DE102020106223A1 - Pain medication - Google Patents

Abstract

Use of a combined preparation for the combined administration of diazepam and diclofenac sodium for the short-term specific treatment of pain due to the indication of herniated disc, lumbar pain, lumbar sciatica, dorsalgia, cervicalgia, cervical neuralgia, sciatica, chronic limb pain, migraine, headache, joint pain, postoperocardial infarction, Bone fractures, burns, tumor or tumor-related pain, rheumatism, toothache, pain from drug withdrawal, pain that cannot be localized or the origin of which is not known, pain caused by fasciae and connective tissue, phantom pain after amputation, combinations of the aforementioned pain and other pain, as tablets , Capsules, injection, infusion, drinking ampoules or drops.

Description

The invention relates to a pain medication, consisting of the two components diazepam and diclofenac sodium, for use in migraines, acute severe back pain and considerable joint problems. It is very powerful and replaces morphine treatments. It is given for a short time and must not be taken with other medicines. The two components have long been known and widely used.

Diazepam was invented in 1950 and has been marketed under the trade name Valium since 1963. In addition to its use for the symptomatic treatment of acute states of tension, excitement and anxiety, diazepam is used in premedication before surgical and diagnostic interventions. It is also used as a muscle relaxant and as an emergency therapeutic agent for the prophylaxis and anticonvulsive treatment of epileptic grand mal seizures and for the treatment of febrile convulsions occurring in children. These applications are well known and can be looked up at Wikipedia at any time. Applications for migraines, acute severe back pain and significant joint discomfort are not known for diazepam alone.

A large number of interactions are well known. Medicines that act on the brain, such as sedatives, sleeping pills, anti-depression drugs, various pain relievers, anti-seizure drugs such as anti-epileptic drugs or muscle relaxants, as well as certain drugs for gastric ulcers, tuberculosis, fungal diseases, asthma or for alcohol cessation, and diazepam all influence each other their effect. When combining diazepam with other centrally acting substances such as alcohol, neuroleptics, anxiolytics, sedatives, antidepressants, hypnotics, anticonvulsants, narcotic analgesics, anesthetics and sedating antihistamines, it must be taken into account that their effects can mutually reinforce one another. However, an enhancement of the effect with Diclofenac Sodium has not yet become known, and Diclofenac Sodium does not belong to any of the aforementioned classes of substances.

Many side effects are also known for diazepam. Reports include tiredness, severe daytime sedation, drowsiness, drowsiness, fatigue, dizziness, headache, ataxia, prolonged reaction time, confusion, anterograde amnesia, overhanging effects such as concentration disorders and residual tiredness, impaired ability to react. Antidotes, such as caffeine, are often used to compensate for these side effects.

Diazepam is broken down by the cytochrome P450 enzyme system. Inhibitors of this enzyme system lead to a slower breakdown of diazepam combined with its prolonged or intensified effect. Furthermore, diazepam increases the effect of other muscle relaxants as well as the effect of nitrous oxide and analgesics. The combined use of diazepam and omeprazole, cimetidine, ketoconazole, fluvoxamine, fluoxetine should be avoided as these substances slow down the breakdown of diazepam. This is important because omeprazole is often used to reduce the gastric disruptive effects of pain relievers, including diclofenac sodium.

It is also generally known that diazepam _{acts as an allosteric modulator of the GABA A} receptor and increases the inhibitory effect of the neurotransmitter GABA. As an agonist, diazepam binds to the benzodiazepine binding site of this receptor and thus causes its conformational change. This increases the receptor sensitivity to GABA. Increased GABA activity results in an increased opening rate at the chloride channel and thus in an increased influx of chloride ions into the cell. The increase in the intracellular chloride concentration leads to a reduced excitability of the cell due to hyperpolarization.

In contrast, the effects of diclofenac, which was invented in 1965, are based on the inhibition of cyclooxygenase and thus reduced prostaglandin synthesis. The reason for this is an inhibition of the cyclooxygenases COX-1 and COX-2, which as a result can no longer produce pro-inflammatory prostaglandins. Diclofenac may be directly involved in lipoxygenase metabolism and suppress the formation of leukotrienes. The analgesic effect of diclofenac is increased by piperine, an ingredient in pepper. Diclofenac is offered as a salt with sodium or potassium. The present invention relates only to the sodium salt diclofenac sodium.

The two mechanisms of action of diazepam and diclofenac are so different that a synergetic effect cannot seem obvious.

Many undesirable effects have also become known for diclofenac. The most common are indigestion, water retention, high blood pressure, rash, headache, dizziness, and drowsiness.

Diclofenac is one of the non-steroidal anti-inflammatory drugs, or NSAIDs for short (non-steroidal anti-inflammatory drugs). This technical term means that it is an anti-inflammatory agent, but neither a cortisone preparation nor a Morphine derivative. Diclofenac has an anti-pain and anti-inflammatory effect and also lowers fever.

Diclofenac is also known to be used against migraines. For example, Diclofenac Potassium, in the form of Voltaren K Migraine 50 mg coated tablets, is prescribed for migraines.

A strengthening or possible combination effect of diazepam and diclofenac is in any case not familiar to the general public and is not suggested by the known mechanisms of action. Nevertheless, a large number of references to both substances in conjunction can be found in the literature.

Combination effects of muscle relaxing agents with analgesic, non-steroidal, anti-inflammatory agents, NSAIDs, are already generally used in US Pat U.S. 4,923,898 A described, whereby a large number of substances and substance classes are mentioned for each of the two groups. These also include diclofenac and diazepam, which in principle apparently have been considered, but neither an example with this combination was given, nor was the combination of diclofenac and diazepam explicitly or generically claimed in the claims. It can therefore be assumed that the reinforcing combination effect has not been recognized and the attention of experts should be directed to other drugs and drug combinations.

In the registration document WO 86/03681 A1 the combined effect with additional caffeine is reported. Here, too, the combination of diclofenac and diazepam is not explicitly mentioned, although both substances were combined with other muscle-relaxing agents and analgesic, non-steroidal, anti-inflammatory agents, as well as with caffeine. So not only was the reinforcing combination effect of diclofenac with diazepam not recognized, but also the fact that further additional agents intended to alleviate the side effects of one of the combined agents would or could at the same time also eliminate the reinforcing effect of the combination.

As a result, a large number of drugs were described which, among many other substances, also contained small admixtures of diclofenac and diazepam; here, too, the reinforcing combination effect was not recognized, or it was unintentionally compensated for by the other components of the mixture. At the same time, reports became known in which mixtures that also contained the two substances resulted in significant side effects. So describes the article "Slide in the legal drug swamp", Der Spiegel 37/1987, pages 228-229, 232, 235, 238, 241, 244-245, 248-249, 252-253 , the death of an athlete from a combination of various pain relievers, including diazepam and diclofenac, among many others.

the WO 02/11700 A1 describes an external application of a combination of diazepam and diclofenac, the product being 1 percent present in the preparation. The product had to be rubbed onto the affected area. It is clear that an application for joint pain, migraines and back pain is out of the question, as this pain is not caused by superficial muscles and an applied solution would not bring any relief, although voltaren ointment with the main component diclofenac is said to act on joint pain. On the other hand, the problem of side effects does not arise from a purely external application.

Investigations were also carried out on the receptors for diclofenac sodium and diazepam, although the aim of the investigation was to measure the displacement by sulfamethoxazole (MDd Kamal Hossain, Amina Khatun, Mahmudur Rahman, Md Nahid Akter, Sadia Afreen Chowdhury, SM Mahbubul Alam: Characterization of the Effect of Drug-Drug-Interaction on Protein Binding in Concurrent Administration of Sulfamethoxazol and Diclofenac Sodium Using Bovine Serum Albumin, Advanced Pharmaceutical Bulletin 2016, 6 (4), 589-595 ). It was found that such a displacement took place and, at the same time, that diclofenac sodium also displaced diazepam from the corresponding receptors. In this respect, an interaction was determined, but no enhancement of the effect by a combination was found or suggested by the results.

A satisfactory effect of the combination of diclofenac sodium and diazepam was found in an Iranian study in operations to remove polyps from the uterus ( Zahra Asgari, Maryam Razavi, Reihaneh Hosseini, Masoumeh Nataj, Mahroo Rezaeinejad, Mahdi Sepidarkish, Evaluation of Paracervical Block and IV Sedation for Pain Management during Hysteroscopic Polypectomy: A Randomized Clinical Trial, Hindawi Pain Research and Management, Volume 2017, Article ID 5309408, 7 pages ). Here, 10 mg diazepam and 100 mg diclofenac were administered once and this was compared with a comparison group with classic anesthesia. No significant differences were found between the comparison groups, and there were no side effects. So there was a comparable effect.

A combination of diazepam and diclofenac is used as preparation for a rectal Operation used in young children. A comparative study ( SM Filatov, GA Baer, MGF Rorarius, M. Oikkonen: Efficacy and safety of premedication with oral ketamine for day-case adenoidectomy compared with rectal diazepam / diclofenac and EMLA, Acta Anaesthesiol Scand 2000, 44, 118-124 ) showed no significant difference to the administration of ketamine. Since there was hardly any pain to be combated preoperatively, synergy effects were not observable.

On the occasion of a study in which the effects of a combination of diclofenac applied rectally and nabumetone, both analgesic, non-steroidal, anti-inflammatory agents (NSAID), were investigated ( Nao Setoguchi, Norito Takamura, Ken-ichi Fujita, Kenji Ogata, Jin Tokunaga, Toyotaka Nishio, Etsuo Chosa, Kazuhiko Arimori, Keiichi Kawai, Ryuichi Yamamoto: A diclofenac suppository-nabumetone combination therapy for arthritic pain relief and a monitoring method for the diclofenac pain relief and a monitoring method binding capacity of HSA site II in rheumatoid arthritis; Biopharmaceutics & Drug Disposition 34, 125-136 (2013) ), diazepam was used for comparison. On the one hand, it turned out that diclofenac binds to site II of HSA, the human serum protein, and not to site I. On the other hand, it was found that diazepam and diclofenac compete for this binding and diazepam displaces diclofenac. As a result, the concentration of free diclofenac in the blood rises again because it is not firmly bound by the HSA and can therefore better penetrate tissue in order to develop its effect. However, the study does not recognize that diclofenac and diazepam work together, but rather concludes the effectiveness of the method for observing HSA binding when a combination of diclofenac and nabumetone is used.

This development of the effectiveness of diclofenac with an increase in the concentration in the blood is not a matter of course, because diazepam can just as well displace the active ingredient diclofenac from other receptors that are built similar to HSA Site II. Then diclofenac would be able to accumulate better in the tissue, but this would not result in a better mechanism of action. The inhibition of cyclooxygenase and thus of the reduced prostaglandin synthesis would therefore neither be intensified nor more targeted.

The release of diclofenac by diazepam also affects metabolism. Free diclofenac, like free diazepam, is broken down more quickly unless the breakdown mechanism is also blocked. The rate-limiting degradation step for diclofenac is determined by the enzyme CYP2C9, for diazepam it is CYP2C19, both of which are enzymes of the cytochrome P450 enzyme system. There does not seem to be any mutual influence here. It should be emphasized, however, that a large number of other common drugs and some foods can have a considerable influence here. This applies to commercially available proton pump blockers, which are used to compensate for the digestive complications of diclofenac, as well as antidepressants, agents that modify blood pressure and other NSAIDs. It is therefore advisable not to take any further medication or to temporarily stop taking it under medical supervision.

Pain is transmitted to the brain by pain sensors called nociceptors, which are located almost everywhere in the body, for example in the skin, intestines or blood vessels. The pain receptors respond when it gets too hot or too cold, or a certain pressure is exceeded, or a chemical irritation occurs, for example when chemical substances are released during an inflammation.

The object of the invention is therefore to provide a new pain medication for symptomatic control and lasting healing of moderate to very severe pain.

• 0: Schmerzfrei.
• 1: Sehr geringer, kaum bemerkbarer Schmerz.
• 2: Geringer Schmerz: ein wenig lästig, vielleicht zeitweise etwas stärker werdend.
• 3: Bemerkbarer Schmerz: Schmerz, der die Aufmerksamkeit auf sich zieht, mit dem sich jedoch gut leben lässt und an den man sich gewöhnt.
• 4: Mittlerer Schmerz: ist der Patient abgelenkt, kann er ihn für einige Zeit ignorieren, aber er ist immer bemerkbar.
• 5: Mittelstarker Schmerz: Betroffene können ihn höchstens für einige Minuten ignorieren und müssen sich aktiv anstrengen, wenn sie konzentriert arbeiten oder an sozialen Aktivitäten teilhaben wollen.
• 6: Mittelstarker Schmerz: stört den Patienten bei allen normalen Alltagshandlungen; es fällt schwer, sich zu konzentrieren.
• 7: Starker Schmerz: dominiert die Wahrnehmungen; soziale Kontakte und die Ausführung von normalen Alltagsaktivitäten sind signifikant beeinträchtigt; auch der Schlaf ist gestört.
• 8: Intensiver Schmerz: körperliche Aktivitäten werden ernsthaft eingeschränkt; Gespräche sind nur unter großen Mühen möglich, entspricht etwa dem Schmerz bei einer natürlichen Geburt.
• 9: Unerträglicher Schmerz: Konversation unmöglich, der Patient schreit oder stöhnt.
• 10: Unbeschreiblicher Schmerz: der Patient kann nicht aufstehen und ist möglicherweise im Delirium.

In practice, pain is usually classified on a pain scale from 0 to 10. In the following, a pain scale with 10 levels is to be used to describe the pain intensity according to www.ratgeber-ache.de/ache/definition/schmerzskala/, whereby internationally used scales are similar, but all suffer from the general lack of objective measurability and usually subjective must be determined:

• 0: Pain-free.
• 1: Very slight, barely noticeable pain.
• 2: Minor pain: a little annoying, maybe getting a little stronger at times.
• 3: Noticeable Pain: Pain that attracts attention but is easy to live with and get used to.
• 4: Moderate pain: if the patient is distracted, he can ignore it for some time, but it is always noticeable.
• 5: Moderate pain: Those affected can ignore it for a few minutes at most and have to make an active effort if they want to concentrate on work or take part in social activities.
• 6: Moderate pain: disturbs the patient in all normal everyday activities; it is difficult to concentrate.
• 7: Severe pain: dominates the perceptions; social contacts and the performance of normal everyday activities are significantly impaired; sleep is also disturbed.
• 8: Intense pain: physical activity is severely restricted; Conversations are only possible with great effort, roughly equivalent to the pain of a natural birth.
• 9: Unbearable pain: Conversation impossible, the patient screams or moans.
• 10: Indescribable pain: the patient cannot stand up and may be delirious.

The invention relates mainly to pain levels 5 to 10, but is also suitable and useful for lower levels of pain in the case of a low dose.

• • Bandscheibenvorfall,
• • Lumbalgie,
• • Lumboischialgie,
• • Dorsalgie,
• • Zervicalgie und Verspannungs-Nackenschmerzen, HWS-Syndrom,
• • Zervikalneuralgie,
• • Ischialgie,
• • Facettensyndrom,
• • chronischen Gliederschmerzen,
• • Gliederschmerzen bei Osteoporose, Arthrose, Arthritis, Weichteilrheuma, Sehnenverletzungen, Ischämien, Übergewicht,
• • Neuralgien, Fibromyalgie, Fibromyalgiesyndrom,
• • Migräne,
• • Kopfschmerzen,
• • Gelenkverschleiß und-schmerzen,
• • Hüftschmerzen, Knieschmerzen, Fersenschmerzen, Zehenschmerzen,
• • Nierenschmerzen,
• • Myokardinfarkt,
• • postoperativen Schmerzen,
• • Knochenbrüchen,
• • Fersensporn,
• • Körperfehlhaltungen,
• • Verbrennungen,
• • Tumorschmerzen oder turmorbedingten Schmerzen einschließlich Krebs und Metastasen,
• • Embolie- und Tromboseschmerzen,
• • Rheuma,
• • Zahn- und Kieferschmerzen,
• • Schmerzen und Depressionserscheinungen bei Drogenentzug,
• • nicht lokalisierbare Schmerzen oder Schmerzen, deren Ursprung nicht bekannt ist,
• • durch Faszien und Bindegewebe ausgelösten Schmerzen,
• • Phantomschmerzen nach Amputationen,
• • Piriformissyndrom,
• • Unterleibsschmerzen, sowohl bei Männern als auch bei Frauen,
• • Endometriose,
• • Hämorrhoiden,
• • Schmerzen mit Depressionen, Schlafstörungen, Angstzuständen,
• • Verbrennungen, Verbrühungen und Verätzungen,
• • Kombinationen der vorgenannten Schmerzen.

It solves the task of symptomatic control and sustainable healing through a combined preparation of the two active ingredients diazepam and diclofenac sodium for the treatment of pain, especially burning and stabbing pain, for the following indications:

• • Disc prolapse,
• • lumbar pain,
• • Lumboischialgia,
• • dorsalgia,
• • cervicalgia and tension neck pain, cervical spine syndrome,
• • cervical neuralgia,
• • sciatica,
• • facet syndrome,
• • chronic pain in the limbs,
• • Pain in the limbs in osteoporosis, arthrosis, arthritis, soft tissue rheumatism, tendon injuries, ischemia, obesity,
• • neuralgia, fibromyalgia, fibromyalgia syndrome,
• • migraines,
• • Headache,
• • joint wear and pain,
• • hip pain, knee pain, heel pain, toe pain,
• • kidney pain,
• • myocardial infarction,
• • post-operative pain,
• • broken bones,
• • heel spur,
• • Bad posture,
• • burns,
• • tumor pain or pain related to tumors including cancer and metastases,
• • embolic and thrombotic pain,
• • rheumatism,
• • tooth and jaw pain,
• • pain and depression symptoms during drug withdrawal,
• • pain that cannot be localized or the origin of which is unknown,
• • pain caused by fascia and connective tissue,
• • phantom pain after amputations,
• • piriformis syndrome,
• • abdominal pain, both in men and women,
• • endometriosis,
• • hemorrhoids,
• • pain with depression, insomnia, anxiety,
• • Burns, scalds and chemical burns,
• • Combinations of the aforementioned pains.

Since physical pain can also result in psychological pain, this is also reduced accordingly. Pain suppression is also beneficial in terms of pain memory.

Administration is preferably carried out orally in the form of tablets or capsules. However, it can also take the form of an injection, infusion, drops or a drinking ampoule. Each of these forms of administration has advantages and disadvantages, administration as an injection or infusion leads to a rapid onset of action, but the effect wears off early. Tablets or capsules that are packaged as sustained-release tablets can cover different periods of action. This principle is already well known with Voltaren Resinat and can also be used to advantage with the combination preparation. The administration as drops has the advantage of fine metering and subsequent metering, however, it must be ensured that no segregation or flocculation takes place in the embedding liquid, which the pharmacist or the user must take into account accordingly.

In the case of a liquid template, make sure that it should not contain any active ingredients, but only substances that are inert in the body, such as water or propylene glycol, which can equally dissolve diclofenac sodium and diazepam.

The dosage depends on the severity of the pain and corresponds to the usual dosages when the individual substances are used orally or otherwise administered. The standard dose contains 5 mg diazepam and 75 mg diclofenac sodium.

The dose may vary in children, the elderly and with pre-existing conditions and is between 1 mg to 100 mg diazepam and 1 mg to 150 mg diclofenac sodium.

The application is short-term or long-term. As a short-term application for a few hours to a few days is intended. In the case of long-term use, it can be taken for several weeks according to a doctor's prescription. For pain of pain severity 1 to 5, a standard dose should be taken once or twice a day, for pain severity 5 to 8 a standard dose two to three times per day and one standard dose three to four times per day for pain severity 8 to 10 to take.

Due to interactions, there should be an interval of at least one hour between taking and taking antibiotics.

An advantage of the invention is that in this way the administration of opioids such as morphine can be avoided even in the case of very severe pain of pain severity 8 to 10. Another advantage is that pain can be relieved or healed over the long term. Long-term intake can usually be dispensed with; continuation is only necessary when the symptoms return due to stress or shock.

QUOTES INCLUDED IN THE DESCRIPTION

This list of the documents listed by the applicant was generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Patent literature cited

• US 4923898 A [0013]
• WO 8603681 A1 [0014]
• WO 0211700 A1 [0016]

Non-patent literature cited

• "Slide in the legal drug sump", Der Spiegel 37/1987, pages 228-229, 232, 235, 238, 241, 244-245, 248-249, 252-253 [0015]
• Kamal Hossain, Amina Khatun, Mahmudur Rahman, Md Nahid Akter, Sadia Afreen Chowdhury, SM Mahbubul Alam: Characterization of the Effect of Drug-Drug-Interaction on Protein Binding in Concurrent Administration of Sulfamethoxazol and Diclofenac Sodium Using Bovine Serum Albumin, Advanced Pharmaceutical Bulletin 2016, 6 (4), 589-595 [0017]
• Zahra Asgari, Maryam Razavi, Reihaneh Hosseini, Masoumeh Nataj, Mahroo Rezaeinejad, Mahdi Sepidarkish, Evaluation of Paracervical Block and IV Sedation for Pain Management during Hysteroscopic Polypectomy: A Randomized Clinical Trial, Hindawi Pain Research and Management, Volume 2017, Article ID 5309408, 7 pages [0018]
• S.M. Filatov, G.A. Baer, M.G.F. Rorarius, M. Oikkonen: Efficacy and safety of premedication with oral ketamine for day-case adenoidectomy compared with rectal diazepam / diclofenac and EMLA, Acta Anaesthesiol Scand 2000, 44, 118-124 [0019]
• Nao Setoguchi, Norito Takamura, Ken-ichi Fujita, Kenji Ogata, Jin Tokunaga, Toyotaka Nishio, Etsuo Chosa, Kazuhiko Arimori, Keiichi Kawai, Ryuichi Yamamoto: A diclofenac suppository-nabumetone combination therapy for arthritic pain relief and a monitoring method for the diclofenac pain relief and a monitoring method binding capacity of HSA site II in rheumatoid arthritis; Biopharmaceutics & Drug Disposition 34, 125-136 (2013) [0020]

Claims (4)

Use of a combined preparation for the combined administration of diazepam and diclofenac sodium for the specific treatment of pain, especially burning and stabbing pain, based on the indication of • Disc prolapse, • lumbar pain, • Lumboischialgia, • dorsalgia, • cervicalgia and tension neck pain, cervical spine syndrome, • cervical neuralgia, • sciatica, • facet syndrome, • chronic pain in the limbs, • Pain in the limbs in osteoporosis, arthrosis, arthritis, soft tissue rheumatism, tendon injuries, ischemia, obesity, • neuralgia, fibromyalgia, fibromyalgia syndrome, • migraines, • Headache, • joint wear and pain, • hip pain, knee pain, heel pain, toe pain, • kidney pain, • myocardial infarction, • post-operative pain, • broken bones, • heel spur, • Bad posture, • burns, • tumor pain or pain related to tumors including cancer and metastases, • embolic and thrombotic pain, • rheumatism, • tooth and jaw pain, • pain and depression symptoms during drug withdrawal, • pain that cannot be localized or the origin of which is unknown, • pain caused by fascia and connective tissue, • phantom pain after amputations, • piriformis syndrome, • abdominal pain, both in men and women, • endometriosis, • hemorrhoids, • pain with depression, insomnia, anxiety, • Burns, scalds and chemical burns, • Combinations of the aforementioned pains. Use after Claim 1 as tablets, capsules, injection, infusion, or drops. Use after one of the Claims 1 or 2 , characterized by a single dose between 1 mg to 100 mg diazepam and 1 mg to 150 mg diclofenac sodium. Use after Claim 3 , characterized by a single dose of 5 mg diazepam and 75 mg diclofenac sodium.