Preemptive Drug Research Articles

Evaluation of Pain by Using Intravenous Paracetamol as Pre-Emptive Drug in Mandibular 3rd Molar Surgery - An Experimental Study

Evaluation of Pain by Using Intravenous Paracetamol as Pre-Emptive Drug in Mandibular 3rd Molar Surgery - An Experimental Study

Is coadministration of preemptive medications an effective strategy for reducing inflammatory clinical events and the need for rescue medication after mandibular third molar surgery? A systematic review of randomized clinical trials.

This study aimed to evaluate the scientific evidence on the effect of preemptive drug coadministration (PDC) for relieving inflammatory events (pain, swelling, and trismus) in mandibular third molar surgery. A PROSPERO-registered systematic review (CRD42022314546) was conducted according to the PRISMA guide. The searches were carried out in six primary databases and the gray literature. Studies not written in languages with the Latin alphabet (Roman) were excluded. Potential randomized controlled trials (RCTs) were screened for eligibility. Cochrane's Risk of Bias-2.0 (RoB) tool was assessed. A synthesis without meta-analysis (SWiM) based on a vote counting and an effect direction plot. Nine studies (low RoB) fulfilled the eligibility criteria and were included for data analysis, with a total of 484 patients. PDC mostly involved corticosteroids (Cort) and non-steroidal anti-inflammatory drugs (NSAIDs). PDC of Cort and other drugs mainly reduced pain scores (6 and 12h postoperatively) and swelling (48h postoperatively). PDC of NSAIDs and other drugs mainly reduced pain scores at 6, 8, and 24h follow-up; swelling and trismus intensity ameliorated at 48h postoperatively. The most frequently prescribed rescue medication was paracetamol, dipyrone, and paracetamol plus codeine. Results from individual studies have shown reduced consumption of ingested rescue analgesics. In summary, the available evidence from clinical trials included in this SWiM suggests that PDC may provide benefits in reducing the severity of inflammatory outcomes related to mandibular third molar surgery, especially the pain scores in the first hours after surgery, and the rescue analgesic consumption during the postoperative period.

The Effect of Pre-emptive Oral Melatonin versus Placebo on Post-operative Analgesia in Infants after Thoracotomy for Closed Cardiac Surgeries: A Randomized Controlled Study

BACKGROUND: Thoracotomy pain is one of the severest types of pain that should be managed properly, especially in children. Opioids are the most widely prescribed analgesics for post-operative pain, but they can have a number of undesirable side effects. Melatonin could be employed as an adjuvant analgesic therapy during procedural discomfort as it had no known major side effects. STUDY DESIGN: This was a double-blinded, controlled randomized study. METHODS: Fifty patients divided randomly into two equal groups. One hour before surgery, children in M group (n = 25) were given 0.5 mg/kg orally of melatonin 3 mg tablets) and patients in Group P (n = 25) received a placebo (5 ml of water by syringe 5 ml) orally. Post-operative pethidine consumption over the 1st 24 h (mg) was recorded, the intraoperative fentanyl consumption (HR and ABP) at baseline, 1 min after induction, at skin incision, and every 30 min till the end of the surgery were recorded. Neonatal Infant Pain Score (NIPS) at 4 h, 6 h, 8 h, 12 h, 18 h, and 24 h postoperatively was recorded. Other reported data include demographic data, extubation time, days of ICU stay, and complications. RESULTS: Total post-operative pethidine consumption (mg) over 24 h was significantly lower in M group than P group (3.48 ± 2.23 vs. 7.68 ± 4.52 p = 0.01). Intraoperative fentanyl consumption (ug) was significantly lower in M group than P group (10.28 ± 4.98 vs. 17.08 ± 7.39 p < 0.001). As regards NIPS, it was statistically lower in M group than P group in all times except at 8 h and 24 h with significant difference. CONCLUSION: Oral melatonin is an effective and safe pre-emptive drug as it reduces the total post-operative pethidine consumption over the first 24 h and decreased post-operative pain scores without any unpleasant effects in pediatrics undergoing closed heart surgery.

Preoperative preemptive drug administration for acute postoperative pain: A systematic review and meta-analysis.

Preoperative administration of pharmacological substances, such as non-steroidal anti-inflammatory drugs or opioids, has been gaining acclaim as a preemptive measure to minimize postoperative pain. This systematic review and meta-analysis aimed at evaluating the effectiveness of this approach in adults undergoing surgical procedures. MEDLINE, EMBASE and the Cochrane Central Register were searched from inception through January 2015. Data from randomized placebo-controlled trials were screened, extracted and assessed for risk of bias according to The Cochrane Collaboration's Tool by two independent authors. The primary outcome measure was reduction in postoperative analgesic consumption during 24h post surgery; effects were described as mean differences between the drug and placebo arms with corresponding 95% confidence intervals (CIs) and were pooled using random-effects models. Potential publication bias was tested using funnel plots and Egger's regression test for funnel plot asymmetry. Screened were 511 records, of which 39 were included in the final synthesis with data from 3172 patients. A significant reduction in postoperative analgesic consumption was observed using preoperative administration of non-steroidal anti-inflammatory drugs (NSAIDs; 95% CI, -0.61 to -0.14; 31 comparisons), chiefly by the COX-2 inhibitors class (95% CI, -0.95 to -0.33; 13 comparisons). Significant reduction was also observed for gabapentin (95% CI, -1.60 to -0.38; 6 comparisons). No significant effects were observed using opioids, propionic acids or oxicam derivatives. WHAT DOES THIS REVIEW ADD?: Current analyses endorse the effectiveness of COX-2 inhibitors and gabapentin in reducing acute postoperative pain when administered preemptively presurgery. Such corroboration is not found for opioids and other NSAID classes.

Intravenous Sildenafil as a Preconditioning Drug Against Hemodynamic Consequences of Warm Ischemia-Reperfusion on the Kidney

We designed an experimental model of renal ischemia-reperfusion to evaluate the preemptive effect of intravenous sildenafil according to the dose administered (0.7 vs 1.4 mg/kg) and the time of administration (30 minutes before ischemia or during ischemia). A total of 20 minipigs were divided into groups of 4 each, including group 1-control, group 2-sildenafil 0.7 mg/kg intravenously 30 minutes before vascular clamping, group 3-sildenafil 0.7 mg/kg intravenously during warm ischemia, group 4-sildenafil 1.4 mg/kg intravenously 30 minutes before vascular clamping and group 5-sildenafil 1.4 mg/kg intravenously during warm ischemia. The ischemia-reperfusion model was applied using laparotomy and right kidney vascular clamping for 30 minutes, followed by unclamping and reperfusion for 45 minutes. Renal vascular flow and systemic mean arterial pressure were recorded for 45 minutes after unclamping. Mean values were compared using Student t test with significance considered at p <0.05. Sildenafil led to a decrease in arterial pressure compared to that in controls, especially at the dose of 1.4 vs 0.7 mg/kg, including 113.77, 109.76, 106.12, 97.41 and 82.85 mm Hg in groups 1 to 5, respectively. Renal vascular flow was significantly higher in groups 2 and 3 than in groups 1, 4 and 5 (112.82 and 111.33 vs 88.25, 87.91 and 84.37 ml per minute, respectively, p = 0.000). The effect of intravenous sildenafil as a preemptive drug against the hemodynamic effects of renal ischemia-reperfusion is dose dependent. The 0.7 mg/kg dose significantly increased reperfusion renal vascular flow with a small decrease in arterial pressure compared to the 1.4 mg/kg dose.

How close are we to individual analgesic adjustment according to a patient's genotype?

on therapeutic outcomes. This has been demonstrated for codeine [7,8], tramadol [9,10] and oxycodone [11,12], when activated by CYP2D6 into their active moieties, morphine, O-desmethyltramadol and oxymorphone, respectively, in terms of pharmacokinetic and pharmacodynamic consequences. In the case of reduced or absent CYP2D6 activity such as in poor metabolizers (PMs) for CYP2D6 (7–10% of Caucasians), reduced or absent metabolite formation and reduced analgesic effects have been observed. After major abdominal surgery, nonresponse rates to tramadol were fourfold higher amongst PMs than other CYP2D6 genotypes [10]. A cohort study demonstrated that children undergoing ineffective pain treatment of sickle cell crisis with codeine were more likely to have reduced CYP2D6 activity [13]. Inversely, ultrarapid metabolizers (UMs) for CYP2D6, with increased enzymatic activity, experienced quicker analgesic effects but were prone to higher μ-opioid-related toxicity after tramadol [14] or oxycodone in the experimental pain setting [12]. Furthermore, case reports have highlighted the risks of codeine use in pediatrics and breastfed neonates in association with the UM genotype [6,15]. The dual serotoninergic and adrenergic inhibitor antidepressants, such as venlafaxine, and the tricyclics used in the treatment of neuropathic pain are also metabolized by CYP2D6. The PM phenotype has been associated with higher risks of tricyclics toxicity [16]. Inversely, UMs may experience reduced effects due to subtherapeutic plasma levels [17]. However, even though dose adjustments according to CYP2D6 (and CYP2C19) have been published for antidepressants, these guidelines relate to psychiatric doses [18] and no investigations in the neuropathic pain setting have been published Over the last decade, the knowledge of genetic modulators of pain and antinociception has increased so that individualized pre-emptive pain therapy adjusted to the patient’s genetic background could move closer to reality [1]. Indeed, in the field of oncology, it is now established that the choice of treatment and/or dose adjustment according to a patient’s genetic make-up is associated with better therapeutic outcomes [2]. In current clinical practice in pain medicine, individual patients are given their own analgesic trial, depending on pain intensity and origin, at a standardized dose followed by individual titration until expected outcomes are achieved. The trial and error approach is progressively adjusted, according to the physician’s experience with patients with related pain or disease conditions. However, studies have shown that doses of opioids administered may vary as much as 40-fold in the clinical setting [3]. Moreover, a significant proportion of patients will experience side effects or inadequate analgesia. The heterogeneity observed in response to pain medication might be due to the underlying disease itself or compliance, but also to the genetic background of the individual. Studies have reported genetic variations in drug absorption, distribution, metabolism and elimination that might ultimately have an impact on the efficacy/safety ratio of a particular drug [4–6]. Evidence for the influence of genetic polymorphisms of drug-metabolizing enzymes, such as cytochromes P450 (CYP), on the response to various analgesics is now established. A prototypical example is illustrated by prodrug opioids that need to be bioactivated by CYP2D6 into active metabolites, with genetic polymorphisms of CYP2D6 having a profound impact “Gene–drug interactions are still poorly understood and there is a need for prospective highly powered studies in phenotyped populations to evaluate the cost–effectiveness of pre-emptive drug selection and dosage according to the genotypic and phenotypic data.”

Does lidocaine more effectively prevent pain upon induction with propofol or etomidate when given preemptively than when mixed with the drug?

Study Objective To compare the efficacy of 2% lidocaine “timing” on alleviation of pain upon induction using propofol or etomidate. Design Prospective, randomized, double-blinded study. Setting Academic teaching hospital. Patients 80 adult, ASA physical status I, II, and III patients scheduled for elective outpatient or inpatient surgery with an intravenous induction agent. Interventions Patients were randomly assigned to two groups. Group A received preemptive saline 4 mL and lidocaine 4 mL mixed with either propofol 20 mL (n = 20) or etomidate 20 mL (n = 20). Group B received preemptive lidocaine 4 mL and saline 4 mL mixed with either propofol 20 mL (n = 20) or etomidate 20 mL (n = 20). The 4 mL dose of preemptive drug dwelled for three minutes. Measurements The induction drug mixture was injected over 60 seconds while the patient was assessed for pain using a 4-point scale (0 = no pain,1 = mild, 2 = moderate, and 3 = severe). Main Results Mean induction pain scores were 1.0 (SD = 0.89) for propofol and 0.9 (SD = 0.90) for etomidate, representing mild induction pain. Mean induction pain scores were 0.93 (SD = 0.92) for the simultaneous treatment groups and 0.98 (SD = 0.87) for the preemptive treatment groups. The observed differences in pain scores between the techniques were not statistically ( P > 0.62) or clinically meaningful. Conclusions Alleviation and intensity of post-injection pain were not significantly influenced by the “timing” of administration of lidocaine 80 mg or by the specific induction drug. Pre-lidocaine and “simultaneous” lidocaine with either propofol or etomidate prevented severe pain in 95% of patients.

Effects of pre-emptive drug treatment on astrocyte activation in the cuneate nucleus following rat median nerve injury

In this study, we examined the relationship between astrocyte activation in the cuneate nucleus (CN) and behavioral hypersensitivity after chronic constriction injury (CCI) of the median nerve. In addition, we also examined the effects of pre-emptive treatment with a number of drugs on astrocyte activation and hypersensitivity development in this model. Using immunohistochemistry and immunoblotting, little glial fibrillary acidic protein (GFAP; an astrocyte marker) immunoreactivity was detected in the CN of the normal rats. As early as 3 days after CCI, there was a significant increase in GFAP immunoreactivity in the lesion side of CN, and this reached a maximum at 7 days, and was followed by a decline. Counting of GFAP-immunoreactive astrocytes revealed that astrocytic hypertrophy, but not proliferation, contributes to increased GFAP immunoreactivity. Furthermore, microinjection of the glial activation inhibitor, fluorocitrate, into the CN at 3 days after CCI attenuated injury-induced behavioral hypersensitivity in a dose-dependent manner. These results suggest that median nerve injury-induced astrocytic activation in the CN modulated the development of behavioral hypersensitivity. Animals received MK-801 (glutamate N-methyl- d-aspartate (NMDA) receptor antagonist), clonidine (α 2-adrenoreceptor agonist), tetrodotoxin (TTX, sodium channel blocker) or lidocaine (local anesthetic) 30 min prior to median nerve CCI. Pre-treatment with MK-801, TTX, and 2% lidocaine, but not clonidine, attenuated GFAP immunoreactivity and behavioral hypersensitivity following median nerve injury. In conclusion, suppressing reactions to injury, such as the generation of ectopic discharges and activation of NMDA receptors, can decrease astrocyte activation in the CN and attenuate neuropathic pain sensations.

Antinociceptive action of 4-methyl-5-trifluoromethyl-5-hydroxy-4, 5-dihydro-1 H-pyrazole methyl ester in models of inflammatory pain in mice

Aims The aim of the present study was to evaluate the antinociceptive effect of the novel pyrazoline methyl ester: 4-methyl-5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazole methyl ester (MPF4). Main methods The effect of MPF4 was assessed in two models of pain: arthritic pain caused by Complete Freund's Adjuvant (CFA) and postoperative pain caused by surgical incision in mice. Key findings MPF4 given intraperitoneally (1.0 mmol/kg, i.p.) produced marked antinociception in inflammatory allodynia caused by CFA. The antinociceptive effect produced by MPF4 was reversed with the pre-treatment of animals with naloxone or naltrindole. Oral administration of MPF4 (1.0 mmol/kg, p.o), dipyrone (1.0 mmol/kg, p.o.) and morphine (0.026 mmol/kg, p.o.) also produced an anti-allodynic effect. However, none of the compounds evaluated reversed the paw edema produced by CFA. Moreover, MPF4, dipyrone and morphine also produced an anti-allodynic effect in the surgical incisional pain model. The maximal inhibitions obtained with preemptive drug treatment were 66 ± 7%, 73 ± 9% and 88 ± 8% for MPF4 (1.0 mmol/kg, p.o.), dipyrone (1.0 mmol/kg, p.o.) and morphine (0.026 mmol/kg, p.o.), respectively. The maximal inhibitions obtained with curative drug treatment were 53 ± 9%, 83 ± 7% and 84 ± 7%, for MPF4, dipyrone and morphine, respectively. Unlike indomethacin, MPF4 did not induce gastric lesions at the dose that caused the highest antinociception (1.0 mmol/kg, p.o). The anti-allodynic action of MPF4, dipyrone and morphine was not associated with impairment of motor activity. Significance The results of the present study suggest that MPF4 represents a potential target for the development of new drugs to treat persistent inflammatory pain.

Prevention of cytomegalovirus disease in solid organ transplant patients: Prophylactic versus preemptive therapy

The advantages and disadvantages of universal prophylaxis and preemptive therapy and current evidence-based recommendations for preventing cytomegalovirus (CMV) disease in solid organ transplant recipients are discussed. Advantages of universal prophylaxis include the ease of implementation, a reduced incidence of CMV disease, and possibly fewer indirect effects of CMV infection. Disadvantages of universal prophylaxis may include prolonged antiviral drug exposure, resistance, toxicity, the development of late-onset CMV disease, and greater drug costs. Advantages of preemptive therapy may include reduced drug exposure and decreased risk for toxicity and resistance. Disadvantages include the logistic demands of laboratory testing, uncertainty about the impact on the indirect effects of CMV disease, and the costs associated with failure to prevent CMV disease. Evidence-based guidelines call for universal prophylaxis for patients at highest risk for CMV disease. Preemptive therapy may be most appropriate for those at a moderate or low risk of CMV. Antiviral drug regimens used for universal prophylaxis depend on the type of organ transplanted and the donor-recipient CMV serostatus. The optimal preemptive drug regimen and laboratory monitoring strategy are unknown. Selection of a strategy for preventing CMV disease in solid organ transplant patients requires consideration of patient-specific risk factors as well as practical considerations, such as available resources.

Changes in neuronal markers in a mononeuropathic rat model: relationship between neuropeptide Y, pre-emptive drug treatment and long-term mechanical hyperalgesia

Using the chronic constriction model (CCI) of Bennett and Xie (1988), changes in the lumbar spinal cord in neuropeptides and lectin IB 4 were examined at 28 days post-nerve constriction and were compared with the degree of mechanical hyperalgesia. Animals following nerve ligation were significantly more hyperalgesic than sham-operated animals ( P < 0.0001). Lectin IB4, a marker of primary afferent C fibres, showed a qualitative decrease in staining intensity in laminae 1–2 with ligation compared with both the unoperated contralateral side and with sham animals. Using fluorescent immunohistochemistry to quantify changes in neuropeptides in the dorsal horn we found that substance P showed significant decreases with ligation compared to sham operation ( P < 0.002). CGRP and galanin showed no significant changes in laminae 1–2 compared to sham-operated animals. Neuropeptide Y (NPY) showed no significant changes in intensity in laminae 1–2; however, in laminae 3–4 there was a significant increase with nerve ligation compared to sham ( P < 0.005). We examined how pre-emptive drug treatment affected these neuronal markers at 28 days. We used (1) clonidine, an α 2-adrenoreceptor agonist (1 mg/kg, i.p.), (2) morphine, a μ-opioid agonist (5 mg/kg, i.p.) or (3) MK-801, an N-methyl- d-aspartate (NMDA) receptor antagonist (0.3 mg/kg, s.c.) administered 30 min prior and 6 h following nerve ligation or sham-operation. Hyperalgesia in the ligated group at 28 days was suppressed by treatment with pre-emptive clonidine ( P = 0.003) or MK-801 ( P = 0.003) but not morphine. With the exception of NPY there was no effect of pre-emptive drug treatment on any neuronal marker examined. Pre-emptive MK-801 reduced the magnitude of the increase in NPY in laminae 3–4 in the ligated group ( P < 0.005) and clonidine showed a similar trend but this did not reach significance. Morphine had no effect on NPY staining. There was a significant correlation between the increase in NPY staining in laminae 3–4 and the degree of hyperalgesia ( r = 0.6, P < 0.001). These results suggest that the increased NPY expression in laminae 3–4 of the spinal cord (the territory of the myelinated sensory input) may be crucial to the development of hyperalgesia in this model.