Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage (IASP definition). It is a subjective and highly personal experience. Due to the subjective nature of pain, its direct measurement is challenging and depends on the individual’s self-report and behavior that provide an estimate of that individual’s experience. There are a great number of factors unique to the individual that make the pain experience specific to each person. Between-person differences in the pain experience are independent of the pain-producing stimulus. It has been demonstrated experimentally that a painful stimulus of standard intensity is perceived differently between individuals. There are inter-individual differences in the cerebral activation evoked by the same painful stimulus that partly reflect differences in brain morphology. The experience of pain is associated with complex and dynamic biological, psychological, and social factors that vary among individuals.
As noted above, there are great individual differences in the development of chronic pain syndromes among individuals as often demonstrated by the transition from acute to chronic pain. Most individuals do not develop chronic neuropathic pain after an injury to the somatosensory system. The intensity of pain cannot be predicted by the severity of an injury. Variability in pain ratings by individuals receiving the same noxious stimulus is associated with variability in pain-evoked cortical activations. There is also great individual variability to the analgesic responses for the same painful condition among patients.
Familial aggregation and twin studies are starting to give insight into these sources of variability noted in patients with neuropathic pain.
The inherited Mendelian disorders whereby a single mutated gene produces a specific disease includes:
These genes encode a variety of ion channels, enzymes, transcription, and trophic factors. A common thread is the involvement of the SCN9A gene that encodes the NaV1.7 sodium channel.
Recent work has demonstrated a wide variety of genes that are associated with clinical neuropathic pain. A meta-analysis of the A1180 polymorphism of the OPRM1 gene that encodes the μ-opioid receptor: while demonstrating concordant preclinical data, no statistical correlation was found between OPRM1 genotype and opioid requirement or pain levels in patients.
The heavily studied candidate genes for pain include:
Difficulties with this research have included:
In addition to linkage and association studies that delineate the effect of DNA variants, trait variance is also determined by:
Some chronic pain states have been demonstrated to have DNA methylation and histone acetylation abnormalities.
The genetic contribution to the perception of pain has demonstrated biological mechanisms that contribute to individual pain responses. Catechol-o-methyltransferase (COMT), an enzyme that metabolizes catecholamines, is associated with pain-related mu-opioid receptor binding in the brain, which correlates with global pain sensitivity in some clinical circumstances. The mu-opioid receptor gene (OPRM1) A118G single nucleotide polymorphism (SNP) is correlated with pressure pain sensitivity and experimental pain responses. Genetic associations with pain vary by sex and ethnic group.
The genetic mechanisms that underpin the variability of pain responses are primarily reported in rare familial mutations that cause gain or loss of function of specific neurons and ion channels in pain pathways. Examples are severe pain disorders, such as erythromelalgia, and congenital insensitivity to pain. These conditions underscore the importance of ion channels such as sodium channel NaV1.7, receptors (NTRK1), growth factors (NGF), and transcription factors, as illustrated by PRDM12. The heritability of pain is buttressed by twin studies. There is strong evidence that experimental pain perception, specific pain syndromes, and vulnerability to chronic pain are sculpted by genetic factors. It is estimated that 25% to 60% of pain conditions have some aspects of heritability depending on the specific condition. Candidate gene and genome-wide association studies (GWAS) are not as revealing as expected due to small sample sizes, low power, and inadequate phenotyping in many conditions. It has also been demonstrated that even large sample studies only detect SNPs in a given phenotype that explain heritability in a fraction of patients. The single whole exome sequencing study does not demonstrate a single variant that is associated at a genome wide level with pain perception. Gene interactions, epistasis, may be another cause of the inability to identify specific gene functions in the perception of pain.
Many environmental factors contribute to the risk of developing chronic pain. These include age, gender, personality traits (catastrophizing), psychological stress, and a history of pain. Studies show that the level of pain prior to a surgical procedure may predict the degree of chronic post-operative pain. Post-physical injuries and pain during infancy may also be linked to the development of chronic pain. Stress is shown in prospective cohort studies to be important in the development of chronic widespread pain. The mechanism for stress effects may be mediated by dysregulation of the hypothalamic-pituitary-adrenal axis that has been associated with neonatal pain-related stress.
Epigenetics, stable molecular modifications exemplified by histone alterations and DNA methylation, are transmitted to daughter cells during mitosis and are essential for normal development and cell differentiation. Epigenetics is now defined as “the study of changes in gene function that are mitotically and/or meiotically heritable and that do not entail a change in the DNA sequence.” Epigenetic modifications also have a crucial role in the silencing and expression of genes. The brain demonstrates hydroxymethylation and neurons are also methylated in a non-cytosine-guanine manner. The usual epigenetic modifications entail histone variants, posttranslational modifications of amino acids on the amino-terminal tail of histones, and covalent alterations of DNA bases. These epigenetic modifications are also important in the silencing and expression of noncoding DNA sequences. The methylation of cytosine bases followed by adenine and guanine methylation is the predominant modification in mammalian DNA: it occurs primarily in CpG dinucleotides but is also seen in non-CpG sequences. Methylation of cytosine in the promoter regions represses gene expression by preventing the binding of transcription factors or by recruiting mediators of chromatin remodeling (histone-modifying enzymes) as well as other repressors of gene expression. As noted above, neurons may be methylated in a non-cytosine (CH) manner which is typical of embryonic stem cells but is absent in differentiated cell lines. In the human brain, more than 80% of cytosine sites are methylated (less than 2% of CH sites are methylated). Methylation of CH sites coincides with synaptic development during childhood and adolescence. Active research is accumulating evidence that specific histone marks delineate transcriptional states. This gives an understanding of how a specific DNA sequence is utilized in different neuronal cell types. Recent experimental work demonstrates that the histone mark H3K4mel is associated with enhancers of pain-relevant genes.
There are age-related differences in pain prevalence across the lifespan. Joint pain, lower extremity pain and neuropathic pain increase with age. Chronic pain increases until middle age and then plateaus. Headache, abdominal pain, back pain, and temporal mandibular disorder pain peak in the third to fifth decade and then decrease in prevalence. Older adults have lower acute pain intensity in some studies while age-related differences in the intensity of chronic pain are not consistently reported.
Experimental pain studies show that older subjects are less sensitive to brief cutaneous pain such as heat pain thresholds, but are more sensitive to sustained pain stimuli from deeper tissue. Older adults demonstrate increased temporal summation. Conditioned pain modulation decreases with age: the pattern of pain perception in older subjects shows enhanced pain facilitation and decreased pain inhibition.
The biopsychosocial factors that may contribute to age-related shifts in pain modulation include:
(1)An increase in frequency of pain related illnesses
(2)Systemic inflammation
(3)The effects of oxidative stress
(4)Altered autonomic function
(5)Changes in neuronal structures and their function
An impact in perceived pain also occurs with impaired cognitive function, decreased sleep quality, and loss of social support, all commonly occurring with age.
There is strong evidence for the association between psychosocial factors and pain. Patients who suffer chronic pain have increased psychological distress, greater life stress, and more somatic symptomatology than individuals without pain. Several studies have demonstrated interactions between genetic and psychological factors in the risk of development of chronic pain.
The multidimensional model of pain as proposed by Melzak and Casey, initiates the concept that there could be a partial separation of affective and motivational components of pain from its sensory discriminative qualities. These specific characteristics are subserved by different anatomical pathways, the medial ascending system for affective motivational features, and a lateral system for sensory discriminative aspects of pain. This model supports:
(1)The concept that pain is a perception that involves the synthesis of sensory, affective, and cognitive dimensions
(2)There is a distinction between pain and nociception
(3)There may be a dissociation between the quality and intensity of pain and tissue damage.
Melzak also noted that nociceptive input is modulated by learning and memory. Later, descending bidirectional pain modulatory circuits, a major component of which is the rostral ventral nuclei of the medulla (RVM), are found to facilitate or inhibit nociceptive signaling depending on context, stress, expectation, motivation and learning. Clinical reports demonstrate specific multiple dimensions of pain by revealing dissociations between its affective, sensory, and cognitive components. The partial dissociation of affect from sensory discriminative features of pain are reaffirmed from cingulatomy surgeries in which pain is received as such but is not associated with suffering. The dissociation between affect and sensory discriminative aspects of pain is demonstrated by functional MRI studies that show pain unpleasantness can be altered independent of its intensity. Opioids are one of the most effective class of drugs used for both acute and chronic pain. They modulate the affective component of pain rather than its sensory-discriminative dimension. Experimental studies show that activation of cortical opioid receptors modulates pain aversiveness without altering evoked pain reflexes, which supports separate central mechanisms that mediate the affective dimension of pain. The aversive qualities of pain are essential for learning and for future decisions to avoid harmful situations.
The neural circuits that underlie aversive learning are thought to use a component of the mesolimbic reward valuation network, a major component of which is the ventral tegmental area and its projections to the nucleus accumbens (NAc). Experiments show that an unexpected reward increases phasic dopamine release in the NAc while the absence of an expected reward decreases it. The difference between an expected and an actual result is a prediction error that is an important component of reinforcement learning. Functional MRI studies demonstrate that pain prediction errors are encoded in the periaqueductal gray (PAG) that is an integrative nucleus for ascending nociceptive input and descending pain modulation. Expected value information is projected to the PAG from the ventromedial prefrontal cortex (PFC). Predictive error signals are relayed to prefrontal cortical regions that initiate behavioral alterations and include the orbitofrontal, anterior midcingulate and dorsomedial prefrontal cortices.
Pain perception is also modulated by motivational, emotional, cognitive and the expectation of pain. Both the expectation of pain and its relief is shown to modulate the degree and quality of pain as well as the efficacy of opioids. Attention and distraction, as well as the emotional state of the patient, alter the perception of pain that is also reflected in the altered activity of pain related circuits as demonstrated by fMRI studies.
Positron emission tomography imaging studies show that placebo analgesia is concomitant with release of dopamine in brain reward nuclei. Functional MRI imaging demonstrates that cessation of a painful stimulation activates the NAc which is a critical component of reward-aversion pain processing. A series of experimental studies show that activation of dopaminergic neurons in the ventral tegmental area (VTA 10) and concomitant activation of dopaminergic receptors in the NAc may mediate the reinforcing effect of pain relief. Another series of experimental studies supports the concept that the mesolimbic motivational/reward circuitry is involved in both the perception and relief of pain. In an fMRI study of healthy subjects, the onset of a painful thermal stimulus is correlated with decreased activity in the NAc and is increased with its cessation.
As noted earlier, the opioid class of drugs is a principal agent for the relief of moderate to severe pain by suppressing its affective quality. The anterior cingulate cortex (ACC) expresses high levels of opioid receptors in humans that are consistent with its clinical efficacy. In experimentally induced pain, there is endogenous release of opioids in this region during pain and its relief. It is posited that relief of the aversive quality of pain is mediated by opioid signaling in the rostral ACC that induces dopamine release in the NAc. Recent imaging studies show that offset of a noxious stimulus activates the NAc in healthy subjects and increases self-reported pleasantness in concordance with activation of brain reward areas. There is also evidence that both decreased negative affect and increased positive affect to the emotion are associated with pain relief. Release of endogenous opioids in the rACC, concurrently with pain relief, support the concept that both positive and negative reinforcement learning participate in the motivation to seek pain relief.
The modulation of nociceptive input to the pain matrix is based on the interpretation of present experience, past pain history, emotional state and stress levels, as well as cognitive appraisal. The modulation of nociceptive signaling is primarily accomplished by “On” and “Off” cells located in the rostral ventral nucleus of the medulla. ”On” cells in the nucleus facilitate pain transmission while “Off” cells mediate descending inhibition. Activation of these neurons is context dependent. Facilitation occurs when attention to a painful stimulus is required for an advantageous behavioral outcome and inhibition is predominant in the other contexts such as chronic neuropathic pain.
Reward circuits are shown to be important in the maintenance of chronic neuropathic pain. It is posited that rewards are a complex psychophysical construct that are composed of two major components. The first is hedonic pleasure, the liking of the emotion and the second is the motivation to obtain the reward. Hedonic qualities are posited to be encoded by the release of endogenous opioids in the orbitofrontal cortex, the ACC, the amygdala and the NAc. The motivation to attain rewards is posited to be driven by dopamine signaling in the mesolimbic circuitry. Both of these circuitries overlap with brain networks that are essential for motivational affective qualities of pain and its relief. Chronic pain alters behavioral goals by diverting attention from other motivations to those associated with pain relief. This shift in long lasting motivational drives and concomitant predominance of the affective qualities of pain are associated with pain chronification. Brain neuroimaging studies support this hypothesis by demonstrating anatomical alterations and molecular changes in gray matter density, white matter connectivity, glutamate, opioids and dopamine transmission. Furthermore, studies of signal changes in the NAc in patients with chronic back pain in response to an acute thermal stimulus differ from healthy controls. A positive phasic NAc signal at pain offset is posited to reflect prediction with the reward associated with pain relief. A negative signal is demonstrated in patients at pain offset that is posited to be due to return of attention to their persistent chronic pain after cessation of the acute stimulus. It is postulated that the motivational value of acute pain offset is altered in chronic pain conditions. A longitudinal study with fMRI of back pain patients demonstrates that intensity of functional connectivity between NAc and PFC predicts recovery or transition to chronic pain. This and other studies support the concept that the shift from sensory/discriminative qualities of pain (the lateral system) to emotional circuitry (medial system) may be a fundamental component of the chronification of acute pain.