We found only two experiments focusing on the effects of zinc ions or zinc deficit on opioid dependence and results are accordant: zinc reduces dependence intensity when administered during dependence induction phase, while zinc chelators increase withdrawal manifestations (jumpings). Both these experiments used morphine and evaluated the intensity of naloxone-precipitated withdrawal [40, 41]. To our knowledge, there are no clinical studies regarding zinc influence on any type of substance-addiction or other addiction-types.

One shortcoming of the mentioned studies (on rats and mice) in terms of predictability for human aspects of addiction is that they did not use self-administration models: the doses of morphine used for dependence induction and the moment of their administration was established by the experimenter, and this represents a considerable difference compared to the characteristics of addiction in humans, where drug-taking habits have a strong determination by social conditions. Animal models of drugs self-administration are more predictive to human patterns of drug-taking compared to dependence animal-models where the drug administration is performed by external factors (such as the experimenter) [99]. Even more, the predictability of such animal experimental studies to humans is questionable, in the context of our hypothesis, especially as zinc was given by intraperitoneal injection in rats [41], whereas zinc salts as dietary supplements in humans are administered orally.

Most probably, the result of cited researches [40, 41] can be, at least partially, be put in relation with zinc ions property of decreasing morphine-binding to receptors, as revealed by in vitro studies. There are no specific data showing decreased morphine receptors-binding by zinc ions, but decreased binding of a μ-specific agonist by zinc was demonstrated [42] and other in vitro studies [43, 78, 79] showed reduced opioids-binding (both agonists and antagonist) to receptors by zinc, evident even at physiological concentration. The μ-receptors type is particularly susceptible to this inhibition type, but in case of δ-receptors, the number of binding sites is also decreased, while the affinity of opioids such as pentazocine to the non-opioid receptor σ is un-affected by zinc deficit [83]. The μ-type of opioid receptors-mediated effects has the most important contribution to addiction development [100]. Apparently in disagreement with the effect of zinc of lowering opioids biological effects by decreasing their binding affinity to receptors (evidenced by in vitro studies) are the evidences from animal experiments showing a positive correlation between the activity of endogenous opioids system and zinc levels [72, 86].

The results of the mentioned animal studies showing reduced morphine withdrawal in zinc-administrating conditions and withdrawal enhancement by zinc chelators [40, 41] suggest that a possible beneficial role of zinc supplementation in humans taking opioid treatment for chronic pain in reducing the risk of addiction development or the severity of addiction and tolerance is worth testing. Indeed, the risk of developing addiction in these patients is low (below 10 %) [101], but tolerance to opioids represents an important problem.

The idea of zinc supplementation in patients with malignant tumours taking opioids for pain suppression is reinforced by human studies documenting reduced zinc levels in opioid-users [44–47, 69]. In these patients, zinc deficit and its consequences as an additional strain to disease or to its associated conditions, can easily be avoided if discovered on time. However, low levels of zinc are mainly documented for the persons where controlled-use (as recreational drugs of abuse) has turned to addiction, and not for patients treated with opioids for chronic pain or other medical purposes. Most of the above-mentioned studies focused only on microelements homeostasis, but not on the feeding-habits. Opioids are known to induce side effects on the gastrointestinal tract, such as constipation, anorexia, vomiting, gastro-oesophageal reflux, abdominal pain [102] which may explain the tendency to malnutrition in opioid-users. One study assessing the changes in nutritional habits of opiates dependent persons during of methadone maintenance treatment revealed that, before enrolling in the treatment, the intake of calcium and magnesium was low, whereas low zinc intake was seen only in the women group; after four years of treatment, low zinc intake was noticed only in the men group. Several minerals and vitamins (such as iron, vitamins B1, B2, C, niacin) low-intake levels were revealed both before and after treatment, but there are significant differences between genders [103]. Apart from the human studies showing the association between decreased zinc levels and opioid-consumption, there are animal studies evidencing reduced brain zinc level following opioid administration [77], while data regarding zinc serum in opioids-treated animals are controversial [75, 77]. So, it is not well-established if opioids induce zinc deficiency or just altered distribution, as, on the other hand, there are also evidences that mild zinc deficiency is not accompanied by reduced brain zinc in rodents, as adaptation of the transporters favours the brain uptake of zinc ions [28, 29].

Zinc deficiency, associated to the depletion of other essential nutrients, including minerals and vitamins, can be considered a consequence of malnutrition. Both cancer and pain are conditions associated with the tendency to deficient feeding [104, 105]. On the other hand, reduced zinc level was proven to determine impaired-feeding in animal models [72, 73], while in humans, zinc administration alone (50 mg elemental zinc/day) is believed to have a role in alleviating feeding-habits in anorexia nervosa, by decreasing the level of depression and anxiety [106]. Reduced zinc also affects taste perception [25].

When discussing the opportunity of zinc administration in cancer patients, it should not be disregarded that zinc deficiency represents a predisposing factor for malignant tumours development, as zinc depletion increases the inflammatory status, impairs the immune system functioning, antioxidant defence, and affects the DNA structure [107]. Zinc deficit is common among cancer patients, which are also more prone to develop infections. So, zinc has a beneficial role in infections prevention by stimulating the immune system [21]. In case of cancer therapy, side effects of antitumor drugs (such as vomiting, diarrhoea) represent further factors which can favour nutrients deficit.

Moreover, decreased zinc has a certain influence on other mechanisms involved in the addiction downward spiral, as it is associated with depression-like symptoms and anxiety in both humans and animal models [26, 27], which are known to induce drug-taking behaviour [108]. Animals studies showed reduced endogenous opioidergic system activity following zinc depletion [72, 85]. Normalizing zinc level in zinc-deficient patients taking opioids for chronic pain could have a contribution to the reduction of the drug-seeking behaviour and of the self-administered opioid doses by attenuating depressive symptoms and enhancing endogenous opioidergic system activity, which may lower the craving.

So, as suggested by animal studies, we have hypothesised in the current review that zinc administration as dietary supplement may reduce the risk of developing dependence in patients with cancer treated with opiates for chronic pain. Apart from the assumption above, in the previous paragraphs, further possible benefits of zinc supplementation in such persons are discussed. To summarize, increasing zinc intake in these patients not only corrects a metabolic misbalance commonly encountered in both cancer and opioid-use (which is most likely not just a consequence of feeding-habits), but it may also improve conditions such as tendency to malnutrition, depressive-symptoms, anxiety, susceptibility to DNA-damage and infections. Other clinical signs and symptoms which would be alleviated by repletion (to which response is believed to appear fast [20]) might include: skin lesions, impaired night vision, altered smell and taste perception, growth retardation, male hypogonadism, impaired wound healing, increased inflammatory status [21–26].

Zinc low toxicity represents one more fact pleading for zinc supplementation in opioid-users [31–33]: when taken orally, even doses tens of times higher than recommended daily allowance determine only non-severe manifestations, mainly digestive.

If in vitro study evidences that zinc inhibition of opioid-agonists binding to receptors could explain, at least in part, reduced opioid dependence under zinc-administration conditions and withdrawal potentiating by zinc-chelators in rodents, the same evidences also raise the problem of decreased opioid analgesia potency under zinc-administrating conditions. Therefore, if zinc co-administration with opioids would decrease the risk and the severity of dependence/addiction development versus opioid-only administration, than this might come with the price of zinc lowering the analgesic effect of opioids. In humans, opioid doses used for pain suppression are self-regulated, and if zinc reduces opioid action at receptor level, it seems logical to consider that opioid potency is also affected, which may lead to increasing opioid administered doses. So, the chance to reduce addiction intensity or susceptibility to addiction becomes debatable. On the other hand, dependence is mainly mediated by μ-receptors [109], while in analgesia δ and κ-opioid receptors are also involved, but ligands affinity to δ and κ receptors is less affected by zinc inhibition, as shown in vitro [42].

In order to have an idea of the extent to which zinc might affect opioid-analgesia, the medical literature was searched to document the effect of zinc on pain perception in opioid-free and opioid-administrating conditions. The search revealed scarce data derived from the human studies. On the other hand, in animals, zinc formulations determine, at non-toxic systemic or local doses, indubitable analgesic effects in different models of pain: acute visceral, mechanical and thermal pain, under regular, inflammatory and neuropathic conditions [48–54]. Zinc effects on chronic pain animal models are less studied. It is, however, questionable if zinc analgesic effect can be additive to opioid-induced pain-suppression. In animal models, potentiation of morphine antinociception by zinc was evidenced in the case of a nano-particals ZnO formulation, but classical formulation does not modify morphine antinociception [54], while systemic zinc administration enhances tramadol-induced analgesia [98]. Our study showed that ZnCl 2 administration during dependence-development does not alter morphine analgesia in tolerant rats [96], but others proved the inhibition of acute morphine antinociception by intrathecal zinc, however accompanied by tolerance inhibition [40]. Another study claims that zinc deficiency decreases opioid-analgesia in mice [97]. To our knowledge, in humans, the effect of zinc on opioid-analgesia (either in non-dependence, tolerance or addictive condition) has not been studied. Zinc supplementation influence on the analgesic effect of an acute opiate dose in dependent/tolerant individuals therefore becomes therefore very difficult to predict. Further clinical studies are needed, as tolerance to opioid is common in patients treated with such substances, especially the tolerance to analgesia [101]. If indeed, there are several data pleading in the favour of our hypothesis regarding the opportunity of zinc supplementation in persons treated with opioid for chronic pain suppression (such as zinc low toxicity, reduced zinc levels following opioid use, depressive symptoms associated with zinc deficiency, zinc lowering morphine dependence documented in rats), the problem of zinc interferences with opioid analgesia remains controversial and seems to represent the main contra-argument to the hypothesis. In case of animal studies, the inhibition of acute tolerance to morphine analgesia by zinc [40] was proven in mice, but it is accompanied by analgesia inhibition. The very few studies on how zinc affects opioid analgesia in opioid-dependent animals have not considered self-administration models [40, 96], but dependence models where administration is performed by the experimenter, whereas in humans, analgesic opioid doses and the moment of their administration are supposed to be self-controlled. Another problem is the lack of correspondence between doses used in acute pain animal models, where zinc is administered parenteral, and zinc levels reached at action site in case of oral supplementation.

We suggest a controlled clinical trial comparing the evolution of opioid doses needed for pain-relief in cancer patients cohorts with adequate nutrition versus adequate nutrition associated with zinc supplementation. It is mandatory to have a survey on the nutrition, associated drug-therapy, and environmental conditions in case of patient groups, as all these can determine the lack or excess of essential nutrients (including vitamins, minerals, aminoacids etc.) and as there is a dynamic cooperation and complex interaction and between these nutrients.

We speculate that zinc supplementation would most probably be beneficial for patients with cancer taking opioids for pain therapy, where dependence is less likely to develop, rather than for people taking them in recreational purposes, where psychological addiction is more frequent and severe [110]. Zinc supplementation for patients receiving methadone or other long-acting opioids maintenance treatment for opioid addiction is also worth being considered, especially as zinc urinary elimination is increased in case of methadone treatment [69].

Zinc ions strongly influence lots of neurotransmitter systems, including dopaminergic, glutamatergic, serotoninergic system; all of these has certain roles in addiction development and addiction-related phenomena, but such influence is not discussed in this review, due to the complexity of such a subject and to the difficulty of data interpretation.