Pain and Addictive Disorders: Challenge and Opportunity

Neurobiology of Addiction

Over the past several decades, basic and clinical research has uncovered neuroscientific explanations of SUDs. These explanations challenge stereotypes that invoke moral weakness as a reason for drug addiction and instead provide scientific reasons for addiction, offering guideposts to treatment-seeking patients and their doctors.

Addictive substances, including opioids, cocaine, amphetamine, ketamine, nicotine, and marijuana, exert powerful effects on dopaminergic neurons, which produce euphoric states exceeding what is typically produced by endogenous levels of dopamine. These sharp increases in feelings of reward can be associated with the environmental stimuli that surround drug use. With chronic drug exposure, wear and tear on dopaminergic neurons begin to suppress the experience of reward itself, which in turn drives craving, anticipation, and the need for more drugs to satisfy drug urges. ^, Notably, individuals with addiction are frequently confused by their ongoing use of drugs that no longer provide pleasure. Addiction can then be understood as a motivational push to avoid the discomfort associated with dysregulated reward circuity and the distress caused by feelings of being without sufficiently numbing, activating, or altering drugs. ^,

In the last decade, a useful heuristic has been developed that delineates the neuroanatomy, circuits, and signaling molecules involved in the cycle of addiction from stages of binge/intoxication to withdrawal/negative affect to preoccupation/anticipation. The delineation of these separable, tractable circuits and the signaling molecules involved establishes a framework for researchers to identify therapeutic targets, potential medications, validated animal models, and clinical trials to test new pharmacologic interventions based on rational therapeutic targets. ^, This heuristic has had critical epistemologic value for the field researchers, clinicians, and patients—and is worth reviewing here.

In the binge/intoxication phase of addiction, drug use is motivated primarily by positive, rewarding experiences subserved by the ventral and dorsal striatum, globus pallidus, and thalamus. Illicit drugs powerfully activate neurons in these brain regions with no connection to purposeful behavior. This overstimulation leads to progressive and insidious dysregulation of the brain’s natural reward mechanisms. Over time, there is a downregulation of positive reward pathways, and increasing drug levels are needed to trigger the brain reward system. Animal and human studies have shown that long term exposure to drugs of abuse impairs dopamine neurons and dopamine signaling in the nucleus accumbens. This effect appears to be mediated by the actual physical shrinkage of dopamine neurons in response to chronic drug administration. This underlying neuroanatomic change reduces the capacity for reward and leaves the addict “unrewarded,” amotivational, and often depressed in the absence of a drug. Research has shown that drugs of abuse decrease the size of dopamine neurons in the ventral tegmentum and nucleus accumbens by depriving the neurons of the crucial nerve growth factor, brain-derived neurotrophic factor. What started off as euphoria in response to unanticipated reward turns over time into overwhelming behavior-modifying drug craving.

During the withdrawal-negative-affect stage, the dopamine systems are compromised, contributing to dysphoric mood states while simultaneously assigning greater salience to drugs and drug related stimuli in the context of these aversive states, and healthy rewards lose motivational power as they fail to satisfy. Drug consumption triggers much smaller increases in dopamine levels in the presence of addiction (in both animals and humans). Over time, the attenuated release of dopamine renders the brain’s reward system much less sensitive to stimulation by both drug related and non drug related rewards. Individuals with addictions often seek a more potent release of dopamine in more explicitly risky settings. The human costs to relationships, community, and vocation increase as the drug produces less euphoria. Adaptations in the circuitry of the extended amygdala in the basal forebrain lead to the emergence of negative emotions.

During the preoccupation-anticipation stage, those with addiction desire and pursue drug use. This stage of the addiction cycle is characterized by chronic relapse frequently triggered by the long term effects of drugs of abuse on the basolateral amygdala, hippocampus, and prefrontal cortex. ^, Notably, the hippocampus is a target of opioid receptor agonists, such as morphine, methadone, heroin, and various short-acting opiates. The opioid system within the hippocampus underlies context-associative learning, which is essential for linking drugs with a particular place and set of events. In addition, chronic drug use impairs the prefrontal cortex and the capacity for self-regulation, decision making, and flexibility. Together, these combined effects in the amygdala, hippocampus, and prefrontal cortex explain how earnest plans to cease substance use are upended by desire, environmental context, and impulsivity.

Finally, in addition to direct brain effects of drugs of abuse, considerable evidence from population-based studies supports a positive association between psychosocial adversity, chronic distress, and addiction. The contribution of stressors to substance use appeared to occur in a dose-dependent manner. Repeated or chronic prolonged stress can induce lasting changes in stress responsivity and the magnitude and duration of stress hormone response to a stressor, which in turn increases the risk of stress-related disorders and addiction. Similar to drugs of abuse, stress exposure increases dopamine release in the nucleus accumbens. Given that both drugs of abuse and stress activate mesolimbic pathways, each results in synaptic adaptations in the ventral tegmental area dopamine neurons and the prefrontal cortex. While persistent and poorly controlled responses to environmental challenges contribute to the persistence of and relapse to self-administration of drugs of abuse and addiction, it is clear that vulnerability to drug use and relapse may exist prior to the use of addictive drugs on a genetic or acquired basis-histories of childhood neglect and abuse, for example, may lead to the acquisition of addiction because of underlying baseline differences in stress responsivity. ^{, ,}

Misconceptions About Physical Dependence and Addiction

Many persons with SUDs report that compared with their first use, they increased the amount of the substance over time to obtain the same effect, or that the amount of the substance used to produce the effect no longer does (i.e. tolerance). They also may report that upon abrupt cessation of substance use, their bodies exhibit a characteristic pattern of symptoms (i.e. withdrawal). Withdrawal symptoms vary according to the category of substances involved (e.g. alcohol and opioids). According to the DSM-5, an individual who takes the substance (or a similar substance) to relieve or avoid withdrawal symptoms is also considered to have met the criterion for withdrawal. Depending on the severity of the addiction and the type of substance, withdrawal symptoms can range from relatively mild (e.g. headache because of caffeine withdrawal) to life-threatening (e.g. seizures because of alcohol withdrawal). However, the presence of tolerance or withdrawal, which are hallmarks of physical dependence, is not associated with the presence of a SUD. Tolerance and withdrawal are related to pharmacologic properties. Both tolerance and withdrawal can occur when patients take prescription medications as prescribed (e.g. anti-depressants and anxiolytics). Consequently, the DSM-5 specifies that for those prescribed opioid analgesics and who take them as prescribed (in the absence of other illicit opioid use), tolerance and withdrawal should not be counted toward the number of criteria needed to meet the diagnostic threshold for OUD.

Opioids

A systematic review estimated that 8%–12% of those on LTOT met the criteria for OUD and 21%–29% met criteria for “opioid misuse.” Conversely, the rate of chronic pain among patients with OUD entering opioid agonist treatment is high, with estimates varying between 37% and 61% who report chronic pain.

Tobacco

Tobacco use is common among those with chronic pain, with prevalence estimates as high as 50% (twice that of the general population). Relatedly, nearly 60% of individuals with tobacco use disorder also experience chronic pain. In a nationally representative sample of 9,282 United States adults, respondents with lifetime chronic neck or back pain were 1.3 times more likely to smoke cigarettes than the general population, 1.8 times more likely to be diagnosed with a lifetime nicotine use disorder, and 2.4 times more likely to meet the criteria for past year nicotine use disorder. Previous research supports the theory that pain may contribute to the development of tobacco use problems, and that tobacco use, in turn, may contribute to the development of painful conditions such as back pain or rheumatoid arthritis.

Cannabis

Approximately 36% of those on LTOT report cannabis use, while as many as 15% of primary care patients report past 30 day cannabis use. Because of the rapidly expanding legalization and availability of cannabis, cannabis use disorder (CUD) is increasingly common in the general population, although the prevalence of CUD among those with chronic non-cancer pain has been understudied. One study identified that the rate of CUD in patients hospitalized for chronic pain increased from 1.9% in 2011 to 3.0% in 2015.

Alcohol and Sedatives

An estimated 25% of patients seeking treatment for pain report moderate to heavy alcohol use. In the general population, those with chronic neck or back pain compared to those without are nearly twice as likely to meet the criteria for alcohol use disorder. Alcohol has been linked to worse pain outcomes, such as increased pain disability and intensity. An estimated 9%–11% of those with chronic pain who are treated in a primary care setting meet the criteria for a sedative use disorder. ^,

Stimulants

Chronic pain may be associated with an increased risk of stimulant use. Among a national sample of adults, stimulant use was almost twice as prevalent among those with versus those without chronic low back pain (cocaine: 22% vs. 14%; methamphetamine: 9% vs. 5%). A prior study of attendees at an outpatient pain management clinic estimated that the rates of cocaine and methamphetamine use were 5% and 2.5%. Importantly, stimulants and opioids influence dopaminergic receptors in the central nervous system either by activating the dopamine receptors directly or by way of the opioid receptors. For this reason, there is an enhanced risk of addiction and adverse events among those who concurrently use stimulants and opioids.

Chronic Pain Among Patients With SUDs

A recent study of participants in a large academic healthcare system found that most of those with SUD had chronic pain (opioid, 75%; cannabis, 64%; alcohol, 59%; tobacco, 60%). Other studies have found that patients receiving opioid agonist treatment with co-occurring chronic pain frequently report using tobacco and alcohol as well as non-medical use of cannabis, opioids, and benzodiazepines to manage pain. ^, Given the extent of the co-prevalence of chronic pain and addiction, it behooves pain providers and addiction providers to be knowledgeable about both chronic medical conditions.