Inappropriate opioid analgesic prescribing for pain is defined as the nonprescribing, inadequate prescribing, excessive prescribing, or continued prescribing despite evidence of ineffectiveness [10]. Appropriate opioid prescribing is essential to achieve pain control, to minimize societal harms from diversion, and to minimize patient risk of abuse, addiction, and fatal toxicity. The foundation of appropriate opioid prescribing is based on thorough patient assessment, treatment planning, and follow-up and monitoring. Essential for proper patient assessment and treatment planning is comprehension of the clinical concepts of opioid abuse and addiction, their behavioral manifestations in patients with pain, and how these potentially problematic behavioral responses to opioids both resemble and differ from physical dependence and pseudodependence. Prescriber knowledge deficit has been identified as a key obstacle to appropriate opioid prescribing and, along with gaps in policy, treatment, attitudes, and research, contributes to widespread inadequate treatment of pain [7]. A 2013 survey measured primary care physician understanding of opioids and addiction. Of the 200 participants, [11]:

The nomenclature related to addiction is often inconsistent, inaccurate, and confusing, partially reflecting the diverse perspectives of those working in the related fields of health care, law enforcement, regulatory agencies, and reimbursement/payer organizations. Changes over time in the fundamental understanding of addiction have also contributed to the persistent misuse of obsolete terminology [15]. The Diagnostic and Statistical Manual of Mental Disorders (DSM), published by the American Psychiatric Association, is perhaps the most influential reference for the diagnosis of addiction and all other psychiatric disorders. Prior to the 2013 release of the DSM-5, previous versions eschewed the term "addiction" in favor of "substance dependence," with a separate diagnostic entity of "substance abuse" representing a lower-grade, less severe version of substance dependence [16]. Also in earlier DSM versions, physiological dependence, manifesting as substance tolerance and withdrawal, was considered a diagnostic criterion of substance dependence. The result was the perpetuation of patient and healthcare professional confusion between physical and psychological dependence and the belief that tolerance and withdrawal meant addiction. This confusion enhanced provider and patient fears over addiction developing from opioid analgesics and contributed to the undertreatment of pain [16]. The DSM-5 has eliminated the categories of substance dependence and substance abuse by combining them into the single diagnostic entity of substance use disorder. The disorder is measured on a continuum from mild to severe [16].

According to the ASAM, the five characteristics of addiction are [18]:

Patients with pain display a continuum of behavioral responses to prescribed opioids. Some develop aberrant behaviors, which are defined as unintended behaviors involving the acquisition or use of prescribed opioids [22]. Depending on the study, researchers have reported that as many as 40% of patients with pain receiving opioid therapy exhibit aberrant behavior; however, in only a minority of these patients does the aberrant behavior reflect an emerging opioid use disorder. It is important to distinguish the underlying basis and the level of risk for opioid use disorder represented in the aberrant behavior. This is accomplished by differential diagnosis (Table 4). To capture the perspective of pain practitioner viewpoints in associating aberrant behaviors and risk of patient opioid problems, 100 pain physicians were instructed to rank a list of 13 aberrant drug-use behaviors from least to most suggestive of emergent opioid use disorder. Selling the prescribed opioid and prescription forgery received highest ranking as most aberrant, and altered route of administration was given the third highest ranking. Lowest ranked were unkempt patient appearance, sporadic unsanctioned dose escalation, and prescribed opioid hoarding [23].

There are certain behaviors that are suggestive of an emerging opioid use disorder. The most suggestive behaviors are [24,25,26]:

Behaviors with a lower level of evidence for their association with opioid misuse include [23,24,25]:

Behaviors with a lower level of evidence for their association with opioid misuse include [23,24,25]:

It is essential for clinicians to consider poorly managed pain or poor coping skills as the basis for aberrant behavior. Even aberrant behaviors highly suggesting opioid abuse may reflect a patient's attempt to feel normal or alleviate emotional or physical distress. This is termed chemical coping and refers to the inappropriate use of a prescribed opioid to treat emotional or psychiatric conditions, commonly depression, anxiety, and insomnia. In these cases, the patient is not technically addicted to the opioid, but he or she fears withdrawal from the opioid and losing the ability to function without the drug and, as a result, may abuse opioids, engage in illegal behavior to obtain opioids, or doctor-shop. Aberrant behavior can also be driven by undertreated pain or a failure of treatment management [27]. Importantly, no single behavioral marker clearly identifies addiction in patients with pain who are prescribed opioids, and while all addicts are abusers, not all abusers are opioid-addicted [27].

The United States has a long history of pain undertreatment as a standard medical practice. This was a consequence of the long-standing emphasis on treating the underlying primary illness, minimizing the importance of addressing pain, and viewing pain as an endurable consequence [1]. Another primary factor historically responsible for pain undertreatment has been a resistance to prescribing opioids, driven by fears of patient addiction and the threat of prosecution and potential loss of licensure if opioid prescribing was deemed inappropriate by the state medical board. The widespread practice of including non-professional lay members on medical boards intensified physician concerns over prejudicial interpretation by board members, even when legitimate medical necessity merited long-term, high-dose opioid prescribing to patients with severe, chronic noncancer pain [28].

During the 1990s, the American Pain Foundation endorsed more aggressive treatment of chronic pain, while the American Pain Society (APS) promoted the position that pain should be considered a fifth vital sign. The APS and the American Academy of Pain Medicine (AAPM) published a landmark consensus statement in 1997 that stated long-term opioid analgesic use for chronic noncancer pain posed minimal risk of overdose or addiction [30,40]. The pharmaceutical industry was also instrumental in the movement toward loosening opioid prescribing constraints and broadening the indications for opioid use in managing chronic pain [30,41]. Professional pain societies wrote consensus statements claiming little risk of addiction or overdose in patients with pain and that long-term opioids were easy to discontinue. In 1997, Congress passed SB402, also known as The Pain Patient's Bill of Rights [42]. In 2001, the Joint Commission issued new standards requiring hospitals to make pain assessment routine and pain treatment a priority. The now familiar pain scale was introduced, with patients asked to rate their pain from 1 to 10 and circle a smiling or frowning face, and pain became the fifth vital sign [43]. Immediately following the release of the new standards, concern was raised that the standards would lead to the inappropriate use of opioids. By 2002, pain as a "fifth vital sign" in the standards was changed to "pain used to be considered the fifth vital sign," and by 2004, this phrase no longer appeared in the Joint Commission's Accreditation Standards manual [44]. The standard that pain be assessed in all patients also remained controversial for two reasons: It seemed inappropriate for some patients due to the nature of their medical condition; and no similar standard existed requiring the universal assessment of other symptoms [44]. Thus, in early 2016, the Joint Commission began revising its pain assessment and management standards, with a focus on acute pain in the hospital setting. Draft standards were published in 2017, implemented in 2018, and revised in 2019 [45,46].

The timing of product launch was fortuitous. Until the 1990s, Schedule II opioids were primarily limited to use in operating rooms and inpatient settings because they required intravenous or intramuscular administration. This posed a serious obstacle to patients with chronic pain who required high-potency opioids. In response to the increasingly permissive climate and by genuine unmet patient need, several high-dose ER formulations of pre-existing opioids were introduced to market. MS Contin, an ER version of morphine sulfate, was introduced in 1985 but was primarily limited to use in cancer pain, partially a result of the stigma surrounding morphine. OxyContin was introduced in late 1995, at the point in time when prescriber attitudes were shifting from fearing iatrogenic addiction to developing a sense of security with prescribing opioid analgesics [43].

The increasing prevalence of chronic pain is the result of multiple factors, including the aging population; rising rates of obesity and obesity-related pain conditions, such as joint deterioration; advances in lifesaving trauma interventions; poorly managed post-surgical pain; and greater public awareness of pain as a condition warranting medical attention [7]. In addition, many armed forces veterans have been returning from military action in Afghanistan and Iraq with traumatic injuries and chronic pain, and veterans' care clinicians have been reporting the perception that long-term pain management is lacking support in the veteran healthcare infrastructure [58].

Worldwide consumption of opioid analgesics has increased dramatically in the past few decades, with the United States driving a substantial proportion of this increase. For example, the 1990 global consumption of hydrocodone was 4 tons (3,628 kg), compared with the 2021 consumption of 26.6 tons (24,131 kg); the majority (26.3 tons) of this were consumed in the United States. Similarly, 3 tons (2,722 kg) of oxycodone were consumed globally in 1990, versus 62 tons (56,246 kg) in 2021, of which 42.3 tons (38,374 kg or 68.2%) were consumed in the United States [61]. With only 4.9% of the world's population, the United States annually consumes more than 85% of all opioid supplies, including [61]:

As of April 2020, 40 states have passed laws that address opioid analgesic prescribing. State-specific legislation, medical and pharmacy boards, Medicaid programs, department of workforce services, and workers' compensation programs have adopted policies, guidelines, and regulations that place limits on prescribing opioid analgesic medications and/or require monitoring of opioid prescriptions. Many insurance companies and managed healthcare organizations have also implemented policies related to limitations on opioid analgesic prescriptions. This has led to a general downward trend in total daily doses of opioids used, use of ER/LA opioid analgesics, and use of high-dose opioids. This trend began even before the release of the 2016 CDC guidelines for opioid prescribing. The use of ER/LA opioid analgesics for chronic pain continues to decline year-over-year. As of 2023, more than 90% of opioid prescriptions have been for immediate-release opioids or short-acting opioids [63].

As of April 2020, 40 states have passed laws that address opioid analgesic prescribing. State-specific legislation, medical and pharmacy boards, Medicaid programs, department of workforce services, and workers' compensation programs have adopted policies, guidelines, and regulations that place limits on prescribing opioid analgesic medications and/or require monitoring of opioid prescriptions. Many insurance companies and managed healthcare organizations have also implemented policies related to limitations on opioid analgesic prescriptions. This has led to a general downward trend in total daily doses of opioids used, use of ER/LA opioid analgesics, and use of high-dose opioids. This trend began even before the release of the 2016 CDC guidelines for opioid prescribing. The use of ER/LA opioid analgesics for chronic pain continues to decline year-over-year. As of 2023, more than 90% of opioid prescriptions have been for immediate-release opioids or short-acting opioids [63].

A decision to prescribe opioids is based on clinician knowledge and judgment and also on patient preference, availability of non-opioid pain treatment approaches, the complexities and bias in third-party reimbursement, aggressive pharmaceutical marketing, and medico-legal concerns. These and other factors have tended to skew the standard of care toward reliance on opioids for long-term chronic pain management in the past few decades [8].

In 2011, the overall admission rate for misuse or abuse of opioid analgesics (excluding adverse reactions) was 134.8 per 100,000, an increase of 153% compared with 2004. In the 13 states involved in the legacy DAWN network, the top four opioid analgesics involved in drug-related ED visits for 2011 were various formulations of oxycodone (175,229), hydrocodone (97,183), methadone (75,693), and morphine (38,416). Between 2004 and 2011, ED admissions increased 74% for methadone, 220% for oxycodone, 96% for hydrocodone, and 144% for morphine. Importantly, there was no meaningful change in ED admission rates involving opioid analgesics between 2009 and 2011. If this is also borne out by subsequent data, it strongly suggests a plateau in the misuse and abuse rates of these agents [71].

In 2021, 9.2 million people reported nonmedical use of opioid analgesics (i.e., use without a prescription or for the non-analgesic effect) and 1.4 million were first-time nonmedical users that year [73]. An estimated 2.6 million people misused oxycodone products (including OxyContin) in the past year (1.2% of the population) [73]. The most frequent initial (past year) drug used was cannabis (52.5 million), followed by nonmedical use of prescription opioids (9.2 million), hallucinogens (7.4 million), nonmedical use of tranquilizers (4.9 million), stimulants (4.9 million), cocaine (4.8 million), methamphetamine (2.5 million), inhalants (2.2 million), and heroin (1.1 million) [73].

In 2021, 9.2 million people reported nonmedical use of opioid analgesics (i.e., use without a prescription or for the non-analgesic effect) and 1.4 million were first-time nonmedical users that year [73]. An estimated 2.6 million people misused oxycodone products (including OxyContin) in the past year (1.2% of the population) [73]. The most frequent initial (past year) drug used was cannabis (52.5 million), followed by nonmedical use of prescription opioids (9.2 million), hallucinogens (7.4 million), nonmedical use of tranquilizers (4.9 million), stimulants (4.9 million), cocaine (4.8 million), methamphetamine (2.5 million), inhalants (2.2 million), and heroin (1.1 million) [73].

The vast majority of people who misused opioids in the past year misused prescription pain relievers. Specifically, 8.7 million people 12 years of age or older misused prescription pain relievers in the past year, compared with 1.1 million people who used heroin [73]. In 2021, the majority (8.1 million) of the 8.7 million misusers of prescription pain relievers misused only prescription pain relievers in the past year—they had not used heroin. An estimated 574,000 people misused prescription pain relievers and used heroin in the past year, and 525,000 people used heroin in the past year but had not misused prescription pain relievers [73].

Among persons 12 years of age or older with a past-year opioid use disorder due to their use of heroin or misuse of prescription pain relievers, 22.1% (533,000 people) received medication-assisted treatment in the past year [73].

Research has more closely defined the location of prescribed opioid diversion into illicit use in the supply chain from the manufacturer to the distributor, retailer, and the end user. This information carries with it substantial public policy and regulatory implications. The 2021 NSDUH data asked nonmedical users of prescription opioids how they obtained their most recently used drugs [73]. Among persons 12 years of age or older, 33.9% obtained their prescription opioids from a friend or relative for free, 39.3% got them through a prescription from one doctor (vs. 34.7% in 2018), 7.3% bought them from a friend or relative, and 7.9% bought them from a drug dealer or other stranger. Less frequent sources included stealing from a friend or relative (3.7%); multiple doctors (3.2%); theft from a doctor's office, clinic, hospital, or pharmacy (0.7%) (vs. 0.7% in 2018); and some other way (4.0%) [73].

The reasons for opioid analgesic overdose fatalities are multifactorial and include prescriber behaviors, patient contributory factors, nonmedical use patterns, and systemic failures. Risk factors identified for fatal opioid toxicity include [6]:

Since the mid-2000s, methadone has become disproportionately represented in cases of opioid analgesic fatality. Based on data showing that 70% of fatalities among those prescribed methadone occurred in the first seven days of treatment, the FDA changed the methadone labeling in 2006 to lengthen dosing intervals from every 3 to 4 hours to every 8 to 12 hours; the initial recommended dose of 2.5–10 mg was unchanged [6,99]. In 2008, use of the highest oral dose preparations, 40 mg, was prohibited from use in pain treatment and restricted to addiction therapy [94].

These results illustrate the uneven geographic distribution of the prescription opioid use epidemic. It is also clear that prevalence rates are stabilizing or declining in all localities. These arrestee data indicate the epidemic has likely peaked and predict the decline in first-time and past-year use and an increase in prescription opioid addiction and treatment-seeking rates. In susceptible persons, progression in severity of a substance use disorder to addiction often occurs over many years. Persons who now meet diagnostic criteria for opioid analgesic addiction, and may be seeking help, probably began their use during an earlier phase of the epidemic.

The 2011 Institute of Medicine report Relieving Pain in America reinforced the importance of framing chronic pain as a unique chronic disease state with complex neurophysiological, emotional, and social components, making its management distinct from that of acute pain [7]. Treating chronic pain differs from acute pain by the duration, multimodal approach, and risk mitigation of the therapy. Clinicians may fear that managing the issues surrounding opioid analgesic prescribing render the practice too difficult or complex [112]. To assist in the dual need of protecting one's clinical practice while reducing opioid abuse, the FSMB released a model policy for opioid analgesic prescribing in 2013. This policy was the result of identification of harmful but remediable factors contributing to pain undertreatment and inappropriate opioid prescribing, including [10]:

The Screener and Opioid Assessment for Patients with Pain–Revised (SOAPP-R) is a patient-administered, 24-item screen with questions addressing history of alcohol/substance use, psychologic status, mood, cravings, and stress. Like the ORT, the SOAPP-R helps assess risk level of aberrant drug-related behaviors and the appropriate extent of monitoring [118].

All patients with pain have a level of risk that can only be roughly estimated initially and modified over time as more information is obtained. There are ten essential steps of opioid prescribing for chronic pain to help mitigate any potential problems [113]:

When implementing a chronic pain treatment plan that involves the use of opioids, the patient should be frequently reassessed for changes in pain origin, health, and function [113]. This can include input from family members and/or the state prescription drug monitoring program (PDMP) [113]. During the initiation phase and during any changes to the dosage or agent used, patient contact should be increased. At every visit, chronic opioid response may be monitored according to the 5 A's [10]:

Initially, testing involves the use of class-specific immunoassay drug panels [10]. If necessary, this may be followed with gas chromatography/mass spectrometry for specific drug or metabolite detection. It is important that testing identifies the specific drug rather than the drug class, and the prescribed opioid should be included in the screen. Any abnormalities should be confirmed with a laboratory toxicologist or clinical pathologist. Immunoassay may be used point-of-care for "on-the-spot" therapy changes, but the high error rate prevents its use in major clinical decisions unless liquid chromatography is coupled with mass spectrometry confirmation.

Urine test results suggesting opioid misuse should be discussed with the patient using a positive, supportive approach. The test results and the patient discussion should be documented.

It is important to appreciate the limitations of UDTs. Healthcare providers are increasingly relying on UDTs as a means to reduce abuse and diversion of prescribed opioids. This has led to a proliferation in diagnostic laboratories that offer urine testing. With this increase have come questions of whether these business interests benefit or hinder patient care, what prescribers should do with the information they obtain, the accuracy of urine screens, and whether some companies and clinicians are financially exploiting the UDT boom [129]. A random sample of UDT results from 800 patients with pain treated at a Veterans Affairs facility found that 25.2% were negative for the prescribed opioid and 19.5% were positive for an illicit drug/unreported opioid [130]. However, a negative UDT result for the prescribed opioid does not necessarily indicate diversion; it may indicate the patient halted its use due to side effects, lack of efficacy, or pain remission. The increasingly stringent climate surrounding clinical decision-making regarding aberrant UDTs is concerning. In many cases, a negative result for the prescribed opioid or a positive UDT serves as the pretense to terminate a patient rather than an impetus to guide him or her into addiction treatment or an alternative pain management program [129].

There are no universal recommendations for the proper disposal of unused opioids, and patients are rarely advised of what to do with unused or expired medications [131]. According to the Office of National Drug Control Policy, most medications that are no longer necessary or have expired should be removed from their containers, mixed with undesirable substances (e.g., cat litter, used coffee grounds), and put into an impermeable, nondescript container (e.g., disposable container with a lid or a sealed bag) before throwing in the trash [132]. Any personal information should be obscured or destroyed. The FDA recommends that certain medications, including oxycodone/acetaminophen (Percocet), oxycodone (OxyContin tablets), and transdermal fentanyl (Duragesic Transdermal System), be flushed down the toilet instead of thrown in the trash [132]. Patients should be advised to flush prescription drugs down the toilet only if the label or accompanying patient information specifically instructs doing so.

The decision to continue or end opioid prescribing should be based on a joint discussion of the anticipated benefits and risks. An opioid should be discontinued with resolution of the pain condition, intolerable side effects, inadequate analgesia, lack of improvement in quality of life despite dose titration, deteriorating function, or significant aberrant medication use [113].

Although opioid ADFs have been introduced into widespread clinical use relatively recently, several studies of their efficacy have already been published. These reports have documented significantly reduced abuse rates of ADF opioids after they have fully replaced the original formulations, but no effect on the overall rates of opioid abuse. For example, data were obtained on 140,496 persons assessed for substance abuse treatment, spanning from one year before ADF OxyContin (Oxy ADF) introduction to two years post-Oxy ADF introduction. Abuse of OxyContin was 41% lower with the ADF versus the original formulation, including a 17% decrease in oral abuse and a 66% decrease in abuse through non-oral routes. Meaningful reductions in ER morphine and ER oxymorphone abuse rates were not found. The authors concluded that conversion of OxyContin to an ADF formulation was successful in reducing non-oral administration that requires tampering [145]. Another study found that following OxyContin ADF introduction, poison center exposures for oxycodone ER abuse declined 38% per population and 32% per unique recipients of dispensed drug. Therapeutic error exposures declined 24% per population and 15% per unique recipients of dispensed drug, and diversion reports declined 53% per population and 50% per unique recipients of dispensed drug. The declines were greater than those observed for other prescription opioids in aggregate [146]. However, several published reports have documented the abandonment of opioid analgesics and a migration to heroin use by previous OxyContin abusers following the introduction of ADF OxyContin [147,148].

As noted, emerging trends and patterns of prescription opioid abuse, addiction, and overdose are monitored by several industry and government agencies through data collection from a variety of sources, including health insurance claims; the Automation of Reports and Consolidated Orders System (ARCOS), a DEA-run program that monitors the flow of controlled substances from manufacturing through distribution to retail sale or dispensing; the Treatment Episode Data Set (TEDS), which monitors treatment admissions; National Center for Health Statistics state mortality data; and the Researched, Abuse, Diversion and Addiction-Related Surveillance (RADARS) System, which monitors prescription drug abuse, misuse, and diversion [155].

The DEA is responsible for formulating federal standards for the handling of controlled substances. In 2011, the DEA began requiring every state to implement electronic databases that track prescribing habits, referred to as PDMPs. Specific policies regarding controlled substances are administered at the state level [156].

Patients with chronic pain who require ultra-high-dose opioids, in some cases more than 2,000 mg/day MED, are likely to be labeled as addicts or abusers by healthcare professionals and family members alike. In general, these patients are profoundly ill, impaired, and/or bed- or house-bound due to severe unremitting pain refractory to analgesic efforts using lower-dose opioids. The reason some patients require ultra-high opioid doses remains unclear, but it is very likely that some, and perhaps the majority, possess a cytochrome P450 polymorphism or other genetic abnormality [163].

The goals of treatment include avoiding harmful use of substances and achieving physical, psychological, and spiritual well-being. In patients with chronic pain with substance abuse disorders, there is a degree of overlap when substance abuse disorder treatment involves a biopsychosocial approach, as it ideally does. Effective approaches for substance abuse disorder include a combination of [178]:

Several pharmacologic aspects of buprenorphine contribute to its safety and effectiveness as therapy for opioid addiction and make it highly suitable for use in primary care [191]. As a partial mu agonist, a ceiling effect exists for its maximal activity—beyond a certain dose, no additional benefit is experienced. In contrast to increases in the dose of pure opioid agonists such as methadone, a greater margin of safety exists from death by respiratory depression. Buprenorphine possesses a short plasma half-life (about four to six hours) and a long duration of action resulting from its high affinity for and slow dissociation from the mu opioid receptor [187]. This slow dissociation likely contributes to a reduction in the severity of withdrawal symptoms during detoxification, and the longer duration of action allows for the potential of alternate-day dosing [192].

The efficacy literature indicates that higher-dose methadone (>50 mg daily, and 60–100 mg per day in particular) is more effective than lower doses in reducing illicit opioid and possibly cocaine use [193]. Higher-dose methadone is comparable to higher-dose buprenorphine (≥8 mg daily) on measures of treatment retention and reduction of illicit opioid use [193]. Although 30–60 mg per day of methadone may be effective in resolving opioid withdrawal symptoms, some patients require a maintenance dose ≥120 mg per day to eliminate illicit opioid use [193]. Patients requiring high-dose methadone for more severe opioid addiction are unlikely to achieve the same benefit from higher-dose buprenorphine [119]. Methadone has been reported to have higher retention rates, whereas buprenorphine has a lower risk of overdose fatality. These risks should be appropriately weighed by the treating or referring physician [191].

Sustained stabilization on methadone or buprenorphine can greatly enhance the capacity for normal functioning, including holding a job, avoiding crime, and reducing exposure to infectious disease from injection drug use or risky sexual behavior. Stabilized patients are much more likely to benefit from counseling and group therapy, essential components of recovery [185]. Although patients may experience sedation during the induction phase, tolerance to this effect develops over several weeks, after which the ability to work safely or operate a car or machinery is no longer impaired. Cognitive research has found that, during stabilization, the methadone-maintained patient is just as capable as a healthy, non-addicted person in job performance, assuming education and skill is comparable and abstinence from opioids and other drugs of abuse is ongoing [194]. Unfortunately, serious stigma surrounds methadone treatment, experienced most acutely by patients but also by professionals, which may pose a barrier to treatment support [195].