfunction, and conflicts with legal or insurance systems. Consequently, care seeking is an integral feature of the pain experience, and excessive use of the healthcare system ensues. The interplay between these biologic, psychological, and social factors results in the persistence of pain and illness behaviors. Treating only one aspect of this complex syndrome (“monomodal” therapy) is obviously insufficient. The biopsychosocial concept was first described by Engel in 1959 but its implementation into daily practice has been tardy, especially concerning chronic pain patients. This concept helps to understand why chronic pain may exist without obvious physical cause or why pathologic somatic findings may remain unnoticed by the patient. Interestingly, the experience and regulation of social and physical pain may share a common neuroanatomic basis. In a multimodal approach, pain management simultaneously addresses physical, psychological, and social skills and underscores the patients’ active responsibility to regain control over life by improving function and well-being. Methods usually include (among others) cognitive-behavioral therapy, physical exercise, and medication management. Cognitive-behavioral therapy aims to correct maladaptive cognitive and behavioral patterns, such as catastrophizing and fear-avoidance-beliefs. It encourages patients to take a proactive versus passive role in their healing process, and to experience life mindfully through defusion, acceptance, and committed action. Functional restoration includes occupational and physical therapy to help the patient gain confidence in physical activity. Activation per se seems to be more important than specific therapeutic techniques. Social support can affect pain intensity and mood by addressing employment and retirement issues as well as other concerns such as financial and legal disputes.

Psychology

The role of the psychologist includes the initial assessment and treatment approaches such as education, cognitive-behavioral therapy, and relaxation training. Assessment of the patient addresses the sensory, affective, cognitive, behavioral, and occupational dimensions of the pain problem. This includes an extensive biographic history and behavioral analysis along with the use of questionnaires. Most questionnaires include scoring systems for pain intensity (e.g., numerical or visual analog scales), but pain behavior (e.g., West-Haven-Yale Multidimensional Pain Inventory), multidimensional pain quality, cognitive coping, fear (e.g., State-Trait-Anxiety-Inventory), depression, and other associated symptoms are far more relevant. Indications for psychological pain management are relevant somatization, depressive disorders, inadequate coping, drug abuse, and high levels of pain behavior reinforced by the environment (e.g., family members). A key factor is motivational change for acceptance of the complex therapeutic program. Some types of pain syndromes, such as chronic headache, inflammatory rheumatic pain, or unspecific back pain may specifically benefit from behavioral therapy. This usually means a complete change of view for the patient, from a purely passive recipient of curative treatment to an active, self-reliant approach to functional restoration, vocational rehabilitation, and reduced healthcare use despite pain. Thus, pain reduction alone is no longer the focus of therapy.

Physical Therapy

The role of the physical therapist includes initial evaluation of the musculoskeletal system, assessment of the patient’s workplace and home, education in active physical coping skills, and management of the physical rehabilitation process. An intensive exercise program emphasizing the patient’s responsibility for self-management is an integral part of comprehensive programs for chronic nonmalignant pain. Improving fitness, mobility, and posture counteracts the effects of disuse and complements behavioral treatment. The physical therapist encourages the adoption of regular exercise into daily life, facilitates repeated exposure to movement as much as possible despite pain, and reinforces education in the biopsychosocial model of pain management. Different techniques of exercise such as muscle conditioning and aerobics are efficacious in improving function, pain, disability, and fear avoidance behavior. On the other hand, passive treatments like massage or chiropractic interventions are not beneficial. The regimen of graded exercise follows the original concept of Fordyce. Patients are instructed to find a baseline tolerance level for each exercise. Next, a program of improvement is negotiated and agreed upon. Patients note improvements on a daily basis and are required to complete the exercise plan regardless of how they feel. Thus, the control over exercise behavior is contingent upon plan rather than pain, since exercise and pain are disconnected. Individual motivation is an important factor determining how well patients learn to manage pain.