Pain and Negative Affect

Pain Is a Multidimensional Experience

Clinicians and those doing basic research have long recognized that pain is a multidimensional percept, composed of unpleasant sensory, affective, and cognitive experiences. Although sensory characteristics of pain are tightly coupled to activation of nociceptors, nociceptor activation does not always produce pain, and pain can occur without an identifiable nociceptive input. This, and the fact that pain experience is affected by contextual and cognitive factors, indicates that pain circuits within the central nervous system are an integral part of the experience of pain. These circuits represent a distributed neuronal network that includes parallel somatosensory, limbic, and other components. Human and animal studies have shown that the different dimensions of the pain experience may arise from activity in different components of this matrix. The “lateral system,” including the somatosensory thalamus and cortex, is thought to be involved primarily in the sensory-discriminative dimension of pain; this dimension reports the location and intensity of pain. The “medial system”—including the mesolimbic structures, medial thalamic nuclei, and the anterior cingulate and the prefrontal cortex—is thought to be involved primarily in the affective-motivational-cognitive dimensions of pain. These relate to feelings of unpleasantness and emotions, and a determination of the appropriate or possible response in a particular situation.

Thus, the conscious experience of pain represents an interpretation of nociceptive stimuli influenced by memories, and emotional, pathological, genetic, and cognitive factors. This explains why the perception of pain cannot be predicted from an analysis of the nociceptive drive or input. Accordingly, 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.”

Indeed, it is intuitive that pain perception is a multidimensional percept, involving sensory and affective components. Most individuals have experienced the effect of mood swings on their perception of pain or on their pain thresholds. Popular literature frequently refers to a “runner’s high” that provides athletes not only with a sense of euphoria, but that can also suppress pain perception. The neurobiological mechanisms underlying such phenomena are beginning to be unraveled. More exotic descriptions of dissociation between affective and sensory pain components include reports of yogi that can consciously modulate their pain perception; this behavioral feat is apparently associated with significant changes in brain activity. The phenomenon of initial painlessness described by wounded soldiers is also often described.

In a laboratory setting, subjects can readily dissociate the degree of unpleasantness from the perceived intensity of different noxious stimulus modalities. Researchers have also showed that hypnotic suggestion can affect the perception of the affective component of pain, while leaving the perception of the intensity of pain constant. In this condition, positron emission tomography reveals changes in the anterior cingulate cortex, but not in the primary somatosensory cortex, suggesting that these cortical areas are differentially involved in the affective and sensory components of pain, respectively. Related to this, other imaging studies suggest that the regions related to the affective components of pain, but not to its sensory-discriminative aspects, are crucial to the empathy for others’ pain. A dramatic demonstration of the fact that the affective and sensory components of pain are not only dissociable, but are subserved by different neuronal pathways, is a report that transecting the corpus callosum eliminates sensation in the cerebral hemisphere ipsilateral to the stimulus, while leaving intact in that hemisphere unpleasantness evoked by noxious stimuli.

Chronic Pain and Negative Affect

The reciprocal influences between the affective and sensory components of pain are relevant to both acute and chronic pain, which are fundamentally and mechanistically different conditions. Acute pain is essential for survival, initiating immediate action by retreating from harm, or by suppressing movement to promote healing. Acute nociceptive pain, triggered by nociceptor activation, is a symptom of an underlying medical condition, tends to correlate with the severity of that condition, and ends with the termination of the medical condition.

Chronic pain, on the other hand, has no obvious survival value. (The IASP recognizes that chronic pain arises from many different conditions, and, therefore, recommends flexibility in the definition of chronic pain. In general, chronic pain is recognized as pain that persists past the normal time of healing, or pain that persists beyond a particular length of time determined by common medical experience.) The transition from acute to chronic pain is difficult to define, but is thought to involve the engagement of central nervous system structures.

Chronic pain affects over 100 million Americans—more than are affected by heart disease, cancer, and diabetes combined. Pain also costs the United States up to $650 billion/year in medical treatment and lost productivity. Chronic pain is the most common complaint of patients in outpatient clinics. Common chronic pain complaints include headache, low back pain, cancer pain, arthritis pain, and neurogenic pain, and can result from a variety of conditions and insults at any level of the peripheral and central nervous systems. In most patients, chronic pain starts within weeks or months after the original insult and includes increased pain with noxious stimulation (hyperalgesia) and pain in response to previously innocuous stimuli (allodynia). Perhaps most debilitating is the presence, in nearly all patients, of tonic, or spontaneous pain, which occurs in the absence of a stimulus.

Although the management and treatment of acute pain is reasonably good, the needs of chronic pain sufferers are largely unmet. For example, analgesics, including opioids, are inefficient in about 70% of patients. This failure is due to a convergence of obstacles, including scientific ignorance, skewed funding and health care priorities, and policy and political considerations. A scientific obstacle is that nearly all previous attempts to reveal the pathophysiology of chronic pain have focused on the lateral, sensory-discriminative system. This is despite the lack of success of this approach to lead to effective therapies, and despite emerging evidence that therapies that target the motivational-cognitive dimensions of pain might prove more promising. Furthermore, there is increasing evidence that the negative affective, cognitive, and psychosocial state of chronic pain is universal in different chronic pain states. Therefore, understanding the role of the affective-motivational pathways in chronic pain may lead to innovative therapies to treat these widespread conditions.

The Vicious Cycle of Pain and Negative Affect

The persistency of chronic pain, with its accompanying negative affective symptoms, may create a self-amplifying stressor, in which pain increases fear, depression, and catastrophizing, and these negative affects, in turn, amplify pain perception. Pain catastrophizing is an important construct, defined as a set of negative emotional and cognitive processes involving amplification of pain-related symptoms, rumination about pain, feelings of helplessness, and pessimism about pain-related outcomes.

Pessimism about pain-related outcomes can strongly influence pain perceptions and negatively affect normal functioning. Fischerauer et al. recently demonstrated that a threshold level of intolerance of uncertainty is required for the development of pain anxiety and its effect on function, and as intolerance of this uncertainty rises, the effect of pain on function goes from being independent of the anxiety to being more and more carried by and through anxiety about pain.

Indeed, pain can be modulated by emotional (fear and anxiety) and cognitive (attention, expectation, or memory) factors. This pain amplification occurs even in newborns: Jones et al recently measured nociceptive behavior, brain activity, and levels of physiological stress in newborn human infants, and found that infants with higher levels of stress exhibit larger-amplitude cortical nociceptive responses, but this this was not reflected in their behavior. This suggests that brain activity evoked by noxious stimulation is enhanced by stress, but this cannot be deduced directly from observation of pain behavior.

Clearly, of particular concern is the emotional tax from chronic pain that commonly results in life-altering events, including suicide.

The influence of affect on pain perception may be immediately relevant for personalizing opioid treatment for patients with chronic pain. Burns et al. demonstrated recently that, in patients with chronic low back pain, depressive symptoms and pain catastrophizing correlate significantly and positively with opioid-induced pain relief. Therefore, these markers may serve to identify individuals who benefit the most from opioid therapy. Of interest, their results suggest also that individuals with greater depressive symptoms, trait anxiety, pain catastrophizing, and perceived disability may have deficits in endogenous opioid function, which may serve as another predictor of enhanced response to opioid analgesics.

Estimating the prevalence of comorbidity of chronic pain and affective disorders is complicated by the fact that the clinical instruments designed to identify depression are often “contaminated” by measures—including sleep disturbances and headaches—that frequently occur in chronic pain. Nevertheless, nearly all studies suggest that chronic pain increases the risk of depression, but data exist to support also that people with a history of depression are at a higher risk for chronic pain. However, the magnitude of this increased risk is thought to be modest—less than twofold—whereas other factors seem more important: Early life stressors, other psychiatric conditions, prior pain, and poor sleep are all stronger predictors of subsequent chronic pain.

Of interest, neuropathic pain affecting the trigeminal system, in particular, is frequently associated with negative affective states, including a high incidence of depression, anxiety, and sleep disorders. This suggests that trigeminal pain is a particularly painful condition, resulting in substantial psychosocial and affective burden.

The relationship between pain and affect has been confirmed also in animal studies aimed at understanding how anticipation and anxiety cause a heightened pain experience. Although these data are at times conflicting—demonstrating, for example, that anxiety can be either pro- or antinociceptive (depending on the animal model and the endpoints)—these studies demonstrate that animals’ pain responses are emotion-specific, suggesting that higher brain centers may determine the behavioral response to the same noxious stimulus.

Stress-induced analgesia is a form of adaptive pain suppression, an evolutionarily conserved response to stress that has survival value. Stress-induced analgesia may be mediated by both opioid and nonopioid mechanisms, the latter including the endocannabinoid system.

Neugebauer et al. and Woodhams et al. demonstrated that stress-induced analgesia is critically dependent on supraspinal sites, including the periaqueductal gray (PAG) and the rostroventral medulla (RVM), key components of the descending pain pathway. As discussed later, these regions are thought to be critically involved in mediating the interactions between affect and pain perception.

Stress and anxiety do not always suppress pain–they can also enhance nociception and exacerbate pain. This phenomenon is referred to as stress-induced hyperalgesia. For example, it has been demonstrated in rats that muscle inflammation followed by stress induces visceral hypersensitivity that persists for months, modeling these human comorbid pain conditions. This stress-induced hyperalgesia phenomenon was accompanied by increased activation of brain regions associated with the affective component of pain. Visceral stress-induced hyperalgesia may involve the endocannabinoid system. Chronic stress in rodent models results not only in visceral stress-induced hyperalgesia, but also in thermal and mechanical stress-induced hyperalgesia. This form of stress-induced hyperalgesia also involves the endocannabinoid system.

Thus stress can evoke both stress-induced analgesia and stress-induced hyperalgesia, and both phenomena appear to involve the endocannabinoid system and descending pain modulatory pathways. Neugebauer, Hohmann, and collaborators proposed that endocannabinoid signaling in key components of the descending pain pathway mediates stress-induced analgesia, whereas a deficit in endocannabinoid signaling may underlie stress-induced hyperalgesia.

The relationship between stress and pain perception is likely related to the curious phenomenon of social transfer of pain. Langford et al. showed that pairs of mice given identical noxious stimuli and tested together display increased pain behaviors, compared to being tested alone, or compared with mice that have not received the noxious stimulus. This “social modulation of pain” is dependent on visual cues. Similarly, mice housed for long periods in the same cage with mice that have peripheral nerve injury exhibit enhanced pain responses to acetic acid. This behavior appears to represent stress-induced hyperalgesia, because the cage mates of the nerve-injured animals displayed anxiety-like behavior on elevated plus maze and the open-field tests. More recently, Smith et al. reported that naïve, “bystander” mice housed and tested in the same room as mice subjected to inflammatory pain develop corresponding hyperalgesia. This form of social transfer of pain appears to be mediated by olfactory cues and appears to occur without affecting anxiety. It is likely that social transfer of pain, as a social cue, provides a recognition of another’s pain that can lead to the avoidance of harm or trigger empathy and caregiving behavior.