Abstract
Objectives:
Dealing with pain is one of the most important issues of medicine. All of the studies aim to find a drug or combination of drugs in order to have more effective analgesia and less side effects. In this study, we aimed to investigate the antinociceptive effects of combination of paracetamol or ketamine with meperidine.
Methods:
In this study, we evaluated the systemic antinociceptive effects of meperidine, paracetamol, and ketamine one by one with their combinations. We used 50 mice (weighing 25–30 g), which were divided into 5 groups with each group consisting of 10 mice. Meperidine was applied to animals with increasing doses and their tail flick latencies (TFL) were noted at 20, 40, 60, 90, 120, 180, and 240 min. The same protocol was repeated after the combination of meperidine with paracetamol or ketamine.
Results:
There was no analgesic effect on low doses of ketamine and paracetamol at TFL measurements. But the combination of low doses of these drugs with meperidine significantly increased TFL (p < 0.05).
Conclusion:
It was observed that meperidine + ketamine and meperidine + paracetamol combinations have potent analgesic effect.
Introduction
Pain is an unpleasant sensory or emotional experience associated with actual or potential tissue damage or described in terms of such damage. The mechanical and thermal stimuli, ischemia, infection, and several chemicals cause an inflammatory environment resulting in pain. Pain perception occurs from periphery to cerebral cortex by neurons that have synapses with each other. Today, there are a lot of drugs and treatment approaches that are used for pain therapy. Especially during pregnancy, there need to be safe analgesic drugs that are not embryotoxic and fetotoxic.
Meperidine and paracetamol are the commonly used drugs with a proven effectiveness in the management of pain.
1
Meperidine is frequently used in the management of pain during labor. It has short half-life.(3–4 h) and neurotoxic side effects and causes symptoms of absence.
2,3
The analgesia caused by paracetamol is found to be related to serotonin system, and also the paracetamol interfere with nociception related to spinal N-methyl-
Little is known about the side effects caused by opioids that mainly exerts central side effects. 1,2 The fear due to side effects of many opioid drugs result in the underuse in the management of chronic pain that causes the failure of the treatment. 3 Thus, the combination of analgesic drugs provides a decrease in the side effects and an increase in the analgesic effects. In this study, we aimed to evaluate the systemic antinociceptive effect of intraperitoneally administered meperidine, paracetamol, and ketamine one by one with their combinations by measuring tail flick latency (TFL) in the mice.
Material and methods
Animals
After the approval by the local ethical commission of Cumhuriyet University Faculty of Medicine, BALB/c adult mice of either sex, weighing 25–30 g, were used throughout the experimental work. The animals were kept in a standard laboratory conditions with water and feed, constant temperature, and humidity (22 ± 3°C temperature and 60 ± 5% humidity), and 12-h light/12-h dark. The animals were seperated into 5 different groups with 10 animals in each group. Each animal was used only once and received only one dose of the drugs tested. The animals were killed by cervical dislocation immediately after the recording period. All of the experiments were performed between 10:00 h and 14:00 h. Ketamin was dissolved in the 100% dimethyl sulfoxide (DMSO). It was reported in the previous studies that DMSO does not affect the TFL. 8 Before starting the experiments, this finding was verified by testing in some of the mice. The paracetamol and meperidine were found as to dissolve in the distilled water. All of the drugs used in the study were administered to the mice intraperitoneally. TFLs were measured with a mean of 2–3 s for each group before the administration of the drug. After administering 10, 25, 50, and 100 mg/kg of meperidine to the first group of the mice, TFL was evaluated in 5, 20, 40, 60, 90, 120, 180, and 240 min, and the results were recorded. After administering 1.25, 2.5 and 5 mg/kg ketamine to the second group of the mice and 2.5, 5, and 10 mg/kg paracetamol to the third group of the mice, TFL was evaluated in 20, 40, and 60 min, and the results were recorded. The % analgesic effect of each drug was calculated with the equation below, and the graph showing dose–response relation was drawn. Also, the measurements of TFL of the combination of meperidine (10 mg/kg) with paracetamol (1.25 mg/kg) and the combination of meperidine (10 mg/kg) with ketamine (2.5 mg/kg) were done. The results were presented with the graphics.
The TFL of each mouse in each group was measured minimum twice and if the difference between the two measurements did not exceed 0.2 s then the mean of the measurements was calculated in all of the experiments. The median effective dose (ED50) value in 95% confidence interval and maximum exposure time of meperidine were calculated with the analysis of the linear part of the dose–response curve using individualized Visual Basic Programme FlashCalc (Michael H.Ossipov, personel communication). Since the analgesic effect of paracetamol and ketamine were not observed in the measurement of TFL singly, ED50 values and maximum exposure times were not calculated.
Antinociception test
A radiant heat, tail-flick device was used to measure the antinociception (May TF 073 Tail.Flick Unit Commat, Ankara, Turkey). After the administration of the drugs to the animals, the radiant heat of the device was focused on the distal 3 cm part of the tail of the animal. The withdrawal time of the tail that was exposed to the radiant heat (tail flick latency) was determined. The two measurements with a difference of 0.2 s to each animal was performed. The intensity of the infrared light was adjusted to do basal TFL as 2.9 ± 0.3 s. The maximum exposure time to the radiant heat was 8 s in order to prevent the tail damage. The animals not responding to the radiant heat for more than 8 s were excluded from the study. According to the results of measurements, % analgesic effect was calculated using the following equation:
Drugs
The drugs used for the experiments were meperidine (Petidin HCL 100 mg ampoule, Gerot Pharmazeutika, Vienna, Austria), paracetamol (Perfalgan 10 mg/mL 100 mL Bristol Myers squibb), ketamine hydrochloride (50 mg/mL, Eczacıbaşı). All of the drugs were prepared daily for the experiments. Meperidine and paracetamol were found as dissolved in water. Ketamine dissolved in the 100% DMSO.
Statistical analysis
The nonparametric tests were used for the statistical analysis. Kruskal–Wallis test (p < 0.05) was used for the statistical significance of two or more groups. Dunnett’s multiple test was used for the individual comparison, and Mann–Whitney U test (p < 0.05) was used to compare between the two groups.
Results
The % analgesic effects of meperidine, ketamine, and paracetamol
At the beginning of the experiments in order to determine the ED50 values, meperidine, ketamine, and paracetamol were injected with increasing doses intraperitoneally. While ketamine (1.25–5 mg/kg) and paracetamol (2.5–10 mg/kg) did not generate the analgesic effect with the doses used at the measurement of the TFL, meperidine effectuated the analgesic effect in a dose-dependent manner. The ED50 value of meperidine was 18.24 ± 1.54.
In order to determine the time-dependent % analgesic effect of meperidine with the doses of 10, 25, 50, and 100 mg/kg, the TFL were measured at 5, 20, 40, 60, 90, 120, 180, and 240 min. When the curves of time-dependent effect of meperidine were evaluated, the % analgesic effect of meperidine was found to reach to maximum at 40 min with all of the doses (28%, 32%, 40%, and 45%, respectively), decrease after 60 min gradually, and reach to the beginning values at 240 min (Figure 1).
The time-dependent % analgesic effect of meperidine.
In order to determine the time-dependent % analgesic effect of ketamine with the doses of 1.25, 2.5, and 5 mg/kg, the TFLs were measured at 20, 40, and 60 min (Figure 2).
The time-dependent % analgesic effect of ketamine.
The intraperitoneal paracetamol with dose of 10 mg/kg and below doses did not generate the analgesic effect (Figure 3).
The time-dependent % analgesic effect of paracetamol.
The % analgesic effects of combination of meperidine–ketamine
In this part of the experiment, the intraperitoneal ketamine (1.25 mg/kg) was injected 20 min before the administration of intraperitoneal meperidine (10 mg/kg). After the injection of meperidine, TFL were measured at 5, 20, 40, 60, 90, 120, and 180 min. The % analgesic effect of meperidine started from 5 min (24%) with the combination of ketamine, and this combination increased the analgesic effect significantly when compared to the administration of meperidine alone (1%). This increase reached to maximum (100%) at 60 min, and the maximum analgesic effect continued throughout 180 min (Figure 4).
The time-dependent % analgesic effect of the combination of meperidine-ketamine. *p < 0.05: % analgesia of meperidine–ketamine group and meperidine group was statistically different.
The % analgesic effects of combination of meperidine–paracetamol
The intraperitoneal paracetamol (2.5 mg/kg) was injected 20 min before the administration of intraperitoneal meperidine (10 mg/kg). After the injection of meperidine, TFLs were measured at 5, 20, 40, 60, 90, 120, and 180 min. The % analgesic effect of meperidine started from 5 min (53%) with the combination of paracetamol, and this combination increased the analgesic effect significantly when compared to the administration of meperidine alone (1%). This increase reached to maximum (100%) at 60 min, and the maximum analgesic effect of the combination of meperidine and paracetamol continued throughout 180 min (Figure 5).
The time-dependent % analgesic effect of the combination of meperidine–paracetamol. *p < 0.05: % analgesia of meperidine-paracetamol group and meperidine group was statistically different.
Discussion
In this study, the antinociceptive effects of meperidine, paracetamol, and ketamine one by one and also with the combinations of low doses of meperidine–paracetamol and meperidine–ketamine were evaluated in the mice. The results demonstrated that while the meperidine generated the dose-dependent antinociceptive effect singly, the paracetamol and ketamine had no antinociceptive effect one by one in low doses. The combinations of meperidine with paracetamol or ketamine, when compared to the analgesic effect with meperidine singly, provided stronger analgesic effect, and this effect was demonstrated to continue for 180 min. It is determined that the combinations of meperidine–ketamine and meperidine–paracetamol achieve a strong analgesic effect and they are safer in the pregnant women as an analgesic in low doses when compared to the other analgesic drugs. 9
The combination of meperidine with cannabinoids inreased the antinociceptive effect that was found to be related to the effect of mu (μ) opioid and delta (d) opioid receptor through pain pathways. NMDA receptors were known to have role in the analgesic effect, drug tolerance, and drug addiction. The dextrometorphan used as an antitussive had opioid-like effects, and with the combination of low doses of opioids, the antinociceptive effects were increased in the tail flick measurements. 10 The sensitivity to opioids was found to differ in different sexes. In a study, the combination of low dose of naltrexone, opioid receptor antagonist, and morphine increased the antinociception in the female rats, but it did not affect the anti-nociception in the male rats. 11
The interactions between opioid agonists are important in the management of chronic pain. 12 The buprenorphine with morphine or other opioids with the analgesic doses applied i.p. resulted in additive and superadditive interaction. The morphine–buprenorphine combination increased the antinociceptive effect in a tail flick study. 13 . In a study, the combination of hydrocodone, a semisynthetic opioid agonist, and nonsteroidal anti-inflammatory drug increased the analgesic effect when compared to the use of hydrocodone alone. 14 The pain due to diabetic neuropathy is a severe medical problem, and, in a study, they investigated the analgesic effects of oxycodone and morphine. The oxycodone was found to be more effective than morphine with regard to the antinociceptive effect. 15 The gabapentin was found to potentiate the analgesic effects of morphine in the chronic constriction injury model of neuropathic pain in a study. 16 In a review, codeine, an opioid analgesic was determined, to be more effective than placebo in cancer patients but with increased risk of nausea, vomiting, and constipation. 17
The analgesic effects of some of the anesthetic drugs were also investigated. ACEA-1328, an NMDA receptor antagonist, increased the potency of opioid analgesics through antagonistic effects on the glycine site of the NMDA receptor. 18 In another study performed with the tail flick test, the NMDA receptor blocker, given intrathecally, increased the nociceptive threshold and with increased doses sustained the analgesic effect. 10 Also, some herbal medicine products such as rosemary essential oil, when combined with conventional analgesics, was determined to maintain some advantages in the management of pain. 19
In this study, with the combination of ketamine, an NMDA receptor antagonist, and meperidine, an opioid agonist, the antinociceptive activity increased apparently. There are many studies indicating the safety and efficacy of the combination of drugs having analgesic effect. The combination of bupivacaine and ketamine was found to provide efficient postoperative analgesia after adenotonsillectomy. 20 The dexmedetomidine–ketamine–fentanyl–atropine combination was found to be superior to pethidine–atropine combination, thereby decreasing the need for analgesia during general anesthesia and prolonged postoperative analgesia. 21 In a study conducted by Tablov et al. it was declared that ketamine in low doses when added to combination morphine/ketoprofen improves postoperative analgesia after gynecological surgery. 22
The combination of paracetamol and meperidine was found to have increased analgesic effect than the administration of meperidine alone in this study. The combination of paracetamol and diclofenac was more efficient than meperidine in terms of postoperative pain control. 23 In a study performed by Gokten et al., the infiltration of levobupivacaine with intravenous paracetamol infusion was demonstrated to be safe and efficient as an analgesia method after percutaneous nephrolithotomy. 24 Herring et al. pointed out that the combination of paracetamol and opioids reduce the total dose of opioids administered on postoperative days 1–2 and perioperatively. 25
In conclusion and recommendation, the use of meperidine–ketamine and meperidine–paracetamol are suitable combinations for strong analgesic effect, and they can be used as effective drugs in the management of pain in pregnant women and postoperative cases.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.