Overall, the findings of the current clinical trial study revealed that zinc supplementation could lower inflammation status and oxidative stress while improving withdrawal symptoms in opioid addicts. Most of the studied patients were male regarding the higher prevalence of opioids in males and the cultural and social conditions, wherein males are more likely to withdraw. The results showed that the studied patients did not have a high underlying disease prevalence, probably due to patients’ low BMI and low mean age. Our study showed that taking 30 mg of zinc gluconate supplementation daily for one month and routine treatment in patients with opioid withdrawal syndrome could effectively reduce oxidative stress (e.g., an increase in TAC) and a reduction in pro-inflammatory cytokine and lipid peroxidation index.
Zinc, the second most abundant element in the body after iron, exerts a wide variety of roles, such as contributing to the body as an antioxidant . It also has an essential role in the structure and function of antioxidant enzymes and biological membranes. More than 15% of people worldwide have zinc deficiency, which is more common in people addicted to opioids . Zinc deficiency in addicted people is highly associated with enhanced urinary excretion. Malnutrition is another cause of zinc deficiency in addicted people . Few studies have investigated the effect of zinc supplementation in patients suffering from opioid withdrawal syndrome. Despite most of the other studies in this regard that are on animals, the present study is on humans. It has been evidenced that oral supplementation can reduce the symptoms of opioid dependence . Results of an animal study performed by Ranjbar et al. demonstrated that zinc sulfate supplementation improves oxidative and reduces MDA and DNA damage compared to the control group. Based on the results of the Ranjbar study, the antioxidant enzyme activity in the liver of rats significantly increased in the zinc-treated group except for the TTG compared to the control group. The mentioned results are consistent with those mentioned in our study. Investigating patients is another strength of the present study. In a survey on morphine-dependent rats, Ciubotariu et al. showed that the use of zinc sulfate is effective in reducing opioid dependence . In another study by Larson et al. (2000) on mice, it was observed that zinc reduced pain in morphine-dependent mice . Xu et al. concluded that antioxidant administration could inhibit oxidative stress and reduce the withdrawal symptoms of heroin . Ba Cemek et al. observed an increase in the level of lipid peroxidation while that of the antioxidants decreased during the withdrawal syndrome. Moreover, the administration of antioxidants such as selenium and vitamin E reduces lipid peroxidation . Pan et al. showed that oxidative stress increases during withdrawal syndrome and t antioxidant administration could inhibit oxidative stress and reduce withdrawal syndrome . In the present study, symptoms of depression, euphoria, and withdrawal showed more improvement in the intervention group. Baker et al. also confirmed that the administration of antioxidants could lower oxidative stress and the severity of withdrawal symptoms . Elsewhere, Klotz et al. showed the defensive and antioxidant effect of zinc .
Prasad et al. observed that zinc deficiency increases oxidative stress and inflammatory factors. It was also reported that the administration of food supplementations or zinc declines two mentioned factors, which conforms with the present study results . According to the results of another study by Prasad et al., in people taking zinc supplementation, the production of oxidative stress markers and the incidence of infection decreased significantly . In line with the present study, a recent study performed in Egypt by Saad-Hussein et al. showed that zinc supplementation in pesticide sprayers was associated with increased antioxidant capacity and decreased MDA . The main mechanism of action zinc in reducing the symptoms of withdrawal syndrome is not yet fully understood. Zinc may reduce the symptoms in these patients by binding to opioid agonist receptors µ . Therefore, generalizing the results of animal studies on a human should be done cautiously because zinc is usually injected into animals while it is used orally in humans. Elsewhere, it was reported that other antioxidant compounds decrease patients’ symptoms and faster recovery during opioid withdrawal. For instance, Mostaghinejad et al. concluded that curcumin might contribute to reducing the withdrawal syndrome in rats in a dose-dependent manner . Salahshour et al. showed that crocin as an antioxidant compound in saffron could effectively produce free radicals caused by morphine consumption . Additionally, Hasani et al. demonstrated the anti-oxidative impact of zinc sulfate on liver oxidative stress in morphine-withdrawal syndrome in rats .
The current study results indicated that TNF-α led to a significant reduction in the intervention group after receiving zinc supplementation. Some other studies reported that inhibitors of this parameter have a major role in the immune system in the development of withdrawal syndrome. It has also been shown that inhibitors of this inflammatory factor mainly contribute to decreasing the symptoms of withdrawal syndrome . Consistent with the present study, it was reported that zinc supplementation increased the immune system and reduced inflammation . Opioid withdrawal also inhibits the immune system, including inhibiting the proliferation of B-lymphocytes, suppressing the production of interleukins 2, 4, and 12 from T lymphocytes, and reducing the activity of killer cells . Withdrawal of opioids inhibits interleukin 12 production, increasing the infection risk .
In the present study, the patients in the intervention group were recommended to take zinc along with food to prevent gastrointestinal side effects. No serious side effect was reported for zinc to discourage patients from zinc supplementation. Taking zinc, especially orally, is associated with side effects such as nausea, vomiting, epigastric pain, lethargy, and extreme fatigue that may occur if consumed more than the allowable level . Like other epidemiological studies, the present study has some limitations. One limitation is relatively small sample sizes. Another limitation of this study was the lack of measuring serum zinc levels in patients and ensuring correct consumption in the intervention group.