EP0376999A1 - Method of reversing the side effects of epidural analgesics - Google Patents
Method of reversing the side effects of epidural analgesicsInfo
- 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- Withdrawn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.
Abstract
Un procédé d'inversion des effets secondaires défavorables d'analgésiques opiacés administrés par voie épidurale, consiste à administrer entre 0,1 et 2,0 mg de nalméfène (6-méthylène-6-désoxy-N-cyclopropylméthyle-14-hydroxydihydronormorphine) avant ou après administration de l'analgésique. On administre le nalméfène par voie parentérale, de préférence par voie intraveineuse, dans une injection de bol ou en doses divisées de manière égale.A method of reversing the unfavorable side effects of opioid analgesics administered by the epidural route, consists in administering between 0.1 and 2.0 mg of nalmefene (6-methylene-6-deoxy-N-cyclopropylmethyl-14-hydroxydihydronormorphine) before or after administration of the pain reliever. Nalmefene is administered parenterally, preferably intravenously, in a bolus injection or in equally divided doses.
Description
METHOD OF REVERSING THE SIDE EFFECTS OF EPIDURAL ANALGESICS
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to methods of reversing the untoward side effects of of opiate analgesics administered epidurally.
2. Description of the Prior Art
The administration of epicural narcotic analgesics, such as morphine, for the relief of postoperative pair, has been well established. Adverse side effects include: nausea, pruritis, urinary retention, and more rarely, severe respiratory depression. Although these side effects are reversible through the administration of 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. Thus, the risk of potentially serious adverse side effects requires close patient surveillance for at least 12-24 hours following epidural administration of an opiate analgesic, and may necessitate the repeated administration of an antagonist such as naloxone.
SUMMARY OF THE INVENTION It is an object of the present invention to provide a methcά of alleviating or reversing the adverse side effects of epidural opiate analgesia,while avoiding the necessity of prolonged patient monitoring and the frequent administration of a narcotic antagonist.
It is a further object of the present invention to provide a method as described above which does not interfere with the analgesic effectiveness of the epidural medication.
It is yet another object of the present invention to provide a method as described above which is safe, reliable and relatively inexpensive.
In keeping with these objects and others that will become apparent hereinafter, 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.
DETAILED DESCRIPTION OF THE INVENTION 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.
For reasons not yet well understood, however, the administration of opiate analgesics epidurally, while relieving pain, stimulates and aggravates pruritis and can lead to urinary retention, nausea and ultimately severe respiratory depression; see, for example, P.V. Scott and H.B.J. Fischer, Brit. Med. J., Vol. 284, pp. 1015-16 (1982); Anaesthesia, Vol. 36(1), pp. 67-β8 (1981); Lancet, Vol. 2 (8187), p. 204 (1980). As indicated previously, 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.
It has now been discovered, however, that the use of the 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. The administration of from about 0.1 to about 2.0 mg of nalmefene parenterally, preferably by the intravenous route, has been found effective in reversing the known adverse effects of epidural opiates.
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.
No adverse side effects have been found to result from the administration of nalmefene in accordance with the method of the invention, and the degree of analgesia provided by the epidurally administered opiate does not appear to diminish to any degree upon parenteral nalmefene administration.
The following 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.
EXAMPLE
Methods Informed consent was obtained from seven healthy male volunteers who agreed to participate in this study. Each subject was required to complete two separate 24 hour sessions spaced approximately 1 week apart. A prestudy EKG and urinary drug screen was performed on each subject. At the beginning of each session the subjects were tested on each of the study variables to obtain baseline control values. Following baseline measurements a
dose of 0.1 mg/kg epidural morphine ("DURAMORPH"-Eikins-Sinn, Inc.) was administered as a bolus. The study incorporated a double blind! crossover scientific design where one arm consisted of 0.2 mg nalmefene administered intravenously immediately after the morphine and repeated at 8 and 16 hours post morphine. The second arm of the design was identical to the first except that a placebo saline was substituted for nalmefene.
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 PaO2, PaCO2, HCO3 , SO2 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.
Statistical analysis employed included two way repeated measures analysis of variance and post-test comparisons of means where appropriate. Comparison of the proportions cf subjects experiencing pruritis cr urinary retention in the nalmefene versus placebo was conducted using the bi-nomial test described by Armirage.
Only one subject reported any alteration cf cutaneous sensation as assessed by pinprick and ice application. That subject experienced the change only during the first five hours of the placebo session. Analyses of variance conducted on the arithmetic mean blood pressure data obtained during cold pressor tests of both the hand and foot revealed a statistically significant difference (p<0.01) between trials (time blocks) within sessions (i.e. drug or placebo). However, there was not a statistically significant difference between the drug and placebo sessions and no interaction (i.e. trial x drug) was found.
Mean ischemic pain tolerance measurement in seconds of
endurance cf exercise following occlusion of blood to the limb by the application of tourniquet failed to reveal a statistically significant difference for session (i.e. drug or placebo), trial (i.e. baseline, 1 hour, 2 hours, etc.) or the interaction of session by trial.
Blocd gas statistical analyses showed statistically significant differences across time for PaCO2 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 PaO2, HCO3, %SO2 or pH measures.
All incidences of pruritis through nalmefene and placebo treatments are set forth in Table 1 hereto. Of the six subjects treated with placebo, only five had records available for pruritis. Four (80%) of those subjects reported multiple incidences of pruritis.
On the contrary, out of seven subjects treated with nalmefene only three (43%) reported slight itching on one or two occasions. In these three subjects the feeling of itching appeared at 4, 5 1/2 and 6 hours after the first dose cf nalmefene. This may be due to the decreased effectiveness of the small dose (0.2 mg) of nalmefene after that period. Nalmefene-treated subjects did not report any itching two hours after the second dose, but placebo-treated subjects complained of itching until long after that time.
Table 2 lists incidences of urinary retention. Records were available far five of the six subjects treated with placebo. Of these five, three (60%) had urinary retention and needed to be catheterized at various times. In nalmefene-treated subjects only two out of seven (29%) needed to be catheterized.
Discussion
Pruritis, caused by epidural morphine, was prevented or diminished by nalmefene. Nalmefene also appeared to diminish urinary retention.
Nalmefene was well tolerated by healthy male volunteers. No clinically significant changes in blood chemistries, hematology or urinalysis were seen. At the dose level used, nalmefene had minimal effects on analσesia.
Table 1
Pruritis
Sub j ect # Nalmefene Placebo 1 6 hrs after first nalmeNot given fene dose itchy face, dry mouth
3 None None 4 None 2 hrs after first dose itching in lower leg
3 1/2 hrs after first dose decreased itching
7 hrs after second dose general body itchinσ 5 5 1/2 hrs after first No record dose itchinσ
2 hrs after second dose itching 6 None 1 1/4 hr after firs; dose itching
5 3/4 hrs after first dose generalized itching
6 3/4 hrs after first dose continued itching
3 hrs after second dose itching
6 hrs after second dose still itching
Table 1 (cont'd.)
Pruritis
Subject # Nalmefene Placebo 7 None 2 hrs after first dose slight itching on lower leg 8 4 hrs after first dose 1 1/2 hrs after slight itching first doseitching in upper thighs and lower abdomen
4 hrs after first dose generalized itching
6 hrs after first dose increased itching, head to toe
1 hr after second dose itching creatly reduced
Table 2
Urinary Retention
Nalmerene Placebo
Subi ect #
Yes Not given 1
No No 2 No Yes 4 No No record 5 No No 6 No Yes 7 Yes Yes 8
It has thus been shown that there are provided methods which achieve the various objects of the invention and which are well adapted to meet the conditions of practical use.
As various possible embodiments might be made of the above intention, and as various changes might be made in the embodiments set forth above, it is to be undestood that all matters herein described are to be interpreted as illustrative and not in a limiting sense.
What is claimed as new and desired to be protected by Letters Patent is set forth in the following claims.
Claims
CLAIMS 1. A method of reversing the adverse side effects of an epidurally administered opiate analgesic in a patient receiving such an epidural analgesic, comprising the parenteral administration to the patient from about 0.1 to about 2.0 mg of nalmefene prior to or after the administration of the epidural analgesic.
2. A method according to claim 1 wherein from about 0.2 to about 1.5 mg of nalmefene are administered to the patient.
3. A method according to claim 1 wherein said nalmefene is administered as a bolus immediately prior to administration of the epidural analgesic.
4. A methcd according to claim 1 wherein said nalmefene is administered as a bolus immediately after the administration of the epidural analgesic.
5. A methcd according to claim 1 wherein said nalmefene is administered in divided doses.
6. A method according to claim 5 wherein said nalmefene is administered in 2-4 equally divided doses with the first of said coses being administered immediately prior to or after the administration of the epidural analgesic and the remaining doses being administered every 6-10 hours thereafter.
7. A method according to claim 1 wherein said nalmefene is administered intravenously.
8. A method according to claim 1 wherein said opiate analgesic is morphine or a salt thereof.
9. A method according to claim 1 wherein said opiate analgesic is pethidine, fentanyl or phenoperidine.
10. A method. according to claim 1 wherein said adverse sice effects include pruritis and urinary retention.
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 (en) | 1990-07-11 |
Family
ID=22685593
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP89905239A Withdrawn EP0376999A1 (en) | 1988-04-27 | 1989-04-07 | Method of reversing the side effects of epidural analgesics |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0376999A1 (en) |
| JP (1) | JPH0660099B2 (en) |
| WO (1) | WO1989010125A1 (en) |
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/en not_active Withdrawn
- 1989-04-07 WO PCT/US1989/001448 patent/WO1989010125A1/en not_active Application Discontinuation
- 1989-04-07 JP JP1505014A patent/JPH0660099B2/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| See references of WO8910125A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0660099B2 (en) | 1994-08-10 |
| JPH02504148A (en) | 1990-11-29 |
| WO1989010125A1 (en) | 1989-11-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Aho et al. | Effect of intravenously administered dexmedetomidine on pain after laparoscopic tubal ligation | |
| Wong et al. | Ketamine potentiates analgesic effect of morphine in postoperative epidural pain control | |
| Lehmann | Tramadol for the management of acute pain | |
| Lanz et al. | Epidural morphine for postoperative analgesia: a double-blind study | |
| Albright et al. | The safety and efficacy of combined spinal and epidural analgesia/anesthesia (6,002 blocks) in a community hospital | |
| Bailey et al. | Continuous epidural infusion of fentanyl for postoperative analgesia | |
| Mecklem et al. | Efficacy of bupivacaine delivered by wound catheter for post‐caesarean section analgesia | |
| Jørgensen et al. | Influence of epidural morphine on postoperative pain, endocrine‐metabolic, and renal responses to surgery. A controlled study | |
| Gordon et al. | Successful treatment of painful crises of Fabry disease with low dose morphine | |
| Howell et al. | Comparison of four local extradural anaesthetic solutions for elective caesarean section | |
| Thien et al. | Diazoxide infusion in severe hypertension and hypertensive crisis | |
| Fassoulaki et al. | Systemic fentanyl enhances the spread of spinal analgesia produced by lignocaine | |
| d'Amours et al. | Postoperative pain management | |
| CA2165446C (en) | Use of ropivacaine in the manufacture of a pharmaceutical with analgetic effect with minimal motor blockade | |
| EP0376999A1 (en) | Method of reversing the side effects of epidural analgesics | |
| Venkateswaran et al. | Management of postoperative pain | |
| Ward | Acute pain and the obstetric patient: recent developments in analgesia for labor and delivery | |
| WO1999040867A1 (en) | Treatment of brain edema using carbonic anhydrase enzyme inhibitor | |
| Wang et al. | Comparison of intravenous nalbuphine infusion versus saline as an adjuvant for epidural morphine | |
| Milligan et al. | The characteristics of analgesic requirements following subarachnoid diamorphine in patients undergoing total hip replacement | |
| Fee et al. | Analgesia after hip replacement surgery: comparison of nalbuphine with morphine | |
| Siler et al. | Lidocaine hydrochloride versus lidocaine bicarbonate for epidural anesthesia in outpatients undergoing arthroscopic surgery | |
| Eldor et al. | Prevention of epidural morphine pruritus by intramuscular promethazine in parturients | |
| Atallah et al. | Presurgical analgesia in children subjected to hypospadias repair | |
| US6110954A (en) | Treatment |
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 |