Analgesic effects of oxycodone hydrochloride injection after laparoscopic cholecystectomy and influence on substance P, 5-hydroxytryptamine, and patient-controlled intravenous analgesia
, , , , , oraz | 23 lip 2023
Article Category: Original Study
Data publikacji: 23 lip 2023
Zakres stron: 42 - 48
Otrzymano: 29 lip 2022
Przyjęty: 03 lut 2023
DOI: https://doi.org/10.2478/ahem-2023-0006
Słowa kluczowe
© 2023 Lei Tan et al., published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Laparoscopic cholecystectomy (LC) is currently a routine procedure for gallbladder surgery, which is characterized by a small incision, less intraoperative blood loss, fast recovery, short length of postoperative hospitalization, and easy acceptance by patients. Pain after LC has a complex mechanism and diverse clinical manifestations, mainly including incision pain, visceral pain, and referred shoulder pain [1,2]. When considering the use of narcotic analgesics, the individual differences among patients are neglected, the duration of persistent pain relief is unclear, and the drug superposition effect can be caused due to multiple dosages. Therefore, it is often difficult to achieve the expected analgesic effect [3]. The main drugs for postoperative analgesia are still opioids, and their analgesic effect and side effects are related to the dose. It has also been clearly confirmed that a variety of pharmacological effects of opioids represented by morphine are exerted through binding to specific opioid receptors [4]. As a new opioid drug, oxycodone is a dual opioid receptor (μ and κ receptors) agonist. It is mainly used for postoperative analgesia and treatment of cancer pain and non-cancer pain. Moreover, oxycodone alone can also achieve a good analgesic effect, and it is generally easy to tolerate the side effects in the therapeutic dose [5,6]. In this study, oxycodone was intravenously injected before withdrawal of tracheal catheter in LC and used for postoperative patient-controlled intravenous analgesia (PCIA). The concentration of the analgesic substance P and 5-hydroxytryptamine (5-HT) in the peripheral blood was measured, and the hemodynamic changes and incidence rate of agitation during the recovery period of patients were recorded, so as to explore the safety of oxycodone during the anesthesia recovery period. Moreover, the visual analogue scale (VAS) score, Ramsay score, and adverse reactions of PCIA were recorded to investigate the postoperative analgesic effect of oxycodone, aiming to provide clinical data for multimodal analgesia of patients, and to improve the quality of perioperative anesthesia.
A total of 120 patients who underwent LC in our hospital from January 2019 to October 2020 were prospectively selected as the subjects. Inclusion criteria were as follows: patients meeting the diagnostic criteria for gallbladder polyps or gallbladder stones in
Preoperative visit: The author visited the patients the day before operation, helped them relax, answered their questions, and patiently comforted them with words, so as to minimize the patients’ psychological stress, and reduce the inducing factors for agitation in the recovery period. Moreover, the basic features of pain after LC were explained, and the application method of VAS was introduced. The usage and general characteristics of PCIA were also introduced.
Anesthesia method: Routine preparation before LC. Anesthesia induction: The unblocked venous access of patients was ensured after entering the operating room, and a monitor (Perlong Medical Equipment Co., Ltd., China) was connected to monitor electrocardiogram (ECG), heart rate (HR), blood pressure (BP), blood oxygen saturation (SpO2), partial pressure of end-tidal carbon dioxide (PetCO2) and bispectral index (BIS). After preparation, anesthesia induction was started when the patients’ vital signs became stable. Sufentanil (0.2–0.25 μg/kg), propofol (1.5–2 mg/kg), midazolam (0.02–0.03 mg/kg), and cisatracurium besilate (0.15–0.20 mg/kg) (Jiangsu Hengrui Pharmaceutical Co., Ltd., China) were intravenously infused successively. After full muscular relaxation and an adequate oxygen reserve, a ventilator (Mindray Medical, Shenzhen, China) was connected through tracheal intubation for mechanical ventilation. The basic parameters of the ventilator were as follows — Respiratory rate: 10–12 times/min, inspiratory/expiratory ratio: 1:2, tidal volume: 8–10 mL/kg. Propofol at 0.8–1 mg/(kg·min), remifentanil at 1–3 μg/(kg·h), and cisatracurium besilate at 2–4 μg/(kg·min) were used for anesthesia maintenance. During operation, the patients’ basic vital signs and PetCO2 were continuously monitored. The ventilator parameters and drug dose for anesthesia maintenance were adjusted based on the PetCO2, BIS, and the condition of patients. Neostigmine (Jiangsu Hengrui Pharmaceutical Co., Ltd., China) was applied when the spontaneous breathing was recovered to 350 mL, and flumazenil (Jiangsu Hengrui Pharmaceutical Co., Ltd., China) was applied when the patients opened their eyes and responded to the call. After extubation, the patients were sent to the post-anesthesia care unit (PACU).
Analgesia method. Intraoperative analgesia: When the gallbladder was removed and the anesthesia maintenance drug was withdrawn, oxycodone (0.07 mg/kg) (Mundipharma Pharmaceutical Co., Ltd., China) was intravenously injected at a diluted concentration of 1 mg/mL in the observation group, while fentanyl (Jiangsu Hengrui Pharmaceutical Co., Ltd., China) was intravenously injected at 0.7 μg/kg in the control group. Postoperative analgesia: The patients were sent to PACU for PCIA. In terms of the PCIA formula, oxycodone hydrochloride injection (0.7 mg/kg) was added into 100 mL of a tropisetron hydrochloride and sodium chloride injection containing 5 mg of tropisetron (Jiangsu Hengrui Pharmaceutical Co., Ltd., China) in the observation group. In the control group, a fentanyl citrate injection (7 μg/kg) was added into 100 mL of a tropisetron hydrochloride and sodium chloride injection. The parameters of PCIA were as follows: continuous basal infusion + patient-controlled analgesia (CBI+PCA), nominal flow rate: 2 mL/h, nominal capacity: 100 mL, PCA liquid dosage: 0.5 mL/time, interval of PCA liquid feeding: 15 min. The application method of PCIA was introduced to patients, and the times of pressing and effective pressing were recorded by them.
The general conditions of patients were recorded, including their gender, age, body weight, height, duration of anesthesia (from anesthesia induction to indications for extubation), operation time, recovery time of spontaneous breathing (from drug withdrawal to spontaneous breathing), and awakening time (from drug withdrawal to extubation).
HR, mean arterial pressure (MAP), and SpO2 were recorded before anesthesia induction (T0), at the time of extubation (T1), and 5 min after extubation (T2). The influence of oxycodone and fentanyl on the circulation of patients before and after extubation was observed, so as to evaluate the safety of oxycodone during the anesthesia recovery period.
Agitation in the anesthesia recovery period: After the spontaneous breathing was recovered, the agitation status was recorded and classified as follows — Mild: No agitation occurred under no external stimuli before extubation, while agitation occurred under the stimulation of sputum suction before and after extubation, and it could disappear once the stimulation stopped or after extubation and verbal comfort. Moderate: Agitation occurred under no external stimuli before extubation, the consciousness could not be fully recovered after extubation, and the patients could not actively cooperate after verbal comfort and needed to be immobilized. Severe: The patients needed to be immobilized using drugs and other methods.
Levels of substance P and 5-HT: 4 mL of venous blood was drawn before anesthesia induction (T0), at the time of extubation (T1), 5 min after extubation (T2), and at the time of leaving the recovery room (T3), placed into heparin sodium test tubes, and centrifuged at 5,000 rpm for 10 min. Then, 1 mL of serum extracted was placed into small test tubes and sealed at −80°C for later test. The levels of substance P and 5-HT were measured by enzyme-linked immunosorbent assay (ELISA) according to the kit's instructions (Abcam, USA).
Postoperative analgesia and sedation by PCIA: The VAS score and Ramsay score before anesthesia induction (T0), after extubation (T1), at the time of leaving the recovery room (T2), 4 h after operation (T3), 12 h after operation (T4), 24 h after operation (T5) and 48 h after operation (T6), and the incidence of adverse reactions at each time point after extubation, were recorded. In terms of VAS, a long linear scale is usually used, with the left end for no pain and the right end for severest pain. The patients needed to point out the current degree of pain, with the numbers 0–10 being at the back of the scale, and the pain degree of patients was evaluated by medical workers according to the corresponding number. 1–4 points indicated a better analgesic effect, while >5 points indicated a severe pain that could not be effectively relieved.
SPSS 26.0 software (IBM Inc., USA) was used for statistical analysis. The count data were expressed as a percentage, and the χ2 test or Fisher's exact test was used for comparison between groups. The measurement data were expressed as mean ± standard deviation. An independent t-test was performed for intergroup comparison, and a paired t-test was conducted for intragroup comparison. Analysis of variance was performed for multigroup comparison. Repeated measure analysis of variance was carried out for comparison at different time points between the groups. First, the intergroup differences between the two groups and the time differences of the measured values were compared. In the case of intergroup differences, the differences at each time point were further compared with the independent samples t-test. The time differences of each group were compared using the Student–Newman–Keuls-q test. P<0.05 suggested a statistically significant difference.
In the observation group, there were 35 males and 25 females aged 22–64 years old, with an average of 45.87±2.43 years old, and the body weight was 41–79 kg, with an average of 62.78±3.41 kg. Gallbladder polyps occurred in 34 cases, and gallbladder stones in 26 cases. In the control group, there were 34 males and 26 females aged 23–65 years old, with an average of 45.91±2.41 years old, and the body weight was 42–79 kg, with an average of 62.84±3.36 kg. Gallbladder polyps occurred in 33 cases, and gallbladder stones occurred in 27 cases. There were no significant differences in the baseline clinical data between the two groups (P>0.05) (Table 1).
Baseline clinical data
| Control group (n=60) | Observation group (n=60) | t/χ2 | P | |
|---|---|---|---|---|
| Gender | χ2=0.034 | 0.853 | ||
| Male | 34 (56.67%) | 35 (58.33%) | ||
| Female | 26 (43.34%) | 25 (41.67%) | ||
| Age (year) | 45.91±2.41 | 45.87±2.43 | t=0.091 | 0.928 |
| Mean body weight (kg) | 62.84±3.36 | 62.78±3.41 | t=0.097 | 0.922 |
| Pathological type | χ2=0.034 | 0.854 | ||
| Gallbladder polyps | 33 (55.00%) | 34 (56.67%) | ||
| Gallbladder stones | 27 (45.00%) | 26 (43.33%) |
There were no significant differences in the duration from drug withdrawal to recovery of spontaneous breathing and the awakening time (from drug withdrawal to extubation) between the observation group and control group (P>0.05) (Table 2).
Recovery time of spontaneous breathing and awakening time
| Group | n | Recovery time of spontaneous breathing (min) | Awakening time (min) |
|---|---|---|---|
| Control | 60 | 11.3±1.4 | 16.3±1.7 |
| Observation | 60 | 10.9±1.1 | 15.8±1.4 |
| t | 1.740 | 1.759 | |
| P | 0.084 | 0.081 |
No significant differences were found in HR, MAP and SpO2 between the two groups at T0 (P>0.05). HR and MAP rose at T1 and T2 compared with those at T0 (P<0.05), while they declined at T2 compared with those at T1 (P<0.05). SpO2 had no significant difference at T2 and T0 (P>0.05), while it declined at T1 compared with T0 (P<0.05).
The HR and MAP in control group were higher than those in the observation group at T1 and T2 (P<0.05), and the difference in HR at t2 was significant (P<0.05). SpO2 was lower in the control group than that in the observation group at t1 (P<0.05) (Table 3).
HR, MAP and SpO2 at different time points
| Index | Group | T0 | T1 | T2 |
|---|---|---|---|---|
| HR (beats/min) | Control | 74.0±5.4 | 90.8±7.2*,# | 87.9±5.4*,#,Δ |
| Observation | 74.5±5.6 | 89.2±6.4# | 80.3±6.3#,Δ | |
| Time difference | F=116.784, P<0.001 | |||
| Intergroup difference | F=127.383, P<0.001 | |||
| Intergroup × time difference | F=121.095, P<0.001 | |||
| MAP (mmHg) | Control | 84.7±5.3 | 95.5±6.8*,# | 92.5±5.8*,#,Δ |
| Observation | 83.5±5.6 | 90.5±8.3# | 87.5±5.4#,Δ | |
| Time difference | F=67.983, P<0.001 | |||
| Intergroup difference | F=127.886, P<0.001 | |||
| Intergroup × time difference | F=89.043, P<0.001 | |||
| SpO2(%) | Control | 98.3±6.7 | 94.3±7.1* | 98.4±6.2 |
| Observation | 98.4±6.3 | 96.4±7.3 | 98.5±6.3 | |
| Time difference | F=73.294, P<0.001 | |||
| Intergroup difference | F=109.675, P<0.001 | |||
| Intergroup × time difference | F=98.042, P<0.001 | |||
After the spontaneous breathing was recovered, agitation had a lower incidence rate and degree in the observation group than those in the control group (P<0.05) (Table 4).
Classification of agitation during anesthesia recovery (n, %)
| Group | n | Mild | Moderate | Severe | Total |
|---|---|---|---|---|---|
| Control | 60 | 6 (10.00) | 7 (11.67) | 0 | 13 (21.67) |
| Observation | 60 | 3 (5.00) | 2 (3.33) | 0 | 5 (8.33) |
| Fisher's probability | - | ||||
| P | 0.036 |
At T1, T2 and T3, the concentration of substance P and 5-HT rose with time in both groups (P<0.05). The levels of substance P and 5-HT had no significant differences between the two groups at T0 (P>0.05), while they were significantly lower in the observation group than those in the control group at T1, T2 and T3 (P<0.05) (Table 5).
Substance P and 5-HT levels
| Index | Group | T0 | T1 | T2 | T3 |
|---|---|---|---|---|---|
| Substance P (ng/L) | Control | 124.5±5.6 | 168.2±7.2# | 188.2±5.4#,Δ | 226.3±5.9#,Δ,▴ |
| Observation | 124.3±5.5 | 151.8±5.8*,# | 174.9±5.9*,#,Δ | 199.2±6.2*,#,▴ | |
| Time difference | F=236.281, P<0.001 | ||||
| Intergroup difference | F=458.992, P<0.001 | ||||
| Intergroup × time difference | F=312.093, P<0.001 | ||||
| 5-HT (ng/mL) | Control | 461.5±10.9 | 614.8±14.5# | 685.7±10.2#,Δ | 774.3±8.3#,▴ |
| Observation | 462.8±10.3 | 548.9±15.1*,# | 609.7±9.4*,#,Δ | 683.2±7.4*,#,▴ | |
| Time difference | F=673.225, P<0.001 | ||||
| Intergroup difference | F=1139.034, P<0.001 | ||||
| Intergroup × time difference | F=899.326, P<0.001 | ||||
The VAS score and Ramsay score were compared before anesthesia induction (T0), after extubation (T1), at the time of leaving the recovery room (T2), 4 h after operation (T3), 12 h after operation (T4), 24 h after operation (T5), and 48 h after operation (T6) (Table 6).
VAS and Ramsay scores
| Index | Group | T0 | T1 | T2 | T3 | T4 | T5 | T6 |
|---|---|---|---|---|---|---|---|---|
| VAS score | Control | 1.13±0.19 | 2.43±0.23 | 2.66±0.43 | 4.04±0.26cd | 4.58±0.43cd | 3.88±0.41ab | 3.68±0.34ab |
| Observation | 1.11±0.20 | 2.32±0.22 | 2.32±0.34 | 3.28±0.31cd | 3.26±0.36cd | 3.91±0.39ab | 3.70±0.35ab | |
| Time difference | F=0.734, P=0.873 | |||||||
| Intergroup difference | F=1.124, P=0.456 | |||||||
| Intergroup × time difference | F=0.917, P=0.671 | |||||||
| Ramsay score | Control | 1.28±0.24 | 3.78±0.43 | 3.61±0.28 | 3.34±0.31cd | 3.28±0.34cd | 1.26±0.32ab | 1.18±0.21ab |
| Observation | 1.27±0.25 | 3.51±0.37 | 3.34±0.27 | 3.16±0.29cd | 3.25±0.35cd | 1.21±0.29ab | 1.16±0.19ab | |
| Time difference | F=0.956, P=0.902 | |||||||
| Intergroup difference | F=1.732, P=0.239 | |||||||
| Intergroup × time difference | F=1.263, P=0.526 | |||||||
The VAS score was higher in both groups after operation than before anesthesia induction (P<0.05). In the control group, the VAS score had no significant difference between T1 and T2 (P>0.05) and between T5 and T6 (P>0.05), while it was the highest at T4. Moreover, it was higher at T4 and T3 than at T5, and also higher at T6 than at T1 and T2 (P<0.05). In the observation group, the VAS score had no significant difference between T1 and T2, between T3 and T4, and between T5 and T6 (P>0.05). It was higher at T5 and T6 than that at T3, and also higher at T4 than that at T1 and T2 (P<0.05).
The Ramsay score was higher in both groups after operation than that before anesthesia induction (P<0.05). The Ramsay score had no significant difference between T5 and T6 (P>0.05) and between T2 and T1 (P>0.05). Moreover, it was higher at T4, T3, T2 and T1 than that at T5 and T6 (P<0.05).
The Ramsay score had a significant difference between the two groups at T0, T4, T5 and T6 (P>0.05), while it was lower in the observation group than that in the control group at T1, T2 and T3 (P<0.05).
The number of cases with adverse reactions (percentage) in the observation group was smaller than that in the control group within 48 h after PCIA (P<0.05) (Table 7).
Incidence rates of adverse reactions after PCIA
| Group | n | Nausea and vomiting (n, %) | Constipation (n, %) | Dizziness (n, %) |
|---|---|---|---|---|
| Control | 60 | 15 (25.00) | 14 (23.33) | 10 (16.67) |
| Observation | 60 | 6 (10.00) | 5 (8.33) | 3 (5.00) |
| χ2 | 4.675 | 5.065 | 4.227 | |
| P | 0.031 | 0.024 | 0.040 |
The main causes for pain after laparoscopic surgery include chemical stimulus, tractive stimulation of phrenic nerves, residual gas in the abdominal cavity, wound drainage, incision pain, operation time, and anesthetic factors [8,9]. The pain after LC is mainly manifested as incision pain and visceral pain, the latter of which is mainly caused by mechanical tractive stimulation due to pneumoperitoneum, and the physicochemical characteristics of gas filled.
Oxycodone is a dual receptor (κ and μ receptors) agonist, which can enhance the analgesic effect effectively, with mild respiratory depression [10,11]. In this study, the number of cases with adverse reactions (percentage) in the observation group was smaller than that in the control group within 48 h after PCIA. A possible reason is that as a dual receptor agonist, oxycodone has milder side effects than simple μ receptor agonists.
Laparoscopic gallbladder surgery has incomparable advantages with traditional open surgery, but the incidence rate of agitation during the recovery period is higher than that of traditional open surgery. There are no special diagnostic criteria for agitation in the recovery period [12,13], the Riker's sedation-agitation score is mostly used in research [14,15], and agitation can also be classified. In this study, HR, MAP, and SpO2 were selected as the observation indexes, and the changes in them were compared before the end of operation and after drug administration. Then, agitation was classified, and its degree was compared between the two groups to reflect the influence of oxycodone and fentanyl on hemodynamics. It was found that in control group and observation group, HR and MAP were higher at T1 and T2 than those at T0, while they declined at T2 compared with those at T1. It can be seen that stimulation by extubation will lead to fluctuations in HR and MAP after extubation, and HR and MAP tend to be normal after the stimulation disappears, but it is difficult to return to the previous normal levels in a short time. Moreover, SpO2 declined at T1 compared with T0, suggesting that extubation has an instantaneous impact on SpO2, and SpO2 is restored quickly. Besides, HR and MAP were lower in the observation group than those in the control group at T1 and T2, indicating that oxycodone can reduce the stress response caused by extubation and the hemodynamic fluctuation compared with fentanyl. SpO2 rose in the observation group compared with the control group at T1, suggesting that oxycodone can reduce the impact on SpO2 compared with fentanyl. After the spontaneous breathing was recovered, agitation had a lower incidence rate and degree in observation group than those in the control group. The reason is that small doses of opioids were applied before extubation, and oxycodone has fast onset of analgesic effect and mild central inhibition.
Substance P, as a neurotransmitter, is a pain transmitter which, after ligand binding, is able to transmit pain and reduce the pain threshold. 5-HT mostly exists in peripheral tissues and platelets. Under the action of substance P, 5-HT and histamine can be degranulated and released simultaneously, leading to hyperalgesia. Substance P and 5-HT are the main transmitters mediating the pain information transmission, and they influence and synergize with each other in the stepwise transmission of pain information [16]. There is a large number of reaction media in the extracellular fluid of damaged tissues. Excessive inhibition on pain conduction can reduce the release of substance P, inflammatory mediators, and catecholamine; weaken the body's sensitivity to pain; and suppress sympathetic nervous excitement; thereby reducing the stress response and high energy consumption state, and protecting the body. Opioids achieve an analgesic effect through not only specifically binding to their receptors, but also inhibiting the release of analgesic substances, such as substance P, 5-HT and acetylcholine. In this study, it was found that the concentration of substance P and 5-HT rose with time in the two groups, but the levels of substance P and 5-HT in the observation group were far lower than those in the control group at the same time point, indicating that oxycodone can reduce the release of 5-HT and substance P compared with fentanyl. In particular, it can be considered that oxycodone has a better analgesic effect than fentanyl at the time of stimulation by extubation. These findings are consistent with the viewpoint that the release of analgesic substances in the peripheral blood is affected by the drug action, thereby weakening the peripheral afferent and central efferent pathways, and realizing analgesia.
Currently, the VAS and Ramsay sedation scoring system have been widely used in professional fields such as anesthesia and critical care medicine, and they are commonly used assessment tools for sedation. In this study, the most commonly used Ramsay sedation scoring system in clinical anesthesia was selected to assess the sedation degree of patients. The sedative and analgesic effects of opioids on patients after operation were evaluated using the Ramsay score combined with VAS score from the perspective of doctors and patients, respectively, namely the combination of behavior assessment and self-assessment. Through analysis of the difference in the sedative and analgesic effects between the two groups, it was found that compared with fentanyl, oxycodone could effectively reduce the sedation score at 1 h after operation, and the analgesic effect of oxycodone was more obvious than that of fentanyl. Therefore, it can be inferred that oxycodone has higher safety and more complete analgesic effects than fentanyl in postoperative PCIA of patients after laparoscopic gallbladder surgery, because its inhibitory effect on the central nervous system is milder than that of pure opioid receptor agonists, and it inhibits the pain conduction after excitation of visceral κ receptors, with small side effects and good analgesic effects. Regardless, this study is limited. This is a single-center study with a relatively small sample size. Further multicenter studies with larger sample sizes are still needed to eliminate possible bias and to verify our findings.
In conclusion, as a clinically novel opioid receptor agonist, oxycodone injection has a significant effect on relieving moderate to severe pain, especially visceral pain. It can be used in multimodal analgesia in anesthesia, which has little influence on circulation and breathing, and reduces the incidence of agitation during the anesthesia recovery period. Moreover, it can reduce the release of substance P and 5-HT, thereby relieving pain and nausea. When applied to PCIA, its analgesic effect is satisfactory, the incidence rate of adverse reactions is lower, and it can significantly improve the quality of anesthesia and enhance the comfort and satisfaction of patients. The specific peripheral and central mechanism of oxycodone can be gradually clarified with laboratory research, and the clinical application value of oxycodone can also be continuously confirmed.