This chapter addresses the scope of the problem of pain in the United States and its association with opioids, and the effectiveness of pharmacologic (both opioid and nonopioid) and nonpharmacologic treatments that may, alone or in combination, help individuals manage pain. The first section summarizes the scope of the problem of pain, focusing in particular on chronic, or persistent, pain, the form most associated with problematic use of opioids. The chapter then presents a detailed discussion of the various pain treatment modalities, reviewing in turn opioid analgesics, nonopioid pharmacologic treatments, interventional pain therapies, and nonpharmacologic treatments. This section is particularly important in helping to contextualize the evidence of effectiveness and limitations for various treatments for pain, given the burden of pain, the risks associated with undertreatment, and the pervasiveness of opioid use and related dose-dependent risks. The next section examines differences in pain experiences and treatment effectiveness among subpopulations, and the final section briefly addresses the intersection between pain and opioid use disorder (OUD) (discussed in greater detail in Chapter 3). A main objective of this chapter is to situate opioids within the broader armamentarium of treatments available for management of pain and to identify potential opportunities for reduced reliance on these medications.
Chronic pain generally is defined as pain lasting 3 or more months or beyond the time of normal tissue healing (Dowell et al., 2016). As described
in the 2011 Institute of Medicine (IOM) report Relieving Pain in America (IOM, 2011), pain is a significant public health problem, although estimates of the number of people living with chronic pain in the United States vary widely in population-level surveys (see Croft et al., 2010; Johannes et al., 2010; Nahin, 2015; Portenoy et al., 2004). Using self-reported data from the 2011 National Health Interview Survey’s Functioning and Disability Supplement, Nahin (2015) estimates that at the time of the survey, 11.2 percent of the adult U.S. population (25.3 million people) was experiencing daily chronic pain (pain every day for the past 3 months).
The 2011 IOM report appropriately calls attention to the substantial burden of pain in the United States and estimates that “chronic pain alone affects approximately 100 million U.S. adults,” a figure that has routinely been quoted in recent years (IOM, 2011, p. 100). The present committee found that it is difficult to formulate a reliable estimate of the prevalence of chronic pain because of differences across surveys in the way pain is defined and measured. The 100 million figure cited in the 2011 IOM report was based on an analysis of data from surveys conducted in 17 developed and developing countries, including the United States, to evaluate differences in the prevalence of common chronic pain conditions by age and sex, as well as the comorbidity of chronic pain conditions with depression and anxiety disorders (Tsang et al., 2008). The age-adjusted prevalence of chronic pain conditions in the previous 12 months for adults in the United States was found to be 43 percent (roughly 100.86 million people based on the total U.S. population aged 18 and over in 2010) (Howden and Meyer, 2011; Tsang et al., 2008). A limitation of that study, in this committee’s view, is that the questions asked of survey participants did not distinguish occasional aches and pains from daily continuous or chronic intermittent pain that may interfere with quality of life.1 As noted by Tsang and colleagues (2008) themselves, one of the limitations of the study is that “the assessment of pain condition did not include severity and duration of pain.” Nonetheless, regardless of the exact number of people living with chronic pain in the United States, it clearly affects the lives of millions of Americans.
Chronic pain is associated with multiple comorbidities, including, among others, impaired memory, cognition, and attention; sleep disturbances; reduced physical functioning; and reduced overall quality of life (Dahan et al., 2014; Fine, 2011; IOM, 2011). Chronic noncancer pain also has been found to be associated with work absenteeism (Agaliotis et
1 Survey participants were asked whether they had ever had “arthritis or rheumatism” in their lifetime. Respondents who replied that they had were asked whether the arthritis or rheumatism had been present in the prior 12 months. Participants also were asked whether they had ever had “chronic back or neck problems” (referred to as back pain), “frequent or severe headaches” (referred to as headaches), and “other chronic pain” in the prior 12 months.
al., 2014). Severe chronic pain at the highest levels is associated with poor health and increased use of medical resources (IOM, 2011), and painful conditions are among the most frequently reported reasons for outpatient visits with physicians in the United States (CDC, 2017). An argument has been made that chronic pain may itself be considered a disease syndrome when it leads to changes in the nervous system over time (IOM, 2011). As discussed later in this chapter, adding to the public health burden of pain are disparities in access to and quality of pain treatment among subpopulations (Anderson et al., 2009; IOM, 2011; Mossey, 2011).
The very real problems of underdiagnosis and undertreatment of pain are valid concerns, but it would be a mistake to infer that greater utilization of opioids would ameliorate these problems. As discussed below, opioids have long been used for the effective management of acute pain (e.g., acute postsurgical and postprocedural pain), but available evidence does not support the long-term use of opioids for management of chronic noncancer pain. On the other hand, evidence indicates that patients taking opioids long-term are at increased risk of OUD and opioid overdose, as well as a number of other adverse outcomes (e.g., cardiovascular events, fractures) (Baldini et al., 2012; Chou et al., 2015; Krashin et al., 2016). Nevertheless, opioids often are used in the management of chronic noncancer pain. As discussed in Chapter 1, for many years physicians prescribed opioids for chronic noncancer pain, sometimes in very high doses, because of the incorrect belief that the risk for the development of substance use disorders and addiction was low (Krashin et al., 2016). Emphasis was appropriately placed on inadequate recognition and treatment of pain. However, these concerns often were not balanced by a similar emphasis on precautions to avoid adverse effects, such as the development of addiction (Kolodny et al., 2015), and the increase in opioid prescribing that began during the 1990s was associated with a parallel increase in opioid-related substance use disorders and opioid-related deaths (Dowell et al., 2016; Kolodny et al., 2015; SAMHSA, 2015). It is estimated that opioid pain relievers (excluding nonmethadone synthetics) directly accounted for more than 17,500 deaths in 2015, up from approximately 6,160 in 1999 (NCHS, 2016). Moreover, these figures do not account for deaths from related conditions (e.g., bloodborne infections associated with OUD; see Chapters 4 and 5 for further detail). There are indications that opioid prescribing is decreasing, but as recently as 2015, tens of millions of opioids were dispensed by U.S. outpatient retail pharmacies (see Figure 1-1 in Chapter 1). The United States consumes the vast majority of opioids worldwide (Hauser et al., 2016).
Acute pain also is relevant to this report. Millions of Americans are diagnosed each year with acute pain conditions (e.g., those associated with surgery, trauma, or acute illness) that typically resolve over days to weeks. Opioids are frequently prescribed to treat these conditions. Opioids may
be effective for managing acute pain when used appropriately, but as with chronic noncancer pain, harms to individuals and society may arise from these uses of opioids (Dowell et al., 2016). See Chapter 5 for discussion of the effectiveness of strategies for addressing these harms.
Little is known about the relationship between or the progression from acute to chronic pain, although preoperative chronic pain is thought to be a risk factor (Gerbershagen et al., 2014). It has been proposed that inadequate management of acute pain may increase an individual’s risk for development of chronic pain (Sinatra, 2010). Indeed, some evidence suggests that appropriate treatment of acute pain, particularly persistent postsurgical pain, could decrease the likelihood of the future development of chronic pain (Clarke et al., 2012). Similarly, the use of gabapentin or pregabalin in the immediate preoperative setting has the potential to decrease the need for postsurgical opioids (Tan et al., 2015a). Research is ongoing to identify strategies that can decrease the risk of acute pain developing into persistent pain (McGreevy et al., 2011).
It is important to emphasize that the term “pain management” has not been clearly defined and sometimes is used erroneously to denote solely pharmacologic tools. Yet pain management may involve the use of a number of tools—both pharmacologic and nonpharmacologic—to relieve pain and improve function and quality of life. Before proceeding to a review of these various treatments, it should be noted that, while each may be used on its own, their integration in multimodal strategies that cut across medical disciplines and incorporate a full range of therapeutic options—including cognitive-behavioral, physical/rehabilitation, pharmacologic, and interventional therapies—has been shown to be most effective in the treatment of chronic pain (Koele et al., 2014; Scascighini et al., 2008). In contrast, use of a single pharmacologic modality such as an opioid analgesic, often used for the relief of acute nociceptive pain, is inherently limited in its ability to provide long-term relief and/or reverse ongoing plasticity changes driving chronic pain. Such pain encompasses a complex condition that has defied simple remedies. As noted, persistent pain is classified as chronic if someone has endured it for at least 3 months. Unfortunately, over this time period, the person experiencing the pain may have changed in complex ways. From the neuroscientist’s perspective, pathologic plasticity changes in the central and peripheral nervous system have taken hold and have become self-perpetuating, signaling pain and frequently limiting meaningful function. Chapter 3 describes the complex neurobiology related to pain (and reward) processing, identifies promising research areas, and highlights knowledge gaps that could be addressed to help improve the management of chronic pain.
Thus, it must be stressed that a single therapeutic switch to turn off the perception of chronic pain has yet to be found and in fact may not exist.
From the perspective of those suffering chronic pain, any remedy, even one that may simply remit the pain for a few hours or days, may be a welcome relief despite risks or side effects. However, just as chronic pain represents a complex pathophysiologic condition that develops over time, its successful management often requires an equally complex and time-intensive approach. Therefore, combining multiple therapeutic modalities, nonpharmacologic and pharmacologic (nonopioid and opioid), holds promise not only to temper the ongoing pain but also to help return the nervous system and its owner back to a less painful and more functional state. It is significant, then, that many of the nonpharmacologic techniques are reimbursed poorly if at all by third-party payers, creating a disincentive to provide this effective care for patients. See Chapter 5 for further discussion of policies regarding reimbursement of comprehensive pain management.
Effectiveness and Risks
Opioid analgesics encompass a wide range of medicinal products that typically share the ability to relieve acute severe pain through their action on the µ opioid receptor—the major analgesic opioid receptor expressed throughout the nervous system. Since the isolation of morphine from crude opium by Sertürner in 1803, there has been a progressive increase in the number of opioid analgesics that differ in their chemical composition, route of administration, uptake, distribution, type/rate of elimination, and ability to bind to opioid receptors. Certain of these drugs have ultra-short durations of action uniquely suited to providing analgesia as a component of a balanced surgical anesthetic. Others have very long durations of action resulting either from the intrinsic properties of the opioid molecule or the pharmaceutical formulation; in either case, these opioids are released at a predictable rate into a patient’s body. An additional feature of these medications contributing to their clinical utility is the availability of oral, intravenous, transdermal, intranasal, epidural, and intrathecal preparations.
Opioids have long been used successfully to treat acute postsurgical and postprocedural pain, and they have been found to be more effective than placebo for nociceptive and neuropathic pain of less than 16 weeks’ duration (Furlan et al., 2011). For other types of acute pain, however, such as low back pain, the efficacy of opioids is less clear (Deyo et al., 2015; Friedman et al., 2015). And as noted earlier, while evidence exists to support the use of opioids for the treatment of some acute and subacute pain, evidence to support their use to treat chronic pain is very limited (Chou et al., 2015; Dowell et al., 2016). The few randomized controlled trials (RCTs) demonstrating the efficacy of opioids have had small sample sizes
and rarely have produced data that extend past 3 months, the length of time after which pain is considered to be chronic.
The average reduction in chronic noncancer pain ascribed to opioids has been found to be approximately 30 percent (Kalso et al., 2004), and data on functional improvement are limited. A Danish epidemiological study evaluating the effects of long-term (>6 months) use of opioids in more than 10,000 patients with chronic noncancer pain failed to show improvement on any of the items in the 36-Item Short Form Health Survey (SF-36) used to score health-related quality of life (Eriksen et al., 2006). A metaanalysis of 26 studies examining various opioid drugs (compared with placebo as well as other treatments, including nonsteroidal anti-inflammatory drugs [NSAIDS]) in chronic noncancer pain found that “all patients with CNCP [chronic noncancer pain] do not respond to opioid analgesics, only 30–50% of carefully screened subjects report decrease in pain with opioids; [and] the results of RCTs cannot be generalized to the CNCP population because clinical trials do not include . . . multiple pain complaints . . . or other psychiatric comorbidities” (Sehgal et al., 2013, p. 1211). There is some evidence that return to work is more often delayed than expedited for patients using opioids chronically (VonKorff, 2013). And today, despite the existence of a number of opioid compounds and formulations, there is no evidence that one opioid analgesic is superior to another in its ability to manage either acute or chronic pain, and there is insufficient evidence on appropriate dosing. A study of 1,477 adults prescribed opioids for chronic pain, for example, showed that patients who used lower or intermittent doses of opioids had pain outcomes similar to those of patients who used regular or higher doses (Turner et al., 2016).
With regard to the risks associated with the use of prescription opioids, it has been shown that once patients have been taking opioids longer than 90 days, the risk that they will continue to take them chronically and develop a substance use disorder increases (Krashin et al., 2016). In addition to substance use disorder, morbidity related to opioid therapy for chronic pain includes reduced testosterone, cardiac abnormalities, fractures, and immunosuppression, among other adverse outcomes (Chou et al., 2015). A 2015 systematic review of studies of adults prescribed oral opioids for chronic pain estimates the prevalence of opioid misuse (defined in the study as “opioid use contrary to the directed or prescribed pattern of use, regardless of the presence or absence of harm or adverse effects”) in the United States to be 21.7–29.3 percent and the prevalence of addiction (defined as continued use despite harm) to be 7.8–11.7 percent (Vowles et al., 2015). In the elderly and other patients with a higher risk of cognitive impairment, opioids may result in further impairment of cognition and executive function (Schiltenwolf et al., 2014). As noted earlier, moreover, there is a risk of death from these drugs due to opioid-induced respiratory depression (Chou et al., 2015).
Of the many long-term consequences of using opioids, tolerance and opioid-induced hyperalgesia (OIH) are commonly cited as reasons for their waning therapeutic effect over time. Strong laboratory evidence demonstrates that these phenomena occur after even short periods of exposure to opioids or after exposure to large doses of the drugs (Angst and Clark, 2006; Trang et al., 2015; Yi and Pryzbylkowski, 2015). Likewise, tolerance and OIH have been demonstrated in people with OUD, and abnormal pain sensitivity in this population is associated with drug craving (Ren et al., 2009). On the other hand, OIH has been observed after short-term exposure to potent, rapidly eliminated opioids such as remifentanil in human volunteers (Angst and Clark, 2006; Eisenach et al., 2015). Correspondingly, patients for whom remifentanil is incorporated into their surgical anesthetic appear to have higher postoperative pain levels or opioid requirements consistent with either tolerance or OIH (de Hoogd et al., 2016; Fletcher and Martinez, 2014). However, the rapidity, severity, and pervasiveness of tolerance and OIH are poorly defined in chronic pain populations, as are possible differences among opioids with respect to causing these adverse consequences. The situation is made more problematic by difficulties in assessing tolerance and OIH in clinical settings. Rapid dose escalation with worsening pain and the spread of painful symptoms have been suggested as indicators of tolerance and OIH, but well-validated clinical methods for quantifying tolerance and OIH in chronic pain patients are lacking (Mao, 2002).
One of the U.S. Food and Drug Administration’s (FDA’s) required post-marketing studies for extended-release/long-acting (ER/LA) opioid analgesics is an ongoing clinical trial to estimate risk for the development of hyperalgesia following long-term use (at least 1 year) of these drugs to treat chronic pain. This study, which includes an assessment of risk relative to efficacy, is anticipated to be completed in 2019 (see Chapter 6, Annex Table 6-1).
It is important to remember that nonopioid pharmacologic therapies carry their own distinct risks. For example, gastrointestinal bleeding and renal dysfunction are known risks associated with NSAIDs. Likewise, hepatotoxicity and unintended death are risks associated with acetaminophen, and acetaminophen toxicity is thought to contribute to at least some opioid-related mortality (Dunn et al., 2010; McLellan and Turner, 2010). Accordingly, some of the most difficult patients for whom to provide pain relief are those with end-stage liver or kidney disease or with bleeding disorders, many of whom end up taking opioids chronically because of the perceived paucity of effective alternatives.
While all prescription opioids interact with opioid receptors, some more recently developed agents possess additional pharmacologic activity, and even newer agents have been engineered to interact with opioid
receptors in ways that may enhance analgesic benefits while minimizing side effects, such as respiratory depression (Dahan, 2016). Therefore, it is likely that additional opioid drugs with properties perhaps superior in important ways to those of existing drugs will be developed for a wide range of painful conditions. On the other hand, these new drugs are likely to rely at least in part on the activation of the µ opioid receptor, a structure closely linked to important side effects of opioids, including respiratory depression and euphoria. Thus, the propensity of opioid medications to cause overdose or misuse is likely to continue to be cause for concern with these new formulations.
Opioid Prescribing Practices
Beyond differences in analgesic potency (e.g., hydrocodone versus morphine versus hydromorphone), one might ask what dictates prescribing of opioid analgesics for chronic pain. Addressing this question is challenging given the lack of a single integrated source of information on the use of prescription opioids in the United States. This is the case despite calls from both governmental and nongovernmental organizations for improved methods for tracking and accountability of opioid prescribing practices, indications, efficacy, or disposal and the more than decade-long development of the opioid epidemic. Government institutions rely in part on private consulting firms and/or literature generated from industry-sponsored research, or when available, post-marketing data (IOM, 2010). Other information comes from academically directed research focused on specific diagnostic areas, such as opioid use in musculoskeletal disorders (rheumatologic, back pain); treatment of specific disease states, such as sickle cell disease; and dental and emergency department practices. Although a full understanding is constrained by the limited information available, the committee compiled a brief summary of opioid prescribing practices in the United States from these accessible resources.
In 2015, 169 million prescriptions for some of the most common ER/LA and immediate-release (IR) opioid analgesics were dispensed by U.S. outpatient retail pharmacies, down from a high of 206 million in 2011 (see Chapter 1, Figure 1-1). The majority of opioid analgesic prescriptions dispensed during 2005–2015 were for IR opioids, whereas the number of ER/LA opioids dispensed remained nearly constant during this period (~12 percent).
During 2007–2012, self-reported use of opioid analgesics was higher among women (7.2 percent) than men (6.3 percent) and higher among non-Hispanic white adults (7.5 percent) than Hispanic adults (4.9 percent), while there was no significant difference in self-reported use between non-Hispanic white and non-Hispanic black adults (Frenk et al., 2015). From
1999–2002 to 2003–2006, the percentage of adults aged 20 and over who reported that they had used a prescription opioid analgesic in the past 30 days increased from 5.0 to 6.9 percent. From 2003–2006 to 2011–2012, the percentage who used an opioid analgesic remained stable at 6.9 percent. From 1999–2002 to 2011–2012, however, the percentage of users of opioid analgesics who were prescribed an opioid analgesic stronger than morphine increased from 17 to 37 percent (Frenk et al., 2015). Such a shift to more potent formulations may represent an important signal if one is attempting to understand the current ecology of prescription opioid use in the United States. Specifically, a shift from opioid analgesics that are weaker than morphine (codeine, dihydrocodeine, meperidine, pentazocine, propoxyphene, and tramadol) and “morphine-equivalent” (hydrocodone, morphine, and tapentadol) to those stronger than morphine (fentanyl, hydromorphone, methadone, oxycodone, and oxymorphone) may represent an unwarranted change in opioid prescribing practices relative to evidence for the treatment of chronic painful conditions (Frenk et al., 2015). Although information is limited, such a shift to more potent opioids may correlate with reports of increased use of some opioid analgesics, such as oxycodone.
Clinical Contexts in Which Opioids Are Commonly Prescribed
An analysis of IMS Health’s national prescription data showed that in 2012, nearly 49 percent of all dispensed opioid prescriptions were accounted for by primary care specialists. Opioid prescribing also varies by provider specialty. In 2012, the rate of opioid prescribing among specialists was highest for specialists in pain medicine (48.6 percent), followed by surgery (36.5 percent) and physical medicine and rehabilitation (35.5 percent). From 2007 to 2012, the greatest increase in the rate of opioid prescribing was among physical medicine and rehabilitation specialists, while the greatest declines were in emergency medicine (–8.9 percent) and dentistry (–5.7 percent) (Levy et al., 2015).
The clinical contexts in which pharmaceutical opioids are used also can be quite diverse. The evaluation of risks and benefits may therefore be different for specific opioids depending on their intended application. A few examples of common clinical contexts in which opioids are used demonstrate some of these differences.
Surgery and Acute Pain
Opioids are used commonly during and following surgery. During a surgical procedure, opioids contribute to the analgesic component of a balanced anesthetic. Often the opioids used are of high potency and short duration of action. In addition to intravenous administration, opioids are
sometimes administered intrathecally or into the epidural space to provide relatively high local concentrations without exposing respiratory centers in the brainstem to the same levels of the drugs.
Postoperatively, opioids are used in the postanesthesia care unit and hospital wards and as predominantly oral medications for a period ranging from days to a month or more during the convalescent period. The rate of discontinuation of opioids after surgery has been studied and is believed to be impacted by ongoing pain, as well as psychological factors and patients’ self-perception of their risk for developing OUD (Carroll et al., 2012; Hah et al., 2015). The rate of discontinuation of opioid therapy after surgery is strongly impacted by preoperative use, and is higher for some types of surgery (e.g., joint replacement) than others (Mudumbai et al., 2016; Sun et al., 2016). It remains unclear how intraoperative exposure to opioids contributes to the risk for OUD. Perisurgical exposure to opioids may be an inciting event for the eventual development of OUD in some patients (Sun et al., 2016). Patients with OUD (e.g., individuals on methadone maintenance) are not necessarily excluded from receiving a short course of opioids for acute or acute postoperative pain. Providing excessive amounts of opioids postoperatively is now discouraged, however, and some health care organizations have attempted to limit the amount of postsurgical take-home opioid medication. The effectiveness of such policies is discussed in Chapter 5.
Another commonly encountered acute pain context leading to opioid exposure is the treatment of acute injuries, such as those due to household, sporting, or motor vehicle accidents. In these situations, limited supplies of opioids may be prescribed by emergency departments, urgent care clinics, specialty physicians, and primary care providers. The prescribing of opioids by emergency departments has been especially closely studied, and an increase was found to coincide with an increase in overall opioid prescribing (Maughan et al., 2015). Prescribing in this context can set the stage for a pattern of more chronic use; indeed, observational evidence suggests that long-term opioid use may begin in the emergency department (with 1 in 48 patients prescribed opioids becoming long-term users) (Barnett et al., 2017). Likewise, the use of prescription opioids by former professional athletes is very high, and participants in interscholastic sports may have an elevated risk of opioid use and misuse relative to their nonathlete counterparts (Veliz et al., 2015). Motor vehicle accidents, particularly severe ones, also appear to lead to chronic opioid use in some patients (Zwisler et al., 2015). Opioid prescribing guidelines targeting emergency departments and other acute care settings might contribute to reducing opioid prescribing and increase the use of such measures as urine drug screening prior to prescribing (Chen et al., 2016; del Portal et al., 2016).
Chronic Pain Syndromes
The use of opioids for the management of chronic pain has generated a great deal of attention, and represents the rationale for the prescribing of a large percentage of overall opioid medication consumed each year in the United States. Common types of pain for which these drugs are prescribed include back pain, arthritis, and neuropathic pain (e.g., pain involving tissue injury). Among the complications now associated with the chronic use of opioids for pain are dependence, tolerance, hyperalgesia, addiction, hypogonadism, falls, fractures, sleep-disordered breathing, increased pain after surgery, and poorer surgical outcomes (Baldini et al., 2012; Chou et al., 2015).
Several meta-analyses now available examine the efficacy of opioids for specific pain conditions, such as neuropathic (Gaskell et al., 2016; McNicol et al., 2013) and back (Abdel Shaheed et al., 2016; Chaparro et al., 2014) pain. Additional analyses have included reports on studies involving participants with mixed types of chronic pain (Chou et al., 2014; Pedersen et al., 2014). In general, these meta-analyses suggest that any positive effects of such opioid use have been demonstrated only for relatively short periods of time and that the size of those effects was small. Data are lacking on long-term (>1 year) outcomes such as pain, function, quality of life, and OUD (Chou et al., 2015). Dropout from studies of the use of opioids for chronic pain due to side effects is common, as is discontinuation of the therapy in clinical settings, making it difficult to estimate the benefits of these drugs. Nonetheless, although opioids are commonly prescribed for chronic pain, no widely accepted guidelines suggest their use as first-line analgesic therapy for a chronic pain condition.
Arthritis According to data from the National Health Interview Survey (NHIS), the prevalence of doctor-diagnosed arthritis among adults in the United States during 2013–2015 was 22.7 percent (54.4 million people), with even higher prevalence among individuals with chronic conditions such as heart disease, diabetes, and obesity (Barbour et al., 2017). It is estimated that by 2040, 78 million adults in the United States (26 percent of those aged 18 and older) will have been diagnosed with arthritis (Hootman et al., 2016). Adults with arthritis made up more than half (53 percent) of adults taking prescribed opioids in 2013 (Hootman et al., 2016). Given the widespread use of opioids for noncancer pain and the fact that individuals with musculoskeletal disorders, including arthritis, represent the largest population using prescription opioids, understanding the factors driving opioid use among these individuals could shed light on the broader landscape of prescribing practices.
In a retrospective cohort study evaluating prescription data on patients with rheumatoid arthritis (RA) (n = 501), which after osteoarthritis is one of the more common forms of arthritis, and comparable non-RA subjects (n = 532) during 2005–2014, total and chronic opioid use2 in 2014 was found to be substantially higher in RA than in non-RA participants (40 versus 24 percent and 12 versus 4 percent, respectively). Opioid use had increased by 19 percent per year in both the RA and non-RA cohorts over the study period (95 percent confidence interval [CI] 1.15, 1.25), with an odds ratio of 3.35 to start first chronic use of opioids within the 10-year study period (Zamora-Legoff et al., 2016). Curiously, factors measuring disease severity for RA were not associated with an increased risk of chronic opioid use, posing the unanswered question of what, if any, pathophysiologic and/or functional factor(s) influence the decision to escalate to more potent and/or long-term opioid therapy (Zamora-Legoff et al., 2016).
Fibromyalgia Ten to 20 percent of patients with RA have fibromyalgia, which often involves widespread musculoskeletal pain. A review of available treatments for the chronic pain of fibromyalgia revealed no evidence from clinical trials that opioids are effective for the treatment of this pain (Goldenberg, 2016). In fact, observational studies found that patients with fibromyalgia receiving opioids had poorer outcomes than those receiving nonopioid therapies, and current guidelines recommend against the use of opioids for treating this pain. Yet despite the lack of efficacy and evidence to the contrary, real-world studies revealed that among patients with fibromyalgia who had been newly prescribed amitriptyline, duloxetine, pregabalin, or gabapentin, opioid use was greater than 50 percent during their baseline period (Kim et al., 2013).
Back pain Back pain is one of the main reasons people visit a primary care or family practice physician, and also predominates in other clinical contexts, such as in the care of veterans. In a study of veterans treated in a regional health care network for chronic noncancer pain, for example, factors associated with use of high-dose opioids (>180 milligrams morphine-equivalent dose), after controlling for demographic factors and facility, included low back pain, neuropathy, and nicotine dependence. Within the high-dose group, approximately equal percentages of patients had received oxycodone IR (48 percent) and/or morphine ER (52 percent) (Morasco et al., 2010). Although the long-term efficacy of opioids in the management of back pain is unknown, the clinical benefits of shorter-term opioid
2 Chronic opioid use was defined as opioid prescriptions for 60 days or more within a 6-month period and use of one or more of the following opioids: transdermal fentanyl, methadone, and oxycodone ER (Zamora-Legoff et al., 2016).
therapy to treat this condition appear to be relatively moderate compared with the many well-documented adverse effects (Deyo et al., 2015). In their review, Deyo and colleagues (2015) note that for seven short-term trials (≤12-week follow-up) examining the use of strong opioids for chronic low back pain, there was moderate evidence of pain reduction and functional improvement compared with placebo. Nevertheless, opioids continue to be used widely in an attempt to manage back pain for longer periods of time. For example, in a large study of a managed care plan (Kaiser Permanente Northwest health care system in Portland, Oregon) examining the pattern of opioid use 6 months before and after an index visit for back pain, 61 percent of the 26,014 eligible patients had received a course of opioid therapy, and 19 percent had become long-term (≥120 days or >90 days with 10 or more fills) opioid users. Among the long-term users, 59 percent had received short-acting (SA) opioids, and 39 percent had received both SA and LA opioids. Psychological and behavioral difficulties appeared to drive long-term opioid use in persons with back pain (Deyo et al., 2011).
Musculoskeletal Conditions and Fractures, Sprains, and Contusions
Tracking of opioid prescriptions currently is not linked to such details as medical indication, whether the patient’s pain is acute or chronic, or other pertinent details of medical history. Rather, the primary tracking factors are the 9th and 10th revisions of the International Classification of Diseases (ICD) (Pan, 2016). On this basis, diseases of the musculoskeletal system and connective tissues (ICD-9 codes 710–739) are among the conditions most commonly associated with the use of opioids (FDA, 2016; Pan, 2016). According to office-based physician reports, in 2015 nearly 54 percent of diagnoses of chronic conditions associated with use of hydrocodone/acetaminophen were for diseases of the musculoskeletal system and connective tissues (which include arthritis and back pain). Among acute conditions, injuries (fractures, sprains, and contusions [ICD-9 codes 800–999]) were the conditions most commonly associated with the use of hydrocodone/acetaminophen (42 percent), followed by diseases of the musculoskeletal system and connective tissues (17 percent) (FDA, 2016). Cumulative ICD data for the period January 2007–November 2011 indicate that the shares of musculoskeletal system and connective tissue diagnoses associated with the use of different types of opioids were as follows: morphine ER (68 percent), morphine IR (56 percent), oxycodone IR (41 percent), hydrocodone combination (25 percent), and oxycodone combination (20 percent) (Pan, 2016). The shares of individuals with fractures, sprains, and contusions using various types of opioids were considerably different, with oxycodone combination (26 percent) and hydrocodone combination (19 percent) dominating, followed by oxycodone IR (8 percent), morphine ER (3 percent),
and morphine IR (4 percent) (Pan, 2016). Based on these data, it appears that oxycodone IR and morphine IR and ER, as opposed to combination products, have been used more frequently to treat chronic pain associated with musculoskeletal and connective tissue disorders.
Cancer-Related Pain and End-of-Life Care
The aggressive use of opioids has long been accepted and strongly promoted for the treatment of pain in patients with cancer or those in end-of-life and palliative care. Foundational work in this area suggested that in most patients, control of pain due to active cancers could be achieved using oral analgesics, including opioids. Such data led to the development of the World Health Organization “Analgesic Ladder,” which outlines the use of progressively stronger analgesics as necessary to control pain in these patients (WHO, 1986). The pain, oncology, and palliative care literatures are replete with studies of various IR and LA opioids used to control cancer pain, generally with positive results. It was within the contexts of cancer and palliative care that the concept of “breakthrough” pain treatment gained popularity. The emergence of this concept has in turn supported the development of fast-acting high-potency opioid preparations such as transmucosal and intranasal products. Overall, the aggressive use of opioids for control of pain in cancer and palliative care patients is common and strongly supported by both the available literature and the medical community (Hadley et al., 2013; Schmidt-Hansen et al., 2015; Wiffen et al., 2016; Zeppetella and Davies, 2013).
However, the use of opioids in these patients is not without caveats. For example, nausea, constipation, sedation, and other side effects are common after the administration of opioids in patients with cancer pain, just as they are in those suffering from other pain conditions. Accidental overdose also can occur. Moreover, studies examining the results of urine drug screens from patients with cancer and in palliative care have provided significant evidence of opioid misuse and diversion (Barclay et al., 2014; Childers et al., 2015), while many cancer pain and palliative care clinics lack formal policies addressing drug misuse and diversion (Tan et al., 2015b). Thus, improperly stored or monitored medications prescribed to cancer or palliative care patients may make their way into the community.
An additional problem increasingly being recognized relates to chronic pain in cancer survivors. In addition to common noncancer-related causes, chronic pain in cancer survivors can result from the sequelae of the disease itself or such treatments as surgery, radiation, and chemotherapy. Opioid use in cancer survivors is common (Carmona-Bayonas et al., 2016), although data with which to quantify its frequency are scarce. Guidelines have been issued suggesting that providers use approaches similar to those
It has been estimated that dentists prescribe 12 percent of all IR opioids (hydrocodone, oxycodone), second only to family physicians (Denisco et al., 2011), although their rates of prescribing may have declined in recent years (Levy et al., 2015). Dentists prescribe opioids mainly for the short term to treat acute postsurgical pain. Third molar extraction, for example, is probably the most common surgical procedure performed in healthy adults. It is estimated that 3.5 million third molar extractions are performed by oral and maxillofacial surgery specialists annually (and this number does not include the extractions performed by general dentists). One study found ibuprofen to be the peripherally acting postsurgical drug of choice among 73.5 percent of oral surgeons; however, 85 percent of them almost always prescribed a centrally acting opioid alone or in combination with another analgesic agent. Hydrocodone is among the opioids most commonly prescribed by oral surgeons; one study found that the combination usually was with acetaminophen, and 20 tablets on average were prescribed (Moore et al., 2006a,b). Based on these data, at least 3.5 million people with an average age of 20 (the average age for third molar extraction) may be exposed to opioids related to dental treatment (Denisco et al., 2011).
Opioids also may be prescribed for dental pain in emergency departments. One study found that 45 percent of emergency department visits for a nontraumatic dental condition ended with an opioid prescription (Okunseri et al., 2014). It is important to note that nontraumatic acute dental pain can be treated with a relatively simple dental procedure in a dental office; however, few emergency departments are equipped, staffed, or designed to provide dental care.
Leftover opioids prescribed by dentists may be a concern if they are shared with friends or family members to help with apparent symptoms of pain, or for other reasons (O’Neil and Hannah, 2010). Therefore, it is recommended that opioids be prescribed only for several days following an oral surgical procedure. Although literature on the duration of pain following oral surgery is scarce, 2–3 days of treatment is often thought to be sufficient (Biron et al., 1996). Moreover, extended severe pain after oral surgery may indicate infection or some other complication, and thus a visit to the dentist is a better option than prolonged treatment with opioids or other pain medications.
Therapy with opioids following third molar extraction or other oral surgery procedures may be indicated as it does provide adequate pain relief (Weiland et al., 2015). However, treatment with peripherally acting anal-
gesic agents, such as ibuprofen and naproxen, has been shown to provide good pain relief as well (Moore et al., 2015) and can be as effective as opioids for many patients who undergo impacted tooth extraction (Hersh et al., 1993). Nonopioid analgesic agents such as NSAIDs may be advisable as the first line of therapy for the routine management of acute postoperative dental-related pain for patients who have no contraindications for their use (Becker, 2010; Donaldson and Goodchild, 2010).
Mandatory checking of data from prescription drug monitoring programs (which are discussed in more detail in Chapter 5) was shown to be effective in changing the prescribing pattern for pain medications among dentists in a dental urgent care clinic in New York State (Rasubala et al., 2015). Before prescribing opioids, it may be beneficial for dentists (as well as other providers; see below) to screen patients for substance misuse as well as substance misuse risk factors. General dentists often have long-term relationships with their patients and therefore are well positioned to perform this screening. Oral surgeons or specialists, who often see patients only for a specific procedure, may consult the referring dentist or physician for this purpose (Denisco et al., 2011).
Decision Making About Opioid Prescribing
The list of factors contributing to the decision of whether to prescribe opioids includes not only the provider’s desire to reduce a patient’s suffering but also the expectations of the patient regarding pain control. Concern has been raised that increased attention to the issues of acute and chronic pain has led to the expectation that patients should experience little or no pain once a provider has been informed of the problem. The prescription of medication represents a rapid method of addressing a pain complaint, certainly accomplished more easily than providing a course of physical therapy, psychological counseling, spinal injection, or many other available approaches to the treatment of pain. For that reason, analgesics including powerful opioid pain relievers are an attractive option. On the other hand, emphasis is increasing on setting reasonable expectations and establishing mutually agreed-upon goals for the control of chronic pain, with an emphasis on communication and safety (Dowell et al., 2016).
Regrettably, providers may feel pressured to provide opioids for fear of poor evaluations of their performance. Measures instituted over the past decade or so that may contribute to this pressure include the designation of pain as the “fifth vital sign” (Lanser and Gessell, 2001) and the increasing attention to patient feedback on surveys regarding pain control as part of their care. Importantly, in 2016 the Centers for Medicare & Medicaid Services issued a proposed rule to remove posthospitalization patient survey questions about pain management from scores that are tied to Medicare
payments in an effort to reduce unnecessary opioid prescribing.3 However, rankings of patient satisfaction remain important to hospitals and providers as the rankings can affect their business, and providers’ pay may be impacted by patient evaluations as well. The precise impact of pain control on patient satisfaction is somewhat unclear, although some have suggested that communication and compassion may be more important than pain control itself in influencing a patient’s survey response (Lee, 2016). Further discussion on the related topics of clinical practice guidelines and industry promotion is included in Chapters 5 and 6, respectively.
Discussions between providers and patients about the use of nonopioid alternatives may be difficult. In some instances, providers may find it easier to write an opioid prescription than to have a discussion with the patient about the balance of risks and benefits of using an opioid versus alternative therapies. This may be the case in particular with patients who have come to believe that opioids are the best treatment for their chronic pain and who feel that alternative forms of treatment will not work as well. As discussed in Chapter 5, educating providers and patients about alternative forms of treatment may be one means of reducing reliance on the use of prescription opioids to manage chronic pain.
Assessment and Mitigation of Risk When Prescribing Opioids
As discussed in Chapter 5, growing recognition of important areas of overlap between opioid therapy for pain and opioid misuse has led to multiple forms of response, including statements, policies, and guidelines issued by federal agencies, state governments, advocacy groups, professional societies, academic panels, and others. Yet while the need for a more cautious approach to opioid prescribing has generally been acknowledged, there has been no overarching effort to coordinate responses among concerned groups. In addition, a tension exists between efforts to curtail prescribing and the interests of at least some groups of patients in maintaining access to opioids.
Many of the recommendations commonly discussed in considering opioids for the management of chronic noncancer pain are encapsulated in the so-called universal precautions of pain medicine (Gourlay et al., 2005). These 10 steps (see Box 2-1) were not proposed for use exclusively when managing opioids, although opioid management is an important area for their application.
Beyond these overarching principles of responsible opioid management are efforts to construct risk assessment tools. Generally, the goal has been to assemble and validate reasonably brief questionnaires useful in clinical
3 81 C.F.R. 45603.
situations that would provide prescribers with information concerning the likelihood of development of opioid misuse should opioids be provided for the management of pain. Several such tools have been developed. Those used commonly include the Screener and Opioid Assessment for Patients with Pain (SOAPP and SOAPP-Revised) (Butler et al., 2004, 2009); the Diagnosis, Intractability, Risk, and Efficacy (DIRE) inventory (Webster and Webster, 2005); and the Opioid Risk Tool (ORT) (Belgrade et al., 2006). Each has been studied, and some information directly comparing their properties is available (Moore et al., 2009). Reviews of the utility of these screening tools suggest some predictive value, yet significant caveats exist (Chou et al., 2009b). For example, the predictive power of these tools is limited, they differ in their definitions of misuse or aberrant behavior, and the body of data validating them is fairly small. See further discussion on the evidence of effectiveness of these tools in Chapter 3.
In addition to initiation of opioids, providers face questions about how to manage patients who are already taking the drugs, some of whom have been maintained chronically on them for months to years. Over the past decades, millions of Americans have been exposed to and many are now maintained chronically on opioid pain medications. The short- and longer-
term risks of opioid use are more serious than previously estimated, and as discussed above, the likely benefits of chronic opioid use for pain are lower for many patients than previously believed. As a result, a large group of “legacy” chronic pain patients are receiving opioids at doses or under circumstances that are inappropriate in light of current knowledge. Information useful in understanding how best to manage this group of patients is lacking in many clinical settings.
The U.S. Centers for Disease Control and Prevention’s (CDC’s) Guideline for Prescribing Opioids for Chronic Pain (see Chapter 5) recommends that patients who have been on high dosages of opioids “be offered the opportunity to re-evaluate their continued use of opioids at high dosages in light of recent evidence regarding the association of opioid dosage and overdose risk” and that providers review the risks and benefits of continued opioid therapy with these patients (Dowell et al., 2016, p. 1638). The guideline further recommends consideration of opioid tapering when there is no evidence of improvement in pain or function, particularly when the opioid dose has reached more than 50 morphine milligram equivalents (MME) with or without added benzodiazepines or signs of harm (Dowell et al., 2016). Implicit here is the importance of assessment and reassessment of patients on chronic opioids. If the patient’s pain and function have not improved significantly with the initiation or increase in the dose of opioids, providers might reconsider continuing use given the risk of adverse effects. Evidence suggests that tapering of opioids prior to elective surgery may decrease the risk of developing chronic pain after surgery, thereby reducing postsurgery analgesic requirements (Chapman et al., 2011). A slow taper is likely better tolerated, particularly in patients taking opioids chronically. The CDC guideline calls for as slow as a 10 percent reduction per month in combination with support from the patient’s clinician and psychological and other specialists as needed (Dowell et al., 2016). A study of a small sample of patients in a primary care setting found that patients considered the risk of increased pain and of withdrawal symptoms from the tapering of opioids to be greater than the risk of overdose from continuing to use the drug. Discussions of tapering with patients may be more successful if these fears are addressed as part of the conversation (Frank et al., 2016).
Practice Tools to Reduce Potentially Harmful Opioid Use in the Course of Pain Treatment
The use of patient–provider agreements (PPAs), also referred to as opioid treatment agreements (OTAs) or pain contracts, has been reported as a possible tool in the clinical management of chronic pain (Fishman et al.,
2002a,b). The precise components of PPAs may vary among practices, but in general they serve to document the understanding between patient and clinician about the treatment plan and its goals. PPAs provide an opportunity to discuss with patients the risks and benefits of opioid therapy. The agreement may describe the roles and responsibilities of the patient and the provider and the grounds for discontinuation or continuation of the opioid treatment based on the risk-benefit ratio (Gourlay et al., 2005; Quill, 1983). Addiction, misuse, significant nonadherence to the agreement, or risk to the public may be the major reasons for discontinuation of treatment.
Despite the potential of such agreements, it is clear that the ability of providers to recognize nonadherence to treatment plans is limited (Osterberg and Blaschke, 2005). The ability to apply the contract may also be limited because patients do not have the choice of whether to agree to it. Moreover, while data on effectiveness are limited, one study reports that the use of PPAs may be relatively low (aside from high-risk patients) and that patients may not always realize when they have signed one, which could limit their utility (Penko et al., 2012). One study showed that more than 60 percent of patients adhered to an OTA with a median follow-up of 22.5 months; 7 percent of OTAs were canceled because of substance misuse and noncompliance (Hariharan et al., 2007). Ongoing ethical debate surrounding PPAs is important to acknowledge. Despite their potential, universal utilization of PPAs is resisted on a variety of grounds, including limited health literacy and concerns about increasing disparities and further stigmatizing pain patients (Payne et al., 2010). Indeed, use of PPAs does not guarantee better care: “[unscrupulous physicians] practicing in ‘pill mills’ regularly require their patients to sign pain contracts” (Payne et al., 2010, p. 11). Overall, while there is no consensus regarding the use of PPAs, they are being used to varying degrees in chronic pain treatment and may facilitate monitoring of adherence to treatment plans. More research could clarify their effective use and outcomes to help improve adherence and monitoring, as well as reduce the potential for unintended negative consequences.
Consultation with and Referral to Pain Specialists
Primary care providers, including those in emergency medicine settings, often are the first point of medical contact for patients with pain. Given the limited number of pain specialists, primary care providers play an essential role in pain management and in overcoming the challenge of undertreatment of pain (IOM, 2011). Yet there are occasions when these providers can benefit from consultation with or referral of patients to pain specialists—providers who have had specialty training in the diagnosis and treatment of painful conditions (often from the fields of anesthesiology, neurology, physical medicine and rehabilitation, psychology, or psychiatry).
Partnership with pain specialists may help primary care providers maximize pain relief and function for patients while minimizing the risk of use of opioids and other treatments. Working in tandem with a pain specialist may help all involved define shared goals in the patient’s pain treatment plan. Establishing expectations at the outset is helpful for both patient and physician;4 setting realistic expectations at the beginning of treatment can affect outcomes and patient satisfaction. Some pain specialists have had specialized training in psychiatry and/or addiction medicine, which can enable them to evaluate whether opioids are appropriate for the individual patient and to treat patients with substance use disorders. There are models for coordination with primary care to treat pain in high-risk patients in the context of a patient-centered medical home (Cheatle et al., 2012).
Pain specialists also may be consulted prior to surgery for recommendations regarding chronic use of opioids as patients’ tolerance for the drugs may adversely affect their postoperative experience. Pain specialists may offer recommendations on maximizing nonopioid therapy prior to surgery and on employing regional anesthetic techniques that may assist in minimizing the use of opioids intra- and postoperatively (Huxtable et al., 2011; McGreevey et al., 2011). Pain specialists that work in the context of multidisciplinary pain centers are able to individualize patient care and treat patients holistically. (The section on clinical research in Chapter 3 includes discussion of improving pain management in the primary care setting despite a relative lack of access to pain specialists, while the discussion of Project ECHO in Chapter 4 describes a model for providing high-quality care through expert teleconsultation with community providers.)
Opioids are widely prescribed in a variety of settings for treatment of both acute and chronic pain, frequently including back pain, pain due to arthritis and other musculoskeletal conditions, and dental pain. However, data are lacking on the longer-term benefits of opioids in the management of chronic noncancer pain. Moreover, studies do show an increased risk for a number of adverse outcomes from long-term use of opioids, including OUD, overdose, and other adverse effects. Moreover, no widely accepted guidelines recommend the use of opioids as a first-line therapy for management of chronic noncancer pain. Despite the lack of evidence
4 A retrospective review of 248 patients for whom treatment expectations and anticipated level of pain relief were documented in the initial intake record found that the expectation in back pain patients was at least 58 percent pain relief. Fibromyalgia patients anticipated 54 percent pain relief from their office visit, along with reduction of other distressing symptoms, while those with migraine expected complete relief without associated side effects (O’Brien et al., 2010).
supporting the practice, however, providers continue to prescribe opioids for extended periods.
Nonsteroidal Anti-Inflammatory Drugs
NSAIDs are commonly used to treat acute pain following trauma or interventional procedures, as well as pain due to some chronic inflammatory musculoskeletal conditions, such as arthritis. These drugs inhibit the cyclooxygenase (COX) enzymes that catalyze the transformation of arachidonic acid to prostaglandins (PGs)—evanescent, locally acting lipid mediators with diverse biological effects. PGs include PGE2 and PGI2, which have been shown to mediate pain and inflammation. COXs are of two types: COX-1, which tends to be ubiquitously expressed and accounts for the greater part of hemostatic and gut barrier integrity; and COX-2, which is readily upregulated by cytokines and mitogens and largely accounts for PG formation in pain, inflammation, and cancer. Older NSAIDs, such as ibuprofen and naproxen, inhibit both COX-1 and COX-2 at therapeutic doses. The development of NSAIDs specifically for inhibition of COX-2, such as rofecoxib and celecoxib, was prompted by serious adverse gastrointestinal (GI) effects of those older agents, attributed to inhibition of platelet COX-1-dependent thromboxane A2 formation (predisposing to bleeding) and disruption of barrier function due to inhibition of COX-1-dependent formation of PGE2 and PGI2 by gastroduodenal epithelium. However, a reduction in the serious adverse GI effects of these earlier drugs was accompanied by an increase in cardiovascular adverse effects, such as myocardial infarction, stroke, and heart failure, resulting from suppression of the cardioprotective properties of COX-2-derived PGI2 and PGE2 in the cardiovascular system (Grosser et al., 2010).
Aspirin, also an NSAID, relieves pain at high (>325 mg) doses that inhibit COX-1 and COX-2. As with other nonspecific NSAIDs, however, such efficacy is accompanied by adverse GI effects. Aspirin is by far more commonly consumed at low (<100 mg/day) doses for cardioprotection, and although the incidence of serious adverse GI effects is roughly doubled with these lower doses, such events are much less common than at higher analgesic doses. Aspirin differs from other NSAIDs in that it covalently modifies COX (the other drugs are competitive active site inhibitors), requiring de novo synthesis of the enzyme for recovery of PG formation from aspirin exposure. In the case of the anucleate platelet, which contains only COX-1, this requires the production of new platelets. Chronic administration of low-dose aspirin suppresses platelet COX-1-derived production of thromboxane A2, a vasoconstrictor and platelet agonist, and this mechanism is
sufficient to explain the efficacy of low-dose aspirin in the secondary prevention of heart attack and stroke (Fitzgerald and FitzGerald, 2013). The place of low-dose aspirin in primary prevention is currently unclear; the number of heart attacks prevented and serious adverse GI effects caused are roughly in balance.
APAP (Paracetamol), or acetaminophen, is another NSAID, inhibiting both COX-1 and COX-2 by ~50 percent at the most commonly used daily dose of 1,000 mg (Catella-Lawson et al., 2001). At this dose, it is effective in relief of mild pain but is commonly used as an antipyretic. A Cochrane review found that ibuprofen in combination with acetaminophen provided better analgesia than either drug alone at the same dose, and with a smaller chance of an adverse event (Derry et al., 2013a). However, it is unclear whether this finding reflects a distinct mechanism of action of acetaminophen or merely more efficient COX inhibition by the combination.
Studies in mice suggest that the antipyretic property of APAP derives from suppression of PGE2-dependent activation of the E prostanoid receptor 3 (EP3) (Ushikubi et al., 1998). This COX/PGE/EP3 pathway is activated by the receptor activator of nuclear factor kappa-B ligand (RANKL) acting on its tumor necrosis factor (TNF) receptor-related RANK receptor in astrocytes (Hanada et al., 2009). While GI complications of APAP are uncommon, indirect higher doses (>4,000 mg/day) may have an adverse GI effect profile similar to that of other nonspecific COX inhibitors. Many effects beyond COX inhibition have been attributed to APAP, but the importance of their contribution to either its efficacy or its adverse effect profile is unclear. The biggest concern with APAP is liver toxicity; overdose may cause fatal acute liver failure (Fontana, 2008). This effect may also be mechanism-based as hepatotoxicity complicates treatment with diclofenac, an older NSAID that turns out to be a quite specific inhibitor of COX-2. The genetic basis for predisposition to hepatotoxicity from lumiracoxib, a diclofenac analog specifically designed to inhibit COX-2, has been established (Singer et al., 2010).
Combination therapy, including APAP and other NSAIDs, was found to be superior to the combination of the opioid hydrocodone and APAP, with fewer side effects, for pain from dental extractions (Moore and Hersh, 2013). And a systematic review comparing oral NSAIDS with opioids for treatment of pain due to knee osteoarthritis over at least 8 weeks’ duration found similar pain relief for both analgesics (Smith et al., 2016b).
Antidepressants—including tricyclic antidepressants (TCAs), combined serotonin-noradrenalin reuptake inhibitors (SNRIs), and selective serotonin reuptake inhibitors (SSRIs)—are one of the oldest pharmacological treat-
ments for chronic pain. Studies have found specific antidepressants (or classes of antidepressants) to be effective for the treatment of various types of pain. For example, amitriptyline improves pain for postherpetic neuralgia (Graff-Radford et al., 2000) and for fibromyalgia (Moore et al., 2012), while duloxetine can improve pain for diabetic peripheral neuropathy (Lunn et al., 2014) and osteoarthritis knee pain (Wang et al., 2015). TCAs and SNRIs are recommended as a first choice (along with gabapentinoids) for postherpetic neuralgia, painful neuropathies, and central pain (Dworkin et al., 2010). SSRIs generally are better tolerated by patients relative to other antidepressants, but the evidence on their efficacy for treating chronic pain is inconclusive (Patetsos and Horjales-Araujo, 2016).
Although depression is common among patients with chronic pain (Fishbain et al., 1997; Iacovides and Siamouli, 2008), the analgesic effect of antidepressants is separate from their effect on depression. Pain relief occurs at lower doses than doses with an antidepression effect (Hameroff et al., 1984; Langohr et al., 1982; Magni, 1991), and has been noted in both depressed and nondepressed patients (Couch and Hassanein, 1976; Jenkins et al., 2012; Lance and Curran, 1964; Max et al., 1987).
The mechanism of action of antidepressants on pain is not fully understood. Antidepressants act mainly by reducing noradrenalin and serotonin reuptake and enhancing the descending inhibition (Gillman, 2007). While both norepinephrine and serotonin have an effect on mood and pain (Sindrup and Jensen, 1999), catecholamine blockade appears to be more important in pain reduction. Indirect mechanisms of action may include (1) enhancement of the effects of endogenous opioids by increasing either their production or expression of opioid receptors (Hamon et al., 1987; Sacerdote et al., 1987), (2) antagonism of N-methyl-d-aspartate (NMDA) receptors (Luccarini et al., 2004), (3) blockade of sodium and/or calcium channels (Gerner et al., 2003; Wang et al., 2015), (4) blockade of histamine or cholinergic receptors (Abdel-Salam et al., 2004; Butler et al., 1985), and (5) increased expression of γ-aminobutyric acid (GABA) type B receptors in the spinal cord (McCarson et al., 2006). It is important to note that attenuation of chronic pain by antidepressants is not immediate; the clinical effect usually is noted only after days or weeks of treatment.
Common side effects of antidepressants include dry mouth, blurred vision, constipation, difficulty in passing urine, weight gain, and drowsiness. The SSRIs are generally better tolerated than other antidepressants, but their side effects can include nausea, tremor, hyperarousal, and drowsiness (Goodman et al., 2001). Adverse effects may be less likely with gradual dose escalation. Combination therapy with gabapentinoids, opioids, and topical agents is sometimes considered in refractory cases (Gilron et al., 2009, 2013).
Anticonvulsant medications, principally gabapentin (and, more recently, pregabalin), have come to serve as first-line therapies in the treatment of chronic neuropathic painful conditions (with the exception of trigeminal neuralgia) (Wiffen et al., 2017), as well as acute perioperative pain (Nir et al., 2016). Gabapentin, an anticonvulsant initially introduced for the treatment of partial complex seizures, is approved in the United States for postherpetic neuralgia (PHN). With the expiration of the exclusivity patent on gabapentin, pregabalin was introduced and obtained FDA approval for the treatment of PHN, as well as diabetic polyneuropathy and fibromyalgia. Independently, gabapentin also has been found effective in the treatment of fibromyalgia, although further research is needed (Cooper et al., 2017). Expert opinion in the form of guideline recommendations has emerged as well, in many cases being updated by societies dedicated to the evidence-based management of neuropathic pain, such as the Neuropathic Pain Special Interest Group (NeuPSIG) (Dworkin et al., 2007, 2010; Sardar et al., 2016). Regrettably, these drugs have an emerging potential for misuse, particularly in individuals with OUD (Evoy et al., 2017; Havens, 2016).
Mechanistically, the goal of these agents is to suppress the sensation of peripheral neuropathic pain, described as arising from both unmyelinated C-type (slowly conducting) nerve fibers, associated with sensations of dull, aching, burning, and poorly localized pain, and thinly myelinated A-delta nerve fibers, which are more rapidly conducting and signal sensations of sharp, stabbing, and often well-localized pain. Central nervous system (CNS)/spinal-glial pathways underlie a combination of signs (hypoesthesia, hyper/hypoalgesia, heat/cold hyperalgesia, allodynia) and symptoms (paraesthesias, sensation of burning and/or shooting pain) that, together with the appropriate clinical context, increase the diagnosis of neuropathic pain (Haanpää et al., 2009).
Unlike opioids, gabapentinoids (gabapentin, pregabalin) act primarily to reduce hyperalgesic states under conditions of inflammation and nerve injury rather than changing pain thresholds under nonpathological conditions (Werner et al., 2001). Therefore, gabapentinoids modulate the pain pathway under pathophysiologic conditions. Under hyperalgesic conditions, gabapentin and pregabalin act supraspinally to enhance the descending inhibitory noradrenergic system onto the dorsal horn of the spinal cord (Hayashida et al., 2007; Tanabe et al., 2008). In addition, it has been proposed that gabapentin and pregabalin act at the level of the spinal cord through binding to alpha2-δ1 subunits of a voltage-gated calcium channel (VGCC) expressed in presynaptic terminals of primary afferent nociceptors (Li et al., 2006). As discussed earlier in the chapter, the use of gabapentin
or pregabalin in the immediate preoperative setting has the potential to decrease the need for postsurgical opioids (Tan et al., 2015a).
Analgesic response rates for peripheral neuropathic painful conditions tend to average approximately 30 percent and rarely if ever exceed 50 percent. Therefore, despite their “effectiveness” in the treatment of PHN, diabetic polyneuropathy, and fibromyalgia, gabapentin and pregabalin have not been proven effective in the treatment of postamputation/phantom limb pain. Nevertheless, they may still offer a benefit to those patients who have failed other analgesic therapy. More recently, gabapentin and pregabalin have been emerging in a widening range of applications initially considered “off-label,” including as single or part of multimodal therapies for perioperative pain management (Chaparro et al., 2013), opioid-sparing strategies and reduction of the risk of opioid-induced hyperalgesia (Stoicea et al., 2015), and neuropathic pain originating from cancer or its treatment (Vadalouca et al., 2012). However, as noted above, misuse of gabapentinoids is of growing concern and the risk for misuse of these drugs may be higher in individuals with a history of opioid misuse (Evoy et al., 2017; Havens, 2016).
Capsaicin Creams and Patches
Persons suffering from chronic neuropathic pain often encounter difficulty with their pharmacotherapy and are unable to tolerate the side effects of such agents as anticonvulsants, antidepressants, and other centrally acting therapies. Moreover, such therapies may be ineffective. Long before the advent of clinical trials, physicians successfully used native plant derivatives to provide pain relief. Among these, medicinal plant derivatives from hot chilies in South America were used as far back as 4000 BC. Capsaicin, the pungent principal ingredient in hot chili peppers, is now recognized as the primary therapeutic agent acting on the capsaicin receptor TRPV1 in many of these medicinal plants (Schumacher, 2010). Acting predominantly on C-type primary afferent nociceptors, capsaicin has long been appreciated as inducing pain following its initial application, but paradoxically, having a topical analgesic effect with repeated application. A series of overlapping capsaicin-induced effects that include desensitization, nociceptor dysfunction, neuropeptide depletion (Cao et al., 1998; Yaksh et al., 1979), and nociceptive terminal destruction (Robbins et al., 1998; Simone et al., 1998) are now understood as underlying the analgesic action of topically applied capsaicin.
Topical creams or patches containing capsaicin can sometimes be effective for certain dermatomally restricted neuropathic conditions. However, several aspects of topical capsaicin treatment appear to limit its overall effectiveness and application in clinical practice: the area of pain has a
restricted pattern of distribution (dermatomal or nondermatomal); repeated capsaicin application (up to four to five times daily) is required to establish and maintain an adequate degree of analgesia; and topical application may cause initial or ongoing pain/irritation. In response to these limitations, the capsaicin content in these preparations tends to be “low-dose” (0.025 or 0.075 percent). When such low-dose capsaicin preparations have been studied or compared with so-called first-line neuropathic pain treatments using a grading system requiring multiple RCTs, they typically have not provided robust neuropathic pain relief and showed poor to moderate efficacy in the treatment of either musculoskeletal or neuropathic symptoms (Attal et al., 2006; Mason et al., 2004).
PHN is one of the most prevalent painful conditions associated with neuropathy that clinicians may encounter. It is driven in the United States by some 800,000 annual cases of primary herpes zoster infection (Schmader, 2002). A Cochrane review examined six studies of topical capsaicin involving 2,073 patients conducted through December 2012, which included RCTs and controlled trials of at least 6 weeks’ duration. Four studies of a combined 1,272 participants with PHN showed estimated numbers needed to treat (NNT) to attain “much improved or very much improved pain” of 8.8 and 7.0, respectively (Derry et al., 2013b).
In one study, high-dose (5 to 10 percent) capsaicin, initially under regional anesthesia and later following topical local anesthetic pretreatment, was used in an attempt to circumvent the limitations of repeated low-dose capsaicin application and resulted in a wide range of posttreatment pain relief (Robbins et al., 1998). The strongest evidence exists for the use of high-dose capsaicin for the management of painful PHN. As with other therapeutic options for the treatment of painful neuropathic conditions, however, there appear to be responders and nonresponders to capsaicin among patients experiencing PHN and a range of other neuropathic conditions. Overall, the quantified magnitude of the analgesic effect of capsaicin is typically modest (10 to 30 percent), although one study showed that among participants followed for 12 months, 10 percent experienced complete resolution of painful symptoms from PHN and other peripheral neuropathic conditions (Mou et al., 2013). Beyond PHN, other painful neuropathic conditions sensitive to the analgesic effects of topical capsaicin (with decreasing levels of evidence) include HIV-associated painful neuropathy (Derry et al., 2013b), painful diabetic neuropathy, and postsurgical neuropathic pain.
Local Anesthetics/Sodium Channel Blockers
The use of local anesthetics for the relief of acute and chronic pain has typically relied on the restricted deposition of the anesthetic within sub-
cutaneous tissues, adjacent to target nerves and/or spinal epidural routes. The analgesic action is based on the ability to block voltage-gated sodium channel (VGSC)-mediated sodium influx into neuronal cells in response to local membrane depolarization. Ideally, the goal is to achieve analgesia through the blockade of sodium currents in small-diameter (nociceptive) neurons of C and Aδ fiber type that are carried by members of the tetrodotoxin (TTX)-resistant sodium channel family (predominantly Nav1.8 and Nav1.9) that are differentially expressed in small-diameter/pain-sensing neurons (Devor et al., 1992; Persaud and Strichartz, 2002). Since increased VGSC subtype expression on primary afferent neurons (nociceptors) is now linked to inflammatory and neuropathic pain, the blockade by local anesthetics represents a plausible mechanistic approach to treatment of chronic pain (Waxman et al., 1999). Accordingly, efforts are under way to develop a new generation of local anesthetics/sodium channel blockers that selectively block sodium channel subtypes in sensory neurons, with the goal of obtaining an analgesic effect while sparing normal touch or motor function (Kort et al., 2008).
However, widespread administration of local anesthetics is limited by toxicity to the CNS and the cardiac conduction system. Selective, continuous infusion of low-dose local anesthetics adjacent to the nerve trunks, such as the brachial plexus or peripheral nerves, as well as through the epidural route, offers advantages over other modes of postoperative analgesia (Guay, 2006). In many cases, these techniques have been extended to cancer and noncancer chronic pain treatments.
Alternatively, continuous systemic infusion of the local anesthetic lidocaine has shown promise in the treatment of a wide range of chronic painful conditions that have not responded to more established analgesic approaches in both adults and pediatric patients (Gibbons et al., 2016; Kandil et al., 2017). Although studies are still emerging, intravenous lidocaine infusion may help reduce intensity of pain and improve activity levels in a selected group of chronic pain patients. Lidocaine infusion also has been used safely and successfully in patients suffering from advanced cancer pain, both in the hospital setting without telemetric monitoring and in palliative care units, hospices, or even patients’ homes, given suitable nursing supervision (Peixoto and Hawley, 2015). The outcomes of lidocaine infusion in perioperative settings are mixed, with focused clinical applications, such as following complex spine surgery, showing promise (Farag et al., 2013). On the other hand, broader application across the spectrum of perioperative pain care may yield less than expected outcomes as there is only low to moderate evidence that lidocaine infusion compared with placebo has a large impact on pain scores, especially in the early postoperative phase (Kranke et al., 2015). Questions that need to be addressed before lidocaine
can be used as a mainstream treatment include precise dosing regimen, infusion duration, and patient selection criteria (Kandil et al., 2017).
Lidocaine (topical) patches (5 percent), represent yet another route of delivery of local anesthetics for the treatment of acute and chronic pain, having been shown to be efficacious for PHN and diabetic neuropathy (Mick and Correa-Illanes, 2012). The efficacy of broader use of lidocaine patches in the treatment of other neuropathic pain ailments is undetermined (Finnerup et al., 2015), and there is as yet no evidence for the effectiveness of lidocaine patches in the relief of postoperative pain (Bai et al., 2015; Mooney et al., 2014).
Alpha 2 (α2) Adrenoreceptor Agonists
Although practitioners may be familiar with the antihypertensive and sedative properties of α2 adrenoreceptor agonists (clonidine, dexmedetomidine), substantial evidence indicates that they function as analgesic agents, having a synergistic effect with opioids and efficacy in opioid-tolerant patients. Anecdotal case reports suggest that α2 adrenoreceptor agonists may offer an alternative analgesic strategy for patients that have failed classic opioid management for painful conditions (Pirbudak et al., 2014).
Two complementary mechanisms couple α2 adrenoreceptor agonists to analgesic action: activation of descending spinal inhibition and direct activation of presynaptic α2 receptors on sensory afferent terminals in the dorsal horn (Buerkle and Yaksh, 1998; Sanders and Maze, 2007). Agonists such as clonidine can directly produce spinal analgesia, and intrathecal administration augments spinal levels of norepinephrine and acetylcholine, both of which may play a role in the consequent spinal analgesia (Hassenbusch et al., 2002; Klimscha et al., 1997). Accordingly, epidural/spinal clonidine has been approved for infusion in the treatment of cancer/neuropathic pain that is refractory to opioid analgesics (Hassenbusch et al., 2002). As there is no apparent cross-tolerance between clonidine and opioid analgesics at a spinal site of action, their ability to synergize with morphine under nerve injury and neuropathic conditions has emerged as a critical translational finding (Ossipov et al., 1997).
Such α2 adrenoreceptor agonists have also been found to be useful in perioperative analgesia for thoracic paravertebral blocks (PVBs) in patients undergoing modified radical mastectomy and for other perineural infusions (Mohamed et al., 2014). In addition, their systemic use in the perioperative period has been found to reduce opioid requirements and improve analgesia, although with common adverse effects such as bradycardia and arterial hypotension (Blaudszun et al., 2012).
The use of systemic clonidine and dexmedetomidine for the treatment of chronic pain has been described, but well-controlled studies are lack-
ing. More commonly, these agents have found a role in opioid-dependent patients and are FDA-approved for the treatment of opioid withdrawal symptoms in the detoxification of opioid dependence. More recently, these agents have appeared in detoxification protocols in the setting of hyperalgesia (Monterubbianesi et al., 2012). Beyond the continuous intrathecal administration of clonidine for intractable pain conditions, the clinical utility of systemic α2 adrenoreceptor agonists in chronic pain or hyperalgesia remains unresolved (Blaudszun et al., 2012).
NMDA Antagonists (Ketamine)
The analgesic action of ketamine is a consequence of its noncompetitive blockade of the NMDA receptor expressed both in the brain (supraspinally) and in the dorsal horn of the spinal cord. Ketamine’s effects are dose dependent and may be broadly categorized as “anesthetic” (high dose), “analgesic” (medium dose), and “opioid-sparing”/antihyperalgesic (low dose). One key principle underlying the action of the low- to medium-dose effects involves blockade of NMDA-mediated neurotransmission under conditions of tissue injury (inflammation/nerve injury).
Following nociceptor activation, excitatory amino acids (glutamate) are released from the central terminals of primary afferent nociceptors onto spinal neurons expressing NMDA receptors. Under persistent nociceptive pain and activation of C-type nociceptors and in turn, activation of ionotropic NMDA receptors, changes occur in neuronal plasticity at the nociceptive processing center of the spinal cord—the dorsal horn (Li et al., 1999). This increase in excitability of dorsal horn spinal cord neurons, which has been described as “central sensitization” (Li et al., 1999; Woolf and Mannion, 1999), encompasses several features, including the spreading of pain sensitivity beyond the original site of injury (secondary hyperalgesia), as well as mechanical allodynia. Blockade of NMDA receptor function in the dorsal horn has been shown selectively to attenuate the pain, hyperalgesia, and allodynia associated with ongoing tissue injury. Importantly, the action of an NMDA antagonist such as ketamine at the dorsal horn can block sensitization but spare the normal signaling of acute pain detection (Yaksh et al., 1999).
The notion that opioid-induced tolerance and hyperalgesia may share a common mechanism with central sensitization has been proposed. Although the exact mechanism of opioid tolerance is not known, it is believed to include the involvement of NMDA receptors, nitric oxide pathway, and µ opioid receptors. Escalating doses of opioids given in an attempt to manage the pain of progressive malignant and nonmalignant diseases in adults and children can drive further pain and hyperalgesia. Under these difficult clinical conditions, low-dose ketamine has been
shown to offer improvement in both pain control and opioid dose reduction that are often greater than 50 percent (Eilers et al., 2001; Loftus et al., 2010). Use of low-dose ketamine is intended to reverse or prevent central sensitization, opioid tolerance, and hyperalgesia while improving pain control (Aggarwal et al., 2013). More recently, the role of low-dose ketamine was investigated in the treatment of complex chronic painful conditions in a study at an outpatient chronic pain clinic, with some promising outcomes (Kosharskyy et al., 2013). Such positive findings are tempered by the variable and dose-dependent profile of ketamine-related adverse effects (psychomimetic), which can limit its clinical application. The development of GRIN2B-directed or other more selective NMDA receptor agents may avoid some of ketamine’s troublesome side effects (Niesters and Dahan, 2012; Preskorn et al., 2008).
Modest reductions in pain and short-term opioid requirements have been observed with the use of perioperative ketamine infusions (Barreveld et al., 2013; Cenzig et al., 2014; Elia and Tramer, 2005; Souzdalnitski et al., 2014; Zakine et al., 2008), but complete avoidance of opioids and other analgesics is generally not achieved. Limited additional evidence (Loftus et al., 2010) suggests that ketamine may reduce the persistence of postoperative pain.
Cannabis and its subcompounds, cannabinoids, have been used for medical and recreational purposes for hundreds of years. The use of cannabis as a recreational drug is illegal in most countries. Recently, however, some countries around the world and several U.S. states have legalized its use for chronically ill patients. Various studies have shown a positive effect of cannabinoids on chronic pain (Whiting et al., 2015), but potential cognitive effects and possible dose-dependent long-term risk for mental illness remain a concern, especially for patients with chronic pain that will require long-term therapy.
More than 100 cannabinoids have been identified in nature or chemically synthesized (ElSohly and Gul, 2014). The best-known cannabinoid is tetrahydrocannabinol (THC), known mainly for its psychosedative effects. Two cannabinoid receptors (CBs) have been cloned. CB1 is present in the brain, the spinal cord, and the peripheral nervous system, as well as in a number of neuronal tissues, including the liver, skeletal muscle, and the gastrointestinal tract; most of its analgesic effect is mediated by the CB1 receptor. CB2 is found mainly in immune cells in the peripheral nervous system or microglia in the CNS and to a lesser extent in the peripheral nervous system, primarily after injury and inflammatory response (Atwood and Mackie, 2010; Howlett, 2002). Several endocannabinoids have been iden-
tified, anandamide and 2-arachidonoylglycerol (2-AG) probably being the best studied. They are synthesized mainly by neurons but also by immune cells (Bisogno et al., 1997; De Petrocellis et al., 2000).
The endogenous action of cannabinoids is not limited to the cannabinoid receptors; it may be associated with calcitonin gene-related peptide (CGRP), transient receptor potential vanilloid (TRPV), and NMDA receptors as well (Mitrirattanakul et al., 2006). In animal studies, the combination of opioids with cannabinoids has shown notable synergistic effects (Cichewicz, 2004). Interestingly, some NSAIDs inhibit anandamide degradation (Duggan et al., 2011). For medical use, cannabinoids can be smoked; inhaled; mixed with food or drinks; or administered orally, sublingually, or even topically. They can be taken in herbal form, extracted naturally from the plant, or manufactured synthetically.
Recent systematic reviews and meta-analyses have found evidence to support the use of cannabinoids for the treatment of such chronic pain conditions as neuropathic pain, cancer-related pain, fibromyalgia, and HIV-associated neuropathy (Lynch and Ware, 2015; Whiting et al., 2015). A recent National Academies of Sciences, Engineering, and Medicine report on the health effects of cannabis and cannabinoids cites substantial evidence that cannabis is an effective treatment for chronic pain in adults and effects improvements for some pain patients with chemotherapy-induced nausea and vomiting. The report also notes a lack of evidence regarding the efficacy, dose, routes of administration, and side effects of cannabis products in the United States (NASEM, 2017). Low- to moderate-quality evidence has been found regarding the ability of cannabinoids to effect improvements in appetite reduction and weight loss in HIV/AIDS patients, sleep outcomes in individuals with certain illness-related sleep disorders, or symptoms of Tourette syndrome. While further research is needed, some studies also have shown that cannabinoids are associated with an increased risk of short-term adverse events such as cognitive and psychiatric effects, nervous systems disorders, dry mouth, and drowsiness (Lynch and Ware, 2015; Whiting et al., 2015).
The precise magnitude and consequences of the risk associated with therapeutic cannabinoid use are presently unknown. However, psychoactivity, memory deficiencies, impaired coordination and performance, and long-term risk for mental illness are the major issues in the development of cannabinoid-based analgesics (Karila et al., 2014; Semple et al., 2005). Alternative approaches to overcome the undesired effects of cannabinoids can include the development of endocannabinoid degradation inhibitors (Lomazzo et al., 2015) and cannabinoids that affect only peripheral receptors (Richardson et al., 1998). More research is necessary to determine the efficacy and safety of cannabinoid-related therapy for chronic pain patients
and whether adjunctive therapies with existing analgesics may enhance its therapeutic effect while reducing unwanted side effects.
Naltrexone is an oral opioid antagonist that is FDA-approved for the treatment of OUD. Some evidence, currently limited to a few case reports, indicates that greatly reduced doses of naltrexone (one-tenth normal) may have analgesic properties for limited chronic pain conditions, such as fibromyalgia and complex regional pain syndrome (CRPS). Although the mechanism of action for analgesia associated with low-dose naltrexone is unclear, it is thought to involve an anti-inflammatory effect through the blocking of toll-like receptor 4 (TLR4) on microglial cells, inhibiting microglial activation. Activated microglia are thought to play a major role in the development of neuropathic pain (Chopra and Cooper, 2013; Tsuda, 2016; Younger et al., 2014). Experimental animal models also demonstrate reversal of neuropathic pain by naltrexone via TLR4 antagonism (Hutchinson et al., 2008). In a small randomized, double-blind, placebo-controlled, crossover design study, 31 women with fibromyalgia were given low-dose naltrexone or placebo. Those taking 4.5 mg of naltrexone daily reported modest pain reduction and improved satisfaction and mood (Younger et al., 2013). Chopra and Cooper (2013) report two cases of long-standing CRPS whose signs and symptoms were significantly improved with 4.5 mg daily low-dose naltrexone. More research, particularly replication of these limited reports, could help ascertain the potential role of low-dose naltrexone in the treatment of chronic pain.
A number of pharmacologic treatments can be used to manage pain. While each nonopioid alternative has its own indications and risks, some are likely to be as effective as opioids or more so for reducing pain associated with the conditions for which they are indicated and when used appropriately, carry lower risk of adverse outcomes. Nonopioids such as cannabinoids and ketamine, which have shown promise for relief of some forms of pain in some pain management settings, also have potential adverse side effects. In cases of opioid tolerance, α2 androreceptor agonists can provide improved analgesia and help reduce signs and symptoms of opioid withdrawal. Subanesthetic doses of NMDA receptor antagonists can be highly effective in blocking/reversing the pain amplification and hyperalgesic states, although dose-dependent side effects, such as altered perceptions and vivid dreams, limit their widespread application.
Interventional pain management involves the use of invasive techniques, such as joint injections, nerve blocks, spinal cord stimulation, and other procedures, to reduce pain. Such techniques are best performed in the context of a multimodal treatment regimen, including physical therapy to maximize functional restoration. There has been a significant increase in the volume of certain interventional procedures over the past 10 years, much of it focused on low back and neck pain with or without radiation to the hip and other lower extremities (Chou et al., 2009a; Friedly et al., 2007). Low back pain is the most common cause of chronic pain in adults in the United States, followed by severe headache or migraine and then neck pain (Freburger et al., 2009; HHS, 2016; Rubin, 2007).
Types of Interventional Pain Therapies
Epidural steroid injections are the most commonly performed interventional pain therapies (Manchikanti et al., 2012), increasing in number each year. This increase, however, has not been matched by similar reductions in disability or improvements in health status among those with low back and leg pain, and may have contributed to the rise in health care costs (Chou et al., 2009a). The injections are commonly given to relieve radicular pain or sciatica associated with disc protrusions. An analysis of all types (cervical, thoracic, and lumbar) and routes (caudal, interlaminar, and transforaminal) of epidural injections using Medicare data from 2000 to 2011 showed an overall procedural increase of 130 percent/100,000 Medicare beneficiaries (representing an increase of 7.5 percent per year), with only an 18 percent increase in new Medicare beneficiaries for the same time period (an increase of 1.5 percent per year). The highest increases were seen for lumbosacral transforaminal injections, at 665 percent/100,000 Medicare beneficiaries, an increase of 20.3 percent per year over the study period (Manchikanti et al., 2013). Epidural steroid injections came under increased scrutiny after reports of serious neurologic events related to contaminated compounded glucocorticoids, in addition to other catastrophic injuries related to the injection itself. Injuries related to the performance of cervical epidurals have garnered significant attention. Guidelines for preventing associated neurologic complications were published in 2015 (Rathmell et al., 2015).
Other interventional pain therapies for axial low back pain include such techniques as trigger-point injections for myofascial pain of the low back, injections involving either the lumbar facet or sacroiliac joints, and denervation of the nerves that supply those joints. Lumbar facet (or zygapophyseal) joints are richly innervated and a source of axial low back pain. The medial branch of the dorsal rami of the spinal nerves innervates
both the facet joints and the overlying multifidus muscle, the interspinous ligament, and surrounding muscle, as well as the periosteum (Cohen and Raja, 2007). Evidence to support the use of intra-articular facet joint injections for long-term pain relief is limited (Chou et al., 2009a). The medial branches are first anesthetized using local anesthetic as a diagnostic tool to confirm the location of the pain. If pain is relieved, the medial branches may be lesioned using radiofrequency (RF) denervation to provide pain relief for an average of 10.5 months (after which the nerves regenerate). The RF may then be repeated for prolonged relief (Schofferman and Kine, 2004). Another type of lesioning, cooled RF, has been used in treating sacroiliac joint pain.
Spinal cord stimulation (SCS) has expanded in scope in recent years, from being utilized mainly for neuropathic pain related to painful postlaminectomy pain syndrome or failed back surgery syndrome to being applied for other neuropathic, sympathetic, vascular, and even visceral pain syndromes (Deer et al., 2014). The therapy involves placing an electrical lead in the epidural space that is connected to a programmable generator to relieve pain. A trial stimulator is first placed percutaneously under image guidance and left in place for up to 1 week, followed by implantation if the trial provides significant pain relief. Traditional SCS has been successful in treating extremity pain, but other areas and types of pain have been difficult to treat. Newer models of SCS utilize higher-frequency stimulation of 10,000 Hz (compared with 40 to 60 Hz) to improve relief of intractable axial low back pain. A comparison study found that the higher-frequency SCS provided superior pain relief (Kapural et al., 2016), and also was not associated with the stimulation-induced paresthesias that can lead to trial failures with traditional SCS (Kapural et al., 2016). Other new forms of SCS include burst stimulation, which uses bursts of five spikes at 40 Hz (De Ridder et al., 2010, 2013), and targeting of SCS at the dorsal root ganglion rather than the central spine (Deer et al., 2014). SCS has the advantage of being reversible and adjustable, and of being capable of providing years of pain relief (Deer et al., 2014). There is evidence for its cost-effectiveness in the relief of pain due to failed back surgery syndrome, CRPS, painful peripheral artery disease, and refractory angina (Kumar and Rizvi, 2013).
Interventional therapies also are offered for pain relief from migraine and other forms of severe headache. Botulinum toxin, a protease exotoxin derived from Clostridium botulinum, may be used for chronic migraine when other therapies have failed (Persaud et al., 2013). Other forms of headache, particularly occipital headache, cervicogenic headache, and headache originating from the upper cervical spine, may be amenable to targeted spinal intervention, such as occipital nerve blocks and cervical medial branch RF denervation.
Careful patient selection is critical to the success of interventional therapies. It is recommended that before such interventions are considered, a targeted history and assessment be performed to rule out the presence of potentially harmful conditions (e.g., malignancy, vascular abnormalities, spinal cord compression, fracture, or infection) and to assess for potential side effects (e.g., adrenal suppression from cumulative steroid use) (Leary and Swislocki, 2013). Complications of interventional pain management are multifactorial and are related to issues including performance of the procedure, patient anatomy, and comorbidities. The use of S.A.F.E. (Safety, Appropriateness, Fiscal neutrality, and Effectiveness) principles has been proposed as a foundation for interventional pain treatment algorithms (Krames et al., 2009). This approach has been used in advocating for early intervention for some pain syndromes (e.g., complex regional pain syndrome) for which the timing of interventional therapies may affect outcomes, and their early application may be cost-effective in the long run despite initial costs (Poree et al., 2013).
Further research is needed to better understand the effectiveness of a variety of interventional techniques for painful conditions, as well as optimal patient selection to improve health outcomes. However, these treatments may provide effective pain relief for many patients with some forms of pain (e.g., low back and neck pain) in the context of a multidisciplinary approach.
The use of acupuncture for the treatment of pain has become widespread in recent decades. Acupuncture is a key component of traditional Chinese medicine that involves insertion of needles through the skin to acupuncture points. Pressure, heat, electrical current, laser light, and other means also may be used to stimulate these points. Investigations have demonstrated that the nervous system, neurotransmitters, and other endogenous substances respond to the needling stimulation to induce analgesia (Foster and Sweeney, 1987). It has been shown that acupuncture analgesia is mediated by opioids produced in the periaqueductal gray and can be reversed by naloxone, an opioid antagonist (Cheng and Pomeranz, 1980). Recent studies also suggest activation of cannabinoid receptors as a possible mechanism of action (Gondim et al., 2012).
Systematic reviews evaluating the effect of acupuncture in treating
pain have revealed mixed results. Some reviews have found minimal or no effect (Lee et al., 2008; Madsen et al., 2009), while others have found acupuncture to be superior to sham acupuncture and placebo (Berman et al., 1999; White et al., 2007), and still others have concluded that data are insufficient to support a recommendation (Furlan et al., 2005; Paley et al., 2015; Smith et al., 2016a; van Tulder et al., 1999). Recent reviews and meta-analyses examining the effect of acupuncture on musculoskeletal pain (neck and back pain, osteoarthritis, chronic headache and shoulder pain, fibromyalgia) have found that overall, acupuncture is superior to sham and no acupuncture, but with relatively modest differences between true and sham acupuncture (Vickers et al., 2012; Yuan et al., 2016). Although it has been suggested that acupuncture is an effective treatment for pain, additional factors, such as potent placebo and context effects, may play a role in its observed effect as well (Linde et al., 2010a,b; Vickers et al., 2012). It also has been suggested that acupuncture may have value in the treatment of chronic and tension headaches (Linde et al., 2009b; Vickers et al., 2012), as well as in prophylactic treatment for migraine (Linde et al., 2009a). Additional RCTs are needed to determine the effect of acupuncture on neuropathic and postsurgical pain.
Manual therapies, including massage and chiropractic and osteopathic manipulation (such as spinal manipulative therapy), are commonly recommended for the treatment of musculoskeletal pain. However, high-quality evidence about these therapies is sparse, and there is little evidence that these therapies are as effective or more so than standard treatments. Cochrane reviews have been conducted on the evidence for these therapies in low back pain. For massage, the quality of the evidence was found to be “low” or “very low,” and the authors “have very little confidence that massage is an effective treatment for low-back pain” (Furlan et al., 2015). Evidence on combined chiropractic interventions shows a slight improvement in pain in the short and medium terms, but there is no evidence showing that chiropractic interventions have a clinically meaningful advantage over other treatments (Walker et al., 2011). Spinal manipulative therapy has not been shown to be different from other common interventions (Rubinstein et al., 2011).
A 2014 systematic review of massage therapy for fibromyalgia pain found that massage therapy of at least 5 weeks’ duration resulted in significant improvement in pain, anxiety, and depression. However, the authors note that larger-scale and longer-term RCTs are needed to confirm these findings (Li et al., 2014).
Physical Therapy and Exercise
Physical therapy and exercise often are included in the treatment plan offered to patients suffering from musculoskeletal pain conditions such as fibromyalgia, arthritis, and back and neck pain. In addition to its direct effect on pain, exercise may improve overall physical and mental health (Iacovides and Siamouli, 2008). The exact mechanisms by which physical therapy and exercise affect pain are unknown. It is believed, however, that activation of the CNS pain modulation pathways (Lannersten and Kosek, 2010) and the release of beta-endorphins play a major role in the palliative effect (Bement and Sluka, 2005; Stagg et al., 2011). Other suggested mechanisms include activation of such neurotransmitters as norepinephrine and serotonin (Dietrich and McDaniel, 2004), interactions with the cardiovascular system (Lovick, 1993), and involvement of the adenosinergic system (Martins et al., 2013). Despite the lack of strict guidelines or protocols for physical activity that may help patients with chronic pain, it appears that various types of physical activity can alleviate pain, including aerobic exercise, strength and flexibility training, walking, and manual therapy. Exercises such as yoga, tai chi, and qi gong have received particular attention for the treatment of pain because of the potential effect of the “mind–body” component of these practices. Systematic reviews have shown that these practices may be effective (Bai et al., 2015; Cramer et al., 2013; Kong et al., 2016), but further high-quality research is needed. Exercise has been shown to be effective for treatment of many types and locations of pain, including fibromyalgia (Busch et al., 2013; Carson et al., 2010; Hauser et al., 2010), back pain (Chang et al., 2016; Hayden et al., 2005; O’Connor et al., 2015; van Middelkoop et al., 2010), osteoarthritis (Fransen et al., 2014; Jansen et al., 2011), whiplash-associated pain (Stewart et al., 2007), and potentially even neuropathic pain (Dobson et al., 2014).
However, there are a number of barriers to the successful use of exercise therapy for pain management. These barriers include patient factors, such as lack of knowledge about exercise, fears of worsening existing pain, depression, excessive deconditioning, and a lack of self-efficacy. Patients also may lack access to a safe place to exercise, time to exercise, and support from family or the workplace. Finally, there are health care delivery barriers, including the system’s overly rigid focus on the biomedical model for pain, a lack of attention to or education about the value of exercise, a lack of supervision to ensure patient safety and comfort (Kroll, 2015), and a lack of insurance coverage of the costs of exercise and physical therapy.
Although it appears that recommending physical activity and exercise is warranted for patients suffering from chronic pain, further research is needed to evaluate the optimal treatment and intensity to recommend, and to explore the benefit of combining physical activity with other non-
pharmacologic therapies and pharmacologic treatment for pain reduction. In particular, there is some evidence that multidisciplinary rehabilitation, which includes physical treatments such as exercise as well as psychosocial interventions, may improve pain and function (Kamper et al., 2015; Lee et al., 2014), but further research is needed.
Cognitive-Behavioral Therapy (CBT)
CBT has been shown to be effective in managing chronic pain, either on its own or together with other pain management tools, such as medication. Over the past half century, evidence has accrued that the experience of pain is not based solely on sensory or neurologic states but is influenced by cognitive and affective processes (Ehde et al., 2014). A person’s thoughts and beliefs about pain can affect a number of pain-related issues, including the intensity of pain, anxiety and depression, physical disability, activity limitations, and catastrophizing (Ehde et al., 2014). Altering these thoughts and beliefs through CBT can change a person’s experience of and adaptation to pain, decreasing its intensity and improving day-to-day functioning and the ability to cope with the pain (Knoerl et al., 2016). CBT usually is delivered through multiple sessions of individual or group therapy in which a variety of strategies are conveyed to participants, including practicing relaxation techniques, reframing negative thoughts, scheduling activity to maximize functionality, and improving sleep patterns (Knoerl et al., 2016).
Numerous studies have demonstrated the efficacy of CBT (e.g., Ehde et al., 2014; Morley et al., 1999; Williams et al., 2012). A 2012 Cochrane review (Williams et al., 2012), for example, found that CBT, compared with treatment as usual at posttreatment, had a small but significant effect on pain intensity and disability and a moderate effect on catastrophizing and anxiety and depression (Knoerl et al., 2016). CBT is currently “the prevailing psychological treatment for individuals with chronic pain conditions such as low back pain, headaches, arthritis, orofacial pain, and fibromyalgia” (Ehde et al., 2014). However, the studies of CBT that have been performed have varied in the method of its delivery, the specific strategies used, and which outcome variables were studied, making it difficult to evaluate whether and to what extent CBT is efficacious for achieving specific pain-related outcomes (Knoerl et al., 2016). Knoerl and colleagues (2016) sought to remedy this evidence gap with an integrative review of 35 studies on CBT and chronic pain. They found that CBT was effective at reducing pain intensity in 43 percent of these trials (only 8 of 35 studies used pain intensity as a primary outcome, although it was measured in all studies); for a wider group of pain-related variables, including physical functioning, anxiety, depression, and quality of life, CBT was effective in
86 percent of trials. The authors note that CBT has been understudied in military veterans and patients with chronic pain related to cancer treatment.
Barriers to the provision of CBT include limited access to providers, inadequate insurance coverage, lack of knowledge about CBT among health care providers, and patients’ perception of stigma associated with CBT (Ehde et al., 2014). A 2016 study (Bee et al., 2016) of the acceptability of CBT among chronic pain patients found that preintervention patients viewed CBT as less relevant to their condition than other interventions (e.g., exercise). Some patients believed that the suggestion of using a psychological approach for a predominantly physical problem implied that the pain was not valid or was the result of “an underlying character weakness” (Bee et al., 2016). However, patients who received the CBT intervention reported high satisfaction, finding that it helped them shift toward proactive pain management (Bee et al., 2016).
In addition to CBT, there are other psychosocial interventions for chronic pain, such as acceptance and commitment therapy (ACT), in which patients are encouraged to change their responses to pain rather than seek a reduction in the pain itself. Studies on ACT have shown promise, but further research is needed (Vowels et al., 2014; Wetherell et al., 2011).
Mindfulness is defined as purposefully paying attention in the present moment, nonjudgmentally (Kabat-Zinn, 2003). Operationalized, it means “(a) regulated, sustained attention to the moment-to-moment quality and character of sensory, emotional and cognitive events, (b) the recognition of such events as momentary, fleeting and changeable (past and future representations of those events being considered cognitive abstractions), and (c) a consequent lack of emotional or cognitive appraisal and/or reactions to these events” (Zeidan et al., 2012). One such intervention, mindfulness-based stress reduction (Kabat-Zinn, 2003), the most studied mindfulness intervention, trains individuals in acquiring and practicing these skills, including for the management of various forms of chronic pain. Although of mixed quality, a large number of studies have found mindfulness interventions to have beneficial effects for patients with pain.
A meta-analysis of 38 RCTs of various forms of mindfulness meditation intervention for chronic pain management found that mindfulness improved pain, reduced symptoms of depression, and improved quality of life compared with treatment as usual, support groups, education, stress management, and waitlist controls (Hilton et al., 2017). Evidence is strongest for the efficacy of mindfulness in reducing symptoms of depression and improving mental health–related quality of life, for which the quality of evidence is
rated high and moderate, respectively. While small, statistically significant effects on pain are promising, these findings are tempered by the low quality of the evidence (e.g., lack of intent-to-treat analysis, low follow-up rate, small samples, inadequately powered studies). Effects on reducing analgesic use were mixed, with some studies showing reductions and others not. The authors conclude that more well-designed RCTs are needed to develop an evidence base on the effectiveness of mindfulness interventions (Hilton et al., 2017).
Beyond demonstrating efficacy, it is important to understand the hypothesized mechanisms underlying the use of mindfulness interventions as therapy for pain management. An understanding of the neuronal and molecular basis of changes in the brain that accompany mindfulness meditation is also nascent (Tang et al., 2015). Nonetheless, emerging evidence is providing useful information on how mindfulness meditation may cause neuroplastic changes in the structure and function of the brain regions involved in regulation of attention, emotion, and self-awareness, which are also factors involved in the cognitive modulation of pain (Zeidan et al., 2012). Accumulating evidence indicates that it can attenuate the subjective experience of pain, and that it shares as well as has distinct neural substrates engaged by cognitive factors known to modulate pain (Hilton et al., 2017).
One question has been whether the analgesic effects of mindfulness meditation are different from those of placebo. Zeidan and colleagues (2015) directly explored this question in healthy volunteers. They conducted an RCT involving four conditions (mindfulness meditation, sham mindfulness meditation, placebo conditioning, and book-listening control). Intervention efficacy was assessed using psychophysical evaluation of experimental pain and functional neuroimaging. The authors found that mindfulness meditation produced significantly greater reductions in pain intensity and unpleasantness relative to the other conditions. Importantly, their findings indicate that mindfulness meditation employs distinct neural mechanisms—specifically, higher-order brain regions, including orbitofrontal and cingulate cortices. They suggest that these findings may foster greater acceptance of meditation as an adjunct pain therapy.
Taken together, this emerging body of work suggests that the practice of mindfulness meditation for pain management may be promising. There is a need for further research with rigorous designs and larger samples that include patients with chronic pain to provide high-quality tests of the efficacy of this therapy. In addition, studies are needed to connect findings from studies of the neuronal and molecular bases of changes in the brain that accompany mindfulness meditation with behavioral measures.
Placebo is a dummy treatment, such as a pharmacologically inert preparation (“sugar pill”) or sham procedure. The difference in treatment effect between a group that has received no treatment and one that has received placebo is considered the “placebo effect.” Pain is one of the areas in which placebo has been most studied.
It has been shown in research and clinical settings that the expectation of pain relief can induce a strong analgesic effect. Placebo analgesic response is the result of this phenomenon. Consistent placebo analgesic effect has been demonstrated in dental pain, postthoracotomy pain, low back pain, irritable bowel syndrome, neuropathic pain, and experimental pain (Enck et al., 2008; Finniss et al., 2010; Kaptchuk and Miller, 2015; Price et al., 2008). The response to placebo is heterogeneous, being affected by individual differences in conditioning (Colloca and Benedetti, 2006; Kantor et al., 1966), expectations (Morton et al., 2010), optimism (Morton et al., 2009), and suggestibility (De Pascalis et al., 2002), as well as the nature of the placebo provided (Kong et al., 2013) and other factors. The placebo effect was found to be as strong as that of 7.5 mg of morphine following third molar extraction (Levine et al., 1981), and open administration of medication has been shown to be more effective than hidden administration (Colloca et al., 2004). Moreover, patients who are told that they are receiving a very potent pain killer have been found to require less of the same opioid than patients who are not (Pollo et al., 2001). And patients provided with a treatment that they believe is good for them benefit more from that treatment (Kalauokalani, 2001).
The “nocebo effect” is the term used to describe an undesirable outcome, such as an increase in pain, due to negative expectations (or conditioning). The nocebo effect is longer-lasting and probably greater than the placebo effect (Colloca et al., 2008). Patients in placebo groups often report side effects similar to those of the active drug if they were exposed to the possible side effects described in the consent form (Barsky et al., 2002).
The placebo effect is associated with activity in the prefrontal cortex, insular cortex, thalamus, forebrain structures, and spinal cord. An opioid antagonist (naloxone) can reverse placebo analgesia (Levine et al., 1978), suggesting involvement of the endogenous opioid system and probably the descending pain modulatory system. It also has been suggested that the endocannabinoid system is involved in placebo’s analgesic effect (Benedetti and Amanzio, 2011). Better understanding of the placebo effect could lead
to the development of independent treatment protocols or methods that would augment the effect of existing treatments.
Focus on Self-Management
An important recommendation of the 2011 IOM report Relieving Pain in America was that health care provider organizations promote and enable self-management of pain as the starting point of pain management (IOM, 2011). Self-management can be defined as “the ability to manage the symptoms, treatment, physical and psychosocial consequences and life-style changes inherent in living with a chronic condition” (Barlow et al., 2002). In the context of chronic pain, self-management may involve acceptance of the painful condition, exercise, pacing, relaxation, and other positive steps toward higher levels of functioning if not immediate reduction in pain intensity. Such approaches tend to deemphasize the role of medications such as opioids. Although significant barriers to pain self-management exist, such as lack of family support, limited resources, and depression (Bair et al., 2009), research on chronic pain self-management and the implementation of self-management programs is expanding. Examples of self-management programs for chronic pain include those designed for low back pain (Slater et al., 2012), knee pain (Button et al., 2015), arthritis (Vermaak et al., 2015), and other forms of chronic pain. It may be hoped that the reliance on opioids as a first-line management strategy by both patients and medical providers will diminish as self-management programs become more common.
Nonpharmacologic interventions for pain treatment, including acupuncture, physical therapy and exercise, CBT, and mindfulness meditation, represent powerful tools in the management of chronic pain. Many are components of successful self-management. While further research is needed to better understand the mechanism of action and the appropriate dosage and delivery for some nonpharmacologic approaches, they may provide effective pain relief for many patients in place of or in combination with pharmacologic approaches.
Part of the committee’s charge was to review the available evidence on differences in the experience of pain and the effectiveness of treatments across subpopulations. This section briefly reviews research findings on
this issue among selected subpopulations in the United States, including findings pertinent to prescription opioids. A review of the effectiveness of all of the available treatments for pain for subpopulations is beyond the scope of this study. For additional discussion of disparities in pain among subpopulations, the reader is encouraged to see the report Relieving Pain in America (IOM, 2011). The discussion here does not address individual (e.g., genetic) differences in susceptibility to pain, which are touched on in Chapter 3.
Research indicates that women are more likely than men to experience chronic pain and report higher sensitivity to pain (Bartley and Fillingim, 2013). Findings have been mixed regarding severity of pain, with women reporting greater severity than men in some studies but no sex differences in severity being found in other studies (Bartley and Fillingim, 2013). Certain chronic pain conditions, such as fibromyalgia, migraine and headache, irritable bowel syndrome, temporomandibular disorders, and interstitial cystitis, are diagnosed more commonly in women than in men (Bartley and Fillingim, 2013). The reasons for differences in the experience of pain by sex are not entirely understood, may be multifactorial, and may depend on the type of pain and/or condition. Possible explanations include differences in genotype and endogenous opioid functioning, sex hormones, psychosocial processes, and stereotypical gender roles that may make men less expressive about pain (Bartley and Fillingim, 2013; Fillingim et al., 2009). Provider beliefs also may play a role in differential rates of diagnosis of painful conditions between men and women.
With respect to prescription opioids, the sex of a patient can impact both the efficacy of an opioid and the likelihood that an opioid-related adverse event will be experienced. In acute administration settings, opioids have been observed to cause more respiratory depression, nausea, and pruritus in female compared with male patients (Angst et al., 2012; Riley et al., 2010). The chronic use of opioids also can alter sex hormones in men and women, leading to impotence in men and menstrual irregularities in women (Rhodin et al., 2010). A review of 18 studies showed lower opioid consumption postoperatively among women than men, but this finding has not been consistent, may depend on the type of procedure performed, and may reflect increased prevalence or reduced tolerance of side effects from opioids in women rather than less need for pain relief (Miaskowski et al., 2000). A meta-analysis found no sex-specific effects for µ opioid analgesia across 25 clinical studies of µ opioids and greater analgesic effects for women when analyses were restricted to patient-controlled analgesia (Niesters et al., 2010).
Race and Ethnicity
Research consistently shows differences in pain experiences among racial and ethnic groups (Hoffman et al., 2016; IOM, 2011). African American patients have been found to be less likely than whites to be prescribed pain medications for both cancer and noncancer pain (Anderson et al., 2009; Goyal et al., 2015; Todd et al., 2000). African Americans also report greater pain than whites for several painful conditions (IOM, 2011). Some experimental data show that African Americans have a lower pain threshold than whites, but these differences are small and may be clinically insignificant. A recent review of research on the pain experiences of Hispanic Americans found that this population reports fewer pain conditions and significantly lower rates of chronic pain compared with non-Hispanic whites in national surveys. However, Hispanic Americans report experiencing more severe pain and higher sensitivity to pain (Hollingshead et al., 2016).
The impact of race and ethnicity on opioid prescribing in particular has been evaluated in several studies. Some research indicates that blacks are less likely than non-Hispanic whites to receive an opioid for chronic noncancer pain (Cintron and Morrison, 2006; Dickason et al., 2016; Ringwalt et al., 2014, 2015), and this disparity appears to be more common in some specialty settings than in others (Ringwalt et al., 2014). These observations are consistent with reports showing that pain in minority versus white patients tends to be underestimated by health care providers (Cintron and Morrison, 2006). Evidence does not strongly suggest that patients of different races/ethnicities are more or less likely to display aberrant behaviors in prescription opioid use (Ives et al., 2006; Vijayaraghavan et al., 2012), although providers may be more likely to believe that a black or Hispanic versus a white patient is misusing prescription opioids (Becker et al., 2011; Vijayaraghavan et al., 2011).
Lower socioeconomic status also is a risk factor for pain and its undertreatment. This association may be due to poorer overall health, employment-related factors (e.g., a higher proportion of individuals employed in occupations with a higher risk of injury), lower access to quality pain care, and other factors. Some of the observed disparity in treatment for pain by race and ethnicity likely is explained by socioeconomic status, as racial and ethnic minority populations are disproportionately low-income or poor (IOM, 2011).
Age is positively associated with increased risk for the development of conditions, such as osteoarthritis and other musculoskeletal conditions,
and chronic diseases, such as diabetes, that can be painful. Yet while some studies show a continual increase in pain prevalence with age, others show a decrease with age, an increase up to ages 75–85 followed by a decrease, or no differences by age (Abdulla et al., 2013). Experimental and clinical studies have found that the elderly are more vulnerable than younger individuals to severe and persistent pain and have reduced ability to tolerate severe pain. In addition, older people are more likely to have comorbidities that complicate diagnosis and treatment of painful conditions (IOM, 2011). Other factors that may influence the severity of pain in the elderly are complex manifestations of pain, underreporting of or reduced ability to report pain, and higher rates of treatment side effects (IOM, 2011).
The aging process can affect the safety of opioid prescribing as a result of alterations in drug metabolism, elimination, and sensitivity. In addition, the presence of comorbid conditions and the use of potentially interacting medications to treat those conditions may increase with age. Concern exists, for example, about the use of opioids for noncancer pain in older adults because of the risks of sedation, overdose, and falls. These risks have prompted recommendations for lower starting doses, slower titration, and avoidance of use of other sedating drugs such as benzodiazepines (Kahan et al., 2011). The use of methadone in the elderly raises particular concern as this is a potent opioid with variable pharmacokinetics and a propensity for drug–drug interactions, and may also cause cardiac dysrhythmias (van Ojik et al., 2012).
Many rural communities in the United States have limited access to providers with training in pain management (Eaton et al., 2014; IOM, 2011). At the same time, residents of rural areas tend to be older and more likely to have painful chronic health conditions relative to those in urban areas (Eaton et al., 2014; Jukkala et al., 2008). As discussed in Chapter 4, states with large rural populations have experienced disproportionate morbidity and mortality from nonmedical use of prescription opioids (Keyes et al., 2014). Telemedicine/Internet-based technologies are one approach that has been used to bridge geographic distance to improve the quality of pain care in communities with limited access to providers with expertise in pain management (Currie et al., 2015; Eaton et al., 2014).
History of Substance Use Disorder
It is common for patients with histories of substance use disorders to also have chronic pain. Among patients receiving methadone maintenance treatment, for example, more than 40 percent have chronic pain (Dunn et
al., 2015; Voon et al., 2015). In addition, patients maintained on methadone and buprenorphine have measurably lower pain thresholds and tolerances than nonopioid-receiving controls (Compton et al., 2001, 2012). Likewise, it is common when looking cross-sectionally at populations of patients managed with opioids to identify a significant percentage with substance use disorders. The percentage of such patients in a treatment population is dependent on such risk factors as younger age and higher overall opioid dosage (Palmer et al., 2015). This complexity is addressed further in Chapter 3, where research on the intersection of pain and OUD is discussed, and knowledge gaps are identified.
A history of substance use disorder is a risk factor for aberrant opioid use among those being treated for pain (Chou et al., 2009b). Opioid risk assessment tools often take this characteristic into account, and such risk assessment is advocated in the CDC Guideline for Prescribing Opioids for Chronic Pain (Dowell et al., 2016).
In summary, differences have been observed among subpopulations in the types and severity of pain experienced and in access to and receipt of quality pain care depending on such factors as sex, age, race and ethnicity, location of residence, and history of substance use disorder. Moreover, while further research is needed, different subpopulations of patients may have different levels of analgesic response to opioids, experience side effects of differing severity, and display drug misuse at different rates.
Pain and reward are considered opponent processes but are processed within overlapping brain structures. Rewarding stimuli can decrease pain sensitivity (Leknes and Tracey, 2008), whereas pain can impair reward processing, leading to an anhedonic state (Elman et al., 2013). Few studies have examined the disruption of this circuitry caused by pain and whether the dopaminergic system contributes to the aversive component of ongoing persistent pain (Navratilova et al., 2012, 2015). Furthermore, how the presence of pain modifies the reinforcing properties of natural rewards or opioids is not known. The mesolimbic pathway is a critical brain circuit altered in opioid addiction, making it an ideal system in which to investigate the mechanistic basis for opioid misuse in the presence of pain (Cui et al., 2014; Fields and Margolis, 2015). Opioid-induced release of dopamine in the nucleus accumbens contributes to opioids’ misuse potential, whereas an allostatic shift in reward signaling leads to the pathological state of addic-
tion (Koob, 2008). µ opioid receptor agonists are positively reinforcing and are used extensively as a first-line treatment for clinical pain. Furthermore, recent research (Blanco et al., 2016) shows that persistent pain may lead individuals to use prescription opioids in patterns different from what their prescribing physician initially intended, resulting in opioid misuse or OUD. The neurobiology of the reward pathway and of the intersection of pain and OUD is described in more in detail in Chapter 3.
Abdel-Salam, O.M.E., A.R. Baiuomy, and M.S. Arbid. 2004. Studies on the anti-inflammatory effect of fluoxetine in the rat. Pharmacological Research 49(2):119-131.
Abdel Shaheed, C., C.G. Maher, K.A. Williams, R. Day, and A.J. McLachlan. 2016. Efficacy, tolerability, and dose-dependent effects of opioid analgesics for low back pain: A systematic review and meta-analysis. JAMA Internal Medicine 176(7):958-968.
Abdulla, A., N. Adamns, M. Bone, A.M. Elliott, J. Gaffin, D. Jones, R. Knaggs, D. Martin, L. Sampson, and P. Schoefield. 2013. Guidance on the management of pain in older people. Age and Ageing 42(Suppl. 1):1-67.
Agaliotis, M., M.G. Mackey, S. Jan, and M. Fransen. 2014. Burden of reduced work productivity among people with chronic knee pain: A systematic review. Occupational and Environmental Medicine 71(9):651-659.
Aggarwal, A., O. Zekry, and S. Gibson. 2013. Long term effectiveness of subanesthetic inpatient intravenous ketamine infusion therapy in the management of chronic non-cancer pain. Presented at 33rd Annual Scientific Meeting of the Australian Pain Society, Canberra, ACT Australia. March 19.
Anderson, K.O., C.R. Green, and R. Payne. 2009. Racial and ethnic disparities in pain: Causes and consequences of unequal care. The Journal of Pain 10(12):1187-1204.
Angst, M.S., and J.D Clark. 2006. Opioid-induced hyperalgesia: A qualitative systematic review. Anesthesiology 104(3):570-587.
Angst, M.S., L.C. Lazzeroni, N.G. Phillips, D.R. Drover, M. Tingle, A. Ray, G.E. Swan, and J.D. Clark. 2012. Aversive and reinforcing opioid effects: A pharmacogenomic twin study. Anesthesiology 117(1):22-37.
Attal, N., G. Cruccu, M. Haanpaa, P. Hansson, T.S. Jensen, T. Nurmikko, C. Sampaio, S. Sindrup, and P. Wiffen. 2006. EFNS guidelines on pharmacological treatment of neuropathic pain. European Journal of Neurology 13(11):1153-1169.
Atwood, B.K., and K. Mackie. 2010. CB2: A cannabinoid receptor with an identity crisis. British Journal of Pharmacology 160(3):467-479.
Bai, Y., T. Miller, M. Tan, L.S. Law, and T.J. Gan. 2015. Lidocaine patch for acute pain management: A meta-analysis of prospective controlled trials. Current Medical Research and Opinion 31(3):575-581.
Bair, M.J., M.S. Matthias, K.A. Nyland, M.A. Huffman, D.L. Stubbs, K. Kroenke, and T.M. Damush. 2009. Barriers and facilitators to chronic pain self-management: A qualitative study of primary care patients with comorbid musculoskeletal pain and depression. Pain Medicine 10(7):1280-1290.
Baldini, A., M. Von Korff, and E.H. Lin. 2012. A review of potential adverse effects of long-term opioid therapy: A practitioner’s guide. Primary Care Companion for CNS Disorders 14(3).
Barbour, K.E., C.G. Helmick, M. Boring, and T.J. Brady. 2017. Vital Signs: Prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation—United States, 2013-2015. Morbidity and Mortality Weekly Report 66(9):246-253.
Barclay, J.S., J.E. Owens, and L.J. Blackhall. 2014. Screening for substance abuse risk in cancer patients using the Opioid Risk Tool and urine drug screen. Supportive Care in Cancer 22(7):1883-1888.
Barlow, J., J. Sheasby, A. Turner, and J. Hainsworth. 2002. Self-management approaches for people with chronic conditions: A review. Patient Education and Counseling 48(2):177-187.
Barnett, M.L., A.R. Olenski, and A.B. Jena. 2017. Opioid-prescribing patterns of emergency physicians and risk of long-term use. New England Journal of Medicine 376(7):663-673.
Barreveld, A.M., D.J. Correll, X. Liu, B. Max, J.A. McGowan, L. Shovel, A.D. Wasan, and S.S. Nedeljkovic. 2013. Ketamine decreases postoperative pain scores in patients taking opioids for chronic pain: Results of a prospective, randomized, double-blind study. Pain Medicine 14(6):925-934.
Barsky, A.J., R. Saintfort, M.P. Rogers, and J.F. Borus. 2002. Nonspecific medication side effects and the nocebo phenomenon. Journal of the American Medical Association 287(5):622-627.
Bartley, E.J., and R.B. Fillingim. 2013. Sex differences in pain: A brief review of clinical and experimental findings. British Journal of Anaesthesia 111(1):52-58.
Becker, D.E. 2010. Pain management: Part 1: Managing acute and postoperative dental pain. Anesthesia Progress 57(2):67-78.
Becker, W.C., J.L. Starrels, M. Heo, X. Li, M.G. Weiner, and B.J. Turner. 2011. Racial differences in primary care opioid risk reduction strategies. Annals of Family Medicine 9(3):219-225.
Bee, P., J. McBeth, G.J. MacFarlane, and K. Lovell. 2016. Managing chronic widespread pain in primary care: A qualitative study of patient perspectives and implications for treatment delivery. BMC Musculoskeletal Disorders 17(1):354.
Beecher, H.K. 1955. The powerful placebo. Journal of the American Medical Association 159(17):1602-1606.
Belgrade, M.J., C.D. Schamber, and B.R. Lindgren. 2006. The DIRE score: Predicting outcomes of opioid prescribing for chronic pain. The Journal of Pain 7(9):671-681.
Bement, M.K., and K.A. Sluka. 2005. Low-intensity exercise reverses chronic muscle pain in the rat in a naloxone-dependent manner. Archives of Physical Medicine and Rehabilitation 86(9):1736-1740.
Benedetti, F., and M. Amanzio. 2011. The placebo response: How words and rituals change the patient’s brain. Patient Education and Counseling 84(3):413-419.
Berman, B.M., J. Ezzo, V. Hadhazy, and J.P. Swyers. 1999. Is acupuncture effective in the treatment of fibromyalgia? Journal of Family Practice 48(3):213-218.
Biron, R.T., E.V. Hersh, H.D. Barber, and R.J. Seckinger. 1996. A pilot investigation: Post-surgical analgesic consumption by dental implant patients. Dentistry 16(3):12-13.
Bisogno, T., M. Ventriglia, A. Milone, M. Mosca, G. Cimino, and V. Di Marzo. 1997. Occurrence and metabolism of anandamide and related acyl-ethanolamides in ovaries of the sea urchin paracentrotus lividus. Biochimica Biophysica Acta 1345(3):338-348.
Blanco, C., M.M. Wall, M. Okuda, S. Wang, M. Iza, and M. Olfson. 2016. Pain as a predictor of opioid use disorder in a nationally-representative sample. American Journal of Psychiatry 173(12):1189-1195.
Blaudszun, G., K. Lysakowski, N. Elia, and M.R. Tramer. 2012. Effect of perioperative systemic 2 agonists on postoperative morphine consumption and pain intensity: Systematic review and meta-analysis of randomized controlled trials. Anesthesiology 116(6):1312-1322.
Buerkle, H., and T.L. Yaksh. 1998. Pharmacological evidence for different alpha 2-adrenergic receptor sites mediating analgesia and sedation in the rat. British Journal of Anaesthesia 81(2):208-215.
Busch, A.J., S.C. Webber, R.S. Richards, J. Bidonde, C.L. Schachter, L.A. Schafer, A. Danyliw, A. Sawant, V. Dal Bello-Haas, T. Rader, and T.J. Overand. 2013. Resistance exercise training for fibromyalgia. Cochrane Database of Systematic Reviews 12:CD010884.
Butler, S.H., Weil-Fugazza, J., F. Godefroy, and J.M. Besson. 1985. Reduction of arthritis and pain behaviour following chronic administration of amitriptyline or imipramine in rats with adjuvant-induced arthritis. Pain 23(2):159-175.
Butler, S.F., S.H. Budman, K. Fernandez, and R.N. Jamison. 2004. Validation of a screener and opioid assessment measure for patients with chronic pain. Pain 112(1-2):65-75.
Butler, S.F., S.H. Budman, K.D. Fernandez, G.J. Fanciullo, and R.N. Jamison. 2009. Cross-validation of a screener to predict opioid misuse in chronic pain patients (SOAPP-R). Journal of Addiction Medicine 3(2):66-73.
Button, K., P.E. Roos, I. Spasic, P. Adamson, and R.W. van Deursen. 2015. The clinical effectiveness of self-care interventions with an exercise component to manage knee conditions: A systematic review. Knee 22(5):360-371.
Cao, Y.Q., P.W. Mantyh, E.J. Carlson, A.M. Gillespie, C.J. Epstein, and A.I. Basbaum. 1998. Primary afferent tachykinins are required to experience moderate to intense pain. Nature 392(6674):390-394.
Carmona-Bayonas, A., P. Jiménez-Fonseca, E. Castañón, A. Ramchandani-Vaswani, R. Sánchez-Bayona, A. Custodio, D. Calvo-Temprano, and J.A. Virizuela. 2016. Chronic opioid therapy in long-term cancer survivors. Clinical & Translational Oncology 19(2): 236-250.
Carroll, I., C.K. Wang, B.M. Wang, M.J. Gillespie, R. McCue, J.W. Younger, J. Trafton, K. Humphreys, S.B. Goodman, F. Dirbas, R.I. Whyte, J.S. Donington, W.B. Cannon, and S.C. Mackey. 2012. A pilot cohort study of the determinants of longitudinal opioid use after surgery. Anesthesia and Analgesia 115(3):694-702.
Carson, J.W., K.M. Carson, K.D. Jones, R.M. Bennett, C.L. Wright, and S.D. Mist. 2010. A pilot randomized controlled trial of the yoga of awareness program in the management of fibromyalgia. Pain 151(2):530-539.
Catella-Lawson, F., M.P. Reilly, S.C. Kapoor, A.J. Cucchiara, S. DeMarco, B. Tournier, S.N. Vyas, and G.A. FitzGerald. 2001. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. New England Journal of Medicine 345(25):1809-1817.
CDC (U.S. Centers for Disease Control and Prevention). 2017. Ambulatory care use and physician office visits. https://www.cdc.gov/nchs/fastats/physician-visits.htm (accessed April 17, 2017).
Cengiz, P., G. Gokcinar, I. Karabeyoglu, H. Topcu, G.S. Cicek, and N. Gogus. 2014. Intraoperative low-dose ketamine infusion reduces acute postoperative pain following total knee replacement surgery: A prospective, randomized double-blind placebo-controlled trial. Journal of the College of Physicians and Surgeons—Pakistan 24(5):299-303.
Chang, D.G., J.A. Holt, M. Sklar, and E.J. Groessl. 2016. Yoga as a treatment for chronic low back pain: A systematic review of the literature. Journal of Orthopedics & Rheumatology 3(1):1-8.
Chaparro, L.E., S.A. Smith, R.A. Moore, P.J. Wiffen, and I. Gilron. 2013. Pharmacotherapy for the prevention of chronic pain after surgery in adults. Cochrane Database of Systematic Reviews 7:CD008307.
Chaparro, L.E., A.D. Furlan, A. Deshpande, A. Mailis-Gagnon, S. Atlas, and D.C. Turk. 2014. Opioids compared with placebo or other treatments for chronic low back pain: An update of the Cochrane Review. Spine (Philadelphia, PA 1976) 39(7):556-563.
Chapman, C.R., J. Davis, G.W. Donaldson, and D. Winchester. 2011. Postoperative pain trajectories in chronic pain patients undergoing surgery. The effects of chronic opioid pharmacotherapy on acute pain. The Journal of Pain 12(12):1240-1246.
Cheatle, M.D., J.W. Klocek, and A.T. McClellan. 2012. Managing pain and high risk patients within the patient centered medical home. Translational Behavior Medicine 2(1):47-56.
Chen, J.H., J. Hom, I. Richman, S.M. Asch, T. Podchiyska, and N.A. Johansen. 2016. Effect of opioid prescribing guidelines in primary care. Medicine (Baltimore) 95(35):e4760.
Cheng, R.S., and B.H. Pomeranz. 1980. Electroacupuncture analgesia is mediated by stereo-specific opiate receptors and is reversed by antagonists of type I receptors. Life Sciences 26(8):631-638.
Childers, J.W., L.A. King, and R.M. Arnold. 2015. Chronic pain and risk factors for opioid misuse in a palliative care clinic. American Journal of Hospice & Palliative Care 32(6):654-659.
Chopra, P., and M.S. Cooper. 2013. Treatment of complex regional pain syndrome (CRPS) using low dose naltrexone (LDN). Journal of Neuroimmune Pharmacology 8(3):470-476.
Chou, R., S.J. Atlas, S.P. Stanos, and R. Rosenquist. 2009a. Nonsurgical interventional therapies for low back pain: A review of the evidence for an American Pain Society clinical practice guideline. Spine (Philadelphia, PA 1976) 34(10):1078-1093.
Chou, R., G.J. Fanciullo, P.G. Fine, C. Miaskoski, S.D. Passik, and R.K. Portenoy. 2009b. 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. The Journal of Pain 10(2):131-146.
Chou, R., R. Deyo, B. Devine, R.Hansen, S. Sullivan, J.G. Jarvik, I. Blazina, T. Dana, C. Bougatsos, and J. Turner. 2014. The effectiveness and risks of long-term opioid treatment of chronic pain. Report no. 14-E005-EF. Rockville, MD: Agency for Healthcare Research and Quality.
Chou, R., J.A. Turner, E.B. Devine, R.N. Hansen, S.D. Sullivan, I. Blazina, T. Dana, C. Bougatsos, and R.A. Deyo. 2015. 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. Annals of Internal Medicine 162(4):276-286.
Cichewicz, D.L. 2004. Synergistic interactions between cannabinoid and opioid analgesics. Life Sciences 74(11):1317-1324.
Cintron, A., and R.S. Morrison. 2006. Pain and ethnicity in the United States: A systematic review. Journal of Palliative Medicine 9(6):1454-1473.
Clarke, H., R.P. Bonin, B.A. Orser, M. Englesakis, D.N. Wijeysundera, and J. Katz. 2012. The prevention of chronic postsurgical pain using gabapentin and pregabalin: A combined systematic review and meta-analysis. Pain Medicine 115(2):428-442.
Cohen, S., and S.N. Raja. 2007. Pathogenesis, diagnosis, and treatment of lumbar zygapophysial (facet) joint pain. Anesthesiology 106(3):591-614.
Colloca, L., and F. Benedetti. 2006. How prior experience shapes placebo analgesia. Pain 124(1-2):126-133.
Colloca, L., L. Lopiano, M. Lanotte, and F. Benedetti. 2004. Overt versus covert treatment for pain, anxiety, and Parkinson’s disease. The Lancet Neurology 3(11):679-684.
Colloca, L., M. Sigaudo, and F. Benedetti. 2008. The role of learning in nocebo and placebo effects. Pain 136(1-2):211-218.
Compton, P., V.C. Charuvastra, and W. Ling. 2001. Pain intolerance in opioid-maintained former opiate addicts: Effect of long-acting maintenance agent. Drug and Alcohol Dependence 63(2):139-146.
Compton, P., C.P. Canamar, M. Hillhouse, and W. Ling. 2012. Hyperalgesia in heroin dependent patients and the effects of opioid substitution therapy. The Journal of Pain 13(4): 401-409.
Cooper, T.E., S. Derry, P.J. Wiffen, and R.A. Moore. 2017. Gabapentin for fibromyalgia pain in adults. Cochrane Database of Systematic Reviews 1:CD012188.
Couch, J.R., and R.S. Hassanein. 1976. Migraine and depression: Effect of amitriptyline prophylaxis. Transactions of the American Neurological Association 101:234-237.
Cramer, H., R. Lauche, H. Haller, and G. Dobos. 2013. A systematic review and meta-analysis of yoga for low back pain. Clinical Journal of Pain 29(5):450-460.
Croft, P., F. M. Blyth, and D. van der Windt (Eds.). 2010. Chronic pain epidemiology: From aetiology to public health. New York: Oxford University Press.
Cui, Y., S. B. Ostlund, A.S. James, C.S. Park, W. Ge, K.W. Roberts, N. Mittal, N.P. Murphy, C. Cepeda, B.L. Kieffer, M.S. Levine, J.D. Jentsch, W.M. Walwyn, Y.E. Sun, C.J. Evans, N.T. Maidment, and Y.X. Yang. 2014. Targeted expression of mu-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward. Nature Neuroscience 17(2):254-261.
Currie, M., L.J. Philip, and A. Roberts. 2015. Attitudes towards the use and acceptance of eHealth technologies: A case study of older adults living with chronic pain and implications for rural healthcare. BMC Health Services Research 15:162.
Dahan, A. 2016. Potent opioid analgesia without respiratory depression: Could it be possible? Anesthesiology 125(5):841-843.
Dahan, A., M. van Velzen, and M. Niesters. 2014. Comorbidities and the complexities of chronic pain. Anesthesiology 121(4):675-677.
de Hoogd, S., S.J. Ahlers, E.P. van Dongen, E.M. van de Garde, B.T.A. Hamilton-Ter, A. Dahan, D. Tibboel, and C.A. Knibbe. 2016. Is intraoperative remifentanil associated with acute or chronic postoperative pain after prolonged surgery? An update of the literature. Clinical Journal of Pain 32(8):726-735.
De Pascalis, V., C. Chiaradia, and E. Carotenuto. 2002. The contribution of suggestibility and expectation to placebo analgesia phenomenon in an experimental setting. Pain 96(3):393-402.
De Petrocellis, L., D. Melck, T. Bisogno, and V. Di Marzo. 2000. Endocannabinoids and fatty acid amides in cancer, inflammation and related disorders. Chemistry and Physics of Lipids 108(1-2):191-209.
De Ridder, D., S. Vanneste, M. Plazier, E. van der Loo, and T. Menovsky. 2010. Burst spinal cord stimulation: Toward paresthesia-free pain suppression. Neurosurgery 66(5):986-990.
De Ridder, D., M. Plazier, N. Kamerling, T. Menovsky, and S. Vanneste. 2013. Burst spinal cord stimulation for limb and back pain. World Neurosurgery 80(5):642-649.
Deer, T., M. Mekhail, D. Provenzano, J. Pope, E. Krames, M. Leong, R.M. Levy, D. Abejon, E. Buchser, A. Burton, A. Buvanendran, K. Dandido, D. Caraway, M. Cousins, M. DeJongste, S. Diwan, S. Eldabe, K. Gatzinsky, R.D. Foreman, S. Hayek, P. Kim, T. Kinfe, D.Kloth, K. Kuman, S. Rizvi, S.P. Lad, L. Liem, B. Linderoth, S. Mackey, G. McDowell, P. McRoberts, L. Poree, J. Prager, L. Raso, R. Rauck, M. Russo, B. Simpson, K. Slavin, P. Staats, M.H. Stanton-Hicks, P. Verrills, J. Wellington, K. Williams, and R. North. 2014. The appropriate use of neurostimulation of the spinal cord and peripheral nervous system for the treatment of chronic pain and ischemic diseases: The Neuromodulation Appropriateness Consensus Committee. Neuromodulation 17(6):515-550.
del Portal, D.A., M.E. Healy, W.A. Satz, and R.M. McNamara. 2016. Impact of an opioid prescribing guideline in the acute care setting. Journal of Emergency Medicine 50(1):21-27.
Denisco, R.C., G.A. Kenna, M.G. O’Neil, R.J. Kulich, P.A. Moore, W.T. Kane, N.R. Mehta, E.V. Hersh, and N.P. Katz. 2011. Prevention of prescription opioid abuse: The role of the dentist. Journal of the American Dental Association 142(7):800-810.
Derry, C.J., S. Derry, and R.A. Moore. 2013a. Single dose oral ibuprofen plus paracetamol (acetaminophen) for acute postoperative pain. Cochrane Database of Systematic Reviews 6:CD010210.
Derry, S., A. Sven-Rice, P. Cole, T. Tan, and R.A. Moore. 2013b. Topical capsaicin (high concentration) for chronic neuropathic pain in adults. Cochrane Database of Systematic Reviews 2:CD007393.
Devor, M., P.D. Wall, and N. Catalan. 1992. Systemic lidocaine silences ectopic neuroma and DRG discharge without blocking nerve conduction. Pain 48(2):261-268.
Deyo, R.A., D.H. Smith, E.S. Johnson, M. Donovan, C.J. Tillotson, X. Yang, A.F. Petrik, and S.K. Dobscha. 2011. Journal of the American Board of Family Medicine 24(6):717-727.
Deyo, R.A., M. VonKorff, and D. Duhrkoop. 2015. Opioids for low back pain. British Medical Journal 350:g6380.
Dickason, R.M., V. Chauhan, A. Mor, E. Ibler, S. Kuehnle, D. Mahoney, E. Armbrecht, and P. Dalawari. 2016. Racial differences in opiate administration for pain relief at an academic emergency department. Western Journal of Emergency Medicine 16(3):372-380.
Dietrich, A., and W.F. McDaniel. 2004. Endocannabinoids and exercise. British Journal of Sports Medicine 38(5):536-541.
Dobson, J.L., J. McMillan, and L. Li. 2014. Benefits of exercise intervention in reducing neuropathic pain. Frontiers in Cellular Neuroscience 8:102.
Donaldson, M., and J.H. Goodchild. 2010. Appropriate analgesic prescribing for the general dentist. General Dentistry 58(4):291-297.
Dowell, D., T.M. Haegerich, and R. Chou. 2016. CDC guideline for prescribing opioids for chronic pain—United States, 2016. Morbidity and Mortality Weekly Report 65(1):1-49.
Duggan, K.C., D.J. Hermanson, J. Musee, J.J. Prusakiewicz, J.L. Scheib, B.D. Carter, S. Banerjee, J.A. Oates, and L.J. Marnett. 2011. (R)-profens are substrate-selective inhibitors of endocannabinoid oxygenation by COX-2. Nature Chemical Biology 7(11):803-809.
Dunn, K.M., K.W. Saunders, C.M. Rutter, C.J. Banta-Green, J.O. Merrill, M.D. Sullivan, C.M. Weisner, M.J. Silverberg, C.I. Campbell, B.M. Psaty, and M. VonKorff. 2010. Opioid prescriptions for chronic pain and overdose: A cohort study. Annals of Internal Medicine 152(2):85-92.
Dunn, K.E., D.A. Tompkins, M. Fingerhood, and E.C. Strain. 2015. Characterizing pain and associated coping strategies in methadone and buprenorphine-maintained patients. Drug and Alcohol Dependence 157:143-149.
Dworkin, R.H., A.B. O’Connor, M. Backonja, J.T. Farrar, N.B. Finnerup, T.S. Jensen, E.A. Kalso, J.D. Loeser, C. Miaskowski, T.J. Nurmikko, R.K. Portenoy, A.S.C. Rice, B.R. Stacey, R. Treede, D.C. Turk, and M.W. Wallace. 2007. Pharmacologic management of neuropathic pain: Evidence-based recommendations. Pain 132(3):237-251.
Dworkin, R.H., A.B. O’Connor, J. Audette, R. Baron, G.K. Gourlay, M.L. Haanpaa, J.L. Kent, E.J. Krane, A.A. Lebel, R.M. Levy, S.C. Mackey, J. Mayer, C. Miaskowski, S.N. Raja, A.S.C. Rice, K.E. Schmader, B. Stacey, S. Stanos, R. Treede, D.C. Turk, G.A. Walco, and C.D. Wells. 2010. Recommendations for the pharmacological management of neuropathic pain: An overview and literature update. Mayo Clinic Proceedings 85(Suppl 3):S3-S14.
Eaton, L.H., D.B. Gordon, S. Wyant, B.R. Theodore, A.R. Meins, T. Rue, C. Towle, D. Tauben, and A.Z. Doorenbos. 2014. Development and implementation of a telehealth-enhanced intervention for pain and symptom management. Contemporary Clinical Trials 38(2):213-220.
Ehde, D.M., T.M. Dillworth, and J.A. Turner. 2014. Cognitive-behavioral therapy for individuals with chronic pain: Efficacy, innovations, and directions for research. American Psychologist 69(2):153-166.
Eilers, H., L.A. Philip, P.E. Bickler, W.R. McKay, and M.A. Schumacher. 2001. The reversal of fentanyl-induced tolerance by administration of “small-dose” ketamine. Anesthesia and Analgesia 93(1):213-214.
Eisenach, J.C., C. Tong, and R.S. Curry. 2015. Failure of intrathecal ketorolac to reduce remifentanil-induced postinfusion hyperalgesia in humans. Pain 156(1):81-87.
Elia, N., and M.R. Tramer. 2005. Ketamine and postoperative pain—A quantitative systematic review of randomised trials. Pain 106(6):1856-1861.
Elman, I., D. Borsook, and N.D. Volkow. 2013. Pain and suicidality: Insights from reward and addiction neuroscience. Progress in Neurobiology 109:1-27.
ElSohly, M.A., and W. Gul. 2014. Handbook of cannabis (Chapter 2). Oxford, UK: Oxford University Press.
Enck, P., F. Benedetti, and M. Schedlowski. 2008. New insights into the placebo and nocebo responses. Neuron 59(2):195-206.
Eriksen, J., P. Sjogren, E. Bruera, O. Ekholm, and N.K. Rasmussen. 2006. Critical issues on opioids in chronic non-cancer pain: An epidemiological study. Pain 125(1-2):172-179.
Evoy, K.E., M.D. Morrison, and S.R. Saklad. 2017. Abuse and misuse of pregabalin and gabapentin. Drugs 77(4):403-426.
Farag, E., M. Ghobrial, D.I. Sessler, J.E. Dalton, J. Liu, J.H. Lee, S. Zaky, E. Benzel, W. Bingaman, and A. Kurz. 2013. Effect of perioperative intravenous lidocaine administration on pain, opioid consumption, and quality of life after complex spine surgery. Anesthesiology 119(4):932-940.
FDA (U.S. Food and Drug Administration). 2016. FDA briefing document. Joint meeting of Anesthetic and Analgesic Drug Products Advisory Committee and Drug Safety and Risk Management Advisory Committee. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/UCM498784.pdf (accessed February 2, 2017).
Fields, H.L., and E.B. Margolis. 2015. Understanding opioid reward. Trends in Neurosciences 38(4):217-225.
Fillingim, R.B., C.D. King, M.C. Ribeiro-Dasilva, B. Rahim-Williams, and J.L. Riley III. 2009. Sex, gender, and pain: A review of recent clinical and experimental findings. The Journal of Pain 10(5):447-485.
Fine, P.G. 2011. Long-term consequences of chronic pain: Mounting evidence for pain as a neurological disease and parallels with other chronic disease states. Pain Medicine 12(7):996-1004.
Finnerup, N.B., N. Attal, S. Haroutounian, E. McNicol, R. Baron, R.H. Dworkin, I. Gilron, M. Haanpaa, P. Hansson, T.S. Jensen, P.R. Kamerman, K. Lund, A. Moore, S.N. Raja, A.S. Rice, M. Rowbotham, E. Sena, P. Siddall, B.H. Smith, and M. Wallace. 2015. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurology 14(2):162-173.
Finniss, D.G., T.J. Kaptchuk, F. Miller, and F. Benedetti. 2010. Biological, clinical, and ethical advances of placebo effects. Lancet 375(9715):686-695.
Fishbain, D.A., R. Cutler, H.L. Rosomoff, and R.S. Rosomoff. 1997. Chronic pain-associated depression: Antecedent or consequence of chronic pain? A review. The Clinical Journal of Pain 13(2):116-137.
Fishman, S.M., P.G. Kreis, and R.N. Jamison. 2002a. The opioid contract. The Clinical Journal of Pain 18(4 Suppl.):S70-S75.
Fishman, S.M., G. Mahajan, S.W. Jung, and B.L. Wilsey. 2002b. The trilateral opioid contract. Bridging the pain clinic and the primary care physician through the opioid contract. Journal of Pain Symptom Management 24(3):335-344.
Fitzgerald, D.J., and G.A. FitzGerald. 2013. Historical lessons in translational medicine: Cyclooxygenase inhibition and P2Y12 antagonism. Circulation Research 112(1):174-194.
Fletcher, D., and V. Martinez. 2014. Opioid-induced hyperalgesia in patients after surgery: A systematic review and a meta-analysis. British Journal of Anaesthesia 112(6):991-1004.
Fontana, R.J. 2008. Acute liver failure including acetaminophen overdose. Medical Clinics of North America 92(4):761-794.
Foster, J.M., and B.P. Sweeney. 1987. The mechanisms of acupuncture analgesia. British Journal of Hospital Medicine 38(4):308-312.
Frank, J.W., C. Levy, D.D. Matlock, S.L. Calcaterra, S.R. Mueller, S. Koester, and I.A. Binswanger. 2016. Patients’ perspectives on tapering of chronic opioid therapy: A qualitative study. Pain Medicine 17(10):1838-1847.
Fransen, M., S. McConnell, G. Hernandez-Molina, and S. Reichenbach. 2014. Exercise for osteoarthritis of the hip. Cochrane Database of Systematic Reviews 4:CD007912.
Freburger, J.K., G.M. Holmes, R.P. Agans, A.M. Jackman, J.D. Darter, A.S. Wallace, L.D. Castel, W.D. Kalseek, and T.S. Carey. 2009. The rising prevalence of chronic low back pain. Archives of Internal Medicine 169(3):251-258.
Frenk, S.M., K.S. Porter, and L.J. Paulozzi. 2015. Prescription opioid analgesic use among adults: United States, 1999–2012. NCHS Data Brief No. 189. https://www.cdc.gov/nchs/data/dataBriefs/db189.pdf (accessed September 13, 2017).
Friedly, J., L. Chan, and R. Deyo. 2007. Increases in lumbosacral injections in the Medicare population. Spine 32(16):1754-1760.
Friedman, B.W., A.A. Dym, M. Davitt, L. Holden, C. Solorzano, D. Esses, P.E. Bijur, and J. Gallagher. 2015. Naproxen with cyclobenzaprine, oxycodone/acetaminophen, or placebo for treating acute low back pain: A randomized clinical trial. Journal of the American Medical Association 314(15):1572-1580.
Furlan, A.D., M. van Tulder, D. Cherkin, H. Tsukayama, L. Lao, B. Koes, and B. Berman. 2005. Acupuncture and dry-needling for low back pain: An updated systematic review within the framework of the Cochrane collaboration. Spine (Philadelphia, PA 1976) 30(8):944-963.
Furlan, A.D., L.E. Chaparro, E. Irvin, A. Mailis-Gagnon. 2011. A comparison between enriched and non-enriched enrollment randomized withdrawal trials of opioids for chronic noncancer pain. Pain Research and Management 16(5):337-351.
Furlan, A.D., M. Giraldo, A. Baskwill, E. Irvin, and M. Imamura. 2015. Massage for low-back pain. Cochrane Database of Systematic Reviews (9):CD001929.
Gaskell, H., S. Derry, C. Stannard, and R.A. Moore. 2016. Oxycodone for neuropathic pain in adults. Cochrane Database of Systematic Reviews 7:CD010692.
Gerbershagen, H.J., E. Pogatzki-Zahn, S. Aduckathil, L.M. Peelen, T.H. Kappen, A.J. van Wijck, C.J. Kalkman, and W. Meissner. 2014. Procedure-specific risk factor analysis for the development of severe postoperative pain. Anesthesiology 120(5):1237-1245.
Gerner, P., A.E. Haderer, M. Mujtaba, Y. Sudoh, S. Narang, S. Abdi, V. Srinivasa, C. Pertl, and G.K. Wang. 2003. Assessment of differential blockade by amitriptyline and its n-methyl derivative in different species by different routes. Anesthesiology 98(6):1484-1490.
Gibbons, K., A. DeMonbrun, E.J. Beckman, P. Keefer, D. Wagner, M. Stewart, D. Saul, S. Hakel, M. Liu, and M. Niedner. 2016. Continuous lidocaine infusions to manage opioid-refractory pain in a series of cancer patients in a pediatric hospital. Pediatric Blood & Cancer 63(7):1168-1174.
Gillman, P.K. 2007. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. British Journal of Pharmacology 151(6):737-748.
Gilron, I., J.M. Bailey, D. Tu, R.R. Holden, A.C. Jackson, and R.L. Houlden. 2009. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: A double-blind, randomised controlled crossover trial. Lancet 374(9697):1252-1261.
Gilron, I., T.S. Jensen, and A.H. Dickenson. 2013. Combination pharmacotherapy for management of chronic pain: From bench to bedside. The Lancet Neurology 12(11):1084-1095.
Goldenberg, D.L. 2016. Is there evidence for any truly effective therapy in fibromyalgia? Pain Management 6(4):325-329.
Gondim, D.V., J.C.B. Araujo, A.L. Cavalcante, A. Havt, J. da Siva Quetz, G.A. de Castro Brito, R. de Albuquerque Ribeiro, and M. Lima Vale. 2012. CB1 and CB2 contribute to antinociceptive and anti-inflammatory effects of electroacupuncture on experimental arthritis of the rat temporomandibular joint. Canadian Journal of Physiology and Pharmacology 90(11):1479-1489.
Goodman, L.S., J.G. Hardman, L.E. Limbird, and A.G. Gilman. 2001. Goodman & Gilman’s: The pharmacological basis of therapeutics. New York: McGraw-Hill.
Gourlay, D.L., H.A. Heit, and A. Almahrezi. 2005. Universal precautions in pain medicine: A rational approach to the treatment of chronic pain. Pain Medicine 6(2):107-112.
Goyal, M.K., N. Kuppermann, S.D. Cleary, S.J. Teach, and J.M. Chamberlain. 2015. Racial disparities in pain management of children with appendicitis in emergency departments. JAMA Pediatrics 169(11):996-1002.
Graff-Radford, S.B., L.R. Shaw, and B.N. Naliboff. 2000. Amitriptyline and fluphenazine in the treatment of postherpetic neuralgia. The Clinical Journal of Pain 16(3):188-192.
Grosser, T., Y. Yu, and G.A. FitzGerald. 2010. Emotion recollected in tranquility: Lessons learned from the COX-2 saga. Annual Review of Medicine 61:17-33.
Guay, J. 2006. The benefits of adding epidural analgesia to general anesthesia: A metaanalysis. Journal of Anesthesia 20(4):335-340.
Haanpää, M.L., M.M. Backonja, M.I. Bennett, D. Bouhassira, G. Cruccu, P.T. Hansson, T.S. Jensen, T. Kauppila, A.S. Rice, B.H. Smith, R.D. Treede, and R. Baron. 2009. Assessment of neuropathic pain in primary care. American Journal of Medicine 122(10 Suppl.):S13-S21.
Hadley, G., S. Derry, R.A. Moore, and P.J. Wiffen. 2013. Transdermal fentanyl for cancer pain. Cochrane Database of Systematic Reviews 10:CD010270.
Hah, J.M., Y. Sharifzadeh, B.M. Wang, M.J. Gillespie, S.B. Goodman, S.C. Mackey, and I.R. Carroll. 2015. Factors associated with opioid use in a cohort of patients presenting for surgery. Pain Research and Treatment 2015:829696.
Hameroff, S.R., J.L. Weiss, J.C. Lerman, R.C. Cork, K.S. Watts, B.R. Crago, C.P. Neuman, J.R. Womble, and T.P. Davis. 1984. Doxepin’s effects on chronic pain and depression: A controlled study. Journal of Clinical Psychiatry 45(3 Pt. 2):47-53.
Hamon, M., H. Gozlan, S. Bourgoin, J.J. Benoliel, A. Mauborgne, H. Taquet, F. Cesselin, and J.A. Mico. 1987. Opioid receptors and neuropeptides in the CNS in rats treated chronically with amoxapine or amitriptyline. Neuropharmacology 26(6):531-539.
Hanada, R., A. Leibbrandt, T. Hanada, S. Kitaoka, T. Furuyashiki, H. Fujihara, J. Trichereau, M. Paolino, F. Qadri, R. Plehm, S. Klaere, V. Komnenovic, H. Mimata, H. Yoshimatsu, N. Takahashi, A. von Haeseler, M. Bader, S.S. Kilic, Y. Ueta, C Pifl, S. Narumiya, and J.M. Penninger. 2009. Central control of fever and female body temperature by RANKL/RANK. Nature 462(7272):505-509.
Hariharan, J., G.C. Lamb, and J.M. Neuner. 2007. Long-term opioid contract use for chronic pain management in primary care practice. A five year experience. Journal of General Internal Medicine 22(4):485-490.
Hassenbusch, S.J., S. Gunes, S. Wachsman, and K.D. Willis. 2002. Intrathecal clonidine in the treatment of intractable pain: A phase I/II study. Pain Medicine 3(2):85-91.
Hauser, W., P. Klose, J. Langhorst, B. Moradi, M. Steinbach, M. Schiltenwolf, and A. Busch. 2010. Efficacy of different types of aerobic exercise in fibromyalgia syndrome: A systematic review and meta-analysis of randomised controlled trials. Arthritis Research & Therapy 12(3):R79.
Hauser, W., F. Petzke, L. Radbruch, and T.R. Tolle. 2016. The opioid epidemic and the long-term opioid therapy for chronic noncancer pain revisited: A transatlantic perspective. Pain Management 6(3):249-263.
Havens, J. 2016. Prescription Drug Abuse in Rural Appalachia: Ushering in the Next Decade of the Epidemic. Presentation to the Committee on Pain Management and Regulatory Strategies to Address Prescription Opioid Abuse, Washington, DC. September 22.
Hayashida, K., S. DeGoes, R. Curry, and J.C. Eisenach. 2007. Gabapentin activates spinal noradrenergic activity in rats and humans and reduces hypersensitivity after surgery. Anesthesiology 106(3):557-562.
Hayden, J.A., M.W. van Tulder, A. Malmivaara, and B.W. Koes. 2005. Exercise therapy for treatment of non-specific low back pain. Cochrane Database of Systematic Reviews 3:CD000335.
Hersh, E.V., S. Cooper, N. Betts, D. Wedell, K. MacAfee, P. Quinn, C. Lamp, G. Gaston, S. Bergman, and E. Henry. 1993. Single dose and multidose analgesic study of ibuprofen and meclofenamate sodium after third molar surgery. Oral Surgery, Oral Medicine, and Oral Pathology 76(6):680-687.
HHS (U.S. Department of Health and Human Services). 2016. Health, United States, 2015: With special feature on racial and ethnic health disparities. Hyattsville, MD: CDC, National Center for Health Statistics. https://www.cdc.gov/nchs/data/hus/hus15.pdf (accessed April 23, 2017).
Hilton, L., S. Hempel, B.A. Ewing, E. Apaydin, L. Xenadis, S. Newberry, B. Colaiaco, A. Ruelaz Maheer, R.M. Shanman, M.E. Sorbero, and M.A. Maglione. 2017. Mindfulness meditation for chronic pain: Systematic review and meta-analysis. Annals of Behavioral Medicine 51(2):199-213.
Hoffman, K.M., S. Trawalter, J.R. Axt, and M.N. Oliver. 2016. Racial bias in pain assessment and treatment recommendations, and false beliefs about biological differences between blacks and whites. Proceedings of the National Academy of Sciences of the United States of America 113(16):4296-4301.
Hollingshead, N.A., L. Ashburn-Nardo, J.C. Stewart, and A.T. Hirsh. 2016. The pain experience of Hispanic Americans: A critical literature review and conceptual model. The Journal of Pain 17(5):513-528.
Hootman, J.M., C.G. Helmick, K.E. Barbour, K.A. Theis, and M.A. Boring. 2016. Updated projected prevalence of self-reported doctor-diagnosed arthritis and arthritis-attributable activity limitation among U.S. adults, 2015-2040. Arthritis & Rheumatology 68(7):1582-1587.
Howden, L.M., and J.A. Meyer. 2011. Age and sex composition, 2010. 2010 Census Briefs. https://www.census.gov/prod/cen2010/briefs/c2010br-03.pdf (accessed April 17, 2017).
Howick, J., F.L. Bishop, C. Heneghan, J. Wolstenholme, S. Stevens, F.D. Hobbs, and G. Lewith. 2013. Placebo use in the United Kingdom: Results from a national survey of primary care practitioners. PLoS One 8(3):e58247.
Howlett, A.C. 2002. The cannabinoid receptors. Prostaglandins & Other Lipid Mediators 68-69:619-631.
Hutchinson, M.R., Y. Zhang, K. Brown, B.D. Coats, M. Shridhar, P.W. Sholar, S.J. Patel, N.Y. Crysdale, J.A. Harrison, S.F. Maier, K.C. Rice, and L.R. Watkins. 2008. Nonstereoselective reversal of neuropathic pain by naloxone and naltrexone: Involvement of toll-like receptor 4 (TLR4). European Journal of Neuroscience 28(1):20-29.
Huxtable, C.A., L.J. Roberts, A. Somogyi, and P.E. Macintyre. 2011. Acute pain management in opioid-tolerant patients: A growing challenge. Anaesthesia and Intensive Care 39(5):804-823.
Iacovides, A., and M. Siamouli. 2008. Comorbid mental and somatic disorders: An epidemiological perspective. Current Opinion in Psychiatry 21(4):417-421.
IOM (Institute of Medicine). 2010. Clinical data as the basic staple of health learning: Creating and protecting a public good: Workshop summary. Washington, DC: The National Academies Press.
IOM. 2011. Relieving pain in America: A blueprint for transforming prevention, care, education, and research. Washington, DC: The National Academies Press.
Ives, T.J., P.R. Chelminski, C.A. Hammett-Stabler, R.M. Malone, J.S. Perhac, N.M. Potisek, B.B. Shilliday, D.A. DeWalt, and M.P. Pignone. 2006. Predictors of opioid misuse in patients with chronic pain: A prospective cohort study. BMC Health Services Research 6:46.
Jansen, M.J., W. Viechtbauer, A.F. Lenssen, E.J. Hendriks, and R.A. de Bie. 2011. Strength training alone, exercise therapy alone, and exercise therapy with passive manual mobilisation each reduce pain and disability in people with knee osteoarthritis: A systematic review. Journal of Physiotherapy 57(1):11-20.
Jenkins, R.W., K. McDonald, and C.S. Greenberg. 2012. Numb chin syndrome in acute myeloid leukemia. The American Journal of the Medical Sciences 344(3):237-240.
Johannes, C., T.K. Le, X. Zhou, J.A. Johnson, and R.H. Dworkin. 2010. The prevalence of chronic pain in United States adults: Results of an Internet-based survey. The Journal of Pain 11(11):1230-1239.
Jukkala, A.M., S.J. Henly, and L.L. Lindeke. 2008. Rural perceptions of continuing professional education. Journal of Continuing Education in Nursing 39(12):555-563.
Kabat-Zinn, J. 2003. Mindfulness-based interventions in context: Past, present, and future. Clinical Psychology Science and Practice 10(2):144-156.
Kahan, M., L. Wilson, A. Mailis-Gagnon, and A. Srivastava. 2011. Canadian guideline for safe and effective use of opioids for chronic noncancer pain: Clinical summary for family physicians. Part 2: Special populations. Canadian Family Physician 57(11):1269-1276, e419-e428.
Kalauokalani, D., D.C. Cherkin, K.J. Sherman, T.D. Koepsell, and R.A. Deyo. 2001. Lessons from a trial of acupuncture and massage for low back pain: Patient expectations and treatment effects. Spine (Philadelphia, PA 1976) 26(13):1418-1424.
Kalso, E., J.E. Edwards, R.A. Moore, and H.J. McQuay. 2004. Opioids in chronic non-cancer pain: Systematic review of efficacy and safety. Pain 112(3):372-380.
Kamper, S.J., A.T. Apeldoorn, A. Chiarotto, R.J. Smeets, R.W. Ostelo, J. Guzman, and M.W. van Tulder. 2015. Multidisciplinary biopsychosocial rehabilitation for chronic low back pain: Cochrane systematic review and meta-analysis. British Medical Journal 350:h444.
Kandil, E., E. Melikman, and B. Adinoff. 2017. Lidocaine infusion: A promising therapeutic approach for chronic pain. Journal of Anesthesia & Clinical Research 8(1):pii:697.
Kantor, T.G., A. Sunshine, F. Laska, M. Meisner, and M. Hopper. 1966. Oral analgesic studies: Pentazocine hydrochloride, codeine, aspirin, and placebo and their influence on response to placebo. Clinical Pharmacology and Therapeutics 7(4):447-454.
Kaptchuk, T.J., and F.G. Miller. 2015. Placebo effects in medicine. New England Journal of Medicine 373(1):8-9.
Kapural, L., C. Yu, M.W. Doust, B.E. Gliner, R. Vallejo, B.T. Stitzman, K. Amirdelfan, D.M. Morgan, T.L. Yearwood, R. Bundschu, T. Yang, R. Benyamin, and A.H. Burgher. 2016. Comparison of 10-kHz high-frequency and traditional low-frequency spinal cord stimulation for the treatment of chronic back and leg pain: 24-month results from a multicenter, randomized, controlled pivotal trial. Neurosurgery 79(5):1-10.
Karila, L., P. Roux, B. Rolland, A. Benyamina, M. Reynaud, H.J. Aubin, and C. Lancon. 2014. Acute and long-term effects of cannabis use: A review. Current Pharmaceutical Design 20(25):4112-4118.
Keyes, K.M., M. Cerda, J.E. Brady, J.R. Havens, and S. Galea. 2014. Understanding the rural-urban differences in nonmedical prescription opioid use and abuse in the United States. American Journal of Public Health 104(2):e52-e59.
Kim, S.C., J.E. Landon, and D.H. Solomon. 2013. Clinical characteristics and medication uses among fibromyalgia patients newly prescribed amitriptyline, duloxetine, gabapentin, or pregabalin. Arthritis Care & Research 65(11):1813-1819.
Klimscha, W., C. Tong, and J.C. Eisenach. 1997. Intrathecal alpha 2-adrenergic agonists stimulate acetylcholine and norepinephrine release from the spinal cord dorsal horn in sheep. An in vivo microdialysis study. Anesthesiology 87(1):110-116.
Knoerl, R., E.M. Lavoie Smith, and J. Weisberg. 2016. Chronic pain and cognitive behavioral therapy: An integrative review. Western Journal of Nursing Research 38(5):596-628.
Koele, R., G. Volker, F. van Vree, M. van Gestel, A. Koke, and T. Vliet Vlieland. 2014. Multidisciplinary rehabilitation for chronic widespread musculoskeletal pain: Results from daily practice. Musculoskeletal Care 12(4):210-220.
Kolodny, A., D. T. Courtwright, C. S. Hwang, P. Kreiner, J. L. Eadie, T.W. Clark, and G.C. Alexander. 2015. The prescription opioid and heroin crisis: A public health approach to an epidemic of addiction. Annual Review of Public Health 36:559-574.
Kong, J., R. Spaeth, A. Cook, I. Kirsch, B. Claggett, M. Vangel, R.L. Gollub, J.W. Smoller, and T.J. Kaptchuk. 2013. Are all placebo effects equal? Placebo pills, sham acupuncture, cue conditioning and their association. PLoS One 8(7):e67485.
Kong, L.J., R. Lauche, P. Klose, J.H. Bu, X.C. Yang, C.Q. Guo, G. Dobos, and Y.W. Cheng. 2016. Tai chi for chronic pain conditions: A systematic review and meta-analysis of randomized controlled trials. Scientific Reports 6:25325.
Koob, G.F. 2008. A role for brain stress systems in addiction. Neuron 59(1):11-34.
Kort, M.E., I. Drizin, R.J. Gregg, M.J. Scanio, L. Shi, M.F. Gross, R.N. Atkinson, M.S. Johnson, G.J. Pacofsky, J.B. Thomas, W.A. Carroll, M.J. Krambis, D. Liu, CC. Shieh, X. Zhang, G. Hernandez, J.P. Mikusa, C. Zhong, S. Joshi, P. Honore, R. Roeloffs, K.C. Marsh, B.P. Murray, J. Liu, S. Werness, C.R. Faltynek, D.S. Krafte, M.F. Jarvis, M.L. Chapman, and B.E. Marron. 2008. Discovery and biological evaluation of 5-aryl-2-furfuramides, potent and selective blockers of the Nav1.8 sodium channel with efficacy in models of neuropathic and inflammatory pain. Journal of Medicinal Chemistry 51(3):407-416.
Kosharskyy, B., W. Almonte, N. Shaparin, M. Pappagallo, and H. Smith. 2013. Intravenous infusions in chronic pain management. Pain Physician 16(3):231-249.
Krames, E., L.R. Poree, R. Deer, and R. Levy. 2009. Rethinking algorithms of pain care: The use of S.A.F.E. Principles. Pain Medicine 10(1):1-5.
Kranke, P., J. Jokinen, N.L. Pace, A. Schnabel, M.W. Hollmann, K. Hahnenkamp, L.H. Eberhart, D.M. Poepping, and S. Weibel. 2015. Continuous intravenous perioperative lidocaine infusion for postoperative pain and recovery. Cochrane Database of Systematic Reviews 7:CD009642.
Krashin, D., N. Murinova, and M. Sullivan. 2016. Challenges to treatment of chronic pain and addiction during the “opioid crisis.” Current Pain and Headache Reports 20(12):65.
Kroll, H.R. 2015. Exercise therapy for chronic pain. Physical Medicine and Rehabilitation Clinics of North America 26(2):263-281.
Kumar, K., and S. Rizvi. 2013. Cost-effectiveness of spinal cord stimulation therapy in management of chronic pain. Pain Medicine 14(11):1631-1649.
Kurita, G.P., and P. Sjogren. 2015. Pain management in cancer survivorship. Acta Oncologica (Stockholm, Sweden) 54(5):629-634.
Lance, J.W., and D.A. Curran. 1964. Treatment of chronic tension headache. Lancet 1(7345):1236-1239.
Langohr, H.D., M. Stohr, and F. Petruch. 1982. An open and double-blind cross-over study on the efficacy of clomipramine (Anafranil) in patients with painful mono- and polyneuropathies. European Neurology 21(5):309-317.
Lannersten, L., and E. Kosek. 2010. Dysfunction of endogenous pain inhibition during exercise with painful muscles in patients with shoulder myalgia and fibromyalgia. Pain 151(1):77-86.
Lanser, P., and S. Gesell. 2001. Pain management: The fifth vital sign. Healthcare Benchmarks 8(6):68-70.
Leary, J., and A. Swislocki. 2013. Hypothalamic-pituitary-adrenal suppression and iatrogenic Cushing’s Syndrome as a complication of epidural steroid injections. Case Reports in Endocrinology 2013(4):617042.
Lee, C., C. Crawford, and S. Swann. 2014. Active Self-Care Therapies for Pain (PACT) Working Group. Multimodal, integrative therapies for the self-management of chronic pain symptoms. Pain Medicine 15(Suppl. 1):S76-S85.
Lee, M.S., B.C. Shin, and E. Ernst. 2008. Acupuncture for rheumatoid arthritis: A systematic review. Rheumatology (Oxford) 47(12):1747-1753.
Lee, T.H. 2016. Zero pain is not the goal. Journal of the American Medical Association 315(15):1575-1577.
Leknes, S., and I. Tracey. 2008. A common neurobiology for pain and pleasure. Nature Reviews Neuroscience 9(4):314-320.
Levine, J.D., N.C. Gordon, and H.L. Fields. 1978. The mechanism of placebo analgesia. Lancet 2(8091):654-657.
Levine, J.D., N.C. Gordon, R. Smith, and H.L. Fields. 1981. Analgesic responses to morphine and placebo in individuals with postoperative pain. Pain 10(3):379-389.
Levy, B., L. Paulozzi, K.A. Mack, and C.M. Jones. 2015. Trends in opioid analgesic-prescribing rates by specialty, U.S., 2007-2012. American Journal of Preventive Medicine 49(3):409-413.
Li, C.Y., X.L. Zhang, E.A. Matthews, K.W. Li, A. Kurwa, A. Boroujerdi, J. Gross, M.S. Gold, A.H. Dickenson, G. Feng, and Z.D. Lou. 2006. Calcium channel alpha2delta1 subunit mediates spinal hyperexcitability in pain modulation. Pain 125(1-2):20-34.
Li, J., D.A. Simone, and A.A. Larson. 1999. Windup leads to characteristics of central sensitization. Pain 79(1):75-82.
Li, Y.H,. F.Y. Wang, C.Q. Feng, X.F. Yang, and Y.H. Sun. 2014. Massage therapy for fibromyalgia: A systematic review and meta-analysis of randomized controlled trials. PLoS One 9(2):e89304.
Linde, K., G. Allais, B. Brinkhaus, E. Manheimer, A. Vickers, and A.R. White. 2009a. Acupuncture for migraine prophylaxis. Cochrane Database of Systematic Reviews 1:CD001218.
Linde, K., G. Allais, B. Brinkhaus, E. Manheimer, A. Vickers, and A.R. White. 2009b. Acupuncture for tension-type headache. Cochrane Database of Systematic Reviews 1:CD007587.
Linde, K., K. Niemann, and K. Meissner. 2010a. Are sham acupuncture interventions more effective than (other) placebos? A re-analysis of data from the Cochrane review on placebo effects. Forschende Komplementarmedizin 17(5):259-264.
Linde, K., K. Niemann, and K. Meissner. 2010b. How large are the nonspecific effects of acupuncture? A meta-analysis of randomized controlled trials. BMC Medicine 8:75.
Loftus, R.W., M.P. Yeager, J.A. Clark, J.R. Brown, W.A. Abdu, D.K. Sengupta, and M.L. Beach. 2010. Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiology 113(3):639-646.
Lomazzo, E., L. Bindila, F. Remmers, R. Lerner, C. Schwitter, U. Hoheisel, and B. Lutz. 2015. Therapeutic potential of inhibitors of endocannabinoid degradation for the treatment of stress-related hyperalgesia in an animal model of chronic pain. Neuropsychopharmacology 40(2):488-501.
Lovick, T.A. 1993. Integrated activity of cardiovascular and pain regulatory systems: Role in adaptive behavioural responses. Progress in Neurobiology 40(5):631-644.
Luccarini, P., L. Perrier, C. Degoulange, A.M. Gaydier, and R. Dallel. 2004. Synergistic antinociceptive effect of amitriptyline and morphine in the rat orofacial formalin test. Anesthesiology 100(3):690-696.
Lunn, M.P., R.A. Hughes, and P.J. Wiffen. 2014. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database of Systematic Reviews 1:CD007115.
Lynch, M.E., and M.A. Ware. 2015. Cannabinoids for the treatment of chronic non-cancer pain: An updated systematic review of randomized controlled trials. Journal of Neuroimmune Pharmacology 10(2):293-301.
Madsen, M.V., P.C. Gotzsche, and A. Hrobjartsson. 2009. Acupuncture treatment for pain: Systematic review of randomised clinical trials with acupuncture, placebo acupuncture, and no acupuncture groups. British Medical Journal 338:a3115.
Magni, G. 1991. The use of antidepressants in the treatment of chronic pain. A review of the current evidence. Drugs 42(5):730-748.
Manchikanti, L., R.M. Buenaventura, K.N. Manchikanti, X. Ruan, S. Gupta, H.S. Smith, P.J. Christo, and S.P. Ward. 2012. Effectiveness of therapeutic lumbar transforaminal epidural steroid injections in managing lumbar spinal pain. Pain Physician 15(3):E199-E245.
Manchikanti, L., V. Pampati, F.J.E. Falco, and J.A. Hirsch. 2013. Assessment of the growth of epidural injections in the Medicare population from 2000 to 2011. Pain Physician 16(4):E349-E364.
Mao, J. 2002. Opioid-induced abnormal pain sensitivity: Implications in clinical opioid therapy. Pain 100(3):213-217.
Martins, D.F., L. Mazzardo-Martins, F. Soldi, J. Stramosk, A.P. Piovezan, and A.R. Santos. 2013. High-intensity swimming exercise reduces neuropathic pain in an animal model of complex regional pain syndrome type I: Evidence for a role of the adenosinergic system. Neuroscience 234:69-76.
Mason, L., R.A. Moore, S. Derry, J.E. Edwards, and H.J. McQuay. 2004. Systematic review of topical capsaicin for the treatment of chronic pain. British Medical Journal 328(7446):991.
Maughan, B.C., M.A. Bachhuber, N. Mitra, J.L. Starrels. 2015. Prescription monitoring programs and emergency department visits involving opioids, 2004–2011. Drug and Alcohol Dependence 156:282-288.
Max, M.B., M. Culnane, S.C. Schafer, R.H. Gracely, D.J. Walther, B. Smoller, and R. Dubner. 1987. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology 37(4):589-596.
McCarson, K.E., V. Duric, S.A. Reisman, M. Winter, and S.J. Enna. 2006. GABA(B) receptor function and subunit expression in the rat spinal cord as indicators of stress and the antinociceptive response to antidepressants. Brain Research 1068(1):109-117.
McGreevy, K., M.M. Bottros, and S.N. Raja. 2011. Preventing chronic pain following acute pain: Risk factors, preventive strategies, and their efficacy. European Journal of Pain Supplement 5(2):365-372.
McLellan, A.T., and B. Turner. 2010. Chronic noncancer pain management and opioid overdose: Time to change prescribing practices. Annals of Internal Medicine 152(2):123-124.
McNicol, E.D., A. Midbari, and E. Eisenberg. 2013. Opioids for neuropathic pain. Cochrane Database of Systematic Reviews 8:CD006146.
Miaskowski, C., R.W. Gear, and J.D. Levine. 2000. Sex-related differences in analgesic responses. In Sex, gender, and pain, edited by R.B. Fillingim. Seattle, WA: IASP Press.
Mick, G., and G. Correa-Illanes. 2012. Topical management with the 5% lidocaine medicated plaster—A review. Current Medical Research and Opinion 28(6):937-951.
Mitrirattanakul, S., N. Ramakul, A.V. Guerrero, Y. Matsuka, T. Ono, H. Iwase, K. Mackie, K.F. Faull, and I. Spigelman. 2006. Site-specific increases in peripheral cannabinoid receptors and their endogenous ligands in a model of neuropathic pain. Pain 126(1-3):102-114.
Mohamed, S.A., K.M. Fares, A.A. Mohamed, and N.H. Alieldin. 2014. Dexmedetomidine as an adjunctive analgesic with bupivacaine in paravertebral analgesia for breast cancer surgery. Pain Physician 17(5):E589-E598.
Monterubbianesi, M.C., J. Capuccini, I. Ferioli, D. Tassinari, D. Sarti, and W. Raffaeli. 2012. High opioid dosage rapid detoxification of cancer patient in palliative care with the Raffaeli model. Journal of Opioid Management 8(5):292-298.
Mooney, J.J., P.S. Pagel, and A. Kundu. 2014. Safety, tolerability, and short-term efficacy of intravenous lidocaine infusions for the treatment of chronic pain in adolescents and young adults: A preliminary report. Pain Medicine 15(5):820-825.
Moore, P.A., and E.V. Hersh. 2013. Combining ibuprofen and acetaminophen for acute pain management after third-molar extractions: Translating clinical research to dental practice. Journal of the American Dental Association 144(8):898-908.
Moore, P.A., H.S. Nahouraii, J.G. Zovko, and S.R. Wisniewski. 2006a. Dental therapeutic practice patterns in the U.S. I. Anesthesia and sedation. General Dentistry 54(2):92-98.
Moore, P.A., H.S. Nahouraii, J.G. Zovko, and S.R. Wisniewski. 2006b. Dental therapeutic practice patterns in the U.S. II. Analgesics, corticosteroids, and antibiotics. General Dentistry 54(3):201-207.
Moore, R.A., S. Derry, D. Aldington, P. Cole, and P.J. Wiffen. 2012. Amitriptyline for neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews 12:CD008242.
Moore, R.A., P.J. Wiffen, S. Derry, T. Maguire, Y.M. Roy, and L. Tyrrell. 2015. Nonprescription (OTC) oral analgesics for acute pain: An overview of Cochrane reviews. Cochrane Database of Systematic Reviews 11:CD010794.
Moraso, B.J., J.P. Duckart, T.P. Carr, R.A. Deyo, and S.K. Dobscha. 2010. Clinical characteristics of veterans prescribed high doses of opioid medications for chronic non-cancer pain. Pain 151(3):625-632.
Morley, S., C. Eccleston, and A. Williams. 1999. Systematic review and meta-analysis of randomized controlled trials of cognitive behaviour therapy and behaviour therapy for chronic pain in adults, excluding headache. Pain 80(1999):1-13.
Morton, D.L., A. Watson, W. El-Deredy, and A.K. Jones. 2009. Reproducibility of placebo analgesia: Effect of dispositional optimism. Pain 146(1-2):194-198.
Morton, D.L., W. El-Deredy, A. Watson, and A.K. Jones. 2010. Placebo analgesia as a case of a cognitive style driven by prior expectation. Brain Research 1359:137-141.
Mossey, J.M. 2011. Defining racial and ethnic disparities in pain management. Clinical Orthopaedics and Related Research 469(7):1859-1870.
Mou, J.F. Paillard, B. Turnbull, J. Trudeau, M. Stoker, and N.P. Katz. 2013. Efficacy of Qutenza® (capsaicin) 8% patch for neuropathic pain: A meta-analysis of the Qutenza Clinical Trials Database. Pain 154(9):1632-1639.
Mudumbai, S.C., E.M. Oliva, E.T. Lewis, J. Trafton, D. Posner, E.R. Mariano, R.S. Stafford, T. Wagner, and J.D. Clark. 2016. Time-to-cessation of postoperative opioids: A population-level analysis of the Veterans Affairs Health Care System. Pain Medicine 17(9):1732-1743.
Nahin, R.L. 2015. Estimates of pain prevalence in severity in adults: United States, 2012. The Journal of Pain 16(8):769-780.
NASEM (National Academies of Sciences, Engineering, and Medicine). 2017. The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Washington, DC: The National Academies Press.
Navratilova, E., J.Y. Xie, A. Okun, C. Qu, N. Eyde, S. Ci, M.H. Ossipov, T. King, H.L. Fields, and F. Porreca. 2012. Pain relief produces negative reinforcement through activation of mesolimbic reward-valuation circuitry. Proceedings of the National Academy of Sciences of the United States of America 109(50):20709-20713.
Navratilova, E., J.Y. Xie, D. Meske, C. Qu, K. Morimura, A. Okun, N. Arakawa, M. Ossipov, H.L. Fields, and F. Porreca. 2015. Endogenous opioid activity in the anterior cingulate cortex is required for relief of pain. Journal of Neuroscience 35(18):7264-7271.
NCHS (National Center on Health Statistics). 2016. National overdose deaths from select prescription and illicit drugs. CDC WONDER.
Niesters, M., and A. Dahan. 2012. Pharmacokinetic and pharmacodynamic considerations for NMDA receptor antagonists in the treatment of chronic neuropathic pain. Expert Opinion in Drug Metabolism & Toxicology 8(11):1409-1417.
Niesters, M., A. Dahan, B. Kest, J. Zacny, T. Stijnen, L. Aarts, and E. Sarton. 2010. Do sex differences exist in opioid analgesia? A systematic review and meta-analysis of human experimental and clinical studies. Pain 151(1):61-68.
Nir, R.R., H. Nahman-Averbuch, R. Moont, E. Sprecher, and D. Yarnitsky. 2016. Preoperative preemptive drug administration for acute postoperative pain: A systematic review and meta-analysis. European Journal of Pain 20(7):1025-1043.
O’Brien, E.M., R.M. Staud, A.D. Hassinger, R.C. McCulloch, J.G. Craggs, J.W. Atchison, D.D. Price, and M.E. Robinson. 2010. Patient-centered perspective on treatment outcomes in chronic pain. Pain Medicine 11(1):6-15.
O’Connor, S.R., M.A. Tully, B. Ryan, C.M. Bleakley, G.D. Baxter, J.M. Bradley, and S.M. McDonough. 2015. Walking exercise for chronic musculoskeletal pain: Systematic review and meta-analysis. Archives of Physical Medicine and Rehabilitation 96(4):724-734.
Okunseri, C., E. Okunseri, Q. Xiang, J.M. Thorpe, and A. Szabo. 2014. Prescription of opioid and nonopioid analgesics for dental care in emergency departments: Findings from the National Hospital Ambulatory Medical Care Survey. Journal of Public Health Dentistry 74(4):283-292.
O’Neil, M., and K.L. Hannah. 2010. Understanding the cultures of prescription drug abuse, misuse, addiction, and diversion. The West Virginia Medical Journal 106(4 Spec. No.): 64-70.
Ossipov, M.H., Y. Lopez, D. Bian, M.L. Nichols, and F. Porreca. 1997. Synergistic antinociceptive interactions of morphine and clonidine in rats with nerve-ligation injury. Anesthesiology 86(1):196-204.
Osterberg, L., and T. Blaschke. 2005. Adherence to medication. New England Journal of Medicine 353(5):487-497.
Paice, J.A., C. Lacchetti, T. Campbell, A. Cheville, M. Citron, L.S. Constine, A. Cooper, P. Glare, F. Keefe, L. Koyyalagunta, M. Levy, C. Miaskowski, S. Otis-Green, P. Sloan, and E. Bruera. 2016. Management of chronic pain in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. Journal of Clinical Oncology 34(27):3325-3345.
Paley, C.A., M.I. Johnson, O.A. Tashani, and A.M. Bagnall. 2015. Acupuncture for cancer pain in adults. Cochrane Database of Systematic Reviews 10:CD007753.
Palmer, R.E., D.S. Carrell, D. Cronkite, K. Saunders, D.E. Gross, E. Masters, S. Donevan, T.R. Hylan, and M. VonKroff. 2015. The prevalence of problem opioid use in patients receiving chronic opioid therapy: Computer-assisted review of electronic health record clinical notes. Pain 156(7):1208-1214.
Pan, G. 2016. Challenges in assessing real world use and abuse of pain medicines. PowerPoint presentation, FDA Science Board meeting, March. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ScienceBoardtotheFoodandDrugAdministration/UCM489209.pdf (accessed April 17, 2017).
Patetsos, E., and E. Horjales-Araujo. 2016. Treating chronic pain with SSRIs: What do we know? Pain Research and Management 2016:2020915.
Payne, R., E. Anderson, R. Arnold, L. Duensing, A. Gilson, C. Green, C. Haywood, S. Passik, B. Rich, L. Robin, N. Shuler, and M. Christopher. 2010. A rose by any other name: Pain contracts/agreements. The American Journal of Bioethics 10(11):5-12.
Pedersen, L., P.C. Borchgrevink, I.I. Riphagen, and O.M. Fredheim. 2014. Long- or short-acting opioids for chronic non-malignant pain? A qualitative systematic review. Acta Anaesthesiologica Scandinavia 58(4):390-401.
Peixoto, R.D., and P. Hawley. 2015. Intravenous lidocaine for cancer pain without electrocardiographic monitoring: A retrospective review. Journal of Palliative Medicine 18(4):373-377.
Penko, J., J. Mattson, C. Miaskowski, and M. Kushel. 2012. Do patients know they are on pain medication agreements? Results from a sample of high-risk patients on chronic opioid therapy. Pain Medicine 13(9):1174-1180.
Persaud, N., and G.R. Strichartz. 2002. Micromolar lidocaine selectively blocks propogating ectopic impulses at a distance from their site of origin. Pain 99(1-2):333-340.
Persaud, R., G. Garas, S. Silva, C. Stamatoglou, P. Chatrath, and K. Patel. 2013. An evidence-based review of botulinum toxin (Botox) applications in non-cosmetic head and neck conditions. JRSM Short Reports 4(2):10.
Pirbudak, L., A. Sevinc, G. Maralcan, and E. Kilic. 2014. Pain management with intrathecal clonidine in a colon cancer patient with opioid hyperalgesia: Case presentation. Agri 26(2):93-96.
Pollo, A., M. Amanzio, A. Arslanian, C. Casadio, G. Maggi, and F. Benedetti. 2001. Response expectancies in placebo analgesia and their clinical relevance. Pain 93(1):77-84.
Poree, L., E. Krames, J. Pope, T.R. Deer, R. Levy, and L. Schultz. 2013. Spinal cord stimulation as treatment for complex regional pain syndrome should be considered earlier than last resort therapy. Neuromodulation 16(2):125-141.
Portenoy, R.K., C. Ugarte, I. Fuller, and G. Haas. 2004. Population-based survey of pain in the United States: Differences among white, African American, and Hispanic subjects. The Journal of Pain 5(6):317-328.
Preskorn, S.H., B. Baker, S. Kolluri, F.S. Menniti, M. Krams, and J.W. Landen. 2008. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-d-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. Journal of Clinical Psychopharmacology 28(6):631-637.
Price, D.D., D.G. Finniss, and F. Benedetti. 2008. A comprehensive review of the placebo effect: Recent advances and current thought. Annual Review of Psychology 59:565-590.
Quill, T.E. 1983. Partnerships in patient care: A contractual approach. Annals of Internal Medicine 98(2):228-234.
Rasubala, L., L. Pernapati, X. Velasquez, J. Burk, and Y.F. Ren. 2015. Impact of a mandatory prescription drug monitoring program on prescription of opioid analgesics by dentists. PLoS One 10(8):e0135957.
Rathmell, J.P., H.T. Benzon, P. Dreyfuss, M. Huntoon, M. Wallace, R. Baker, K.D. Riew, R.W. Rosenquist, C. Aprill, N.S. Rost, A. Buvanendran, D.S. Kreiner, N. Bogduk, D.R. Fourney, E. Fraifeld, S. Horn, J. Stone, K. Vorenkamp, G. Lawler, J. Summers, D. Kloth, D. O’Brien, and S. Tutton. 2015. Safeguards to prevent neurologic complications after epidural steroid injections: Consensus opinions from a multidisciplinary working group and national organizations. Anesthesiology 122(5):974-984.
Ren, Z.Y., J. Shi, D.H. Epstein, J. Wang, and L. Lu. 2009. Abnormal pain response in pain-sensitive opiate addicts after prolonged abstinence predicts increased drug craving. Psychopharmacology (Berlin) 204(3):423-429.
Rhodin, A., M. Stridsberg, and T. Gordh. 2010. Opioid endocrinopathy: A clinical problem in patients with chronic pain and long-term oral opioid treatment. Clinical Journal of Pain 26(5):374-380.
Richardson, J.D., S. Kilo, and K.M. Hargreaves. 1998. Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 75(1):111-119.
Riley, J.L., 3rd, B.A. Hastie, T.L. Glover, R.B. Fillingim, R. Staud, and C.M. Campbell. 2010. Cognitive-affective and somatic side effects of morphine and pentazocine: Side-effect profiles in healthy adults. Pain Medicine 11(2):195-206.
Ringwalt, C., H. Gugelmann, M. Garrettson, N. Dasgupta, A.E. Chung, S.K. Proescholdbell, and A.C. Skinner. 2014. Differential prescribing of opioid analgesics according to physician specialty for Medicaid patients with chronic noncancer pain diagnoses. Pain Research and Management 19(4):179-185.
Ringwalt, C., H. Gugelmann, and A.C. Skinner. 2015. Racial disparities across provider specialties in opioid prescriptions dispensed to Medicaid beneficiaries with chronic noncancer pain. Pain Medicine 16(4):633-640.
Robbins, W.R., P.S. Staats, J. Levine, H.L. Fields, R.W. Allen, J.N. Campbell, and M. Pappagallo. 1998. Treatment of intractable pain with topical large-dose capsaicin: Preliminary report. Anesthesia and Analgesia 86(3):579-583.
Rubin, D.I. 2007. Epidemiology and risk factors for spine pain. Neurology Clinics 25(2):353-371.
Rubinstein, S.M., M. van Middelkoop, W.J. Assendelft, M.R. de Boer, and M.W. van Tulder. 2011. Spinal manipulative therapy for chronic low-back pain. Cochrane Database of Systematic Reviews (2):CD008112.
Sacerdote, P., A. Brini, P. Mantegazza, and A.E. Panerai. 1987. A role for serotonin and beta-endorphin in the analgesia induced by some tricyclic antidepressant drugs. Pharmacology, Biochemistry, and Behavior 26(1):153-158.
SAMHSA (Substance Abuse and Mental Health Services Administration). 2015. Treatment Episode Data Set (TEDS) 2003–2013. National Admissions to Substance Abuse Treatment Services. https://www.samhsa.gov/data/sites/default/files/2003_2013_TEDS_National/2003_2013_Treatment_Episode_Data_Set_National.pdf (accessed January 10, 2017).
Sanders, R.D., and M. Maze. 2007. Alpha2-adrenoceptor agonists. Current Opinion in Investigational Drugs 8(1):25-33.
Sardar, K., M.A. Rashid, M.R. Khandoker, and A.N.M.N. Khan. 2016. Anticonvulsants and antidepressants in chronic pain management. Journal of Recent Advances in Pain 2(3):90-93.
Scascighini, L., V. Toma, S. Dober-Spielmann, and H. Sprott. 2008. Multidisciplinary treatment for chronic pain: A systematic review of interventions and outcomes. Rheumatology (Oxford) 47(5):670-678.
Schiltenwolf, M., M. Akbar, A. Hug, U. Pfuller, S. Gantz, E. Neubauer, H. Flor, and H. Wang. 2014. Evidence of specific cognitive deficits in patients with chronic low back pain under long-term substitution treatment of opioids. Pain Physician 17(1):9-20.
Schmader, K.E. 2002. Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy. Clinical Journal of Pain 18(6):350-354.
Schmidt-Hansen, M., M.I. Bennett, S. Arnold, N. Bromham, and J.S. Hilgart. 2015. Oxycodone for cancer-related pain. Cochrane Database of Systematic Reviews 2:CD003870.
Schofferman, J., and G. Kine. 2004. Effectiveness of repeated radiofrequency neurotomy for lumbar facet pain. Spine (Philadelphia, PA 1976) 29(21):2471-2473.
Schumacher, M.A. 2010. Transient receptor potential channels in pain and inflammation: Therapeutic opportunities. Pain Practice 10(3):185-200.
Sehgal N., J. Colson, and H.S. Smith. 2013. Chronic pain treatment with opioid analgesics: Benefits versus harms of long-term therapy. Expert Review in Neurotherapeutics 13(11):1201-1220.
Semple, D.M., A.M. McIntosh, and S.M. Lawrie. 2005. Cannabis as a risk factor for psychosis: Systematic review. Journal of Psychopharmacology 19(2):187-194.
Simone, D.A., M. Nolano, T. Johnson, G. Wendelschafer-Crabb, and W.R. Kennedy. 1998. Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: Correlation with sensory function. Journal of Neuroscience 18(21):8947-8959.
Sinatra, R. 2010. Causes and consequences of inadequate management of acute pain. Pain Medicine 11(12):1859-1871.
Sindrup, S.H., and T.S. Jensen. 1999. Efficacy of pharmacological treatments of neuropathic pain: An update and effect related to mechanism of drug action. Pain 83(3):389-400.
Singer, J.B., S. Lewitzky, E. Leroy, F. Yang, X. Zhao, L. Klickstein, T.M. Wright, J. Meyer, and C.A. Paulding. 2010. A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nature Genetics 42(8):711-714.
Slater, H., A.M. Briggs, S. Bunzli, S.J. Davies, A.J. Smith, and J.L. Quintner. 2012. Engaging consumers living in remote areas of Western Australia in the self-management of back pain: A prospective cohort study. BMC Musculoskeletal Disorders 13:69.
Smith, C.A., M. Armour, X. Zhu, X. Li, Z.Y. Lu, and J. Song. 2016a. Acupuncture for dysmenorrhoea. Cochrane Database of Systematic Reviews 4:CD007854.
Smith, S.R., B.R. Deshpande, J.E. Collins, J.N. Katz, and E. Losina. 2016b. Comparative pain reduction of oral non-steroidal anti-inflammatory drugs and opioids for knee osteoarthritis: Systematic analytic review. Osteoarthritis and Cartilage 24(6):962-972.
Souzdalnitski, D., G.R. Rech, A. Naydinskiy, D. Suzdalnitskaya, R.V. Isakov, and M. Guirguis. 2014. Ketamine in perioperative analgesia for knee surgeries: Review of evidence from randomized controlled trials. Techniques in Regional Anesthesia and Pain Management 18(4):130-136.
Stagg, N.J., H.P. Mata, M.M. Ibrahim, E.J. Henriksen, F. Porreca, T.W. Vanderah, and T. Philip Malan. 2011. Regular exercise reverses sensory hypersensitivity in a rat neuropathic pain model: Role of endogenous opioids. Anesthesiology 114(4):940-948.
Stewart, M.J., C.G. Maher, K.M. Refshauge, R.D. Herbert, N. Bogduk, and M. Nicholas. 2007. Randomized controlled trial of exercise for chronic whiplash-associated disorders. Pain 128(1-2):59-68.
Stoicea, N., D. Russell, G. Weidner, M. Durda, N.C. Joseph, J. Yu, and S.D. Bergese. 2015. Opioid-induced hyperalgesia in chronic pain patients and the mitigating effects of gabapentin. Frontiers in Pharmacology 6:104.
Sun, E.C., B.D. Darnall, L.C. Baker, and S. Mackey. 2016. Incidence of and risk factors for chronic opioid use among opioid-naive patients in the postoperative period. JAMA Internal Medicine 176(9):1286-1293.
Tan, M., L.S. Law, and T.J. Gan. 2015a. Optimizing pain management to facilitate enhanced recovery after surgery pathways. Canadian Journal of Anaesthesia 62(2):203-218.
Tan, P.D., J.S. Barclay, and L.J. Blackhall. 2015b. Do palliative care clinics screen for substance abuse and diversion? Results of a national survey. Journal of Palliative Medicine 18(9):752-757.
Tanabe, M., K. Takasu, Y. Takeuchi, and H. Ono. 2008. Pain relief by gabapentin and pregabalin via supraspinal mechanisms after peripheral nerve injury. Journal of Neuroscience Research 86(15):3258-3264.
Tang, Y.Y., B.K. Holzel, and M.I. Posner. 2015. The neuroscience of mindfulness meditation. Nature Reviews Neuroscience 16(4):213-225.
Todd, K.H., C. Deaton, A.P. D’Adamo, and L. Goe. 2000. Ethnicity and analgesic practice. Annals of Emergency Medicine 35(1):11-16.
Trang, T., R. Al-Hasani, D. Salvemini, M.W. Salter, H. Gutstein, and C.M. Cahill. 2015. Pain and poppies: The good, the bad, and the ugly of opioid analgesics. Journal of Neuroscience 35(41):13879-13888.
Tsang, A., M. Von Korff, S. Lee, J. Alonso, E. Karem, M.C. Angermeyer, G.L. Borges, E.J. Bromet, K. Demytteneare, G. de Girolamo, R. de Graaf, O. Gureje, J.P. Lepine, J.M. Haro, D. Levinson, M.A. Oakley Brown, J. Posada-Villa, S. Seedat, and M. Watanabe. 2008. Common chronic pain conditions in developed and developing countries: Gender and age differences and comorbidity with depression-anxiety disorders. The Journal of Pain 9(10):883-891.
Tsuda, M. 2016. Microglia in the spinal cord and neuropathic pain. Journal of Diabetes Investigation 7(1):17-26.
Turner, J.A., S.M. Shortreed, K.W. Saunders, L. LeResche, and M. Von Korff. 2016. Association of levels of opioid use with pain and activity interference among patients initiating chronic opioid therapy: A longitudinal study. Pain 157(4):849-857.
Ushikubi, F., E. Segi, Y. Sugimoto, T. Murata, T. Matsuoka, T. Kobayashi, H. Hizaki, K. Tuboi, M. Katsuyama, A. Ichikawa, T. Tanaka, N. Yoshida, and S. Narumiya. 1998. Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3. Nature 395(6699):281-284.
Vadalouca, A., E. Raptis, E. Moka, P. Zis, P. Sykioti, and I. Siafaka. 2012. Pharmacological treatment of neuropathic cancer pain: A comprehensive review of the literature. Pain Practice 12(3):219-251.
van Middelkoop, M., S.M. Rubinstein, A.P. Verhagen, R.W. Ostelo, B.W. Koes, and M.W. van Tulder. 2010. Exercise therapy for chronic nonspecific low-back pain. Best practice and research. Clinical Rheumatology 24(2):193-204.
van Ojik, A.L., P.A. Jansen, J.R. Brouwers, and E.N. van Roon. 2012. Treatment of chronic pain in older people: Evidence-based choice of strong-acting opioids. Drugs & Aging 29(8):615-625.
van Tulder, M.W., D.C. Cherkin, B. Berman, L. Lao, and B.W. Koes. 1999. The effectiveness of acupuncture in the management of acute and chronic low back pain. A systematic review within the framework of the Cochrane collaboration back review group. Spine (Philadelphia, PA 1976) 24(11):1113-1123.
Veliz, P., Q. Epstein-Ngo, E. Austic, C. Boyd, and S.E. McCabe. 2015. Opioid use among interscholastic sports participants: An exploratory study from a sample of college students. Research Quarterly for Exercise and Sport 86(2):205-211.
Vermaak, V., N.K. Briffa, B. Langlands, C. Inderjeeth, and J. McQuade. 2015. Evaluation of a disease specific rheumatoid arthritis self-management education program, a single group repeated measures study. BMC Musculoskeletal Disorders 16:214.
Vickers, A.J., A.M. Cronin, A.C. Maschino, G. Lewith, H. MacPherson, N.E. Foster, K.J. Sherman, C.M. Witt, and K. Linde. 2012. Acupuncture for chronic pain: Individual patient data meta-analysis. Archives of Internal Medicine 172(19):1444-1453.
Vijayaraghavan, M., J. Penko, D. Guzman, C. Miaskowski, and M.B. Kushel. 2011. Primary care providers’ judgments of opioid analgesic misuse in a community-based cohort of HIV-infected indigent adults. Journal of General Internal Medicine 26(4):412-418.
Vijayaraghavan, M., J. Penko, D. Guzman, C. Miaskowski, and M.B. Kushel. 2012. Primary care providers’ views on chronic pain management among high-risk patients in safety net settings. Pain Medicine 13(9):1141-1148.
Volkow, N., and A.T. McClellan. 2016. Opioid abuse in chronic pain: Misconceptions and mitigation strategies. New England Journal of Medicine 374:1253-1263.
VonKorff, M. 2013. Opioids for chronic musculoskeletal pain: Putting patient safety first. Pain 154(12):2583-2585.
Voon, P., K. Hayashi, M.J. Milloy, P. Nguyen, E. Wood, J. Montaner, and T. Kerr. 2015. Pain among high-risk patients on methadone maintenance treatment. The Journal of Pain 16(9):887-894.
Vowles, K.E., K. Witkiewitz, G. Sowden, and J. Ashworth. 2014. Acceptance and commitment therapy for chronic pain: Evidence of mediation and clinically significant change following an abbreviated interdisciplinary program of rehabilitation. Journal of Pain 15(1):101-113.
Vowles, K.E., M.L. McEntee, P.S. Julnes, T. Forhe, J.P. Ney, and D.N. van der Goes. 2015. Rates of opioids misuse, abuse and addiction in chronic pain: A systematic review and data synthesis. Pain 156(4):569-576.
Walker, B.F., S.D. French, W. Grant, and S. Green. 2011. A Cochrane review of combined chiropractic interventions for low-back pain. Spine (Philadelphia, PA 1976) 36(3):230-242.
Wang, Z.Y., S.Y. Shi, S.J. Li, F. Chen, H. Chen, H.Z. Lin, and J.M. Lin. 2015. Efficacy and safety of duloxetine on osteoarthritis knee pain: A meta-analysis of randomized controlled trials. Pain Medicine 16(7):1373-1385.
Waxman, S.G., T.R. Cummins, S. Dib-Hajj, J. Fiell, and J.A. Black. 1999. Sodium channels, excitability of primary sensory neurons, and the molecular basis of pain. Muscle & Nerve 22(9):1177-1187.
Webster, L.R., and R.M. Webster. 2005. Predicting aberrant behaviors in opioid-treated patients: Preliminary validation of the Opioid Risk Tool. Pain Medicine 6(6):432-442.
Weiland, B.M., A.G. Wach, B.P. Kanar, M.T. Castele, M.F. Sosovicka, M.R. Cooke, and P.A. Moore. 2015. Use of opioid pain relievers following extraction of third molars. Compendium of Continuing Education in Dentistry 36(2):107-111.
Werner, M.U., F.M. Perkins, K. Holte, J.L. Pedersen, and H. Kehlet. 2001. Effects of gabapentin in acute inflammatory pain in humans. Regional Anesthesia and Pain Medicine 26(4):322-328.
Wetherell, J.L., N. Afari, T. Rutledge, J.T. Sorrell, J.A. Stoddard, A.J. Petkus, B.C. Solomon, D.H. Lehman, L. Liu, A.J. Lang, and J.H. Atkinson. 2011. A randomized, controlled trial of acceptance and commitment therapy and cognitive-behavioral therapy for chronic pain. Pain 152(9):2091-2107.
White, A., N.E. Foster, M. Cummings, and P. Barlas. 2007. Acupuncture treatment for chronic knee pain: A systematic review. Rheumatology (Oxford) 46(3):384-390.
Whiting, P.F., R.F. Wolff, S. Deshpande, M. Di Nisio, S. Duffy, A.V. Hernandez, J.C. Keurentjes, S. Lang, K. Misso, S. Ryder, S. Schmidlkofer, M. Westwood, and J. Kleijinen. 2015. Cannabinoids for medical use: A systematic review and meta-analysis. Journal of the American Medical Association 313(24):2456-2473.
WHO (World Health Organization). 1986. Cancer pain relief. Geneva, Switzerland: WHO.
Wiffen, P.J., B. Wee, and R.A. Moore. 2016. Oral morphine for cancer pain. Cochrane Database of Systematic Reviews 4:CD003868.
Wiffen, P.J., S. Derry, R.B. Bell, A.S. Rice, T.R. Tölle, T. Phillips, and R.A. Moore. 2017. Gabapentin for chronic neuropathic pain in adults. Cochrane Database of Systematic Reviews 6:CD007938.
Williams, A.C., C. Eccleston, and S. Morley. 2012. Psychological therapies for management of chronic pain (excluding headache) in adults. Cochrane Database of Systematic Reviews 11:CD007407.
Woolf, C.J., and R.J. Mannion. 1999. Neuropathic pain: Aetiology, symptoms, mechanisms, and management. Lancet 353(9168):1959-1964.
Yaksh, T.L., D.H. Farb, S.E. Leeman, and T.M. Jessell. 1979. Intrathecal capsaicin depletes substance P in the rat spinal cord and produces prolonged thermal analgesia. Science 206(4417):481-483.
Yaksh, T.L., X.Y. Hua, I. Kalcheva, N. Nozaki-Taguchi, and M. Marsala. 1999. The spinal biology in humans and animals of pain states generated by persistent small afferent input. Proceedings of the National Academy of Sciences of the United States of America 96(14):7680-7686.
Yi, P., and P. Pryzbylkowski. 2015. Opioid induced hyperalgesia. Pain Medicine 16(Suppl. 1):S32-S36.
Younger, J., N. Noor, R. McCue, and S. Mackey. 2013. Low-dose naltrexone for the treatment of fibromyalgia: Findings of a small, randomized, double blind, placebo controlled, counter balanced, crossover trial assessing daily pain levels. Arthritis & Rheumatology 65(2):529-538.
Younger, J., L. Parkitny, and D. McLain. 2014. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clinical Rheumatology 33(4):451-459.
Yuan, Q.L., P. Wang, L. Liu, F. Sun, Y.S. Cai, W.T. Wu, M.L. Ye, J.T. Ma, B.B. Xu, and Y.G. Zhang. 2016. Acupuncture for musculoskeletal pain: A meta-analysis and meta-regression of sham-controlled randomized clinical trials. Scientific Reports 6:30675.
Zakine, J., D. Samarcq, E. Lorne, M. Moubarak, P. Montravers, S. Beloucif, and H. Dupont. 2008. Postoperative ketamine administration decreases morphine consumption in major abdominal surgery: A prospective, randomized, double-blind, controlled study. Anesthesia and Analgesia 106(6):1856-1861.
Zamora-Legoff, J.A., S.J. Achenbach, C.S. Crowson, M.L. Krause, J.M. Davis, and E.L. Matteson. 2016. Opioid use in patients with rheumatoid arthritis 2005-2014: A population-based comparative study. Clinical Rheumatology 35(5):1137-1144.
Zeidan, F., J.A. Grant, C.A. Brown, J.G. McHaffie, and R.C. Coghill. 2012. Mindfulness meditation-related pain relief: Evidence for unique brain mechanisms in the regulation of pain. Neuroscience Letters 520(2):165-173.
Zeidan, F., N.M. Emerson, S.R. Farris, J.N. Ray, Y. Jung, J.G. McHaffie, and R.C. Coghill. 2015. Mindfulness meditation-based pain relief employs different neural mechanisms than placebo and sham mindfulness meditation-induced analgesia. The Journal of Neuroscience 36(46):15307-15325.
Zeppetella, G., and A.N. Davies. 2013. Opioids for the management of breakthrough pain in cancer patients. Cochrane Database of Systematic Reviews 10:CD004311.
Zwisler, S.T., J. Hallas, M.S. Larsen, G. Handberg, S. Mikkelsen, and T.P. Enggaard. 2015. Opioid prescriptions before and after high-energy trauma. Journal of Opioid Management 11(4).
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