Despite the lack of guidance available for practitioners, extensive polypharmacy has become the primary method of treating patients with severe and chronic mood, anxiety, psychotic or behavioral disorders. This ground-breaking new book provides an overview of psychopharmacology knowledge and decision-making strategies, integrating findings from evidence-based trials with real-world clinical presentations. It adopts the approach and mind-set of a clinical investigator and reveals how prescribers can practice 'bespoke psychopharmacology', tailoring care to the individualized needs of patients.
Addiction and the Reward Pathway
I have absolutely no pleasure in the stimulants in which I sometimes so madly indulge. It has not been in the pursuit of pleasure that I have periled life and reputation and reason. It has been the desperate attempt to escape from torturing memories, from a sense of insupportable loneliness and a dread of some strange impending doom.
▢ Understand the mechanics of the mesolimbic reward pathway, its dysregulation in addiction, and the rationale for pharmacotherapies targeting its circuitry
▢ Describe evidence-based pharmacotherapies and strategies for managing acute withdrawal from alcohol and controlled substances
▢ Discuss the efficacy of antidepressants, anticonvulsants, opiate antagonists, antipsychotics, and antiglutamatergic drugs for relapse prevention in chemical addictions
▢ Describe controversies and pharmacological management strategies for the phenomenon of postacute withdrawal syndromes
▢ Describe the strengths and limitations of currently available pharmacotherapies to treat behavioral addictions, including compulsive gambling
Addictions are, fundamentally, disorders of the reward pathway. Clinicians, patients or family members are sometimes dissatisfied with the pronouncement that an addiction is its own diagnosis, preferring instead to search for additional psychiatric conditions (such as mood or anxiety disorders) from which addiction behaviors might be secondary offshoots – perhaps in part because of the more extensive range of pharmacotherapy options available to treat mood and anxiety disorders than addictions. True dual diagnoses certainly exist, in which mood or thinking problems occur as free-standing entities, but unless they chronologically antecede an addiction it becomes difficult if not impossible to discriminate them from the symptoms caused by repeated intoxication and withdrawal states. Still, intrinsic disorders of the reward pathway can be complex and often inherently involve problems with mood, thinking, perception, impulse control, self-regulation, compulsivity, and a host of psychopathology dimensions described in earlier chapters. In this chapter we will focus on the pharmacotherapy of primary addictions – that is, the pathological pursuit of chemical or behavioral experiences that activate the reward pathway despite disrupting adaptation and functioning.
Some observers point out that social isolation may be a mediating factor in the pathogenesis of addiction. Preclinical studies suggest that social deprivation in early life alters synaptic plasticity in the reward pathway and may predispose to addiction (Whitaker et al., 2013).
At the risk of oversimplification, and for purposes of anticipating pharmacotherapy targets and their likely outcomes, let us grossly divide addiction behaviors into those driven by relief-seeking and reward-seeking. The former implies an internal emotional discomfort or negative affective state for which certain kinds of high-intensity chemical or behavioral stimuli are pursued mainly to alleviate distress. The latter, in contrast, bears less on seeking relief from internal distress than on procuring high-intensity positive affective states. Neuroscientists who conceptualize addictions as disorders of the reward pathway (see Figure 18.1) posit that an inordinately high threshold of dopaminergic stimulation is needed to overcome dysregulation of motivational circuitry.
Taking this model a step further, some authors (perhaps including Edgar Allan Poe, as noted above) describe dysfunction in three domains as underlying the compulsive behavior associated with addiction behavior: (1) binge-intoxication (involving DA and opioid-based circuitry in the basal ganglia (called “exaggerated incentive salience,” driving craving and the pursuit of reward)), (2) withdrawal and negative affect (involving negative emotional states and distress intolerance related to amygdala and habenula circuitry), and (3) preoccupation and anticipation (involving craving, impulsivity, and executive dysfunction, reflecting dysregulation of the PFCx and insula) (Koob and Volkow, 2016). An appeal of this model for clinicians is that it accommodates various psychiatric symptoms (anxiety, dysphoria, compulsivity, and impulsivity, among others) as it falls squarely within the addiction framework without the need necessarily to invoke additional disorders when identifying pharmacotherapy rationales and goals.
Alcohol cues (e.g., pictures) activate the ventral striatum, a phenomenon blocked by naltrexone ± ondansetron (Myrick et al., 2008).
The term “dry drunk,” originating from Alcoholics Anonymous (AA), is meant to describe individuals with the disease of alcoholism who abstain from drinking but continue to encounter problems with unmanageability (put in the language of AA) – that is, craving, emotional dysregulation, preoccupation, and interpersonal or other psychosocial consequences of past use.
Medication strategies to manage addictions are often underused, perhaps because they are limited in number and breadth of spectrum. The few that carry FDA indications for chemical addictions (none do for behavioral addictions) are limited to alcohol (e.g., naltrexone, disulfiram, acamprosate) or opiates (e.g., methadone, buprenorphine) and tend to have modest effect sizes. The evidence base for pharmacotherapies useful for other abusable substances (e.g., sedative-hypnotics, stimulants/cocaine, cannabis, hallucinogens, organic solvents) is modest, confined mostly to small proof-of-concept trials, and largely nonreplicated. Ancillary pharmacotherapies (e.g., targeting anxiety, impulse control, dysphoria, or executive dysfunction) are largely more rationale- than evidence-based. The evidence base is also unfortunately scant for treating addictions in patients with established comorbid major psychiatric disorders (e.g., alcoholism in schizophrenia or bipolar disorder; stimulant use disorders in adults with ADHD). Ancillary to pharmacotherapies and support groups such as 12-step programs for managing addictions, clinical trials also sometimes involve adjunctive behavioral interventions such as contingency management, described in Box 18.1.
Substance-abuse treatment studies often include comparisons with contingency management (CM), an evidence-based behavioral therapy involving motivational incentives (e.g., rewards such as monetary vouchers or prizes) shown to enhance retention in treatment studies of stimulant-, opiate-, cannabis-, alcohol-, and benzodiazepine-use disorders; CM also appears efficacious in nicotine dependence and weight loss/exercise programs.
We will consider each of the above issues as practical challenges, organizing our discussion around the pharmacotherapy base for specific addictions rather than overviewing every potentially relevant agent with respect to every conceivable form of addiction (but recognizing that many individuals with addictions nevertheless incur problems with more than one substance of abuse). Lastly, while DSM-5 has replaced the nosological categories of substance abuse and dependence with the overarching term “substance use disorders,” we will maintain our focus on the construct of addiction per se in keeping with the types of target symptoms described above.
Objective clinical measures are useful for tracking outcomes when targeting substance misuse as a focus of pharmacotherapy. In addition to performing random urine toxicology screens, clinical intervention studies often track variables related to the frequency and quantity of use. For example, in the case of alcohol use, common outcome measures involving consumption include:
the number of drinks per drinking day,
the proportion of heavy drinking days, and
number of drinks per heavy drinking day.
The urge to drink is often measured using the Obsessive-Compulsive Drinking Scale (Anton et al., 1996), a 14-item self-administered scale adapted from the YBOCS. It was developed based on conceptual similarities between OCD and the compulsivity and persistent urges associated with alcoholism, alongside observations that the term “craving” can be ambiguous and fails to capture the strong driving elements of urgency associated with addictions.
During acute detoxifications, objective measures (mostly reflecting autonomic parameters) include the Clinical Institute Withdrawal Assessment for Alcohol Revised (CIWA-Ar), a 10-item scale which tracks nausea/vomiting, tremor, sweating, anxiety, agitation, tactile sensations, auditory or visual disturbances, headache, and orientation, with each item scored from 0 to 7 (except for orientation, scored from 0 to 4) and a maximum score of 67 (Sullivan et al., 1989); scores of 0–8 indicate minimal withdrawal, 9–15 indicate moderate withdrawal, and >16 indicate severe withdrawal. The CIWA-Ar counterpart measure in opiate withdrawal, the Clinical Opiate Withdrawal Scale (COWS), is an 11-item scale that captures autonomic phenomena (e.g., heart rate, pupillary dilatation, tremor, piloerection) and related somatic features (e.g., yawning, bone aches, rhinorrhea) (Wesson and Ling, 2003). Scores of 5–12 are considered to reflect “mild” withdrawal, 13–24 = “moderate,” 25–36 = “moderately severe,” and >36 = “severe” withdrawal.
Laboratory markers relevant for tracking actual substance use include urine toxicology screens (summarized in Table 18.1) as well as breathalyzer tests for alcohol, which can detect alcohol for up to 24 hours. Alcohol has a half-life of about four to five hours and is metabolized at a rate of about 0.15% per hour. This means that a blood alcohol level of 0.08 (equivalent to two drinks in a 120 pound woman or four drinks in a 180 pound man) will require about five hours to clear to 0. Table 18.2 at the end of this chapter provides a summary of drugs that are commonly known to cause false-positive findings for illicit or controlled substances on commercial drug toxicology screens.
|Drug||Analyte tested||Approximate detection window in urine|
|Barbiturates||Amobarbital, pentobarbital, secobarbital (short-acting); phenobarbital (long-acting)||2–4 days for short-acting, up to 30 days for long-acting|
|Buprenorphine||Buprenorphine, norbuprenorphine||1–7 days|
|Codeine||Codeine, morphine||1–2 days|
|Ecstasy (3,4-methylenedioxy-methamphetamine; MDMA)||3,4-Methylenedioxy-methamphetamine; 4-hydroxy-3-methoxy-amphetamine (HMA)||2–4 days|
|Ethanol||Ethanol; ethyl gluconoride (EtG) or ethyl sulfate (EtS)||
|Heroin||Morphine; 6-acetylmorphine||1–3 days|
|Hydrocodone||Hydrocodone; hydromorphone||1–2 days|
|Ketamine||Ketamine, norketamine||1–4 days|
|Lysergic acid diethylamide (LSD)||Lysergic acid diethylamide||8–96 hours|
|Marijuana||Tetrahydrocannabinol||1–3 days for casual use; up to 30 days for chronic use|
|Morphine, oxycodone||Morphine||1–3 days|
|Phencyclidine||Phencyclidine||Up to 8 days in chronic users|
|False-positive findings of …||… May be caused by …|
|Amphetamines||Amantadine, atomoxetine, brompheniramine, bupropion, chlorpromazine, desipramine, desoxyephedrine, doxepin, ephedrine, isometheptene, isoxsuprime, labetolol, metformin, phentermine, phenylephrine, phenylpropanolamine, promethazine, pseudoephedrine, ranitidine, selegiline, thioridazine, trazodone, trimethobenzamide, trimipramine|
|Benzodiazepines||Efavirenz, oxaprozin, sertraline|
|Cannabinoids||Dronabinol, efavirenz, ibuprofen, naproxen, piroxicam, promethazine, proton pump inhibitors, sulindac, tolmetin|
|Lysergic acid diethylamide (LSD)||Amitriptyline, dicyclomine, sumatriptan|
|Methadone||Chlorpromazine, clomipramine, diphenhydramine, doxylamine, ibuprofen, quetiapine, thioridazine, verapamil|
|Opiates||Dextromethorphan, diphenhydramine, fluoroquinolones, naltrexone, poppy seeds, rifampin|
|Phencyclidine||Dextroamphetamine, dextromethorphan, diphenhydramine, ibuprofen, imipramine, ketamine, lamotrigine, meperidine, thioridazine, tramadol, venlafaxine, zolpidem|
a Findings as reported by Li et al., 2019
Detectable biological consequences of heavy use are available mostly in the case of alcohol. Relevant laboratory measures include serum carbohydrate-deficient transferrin (CDT), a biomarker for heavy alcohol use over the preceding two weeks (typically reflected by a %CDT >2.6). Heavy alcohol use (more than five drinks/day) interferes with the ability of hepatocytes to manufacture transferrin (an iron transport glycoprotein) with its normal complement of carbohydrate side chains (hence the name). Once a baseline CDT value is established, clinicians sometimes gauge abstinence or resumption of heavy drinking over time based on an observed CDT decrease or increase, respectively, of at least 30%. Other hepatic enzymes relevant to heavy drinking include serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Both are often elevated in the context of recent acute alcohol intoxication, with an AST:ALT ratio >2 often seen in the setting of alcoholic liver disease, particularly when accompanied by elevated gamma-glutamyl transferase (GGT; sometimes also referred to as gamma-glutamyl-transpeptidase). Additional biological stigmata of heavy alcohol use include high mean corpuscular volume (MCV) anemia.