JP2002541203A - Pain management after joint surgery - Google Patents

Abstract

  (57) [Summary] A method of managing pain and immobility resulting from joint surgery, comprising administering an analgesically effective amount of morphine-6-glucuronide (M6G) to the cavity of the operated joint. A surgically operated joint cavity comprising a pharmaceutical composition for use in the method, a single dose of such a composition, a hypodermic syringe filled with the single dose, and an analgesically effective amount of morphine-6-glucuronide. For the preparation of a medicament for injection into a pill. [Effect] The analgesic effect lasts for a long time and there are no side effects.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a method for managing pain and immobility (immobilization) resulting from joint surgery, a composition used in the method, and a method for producing the composition.

[0002]

[Prior art]

Post-operative pain that occurs after joint surgery, such as knee surgery, is often severe and results in immobility for long periods. The pain is also at rest and worsens while moving. Pain can impede early movement after surgery and prolong hospital and outpatient treatment. Less movement increases the risk of vascular thrombosis and pulmonary embolism.
It is therefore very important to reduce pain in patients who have undergone joint surgery.

[0003] Currently, patients who have undergone knee or other types of orthopedic surgery are very often managed with intravenous or intramuscular morphine or other opoid-based therapies. This usually results in short-lived and often inadequate analgesia, nausea,
May be accompanied by side effects such as vomiting and decreased respiratory function. Alternatively, intravenous or intramuscular NSAIDs (non-steroidal anti-inflammatory drugs) such as diclofenac
(diclofenac), ketoprofen or ketorolac. However, such treatment is less efficient than administration of opoids,
It is associated with the risk of other side effects such as gastric ulcers, asthma, and severe skin reactions. Therefore, better management of post-operative pain is desired.

[0004] Morphine, when given systemically, mainly converts to 3- and 6-glucuronide in the liver. 6-glucuronide (M6G) is also a potent opoid antagonist. It is substantially more hydrophilic than most opoids for clinical use. Thus, M6G has a reduced tendency to penetrate the blood / brain barrier, thus reducing the risk of adverse effects on the central nervous system.

[0005] Morphine-6-glucuronide is a pre-intradermal analgesic for total lumbar replacement (D. Grace et al., Anest. Analg. 83 (1996) 1055-105).
9) and for reducing post-operative pain in knee surgery (Brit. J. Anaest, 69 (1992) 2). In both studies, delayed respiratory depression was observed, warning of such use of M6G.

[0006]

[Problems to be solved by the invention]

It is an object of the present invention to provide a method of managing pain and immobility resulting from joint surgery. Another object of the present invention is to provide a means of managing pain and immobility arising from joint surgery. Other objects of the present invention will become apparent from the following brief description of the invention, the description of the preferred embodiments, and the claims.

[0007]

[Means for Solving the Problems]

According to the present invention, an analgesically effective amount of morphine-6-glucuronide (M6G)
There is provided a method as described above, characterized in that the method is administered to the cavity of a operated joint.

[0008]

Preferred Embodiment of the Invention

Since topical opioid analgesia may begin to act slowly in the immediate post-operative period as the opioid receptor begins to regulate gradually, administration of M6G may be of moderate or long duration, for example up to 3 hours. Lidocaine that gives more pain relief (lidoc
It is advantageous to combine the onset of action with short-acting local analgesics, such as aine), bupivacaine, mepivacaine and ropivacaine. Topical analgesics are immediate but short lasting,
On the other hand, the onset of action of M6G is slow but its effect will be substantially longer than that of local analgesics. The combination of a topical analgesic with M6G will provide a beneficial analgesic effect for as long as 48 hours or more after administration. This long lasting analgesic action will allow the patient to move faster and reduce the risk of adverse effects associated with post-operative immobility, such as vascular thrombosis and pulmonary embolism. Early movements are also reflected in lower health care costs.

[0009] An advantageous aspect of the present invention is that only a small amount of M6G is required to achieve an analgesic effect comparable to that obtained with morphine (measured at a predetermined time after surgery). In the systemic circulation, the concentration of M6G will be very low; it can be below the limit of detection. This substantially reflects central nervous system effects as well as reduced adverse effects, which can be imperceptible. The preferred dose for obtaining analgesia in large joints is 0.05-10 mg. In the description of the present application, "large joint" refers to joints such as knee joints, hip joints, shoulder joints, elbow joints and ankle joints.
The preferred dose of the topical analgesic, which is to be started in a short time, depends on its nature. For bupivacaine and mepivacaine, a dose of 5 mg to 100 mg is preferred.

Another advantageous aspect of the invention is the long duration analgesic effect obtained with M6G. This is because M6G is hydrophilic, so that synovial fluid of the joint to which M6G has been administered has M6G.
Is likely to be held for a long time. This retention will substantially reduce the risk of adverse effects on the central nervous system.

Administration of M6G, or M6G in combination with a short-acting local analgesic, is placed in the capsule of the joint at the end of surgery, before closing the capsule, or at the completion of surgery.

According to yet another advantageous aspect of the present invention, the method of the present invention comprises a non-steroidal anti-inflammatory drug (NSAID) such as diclofenac, ketorolac (k
etorolac), ketoprofen (ketoprofen), ibuprofen (ibuprofen), naproxen (naproxen), indomethacin (indometacin), celecoxib (celecoxib),
And their pharmaceutically acceptable salts, or another non-selective NSAID (COX1 / COX
2) or COX2 selective drug administration.

According to the present invention, an effective amount of morphine-6 to provide post-operative analgesia to a joint.
Disclosed is a pharmaceutical composition for administration to a joint, comprising glucuronide (M6G) and a pharmaceutically acceptable carrier. In particular, an analgesically effective amount of M6G is selected to provide an analgesic effect of at least 24 hours, more preferably at least 48 hours. The composition is a short acting topical analgesic, such as lidocaine, bupivacaine, mepivacaine and ropivacaine, and pharmaceutically acceptable salts thereof, but with a relatively short duration of action, e.g. Preferably up to 3 hours or up to 3 hours.

The pharmaceutically acceptable carrier may simply be saline, but other carriers are also conceivable, for example an aqueous solution of hyaluronic acid as a substitute for synovial fluid. This extends the duration of the analgesic.

[0015] In addition to applications in the context of joint surgery, the compositions of the present invention have other uses, such as treatment of joint inflammation.

[0016]

【Example】

In the following the invention will be described in more detail with reference to preferred non-limiting embodiments. Example 1 Immediately after knee arthroplasty (3 patients; male 35 years; male 18 years; male 20 years), 0.5 mg M6G and 25 mg bupivacaine hydrochloride in 2 ml saline were injected into the joint space. Injected. The patient was first moved the next day and was discharged from the hospital on the second day after the operation. The patient did not complain of side effects and remained substantially painless until discharge. At the same hospital, a conventional joint painkiller (morphine 1)
0 mg; bupivacaine 25 mg) is usually discharged on the third day after surgery or later. Many of them experience adverse effects such as nausea and vomiting caused by morphine.

Example 2 A composition of the present invention for intra-articular administration in the form of a single dose for large surgery is treated with 0.1%
5 mg of morphine-6-glucuronide (Pharmacia Nordica) and 25 m
A multiple of g of bupivacaine hydrochloride was prepared by dissolving in 2 ml of saline and filled in a hypodermic syringe under sterile conditions. The composition is ready for use.

Example 3 A composition of the present invention that is similar to Example 2 but provides an extended sustained effect was prepared by adding a saline solution to an aqueous solution of sodium hyaluronate [Sinvisc ™, Roche, 1 m
per liter containing 8 mg sodium hyaluronate, 8.5 mg sodium chloride, 0.17 mg disodium hydrogen phosphate and 0.03 mg sodium dihydrogen phosphate].

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/407 A61K 31/407 31/4152 31/4152 31/445 31/445 45/00 45/00 A61P 19/02 A61P 19/02 25/04 25/04 29/00 29/00 43/00 121 43/00 121 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM ), AE, AG, AL, AM, T, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH , GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN , YU, ZA, ZW (72) Inventor Brunsson, Sveinbjörn Sweden S-433 60 Save Daren Lovkravegen 13 F term (reference) 4C084 AA19 AA23 BA44 CA62 MA17 MA66 NA05 NA06 ZA082 ZA961 ZB112 ZC752 4C0A A01 BC15 BC21 BC36 CB03 CB23 MA01 MA02 MA0 3 MA04 MA17 MA66 NA05 NA06 ZA08 ZA96 ZB11 ZC75 4C206 AA01 AA02 DA22 DA24 DA25 FA31 GA31 KA01 MA01 MA02 MA03 MA04 MA14 MA17 MA37 MA86 NA05 NA06 ZA08 ZA96 ZB11 ZC75

Claims (21)

[Claims] 1. An analgesically effective amount of morphine-6-glucuronide (M6G).
A method for managing pain and immobility resulting from joint surgery, comprising administering to a cavity of a joint where surgery has been performed. 2. The method according to claim 1, wherein an analgesically effective amount of a local analgesic which starts to act in a short time is administered. 3. The method of claim 2, wherein said local analgesic is selected from the group consisting of lidocaine, bupivacaine, mepivacaine and ropivacaine, and pharmaceutically acceptable salts thereof. 4. An effective amount of M6G is from 0.05 mg to 1 for large joints.
The method according to any one of claims 1 to 3, wherein the amount is 0 mg. 5. The method according to claim 2, wherein the effective amount of the local analgesic is 1 mg to 100 mg. 6. The method according to claim 1, wherein a pharmaceutically effective amount of a nonsteroidal anti-inflammatory drug (NSAID) is administered into the cavity of the joint or systemically. 7. The method of claim 6, wherein the NSAID is selected from the group consisting of diclofenac, ketorolac, ketoprofen, ibuprofen, naproxen, indomethacin, celecoxib, and pharmaceutically acceptable salts thereof. 8. A surgical joint cavity for the management of pain and immobility arising from joint surgery, comprising an analgesically effective amount of morphine-6-glucuronide (M6G) and a pharmaceutically acceptable carrier. Pharmaceutical composition for injection. 9. The composition according to claim 8, wherein the amount of M6G is 0.05 mg to 10 mg. 10. A composition according to claim 8 or claim 9 comprising an analgesically effective amount of a local analgesic which has a short onset of action. 11. The composition of claim 10, wherein said local analgesic is selected from the group consisting of lidocaine, bupivacaine, mepivacaine and ropivacaine, and pharmaceutically acceptable salts thereof. 12. The composition of claim 8, comprising a nonsteroidal anti-inflammatory drug (NSAID).
A composition according to any one of claims 1 to 11. 13. The composition of claim 12, wherein the NSAID is selected from the group consisting of diclofenac, ketorolac, ketoprofen, ibuprofen, naproxen, indomethacin, celecoxib, and pharmaceutically acceptable salts thereof. 14. The composition according to any one of claims 8 to 13, comprising means for retaining M6G in the joint cavity. 15. The composition according to claim 14, wherein said means is hyaluronic acid or a pharmaceutically acceptable salt thereof. 16. A single dose of a pain relieving composition for intra-articular administration comprising 0.05 to 10 mg of morphine-6-glucuronide and a pharmaceutically acceptable carrier. 17. A member selected from the group consisting of lidocaine, bupivacaine, mepivacaine, ropivacaine and a pharmaceutically acceptable salt thereof, of 1 mg to 100 m
17. The single dose of claim 16, comprising g. 18. A hypodermic syringe filled with a single dose of claim 16. 19. A method of preparing a medicament for injecting into a cavity of a surgically operated joint, comprising a analgesically effective amount of morphine-6-glucuronide (M6G). 20. The method according to claim 19, wherein the amount of M6G is 0.1 mg to 10 mg.
Production method as described. 21. The method according to claim 19, wherein the medicament comprises an analgesically effective amount of a local analgesic which starts to act in a short time.