Use of STA-013 in the preparation of a medicament for assisting in the enhancement of the analgesic effect of an opioid and pharmaceutical compositions

Abstract

This application discloses the use of STA-013 in the preparation of medicaments that enhance the analgesic effect of opioids and related pharmaceutical compositions. This application provides a novel use of STA-013 in the preparation of medicaments that enhance the analgesic effect of opioids, where STA-013 is used in combination with opioids for the treatment of pain. A pharmaceutical composition comprising STA-013 and a pharmaceutically acceptable carrier has also been developed. The pharmaceutical composition of this application can significantly enhance the immediate analgesic effect of opioids and delay the development of tolerance, which has significant clinical significance and market value for the treatment of severe pain and long-term use of opioids.

Description

Technical Field

[0001] This application relates to the field of adjuvant analgesia technology, and in particular to the use of STA-013 in the preparation of medicaments that enhance the analgesic effect of opioids and pharmaceutical compositions thereof. Background Technology

[0002] Neuropathic pain and cancer pain are common types of chronic pain in clinical practice. Neuropathic pain can be caused by mechanical compression, nerve damage after chemotherapy for tumors, nerve damage associated with diabetes, and herpes zoster, among other factors. It not only causes physical pain but also leads to emotional disturbances such as depression, fear, anxiety, and irritability. Cancer pain often occurs in patients with primary osteosarcoma or those with distant metastases from non-primary bone tumors (such as lung, breast, thyroid, and bladder tumors). Cancer pain is often accompanied by comorbidities including depression, anxiety, and impaired motor and social functioning, significantly reducing patients' quality of life. Clinical studies show that approximately 75% of patients with advanced cancer experience moderate to severe pain, and more than half of cancer pain patients report that current drug therapies are insufficient to relieve their pain.

[0003] Opioids, represented by morphine, are the gold standard for treating moderate to severe pain in clinical practice. However, long-term use of opioids can lead to a significant decrease in analgesic efficacy and morphine tolerance, necessitating continuously increasing the dosage and causing more serious side effects such as nausea, vomiting, addiction, and withdrawal symptoms. Currently, nonsteroidal anti-inflammatory drugs (NSAIDs) can be used as adjunctive therapy to treat mild to moderate pain, but there is a lack of effective adjunctive drugs to assist opioid analgesia and delay the development of tolerance in the treatment of severe pain. Therefore, finding new adjunctive analgesics to improve the analgesic effect of opioids has become an urgent clinical problem to be solved. Summary of the Invention

[0004] The purpose of this application is to provide the use of STA-013 in the preparation of a medicament for assisting in enhancing the analgesic effect of opioids, and a pharmaceutical composition thereof.

[0005] To achieve the above objectives, this application adopts the following technical solution:

[0006] This application discloses the use of STA-013 in the preparation of a drug that helps enhance the analgesic effect of opioids, wherein STA-013 is used in combination with opioids for the treatment of pain.

[0007] It should be noted that the study in this application found that STA-013 interferes with the signaling pathways for the formation of morphine tolerance by inhibiting molecular targets related to morphine tolerance, thereby significantly enhancing the immediate analgesic effect of opioids and delaying the development of tolerance when administered in combination with opioids. This enhancement effect was experimentally verified in both physiological states (acute pain) and pathological pain states (bone cancer pain, neuropathic pain).

[0008] In some implementations, the pain is chronic. Patients with chronic pain rely on opioids for long-term analgesia and are more prone to developing morphine tolerance. Therefore, the combined use of STA-013 and opioids for the treatment of chronic pain has more significant clinical implications.

[0009] In some implementations, chronic pain is cancer pain. Cancer pain patients often require long-term, high-dose use of opioids, with morphine tolerance being a particularly prominent issue. The adjunctive analgesic effect of STA-013 has been experimentally confirmed in a bone cancer pain animal model (TCI model).

[0010] In some implementations, cancer pain is referred to as bone cancer pain. In a bone cancer pain model induced by tibial medullary cavity tumor cell transplantation, intraperitoneal injection of STA-013 significantly enhanced the analgesic effect within 0 to 2 hours following intrathecal morphine injection.

[0011] In some implementations, the pain is neuropathic. In a neuropathic pain model induced by partial sciatic nerve ligation, intraperitoneal injection of STA-013 significantly enhanced the mechanical pain threshold and thermal pain latency within 0 to 3 hours after intrathecal morphine injection.

[0012] In some implementations, the opioid is morphine. Morphine is the gold standard for treating moderate to severe pain in clinical practice. The adjunctive analgesic effect of STA-013 combined with morphine has been fully validated by various behavioral methods, including the tail-flick test, hot plate test, mechanical pain threshold test, and thermal pain threshold test.

[0013] It should be noted that in some implementations of this application, STA-013 is administered via intraperitoneal injection, while opioids are administered via intrathecal injection. Intraperitoneal injection of STA-013 enables systemic administration, while intrathecal injection of morphine directly targets the spinal cord analgesia. The combination of these two routes of administration has been experimentally demonstrated to produce a significant synergistic analgesic effect. The dosage of STA-013 is 25 mg / kg. This dosage has shown significant adjunctive analgesic effects in acute pain, bone cancer pain, and neuropathic pain models, with statistically significant differences (p<0.05 to p<0.001).

[0014] This application also discloses a pharmaceutical composition comprising STA-013 and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be injectable saline or other commonly used clinical pharmaceutical excipients, and the choice of carrier does not affect the adjuvant analgesic activity of STA-013.

[0015] In some implementations, the pharmaceutical composition also includes an opioid, specifically morphine. The pharmaceutical composition of this application combines STA-013 with an opioid to facilitate simultaneous clinical administration.

[0016] In some implementations, the pharmaceutical composition is an injectable formulation.

[0017] It should be noted that the pharmaceutical composition of this application is intended for use in combination with opioid drugs to enhance the analgesic effect of the opioids; the preferred opioid is morphine. The combination of the pharmaceutical composition containing STA-013 with opioid drugs can synergistically enhance the analgesic efficacy of the opioids by inhibiting molecular targets related to morphine tolerance. The pharmaceutical composition is an injectable formulation, and the injectable dosage form is compatible with the intraperitoneal injection route, which facilitates the rapid absorption of STA-013 and its adjunctive analgesic effect.

[0018] Due to the adoption of the above technical solutions, the beneficial effects of this application are as follows:

[0019] This application provides a novel use of STA-013 in the preparation of drugs that enhance the analgesic effect of opioids, which can significantly enhance the immediate analgesic effect of opioids and delay the development of tolerance, and has important clinical significance and market value for the treatment of severe pain and long-term use of opioids. Attached Figure Description

[0020] Figure 1 This is a schematic diagram of the experimental results of intraperitoneal injection of STA-013 enhancing the analgesic effect of intrathecal morphine in an embodiment of this application; wherein, Figures A and B show the results of the tail-flick test, indicating that intraperitoneal injection of STA-013 enhances the analgesic effect of intrathecal morphine, Figure A is the %MPE-time curve, and Figure B is the area under the curve; Figures C and D show the results of the hot plate test, indicating that intraperitoneal injection of STA-013 enhances the analgesic effect of intrathecal morphine, Figure C is the %MPE-time curve, and Figure D is the area under the curve;

[0021] Figure 2 This is a schematic diagram of the experimental results of intraperitoneal injection of STA-013 to enhance the analgesic effect of intrathecal morphine in a bone cancer pain model according to an embodiment of this application; wherein, Figure A is the mechanical pain sensitivity result and Figure B is the thermal pain sensitivity result;

[0022] Figure 3This is a schematic diagram of the experimental results of intraperitoneal injection of STA-013 to enhance the analgesic effect of intrathecal morphine in a neuropathic pain model according to an embodiment of this application; wherein, Figure A shows the mechanical pain sensitivity results and Figure B shows the thermal pain sensitivity results;

[0023] Figure 4 The structural formula of STA-013 in the embodiments of this application is shown below;

[0024] Figure 5 The figures shown are the results of intraperitoneal injection of STA-013 to delay morphine tolerance in the embodiments of this application; where Figure A is the result of the tail-flick test and Figure B is the result of the hot plate test.

[0025] Figure 6 The following figures show the results of intraperitoneal injection of STA-013 in delaying sufentanil tolerance in the embodiments of this application; where Figure A shows the results of the tail-flick test and Figure B shows the results of the hot plate test.

[0026] Figure 7 The figures show the test results of intraperitoneal injection of STA-013 enhancing the analgesic effect of intrathecal morphine in an inflammatory pain model in this application embodiment; where Figure A shows the mechanical pain sensitivity results and Figure B shows the thermal pain sensitivity results. Detailed Implementation

[0027] To address the existing technologies that address the problems of morphine tolerance and progressive decline in analgesic efficacy due to long-term use of opioids, as well as the lack of adjunctive medications that can effectively assist opioid analgesia and delay the development of tolerance in the field of severe pain treatment.

[0028] This application presents an inventive study that found STA-013 can enhance the analgesic effect of opioids. Therefore, this application proposes a novel use of STA-013 in the preparation of medicaments that enhance the analgesic effect of opioids. Based on this, a novel pharmaceutical composition comprising STA-013 and a pharmaceutically acceptable carrier has been developed.

[0029] The novel use and pharmaceutical composition of this application have the following advantages compared with the prior art:

[0030] (1) When STA-013 is used in combination with opioids (represented by morphine), it can significantly enhance the analgesic effect of morphine in both physiological (acute pain) and pathological pain (bone cancer pain, neuropathic pain). Experimental data show that intraperitoneal injection of STA-013 (25 mg / kg) can significantly increase the percentage of maximum possible effect (%MPE) and area under the curve (AUC) within 45 minutes to 3 hours after intrathecal injection of morphine. In bone cancer pain and neuropathic pain models, it can significantly increase the mechanical pain threshold and thermal pain latency within 0 to 2 hours or 0 to 3 hours after administration, with statistically significant differences (p<0.05 to p<0.001), filling the clinical gap in the treatment of severe pain by the lack of effective opioid adjunctive analgesics.

[0031] (2) STA-013 inhibits morphine tolerance-related molecular targets and intervenes in key signaling pathways for the formation of morphine tolerance. Combined use can delay the development of morphine tolerance, thereby reducing the dosage of opioids required to maintain analgesia in clinical practice and avoiding the medication safety risks caused by forced continuous dosage increases.

[0032] (3) By reducing the dosage of opioids, the risk of opioid-related side effects such as nausea, vomiting, addiction, withdrawal reactions and respiratory depression can be reduced accordingly, which helps to improve the medication safety and quality of life of patients who use opioids for a long time.

[0033] Unless otherwise specified, all reagents used in the following examples are commercially available. STA-013 was purchased from MedChemExpress, catalog number HY-179572; morphine was purchased from Northeast Pharmaceutical; and physiological saline was injectable physiological saline (sodium chloride injection, 0.9%). Adult male C57BL / 6 mice, weighing 18–22 g, were housed in a standard SPF environment. Statistical analysis was performed using two-way ANOVA and unpaired Student's t-test. Data are expressed as mean ± standard error (Mean ± SEM).

[0034] The present application will be further described in detail below through specific embodiments. These embodiments are merely illustrative and should not be construed as limiting the present application. In the following embodiments, many details are described to facilitate a better understanding of the present application. However, those skilled in the art will readily recognize that some features may be omitted in different situations, or may be replaced by other devices, materials, or methods. In some cases, certain operations related to the present application are not shown or described in the specification to avoid obscuring the core parts of the present application with excessive description. For those skilled in the art, detailed description of these related operations is not necessary; a complete understanding of the related operations can be obtained from the description in the specification and general technical knowledge in the art.

[0035] Example 1

[0036] Preparation of STA-013 solution: Dissolve and dilute STA-013 with physiological saline to prepare a STA-013 solution with a concentration of 2.5 mg / mL, and administer intraperitoneally at a dose of 25 mg / kg.

[0037] Preparation of morphine solution: Take morphine, dissolve and dilute it with physiological saline to prepare a morphine solution with a concentration of 0.4 mM, and administer it intrathecally at a volume of 5 μL / animal.

[0038] Example 2

[0039] Validation of the enhanced analgesic effect of STA-013 on intrathecal morphine in an acute pain model.

[0040] Adult male C57BL / 6 mice were randomly divided into two groups: the Vehicle + morphine group (intraperitoneal injection of physiological saline) and the STA-013 + morphine group (intraperitoneal injection of STA-013, 25 mg / kg). Forty-five minutes after intraperitoneal administration, all mice were intrathecally injected with 5 μL (0.4 mM) of morphine solution.

[0041] Tail-flick test: The mouse is placed in a restraint device with its tail outside the device. The distal end of the tail, about 2-3 cm, is vertically immersed in 50°C hot water, and the time is started. A positive pain response is indicated when the mouse flicks its tail out of the hot water or removes it from the water. The response time is 15 seconds.

[0042] Each mouse was recorded three times, with each recording taken 3 minutes apart. The average value was used as the tail-flick latency. Data were expressed as percentage of maximum possible effect (%MPE), calculated as MPE (%) = 100 × [(latency after administration - baseline latency) / (cutoff time - baseline latency)]. %MPE data at each time point were converted to the area under the curve (AUC) for statistical analysis.

[0043] Hot plate test: Mice were placed on a 55°C hot plate with a transparent plastic cover around them to prevent escape. A positive pain response was indicated by jumping, waving paws, or licking paws. The cutoff time for the response was 40 seconds. Each mouse was recorded three times, with each recording 3 minutes apart. The average value was taken as the hot plate latency. Data are expressed as %MPE and AUC, calculated using the same method as the tail-flick test.

[0044] Experimental results are as follows Figure 1 As shown. Results of the tail-flick experiment ( Figure 1 A and B show that compared with the Vehicle + morphine group, the STA-013 + morphine group had a significantly higher %MPE within 45 minutes to 2 hours after intrathecal morphine injection (Two-way ANOVA, compared with the Vehicle + morphine group, *P<0.05, **P<0.01, ***P<0.001), and a significantly increased cumulative analgesic effect (AUC) of morphine within 3 hours (Unpaired Student's t-test, **P<0.01).

[0045] Hot plate experiment results ( Figure 1 C and D show that, compared with the Vehicle + morphine group, the STA-013 + morphine group had a significantly higher %MPE within 1.5 to 2 hours after intrathecal morphine injection (Two-way ANOVA, *P<0.05, **P<0.01) and a significantly increased cumulative analgesic effect (AUC) within 3 hours (Unpaired Student's t-test, **P<0.01).

[0046] The above results indicate that, under physiological conditions, intraperitoneal injection of STA-013 (25 mg / kg) can significantly enhance the immediate and cumulative analgesic effects of intrathecal morphine.

[0047] Example 3

[0048] Validation of the enhanced analgesic effect of STA-013 on intrathecal morphine in a bone cancer pain model (TCI model).

[0049] Establishment of a bone cancer pain model: Before surgery, Lewis lung cancer cells (Procell, catalog number CL-0140) were resuspended in PBS solution and stored on ice, diluted to a cell density of 1×10⁻⁶. 7 Mouse anesthesia was induced and maintained with 2% isoflurane. The skin of the upper 1 / 3 of the right tibial tuberosity was disinfected with 75% alcohol, and a skin incision of about 0.5 cm was made to expose the tibia.

[0050] A microsyringe was inserted deep into the bone marrow cavity, and 2 μL of PBS solution containing cancer cells was slowly injected. After the injection was completed, the syringe was slowly withdrawn, and the wound was sutured. The patient was fed normally after the operation. On the 14th day post-operation, after significant mechanical hyperalgesia and thermal hyperalgesia were confirmed, a drug administration experiment was conducted.

[0051] Dosing regimen: Mice that successfully developed the model were randomly divided into the Vehicle+morphine group and the STA-013+morphine group, and the dosing regimen was the same as in Example 2.

[0052] Mechanosensory threshold test: The mouse is placed in a transparent acrylic plastic box on a perforated metal mesh frame at the bottom. A von Frey fiber is slowly applied to the sole of the mouse's affected hind limb, with a uniform, vertical upward force applied to bend the fiber and hold it for 2-3 seconds. A positive reaction is indicated by the mouse rapidly retracting its hind paw or licking its hind paw.

[0053] Measurements were taken starting with 0.16 g of fiber. If no positive reaction was observed, a higher intensity was used (maximum 2.56 g). If a positive reaction was observed, a lower intensity was used (minimum 0.02 g). A total of 6 measurements were taken, and the mechanical pain threshold (mN) was calculated using a formula.

[0054] Thermal sensory threshold detection: Mice were placed in a transparent acrylic plastic box on a constant temperature heating plate (30℃). The heat source was directed at the sole of the affected hind limb of the mouse. Timing was started after the heat source was turned on. A positive reaction was indicated by the mouse rapidly retracting its hind paw or licking its hind paw. The cutoff time was 20 seconds. Each mouse was recorded 3 times, with each recording 3 minutes apart. The average value was taken as the thermal pain latency (s).

[0055] Experimental results are as follows Figure 2 As shown. Compared with the Vehicle + morphine group, the STA-013 + morphine group had a lower mechanical pain threshold on the affected side within 0 to 2 hours after intrathecal morphine injection (as shown). Figure 2 A) and the latent period of heat pain ( Figure 2 B) Both were significantly improved (Two-way ANOVA, *P<0.05, **P<0.01).

[0056] The above results indicate that, under the pathological condition of bone cancer pain induced by tibial bone marrow tumor cell transplantation, intraperitoneal injection of STA-013 (25 mg / kg) can significantly enhance the analgesic effect of intrathecal morphine within 0 to 2 hours.

[0057] Example 4

[0058] Validation of the enhanced analgesic effect of STA-013 on intrathecal morphine in a neuropathic pain model (PSNL model).

[0059] Establishment of a neuropathic pain model: Mice were induced and maintained under anesthesia with 2% isoflurane. The skin and muscles of the left femur were incised with a scalpel to expose the sciatic nerve. The sciatic nerve trunk was longitudinally separated with a glass needle, and half of the sciatic nerve was tightly ligated with 4-0 sutures. Finally, the wound was sutured shut.

[0060] Postoperatively, patients were fed normally. On day 14 postoperatively, significant mechanical and thermal hyperalgesia was confirmed, and a drug administration experiment was conducted. The drug administration regimen and the methods for detecting mechanical and thermal sensory thresholds were the same as in Example 3.

[0061] Experimental results are as follows Figure 3 As shown. Compared with the Vehicle + morphine group, the STA-013 + morphine group had a lower mechanical pain threshold on the affected side within 0 to 3 hours after intrathecal morphine injection (as shown). Figure 3 A) and the latent period of heat pain ( Figure 3 B) Both were significantly improved (Two-way ANOVA, *P<0.05, **P<0.01).

[0062] The above results indicate that, under the pathological state of neuropathic pain induced by partial sciatic nerve ligation, intraperitoneal injection of STA-013 (25 mg / kg) can significantly enhance the analgesic effect of intrathecal morphine within 0 to 3 hours, and the enhancement time window (0 to 3 hours) is longer than that of the bone cancer pain model (0 to 2 hours).

[0063] Comparative Example 1

[0064] The analgesic effect of intrathecal morphine alone (without STA-013).

[0065] Adult male C57BL / 6 mice (acute pain state, TCI bone cancer pain model and PSNL neuropathic pain model) were set up as Vehicle+morphine group. They were injected intraperitoneally with an equal volume of physiological saline, and 5 μL (0.4 mM) of morphine solution was injected intrathecally 45 minutes later. The analgesic effect was evaluated using the same behavioral detection methods as in Examples 2, 3 and 4.

[0066] The results showed that intrathecal morphine alone (Vehicle + morphine) produced a certain analgesic effect in the acute pain model, but the %MPE and AUC were significantly lower than those of the STA-013 + morphine combination group (Example 2). In the bone cancer pain model and the neuropathic pain model, the mechanical pain threshold and thermal pain latency of the morphine alone group were significantly lower than those of the STA-013 + morphine combination group (Examples 3 and 4) at all time points after administration, and the statistical differences were significant (*P<0.05 to **P<0.01).

[0067] The comparison between Examples 2, 3, and 4 and Comparative Example 1 shows that, under three pain states—acute pain, bone cancer pain, and neuropathic pain—the combined administration of STA-013 and morphine significantly enhanced the analgesic effect of morphine. In contrast, the analgesic effect of morphine alone was significantly weaker than that of the combined administration group. This indicates that STA-013 is a key active ingredient that helps enhance the analgesic effect of opioids, and this enhancement effect was unexpected. Analysis suggests that STA-013's ability to enhance the analgesic effect of morphine is due to its primer. STA-013 is an EphB receptor inhibitor (PMID: 40769385). EphB receptor involvement in morphine tolerance has been reported in the literature. Inhibition of EphB1 receptors in the EphB1 receptor family using pharmacological methods or knockout of EphB1 receptors using genetic methods can inhibit morphine tolerance (PMID: 21555368). Therefore, STA-013, as an EphB receptor inhibitor, can help enhance the analgesic effect of morphine. The structural formula of STA-013 is as follows: Figure 4 As shown.

[0068] Example 5

[0069] Based on Example 2, an experiment was conducted to test the effect of intraperitoneal injection of STA-013 in delaying morphine tolerance. Specifically, 10 mg / kg of morphine was injected intraperitoneally daily, along with 25 mg / kg of STA-013. The analgesic effect of morphine was measured 1 hour after injection, and the experiment was repeated for 6 consecutive days. The results are as follows: Figure 5 As shown. Figure 5 Figure A shows the tail-flip test results, and Figure B shows the hot plate test results, demonstrating that daily intraperitoneal injection of STA-013 delays morphine tolerance. %MPE-time curves are also shown. Two-way ANOVA analysis was used; compared with the Vehicle group, *P < 0.05, **P < 0.01, ***P < 0.001.

[0070] Figure 5 The results showed that daily intraperitoneal injection of STA-013 could delay the progression of morphine tolerance.

[0071] Example 6

[0072] Based on Example 2, an experiment was conducted to test the effect of intraperitoneal injection of STA-013 in delaying sufentanil tolerance. Specifically, 35 μg / kg of morphine was injected intraperitoneally daily, along with 25 mg / kg of STA-013. The analgesic effect of sufentanil was assessed 1 hour after injection, and this was repeated for 5 consecutive days. The results are as follows: Figure 6 As shown. Figure 6Figure A shows the tail-flick test results, and Figure B shows the hot plate test results, demonstrating that daily intraperitoneal injection of STA-013 delayed sufentanil tolerance. %MPE-time curves are also shown. Two-way ANOVA analysis was used to compare with the Vehicle group; *P < 0.05, **P < 0.01, ***P < 0.001.

[0073] Figure 6 The results showed that daily intraperitoneal injection of STA-013 could delay the development of sufentanil tolerance.

[0074] Example 7

[0075] Verification of the analgesic effect of intrathecal morphine in an inflammatory pain model.

[0076] Establishment of the inflammatory pain model: 20 μL of Complete Freund's Adjuvant was injected subcutaneously into the left foot of mice using a microsyringe.

[0077] One day after a plantar injection of CFA, STA-013 was injected intraperitoneally and morphine was injected intrathecally. The dosing regimen and the methods for detecting the mechanosensory threshold and thermal sensory threshold were the same as in Example 3.

[0078] Experimental results are as follows Figure 7 As shown. Figure 7 In the figure, A represents mechanical pain sensitivity and B represents thermal pain sensitivity. Two-way ANOVA analysis was used to compare with the Vehicle group. **P < 0.01, ***P < 0.001.

[0079] Figure 7 The results showed that intraperitoneal injection of STA-013 enhanced the analgesic effect of intrathecal morphine in the CFA-induced inflammatory pain model.

[0080] It is understood that opioids are not limited to morphine, but can also include other opioid analgesics such as fentanyl, codeine, and oxycodone. The route of administration for STA-013 is not limited to intraperitoneal injection; other routes of administration, such as intravenous or subcutaneous injection, can be used as needed clinically. The route of administration for opioids is not limited to intrathecal injection; oral and intravenous administration are also commonly used clinical methods. The dosage of STA-013 is not limited to 25 mg / kg and can be adjusted according to the patient's weight, pain level, and clinical needs. Pharmaceutically acceptable carriers are not limited to physiological saline; water for injection, phosphate-buffered saline (PBS), or other commonly used pharmaceutical excipients can also be used. Pain is not limited to bone cancer pain and neuropathic pain; it can also include inflammatory pain, visceral pain, and other types of pain.

[0081] The above description, in conjunction with specific embodiments, provides a further detailed explanation of this application and should not be construed as limiting the specific implementation of this application to these descriptions. Those skilled in the art to which this application pertains can make several simple deductions or substitutions without departing from the concept of this application.

Claims

1. The use of STA-013 in the preparation of drugs that assist in enhancing the analgesic effect of opioids, characterized in that: The STA-013 is used in combination with opioids for the treatment of pain.

2. The use according to claim 1, characterized in that: The pain described is chronic pain.

3. The use according to claim 2, characterized in that: The chronic pain mentioned is cancer pain.

4. The use according to claim 3, characterized in that: The cancer pain mentioned is bone cancer pain.

5. The use according to claim 1, characterized in that: The pain described is neuropathic pain.

6. The use according to any one of claims 1-4, characterized in that: The opioid drug in question is morphine.

7. A pharmaceutical composition, characterized in that: It contains STA-013 and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7, characterized in that: It also includes opioids.

9. The pharmaceutical composition according to claim 8, characterized in that: The opioid drug in question is morphine.

10. The pharmaceutical composition according to any one of claims 7-9, characterized in that: The pharmaceutical composition is an injectable preparation.

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