**Abstract**

Though there has been a 44.4% decrease in the number of prescriptions written for opioid analgesics between the years 2011–2020 in the United States, drug overdose rates continue to climb sharply, reaching nearly 107,000 for a prior 12-months period as of early 2022, driven primarily by the use of illicit opioids. It is estimated that 80–90% of individuals with a substance use disorder (SUD) receive no treatment, and for those with opioid use disorder (OUD) who do find their way to treatment, less than half are offered potentially life-saving medication. Contemporaneously, chronic pain is one of the most common and most disabling health conditions, and frequently involves complex decision-making between the patient and the health care team regarding the treatment approach. Though prescribing trends have ebbed in recent years, opioids continue to be the most prescribed class of drug in the United States despite well-publicized associated harms. It is more critical than ever that stakeholders urgently work to facilitate and destigmatize evidence-based substance use disorder treatment, and promote safe, effective, and holistic care pathways for patients suffering from chronic pain.

**Keywords:** chronic pain, opioid use disorder, prescription opioids, substance use

## **1. Introduction**

The "opioid crisis" as a major public health problem in the United States has been prominently recognized in medical literature and the press for at least a decade. Prompted by a variety of factors, the first of three defined "waves" of the crisis began with a dramatic increase in written prescriptions for opioid analgesics starting in the mid-1990's [1]. In lockstep with the surge in opioid prescribing, there was a coincident fourfold increase in overdose deaths and admissions to substance use disorder treatment programs. In 2015, more than 33,000 Americans died of opioid overdoses, and an estimated 2 million individuals suffered from substance use disorders related to prescription opioids [2].

There were multiple factors contributing to a threefold increase in the number of opioid prescriptions written in the United States between 1999 and 2011 [3]. The first relates to changing clinical practice norms, where indications for use of opioids for the treatment of chronic non-cancer pain widened significantly in response to escalating concerns about perceived widespread undertreatment of chronic pain. For example, at that time, the American Pain Society in its 1996 guidelines encouraged providers

to assess pain as "the fifth vital sign" at each clinical encounter to avoid failing to actively address patients' pain symptoms. At the same time, aggressive marketing of opioids by pharmaceutical manufacturers, particularly the makers of Oxycontin™ following its 1996 FDA approval, served to amplify and drive this shift in prescribing culture, with sophisticated methodologies to increase provider prescribing patterns, and with the dissemination of now-discredited scientific information alleging low risk of misuse or addiction related to prescription opioids [4]. Payers limited access to other evidence-based pain interventions such as multidisciplinary pain rehabilitation, bodywork treatment, and psychological counseling, and these modalities of treatment thus became more difficult to access, increasing patients' reliance on pharmacotherapy, and doctors' willingness to prescribe opioids. Taken together, these factors created a prescribing climate which normalized opioids as a common treatment for chronic non-cancer pain [3].

Alongside the challenge of containing the harms caused by overprescription of opioid analgesics exists the very high prevalence and burden of suffering from chronic pain. The debilitating effects of chronic pain on quality of life involve not only physical symptoms, but also emotional well-being, identity, and interpersonal relationships [3]. Among patients with chronic pain who are newly prescribed opioids for longer than 90 days, approximately 6% develop OUD, with the likelihood increasing dramatically with an escalation in dose and extended duration [5]. In 2016, the Centers for Disease Control and Prevention issued guidelines for prescribing opioids for chronic pain which recommended soft limitations on dose levels to lower than 90 mg morphine equivalents per day (MED), and implementation of clinical practices to assess and prevent harm to use and misuse, such as urine toxicology screening and use of state prescription monitoring program [6]. This document strongly influenced prescriber practices nationwide, contributing to a general decrease of 40–60% in aggregate opioid prescriptions across the US from peak levels in the mid-2000s. Unfortunately, not all consequences of this shift in prescribing patterns have been positive. Many patients who had been using opioids over the long term, especially at higher doses, were forced by their prescriber to undergo dose tapering or discontinuation despite evident clinical stability, due to misapplication of the CDC guidelines, with associated harmful adverse events and outcomes, including increased rates of illicit drug use, emergency department visits and hospitalizations, and overdose deaths [7]. There have been recent attempts to better understand the disruptive power these changing norms and policies have continued to have on patients' pain management experiences [8].

This change in prescribing practices and the resultant barrier to patients receiving prescription opioids legitimately for pain was exacerbated by abrupt closures of "pill mill" clinics by law enforcement. These clinics operated on a profit-based model and provided substandard care and monitoring while prescribing outsized quantities of opioids and other controlled substances. As a result of these factors, proactive networks of drug traffickers primarily from Mexico were able to capitalize on a ready-made source of demand for cheaper and more reliably available illicit opioids, ushering in the second wave of the opioid crisis by 2015: increased heroin use [1, 9]. Sources from Mexico accounted for 90% of the US heroin market share by 2016 [9, 10]. Within a few more years, fentanyl, a synthetic opioid that is much cheaper, more potent, and easier to manufacture and distribute than heroin, took over the illicit opioid market. Showing no signs of slowing, fentanyl-related overdose death rates have only worsened as the so-called third wave of the opioid crisis continues [1].

### *Management of Co-Occurring SUD and Chronic Pain DOI: http://dx.doi.org/10.5772/intechopen.105721*

In this context, management of chronic pain in the US has undergone systematic re-examination to elucidate best practices for patient safety and treatment effectiveness [8]. Elsewhere in the world, countries are attempting to learn from the mistakes of the US and prevent or mitigate major prescription opioid-related public health problems [11]. As providers are regularly tasked to straddle the intersecting realms of chronic pain disorders, substance use and mental health disorders, treatment approaches must emphasize evidence-based, compassionate, inclusive, patient-centered, safe, and sustainable interventions. Effective solutions to the crisis will include not only optimization of care delivery, but also relevant non-clinical aspects such as the roles of law enforcement and drug marketing and regulation [12]. Some countries have already made a marked shift in policy toward harm reduction, such as Canada, which has provided safe consumption sites for drug users, and the Netherlands and Portugal, which have decriminalized all drug use in favor of approaches emphasizing safety and access to treatment [13]. Though these measures have improved opioidrelated death rates, countries outside the US have seen use of prescription opioids grow substantially (47% increase in Europe between 2004 and 2016) even though it is illegal to market drugs directly to patients in Europe and other parts of the world [13].

In this chapter, we will review the complex intersection of SUD and chronic pain disorders in several subcategories: 1) understanding the scope of the problem and its neurobiological underpinnings, including risk factors, and biopsychosocial mechanisms of chronic pain and substance use disorders; 2) the controversial role of opioids in chronic pain care; 3) best practices in chronic pain and SUD treatment.

## **2. Key concepts in understanding Co-occurring chronic pain and SUD**

### **2.1 Epidemiology and neurobiology**

The prevalence of either regional or widespread chronic pain in adults has been estimated at 30% [14]. About 20% of US adults (50 million people) report a moderate to severe level of pain which affects their daily quality of life and activity, while in the United Kingdom, chronic pain is estimated to affect 20–50% of the adult population. Worldwide, chronic low back pain is the single leading cause of disability across all age ranges, genders, and demographics [15]. Several other chronic pain conditions including chronic headache and peripheral joint pain from arthritis are also in the top 10 causes of disability worldwide. Factors that are consistently associated with disability from chronic low back pain include older age, poor general health, increased psychological or psychosocial stress, worse baseline functional disability, sciatica, and the presence of compensation related to disability [5]. Social determinants of health that are known to predict poor outcomes related to disability from chronic low back pain include low socioeconomic status and/or low income, unemployment, and occupational factors such as lack of adequate support staff, manual lifting, and frequent overtime work hours [16].

The prevalence of opioid use disorder (OUD) in patients with chronic pain has been notoriously difficult to determine with specificity. Through the historical lens of the opioid crisis, it was dramatically underestimated in the years preceding and including the spike in opioid prescribing starting in the 1990s. In a letter that was published in 1980 in the New England Journal of Medicine, authors Porter and Jick described a crude study in which charts were pulled for patients in a hospitalized setting who had been given opioids for a variety of indications, with neither dosing nor duration of treatment identified. The investigators concluded that only 4 of these 11,882 hospitalized patients that were treated with an opioid medication were subsequently diagnosed with an "addiction". Unfortunately, this study was widely cited as "proof" that there was only about a 1% risk that a patient treated with opioids for pain (even in an outpatient setting, even long-term) would develop opioid addiction. More recently, it has been recognized that the real prevalence of OUD is much higher, with various estimates ranging from 3.2 to 27%, with most of these estimates falling in the 20–25% range [17]. Though the level of prescription opioid use, and opioid-related deaths in most European countries and worldwide is still much lower than that of the US, as noted above Europe has seen a steady increase in prescription opioid use over the past 15 years, mainly due to increased tramadol, fentanyl, and oxycodone prescriptions; there are calls for proactive investigation into these trends and their potential subsequent harms [11].

Over the past several decades, significant progress has been made in understanding the neurobiology of pain and addiction. CNS receptor binding targets and associated neural circuitry has been elucidated to explain the rewarding effects of substances with known abuse potential. Moreover, we know that repeated drug exposure over time causes adaptations in the brain's reward pathways which are evident even on a gross structural level via neuroimaging [17]. Affected areas include the following:


Substances with potential for abuse that affect these areas of the brain, such as alcohol, opioids, cannabis, stimulants, sedatives, and nicotine, enhance specific brain neurochemical pathways in ways similar to that produced by other natural rewards such as food and sex, but in a sometimes more acutely intense and prolonged manner. Conversely, when long-term use of such substance is interrupted, a pronounced sense of dysphoria is typically experienced, which has been referred to as *hyperkatifeia* [18]. The threat of this unpleasant state produces a desire to avoid interruption in use, due to the behavioral negative reinforcement that the undesired state exerts over the individual, who otherwise recognizes the benefits of stopping the behavior and genuinely prefers and seeks to do so. In addition, the rewarding effect of use is itself diminished with prolonged use as tolerance is developed to the effects of the substance, and the ability of natural rewards to activate the reward pathways is likewise compromised. In this fashion, over time, these substances strongly influence the choices and behavior of the individual [19].

Chronic pain is best viewed as a distinct diagnosis and medical condition, with its own definition and taxonomy [14]. It has been associated with multiple physical, psychological, and social factors which affect its level of impact on a given individual [15]. The diagnosis of a chronic pain disorder can be made based on objective evaluation, as with an imaging test or a blood test, for example, with relatively clear etiology and a specifically identifiable pain generator. However, even in cases where the diagnosis

is clear, patients with very similar objective findings might have a completely different "pain experience" based on other less quantifiable factors. These include:


Moreover, many chronic pain disorders are not typically associated with specific identifiable anatomic pathology. In the case of chronic low back pain, 85–95% of patients presenting to primary care providers do not have a clearly identifiable etiology for their symptoms [5]. Some pain syndromes are inherently caused or defined by a CNS-mediated pain state, such as fibromyalgia (prevalence estimated at 2–8% of the population). Other examples of this include headache syndromes, irritable bowel syndrome, temporomandibular joint syndrome, and interstitial cystitis. It should be noted, however, that what may have started as a focal, well-defined pain condition, such as low back pain from degenerative disc disease or lumbar facet arthropathy, may become a chronic, CNS-mediated pain state, such as in the case of failed surgical back syndrome [20]. Thus, it is incumbent upon care providers to recognize the complex role of the CNS in all chronic pain states, and to utilize treatment approaches that address the patient as a whole person rather than just as a structural or anatomic abnormality [21].

Pain can generally be subdivided into three general types, including nociceptive, inflammatory, and neuropathic [12]. Nociceptive pain is our bodies' sensory response to an actual painful stimulus, divided further into visceral (such as gastrointestinal) and somatic (such as musculoskeletal) pain. Inflammatory pain is a biological response within the body to facilitate tissue repair due to injury and can be either acute or chronic in nature. Acute inflammatory pain is exemplified by a sprained ankle, whereas chronic inflammatory pain is exemplified by osteoarthritis of a peripheral joint such as the hip. Neuropathic pain is typically defined by nerve injury or impairment leading to central pain sensitization (defined below), which results in a persistent pain response without a stimulus and is generally pathologic or maladaptive because it does not serve a useful purpose. Both the CNS and the peripheral nervous system (PNS) are involved in all 3 types of pain. The PNS comprises nerves and ganglia outside the brain and spinal cord, which define the CNS.

An individual's response to pain signals can be viewed in a general sense as either adaptive or maladaptive, with their emotional state playing a key role in this determination. In a person with normal pain sensitivity, pain signals from a twisting back injury would be transmitted from the dorsal horn of the spinal cord through ascending spinal pathways to be received by the brain, and the signals would then be modulated by descending inhibitory interneuron signals which serve to dampen the severity of the excitatory pain signals, in accordance with the now-classic gate control theory of pain as first proposed by Melzack and Wall in 1965, still supported in concept by the International Association for the Study of Pain [5]. Facilitating less distress and greater functional capacity, this normal sequence of pain processing is considered adaptive to the organism and species.

The same pain stimulus could be processed quite differently for a patient with chronic pain. Due to the emotional response caused by chronic pain signals, the inhibitory interneuron modulation of the descending pathway could be decreased, which leads to an increase in relative excitatory pain signaling input, with some relief coming from accompanying increase in endorphin release from the periaqueductal gray (PAG) and the dorsal horn of the spinal cord. Over time, via a process termed central sensitization, pain processing in the CNS recalibrates to adjusted thresholds for modulation of both ascending excitatory and descending inhibitory signals, resulting in the patient experiencing greater baseline pain sensitivity, and a higher level of distress with exacerbations of pain. The affective or emotional component, then, is recognized to have a significant influence on the ongoing physical experience of pain [22]. Moreover, this increased baseline pain sensitivity does not serve a functional purpose and would therefore be considered maladaptive [5].

When exogenous opioids are added longitudinally to this scenario, there is an accompanying decrease in the production and release of pain-relieving endogenous opioids from the PAG and dorsal horn, resulting in an increase in pain signaling along the ascending pathway. In addition to these effects on pain processing, prolonged opioids will also affect the pain experience by influencing the brain's limbic system (emotional circuitry, see below) and sleep patterns. These gradual changes in the CNS persist, even long after the opioid has been discontinued [19]. Such long-term CNS changes clearly have major implications in designing and implementing effective treatment approaches for both chronic pain and opioid use disorder/opioid physiologic dependence.

Despite the gains in knowledge and active investigation into the neurophysiology of pain and addiction, there is still a great deal that is incompletely understood. Much of our knowledge comes from laboratory and animal studies rather than from the actual patients who present for care. The influence of environmental factors such as trauma, for example, has been studied and shown to be quite impactful on the development of pain sensitivity, cognitive capability, memory, emotional resilience, and the likelihood of developing a SUD [17]. Also, very influential is the role of organic mental illness on the behaviors and brain function of a patient with chronic pain. In addition, issues such as genetics, social/housing instability, discriminatory disparities in accessing health care, and others, are known to greatly affect clinical outcomes for all patients experiencing chronic pain and addiction [6].

### **2.2 The duality of opioids: a brief review of general opioid pharmacology**

Opioids have played a central role in the relief of human suffering for millennia; they are also a direct cause of great harm. They are a class of prescription drugs derived from the opium poppy plant, some directly and some via laboratory synthesis using similar chemical structures. They contain chemicals that can relieve pain and relax the body. They can also produce a euphoric effect which gives them potential for misuse. Further, they can induce depression of the respiratory drive, leading to an overdose death. For these reasons, prescription opioids are regulated by the Drug Enforcement Agency of the US government, and by analogous agencies elsewhere. Some common examples of prescription opioids are oxycodone, morphine, hydrocodone, codeine, tramadol, fentanyl, buprenorphine, and methadone. In individuals with co-occurring chronic pain and SUD, consideration of treatment with the use of

### *Management of Co-Occurring SUD and Chronic Pain DOI: http://dx.doi.org/10.5772/intechopen.105721*

opioids or other controlled substances that have the potential to be misused and cause harm is a common clinical dilemma for health care providers, as well as a quality assurance and risk management issue for policymakers. In the years since the advent of the current opioid crisis, which as noted above began with exponential increases in the widespread use of prescription opioids to treat chronic non-cancer pain, there has been increased effort to define best practices for dispensing prescription opioids for appropriate indications, for appropriate patients, and for the appropriate length of time [23].

Opioids can be classified in various ways, such as by potency, half-life, opioid receptor activity, or specific opioid chemical class. It is useful to start with categorizing opioids based on the way they are synthesized:


Opioid pharmacodynamics, or the activity of the drug at the opioid receptor and the resultant physiologic and clinically relevant response, is at the heart of the question of how these drugs can be safely and effectively administered by clinicians [24]. Potency is certainly a key factor in this equation, and it is important that medical providers have a solid understanding of the relative potencies and basic pharmacologic properties of various opioid medications. Ranging from opioid partial agonists such as tramadol to high potency full agonists such as fentanyl, these potencies are classified by the World Health Organization on their "Analgesic Ladder" [11]. Of note, opioids with the highest potency also have the greatest addiction liability and highest risk of overdose death. The recent emergence of illicit synthetic analogs of fentanyl on the street has exposed users to levels of potency not seen before in clinical medicine; carfentanil, one such analog, is 100 times more potent than prescription fentanyl, which is itself 100 times more potent than morphine [25]. It is therefore not surprising that even users who are very experienced with other less potent opioids are highly susceptible to overdose when using substances containing illicit fentanyl.

Other important factors influencing the clinical effect of an opioid besides potency include half-life and route of administration. Typically, short-acting opioids have a more rapid onset and decay, which can be useful in treating acute pain, but can frequently create a pattern of unstable levels of drug when dosed repeatedly, resulting in both positive and negative reinforcement driving continued use. Moreover, use of short-acting opioids leads to more rapid neuroadaptation, or CNS sensitization/ homeostasis, whereby the stronger the opioid and the more rapidly it reaches the brain, the greater the neuroadaptive response [26]. This neuroadaptation is what leads to development of tolerance and physiologic dependence, which tend to occur much earlier with short-acting opioids than with longer-acting opioids.

Longer-acting opioids are typically used only in chronic rather than acute pain. Many such drugs are simply "extended-release" versions of short-acting opioids with an insoluble substance matrix that delays intestinal absorption and metabolism. Others, such as methadone and buprenorphine, are long-acting by design, primarily due to their high affinity for the opioid receptor. Though long-acting opioids may not be quite as reinforcing as short-acting opioids, clinicians should not assume that they are safer or less addictive than short-acting opioids. Importantly, long-acting opioids such as the prior version of Oxycontin™ were commonly tampered with by misusers to instantly produce high levels of the short-acting form of the drug, oxycodone. Abuse-deterrent extended-release formulations have helped to curb this widespread misuse technique (Oxycontin was reformulated in 2010), but not all available long-acting opioids have this technology. Notably, long-acting formulations have been associated with higher rates of overdose, in part due to the above, as well as the fact that combining a long-acting opioid with a CNS depressant such as alcohol or a prescription sedative may be more likely to produce a lengthier and therefore deadlier respiratory depression effect. Even without a second substance, accumulated dosing of long-acting opioids taken at higher levels of frequency than prescribed presents elevated overdose risk, particularly at the initiation stage of use. It typically takes roughly 5 half-lives of a long-acting drug to achieve steady-state in the circulation, which amounts to five full days with methadone, and patients who are impatient to achieve either pain relief or euphoric effect may increase dosing frequency before steady state is reached and before protective tolerance to the drug has begun [27].

### **2.3 The role of opioids in the treatment of chronic pain**

Regarding the controversial therapeutic value of opioids in the treatment of chronic non-cancer pain, there is very little high-quality research evidence. In a widely publicized 2018 JAMA study known as the SPACE trial, done in a Minnesota Veterans population, opioid-naïve patients with chronic back pain, or hip or knee osteoarthritis, were placed on a 12-months period of medication management and randomized to either opioid or non-opioid medications. The primary outcome was pain-related function, measured via Brief Pain Inventory scale; secondary outcomes were pain intensity and medication-related symptoms. The trial results showed no difference between the two groups in pain-related function, lower pain intensity in the non-opioid group, and more common adverse medication-related symptoms in the opioid group. The authors concluded that treatment with opioids was not superior to treatment with non-opioid medications for improving pain-related function over 12 months for moderate to severe chronic back pain or hip or knee osteoarthritis pain [28].

There are other views in the literature more favorable to the appropriate use of prescription opioids for chronic non-cancer pain, particularly in the current context of the ongoing escalation of overdose deaths driven primarily by the use of illicit opioids rather than prescription opioids. In a 2021 analytic review of evidence, Nadeau argued that restricting physicians from prescribing opioids for reasonable indications is a "failed strategy", opining that it was "pill mill" clinics rather than the average medical provider that was responsible for flooding much of the country with large supplies of prescription opioids, prior to a widespread law enforcement crackdown [25]. These clinics not only provided voluminous quantities of opioids, but they also delivered substandard care without appropriate support and supervision, which exacerbated the risk of misuse, diversion, and development of substance use disorders. These effects were prevalent not only in places with large local pill

### *Management of Co-Occurring SUD and Chronic Pain DOI: http://dx.doi.org/10.5772/intechopen.105721*

mill distribution networks, but also in more remote areas that were perhaps more susceptible to the lure of opioids because of poverty, mental illness, hopelessness, and other psychosocial factors [29]. According to Nadeau, well-designed studies have demonstrated that the annual case fatality rate attributable to prescribed opioids >100 mg daily morphine-equivalent dose (MED) is in the vicinity of 0.25% per year, which is similar to the risk of death from anticoagulation for stroke prophylaxis for a patient with atrial fibrillation. The twin crisis of high-impact chronic pain, which as noted affects approximately 20 million US adults and an estimated 30% of adults worldwide, necessitates a balanced approach. It remains unclear, however, whether future studies of the effectiveness of long-term use of opioids to ameliorate pain and improve functioning will support or refute the arguments of those who advocate for loosening current restrictions on the prescription of opioids for chronic pain.

Prescription opioid misuse is defined as use of the opioid "in any way other than how the provider directed the use, including greater amount, greater frequency, greater duration, using it for an effect other than intended, using someone else's medication, or using via unauthorized route of administration" [30]. In a 2017 "review of reviews" on chronic pain and opioid misuse, the prevalence of chronic non-cancer pain in individuals known to be misusing prescription opioids is estimated at 48–60%, which is substantially higher than the prevalence of chronic pain in the general population (11–19%) [31]. This finding highlights chronic pain as a major driver of opioid misuse. Reviews were noted to be commonly compromised by limitations including inconsistencies, imprecision, and lack of standardized assessment instruments and definitions of SUD, misuse, addiction, and abuse. They cited an overall lack of high-quality evidence on prevalence, risk factors, optimal clinical assessment, and treatment approaches related to co-occurring chronic pain and substance misuse.

### **2.4 Opioid use disorder vs. prescription opioid dependence**

Development of physiologic dependence on a substance should be viewed as distinct from the development of a substance use disorder (SUD) as defined by DSM-5. Tolerance to a substance is typically expected with prolonged use, and withdrawal symptoms upon cessation of the substance are also part and parcel of physiologic dependence, even without aberrant drug-taking behavior, misuse, craving, or other behavioral components more consistent with substance use disorder [32].

Patients who fall into the category of longtime users of prescription opioids for pain who have developed associated tolerance, physiologic dependence, and fear of physical and emotional distress and withdrawal symptoms when presented with the idea of tapering, have been classified as having a variant of dependence to opioids called complex persistent opioid dependence [33]. This is a distinct phenomenon from opioid use disorder. It is also distinct from simple persistent opioid dependence, in which the patient may have developed tolerance and physiologic dependence but does not approach the idea of tapering or dose adjustment with the degree of fear and/or resistance as does the patient with complex persistent opioid dependence. Given the sheer volume of patients classifiable in one of these two categories, providers in the era of the opioid crisis have been faced with the challenge of how to safely and humanely help them reduce their opioid usage, if/when indeed that is an appropriate and patient-centered goal to pursue. As noted previously, there are significant known harms that can come to patients for whom tapers have been non-consensual, overly rapid, and/or unskillfully executed [7].
