A Perfect Platform: Combining Contingency Management with Medications for Drug Abuse

Abstract

Contingency management (CM) procedures, which provide concrete reinforcers or rewards contingent on verification of discrete targeted behaviors, such as drug-free urines, have been demonstrated to be effective in a number of clinical trials. However, to date there have been only a few that have capitalized on the unique strengths and capabilities of CM as an ideal platform to improve response to or address weaknesses of many pharmacotherapies used in the treatment of drug abuse. In this review, we describe the multiple potential uses of CM as a platform for pharmacotherapy, including reducing illicit drug use in the context of agonist therapies; fostering medication compliance with antagonists, aversive agents and HIV medications; fostering a period of abstinence prior to initiation of agents used to treat comorbid psychiatric conditions or in the context of vaccines to foster adequate periods of abstinence while titer levels are building; and to enhance the effectiveness of anticraving agents through additive or synergistic effects. Although its multiple strengths render it an almost perfect platform, CM does have some weaknesses that have limited its use to date, including cost, the short-term nature of its effects, and need for training. Future treatment development of CM as a medication platform needs to counter these issues by focusing on CM applications with large potential benefit, developing simple or automated methods for CM delivery and placing greater emphasis on the process of transitioning away from formal CM treatment.

There has been enormous progress in recent years in the identification of empirically-supported behavioral (1) and pharmacological (2, 3) treatments for a range of drug use disorders. However, despite growing consensus that combined treatments are often the more effective than monotherapies (4, 5), the bulk of the literature is based on trials in which a single treatment is systematically varied, and simultaneous testing of combined treatments is comparatively rare (6). There remains much room for improvement, however, as even for our most effective therapies response is often only partial or transient for many patients, while others fail to respond at all. Furthermore, the potential effectiveness of many behavioral and pharmacologic strategies is undercut by poor compliance (e.g., attrition, not taking medication as prescribed, not following through on treatment goals) in many patients. Thus, combined approaches incorporating both behavioral and pharmacologic strategies are generally seen as more effective than single approaches (7, 8); when combined behavioral and pharmacologic strategies may address a broader range of symptoms and problems and may complement each other by addressing the relative weakness of either treatment delivered alone (9, 10). For example, addition of a supportive behavioral therapy may encourage a patient to persist with pharmacotherapies that take several weeks to exert their effects or which cause unpleasant symptoms or adverse effects; conversely, provision of a stabilizing medication may foster retention in a behavioral therapy until trust is developed or the patient's cognitive state has improved enough to benefit from a behavioral approach.

The article by Moeller and colleagues in this issue (11) is one of only a handful of studies using combined behavioral and pharmacologic therapies, in this case contingency management (CM) and citalopram. CM approaches provide rewards or incentives for verifiable, targeted behaviors, such as take-home doses for methadone maintained patients who abstain from cocaine (12, 13), vouchers redeemable for goods and services to cocaine users who provide drug free urine samples (14, 15), and variable-ratio reinforcement of abstinence (low-cost contingency management) where patients can earn the opportunity to draw lots for prizes contingent on abstinence (16, 17).

CM interventions are among the most powerful interventions for substance abuse and have the unique advantage in that they can be used to target very specific goals and thus can be used in pharmacotherapy trials to address specific weaknesses of medications (18–20). However, they remain highly underutilized both in clinical practice and as a potential platform for pharmacotherapy trials (6); the Moeller article is one of only a handful that have used CM as a platform. Thus, in this article, we will attempt to identify ways to build on the comparatively sparse literature on CM combined with medications for addictions by (a) identifying promising targets for CM, (b) reviewing the challenges to applying CM as a pharmacotherapy platform and for medication compliance enhancement and (c) suggesting directions for refinements of CM that combat these challenges.

The great strength of CM is its ability to make a strong impact on a circumscribed set of well-defined behaviors. As a component of drug abuse treatment, the target behaviors fall into three general categories (detailed examples are presented below): First, CM can be used to address substance use itself (most commonly detected with biological assessments such as urine specimens collected frequently enough to detect new occurrences of substance use). In this strategy, CM is used to interrupt or reduce substance use, and when combined with pharmacotherapy, may have additive or synergistic effects. For example, a medication may be more effective among patients who have significantly reduced or stopped their drug use than those who continue to use. Second, CM can be used to reinforce specific treatment goals, such as attending counseling sessions or completing specific activities associated with getting a job (e.g., preparing a resume, going to interviews) (21–23). In extended trials where it may be difficult to encourage patients to continue to attend data collection sessions, CM has been used specifically to reward patients for attending consecutive assessment sessions, for completing all scheduled follow-up evaluations and to reduce the rate of no-shows at assessment sessions (24). The third general target behavior is in treatment compliance, and, in particular, compliance with medications. Because CM can be used to directly reinforce medication compliance, it can substantially improve compliance in medication trials or treatment where compliance is not strongly reinforced by benefits rapidly derived from the treatment itself (23, 25).

Pharmacotherapy in the Treatment of Addictions

Pharmacotherapies for substance use disorders are a growing part of the treatment regimen although still only utilized by a minority of substance abusers in treatment (26–28). The role of medications in treatment of addictions include (a) drugs to reduce substance use including agonists (e.g., methadone for opioids), antagonists (e.g., naltrexone for opioids), aversive agents (e.g., disulfiram for alcohol), and anti-craving agents (e.g., naltrexone for alcohol, buproprion for nicotine), (b) HIV treatments (e.g., Highly Active Anti-Retroviral Therapy [HAART] for HIV positive individuals) and antibiotics (e.g., anti-tuberculosis regimens), and (c) medications to treat comorbid mental disorders (e.g., antipsychotics, antidepressants).

Compliance enhancement is particularly salient for substance-abusing populations because of generally low or mixed motivations to curtail substance use in the majority of treatment seeking patients (29), high rates of HIV and other infections in substance abusers (30, 31), and high rates and negative prognostic significance of comorbid psychopathology in substance abusing patients (32–34). Factors underlying poor compliance among substance using patients include (a) lack of immediate benefit from taking the medication, (b) ambivalence about giving up drugs, (c) adverse reactions, (d) need for protracted treatment, and (e) complexity of dosing schedules (35).

The most salient limitation of most of these types of medications is the lack of immediate rewarding effects. Medications prescribed for drug abusers generally represent the converse of abused substances in terms of the immediacy of positive reinforcement. Abused drugs tend to have immediate positive effects followed by delayed adverse effects. With few exceptions, prescribed medications provide either no immediate reward or cause initial side effects and generate positive reinforcements that are delayed and/or subtle. For medicines prescribed with the aim of curtailing or reducing drug use, the immediate effect on the addict is to take away a valued reinforcer. One exception to the tendency to provide delayed benefits is the group of agonist treatments, in which a longer acting agent is substituted for an abused substance that has greater short term effects. Agonist agents are well-accepted by substance abusers and no studies have evaluated CM to enhance medication-taking for agonist treatments, although CM has frequently been combined with methadone maintenance in order to reduce use of illicit opiates (e.g., 12, 13). Other medications that provide relatively rapid reinforcing benefits are painkillers and quick-acting antibiotics.

In the sections below, we will review how CM has been combined with agents for drug reduction (agonists, antagonists, and anti-craving agents, respectively, as well as treatment for HIV and other medical conditions, and comorbid psychopathology). We will review the literature evaluating CM in combination with each of these types of medications for drug abuse with attention to the targets chosen for the CM intervention: a) drug use reduction, b) achievement of treatment goals, and c) medication compliance.

Medications to Reduce Drug Use

Agonists

The bulk of the large body of literature on the effectiveness of methadone maintenance points to the success of methadone maintenance in retaining opioid addicts in treatment and reducing their illicit opioid use and illegal activity (36, 37). However, there is a great deal of variability in the success across different methadone maintenance programs, which is likely to be the result of variability in delivery of adequate dosing of methadone as well as variability in provision and quality of psychosocial services (36, 38). Methadone maintenance, especially when provided at adequate doses and combined with drug counseling, substantially decreases illicit opioid use, injection drug use, criminal activity, and morbidity and mortality risk (36, 38, 39). However, there are several problems with methadone maintenance, particularly diversion as well as concurrent use of other substances such as cocaine, benzodiazepenes, and alcohol.

These practical problems with methadone maintenance led directly to the first applications of CM to address the specific weaknesses of a pharmacotherapy. Capitalizing on the availability of naturally-occurring, low-cost reinforcers in this context, Stitzer, Bigelow, and their colleagues first evaluated the efficacy of providing access to take-home methadone contingent on the provision of drug-free urine specimens (12, 40) and have also demonstrated the value of other low-cost reinforcers such as contingent methadone dose increases (13). Silverman and colleagues subsequently demonstrated the efficacy of voucher-based contingencies to reduce cocaine use in the context of methadone maintenance (41, 42) as well as the effectiveness of a therapeutic work place, where methadone maintained individuals with chronic employment problems had access to paid employment contingent on submission of drug free-urine samples (43, 44). Svikis and colleagues have used CM to reduce illicit drug use among pregnant and post-partum women enrolled in methadone maintenance. Thus, provided that CM interventions are appropriately implemented (clear behavioral targets, immediate reinforcement, consistent monitoring, adequate levels of reinforcers), they are remarkably consistent and effective means of reducing drug use in the context of methadone maintenance (see meta-analysis by Griffith et al. (18), Lussier et al. (23), and Prendergast et al. (25).

Antagonists and Aversive Therapies

Unlike agonist therapies, which are inherently reinforcing and thus desirable to take, a major problem with available antagonist and aversive agents has been with compliance. The need for CM to reinforce medication compliance is hence most marked for those agents that are highly effective in producing abstinence, like naltrexone for opioid dependence and disulfiram for alcoholism. Both of these agents require detoxification prior to use and both more or less preclude continued substance use as long as the medication is taken as directed. Hence, compliance with these agents is nearly equivalent to treatment success (45–47). Not surprisingly, these two agents figure prominently in the CM literature on medication compliance (23).

Systematic evaluations of the effect of CM on naltrexone compliance and outcome have consistently demonstrated positive, if modest, results (23, 25). As early as the 1970's, several investigators (48, 49) reported success using comparatively small contingency payments as reinforcements for naltrexone consumption. More recently, some of the most promising data regarding strategies to enhance retention and outcome in naltrexone treatment has come from investigators evaluating contingency management approaches. Preston and colleagues (50) evaluated voucher based reinforcement of compliance with thrice-weekly naltrexone vs. noncontingent vouchers and no vouchers in 58 outpatients. Contingent vouchers were associated with significant improvements in retention and compliance with naltrexone compared with the other two conditions; however, marked differences in rates of drug use were not seen.

To evaluate whether drug use as well as compliance could be improved by also reinforcing drug-free urines, two studies by our group provided voucher-based reinforcement both for verified compliance with thrice weekly naltrexone treatment and for submission of drug-free urine specimens. In the first study (51), 127 recently-detoxified opioid dependent individuals were randomly assigned to one of three conditions: (1) Naltrexone plus weekly cognitive-behavioral therapy (CBT), (2) Naltrexone and CBT plus CM with delivery of vouchers contingent on naltrexone compliance and drug-free urine specimens, or (3) Naltrexone, CBT, CM plus significant other involvement (SO), where a family member was invited to participate in up to six family counseling sessions. CM was associated with significant improvements in both retention (and hence naltrexone compliance) as well as reduction in opioid use. In a parallel study which was designed to evaluate the effect of magnitude of reinforcement on compliance and outcome in this population (52), 55 detoxified opioid dependent individuals were randomly assigned to either standard naltrexone maintenance; standard naltrexone plus lower-value contingency management (maximum value $561); or standard naltrexone plus higher value contingency management (maximum value $1,152). Assignment to either contingency management condition was associated with significant reductions in opioid use over time compared with standard naltrexone treatment. However, contrasts of higher- versus lower-value reinforcement magnitude were not significant, suggesting no relative value of higher- over lower-value incentives in this population. A recent study by Nunes and colleagues that compared standard naltrexone maintenance with combined voucher-based CM plus cognitive behavioral and family network therapy found significant effects for the combined condition on retention, but noted that the 6-month retention rates in both condition were modest (53).

For the disulfiram treatment of alcoholism, the most important factor in treatment success is medication compliance and patients must accept a treatment goal of complete abstinence from alcohol as long as medication is taken. Notably, despite the intrinsically powerful effects of disulfiram to curtail alcohol use, in clinical settings it has been found to be no more powerful than placebo because of high rates of noncompliance when no extrinsic contingencies for pill-taking are provided (45). In contrast, a number of CM strategies have been shown to increase compliance with disulfiram with robust effects on reduced alcohol use and other alcohol-related outcomes. First, disulfiram for alcoholism has been shown to be highly powerful when prescribed within the context of behavioral family treatments that include a contract for spouse-administered treatment (54–56). In addition to reinforcing medication compliance per se, family behavioral contracts can target the problem of delayed benefits from stopping drinking by including agreements by family members to provide rewards for continued abstinence. Second, in patients with concurrent opioid dependence and alcoholism, making provision of methadone contingent on disulfiram ingestion has been reported to increase compliance in an uncontrolled case series (57) and a randomized clinical trial (58). Third, disulfiram compliance has been enhanced in an uncontrolled trial of alcoholic volunteers using a security-deposit box contingency contracting approach (59). Therapists deposit an agreed-upon amount of the patient's own money into a safe deposit box with return of the full sum contingent on disulfiram compliance and achievement of specified treatment goals. Failure to take disulfiram or to achieve specified treatment goals results in specified sums of money to be removed from the deposit box and donated to charity. In addition to its efficacy, this strategy has the advantage of defraying the costs of incentives by using the patient's own funds. Fourth, linking disulfiram compliance with directly observed administration in a workplace setting was shown to reduce absenteeism in an uncontrolled trial of volunteer industrial workers who had a history of alcohol-related workplace incidents (60). In all of these strategies, disulfiram compliance is enhanced by providing comparatively strong social (marital, job), pharmacological (contingent methadone), or financial (safe-deposit box) incentives that antedate and supplement intrinsic rewards from being abstinent from alcohol.

Anti-Craving Agents

In contrast to antagonist/aversive medications, compliance is less of a problem with anti-drug agents that have more subtle and partial effects on drug use, such as naltrexone for alcoholism and buproprion for tobacco dependence. Thus, in studies evaluating these agents which have partial effects or may take several weeks for effects to emerge, there have been no studies with these agents where CM has been used to specifically enhance compliance. Instead, as in the Moeller et al. study (11), with these agents CM has been used either as a platform or has been evaluated for its potential to enhance or potentiate medication effects via reinforcing abstinence (and because participants must come to the clinic to provide urines and receive reinforcement, retention invariably increases as well).

An issue with many agents aimed at reducing craving is that they may take several weeks to exert their effects. Before beneficial medication effects occur, patients are effectively receiving only behavioral treatment. In addition to receiving no initial positive benefit from medications with delayed actions, patients also must frequently tolerate unpleasant side effects that may occur immediately. When medication effects are known to be delayed, treatment should commence with a comparatively intensive behavioral treatment to keep patients engaged in treatment, manage aversive medication effects and foster abstinence or reduced drug use. This approach has been used successfully in several antidepressant studies with substance abusers (61–65). The intensity of the behavioral approach can then be reduced following the optimal titration of medication dose. For example, contingency management could be used to initiate abstinence (through providing high-value incentives for abstinence) prior to the start of the randomized medication phase, and at the point of randomization, the contingencies could be changed such that medication compliance rather than abstinence would be reinforced to foster retention and adherence in the trial (6). Similarly, Robles and colleagues have proposed the Brief Abstinence Test (66), a paradigm where cocaine users are given very high levels of reinforcement over a brief period of time to increase abstinence, that could easily be used as a tool for more inexpensively initiating abstinence (compared to hospitalization) in studies evaluating medications aimed at preventing relapse. This concept of initial abstinence also appears important for the pharmacotherapy of other abused substances such as alcohol, where naltrexone is best at reducing relapse after an initial alcohol-free period through detoxification, for example (67, 68).

Noting that previous studies of antidepressants had suggested mixed and at best modest effects on cocaine use, Kosten and colleagues (69) evaluated desipramine with and without voucher-based CM and found significant interactions, with markedly reduced cocaine use for those receiving desipramine and CM compared to either treatment alone. Enhanced effects for medication/CM combinations effects were also found in a randomized trial evaluating CM and buproprion for cocaine-using methadone maintained patients, where outcomes, including duration of abstinence, were significantly better for those assigned to buproprion and voucher-based CM compared with either treatment alone (70).

The mechanism for these effects unknown, as well as whether these represent synergistic or additive effects (cf. 71). In the case of additive effects, the antidepressants and CM would each exert their effects on cocaine use independently, with the enhanced efficacy of the combined conditions simply reflecting the additive effects of those independent effects. Synergistic effects would occur in the case where the magnitude of the effects of the combined condition was larger than the magnitude of the independent effects of each treatment added together. Given that neither desipramine or buproprion has a strong track record of main effects on cocaine use (72) and thus the expected independent effect of the antidepressants on cocaine use would be modest at best, the strong effects seen for the medication/CM combination conditions in the Poling and Kosten studies suggest synergy is possible. The mechanism for this apparent synergy is not clear. On the one hand, it is possible that even mild medication-associated reductions in cocaine use facilitated higher levels of exposure to the reinforcers, and thus enhanced CM effects. Conversely, reductions in cocaine use via CM may have reduced cocaine use to a level that made it possible for the medication effects to emerge. Several studies have noted that early abstinence can be a significant prognostic indicator in medication studies (73, 74); hence, CM may enhance medication effectiveness by rendering more of the individuals treated as “good” rather than poor prognosis patients.

Vaccines

Vaccines aimed at inactivating abused drugs are costly but potentially powerful, and might benefit from reinforcement of taking injections. At present, the type of vaccine with the most promise targets cocaine dependence (75). While the anti-cocaine antigen titers are potentially long lasting and promise to convey sustained benefit, repeated vaccine injections over an 8-week period are needed to achieve clinically significant antigen titers (76). During that time, both compliance with vaccine injection schedules and maintenance of abstinence are vitally important to ensure success. If patients continue to use cocaine when anti-cocaine titers are low, they are likely to perceive the treatment as completely ineffective and to drop out prematurely or to simply raise the dose of abused cocaine to compensate for the vaccine's effect. This initial 10-week treatment induction period is an ideal time to use powerful, voucher-based CM conditions with escalating rewards (77). Adequate anti-cocaine antigen titers can then potentially prevent the re-emergence of cocaine use that often accompanies the withdrawal of the comparatively expensive incentives used in this approach (35).

Anti-Retroviral Therapy for HIV

While untreated HIV is associated with severe illness and high death rates within 6 years of infection, increasingly powerful HAART regimens greatly reduce the morbidity and mortality associated with HIV infection (78, 79). Indeed, many adequately treated patients experience few symptoms and appear to have nearly normal life expectancy. Intuitively, the literally live-saving and life-enhancing effects of HAART would seem to provide more than sufficient motivation for HIV+ patients to comply with treatment. Nonetheless, HIV-infected drug abusers have been reported to display high rates of medication noncompliance (80). Factors working against medication compliance include unpleasant medication side effects, complexity of many HIV medication regimens, slow progression of HIV symptoms, cognitive deficits in many HIV+ drug abusers, the irregular schedules kept by many drug abusers, stigma associated with positive HIV status, and strong motivation for denial of this life-threatening infection (81–83). The interrelated phenomena of non-adherence and drug resistance are thought to be the most important reasons for failed treatment (84). Patients who intermittently adhere to HAART may temporarily select for partially resistant virus and then allow the virus to multiply unchecked (85). Economic factors also underscore the value of anti-retroviral medication compliance as the average costs of HAART, including associated monitoring, have been estimated to exceed $10,000 per year for each treated patient (86, 87).

Use of CM to enhance anti-retroviral medication compliance makes use of the general strategy of providing short-latency, tangible incentives to make up for the delayed benefits and immediate negative aspects of adherence with treatment. Applying CM for this indication entails numerous challenges because HAART involves multiple medications, complex medication schedules, and need for compliance with other aspects of treatment such as blood draws. Rosen and colleagues applied CM to this problem by linking monetary incentives to evidence of timely medication use of a single agent monitored by an electronic sensor embedded in the cap of the medication dispenser (MEMS cap) (88). The MEMS cap data is then downloaded to a computer to provide a printout listing the date and time of each bottle opening over the preceding months. In addition to providing incentives for MEMS-verified medication taking, this CM approach is combined with training in which the counselor helps the client identify environmental cues to prompt medication taking (89). In an initial trial of this approach, 4 weeks of CM resulted in an average of 92% of doses taken on time in comparison with 70% in the non-CM controls. Notably, reinforcement of a single component of the HAART regimen was associated with increased compliance with other nonreinforced medications in the regimen. Also, compliance with anti-retroviral medications was not contingent on maintaining drug abstinence as there was no association between anti-retroviral medication compliance and number of days of substance abuse. More recently, Sorensen et al. (90) and Rosen (91) have replicated these findings in larger samples, using a longer duration of CM treatment and, significantly, have documented reductions in viral load as well.

Medications for Comorbid Psychopathology

Community surveys and reports from substance abuse clinical settings have repeatedly documented excess rates of comorbid mental illness in treated substance abusers (32, 92) and the poorer prognosis conveyed by psychiatric comorbidity (93, 94). Many of these comorbid mental illnesses are readily treated with medications, most notably antidepressant, anti-manic, and antipsychotic agents (39). Particular challenges in treatment of dual diagnosis populations are associated with (a) the complexities of making reliable psychiatric diagnoses in the context of ongoing substance use, and (b) poor compliance with medications used to treat psychiatric symptoms.

It has long been established that chronic substance abuse can initiate or worsen psychiatric syndromes (e.g., depression associated with chronic alcohol or cocaine dependence), and that attempts to cope with psychiatric syndromes can prompt substance use or abuse (e.g., drinking to cope with anxiety) (95). Moreover, while psychiatric medications have often been found to be effective in treating depression, anxiety, and psychotic symptoms in substance users, continued substance use may undermine potential benefits to be derived from these treatments. Also, failure to achieve abstinence can increase the challenge of making an accurate diagnosis of presence and type of psychiatric comorbidity. While a range of strategies for accurate psychiatric diagnosis have been recommended for use with substance abusers (96, 97) (e.g., by evaluating the relative onset of either disorder, making the primary/secondary distinction), the most reliable means of making a definitive psychiatric diagnosis in a substance abuser is after a sustained period of abstinence (98). Thus, both to enhance effects of psychiatric medications and improve accuracy of psychiatric diagnosis, CM focused on initiating and sustaining abstinence can be an important component of clinical trials of dually diagnosed substance abusers.

Medication noncompliance in substance abusers with psychiatric comorbidity has been shown to be prevalent and associated with relapse to both types of disorders (99). For example, rehospitalization in schizophrenic patients is frequently precipitated by an episode of substance abuse combined with discontinuation of antipsychotic medications (100). For example, Nunes and colleagues' study (101) of the efficacy of the tricyclic antidepressant imipramine for reducing depression and illicit drug use among depressed methadone maintained patients reported a 38.7% rate of completion of an “adequate trial” of 6 weeks of imipramine, as measured by self-report and directly observed ingestion (direct observation was for approximately half of the doses). This rate of adherence is similar to other rates of adherence in other pharmacologic studies of depressed cocaine or opioid dependent patients (102). Thus, promising strategies (but as yet unstudied) for using CM with agents targeting psychiatric medications include (1) using CM to initiate abstinence so that reliable diagnoses can be made before initiating treatment, (2) enhancing compliance with psychiatric medications, and (3) as suggested in the section on anti-craving medications above, using CM to reduce drug use and hence provide an opportunity for weaker medication effects to emerge, through the additive or synergistic processes described above.

Addressing Weaknesses of CM as a Platform

Our review has highlighted the strengths of CM as a component of drug abuse treatment, most notably its ability to shape behaviors that are discrete and clearly identified, including reducing or stopping drug use, meeting targeted treatment goals, and complying with medication instructions. While these properties make it an almost ideal platform or combination treatment with medications, several weaknesses have constricted its widespread use either in clinical trials or in treatment settings. CM remains underutilized in practice and even in pharmacologic research there are to date only the handful of studies reviewed above that have utilized CM as a platform to evaluate possible synergistic or additive effects (69, 70), or as a strategy to maximize medication compliance (50, 103). If CM is to be more widely used, strategies are needed to address these barriers.

First, the costs of providing material incentives are not provided for in budgets of typical substance abuse or primary care medical settings. Given the novelty of CM treatments for these applications, there are no ready ways for program administrators to recover these costs using third-party payment procedure codes. Second, the skills needed to apply CM are generally unfamiliar to medically trained personnel. In addition, the types of record-keeping required to keep track of anything but the simplest reinforcement schedules are likely to be burdensome in a busy primary care clinic. Third, overall significant effects of CM in complete samples fail to highlight the fact that many addicts do not respond to CM often because they do not provide a single example of the targeted behavior and receive no contingent reward (104). Fourth, provision of tangible incentives can be seen as enhancing only extrinsic motivation to perform the desired behavior while failing to address intrinsic motivations to comply with prescribed treatments (52, 105). This criticism of current CM approaches has been validated by those studies which have documented substantial reductions in targeted behaviors when incentives are removed (25, 103).

Offset Costs: Select Applications with Large Potential CM Benefits

Given the costs and other barriers to widespread use of CM to enhance medication effects and compliance, it is important to pick applications in which the potential benefits far outweigh these costs. As a primary consideration, CM should be reserved for those applications when the medication is crucial to reach treatment goals and the consequences of continued drug use or medication noncompliance are severe. Notably, these conditions prevail for many of the applications reviewed above, particularly (a) naltrexone for opioid dependence and disulfiram for alcoholism, where compliance is synonymous with abstinence, (b) anti-retroviral treatment for HIV infection, for which high rates of compliance are needed not only to achieve benefits but also to prevent emergence of new medication resistant strains of HIV, and (c) medications to treat severe comorbid psychopathology (e.g., antipsychotic and anti-manic agents) that can prevent the need for costly rehospitalizations.

Several additional secondary factors should be considered when choosing medications to target with CM. First, it should be reserved for medications in which other, less intensive compliance enhancements are not available or ineffective. For example, because patients prescribed daily antipsychotic medications can simply be switched to long-acting depot formulations, adding CM to improve anti-psychotic pill compliance may not be the most cost-effective course of action. Second, CM is likely to be necessary only for medications with characteristics that reduce the likelihood of compliance such as low or highly delayed perceived benefit, aversive side effects, need for sustained use and complex dosing schedules. As noted above, these characteristics apply to all of the types of medications that have been targeted for clinical trials of CM with substance abusers and generally do not apply with other types of medications prescribed for drug abusers. Hence, the major solution to the problem of CM costs is the choice of applications in which these costs can be readily offset.

Reduce Training Burdens: Simplify/Enhance Efficiency of CM

Even though compliance with prescribed medications can make the difference between treatment success and treatment failure, behavioral aspects of medical treatment are seldom emphasized in medical/nursing education and the time allotted for each patient contact is highly limited, particularly in managed-care settings. Hence, the likelihood that a CM abstinence or compliance enhancement scheme will be adopted is directly proportional to the brevity and simplicity of administering this intervention. The need for enhancing compliance over extended time periods adds further to the need for quick and simple strategies. Unfortunately, some of the strategies that have been found to be most efficacious for treating abusers are somewhat complex including the voucher based, escalating dose strategy devised by Higgins and colleagues (106) and the variable ratio, prize incentive method pioneered by Petry (16). Simple, fixed ratio reinforcement schedules have tended to be less effective when applied in substance abuse populations (104). Simple or easily applied reinforcement schedules may be more feasible that the comparatively complex and/or intensive CM interventions applied over a comparatively brief time period that are typical of published clinical trials. In practice settings, even simple CM interventions still require considerable staff training and more intensive short-term efforts might have to be performed by specially trained behavioral therapy consultants. Ideally, the simpler strategies could be used throughout the course of medication treatment.

The use of computer technology shows great promise for facilitating the general strategy of developing simple, user-friendly compliance enhancement methods. One computer-delivered CM intervention that showed preliminary evidence of efficacy involved reinforcing smokers for daily abstinence. Abstinence was verified by carbon monoxide readings that were e-mailed to a web-server (107, 108). Even complex reinforcement schedules can be programmed to calculate the amount of rewards for target behaviors and to even provide automatic feedback to patients when the behavior is performed (109).

Enhance Durability of Effect: Strategies to Increase Intrinsic Motivation

Long-term abstinence or compliance with prescribed treatments requires either continued application of incentives or the development of intrinsic motivation to continue medication taking. In substance abusing samples, post-treatment CM effects on abstinence have generally been shown to drop off substantially in the small number of studies in which treatment durability has been addressed (110, 111) and a lack of sustained benefits was also seen when CM was applied to anti-retroviral adherence (90, 91). Given the need for extended medication compliance for applications we have reviewed, this is the most important weakness for future research to address. We will briefly outline several general approaches.

First, increase attention to beneficial effects of abstinence medication compliance. However, many of the effects of available medications may be delayed, subtle, or mixed. A comparatively simple strategy to enhance the salience of these benefits would utilize clear feedback on progress toward treatment goals. For example, charting of successive test results (e.g., Beck Depression Inventory scores, viral loads) may provide tangible reminders that treatment is helping. For medications that eliminate illicit drug use such as naltrexone for opioids, gradually increasing benefits of sustained abstinence are often apparent with each successive week. Providing formal ratings of these changes to the patient and/or significant others may increase motivation to sustain recovery.

Second, manage the transition away from CM. The most straightforward approach to manage cessation of incentive delivery is to develop a tapering scheme that utilizes basic behavior strategies that foster sustained behavior. These include transitioning from fixed ratio schedules to intermittent or variable-ratio reinforcement schedules (112). A second general approach entails attempting to shift the type of incentive away from artificial and costly extrinsic rewards provided by the treater (e.g., prizes) to incentives that can be delivered in outside-the-treatment setting, such as receiving praise or support from family members. A third general strategy entails broadening the types of target behaviors that will result in delivering contingent rewards. Clearly, medication compliance is a single behavior in the complex repertory of behaviors that foster recovery including use of skills to avoid drug exposure and development of rewarding behaviors that substitute for incentives provided by drug use. Hence, in addition to or as a substitute for providing incentives for pill-taking, clinicians may incentivize other behaviors that may have more enduring impact on substance use such as attendance at substance abuse treatment, completing homework assignments in CBT (113), meeting short-term treatment goals (114), or engaging in rewarding social activities (21). Timing of interventions is a key issue in bringing about the shift from therapist-delivered tangible incentives for narrowly targeted behaviors such as compliance to naturally occurring rewards for a broad range of recovery behaviors. Such a transition entails moving from a discrete, easily identified target behavior with comparatively simple rewards to complex behaviors and less tangible rewards. Hence, a period of combined reinforcement schedules is likely to be needed in order to facilitate a smooth withdrawal of tangible incentives.