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.

Comorbidity

Indeed, affective, anxiety, and behavior disorders are early risk factors for developing chronic pain. For example, patients with depression and anxiety, or who have a tendency to catastrophize, report more intense pain experiences. Similarly, chronic pain shows significant comorbidity with clinical depression. The majority of patients with depression report at least one pain complaint, and depression is present in 5% to 85% (depending on the study setting) of patients with pain conditions. Patients with chronic pain often have affective disorders, such as anxiety, and anxiety is a risk factor for developing chronic pain.

Several large studies of individuals, including twins, found a greater than chance association between chronic pain conditions—such as low back pain, joint pain, headaches, temporomandibular joint pain—and affective disorders, including major depression, panic attacks, and posttraumatic stress disorder, suggestive of a common etiology for these conditions.

Fibromyalgia is a syndrome that is characterized by chronic widespread pain, muscle tenderness, and emotional distress. The frequent comorbidity of fibromyalgia with stress-related disorders, such as chronic fatigue, posttraumatic stress disorder, irritable bowel syndrome, and depression, as well as the similarity of many CNS abnormalities, suggests at least a partial common substrate for these disorders. Despite the numerous cerebral alterations associated with it, fibromyalgia might not be a primary disorder of the brain but rather may be a consequence of early life stress or prolonged or severe stress affecting brain modulatory circuitry of pain and emotions in genetically susceptible individuals.

The comorbidity of affective disorders and chronic pain often results in misdiagnosis of and treatment of depression and similar disorders. As Bair et al. remind us, more than 75% of patients in primary care settings who have depression present exclusively with physical complaints, and their affective disorders are rarely diagnosed.

Pain as a Negative Reward

There is a growing realization that pain, and in particular its affective facets, may be causally related to impaired reward and motivation functions. As reviewed by Elman and Borsook, the notion of unity of negative and positive rewards dates to the early Greek and Chinese scholars and physicians, and was later refined by Fichte and Hegel. Elman and Borsook also remind us that “Dostoevsky and Nietzsche expanded this concept to the holistic and indivisible pain-pleasure amalgamation, while Spinoza upheld the pain-pleasure continuum by designating them opposite anchors of the perfection scale.” In this context, behaviors that result in pain relief, or in the prevention of painful states, are rewarding.

These rewarding behaviors appear to depend on dopamine transmission in mesolimbic centers, in particular in the nucleus accumbens (NAc). This nucleus is a key node in the reward circuitry, as it integrates inputs from mesencephalic dopaminergic neurons and from neurons in the ventral hippocampus, amygdala, and frontal cortical areas, all structures that process affective information. Anatomical and functional changes in these reward/motivation circuits in chronic pain may lead to the comorbid affective and cognitive disorders observed in these patients. NAc activity in humans appears to encode its predicted value and anticipates its analgesic potential on chronic pain. In patients with fibromyalgia, for example, dopaminergic responses to pain appear to be abnormal : Patients with fibromyalgia experience noxious stimuli as more painful than healthy controls do, and control subjects release dopamine in the basal ganglia during the painful stimulation, whereas patients with fibromyalgia do not. Hypersensitivity to pain and high rates of comorbid chronic pain are common in several disorders linked with deficits in dopamine system function, including disorders of mood and affect, substance abuse, and Parkinson disease. In contrast, hyposensitivity to pain is common in patients with schizophrenia, which is linked to excessive dopamine neurotransmission.

Nerve injury, in either rats or mice, increases the excitability of NAc neurons, and this amplified activity appears to be causally related to injury-induced pain. The NAc neurons, the activity of which is amplified, are known to drive descending pain modulatory pathways, and to regulate aversive responses. The activity of dopaminergic neurons is also profoundly affected by painful stimuli that depress the majority of mesolimbic dopamine neurons (value-coding neurons) and increase activity in a subset of neurons (salience-coding neurons).

In rats with chronic pain, peripheral nerve block results in conditioned place preference (a positive-reward behavior) and evokes dopamine release in NAc. Similar behavioral and neurochemical events occur after pharmacological pain relief. The relief of ongoing pain requires opioid signaling in the cingulate cortex and subsequent downstream activation of dopamine activity in the NAc, mediating the reward of pain relief. Indeed, dopamine release in the NAc may emerge as a biomarker of pain relief reward that reflects analgesic efficacy.

Extensive evidence for an overlap in neuronal circuits subserving both pain perception and reward/motivation strongly supports the notion that pain may be related to impaired reward functions. For example, brain areas involved in the reward-aversion neuronal circuitry that are important for decision-making are also implicated in pain processing: They respond to noxious stimuli and their activation or inhibition modulates the level of perceived pain. Several lines of evidence suggest that chronic pain leads to a hypodopaminergic state that impairs motivated behavior. The resulting decreased responsiveness to rewards may be related to the anhedonia and depression common with chronic pain. Thus, strategies to restore dopamine signaling may represent a novel approach to manage the affective sequelae of chronic pain.

That chronic pain involves impaired reward function relates directly to the epidemiological and mechanistic links between pain and addiction. Because addiction is driven by changes in reward pathways, and because these same reward pathways are apparently involved in chronic pain (see preceding text), addiction should be considered, with negative affect and with chronic pain, as mutually reinforcing maladaptive mechanisms.

Chronic pain is linked to other addictions. For example, alcohol use disorder is highly comorbid with chronic pain.

Shared Brain Circuits

The pathogenesis of chronic pain, as well as that of affective disorders, involves neuronal networks distributed throughout the nervous system. Similarly, the perception of both pain and negative affect involves distributed CNS networks. Therefore, it is unlikely that the reinforcing interactions of pain and negative affect will be restricted to a single locus. However, there exist several loci at which negative affect may amplify pain, and where pain may exacerbate affective disorders.

The Amygdala

The amygdala is one of the key sites for interactions between chronic pain and negative affect. It is well established that the amygdala has an important role in emotions and affective disorders. Anatomical, neurochemical, electrophysiological, and behavioral studies support its role in the emotional–affective dimension of pain. This almond-shaped brain area in the medial temporal lobe is closely associated with cortical and subcortical structures relevant to both pain processing and emotions. The amygdala affects the insular, orbital, and medial prefrontal cortex; basal forebrain nuclei; bed nucleus of the stria terminalis; and medial dorsal thalamus; as well as the hypothalamus and key brainstem areas. The amygdala projects to key structures in the descending modulation of pain (described in subsequent text), including the PAG, parabrachial nucleus (PB), reticular formation, dorsal nucleus of the vagus, solitary tract nucleus, and ventrolateral medulla.

Amygdala inputs to the medial prefrontal cortex are thought to provide emotion and value-based information to guide decision-making and behavior control. A complex network of connections intrinsic to the amygdala regulates the outputs from this structure, thereby modulating emotional responses and pain-related outputs and behaviors. Through interactions with cortical areas, the amygdala also contributes to cognitive aspects of the pain experience, such as pain-related decision-making deficits. An example of the role of these amygdala-related interactions comes from findings demonstrating that activation of the amygdala differentiates fibromyalgia patients with and without major depression.

Thus, the amygdala interacts with brain regions and systems involved in nociception and pain perception, fear and anxiety, attention and cognition, as well as autonomic function. Neugebauer and collaborators have promoted the hypothesis, and provided evidence to support it, that impaired cortical cognitive control leading to amygdalar disinhibition results in the persistence of pain and its affective dimension.

Descending Pain Modulation

Pain perception is strongly influenced by cognitive factors, including attentional state, emotional context, attitudes, expectations, hypnotic suggestions, or anesthesia-induced changes in consciousness, Cognitive influences on pain perception are attributed to cortical circuits whose descending outputs modulate information processing at spinal and brainstem levels.

The most completely characterized descending pain modulating circuit is the periaqueductal gray–rostroventral medulla (or PAG-RVM) system. These descending pathways exert bidirectional control over nociception; imbalance in this circuitry toward facilitation of postsynaptic targets may promote and maintain chronic pain. The RVM includes the raphe magnus, nucleus reticularis gigantocellularis-pars alpha, and the nucleus paragigantocellularis lateralis. It is the final common relay in the descending modulation of pain, integrating inputs from PAG and other subcortical and cortical structures to the spinal dorsal horn as well as the trigeminal nucleus caudalis (SpVc). There is growing evidence that imbalance between facilitatory and suppressive outputs from RVM to spinal neurons contributes to chronic pain states (reviewed in Denk et al., Heinriche et al., and Ossipov et al. ).

Both the PAG and RVM are implicated directly in mediating negative affect, and in affective disorders. As mentioned earlier, Hohmann, Neugebauer, and their collaborators demonstrated that stress-induced analgesia is critically dependent on both the PAG and the RVM. In rats, prolonged electrical stimulation of PAG produces lasting and profound increases in measures of negative affect. Buhle et al. showed that two conditions known to elicit strong emotional responses—physical pain and negative image viewing—both enhance negative affect and PAG activity in humans.

Human imaging suggests that patients with fibromyalgia have significant disruptions in the functional connectivity of the PAG, particularly with brain regions implicated in negative affect, and that these reductions are associated with worse fibromyalgia impact scores. These findings suggest that the PAG is a site of dysfunction contributing to the clinical manifestations and pain. In addition, human imaging studies reveal representation of aversive prediction errors in the PAG.

“Social pain” is thought of as a painful perception elicited by impactful life experiences, such as romantic rejection. Koban et al. recently compared, in human subjects, the effects of placebo treatment on both noxious (heat) stimuli and on social pain. Placebo treatment reduced both social and physical pain, and increased activity in the prefrontal cortex in both modalities. Placebo further altered the relationship between affect and both prefrontal cortex and PAG activity during social pain. Koban et al. also demonstrated that the effects on behavior were mediated by a pathway connecting prefrontal cortex to the PAG. These findings suggest that placebo treatments reduce emotional distress by altering affective representations in frontal brainstem systems.

Corticotrigeminal Pathways

Besides these indirect pathways, the neocortex provides dense anatomical projections that directly target second-order neurons in the spinal cord and the trigeminal nuclei. Brodal et al. provided one of the first descriptions of direct projections from cortical areas, in the cat, to sensory trigeminal nuclei. Subsequent work in cats showed direct inputs from primary somatosensory cortex (SI) and the second somatosensory cortex (SII) to the spinal subnucleus caudalis (or SpVc), the target of primary nociceptive afferents from the head and neck. In rats, direct inputs to SpVc arise from SI, SII, and from the insula, ^, and the inputs from SI are somatoscopically organized. Efferents from SI and SII in the rat diverge to target overlapping regions in SpVc. SI projects directly to trigeminal nuclei also in the mouse.

That these corticotrigeminal pathways affect sensory processing was demonstrated more than a century ago. Researchers showed that corticotrigeminal inhibitory influences may occur through both presynaptic and postsynaptic mechanisms. We, and others, have shown that these influences strongly affect nociceptive processing in trigeminal nuclei, and thereby modulate pain perception.

As discussed in the following section, cortical areas contributing—both directly (e.g. corticotrigeminal) or indirectly (via PAG/RVM)—to descending pain modulation are critically involved also in regulating affect. Therefore, these pathways are likely involved in interactions between pain and negative affect.

Thalamus and Cortex

Thalamocortical and corticothalamic interactions gate, modulate, and process information related to nearly all aspects of sensation, perception, affect, cognition, and motor control. It is therefore not surprising to find evidence that thalamocortical-corticothalamic pathways are critically involved in pain-affect interactions. Neuroimaging studies demonstrate that nociceptive inputs almost always result in activation in SI and SII cortex, insular cortex, anterior cingulate cortex (ACC), and related thalamic nuclei. At the risk of phernological simplification, it can be stated that SI is associated with sensory-discriminative aspects of pain, SII has both sensory and affective/cognitive functions, and the insula and ACC are important for affective-motivational and certain cognitive aspects of pain, including anticipation, attention, and evaluation. The medial prefrontal cortex (mPFC) has important interactions with both the amygdala and descending pain modulatory pathways—both described earlier—through which pain and affect can modulate each other.

Such interactions have been demonstrated in human imaging studies. These studies have shown, for example, that negative affect, pain, and cognitive control activate overlapping regions in the cingulate cortex. Emotional states affect pain unpleasantness, and the magnitude of this effect often correlates with altered pain-evoked ACC activations. In addition, combining imaging with a delayed-discrimination task in healthy volunteers showed that brain regions involved in this working memory encoding process are dissociable, according to whether the stimulus was painful. The medial thalamus and the cingulate cortex were found to encode painful stimuli, and SI encoded innocuous stimuli. Furthermore, encoding of painful stimuli significantly enhanced functional connectivity between the thalamus and mPFC. Tseng et al. also found that participants with higher anxiety levels showed significant performance advantages when encoding painful stimuli. It is notable that only during the encoding of pain were the interindividual differences in anxiety associated with the strength of coupling between medial thalamus and mPFC, which was furthermore related to activity in the amygdala.