A Review of Chronic Noncancer Pain: Epidemiology, Assessment, Treatment, and Future Needs

The International Association for the Study of Pain (IASP) (1) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” By contrast, nociception refers to activation of neural stimuli in the periphery that are potentially or actually damaging. Although nociception (or the amount of tissue damage) may be related to pain, it does not encompass the entire experience of pain. Pain is a conscious experience that requires an intact conscious brain for perception (2). Initially, pain functions as a fundamental protective mechanism representing the consequences of direct tissue injury. Across time, persistent pain, often in the absence of tissue injury or after tissue healing, can become a disease itself. This complex chronic pain condition not only affects an individual’s physical and mental functioning, quality of life, and productivity, but it also significantly burdens the patient’s family, friends, employers, community, and society as a whole (3).

The IASP (1) also notes that pain is always subjective, is highly individualized, and is an emotionally unpleasant experience. Sometimes, pain in the absence of any pathophysiological cause or tissue injury can be linked to psychological factors. Patients without identifiable pathophysiology report similar painful experiences with associated negative effects on the individual and his or her environment. Nonetheless, the IASP emphasizes that these patients’ experiences should also be viewed as pain. With the increasing chronicity of pain, the line is often blurred between pain because of pathophysiology or psychological factors, and patients suffering from chronic pain present with a complex mixed etiology of their disease (1).

Pain may be classified as acute or chronic pain. Acute pain typically has a rapid onset and is usually short lived. It serves a vital function as a critical warning signal, resulting in protective responses such as withdrawing, seeking help, resting, or seeking medical treatment. Conditions resulting in recurrent episodes with pain-free intervals, such as sickle cell disease, migraines, or endometriosis, can contribute to repeated bouts of acute pain (3). Acute pain is often caused by ongoing nociceptor stimulation, inflamed tissue, or abnormal sensitization of neurons in the central nervous system (4).

Alternatively, chronic pain is often defined chronologically as pain lasting at least 3–6 months, and chronic pain can be refractory to treatment proportional to the duration of the pain (3). Another approach to defining chronic pain is any pain extending beyond the expected duration of tissue healing (4). However, in many instances, the expected duration of tissue healing is widely variable among individuals; depending on the cause of the pain, an expected duration of healing has not been adequately characterized, which results in further confusion. Causes of chronic pain are numerous and include medical conditions, injury, surgery, and inflammation (3). Although research is ongoing to delineate mechanisms of specific diseases, a number of chronic pain conditions, including fibromyalgia, vulvodynia, and chronic headaches, do not present from a clear-cut cause (3). These pain conditions can appear in the absence of tissue injury or other definable causes. Chronic pain is associated with changes in the peripheral nervous system and in the central nervous system, which can result in worsening of symptoms across time and can ultimately lead to chronic pain being a disease itself (5). These changes may be elicited by factors that are both pathogenetically and physically distinct from the original inciting event (4). Across time, with persistent, unrelenting pain, psychosocial and environmental factors contribute to the emotional distress and physical disability of afflicted patients, which further complicates the management of chronic pain (4).

According to the 2011 Institute of Medicine report Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research (3), pain perception, the evolution of pain, and the effectiveness of treatment depend on three main factors. Biological factors determine the extent of illness or injury, and specific predisposing factors may affect individual pain tolerance and thresholds (3). Psychological factors, including anxiety, fear, and depression, can perpetuate sinister beliefs about pain (beliefs that pain represents something worse) and can promote feelings of helplessness (3). Social factors represent a significant other’s response to pain (support, enabling behavior, or criticism), an individual’s work environment, and a family’s attitudes and beliefs (3). This complex biopsychosocial model of chronic pain underpins both the assessment and treatment of affected individuals, and it often requires both interdisciplinary assessment and treatment for optimal results—particularly in complex chronic pain conditions (5).

Epidemiology

The 2011 Institute of Medicine report (3) estimates that an astounding 100 million American adults are affected by chronic pain, exceeding the numbers of those affected by diabetes, cancer, and heart disease combined. These estimates of chronic pain do not include adults affected by acute pain, children with either acute or chronic pain, or adults living in long-term care facilities, serving in the military, or serving in prison (5). Pain affects millions of Americans throughout their lifetime, increases disability, consumes resources in the health care system, and results in a significant economic burden for the entire nation. The staggering socioeconomic burden of pain is thought to exceed one-half trillion dollars per year (3).

One of the current challenges of chronic pain is that it is difficult to obtain clear numbers on the incidence and prevalence of pain, because it is often treated as a symptom of another medical condition. Thus, research indirectly targets conditions associated with pain such as arthritis. However, it is unclear whether pain is the overriding symptom prompting a patient to seek medical care. Similarly, the reason for physician visits may be associated with a specific diagnosis, such as chronic pancreatitis, but it is unclear which visits may have been prompted primarily by pain as opposed to other symptoms. The Institute of Medicine report (3) cites a number of reasons that contribute to the paucity of data on pain prevalence in the United States, including lack of standardized research methods to obtain population-level data on pain, exclusion of key groups from national population-based health surveys (e.g., children, people serving in the military, adults living in nursing homes or long-term care facilities, and individuals serving in correctional facilities), inclusion of only a few painful diseases in existing research studies, and failure to distinguish between acute and chronic pain.

Tsang et al. (6) estimated that the age-standardized prevalence of chronic pain conditions (headache, back or neck pain, arthritis or joint pain, and other chronic pain) is 37.3% averaged across all developed countries. In the United States, the age-standardized prevalence of chronic pain conditions is 43% (6). In both developed and undeveloped countries, a higher prevalence of chronic pain was found among females and with increasing age. In addition, depression and anxiety disorders were associated with chronic pain in both developed and undeveloped countries (6). Overall, according to the Institute of Medicine report (3), musculoskeletal pain (joint pain and back pain) is the most common type of chronic pain, but most people with chronic pain have multiple areas of pain. The annual prevalence of chronic low-back pain ranges from 15% to 45% (7). According to the 2002 National Health Interview Survey (8), low-back pain was the most frequently reported pain, followed by migraines or severe headaches, neck pain, and face or jaw pain. The survey showed that 26.4% of respondents reported low-back pain in the past 3 months, corresponding to an estimate of >54 million adults in the United States experiencing back pain. The survey results also revealed that females were more likely to report back pain. In addition, American Indians and Alaska Natives reported the highest prevalence of back pain, whereas Asian Americans reported the lowest prevalence (8). From a socioeconomic standpoint, the prevalence of back pain decreased with higher levels of education, and higher levels of family income (8). Similarly, certain groups have been identified as having an increased risk for chronic pain, including those with English as a second language, particular racial/ethnic groups (African Americans, Hispanics, American Indians, and Alaska Natives), people with lower levels of income and education, females, children, military veterans, people with cognitive impairments, surgical patients, cancer patients, and those at the end of life (3).

The prevalence of chronic pain is likely to continue increasing because of a number of factors, including aging of the U.S. population and an increasing prevalence of geriatric illnesses associated with chronic pain, the rising prevalence of obesity and associated chronic diseases (diabetic peripheral neuropathy) and orthopedic issues (joint pain) with pain, a greater proportion of people surviving catastrophic injuries with subsequent chronic pain, acute and chronic pain resulting from surgery, greater public awareness of chronic pain syndromes, and increased health care access (3).

Chronic pain has a myriad of deleterious effects on both the individual and society as a whole. One notable effect is impaired performance of activities of daily living. In patients with low-back pain, increasing self-reported pain severity has been associated with increasing pain interference with function as well as impairment while working (9). Work productivity is a significant issue, as noted by the Institute of Medicine report (3). People with severe pain missed an average of 5.0–5.9 more days of work per year compared with people with no pain. The resulting cost of workdays missed ($11.6 billion to $12.7 billion), work hours lost ($95.2 billion to $96.5 billion), and wages lost ($190.6 billion to $226.3 billion) to pain is staggering (3).

Health-related quality of life assesses the quality of life in the context of both clinical medicine and research, and it encompasses physical, emotional, and cognitive functioning as well as the ability to participate in meaningful activities within the family, workplace, and community as a whole (10). In the context of chronic pain, health-related quality of life measures patients’ perspectives on their pain experience and the effect it has on their lives (10). A number of chronic pain conditions negatively affect quality of life, including neuropathic pain (11), osteoporosis (12), chronic pelvic pain (13), and neck pain (14).

Chronic pain also has a negative effect on an individual’s psychological well-being. At an extreme, the Institute of Medicine report (3) notes that the risk for suicide is doubled among people with chronic pain compared with control groups, with a lifetime prevalence of suicide attempts ranging from 5% to 14% (3). Psychiatric comorbidities are common among patients with chronic pain. For example, patients suffering from chronic daily headaches present with comorbid depression and anxiety disorders, further increasing the risk for suicide (15). Furthermore, these psychiatric comorbidities are likely to affect the prognosis and treatment of chronic pain conditions.

Overall, chronic pain has significant effects on the individual, which are related to physical functioning, quality of life, and psychological well-being. In addition, the annual cost of pain in the United States is estimated at $560 billion to $635 billion when the cost of health care and lost productivity to pain is combined, resulting in a significant economic burden on society as a whole (3).

Natural History

Although many instances of pain start after an injury or trauma, the natural history of pain has not been well characterized. Surgery represents a useful real-life context, in which patients undergo reproducible injury, resulting pain, and expected recovery. The vast majority of the 45 million Americans undergoing surgery every year experience acute pain (16), and it is postulated that 10% of these patients will not experience resolution of postoperative pain, leading to the development of chronic postsurgical pain (17). Understanding this transition is critical for a number of reasons. Specifically, future treatments could be targeted to promote pain resolution in patients undergoing surgery. Most importantly, there may be important parallels between the mechanisms promoting continued postsurgical pain and the indefinite persistence of pain leading to chronic pain.

Current research has emphasized the assessment and reduction of perioperative pain intensity and pain thresholds, rather than characterizing this temporal aspect of acute pain (pain duration). Typically, postoperative pain is assessed through examination of intermittent time points (1, 3, and 6 months postoperatively) after surgery, with assessment of pain severity at that time. This methodology does not necessarily capture waxing-and-waning pain symptoms across time, and it may introduce certain incorrect assumptions regarding postoperative pain recovery. For example, a patient may report that he or she is no longer experiencing pain at the surgical site on the day of assessment, and it may be assumed that this patient has recovered after surgery. However, the patient may undergo physical therapy the next day and may experience resumption of pain and symptoms. Capturing this scenario is only possible with more longitudinal and close follow-up. By examining intermittent time points after surgery, reported predictors of postsurgical pain include anxiety (18–20), state anxiety (21), catastrophizing pain (19, 22), preoperative pain (both remote and at the surgical site) (20, 21, 23), severity of acute postoperative pain (21, 24, 25), preoperative opioid use (21), and depression (26, 27). These predictors will be valuable targets for interventions to reduce postoperative pain intensity in future studies.

Prescription opioids are one of the primary modalities for postoperative pain management (28–32). Although the amount of opioids prescribed for any particular surgery may be fairly uniform, patients exhibit wide variability in opioid needs after similar surgeries (33, 34). Furthermore, continued opioid use after surgery has the potential to lead to opioid misuse, abuse, and even addiction. In the context of increasing death rates from prescription opioid overdose, prescription opioid sales, and substance abuse treatment admissions (35–37), patients undergoing surgery represent a particularly vulnerable population experiencing injury and obligatory prescription opioid use in the postoperative period. We previously described a novel approach to characterizing time to postoperative prescription opioid cessation and time to pain resolution through a Cox proportional hazards regression model (38, 39). In our prospective study, patient follow-up spanned 4–859 days after surgery. Prescription opioid use and pain cessation were longitudinally assessed through daily phone calls for the first 3 months, weekly phone calls up to 6 months after surgery, and monthly calls thereafter. Among this surgical cohort, pain duration, pain severity at the time of opioid cessation, preoperative baseline pain severity at the surgical site, preoperative baseline pain severity at locations other than the surgical site, preoperative illicit opioid use, and any preoperative opioid use all did not predict delayed opioid cessation (38). By contrast, elevated preoperative depressive symptoms, preoperative self-perceived susceptibility to addiction, and legitimate preoperative opioid use each predicted delayed cessation of prescription opioid use after surgery (38). In addition, a follow-up factor analysis of the preoperative depressive symptoms in this surgical cohort showed that self-loathing symptoms, rather than more motivational and emotional symptoms of depression, independently predicted a significant decrease in opioid cessation after surgery (39). Future work is necessary to replicate these findings examining other surgical populations.

Although chronic pain is often thought of as a lifelong condition, its natural history is not well characterized. Through examination of postsurgical pain, important mechanisms underlying pain persistence may be revealed. Through further research, measures to prevent continued pain after surgery and the development of chronic pain could be developed to target these underlying mechanisms. Current therapeutic modalities that may be beneficial for reducing persistent pain after surgery include the use of regional anesthetic techniques, perioperative ketamine, gabapentanoids (gabapentin, pregabalin), intravenous lidocaine, and management of patient expectations (40, 41). However, research will be necessary to also determine whether these modalities are able to promote pain resolution and decrease pain duration after surgery.

The Challenge of Prescription Opioids

Prescription opioids currently remain one of the most commonly prescribed medications to treat various chronic pain conditions. During the past decade, there has been a dramatic increase in the prescription of opioids for the management of chronic pain conditions. This transition toward increased opioid prescribing in the 1990s was sparked by interpretations of the safety and efficacy of opioids in treating chronic noncancer pain conditions, concerns regarding the long-term safety of alternate analgesics (nonsteroidal anti-inflammatory drugs), promotion of opioids to primary care physicians, and the endorsement by national organizations to encourage liberal opioid use for chronic pain conditions (42).

The long-term effectiveness and safety of opioids in the treatment of patients with chronic noncancer pain remain to be determined. Variable conclusions have been presented by both systematic reviews and recent randomized controlled trials. Despite this context of uncertainty and the lack of a clear consensus of the utility and efficacy of opioids in the treatment of chronic noncancer pain, opioid prescribing for noncancer pain has dramatically increased during the past decade (43, 44). Systematic reviews of opioids for chronic noncancer pain examining randomized controlled trials have shown at least moderate improvements in pain, function, and disability for opioids compared with placebo (45–51). However, a major limitation of systematic reviews examining only randomized controlled trials is the shorter duration of studies over weeks, combined with a high attrition rate (46, 47). These issues preclude conclusions regarding the safety and efficacy of long-term prescription opioid therapy to treat chronic noncancer pain conditions. In comparison, Noble et al. (52) included any prospective studies, such as randomized controlled trials and case series, in their systematic review examining the efficacy and safety of long-term opioids for chronic noncancer pain. The most prevalent specified painful conditions in this systematic review were back pain, osteoarthritis, neuropathic pain, myofascial pain, osteoporotic vertebral fractures, and trigeminal neuralgia. The most common adverse effects included gastrointestinal side effects (constipation, nausea, or dyspepsia), headache, fatigue, and urinary issues (hesitancy or retention) (52). In addition, the authors estimated a 0.14%–0.27% rate of addiction among the included studies. Although the authors stated that patients taking oral opioids for 6 months demonstrated clinically meaningful pain relief, significant heterogeneity of the study results precluded any firm conclusions. Similar to the previously mentioned systematic reviews, participant dropout as a result of adverse effects and insufficient pain relief also introduced bias regarding the efficacy and safety of long-term opioid therapy for chronic noncancer pain (52). Beyond systematic reviews, an examination of individual studies provides contradictory evidence pointing to the association between long-term opioid use and minimal improvements in pain, function, and quality of life (53, 54). Baseline opioid use was associated with higher 6-month disability in a prospective cohort study of patients with low-back pain in primary care (55). Overall, insufficient evidence currently exists to determine the safety and efficacy of long-term opioid therapy for chronic pain. It should be noted that this conclusion could be made of most pharmacological treatments for chronic pain and is not restricted to just opioids. Ultimately, better data regarding outcomes beyond 1 year are necessary to provide a complete narrative on the efficacy and safety of prescription opioids (and all therapies) in the treatment of chronic pain conditions.

Prescription opioid–related overdose deaths in the United States, prescription opioid sales, and substance abuse treatment admissions have climbed in parallel during the past decade (35–37). Medical and nonmedical use of prescription opioids has created an epidemic of prescription opioid overdose, emergency department admissions, addiction, diversion, and death. The economic cost of nonmedical prescription opioid use in the United States is >$50 billion annually (37). In fact, nonmedical prescription opioid use costs insurance companies $72.5 billion annually in health care costs (36).

Prescription opioids were involved in 16,917 overdose deaths in 2011 (56), and 31% of these deaths also involved benzodiazepine sedatives (56). Overall, the death rate from prescription opioids (4.2 per 100,000 population) was four times the rate for heroin and cocaine combined in 2010 (57). The trend among women is particularly concerning. Deaths from prescription painkiller overdoses have increased 415% in women since 1999 compared with 265% in men, perhaps because of increased opioid prescribing to women (57). However, men are still more likely to die of prescription painkiller overdoses (57).

Despite the intense scrutiny of prescription opioids, it is important to recognize that many unintentional or accidental polysubstance deaths in the United States involve a combination of opioids and benzodiazepines (58–60). In West Virginia, 41% of unintentional pharmaceutical overdose fatalities involving opioid analgesics also included benzodiazepines (61). Similarly, in a study of unintentional overdose deaths in New York City from 2005 to 2010, 53% of deaths involving an opioid analgesic also involved a benzodiazepine (62). Research continues to pinpoint the markedly increased risk for fatal prescription opioid intoxications in decedents concurrently using one or more benzodiazepines (63). These findings are mirrored outside of the United States. In Norway, a 1-year observational study reported that 76% of fatal poisonings involved opioids, and 76% of fatal poisonings involved benzodiazepines (64). In the midst of mounting evidence of the combined role of prescription opioids and benzodiazepines in unintentional overdose deaths, many professional societies have released guidelines to encourage safe opioid prescribing in the context of preexisting or concurrent benzodiazepine use (65–68).

The treatment of comorbid chronic pain and substance use disorders is particularly challenging. The incidence of dependence ranges from 0% to 24%, and the prevalence of dependence ranges from 0% to 31% in patients receiving prescription opioids for pain relief (69). In a randomized trial of a more conservative versus a more liberal opioid-prescribing strategy of 135 patients in a Veterans Affairs hospital pain clinic, 27% of patients were discharged because of opioid misuse or noncompliance issues, including concurrent alcohol/illicit substance abuse, medication misuse, or noncompliance with clinic procedures (e.g., refusing to complete urine toxicology testing). There was no difference in the rate of opioid misuse or noncompliance between groups (70). Similarly, in a study of 705 patients receiving four or more opioid prescriptions in the preceding 12 months for noncancer pain, rates of lifetime and current opioid dependence concordant with DSM-IV criteria were reported as 35.5% and 26%, respectively (71). In addition, current opioid dependence was associated with age <65 years, opioid abuse history, higher severity of opioid dependence, major depression, and use of psychotropic medications (71). Clinicians need to be aware of both preexisting substance use disorders and the development of substance use disorders while treating chronic pain patients with prescription opioids.

In the context of treating chronic pain, potential risks associated with persistent opioid use are numerous and include increased risks for medication overdose, opioid abuse, and overall morbidity (72). The adverse effects of prescription opioids are well described. The presence of tolerance and physical dependence can occur even at prescribed doses (73–78). Opioids are associated with immunosuppression and opioid-induced endocrinopathy (sexual dysfunction, depression, or decreased energy) (79–85). Opioids are implicated in opioid-induced hyperalgesia or increased pain sensitivity despite increasing doses of opioids. Despite opioid-induced hyperalgesia being demonstrated in animal studies and acute perioperative studies, its existence and meaning in chronic pain populations remain unclear (86–88). For instance, in the largest clinical trial to date, testing for the presence of opioid-induced hyperalgesia was only able to demonstrate tolerance without demonstrable opioid-induced hyperalgesia (89).

More concerning is the association between long-term prescription opioid use, affective disorders, and substance abuse. Increased rates of substance abuse and depression exist in long-term prescription opioid users compared with nonusers with chronic pain, and pain intensity does not predict treatment with opioids versus nonopioid analgesics (90). Other research shows that depression and anxiety contribute to substance use disorders among long-term opioid users (91). In addition, opioid addicts >45 years old have higher rates of severe pain and psychiatric illness (92). These results point to the importance of acknowledging psychological vulnerability or comorbidity in the development of substance abuse disorders in patients with chronic pain treated with long-term prescription opioids.

Clearly, long-term prescription opioid therapy for chronic pain is not a panacea, because one-third of patients with chronic pain do not tolerate prescription opioids or find long-term opioid therapy to be ineffective (93). Before therapy is initiated, it is essential for the clinician to weigh the risks and benefits of treatment. During ongoing treatment of chronic pain with prescription opioids, and in the context of tolerance, difficulties in assessment will arise as patients continue to dose escalate either in the context of increased pain or opioid misuse (93). With continued treatment, providers will need to monitor for iatrogenic drug dependence, opioid misuse, and opioid diversion. Patients with a history of addiction are at risk for relapse when opioids are prescribed, and patients with active substance use disorders are likely to be noncompliant and difficult to engage in nonopioid strategies for pain control. Given the chronology of chronic pain conditions and the relatively small number of patients who experience complete resolution of their painful conditions, prescription opioids need to be safe and sustainable for long-term use.

The Biopsychosocial Underpinnings of Chronic Pain

The biopsychosocial model of pain and disability is currently the most widely accepted approach to understanding and treating chronic pain conditions (94). In this model, pain and disability have complex interactions among physiological, psychological, and social factors, which perpetuate and worsen a patient’s clinical condition and result in chronic, complex pain syndromes (95). The biopsychosocial model encompasses both disease and illness. Disease refers to an objective biological event, which disrupts body structures or organ systems. By contrast, illness describes the subjective experience of the disease through interaction with biological, psychological, and social factors (94). Although emotion is the immediate reaction to nociception, cognition attaches meaning to the emotional experience of pain; these pain-related cognitions can augment the experience of pain by triggering additional emotional and behavioral reactions (95). Thus, pain is an individualized and unique experience, and psychosocial factors often modulate symptoms and disability (94). The biopsychosocial model acknowledges how pain and disability trigger psychosocial responses and cause emotional distress (anxiety, depression, or fear) (96). This model contrasts greatly with a more traditional biomedical approach, which assumes that pain has a specific physical pathology. Treatment through this model often centers on cutting or blocking pain through pharmacological or surgical methods (96). Unfortunately, many chronic pain syndromes do not have clearly established mechanisms, and pathophysiology has not been clearly explained. More importantly, no “cure” has been established for many chronic pain diagnoses. Using the traditional biomedical approach to treating patients with chronic pain is likely to increase health care costs and lead to inappropriate expectations and frustrations for patients expecting complete recovery.

The biopsychosocial model of pain has diversified the treatment options for patients with chronic pain conditions and has allowed treatment to move forward beyond solely targeted biological approaches. Individualized treatment allows clinicians to acknowledge the complex physiological, psychological, and social dynamics involved in the perpetuation of pain. Clinicians should be mindful of a patient’s emotional concerns, centering on the implications regarding prognosis, function, and ability to return to work throughout treatment. Comprehensive interdisciplinary pain programs address the dimensions of the biopsychosocial model of pain, and they have demonstrated both short-term and long-term efficacy for a number of important pain and psychosocial outcomes.

Assessment and Differential Diagnosis

Pain may initially be viewed as a symptom of an underlying disease. However, with persistent pain, an unclear etiology, or lack of improvement with initial therapy, pain becomes a disease itself that necessitates a comprehensive assessment. A multidimensional assessment is particularly important for patients with chronic pain because multiple aspects of life are affected; various stakeholders have different interests in patient outcomes (family versus third-party payers), and relevant outcomes (pain, quality of life, and health care utilization) do not necessarily improve simultaneously (96).

In the context of recalcitrant chronic pain, it is especially important to proceed with an accurate, detailed history and physical examination before establishing an interdisciplinary, comprehensive treatment plan. The description of pain should span onset, location, radiation, intensity, and character (sharp, stabbing, dull, or aching). Although patients may present with established diagnoses, the pain specialist should review all history, physical examinations, and diagnostic tests for additional pathology. Through this process, referrals to other specialists may be necessary (e.g., referral to a gastroenterologist for ongoing abdominal pain). Functional limitations related to activities of daily living, work, socializing, sex, and self-care should be quantified (97). Responses to previous treatments should be documented, including medication trials (e.g., opioids, nonsteroidal anti-inflammatory drugs, antidepressants, or anticonvulsants), surgical procedures, interventions, physical/occupational therapy, psychological interventions, and complementary and alternative medicine modalities.

Substance abuse history should span nicotine, alcohol, marijuana, prescription medications (e.g., opioids or benzodiazepines), and other illicit drugs. Patients receiving prescription opioids should describe analgesia, activity level, aberrant behaviors, and adverse effects associated with opioid therapy. Patients should quantify the degree of analgesia that they receive from their opioids as well as the amount of increased function that they associate with opioids. Patients should also be assessed for self-reported aberrant behaviors such as running out of medications early and opioid-associated adverse effects (e.g., constipation, nausea, or vomiting).

Given the high likelihood of comorbid psychiatric diagnoses, patients should be screened for a number of mood disorders, including anxiety, depression, and posttraumatic stress disorder. Inquiry regarding past suicidal ideations or attempts and previous psychiatric hospitalizations is also important. With any comorbid psychiatric diagnoses or symptoms, referral to a pain psychologist is further beneficial to aid in the comprehensive interdisciplinary evaluation of the patient with chronic pain. Assessment of social history relating to marital status, employment, income, and living arrangements reflects a patient’s quality of life and support system. Litigation, especially related to a chronic pain condition, can prolong disability. In addition, trauma throughout life starting in childhood is important to assess, given its connection to increased somatic symptoms such as pain (97).

A comprehensive physical examination is a necessary complement to the detailed history in the assessment of a patient with chronic pain. Goals of examination center on developing patient trust, quantifying physical functioning in the context of pain, and accurately identifying potential pain generators (2). A comprehensive neurologic examination is essential to characterize sensation, motor function, reflexes, and coordination and is combined with a focal regional examination in order to accurately diagnose or rule out common and rare pain conditions (2). A thorough physical examination can often prevent the pursuit of costly imaging studies or more invasive testing.

Choosing Wisely is a campaign specifically encouraging physicians and patients to have a discussion regarding unnecessary treatments, tests, or procedures. The American Board of Internal Medicine Foundation launched the campaign in 2012, and medical specialty societies have created lists of tests, treatments, or procedures that have demonstrated strong scientific evidence of overuse as well as the potential for harm or increased cost (98). All of these lists are available at www.choosingwisely.org. As part of the campaign, the American Society of Anesthesiologists Committee on Pain Medicine set forth a list of five items that physicians and patients should question. Specifically, the recommendations state “Avoid imaging studies (MRI, CT, or X-rays) for acute low-back pain without specific indications” (98). The committee recommends avoiding imaging for low-back pain in the first 6 weeks in the absence of specific red flags (e.g., cancer with potential metastasis, known aortic aneurysm, or a progressive neurological deficit). The committee points out that imaging may reveal incidental findings that increase the patient’s risk of undergoing an unnecessary surgical procedure. In addition, the recommendations state “Don’t prescribe opioid analgesics as long-term therapy to treat chronic non-cancer pain until the risks are considered and discussed with the patient” (98). The committee emphasizes discussing the risks associated with opioid therapy with patients (including the risk for addiction), reviewing and signing a written agreement between the physician and the patient regarding responsibilities and consequences of noncompliance, and using caution in the coprescription of opioids and benzodiazepines.

Proper patient selection is paramount, with ample consideration of the risks and benefits associated with initiating opioid therapy for chronic noncancer pain. Universal risk assessment and stratification are necessary, given that the estimates of aberrant drug-related behaviors, drug misuse, and abuse in patients with chronic noncancer pain are as high as 50% (99). As outlined above, an accurate and detailed history is essential to identify risk factors of opioid misuse, abuse, and addiction. A personal or family history of drug or alcohol abuse strongly predicts aberrant opioid-related behaviors, opioid misuse, and abuse after initiation of therapy (99). Additional risk factors for opioid use should be assessed, including euphoria associated with use, other substance abuse diagnoses, mental health disorders, male sex, younger age, preexisting substance use disorders (42, 92, 100), and specific characteristics of opioid prescriptions (e.g., longer supply, higher average doses, and use of schedule II opioids) (100). Patients with chronic pain and active substance use disorders present a particular challenge. Pain medicine specialists should work closely with an addictionologist, who can directly assess and treat the comorbid substance use disorder, during ongoing interdisciplinary care. These patients will require optimization of nonopioid and behavioral therapy as well as close follow-up for management of their chronic pain condition and substance use disorder (92).

Although screening tools may be helpful for risk stratification, more data are necessary to understand how routine use of these tools predicts aberrant behaviors and ultimately affects clinical outcomes. The Diagnosis, Intractability, Risk, and Efficacy instrument is clinician administered and assesses potential efficacy and harm associated with opioid therapy. This tool identifies appropriate candidates for long-term opioid therapy based on scoring of seven factors, with risk divided into psychological, chemical health, reliability, and social support categories (99). In addition to the Diagnosis, Intractability, Risk, and Efficacy instrument, a number of self-report screening tools may be useful. The Opioid Risk Tool is a 10-item scale that is used to stratify patients at high, moderate, and low risk for development of aberrant behaviors when receiving long-term opioid therapy (42). Drawbacks of the Opioid Risk Tool include limited face validity. In addition, this tool has not yet been cross-validated in a separate population (42). The Screener and Opioid Assessment for Patients With Pain–Revised is a self-reported measure of the risk potential for aberrant medication behavior among people with chronic pain (101). This tool has been validated as a screening tool in this population and is intended for administration to patients being considered for long-term opioid therapy (101). Among a cross-validation sample for this assessment, 33.5% of patients had a score of ≥18, which was reported as a cutoff score with 80% sensitivity and 52% specificity in identifying at-risk patients. In other words, at this cutoff score, the Screener and Opioid Assessment for Patients with Pain–Revised tool has a higher chance of identifying false positive results because of this lower specificity. Nonetheless, this tool has demonstrated superiority over other self-report measures, including the Pain Medication Questionnaire and Opioid Risk Tool, to predict discharge from opioid treatment and the presence of aberrant drug-related behavior (102). Unlike these screening tools, which identify the risk potential for aberrant medication behaviors, the Current Opioid Misuse Measure assesses ongoing aberrant medication-related behaviors in patients prescribed opioids for chronic pain conditions (103). Use of the Current Opioid Misuse Measure may assist providers in determining the level of continued monitoring appropriate for any given patient receiving opioids to treat chronic pain (104). In addition, the Current Opioid Misuse Measure shows promise as a reliable self-report tool to identify prescription drug use disorder among primary care patients with chronic pain who have been prescribed opioids (105). Despite the potential limitations of these and other screening tools for predicting opioid misuse, abuse, and addiction before initiating patients on long-term opioid therapy or identifying ongoing opioid misuse and abuse, their use has been advocated by a number of clinical guidelines and will continue to play a role in the initial assessment of patients with chronic noncancer pain (106).

Treatment and Outcomes

The Importance of an Interdisciplinary Approach

In line with the biopsychosocial model of pain, the interdisciplinary approach to pain management acknowledges the increased emotional distress (anxiety, depression, or anger), maladaptive cognitions (catastrophizing or poor coping skills), functional deficits, and physical deconditioning prevalent among patients with chronic pain, and this approach recognizes the importance of treating all of these variables in order to maximize treatment efficacy (94). Comprehensive pain programs are particularly effective, with demonstrated long-term efficacy in reducing pain disability and pain intensity for a variety of chronic pain conditions, including temporomandibular joint disorder, fibromyalgia, headache, neck pain, and many other musculoskeletal disorders (96). Functional restoration is one example of a comprehensive pain program for patients with low-back pain with significant disability and deconditioning. Physical rehabilitation progress is monitored through ongoing quantification of physical deficits, and assimilation of behavior-oriented interventions is similarly assessed through psychosocial and socioeconomic assessments. In addition, cognitive-behavioral approaches are used to manage disability, and psychopharmacological interventions allow for medication optimization and augment psychological management (96). An interdisciplinary medical team consisting of physicians, mental health providers, physical or occupational therapists, and nurses is required to coordinate these interventions and continue assessment through frequent team conferences. In contrast with multidisciplinary care, in which multiple health care providers may treat a patient but are not necessarily colocated, interdisciplinary care requires a shared emphasis on rehabilitation, daily communication among treatment team members, and a focus on active patient involvement (95). The structure of these comprehensive pain programs often spans 6–8 hours daily for 3–6 weeks. Because these interdisciplinary programs often involve short-term care, recent emphasis has been placed on integrating a patient’s primary care provider into the interdisciplinary treatment plan to improve treatment adherence and long-term outcomes after discharge (95). These programs have demonstrated improvements in socioeconomic outcomes across the United States and even in different countries, with proven cost-effectiveness compared with more traditional medical interventions, including surgery (96).

Treatment Modalities

Pharmacological treatment.

As part of a comprehensive pain program or ongoing ambulatory treatment with an interdisciplinary team of providers, a number of treatment modalities play a vital role in the treatment of patients with chronic pain. Medications continue to remain one of the primary modalities in the management of chronic pain. Aside from opioids and their associated controversy in the treatment of chronic noncancer pain, a number of other classes of medications are often used to treat various chronic pain conditions. Nonsteroidal anti-inflammatory drugs have shown efficacy for treating osteoarthritis, rheumatoid arthritis, and back pain (107). They are available over the counter or by prescription, and they are formulated as oral or topical medications. Compared with traditional nonsteroidal anti-inflammatory drugs, selective cyclooxygenase-2 inhibitors have a lower risk for serious gastrointestinal side effects (e.g., peptic ulcers, bleeding, perforation, or obstruction), but all nonsteroidal anti-inflammatory drugs increase the risk for gastrointestinal side effects based on varying degrees of cyclooxygenase-1 selectivity and higher doses (108). Early data showed a possible increased risk for serious cardiovascular events, including myocardial infarction and stroke specific to cyclooxygenase-2 inhibitors (108). However, newer research has shown the cardiovascular safety of traditional nonsteroidal anti-inflammatory drugs (except naproxen and low-dose ibuprofen) to be comparable to cyclooxygenase-2 inhibitors (108). Thus, given the serious adverse effects associated with nonsteroidal anti-inflammatory drug use, opioids still remain popular in the treatment armamentarium of chronic pain.

Specific antidepressants are efficacious in the treatment of chronic pain, with moderate effects on pain reduction (107). Research has demonstrated efficacy of antidepressants for neuropathic pain, fibromyalgia, low back pain, and headaches (107). Tricyclic antidepressants work by blocking serotonin and norepinephrine reuptake, with analgesia independent of mood-stabilizing effects (2). Tricyclic antidepressants are also thought to produce analgesia through blockade of sodium channels, muscarinic and nicotinic acetylcholine receptors, alpha adrenergic receptors, and N-methyl-d-aspartic acid receptors (2). However, treatment is often limited by intolerable or serious side effects, including dry mouth, constipation, weight gain, and cardiotoxicity (2). Selective serotonin norepinephrine reuptake inhibitors, such as duloxetine and milnacipran, appear efficacious for treating fibromyalgia. Duloxetine is also effective for the treatment of neuropathic and musculoskeletal pain. Selective serotonin norepinephrine reuptake inhibitors result in fewer side effects than tricyclic antidepressants, and they potentially result in comparable analgesia (2). Because patients with chronic pain often have comorbid psychiatric diagnoses, these specific antidepressants remain popular adjunctive medications for the treatment of various chronic pain conditions.

Another major class of adjuvant medications includes anticonvulsants such as gabapentin, pregabalin, carbamazepine, and oxcarbazepine. Most of these medications have shown efficacy in the treatment of neuropathic pain (107). In addition, muscle relaxants are also used as adjuvant agents for short-term relief (107). Despite the range of pharmacological options available for treating chronic pain, treatment is currently largely trial and error and requires multiple medication trials, often to the frustration of both the patient and provider. Future research should focus on identifying optimal patient characteristics for specific pharmacological therapies. In addition, ongoing drug development is likely to result in new classes of medications for the treatment of chronic pain.

Therapeutic treatments.

Psychological treatments include both theoretical-based approaches and specific techniques. The most common theoretical approaches are operant conditioning and cognitive-behavioral therapy (107). These approaches stress patient coping, adaptation, self-management, and disability reduction (107). An overarching goal of psychological therapy is to shift the patient’s mindset from being passive, dependent, and helpless in managing the pain condition to becoming more active and resourceful in coping with his or her pain (107).

Cognitive-behavioral therapy centers on replacing maladaptive behaviors and cognitions with more adaptive responses to chronic pain (96). An individual’s belief about his or her own chronic pain condition and associated coping skills correlates highly with the degree of emotional and physical disability exhibited by the patient (96). Specific psychological techniques include cognitive therapy, self-instruction, relaxation or biofeedback, development of proper coping strategies, modification of maladaptive pain beliefs, and goal setting. The effects of cognitive-behavioral therapy span decreased pain, decreased disability, increased activity, better quality of life, and improved mood (96, 109). Given the biopsychosocial model of pain, ongoing psychological assessment and intervention are paramount to treating patients with chronic pain and enabling them to adapt active pain-coping strategies.

Physical therapy can be administered in inpatient, ambulatory care, and home-based formats. As part of comprehensive interdisciplinary pain programs, physical therapy can help to significantly reduce pain and the use of pain medications (3). A number of modalities are available, including physical and functional restoration techniques, heat therapy, mechanical traction, massage, ultrasonography, transcutaneous electrical nerve stimulation, and aquatherapy (3). Specific exercises can be targeted for certain chronic pain conditions. Walking exercises appear to significantly improve pain and function in patients with chronic musculoskeletal pain (110). Routine exercise reduces pain, increases cutaneous sensitivity, increases vibration sensitivity, improves proprioception, and increases functional mobility in patients with neuropathic pain (111). Exercise therapy consisting of an individualized program, delivered with supervision, reduces pain and improves function in patients with chronic back pain. In this population of patients, stretching and muscle-strengthening exercises have demonstrated efficacy for improving pain and function, respectively (112). Physical therapy and specific exercises are an essential component of the armamentarium to encourage patients to actively manage their chronic pain conditions. In addition, ongoing functional assessment provides an objective marker of improvement with continued treatment.

Other interventions.

Procedural interventions can be used to diagnose or localize a source of pain and to provide pain relief. Nerve blocks usually involve delivery of local anesthetic and adjuvant medications to visceral and peripheral nerves in order to interrupt nociception and reduce inflammation (107). Indications, locations, and medications administered vary widely across all different types of nerve blocks. A particular challenge of defining the role of interventions and procedures in pain management is the lack of consensus regarding technical aspects of these injections, optimal patient selection, frequency, and timing of injections in relationship to the course of pain (acute versus chronic) (107). Although epidural steroid injections are the most commonly performed pain management procedure in the United States, clear data do not exist regarding the long-term efficacy of this intervention for different indications (107). Epidural steroid injections appear to prevent the need for spinal surgery, decrease pain, and improve function in the short term; however, long-term efficacy is less clearly defined, and contrasting evidence has been reported from various studies (113, 114). Fewer data examining the efficacy of less common interventions are available.

More invasive modalities specific to pain management include the use of implantable devices, which are usually reserved for patients who fail more conservative interdisciplinary management. Spinal cord or peripheral nerve stimulation involves implantation of epidural electrodes or electrodes near peripheral nerves, respectively, and this treatment is thought to modulate pain processing and inhibit nociceptive signals (107). Patients with refractory neuropathic pain receiving spinal cord stimulation have demonstrated reduced pain, improved quality of life, reduced medication consumption, and return to work (107). Randomized controlled trials support the use of spinal cord stimulation to treat failed back surgery syndrome and complex regional pain syndrome (115). Optimal patient selection with a full interdisciplinary evaluation before proceeding with these more invasive modalities is critical to maximizing the benefits and minimizing the risks associated with these procedures. Epidural and intrathecal drug delivery systems have been used to treat intractable chronic noncancer pain, with moderate improvements in function and pain (107). Only morphine and ziconotide are currently approved by the U.S. Food and Drug Administration for intrathecal administration. Advantages of intrathecal drug delivery include significantly lower cumulative doses of medication, fewer adverse effects, and the ability to simultaneously deliver a combination of analgesics (116). Disadvantages include adverse effects specific to intrathecal drug delivery (e.g., granuloma formulation) as well as adverse medication effects, including respiratory depression and tolerance to morphine (116). Ziconotide can cause a number of neurologic side effects (e.g., dizziness, nystagmus, or confusion) and has been associated with an increased risk for suicide in patients with a history of depression (116). Given the potential for serious adverse effects, interdisciplinary assessment is essential to determining whether a patient is an appropriate candidate for implantable devices. Patient expectations should be assessed and adjusted as needed in the context of these therapies.

Although definitions of complementary and alternative medicine differ, accepted therapies include acupuncture, chiropractic spinal manipulation, magnets, massage therapy, yoga, dietary supplements, herbs, and meditation (3). Spinal manipulation is the most commonly used complementary and alternative medicine treatment for low-back pain. Although spinal manipulation appears to be more efficacious than certain modalities such as bed rest, it does not appear to be more beneficial than other proven treatments for low-back pain, including analgesics, physical therapy, and exercises (117). Acupuncture has demonstrated analgesic effects. However, mechanisms have not been clearly elucidated to explain the benefit that acupuncture provides for chronic pain. However, significant differences in pain relief between true and sham acupuncture suggest a true effect beyond placebo (118). Acupuncture may be effective for the treatment of low-back pain, fibromyalgia, osteoarthritis, chronic headaches, and neck pain (107, 118).

Active self-care complementary and alternative medicine therapies acknowledge the patient’s role in healing, blend complementary and conventional medicine approaches, and can be performed by patients on their own after completion of training (119). Modalities include mind-body therapies, movement therapies, physically oriented therapies, sensory art therapies, and multimodal integrative approaches. The majority of these therapies are focused on improving pain-coping skills (120). Specific modalities include biofeedback, autogenic training, guided imagery or self-hypnosis, mindfulness or meditation, relaxation, yoga, tai chi, Qi Gong, self-correcting exercises, acupressure, transcutaneous electrical nerve stimulation, music therapy, journaling, and storytelling (121). In a systematic review of active self-care complementary and alternative medicine therapies, relaxation training improved pain in college students with migraine and tension headaches, autogenic training and cognitive self-hypnosis decreased pain in patients with chronic headaches, and self-hypnosis training showed potential for decreasing pain in patients with spinal cord injury (120). Although there is potential for efficacy and inherent safety with active self-care complementary and alternative medicine treatments, more research is needed to determine the efficacy and safety of specific modalities for distinct chronic pain conditions.

Long-term opioid therapy.

The use of long-term opioid therapy in the treatment of chronic noncancer pain is one aspect of chronic pain treatment that has received a great deal of scrutiny. There are currently no well-validated methods to identify the optimal patient with chronic pain who will receive long-term opioid therapy and experience analgesia at stable doses, with minimal to no side effects and no signs of opioid misuse or abuse (93). Although most clinical guidelines for mitigating risks when prescribing opioids are supported by lower-quality evidence (e.g., observational studies) or expert opinion, there are repetitive themes across guidelines regarding certain recommendations, including avoidance of daily doses >90–200 mg morphine equivalents, prescribing of methadone limited to experienced providers because of the risks for QTc prolongation and respiratory depression, reserving the fentanyl patch for opioid-tolerant patients, increasing awareness of unpredictable fentanyl patch absorption in certain settings (e.g., fever, exercise, or heat exposure), and reducing opioid doses by 25%−50% during rotation (106). With respect to initiating opioid therapy in patients with chronic pain, most guidelines advocate a trial period, individualized therapy based on an initial risk assessment, continued interdisciplinary assessment, gradual dose increases, and regular follow-up visits.

Although evidence supporting the use of opioid risk assessment tools, treatment agreements, urine drug testing, and prescription drug monitoring programs is weak, guidelines recommend consideration of their use to monitor ongoing treatment with prescription opioids (106, 122). Aside from these measures, ongoing assessment and follow-up of patients are important in monitoring outcomes. Specifically, all patient follow-up visits should document pain scores and function. The four “A’s” of pain medication, including analgesia, activity, adverse effects, and aberrant behaviors, should be assessed in addition to reviewing pain diagnoses and comorbid conditions (123).

Guidelines for urine drug testing vary from mandatory universal testing to testing of only high-risk patients. Part of the variability in recommendations rests with the complexities of urine drug testing, including timing tests, choosing tests, interpreting results, and obtaining confirmatory testing. False negative and false positive results can occur for a variety of reasons. Unexpected negative results can be attributable to nonadherence, diversion, tampering, and lactic acidosis (106). Unexpected positive results can be due to abuse, obtaining prescriptions from multiple providers, self-treatment, laboratory error, and medication interference (106). It is important for clinicians utilizing urine drug testing to understand the limitations of these tests. Unexpected results should be discussed with patients, and clinicians should interpret the results of urine drug testing in the context of other objective evidence of medication nonadherence or addiction.

Prescription drug monitoring programs (PDMPs) require pharmacies to submit information on prescriptions filled for controlled substances to a central office, such as the state health department or board of pharmacy (124). This information is subsequently provided to prescribers to capture patients obtaining substances from multiple prescribers or pharmacies, and law enforcement may be informed regarding aberrant prescribing behaviors (124). As of August 2014, a total of 48 states and one U.S. territory had an operational PDMP (124). Most PDMPs monitor schedule II–V substances. Some states even currently require prescribers and dispensers to register with their respective PDMPs, and some states require prescribers to check the PDMP database before prescribing controlled substances (124). Although some study results examining the effect of PDMPs seem promising, including decreased use of multiple providers or pharmacies and decreased substance abuse treatment admissions, research has not demonstrated significant differences in opioid prescribing or overdose mortality owing to the implementation of PDMPs. The main limitations of current research examining the efficacy of PDMPs include lack of data on prescribing patterns before the implementation of PDMPs and lack of research examining how specific features of PDMPs increase efficacy (124). Given the wide implementation of PDMPs throughout the United States, future research is needed to characterize the most effective aspects of these programs, while balancing the restrictions and regulations created for opioid prescribers and dispensers.

Many clinical guidelines advocate the use of opioid treatment agreements when initiating opioid therapy in patients with chronic pain. The purpose of these agreements centers on educating patients about risks, documenting informed consent, delineating patient and provider expectations, setting consequences for breaches in conduct, describing clinic policies (e.g., use of urine drug testing and PDMP programs), and setting treatment goals (restoration of function or participation in rehabilitation) (92). These opioid treatment agreements create a useful outline for providers and patients to have a frank discussion regarding long-term opioid therapy for the management of chronic pain. Ultimately, these agreements may improve patient adherence and provider willingness to prescribe opioids, but more research is needed to establish the role of these opioid treatment agreements in clinical care (106).

Patients with comorbid pain and substance use disorders, both active and in remission, represent a particularly challenging subset of patients, especially in regard to consideration of long-term opioid therapy to treat pain. Barriers to optimal care include ongoing concerns for relapse, premature discharge from pain treatment as a result of drug-seeking behaviors that are mistaken for addiction, and providers with insufficient training in addiction (123). Interdisciplinary collaboration with addiction specialists and primary care providers from the outset is essential to optimal treatment of these patients. Furthermore, clear boundaries and expectations should be established as part of treatment agreements with these patients, including ongoing participation in addiction treatment, more frequent office visits, limited total opioid prescriptions (biweekly versus monthly), pill counts, and urine drug testing before the initiation of and during opioid therapy (123).

Patients with chronic noncancer pain and active addiction may not be appropriate candidates for long-term opioid therapy, and they should be referred for addiction treatment. The pain specialist and the addiction specialist should work closely to monitor pain and substance use behaviors throughout treatment (123). Patients with chronic pain and addiction who are in remission should continue to focus on improving function and pain—akin to all other patients with chronic pain. Aside from monitoring for compliance, these patients should be encouraged to engage in psychological approaches to pain management to optimize pain-coping skills. Patients receiving opioid substitution therapy with methadone or buprenorphine may need more divided and frequent dosing for optimal pain relief beyond control of withdrawal and craving symptoms (123). Also, a number of promising psychotherapeutic interventions may improve opioid compliance in patients with chronic pain. For instance, a brief behavioral intervention consisting of group and individual motivational counseling sessions focusing on substance misuse awareness and recovery increased opioid compliance among patients with chronic back pain who were identified as being at high risk for prescription opioid misuse (125). Throughout treatment, relapse prevention is paramount. When these patients are identified, they should be offered a viable plan for addiction treatment, rather than be prematurely discharged from pain treatment. Thus, having an addiction specialist as part of the interdisciplinary team for patients with a history of a substance use disorder will facilitate prompt treatment of remission and will continue to facilitate ongoing pain treatment (123).

Despite the numerous modalities available to treat chronic pain, overall treatment efficacy remains inconsistent and highly variable. Although patients may experience pain relief, they do not necessarily experience concordant improvements in other important outcomes, including quality of life with respect to different treatments. Future research efforts should focus on identifying optimal candidates for existing therapies as well as developing new treatments that are safe and have proven efficacy in certain patient subsets.

Future Needs and Conclusions

Evidence-based medicine is the standard for supporting clinical decision making. However, given the paucity of prospective, placebo-controlled randomized trials in pain medicine owing to the large amount of resources required to conduct such research, there is an urgent need to accurately and consistently measure relevant patient outcomes in order to characterize the most efficacious treatments. There is a need to standardize the assessment and reporting of outcomes to allow for comparison across studies and different patient populations as well as to facilitate consolidation of results in systematic reviews and meta-analyses.

In addition to prospective, placebo-controlled randomized trials, which can be difficult to generalize because of participant homogeneity and requirement of a large amount of resources (because of sample size), systematic practice-based evidence may provide more useful data in the form of prospective, observational, cohort studies (93). Standardized data capture can be included as part of ongoing routine clinical pain management from both patients and providers. In addition, combining computerized systems for patient self-reported outcomes, such as the Patient-Reported Outcomes Measurement Information System (PROMIS) from the National Institutes of Health (NIH), has the potential with electronic medical record data to rapidly identify subsets of patients who will respond favorably to specific treatments (93).

NIH developed PROMIS to create a standardized measurement system to improve interpretation and comparison of outcomes across populations and studies. The item banks of PROMIS assess multiple domains across physical, social, mental, and global health. The Pain Registry includes item banks for pain intensity, pain interference, pain behavior, anxiety, depression, anger, fatigue, sleep disturbance, and sleep interference.

The Stanford-NIH Collaborative Health Outcomes Information Registry (CHOIR; CHOIR.stanford.edu) was developed in response to the Institute of Medicine report Relieving Pain in America (3), which emphasized the need to improve the collection and reporting of data on pain. This open-source, open-standard, free, secure, electronic learning health care system is designed to capture detailed, longitudinal patient-reported outcomes data on physical, psychological, and social health. PROMIS measures have been integrated into CHOIR to maximize efficiency in data capture through cloud-based computation, with adaptive algorithms for items with wide dynamic range and computerized adaptive testing. This testing has been shown to reduce patient response burden by as much as 70% and will facilitate continued patient participation. Ultimately, CHOIR will allow for low-cost, large, prospective, observational studies on thousands of patients in a “real-world” clinic setting. CHOIR has the potential to address many fundamental questions regarding pain treatment and efficacy, and CHOIR will allow for further characterization of optimal patients for specific therapies. Other applications of CHOIR include reverse translation to identify new analgesic drug targets and to facilitate enriched patient selection for prospective, randomized controlled trials (93).

In addition to the broad research utility of CHOIR, the system provides computer-assisted documentation, which has proven indispensable and invaluable in delivering comprehensive, targeted interdisciplinary pain treatment. The platform is designed to be customizable to different settings (inpatient and ambulatory), providers, and disease conditions. Use of CHOIR will facilitate real-time comparison of patient data to clinic, national, and disease-specific norms. CHOIR has demonstrated efficiency, low cost, and minimal burden to staff, providers, and patients, while augmenting clinical care. CHOIR provides rapid real-time, longitudinal feedback to clinicians regarding standardized quantitative outcomes to guide decision making regarding various treatments (93).

Beyond learning health care systems, future efforts must focus on improved data collection in population-level databases. The National Pain Strategy Task Force acknowledges the need to improve both state- and national-level data to monitor changes in the incidence and prevalence of chronic pain, document treatment rates of pain and barriers to pain treatment, assess the health and societal consequences of pain, and evaluate the effect of public policy, payment, and treatment changes. Short-term priorities, as defined by the Population Research Working Group of the National Pain Strategy Task Force, include delineating standardized questions and indicators of chronic pain and identifying essential electronic medical record components. These standardized questions will be vital to assess the prevalence and effect of chronic pain in the general population and to evaluate the efficacy of public health interventions. Additional standardized questions will be imperative for clinical care to screen patients for pain, to assess patients with pain, and to guide clinical treatment decisions. Components of the electronic medical record need to be streamlined to identify patients with chronic pain and to assess the quality, safety, and efficacy of treatments.

Personalized strategies need to be researched and developed to predict who will experience chronic pain after injury and who will develop a substance use disorder during long-term opioid therapy. Moreover, strategies are needed to designate responders and nonresponders to various pain treatments, including prescription opioid therapy. Research has demonstrated the contribution of genetic factors in regard to opioid dependence, pain perception, analgesic response to opioids, and tolerance and physical dependence resulting from opioid analgesic therapy (93). To move forward with personalized opioid prescribing, genome-wide association studies will need to target individuals with carefully selected phenotypes regarding opioid analgesic response, hyperalgesia, tolerance, and physical dependence. Furthermore, research will need to account for pharmacogenomic influences on opioid pharmacokinetics and pharmacodynamics. Additional factors to consider in identifying responders versus nonresponders include accounting for clinical characteristics of chronic pain mechanisms, brain and neurotransmitter changes associated with chronic pain, and other biomarkers (93).

As noted earlier, improved tools are needed to monitor compliance with prescription opioid therapy. Beyond ongoing individual assessment, public policy has the potential to influence and develop national strategies for monitoring compliance with prescription opioid therapy. For example, an integrated national PDMP across states would provide more comprehensive monitoring of dispenser, prescriber, and patient behaviors. PDMPs have currently been implemented on a statewide level, but limitations in interpretation apply when treating patients who have recently moved from other states or who travel to other states to seek pain treatment. Beyond clinical guidelines, risk assessment tools need to be validated and tested in different populations to assess generalizability and clinical utility.

The Institute of Medicine report (3) highlights the existence of knowledge deficits on opioid-related topics among providers, especially in the context of prescription opioid diversion to nonmedical use. The overall increase in opioid use and diversion has further created reactionary backlash against the medical use of opioids, causing restrictive public policies, reduced access to opioid medications, and individual and family concerns regarding the medical use of opioids. Overall, there is a need to create a curriculum for health care professionals to improve pain education and to provide guidance on the balance of prescribing opioids while minimizing associated harms. Furthermore, public education efforts are needed to promote the proper use and disposal of prescription opioids to maximize their safety.

Given the millions of Americans suffering from pain and the enormous socioeconomic burden resulting from pain, it is necessary for many different stakeholders, including providers, patients, third-party payers, and policy makers, to understand the necessities of appropriate, precise assessment and treatment of patients with chronic noncancer pain. Given the complexities of the biopsychosocial model of pain, an interdisciplinary approach to pain management is essential. Furthermore, despite the ongoing controversy surrounding the use of prescription opioids to treat chronic noncancer pain, accurate initial and ongoing assessment of opioid misuse, abuse, and addiction is essential to curtail the epidemic of prescription opioid overdoses. Future directions in research and public policy are needed to address knowledge gaps and to ultimately develop personalized multimodal treatment strategies for all patients with pain.