Addiction and Substance Dependence

In an effort to use a common taxonomy, the American Society of Addiction Medicine, the American Pain Society, and the American Academy of Pain Medicine formed a consensus panel to define tolerance, physical dependence, and addiction. They adopted the following definition :

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.

Since the biologic changes that are the essence of addiction are not clinically detectable, the diagnosis must be based on behavioral abnormalities and patient reports. The current standard criteria for substance dependence are those of the DSM-IV ; however, these criteria will be obviated by the publication of DSM-V, scheduled for May 2013. The DSM-IV term substance dependence disorder closely approximates what is generally considered to be addiction; nonetheless, accurate diagnosis is contingent on attention to the paragraph preceding the bulleted criteria, which requires “a maladaptive pattern of substance use” that leads to “clinically important distress or impairment.” Without this, many nonaddicted patients receiving COT would meet the criteria for a substance use diagnosis. These and other criteria not only risk diagnosing addiction in its absence but can also contribute to failure to diagnose the condition when present because the detrimental effects of drug use on lifestyle and psychosocial functioning may be less evident in pain patients and, when they do occur, are likely to be ascribed to pain rather than to drug use.

The proposed DSM-V criteria for “opioid use disorder” will require a maladaptive pattern of use leading to significant impairment or distress, as manifested by at least two of the following occurring within a 12-month period (the criteria have been abbreviated) :

• 1.
  

  The opioid is often taken in larger amounts or over a longer period than intended.

  
  
• 2.
  

  There is a persistent desire or unsuccessful efforts to cut down or control use.

  
  
• 3.
  

  A great deal of time is spent on activities necessary to obtain, use, or recover from the effects of the opioid.

  
  
• 4.
  

  Recurrent use results in failure to fulfill major role obligations.

  
  
• 5.
  

  Use is continued despite persistent or recurrent social or interpersonal problems caused or exacerbated by the substance.

  
  
• 6.
  

  Important social, occupational, or recreational activities are reduced because of use.

  
  
• 7.
  

  Use occurs in situations in which it is physically hazardous.

  
  
• 8.
  

  Use is continued despite knowledge of a persistent or recurrent physical or psychological problem likely to have been caused or exacerbated by the opioid.

  
  
• 9.
  

  Tolerance is present (not counted for those taking medications under medical supervision).

  
  
• 10.
  

  Withdrawal occurs (not counted for those taking medications under medical supervision).

  
  
• 11.
  

  There is craving or a strong desire or urge to use the opioid.

There are many idiosyncratic definitions created by governmental and health-related organizations. For example, the Controlled Substances Act defines an “addict” as a person who “habitually uses any narcotic drug so as to endanger the public morals, health, safety, or who is so far addicted to the use of narcotic drugs as to have lost power of self-control with reference to his addiction.”

Physical Dependence

It must be emphasized that “drug dependence” is not synonymous with “physical dependence,” which is normal and to be expected with prolonged use of opioids and does not indicate the presence of any disorder. In fact, physical dependence, as manifested by withdrawal on administration of naloxone, can be elicited in normal subjects following a single dose of morphine, which confirms that this phenomenon is not useful as a diagnostic criterion in patients taking prescribed opioids.

Physical dependence is neither necessary nor sufficient for the diagnosis of SUD. It commonly occurs with substances that lack addictive potential and is universal in those taking significant doses of prescribed opioids or benzodiazepines on a continuous basis. It is said to be present if a withdrawal syndrome occurs on cessation of use, dose reduction, or administration of an antagonist. Physical dependence can be a major issue in addiction to opioids and alcohol, is minimal with cocaine and amphetamines, and is absent in addiction to hallucinogens and inhalants. It can be a major problem with discontinuation of such nonreinforcing substances as paroxetine, venlafaxine, some antiepileptics, clonidine, and baclofen.

Tolerance

Tolerance is a state of adaptation in which exposure to a substance induces physiologic changes that diminish its effects. It develops more rapidly in some individuals than in others. It develops with effects such as sedation from antiepileptics, nausea from serotonin-norepinephrine reuptake inhibitors, and hypotension from clonidine. Tolerance usually develops rapidly to opioid-induced sedation, itching, and nausea and more slowly to analgesia and may not develop at all to constipation. Because of tolerance, patients who take a stable dose of opioids on a scheduled basis can usually safely return to work and drive.

Analgesic tolerance is one of the reasons that opioids are more effective for acute than for chronic pain. Clinically, patients who have severe pain despite high doses of opioids often report that low to moderate doses of opioids initially produced satisfactory analgesia. It is important to explain tolerance to patients. They should understand that efforts to regain initial analgesia through repeated dose escalation can lead to falls, fractures, and fatalities, as well as side effects such as low testosterone and opioid-induced hyperalgesia. Strategies for reducing tolerance include opioid rotation and the addition of adjunctive medications that are opioid sparing.

Pseudoaddiction

Pseudoaddiction describes a state in which inadequate analgesia leads to behavior that mimics addictive behavior. This drug-seeking behavior improves when the pain is controlled. Although the concept is simple, in practice, both undermedicated patients in pain and patients with actual addiction may be drug seeking, and both cease drug seeking, at least transiently, when their needs are met. So the distinction is often made with difficulty and usually in retrospect (i.e., when the patient’s behavior normalizes for an extended period after adequate pain control is provided).

Drug Misuse

Drug abuse and misuse are defined in various ways that have in common the fact that the drugs either were not prescribed or were used in a manner different than instructed. They differ from addiction in that those who abuse drugs can choose to quit in the event of adverse consequences. The term chemical coping has been used to describe persons who use opioids to ameliorate uncomfortable emotion. For example, opioids may reduce fear of cancer. They temporarily decrease depression, anxiety, anger, and symptoms of post-traumatic stress disorder (PTSD). In fact, there is some evidence that PTSD may share a common neurobiology with addiction, which in part accounts for their high comorbidity (for review, see Logrip and colleagues ).

Addiction and Substance Dependence

In an effort to use a common taxonomy, the American Society of Addiction Medicine, the American Pain Society, and the American Academy of Pain Medicine formed a consensus panel to define tolerance, physical dependence, and addiction. They adopted the following definition :

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.

Since the biologic changes that are the essence of addiction are not clinically detectable, the diagnosis must be based on behavioral abnormalities and patient reports. The current standard criteria for substance dependence are those of the DSM-IV ; however, these criteria will be obviated by the publication of DSM-V, scheduled for May 2013. The DSM-IV term substance dependence disorder closely approximates what is generally considered to be addiction; nonetheless, accurate diagnosis is contingent on attention to the paragraph preceding the bulleted criteria, which requires “a maladaptive pattern of substance use” that leads to “clinically important distress or impairment.” Without this, many nonaddicted patients receiving COT would meet the criteria for a substance use diagnosis. These and other criteria not only risk diagnosing addiction in its absence but can also contribute to failure to diagnose the condition when present because the detrimental effects of drug use on lifestyle and psychosocial functioning may be less evident in pain patients and, when they do occur, are likely to be ascribed to pain rather than to drug use.

The proposed DSM-V criteria for “opioid use disorder” will require a maladaptive pattern of use leading to significant impairment or distress, as manifested by at least two of the following occurring within a 12-month period (the criteria have been abbreviated) :

• 1.
  

  The opioid is often taken in larger amounts or over a longer period than intended.

  
  
• 2.
  

  There is a persistent desire or unsuccessful efforts to cut down or control use.

  
  
• 3.
  

  A great deal of time is spent on activities necessary to obtain, use, or recover from the effects of the opioid.

  
  
• 4.
  

  Recurrent use results in failure to fulfill major role obligations.

  
  
• 5.
  

  Use is continued despite persistent or recurrent social or interpersonal problems caused or exacerbated by the substance.

  
  
• 6.
  

  Important social, occupational, or recreational activities are reduced because of use.

  
  
• 7.
  

  Use occurs in situations in which it is physically hazardous.

  
  
• 8.
  

  Use is continued despite knowledge of a persistent or recurrent physical or psychological problem likely to have been caused or exacerbated by the opioid.

  
  
• 9.
  

  Tolerance is present (not counted for those taking medications under medical supervision).

  
  
• 10.
  

  Withdrawal occurs (not counted for those taking medications under medical supervision).

  
  
• 11.
  

  There is craving or a strong desire or urge to use the opioid.

There are many idiosyncratic definitions created by governmental and health-related organizations. For example, the Controlled Substances Act defines an “addict” as a person who “habitually uses any narcotic drug so as to endanger the public morals, health, safety, or who is so far addicted to the use of narcotic drugs as to have lost power of self-control with reference to his addiction.”

Physical Dependence

It must be emphasized that “drug dependence” is not synonymous with “physical dependence,” which is normal and to be expected with prolonged use of opioids and does not indicate the presence of any disorder. In fact, physical dependence, as manifested by withdrawal on administration of naloxone, can be elicited in normal subjects following a single dose of morphine, which confirms that this phenomenon is not useful as a diagnostic criterion in patients taking prescribed opioids.

Physical dependence is neither necessary nor sufficient for the diagnosis of SUD. It commonly occurs with substances that lack addictive potential and is universal in those taking significant doses of prescribed opioids or benzodiazepines on a continuous basis. It is said to be present if a withdrawal syndrome occurs on cessation of use, dose reduction, or administration of an antagonist. Physical dependence can be a major issue in addiction to opioids and alcohol, is minimal with cocaine and amphetamines, and is absent in addiction to hallucinogens and inhalants. It can be a major problem with discontinuation of such nonreinforcing substances as paroxetine, venlafaxine, some antiepileptics, clonidine, and baclofen.

Tolerance

Tolerance is a state of adaptation in which exposure to a substance induces physiologic changes that diminish its effects. It develops more rapidly in some individuals than in others. It develops with effects such as sedation from antiepileptics, nausea from serotonin-norepinephrine reuptake inhibitors, and hypotension from clonidine. Tolerance usually develops rapidly to opioid-induced sedation, itching, and nausea and more slowly to analgesia and may not develop at all to constipation. Because of tolerance, patients who take a stable dose of opioids on a scheduled basis can usually safely return to work and drive.

Analgesic tolerance is one of the reasons that opioids are more effective for acute than for chronic pain. Clinically, patients who have severe pain despite high doses of opioids often report that low to moderate doses of opioids initially produced satisfactory analgesia. It is important to explain tolerance to patients. They should understand that efforts to regain initial analgesia through repeated dose escalation can lead to falls, fractures, and fatalities, as well as side effects such as low testosterone and opioid-induced hyperalgesia. Strategies for reducing tolerance include opioid rotation and the addition of adjunctive medications that are opioid sparing.

Pseudoaddiction

Pseudoaddiction describes a state in which inadequate analgesia leads to behavior that mimics addictive behavior. This drug-seeking behavior improves when the pain is controlled. Although the concept is simple, in practice, both undermedicated patients in pain and patients with actual addiction may be drug seeking, and both cease drug seeking, at least transiently, when their needs are met. So the distinction is often made with difficulty and usually in retrospect (i.e., when the patient’s behavior normalizes for an extended period after adequate pain control is provided).

Drug Misuse

Drug abuse and misuse are defined in various ways that have in common the fact that the drugs either were not prescribed or were used in a manner different than instructed. They differ from addiction in that those who abuse drugs can choose to quit in the event of adverse consequences. The term chemical coping has been used to describe persons who use opioids to ameliorate uncomfortable emotion. For example, opioids may reduce fear of cancer. They temporarily decrease depression, anxiety, anger, and symptoms of post-traumatic stress disorder (PTSD). In fact, there is some evidence that PTSD may share a common neurobiology with addiction, which in part accounts for their high comorbidity (for review, see Logrip and colleagues ).

Cross-Addiction

A tenant of most addiction treatment and education is the concept that a person addicted to one reinforcing substance is at high risk for addiction to all such substances and should therefore abstain even from substances that have never been problematic. This caution is based on two considerations: (1) a person who takes an intoxicant is less able to resist other temptations (e.g., a person working on nicotine abstinence is more likely to relapse after a few drinks), and (2) the neurologic changes that occur with addiction appear to be common to most substances (i.e., the changes in people with alcohol dependence and those with opioid dependence are similar). Thus, it makes sense to caution those attempting to recover from opioid dependence to avoid alcohol, benzodiazepines, carisoprodol, and illicit substances. Unfortunately, there are few data to confirm these beliefs other than the high prevalence of polysubstance abuse or dependence, which shows that people who develop one SUD often develop several (see Compton and colleagues ).

Iatrogenic Addiction

Although COT can cause physical dependence, trigger relapse in those recovering from addiction, and elicit addiction in some, it is clear that preexisting vulnerability plays a critical role in this process. Early in the last century it was often believed that anyone who used opioids chronically became addicted. However, the distinction between physical dependence and addiction was not appreciated and therefore addiction rates were probably exaggerated.

Until recently, many believed that addiction was rare in those who took long-term opioids to treat pain, unlike those who sought euphoria or relief from emotional distress. Now, concern is being raised that opioid therapy is causing a wave of addiction. Probably much of the uncertainty and disagreement relate to the distinction between those who have an addiction and are treated with COT versus those who have an addiction because they were treated with COT. The ambiguity surrounding triggering addiction versus triggering relapse is also a confounder.

Even though most pain specialists believe that iatrogenic addiction is uncommon, there are few data to determine its exact incidence. Extant studies are largely poorly done and brief. Accurate data are frequently difficult to obtain, and there is often ambiguity not only about the presence of addiction but also about the time of its onset. It is widely believed that the risk for inducing an addictive disorder with short-term opioid therapy is extremely low, around 3 per 1000. However, there seems to be no data on this question beyond two very old studies, both widely cited and widely criticized on methodologic grounds. Nonetheless, clinical experience supports their findings in that it is quite rare to see patients in whom iatrogenic addiction has developed as a result of brief treatment. Unfortunately, these early studies addressing acute opioid therapy have been cited as evidence of the safety of chronic opioid therapy, which they did not address.

Iatrogenic Relapse

Several studies suggest that the vast majority of patients who manifested addiction while being treated long-term with opioids had preexisting drug or alcohol disorders. For example, in a retrospective study of 48 patients hospitalized for addiction to oxycodone (OxyContin), Potter and associates found that 77.1% reported previous nonopioid substance use problems (including alcohol) and 48% had prior problems with other opioids. Similarly, an older study of 200 patients with chronic low back pain found that substance abuse preceded the pain in 94% of those with both conditions. In a highly selected group of patients undergoing pain rehabilitation, our group found that of those with an addictive disorder, medical exposure was responsible in 33%, recreational use in 64%, and undetermined causes in 3%. Needless to say, the proportion of patients in a pain clinic who became addicted medically would be much higher than the proportion in the community.

It seems that most patients thought to have iatrogenic addiction instead had a recreationally induced addiction that transformed into prescription use or were abstinent addicts who relapsed on re-exposure to opioids. The latter is predictable given that animal and human studies have demonstrated that one of the most powerful stimuli for eliciting resumption of dormant drug-seeking behavior is re-exposure to the drug of choice. A recovering heroin addict came to our attention who had maintained sobriety for longer than 1 year until exposed to intravenous midazolam for procedural sedation. He experienced an immediate onset of drug craving, subsequently obtained and injected heroin, to which he was no longer tolerant, and died. Studies are lacking to clarify the risk for relapse if, for example, a patient who has been sober from alcoholism for a number of years is exposed to COT. However, based on animal studies and observation, most addiction specialists believe that ingestion of alcohol or any reinforcing drug may increase craving for the addict’s drug of choice and other reinforcing drugs.

The brain changes that underlie addiction are multifactorial, and it appears that the development of addiction is a function of the molecule involved, dose administered, duration of use, genetic and personal vulnerability, and perhaps route and rate of administration. Thus, in a patient with no predisposition, COT would be unlikely to trigger addiction, whereas in those with high vulnerability, addiction might develop easily and early. Such patients would be likely to have a history of nicotine dependence or overuse of alcohol or other substances.

In addition to vulnerability and length of exposure, the substance itself plays a role. For example, drugs that rapidly and markedly increase dopamine (e.g., crack cocaine) often produce addictive behavior quickly. Other drugs, such as alcohol, seem to take much longer for most. Furthermore, the delivery system plays a role, with slow-onset preparations such as chewed tobacco or coca leaves producing addiction more slowly than cigarettes or smoked cocaine. This suggests that opioids that rapidly enter the central nervous system (CNS), such as fentanyl given by the intravenous or transmucosal route, may be more likely to trigger addiction or relapse than the same molecule administered transdermally.

Screening and Universal Precautions

Appropriate screening takes considerable time, which can lead providers to neglect it. A self-report questionnaire can facilitate this task and help ensure adequate information to guide the prescriber. If the state has an electronic prescription-monitoring program (42 of 50 do so as of this writing ), this should be reviewed and compared with the patient’s information. One of the most valuable ways to detect addiction is by interviewing the patient’s relatives or significant others. They may be both more honest in revealing signs of addiction and more aware than the patient of such issues as drug-induced sedation, cognitive impairment, and changes in personality.

Legitimate patients (as opposed to scammers) generally understand that prescription opioids are a public health concern and that prescribers have a responsibility to mitigate societal risk. Patients should be informed of clinic rules and philosophies before the initial prescription. Some find it helpful to frame the first appointment as a screening and compatibility visit and to make it clear that controlled medications will not be prescribed on the first visit.

Gourlay and colleagues developed guidelines for opioid prescribing that they liken to the universal precautions used for infection control. The rationale is that providing the same standard of care to all patients minimizes risk to both the patient and provider. The guidelines recommend that such things as thorough assessment, documentation, testing, and follow-up standards be applied to all who are prescribed COT, regardless of perceived risk for aberrant behavior ( Box 50.1 ).

Screening for Liability to Addiction

Instruments have been devised to alert the clinician to the likelihood that a patient has or is at risk for drug-related difficulties ( Box 50.2 ). Positive screening does not necessarily exclude patients from opioid therapy; rather, it identifies those who have a lower than usual benefit-to-harm ratio and who therefore require more thorough assessment, closer monitoring and accountability, and possibly referral for addiction treatment. Simple questioning may fail to reveal SUDs because of concealment, unawareness, or forgetfulness on the part of patients. In a study of 109 patients with CNCP, Berndt and associates found that 32% of the toxicology results were discordant with patients’ reports and that 21% concealed drug use.

The Screener and Opioid Assessment for Patients with Pain (SOAPP) comes in 5-, 14-, and 24-question versions, in addition to the Revised SOAPP (SOAPP-R). These questionnaires assess the risk for prescription opioid abuse. The test may be used in conjunction with other information to help assess patient suitability for COT, as well as to identify the need for more intense monitoring. The drug abuse screening test (DAST), though not developed for patients taking prescribed drugs, does contain several items that screen for drug use problems. The SOAPP-R and the Opioid Risk Tool (ORT) are widely used to help assess the risk for aberrant opioid use behavior in patients being considered for a trial of COT. The ORT is a questionnaire that asks yes or no questions about risk factors such as family and personal substance abuse history, age, preadolescent sexual abuse, and psychological comorbidity. Though brief and easy, the questions are not disguised and stand out as screening questions and thus may invite dishonesty if the patient is seeking to obtain controlled medications.

Unlike these self-report instruments, the Diagnosis, Intractability, Risk, Efficacy (DIRE) score is a tool for use by clinicians to aid in determining the risks and benefits likely to accrue from COT. A comparison of these screens suggests that all have value and are most useful when supplemented by clinical interview.

Red Flags

The dividing line between characteristics that predict substance use and those that ascertain its presence is somewhat arbitrary. All the signs are clinically important.

Toxicologic Studies

It is necessary to verify that patients are taking prescribed medications and not using illicit drugs. Urine drug testing (UDT) and hair testing can help provide this information and assist the patient in maintaining compliance by providing accountability. Additionally, UDT results can be of value to patients who need to document treatment adherence for reasons that range from child custody to probation. An excellent primer of UDT is available in a monograph prepared for the California Academy of Family Physicians that is available online. It is important to understand the limitations of the testing used, and most companies have experts available to assist in interpretation.

In clinical practice, UDT is the mainstay because it is relatively inexpensive and noninvasive and provides a reasonable window of detection. The initial office screening test is usually an immunoassay. These “dipsticks” are economical and consist of antibodies that react with the drug or its metabolite. A positive test can be confirmed with gas chromatography–mass spectrometry or equivalent testing. Standard tests, such as the Substance Abuse and Mental Health Services Administration’s standard workplace drug panel (SAMHSA 5), are often insufficient in the pain clinic setting because of limited detection capability. The SAMHSA 5 detects only marijuana, cocaine, morphine, phencyclidine, and amphetamines. Heroin and codeine are metabolized to morphine and are therefore detected; however, synthetic and semisynthetic opioids are not. Other screening tests are available that may include methadone, propoxyphene, benzodiazepines, barbiturates, and EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine)—a methadone metabolite.

UDT can lead to erroneous conclusions for several reasons. Immunoassays are vulnerable to cross-reactivity; for instance, decongestants may test as amphetamines. Misleading results can occur when a prescribed substance is converted to another nonprescribed substance (e.g., hydrocodone and morphine can be converted to hydromorphone ). Spurious results can also occur from the consumption of legal substances; for example, poppy seeds contain morphine and some nasal inhalers contain l-methamphetamine.

In contrast, a finding of cocaine or THC is reliable and, in the case of THC, cannot be caused by being in a room in which a great deal of marijuana is being smoked. A urine screen that fails to contain a prescribed opioid may indicate diversion, but it can also mean that the patient exhausted the supply of medication several days before the test or that the patient used someone else’s urine to conceal the use of illicit drugs.

It is helpful to have a breathalyzer available since alcohol is often not detected by urine drug testing. Ethyl glucuronide testing is widely available and can detect alcohol consumption for the previous 3 days; however, the test is so sensitive that exposure to alcohol from mouthwash or hand cleaner can produce a positive result. If levels exceed 500 ng/mL, deliberate alcohol ingestion is probable.

Drug testing should be performed before initiation of COT and randomly during treatment. Importantly, testing should not be limited to patients suspected of abuse because this strategy is open to bias (e.g., disproportionate testing of minorities) and has been shown to miss 50% of those using nonprescribed or illicit drugs.

Even though there are safeguards, urine drug screens can be defeated. “Clean” urine may be obtained via the Internet or from friends and delivered by ingenious worn devices that are difficult to detect even with direct observation. These devices can even maintain urine at an appropriate temperature, typically, 90° F to 100° F within 4 minutes of voiding.

The most common strategy for avoiding detection is to dilute the urine through aggressive fluid ingestion or by adding tap water. Therefore, reasonable care should be taken that the sample is not obtained in a room with access to water for dilution and that the color and temperature are appropriate. Urine creatinine, specific gravity, and pH should be determined.

Hair and saliva testing is now available. Hair testing is extremely accurate and virtually impossible to defeat and can detect use in the past 2 or more months since hair grows about half an inch per month. Recent use will be missed because it takes about 1 week for hair to grow from the follicle to a length at which it can be collected. THC levels are relatively low in hair follicles in comparison to most other drugs, and occasional use can be missed. Hair testing cannot be defeated by coloring or bleach since the chemicals tested are at the core. If scalp hair is absent, body hair may be used. The cost of hair testing is no longer prohibitive, and its use in monitoring is increasing. For example, the Florida Physicians Health Program has used hair testing to monitor recovering physicians since 2006.

It is reasonable for the clinician, without getting into a dispute about patients’ rights to use substances or the benefits of “medical marijuana,” to make access to opioid therapy contingent on the patient’s willingness to produce urine that is free of illicit substances. This can be presented in a nonjudgmental manner as a way to ensure the patient’s access to treatment and the provider’s continued ability to prescribe. If the person is unwilling to relinquish recreational use, it suggests that the pain problem does not warrant COT. If the patient is unable to relinquish the drugs, addiction treatment is indicated.