EP0376999A1 - Verfahren zur umkehrung der nebenwirkungen epiduraler analgetika - Google Patents
Verfahren zur umkehrung der nebenwirkungen epiduraler analgetikaInfo
- Publication number
- EP0376999A1 EP0376999A1 EP89905239A EP89905239A EP0376999A1 EP 0376999 A1 EP0376999 A1 EP 0376999A1 EP 89905239 A EP89905239 A EP 89905239A EP 89905239 A EP89905239 A EP 89905239A EP 0376999 A1 EP0376999 A1 EP 0376999A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- nalmefene
- administered
- epidural
- administration
- analgesic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 22
- 230000000694 effects Effects 0.000 title claims abstract description 19
- 229940035676 analgesics Drugs 0.000 title description 7
- 239000000730 antalgic agent Substances 0.000 title description 7
- WJBLNOPPDWQMCH-MBPVOVBZSA-N Nalmefene Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 WJBLNOPPDWQMCH-MBPVOVBZSA-N 0.000 claims abstract description 31
- 229960005297 nalmefene Drugs 0.000 claims abstract description 31
- 208000003251 Pruritus Diseases 0.000 claims description 27
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 26
- 229940127240 opiate Drugs 0.000 claims description 17
- 230000000202 analgesic effect Effects 0.000 claims description 13
- 229960005181 morphine Drugs 0.000 claims description 13
- 206010046555 Urinary retention Diseases 0.000 claims description 9
- 230000002411 adverse Effects 0.000 claims description 8
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 claims description 2
- 229960002428 fentanyl Drugs 0.000 claims description 2
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 claims description 2
- 229960000482 pethidine Drugs 0.000 claims description 2
- 229960004315 phenoperidine Drugs 0.000 claims description 2
- IPOPQVVNCFQFRK-UHFFFAOYSA-N phenoperidine Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC(O)C1=CC=CC=C1 IPOPQVVNCFQFRK-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims 1
- 238000002347 injection Methods 0.000 abstract description 3
- 239000007924 injection Substances 0.000 abstract description 3
- 239000000014 opioid analgesic Substances 0.000 abstract 1
- 229940005483 opioid analgesics Drugs 0.000 abstract 1
- 229940124641 pain reliever Drugs 0.000 abstract 1
- 230000007803 itching Effects 0.000 description 15
- 239000000902 placebo Substances 0.000 description 14
- 229940068196 placebo Drugs 0.000 description 14
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000036592 analgesia Effects 0.000 description 4
- 239000003887 narcotic antagonist Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 3
- 206010038678 Respiratory depression Diseases 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 230000000302 ischemic effect Effects 0.000 description 3
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 3
- 229960004127 naloxone Drugs 0.000 description 3
- 230000036407 pain Effects 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- 208000036741 Pruritus generalised Diseases 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 230000035807 sensation Effects 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- 229940089529 duramorph Drugs 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229960004715 morphine sulfate Drugs 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 230000037325 pain tolerance Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000036387 respiratory rate Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000002820 sympathetic nervous system Anatomy 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 238000002562 urinalysis Methods 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
Definitions
- the invention relates to methods of reversing the untoward side effects of of opiate analgesics administered epidurally.
- epicural narcotic analgesics such as morphine
- Adverse side effects include: nausea, pruritis, urinary retention, and more rarely, severe respiratory depression.
- narcotic antagonists such as naloxone
- the relatively short duration of action of nalaxone together with the long duration of action of the opiate analgesic permits the recurrence of the Side effects, often for as long as 24 hours after the epicural administration.
- the present invention resides in the administration of the narcotic antagonist nalmefene (6-methylene- 6-desoxy-N-cyclopropylmethyl-14-hydroxydihydronormorphine) parenterally following (or immediately preceding) epidural administration of opiate analgesics.
- nalmefene 6-methylene- 6-desoxy-N-cyclopropylmethyl-14-hydroxydihydronormorphine
- the opiate analgesic most commonly administered by the epidural route is morphine and/or salts thereof such as morphine sulfate, although pethidine, fentanyl and phenoperidine have been administered epidurally as well. Excellent analgesia is attained through this method without sedation and certain other central nervous system effects of intravenous opiates.
- naloxone has been utilized to antagonize the adverse side effects of epidural opiates, but has been found somewhat unsatisfactory because of its short duration of action.
- narcotic antagonist nalmefene provides relief of long duration from the side effects of epidural opiates. Nalmefene can even be used prophylactically to avoid the onset of such side effects.
- the dosage range of epidurally administered opiates, particularly morphine varies from about 0.03 to about 0.15 mg/kg, with the most common dosage being 0.1 mg/kg.
- a more preferred dosage range for the administration of of nalmefene in the method of the present invention is from about 0.2 to about 1.5 mg administered as a bolus injection immediately prior to or after epidural analgesics or in 2 to 4 equally divided doses, with the first dose immediately prior to or after adminis tration of the analgesic and the succeeding doses every 6-10 hours thereafter.
- Example provides a detailed illustration of the method of the present invention for alleviating or reversing the side effects of epidurally administered opiates.
- the Example is not intended, however, to limit or restrict the scope of the invention in any way, and should not be construed as providing dosage regimens or methods of administration which must be utilized exclusively to practice the present invention.
- Presence of cutaneous sensation was assessed by both the pinprick and ice application methods at time 0 and at the end of each of the first six hours following epidural morphine and again at 12, 18 and 24 hours post morphine.
- the cold presscr test was administered pre-morphine and retested 1/2 hour after injection and again every three hours post epidural morphine throughout the 24 hour period.
- One hand and one foot were successively immersed in ice water for a period of 90 seconds. Blood pressure changes were obtained in an effort to assess the integrity of the sympathetic nervous system.
- Tourniquet-induced ischemic pain was utilized to assess analgesia levels at baseline and at end of each hour post morphine for the first twelve hours and then every three hours throughout the session.
- the bladder of a B.P. cuff was inflated to 20 mmHg above systolic pressure and subjects were required to continuously squeeze a rubber bulb until it became too painful to carry on. Endurance of ischemic pain was measured in seconds.
- Blood gas analyses were conducted every four hours and values were obtained for PaO 2 , PaCO 2 , HCO 3 , SO 2 and pH.
- Base excess (E.E.) nurses monitored the subjects throughout the twenty four hour period for evidence of urinary retention, pruritis cr respiratory depression. Blood pressure, respiratory rate and pulse were monitored every 15 minutes throughout the session.
- Blocd gas statistical analyses showed statistically significant differences across time for PaCO 2 and B.E. Neither the difference between sessions (i.e. drug-placebo) nor the interaction cf sessions by time was found to be significant for these two bleed measures. No significant difference was found for the PaO 2 , HCO 3 , %SO 2 or pH measures.
- Pruritis caused by epidural morphine, was prevented or diminished by nalmefene. Nalmefene also appeared to diminish urinary retention.
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Toxicology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US18660788A | 1988-04-27 | 1988-04-27 | |
| US186607 | 1998-11-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0376999A1 true EP0376999A1 (de) | 1990-07-11 |
Family
ID=22685593
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP89905239A Withdrawn EP0376999A1 (de) | 1988-04-27 | 1989-04-07 | Verfahren zur umkehrung der nebenwirkungen epiduraler analgetika |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0376999A1 (de) |
| JP (1) | JPH0660099B2 (de) |
| WO (1) | WO1989010125A1 (de) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5931809A (en) * | 1995-07-14 | 1999-08-03 | Depotech Corporation | Epidural administration of therapeutic compounds with sustained rate of release |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3896226A (en) * | 1971-11-26 | 1975-07-22 | Lewinstein Evalina | 6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts thereof, and use of the same as a narcotic antagonist |
-
1989
- 1989-04-07 EP EP89905239A patent/EP0376999A1/de not_active Withdrawn
- 1989-04-07 JP JP1505014A patent/JPH0660099B2/ja not_active Expired - Lifetime
- 1989-04-07 WO PCT/US1989/001448 patent/WO1989010125A1/en not_active Application Discontinuation
Non-Patent Citations (1)
| Title |
|---|
| See references of WO8910125A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1989010125A1 (en) | 1989-11-02 |
| JPH02504148A (ja) | 1990-11-29 |
| JPH0660099B2 (ja) | 1994-08-10 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 19891218 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE FR GB IT LI LU NL SE |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN |
|
| 18W | Application withdrawn |
Withdrawal date: 19910226 |
|
| R18W | Application withdrawn (corrected) |
Effective date: 19910226 |