Opioid dependence is an increasing clinical and public health problem. Current pharmacotherapies have limited efficacy and cause serious side effects. Increasing bodies of evidences suggest the neuropeptide, oxytocin (OT), as a potential treatment for drug abuse disorders. The current study was designed to evaluate the effect of OT on withdrawal, craving and anxiety scores, cortisol and dehydroepiandrosterone sulphate (DHEAS) blood level in heroin-dependent male patients. This randomized, double-blind placebo-controlled clinical trial was conducted on 58 males with opioid dependence by Abstinence Center of Addictive People in Iran. The participants were randomly allocated to receive intranasal OT (single dose; 40 IU, n = 29) or placebo (n = 29). Heroine withdrawal, craving and anxiety scores were measured using the Opioid Withdrawal Scale, Visual Analogue Scale and (Desire for Drug Questionnaire), and Hamilton checklist respectively. The cortisol and DHEAS levels at baseline and different post-intervention time were measured using a competitive immunoanalysis method. Acute OT administration reduced craving and withdrawal scores but did not change anxiety significantly. Single dose of OT decreased the level of cortisol and improved the cortisol/DHEAS ratio in the heroin users during abstinence (p < 0.01). These results suggest that OT may be useful in the attenuation of craving, withdrawal symptom in heroin-dependent patients and might be considered a new potential treatment for heroin dependence where positive effects of OT on stress-related hormones may be involved in this effect of OT.

About 31 million people worldwide are affected by drug use disorders. According to WHO, roughly 450,000 people died as a result of drug use in 2015. Opioids continued to cause the most harm, accounting for 76% of the deaths where drug use disorders were implicated. The recent increase of opium production has resulted in an increase in heroin use in many nations [1]. Heroin dependence is a devastating, chronic psychiatric disorder. It is a maladaptive state associated with a withdrawal syndrome and intense craving. Heroin dependents experience an extreme amount of stress for a long period of time after they stop drug abuse. Treatment strategies in drug dependence are usually aimed at achieving control of withdrawal syndromes and reducing relapse and craving. Several protocols of treatment are available for heroin dependence including both behavioural and pharmacological interventions [2]. Methadone maintenance therapy (MMT) has become a treatment of choice for chronic opioid-dependent patients who cannot achieve abstinence. It has been shown that MMT can reduce heroin use, risk of HIV transmission, mortality, and crime [3]. However, MMT have limited effectiveness for some patients due to a variety of pharmacological and individual factors, while long-term methadone use can cause damage to the nerves, liver and cardiovascular system. This has led to the development of alternative forms of maintenance treatments [4].

Oxytocin (OT) is a neuropeptide that is produced by the hypothalamus and plays an important role in reward, social affiliation and bonding, associative learning, memory and stress responses [5, 6]. There is now strong evidence that OT is a possible candidate for the treatment of maladaptive processes associated with addiction [7]. OT inhibits opioid tolerance [8], reduces opiates self-administration and decreases craving and stress response in marijuana dependent individuals [9]. A negative relationship between plasma OT levels and novelty seeking and increased negative affect and stress in different types of drug abuse have also been demonstrated [10, 11]. Abstinent heroin-dependent patients experience negative affective state characterized by dysphoria, irritability, anxiety, as well as abnormal stress reactivity that drives drug seeking behaviours. These patients show elevated stress reactivity during withdrawal syndrome, which is related to heightened craving and symptoms of withdrawal [12]. Indeed, the activation of the hypothalamic-pituitary-adrenocortical axis and the elevated cortisol levels have been reported during opioid withdrawal syndromes, while opioid agonist administration reduced cortisol secretion, craving scores and amygdala activity in heroin-dependent patients [13]. Furthermore, dehydroepiandrosterone sulphate (DHEAS) may buffer the effects of cortisol and play a role in the resilience and in successful adaptation to the stress. Cortisol and DHEAS and especially cortisol/DHEAS ratio are assaying as neuroadaptive stress hormones to predict health outcome [14, 15]. Given the established strong link between stress, drug use and relapse as along with the known dysregulation of hypothalamic pituitary adrenal (HPA) axis activity associated with substance-use disorders [16], the effects of OT on the stress system have received a lot of attention. Therefore, the current study was designed to evaluate the acute effect of OT administration on withdrawal, craving, anxiety scores, and neuroadaptive stress hormones levels in the male heroin-dependent individuals.

Trial Design and Participants

This randomized, double-blind placebo-controlled clinical trial was registered in the Iranian website for registration of clinical trials as http://www.irct.ir: IRCT (2015103024792N1). This research was carried out in accordance with the Declaration of Helsinki and received approval from the Ethics Committee of Kashan University of Medical Sciences (KAUMS). The participants were recruited from an inpatient treatment centre of (Behzisti Addiction Rehabilitation Center, Isfahan, Iran), between December 2016 and March 2017. The participants (58 males) were selected by trained staff at the clinic following a blindness method. Due to the inadequacy of female heroin-dependent patients (only 4), the trial was carried out with only male patients referred to the centre. During a distinctive period of time (6–9 days from abstinence), the subjects were prevented from taking any kind of illicit drugs including narcotic medicines. Only those participants who met the DSM-IV criteria for heroin dependence were selected. The participants were 20–60 years old. Exclusion criteria included other current substance abuse or dependence along with use of any psychoactive medication or medication known to alter HPA axis function. Drug urine tests were carried out to ensure that the subjects remained drug-free during the experiment. The procedure was fully described for each subject before starting the project and written informed consent was obtained [17].

Randomization

The subjects were assigned randomly to the treatment condition via a computer-generated random number by the aid of a trained staff at the clinic blindly.

Laboratory Procedures

An indwelling catheter was inserted at least 3 h before the sampling at 7 a.m. on the test day. The first cortisol and DHEAS blood sample were collected at 10 a.m. and then heroine withdrawal symptom was measured using the Clinical Opioid Withdrawal Scale [18]. The craving scores were assessed by Visual Analogue Scale [19] and Desire for Drug Questionnaire [20], while the anxiety was evaluated by Hamilton checklist [21]. Basal cortisol and DHEAS levels were assessed using a competitive immunoanalysis method on the COBAS E411 device. Referent intervals for morning cortisol and DHEAS were 138–690 nmol/L and 3–11 μmol/L respectively. The participants were provided with a light lunch. Then, medication was provided by the manufacturer of intranasal OT spray purchased from Novartis, Switzerland and the placebo spray (normal saline) purchased from Raha Company, Iran. At 13: 15 p.m., 40 IU of OT or normal saline was administered intranasally according to the previous studies [22, 23]. The participants were tested cue-induced craving task at 14 p.m. The task was a pictorial design consisted of heroin-related stimuli (heroine, pack, lighter, foil, heroine smoking, meeting a drug-using peer, watching others preparing and smoking) and neutral stimuli [24, 25]. At 14: 15 p.m., the task was completed. Withdrawal, craving and anxiety measurements were assessed again and then cortisol and DHEAS blood samples were collected from the participants at 30 and 60 min after the commencement of the task.

Statistical Analysis

To establish the normal distribution of the variables, the Kolmogorov-Smirnov test was used. The analyses were carried out based on the intention-to-treat protocol. Demographic, clinical and biological variables between the case and control groups were compared using the independent sample t test and 1-way repeated measures analysis of variance respectively. Differences in the proportions were assessed by the chi square test. Data is presented as mean ± SD or as median. The cortisol/DHEAS ratio was calculated as cortisol/DHEAS (* 100).

Demographics

A total of 68 individuals were interviewed and assessed for the study participation. The reasons for the study exclusion were medical issues (n = 5) and inability to provide a negative urine drug screen (n = 5). Therefore, this clinical trial was conducted on 58 male heroine addicted patients allocated to receive intranasal OT (single dose; 40 IU, n = 29) or placebo (n = 29) randomly. During the treatment phase of the study, 4 patients from the control and 3 patients from the treatment groups could not complete the trail (Fig. 1). Finally, our analysis sample included 51 participants (OT [n = 27] and placebo [n = 24]). The mean age of the participants was 33.8 years (SD ± 8.8 years). There were no significant differences between the 2 groups in terms of demographic information such as marital status and educational level (Table 1).

Table 1.

General characteristics of the study participants

General characteristics of the study participants
General characteristics of the study participants
Fig. 1.

Summary of the patient flow diagram.

Fig. 1.

Summary of the patient flow diagram.

Close modal

The Effects of OT on Withdrawal, Craving and Anxiety Scores

As shown in Table 2, intranasal administration of a single dose of OT significantly improved Desire for Drug Questionnaire (–17.16 ± 4.36 vs. 3.51 ± 1.24 p < 0.001) and Visual Analogue Scale (–8.42 ± 3.86 vs. 2.1 ± 5.11 p < 0.005) as craving scores. In addition, the acute administration of OT significantly reduced the withdrawal symptom as measured by Clinical Opioid Withdrawal Scale (–10.45 ± 2.99 vs. 2.45 ± 2.71 p < 0.001). However, OT therapy did not significantly affect the mean differences of the anxiety scores compared with the placebo group (–9.12 ± 1.89 vs. –6.39 ± 1.05 p < 0.11).

Table 2.

Means ± SD of craving scores; DDQ and VAS, COWS, and anxiety at baseline and after the oxytocin therapy in heroin-dependent patients. p values show the differences between after and before the study in each group and result from the paired t test

Means ± SD of craving scores; DDQ and VAS, COWS, and anxiety at baseline and after the oxytocin therapy in heroin-dependent patients. p values show the differences between after and before the study in each group and result from the paired t test
Means ± SD of craving scores; DDQ and VAS, COWS, and anxiety at baseline and after the oxytocin therapy in heroin-dependent patients. p values show the differences between after and before the study in each group and result from the paired t test

The Effects of OT on Stress-Related Hormones

The assessment of the serum cortisol level in the baseline did not show any significant difference between the control and the OT groups (20.28 ± 1.34 vs. 19.81 ± 2.38 µg/dL). The cortisol levels at 30 and 60 min after the stress test were 21.21 ± 1.51 and 22.34 ± 1.40 in the control group and 16.14 ± 1.57 and 15.21 ± 2.22 in the OT treatment group (Fig. 2). These results demonstrated that in comparison with the placebo group, the OT treatment significantly decreased serum cortisol level (p value < 0.01). The baseline DHEAS levels were 311.15 ± 12.69 and 312.69 ± 10.33 in the control and the OT group respectively. The DHEAS levels in 30 and 60 min after the stress test were 306.46 ± 10.45 vs. 314.47 ± 9.52 and 308.22 ± 11.06 vs. 317.53 ± 10.63 (Fig. 3). Results showed that there were no significant differences in DHEAS levels between the control and the treatment groups (p value = 0.133). However, as shown in Figure 4, the Cortisol/DHEAS ratio at 60 min after the stress test showed a significant difference (p value < 0.05) between the placebo (6.89 ± 0.84) and the OT groups (4.28 ± 0.81; Fig. 4).

Fig. 2.

The serum cortisol level (µg/dL) in the baseline and after cue-induced craving task (min) in control and OT groups. The results are expressed as mean ± SEM. ** p < 0.01 versus control group. OT, oxytocin.

Fig. 2.

The serum cortisol level (µg/dL) in the baseline and after cue-induced craving task (min) in control and OT groups. The results are expressed as mean ± SEM. ** p < 0.01 versus control group. OT, oxytocin.

Close modal
Fig. 3.

The serum DHEAS level (µg/dL) in the baseline and after cue-induced craving task (min) in control and OT groups. Results are expressed as mean ± SEM. DHEAS, dehydroepiandrosterone sulfate; OT, oxytocin.

Fig. 3.

The serum DHEAS level (µg/dL) in the baseline and after cue-induced craving task (min) in control and OT groups. Results are expressed as mean ± SEM. DHEAS, dehydroepiandrosterone sulfate; OT, oxytocin.

Close modal
Fig. 4.

The cortisol/DHEAS ratio (* 100) in the baseline and after cue-induced craving task (min) in control and OT groups. Results are expressed as mean ± SEM. DHEAS, dehydroepiandrosterone sulfate; OT, oxytocin.

Fig. 4.

The cortisol/DHEAS ratio (* 100) in the baseline and after cue-induced craving task (min) in control and OT groups. Results are expressed as mean ± SEM. DHEAS, dehydroepiandrosterone sulfate; OT, oxytocin.

Close modal

To our knowledge, the present study is the first randomized, double-blind placebo-controlled clinical trial on the effects of OT on withdrawal, craving and stress response in heroin-dependent patients. In this research, intranasal administration of OT (single dose; 40 IU) improved withdrawal symptoms, craving, cortisol level and cortisol/DHEAS ratio in the therapeutic group.

Numerous preclinical researches on the effects of OT on opioid-related behaviour have been done. Peripheral administration of OT has been shown to inhibit the development of the tolerance and withdrawal to opioids. This effect seems to be centrally mediated ([7, 26] for review). The mechanisms by which the OT changes the behavioural response to opioids are about to be understood. It has been shown that chronic morphine treatment inhibits OT synthesis in rats with a decrease in the supraoptic nucleus and nucleus accumbens and an increase in the ventral tegmentum area and locus ceroleus [27]. Also, repeated morphine administration has enhanced the OT receptor binding in the olfactory nuclei, piriform cortex, septum and amygdala, while it has decreased the OT peptide level in the hypothalamus. Administration of exogenous OT may reverse these changes in OT synthesis and receptors and this might translate to reversal of addictive behaviour [28].

Recent studies indicate that social attachments protect against addiction and health consequences of stress, whereas drug abuse and chronic stress can undermine social attachment [29, 30]. Indeed, negative social experiences generally increase the vulnerability to drug abuse, while the development of strong social attachments, including parent-offspring and adult pair bonding may buffer substance abuse [31]. It is suggested that OT increases resilience against addiction and stress through the interaction with the central dopaminergic, serotonergic and the endogenous opioid system. This is done by facilitating the process of social bonding and attachment-related information and its consolidation in internal working models. Thus, it contributes to promoting a shift from novelty seeking towards preference of social familiarity through the cortical route [32]. The increasing body of evidence shows that stress exposure is an important contributing factor to drug dependence and suggests that cortisol release induced by stress of withdrawal, increases drug reinforcement. Our clinical data suggest that the OT may be useful to reduce craving and withdrawal symptoms through its effects on the HPA axis and attenuating stress-related physiological and subjective response [16]. Our results indicate that OT does not affect subjective self-reporting of anxiety. Lack of effect on subjective stress may be attributable to inefficient OT’s dose or to the method used to assess stress (i.e., reliance on a blood venipuncture instead of salivary sample).

The present data demonstrates that intranasal OT decreased the serum cortisol level and improved the cortisol/DHEAS ratio, which has been proved to be a reliable predictor for health and stress. These findings are in agreement with the previous finding. It has been shown that intranasal OT significantly increased positive communication behaviour and reduced salivary cortisol levels during the couple conflict discussion compared with the placebo [33]. It has also been shown that exogenous OT administration has a boosting effect on the baseline activity of the brain OT system by raising brain OT levels [34, 35]. OT has been suggested to reduce HPA axis activation during the stress. It has been shown that the activation of the OT receptor in the paraventricular nucleus delays the transcription of the gene-encoding corticotropin-releasing factor, which is the main regulator of the stress response [36]. Molecular studies have shown localized OT receptors in the mesolimbic dopamine reward circuit, including the amygdala, the nucleus accumbens, the ventral tegmental area, and the corticotrophin-releasing factor stress systems [37]. OT and DHEAS are thought to influence central dopamine release considering the fact that the dopamine plays a major role in drug-induced reward. It is possible that OT administration also reduces craving and withdrawal-induced stress through interaction with the mesocorticolimbic dopaminergic system and other neurotransmitter systems involved in addiction [38]. It is a fact that OT itself does not have rewarding effects and makes it a potential adjunct treatment for heroin addiction [39].

Our study showed that intranasal OT reduced craving and withdrawal scores but did not change anxiety significantly in the heroin users during the abstinence. Also, the positive effects of OT on stress-related hormones may be involved in this effect of OT. Overall, this study suggest that OT may play a role in the attenuation of craving, withdrawal symptom in heroin-dependent patients, and can be considered a new potential treatment for heroin addiction.

Limitation

The relatively small number of the subjects enrolled in this study requires that our results be considered preliminary. Future studies of considerably larger sample size will be necessary to adequately test the validity of our findings. The long-term intervention might lead to better effects of OT. Finally, all participants were male and the current results need to be replicated in female groups.

The present study was supported by a grant from the Vice-chancellor for Research of KUMS in Iran. The authors would like to thank the Welfare of Isfahan Province for their assistance in this project.

This randomized, double-blind placebo-controlled clinical trials was registered in the Iranian website for registration of clinical trials as http://www.irct.ir: IRCT (2015103024792N1). This research was carried out in accordance with the Declaration of Helsinki and received approval from the Ethics Committee of Kashan University of Medical Sciences (KAUMS).

The authors declare that there are no conflicts of interests regarding the publication of this paper.

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