Steven Hyman, former director of the National Institute of Mental Health (2012), argued that neuroscience research in psychiatry frequently inherits the DSM's assumption that disorders are discrete entities, even though empirical boundaries between conditions are often porous. In response, Hyman and colleagues advanced the Research Domain Criteria (RDoC), which organizes psychopathology around core neurobiological domains that cut across diagnoses. In a conceptually similar direction, Blum (1995) introduced Reward Deficiency Syndrome (RDS) as a transdiagnostic construct intended to unify substance-related and behavioral addictions. To date, PubMed includes more than 1,650 reports referencing "reward deficiency" and 281 specifically referencing RDS. Recent genome-wide association and pharmacogenomic findings in very large cohorts (88.8 million subjects) are interpreted as supporting dopaminergic dysregulation as a key phenotype underlying RDS vulnerability. The Genetic Addiction Risk Severity (GARS®) panel was developed to estimate liability for RDS and "preaddiction." Notably, many conditions listed in DSM-5 share overlapping genetic polymorphisms, with frequent convergence on pathways involved in dopaminergic neurotransmission. Building on this framework, we propose a biphasic prevention and treatment strategy for both substance (e.g., alcohol, nicotine) and non-substance (e.g., highly palatable food/glucose-related) addictive behaviors. In the acute setting, harm-reduction approaches may require targeted modulation of postsynaptic dopamine receptors (D1-D5) within the nucleus accumbens (NAc). Over longer time horizons, however, durable recovery may depend on restoring dopamine signaling-specifically, promoting dopamine activation and release within the NAc to support dopamine homeostasis. Failure to balance short-term and long-term dopaminergic interventions may contribute to affective instability, maladaptive behavior, and, in vulnerable individuals, suicidal ideation. Individuals with serotonergic/dopaminergic receptor deficits and/or high catechol-O-methyltransferase (COMT) activity may be more likely to self-medicate using substances or behaviors that transiently increase dopamine release. A growing body of evidence suggests that increasing D2 receptor expression in genetically vulnerable populations could reduce addictive risk. Although D2 agonists can downregulate receptors in vivo, in vitro work indicates that sustained stimulation may promote receptor proliferation, and gene-transfer studies producing DRD2 overexpression reduce alcohol and cocaine seeking in rodent models. Finally, naturalistic dopaminergic repletion strategies may represent a safer long-term approach to normalize dopaminergic function, support recovery, and improve quality of life across RDS-related behaviors. (WC 286).

Recent articles have suggested that the agonistic effects of GLP-1 in alcohol use disorder and substance use disorder are mediated centrally, partly through the downregulation of dopamine signaling. This hypothesis, from a consortium of multidisciplinary scientists and clinicians, explores the role of GLP-1 receptor agonists as compounds with broad antiaddiction properties. Short-term dopamine downregulation is relevant in treating metabolic disorders to reduce hyperdopaminergia, which increases insulin resistance and decreases insulin secretion. Single-nuclei transcriptomics and Fluorescent in situ Hybridization (FISH) studies revealed that GLP-1Rs are expressed primarily on GABA neurons in the VTA. Scientists using in-vivo fiber photometry found that the efficacy of a systemic GLP-1R agonist to attenuate cocaine seeking was associated with increased activity of VTA GABA neurons and decreased activity of VTA dopamine neurons. However, to our knowledge, this is the first hypothesis to expose the potential of GLP-1 receptor agonists for heightened addictive reward-seeking behavior. Therefore, we caution against promoting chronic stimulation via GLP-1 agonists. Indeed, basic research findings have linked GLP-1 receptor agonists and several genes within the dopaminergic reward pathway. Therefore, stimulation of GLP-1 receptor agonists, especially chronically, can lead to the dysregulation of the dopaminergic pathway, which in turn can putatively cause depression, suicidality, and other mood disturbances. We therefore hypothesize that while employing GLP-1 agonism offers therapeutic benefits in instances of recognized hyperdopaminergia, it could be detrimemtal in patients with hypodopaminergia at risk for SUD.

Aim : This study evaluated the Genetic Addiction Risk Severity (GARS) panel, which assesses genetic predisposition to addictive disorders by examining eleven polymorphisms in ten genes associated with dopaminergic reward system functioning. Methods : The GARS registered mark instead panel includes six single-nucleotide polymorphisms [DRD1, DRD2, DRD3, DRD4, OPRM1, and catechol-O-methyltransferase (COMT )], four simple sequence repeats (5HTT, DAT1, DRD4, and MAOA ), and one dinucleotide repeat (GABRA3 ). Criterion validity was tested in 393 polydrug abusers by correlating GARS scores with Addiction Severity Index-Multimedia Version (ASI-MV) alcohol and drug severity scores. Results : We identified a significant correlation between GARS and the ASI-MV alcohol severity score. While individuals with elevated drug severity also exhibited increased GARS, the relationship did not follow a strictly linear pattern. Variations in multiple genes involved in dopaminergic signaling contributed to risk in an additive manner, with age serving as a significant covariate. A greater number (≥ 7) of reward gene polymorphisms associated with moderate reductions in dopamine signaling demonstrated a significant association with higher ASI-MV alcohol severity scores. In contrast, individuals possessing four or more reward gene polymorphisms associated with moderate reductions in dopamine signaling exhibited significantly elevated ASI-MV drug severity scores. Conclusion: Our findings align with previous research implicating dopaminergic pathways in the progression of alcoholism and substance abuse. Additionally, they build upon prior work by identifying a potential pre-existing polygenic risk factor, as defined by the GARS panel, that may be influenced by age-related physiological changes and environmental factors. Further research is warranted to explore associated endophenotypes, with particular emphasis on the role of Reward Deficiency Syndrome linked to dysfunction within the dopaminergic reward system.

Addictions are alarmingly prevalent worldwide, leading to severe health issues, disruptive relationships, diminished productivity, and increased criminal behavior, which collectively impose substantial and tragic costs on individuals, families, and society. Addiction arises from a complex interplay of factors, including genetic predispositions, environmental triggers, and individual behavioral patterns, rendering addiction research and treatment particularly challenging. Although considerable data on the neurophysiology of addiction exists and pharmacological interventions are available, patient compliance and motivation remain crucial factors that have been relatively overlooked. Spirituality may play a significant role in fostering healing behaviors and deserves more attention in addiction treatment. Due to the unique interaction between genetic and environmental factors, healthy spirituality may come more naturally to some individuals than others. This hypothesis is supported by the literature we review, which situates spirituality within the cognitive and emotional processes of self-identity and religiosity. Evidence suggests that recovery from substance use disorders is often more successful when individuals have well-defined life goals. The brain's Default Mode Network (DMN) may be instrumental in this context. We introduce the novel concept of the Neurospirituality Connectome, which we posit as central to the understanding of reward processing. This proposed synergy between the psycho-neural substrates of cognition, emotion, and spirituality could provide a self-sustaining impetus and framework, aiding patients in navigating the complex psychophysiological landscape of addiction recovery.

In 2021, over 100,000 people died prematurely from opioid overdoses. Neuropsychiatric and cognitive impairments are underreported comorbidities of reward dysregulation due to genetic antecedents and epigenetic insults. Recent genome-wide association studies involving millions of subjects revealed frequent comorbidity with substance use disorder (SUD) in a sizeable meta-analysis of depression. It found significant associations with the expression of NEGR1 in the hypothalamus and DRD2 in the nucleus accumbens, among others. However, despite the rise in SUD and neuropsychiatric illness, there are currently no standard objective brain assessments being performed on a routine basis. The rationale for encouraging a standard objective Brain Health Check (BHC) is to have extensive data available to treat clinical syndromes in psychiatric patients. The BHC would consist of a group of reliable, accurate, cost-effective, objective assessments involving the following domains: Memory, Attention, Neuropsychiatry, and Neurological Imaging. Utilizing primarily PUBMED, over 36 years of virtually all the computerized and written-based assessments of Memory, Attention, Psychiatric, and Neurological imaging were reviewed, and the following assessments are recommended for use in the BHC: Central Nervous System Vital Signs (Memory), Test of Variables of Attention (Attention), Millon Clinical Multiaxial Inventory III (Neuropsychiatric), and Quantitative Electroencephalogram/P300/Evoked Potential (Neurological Imaging). Finally, we suggest continuing research into incorporating a new standard BHC coupled with qEEG/P300/Evoked Potentials and genetically guided precision induction of “dopamine homeostasis” to diagnose and treat reward dysregulation to prevent the consequences of dopamine dysregulation from being epigenetically passed on to generations of our children.

Millions of Americans experience pain daily. In 2017, opioid overdose claimed 64,000 lives increasing to 84,000 lives in 2020, resulting in a decrease in national life expectancy. Chronic opioid use results in dependency, drug tolerance, neuroadaptation, hyperalgesia, potential addictive behaviors, or Reward Deficiency Syndrome (RDS) caused by a hypodopaminergia. Evaluation of pain clinic patients with the Genetic Addiction Risk Score (GARS) test and the Addiction Severity Index (ASI- Media Version V) revealed that GARS scores equal to or greater than 4 and 7 alleles significantly predicted drug and alcohol severity, respectively. We utilized RT-PCR for SNP genotyping and multiplex PCR/capillary electrophoresis for fragment analysis of the role of eleven alleles in a ten-reward gene panel, reflecting the activity of brain reward circuitry in 121 chronic opioid users. The study consisted of 55 males and 66 females averaging ages 54 and 53 years of age, respectively. The patients included Caucasians, African Americans, Hispanics, and Asians. Inclusion criteria mandated that the Morphine Milligram Equivalent (MME) was 30–600 mg/day (males) and 20 to 180 mg/day (females) for treatment of chronic pain over 12 months. Ninety-six percent carried four or more risk alleles, and 73% carried seven or more risk alleles, suggesting a high predictive risk for opioid and alcohol dependence, respectively. These data indicate that chronic, legally prescribed opioid users attending a pain clinic possess high genetic risk for drug and alcohol addiction. Early identification of genetic risk, using the GARS test upon entry to treatment, may prevent iatrogenic induced opioid dependence.

This commentary explores the neurobiology of spirituality and asks whether it is possible or desirable to apply genetic engineering to increase human spiritual and religious experience - (gene-spirituality) to deal better with the ever-increasing catastrophes that face humanity? Neurological connections between spirituality and reward genes, reward deficiencies (RDS) (hypodopaminergia), the mirror neuron system, and the default mode network are examined. Some interventions from addiction medicine that may be useful to enhance the neuro-spirituality connectome identified as a cornerstone of the Purpose and Meaning of Life as Reward (PMLR) are identified as reasonable targets for interventions to treat RDS and balance DMN activity.

A recent analysis from Stanford University suggested that without any changes in currently available treatment, prevention, and public health approaches, we should expect to have 510,000 deaths from prescription opioids and street heroin from 2016 to 2025 in the US. In a recent review, Mayo Clinic Proceedings (October 2019), Gold and colleagues at Mayo Clinic reviewed the available medications used in opioid use disorders and concluded that in private and community practice adherence is more important as a limiting factor to retention, relapse, and repeat overdose. It is agreed that the primary utilization of known opioid agonists like methadone, buprenorphine and naloxone combinations, while useful as a way of reducing societal harm, is limited by 50% of more discontinuing treatment within 6 months, their diversion, and addiction liability. Opioid agonists may have other unintended consequences, like continuing the down regulation of dopamine systems. While naltrexone would be expected to have opposite effects, adherence is also low even after detoxification and long acting naltrexone injections. Recent studies have shown Naltrexone is beneficial by attenuation of craving via "psychological extinction" and reducing relapse. Buprenorphine is the MAT of choice currently but injectable Naltrexone plus an agent to improve dopaminergic function and tone may renew interest amongst addiction physicians and patients. Understanding this dilemma there is increasing movement to opt for the non-addicting narcotic antagonist Naltrexone. Even with extended injectable option there is still poor compliance. As such, we describe an open label investigation in humans showing improvement of naltrexone compliance and outcomes with dopamine augmentation with the pro- dopamine regulator KB220 (262 days) compared to naltrexone alone (37days). This well studied complex consists of amino-acid neurotransmitter precursors and enkephalinase inhibitor therapy compared to treatment as usual. Consideration of this novel paradigm shift may assist in not only addressing the current opioid epidemic but the broader question of reward deficiency in general.

The interaction of neurotransmitters and genes that control the release of dopamine is the Brain Reward Cascade (BRC). Variations within the BRC, whether genetic or epigenetic, may predispose individuals to addictive behaviors and altered pain tolerance. This discussion authored by a group of concerned scientists and clinicians examines the Genetic Addiction Risk Score (GARS), the first test to accurately predict vulnerability to pain, addiction, and other compulsive behaviors, defined as Reward Deficiency Syndrome (RDS). Innovative strategies to combat epidemic opioid, iatrogenic prescription drug abuse and death, based on the role of dopaminergic tone in pain pathways, are proposed. Sensitivity to pain may reside in the mesolimbic projection system, where genetic polymorphisms associate with a predisposition to pain vulnerability or tolerance. They provide unique therapeutic targets that could assist in the treatment of pain, and identify risk for subsequent addiction. Pharmacogenomic testing of candidate genes like CB1, mu receptors, and PENK might result in pharmacogenomic, personalized solutions, and improved clinical outcomes. Genetically identifying risk for all RDS behaviors, especially in compromised populations, may be a frontline tool to assist municipalities to provide better resource allocation.

Following 25 years of extensive research by many scientists worldwide, a panel of ten reward gene risk variants, called the Genetic Addiction Risk Score (GARS), has been developed. In unpublished work, when GARS was compared to the Addiction Severity Index (ASI), which has been used in many clinical settings, GARS significantly predicted the severity of both alcohol and drug dependency. In support of early testing for addiction and other RDS subtypes, parents caught up in the current demographic of 127 people, both young and old, dying daily from opiate/opioid overdose, need help. In the past, families would have never guessed that their loved ones would die or could be in real danger due to opiate addiction. Author, Bill Moyers, in Parade Magazine, reported that as he traveled around the United States, he found many children with ADHD and other spectrum disorders like Autism, and noted that many of these children had related conditions like substance abuse. He called for better ways to identify these children and treat them with approaches other than addictive pharmaceuticals. To our knowledge, GARS is the only panel of genes with established polymorphisms reflecting the Brain Reward Cascade (BRC), which has been correlated with the ASI-MV alcohol and drug risk severity score. While other studies are required to confirm and extend the GARS test to include other genes and polymorphisms that associate with an hypodopaminergic trait, these results provide clinicians with a non-invasive genetic test. Genomic testing, such as GARS, can improve clinical interactions and decision-making. Knowledge of precise polymorphic associations can help in the attenuation of guilt and denial, corroboration of family gene-o-grams; assistance in risk-severity-based decisions about appropriate therapies, including pain medications and risk for addiction; choice of the appropriate level of care placement (i.e., inpatient, outpatient, intensive outpatient, residential); determination of the length of stay in treatment; determination of genetic severity-based relapse and recovery liability and vulnerability; determination of pharmacogenetic medical monitoring for better clinical outcomes (e.g., the A1 allele of the DRD2 gene reduces the binding to opioid delta receptors in the brain, thus, reducing Naltrexone's clinical effectiveness); and supporting medical necessity for insurance scrutiny.

BACKGROUND:Buprenorphine and naloxone (bup/nal), a combination partial mu receptor agonist and low-dose delta mu antagonist, is presently recommended and used to treat opioid-use disorder. However, a literature review revealed a paucity of research involving data from urine drug tests that looked at compliance and abstinence in one sample. METHOD:Statistical analysis of data from the Comprehensive Analysis of Reported Drugs (CARD) was used to assess compliance and abstinence during treatment in a large cohort of bup/nal patients attending chemical-dependency programs from eastern USA in 2010 and 2011. RESULTS:Part 1: Bup/nal was present in 93.4% of first (n = 1,282; p <.0001) and 92.4% of last (n = 1,268; p <.0001) urine samples. Concomitantly, unreported illicit drugs were present in 47.7% (n = 655, p =.0261) of samples. Patients who were compliant to the bup/nal prescription were more likely than noncompliant patients to be abstinent during treatment (p =.0012; odds ratio = 1.69 with 95% confidence interval (1.210, 2.354). Part 2: An analysis of all samples collected in 2011 revealed a significant improvement in both compliance (p < 2.2 × 10-16) and abstinence (p < 2.2 × 10-16) during treatment. Conclusion/Importance: While significant use of illicit opioids during treatment with bup/nal is present, improvements in abstinence and high compliance during maintenance-assisted therapy programs may ameliorate fears of diversion in comprehensive programs. Expanded clinical datasets, the treatment modality, location, and year of sampling are important covariates, for further studies. The potential for long-term antireward effects from bup/nal use requires consideration in future investigations.

This article reviews clinical, toxicological, and legal issues related to designer drug abuse, with a focus on synthetic cathinones (bath salts). Synthetic cathinones are amphetamine-type central nervous system (CNS) stimulants that produce similar effects to amphetamine. Like amphetamine, synthetic cathinones can also result in neurological and cardiovascular side-effects consistent with sympathomimetic toxicity. The differential for a patient presenting with the signs and symptoms of synthetic cathinone toxicity is broad, and laboratory testing for synthetic cathinones is of limited value in acute management. If a diagnosis of cathinone-induced delirium is suspected, treatment efforts should focus on controlling agitation and then treating medical complications such as metabolic acidosis. Physicians should be aware of these new drugs, not only to optimally treat patients, but also to raise awareness of the dangers of designer drug use through patient counseling and community outreach programs.

There are some who suggest that alcoholism and drug abuse are not diseases at all and that they are not consequences of a brain disorder as espoused recently by the American Society of Addiction Medicine (ASAM). Some would argue that addicts can quit on their own and moderate their alcohol and drug intake. When they present to a treatment program or enter the 12 Step Program & Fellowship, many addicts finally achieve complete abstinence. However, when controlled drinking fails, there may be successful alternatives that fit particular groups of individuals. In this expert opinion, we attempt to identify personal differences in recovery, by clarifying the molecular neurobiological basis of each step of the 12 Step Program. We explore the impact that the molecular neurobiological basis of the 12 steps can have on Reward Deficiency Syndrome (RDS) despite addiction risk gene polymorphisms. This exploration has already been accomplished in part by Blum and others in a 2013 Springer Neuroscience Brief. The purpose of this expert opinion is to briefly, outline the molecular neurobiological and genetic links, especially as they relate to the role of epigenetic changes that are possible in individuals who regularly attend AA meetings. It begs the question as to whether "12 steps programs and fellowship" does induce neuroplasticity and continued dopamine D2 receptor proliferation despite carrying hypodopaminergic type polymorphisms such as DRD2 A1 allele. "Like-minded" doctors of ASAM are cognizant that patients in treatment without the "psycho-social-spiritual trio," may not be obtaining the important benefits afforded by adopting 12-step doctrines. Are we better off with coupling medical assisted treatment (MAT) that favors combining dopamine agonist modalities (DAM) as possible histone-deacetylase activators with the 12 steps followed by a program that embraces either one or the other? While there are many unanswered questions, at least we have reached a time when "science meets recovery," and in doing so, can further redeem joy in recovery.

As addiction professionals, we are becoming increasingly concerned about preteenagers and young adults' involvement with substance abuse as a way of relieving stress and anger. The turbulent underdeveloped central nervous system, especially in the prefrontal cortex (PFC), provides impetus to not only continue important neuroimaging studies in both human and animal models, but also to encourage preventive measures and cautions embraced by governmental and social media outlets. It is well known that before people reach their 20s, PFC development is undergoing significant changes and, as such, hijacks appropriate decision making in this population. We are further proposing that early genetic testing for addiction risk alleles will offer important information that could potentially be utilized by their parents and caregivers prior to use of psychoactive drugs by these youth. Understandably, family history, parenting styles, and attachment may be modified by various reward genes, including the known bonding substances oxytocin/vasopressin, which effect dopaminergic function. Well-characterized neuroimaging studies continue to reflect region-specific differential responses to drugs and food (including other non-substance-addictive behaviors) via either "surfeit" or "deficit." With this in mind, we hereby propose a "reward deficiency solution system" that combines early genetic risk diagnosis, medical monitoring, and nutrigenomic dopamine agonist modalities to combat this significant global dilemma that is preventing our youth from leading normal productive lives, which will in turn make them happier.

In this issue’s historical article, “Freeman Allen: Boston’s Pioneering Physician Anesthetist,” we learn of Dr. Allen’s many contributions to the field of anesthesiology as well as his qualities as a sensitive, moral, and highly intelligent human being.1 We also learn that he is the first documented and prominent physician anesthesiologist to become addicted to morphine. The article describes his tragic death from suicide during one of several hospitalizations for morphine addiction at Butler Hospital in Providence, RI. What do we know about substance use disorders today that we did not know in the early 1900s? In 1935, pioneers of drug abuse research began to study and treat heroin addicts at the Addiction Research Center at the Public Health Service Hospital in Lexington, KY. When Congress created the National Institute on Drug Abuse (NIDA) in 1974, the Addition Research Center was folded into NIDA’s Intramural Research Program. NIDA was created in response to the rising problem of drug abuse and addiction in the late 1960s and the resultant societal consequences. Research largely funded by NIDA has produced an explosion of knowledge in the neurobiology of addiction, as well as epidemiology, prevention, diagnosis, treatment, and monitoring of individuals with substance use disorders. We now know that addiction is not a moral deficiency but a primary chronic disease, much like diabetes.a,b In diabetes, the defective organ is the pancreas. The result is altered glucose homeostasis. Some the consequence are foot ulcers and blindness. In addiction, the defective organ is the brain. The result is altered neurotransmitter homeostasis. The consequences include lying, cheating, stealing, and general badness. The socially unacceptable behaviors associated with addiction naturally elicit a response to blame the addict for his or her behavior. However, addiction is not a disease of choice.a Addiction is a disease that impairs areas of the brain’s ability to make healthy choices. Like other chronic diseases, addiction is relapsing in nature, is rarely cured, and requires sustained treatment, including addressing the biopsychosocial and spiritual factors that influence the development and manifestation of addiction. As defined by McCauley,2 “Addiction is a stress-induced defect acting on a genetic vulnerability in the reward learning areas of the mid brain and the emotion choice areas of the frontal cortex.” The defining behaviors of addiction are loss of control, craving, compulsion, and continued use despite harm.c Addiction is considered a substance use disorder, along with illicit drug use, problematic drug use, drug misuse, and drug abuse. The DSM-5 divides substance abuse disorders into mild, moderate, and severe categories depending on how many diagnostic criteria out of 11 a given patient meets. Craving has been added as a diagnostic criteria in DSM-5, while legal issues have been eliminated.d The definition of addiction adopted by the American Society of Addiction Medicine in 2011 is an important contribution and reflects our current understanding of substance use disorders.c Genetic load accounts for about 50% of the risk of addiction.3 Additional major risk factors include Axis I/II disorders, adverse childhood experiences,4 and early initiation of substances of abuse including alcohol and tobacco.5 Contributing risk factors include poor coping skills to deal with stress, dysphoria, and anxiety as well as a lack of resilience. Traits such as impulsivity, compulsivity, control issues, risk taking, and the desire for immediate gratification can be seen in people with substance use disorders. It seems intuitive that all human beings including physicians can have risk factors for addiction. It follows that if appropriate environmental triggers are present, physicians may develop substance use disorders. It is therefore no surprise that such prominent physicians as the neurologist Sigmund Freud and the surgeon William Halsted developed substance use disorders. Both of these giants of medicine were practicing in the 1880s, Freud in Vienna and Halsted at New York’s Bellevue Hospital. Freud used cocaine as a treatment for morphine addiction, which was overprescribed then as it is now, and as a treatment for depression. Freud began to experiment on himself with cocaine. The resulting article, Uber Coca, published in 1884, described cocaine’s physiological and potential therapeutic effects but essentially ignored cocaine’s local anesthetic properties. This fascination with cocaine’s perceived positive effect on his own depression may have contributed to Freud’s abandoning basic neurobiology research and instead focusing on the human mind.6 Meanwhile Freud’s colleague at the Vienna Allgemeines Krankenhaus, Carl Koller, focused on the local anesthetic properties of cocaine for cataract surgery while working as an intern in Ophthalmology. At Bellevue Hospital, William Halsted was aware of Carl Koller’s work and began to inject cocaine into his arm. He ultimately became addicted to cocaine. Halsted was hospitalized on several occasions for cocaine addiction at Butler Hospital in Rhode Island, the same hospital where Freeman Allen was treated for morphine addiction and committed suicide. Much of what we know about William Halsted’s substance use disorder is based on a Journal of the American Medical Association article in 1969 by Penfield,7 the famous Canadian neurosurgeon, titled “Halsted of Johns Hopkins: The Man and His Problem as Described in the Secret Records of William Osler.” Sir William Osler, another renowned Canadian physician, revealed that Halsted was addicted to morphine as well as cocaine by the age of 34 when he was invited to join Osler, Welch, and Billings in what would later be called the “Big Four” founders of Johns Hopkins Medical School. At first, Halsted was given a minor appointment as Welch knew of his addiction. Eventually, this was overlooked because of Halsted’s brilliant surgical skills. Osler and Welch assumed Halsted was “cured” because of his excellent performance and promoted him to full surgeon. Osler describes that several months after Halsted’s promotion he observed Halsted in morphine withdrawal. Subsequently, Halsted admitted to not being able to wean himself below 180 mg morphine daily. The contributions to medicine and mankind of Freud, Halsted, and Allen and many other addicted physicians should motivate us to provide treatment to our colleagues with substance use disorders. We are motivated because addicted colleagues are often both personal friends and suffering patients. However, we too easily forget the substantial contributions to society by many addicted individuals, including physicians. One of the lessons of Freeman Allen’s story is that addicted colleagues, properly treated, may make lasting contributions. In light of what we know today about substance use disorders, what can we say about Freeman Allen’s struggle with his addiction to morphine? Dr. Allen had a genetic load for addiction. We know his mother was addicted to morphine. Less well known is that his uncle, Fredrick William Stowe, was an alcoholic.e Fredrick attended Harvard Medical School but left to enlist in the Union Army for the Civil War. He was wounded in the Battle of Gettysburg. Fredrick had a lifelong struggle with alcohol addiction. It appears that Fredrick was the inspiration for the character Tom Bolton in My Wife and I and We and Our Neighbors, written by his mother, Harriet Beecher Stowe. As noted on the Harriet Beecher Stowe Center Web site, “Stowe insightfully described alcoholism as an illness, at a time when most people believed it was a moral failure.”f As is common among addicts, Freeman Allen was a risk taker, exposing himself to yellow fever. Perhaps risk-taking behavior was necessary for anesthetists of his time, given the risks imposed by the limited knowledge and primitive technology applied to the profound physiologic trespass of the new discipline. We can conjecture that he was desensitized to using morphine, which he championed as a premedication for his patients. He certainly had ready access to morphine. We also know that he was despondent, depressed, and ultimately committed suicide. Little was known about substance use disorders or their treatment during his life. That is, in part, why he succumbed to his disease. So what do we know today about physicians in general, and anesthesiologists in particular, with substance use disorders? The lifetime prevalence of substance abuse disorder in the general population is approximately 10% to 14%.8–10 The lifetime prevalence in physicians is thought to be similar. This means that among the approximately 850,000 physicians and 50,000 anesthesiologists in the United States, there may be as many as 120,000 physicians and 7000 anesthesiologists who will be affected by a substance use disorder during their lifetime. If these figures are even remotely accurate, this represents an important public health issue, given the risks of being cared for by an impaired physician. The problem of substance use disorders among physicians has been addressed, in part, by the creation of physician health programs (PHPs)11 to treat affected physicians. Unfortunately, data suggest that only 1% of physicians with a lifetime prevalence of substance use disorders are referred to a PHP.12 As part of our dedication to patient safety, physicians in general, and anesthesiologists in particular, must do a better job of identifying colleagues with substance abuse disorders to facilitate intervention, diagnosis, and earlier referral to treatment. This can be accomplished, in part, by educating colleagues and their families about substance abuse disorders. There are also policies that can be put into place, such as random urine and/or hair drug testing, and mandatory drug testing when substance abuse is suspected. Knowledge and understanding of signs and behaviors that may signal a substance use disorder and active surveillance in anesthesia training programs and practice sites increase early referral and patient safety. Data suggest that anesthesiologists, emergency department physicians, and psychiatrists are overrepresented among physicians referred to PHPs.13 However, because very few physicians with substance abuse disorders are referred to PHPs, we do not know whether anesthesiologists, emergency department physicians, and psychiatrists are at a higher risk of substance use disorders, or are simply more likely to be detected (or to self-identify) and be referred for treatment. There are several unique features of substance abuse disorders in anesthesiologists. First, no other specialty has easier access to the equipment (needles, syringes) than anesthesiologists. Second, no other specialty has greater proficiency at venous cannulation. Third, no other specialty has easier access to commonly abused IV drugs, including potent IV opioids. Last, no other specialty is as skilled at precisely controlling the effects of IV opioids and other abusable drugs. This combination of access to equipment and drugs, and proficiency with both, creates a unique risk for abuse among anesthesiologists confronted with biological, psychological, social, or spiritual stressors. Occasional self-administration of IV short-acting opioids can lead to tolerance, escalating doses, and full-blown addiction in a matter of weeks to months. Death may follow quickly if the addiction is not discovered and treated. Opioid addicts often paradoxically describe opioids as energizing, which may explain why addicted physicians can appear to function well, at least initially, while actively injecting into a hidden IV port. Anesthesiologists are especially stigmatized for opioid addiction. This may be due to the fact that an anesthesiologist trusted to provide care for the patient is instead diverting the opioid from the patient, who needs opioids for analgesia, to his or her own use. The addicted anesthesiologist steals from the patient, which is a crime. This stigma causes further shame and guilt in the addicted anesthesiologist, which he or she already has no shortage of, furthering the need for relief with more opioids. Thus, the rapid downward cycle may reflect not only the pharmacology of short-acting IV opioids, but also the overwhelming psychosocial and spiritual turmoil of the addicted anesthesiologist. The unique risk factors for substance abuse disorders among anesthesiologists may explain why anesthesiologists have a much higher rate of IV drug abuse than other physicians (odds ratio, 6.3)12 when enrolled in a PHP. Fortunately, anesthesiologists in rigorous PHPs have excellent outcomes, similar to other specialties in terms of survival, abstinence, completion of monitoring, and return to work in their specialty. They are also less likely to fail a drug test during monitoring. These favorable outcomes for anesthesiologists may be due to additional features in treatment and monitoring not used for other physicians, including witnessed naltrexone administration (or more recently the advent of sustained release parenteral naltrexone), regular hair drug testing, and increased technological surveillance in the operating room suite.14 It is our view that anesthesiologists who have a substance use disorder should sign a contract with a PHP and generally undergo residential care for a minimum of 90 days in a physician-oriented program. After completing adequate treatment, the PHP provides subsequent outpatient monitoring, including appropriate drug testing, counseling, group therapy, and attendance in a 12-step–based support group such as Narcotics Anonymous for at least 5 years. It is controversial whether anesthesiologists with substance use disorders should return to work in their specialty. We recommend that each anesthesiologist be evaluated on a case-by-case basis by a qualified addictionologist with experience in treating anesthesiologists. Relapses among anesthesia providers have produced strong, even visceral reactions in the medical community. Some question whether any anesthesiologist should return to the operating room environment. We believe systematic assessment tools and clinical research should guide who should and who should not safely return to a high drug access environment. If return to work is deemed appropriate, it should be done slowly and in combination with the above steps to detect relapse and protect our patients. It is important and possible for all those suffering from a substance abuse disorder to achieve biological, psychological, social, and most importantly spiritual recovery. Quoting Dr. Thomas Hora, “all problems are psychological, but all solutions are spiritual.”15 Freeman Allen was never was given an opportunity for recovery. He died of his disease. The lesson of his tragic trajectory is that we must all be vigilant to substance use disorders in our friends, family, and professional colleagues. We owe it to ourselves. We owe it to our colleagues. Most critically, as physicians, we also owe it to our patients. DISCLOSURES Name: Gabriel Schonwald, MD. Contribution: This author helped in manuscript preparation. Attestation: Gabriel Schonwald approved the final manuscript. Name: Gregory E. Skipper, MD, FASAM. Contribution: This author helped in manuscript preparation. Attestation: Gregory E. Skipper approved the final manuscript. Name: David E. Smith, MD, FASAM, FAACT. Contribution: This author helped in manuscript preparation. Attestation: David E. Smith approved the final manuscript. Name: Paul H. Earley, MD, FASAM. Contribution: This author helped in manuscript preparation. Attestation: Paul H. Earley approved the final manuscript. This manuscript was handled by: Steven L. Shafer, MD.

This is the first quantitative analysis of data from urine drug tests for compliance to treatment medications and abstinence from drug abuse across ''levels of care'' in six eastern states of America. Comprehensive Analysis of Reported Drugs (CARD) data was used in this post-hoc retrospective observational study from 10,570 patients, filtered to include a total of 2,919 patients prescribed at least one treatment medication during 2010 and 2011. The first and last urine samples (5,838 specimens) were analyzed; compliance to treatment medications and abstinence from drugs of abuse supported treatment effectiveness for many. Compared to non-compliant patients, compliant patients were marginally less likely to abuse opioids, cannabinoids, and ethanol during treatment although more likely to abuse benzodiazepines. Almost 17% of the non-abstinent patients used benzodiazepines, 15% used opiates, and 10% used cocaine during treatment. Compliance was significantly higher in residential than in the non-residential treatment facilities. Independent of level of care, 67.2% of the patients (n = 1963; P<.001) had every treatment medication found in both first and last urine specimens (compliance). In addition, 39.2% of the patients (n = 1143; P<.001) had no substance of abuse detected in either the first or last urine samples (abstinence). Moreover, in 2010, 16.9% of the patients (n = 57) were abstinent at first but not at last urine (deteriorating abstinence), the percentage dropped to 13.3% (n = 174) in 2011; this improvement over years was statistically significant. A longitudinal analysis for abstinence and compliance was studied in a randomized subset from 2011, (n = 511) representing 17.5% of the total cohort. A statistically significant upward trend (p = 2.353 x 10(-8)) of abstinence rates as well as a similar but stronger trend for compliance ((p = 2.200 x 10(-16)) was found. Being cognizant of the trend toward drug urine testing being linked to medical necessity eliminating abusive screening, the interpretation of these valuable results require further intensive investigation.

Misuse of prescription opioids, particularly by adolescents, is a growing problem in the United States. It is a leading cause of death and disability in this age group. The primary form of treatment available to adolescents is drug free psychosocial programs. For the high risk group that has relapsed after traditional psychosocial treatment, pharmacotherapy needs to be explored. Two primary issues need to be addressed: the development of effective treatment, including the use of opiate antagonists and ongoing monitoring, and education and training of clinicians regarding appropriate prescribing practices in pain management, with better identification of those who misprescribe for personal gain.

While it is well established that the principal ascending pathways for pain originate in the dorsal horn of the spinal cord and in the medulla, the control and sensitivity to pain may reside in additional neurological loci, especially in the mesolimbic system of the brain (i.e., a reward center), and a number of genes and associated polymorphisms may indeed impact pain tolerance and or sensitivity. It is hypothesized that these polymorphisms associate with a predisposition to intolerance or tolerance to pain. It is further hypothesized that identification of certain gene polymorphisms provides a unique therapeutic target to assist in the treatment of pain. It is hereby proposed that pharmacogenetic testing of certain candidate genes (i.e., mu receptors, PENK etc.) will result in pharmacogenomic solutions personalized to the individual patient, with potential improvement in clinical outcomes.

A recent federal report indicates that prescription drug abuse is now the second leading category of illicit drug use, following marijuana use. Control strategies typically focus on reducing the diversion of prescription drugs from legitimate sources. The proliferation of unregulated Internet sources, however, has rendered control strategies less effective. This study examines a new approach that focuses on reducing abusability through the use of abuse-resistant drug designs. Drugs with and without such designs are compared and abuse levels assessed using multiple sources. In every instance, drugs employing abuse-resistant designs were found to have significantly lower levels of abuse than comparator drugs without such designs.