CA2930563A1 - Multidrug infusion for pain control - Google Patents
Multidrug infusion for pain control Download PDFInfo
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- CA2930563A1 CA2930563A1 CA2930563A CA2930563A CA2930563A1 CA 2930563 A1 CA2930563 A1 CA 2930563A1 CA 2930563 A CA2930563 A CA 2930563A CA 2930563 A CA2930563 A CA 2930563A CA 2930563 A1 CA2930563 A1 CA 2930563A1
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Abstract
Description
BACKGROUND
(a) Field [0001] Achieving effective, durable, and safe pain relief, especially in aged patients and end-stage malignancies can be a clinical challenge. Despite multimodal systemic approaches with the least doses of drugs to decrease systemic side effects, the pain is often poorly controlled with unacceptable side effects in some patients.
SUMMARY
= an opioid;
= a Na channel blocker;
= an alpha2-receptor agonist;
= an opioid mu or delta receptor competitive antagonist; and = an intravenous anesthetic and/or a neurologic acting agent.
File No. P2867CA01
other compounds acting on adenosine receptors (A1, A2, A3), neostigmine, magnesium, atropine, dexamethasone, ketorolac and other NSAID, octreotide, ziconitide, droperidol, and haloperidol.
= a catheter optionally connected to a PORT-A-CATHTm; and a reservoir placed under the skin. The medication is injected in the reservoir either as a bolus or a continuous infusion through an external perfusion device is done.
File No. P2867CA01 = a reservoir connected to an implanted pump for receiving a formulation of the present invention and wherein the reservoir is to be connected to the catheter (no external infusion system).
= an opioid;
= a Na channel blocker;
= an alpha2-receptor agonist;
= an opioid mu or delta receptor competitive antagonist; and an intravenous anesthetic and/or a neurologic acting agent for administration epidurally, paraverthebrally, at the peripheral nerves level, at the nerve plexus level, intra-articularly, in a synovial bursa, sub-cutaneously, and intravenously, or combination thereof.
File No. P2867CA01
other compounds acting on adenosine receptors (A1, A2, A3), neostigmine, magnesium, atropine, dexamethasone, ketorolac and other NSAID, octreotide, ziconitide, droperidol, and haloperidol.
= an opioid;
= a Na channel blocker;
= an alpha2-receptor agonist;
= an opioid mu or delta receptor competitive antagonist; and = an intravenous anesthetic and/or a neurologic acting agent, for pain control and/or cognitive function improvement, File No. P2867CA01 wherein said use is epidural, paraverthebral, at the peripheral nerves level, at the nerve plexus level, intra-articular, in a synovial bursa, sub-cutaneous, and intravenous, or combination thereof.
= an opioid;
= a Na channel blocker;
= an alpha2-receptor agonist;
= an opioid mu or delta receptor competitive antagonist; and = an intravenous anesthetic and/or a neurologic acting agent, for the preparation of a medicament for use in pain control and/or cognitive function improvement, wherein said medicament is for epidural use, paraverthebral use, use at the peripheral nerves level, use at the nerve plexus level, intra-articular use, use in a synovial bursa, sub-cutaneous use, and intravenous use, or combination thereof.
File No. P2867CA01
other compounds acting on adenosine receptors (A1, A2, A3), neostigmine, magnesium, atropine, dexamethasone, ketorolac and other NSAID, octreotide, ziconitide, droperidol, and haloperidol.
Accordingly, the pharmaceutical compositions or other compositions in general of File No. P2867CA01 the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
By "pharmaceutically acceptable" or "acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
is intended to mean a drug, compound or active ingredient having a neurological effect on the subject in need thereof. For example, according to an embodiment, the neurological agent may treat, diminish, or alleviate the symptoms of a given neurological disorder. Examples of symptoms of neurological disorder include paralysis, muscle weakness, poor coordination, loss of sensation, seizures, confusion, pain and altered levels of consciousness, depression psychosis.
BRIEF DESCRIPTION OF THE DRAWINGS
Solution contains bupivacaine 1mg/ml, ketamine 100 pg/ml, morphine 0.01 mg/ml in NaCI 0.9% 50 ml plastic bag. The concentration of ketamine and bupivacaine is stable but morphine's concentration decreases 15% on first day and then stays mostly unchanged during the following days.
DETAILED DESCRIPTION
= an opioid;
= a Na channel blocker;
File No. P2867CA01 = an alpha2-receptor agonist;
= an opioid mu or delta receptor competitive antagonist; and = an intravenous anesthetic and/or a neurologic acting agent.
= an opioid;
= a Na channel blocker;
= an alpha2-receptor agonist;
= an opioid mu or delta receptor competitive antagonist; and = an intravenous anesthetic and/or a neurologic acting agent.
File No. P2867CA01
= an opioid;
= a Na channel blocker;
= an alpha2-receptor agonist;
= an opioid mu or delta receptor competitive antagonist; and = an intravenous anesthetic and/or a neurologic acting agent.
= an opioid;
= a Na channel blocker;
= an alpha2-receptor agonist;
= an opioid mu or delta receptor competitive antagonist; and = an intravenous anesthetic and/or a neurologic acting agent.
= an opioid;
= a Na channel blocker;
= an alpha2-receptor agonist;
= an opioid mu or delta receptor competitive antagonist; and = an intravenous anesthetic and/or a neurologic acting agent.
File No. P2867CA01
= an opioid;
= a Na channel blocker;
= an alpha2-receptor agonist;
= an opioid mu or delta receptor competitive antagonist; and = an intravenous anesthetic and/or a neurologic acting agent.
= an opioid;
= a Na channel blocker;
= an alpha2-receptor agonist;
= an opioid mu or delta receptor competitive antagonist; and = an intravenous anesthetic and/or a neurologic acting agent.
= an opioid;
= a Na channel blocker;
= an alpha2-receptor agonist;
= an opioid mu or delta receptor competitive antagonist; and = an intravenous anesthetic and/or a neurologic acting agent.
File No. P2867CA01
= an opioid;
= a Na channel blocker;
= an alpha2-receptor agonist;
= an opioid mu or delta receptor competitive antagonist; and = an intravenous anesthetic and/or a neurologic acting agent.
= an opioid;
= a Na channel blocker;
= an alpha2-receptor agonist;
= an opioid mu or delta receptor competitive antagonist; and = an intravenous anesthetic and/or a neurologic acting agent, for pain control and/or cognitive function improvement, wherein said use is epidural, paraverthebral, at the peripheral nerves level, at the nerve plexus level, intra-articular, in a synovial bursa, sub-cutaneous, and intravenous, or combination thereof.
= an opioid;
= a Na channel blocker;
= an alpha2-receptor agonist;
= an opioid mu or delta receptor competitive antagonist; and = an intravenous anesthetic and/or a neurologic acting agent, File No. P2867CA01 for the preparation of a medicament for use in pain control and/or cognitive function improvement, wherein said medicament is for epidural use, paraverthebral use, use at the peripheral nerves level, use at the nerve plexus level, intra-articular use, use in a synovial bursa, sub-cutaneous use, and intravenous use, or combination thereof.
= a catheter optionally connected to a PORT-A-CATHTm; and a reservoir placed under the skin. The medication is injected in the reservoir either as a bolus or a continuous infusion through an external perfusion device is done.
= a reservoir connected to an implanted pump for receiving a formulation of the present invention and wherein the reservoir is to be connected to the catheter (no external infusion system).
PAIN MANAGEMENT THROUGH INTRATHECAL INFUSION
File No. P2867CA01
Starting rate was 1 ml/h. The pain was mostly controlled with a rate of less than 1 ml/h. Opioid consumption was reduced dramatically. Catheter was kept for one month in first and third patient and for 6 months in the second one until his death.
No major side effects such as hypotension, constipation, muscle weakness, sphincter dysfunction and cognitive or mood deterioration were observed with this approach. One patient had urinary tract infection followed by sepsis and meningitis which was easily cured by antibiotics. Catheter was removed in this patient. Intrathecal infusion with a low-concentration multi-drugs mixture could be considered as an alternative modality for intractable pain relief in elderly or malignancies. The cognitive functions of all patients were also greatly improved.
infusion (Table -1).
File No. P2867CA01 Comparison of opioid consumption before and after intrathecal catheter insertion Patient Age sex Cause of Equivalent Equivalent Maximal (years) pain oral oral inpatient morphine morphine IT
before IT after IT
infusion (mg/d)* (mg/d)* rate (ml/h) 1 69 F Bed sore 220 30 1 Pelvic 375 2 64 M metastatic +methadone 60 2.5**
cancer 24 mg/d Ribs and 3 94 F thoracic 200 30 1 vertebra fracture *Calculated on the basis of opioid equianalgesic dose conversion table (Montreal University Hospital-CHUM) **In this patient, the concentration of drugs were modified to avoid passing maximum intrathecal daily dose of bupivacaine IT Intrathecal; F female; M male
Attempt was made to control the pain by prescribing hydromorphone up to 10-15 mg orally or parenterally per day, acetaminophen 4 g/day, celecoxib 200 mg/day, and fentanyl patch up to 50 pg/h every three days. Despite high dose opioid and remarkable side effects, pain was not successfully controlled. Severe pain made the patient unable to exit from complete bedridden situation.
Acetaminophen was continued as 3-4 g/day in all of them. Infusion rate was File No. P2867CA01 adjusted during the following days according to patients' requirement and pain relief (on the basis of visual analog scale in rest time and normal daily activities).
Patient analgesic requirement stayed stable with an infusion rate of 1 ml/h or less. The infusion bag was changed every 24 hours. Meanwhile, bed sore healed almost completely. After one month of this regimen, following a fever episode, a sepsis work up was done that showed a urinary and cerebrospinal fluid (CSF) reaction. In spite of immediate parenteral antibiotics, the fever continued.
So the catheter was removed. Klebsiella pneumoniae was detected in urine and CSF
culture. Surprisingly, despite catheter removal, the patient did not request pain medication more than before. She left hospital in good condition without any sequels.
Patient had a history of allergy to morphine. So, a mixture with equivalent dose of preservative-free hydromorphone (a hydromorphine-morphine ratio of 1 to 5) was prepared. Following catheter insertion, pain dramatically decreased with an infusion rate of 1 ml/h. Hydromorphone was used as breakthrough pain control.
Due to patient's need, infusion rate was increased to 2.5 ml/h, but to avoid passing the limit of intrathecal bupivacaine daily dose, we changed the mixture as follows: hydromorphone 3 pg/ml, clonidine 1.25 pg/ml, naloxone 2 ng/ml, ketamine 100 pg/ml and bupivacaine 0.7 mg/ml. The infusion bag was changed every 24 hours. At this point, patient occasionally requested hydromorphone.
Methadone was decreased and stopped during the following days. Infusion rate File No. P2867CA01 was gradually decreased to 1 ml/h and patient left hospital in good condition.
For sterility concern, we increased the drugs' concentration during outpatient period.
That let us to decrease infusion rate (having the same daily dose) and to change the bag every 72 hours. The catheter was kept in place up to five months out of hospital under the supervision of a family physician. The patient died of his cancer after five months. During the last days of his life, the infusion rate was increased to control the pain and make a comfortable state in terminal phase.
File No. P2867CA01
prescription .
In neuroaxial analgesia, IT has less undesirable drug-related side effects due to fewer doses. Moreover, the evidence shows better results for IT approach in comparison with epidural approach in cancer-related pain (2B+ and 2C+
respectively). Morphine, baclofen and ziconotide are the only FDA-approved medications for IT use. Apart from bupivacaine, the others have been used successfully via IT approach at a greater dose than the one we used in our patients (Table-2).
Comparison of recommended intrathecal daily drugs' doses and our doses Product Recommended dose (9) Our dose*
Morphine 1-20mg 0.08-0.24 mg Bupivacaine 4-30 mg 8-24mg Clonidine 30-1000 pg 6-18 pg Naloxone no data available 0.2-0.5 ng Ketamine 1-50 mg 1-2.4 mg *Calculated on the basis of 51 ml/h infusion rate
administration. It has hydrophilic properties, so, morphine will spread more than fentanyl (and sufentanil) after IT administration and thus extend the area of analgesia. Its presynaptic and postsynaptic effects are via G-protein-linked opioid mu (mainly), delta and kappa receptors. Presynaptic interaction inhibits the File No. P2867CA01 release of substance-P and calcitonin gene-related peptide by means of interactions with N-type voltage-dependent calcium channels and reduced calcium influx. Postsynaptic activation of opioid receptors leads to inhibition of adenylate cyclase and also results in opening of potassium channels which, in turn causes hyperpolarization, rendering the postsynaptic second-order neuron less responsive.
administration of clonidine (average daily dose range from 50 to 200 pg) reduces the risk of morphine tolerance and thus lessens the risk for opioid-related adverse effects due to dose escalation. Side effects include dry mouth, sedation, bradycardia and hypotension. Sudden discontinuation of long-term IT therapy may lead to rebound hypertension, panic attacks, and psychotic behavior.
naloxone plus morphine in rodents, have not demonstrated signs of spinal cord toxicity. Even, some studies show neural protection of naloxone against ischemic situations. Due to chemical characteristics, ultra-low concentration and animal studies, it seems unlikely that IT naloxone would produce spinal cord toxicity. At File No. P2867CA01 the time of our (current) study, naloxone was not available as a formulation without preservative.
Ketamine is an intravenous anesthetic which has analgesic effect in sub-anesthetic doses. Besides, it has anti-hyperalgesic effect due to the impact on NDMA receptors and anti-allodynic effect by suppressing TLR (toll-like receptor)-mediated signal transduction. It could be used as IT approach in end-stage cancer related pain. Ketamine possesses a plethora of other actions that enhance its analgesic properties. These include blocking non-NMDA glutamate and muscarinic cholinergic receptors, facilitating GABA-A signaling, weakly binding to opioid receptors, and possessing local anesthetics and possibly neuroregenerative properties. It has been used successfully to control cancer and non-cancer pain. But the main concern is possible neurotoxic effect during long-term IT use (even with preservative-free S (+) enantiomer). In one recent animal study, IT injection of a large dose of 1mg/kg in dogs had no histological alterations of spinal tissue or meninges. Besides, there is more evidence which shows that IT infusion of ketamine would be useful in end-stage cancer related pain. Despite some studies reporting neurotoxicity following IT ketamine, our used dose is much less than the one in these reports and as mentioned previously, the other studies do not show neurotoxic effects in animal models.
On the other hand, we should not neglect its beneficial effects in inflammatory process and post-operative outcome. Ketamine is an immunomodulator which prevents the exacerbation and the extension of local inflammation without blunting the local process and delaying inflammatory resolution. This can explain some beneficial aspects of ketamine in post-operative outcome and cognitive dysfunction. Moreover, repeated high dose ketamine might have neurotoxic effect in immature brains in the absence of noxious stimuli whereas it may be neuroprotective in the same brains in the presence of strong painful stimuli.
Controversy continues about IT ketamine, but utilizing low-dose preservative-free File No. P2867CA01 ketamine in elderly and end-stage malignancies suffering from intractable pain would be a reasonable choice in pain management.
Direct IT infusion, synergistic effect and different mechanisms of action could explain sufficient analgesic effect of our drug combination even at lower concentrations. Due to very low concentration of the drugs (especially ultra-low dose for naloxone), absorption and systemic effect could not be very important in analgesic effect of the mixture.
File No. P2867CA01 PAIN MANAGEMENT THROUGH INFUSION IN THE RIGHT BRACHIAL
PLEXUS
Such File No. P2867CA01 modifications are considered as possible variants comprised in the scope of the disclosure.
Claims (38)
.cndot. an opioid;
.cndot. a Na channel blocker;
.cndot. an alpha2-receptor agonist;
.cndot. an opioid mu or delta receptor competitive antagonist; and .cndot. an intravenous anesthetic and/or a neurologic acting agent, for administration epidurally, paraverthebrally, at the peripheral nerves level, at the nerve plexus level, intra-articularly, in a synovial bursa, sub-cutaneously, and intravenously, or combination thereof.
.cndot. an opioid;
.cndot. a Na channel blocker;
.cndot. an alpha2-receptor agonist;
.cndot. an opioid mu or delta receptor competitive antagonist; and .cndot. an intravenous anesthetic and/or a neurologic acting agent, for pain control and/or cognitive function improvement, wherein said use is epidural, paraverthebral, at the peripheral nerves level, at the nerve plexus level, intra-articular, in a synovial bursa, sub-cutaneous, and intravenous, or combination thereof.
.cndot. an opioid;
.cndot. a Na channel blocker;
.cndot. an alpha2-receptor agonist;
.cndot. an opioid mu or delta receptor competitive antagonist; and .cndot. an intravenous anesthetic and/or a neurologic acting agent, for the preparation of a medicament for use in pain control and/or cognitive function improvement, wherein said medicament is for epidural use, paraverthebral use, use at the peripheral nerves level, use at the nerve plexus level, intra-articular use, use in a synovial bursa, sub-cutaneous use, and intravenous use, or combination thereof.
.circle. an opioid;
.circle. a Na channel blocker;
.circle. an alpha2-receptor agonist;
.circle. an opioid mu or delta receptor competitive antagonist; and .circle. an intravenous anesthetic and/or a neurologic acting agent, for pain control and/or cognitive function improvement, wherein said use is an epidural use, paraverthebral use, use at the peripheral nerves level, use at the nerve plexus level, intra-articular use, use in a synovial bursa, sub-cutaneous use, and intravenous use, or combination thereof.
a) a first container comprising at least one of the following compounds:
.circle. an opioid;
.circle. a Na channel blocker;
.circle. an alpha2-receptor agonist;
.circle. an opioid mu or delta receptor competitive antagonist; and .circle. an intravenous anesthetic and/or a neurologic acting agent;
b) at least a second container comprising at least one of the following compound different from the compound in said first container:
.circle. an opioid;
.circle. a Na channel blocker;
.circle. an alpha2-receptor agonist;
.circle. an opioid mu or delta receptor competitive antagonist; and .circle. an intravenous anesthetic and/or a neurologic acting agent;
wherein said medicament comprises said opioid, said alpha2-receptor agonist, said alpha2-receptor agonist, said opioid mu or delta receptor competitive antagonist, and said intravenous anesthetic and/or a neurologic acting agent.
.cndot. a catheter optionally connected to a PORT-A-CATH .TM., a reservoir placed under the skin, .cndot. a reservoir connected to an implanted pump for receiving a formulation of any one of claims 1 to 17 and wherein the reservoir is to be connected to the catheter.
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
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CA2930563A CA2930563A1 (en) | 2016-05-18 | 2016-05-18 | Multidrug infusion for pain control |
RU2016123345A RU2016123345A (en) | 2016-05-18 | 2016-06-14 | MULTI-DRUG INFUSION FOR CONTROL OF PAIN |
EP20176727.4A EP3741363A1 (en) | 2016-05-18 | 2016-07-01 | Multidrug infusion for pain control |
EP16177609.1A EP3246023A1 (en) | 2016-05-18 | 2016-07-01 | Multidrug infusion for pain control |
CN201710338921.2A CN107412774A (en) | 2016-05-18 | 2017-05-15 | Multiple medicine for Pain management injects |
AU2017203290A AU2017203290B2 (en) | 2016-05-18 | 2017-05-16 | Multidrug infusion for pain control |
JP2017098413A JP2018027931A (en) | 2016-05-18 | 2017-05-17 | Multidrug infusion for pain control |
TW106116242A TW201742635A (en) | 2016-05-18 | 2017-05-17 | Multidrug infusion for pain control |
KR1020170061664A KR20170130312A (en) | 2016-05-18 | 2017-05-18 | Multidrug infusion for pain control |
JP2022116552A JP2023009033A (en) | 2016-05-18 | 2022-07-21 | Multidrug infusion for pain control |
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CA2930563A CA2930563A1 (en) | 2016-05-18 | 2016-05-18 | Multidrug infusion for pain control |
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