Postherpetic neuralgia is defined as pain persisting or recurring at the site of shingles at least 3 months after the onset of the acute varicella zoster viral rash. Postherpetic neuralgia occurs in about 10% of patients with acute herpes zoster. More than half of patients over 65 years of age with shingles develop postherpetic neuralgia, and it is more likely to occur in patients with cancer, diabetes mellitus, and immunosuppression. Other risk factors include greater acute pain and rash severity, sensory impairment, and psychological distress. Most cases gradually improve over time, with only about 25% of patients with postherpetic neuralgia experiencing pain at 1 year after diagnosis. Approximately 15% of referrals to pain clinics are for the treatment of postherpetic neuralgia.
Although degeneration and destruction of motor and sensory fibers of the mixed dorsal root ganglion characterize acute varicella zoster, other neurological damage may include inflammation of the spinal cord, myelin disruption, axonal damage, and decreases in the number of nerve endings from the affected skin. These injuries persist in postherpetic neuralgia patients, but the actual mechanism of pain is not well understood. Studies have suggested the role of both peripheral and central mechanisms resulting from the loss of large-caliber neurons and subsequent central sensitization or adrenergic receptor activation and alterations in C-fiber activity. Early treatment of varicella zoster with low-dose amitriptyline reduced the prevalence of pain at 6 months by 50%. Tricyclic antidepressants (TCAs), anticonvulsants, and opioids are the most common effective treatments for postherpetic neuralgia and may have potential for its prevention.
Peripheral Neuropathy Pain
Sensory neurons are damaged by many diseases, both directly and indirectly. Approximately 2 5 % of patients with diabetes mellitus will experience painful diabetic neuropathy, with duration of illness and poor glycemic control contributing risk factors. If C-fiber input is preserved but large-fiber input is lost, paresthesias and pain are the predominant sensory experiences. The pain of a peripheral neuropathy can range from a constant burning to pain that is episodic, paroxysmal, and lancinating in quality. These phenomena are primarily the result of axonal degeneration and segmental demyelination. Sites of ectopic impulse generation can be found at any point along the peripheral nerve, including the dorsal root ganglion, regardless of where the nerve is actually damaged. Other changes can alter the magnitude and frequency of impulse generation, such as sensitivity to mechanical or neurochemical stimuli.
The paroxysms of pain that result from stimulation of hyperexcitable damaged neurons and subsequent recruitment of nearby undamaged sensory afferents may be explained by several forms of nonsynaptic (ephaptic) and prolonged (afterdischarge) impulse transmission described in models of peripheral neuropathic pain. Voltage-dependent sodium channels in the dorsal root ganglion undergo both up- and downregulation depending on the subpopulation. When a peripheral nerve is damaged, central sensitization amplifies and sustains neuronal activity by a variety of mechanisms, such as reduced inhibition of dorsal horn cells.
Pharmacological treatments have been almost identical to those used for postherpetic neuralgia, but the new norepinephrine-serotonin reuptake inhibitor duloxetine has been the first agent to be approved by the U.S. Food and Drug Administration (FDA) for treatment of diabetic peripheral neuropathy pain.
Pain is the most common sensory manifestation of Parkinson’s disease and reported by half of patients. The pain is typically described as cramping and aching, located in the lower back and extremities, but not associated with muscle contraction or spasm. These pains often decrease when the patient is treated with levodopa, which suggests a central origin. The loss of dopaminergic input could explain how pain is produced, perhaps through a loss of descending inhibition in the spinal cord.
Central Poststroke Pain
Approximately 5% of patients who have suffered a stroke experience intractable pain in addition to other neurological deficits. Patients typically have hemi-body sensory deficits and pain associated with dysesthesias, allodynia, and hyperalgesia. Radiographic lesions are present in the thalamus, although other sites are often involved. Excitatory amino acids may be involved in the development of this syndrome. Pharmacological treatment is usually not effective, and even ketamine, an A’-methyl-D-aspartate (NMDA) receptor antagonist, reduced pain in less than 50% of patients. Fluvoxamine significantly improved pain ratings but only in patients within 1 year after stroke. In contrast, patients with spinal cord injury experienced reductions in continuous and evoked pain with ketamine and mu opioid receptor agonists, suggesting different mechanisms in different central pain states.
Migraine and Chronic Daily Headache
The International Headache Society has published guidelines for the classification of headache (“Neurology and Neurosurgery”). The peak incidence of migraine occurs between the third and sixth decades of life and then decreases with age. Over the life span, 18% of women and 6% of men will suffer from migraine. Theories of pathogenesis include the involvement of the trigeminovascular system and plasma protein extravasation, antagonism of serotonin receptors, modulation of central aminergic control mechanisms, stabilizing effects on membranes through action at voltage-sensitive calcium channels, and involvement of substance P. Common migraine is defined as a unilateral pulsatile headache, which may be associated with other symptoms such as nausea, vomiting, photophobia, and phonophobia. The classic form of migraine adds visual prodromal symptoms such as scintillating scotomata. Complicated migraine includes focal neurological signs such as cranial nerve palsies and is often described by the name of the primary deficit (e.g., hemiplegic, vestibular, or basilar migraine).
Calcium channel blockers, beta-blockers, antidepressants, and anticonvulsants are the treatments with best-documented efficacy. A group-based multidisciplinary treatment consisting of stress management, supervised exercise, dietary education, and massage therapy significantly improved pain characteristics, functional status, quality of life, depression, and pain-related disability in patients with migraine.
Headache is the most common pain condition reported by the U.S. workforce as the reason for lost productive time. Chronic daily headache affects about 5% of the population and is composed of constant (transformed) migraine, chronic tension-type headaches, new-onset daily persistent headache, and hemicrania continua. Patients with chronic daily headache are more likely to overuse medication, leading to rebound headache; have psychiatric comorbidity such as depression and anxiety; report functional disability; and experience stress-related headache exacerbations. Patients with transformed migraine have poor quality of life, having been found to have the worst SF-36 Health Survey profile compared with patients with episodic migraine or chronic tension-type headaches. Chronic tension-type headaches typically manifest as daily pain that is difficult to manage and unresponsive to many treatments.
A variety of medications have been recommended in addition to the traditional prophylactic agents and include serotonin agonists, serotonin antagonists, and alpha2-adrenergic agonists. Olanzapine decreased headache severity and frequency in patients with refractory headaches who had undergone unsuccessful treatment with at least four preventive medications. Topiramate decreased migraine frequency, severity, number of headache days, and use of abortive medications in patients with both episodic and transformed migraine. TCAs and stress management therapy significantly reduced headache activity, analgesic medication use, and headache-related disability. Combined medication and cognitive-behavioral psychotherapy are more effective than either treatment alone.
Low Back Pain
Low back pain (LBP) is one of the most common physical symptoms, and the most expensive condition when including lost productivity and health care costs. Psychological factors are highly correlated with LBP; these factors include distress, depressed mood, and somatization, which predict the transition from acute to chronic LBP. A minority of patients with acute low back pain will develop chronic low back pain with disproportionate distress and disability. In one prospective cohort study of 1,246 patients with acute low back pain who sought treatment, about 8% had chronic, continuous symptoms for 3 months, and less than 5% had unremitting pain for 22 months. Two-thirds of patients with chronic low back pain at 3 months exhibited functional disability at 22 months. The most powerful predictor of chronicity was poor functional status 4 weeks after seeking treatment. In a study of secondary gain, both economic and social rewards were associated with higher levels of disability and depression in patients with chronic nonmalignant back pain. Depression has been identified as a presurgical risk factor associated with poor outcome in long-term follow-up of compensated workers who underwent posterolateral lumbar fusion. Specifically, anxiety, depression, and occupational mental stress predicted lower rates of return to work in patients undergoing lumbar surgeries. Despite an extensive array of pain scales and functional instruments available to evaluate outcome, patient global assessment has been found a valid and responsive measure of overall treatment effect.
The presence of a depressive disorder has been demonstrated to increase the risk of developing chronic mus-culoskeletal pain 3 years later. In a 15-year prospective study of workers in an industrial setting, initial depression symptom scores were predictive of low back pain and a positive clinical back examination in men but not women. In a study of health care workers examined over 3 years with the Zung Depression Index, affective distress contributed to new-onset LBP. In a community-based sample, depression was associated with a nearly fourfold increase in the likelihood of seeking a consultation for the new complaint of back pain lasting greater than 3 months at follow-up. In a 13-year follow-up study that examined the longitudinal relationship between low back pain and depressive disorder, using lifetime reports of symptoms, and excluded other forms of affective distress such as demoralization, grief, and adjustment disorders, depressive disorder was a significant risk factor for incident LBP. While it is understandable that patients with low back pain would experience reactive affective distress, a significant relationship between low back pain and the subsequent onset of incident depressive disorder was not found. In another prospective analysis, participants who did not have current low back pain were followed for 12 months. Patients with higher levels of distress at baseline were almost twice as likely to report a new episode of back pain. This study concluded that as much as 16% of low back pain in the general population may be attributable to psychological distress.
The treatment of chronic low back pain has been pursued with multiple modalities alone and in combination. Patients with chronic low back pain exemplify the complexity of chronic pain treatment. Their symptoms may represent numerous diagnoses and require multimodal treatment plans. Although treatments often produce symptom reductions, there is conflicting evidence about their ability to improve functional status, particularly with respect to returning to work (). Conservative interventions such as education, exercise, massage, and TENS produce inconsistent results. Studies of behavior therapies support their effectiveness in comparison with wait-list or no-treatment control conditions, but the efficacy data are less convincing for these therapies compared with usual treatment for chronic LBP. There is evidence that surgery may be effective for a carefully selected group of patients with chronic LBP. Multidisciplinary rehabilitation programs usually offer the best outcomes, but such programs are the most expensive approach, and high-quality randomized, controlled trials are still needed to document their efficacy. The patient’s perception of disability is a critical factor that must be addressed for treatment to succeed.
Complex Regional Pain Syndrome (Causalgia and Reflex Sympathetic Dystrophy)
The term complex regional pain syndrome (CRPS) now replaces reflex sympathetic dystrophy (CRPS type I) and causalgia (CRPS type II). Type I involves ongoing spontaneous burning pain that is precipitated by a specific noxious trauma or cause of immobilization and is usually associated with hyperalgesia or allodynia to cutaneous stimuli. The symptoms are not limited to a single peripheral nerve, and there is often evidence of edema, blood flow abnormalities, or sudomo-tor dysfunction in the region of pain, usually an extremity. Motor changes such as tremor, weakness, and limitations in movement are common. If nerve injury is present, complex regional pain syndrome type II is appropriately diagnosed. Although the natural history varies, three clinical stages are classically described. Stage 1 (acute, early) is characterized by an inflammatory onset with constant aching or burning pain. Stage 2 (dystrophic, intermediate) is notable for cool, pale, and cyanotic skin. Stage 3 (atrophic, late) manifests as atrophy and wasting of multiple soft tissues, fixed joint contractures, and osteoporosis. When pain is relieved by blockade of the efferent sympathetic nervous system, the modifier, sympathetically maintained pain, is added. Patients with sympathetically maintained pain often report hyperalgesia to cold stimuli.
Patients with complex regional pain syndrome often exhibit emotional distress and psychological dysfunction. The reported prevalence of psychiatric disorders in patients with complex regional pain syndrome ranges from 18% to 64%. Examination using the Structured Clinical Interview for DSMTV (SCID) demonstrated a high frequency of affective (46%), anxiety (27%), and substance abuse disorders (14%) in patients with complex regional pain syndrome (). Some patients with complex regional pain syndrome may exhibit signs of conversion disorder, such as the normalization of hypoesthesia by nerve blocks. Non-anatomic and expansive areas of hypoesthesia or hyperalgesia with normal peripheral sensory nerve conduction or somatosensory evoked potentials in patients with complex regional pain syndrome type I are probably psychogenic in origin. Neurophysio-logical investigation suggests that certain positive motor signs (dystonia, tremors, spasms, irregular jerks) identified in patients with complex regional pain syndrome type I represent pseudoneurological illness (). A review of studies that used the Minnesota Multiphasic Personality Inventory (MMPI) concluded that patients with CRPS, like other patients with chronic pain, are somatically preoccupied, are depressed, and use repression as a psychological defense mechanism. However, there are no consistent differences in psychological characteristics or psychiatric diagnoses between complex regional pain syndrome and non-CRPS pain patients.
Several literature reviews have examined whether psychological dysfunction was the cause or effect of CRPS. The majority of studies suffered flaws in methodology such as a lack of homogenous diagnostic groups, lack of control groups, and incorrect use of psychiatric or psychological terminology. Depression, anxiety, and fear of movement are common, but no unique personality traits or profile predisposes one to develop CRPS. In patients with CRPS, a recent study of daily diaries demonstrated that the prior day’s depressed mood contributed to the present day’s increased pain and that yesterday’s pain also contributed to today’s depression, anxiety, and anger.
In summary, most authors have concluded that co-morbid psychopathology in patients with complex regional pain syndrome is a consequence of the chronic pain rather than its cause. However, psychiatric conditions should be treated as primary barriers to functional rehabilitation. In addition, treatment for complex regional pain syndrome usually combines a variety of anesthetic blocks, typically regional sympathetic blocks, with oral sympatholytics, reactivating physical therapies, adjuvant analgesic medications, electrical stimulation, and possibly even surgical sympathectomy.
Trigeminal neuralgia (tic douloureux) is a chronic pain syndrome with severe, paroxysmal, recurrent, lancinating pain in the distribution of cranial nerve V that is unilateral and most commonly involves the mandibular division. Sensory or motor deficits are not usually present. Episodes of pain can be spontaneous or evoked by nonpainful stimuli to trigger zones, activities such as talking or chewing, or environmental conditions. Between episodes, patients are typically pain-free. Less common syndromes involving the intermedius branch of the facial nerve or the glossopharyngeal nerve present with pain that can involve the ear, posterior pharynx, tongue, or larynx. Other related conditions include cluster headache, which occurs predominantly in men with an onset before age 25 and presents with pain that is episodic, unilaterally surrounding the eye, excruciating, lasts minutes to hours, and is associated with autonomic symptoms. Short-lasting, unilateral, neuralgiform pain with conjunctival injection and tearing (SUNCT) syndrome is a rare condition that more commonly affects older males. Tolosa-Hunt syndrome manifests as pain in the ocular area accompanied by ipsilateral paresis of oculomotor nerves and the first branch of the trigeminal nerve that is associated with compromise of ophthalmic venous circulation, and improves with steroids. The residual category of atypical facial pain is more commonly associated with psychopa-thology or other psychological factors that amplify the patient’s pain, distress, and disability.
The majority of patients with classical trigeminal neuralgia show evidence of trigeminal nerve root compression by blood vessels (85%), mass lesions, or other diseases that cause demyelination and hyperactivity of the trigeminal nucleus (multiple sclerosis, herpes zoster, post-herpetic neuralgia). The ignition hypothesis postulates that afferent fibers become hyperexcitable as a result of injury and that paroxysms of pain are the manifestation of synchronized afterdischarge activity. Uncontrolled pain with frequent or severe prolonged attacks increases the risk of insomnia, weight loss, social withdrawal, anxiety, and depression, including suicide. Pharmacological treatment includes anticonvulsants, antidepressants, baclofen, mexiletine, lidocaine, and opioids. When pharmacological treatments fail, a variety of surgical procedures, such as microvascular decompression via suboccipital craniectomy, percutaneous gangliolysis, and stereotactic radiosurgery, may be undertaken.
Temporomandibular disorder (TMD) is a general term referring to complaints that involve the temporomandibular joint, muscles of mastication, and other orofacial musculoskeletal structures. Pain most commonly arises from the muscles of mastication and is precipitated by jaw function, such as opening the mouth or chewing. Associated symptoms include feelings of muscle fatigue, weakness, and tightness as well as changes in bite (malocclusion) or the ability to open/close the jaw. In contrast to the vague, diffuse pain of myalgia, temporomandibular joint dysfunction causes sharp, sudden, and intense pain with joint movement that is often localized to the preauricular area. Joint sounds such as clicking, popping, and crepitation are common. Patients may experience limitations in jaw movements, such as catching sensations or actual locking of the jaw. Joint problems are classified as relating to the condyle-disk complex, structural incompatibility of the articular surfaces, and inflammatory joint disorders.
Psychological distress is common in patients with temporomandibular disorder. Patients with pain of muscular origin are usually more distressed and depressed, with greater levels of disability, than those with TM joint pain. These factors are responsive to treatment. Longitudinal data suggest that negative affect in patients with orofacial pain is more likely than pain to cause poor sleep quality. Patients with TMD classified as either “dysfunctional” or “interpersonally distressed” were at higher risk to develop chronic pain without treatment, suggesting a role for proactive prevention programs during the initial acute stages of illness or injury. In treatment trials for patients with TMD, the dysfunctional group showed the best response to multidisciplinary treatment, with greater improvements in pain intensity, interference, catastrophizing, depression, and negative thoughts when compared with the other groups. Patients with low levels of psychosocial dysfunction experienced significantly decreased pain, pain-related interference, numbers of painful muscles, and visits for temporomandibular disorder treatment when they received a less intensive self-care treatment program.
Burning mouth syndrome (BMS) is characterized as pain in oral and pharyngeal cavities, especially the tongue, often associated with dryness and taste alterations. Most cases are idiopathic, but BMS may coincide with a plethora of conditions such as bruxism, poorly fitting dentures, oral candidiasis, xerostomia, malnutrition, food allergies and contact dermatitis, gastroesophageal reflux disease, diabetes mellitus, hypothyroidism, neoplasia, menopause, and psychiatric conditions such as depression, anxiety, and somatoform disorders. The condition mainly affects middle-aged and postmenopausal women, and the oral mucosa is usually normal. Psychological factors such as severe life events have been associated with the condition.
Theories of etiology and pathogenesis include brain stem pathology, hyperactivity of sensory and motor components of the trigeminal nerve following loss of central inhibition that resulted from damage to the chorda tympani or glossopharyngeal nerves, disorders of the dopaminergic system, and small sensory fiber dysfunction. Potential underlying etiologies — such as depression/anxiety, nutritional deficiencies (iron, folate, B12, and other B vitamins), maladaptive oral habits, and iatrogenic causes such as medications — should be identified and treated. Treatment with TCAs or anticonvulsants has brought pain relief in some patients with burning mouth syndrome. Other treatments include benzodiazepines, topical analgesics, soft desensitizing oral appliances, serotonin reuptake inhibitors, vitamin and hormonal supplements, and habit awareness counseling.
Selections from the book: “Textbook of Psychosomatic Medicine”, 2005.