Neurobiology of Addiction to Opioids

Any drug addiction is now understood to be a disease that is very much brain based. This phenomenon is a consequence of repeated exposure to the addictive drugs that leads to behavior characterized by loss of control over the use of such drugs. The behavioral abnormalities are connected to physiologic underpinnings, which mutually reinforce each other, and substance use disorders can be thought of as disorders of motivated behavior. Effective treatment involves simultaneously changing behavior and addressing the underlying physiologic drives sustaining the aberrant behavior. Addiction can be conceptualized as a chronic neurobiologic disease and a model of the relationship between the brain and behavior.

There remains a great deal of uncertainty regarding the exact neural correlates of addiction. Nonetheless, it is believed that key brain regions constituting the brain networks for addiction are found within the mesocorticolimbic dopamine systems, which start in the ventral tegmental area and connect to the amygdala, prefrontal cortex, and nucleus accumbens ( Fig. 51.1 ).

Dopamine reward pathway.

(This slide is made available to the public through the National Institute on Drug Abuse Web page at www.nida.nih.gov/Teaching/largegifs/slide-9.gif .)

This pathway has been called the “dopamine reward pathway,” and all addictive drugs ultimately act through different mechanisms to potentiate euphoria or other positive reward symptoms that subsequently reinforce behavior for ongoing use of the drug. Opioids, in particular, work by inducing the release of dopamine in the ventral tegmental area and by binding to receptors in the nucleus accumbens. It has been postulated that the experience of withdrawal uses this same pathway to create the negative reinforcement that contributes to compulsive behavior and cravings.

Moreover, some of the biologic correlates connecting negative affect, increased pain, and opioid use have been described. These include the spinolimbic pathway, also known as the “medial pain system.” This pathway travels parallel to the spinothalamic tracts in the spinal cord and receives direct input from the dorsal horn of the spinal cord. This pathway will lead to regions in the brain, such as the anterior cingulate cortex, insula, and prefrontal cortex, that not only process both pain and affect but are also regions with a very high concentration of opioid receptors.

Vulnerability to the development of addiction is very much linked to genetic factors, as shown by genetic epidemiologic studies using twin, family, and adoption designs. Heritability can range from 0.3 to 0.5, depending on the drug of use. Although a specific “addiction gene” has not been identified, these studies point to a very strong biologic influence of addiction, whose assessment must be incorporated into the everyday clinical practice of addiction medicine and pain medicine. Thus, taking a detailed family history, including a family history of substance abuse, is valuable in providing data for comprehensive pain assessment. The different terminology used in the context of chronic pain with addiction and opioid misuse or abuse is summarized in Box 51.1 .

Nosology of Prescription Opioid Misuse, Abuse, and Addiction

Many terms are used to describe substance use disorders in patients with chronic non–cancer-related pain, and clarification of the terminology is important. The American Academy of Pain Medicine (AAPM), the American Pain Society, and the American Society of Addiction Medicine (ASAM) define prescription opioid addiction in patients with pain as “a primary, chronic, neurobiologic disease that 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.” As noted, the behavioral characteristics of prescription opioid addiction may be perpetuated by a physiologic drive that comes with using prescription opioids ; in this case the mesolimbic motivational circuits are “hijacked” to perpetuate a disorder of motivated behavior.

For many pain medicine and addiction specialists, this definition of addiction is preferred in patients prescribed opioids for pain over the Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition (DSM-IV), definition of substance dependence because physical dependence in these patients, as evidenced by tolerance and withdrawal, is normal. Although the DSM-IV definition does not require tolerance or withdrawal to make the diagnosis of substance dependence, these conditions do fulfill two of three major criteria required to make the diagnosis ( Table 51.1 ). Thus, there are phenomenologic quandaries in applying the DSM-IV criteria for evaluation of substance dependence in patients prescribed opioids for pain. Given these issues, the AAPM and ASAM refer to substance misuse in this patient group as the use of any drug in a manner other than how it is indicated or prescribed. Substance abuse is defined as the use of any substance when such use is unlawful or detrimental to the user or others.

Hence, opioid misuse may indicate a treatment compliance issue or may signal a more serious addiction problem if accompanied by a lack of control over use despite negative consequences. These distinctions are somewhat blurry, and in a clinical pain medicine practice it is often unclear whether a patient is simply noncompliant with the medication or is truly dependent. The presence of craving is central to this distinction in applying the AAPM and ASAM criteria for prescription opioid addiction. Moreover, DSM-V will add craving to the diagnostic criteria for opioid addiction and is changing the terminology from opioid dependence to opioid addiction . However, it remains unclear to what extent craving is indicative of prescription opioid dependence or addiction since those without opioid dependence who are taking prescription opioids have appropriately also reported some craving. Furthermore, across many different substances, reporting craving is significantly associated with a substance use disorder. A few studies have examined craving in patients with pain who have been prescribed opioids, and craving is significantly associated with an elevated risk for opioid misuse.

Nosology of Prescription Opioid Misuse, Abuse, and Addiction

Many terms are used to describe substance use disorders in patients with chronic non–cancer-related pain, and clarification of the terminology is important. The American Academy of Pain Medicine (AAPM), the American Pain Society, and the American Society of Addiction Medicine (ASAM) define prescription opioid addiction in patients with pain as “a primary, chronic, neurobiologic disease that 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.” As noted, the behavioral characteristics of prescription opioid addiction may be perpetuated by a physiologic drive that comes with using prescription opioids ; in this case the mesolimbic motivational circuits are “hijacked” to perpetuate a disorder of motivated behavior.

For many pain medicine and addiction specialists, this definition of addiction is preferred in patients prescribed opioids for pain over the Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition (DSM-IV), definition of substance dependence because physical dependence in these patients, as evidenced by tolerance and withdrawal, is normal. Although the DSM-IV definition does not require tolerance or withdrawal to make the diagnosis of substance dependence, these conditions do fulfill two of three major criteria required to make the diagnosis ( Table 51.1 ). Thus, there are phenomenologic quandaries in applying the DSM-IV criteria for evaluation of substance dependence in patients prescribed opioids for pain. Given these issues, the AAPM and ASAM refer to substance misuse in this patient group as the use of any drug in a manner other than how it is indicated or prescribed. Substance abuse is defined as the use of any substance when such use is unlawful or detrimental to the user or others.

Hence, opioid misuse may indicate a treatment compliance issue or may signal a more serious addiction problem if accompanied by a lack of control over use despite negative consequences. These distinctions are somewhat blurry, and in a clinical pain medicine practice it is often unclear whether a patient is simply noncompliant with the medication or is truly dependent. The presence of craving is central to this distinction in applying the AAPM and ASAM criteria for prescription opioid addiction. Moreover, DSM-V will add craving to the diagnostic criteria for opioid addiction and is changing the terminology from opioid dependence to opioid addiction . However, it remains unclear to what extent craving is indicative of prescription opioid dependence or addiction since those without opioid dependence who are taking prescription opioids have appropriately also reported some craving. Furthermore, across many different substances, reporting craving is significantly associated with a substance use disorder. A few studies have examined craving in patients with pain who have been prescribed opioids, and craving is significantly associated with an elevated risk for opioid misuse.

Signs of Problematic Opioid Use

One major concern for the long-term use of opioids in patients with chronic non–cancer-related pain is their potential for misuse and abuse. Multiple cross-sectional studies in clinic populations have indicated that treatment of noncancer pain with opioids is associated with a 40% prevalence of opioid misuse. Clinicians have reported several types of aberrant drug-related behavior (ADRB) that may be indicative of opioid misuse. Although such behavior is problematic and indicative of nonadherence to opioid therapy at the very least, many have not been empirically tested to distinguish opioid misuse without negative consequences from prescription opioid addiction. Of course, certain types of extreme behaviors, such as injecting oral formulations or compulsive, uncontrolled use of medication, have face validity suggestive of addiction. According to Portenoy, there are three major types of ADRBs: loss of control over the drug, compulsive drug use, and continued use despite harm. He suggested the following sets of drug-related behavior that may cause suspicion about problematic use in opioid-treated pain patients:

ADRB more predictive of addiction

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  Prescription forgery

  
  
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  Stealing or “borrowing” drugs from others

  
  
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  Injecting oral formulations

  
  
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  Obtaining prescription drugs from nonmedical sources

  
  
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  Concurrent abuse of alcohol or illicit drugs

  
  
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  Multiple dose escalation or other noncompliance with therapy despite warnings

  
  
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  Multiple episodes of prescription “loss”

  
  
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  Repeatedly seeking prescriptions from other clinicians or from emergency departments (EDs) without informing the prescriber or after a warning to desist

  
  
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  Evidence of deterioration in the ability to function at work, in the family, or socially that appears to be related to use of the drug

  
  
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  Repeated resistance to changes in therapy despite clear evidence of adverse physical or psychological effects from the drug

  
  
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  Selling prescription drugs (which is termed diversion and is not indicative of a substance use disorder per se but does signify a major ADRB)

ADRB less predictive of addiction (may be more indicative of poorly controlled pain or misuse without significant negative consequences)

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  Aggressive complaining about the need for more drug

  
  
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  Drug hoarding during periods of reduced symptoms

  
  
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  Requesting specific drugs

  
  
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  Openly acquiring similar drugs from other medical sources

  
  
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  Unsanctioned dose escalation or other noncompliance with therapy on one or two occasions

  
  
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  Unapproved use of the drug to treat another symptom

  
  
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  Reporting psychic effects not intended by the clinician

  
  
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  Resistance to change in therapy associated with “tolerable” adverse effects with expressions of anxiety related to the return of severe symptoms

Savage in 2002 also formulated a short list of patterns that may suggest addiction (“look for the four C’s”):

Adverse C onsequences/harm as a result of use

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  Intoxicated, somnolent, sedated

  
  
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  Declining activity

  
  
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  Irritable, anxious, labile mood

  
  
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  Increasing sleep disturbances

  
  
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  Increasing pain complaints

  
  
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  Increasing relationship dysfunction

Impaired C ontrol over use/ C ompulsive use

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  Reports lost or stolen prescriptions or medication

  
  
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  Frequent early renewal requests

  
  
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  Urgent calls or unscheduled visits

  
  
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  Abusing other drugs or alcohol

  
  
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  Cannot produce medication on request

  
  
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  Withdrawal noted at clinic visits

  
  
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  Observers reporting overuse or sporadic use

Preoccupation with use because of C raving

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  Frequently missed appointment unless opioid renewal expected

  
  
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  Does not try nonopioid treatments

  
  
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  Cannot tolerate most medications

  
  
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  Requests medication with high reward

  
  
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  No relief with anything else except opioids

It is important to remember that many of the types of behaviors listed may occur occasionally in isolation in patients using opioids appropriately, for the most part in the treatment of their chronic pain. However, a pattern of such behavior in the context of titrated pain therapy may suggest the need for further evaluation to determine the presence of prescription opioid addiction. It is still unclear exactly which constellations of symptoms or behaviors accurately distinguish misuse from abuse and addiction. These are thought to exist on a continuum, with the most severe form of nonadherence—addiction—characterized by the four “C’s.”

Early and proper identification, as well as careful monitoring for signs of problematic opioid use and ADRB, is warranted. Once identified, several measures may be taken by the prescribing physician to control for such aberrant behavior and reduce risk for the subsequent development of an addiction problem, including the following:

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  Writing an opioid pain treatment agreement, if one is not available, in which expectations and conditions for termination of opioid prescription are clearly outlined

  
  
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  Increasing the number of office visits and more frequent monitoring

  
  
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  Decreasing the number of medication dispensed per visit

  
  
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  Performing random pill counts on visits

  
  
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  Recommending the use of only one pharmacy

  
  
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  Using prescription drug–monitoring programs (PDMPs) to determine whether the patient has been getting prescriptions from multiple providers, EDs, or both

  
  
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  Avoiding early prescriptions and excluding any replacement of lost or stolen prescriptions

  
  
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  Requiring police reports for stolen medications

  
  
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  Performing random urine drug screens and considering consultation with an addiction specialist if true addiction to the opioid medication is suspected

Careful assessment is essential to determine the underlying cause and co-occurring physical and mental comorbid conditions that may contribute to such behavior. Reliance on patient self-reports of medication use to determine inappropriate behavior has been shown to be notoriously unreliable and inaccurate since patients tend to underestimate their medication use. Cook and colleagues found that when patients’ self-reports were compared with urine toxicology screens, the actual prevalence rate of drug use was approximately 50% higher than the estimate produced by self-reports. Berndt and coauthors also reported that 32% of patients’ self-reports of their use of medication did not match with their urine tests.

In addition, “gut feelings” by some prescribers who are confident that they can identify vulnerable individuals should be avoided since empirical evidence has shown them to be ineffective. Wasan and associates found that even though prescribers had judged only 14% of their chronic pain patients to have ADRB, approximately 50% were found to have positive urine drug screens for illicit drugs and 8.7% had no evidence of any opioids in their urine.

In an attempt to decrease the risk for opioid misuse and iatrogenic addiction to prescribed opioid medications, Gourlay and coworkers recommended establishing a policy of “universal precautions” when prescribing opioid analgesics:

• 1.
  

  Making a diagnosis with appropriate differential

  
  
• 2.
  

  Psychological assessment, including risk for addictive disorders

  
  
• 3.
  

  Informed consent

  
  
• 4.
  

  Treatment agreement (previously called an “opioid contract”)

  
  
• 5.
  

  Preintervention and postintervention assessment of pain level and function

  
  
• 6.
  

  Appropriate trial of opioid therapy with or without adjunctive medication

  
  
• 7.
  

  Reassessment of pain score and level of function

  
  
• 8.
  

  Regular assessment of the “four A’s” of pain medicine (analgesia, activity, adverse effects, and aberrant behavior)

  
  
• 9.
  

  Periodic review of the pain diagnosis and comorbid conditions

  
  
• 10.
  

  Proper documentation

Screening/Risk Tools for Substance Abuse

Screening for risk for addiction should be performed before chronic opioid therapy is initiated to provide the treating physician with clues about the necessity for increased monitoring in susceptible individuals and to assist in making the decision of whether to prescribe opioids at all. If opioid treatment results in good pain control, a better level of functioning, and improved overall quality of life, opioid treatment could reasonably be continued even in patients susceptible to addiction. However, the important point is that patients thought to be at greater risk for opioid misuse will require special attention with a focus on compliance and with proper communication about the potential risks and consequences if opioid treatment is getting out of control.

The ideal screening tool for medication misuse or abuse in patients with chronic pain should be easy to administer, reliable, and well validated. An outline of such different screening tools is summarized in Box 51.2 .

Though conceptually distinct from instruments designed to detect existing addictive disorders, measures whose purpose is to predict aberrant prescription opioid–related behavior in pain patients are closely related, with identification of similar risk factors. As a whole, this body of research is remarkably consistent in identifying the most significant risk factors for predicting prescription opioid misuse: current reports of misuse, past or current history of an addiction disorder to any substance (except perhaps for alcohol dependence in remission for several years), concurrent negative affective disorder (such as major depression or an anxiety disorder), previous or current history of sexual or physical abuse, family history of substance use disorders, and a history of illegal activities. Remarkably, ongoing pain levels have not been shown to be strong, consistent predictors of opioid misuse, albeit some misuse behavior may purely be a consequence of underdosing of opioids (pseudo-addiction).