78: Pain

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Pain, as determined by the International Association for the Study of Pain (IASP), is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.”1 This chapter will describe the physiological aspects of pain transmission, pain terminology, and pain assessment; discuss the major classes of medications used to relieve pain; and outline the diagnosis and treatment of psychiatric conditions that often affect patients with chronic pain.


Psychiatric co-morbidity (e.g., anxiety, depression, personality disorders, and substance use disorders [SUDs]) afflicts those with both non–cancer-related and cancer-related pain. Epidemiological studies indicate that roughly 30% of those in the general population with chronic musculoskeletal pain also have depression or an anxiety disorder.2 Similar rates exist in those with cancer pain. In clinic populations, 50% to 80% of pain patients have co-morbid psychopathology, including problematic personality traits. The personality (i.e., the characterological or temperamental) component of negative affect has been termed neuroticism, which may be best described as “a general personality maladjustment in which patients experience anger, disgust, sadness, anxiety, and a variety of other negative emotions.”3 Frequently, in pain clinics, maladaptive expressions of depression, anxiety, and anger are grouped together as disorders of negative affect, which have an adverse impact on the response to pain.4

Rates of substance dependence in chronic pain patients are also elevated relative to the general population, and several studies have found that 15% to 26% of chronic pain patients have a co-morbid substance (e.g., illegal drugs or prescription medications) dependence disorder.5 Prescription opiate addiction is a growing problem that affects approximately 5% of those who have been prescribed opiates for chronic pain (although good epidemiology studies are lacking). Other chapters in this textbook focus more specifically on SUDs. This chapter will concentrate on those with affective disorders and somatoform disorders in the setting of chronic pain.

While many chronic pain patients somatize and have difficulty adapting to it, a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnosis of somatization disorder per se, is less frequently encountered by those who treat patients with chronic pain. The DSM-IV-TR accounts for this distinction by classifying the somatoform component of a pain disorder into several categories (such as pain disorder associated with psychological factors, pain disorder associated with psychological factors and a general medical condition, and somatization disorder).


Detection of noxious stimuli (i.e., nociception) starts with the activation of peripheral nociceptors (resulting in somatic pain) or with the activation of nociceptors in bodily organs (leading to visceral pain).

Tissue injury stimulates the nociceptors by the liberation of adenosine triphosphate (ATP), protons, kinins, and arachidonic acid from the injured cells; histamine, serotonin, prostaglandins, and bradykinin from the mast cells; and cytokines and nerve growth factor from the macrophages. These substances and decreased pH cause a decrease in the threshold for activation of the nociceptors, a process called peripheral sensitization. Subsequently, axons transmit the pain signal to the spinal cord, and to cell bodies in the dorsal root ganglia (Figure 78-1). Three different types of axons are involved in the transmission of pain from the skin to the dorsal horn. A-β fibers are the largest and most heavily myelinated fibers that transmit awareness of light touch. A-Δ fibers and C fibers are the primary nociceptive afferents. A-Δ fibers are 2 to 5 mcm in diameter and are thinly myelinated. They conduct “first pain,” which is immediate, rapid, and sharp, with a velocity of 20 m/sec. C fibers are 0.2 to 1.5 mcm in diameter and are unmyelinated. They conduct “second pain,” which is prolonged, burning, and unpleasant, at a speed of 0.5 m/sec.


Figure 78-1 Schematic diagram of neurological pathways for pain perception.

(From Hyman SH, Cassem NH: Pain. In Rubenstein E, Fedeman DD, editors: Scientific American medicine: current topics in medicine, subsection II, New York, 1989, Scientific American. Originally from Stern TA, Herman JB, editors: Psychiatry update and board preparation, 2004, McGraw-Hill.)

A-Δ and C fibers enter the dorsal root and ascend or descend one to three segments before synapsing with neurons in the lateral spinothalamic tract (in the substantia gelatinosa in the gray matter) (see Figure 78-1). Second pain transmitted with C-fibers is integrally related to chronic pain states. Repetitive C-fiber stimulation can result in a progressive increase of electrical discharges from second-order neurons in the spinal cord. NMDA receptors play a role when prolonged activation occurs. This pain amplification is related to a temporal summation of second pain or “wind-up.” This hyperexcitability of neurons in the dorsal horn contributes to central sensitization, which can occur as an immediate or as a delayed phenomenon. In addition to wind-up, central sensitization involves several factors: activation of A-beta fibers and lowered firing thresholds for spinal cord cells that modulate pain (i.e., they trigger pain more easily); neuroplasticity (a result of functional changes, including recruitment of a wide range of cells in the spinal cord so that touch or movement causes pain); convergence of cutaneous, vascular, muscle, and joint inputs (where one tissue refers pain to another); or aberrant connections (electrical short-circuits between the sympathetic and sensory nerves that produce causalgia). Inhibition of nociception in the dorsal horn is functionally quite important. Stimulation of the A-Δ fibers not only excites some neurons, but it also inhibits others. This inhibition of nociception through A-Δ fiber stimulation may explain the effects of acupuncture and transcutaneous electrical nerve stimulation (TENS).

The lateral spinothalamic tract crosses the midline and ascends toward the thalamus. At the level of the brainstem more than half of this tract synapses in the reticular activating system (in an area called the spinoreticular tract), in the limbic system, and in other brainstem regions (including centers of the autonomic nervous system). Another site of projections at this level is the periaqueductal gray (PAG) (Figure 78-2), which plays an important role in the brain’s system of endogenous analgesia. After synapsing in the thalamic nuclei, pain fibers project to the somatosensory cortex, located posterior to the Sylvian fissure in the parietal lobe, in Brodmann’s areas 1, 2, and 3. Endogenous analgesic systems involve endogenous peptides with opioid-like activity in the central nervous system (CNS) (e.g., endorphins, enkephalins, and dynorphins). Different opioid receptors (mu, kappa, and delta receptors) are involved in different effects of opiates. The centers involved in endogenous analgesia include the PAG, the anterior cingulate cortex (ACC), the amygdala, the parabrachial plexus (in the pons), and the rostral ventromedial medulla.

The descending analgesic pain pathway starts in the PAG (which is rich in endogenous opiates), projects to the rostral ventral medulla, and from there descends through the dorsolateral funiculus of the spinal cord to the dorsal horn. The neurons in the rostral ventral medulla use serotonin to activate endogenous analgesics (enkephalins) in the dorsal horn. This effect inhibits nociception at the level of the dorsal horn since neurons that contain enkephalins synapse with spinothalamic neurons. Additionally, there are noradrenergic neurons that project from the locus coeruleus (the main noradrenergic center in the CNS) to the dorsal horn and inhibit the response of dorsal horn neurons to nociceptive stimuli. The analgesic effect of tricyclic antidepressants (TCAs) and the serotonin-norepinephrine reuptake inhibitors (SNRIs) is thought to be related to an increase in serotonin and norepinephrine that inhibits nociception at the level of the dorsal horn, through their effects on enhancing descending pain inhibition from above.


Advances in neuroimaging have linked the function of multiple areas in the brain with pain and affect. These areas (e.g., the ACC, the insula, and the dorsolateral prefrontal cortex [DLPFC]) form functional units through which psychiatric co-morbidity may amplify pain and disability (see Figure 78-2). These areas are part of the spinolimbic (also known as the medial) pain pathway,6 which runs parallel to the spinothalamic tract and receives direct input from the dorsal horn of the spinal cord. The interactions among the function of these areas, pain perception, and psychiatric illness are still being investigated. The spinolimbic pathway is involved in descending pain inhibition (which includes cortical and subcortical structures), whose function may be negatively affected by the presence of psychopathology. This, in turn, could lead to heightened pain perception. Coghill and colleagues7 have shown that differences in pain sensitivity between patients can be correlated with differences in activation patterns in the ACC, the insula, and the DLPFC. The anticipation of pain is also modulated by these areas, suggesting a mechanism by which anxiety about pain can amplify pain perception. The disruption or alteration of descending pain inhibition is a mechanism of neuropathic pain, which can be described as central sensitization that occurs at the level of the brain, a concept supported by recent neuroimaging studies of pain processing in the brains of patients with fibromyalgia.8 The ACC, the insula, and the DLPFC are also laden with opioid receptors, which are less responsive to endogenous opioids in pain-free subjects with high negative affect.9 Thus, negative affect may diminish the effectiveness of endogenous and exogenous opioids through direct effects on supraspinal opioid binding.


The majority of patients with chronic pain and a psychiatric condition have an organic or physical basis for their pain. However, the perception of pain is amplified by co-morbid psychiatric disorders, which predispose patients to develop a chronic pain syndrome. This is commonly referred to as the diathesis-stress model, in which the combination of physical, social, and psychological stresses associated with a pain syndrome induces significant psychiatric co-morbidity.4 This can occur in patients with or without a pre-existing vulnerability to psychiatric illness (e.g., a genetic or temperamental risk factor). Regardless of the order of onset of psychopathology, patients with chronic pain and psychopathology report greater pain intensity, more pain-related disability, and a larger affective component to their pain than those without psychopathology. As a whole, studies indicate that it is not the specific qualities or symptomatology of depression, anxiety, or neuroticism, but the overall levels of psychiatric symptoms that are predictive of poor outcome.10 Depression, anxiety, and neuroticism are the psychiatric conditions that most often co-occur in patients with chronic pain, and those with a combination of pathologies are predisposed to the worst outcomes.


Acute pain is usually related to an identifiable injury or to a disease; it is self-limited, and resolves over hours to days or in a time frame that is associated with injury and healing. Acute pain is usually associated with objective autonomic features (e.g., tachycardia, hypertension, diaphoresis, mydriasis, or pallor).

Chronic pain (i.e., pain that persists beyond the normal time of healing or lasts longer than 6 months) involves different mechanisms in local, spinal, and supraspinal levels. Characteristic features include vague descriptions of pain and an inability to describe the pain’s timing and localization. It is usually helpful to determine the presence of a dermatomal pattern (Figure 78-3), to determine the presence of neuropathic pain, and to assess pain behavior.


Figure 78-3 Schematic diagram of segmental neuronal innervation by dermatomes.

(From Hyman SH, Cassem NH: Pain. In Rubenstein E, Fedeman DD, editors: Scientific American medicine: current topics in medicine, subsection II, New York, 1989, Scientific American. Originally from Stern TA, Herman JB, editors: Psychiatry update and board preparation, 2004, McGraw-Hill.)

Neuropathic pain is a disorder of neuromodulation. It is caused by an injured or dysfunctional central or peripheral nervous system; it is manifest by spontaneous, sharp, shooting, or burning pain, which may be distributed along dermatomes. Deafferentation pain, phantom limb pain, complex regional pain syndrome, diabetic neuropathy, central pain syndrome, trigeminal neuralgia, and postherpetic neuralgia are examples of neuropathic pain. Qualities of neuropathic pain include hyperalgesia (an increased response to stimuli that are normally painful); hyperesthesia (an exaggerated pain response to noxious stimuli [e.g., pressure or heat]); allodynia (pain with a stimulus not normally painful [e.g., light touch or cool air]); and hyperpathia (pain from a painful stimulus with a delay and a persistence that is distributed beyond the area of stimulation). Both acute and chronic pain conditions can involve neuropathic processes in addition to nociceptive causes of pain.

Idiopathic pain, previously referred to as psychogenic pain, is poorly understood. The presence of pain does not imply or exclude a psychological component. Typically, there is no evidence of an associated organic etiology or an anatomical pattern consistent with symptoms. Symptoms are often grossly out of proportion to an identifiable organic pathology.

Myofascial pain can arise from one or several of the following problems: hypertonic muscles, myofascial trigger points, arthralgias, and fatigue with muscle weakness. Myofascial pain is generally used to describe pain from muscles and connective tissue. Myofascial pain results from a primary diagnosis (e.g., fibromyalgia) or, as more often is the case, a co-morbid diagnosis (e.g., with vascular headache or with a psychiatric diagnosis).


The evaluation of pain focuses first on five questions: (1) Is the pain intractable because of nociceptive stimuli (e.g., from the skin, bones, muscles, or blood vessels)? (2) Is the pain maintained by non-nociceptive mechanisms (i.e., have the spinal cord, brainstem, limbic system, and cortex been recruited as reverberating pain circuits)? (3) Is the complaint of pain primary (as occurs in disorders such as major depression or delusional disorder)? (4) Is there a more efficacious pharmacological treatment? (5) Have pain behavior and disability become more important than the pain itself? Answering these questions allows the mechanism(s) of the pain and suffering to be pursued. A psychiatrist’s physical examination of the pain patient typically includes examination of the painful area, muscles, and response to pinprick and light touch (Table 78-1).

Table 78-1 General Physical Examination of Pain by the Psychiatrist

Physical Finding Purpose of Examination
Motor deficits

Trigger points in head, neck, shoulder, and back muscles Evanescent, changeable pain, weakness, and numbness Does the psychological complaint preempt the physical? Abnormal sensory findings Sympathetic or vascular dysfunction Is there swelling, skin discoloration, or changes in sweating or temperature that suggest a vascular or sympathetic element to the pain? Uncooperativeness, erratic responses to the physical examination Is there an interpersonal aspect to the pain, causing abnormal pain behavior, as in somatoform disease?

The experience of pain is always subjective. However, several sensitive and reliable clinical instruments for the measurement of pain are available. These include the following: