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JP-7857276-B2 - Management of postoperative surgical pain

JP7857276B2JP 7857276 B2JP7857276 B2JP 7857276B2JP-7857276-B2

Inventors

  • エバンス，スティーブ
  • カリニチェフ，ミハイル
  • ポンス，ローラン
  • コルネット，シルビー
  • レズミ，ステファン

Assignees

  • イプセン バイオファーム リミテッド

Dates

Publication Date
20260512
Application Date
20210716
Priority Date
20200717

Claims (11)

  1. A pharmaceutical preparation containing botulinum neurotoxin serotype A (BoNT/A) for use in the treatment of postoperative surgical pain in patients. The treatment comprises administering BoNT/A to the patient 5 to 20 days prior to surgery, wherein BoNT/A is administered intradermally, and the postoperative surgical pain in the patient is caused by a surgical intervention including (i) skin and (ii) surgical incision of fascia, muscle, bone, and/or organs.
  2. The pharmaceutical product according to claim 1. Here, a) BoNT/A is administered 10 to 20 days before surgery; b) BoNT/A is administered 14 to 16 days before surgery; c) Administration of BoNT/A substantially reduces the patient's perception of postoperative surgical pain, and this reduced perception of postoperative surgical pain is maintained for 24 hours immediately following surgery; and/or d) Substantially all reduced postoperative surgical pain sensation is maintained for 3, 4, 5, 6, 7, or 8 days immediately following surgery.
  3. BoNT/A is the pharmaceutical product according to claim 1, administered 5 to 15 days prior to surgery.
  4. The pharmaceutical product according to claim 2(c) or (d), wherein the level of reduced pain perception observed at a specified time immediately following surgery is at least 50% of the maximum level of reduced pain perception observed at any time after administration of BoNT/A.
  5. A pharmaceutical product according to any one of claims 1 to 4. Here, a) BoNT/A treats postoperative surgical pain and reduces or suppresses postoperative anxiety; and/or b) The postoperative surgical pain is caused by the surgical intervention, and BoNT/A is administered distal to the site of the surgical intervention, with the distal site of the surgical incision being at least 15 cm from the site of the surgical intervention.
  6. A pharmaceutical product according to any one of claims 1 to 5. Herein, after administration, BoNT/A travels to the spinal cord by retrograde transport and performs SNARE protein cleavage or SNAP-25 protein cleavage within the spinal cord.
  7. A pharmaceutical product according to any one of claims 1 to 6. Herein, BoNT/A is administered intradermally, and after administration of BoNT/A, minimal or no SNARE protein cleavage or SNAP-25 protein cleavage by BoNT/A is observed in or near the intradermal site.
  8. A pharmaceutical product according to any one of claims 1 to 7. Here, a) Postoperative surgical pain is acute postoperative surgical pain; b) Postoperative surgical pain is chronic postoperative surgical pain; and/or c) The above procedure does not include intramuscular administration of BoNT/A.
  9. A pharmaceutical product according to any one of claims 1 to 8. Here, a) The patient is administered 100–500 U of BoNT/A; b) The patient is administered a total dose of 1–3 ng of BoNT/A; c) The patient is administered 80–250 pg of BoNT/A per kg (body weight); d) BoNT/A is administered at two or more injection sites.
  10. The pharmaceutical product according to claim 9, wherein the patient is administered 10 to 170 pg of BoNT/A per injection site.
  11. The pharmaceutical product according to claim 9, wherein the patient is administered BoNT/A at a dose of 1 to 14 pg/kg body weight per injection site.

Description

This invention relates to the treatment of surgical pain resulting from surgery (e.g., postoperative surgical pain) and/or surgery-induced anxiety (e.g., postoperative anxiety). More specifically, this invention provides a method of treatment comprising the administration of Clostridium neurotoxin, and in particular, a method of treating postoperative surgical pain and anxiety using botulinum neurotoxin. Postoperative surgical pain is an unpleasant sensation resulting from the surgical procedure. It can be caused by tissue damage resulting from the surgical intervention, the surgical procedure itself, wound closure, or forces applied during the procedure. Postoperative surgical pain (e.g., postoperative surgical pain) can also stem from factors associated with the surgery. For example, a patient may experience back pain due to how they are positioned on the surgical table, or chest pain due to surgical intervention in the thoracic region. Furthermore, sore throat may occur after general anesthesia due to irritation from the insertion of a breathing tube. However, the most common cause of postoperative surgical pain is incisions in the skin and muscles resulting from the surgical intervention. For example, surgical intervention (or more specifically, surgical incision) can represent a "noxious stimulus" that causes pain. A noxious stimulus, i.e., a stimulus that can cause tissue damage, can activate the release of neurotransmitters from nociceptive afferent terminals and neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) from sensory terminals. This noxious information is then transmitted from the peripheral nervous system to the central nervous system, where pain is perceived by the individual. Postoperative surgical pain can be caused by a combination of inflammation and nerve tissue damage at the site of surgical intervention. Some inflammation and/or nerve tissue damage occurs in addition to postoperative surgical pain. For example, the release of various substances, including proteases, cytokines, and serotonin, may occur as a result of degranulation of mast cells activated in response to tissue trauma. These substances can sensitize primary afferent neurons (activating them at the lower threshold), leading to pain hypersensitivity. Because tissues are innervated over a wide area, any area of the body is sensitive to nerve damage from surgery. Postoperative anxiety may accompany patients experiencing physical symptoms and behavioral changes, including but not limited to fatigue, difficulty concentrating and sleeping, and muscle tension. Furthermore, patients may experience emotional symptoms of anxiety, such as restlessness, irritability, difficulty controlling fear or worry, phobias, and panic. Postoperative anxiety can also be caused by the effects of anesthesia, the surgery itself, postoperative surgical pain, and/or stress from the hospital environment. For example, surgical patients are often under considerable mental, physical, and emotional stress both before and after surgery (e.g., stress arising from anticipation of surgery), and this stress can manifest as anxiety symptoms. Existing methods for managing surgical (e.g., postoperative) pain typically involve targeting neurotransmitters and peptides, and using nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, local anesthetic blocks, or combinations thereof. However, these methods produce various side effects and, obviously, often induce dependence (e.g., addiction). In addition, these methods only provide relief for acute postoperative surgical pain, for example, providing relief only for a short period after administration, thus requiring continuous/repeated administration (exacerbating the problem of patient dependence/addiction to analgesics). Failure to effectively manage acute postoperative surgical pain can increase the patient's chances of developing chronic postoperative surgical pain. Such pain management methods (requiring continuous drug administration) also often lead to drug resistance. A further problem associated with these prior methods for managing postoperative surgical pain is the need for high doses of analgesics to provide analgesic effects, often accompanied by side effects that increase in proportion to the dose. Thus, current methods for managing surgical pain are neither adequate (e.g., sufficient) for managing/alleviating postoperative surgical pain, particularly moderate to severe postoperative surgical pain, nor do they provide adequate management of postoperative anxiety experienced by patients (the latter generally requiring alternative/additional medications). Therefore, there is an increasing need for alternative/improved methods for managing postoperative surgical pain and/or postoperative anxiety. The present invention addresses one or more of these problems by providing a method for the long-term sustained management of postoperative surgical pain/anxiety (including a reducing t