The use of opioids is an effective method of treatment for severe and acute pain; however, when they used inappropriately, in addition to their powerful pain-relieving properties, opioids cause significant side effects. The initial changes in the human body caused by the use of narcotic substances (opiates) are detected in the oral cavity, in particular, in the salivary glands. The earliest manifestations of pathological changes in the oral cavity are caries, stomatitis, gingivitis, periodontitis and xerostomia. Based on the results of our research and the study of the effect of opioids on other organs, we can conclude that long-term use of opioids has a significant negative effect on the structure of the submandibular gland and homeostasis of the oral cavity as a whole. The presence of a number of unsolved questions regarding the problems of structural reconstruction of the salivary glands during the use of narcotic agents, as well as the possibility of selecting the most effective methods of treatment and prevention of salivary gland diseases determined the choice of this research topic. Materials and methods. The research was performed on 15 mature, white, male rats with body weight 200–220 g, aged 4.5–6 months, which were kept under standard conditions at the vivarium of the Danylo Halytsky Lviv National Medical University. Animals were divided into two groups: experimental and control. In the experimental group, animals (10 rats) were daily administered an opioid analgesic (nalbuphine) intramuscularly according to the following schedule: 1st week – 8 mg/kg, 2nd week – 15 mg/kg, 3rd week – 20 mg/kg, 4th week – 25 mg/kg, V week – 30 mg/kg. Controls were 5 rats that were injected with 0.9% sodium chloride solution in a volume of 1 ml for 5 weeks. We used the histological method to conduct the research. Results. Damage to the organs of the oral cavity and the submandibular gland, in particular, is an element of comorbid pathology caused by long-term use of opioids. During the 5-week administration of the opioid, we observed irreversible destructive changes in the structural organization of the submandibular gland, which was characterized by the dilation of the vessels of the microcirculation, dystrophic and necrotic changes of the final serous and mucous secretory acini, necrosis of serocytes. Such pathological processes in the structural organization of the submandibular gland can cause an imbalance in the quantitative and qualitative composition of saliva and, as a result, a violation of the homeostasis of the oral cavity and the upper parts of the gastrointestinal tract. Conclusions. The results of the research demonstrate the negative impact of long-term opioid exposure on the structural organization of the submandibular gland and are similar to changes in other organs and body systems during long-term opioid exposure. The damage to microcirculation vessels is the starting and primary mechanisms in this process with the subsequent increase of irreversible destructive changes of the submandibular gland. The data of the scientific work have a wide practical and theoretical significance for morphologists, pathomorphologists and dentists in the aspect of developing new methods of diagnosis, prevention and treatment of salivary gland pathology in patients with opiomania and make it possible to establish safe terms of use of «nalbuphine».