Patent Application
20220313727
The invention relates to a gas mixture containing 50% of nitrous oxide (mol %) and oxygen, preferably 50% of oxygen (mol %), used as an inhalable drug for therapeutically treating patients continuing to experience chronic pain, in particular chronic peripheral neuropathic pain, despite taking at least two other different pain treatments, i.e. drug substances or compounds belonging to at least two classes different therapeutic classes, in particular patients who are refractory to said drug substances or compounds belonging to at least two different therapeutic classes.
Chronic pain can have a significant impact on the quality of life of many patients, in particular their functional activity, their sleep, their levels of anxiety and depression, etc. As a result, patients suffering from chronic pain, in particular from peripheral neuropathies, must be treated therapeutically, that is to say, must follow basic drug treatments aimed at reducing or eliminating their pain.
To this end, it is recommended that they first be administered first-line drug treatments, namely tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitor antidepressants (e.g. duloxetine) or even antiepileptics which act on sodium or calcium channels (e.g. gabapentin, pregabalin, etc.).
However, it has been found that these drugs are not efficacious in some patients since the pain persists despite taking these drugs. Moreover, other patients do not tolerate these treatments because these drugs lead in these patients to negative side effects, such as nausea, vomiting, drowsiness, dizziness, respiratory distress, etc. In point of fact, these side effects are difficult to bear, i.e. poor tolerance.
It is then necessary to resort to other drugs, such as for example opioids, or compounds or substances which are targeted more locally, such as qutenza.
However, the more patients are treated, the less they generally respond to new treatments. In addition, these patients are also the most vulnerable and therefore often have difficulty tolerating combinations of different treatments/drugs, in particular combinations of drug substances or drug compounds belonging to at least two different therapeutic classes, in particular combinations between opioids, antidepressants, antiepileptics and/or other local anesthetics.
In other words, it is difficult to provide relief to certain particular categories of patients suffering from chronic pain, in particular from peripheral neuropathies, and who are treated with combinations of different treatments, that is to say who are receiving drug substances or drug compounds from at least two different therapeutic classes because these patients have poor tolerance to these combinations and/or are less responsive to these combinations, in particular combinations between opioids, antidepressants, antiepileptics and/or other local anesthetics.
Moreover, FR-A-2981276 is known which describes the use of xenon or of N2O for treating particular neuropathic pain, namely pain induced by platinum salts (i.e., cisplatin, oxaliplatin, carboplatin) or another anticancer substance in a particular patient population, namely patients suffering from cancer. Contents ranging up to 70% by volume of xenon or of N2O are given, but it is specified that the preferential contents are less than 30% by volume.
In addition, FR-A-2944969 teaches the use of N2O for treating neuropathic pain in a patient, in a content of between 5 and 45% by volume, preferably less than 35% by volume.
None of these documents relates to the particular patient population mentioned above, namely patients receiving and/or having already received at least two treatments (i.e. drug substances or compounds) from different therapeutic classes, i.e. patients suffering from chronic pain, in particular peripheral neuropathic pain, and already treated by repeated administration of at least two drug substances from different therapeutic classes, whether these treatments have been carried out in the past and/or are still ongoing, in particular combinations of opioids, antidepressants, antiepileptics and/or other local anesthetics.
One problem is therefore that of being able to provide an improved drug making it possible to effectively provide relief to patients suffering from chronic pain, in particular chronic peripheral neuropathic pain, and who are otherwise treated by administration from at least two drug substances from different therapeutic classes, that is to say a drug combination of several therapeutic compounds, whether or not these drug substances are still being administered to the patients, preferably with the drug acting over several weeks, this being outside any anesthesia procedure.
In other words, there is a persistent medical need in the management of chronic pain, in particular chronic peripheral neuropathic pain, in particular by treatments that are more efficacious and better tolerated by patients than current strategies, in particular in the population of patients already treated with at least two drug substances (i.e. compound or product) from different therapeutic classes, in particular patients who are refractory to treatments with said at least two drug substances from different therapeutic classes, this being in particular with a view to improving the benefit/risk ratio of such treatments.
In other words, it is desirable to be able to improve the efficacy and tolerance of patients suffering from chronic pain, in particular from chronic peripheral neuropathic pain, and treated with at least two drug substances (i.e. compound or product) from different therapeutic classes used for the treatment of chronic pain, which patients are refractory to said at least two drug substances from different therapeutic classes.
A solution according to the invention relates to a gas mixture containing 50% of nitrous oxide (N2O) and at least 20% of oxygen (O2) (mol %) for use as an inhalable drug for treating chronic pain in a human patient treated with several drugs from at least two different therapeutic classes, preferably a patient refractory to said drugs from at least two classes different therapeutic classes.
In other words, the gas mixture containing 50% of nitrous oxide (N2O) and at least 20% of oxygen (O2) (mol %) is used in the context of the invention as an inhalable drug for treating chronic pain in a human patient who has already been treated with several types of drug compounds belonging to different therapeutic classes which also have an action against chronic pain but which have shown little or no efficacy and/or which have led to intolerance in the patient in question, that is to say a patient refractory to these treatments.
In addition, surprisingly, when a gas mixture containing 50% N2O and at least 20% of oxygen O2, in particular EMONO, according to the invention was administered to patients previously treated with several types of drug compounds belonging to different therapeutic classes, the results in terms of efficacy and tolerance are better than those obtained in patients treated with only one of these drug compounds.
In the context of the present invention:
According to the embodiment considered, the gas mixture used as inhalable drug according to the invention may comprise one or more of the following characteristics:
The invention also relates to a use of an N2O/O2 gas mixture containing 50% of nitrous oxide (N2O) and at least 20% of oxygen (O2) (mol %) according to the invention, preferably an equimolar 50%/50% N2O/O2 mixture, for producing an inhalable drug making it possible to effectively provide relief to patients suffering from chronic pain, in particular chronic peripheral neuropathic pain (CPNP), said patients being or having been treated with several drug substances from at least two different therapeutic classes, in particular antiepileptic, antidepressant, opiate (i.e. opioid) and/or local anesthetic drug substances, in particular patients refractory to said drug substances from at least two different therapeutic classes.
Furthermore, the invention also relates to a treatment method which makes it possible to provide relief to a patient suffering from one or more types of chronic pain, in particular chronic peripheral neuropathic pain (CPNP), and needing an additional treatment to at least partially relieve his or her chronic pain, wherein:
a) a patient receiving and/or having received, in an attempt to treat this chronic pain, several drug substances from at least two different therapeutic classes is selected, that is to say a patient in a more advanced stage of the disease, preferably patients refractory to said drug substances from at least two different therapeutic classes, and
b) an N2O/O2 gas mixture containing 50% of nitrous oxide (N2O) and at least 20% of oxygen (O2) (mol %) according to the invention, preferably an equimolar 50%/50% N2O/O2 mixture, is administered by inhalation to said patient.
Depending on the embodiment under consideration, the treatment method of the invention can comprise one or more of the following features:
According to another aspect, the invention also relates to a pressurized gas container containing a gas mixture according to the invention, in particular an equimolar 50%/50% N2O/O2 mixture.
According to yet another aspect, the invention also relates to a system for administering an N2O/O2 gas mixture according to the invention, comprising:
Depending on the embodiment under consideration, the administration system according to the invention can comprise one or more of the following features:
The invention will now be understood more clearly by virtue of the following detailed description, given by way of nonlimiting illustration, in the appended
Preferably, the gas mixture consists of 50% of nitrous oxide (N2O) and 50% of oxygen (O2), and optionally unavoidable impurities resulting, for example, from the method for producing the gas mixture. This equimolar (50%/50%) N2O/O2 binary gas mixture is referred to as EMONO for Equimolar Mixture of Oxygen and Nitrous Oxide.
This administration system 1 comprises a gas cylinder 2 fitted with an integrated regulator valve 3, containing the N2O/O2 gas mixture, such as EMONO, which is packaged therein at a pressure that can be up to 300 bar abs, referred to as “high pressure”. The integrated regulator valve 3 makes it possible to reduce the pressure of the N2O/O2 gas mixture down to a lower pressure, referred to as “low pressure” or “outlet pressure”, for example of 5 bar abs or less, which is delivered by an outlet connector 4 of the integrated regulator valve 3.
The N2O/O2 mixture is conveyed to the patient P, via a flexible pipe 5, which is in fluid communication, on the one hand, with the outlet connector 4 of the integrated regulator valve 3 and, on the other hand, with a gas distribution interface 6, like a breathing mask.
Preferably, a buffer vessel 7, such as a flexible balloon, can be inserted upstream of the breathing interface 6 in order to facilitate the administration of the gas to the patient P.
Of course, it is possible to use other administration devices suitable for supplying this mixture to the patient.
The N2O/O2 gas mixture is an inhalable drug used to treat chronic pain, in particular chronic neuropathic pain, of peripheral origin, in patient P who has elsewhere already received several drug substances, i.e. at least two, from at least two different therapeutic classes (i.e. these prior treatments may have been stopped or may be still in progress), which drug substances did not or do not allow the patient's pain to disappear, for example due to a lack of efficacy, in particular a patient refractory to said drug substances.
These drug substances can be, for example, one or more antiepileptics (AEs) of the pregabalin or gabapentin type, one or more antidepressants (ADs) of the fluoxetine type or the like, or one or more opioids, or one or more local anesthetics.
In general, chronic neuropathic pain is distinguished by its pathophysiology and its clinical expression. It has been defined, by the International Association for the Study of Pain, as pain secondary to injury or disease affecting the somatosensory system. It can be of peripheral or central origin.
In the context of the present invention, consideration is preferentially given to chronic neuropathic pain having a peripheral component, also referred to as chronic peripheral neuropathic pain (CPNP). This occurs, for example, as a result of a lesion or irritation, of traumatic, toxic, metabolic, ischemic, immunoallergic or infectious origin, of the peripheral nerves.
It is selected in particular from postherpetic pain, diabetic neuropathy pain, polyneuropathy, and post-traumatic or post-operative pain.
It is characterized by spontaneous and/or provoked pain.
Spontaneous pain may be continuous and/or superficial (e.g. burning sensation) or deep (e.g. feeling of tightening by a vice or compression), and may cause the occurrence of breakthrough pain (i.e. sensation of electric shock) and paresthesia/dysesthesia. Provoked pain is characterized by hypersensitivity to hot, to cold, to touch and is also referred to as “hyperalgia” or “allodynia”.
In order to show the efficacy of the inhalable N2O/O2 drug according to the invention, the following comparative examples were carried out.
Comparative trials were carried out in 2 countries and in 22 hospitals, using EMONO (50/50% N2O/O2) according to the invention and medical air acting as a control (i.e. placebo gas).
These gas mixtures were administered by inhalation to adult patients suffering from chronic peripheral neuropathic pain (CPNP) and already treated (i.e. treatments in progress or having been stopped) with one or more drug substances, in particular at least two drug substances from at least two different therapeutic classes or, by way of comparison, untreated patients, using the same administration system as described in
Drug substances from at least two different therapeutic classes are one or more opioids, antiepileptics (AEs), antidepressants (ADs) and local anesthetics.
Patients were drawn to receive either EMONO or medical air. However, patients are not told which gas they are inhaling. The patients receive the gases tested while they are awake and conscious (i.e. without any anesthesia).
The treatments were administered for 1 hour per day for 3 consecutive days. Each patient in the study was followed up for 4 weeks and had to complete several questionnaires throughout the follow-up (i.e. NRS, SF-12, NPSI, PGIC) making it possible to assess the change:
The results of the trials are obtained on patients having received three administrations, either of EMONO or of placebo (i.e. air), including at least one complete administration (i.e. duration of administration ranging from 55 to 65 minutes with cumulative breaks not exceeding 5 minutes), and having done at least 4 assessments of the intensity of their pain during the first week after treatment.
The results are collated in the following tables wherein:
Table 1 collates the results of the change in pain intensity (NRS score) after 1 week of follow-up on the overall population of CPNP patients in the study, and
Table 2 collates the results of the change in pain intensity (NRS score) over the 4 weeks of follow-up in the CPNP patients in the study.
In each cell of Table 1, the following are given: the number of patients involved, the difference in the NRS score between the 1st week following treatment and the week before treatment, and standard deviation of this difference.
It is noted, surprisingly, in view of the results of Table 1, that the patients who were treated with at least two drug substances used to relieve their chronic pain (i.e. opioids, AEs, ADs and/or local anesthetics) have a higher level of response to EMONO than that of the patients who were treated with only one drug substance or than that of those who had no prior treatment for their chronic pain.
In other words, the results obtained show a statistically significant difference in favor of EMONO concerning the reduction in pain intensity for patients treated with EMONO and having received two or three other drug substances used to relieve their chronic pain compared to the other patients, i.e. those treated either with medical air (placebo) regardless of the number of drug substances having been administered to them elsewhere, or EMONO and at most one other drug substance (i.e. 1 or 0).
This is surprising since, in general, the level of response of naive or barely treated patients is usually better than that of extensively treated patients. However, in this case it is the opposite.
This demonstrates the efficacy of the administration by inhalation of a gas mixture according to the invention containing 50% of nitrous oxide (N2O) and at least 20% of oxygen (O2) (mol %) to patients treated elsewhere with several drug substances, i.e. at least two drug substances, which belong to different therapeutic classes, namely AEs, ADs, opioids or local anesthetics, in order to treat their chronic pain, in particular peripheral neuropathic pain.
Table 2 makes it possible to compare the efficacy of EMONO in patients treated with 0 to 3 other drug substances such as AEs, ADs, opioids or local anesthetics, more particularly in patients with a 30% drop in their NRS score.
The results obtained clearly show a higher proportion (%) of patients attesting to a reduction in the intensity of their chronic pain from week 1 to week 4, in the group of patients according to the invention, that is to say who have received elsewhere at least 2 drug substances belonging to different therapeutic classes (i.e. AEs, ADs, opioids, local anesthetics).
This difference appears from the start, becomes more significant from the second week and continues for 4 weeks.
These results are surprising for several reasons.
First of all, they confirm that the drug according to the invention containing 50% of N2O has a targeted efficacy in combating pain in a particular (sub)population of patients, namely patients treated with several drug substances (i.e. AEs, ADs, opioids, local anesthetics), while its efficacy is less in those treated with a single drug substance or none.
They then demonstrate a persistence of the efficacy of the inhalable drug according to the invention, in this case EMONO, for a period of several weeks, namely in this case 4 weeks, in these same patients after a short administration. This second surprising effect does not exist with any of the other systemic background treatments received by the patients.
Finally, it should be emphasized that none of these patients showed a secondary reaction to EMONO, that is to say that the tolerance of EMONO is satisfactory in this (sub)population of patients, i.e. patients treated by several drug substances from different classes (i.e. AEs, ADs, opioids, local anesthetics).
While the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, it is intended to embrace all such alternatives, modifications, and variations as fall within the spirit and broad scope of the appended claims. The present invention may suitably comprise, consist or consist essentially of the elements disclosed and may be practiced in the absence of an element not disclosed. Furthermore, if there is language referring to order, such as first and second, it should be understood in an exemplary sense and not in a limiting sense. For example, it can be recognized by those skilled in the art that certain steps can be combined into a single step.
The singular forms “a”, “an” and “the” include plural referents, unless the context clearly dictates otherwise.
“Comprising” in a claim is an open transitional term which means the subsequently identified claim elements are a nonexclusive listing (i.e., anything else may be additionally included and remain within the scope of “comprising”). “Comprising” as used herein may be replaced by the more limited transitional terms “consisting essentially of” and “consisting of” unless otherwise indicated herein.
“Providing” in a claim is defined to mean furnishing, supplying, making available, or preparing something. The step may be performed by any actor in the absence of express language in the claim to the contrary.
Optional or optionally means that the subsequently described event or circumstances may or may not occur. The description includes instances where the event or circumstance occurs and instances where it does not occur.
Ranges may be expressed herein as from about one particular value, and/or to about another particular value. When such a range is expressed, it is to be understood that another embodiment is from the one particular value and/or to the other particular value, along with all combinations within said range.
All references identified herein are each hereby incorporated by reference into this application in their entireties, as well as for the specific information for which each is cited.
| Number | Date | Country | Kind |
|---|---|---|---|
| 1904626 | May 2019 | FR | national |
This application is a 371 of International Application No. PCT/FR2019/052400, filed Oct. 10, 2019, which claims priority to French Patent Application No. 1904626, filed May 2, 2019, the entire contents of which are incorporated herein by reference.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/FR2019/052400 | 10/10/2019 | WO |
