Pharmacological means of reducing human drug dependence: a selective and narrative review of the clinical literature

Abstract

Substance abuse or addictive disorder is a global problem. A greater understanding of the associated changes in brain pathophysiology supports the notion that pharmacological treatments are part of the necessary treatment options. Craving is a core symptom of addictive disorder. It refers to a strong desire to use drugs again either to re-experience positive effects or to diminish negative experiences. Currently there are a number of medicines that are effective in the treatment of addictive disorders. These medications can either be for substitution (same pharmacological effect as the abused substance) or anticraving (decrease the craving of the abused substance). In this MEDLNE based review, specific compounds (naltrexone, acamprosate, topiramate, disulfiram, baclofen, N-acetylcysteine and bupropion) were selected that are known to diminish desire to use (anticraving effect) and that have been trialled for a number of different substance addictive disorders. Their therapeutic potential in clinical practice is discussed in light of their efficacy.

Introduction

In general, the term ‘addiction’ is used to refer to any behaviour that is out of control in some way. People often describe themselves as being addicted, for example, to a TV show or to clothes shopping. Historically, addiction in psychiatry has been regarded as a disorder that has physical and psychological dependence on psychoactive substances (for example alcohol, tobacco, heroin, cocaine and other drugs). The prevalence of addiction has increased markedly for recreational substances such as alcohol and nicotine and illicit drugs such as marijuana, amphetamine, cocaine and opioids. Internet addiction and pathological gambling are also problems found in most countries.

A short definition of addiction proposed by the American Society of Addiction Medicine [1] states that addiction is a primary, chronic disease of brain reward, motivation, memory and related circuitry. Addiction is characterized by an inability to abstain consistently, impairment in behavioural control, craving, diminished recognition of significant problems with one's behaviours and interpersonal relationships, and a dysfunctional emotional response. For a broader definition, addiction is not necessarily limited to substance use, and it can include behaviour addictions such as internet [2], eating [3], gambling [4] and sex [5]. Craving is the core symptom of addiction. In general use, craving can occur across a dimension from a very weak desire (urge) to very strong desire to use substances or do something [6]. In clinical practice, craving usually refers to a strong desire or intense urge for some particular thing that one has previously experienced. Patients with substance dependence always have this symptom, and loss of control over substance use is considered a hallmark of addiction and is critical in relapse [7]. The ICD-10 diagnostic criteria of dependence syndrome refers to craving as a strong desire or sense of compulsion to take the substance [8]. In the Diagnostic and Statistical Manual of Mental Disorders [9], ‘positive’ craving is not included in the criteria due to it being the psychological momentum of an individual that is not easily measured in quantity or observed from external observations. Rather, the criteria ‘substance is taken to relieve or avoid withdrawal symptoms’ can be regarded as ‘negative craving’.

When addicted patients stop using a substance, places, people, actions and sensations associated with past drug use and their collection as episodic memories thus represent conditioned cues that trigger drug craving as a conditioned response [10]. Craving shares some common characteristics with obsession/compulsion in terms of ruminative thinking and repeated behaviour. An individual may be obsessive/compulsive to relieve an anxious mood, or take drugs to relieve the craving. However, the common pathway is to satisfy the reward system [11,12].

Measurement of craving

Since craving is an internal psychological momentum, it is not easily measured by laboratory examinations or external observations. Hence, the degree of craving is usually reported subjectively and can be measured in different aspects for predicting relapse or intervention effects. One commonly used tool of assessing craving is the single item Likert type or visual analogue scale (VAS). When responding to a VAS, respondents specify their level of craving from none to extreme on a 100 mm line. There are also a lot of multiple item questionnaires and Rosenber [13] has reviewed a series of published rating scales regarding the subjective experience of craving to different substances. The author concluded that these self-report questionnaires were correlated significantly with the single item scale. Recently, biological indicators have been reported such as plasma concentrations of stress hormone [14] and brain-derived neurotrophic factor for the severity of withdrawal symptoms [15] or craving [16,17]. However, further investigation and validation of these findings are required [18].

Definition of anticraving

As with antidepressant or antipsychotic medication, an anticraving medication has positive effects on craving, either by reducing the degree or counteracting the suffering of craving. In a review article, O'Brien [19] proposed that anticraving medication is possibly a new class of psychoactive medication. According to his broad definition, any medication that shows an effect for the prevention of relapse can be regarded as anticraving. In this context, it also includes the medication used in replacement therapy and substitution therapy, such as a nicotine patch or gum for nicotine dependence, or methadone for heroin dependence. However, from a pharmacological point of view, the function of an anticraving medication is to decrease or ameliorate the ‘craving’ rather than to supply the ‘craving agent’. Therefore, I have focused on the medications that have shown anticraving properties in this review.

Anticraving and reward system

Almost all abused drugs increase dopamine release in the mesolimbic pathway, which is crucial in the cascade reaction of the brain reward system [20]. This burst response depends on the activation and plasticity of glutamatergic N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors located on dopamine neurons [21,22]. The mesopontine rostromedial tegmental nucleus (RMTg) is a recently discovered brain structure which is thought to influence profoundly reward-related pathways [23]. The RMTg is prominently GABAergic, receives dense projections from the lateral habenula and projects strongly to the midbrain ventral tegmental area and substantia nigra compacta [24]. Drugs of abuse can hijack synaptic plasticity mechanisms in key brain circuits, and reversing or preventing these drug-induced synaptic modifications may prove beneficial in the treatment of addiction disorders [25]. Most compounds showing an anticraving effect possess the ability to alternate or modulate the reward system.

Method

In this review, the author has selected specific compounds with anticraving characteristics that have been used in trials in human subjects regarding different substances (alcohol, nicotine, cocaine, opiates, amphetamines and cannabis) or behavioural (internet, gambling, binge eating/obesity) addictive disorders using the MEDLINE database, and categorized them into four levels: (i) positive effect by double-blind controlled trials, (ii) positive effect by open trials or case series reports, (iii) controversial effect and (iv) negative effect (Table 1).

Table 1.

Anticraving effect on substance and other addictions

	Alcohol	Nicotine	Opioids	Cocaine	Amphetamine	Cannabis	Internet addiction	Pathological gambling	Binge eating/obesity
Naltrexone	++	±	++	±	+	−	+	++	+*
Acamprosate	++	0	0	−	0	0	0	−	±
Topiramate	++	±	0	+	±	0	0	0	++
Disulfiram	++	0	0	++	0	0	0	+	0
Baclofen	+	+	±	−	0	−	0	0	0
N-acetylcysteine	0	±	0	+	0	+	0	+	0
Bupropion	0	++	0	−	±	−	0	±	+

++: positive effect by double-blind controlled trials; +: positive effect by open trials or case series reports; ±: controversial effect; −: negative effect; 0: no trial reported; ^*: combine with bupropion.

Naltrexone

Naltrexone and its active metabolite 6-β-naltrexol are competitive antagonists at μ-and κ-opioid receptors, and to a lesser extent at δ-opioid receptors. Naltrexone was developed to treat opioid dependence because of its effect of blocking the euphoric effects of opioids [26,27]. In a meta-analysis of 26 randomized controlled trials (RCTs) 28, the author concluded that oral naltrexone appeared to have some limited benefits in helping formerly opioid-dependent individuals to remain abstinent, although the quality of the evidence was relatively poor and heterogeneous. Naltrexone has been reported to have a lack of patient adherence and low treatment retention, and is only suggested as a second line medication after methadone or buprenorphine for opioid dependence by the World Federation of Societies of Biological Psychiatry [29]. The NICE guideline recommends naltrexone as a treatment option for people who have been opioid dependent but who have stopped using opioids, and who are highly motivated to stay free from the drugs in an abstinence programme. Naltrexone has a craving reduction effect on heroin [30,31], while in other contexts of substance use, naltrexone has also shown an anticraving effect.

Naltrexone has been given to patients with alcoholism due to its effect of altering ethanol self-administration in animal studies, after the observation that alcohol activates the endogenous opioid system [32,33]. Two separate randomized blind placebo-controlled trials [34,35] demonstrated the efficacy of naltrexone on alcohol dependence, and it was licensed to treat this disorder in North America and Europe. Subsequently an animal study [36] demonstrated that the suppression of ethanol-reinforced behaviour by naltrexone is associated with attenuation of the ethanol-induced increase in dialysate dopamine concentrations in the nucleus accumbens. Taken together, this evidence suggests that naltrexone modulates the reward system by blocking opioid receptors to produce an anticraving effect. Although there were two subsequent negative clinical trials [37,38], trajectory-based re-analyses by the same group did support that naltrexone may have a clinically meaningful effect for alcohol dependent patients with a high chance of consistent drinking, even in studies where it failed to show efficacy in planned analyses [39]. Since naltrexone does not show any drug–drug interaction effect with ethanol or its metabolism, the phenomenon of decreasing the amount of alcohol drinking with naltrexone can be attributed to an ‘anticraving’ effect. Naltrexone can therefore be regarded as a prototype of anticraving medication. For another opioid antagonist nalmefene, early studies did not show efficacy on alcoholism [40,41], although the latter RCT showed it was significantly better than a placebo in reducing heavy drinking days, very heavy drinking days, drinks per drinking day and in increasing abstinent days [42 ].

There is only one RCT on naltrexone with regards to cocaine dependence [43]. The results showed no significant effect of treatment on time to first cocaine-positive urine or craving, and only some effect on less cocaine use over time. When trialled on dual dependences of cocaine and alcohol, the results were controversial [44–46].

Naltrexone has been tested in amphetamine dependent subjects, and was found to attenuate significantly the subjective effects produced by dexamphetamine, and significantly block the craving for dexamphetamine [47]. Results from the same group in an open trial [48] showed a moderate effect and a RCT [49] showed that those taking naltrexone had a significantly higher number of negative urine samples and higher rate of continuous abstinence. Grant et al. [50] used N-acetyl cysteine plus naltrexone for methamphetamine dependence but did not detect any significant effects in a small group RCT (n = 31).

Naltrexone has been studied in nicotine dependence, also with controversial results [51–53]. In heavy marijuana smokers, naltrexone was found potentially to increase the abuse liability and cardiovascular risks of cannabinoids [54].

Naltrexone has been shown to reduce weight gain in mice [55], but subsequent RCTs in humans have not supported this effect [56,57]. Recently, a combination regimen of naltrexone and bupropion has been tested, with a moderate effect in decreasing body weight [58,59].

Naltrexone has been studied in pathologic gambling [60–62] with positive results, and positive results have also been seen with another opioid antagonist, nalmefene [63]. For internet addiction, one case report found that naltrexone had promising efficacy in suppressing a euphorically compulsive and interpersonally devastating addiction to internet pornography [64].

Since the major issue of concern for naltrexone's efficacy on opioid and alcohol dependence is the medication compliance, its long-acting depot form was developed. In a review article [65], the authors concluded that naltrexone depot formulations have the potential to improve significantly medication compliance in opioid and alcohol dependence, and in certain circumstances, they may constitute a promising new treatment option. In a recently published RCT [66], a naltrexone implant was trialled on patients with polydrug dependence, and the results showed that the active group had higher retention, decreased heroin and amphetamine use, and improved clinical condition.

The most common side effects reported with naltrexone are non-specific gastrointestinal complaints such as diarrhoea and abdominal cramping. Hepatotoxicity has been reported in high dose use [30]. Long term exposure (up to 3.5 years) to naltrexone may only selectively inhibit the pleasure associated with drinking alcohol and gambling, and not to listening to music, sex, reading, being with friends, eating good food, eating spicy food and playing video/card games [67].

Acamprosate

Acamprosate is a synthetic compound and an analogue of γ-aminobutyric acid (GABA) and taurine, and has been approved by the FDA in 2004 to treat alcohol dependence, years after its wide use in Europe. Pharmacologically, acamprosate binds to a specific spermidine-sensitive site that modulates the NMDA receptor in a complex way, and is regarded to be a ‘partial co-agonist’ [68]. This means that acamprosate is an indirect partial agonist of the NMDA-glutamate receptor, and antagonist of metabotropic glutamate receptors [69]. The concept is similar to the pharmacological effect of the dopamine D₂-receptor partial agonist aripiprazole on dopamine neurotransmission with a stabilizing effect, and is called a dopamine system stabilizer [70]. Acamprosate can be regarded as a glutamate system stabilizer and can decrease the craving for alcohol during withdrawal and abstinence [71]. A recently published systematic review based on 24 RCTs with 6915 participants [72] concluded that acamprosate appears to be an effective and safe treatment in alcohol dependent patients. Three trials compared acamprosate and naltrexone, and none of them indicated a superior effect of one drug over the other [72]. Acamprosate was not found to be effective for acute alcohol withdrawal symptoms in two RCTs [73,[74], indicating that it should be used after detoxification has been completed.

Acamprosate was trialled in a 9 week RCT design for cocaine dependence but the results were not encouraging [75]. In a small size (n = 40) RCT for binge eating disorder [76], acamprosate was not found to more beneficial than a placebo on any outcome variable. However the results of the endpoint and completer analyses suggested that the drug may have some utility in binge day frequency and measures of obsessive-compulsiveness of binge eating, food craving, and quality of life. In a small group trial, acamprosate did not prove effective in treating pathological gambling [77]. Currently no trials of acamprosate for other addictive disorders have been conducted. Interestingly, acamprosate was shown to improve tinnitus in one RCT study [78], and it seemed to be effective in autistic disorder in an open trial of six subjects [79].

Topiramate

Topiramate is an anticonvulsant with a unique pharmacological profile including a blockage of voltage-dependent sodium channels, an augmentation of GABA activity at some subtypes of the GABA-A receptor, antagonism of the AMPA/kainate subtype of the glutamate receptor and inhibition of the carbonic anhydrase enzyme, particularly isozymes II and IV. It has been hypothesized that these effects lead to neurostabilization and downstream reduction of dopamine release in the corticomesolimbic system and to possessing an anticraving effect. Shinn & Greenfield [80] published an extensive review on topiramate in the treatment of substance-related disorders, and summarized that topiramate is efficacious for the treatment of alcohol dependence, shows mixed results with nicotine dependence and promising effects on cocaine dependence. However, their findings are limited by the small sample size. A RCT for methamphetamine addiction found that topiramate did not appear to promote abstinence in methamphetamine users but it could reduce the amount taken and reduce relapse rates in those who were already abstinent [81]. There have been some RCTs [82–85] of topiramate for binge eating disorder or bulimia nervosa, and all of the results showed efficacy in decreasing the frequency of binge eating, and body weight was also decreased. The side effects of topiramate include paresthesia (numbness and tingling), nausea and psychomotor slowing, which has limited its widespread use as an anticraving medication.

Disulfiram

Disulfiram has been used for about 60 years in the treatment of alcoholism [86,87]. Disulfiram inhibits aldehyde dehydrogenase (ALDH), which results in the accumulation of acetaldehyde on ethanol ingestion. This toxic metabolite produces aversive symptoms, such as flushing, nausea and vomiting and a desire to avoid this reaction encourages abstinence. This kind of reaction deters alcohol consumption and is categorized as ‘aversive therapy’ or a ‘psychological threat’ pill [88,89]. Because 50–90% of patients who abuse cocaine also abuse alcohol [90], it was thought that discouraging alcohol consumption in cocaine-and alcohol-dependent individuals may also lower cocaine use. Indeed, disulfiram has been found to reduce alcohol and cocaine intake in this patient population [91,92]. Surprisingly, further studies have revealed that disulfiram is also effective in treating cocaine addicts who do not consume alcohol [93].

It is likely that an ALDH-independent mechanism (non-aversive effect) is responsible for the ability of disulfiram to promote cocaine abstinence [94]. The mechanism of the anticraving effect of disulfiram is rather complex and many hypotheses have been proposed. Schroeder et al. [95] used a laboratory animal model to investigate whether the inhibitory effect of disulfiram on dopamine β-hydroxylase (DBH), the catecholamine biosynthetic enzyme that converts dopamine to norepinephrine in noradrenergic neurons, underlies the drug's ability to treat cocaine dependence and whether it can prevent drug exposure and stress from precipitating relapse. Their results suggest that disulfiram's efficacy in the treatment of cocaine addiction is associated with the inhibition of DBH and interference with the ability of environmental stimuli to trigger relapse. Yao et al. [96] uncovered another potential effect of disulfiram through the inhibition of ALDH-2 by using a specific inhibitor, ALDH-2i. ALDH-2i blocks the conversion of 3,4-dihydroxyphenylacetaldehyde (DOPAL) to 3,4-dihydroxyphenyl-acetic acid (DOPAC) in the dopamine biosynthetic pathway, increasing DOPAL concentrations and tetrahydropapaveroline production, thereby inhibiting tyrosine hydroxylase to reduce dopamine biosynthesis. This in turn blunts the rewarding/reinforcing effects of cocaine and cocaine-associated cues.

An earlier study by Nagendra et al. [97] showed that the disulfiram metabolite DETC-MeSO could block glutamate binding to receptors in mouse brains. In addition, the disulfiram metabolite carbamathione is a partial non-competitive NMDA glutamate antagonist and does not inhibit ALDH-2. It has been found to possess an anticraving effect and has been proposed to be responsible for the efficacy of disulfiram in cocaine dependence [98].

Disulfiram has been trialled in pathological gambling in several case reports [99,100] and the authors suggested that it deserves further investigation. No other addictive disorder has been trialled with disulfiram. Besides its anticraving effects, disulfiram is also an affordable and promising anticancer drug [101] and has potential therapeutic use for fungal infections [102].

Baclofen

Baclofen is a derivative of GABA and can activate the GABA_B receptor with no known abuse potential. It has muscle relaxant and sedative properties and is primarily used to treat spasticity of neurological disorders, such as spinal cord injury, cerebral palsy and multiple sclerosis [103]. Baclofen was first reported in one open (n = 10) [104] and one small scale (n = 39) RCT 105, and was proven to be effective in inducing abstinence from alcohol and reducing alcohol craving. Subsequently, the same group reported that baclofen was effective and well tolerated in alcohol-dependent patients with liver cirrhosis [106], and that a higher dose (20 mg three times daily) had a greater effect than the common dose (10 mg three times daily) [107]. However, in another larger scale RCT (n = 80) [108], baclofen was not found to be superior to placebo in percentage of heavy drinking days and days abstinent, time to first drink, or time to relapse to heavy drinking; while it was associated with a significant reduction in state anxiety in the treatment of alcohol dependence. A very high dose (270 mg day⁻¹) of baclofen was suggested by Ameisen [109] in his own experience case report to suppress successfully the craving for alcohol. Recently, an article reported that a high dose (75–125 mg day⁻¹) regimen of baclofen was effective in four cases of treatment-resistant alcohol dependence [110]. To evaluate the effectiveness of a high dose of baclofen in the treatment of alcohol dependence, well controlled trials are warranted to confirm these findings [111,112]. One multicentre trial of baclofen (60 mg day⁻¹) for abstinence initiation in severe cocaine dependence found negative results [113]. In a recent comprehensive review, the authors concluded that baclofen seems to be safe and well-tolerated, even in patients with liver cirrhosis [114]. In a 12 week RCT on opioid dependence [115], patients treated with baclofen had a higher retention rate and favourable responses of opioid craving, but no significant difference was seen in the rates of opioid-positive urine tests. Baclofen showed no effect on a laboratory model of marijuana withdrawal and relapse [116]. Baclofen has been trialled on contemplating smokers [117] and showed an effect of reducing cigarettes smoked per day in a 9 week RCT.

N-acetylcysteine

N-acetylcysteine (NAC) is used primarily as a mucolytic agent and in the management of paracetamol (acetaminophen) overdose. Through its metabolic contribution to glutathione production, cysteine participates in the general antioxidant activities of the body. NAC has also been shown to modulate neurotransmitter pathways, including glutamate and dopamine [118]. These properties are the hypothetical basis for NAC having an anticraving effect.

NAC has been trialled in a variety of psychiatric disorders such as schizophrenia, bipolar disorder and addictive disorders. The addictive disorders include cocaine [119–121], marijuana [122], nicotine [123], pathological gambling [124] and trichotillomania [125]. Most of these trials were small in scale; however, the results appear to be promising in the treatment of psychiatric disorders including addictive disorders. In the review article by Dean et al. [118], the authors suggested that NAC is a readily available and affordable nutritional supplement. Further research is warranted to clarify the appropriate dosing range and duration for specific disorders, and for any unforeseen side effects related to long term treatment.

Bupropion

Bupropion is a popular antidepressant in clinical practice. It is a derivative of substituted amphetamine and its primary pharmacological action is thought to be norepinephrine-dopamine re-uptake inhibition. Bupropion is also an antagonist of nicotine receptors [126] and is an efficacious medication for smoking cessation [127]. Patients on bupropion have reported less nicotine craving [128]. In the treatment of methamphetamine dependence [129,130], bupropion has only shown effectiveness in light users. Bupropion shows no effect on cocaine [131] or cannabis [132] dependence.

Bupropion has also shown a moderate effect in the treatment of obesity [133]. Seizure is a troublesome side effect and is highly dose-dependent. This side effect can be attenuated with the use of an extended release dosage form [134].

Others

Other medications which have been trialled include ondansetron (serotonin 5-HT₃-receptor antagonist) and tiagabine (GABAergic anticonvulsant). Ondansetron has shown a positive effect for early onset alcoholism [135], but not in the dependence of opioids [136], methamphetamine [137] and cocaine 138. Tiagabine has been involved in trials for cocaine dependence with controversial results [139,140].

Conclusion

Addiction is a chronic, relapsing disorder with heterogeneous conditions. Maintenance medications for addiction include substitution, aversive and anticraving drugs. However, some forms of addictive disorder are not only substance dependence, but by a broader definition include unhealthy behaviour such as pathological gambling, internet addiction, binge eating and trichotillomania. The pathophysiology of addiction is not well understood. It is generally believed that the reward system is involved in the formation of addiction, and that any compound that can modulate this system will have the potential to be an anticraving medication.

This review summarizes specific anticraving medications that have been involved in trials for different substance and behavioural addictive disorders. It is important to treat addictive patients with psychosocial intervention and anticraving medications can also play a role in relapse prevention. Further well-designed and larger scale RCTs are needed to examine the real efficacy of a specific compound to a specific addictive disorder.

Competing Interests

The author has no competing interests to declare regarding the content of this article.

The author Shih-Ku Lin has completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf and declares he had support from the Taiwanese National Science Council for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.

This study was supported by NSC 95-2314-B-532-009-MY3. The author thanks Mr Yan-Lung Chui for his assistance in the preparation of the manuscript.