The Treatment of Chronic Pain in Patients with History of Substance Abuse

Howard A. Heit

Douglas L. Gourlay

Chronic pain has no positive physiologic value, whereas acute pain is an adaptive, beneficial response necessary for the preservation of tissue integrity.¹ Recurrent migraine headache, painful peripheral neuropathy, or metastatic bone cancer serves no useful physiologic purpose. In addition, pain remains the most common complaint presenting to the primary health care professional and should be treated in all populations.²^,³ This is no less true in those persons suffering from an active or remote history of substance misuse disorder. A substance use disorder does not decrease the likelihood of a treatable pain condition, it simply complicates it.

The U.S. Census Bureau reported in 2016 that the nation’s population had reached ˜323 million.⁴ Approximately 16% to 23% (˜52 to 74 million) of the population suffers pain which is undertreated or not treated at all.²^,⁵ In the third world, the statistics are even grimmer. Three percent to 16% of the American population may have the disease of addiction.⁶ Substance use disorders alone pose a heavy societal burden, endangering individual and family health and well-being and sapping resources from the health care system.⁷ In fact, the current data on prevalence of addiction is extremely difficult to interpret. Part of the reason for this is the continued interchangeable use of the terms addiction and dependence.⁸ For example, in a recent article in The New England Journal of Medicine, the authors cite Centers for Disease Control and Prevention (CDC) Guideline data which states that the prevalence of opioid dependence may be as high as 26% among patients in primary care receiving opioids for chronic noncancer-related pain.⁹ Because we know that there is some degree of physical dependency associated with the chronic use of opioid agonist class of drugs in all patients, the term opioid dependency seems to be used to denote opioid addiction. This uncertainty in terminology makes data collection, interpretation, and comparisons between studies extremely difficult. This also makes the determination of incidence and percentage of chronic pain and addiction in other developed countries equally difficult. Furthermore, in certain subsets of the general population, we expect the incidence of pain to be considerably greater as has been reported, for example, in methadone maintenance treatment (MMT) programs.¹⁰ Opioids may be indicated in a small percentage of these MMT patients with moderate to severe pain. However, this population is at increased risk for relapse even in the context of a comprehensive treatment plan that includes “rational pharmacotherapy.” In addition, regulatory scrutiny often leaves the health care professional in a position of real or perceived vulnerability when prescribing a controlled substance. This may put both health care professionals and their patients at risk of a suboptimal outcome for an often-treatable medical condition.

The use of controlled substances including opioids in persons who may suffer from concurrent substance use disorders presents additional challenges to the health care professional. Success in the treatment of either condition requires an approach that encompasses the entire biopsychosocial needs of the patient. Pain management necessitates the need for careful boundary setting within the therapeutic relationship. Unfortunately, it is impossible to determine beforehand, with any degree of certainty, who will become problematic users of prescription medications.¹¹ Despite our best efforts, no risk assessment tool has been developed which can reliably define risk of aberrant drug-taking behavior in patients prescribed opioids for the treatment of chronic pain.¹²^,¹³ Risk is a part of the human condition: “If you have a pulse, you have a risk.” What is more important is to make a credible attempt at assessing these risks in all patients and to manage these risks to the best of our abilities. By recognizing the need to carefully assess all patients, in a biopsychosocial model, stigma can be reduced, patient care improved, and overall risk contained.¹⁴ The fact is that no matter how carefully we try to limit the use of opioids to the “lowest class of risk,” there will always be a need to assess treatment goals and outcomes and modify them according to specific patient needs.

The goals of this chapter are to address the complex issues associated with the treatment of pain in persons with problematic behavior and to offer the health care professional an approach that may reduce risk and, hopefully, improve outcome.

Principle of Balance

Health care professionals who treat patients at the interface of pain and addiction and officials who formulate and enforce regulations must understand the central principle of “balance” as it relates to the use of any controlled substance including opioids.

That principle provides for a system of controls to reduce the risk of diversion, abuse, or trafficking of opioids, balanced against the assurance of the availability of opioids for legitimate medical and scientific purposes and accessibility of opioids to all who need them for the relief of pain.¹⁵ Health care professionals must embrace this principle as should our patients, dispensing pharmacists, and our communities.

By applying the principle of balance, it stands to reason that health care professionals should be able to treat pain in patients with the disease of addiction who are willing to simultaneously address both conditions. One can successfully treat acute pain in the face of an active addiction, but one will not achieve the stated goals in chronic pain management with an untreated substance use disorder.¹¹ Mutual support programs such as Alcoholics Anonymous and Narcotics Anonymous are quite clear in terms of their position on the management of any medical condition: These are side issues and should not interfere with the 12 steps and traditions of their respective programs.¹⁶ Inappropriate use of prescription medications, even when legitimately prescribed by a licensed professional, can interfere in the recovery process. A legitimate indication for a given drug does not necessarily imply an “appropriate” indicate for that drug. For this reason, patients “in recovery” from drug or alcohol misuse need to ensure that their physicians are knowledgeable in the recovery process or have guidance from someone with such knowledge involved in their care.

THE IMPORTANCE OF THE DEFINITIONS

Using precise definitions at the interface of pain and addiction medicine will allow health care providers to improve their clinical practice of pain management (Table 59.1).¹⁷^,¹⁸^,¹⁹

Confusion between physical dependence and addiction may contribute to the undertreatment of chronic pain. Ballantyne and LaForge²⁰ have expressed concern over the apparent lack of distinction between physical and psychological dependence in the diagnosis of addiction, preferring to consider these as entirely separable phenomena. Although the following definitions share many elements in common, “continued use despite harm” remains the behavioral marker in the chronic pain patient that will define, over time, an addictive disorder, if present.²¹ Physical dependence does not mean addiction, nor is it necessarily devoid of psychological components. Physical dependence and addiction can coincide, but physical dependence is neither necessary nor sufficient to make a diagnosis of addiction. Physical dependence is an expected, neuropharmacologic adaptation that occurs because of chronic exposure to an agonist class of drug. Addiction is a much more complex biobehavioral phenomenon.¹⁷^,¹⁸^,¹⁹

TABLE 59.1 Definitions

Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.
Physical dependence is a state of adaptation that is manifested by a drug class-specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.
Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.
Pseudoaddiction is a syndrome that causes patients to seek additional medications due to inadequate pharmacotherapy being prescribed. Typically when the pain is treated appropriately, the inappropriate behavior ceases.
Pseudotolerance is the need to increase medication such as opioids for pain when other factor(s) are present such as disease progression, new disease, increased physical activity, lack of compliance, change in medication, drug interaction, addiction, and/or deviant behavior.
Iatrogenic addiction occurs when a patient, with a negative personal or family history for alcohol or drug addiction or abuse, is appropriately prescribed a controlled substance and subsequently in the therapeutic course meets the diagnostic criteria for addiction to that substance.
Misuse is use of a medication (for a medical purpose) other than as directed or as indicated, whether willful or unintentional, and whether harm results or not.
Abuse is any use of an illicit drug with the intentional self-administration of a medication for nonmedical purpose such as altering one’s state of consciousness (e.g., getting high). A licit substance such as alcohol can be abused.
Diversion is the intentional removal of a medication from legitimate distribution and dispensing channels for illicit sale or distribution.
Aberrant behavior is when the patient steps outside the boundaries of the agreed-on treatment plan which is established as early as possible in the doctor-patient relationship.

From Passik SD, Weinreb HJ. Managing chronic nonmalignant pain: overcoming obstacles to the use of opioids. Adv Ther 2000;17(2):70-83; Weissman DE, Haddox JD. Opioid pseudoaddiction—an iatrogenic syndrome. Pain 1989;36(3):363-366; Pappagallo M. The concept of pseudotolerance to opioids. J Pharm Care Pain Symptom Control 1998;6:95-98. Katz NP, Adams EH, Chilcoat H, et al. Challenges in the development of prescription opioid abuse-deterrent formulations. Clin J Pain 2007;23(8):648-660; and Gourlay DL, Heit H. Pain and addiction: managing risk through comprehensive care. J Addict Dis 2008;27(3):23-30.

Physical dependence is a natural expected neuroadaptive response that can occur with opioids, alcohol, benzodiazepines, corticosteroids, antidepressants, diabetic agents, cardiac medications, and many other medications used in clinical medicine. Abrupt cessation of these medications can produce a withdrawal syndrome that can include, but is not limited to, nausea, vomiting, diaphoresis, diarrhea, abdominal cramps, seizures, anhedonia, dysphoria, and, in some cases, even death.¹⁷^,¹⁸^,¹⁹ For example, a heroin addict may be both physically dependent and addicted to the narcotic, whereas the pain patient taking opioids is physically dependent but not necessarily addicted. Both will experience some degree of withdrawal if the drug is abruptly stopped. In the pain patient, physical dependence with withdrawal may also be associated with withdrawal-mediated hyperalgesia.²²

In fact, one of the greatest challenges in the interpretation of adverse outcomes in the context of opioid medication management is that related to equivalency of dose, given the wide range of medications we have within the opioid class of drugs.

The concept of morphine milligram equivalence (MME) has come under significant fire in recent years due to the perceived shortcomings of trying to equate molecules of different therapeutic potencies and intrinsic activities. The concept, however flawed, is in our opinion a worthwhile one.

Although the debate rages on as to what effect chronic versus acute exposure, medication tolerance, and individual pharmacogenetics variabilities to mention only a few of the relevant variables have on equivalent doses, there are several immutable points to consider.

The first is that there is, without a doubt, a significant prescription drug abuse problem in America.²³ Although many drug classes are abused, the opioid class of medication has come under direct fire in terms of increased morbidity and mortality as drugs of abuse.

The second point is that regardless of where the line is drawn, be it 90-mg morphine equivalence or 200-mg morphine equivalences per day, risk clearly rises as daily dose increases.²⁴^,²⁵

The final point, and perhaps one that might be open to the greatest expert debate, is that as dose of drug continues to increase, despite inadequate therapeutic response, the probability of achieving a successful therapeutic outcome diminishes.⁹ What impact the comorbid conditions of substance abuse and/or addiction might contribute toward adverse outcomes in this context remains to be seen.

Iatrogenic addiction is not clearly defined in the literature.³^,²⁶ The true incidence of iatrogenic addiction to opioids is not known.²⁶ It is therefore important to set limits and boundaries for all patients before writing the first prescription.¹⁴

It is only by careful evaluation and rational pharmacotherapeutic management of the pain that concurrent diagnoses such as addiction or pseudoaddiction²⁷ can be confirmed. Although a diagnosis of addiction is made prospectively over time, a diagnosis of pseudoaddiction is usually made retrospectively.¹¹ When reasonable limits and boundaries are placed on a patient, and yet they continue to step out of bounds, addiction or drug abuse should be considered.

Health care professionals with improved understanding of the definitions on basic scientific and clinical levels will be better able to more effectively evaluate and treat chronic pain patients with or without the disease of addiction.

Basic Science of the Disease of Addiction

Drugs of misuse act at local cellular and membrane sites that are within a neurochemical system that is called the reward and withdrawal pathway (Fig. 59.1).²⁸ This pathway is in the mesolimbic dopamine system, and it involves, among other structures, the ventral tegmental area, nucleus accumbens,
amygdala, and prefrontal cortex of the primitive brain. Addiction is a neurobiologic disease that causes disruption of these pathways. This disruption is mediated via receptor sites and neurotransmitters. Central to this reward and withdrawal pathway is the neurotransmitter dopamine, which has been shown to be relevant not only to drug reward but also to food, drink, sex, and social reward.²⁹^,³⁰ Disruption of this neurochemical pathway by drugs of abuse may lead to addiction. Drug withdrawal can intensify with repeated drug use and can persist during prolonged periods of drug abstinence, a symptom complex known as the protracted abstinence syndrome.³¹ This sensitization of a neural process related to drug cravings or to environmental stimuli such as sights, smells, and sounds associated with drugs (referred to as cues) leads to the progressive increase in drug-seeking behavior that characterizes addiction. Such sensitization appears to increase the attractiveness of the drug taking and that of the drug-associated stimuli.³²

One of the most common reasons for relapse is stress.²⁸ It stands to reason that if a chronic pain patient is in recovery from drug or alcohol use and his or her pain is inadequately treated, he or she may turn to the street for licit or illicit drugs and/or alcohol to cope with the pain.

The health care professional must recognize addiction as a treatable brain disease³³^,³⁴; that is, a distinct medical condition that may or may not be associated with the patient’s pain syndrome. However, when these do coexist, the successful treatment of either will require addressing both problems. In fact, as a general principle, all pain doctors should be talented amateurs in the context of identifying and treating substance use disorders (D. L. Gourlay, personal communication, verbal, July 2017).

Opioids can cause physical dependence and, upon abrupt discontinuation, withdrawal as a result of upregulation of the cyclic adenosine monophosphate (cAMP) pathway at the locus coeruleus.³¹ This is a normal physiologic response to this class of medications. It should be noted that most of the medications capable of producing physical dependence are not associated with the disease of addiction.

Tolerance is also a natural, expected physiologic response that can occur with exposure to certain classes of drugs, especially alcohol and opioids. The key to this definition is that all other factors remain stable so that just the physiologic response to the drug can be evaluated.¹⁷ In fact, tolerance is neither good nor bad. It occurs at different rates, to different effects in different people, over time. So, although there is relatively rapid tolerance development to the cognitive blunting effects of the opioid class of drug, tolerance to the constipating effects of opioids rarely occurs. Unappreciated disease progress that is associated with dose escalation is termed pseudotolerance,³⁵ a term that was coined to describe the apparent loss of analgesic effect in cancer patients with unrecognized increases in tumor burden.³⁵ Pharmacodynamic tolerance involves adaptations that occur at both the site of the drug action (e.g., receptor, ion channel, as well as in related systems more distal to it). For example, pharmacodynamic tolerance to opioids is evident at both the level of the opioid receptor in the locus coeruleus (primary) and in the dopaminergic reward pathways afferent to the site of this discrete drug action (secondary).³² Persons addicted to heroin and chronic pain patients taking opioids can both exhibit tolerance to the drug.

FIGURE 59.1 Common reward pathway: mesocorticolimbic dopamine system. 5-HT, 5-hydroxytrypophan; DA, dopamine; GABA, gamma aminiobutyric acid; GLU, glutamate; NE, norephinephrine. (Reproduced from Cami J, Farre M. Drug addiction. N Engl J Med 2003;349[10]:975-986. Copyright © 2003 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)

BINARY CONCEPT OF PAIN AND ADDICTION

In the past, the literature has suggested that pain conditions and addictive disorders might be dichotomous phenomena.¹¹^,¹⁴, 36 It has been said that in the context of a “legitimate” pain diagnosis, which usually meant a condition that made sense to the assessing health care professional, the likelihood of there being an addictive disorder was so small as to not even merit investigation. Unfortunately, if the patient had an obvious substance use disorder, very real and treatable pain conditions were often ignored. With time, this thinking was tempered somewhat to suggest that in the absence of a current or past personal or family history of a substance use disorder, the risk of addiction was very low indeed.¹⁴ This dichotomous approach to pain and addiction has not served patients, health care professionals, or society well.

In reality, there is nothing about a genuine pain condition that is protective against having a concurrent substance use disorder³; however, untreated pain, as a stressor, should always be considered in the assessment of relapse risk.²⁸ Although there are some data in the animal literature to suggest that acute pain may blunt the euphoric reward of some drugs including opioids,³⁷^,³⁸ this concept has largely been discounted. Patients with a substance use disorder are often disproportionate consumers of health care resources, especially in the context of trauma.³⁹^,⁴⁰ The presence of a preexisting substance use
disorder is not mitigated by a concurrent pain problem; it is complicated by it.

Although there is no evidence in the literature to suggest that those patients without past histories or apparent increased risk of substance use disorders become addicted as a result of rational pharmacotherapy for the treatment of any medical condition, including chronic pain, there is little credible evidence to the contrary either. Perhaps more relevant questions to ask are whether rational pharmacotherapeutic management of acute or chronic pain can reactivate a previously dormant substance use disorder or express an as yet unidentified genetic predisposition³ toward substance misuse or addiction. In the authors’ opinion, the answer to both questions very likely is “Yes.”¹¹

Risk, of course, varies with circumstance. For example, the prevalence of alcoholism in the hospitalized general medical population is estimated at 19% to 26%,⁴¹ whereas in the trauma subset, the prevalence rises to 40% to 62%.⁴⁰ Regardless of what the actual risk is, it is clear that no one specific marker can reliably identify the at-risk pain patient, so careful boundary setting for all patients is strongly recommended.¹⁴ However, boundary setting is not without potential risk. It is interesting to note that in some cases, aberrant behavior on the part of the patients may be driven, if not created by overly proscriptive rules and demands placed on them by their treatment provider/team.

Take, for example, the patient that is forced to provide urine drug samples on a twice-weekly basis. It might be considered “aberrant” if the patient appears unwilling to comply. In fact, many would consider even weekly urine drug testing (UDT) onerous and so the disruption in the patients’ life might well be considered unacceptable. If boundaries and limits are set excessively tight, even “normal” patients will be forced to step out of bounds. Not only is this excessive, but there is no evidence in the literature to suggest this pattern of testing is either clinically useful or medically necessary.⁴²

Not all aberrant behavior reflects drug misuse or addiction. Some individuals who do not meet the diagnostic criteria for addiction may also use medications and other drugs problematically. This group is sometimes referred to as “chemical copers.”⁴³ These individuals lack the skills commonly acquired during childhood and adolescence and tend to turn to external sources for support in dealing with life’s problems. Often, however, these patients suffer from complex, multidimensional problems that may only be partially responsive to even optimum pharmacotherapy in the absence of a biopsychosocial treatment plan. Unidimensional problems may respond to unidimensional pharmacologic solutions. Multidimensional problems however may transiently respond to pharmacologic interventions but rarely in a sustainable fashion.¹¹

It is only by aggressive investigation and rational pharmacotherapeutic management of the pain that this diagnosis can be made. The diagnosis of addiction is often made prospectively over time.¹¹ When the patient’s behavior remains aberrant despite the appropriate management of the underlying painful condition with reasonably set limits, substance misuse or addiction should be considered. In contrast, the diagnosis of pseudoaddiction is made retrospectively,¹¹ meaning that with appropriate management of pain, aberrant behavior is reduced or eliminated.¹¹^,¹⁴ Boundary setting may include interval dispensing and contingency prescribing. Interval dispensing requires the patient to see other members of the health care team, such as a staff member of the prescriber or the pharmacist, on a more frequent basis than the actual prescriber. Thus, interval dispensing can be a simple and effective means to help patients keep from “borrowing (medications) from tomorrow to pay for today,” thereby reducing the risk of running out of medications early. With contingency prescribing, receiving the next prescription is contingent on something such as bringing bottles in for “pill counts” or mandatory attendance at all appointments.

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