J. Greg Hobelmann, M.D., M.P.H.
Michael R. Clark, M.D., M.P.H., M.B.A.
In this chapter, we first review definitions, assessment, and epidemiology of pain. We then discuss selected acute and chronic pain syndromes, followed by the major psychiatric comorbidities of chronic pain, including somatization, substance use, depression, anxiety, and other emotional states. Finally, we review treatments for pain, including medications, psychological therapies, and interdisciplinary programs.
Pain is a complex experience that integrates affective, cognitive, and behavioral factors with an extensive neurobiology. Pain has been defined by the International Association for the Study of Pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (Merskey 2007). This definition recognizes that pain may be experienced in the absence of tissue damage and is, therefore, a subjective experience. Many terms are used to describe different types of painful experiences (Table 34–1).
Type of pain |
Description |
Allodynia |
Pain from a stimulus that does not normally provoke pain |
Deafferentation pain |
Pain resulting from loss of sensory input into the central nervous system |
Dysesthesia |
Unpleasant, abnormal sensation that can be spontaneous or evoked |
Hyperalgesia |
Increased response to a stimulus that is normally painful |
Hyperesthesia |
Abnormal increase in sensitivity to stimuli |
Hypoesthesia |
Abnormal decrease in sensitivity to stimuli |
Neuropathic pain |
Pain arising from a lesion or disease of the somatosensory system that is often accompanied by maladaptive changes in the nervous system |
Nociception |
Detection of tissue damage by transducers in skin and deeper structures and central propagation of this information via A delta and C fibers in the peripheral nerves |
Paresthesia |
Abnormal sensation, spontaneous or evoked, that is not unpleasant |
Sensitization |
Lowered threshold for pain and prolonged/enhanced response to stimulation |
Source. Adapted from Merskey et al. 1986.
Pain is a subjective experience and is difficult to assess, especially in patients with terminal illnesses or significant cognitive impairment (Nikolaus 1997). Pain rating scales attempt to measure the severity and intensity of pain. Many factors can influence ratings, including disease states, mental disorders, distress, personality traits, and the meanings assigned to symptoms based on personal beliefs. A variety of verbal and behavioral assessment tools can be used for rating pain in elderly populations (Kaasalainen and Crook 2003).
Pain is the number one reason that patients present to physicians and is the cause of considerable societal burden (Cherry et al. 2003). Prevalence estimates of chronic pain vary considerably because of varying definitions of chronic pain as well as a lack of patient databases for pain statistics (Henschke et al. 2015). However, a recent study used National Health Interview Survey data to calculate the point prevalence of persistent pain, defined as constant or frequent pain persisting for at least 3 months (Kennedy et al. 2014). Findings showed that about 19% of adults in the United States report persistent pain, with rates being higher among women, adults ages 60–69 years, adults who rated their health as fair to poor, adults who were overweight or obese, and adults who were hospitalized one or more times in the preceding year. Patients with chronic pain utilize about twice as many health care resources as the general population. In 2010, U.S. health care costs secondary to pain ranged from $560 billion to $635 billion (Gaskin and Richard 2012).
The Joint Commission (formerly the Joint Commission on Accreditation of Healthcare Organizations) has implemented pain management standards for all patient encounters (Phillips and Joint Commission on Accreditation of Healthcare Organizations 2000). Acute pain is usually the result of trauma from a surgery, an injury, or an exacerbation of chronic disease, especially musculoskeletal conditions. Treatment is focused on controlling inflammation, preventing tissue destruction, and repairing injury, with more emphasis placed on pain relief to facilitate reaching these goals.
The approach to acute pain management usually will be successful with straightforward strategies such as relaxation, immobilization, analgesics (aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs], opioids), massage, and transcutaneous electrical nerve stimulation (Institute for Clinical Systems Improvement 2008). The absence of signs consistent with acute pain, such as elevated heart rate and blood pressure or diaphoresis, does not rule out the presence of pain. Acute pain management initiated as early as possible and focused on preventing occurrence and reemergence of pain may reduce dosage requirements for analgesics. Analgesics, especially opioids, should be prescribed only for pain relief (Manchikanti et al. 2012a, 2012b). Although analgesia may produce many benefits, other symptoms commonly coinciding with acute pain (e.g., insomnia, anxiety) should be managed separately from pain. Sleep deprivation and anxiety may intensify the sensation of pain and lead to increased requests for more medication. Alleviating anxiety and insomnia may reduce analgesic requirements.
In acute pain management, psychiatric consultation is requested when a patient requires more analgesia than expected or has a history of substance abuse. Patients with an active or recent history of opioid addiction and those receiving opioid agonist maintenance therapy usually have developed tolerance to opioids and when receiving short-acting opioids for acute pain management may require doses up to 50% higher than those required by opioid-naive patients (see Chapter 16, “Substance-Related Disorders”). Although it is important to monitor opioid use carefully in these patients, adequate treatment of acute pain is a priority. Inadequate dosing is significantly more common than abuse or diversion in these patients.
When a medical cause for pain cannot be identified, many clinicians begin to seek psychological causes. The concept of pain “caused” by emotional factors first appeared in DSM-II (American Psychiatric Association 1968) under psychophysiological disorders, and DSM-III (American Psychiatric Association 1980) introduced psychogenic pain disorder, which in DSM-III-R (American Psychiatric Association 1987) was revised to somatoform pain disorder.
Prevalence estimates depend on the diagnostic criteria used to define the pain condition. For example, the DSM-III-R diagnosis of somatoform pain disorder had an estimated lifetime prevalence of 34% and a 6-month prevalence of 17% in the general population. The updated DSM-IV (American Psychiatric Association 1994) diagnosis of pain disorder included a new requirement for “significant distress or psychosocial impairment due to somatoform pain” that reduced the lifetime prevalence to 12% and the 6-month prevalence to 5%, with a female:male ratio of 2:1 (Grabe et al. 2003). The diagnosis pain disorder was eliminated in DSM-5 (American Psychiatric Association 2013), and a new diagnostic category, somatic symptom and related disorders, was introduced, along with its prototype, somatic symptom disorder (SSD). Criteria for SSD differed from those for the DSM-IV diagnosis of somatization disorder, with the most significant change being abolition of the distinction between medically explained and medically unexplained somatic complaints (for a detailed discussion, see Chapter 11, “Somatic Symptom Disorder and Illness Anxiety Disorder”). There is little research on SSD to date, because it was recently introduced in DSM-5.
Even when pain is the chief complaint, the experience of pain is influenced by psychological factors. Injured workers who developed DSM-III-R somatoform pain disorder had more sites of pain with spread of pain beyond the area of original injury, more opioid and benzodiazepine use, and greater involvement with compensation and litigation compared with workers who did not develop this disorder (Streltzer et al. 2000). Pain disorder was often equated with “psychogenic” pain that has no “real” cause. However, neuroimaging studies in patients with DSM-IV pain disorder showed significant decreases in gray matter density in prefrontal, cingulate, and insular cortexes, regions that are known to modulate the subjective experience of pain (Valet et al. 2009). Unfortunately, the diagnosis retains an inherent either/or dualism regarding psychological versus physical domains instead of pointing the way toward an appreciation of how those domains interrelate. Regardless of the etiology of pain, the physical and/or psychological distress resulting from pain can cause significant reductions in quality of life (QOL) (Rief and Martin 2014).
Whereas multiple pain complaints were typical in DSM-IV somatization disorder, patients with chronic pain rarely received this diagnosis. Rather, the somatization disorder diagnosis was more commonly given to patients with multiple painful and other somatic complaints (especially in primary care settings) who had high rates of symptom persistence and health care use (Jackson and Kroenke 2008). In DSM-5, such patients would be considered for a diagnosis of SSD. These patients are more likely to have catastrophic thinking, to believe that the cause of their pain is a mysterious medical disease, to have feelings of losing control, and to think that their physicians judge their pain to be imaginary (Jackson and Kroenke 2008). Patients with chronic pain and multiple somatic symptoms also are at risk of iatrogenic consequences such as excessive diagnostic tests, inappropriate medications, and unnecessary surgery. Overlap between SSD and related disorders and depressive or anxiety disorders is common. Patients with multiple somatic complaints that are not able to be medically explained experience significant functional disability and role impairment independent of psychiatric and medical comorbidity (Harris et al. 2009).
The prevalence of DSM-IV substance dependence or addiction in patients with chronic pain has been estimated to range from 3% to 48%, depending on the population sampled (Morasco et al. 2011). The essential criteria for a substance use disorder in patients with chronic pain include loss of control over the use of pain medication, excessive preoccupation with obtaining the medication despite adequate analgesia, and adverse consequences associated with the medication’s use (Compton et al. 1998). The availability of opioids has risen exponentially over the past 25 years. The number of opioid prescriptions written annually has also increased dramatically, from 76 million in 1991 to 207 million in 2013, and a significant rise in opioid abuse has followed, including a major increase in heroin abuse over the past few years (Kanouse and Compton 2015). Americans represent less than 5% of the world’s population but consume 80% of the global opioid supply, including 99% of the hydrocodone produced (Manchikanti and Singh 2008).
Aberrant medication-taking behaviors can be mistaken for addiction. Persistent pain can lead to an increased preoccupation with obtaining opioids, with the patient taking measures to ensure an adequate medication supply. Patients understandably fear the reemergence of pain and withdrawal symptoms that will occur if they run out of medication. Medication-seeking behavior may be the result of an anxious patient trying to maintain a previous level of pain control or improve on a partial but inadequate response to analgesics. However, rather than representing a true addiction, these actions may indicate pseudoaddiction arising from therapeutic dependence and current or potential undertreatment (Kirsh et al. 2002). The distinction between pseudoaddiction and true addiction is based on how the patient responds to adequate analgesic therapy—i.e., whether the behaviors abate and functioning improves, or, alternatively, the behaviors persist in the context of deteriorating function. However, empirical evidence supporting pseudoaddiction as a diagnosis distinct from addiction has not emerged, so clinicians should always maintain a high index of suspicion (Greene and Chambers 2015).
Patterns of nonadherence to or misuse of prescribed medications have complex associations with emotional distress, disability, perceived need for medication, and patients’ concerns about addiction and excessive scrutiny of medication use by others (McCracken et al. 2006). These factors influence the risk of developing an addiction to prescribed medications. During the first 5 years after the onset of a chronic pain problem, patients are at increased risk for developing new substance use problems and disorders. The risk is highest among those with a history of substance use disorder or psychiatric comorbidity. Not infrequently, a history of substance abuse emerges only after the current misuse of medications has been identified, thus requiring physicians to monitor treatment closely.
Although patients exposed to long-term opioid therapy are at significant risk of developing addiction, they are at much higher risk of aberrant medication-taking behaviors and illicit drug use, reinforcing the need for risk screening and monitoring (Fishbain et al. 2008). Aberrant medication-taking behaviors occur in approximately 50% of patients with chronic pain receiving long-term opioid analgesic therapy, with even higher rates in patients with a history of substance abuse (Passik et al. 2006). Risk-prediction instruments such as the Screener and Opioid Assessment for Patients with Pain (SOAPP), the Opioid Risk Tool (ORT), and the Current Opioid Misuse Measure (COMM) offer valuable guidance but have significant limitations (Chou et al. 2009). Strategies to optimize outcomes and minimize abuse require careful analysis of the behaviors of both patients and physicians (Passik and Kirsh 2008).
From the opposite perspective, patients with substance use disorders have increased rates of chronic pain. Although it is true that opioid-dependent patients with chronic pain have relatively high rates of substance abuse (Peles et al. 2005; Rosenblum et al. 2003), they are at risk of stigmatization and undertreatment. Integrating care for chronic pain with innovative stepped-care models of substance abuse treatment would likely improve outcomes by bringing together both types of expertise (Bair et al. 2015; Haibach et al. 2014).
The relation between pain and depression is intimate and bidirectional. Physical symptoms are common in patients with major depressive disorder (MDD). Approximately 60% of patients with depression report pain symptoms at diagnosis. A study using World Health Organization research data from 14 countries on 5 continents found that 69% (range: 45%–95%) of patients with depression presented with only somatic symptoms, of which pain complaints were most common (Simon et al. 1999). It has been estimated that patients with depression have about a fourfold increase in the prevalence of pain conditions (Ohayon and Schatzberg 2003). Additionally, baseline depressive symptoms more accurately predict future pain and disability than do initial ratings of the actual pain (Schieir et al. 2009).
Individuals with chronic physical complaints have higher rates of lifetime MDD. Among patients presenting to clinics specializing in chronic pain, one-third to more than half met criteria for current MDD (Dersh et al. 2007; Rayner et al. 2016). Depression in patients with chronic pain is associated with greater pain intensity; more pain persistence; application for early retirement; and greater interference from pain, including more pain behaviors observed by others (Rayner et al. 2016). High levels of depression my worsen pain and pain-related disability (Lerman et al. 2015). Depression is a better predictor of disability than are pain intensity and duration. In a study of more than 15,000 employees who filed health claims, the cost of managing chronic conditions such as back problems was almost doubled when the employees had comorbid depression (Druss et al. 2000).
Most chronic pain conditions have been associated with an increased risk of suicide (Ilgen et al. 2013). In an Australian study in 1,514 individuals receiving prescribed opioids, 36.5% reported experiencing suicidal ideation in the past 12 months, and 16.4% reported a lifetime suicide attempt (Campbell et al. 2016). Patients with chronic pain complete suicide at two to three times the rate of people in the general population (Fishbain et al. 1991). Although other psychosocial variables play a role, it is depression that most consistently and strongly predicts suicidal ideation and behaviors in patients with chronic pain (Braden and Sullivan 2008). Pain is even more likely to be an independent risk factor for suicide in patients with headache or multiple types of pain (Ilgen et al. 2008).
Depression with comorbid chronic pain can be more resistant to treatment than depression without pain (Kroenke et al. 2008). Depression should be treated aggressively and not simply “understood” as an expected outcome of suffering with chronic pain. Pain often subsides with improvement in depressive symptoms, resulting in improvement in function and QOL. This effect is independent of the direct treatment of pain and may be explained by overlap between the neurobiology of pain and depression (Bair et al. 2003).
Anxiety symptoms are present in almost half of patients with chronic pain. Up to 30% of these patients meet criteria for an anxiety disorder (e.g., generalized anxiety disorder, panic disorder, agoraphobia) or for posttraumatic stress disorder (PTSD) (Outcalt et al. 2015). PTSD is increasingly recognized as a comorbid condition with significant consequences for patients with medical illnesses, especially chronic pain disorders (Liebschutz et al. 2007). PTSD has strong independent negative associations with pain, disability, psychological status, and QOL (Outcalt et al. 2015). A follow-up reassessment of people who had sustained a severe accident 3 years earlier found that PTSD symptoms and other psychological factors were stronger predictors of the development of chronic pain than were sociodemographic and accident-related variables (Jenewein et al. 2009). Conversely, anxiety symptoms and disorders are associated with high levels of somatic preoccupation and physical symptoms. In a study in 139 patients with panic disorder, almost two-thirds reported at least one current pain symptom (Schmidt et al. 2002). Pain was associated with higher levels of anxiety symptoms, panic frequency, and panic-related cognitive variables (e.g., anxiety sensitivity) (Schmidt et al. 2002). Patients with pain and comorbid anxiety have worse outcomes than do pain patients without an anxiety disorder (Jordan and Okifuji 2011).
Fear of pain, of movement, of reinjury, and of other negative consequences leads to avoidance of activities and promotes initiation and maintenance of chronic pain disability (Greenberg and Burns 2003). Restriction of activities can result in physiological changes, such as weight gain and muscle atrophy, and functional deterioration (Verbunt et al. 2003). This process is reinforced by low self-efficacy, catastrophic interpretations, and increased expectations of failure regarding attempts to engage in rehabilitation. The fear–avoidance model of musculoskeletal pain (Leeuw et al. 2007) incorporated elements such as pain severity, pain catastrophizing, hypervigilance to pain, pain-related fear, escape or avoidance behavior, disability, disuse, and individual vulnerabilities to explain the transition from acute to chronic low back pain (LBP). Pain-related fear and avoidance represent one of the most significant predictors of failure to return to work in patients with chronic LBP and are also predictive of poor adjustment to chronic pain (Hasenbring et al. 2001).
Catastrophic thinking can be described as the amplification of threatening information. Catastrophic thinking about pain interferes with patients’ ability to remain involved in productive activities (Crombez et al. 1998). It intensifies the experience of pain and increases emotional distress and self-perceived disability (Sullivan et al. 2001). Although catastrophic thinking is often conceptualized as a psychological entity, Campbell and Edwards (2009) theorized that catastrophizing exerts biological effects that may account for some of its negative consequences. For example, a follow-up study of participants in a Dutch population-based questionnaire survey found that high levels of catastrophizing and fear of injury prospectively predicted disability due to new-onset LBP 6 months later (Picavet et al. 2002). Similarly, a systematic review found that catastrophizing was an independent risk factor for chronic pain after total knee arthroplasty (Burns et al. 2015). Pain-related catastrophizing has been shown to be a predictor of suicidal ideation independent of depressive symptoms and pain severity (Edwards et al. 2006).
There is ample evidence to suggest that pain and sleep are related, but the association between these two conditions is complex. The prevailing view has been that they are reciprocally related. However, emerging evidence from population-based longitudinal studies suggests that sleep problems may exert a greater influence on pain than pain does on sleep problems (Finan et al. 2013). A study examining associations between self-reported sleep measures (including sleep duration, sleep-onset latency, sleep efficiency, and frequency/severity of insomnia)—and pain sensitivity found that all parameters except sleep duration were significantly associated with reduced pain tolerance (Sivertsen et al. 2015). Further study is needed to guide clinical efforts to develop and improve treatments for chronic sleep disturbance in the setting of chronic pain.
Postherpetic neuralgia (PHN) is defined as pain persisting or recurring at the site of shingles (herpes zoster) at least 3 months after the onset of the acute varicella zoster viral rash. PHN occurs in about 10% of patients with acute herpes zoster. More than half of patients older than 65 years with shingles develop PHN, and it is more likely to occur in patients with cancer, diabetes mellitus, systemic lupus erythematous, recent trauma, or severe immunosuppression (Forbes et al. 2016). It occurs in less than 6% of immunocompetent people, however (Johnson and Rice 2014). Other risk factors for PHN are longer duration of prodromal symptoms, greater acute pain and rash severity, sensory impairment, and psychological distress (Volpi et al. 2008). Most cases gradually improve over time, with only about 25% of patients with PHN experiencing pain at 1 year after diagnosis. Approximately 15% of referrals to pain clinics are for the treatment of PHN.
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 in the affected skin. 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 (Truini et al. 2008). Approaches to management of PHN include prevention with vaccination or antiviral medication and treatment of resulting pain. Current guidelines recommend treating the pain in a hierarchical manner with anticonvulsants, tricyclic antidepressants (TCAs), and topical lidocaine as first-line agents (Mallick-Searle et al. 2016).
The most common cause of painful peripheral neuropathy is diabetes mellitus (Veves et al. 2008; Zochodne 2008). Up to 90% of patients with diabetes will experience pain from diabetic neuropathy; risk factors include longer duration of illness and poor glycemic control (Schreiber et al. 2015). The pain of a peripheral neuropathy can range from constant burning to pain that is episodic, paroxysmal, and lancinating in quality (Mendell and Sahenk 2003). These phenomena are primarily the result of axonal degeneration and segmental demyelination (Tomlinson and Gardiner 2008). Diabetic peripheral neuropathic pain is a stronger predictor of depression than other diabetic complications (D’Amato et al. 2016). Patients with diabetic neuropathic pain who have depression or anxiety receive greater amounts of pain medication and have higher health care utilization (Boulanger et al. 2009). Often, a combination of treatment modalities with different mechanisms of action is required to manage the pain. Medication with proven efficacy include TCAs, serotonin–norepinephrine reuptake inhibitors (SNRIs), anticonvulsants, and topical lidocaine. Adjuvant treatments such as acupuncture, transcutaneous electrical nerve stimulation, cognitive-behavioral therapy (CBT), and neuromodulation have also demonstrated effectiveness (Rosenberg and Watson 2015).
Pain associated with central nervous system lesions is common after stroke (8%) or spinal cord trauma (60%–70%) (Finnerup 2008; Singer et al. 2017). Symptoms of spinal cord injury (SCI) pain or central poststroke pain are independent of sensory deficits and often are poorly localized, vary over time, and include allodynia (>50% of patients with central poststroke pain), hyperalgesia, dysesthesias, lancinating pain, and muscle and visceral pain. Pain is described as burning, aching, lacerating, or pricking. Radiological studies may reveal lesions in the thalamus, although other sites, such as the spinothalamic tracts, are often involved, especially in SCI (Hari et al. 2009). Excitatory amino acids are likely involved in the development of central sensitization associated with central pain, and the onset of pain can occur more than a month after the stroke, suggesting multiple processes (Hains and Waxman 2007; Hulsebosch et al. 2009; Oh and Seo 2015).
As a result of its complexity and symptom heterogeneity, central poststroke pain is difficult to treat, and there is no universal consensus regarding effective treatment (Mulla et al. 2015). Antidepressants, anticonvulsants, and opioids are used, often in combination (Seifert et al. 2013). For patients who are nonresponsive to medical management, motor cortex stimulation, deep-brain stimulation, and repetitive transcranial magnetic stimulation have been used (Hirabayashi et al. 2011).
The International Headache Society has published guidelines for the classification of headache. Over the life span, 18% of women and 6% of men will experience migraine headaches, with peak incidence between the ages of 30 and 40 years (Lipton et al. 2007; Silberstein et al. 2007). Common migraine is a unilateral pulsatile headache that may be associated with other symptoms, such as nausea, vomiting, photophobia, and phonophobia. The classic form of migraine includes 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). Anxiety and depression are the psychiatric comorbidities most commonly associated with migraine, and anxiety is more robustly associated with increase in migraine risk than is depression. In addition, the physical symptoms of depression are more closely linked to migraine than are the emotional symptoms (Peres et al. 2017). The primary goals of migraine treatment are relieving pain, restoring function, and reducing headache frequency (Lipton and Silberstein 2015).
Evidence from placebo-controlled clinical trials supports the use of NSAIDs and triptans for acute treatment of migraine attacks, with propranolol, metoprolol, flunarizine, valproate, topiramate, and onabotulinumtoxinA (botulinum toxin A) recommended as the best prophylactic agents (Becker 2015; Mulleners and Chronicle 2008; Silberstein 2015). In general, calcium channel blockers, β-blockers, antidepressants, and anticonvulsants are the treatments of choice for more refractory migraine (Silberstein 2008). Behavioral treatments such as CBT and biofeedback or relaxation training are effective therapies (Carod-Artal 2014). A group-based multidisciplinary treatment for migraine consisting of stress management, supervised exercise, dietary education, and massage therapy significantly improved pain outcomes (i.e., self-perceived pain intensity, frequency, and duration) as well as functional status, QOL, depression, and pain-related disability (Lemstra et al. 2002).
Chronic daily headache affects about 5% of the population and encompasses constant (transformed) migraine, medication-overuse headache, chronic tension-type headaches, new-onset daily persistent headache, and hemicrania continua (Dodick 2006). Individuals with chronic daily headache are more likely than those without daily headaches to overuse analgesics, leading to rebound headache; to have psychiatric comorbidity such as depression and anxiety; to report functional disability; and to experience stress-related headache exacerbations (Fernández-de-las-Peñas and Schoenen 2009). Chronic daily headache is difficult to manage and is often unresponsive to medication (Halker et al. 2011). Evidence from placebo-controlled clinical trials is sparse but supports the use of amitriptyline, gabapentin, tizanidine, mirtazapine, topiramate, memantine, and onabotulinumtoxinA (Dodick 2006). Various medications have been recommended, including serotonin agonists, serotonin antagonists, and α2-adrenergic agonists. Combined medication and CBT are more effective than either treatment alone (Lipchik and Nash 2002).
Fibromyalgia is a chronic pain syndrome characterized by widespread musculoskeletal pain in all four limbs and trunk, stiffness, and exaggerated tenderness. These symptoms are usually accompanied by poor sleep, cognitive difficulties, depression, and fatigue. There is little evidence to support theories of inflammatory, autoimmune, or infectious etiologies (Borchers and Gershwin 2015). Placebo-controlled trials have demonstrated the effectiveness of cyclobenzaprine, milnacipran, gabapentin, pregabalin, duloxetine, and tramadol in fibromyalgia (Crofford 2008). In addition to these medications, treatment should include education, patient support, physical therapy, nutrition, and exercise (Borchers and Gershwin 2015).
Fibromyalgia is discussed in detail in Chapter 25, “Chronic Fatigue and Fibromyalgia Syndromes.”
Pain in a body part that has been removed occurs in 40%–80% of amputees within a year of the amputation (Schley et al. 2008). Phantom limb pain, considered to be neuropathic and described as stabbing, throbbing, burning, or cramping, is more intense in the distal portion of the phantom limb. Any area of the body can manifest phantom pain; for example, phantom breast sensations and pain are common after mastectomy (Luo and Anderson 2016). Although TCAs, gabapentin, and carbamazepine are considered the first-line treatments for phantom pain, no controlled trials support their use. Newer antidepressants and anticonvulsants generally cause fewer side effects and may be more effective in treating phantom limb pain if patients can tolerate higher doses. In controlled studies, morphine, calcitonin, and ketamine have been shown to reduce phantom pain in the short term. Controlled trials have discredited anecdotal reports of the effectiveness of neural blockade and onabotulinumtoxinA (Alviar et al. 2016).
Complex regional pain syndrome (CRPS; formerly called reflex sympathetic dystrophy and causalgia) represents an array of painful conditions characterized by ongoing spontaneous burning pain that is precipitated by a specific noxious trauma or cause of immobilization and often is associated with hyperalgesia or allodynia in response to cutaneous stimuli (Hsu 2009; Sharma et al. 2009). It occurs in about 7% of patients following limb fractures, limb surgeries, or other injuries (Bruehl 2015). Pain is regional but is not limited to a single peripheral nerve or dermatome. Edema, blood flow abnormalities, or sudomotor dysfunction is often evident in the pain region (Albazaz et al. 2008). Motor changes such as weakness, tremor, dystonia, and limitations in movement are common (Harden et al. 2007). Sympathetically maintained pain is present in most, but not all, cases (Gibbs et al. 2008). Patients with sympathetically maintained pain often report hyperalgesia to cold stimuli and temporary relief with sympathetic blockade (Pontell 2008). Patients with CRPS commonly have comorbid mood (46%), anxiety (27%), and substance use (14%) disorders, which are generally considered to be a consequence of chronic pain rather than its cause, when coupled with maladaptive personality traits and coping styles (Bruehl and Chung 2006). In addition, anxiety, pain-related fear, and disability have been associated with poorer outcomes in CRPS and should be considered as target variables for early treatment (Bean et al. 2015). Studies have also shown a relationship between CRPS and suicide risk. Significant risk factors for suicidal ideation in patients with CRPS include greater severity of pain, presence of depressive symptoms, and decreased functioning (Lee et al. 2014).
Pharmacotherapy for CRPS has showed limited benefit, and relatively few randomized controlled trials (RCTs) are available to guide treatment selection (Mackey and Feinberg 2007). Symptoms often improve with NSAIDs or corticosteroids in the acute, or inflammatory, stage of the disease. Evidence suggests efficacy for gabapentin, pregabalin, carbamazepine, TCAs, and opioids. RCTs of calcitonin and bisphosphonates in CRPS found reduced pain and improved joint mobility. Clinical trials of local anesthetic sympathetic blockade, once considered the gold standard therapy for CRPS, have been inconclusive (Sharma et al. 2006). Multidisciplinary care, which centers on functionally focused therapies, is recommended (Bruehl 2015).
Trigeminal neuralgia (tic douloureux) is a chronic pain syndrome with a prevalence of 0.015% (Montano et al. 2015) characterized by severe, paroxysmal, recurrent, lancinating unilateral pain localized to the sensory distribution of cranial nerve V, most commonly involving the mandibular division (Obermann and Katsarava 2009; Prasad and Galetta 2009). 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. Uncontrolled pain with frequent or severe prolonged attacks increases the risk of insomnia, weight loss, social withdrawal, anxiety, and depression, including suicide (Wu et al. 2015).
Pharmacological treatment includes anticonvulsants, antidepressants, baclofen, mexiletine, lidocaine, and opioids (Bescós et al. 2015). Placebo-controlled trials have identified carbamazepine (number needed to treat of 1.8) as the first-line treatment, with oxcarbazepine and lamotrigine as additional options. Evidence is insufficient to recommend clonazepam, gabapentin, phenytoin, tizanidine, topical capsaicin, valproate, or onabotulinumtoxinA (Cruccu et al. 2008). Given the pathophysiological similarities between trigeminal neuralgia and PHN and painful peripheral neuropathies, other medications, such as TCAs and SNRIs, would be appropriate options to consider. When pharmacological treatments fail, a variety of surgical procedures may be undertaken (Al-Quliti 2015; Montano et al. 2015).
Temporomandibular disorder (TMD) is a general term referring to complaints involving the temporomandibular joint, muscles of mastication, and other orofacial musculoskeletal structures, often precipitated by jaw movement (e.g., opening the mouth or chewing). 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. Associated symptoms include feelings of muscle fatigue, weakness, and tightness as well as changes in bite (malocclusion) or in the ability to open or close the jaw. Joint sounds such as clicking, popping, and crepitation are common. TMD is often associated with psychological stress, but no evidence is available to compare the clinical effectiveness of usual treatment (occlusal splint therapy) versus psychological interventions (Roldán-Barraza et al. 2014). Treatment should initially be based on conservative and evidence-based therapeutic modalities, with more invasive interventions reserved for refractory pain (Dugashvili et al. 2013).
Burning mouth syndrome is covered in Chapter 19, “Gastrointestinal Disorders.”
LBP is extremely common, with a lifetime risk greater than 80% (Patrick et al. 2016). It is the most expensive medical condition when lost productivity and health care costs are included (Deyo et al. 2009). Psychological factors, including distress, depressed mood, and multiple somatic symptoms that have not received an adequate medical explanation, are highly correlated with LBP and predict the transition from acute to chronic pain. The most powerful predictor of chronicity is poor functional status beyond 1 month of seeking treatment. In patients with chronic nonmalignant back pain, the presence of both economic (e.g., disability income) and social rewards (e.g., avoidance of onerous tasks) was associated with higher levels of disability and depression (Ciccone et al. 1999). The presence of a depressive disorder has been shown to increase the risk of developing musculoskeletal pain in general, and chronic LBP in particular (Pinheiro et al. 2016). Depression has been associated with a nearly fourfold increase in the likelihood of seeking treatment for new-onset LBP. Conversely, chronic LBP can increase the risk of developing psychopathology that affects outcome and treatment response (Dersh et al. 2007).
Treatment of chronic LBP has been pursued with multiple modalities alone and in combination (Deyo and Weinstein 2001). Recommendations for managing LBP emphasize patient education, short-term use of NSAIDS, physical therapy, back exercises, and behavioral therapy. Short-term opioid treatment should be used only for severe acute exacerbations (Dagenais et al. 2010). Few RCTs have evaluated the effectiveness of adjuvant treatment with anticonvulsants or antidepressants; although these agents can provide significant pain relief, they are also associated with side effects that may outweigh their benefits (Chung et al. 2013). Evidence indicates that surgery may be effective for a carefully selected group of patients with chronic LBP (Fritzell et al. 2001). Although treatments often produce symptom reduction, evidence for their ability to improve functional status—particularly with respect to returning to work—is conflicting (Staiger et al. 2003). The patient’s perception of disability is a critical factor that must be addressed in order for treatment to succeed.
Numerous medications are used in the treatment of chronic pain (Moulin et al. 2007). The pharmacological targets are mechanisms of peripheral and central nervous system sensitization, such as sodium and calcium channel upregulation, spinal hyperexcitability, descending modulation, and aberrant sympathetic–somatic nervous system interactions. Many classes of medication have been used alone or in combination, but no algorithm can provide a simple, straightforward approach to the complexities encountered during the treatment of chronic pain.
Opioids reduce the sensory and affective components of pain by interacting with μ, δ, and κ opioid receptors located in both the peripheral and the central nervous systems. Controversy surrounds the long-term use of opioids for chronic nonmalignant pain because of concerns about long-term efficacy and safety, particularly the risk of tolerance, dependence, abuse, and fatal overdose (Noble et al. 2010). Studies of opioid efficacy generally last less than 18 months and are complicated by high rates of discontinuation due to adverse events or insufficient pain relief. Evidence suggests that the risk of serious side effects from opioids is dose dependent (Chou et al. 2015). Opioids should be slowly tapered to avoid withdrawal and should be completely discontinued if the risks (side effects, toxicities, aberrant drug-related behaviors) outweigh the objective benefits (analgesia, functional improvements).
Successful treatment with opioids requires the assessment and documentation of improvement in pain, function, and analgesia without adverse side effects or aberrant behaviors. Guidelines have been established for the use of opioids in chronic pain that help balance the beneficial effects against the unwanted adverse effects (Manchikanti et al. 2012a, 2012b). Appropriate patients are those with moderate or severe pain that has persisted for more than 3 months and that adversely affects functioning or QOL. Before initiating opioid therapy, additional factors—such as the patient’s specific pain syndrome, response to other therapies, and potential for aberrant drug-related behaviors—should be considered (Ballantyne and LaForge 2007). A patient’s suitability for long-term opioid therapy can be assessed with standardized questionnaires such as the ORT, the SOAPP, and the Diagnosis, Intractability, Risk, Efficacy (DIRE) assessment tool. Treatment outcomes, including adequacy of analgesia, performance of activities of daily living, adverse events, and potential aberrant drug-related behaviors, can be assessed with the Pain Assessment and Documentation Tool (PADT; Passik et al. 2004). The COMM instrument can be used to evaluate opioid-treated patients for concurrent signs or symptoms of intoxication, emotional volatility, poor response to medication, addiction, inappropriate health care use, and problematic medication behaviors.
Clinically available opioids include naturally occurring compounds (morphine and codeine), semisynthetic derivatives (hydromorphone, oxymorphone, hydrocodone, oxycodone, dihydrocodeine, and buprenorphine), and synthetic opioid analgesics (meperidine, fentanyl, methadone, tramadol, pentazocine, and propoxyphene). Morphine, because of its hydrophilicity, has poor oral bioavailability (22%–48%) as well as delayed central nervous system absorption and onset of action. This delay prolongs the analgesic effect of morphine relative to its plasma half-life, which reduces the potential for accumulation and toxicity with repeated dosing. Oxycodone has higher oral bioavailability (>60%), a faster onset of action, and more predictable plasma levels compared with morphine. Although its analgesic efficacy is similar to that of morphine, oxycodone releases less histamine and is less likely to cause hallucinations (Riley et al. 2008). Hydrocodone is similar to oxycodone, with rapid oral absorption and onset of analgesia. Hydrocodone is metabolized by N-demethylation to hydromorphone, which has properties similar to those of morphine but fewer side effects. Fentanyl is highly lipophilic, which allows for transdermal or transmucosal delivery; however, it is the most potent opioid and therefore is associated with greater risk of fatal overdose. The duration of action of transdermal preparations is up to 72 hours, but individual variability is considerable. Meperidine can cause seizures and an agitated delirium and is now rarely used to treat pain. Tramadol is a “semi-opioid” that weakly binds to opioid receptors and weakly inhibits the reuptake of serotonin and norepinephrine.
Methadone is notable for its association with injection drug addiction, low cost, high bioavailability, rapid onset of action, slow hepatic clearance, multiple receptor affinities, lack of neurotoxic metabolites, and incomplete cross-tolerance with other opioids. Compared with other opioids, methadone, due to its uniquely long half-life, carries a significantly greater risk of overdose because of the longer time needed for adaptation with oral use and greater variations in plasma half-life (15–120 hours) (Sandoval et al. 2005). Methadone is unique among opioids in its heightened propensity to cause QTc interval prolongation and torsades de pointes (Pani et al. 2013). The drug’s extensive tissue distribution and prolonged half-life prevent withdrawal symptoms with once-daily dosing. However, methadone elimination is biphasic, and the more rapid elimination phase effectively limits the duration of analgesic effects to approximately 6 hours. Repeated dosing, with accumulation in tissue, may increase the duration of analgesia to 8–12 hours.
The most common side effect of long-term opioid therapy is decreased gastrointestinal motility, causing constipation, vomiting, and abdominal pain. Oral opioid agents differ in their propensity to cause these symptoms. Long-term opioid administration may lead to analgesic tolerance or opioid-induced hyperalgesia (Mitra 2008). When tolerance develops, coadministration of other analgesics, opioid rotation to a more potent agonist, or intermittent cessation of certain agents may restore analgesic effects (Dumas and Pollack 2008). Readers are referred to Chapter 16, “Substance-Related Disorders,” for a more detailed discussion of treatment of pain in patients receiving methadone or buprenorphine maintenance treatment.
The analgesic properties of antidepressants remain underappreciated (McCleane 2008). The TCAs and SNRIs, in particular, are effective treatments for many chronic pain syndromes, including diabetic neuropathy, PHN, central pain, poststroke pain, tension-type headache, migraine, and orofacial pain, but not for nonspecific LBP (Verdu et al. 2008). The analgesic effect of antidepressants is thought to be independent of their antidepressant effect and is mediated primarily by the blockade of norepinephrine and serotonin reuptake, thereby enhancing the activation of descending inhibitory neurons in the dorsal horn of the spinal cord (McCleane 2008; Micó et al. 2006). However, antidepressants may produce antinociceptive effects through a variety of pharmacological mechanisms, including modulation by monoamines; interactions with opioid systems; inhibition of ion channel activity; and inhibition of N-methyl-D-aspartate, histamine, and cholinergic receptors (Dick et al. 2007).
Meta-analyses of RCTs have concluded that TCAs are the most effective agents for neuropathic pain and that they are also effective for headache syndromes (Finnerup et al. 2015). TCAs have been shown to effectively treat central poststroke pain, PHN, many types of painful polyneuropathies, and postmastectomy pain syndrome, but have not been shown to benefit SCI pain, phantom limb pain, or painful HIV neuropathy. The various TCAs are equally effective for pain, but secondary-amine TCAs (e.g., nortriptyline) are better tolerated than tertiary agents (e.g., amitriptyline) (Dworkin et al. 2007). In the treatment of pain, TCAs generally produce analgesia at lower dosages than those used to treat depression, with an earlier onset of effect (Rojas-Corrales et al. 2003). Lack of analgesic effects may be a result of inadequate dosing; therefore, careful titration guided by serum-level monitoring should be used to achieve optimal response. Chronic pain in PHN and diabetic peripheral neuropathy has been treated successfully with TCAs at average dosages of 100–250 mg/day (Max 1994). In contrast, a study using a U.S. health insurance claims database to examine TCA use for neuropathic pain in older patients (≥65 years) found that the average dosage was only 23 mg/day, suggesting unrealized potential for additional pain relief (Berger et al. 2006).
Duloxetine, venlafaxine, desvenlafaxine, and milnacipran inhibit the presynaptic reuptake of serotonin, norepinephrine, and (to a lesser extent) dopamine. Although SNRIs are associated with fewer side effects and less toxicity than TCAs, they cannot be monitored with serum levels.
In placebo-controlled trials, venlafaxine significantly reduced neuropathic pain following breast cancer treatment (Tasmuth et al. 2002). It is effective in migraine prophylaxis (Dharmshaktu et al. 2012; Ozyalcin et al. 2005) and reduces allodynia and hyperalgesia in neuropathic pain (Yucel et al. 2005). Venlafaxine also may be effective for fibromyalgia (VanderWeide et al. 2015). Duloxetine has demonstrated analgesic efficacy both in preclinical models and in clinical populations including patients with fibromyalgia (Arnold et al. 2005), painful diabetic neuropathy (Wernicke et al. 2006), or osteoarthritis (Micca et al. 2013). A Cochrane review recommends duloxetine as an effective treatment for neuropathic pain (Lunn et al. 2014). The efficacy of duloxetine in painful diabetic neuropathy was greater in patients with more severe pain but was not related to the severity of diabetes or neuropathy (Ziegler et al. 2007). Patients with depression and painful somatic symptoms experienced relief when taking duloxetine, but the analgesic effects were independent of the drug’s antidepressant actions (Perahia et al. 2006).
In clinical trials, the efficacy of selective serotonin reuptake inhibitors (SSRIs) in chronic pain syndromes has been inconsistent, especially in the treatment of neuropathic pain (Finnerup et al. 2005). A Cochrane review found SSRIs no more efficacious than placebo for migraine and less efficacious than TCAs for tension-type headache (Banzi et al. 2015). However, fluoxetine improved outcome measures (i.e., pain impact and severity) in women with fibromyalgia (Arnold et al. 2002) and was comparable to amitriptyline in significantly reducing rheumatoid arthritis pain (Rani et al. 1996). Citalopram improved abdominal pain in irritable bowel syndrome, and its therapeutic effects on pain were independent of its effects on anxiety and depression (Tack et al. 2006). Paroxetine and citalopram, but not fluoxetine, decreased the pain of diabetic peripheral neuropathy in some controlled studies (Goodnick 2001). In a study comparing gabapentin, paroxetine, and citalopram for painful diabetic peripheral neuropathy, the three agents had similar efficacy for pain, but patients reported better satisfaction, compliance, and mood with the SSRIs (Giannopoulos et al. 2007). Overall, SSRIs are not recommended as a first-line therapy for chronic pain but may be worth considering when comorbid depression is present.
Few controlled trials have examined the efficacy of novel antidepressants, such as mirtazapine, bupropion, trazodone, vortioxetine, and vilazodone, in pain syndromes, but their pharmacology suggests antinociceptive properties. In controlled trials, mirtazapine reduced the duration and intensity of chronic tension-type headaches (Bendtsen and Jensen 2004), and bupropion reduced pain intensity and interference of pain with QOL (Semenchuk et al. 2001). Trazodone can be useful in treating chronic pain, but sedation can hinder titration to the effective dose (Bossini et al. 2015). Vortioxetine and vilazodone are too new to have accumulated evidence of efficacy in treating pain.
Anticonvulsants reduce pain by inhibiting excessive neuronal activity. They have shown efficacy in treating a variety of neuropathic pain syndromes, such as trigeminal neuralgia, diabetic neuropathy, and PHN, as well as in prevention of migraine recurrence (Seidel et al. 2013). Anticonvulsants have also demonstrated efficacy in neuropathic pain (number needed to treat ranging from ~2 to ~4), and are associated with better medication adherence compared with TCAs because they have fewer adverse effects (Finnerup et al. 2005).
Phenytoin was first reported as a successful treatment for trigeminal neuralgia in 1942 (Bergouignan 1942). Carbamazepine is the most widely studied anticonvulsant in neuropathic pain (Wiffen et al. 2014a). Valproate is most commonly used for prophylaxis of migraine headaches, but it is also effective for neuropathic pain (Gill et al. 2014).
Second-generation anticonvulsants include gabapentin, pregabalin, lamotrigine, and topiramate. Pregabalin and gabapentin are effective for the treatment of painful diabetic neuropathy, PHN, fibromyalgia, postamputation phantom limb pain, and central neuropathic pain associated with SCI (Moore et al. 2014; Ogawa et al. 2016). In patients with PHN, flexible titration strategies result in fewer discontinuations, higher final dosages, and slightly better pain relief compared with fixed-dosage schedules (Stacey et al. 2008). Gabapentin and pregabalin are entirely renally excreted, so lower dosages must be used in patients with impaired renal function (Atalay et al. 2013).
Lamotrigine is effective in treating HIV-related neuropathy and central poststroke pain but has not shown efficacy in other neuropathic conditions (Wiffen and Rees 2007). Dosages greater than 300 mg/day were more effective than lower dosages in the treatment of painful diabetic neuropathy (Vinik et al. 2007). Topiramate offers the advantages of minimal hepatic metabolism and unchanged renal excretion, few drug interactions, a long half-life, and the unusual side effect of weight loss. Topiramate has shown efficacy in migraine prophylaxis and in treatment of chronic LBP and pain from lumbar radiculopathy and diabetic neuropathy; however, its benefits are not clearly established, and it can impair cognition (Wiffen et al. 2013a).
Oxcarbazepine is a carbamazepine derivative with an improved safety and tolerability profile that is effective for the treatment of diabetic peripheral neuropathy but not other neuropathic pain (Zhou et al. 2013). Tiagabine, vigabatrin, retigabine, levetiracetam, and zonisamide are new anticonvulsants with a spectrum of pharmacological actions and antinociceptive effects in animal models, but few clinical studies exist to support their use as first-line therapy for chronic pain (Wiffen et al. 2013b, 2014b). Combinations of anticonvulsants with complementary mechanisms of action may increase effectiveness and decrease adverse effects of treatment, but this has not been clearly established.
Benzodiazepines are commonly prescribed for insomnia, anxiety, and spasticity. Although there is some evidence that benzodiazepines have antihyperalgesic (reduction of increased sensitivity to pain) properties (Howard et al. 2014), their use in conjunction with opioids may be countertherapeutic (Gauntlett-Gilbert et al. 2016) and potentially dangerous: the combination of benzodiazepines with opioids in treatment of chronic pain significantly increases the risk of fatal overdose (Sun et al. 2017). Benzodiazepines cause sedation and cognitive impairment, especially in elderly and other vulnerable patients. In patients with chronic pain, benzodiazepines, but not opioids, were associated with reduced activity levels, increased rates of health care utilization and depression, and increased disability days (Ciccone et al. 2000).
Antipsychotics have been used in diabetic neuropathy, PHN, headache, facial pain, pain associated with AIDS and cancer, and musculoskeletal pain, with increasing evidence supporting their effectiveness, mainly as an add-on therapy to other agents (Fishbain et al. 2004; Seidel et al. 2013). However, a meta-analysis of 11 controlled trials concluded that the evidence was mixed regarding use of antipsychotics as add-on therapy in the treatment of painful conditions (Seidel et al. 2013). Compared with typical antipsychotics, atypical antipsychotics offer a broader therapeutic spectrum and lower rates of extrapyramidal side effects; however, these benefits have been offset by concerns about their adverse metabolic effects.
Topical lidocaine has been approved for the treatment of PHN and does not produce significant serum levels (Khaliq et al. 2007), but the evidence to date in neuropathic pain is not strong (Derry et al. 2014). Oral mexiletine has been used for various types of neuropathic pain, but supportive evidence is lacking.
Capsaicin is derived from the chili pepper and has been used for centuries as a natural pain reliever. Although low-dose topical capsaicin has limited effectiveness in pain, high-dose capsaicin, when tolerated, has shown benefit in the treatment of chronic musculoskeletal pain and neuropathic pain (Smith and Brooks 2014). Topical capsaicin may also be useful for patients who are unresponsive or intolerant to other treatments (Mason et al. 2004).
Psychological treatment for chronic pain was pioneered by Fordyce, who used an operant conditioning behavioral model (Fordyce et al. 1973). The behavioral approach focuses on understanding pain in a social context. The behavior of a patient with chronic pain not only influences and shapes the behaviors of others (including physicians) but also is reinforced and shaped by the behaviors of others. Behaviors signifying pain, such as facial expressions (grimacing), nonverbal utterances (moans), and body movements (guarding) have well-recognized features that define and differentiate them from behaviors associated with other states (Keogh 2014). The behavioral model assumes that if pain behaviors persist, pain and disability will likewise persist. In treatment, healthy behaviors are targeted for reinforcement to replace extinguished pain behaviors.
Since the initial applications of CBT to chronic pain, much research has established the importance of cognitive and behavioral processes in how individuals adapt to chronic pain (Ehde et al. 2014). The cognitive-behavioral model of chronic pain assumes that individual beliefs, attitudes, and expectations affect emotional and behavioral reactions to life experiences. Pain and the resultant pain behaviors are influenced by biomedical, psychological, and socioenvironmental variables.
If patients believe that pain, depression, and disability are inevitable and uncontrollable, then they will likely experience more negative affective responses, increased pain, and even more impaired physical and psychosocial functioning. The components of CBT, such as relaxation, guided imagery, biofeedback, meditation, hypnosis, motivational interviewing, external reinforcement, cognitive restructuring, and coping self-statement training, interrupt this cycle of disability. Patients are taught to become active participants in the management of their pain by using methods that minimize distressing thoughts and feelings. Regardless of the techniques used, the goals of CBT focus the patient on self-control and self-management to increase activity, independence, and resourcefulness. A recent review revealed that CBT reduced pain intensity in 43% of trials and that online and in-person formats had comparable efficacy (Knoerl et al. 2016). A Cochrane review concluded that CBT had significant but small effects on pain and disability and moderate effects on mood and catastrophizing (Williams et al. 2012). The benefits of CBT have been found to continue up to 6 months after the completion of active treatment sessions.
In CBT, pain beliefs are conceptualized as the thoughts of an individual about his or her personal pain problem (Morley and Wilkinson 1995). Psychosocial dysfunction has been correlated with receiving overly solicitous responses from family, believing emotions are related to pain, and attributing the inability to function to pain (Jensen et al. 1994b). In contrast, although physical disability was correlated with beliefs about pain interfering with function, patients also endorsed the belief that pain signifies injury, and therefore that activity should be avoided. A change in perceived control over pain was the most significant predictor of beneficial effects of CBT for chronic TMD pain (Turner et al. 2007).
Cognitive variables derived from social learning theory that are relevant to chronic pain include self-efficacy, outcome expectancies, and locus of control (Solberg Nes et al. 2009). A self-efficacy expectancy is a belief about one’s ability to perform a specific behavior, whereas an outcome expectancy is a belief about the consequences of performing a behavior. Individuals are thought to be more likely to engage in coping efforts they believe are within their capabilities and will result in a positive outcome. Patients with a variety of chronic pain syndromes who score higher on measures of self-efficacy or who have an internal locus of control report lower levels of pain, higher pain thresholds, increased exercise performance, and more positive coping efforts. Interestingly, physician expectations of pain relief were significant predictors of patient pain relief ratings, a finding that supports the important role of other persons in an individual’s chronic pain experience.
Acceptance of chronic pain is a two-factor construct (activity engagement and pain willingness) associated with multiple domains of the experience of chronic pain. Acceptance of pain was found to be associated with reports of lower pain intensity, less pain-related anxiety and avoidance, less depression, less physical and psychosocial disability, more daily uptime, and better work status (McCracken 1998). Acceptance has been found to mediate the effects of catastrophizing on depression, avoidance, and functioning in patients with chronic pain (Vowles et al. 2008). A patient’s acceptance of chronic pain predicts his or her adjustment to the illness and is independent of catastrophizing, coping skills, and pain-related beliefs and cognitions (Esteve et al. 2007; Vowles et al. 2007).
Coping can be defined as “a person’s cognitive and behavioral efforts to manage the internal and external demands of the person–environment transaction that is appraised as taxing or exceeding the person’s resources” (Folkman et al. 1986, p. 571). Coping strategies support the cognitive-behavioral model of chronic pain, whether active versus passive or adaptive versus maladaptive (Jensen 2009). However, patients who remain passive or who continue to use maladaptive coping strategies—such as catastrophizing, ignoring or reinterpreting pain sensations, or diverting attention from pain—have higher disability (Jensen et al. 1994a).
The effectiveness of particular coping strategies depends on many aspects of the patient’s experience with pain. For example, reinterpreting pain sensations as not being signs of ongoing injury typically has been formulated as useful for reducing the effects of experimentally induced pain. However, focusing on pain and disability for greater periods of time, such as is needed in CBT, can be detrimental if it diverts patients from engaging in social activities and healthy behaviors. Catastrophic thinking about pain involves amplification of threatening somatic information and disruption of the attentional focus needed for patients to maintain involvement in productive rather than pain-related activities (Crombez et al. 1998). In one study, high levels of catastrophizing combined with lower levels of active pain coping predicted higher levels of depressive symptoms and disability (Buenaver et al. 2008). The use of adaptive coping skills decreased pain and disability when patients perceived an increase in the effectiveness of their new skills and reduced their use of maladaptive coping strategies such as catastrophic thinking.
Placebos are arguably the most commonly prescribed drug across cultures and throughout history (Gold and Lichtenberg 2014). Placebo effects and patient responses to them are complex phenomena but are similar to the effects of and patient responses to active treatments (Kleinman et al. 1994). There is not a single placebo effect, but many effects (Benedetti 2006). Placebo analgesia is a biologically measurable phenomenon (Greene et al. 2009). In a clinical setting, it is difficult to separate “true” improvements from placebo responses. The expectations and previous experiences of both patients and physicians are well-established key mediators of placebo effects (Reicherts et al. 2016). How physicians communicate with patients influences the magnitude of placebo effects (Czerniak et al. 2016).
Historically, placebo interventions were a part of paternalistic medicine’s treatment armamentarium (Kaptchuk 1998). In the era of RCTs, placebos may be used if informed consent is obtained. The clinical use of placebos without patients’ knowledge is unethical (Gold and Lichtenberg 2014). Use of placebos to determine whether the patient’s pain is “real” or to “cure” a psychogenic condition by replacing an analgesic with a “neutral” substance is dishonest, misleading, and counterproductive. A positive placebo response neither proves that the patient’s pain is psychogenic nor shows that the patient would not benefit from an active treatment. Such an intervention also can result in loss of the patient’s trust and render future treatment less effective.
Patients with chronic pain report lower levels of physical, psychological, and social well-being and greater impairments in health-related QOL compared with patients with almost all other medical conditions (O’Connor 2009). Interdisciplinary pain rehabilitation programs provide a full range of treatments for the most difficult pain syndromes within a framework of collaborative ongoing communication among team members, patients, and other interested parties (Stanos and Houle 2006).
Substantial evidence indicates that interdisciplinary pain rehabilitation programs improve functioning in several areas for patients with various chronic pain syndromes, even those with severe disability (Lake et al. 2009; van Wilgen et al. 2009). A recent Cochrane review concluded that for chronic LBP, interdisciplinary rehabilitation interventions were more effective than usual care and physical treatments in decreasing pain and disability (Kamper et al. 2015). The goal of treating chronic pain is to end disability and return people to work or other productive activities, and interdisciplinary interventions do show efficacy in returning patients to work (Norlund et al. 2009). Overall, evidence suggests that interdisciplinary programs allow early treatment and reduce unnecessary health costs (Malaty et al. 2014).
Chronic pain is a significant public health problem and is frustrating to everyone affected by it, especially patients, who may feel that health care has failed them. Psychiatrists as medical specialists should take an active role in the care of these patients because pharmacological and psychological treatments are now recognized as being effective in the management of chronic pain. Recent advances in the treatment of chronic pain include diagnosis and treatment of psychiatric comorbidity, application of psychiatric treatments to chronic pain, and development of interdisciplinary efforts to provide comprehensive health care to patients with disabling and refractory chronic pain syndromes. Specifically, the psychiatrist provides expertise in examining mental life and behavior as well as in understanding the individual person and the systems in which he or she interacts. Finally, psychiatrists can facilitate the integration of medical care delivery with mental health care and specialist care in a collaborative interdisciplinary environment.
Albazaz R, Wong YT, Homer-Vanniasinkam S: Complex regional pain syndrome: a review. Ann Vasc Surg 22(2):297–306, 2008 18346583
Al-Quliti KW: Update on neuropathic pain treatment for trigeminal neuralgia. The pharmacological and surgical options. Neurosciences (Riyadh) 20(2):107–114, 2015 25864062
Alviar MJ, Hale T, Dungca M: Pharmacologic interventions for treating phantom limb pain. Cochrane Database Syst Rev (10):CD006380, 2016 27737513
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 2nd Edition. Washington, DC, American Psychiatric Association, 1968
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition. Washington, DC, American Psychiatric Association, 1980
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, Revised. Washington, DC, American Psychiatric Association, 1987
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC, American Psychiatric Association, 1994
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Arlington, VA, American Psychiatric Association, 2013
Arnold LM, Hess EV, Hudson JI, et al: A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. Am J Med 112(3):191–197, 2002 11893345
Arnold LM, Rosen A, Pritchett YL, et al: A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain 119(1–3):5–15, 2005 16298061
Atalay H, Solak Y, Biyik Z, et al: Cross-over, open-label trial of the effects of gabapentin versus pregabalin on painful peripheral neuropathy and health-related quality of life in haemodialysis patients. Clin Drug Investig 33(6):401–408, 2013 23572323
Bair MJ, Robinson RL, Katon W, et al: Depression and pain comorbidity: a literature review. Arch Intern Med 163(20):2433–2445, 2003 14609780
Bair MJ, Ang D, Wu J, et al: Evaluation of stepped care for chronic pain (ESCAPE) in veterans of the Iraq and Afghanistan conflicts: a randomized clinical trial. JAMA Intern Med 175(5):682–689, 2015 25751701
Ballantyne JC, LaForge KS: Opioid dependence and addiction during opioid treatment of chronic pain. Pain 129(3):235–255, 2007 17482363
Banzi R, Cusi C, Randazzo C, et al: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the prevention of tension-type headache in adults. Cochrane Database Syst Rev (5):CD011681, 2015 25931277
Bean DJ, Johnson MH, Heiss-Dunlop W, et al: Do psychological factors influence recovery from complex regional pain syndrome type 1? A prospective study. Pain 156(11):2310–2318, 2015 26133727
Becker WJ: Acute migraine treatment. Coninuum (Minneap Minn) 21(4, Headache):953–972, 2015 26252584
Bendtsen L, Jensen R: Mirtazapine is effective in the prophylactic treatment of chronic tension-type headache. Neurology 62(10):1706–1711, 2004 15159466
Benedetti F: Placebo analgesia. Neurol Sci 27 (suppl 2):S100–S102, 2006 16688609
Berger A, Dukes EM, Edelsberg J, et al: Use of tricyclic antidepressants in older patients with painful neuropathies. Eur J Clin Pharmacol 62(9):757–764, 2006 16802165
Bergouignan M: Cures heureuses de nevralgies faciales essentielles par le diphenyl-hydantoinate de soude. Rev Laryngol Otol Rhinol (Bord) 63:34–41, 1942
Bescós A, Pascual V, Escosa-Bage M, et al: Treatment of trigeminal neuralgia: an update and future prospects of percutaneous techniques [in Spanish]. Rev Neurol 61(3):114–124, 2015 26178516
Borchers AT, Gershwin ME: Fibromyalgia: a critical and comprehensive review. Clin Rev Allergy Immunol 49(2):100–151, 2015 26445775
Bossini L, Coluccia A, Casolaro I, et al: Off-label trazodone prescription: evidence, benefits and risks. Curr Pharm Des 21(23):3343–3351, 2015 26088119
Boulanger L, Zhao Y, Foster TS, et al: Impact of comorbid depression or anxiety on patterns of treatment and economic outcomes among patients with diabetic peripheral neuropathic pain. Curr Med Res Opin 25(7):1763–1773, 2009 19505204
Braden JB, Sullivan MD: Suicidal thoughts and behavior among adults with self-reported pain conditions in the national comorbidity survey replication. J Pain 9(12):1106–1115, 2008 19038772
Bruehl S: Complex regional pain syndrome. BMJ 351:h2730, 2015 26224572
Bruehl S, Chung OY: Psychological and behavioral aspects of complex regional pain syndrome management. Clin J Pain 22(5):430–437, 2006 16772797
Buenaver LF, Edwards RR, Smith MT, et al: Catastrophizing and pain-coping in young adults: associations with depressive symptoms and headache pain. J Pain 9(4):311–319, 2008 18165160
Burns LC, Ritvo SE, Ferguson MK, et al: Pain catastrophizing as a risk factor for chronic pain after total knee arthroplasty: a systematic review. J Pain Res 8:21–32, 2015 25609995
Campbell CM, Edwards RR: Mind-body interactions in pain: the neurophysiology of anxious and catastrophic pain-related thoughts. Transl Res 153(3):97–101, 2009 19218091
Campbell G, Bruno R, Darke S, et al: Prevalence and correlates of suicidal thoughts and suicide attempts in people prescribed pharmaceutical opioids for chronic pain. Clin J Pain 32(4):292–301, 2016 26295378
Carod-Artal FJ: Tackling chronic migraine: current perspectives. J Pain Res 7:185–194, 2014 24748814
Cherry DK, Burt CW, Woodwell DA: National Ambulatory Medical Care Survey: 2001 summary. Adv Data (337):1–44, 2003 12924075
Chou R, Fanciullo GJ, Fine PG, et al: Opioids for chronic noncancer pain: prediction and identification of aberrant drug-related behaviors: a review of the evidence for an American Pain Society and American Academy of Pain Medicine clinical practice guideline. J Pain 10(2):131–146, 2009 19187890
Chou R, Turner JA, Devine EB, et al: The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med 162(4):276–286, 2015 25581257
Chung JW, Zeng Y, Wong TK: Drug therapy for the treatment of chronic nonspecific low back pain: systematic review and meta-analysis. Pain Physician 16(6):E685–E704, 2013 24284847
Ciccone DS, Just N, Bandilla EB: A comparison of economic and social reward in patients with chronic nonmalignant back pain. Psychosom Med 61(4):552–563, 1999 10443765
Ciccone DS, Just N, Bandilla EB, et al: Psychological correlates of opioid use in patients with chronic nonmalignant pain: a preliminary test of the downhill spiral hypothesis. J Pain Symptom Manage 20(3):180–192, 2000 11018336
Compton P, Darakjian J, Miotto K: Screening for addiction in patients with chronic pain and “problematic” substance use: evaluation of a pilot assessment tool. J Pain Symptom Manage 16(6):355–363, 1998 9879160
Crofford LJ: Pain management in fibromyalgia. Curr Opin Rheumatol 20(3):246–250, 2008 18388513
Crombez G, Eccleston C, Baeyens F, et al: When somatic information threatens, catastrophic thinking enhances attentional interference. Pain 75(2–3):187–198, 1998 9583754
Cruccu G, Gronseth G, Alksne J, et al; American Academy of Neurology Society; European Federation of Neurological Society: AAN-EFNS guidelines on trigeminal neuralgia management. Eur J Neurol 15(10):1013–1028, 2008 18721143
Czerniak E, Beigon A, Ziv A, et al: Manipulating the placebo response in experimental pain by altering doctor’s performance style. Front Psychol 7:874, 2016 27445878
Dagenais S, Tricco AC, Haldeman S: Synthesis of recommendations for the assessment and management of low back pain from recent clinical practice guidelines. Spine J 10(6):514–529, 2010 20494814
D’Amato C, Morganti R, Greco C, et al: Diabetic peripheral neuropathic pain is a stronger predictor of depression than other diabetic complications and comorbidities. Diab Vasc Dis Res 13(6):418–428, 2016 27334483
Derry S, Wiffen PJ, Moore RA, et al: Topical lidocaine for neuropathic pain in adults. Cochrane Database Syst Rev (7):CD010958, 2014 25058164
Dersh J, Mayer T, Theodore BR, et al: Do psychiatric disorders first appear preinjury or postinjury in chronic disabling occupational spinal disorders? Spine 32(9):1045–1051, 2007 17450081
Deyo RA, Weinstein JN: Low back pain. N Engl J Med 344(5):363–370, 2001 11172169
Deyo RA, Mirza SK, Turner JA, et al: Overtreating chronic back pain: time to back off? J Am Board Fam Med 22(1):62–68, 2009 19124635
Dharmshaktu P, Tayal V, Kalra BS: Efficacy of antidepressants as analgesics: a review. J Clin Pharmacol 52(1):6–17, 2012 21415285
Dick IE, Brochu RM, Purohit Y, et al: Sodium channel blockade may contribute to the analgesic efficacy of antidepressants. J Pain 8(4):315–324, 2007 17175203
Dodick DW: Clinical practice. Chronic daily headache. N Engl J Med 354(2):158–165, 2006 16407511
Druss BG, Rosenheck RA, Sledge WH: Health and disability costs of depressive illness in a major U.S. corporation. Am J Psychiatry 157(8):1274–1278, 2000 10910790
Dugashvili G, Menabde G, Janelidze M, et al: Temporomandibular joint disorder (review). Georgian Med News 215(215):17–21, 2013 23482357
Dumas EO, Pollack GM: Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective. AAPS J 10(4):537–551, 2008 18989788
Dworkin RH, O’Connor AB, Backonja M, et al: Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 132(3):237–251, 2007 17920770
Edwards RR, Smith MT, Kudel I, et al: Pain-related catastrophizing as a risk factor for suicidal ideation in chronic pain. Pain 126(1–3):272–279, 2006 16926068
Ehde DM, Dillworth TM, Turner JA: Cognitive-behavioral therapy for individuals with chronic pain: efficacy, innovations, and directions for research. Am Psychol 69(2):153–166, 2014 24547801
Esteve R, Ramírez-Maestre C, López-Marínez AE: Adjustment to chronic pain: the role of pain acceptance, coping strategies, and pain-related cognitions. Ann Behav Med 33(2):179–188, 2007 17447870
Fernández-de-las-Peñas C, Schoenen J: Chronic tension-type headache: what is new? Curr Opin Neurol 22(3):254–261, 2009 19300250
Finan PH, Goodin BR, Smith MT: The association of sleep and pain: an update and a path forward. J Pain 14(12):1539–1552, 2013 24290442
Finnerup NB: A review of central neuropathic pain states. Curr Opin Anaesthesiol 21(5):586–589, 2008 18784483
Finnerup NB, Otto M, McQuay HJ, et al: Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 118(3):289–305, 2005 16213659
Finnerup NB, Attal N, Haroutounian S, et al: Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 14(2):162–173, 2015 25575710
Fishbain DA, Goldberg M, Rosomoff RS, et al: Completed suicide in chronic pain. Clin J Pain 7(1):29–36, 1991 1809412
Fishbain DA, Cutler RB, Lewis J, et al: Do the second-generation “atypical neuroleptics” have analgesic properties? A structured evidence-based review. Pain Med 5(4):359–365, 2004 15563321
Fishbain DA, Cole B, Lewis J, et al: What percentage of chronic nonmalignant pain patients exposed to chronic opioid analgesic therapy develop abuse/addiction and/or aberrant drug-related behaviors? A structured evidence-based review. Pain Med 9(4):444–459, 2008 18489635
Folkman S, Lazarus RS, Gruen RJ, et al: Appraisal, coping, health status, and psychological symptoms. J Pers Soc Psychol 50(3):571–579, 1986 3701593
Forbes HJ, Thomas SL, Smeeth L, et al: A systematic review and meta-analysis of risk factors for postherpetic neuralgia. Pain 157(1):30–54, 2016 26218719
Fordyce WE, Fowler RS Jr, Lehmann JF, et al: Operant conditioning in the treatment of chronic pain. Arch Phys Med Rehabil 54(9):399–408, 1973 4729785
Fritzell P, Hägg O, Wessberg P, Nordwall A; Swedish Lumbar Spine Study Group: Lumbar fusion versus nonsurgical treatment for chronic low back pain: a multicenter randomized controlled trial from the Swedish Lumbar Spine Study Group. Spine 26(23):2521–2532, discussion 2532–2534, 2001 11725230
Gaskin DJ, Richard P: The economic costs of pain in the United States. J Pain 13(8):715–724, 2012 22607834
Gauntlett-Gilbert J, Gavriloff D, Brook P: Benzodiazepines may be worse than opioids: negative medication effects in severe chronic pain. Clin J Pain 32(4):285–291, 2016 25968447
Giannopoulos S, Kosmidou M, Sarmas I, et al: Patient compliance with SSRIs and gabapentin in painful diabetic neuropathy. Clin J Pain 23(3):267–269, 2007 17314587
Gibbs GF, Drummond PD, Finch PM, et al: Unravelling the pathophysiology of complex regional pain syndrome: focus on sympathetically maintained pain. Clin Exp Pharmacol Physiol 35(7):717–724, 2008 18215185
Gill D, Derry S, Wiffen PJ, et al: Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev (10):CD009183, 2014 21975791
Gold A, Lichtenberg P: The moral case for the clinical placebo. J Med Ethics 40(4):219–224, 2014 23750027
Goodnick PJ: Use of antidepressants in treatment of comorbid diabetes mellitus and depression as well as in diabetic neuropathy. Ann Clin Psychiatry 13(1):31–41, 2001 11465683
Grabe HJ, Meyer C, Hapke U, et al: Somatoform pain disorder in the general population. Psychother Psychosom 72(2):88–94, 2003 12601226
Greenberg J, Burns JW: Pain anxiety among chronic pain patients: specific phobia or manifestation of anxiety sensitivity? Behav Res Ther 41(2):223–240, 2003 12547382
Greene CS, Goddard G, Macaluso GM, et al: Topical review: placebo responses and therapeutic responses. How are they related? J Orofac Pain 23(2):93–107, 2009 19492534
Greene MS, Chambers RA: Pseudoaddiction: fact or fiction? An investigation of the medical literature. Curr Addict Rep 2(4):310–317, 2015 26550549
Haibach JP, Beehler GP, Dollar KM, et al: Moving toward integrated behavioral intervention for treating multimorbidity among chronic pain, depression, and substance-use disorders in primary care. Med Care 52(4):322–327, 2014 24556895
Hains BC, Waxman SG: Sodium channel expression and the molecular pathophysiology of pain after SCI. Prog Brain Res 161:195–203, 2007 17618978
Halker RB, Hastriter EV, Dodick DW: Chronic daily headache: an evidence-based and systematic approach to a challenging problem. Neurology 76(7) (suppl 2):S37–S43, 2011 21321350
Harden RN, Bruehl S, Stanton-Hicks M, et al: Proposed new diagnostic criteria for complex regional pain syndrome. Pain Med 8(4):326–331, 2007 17610454
Hari AR, Wydenkeller S, Dokladal P, et al: Enhanced recovery of human spinothalamic function is associated with central neuropathic pain after SCI. Exp Neurol 216(2):428–430, 2009 19162017
Harris AM, Orav EJ, Bates DW, et al: Somatization increases disability independent of comorbidity. J Gen Intern Med 24(2):155–161, 2009 19031038
Hasenbring M, Hallner D, Klasen B: Psychological mechanisms in the transition from acute to chronic pain: over- or underrated? [in German]. Schmerz 15(6):442–447, 2001 11793149
Henschke N, Kamper SJ, Maher CG: The epidemiology and economic consequences of pain. Mayo Clin Proc 90(1):139–147, 2015 25572198
Hirabayashi H, Kawata K, Hoshida T, et al: Neuromodulation therapy for neuropathic pain (recent advances in neuromodulation). Japanese Journal of Neurosurgery 20(2):93–102, 2011
Howard P, Twycross R, Shuster J, et al: Benzodiazepines. J Pain Symptom Manage 47(5):955–964, 2014 24681184
Hsu ES: Practical management of complex regional pain syndrome. Am J Ther 16(2):147–154, 2009 19300041
Hulsebosch CE, Hains BC, Crown ED, et al: Mechanisms of chronic central neuropathic pain after spinal cord injury. Brain Res Brain Res Rev 60(1):202–213, 2009 19154757
Ilgen MA, Zivin K, McCammon RJ, et al: Pain and suicidal thoughts, plans and attempts in the United States. Gen Hosp Psychiatry 30(6):521–527, 2008 19061678
Ilgen MA, Kleinberg F, Ignacio RV, et al: Noncancer pain conditions and risk of suicide. JAMA Psychiatry 70(7):692–697, 2013 23699975
Institute for Clinical Systems Improvement: Health Care Guideline: Assessment and Management of Acute Pain, 6th Edition. March 2008
Jackson JL, Kroenke K: Prevalence, impact, and prognosis of multisomatoform disorder in primary care: a 5-year follow-up study. Psychosom Med 70(4):430–434, 2008 18434494
Jenewein J, Moergeli H, Wittmann L, et al: Development of chronic pain following severe accidental injury: results of a 3-year follow-up study. J Psychosom Res 66(2):119–126, 2009 19154854
Jensen MP: Research on coping with chronic pain: the importance of active avoidance of inappropriate conclusions. Pain 147(1–3):3–4, 2009 19692180
Jensen MP, Turner JA, Romano JM: Correlates of improvement in multidisciplinary treatment of chronic pain. J Consult Clin Psychol 62(1):172–179, 1994a 8034820
Jensen MP, Turner JA, Romano JM, et al: Relationship of pain-specific beliefs to chronic pain adjustment. Pain 57(3):301–309, 1994b 7936708
Johnson RW, Rice AS: Clinical practice: postherpetic neuralgia. N Engl J Med 371(16):1526–1533, 2014 25317872
Jordan KD, Okifuji A: Anxiety disorders: differential diagnosis and their relationship to chronic pain. J Pain Palliat Care Pharmacother 25(3):231–245, 2011 21882977
Kaasalainen S, Crook J: A comparison of pain-assessment tools for use with elderly long-term-care residents. Can J Nurs Res 35(4):58–71, 2003 14746121
Kamper SJ, Apeldoorn AT, Chiarotto A, et al: Multidisciplinary biopsychosocial rehabilitation for chronic low back pain: Cochrane systematic review and meta-analysis. BMJ 350:h444, 2015 25694111
Kanouse AB, Compton P: The epidemic of prescription opioid abuse, the subsequent rising prevalence of heroin use, and the federal response. J Pain Palliat Care Pharmacother 29(2):102–114, 2015 26095479
Kaptchuk TJ: Powerful placebo: the dark side of the randomised controlled trial. Lancet 351(9117):1722–1725, 1998 9734904
Kennedy J, Roll JM, Schraudner T, et al: Prevalence of persistent pain in the U.S. adult population: new data from the 2010 national health interview survey. J Pain 15(10):979–984, 2014 25267013
Keogh E: Gender differences in the nonverbal communication of pain: a new direction for sex, gender, and pain research? Pain 155(10):1927–1931, 2014 24997352
Khaliq W, Alam S, Puri N: Topical lidocaine for the treatment of postherpetic neuralgia. Cochrane Database Syst Rev (2):CD004846, 2007 17443559
Kirsh KL, Whitcomb LA, Donaghy K, et al: Abuse and addiction issues in medically ill patients with pain: attempts at clarification of terms and empirical study. Clin J Pain 18 (4 suppl):S52–S60, 2002 12479254
Kleinman I, Brown P, Librach L: Placebo pain medication: ethical and practical considerations. Arch Fam Med 3(5):453–457, 1994 8032507
Knoerl R, Lavoie Smith EM, Weisberg J: Chronic pain and cognitive behavioral therapy: an integrative review. West J Nurs Res 38(5):596–628, 2016 26604219
Kroenke K, Shen J, Oxman TE, et al: Impact of pain on the outcomes of depression treatment: results from the RESPECT trial. Pain 134(1–2):209–215, 2008 18022319
Lake AE 3rd, Saper JR, Hamel RL: Comprehensive inpatient treatment of refractory chronic daily headache. Headache 49(4):555–562, 2009 19245391
Lee DH, Noh EC, Kim YC, et al: Risk factors for suicidal ideation among patients with complex regional pain syndrome. Psychiatry Investig 11(1):32–38, 2014 24605121
Leeuw M, Goossens ME, Linton SJ, et al: The fear-avoidance model of musculoskeletal pain: current state of scientific evidence. J Behav Med 30(1):77–94, 2007 17180640
Lemstra M, Stewart B, Olszynski WP: Effectiveness of multidisciplinary intervention in the treatment of migraine: a randomized clinical trial. Headache 42(9):845–854, 2002 12390609
Lerman SF, Rudich Z, Brill S, et al: Longitudinal associations between depression, anxiety, pain, and pain-related disability in chronic pain patients. Psychosom Med 77(3):333–341, 2015 25849129
Liebschutz J, Saitz R, Brower V, et al: PTSD in urban primary care: high prevalence and low physician recognition. J Gen Intern Med 22(6):719–726, 2007 17503105
Lipchik GL, Nash JM: Cognitive-behavioral issues in the treatment and management of chronic daily headache. Curr Pain Headache Rep 6(6):473–479, 2002 12413406
Lipton RB, Silberstein SD: Episodic and chronic migraine headache: breaking down barriers to optimal treatment and prevention. Headache 55 (suppl 2):103–122, quiz 123–126, 2015 25662743
Lipton RB, Bigal ME, Diamond M, et al; AMPP Advisory Group: Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 68(5):343–349, 2007 17261680
Lunn MP, Hughes RA, Wiffen PJ: Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev (1):CD007115, 2014 24385423
Luo Y, Anderson TA: Phantom limb pain: a review. Int Anesthesiol Clin 54(2):121–139, 2016 26967805
Mackey S, Feinberg S: Pharmacologic therapies for complex regional pain syndrome. Curr Pain Headache Rep 11(1):38–43, 2007 17214920
Malaty A, Sabharwal J, Lirette LS, et al: How to assess a new patient for a multidisciplinary chronic pain rehabilitation program: a review article. Ochsner J 14(1):96–100, 2014 24688340
Mallick-Searle T, Snodgrass B, Brant JM: Postherpetic neuralgia: epidemiology, pathophysiology, and pain management pharmacology. J Multidiscip Healthc 9:447–454, 2016 27703368
Manchikanti L, Singh A: Therapeutic opioids: a ten-year perspective on the complexities and complications of the escalating use, abuse, and nonmedical use of opioids. Pain Physician 11 (2 suppl):S63–S88, 2008 18443641
Manchikanti L, Abdi S, Atluri S, et al; American Society of Interventional Pain Physicians: American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain, part I—evidence assessment. Pain Physician 15 (3 suppl):S1–S65, 2012a 22786448
Manchikanti L, Abdi S, Alturi S, et al; American Society of Interventional Pain Physicians: American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain, part 2—guidance. Pain Physician 15 (3 suppl):S67–S116, 2012b 22786449
Mason L, Moore RA, Derry S, et al: Systematic review of topical capsaicin for the treatment of chronic pain. BMJ 328(7446):991, 2004 15033881
Max MB: Treatment of post-herpetic neuralgia: antidepressants. Ann Neurol 35 (suppl):S50–S53, 1994 8185299
McCleane G: Antidepressants as analgesics. CNS Drugs 22(2):139–156, 2008 18193925
McCracken LM: Learning to live with the pain: acceptance of pain predicts adjustment in persons with chronic pain. Pain 74(1):21–27, 1998 9514556
McCracken LM, Hoskins J, Eccleston C: Concerns about medication and medication use in chronic pain. J Pain 7(10):726–734, 2006 17018333
Mendell JR, Sahenk Z: Clinical practice. Painful sensory neuropathy. N Engl J Med 348(13):1243–1255, 2003 12660389
Merskey H: The taxonomy of pain. Med Clin North Am 91(1):13–20, vii, 2007 17164101
Merskey H, Lindblom U, Mumford JM, et al: Pain terms: a current list with definitions and notes on usage. Pain 24 (suppl 1):S215–S221, 1986
Micca JL, Ruff D, Ahl J, Wohlreich MM: Safety and efficacy of duloxetine treatment in older and younger patients with osteoarthritis knee pain: a post hoc, subgroup analysis of two randomized, placebo-controlled trials. BMC Musculoskelet Disord 14:137, 2013 23590727
Micó JA, Ardid D, Berrocoso E, et al: Antidepressants and pain. Trends Pharmacol Sci 27(7):348–354, 2006 16762426
Mitra S: Opioid-induced hyperalgesia: pathophysiology and clinical implications. J Opioid Manag 4(3):123–130, 2008 18717507
Montano N, Conforti G, Di Bonaventura R, et al: Advances in diagnosis and treatment of trigeminal neuralgia. Ther Clin Risk Manag 11:289–299, 2015 25750533
Moore RA, Wiffen PJ, Derry S, et al: Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev (4):CD007938, 2014 24771480
Morasco BJ, Gritzner S, Lewis L, et al: Systematic review of prevalence, correlates, and treatment outcomes for chronic non-cancer pain in patients with comorbid substance use disorder. Pain 152(3):488–497, 2011 21185119
Morley S, Wilkinson L: The Pain Beliefs and Perceptions Inventory: a British replication. Pain 61(3):427–433, 1995 7478685
Moulin DE, Clark AJ, Gilron I, et al; Canadian Pain Society: Pharmacological management of chronic neuropathic pain: consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag 12(1):13–21, 2007 17372630
Mulla SM, Wang L, Khokhar R, et al: Management of central poststroke pain: systematic review of randomized controlled trials. Stroke 46(10):2853–2860, 2015 26359361
Mulleners WM, Chronicle EP: Anticonvulsants in migraine prophylaxis: a Cochrane review. Cephalalgia 28(6):585–597, 2008 18454787
Nikolaus T: Assessment of chronic pain in elderly patients [in German]. Ther Umsch 54(6):340–344, 1997 9289872
Noble M, Treadwell JR, Tregear SJ, et al: Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev (1):CD006605, 2010 20091598
Norlund A, Ropponen A, Alexanderson K: Multidisciplinary interventions: review of studies of return to work after rehabilitation for low back pain. J Rehabil Med 41(3):115–121, 2009 19229442
Obermann M, Katsarava Z: Update on trigeminal neuralgia. Expert Rev Neurother 9(3):323–329, 2009 19271941
O’Connor AB: Neuropathic pain: quality-of-life impact, costs and cost effectiveness of therapy. Pharmacoeconomics 27(2):95–112, 2009 19254044
Ogawa S, Arakawa A, Hayakawa K, et al: Pregabalin for neuropathic pain: why benefits could be expected for multiple conditions. Clin Drug Investig 36(11):877–888, 2016 27448285
Oh H, Seo W: A comprehensive review of central post-stroke pain. Pain Manag Nurs 16(5):804–818, 2015 25962545
Ohayon MM, Schatzberg AF: Using chronic pain to predict depressive morbidity in the general population. Arch Gen Psychiatry 60(1):39–47, 2003 12511171
Outcalt SD, Kroenke K, Krebs EE, et al: Chronic pain and comorbid mental health conditions: independent associations of posttraumatic stress disorder and depression with pain, disability, and quality of life. J Behav Med 38(3):535–543, 2015 25786741
Ozyalcin SN, Talu GK, Kiziltan E, et al: The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache 45(2):144–152, 2005 15705120
Pain-Topics.org: Pain Treatment Topics: Opioid Risk Management. 2010. Available at: www.pain-topics.org/opioid_rx/risk.php#AssessTools. Accessed October 14, 2017.
Pani PP, Trogu E, Maremmani I, et al: QTc interval screening for cardiac risk in methadone treatment of opioid dependence. Cochrane Database Syst Rev (6):CD008939 2013 23787716
Passik SD, Kirsh KL: The interface between pain and drug abuse and the evolution of strategies to optimize pain management while minimizing drug abuse. Exp Clin Psychopharmacol 16(5):400–404, 2008 18837636
Passik SD, Kirsh KL, Whitcomb L, et al: A new tool to assess and document pain outcomes in chronic pain patients receiving opioid therapy. Clin Ther 26(4):552–561, 2004 15189752
Passik SD, Kirsh KL, Donaghy KB, et al: Pain and aberrant drug-related behaviors in medically ill patients with and without histories of substance abuse. Clin J Pain 22(2):173–181, 2006 16428952
Patrick N, Emanski E, Knaub MA: Acute and chronic low back pain. Med Clin North Am 100(1):169–181, 2016 26614726
Peles E, Schreiber S, Gordon J, et al: Significantly higher methadone dose for methadone maintenance treatment (MMT) patients with chronic pain. Pain 113(3):340–346, 2005 15661442
Perahia DG, Pritchett YL, Desaiah D, et al: Efficacy of duloxetine in painful symptoms: an analgesic or antidepressant effect? Int Clin Psychopharmacol 21(6):311–317, 2006 17012978
Peres MFP, Mercante JPP, Tobo PR, et al: Anxiety and depression symptoms and migraine: a symptom-based approach research. J Headache Pain 18(1):37, 2017 28324317
Phillips DM; Joint Commission on Accreditation of Healthcare Organizations: JCAHO pain management standards are unveiled. JAMA 284(4):428–429, 2000 10904487
Picavet HS, Vlaeyen JW, Schouten JS: Pain catastrophizing and kinesiophobia: predictors of chronic low back pain. Am J Epidemiol 156(11):1028–1034, 2002 12446259
Pinheiro MB, Ferreira ML, Refshauge K, et al: Symptoms of depression as a prognostic factor for low back pain: a systematic review. Spine J 16(1):105–116, 2016 26523965
Pontell D: A clinical approach to complex regional pain syndrome. Clin Podiatr Med Surg 25(3):361–380, vi, 2008 18486850
Prasad S, Galetta S: Trigeminal neuralgia: historical notes and current concepts. Neurologist 15(2):87–94, 2009 19276786
Rani PU, Naidu MU, Prasad VB, et al: An evaluation of antidepressants in rheumatic pain conditions. Anesth Analg 83(2):371–375, 1996 8694321
Rayner L, Hotopf M, Petkova H, et al: Depression in patients with chronic pain attending a specialised pain treatment centre: prevalence and impact on health care costs. Pain 157(7):1472–1479, 2016 26963849
Reicherts P, Gerdes AB, Pauli P, et al: Psychological placebo and nocebo effects on pain rely on expectation and previous experience. J Pain 17(2):203–214, 2016 26523863
Rief W, Martin A: How to use the new DSM-5 somatic symptom disorder diagnosis in research and practice: a critical evaluation and a proposal for modifications. Annu Rev Clin Psychol 10:339–367, 2014 24387234
Riley J, Eisenberg E, Müller-Schwefe G, et al: Oxycodone: a review of its use in the management of pain. Curr Med Res Opin 24(1):175–192, 2008 18039433
Rojas-Corrales MO, Casas J, Moreno-Brea MR, et al: Antinociceptive effects of tricyclic antidepressants and their noradrenergic metabolites. Eur Neuropsychopharmacol 13(5):355–363, 2003 12957334
Roldán-Barraza C, Janko S, Villanueva J, et al: A systematic review and meta-analysis of usual treatment versus psychosocial interventions in the treatment of myofascial temporomandibular disorder pain. J Oral Facial Pain Headache 28(3):205–222, 2014 25068215
Rosenberg CJ, Watson JC: Treatment of painful diabetic peripheral neuropathy. Prosthet Orthot Int 39(1):17–28, 2015 25614498
Rosenblum A, Joseph H, Fong C, et al: Prevalence and characteristics of chronic pain among chemically dependent patients in methadone maintenance and residential treatment facilities. JAMA 289(18):2370–2378, 2003 12746360
Sandoval JA, Furlan AD, Mailis-Gagnon A: Oral methadone for chronic noncancer pain: a systematic literature review of reasons for administration, prescription patterns, effectiveness, and side effects. Clin J Pain 21(6):503–512, 2005 16215336
Schieir O, Thombs BD, Hudson M, et al: Symptoms of depression predict the trajectory of pain among patients with early inflammatory arthritis: a path analysis approach to assessing change. J Rheumatol 36(2):231–239, 2009 19132790
Schley MT, Wilms P, Toepfner S, et al: Painful and nonpainful phantom and stump sensations in acute traumatic amputees. J Trauma 65(4):858–864, 2008 18849803
Schmidt NB, Santiago HT, Trakowski JH, et al: Pain in patients with panic disorder: relation to symptoms, cognitive characteristics and treatment outcome. Pain Res Manag 7(3):134–141, 2002 12420022
Schreiber AK, Nones CF, Reis RC, et al: Diabetic neuropathic pain: physiopathology and treatment. World J Diabetes 6(3):432–444, 2015 25897354
Seidel S, Aigner M, Ossege M, et al: Antipsychotics for acute and chronic pain in adults. Cochrane Database Syst Rev (8):CD004844, 2013 23990266
Seifert CL, Mallar Chakravarty M, Sprenger T: The complexities of pain after stroke—a review with a focus on central post-stroke pain. Panminerva Med 55(1):1–10, 2013 23474660
Semenchuk MR, Sherman S, Davis B: Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain. Neurology 57(9):1583–1588, 2001 11706096
Sharma A, Williams K, Raja SN: Advances in treatment of complex regional pain syndrome: recent insights on a perplexing disease. Curr Opin Anaesthesiol 19(5):566–572, 2006 16960493
Sharma A, Agarwal S, Broatch J, et al: A Web-based cross-sectional epidemiological survey of complex regional pain syndrome. Reg Anesth Pain Med 34(2):110–115, 2009 19282709
Silberstein SD: Treatment recommendations for migraine. Nat Clin Pract Neurol 4(9):482–489, 2008 18665146
Silberstein SD: Preventive migraine treatment. Continuum (Minneap Minn) 21(4 Headache):973–989, 2015 26252585
Silberstein S, Loder E, Diamond S, et al; AMPP Advisory Group: Probable migraine in the United States: results of the American Migraine Prevalence and Prevention (AMPP) study. Cephalalgia 27(3):220–229, 2007 17263769
Simon GE, VonKorff M, Piccinelli M, et al: An international study of the relation between somatic symptoms and depression. N Engl J Med 341(18):1329–1335, 1999 10536124
Singer J, Conigliaro A, Spina E, et al: Central poststroke pain: a systematic review. Int J Stroke 12(4):343–355, 2017 28494691
Sivertsen B, Lallukka T, Petrie KJ, et al: Sleep and pain sensitivity in adults. Pain 156(8):1433–1439, 2015 25915149
Smith H, Brooks JR: Capsaicin-based therapies for pain control. Prog Drug Res 68:129–146, 2014 24941667
Solberg Nes L, Roach AR, Segerstrom SC: Executive functions, self-regulation, and chronic pain: a review. Ann Behav Med 37(2):173–183, 2009 19357933
Stacey BR, Barrett JA, Whalen E, et al: Pregabalin for postherpetic neuralgia: placebo-controlled trial of fixed and flexible dosing regimens on allodynia and time to onset of pain relief. J Pain 9(11):1006–1017, 2008 18640074
Staiger TO, Gaster B, Sullivan MD, et al: Systematic review of antidepressants in the treatment of chronic low back pain. Spine 28(22):2540–2545, 2003 14624092
Stanos S, Houle TT: Multidisciplinary and interdisciplinary management of chronic pain. Phys Med Rehabil Clin N Am 17(2):435–450, vii, 2006 16616276
Streltzer J, Eliashof BA, Kline AE, et al: Chronic pain disorder following physical injury. Psychosomatics 41(3):227–234, 2000 10849455
Sullivan MJ, Thorn B, Haythornthwaite JA, et al: Theoretical perspectives on the relation between catastrophizing and pain. Clin J Pain 17(1):52–64, 2001 11289089
Sun EC, Dixit A, Humphreys K, et al: Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis. BMJ 356:j760, 2017 28292769
Tack J, Broekaert D, Fischler B, et al: A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome. Gut 55(8):1095–1103, 2006 16401691
Tasmuth T, Härtel B, Kalso E: Venlafaxine in neuropathic pain following treatment of breast cancer. Eur J Pain 6(1):17–24, 2002 11888224
Tomlinson DR, Gardiner NJ: Diabetic neuropathies: components of etiology. J Peripher Nerv Syst 13(2):112–121, 2008 18601656
Truini A, Galeotti F, Haanpaa M, et al: Pathophysiology of pain in postherpetic neuralgia: a clinical and neurophysiological study. Pain 140(3):405–410, 2008 18954941
Turner JA, Holtzman S, Mancl L: Mediators, moderators, and predictors of therapeutic change in cognitive-behavioral therapy for chronic pain. Pain 127(3):276–286, 2007 17071000
Valet M, Gündel H, Sprenger T, et al: Patients with pain disorder show gray-matter loss in pain-processing structures: a voxel-based morphometric study. Psychosom Med 71(1):49–56, 2009 19073757
VanderWeide LA, Smith SM, Trinkley KE: A systematic review of the efficacy of venlafaxine for the treatment of fibromyalgia. J Clin Pharm Ther 40(1):1–6, 2015 25294655
van Wilgen CP, Dijkstra PU, Versteegen GJ, et al: Chronic pain and severe disuse syndrome: long-term outcome of an inpatient multidisciplinary cognitive behavioural programme. J Rehabil Med 41(3):122–128, 2009 19229443
Verbunt JA, Seelen HA, Vlaeyen JW, et al: Disuse and deconditioning in chronic low back pain: concepts and hypotheses on contributing mechanisms. Eur J Pain 7(1):9–21, 2003 12527313
Verdu B, Decosterd I, Buclin T, et al: Antidepressants for the treatment of chronic pain. Drugs 68(18):2611–2632, 2008 19093703
Veves A, Backonja M, Malik RA: Painful diabetic neuropathy: epidemiology, natural history, early diagnosis, and treatment options. Pain Med 9(6):660–674, 2008 18828198
Vinik AI, Tuchman M, Safirstein B, et al: Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies. Pain 128(1–2):169–179, 2007 17161535
Volpi A, Gatti A, Pica F, et al: Clinical and psychosocial correlates of post-herpetic neuralgia. J Med Virol 80(9):1646–1652, 2008 18649332
Vowles KE, McCracken LM, Eccleston C: Processes of change in treatment for chronic pain: the contributions of pain, acceptance, and catastrophizing. Eur J Pain 11(7):779–787, 2007 17303452
Vowles KE, McCracken LM, Eccleston C: Patient functioning and catastrophizing in chronic pain: the mediating effects of acceptance. Health Psychol 27(2S)(suppl):S136–S143, 2008 18377155
Wernicke JF, Pritchett YL, D’Souza DN, et al: A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology 67(8):1411–1420, 2006 17060567
Wiffen PJ, Rees J: Lamotrigine for acute and chronic pain. Cochrane Database Syst Rev (2):CD006044, 2007 17443611
Wiffen PJ, Derry S, Lunn MP, et al: Topiramate for neuropathic pain and fibromyalgia in adults. Cochrane Database Sys Rev (8):CD008314, 2013a 23996081
Wiffen PJ, Derry S, Moore RA, et al: Antiepileptic drugs for neuropathic pain and fibromyalgia: an overview of Cochrane reviews. Cochrane Database Syst Rev (11):CD010567, 2013b 24217986
Wiffen PJ, Derry S, Moore RA: Carbamazepine for neuropathic pain and fibromyalgia in adults. Cochrane Database Sys Rev (4):CD005451, 2014a 24719027
Wiffen PJ, Derry S, Moore RA, Lunn MP: Levetiracetam for neuropathic pain in adults. Cochrane Database Syst Rev (7):CD010943, 2014b 25000215
Williams AC, Eccleston C, Morley S: Psychological therapies for the management of chronic pain (excluding headache) in adults. Cochrane Database Syst Rev (11):CD007407, 2012 23152245
Wu TH, Hu LY, Lu T, et al: Risk of psychiatric disorders following trigeminal neuralgia: a nationwide population-based retrospective cohort study. J Headache Pain 16:64, 2015 26174508
Yucel A, Ozyalcin S, Koknel TG, et al: The effect of venlafaxine on ongoing and experimentally induced pain in neuropathic pain patients: a double blind, placebo controlled study. Eur J Pain 9:407–416, 2005 15979021
Zhou M, Chen N, He L, et al: Oxcarbazepine for neuropathic pain. Cochrane Database Syst Rev (3):CD007963, 2013 23543558
Ziegler D, Pritchett YL, Wang F, et al: Impact of disease characteristics on the efficacy of duloxetine in diabetic peripheral neuropathic pain. Diabetes Care 30(3):664–669, 2007 17327338
Zochodne DW: Diabetic polyneuropathy: an update. Curr Opin Neurol 21(5):527–533, 2008 18769245