Drug Addiction

Etiology

A complex interplay of neurobiology, genetics, and the environment accounts for the development of addiction, alcohol, and other drug use disorders. Reward activity is a piece of available evidence that supports the neurobiological underpinnings of addiction. However, observations implicating the dopamine reward system may downplay the potential contribution of learning and memory in the hippocampus and emotional regulation in the amygdala as possible etiologies in developing and maintaining an addiction.[3][4][5]

The implication of genetics across addictive behaviors was suggested via the transcription factor Delta-FosB. Delta-FosB is among the mechanisms by which the abuse of drugs can produce changes in the brain and contribute to the addiction phenotype. Delta-FosB, a member of the Fos family of transcription factors, accumulates within a subset of neurons of the nucleus accumbens and dorsal striatum after multiple administrations of illicit drugs. Studies also found a similar accumulation of Delta-FosB in the brain after compulsive running, suggesting that Delta-FosB may accrue in many types of compulsive behaviors.[6][7]

Furthermore, how individuals handle stress psychologically, physically, and biochemically plays a significant role in the context of parental use, psychological or cognitive deficits, and levels of stress.[1]

Preclinical research has shown that stress exposures, especially in early life with child maltreatment and regular adversity, enhance drug self-administration and precipitate many relapses in individuals with addiction. Specifically, there are notable changes in the corticotropin-releasing factor, the hypothalamic-pituitary-adrenal axis (CRF/HPA), and autonomic arousal.[8] In essence, stress refers to processes that involve perception, appraisal, and response to harmful, threatening, or challenging events or stimuli.[8] Stress can be helpful, and persevering through stress results in feelings of mastery and accomplishment. However, any 'stress' that is prolonged or chronic can become unpredictable and uncontrollable, resulting in a loss of sense of accomplishment or adaptability and the development of homeostatic dysregulation. This homeostatic dysregulation creates the potential for drug-seeking behaviors and possibly addiction.

Studies in Latin American laboratories highlight the association between single nucleotide polymorphisms (SNPs) in stress-related genes and addiction. SNPs may interact with stress hormones, transcription factors, and cytokines. This interaction may be a pathway to identify reliable biomarkers of vulnerability to drug abuse and relapse. Other studies also suggest that CRF receptors in the lateral septum and the ventral tegmental area (VTA), specifically the CRF2-alpha-R isoform, are a potential therapeutic target for drug addiction. The Wnt family of secreted glycolipoproteins and their interplay could explain the interaction between stress and addictive behavior. Researchers also studied the cannabinoid system as a promising target for stress-induced relapse on drugs.[9]

In summary, addiction consistently finds roots in stressful contexts, particularly when prolonged throughout early childhood. Environmental risk factors such as impulsivity, inadequate parental supervision, and delinquency are common across chemical and behavioral expressions of addiction. Studies suggest that individuals who engage in one problem behavior are likely to engage in another problem behavior. Sociodemographic risk factors related to poverty, geography, family, and peer groups also influence the onset and course of substance and non-substance addiction.

Epidemiology

A study in 2005, reflecting on the 2001 National Household Survey of Drug Abuse, found that out of 55561 subjects, 33576 reported alcohol use within the past year. Ultimately, the study found a slightly higher prevalence of abuse-to-dependence in males and females with (2.1 to 1) and (1.6 to 1).[10] Per a research study in 2014, 7% of the American population meets the criteria for the diagnosis of alcohol misuse or alcoholism.[10] In 2010, the World Health Organization (WHO) estimated about 208 million people worldwide have alcohol use disorder. In 2016, globally, alcohol dependence was the most prevalent substance use disorder, but the most common drug use disorders in 2016 were cannabis and opioids. Amphetamine and cocaine use was less frequent.[11]

Designer drugs are illicitly produced chemical analogs to preexisting psychoactive or analgesic molecules. These drugs are more potent than known controlled or uncontrolled substances. There is a growing international concern that designer drugs are manufactured and distributed to circumvent drug laws and evade interdiction.[12] Designer drugs keep changing depending on the location. Among them are the following:

• Synthetic stimulants like bath salts, a synthetic cathinone
• A synthetic version of tetrahydrocannabinol (THC) called k2 or spice
• A norepinephrine-dopamine reuptake inhibitor and a member of the cathinone and pyrovalerone classes called flakka
• Synthetic designer hallucinogens called N-bomb and solaris[12]
• Synthetic opioid-non-fentanyl derived ones, such as U-47700, called "U4," "pink," or "pinky, U-49900, AH-7921, or MT-45[13]
• Methylenedioxy-derivatives of amphetamine and methamphetamine

The most used chemical is 3,4-methylenedioxymethamphetamine (MDMA-ecstasy).[14] The use of designer drugs is mostly encountered among young males who are 15 to 25 years old and who frequent clubs, raves, and house parties. In 1993, the National Institute on Drug Abuse survey reported an estimate of 2% of all American college students admitted to using MDMA in the previous 12 months.[12] Several studies estimated that 6% to 17% of American college students had used synthetic cannabinoid drugs at least once.[15] Around 1% of young Europeans between the ages of 14 and 18 used synthetic cannabinoid drugs at least once in their lifetime.[16]

Deaths by overdose were increased by adulterants in products sold as heroin or as counterfeit painkillers in North America and Canada. In a city like Miami, there was an increase of 600% in fentanyl-related deaths reported from 2014 to 2015. Fatalities from these novel synthetic opioids were also reported in North America, Latin America, Canada, Asia, Europe, and Africa.[17][18]

Abuse of prescription medicines involves:

• Central nervous depressants (benzodiazepines, non-benzodiazepines, and barbiturates).
• Prescription opioids (hydrocodone, oxycodone, fentanyl, and codeine).
• Prescription stimulants (dextroamphetamine, dextroamphetamine or amphetamine combination product, and methylphenidate).

Deaths from prescription opioid overdose were 5 times higher in 2016 than in 1999. In 2012, the National Center for Health Statistics reported that pain relievers (opioids) were involved in more "drug poisoning deaths" than heroin and cocaine.[19]

Around 9.7% of students in grades 7 to 12 reported using dextromethorphan recreationally in 2013, compared with 6.9% in 2011, based on the Ontario Student Drug Use and Health Survey. Most of the calls to poison control were related to dextromethorphan, which involved adolescent males.[19] Acetylsalicylic acid (ASA) or acetaminophen use of more than 4 g per day for an extended time is considered misuse.[20]

Extracts of many leaves have been found to possess a powerfully addictive substance. One such example is an extract from the Mitragyna speciosa (kratom) tree. Kratom is the subject of attention worldwide. Reports suggest that calls to poison centers related to kratom use, by year, increased from 2010 to 2015. Kratom (M speciosa) misuse appears to be rising in the Western world at an alarming rate, with reported deaths.[21]

Pathophysiology

The pathophysiology of addiction revolves around the concepts of synaptic plasticity, specifically long-term potentiation (LTP) and long-term depression (LTD). Long-term potentiation is the phenomenon of strengthened neural connections over time and with increased stimuli. Long-term depression is the decrease in the responsiveness of a neural signal with stimulation. These are the same processes involved in learning and habit formation. The biochemical proof in drug addiction is founded in the same molecules undergoing upregulation in both cases—extracellular signal-regulated protein kinase (ERK), cyclic AMP response element-binding (CREB), ELK-1, and Fos.[22] Rats treated to suppress ERK stopped preferring the caged area with cocaine over the caged area with normal saline.[22] Eventually, CREB, ELK-1, and Fos decreased, each known to be involved with LTP and drug misuse.[22]

Biochemical studies have shown the involvement of a dynorphin A (DYN) and K-opioid receptor (KOPr) system.[23] This system is found throughout the brain and spinal cord. Specifically, KOPr is found within brain circuits that regulate mood and motivation through dopaminergic and glutamatergic neurotransmitters. Studies have shown that dysregulation in this system has led to not only the anhedonia and depressive symptomatology of withdrawal but also drug-craving and drug-seeking behaviors.[23] These 2 systems are involved in addiction development. Further research continues to study the process of addiction.

Furthermore, research indicates that dopamine is a critical player in terms of neurological changes in the brain of an individual with addiction. A quick and significant rise is associated with the onset and maintenance of an addiction.[24] As the habit becomes chronic, dopamine decreases and eventually changes the prefrontal region of the brain, specifically the orbitofrontal cortex and cingulate gyrus.[24]

Toxicokinetics

Being the most common and costly intoxication, it is essential to review the toxicokinetics of alcohol intoxication. Upon intake, alcohol begins metabolism with extensive first-pass metabolism catalyzed by the enzyme alcohol dehydrogenase (ADH).[25] While all the cells in our body can metabolize alcohol, most occur in the liver with ADH and CYP2E1 (though CYP450 enzymes are inactive until reaching chronic abuse or ingesting substantial amounts). Ethanol is metabolized initially to acetaldehyde, which gets further metabolized in mitochondria to acetate via acetaldehyde dehydrogenase. While acetate enters the peripheral circulation for utilization in various reactions as the key intermediate acetyl CoA, acetaldehyde forms in addicts, causing injury by activating immune processes.

This reaction finds particular relevance in alcoholic liver disease as ADH and ALDH1 reduce all stores of NAD+ to NADH. The eventual damage is the result of reactive oxygen species (ROS). Typically, glutathione (GSH) stores neutralize ROS, but alcohol depletes GSH stores, leaving ROS unchecked. For example, ROS interacts with lipids to undergo lipid peroxidation, resulting in malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE), which can form protein adducts.[25] Thus, alcohol metabolism, specifically through the generation of ROS and depletion of reducing agents such as GSH, causes damage to multiple organs in the body, such as the liver, lungs, muscles, and brain.[25]

For reference, the average rate of alcohol metabolism is 7 g/h or roughly one drink/h.

History and Physical

History and physical examination of individuals with addiction vary depending on the type of addiction, substance ingested, time since ingestion, and route. For example, most forms of alcohol intoxication present with slurred speech, ataxia, and impaired judgment. Depending on the dose and time frame of ingestion, this process can quickly spiral toward CNS depression, coma, and multiorgan failure. This progression applies to ethanol, methanol, isopropanol, and ethylene glycol.

Regarding cocaine and other stimulants, expect an acute patient with anxiety, potential psychosis, and sympathetically-driven vital signs (tachycardia, tachypnea, high blood pressure, etc).[26] Management begins with decreasing stress, stabilizing vitals, and preparing rapid response teams for deteriorating patients.

Also, significant variations are based on the stage of addiction and addictive substances.

The 5 stages of addiction are as follows:

1. First Use: These are naïve patients because they have not yet felt the effects of their substance. It could be a new pain medication prescription or peer-pressure-imposed experimentation.
2. Continued Use: Individuals begin to return to a medication they no longer “need” but want as they notice the post-high sensation does not clear as quickly.
3. Tolerance: Patients in this stage realize they need large doses of the drug to feel prior levels of high.
4. Dependence: Patients begin to show physical signs of withdrawal from discontinuing use. In addition, patients do not feel “normal” without their substance.
5. Addiction: These patients can be on one of 2 sides of the coin. They may be distressed by continued use but require it despite serious life problems that have resulted, or they may be in denial of the addiction and continue to spiral further.

The above descriptions of stages reveal the expected presentation of the addicted patient. History and physical examination will vary based on the stage of the condition. When presenting, a first-use patient is not in acute distress (barring active trauma or chronic pain) or has physical withdrawal signs. The tolerant patient will typically present with a story that necessitates increasing the dose of medication or an unexpected refill. The patient with full addiction can present in acute withdrawal with symptoms that vary based on the substance. Alcohol withdrawal will present with signs of autonomic dysregulation to the most worrisome, delirium tremens and seizures.[27]

Evaluation

Lab values (blood and urine), imaging, and specific tests vary depending on the cause of the addiction. If it is a psychoactive substance, there may be apparent derangements in the comprehensive metabolic panel (CMP) and complete blood count (CBC) values, as well as in the psychoanalysis and behavioral screening. The following is an abbreviated list of commonly used substances:

1. Alcohol
   1. CBC – Chronic use can cause an elevated mean corpuscular volume (MCV) with megaloblastic anemia from folate deficiency.[28]
   2. CMP – Blood urea nitrogen/creatinine ratio (BUN/Cr) may be above baseline, glucose may be chronically low, and electrolytes may be deranged from dehydration.
      1. The anion gap is elevated in acute intoxication with a decreased CO₂ and decreased bicarbonate, reflecting an acidotic state.
   3. Methanol is the same with an addition of ophthalmologic issues.[29] It requires regular and serial eye examinations in the emergency department.
   4. Ethylene glycol leads to renal failure, necessitating serial BUN/Cr levels and GFR to monitor renal function; oxalic acid kidney stones commonly result in bloody urine on urinalysis (UA).
2. Cocaine: An apparent sympathetic drive is expressed through elevated vitals. Patients are typically tachycardic and tachypneic. In addition, patients may present with acute psychosis. Intoxications may necessitate serial troponins, cardiac stress tests, and cardiac catheterization.[30] Due to the vasoconstriction of coronary vessels, troponins are regularly elevated.
3. Opioids: Opposite to stimulants like cocaine, opioids present with parasympathetic symptoms such as bradycardia, hypotension, miosis, hypothermia, and sedation. The worrisome factor is sedation, leading to respiratory depression.

Please refer to the clinical pearls section for detailed screening criteria, such as CAGE, AUDIT, and the CIWA criteria.

An evaluation commonly used for addiction screening is the Addiction Severity Index (ASI). The screening evaluates 7 domains:

1. Medical status
2. Employment and support
3. Drug use
4. Alcohol use
5. Legal status
6. Family/social status
7. Psychiatric status

The screening does not cover all special populations, such as the homeless; it is extensively cross-reviewed to show significant reliability and validity as the foundation of treatment plans for patients with addiction.[31]

Imaging

Although not routine in clinical practice, imaging may be integrated into the evaluation panel of addiction. Researchers found that reduced dopamine (DA D2) receptors correlated with decreased activity in the anterior cingulate gyrus and orbitofrontal cortex in detoxified cocaine abusers.[32]

Liquid Chromatography, Mass Spectrometry, and Ion Mobility Spectrometry

Some substances, such as kratom and bath salts, are unidentifiable on a regular urine drug screen or blood work. Techniques such as liquid chromatography, mass spectrometry, and ion mobility spectrometry (IMS) are helpful.[21]

Treatment / Management

Intoxications go hand-in-hand with addictions as they can either be the subject of the addiction or the propelling factor toward behavioral disruptions and suicidal tendencies. Further management involves monitoring and maintaining the patient's vital signs. This is dependent on the stage of presentation of the patient and the subject of the addiction. Multiple pharmacological treatments are available for the 2 most common substance addictions (tobacco and alcohol), such as group meetings and psychological and social support.

Pharmacologically, alcohol dependence is treatable with disulfiram, naltrexone, and acamprosate.[33] Each has its place in alcohol dependence and addiction. Disulfiram is effective in managing a patient who recently quit and needs help maintaining abstinence, as any consumed alcohol causes relatively quick hangover-type symptoms to deter further drinking. Naltrexone removes the sensation of reward or pleasure with drinking, and acamprosate minimizes the initial withdrawal symptoms. Alcohol intoxication during episodes of relapse is treatable with long-acting benzodiazepines such as chlordiazepoxide or diazepam.[34](A1)

For tobacco dependence, there is currently bupropion and varenicline. Off-label uses exist for drugs like clonidine, an alpha-2 agonist for managing high blood pressure. Also, there is nortriptyline, a member of the TCA class of antidepressants. Both of the latter drugs are effective if started before quitting. As for bupropion, the pill cuts down the craving for tobacco.[35] Varenicline helps curb the craving for nicotine as well as decrease withdrawal symptoms.[35] Along with these options are nicotine patches, gums, sprays, and lozenges.

Ultimately, however, these pharmacological interventions are combined with non-pharmacological methods for optimal efficacy and to limit and prevent substance use from developing into misuse to dependence. For example, regarding nicotine dependence, pharmacological treatments employed with the clinician's advice and empathy result in approximately double the long-term abstinence.[35]

Of interest, more people have overcome their addiction than those enrolled in a program (eg, 12-step, CBT).[36] For these reasons, consideration is necessary to treat an individual with addiction or not. If one plans to initiate treatment, a joint plan involving the patient's input yields better results.

Differential Diagnosis

In terms of addictions, the differential should include ruling out the root causes of the addiction. Potential root causes are as follows:

Bipolar disorder – more than half of patients with substance abuse disorder have bipolar disorder, and significant mood fluctuations can present in the patient.[37]

Post-traumatic stress disorder (PTSD) – common concurrence among alcohol abusers. PTSD should be screened in all addicts. While the 2 are different conditions with separate signs and symptoms, treating the cause of PTSD can mitigate or eliminate the underlying addiction.

Since most cases of intoxication involve episodes of altered mental status, a helpful mnemonic for the emergency department physician is the following:

• A - alcohol
• E – encephalopathy (hypertensive, hepatic), electrolytes, endocrine, environmental
• I – insulin
• O – opiates, oxygen
• U – uremia
• T – trauma, toxins
• I – infection, increased intracranial pressure
• P – psychosis, poisoning, porphyria
• S – stroke, shock, seizure

Staging

Stages of addiction: refer above to the history and physical discussion to review the steps of addiction.

Stages of recovery and change from addiction include:

1. Precontemplation: the patient still has yet to acknowledge the problem
2. Contemplation: the patient has recognized the problem but not yet dealing with it
3. Preparation: the patient makes an appointment to discuss receiving help
4. Action: the patient begins treatment to reach and maintain abstinence
5. Maintenance: the patient has become abstinent and is maintaining positive coping strategies
6. Relapse: during the maintenance phase, patients may fall into the relapse stage from time to time and restart the recovery process [38]

Prognosis

The evidence is quite clear on the long-term effects of drug dependence, with those diagnosed dying 22.5 years earlier than those without the diagnosis. This lifespan is related to the toxic effects of substances on multiple systems, including, but not limited to, the cardiac, respiratory, and neurological systems. Also, a 5-year study on alcohol and drug rehabilitation treatment found that older adults have favorable long-term outcomes versus young adults, especially older women, who had 52% 30-day abstinence rates versus a 40% younger adult rate.[39][40] Factors such as social networks and gender play a role alongside age in these numbers.

Based on the current research on addiction, practitioners need to shift the management of patients from an acute paradigm to a chronic disease paradigm.[39] Furthermore, we must bolster the condition's screening, intervention, and overall management. Urgency is necessary for this shift as 6.9 million, or 2.8% of the US population, have the mortality risk associated with illicit drug use.[39] However, before any change gains traction, current research must bolster the evidence of decreased mortality with decreases in the prevalence and incidence of addiction.

Currently, there is a clear relationship between the changes in mortality risk and when patients begin treatment.[39] The prognosis depends on these factors.

Complications

Regarding chronic alcohol use, Wernicke encephalopathy and Korsakoff syndrome are expected complications. The Wernicke encephalopathy consists of the triad of confusion, ophthalmoplegia, and ataxia (though usually, only one is present 20% of the time).[41] Classic findings on CT and MRI scanning include atrophy of the bilateral mammillary bodies and hippocampal areas.[41]

Hepatic steatosis is a common complication of chronic alcohol use that results from cholesterol esters, phospholipids, and triglycerides formed ultimately from alcohol-induced ROS formation, altering lipid metabolism. Chronic heavy alcohol consumption is the most critical risk factor for chronic pancreatitis. The process begins with acute heavy consumption, which, through the toxic effects of alcohol metabolism, induces inflammatory and fibrotic changes in the pancreas over time. Specifically, the pancreatic stellate cells are activated, resulting in the expected fibrotic changes.

Cardiomyopathy is another documented complication expected due to chronic alcohol use resulting from oxidative stress, disruptions in proper calcium handling, and mitochondrial dysfunction.[42] Cocaine addiction and intoxication lead to myocardial ischemia, psychosis, and fatal arrhythmias that require acute management to mitigate effects.[43] From a behavioral perspective, addiction leads to multiple episodes of withdrawal and relapses.