METHOD OF REVERSING THE SIDE EFFECTS OF EPIDURAL ANALGESICS

Abstract: A method of reversing the adverse side effects of epidurally administered opiate analgesics comprises the administration of from 0.1 to 2.0 mg of nalmefene (6-methylene-6-desoxy-N-cyclopropylmethyl-14-hydroxydihydronormorphine) before or after administration of the analgesic. The nalmefene is administered parenterally, preferably intravenously, in a bolus injection or in equally divided doses.

Description: -1- METHOD OF REVERSING THE SIDE EFFECTS OF EPIDURAL ANALGESICS BACKGROUND 0? TH5 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, suc 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 depres¬ sion. Although these side effects are reversible through the administration of narcotic antagonists such as naloxcne, the relatively short duration of action of nalaxone together with the long duration of action of the opiate analgesic permits the recurrence cf 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 Or THE INVENTION It is an object of the present invention to provide a ethcά of alleviating or reversing the adverse side effects of epidural opiate analgesia # wh #ile avoiding the necessity of pro- longed 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-meth ler.e- δ-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. -3- 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 therea er. No adverse side effects have bee ' n 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 revers¬ ing 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 ose of 0.1 mg/kg epicural morphine ("DURAMORPH"-Ξikins-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 followinc 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. Bleed pressure changes were obtained in an effort to assess the integrity of the sympa¬ thetic 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 bul 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 -6- for PgCi, ? C02, S Z t ?:-:. Base excess (Ξ.Ξ.) nurses monitored the subjects throughout the twenty four hour period for evidence cf .urinary retention, pruritis cr respiratory depression. Blocd 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 place c was conducted using the ci-ncmiai test described by Amirage. 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 signifi¬ cant difference * (p<0.C1 ) 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 endurancs cf exercise following occlusion cf blocd 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 PaCθ2 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 Paθ2, ΞCO3, %Sθ2 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 pruri¬ tis. 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 nalme¬ fene. 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 wa^ .well tolerated by healthy male volunteers. No clinically significant changes in blood chemistries, he atology or urinalysis were seen. At the dose level used, nalmefene had minimal effects on analσesia. Table 1 Pruritis Sub-tect £ Nalmefene Placebo * 6 hrs after first nalme¬ Not 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 de¬ creased itching 7 hrs after second dose general body itchinσ 5 1/2 hrs after first No record dose itchinσ 2 hrs after second dose itching None 1 1/4 hr after firs; dose itching 5 3/4 hrs after first dose gene¬ ralized itching 6 3/4 hrs after first dose con¬ tinued itching 3 hrs after second dose itching 6 hrs after second dose still itching -10- Table 1 (cont'd. Pruritis Subject g Nalmefene Placebo 7 None 2 hrs after first dose slight itching on lower leg 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 creatlv reduced Table 2 Urinary Retention N almerene Placebo Subi ect fl γes Not given 1 No No 2 No Yes 4 No No record 5 No No 6 No Yes 7 Yes Yes 8 t has thus been shown that there are provided methcds 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: -13- C AI S 1. A methcd of reversing the adverse side ef ects of an epidurally administered opiate analgesic in a patient receiving such an epidural analgesic, comprising the parenteral administra- tion 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 methcd 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 methcd according to claim 1 wherein said opiate analgesic is morphine or a salt thereof. 9. A methcd according to claim 1 wherein said opiate analgesic is pethidine, fentanyl or phenoperidine. . 10.- A methcd. according to claim 1 wherein said advers sice effects include pruritis and urinarv retention.

Inventors: BIKHAZI GEORGE, FISHMAN JACK, BIKHAZI, GEORGE, FISHMAN, JACK
Applicants: BAKER CUMMINS PHARMA, BAKER CUMMINS PHARMACEUTICALS, INC
Application year: 1989
Main classification: A61K31
IPC codes: A61K31, A61K45, A61P25, A61P39