Treatment of opioid withdrawal syndrome

FEDERAL MEDICAL RESEARCH CENTRE OF PSYCHIATRY AND NARCOLOGY

OF THE MINISTRY OF HEALTH OF THE RUSSIAN FEDERATION

NATIONAL SCIENTIFIC CENTER OF NARCOLOGY
OF THE MINISTRY OF HEALTH OF THE RUSSIAN FEDERATION
LLC "AKELA-N"

Xenon in the treatment of opioid withdrawal syndrome 

The methods of use of xenon in narcology described just far have involved the use of anesthetic and respiratory equipment, and an anesthesiological approach. This circumstance not only required that medical institutions had to be equipped with specialized medical technologies, but also introduced additional requirements for the qualifications of the medical personnel authorized to perform the procedure.

The effectiveness of the method was evaluated in accordance with the study protocol "Evaluation of the efficacy and safety of using XeMed® medicine for the treatment of withdrawal syndrome and post-withdrawal state in patients with opiate dependence".

A study conducted at the FSBI "NSCN" of the Ministry of Health of the Russian Federation not only proved the effectiveness of using xenon in the treatment of opiate withdrawal syndrome, but also showed the advantage of using subnarcotic gas concentrations due to improving patient safety, reducing risk of hypoxia, and reducing xenon consumption during the procedure.

The developed method will significantly expand the circle of specialists authorized to perform the procedure and, as a result, increase the number of medical institutions of narcological profile, which will have the opportunity to implement a modern, highly effective method of treating opium withdrawal syndrome.

Justification of the choice of the optimal xenon concentration and duration of the procedure

One of the objectives of the study was to determine the optimal concentration of xenon in the breathing mixture and the duration of inhalation. The study was conducted in two groups. The main group included 45 men diagnosed with "opioid dependence, withdrawal syndrome", in accordance with ICD 10 criteria.

The group did not include patients with concomitant mental illness, acute somatic and neurological diseases, or chronic somatic neurological diseases in acute stage. The control group included 45 healthy men who received xenon as an adaptogen in order to increase the tolerance to physical and emotional stress.

All subjects of the study received a single inhalation of xenon-oxygen mixture by apparatus Circuit therapeutic inhalative xenon KNP-01. Safety of the subjects was ensured by visual observation of the patient's condition, monitoring of the main indicators of the quality of the gas mixture in the breathing circuit, and vital signs of the subject of the study. Blood pressure, heart rate and blood oxygen saturation were measured using a Nihon Kohden PVM 2701 bedside monitor over a period of time.

Each group was randomly divided into 3 equal subgroups, differing in xenon concentration in the breathing mix: 15%, 25% and 35%.

The duration of the procedure was proposed to be regulated by the subjects of the study - they could breathe xenon-oxygen mixture until they developed signs of fatigue, or mental discomfort, and then they could interrupt the study. The maximum duration of the uninterrupted procedure was 30 minutes. During the study, the following data were recorded: the occurrence of psychomotor excitement, illusions or hallucinations during the procedure; the duration of the procedure; the number of interrupted procedures; the number of patients who have reached full xenon saturation.

It is necessary to clarify that xenon, when it enters the lungs, rapidly diffuses through the alveolar membrane and is distributed throughout the body. If the inhalation is carried out on a closed circuit, then after a while the alveolar and arterial concentrations of xenon become equal and equilibrium occurs. Due to the fact that xenon does not enter into chemical reactions and does not undergo metabolism in the body, in practice the onset of saturation is characterized by the absence of the need to supply xenon to the respiratory circuit. The fact of saturation is recorded if maintenance of the target concentration did not require the addition of xenon to the breathing circuit within 1 minute. The introduction of this parameter was necessary to understand whether the subject who interrupted the procedure has received a therapeutic dose of xenon or not.

In addition, in the group of opioid withdrawal syndrome (OWS), the duration of effect of the monotherapy with xenon-oxygen mixture (XOM), i.e. the time elapsed from the completion of the procedure to the appearance of complaints of disorders characteristic of OWS, was estimated,. After that, patients were treated in accordance with the standards of treatment of this condition.

The results of the study. It was noted that when a xenon concentration in the breathing mixture reached 25-30 vol. % and higher, apparently individual level for each subject, a number of subjects of both groups developed psychopathological disorders in the form of anxiety, fear, as a rule in combination with poorly controlled psychomotor agitation. The majority of patients in the OWS group interrupted the procedure, when such disorders occurred. In the control group, such violations were observed less frequently and, even if they occurred, the subjects controlled themselves better - only in one case the procedure was interrupted. Deceptions of perception in the form of illusions or hallucinations were observed in some subjects of the OWS3 subgroup. Patients "heard" a series of clicks, ringing, and monotonous buzzing. In the sounds of working equipment, or quiet conversation in the next room, they "recognized" a dialogue about themselves, sometimes of condemning, or accusatory nature. False recognitions, as well as visual hallucinations were observed. At the same time, anxiety, or psychomotor agitation was not always observed. Often, patients positively, with interest, responded to what was happening, being completely certain that it was real. After the procedure was completed, the state of the subjects returned to norm very quickly, in less than a minute; literally before our eyes, a confidence in reality of what was experienced transformed into an understanding that these were only deceptions of perception. Participants willingly, with the smallest details, told about what they saw, heard, and felt, perceiving the experience as an interesting adventure.

After inhalation of the xenon-oxygen mixture a temporary disappearance of withdrawal disorders lasting from less than an hour to a day has been always observed in patients of the OWS group.

In the case of recurrence of withdrawal symptoms, patients with OWS were prescribed standard treatment for opiate withdrawal syndrome. Table 1 shows the quantitative results of the study. 

Table 1. Study results 

The obtained data were statistically processed, as a result of which the following patterns were established:

1 During xenon inhalation in the main group (OWS) psychopathological disorders were observed much more frequently than in the control group (CON).

2 In the OWS3 subgroup (xenon concentration of 35 vol.%), unlike the OWS1, OWS2 subgroups and the entire CON group, psychotic disorders in the form of verbal and visual illusions and hallucinations were observed.

3 The number of interrupted procedures was significantly higher in the OWS group.

4 The number of psychopathological disorders in the OWS group is in direct proportion to the concentration of xenon in the respiratory circuit.

5 In the OWS group the average duration of the effect of a single inhalation of XOM directly depends on the fact of xenon saturation.

6 In the OWS group the average duration of the effect of a single inhalation of XOM does not depend on the duration of the procedure, if the "Xenon saturation" parameter is excluded.

7 In the OSA group the average duration of the effect of a single inhalation procedure does not depend on the age of the patient.

The study has shown that the duration of procedure of the xenon inhalation for the treatment of OWS should not exceed 20 minutes (the average duration of the procedure that the patient can "endure").

The concentration of xenon in the breathing mix should not exceed 25% due to the risk of developing psychopathological disorders.

An important parameter affecting the effectiveness of treatment of OWS is saturation of the body with xenon, since there is a direct relationship between these two parameters. In this case, the fact of complete saturation, but not the duration of the procedure itself plays the key role.

Xenon in the treatment of opioid withdrawal syndrome

The main group included 33 male patient diagnosed with "opioid dependence, withdrawal syndrome", in accordance with ICD 10 criteria. The group did not include patients with concomitant mental illness, acute somatic and neurological diseases, or chronic somatic neurological diseases in acute stage. The distribution of the subjects by age is shown in table 4.

All patients were given daily inhalations of the xenon-oxygen mixture for 10 days according to the methodology described above. The duration of each procedure was 20 minutes, the concentration of xenon in the breathing mixture was maintained at 25%. During the study, the following data were recorded: the weight of the patient; the duration of regular use of the drug (according to patients' self-reported information); daily dose of the drug; the time from the start of the procedure to the onset of saturation with xenon; the amount of consumed xenon, the duration of the effect of monotherapy with xenon-oxygen mixture (the time elapsed from the moment of completion of the procedure to the appearance of complaints of disorders characteristic of OWS).

If a patient developed complaints during the study, he/she was prescribed medications in accordance with the standards of treatment of OWS. The main results are presented in Fig. 7.

Fig. 7. Changes in the duration of the effect of xenon inhalation

The following results were obtained from a statistical analysis:

1 A correlation between the duration of the effect of xenon inhalation and the daily dose of the drug was found, and this dependence was observed only during the first three inhalations.

2 The duration of the effect of xenon inhalation does not depend on the duration of chronic opioid intoxication.

3 The amount of xenon consumption does not depend on the patient weight.

4 There is no correlation between the duration of the effect and the amount of xenon which has been consumed.

5 There is no relationship between the duration of the effect and the xenon saturation time.

6 There is a direct correlation between the amount of xenon consumption and the saturation time.

The study has found that as the number of procedures increases, both the xenon consumption and the saturation time of xenon decrease, and there is a probabilistic relationship between these parameters. At the same time, the average duration of the effect remains approximately at the same level - 17-20 hours, while the xenon consumption and the saturation time decrease almost twofold. That is, there is an accumulation effect, possibly associated with metabolic or structural changes in the central nervous system due to the action of xenon. This conclusion can be made, since there is no correlation between the patient weight and the amount of xenon consumption, otherwise it would be possible to assume that this effect is due to the deposition of xenon in the body (this gas has a high lipid solubility coefficient).

The average xenon saturation time decreased from 11 minutes in the first procedure to 4.5 minutes at the end of the course of treatment. Taking into account the standard deviation, a sufficient duration of the procedure was calculated: about 20 minutes. This approach allows optimizing employment of a doctor and an operative time of medical equipment.

Differences in the duration of the effect of repeated xenon inhalations reflect the well-known dynamics of withdrawal disorders during opioid discontinuation, which reach maximum on the 3-4th day with subsequent reduction. Subsequently, starting from the 7-8 th day, post-withdrawal disorders increase, and the duration of the effect of xenon inhalation decreases again.

Interestingly enough, there is a correlation between the daily dose of the drug and the duration of the effect of xenon inhalation. Opioids are known to cause still not fully studied changes in metabolism in the CNS. Recently, strong evidence has been found of the close relationship between the opiate and glutamate systems. It can be assumed that xenon, as a blocker of NMDA receptors, has a regulating effect on the disturbed neurotransmitter metabolic processes in patients with OWS. This can be judged on the basis of a gradual decrease and then disappearance of the correlation between the daily dose of the drug, and the duration of the effect of xenon inhalation.

All subjects had a good tolerance of xenon therapy procedures. Only in 6 patients during the first inhalation moderate anxiety with motor agitation, restricted to the bed, was observed. In this case, the patients were in contact with the doctor, quickly calmed down, the procedure was never interrupted. Inhalation of xenon in therapeutic dosages according to the method described above is safe - parameters of oxygenation and vital functions during the procedures were within physiological limits.

The use of xenon made it possible to significantly reduce the drug load in the patients; side effects characteristic of traditional psychopharmacotherapy (neurolepsy, excessive sedation, orthostatic disorders) were not observed in the study group.

Conclusion

The use of therapeutic dosages of xenon is effective for the treatment of opium withdrawal syndrome and post-abstinent conditions in opiate addiction, especially in patients with intolerance to specific pharmaceuticals used in the treatment of drug dependence. At the same time, the saturation of the body with xenon is essential for this method.

The effectiveness of xenon in the treatment of opioid withdrawal syndrome depends on the initial dose of the opioid regularly taken by the patient and does not depend on the duration of the abuse, if it lasted at least 3 years. The effectiveness of the method increases with repeated procedures.

Therapy with xenon significantly reduces the manifestations of autonomic disorders, almost completely relieves pain, allows to reduce the drug burden on the patient and to avoid adverse reactions of ongoing psychopharmacotherapy. This is most relevant for patients with toxic hepatitis, since the appointment of psychotropic drugs in these patients, even in moderate doses, can lead to drug intoxication, severe adverse reactions.

Inhalation method of administration of xenon is safe, provides a quick start and good controllability of pharmacological effect.