The effect of methadone on depression among addicts: a systematic review and meta-analysis

Drug addiction and opioids misuse are among some of the key challenges and concerns of contemporary societies; they are even considered as the fourth major societal challenges after nuclear issues, population increase, and environmental pollution [1]. The addiction phenomenon initially reflects an image of a risky individual problem, while it is a social, economic, health, and security concern in different countries [2]. The prevalence of drug addiction is increasing rapidly in Iran and globally, with youth and adolescents making up a large percentage of drug addicts [3]. For instance, the rate of drug abuse has increased 3 times more than the population growth rate in Iran over the past 20 years [4]. Hence, it is important to control addition to opioid among the general population. Considering 1925 km of common border with Afghanistan and Pakistan, which are the major sources of poppy cultivation and opium and heroin production in the world, Iran is particularly vulnerable, since it is on the path of transit of opiates from these countries to Europe [1]. Heroin, for instance, is expensive and it is difficult to treat its addiction and break its defective cycle, and hence requires a comprehensive treatment system with different approaches of drug therapy, psychotherapy and rehabilitation. Prevention is logically the preferred option compared to treatments. Nowadays, the addiction problem is not only a family concern, but is also a sociodemographic challenge. It has negative effects on the mental health of the addict and addicts and their families [5]. One of the top priorities in today’s societies should be to identify addiction-related problems and plan to control and reduce the number of addicts [1].

Nearly 90% of opioid addicts have some form of mental disorder, among which are depression, antisocial personality disorder, and anxiety [6]. According to the diagnostic and statistical manual of mental disorders (4th edition)—text revision (DSM-IV-TR), depression is characterized by sadness, low self-confidence, and a lack of interest in any kind of daily activity and enjoyment. Depression can lead to a significant disorder negatively affecting one’s personal and social life, and employment. It also disturbs one's daily performance i.e. eating, sleeping and health [7]. Depression may be a sign of helplessness among addicts; it is considered as a barrier to effective behaviors to combat addiction or to exploit coping resources available to substance abusers [8]. The prevalence of major depressive disorder and minor depression among addicts are approximately 50–60% and 10% respectively [9]. Blanchard (2000) studied 872 methadone-treated patients and examined the presence of axis I and II disorders. He demonstrated that if an opioid addict had one of the first axis disorders, would need the drug addiction therapies, and psychotherapy, combined with methadone maintenance treatment (MMT) [10].

Methadone is used as one of the biological therapies for detoxification and maintenance treatment of heroin addiction and other opioid-like substances. The low cost of methadone, along with its high potency in controlling the physical and psychological conditions of opioid-like addiction, has made it a useful drug in the treatment of addicts [11]. Although MMT is considered a form of physical addiction to this drug, it is not considered equal to addiction, since by the regular use of the drug, the patient gets rid of euphoria, hangover and compulsive drug use. Such deification allows the patients to return to their communities and focus on other areas of life [12]. Previous research works have reported inconsistent results on the effect of MMT on addicts' mental health; for instance, some studies have shown that methadone-treated addicts have a high level of mental health problems compared to the general population and most have experienced mood and emotional disorders such as depression and anxiety [13]. In MMT, the substance is administered to patients in an oral syrup in a controlled manner. Experts believe methadone replacement reduces the prevalence of injection drug addiction and dangerous diseases such as AIDS, and on the other hand, breaks the link between drug addicts with drug dealers and decreases the likelihood of delinquency [1].

There have been several preliminary studies on the effect of methadone on depression in addicts, which yielded contradictory results. One of the applications of meta-analysis studies is to respond to these assumptions and resolve such contradictions. Therefore, the aim of the present study is to determine the effect of methadone on depression in addicts in the world using a meta-analysis approach.

This study was a systematic review and meta-analysis including articles published in databases of SID, MagIran, IranMedex and IranDoc and Cochrane, Embase, ScienceDirect, Scopus, PubMed and Web of Science (WoS) were searched in order to find relevant articles published from 2006 to 2019 in Persian and English language (In order to access quality articles and present more up-to-date results, the desired time frame was selected), matching the selected search keywords. These articles were obtained based on PRISMA statement and the initial article search process, removal of duplicate articles, review of articles in terms of relevance, as well as quality evaluation and finally final extraction of articles.

Data from all articles entered into the meta-analysis were extracted using a different pre-prepared checklist. The checklist included article’s title, first author's name, year of publication, place of study, sample size, sample size of intervention group, mean sample before and after intervention, and standard deviation of sample before and after intervention. The type of interventions mentioned in each study are reported in Table 1.

In this work, studies were reviewed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Initially, 1182 articles were identified, and following different PRISMA phases, a number of articles were excluded. Finally, 19 studies were selected for meta-analysis (Fig. 1).

The total amalgamated sample size was 1948. The details of the systematically reviewed studies are provided in Table 1. All studies were clinical trials; Nine articles were written in English and 10 in Persian (Table 1).

Considering the available data, the standardized mean difference indices were used to determine the outcome of the effects of the studies. The standardized mean difference index was used in the meta-analysis of studies where results were reported using standard deviation of mean ± SD. The results of meta-analysis showed that there was heterogeneity between studies and pre- and post- intervention heterogeneity values were I² = 99.9 and I² = 99.9 respectively; thus, the random effects method was used to amalgamated the reported results of the selected studies and determine an overall outcome.

According to the results of the meta-analysis, the pre- and post- intervention standardized mean difference in the intervention group was estimated to be 26.5 ± 4.6 and 18.2 ± 4.6, respectively, indicating that methadone reduces depression. The accumulation diagrams (Figs. 2 and 3) show the standardized mean difference index and 95% confidence interval in each study as well as the final estimation of the index obtained from the combination of all results. The diagram demonstrates the weight of each study in the final combined value, and the size of each square is proportional to the weight of each study in the meta-analysis. The horizontal line of each square also denotes a 95% confidence interval. The Egger's test was used to investigate the publication bias in the articles, and the results showed no publication bias in the pre-and post-intervention studies (P = 0.184, P = 0.052, respectively) (Figs. 4 and 5).

The lifetime prevalence of substance abuse is about 20% [34]. Nowadays, since drug abuse is one of the most important health problems in societies, health promotion practitioners are still in search of solutions to combat addiction and the associated problems. The aim of this study was thus to determine the effect of methadone on depression in addicts in Iran and around the world using a meta-analysis approach.

The results of this study show that the prevalence of depression among addicts is high, which indicates the impacts of addiction on all aspects of addicts' lives. Therefore, it is necessary to intervene in lifestyle changes, offer regular control of depression in people to prevent the disorder, and reduce its complications. In addition, since depression is primarily preventable and can be controlled and treated in the event of a complication, it is necessary to provide people with complete education about depression and how to prevent its complications, as well as early and timely diagnosis of the complications. Due to the high prevalence of depression among addicts, it is recommended that physicians pay more attention to the symptoms of this disorder among drug abuse patients; education should also be offered through various suitable media with the aim of raising awareness, and to reduce delays in the diagnosis.

The results also show a significant difference between the mean scores of depression severity in the intervention group before and after intervention. The results of the present study reported a mean depression severity of 26.4 ± 5.6 in the patients of the intervention group in the pretest phase, while it was significantly reduced to 18.2 ± 4.6 in the posttest phase.

The most comprehensive study in terms of sample size was the work of Yin et al. [27] in China, which reported the mean severity of depression in the pretest phase as 50.52 ± 10.99 and 48.22 ± 10.06 in the posttest. Furthermore, one of the most high-quality research works (according to the CONOSRT checklist) was conducted by El Hage et al. in Canada [33] which reported the mean severity of depression in the pre-test 34.3 ± 1.5 and the post-test 17.3 ± 2.3; the results are consistent with the overall results of our work.

Depression is characterized by symptoms such as helplessness and hinders the cessation of addiction and the use of available coping resources. However, the results of some studies suggest that treatment of addiction-related mood disorders may decrease the onset and recurrence [35].

Methadone is one of the medications used to treat addiction. Methadone maintenance treatment was proposed by Vincent Dole and Marie Nyswander in 1964, with the hypothesis that high methadone doses can eliminate the thirst for substance use and interrupt any euphoria of self-heroin resulting from cross tolerance. Thus, opiate users are free from mental occupation with substance-seeking and substance-seeking behaviors, and their body enzymes can therefore be redirected to more efficient pathways [36].

There have been very few studies comparing the efficacy of methadone maintenance therapy and other common treatments, including non-pharmacological treatments, on the psychiatric disorders of the population of drug abusers. Evidences from reviewed experimental studies suggest the efficacy of opioid dependence and agonist maintenance therapies, especially methadone maintenance therapy, as a common treatment in most countries [37].

One of the characteristics that makes methadone suitable for the addiction treatment is the efficacy of this drug in eliminating the withdrawal symptoms, that are occurring due to suspension of drugs intake for 24 h or longer. Methadone is a long-acting pure agonist that resides on μ receptors and removes withdrawal symptoms [38].

Broers et al. referred to the role of methadone as a protective factor in reducing injections and common syringe use [39]; similarly, Beoers et al. highlighted the role of methadone treatment in significantly reducing AIDS and hepatitis B and C among addicts [40]. Dolan et al. also reported that methadone therapy (over 60 mg/day) is effective in reducing injections in addicts [41].

In a study comparing two groups of methadone-treated addicts (n = 62), Lollis et al. concluded that methadone-treated groups had less risky sexual partners and were more likely to use safe sex, and there was a significant difference between the two groups in this regard [42]; their findings are consistent with the results of the research work conducted by Gossop et al. [43].

To investigate the effect of factors affecting heterogeneity, the meta-regression test was used for the two factors of ‘sample size’ and ‘year of the study’. The results show that before and after the intervention, with increasing sample size, the average depression scores increase. Moreover, before and after the intervention, with increasing year of study, the average scores of depression decrease, which may be due to the development of treatment and diagnostic methods for depression in recent years.

Methadone use clearly reduces risky behaviors such as injections, tattoos, self-harm, unsafe sexual behaviors, and imprisonment. Given the prevalence of addiction in communities and the detrimental consequences of such high-risk behaviors, particularly transmission of infections such as AIDS, hepatitis B and C, and the associated costs, the development of addiction treatment centers, encouragement of addicts to use therapies offered at these centers, and provision of related facilities are recommended.

The results of the present study show that methadone significantly reduces depression among substance abusers. It is recommended to treat addicts using methadone under the supervision of a psychiatrist and along with counseling in addiction treatment centers.