Risk/Benefit Discussion of Alcohol Use Disorder Medications: Behavioral Economic Considerations and General Recommendations

Background: Despite the development of several relatively safe and effective medications to treat alcohol use disorder (AUD), underutilization of these medications continues to be a challenge. With other factors, judgments about medications’ risks and benefits can influence prescribers’ practices and patients’ acceptance of these medications. Objective: Describe how behavioral economic principles and presentation of risks/benefits of AUD medications can impact these medications’ utilization and suggest guidelines for how prescribers should describe these medications to patients. Methods: Literature selected by the authors was used in this commentary and formulation of guidelines. Results: Behavioral economic principles relevant to judging risks and benefits of AUD medications include salience, recency, the halo effect, narrative thinking, avoiding cognitive dissonance, and patients’ interoceptive effects. Benefits of reduced alcohol use may be too abstract without elaboration. Medications are more likely to be taken by patients who envision their benefits as salient, prompt, and consistent with other ideas they have about their alcohol use and/or tailored to their psychological state. Explaining risks and benefits using established quantitative and qualitative terms has predictable effects on patients’ perceptions. Risk/benefit discussion should be bi-directional between patient and provider, personalized to issues valued by each patient, and tailored to the individual’s alcohol-induced state. We propose methods to improve information transfer and reduce biased decision making. Conclusion: Whether and how a risk/benefit discussion of AUD medications is conducted can influence utilization of these medications.


Introduction
Data from a recent national epidemiologic study indicate that 14% of the United States (US) population meet DSM-5 criteria for a current alcohol use disorder [AUD] [1]. Several relatively effective and safe medications have been developed to treat people with AUD [2][3][4]. To date, the US Food and Drug Administration (FDA) have approved four medications for the indication of reducing heavy alcohol drinking or promoting abstinence: orally administered disulfiram, naltrexone and acamprosate and injectable sustained-release naltrexone. In addition to these approved medications, physicians have prescribed other medications off-label for the purpose of reducing heavy alcohol use. FDA phase II randomized placebo-controlled trials have found efficacy for reducing heavy drinking or promoting abstinence for gabapentin [5][6][7] and topiramate [8][9][10][11][12][13]; baclofen was efficacious in some trials [14][15][16], but not in others [17,18].
Use of AUD pharmacotherapy varies considerably across locales, in part, due to system-level barriers such as differential access to these medications via formularies [19]. Surveys during the past 15 years have indicated that only 2-12% of AUD patients received pharmacotherapy [20][21][22], despite some increases over time [23]. The likelihood of a person with AUD being prescribed pharmacotherapy is much lower than the rate of someone with depression being prescribed an antidepressant [23,24].
There are numerous challenges translating the modest efficacy of these agents into real-world use. Individual patients may have limited coping and recovery skills and prefer psychosocial approaches to AUD medications for their AUD treatment [25]. A neurobiological framework is another way to explain limitations some patients' reluctance to adopt and adhere to treatment; e.g. neuroadaptation in the brain that determines motivation may cause avoidance of AUD medications [26]. Additionally, psychosocial factors including system of care and pharmacy formularies influence adoption of and adherence to AUD medications.
Another approach to better understand utilization of AUD medications is by analyzing the way in which prescribers and patients weigh risks and benefits, and how this discussion is presented in a way that encourage patients to take a given medication. The most commonly reported barriers among providers to prescribing AUD medications-lack of knowledge and lack of confidence in effectiveness of the drug [19,20,27]-reflect provider (mis)judgements about these medications' risks and benefits. Another reported reason for under prescribing-lack of demand by patients [20] also reflects a risk/benefit (mis)calculation.
A prescriber's risk/benefit analysis should mediate whether to prescribe a medication to a patient, and the patient's understanding of risks and benefits is likely to determine whether a patient will agree to take the prescribed medication. Behavioral economists have described how perceived gains (benefits) and losses (risks) impact decision making [28]. These principles are applicable to AUD pharmacotherapy decision-making.
Herein we suggest that it is essential for prescribers to have a carefully crafted risk/benefit explanation to present to patients. We begin by applying an extensive literature from behavioral economics about how people more generally understand potential gains and losses to how the risks and benefits of AUD pharmacotherapy are understood. We then describe the modalities used to present risks and benefits. Based on this review, we make recommendations for presenting AUD pharmacotherapies to patients, considering each patient's particular characteristics including health literacy. Table 1 list psychological principles about how potential gains and losses are weighted (by prescribers and patients) that are particularly salient for AUD pharmacotherapy.

Principle
Explanation Example of principle applied to AUD pharmacotherapy

Recency/Salience
More recent, vivid events have a disproportionate impact on decision making [1].
Side effects that occur to a person that the provider or the patient knew (compared with an anonymous patient) have a disproportionate impact on decision-making and can lead to overestimation of the risk.
Avoiding cognitive dissonance Tendency to hold ideas/beliefs that are consistent with one's actions.
Prescribers lacking knowledge about naltrexone believed that patients were not interested in it [2]. Thus prescribers' beliefs about patients' attitudes were congruent with their not learning about naltrexone.

Halo effect
Attributes are not judged separately.
Features of an object influence judgment about other features (e.g. someone who is attractive is also perceived to be nice) [3].
Prescribers make medications' risks and benefits correlate with each other in experimental paradigm [4]. Thus, patients' general attitudes towards a medication determine their weighing of individual features.

Use of schemas instead of deductive reasoning
Information is processed using mental shortcuts, preconceived ideas and ideas about how things are linked (e.g. narratives) [5]. This can result in perceiving two events that occur sequentially by chance as being causally related to each other.
People who believe addiction is caused by personal weakness hold a belief that may not support their taking AUD medications.
Framing effects (e.g. loss aversion) The displeasure associated with a loss is greater than the pleasure associated with a gain of the same amount [6]. Therefore, when the more certain choice is a substantial loss, individuals will be riskseeking.
People who perceive their alcohol use to be harming them should be more willing to gamble on taking a medication to avoid certain loss (continue to drink and its consequences), even though the medication may have risks.

Influence of interoceptive stimuli
Decision-making is impacted by one's current physical and psychological state [7,8].
Signs and symptoms of AUDs impact decision-making, e.g. people made anxious by alcohol withdrawal worry more (are more anxious about) side effects. The following psychological principles shed light on the decisionmaking that influences prescribers' utilization and patients' acceptance of medications. It is noteworthy that these behavioral economic principles can apply to any medication; however, we applied them to the specific settings and actors in AUD medication use.

Recency/salience
Recent and/or vivid events disproportionately impact decisionmaking [29,30]. A study using case scenarios and a computerized analytic model to evaluate physician decision-making concerning antihypertensive medications showed that individuals tend to anchor their decisions based on recent and/or salient experiences and suggested that the occurrence of a medication's adverse effect could influence a prescriber to abandon an useful therapeutic agent even when the likelihood of this adverse effect was rare [31]. These can lead the physician to overestimate the probability of a recent versus a distal event, and to overestimate the likelihood of vivid events compared to less distinct ones. The effects of these biased responses were corrected when physicians were given probability estimates of the efficacy and adverse effects of the medications, and their decisions became more consistent with the computerized analytic model [31]. Unfortunately, side effects of AUD pharmacotherapy can be vivid, whereas reductions in alcohol use may not be as vivid. For example, the possibility of someone taking naltrexone not being able to respond to opioid analgesics is arguably not particularly important (and can be overridden) but it is vivid.
A common error in risk estimation is to overreact to a risk that receives substantial notoriety, such as the media attention given to a boxed warning; this reflects the bias towards considering information that is most available rather than that which is most relevant [29]. For example, FDA safety warnings about suicidal ideation in adolescents treated with SSRI antidepressants have resulted in reduced prescribing for youth with depressive disorders, but an unintended consequence has been a reduction in prescribing for other age groups for whom there is no evidence of this adverse effect [32][33][34]. Other common errors are to overestimate very small risks and to underestimate large risks [35]. Additionally, a prescriber may inaccurately estimate the likelihood of a medication side effect based on the risk of other related medication that is familiar to him/her [29,35]. These particular biases can impact how prescribers select an AUD medication.
The principle of salience is particularly important for AUD pharmacotherapy and it applies to patients, too. For instance, disulfiram produces a very vivid adverse reaction when the patient ingests alcohol; therefore, many patients are unwilling to take it. Disulfiram was the only medication available to treat AUD for many years. Thus, when any other AUD medication is discussed, especially with an older patient, patients may be fearful of a disulfiram-type reaction.

Avoiding cognitive dissonance
As expected, a physician's perceptions of the effectiveness and safety of naltrexone have been shown to relate to his/her decision to prescribe [36]. In this particular study data was collected from a survey of US physicians in addiction treatment centers and it showed that physicians who did not prescribe naltrexone perceived the medication to have more side effects than those who did prescribe it and they reported patient's lack of interest as the main reason not to prescribe it. Prescribers who had access to accurate information about naltrexone were more likely to prescribe it. This study's findings suggest that believing patients are uninterested in naltrexone might be an attempt to rationalize the lack of knowledge about naltrexone and thus resolve the cognitive dissonance between prescribers' beliefs and actions. Unfortunately, people (including prescribers) tend to be overly confident about the extent and accuracy of their knowledge [29] and prescribers may change their understanding of the facts they are told to fit their firmly held, if inaccurate opinions, rather than changing the opinions.
Similar to physicians, patients also harmonize their beliefs, attitudes and decision-making to make them consistent with each other. For example, patients' positive beliefs about bupropion to facilitate smoking cessation were related to greater intentions, motivations, confidence and desire to quit smoking, as well as better treatment adherence [37].

Halo effect and narrative thinking
Individuals form general attitudes towards the potential gains and losses of a course of action, rather than mathematically weighing individual features [38,39]. A compelling demonstration that judgment of risk and benefit are not simply added mathematically is that multiple studies have found that judgments of a given treatment's risks and benefits are inversely correlated.
Activities that individuals judged to be high-risk also tended to be judged low-benefit and vice versa, as if a global judgment (halo) leads to a medication being judged as good or bad, and the judgment of risks and benefits is adjusted to better match the gestalt view of the medication. For example, students rated radiation therapy to be highrisk and low-benefit, whereas vaccines were judged to be high-benefit and low-risk, even though evidence indicates that radiation therapy has substantially greater benefit because it can cure cancer, an otherwise fatal disease [39]. This psychological study showed how perceived risk and benefit were almost unrelated when the risk level was perceived to be low or moderate; however, when the risk increased, the perceived benefit dropped substantially [39]. Applying these principles to the present context, it seems likely that when a prescriber emphasizes that the risk of AUD medication is high; this will reduce the patient's perception that the medication is effective.
When processing complex information (such as weighing risks and benefits), people are inclined to take mental shortcuts, i.e., engage in schematic thinking [40]. These mental heuristics include fitting the novel information into a narrative that incorporates their pre-existing ideas. However, this can lead to several unintended biases. For instance, in a discrete-choice study that evaluated provider decisionmaking, when a theoretical AUD medication was assigned optimal attributes, physicians still would prescribe it to only 53% of the patients [41].
This finding suggests that factors other than medication attributes are biasing prescribers away from prescribing AUD medications. These biases may include the narrative belief that people who develop AUD did so by making bad choices. The belief that patients brought about their condition may be coupled with a belief they should "fix it" on their own. This narrative leaves little place for AUD medications.

Framing effect (gain and loss frames)
The way in which health information is presented influences people's treatment choices [28,42,43]. A physician's message when introducing treatment options can have a positive "gain" frame that focuses on the advantages of stopping the risky behavior (e.g. improved health and function by ceasing heavy drinking) or a negative "loss" frame that emphasizes the disadvantages of the status quo (e.g. worsening health due to continued heavy drinking). In other types of health scenarios, a positively framed message might present the benefits of the intervention (survival rate) whereas a negatively framed message might present the risks of the treatment intervention (mortality rate).
Alcohol cessation messages have, in several studies [42,44,45], been most effective when they emphasized the gains of stopping drinking. This observation has been explained by loss aversion. The literature on decision-making suggests that individuals tend to be risk-averse (decrease risky behavior) when considering gains but are generally more willing to continue risky behavior when faced with potential losses. Therefore if a gain is made salient, people will tend to avoid risk, and when the loss is made important individuals will tend to be riskseeking [28]. Thus, prescribers may consider the patients' perspective on whether the consequence of the status quo (without medication) is seen by the patient as a likely loss or gain.
Another finding impacting choice framing is that people with AUD discount the value of future gains more than non-affected controls [46], which suggests they are particularly likely to devalue gains that only will emerge far in the future.
implication for an AUD risk/benefit discussion is that a patient who is presently craving alcohol is primed to hear the risks of AUD medications as being more salient and the benefits as less alluring. In multiple other domains, physiological conditions impact preference. High arousal (which may be associated with positive or negative affect) is associated with risk taking and low arousal with risk aversion [48]. In a different scenario, Ariely and Lowenstein found that risky and morally questionable behaviors were considered more attractive when male participants were sexually aroused than when they were not [49].
The physiological and structural changes that alcohol causes in the brain can impair rational decision-making. Decisions can become more impulsive, and more focused on the short-term at the expense of longer-term considerations [50].

Formats of medication risk presentation
The upper half of Table 2 summarizes the common formats used to present the likelihood of harms: adjectives (e.g. "common" or "rare"), numbers, and graphs/pictures [51]. Qualitative formats tend to be easily grasped, but they are imprecise leading to overestimation of the risk. For example, patients who were told that a side effect of their lipid-lowering medication was "common, " which is standardized in European Union (EU) guidelines as having an estimated frequency of 2.5%, thought the likelihood of the side effect was in fact much higher (34%) [52]; and they similarly estimated that a side effect described as "rare" (0.04% per EU verbal descriptors guidelines) occurred more frequently (18%).
Patients prefer numerical representations of the likelihood of adverse events even when the numerical format (frequency, percentage) is more difficult to understand [29,[51][52][53]. Simple frequency (e.g. 1 out of 50) is the easiest number to understand, followed by percentage [51]. Visual representation (pictograph) of frequencies-using stick figures to represent the numbers of patients affected and unaffected by side effects-results in better comprehension and recall of information [51].

What is being presented Format Illustration Impact on patient's decision Recommendation
Likelihood of side effects Qualitative (verbal): e.g. "common" or "rare" Suicidal ideation is a rare side effect of naltrexone Patients think these words connote more risk than providers intend to convey Use when exact probability of outcome is unknown

Formats of medication benefit presentation
The formats used to present risks can also be used to present benefits. The lower half of Table 2 summarizes additional formats used to present the likelihood of benefits: absolute risk reduction, relative risk reduction, and number needed to treat. Absolute risk reduction is the absolute difference between the outcome rates of the experimental (e.g. medication) group and the control group. For example, if in a study of people who all drank heavily at enrolment, naltrexone is associated with a 40% likelihood of heavy drinking after 12 weeks and placebo is associated with a 55% rate, the absolute risk reduction is 55% minus 40% equals 15%.
Relative risk reduction indicates how much risk (e.g. persistent heavy drinking) is reduced in the experimental group compared to a control group, and thus incorporates the baseline rate into the calculation. Using the example above, the relative risk reduction would be a 15% reduction in drinking divided by a 55% reduction in the control group, equaling 27%. The number needed to treat refers to the number of patients who need to be treated, compared with a control, to get the desired outcome in one patient. Number needed to treat is calculated by dividing 1 by the absolute risk reduction (in this case, 1 ÷ 15%=7). In this example, 7 people would need to be treated to see a benefit. Studies consistently report that relative risk formats produce more favorable evaluation of treatments [54], perhaps because this format involves larger absolute numbers.

Recommendations General considerations about risk/benefit ratio discussion
The following recommendations incorporate important elements from the shared decision-making model of care. This model is characterized by information and responsibility sharing between prescriber and patient, and by the patient's active engagement in discussing risks and benefits with the goal of optimizing a decision that is congruent with the patient's values and preferences [55,56]. This model has led to more accurate risk perceptions by patients, a greater number of decisions consistent with patients' values, and a reduced level of internal decisional conflict for patients [57].
It is important to present both risks and benefits of an indicated AUD medication systematically and thoroughly. Patients generally want to receive information about the benefits of their medications. In one representative study, patients in a focus group endorsed having benefits information placed in medicine leaflets, with some stating this procedure would increase their likelihood of taking the medication [53]. Medication risks are often not mentioned during medical encounters [29,58], despite the clear importance of doing so, both for patient safety and for ethical reasons (i.e., autonomy). When risks are discussed, usually they are described in non-specific qualitative formats that result in poor recall of the discussion by the patient [58]. Table 3 summarizes how to present risks and benefits to patients considering AUD medications.

Attributes to present to patients Process/communication skills Example
Pharmacological properties Consider patient's health literacy so patient understands the message "Naltrexone blocks pain receptors in your brain and cuts down craving for alcohol.
People who take it spend fewer days drinking heavily. We can start with 50 mg once a day. It can help you drink less and help you be more available to your family. The medicine will help with some of the chemical problems that alcohol use has caused in your brain, but you also have to learn to do things that will help you lead a healthy life with less alcohol".

Efficacy
Discuss efficacy for different outcomes Explain the benefits for the patient's specific complaints.

Side effects
Relate side effects to patient's personal situation "Naltrexone causes stomach upset and headache in 1 out of 10 patients. One out of 100 patients will develop suicidal thoughts and even more rarely, naltrexone can irritate the liver. We will monitor your liver with blood tests. If you have any of these problems, we will stop the naltrexone and that will almost always make the side effects go away".

Discuss likelihood and permanence
Offer solutions for possible side effects Show expertise and be available Table 3: Presentation of risk/benefit ratio of AUD medications.
When presenting information to someone with short-term memory deficits often seen with chronic alcohol use [59], providers may present the information more than once or present written materials that the patient can refer to later. Another way to bolster the patient's decisionmaking capacity, and perhaps their recovery-oriented choosing, is to conduct the risk/benefit discussion with someone whom the patient trusts to help the patient weigh these considerations. As has been shown for a variety of medical discussions [60,61], the presentation of risk/benefit will be better received if it is a bilateral discussion, rather than a speech from the prescriber.

Pharmacological properties
The physician will explain the attributes of the medication including the name, class and mechanism of action, taking into account the patient's health literacy. Avoiding medical jargon will enhance the patient's understanding. The medication recommended and its indication should be personalized to the patient's particular needs. The patient will want to know the route of administration and dosing.

Efficacy
The medication's efficacy is better understood when it is stated clearly, not only for abstinence but also for other drinking outcomes (e.g. heavy drinking days, improved liver function). This is consistent with recent changes in FDA guidance on the design of medication clinical trials that emphasize reduction in heavy drinking over total abstinence [2]. If the medication's benefits accrue at some delay after starting treatment, this should be explained.
Combining the medication's benefits with a plan for psychosocial interventions can ensure better outcomes. There are cognitivebehavioral skills (relapse prevention strategies) that will help in conjunction with the medication.

Side effects
It is necessary to disclose any regulatory warning. Clarification of permanence (side effect lasting a week or permanent), timing (at the beginning of treatment or later during treatment), and the probability of the expected outcome are of great importance [29]. The patient will appreciate if he is informed about appropriate measures to be taken to prevent or manage any adverse event. Monitoring vital signs, blood tests, and mood can minimize adverse events.
It is important that providers consider the effects of verbal, numerical or graphical representation in relation to the patient's perception of the level of risk. They can do so by choosing a risk presentation format that the patient is most likely to understand. It is important to tell the patient about side-effect management strategies they can use on their own and those for which they should call the prescriber.
The risk of leaving AUD untreated is part of the risk discussion [29]. Unchecked AUD is associated with significant morbidity and mortality and declining an AUD medication risks the psychosocial and medical consequences of drinking.

Personalization of risk/benefit ratio
A risk/benefit discussion tailored to patients' needs is optimal [29]. For example, if a patient is experiencing insomnia, in addition to urges that foreshadow relapse to drinking, the patient may prefer an AUD medication that is sedating and can be taken at night (e.g. gabapentin). This approach also takes advantage of the previously mentioned observation that AUD patients are particularly likely to value immediate (versus deferred) benefits. For other patients with ambivalence about the goal of reducing alcohol use and resistance to take AUD medications, the prescriber might use Motivational Interviewing to promote change. Prescribers can also personalize the description of side effects that are highly unlikely in a particular patient, e.g. "Naltrexone produces undesirable symptoms in patients taking opioid pain relievers, however, you are not likely to be affected by this because you don't have a disease that requires opioid pain medications". Conversely, providers will understand the risks a patient will be particularly sensitive to. For example, a patient with a cognitively demanding job may consider the risk of cognitive slowing from topiramate to be extremely distressing.
It is not uncommon for patients to form unrealistic expectations about a medication's effects. This issue has been studied with medications that promote weight loss [62]. Patients' average expectations of weight loss pharmacotherapies are that 35% of body weight will be lost, which can lead to disappointment and stopping the medication because it "isn't working. " In the context of AUD pharmacotherapy, a pivotal study of naltrexone coupled with either therapy targeted at coping with relapses or supportive therapy, the patients who were taught coping skills were less likely to relapse to alcohol use [63]. Therefore, when presenting the attributes of naltrexone, therapists aiming to minimize relapses can clarify that the medication alone is not expected to stop alcohol craving completely and that a slip to drinking does not represent a treatment failure.

Summary
Inferences from cognitive psychology and behavioral economic choice theory suggest that how risk-benefit information is presented significantly affects choices that patients and providers make about the use of AUD medications [64]. Herein, we have proposed a framework for risk/benefit discussion in the setting of AUD. Further studies are necessary to describe how prescribers currently understand the risks and benefits of each AUD-targeting medication, how they communicate them to patients, and how patients perceive the risks and benefits. Studies of structured interventions that present this information will be important to identify the best ways to ensure that patients are informed, and may change aggregate decision-making in the direction of more prescribing, initiation of, and adherence to AUD medication they communicate them to patients, and how patients perceive the risks and benefits. Studies of structured interventions that present this information will be important to identify the best ways to ensure that patients are informed, and may change aggregate decisionmaking in the direction of more prescribing, initiation of, and adherence to AUD medications.