This study seeks to ascertain whether the addition of ketamine to morphine for acute post- thoracotomy pain management enhances analgesic effectiveness and lowers pain intensities when judged against morphine alone. The significance of the study lies in the establishment of the appropriateness of ketamine plus morphine or morphine alone in a patient controlled analgesia situation for severe post-thoracotomy pain. The objective of the study was to establish whether ketamine plus morphine offers a relevant decrease in severe pain following thoracotomy when compared to morphine alone. This study is a systematic review of the peer-reviewed articles published in reputable journals in the last fifteen years. The search was done through Google Scholar, Medline, and PubMed database. While the independent variables are morphine and morphine plus ketamine, the dependent variables are the pain score, crucial signs, and undesirable effects. The morphine alone group indicated a less rapid decrease in pain strength than that of the ketamine plus morphine group.
Morphine vs. Ketamine + Morphine in Post-Thoracotomy Pain
There is a significant argument regarding optimal patient-controlled analgesia for acute post-thoracotomy pain. Morphine is usually employed; nevertheless, there is inadequate proof regarding whether it acts as the optimal analgesia for post- thoracotomy pain (Akhavanakbari, Mohamadian, and Entezariasl 85). In the contemporary world, there is a tendency of employing morphine as the preferred drug because of its analgesic impact to assist patients to triumph over great pain. Nevertheless, the application of opioids has had negative effects and restricted availability in the underdeveloped and developing nations, which has called for the search for alternative ways of post-thoracic pain control. The success of opioid analgesia for post-thoracic pain could be hampered by unnecessary sedation, respiratory distress, and queasiness. Ketamine is an agent that has analgesic qualities. It is expansively being employed across the globe in acute care therapy. When judged against morphine, ketamine has a low likelihood of serious, negative impacts and slight influence on heart rate and blood pressure. Of late, interest has been centered on the role of NMDA (N-methyl-D-aspartate) receptor antagonists in the control of postoperative pain. Particularly, ketamine has been in the limelight for its analgesics impacts at little doses as a standalone medicine or as an adjunct to other analgesics, such as morphine. Nonetheless, ketamine has its demerits too just like opioids. This study seeks to establish whether adding ketamine to morphine for a patient controlled analgesia setting for acute post-thoracotomy pain increases analgesic effectiveness and lowers pain levels when judged against morphine alone.
Purpose of the Study. If not well managed, post-thoracic pain is usually associated with detrimental impacts and is a significant contributor to disability after 72 hours of surgery. The effective control of pain is of great significance both short-term and long-term, particularly for post- thoracotomy pain. The significance of this study lies in the determination of the suitability of ketamine plus morphine or morphine alone in a patient controlled analgesia setting for acute post-thoracotomy pain. The knowledge of the best analgesia could greatly assist patients in the management of pain after thoracotomy and prevention of possible adverse effects after surgery. The study does this by reviewing existing studies and evaluating the occurrence of unfavorable impacts and influences of the agents under comparison on crucial signs.
- To determine whether ketamine added to morphine in patient-controlled analgesia (PCA) provides a clinically relevant reduction in acute post-operative pain following thoracotomy, opioid requirements, and adverse events when compared to morphine PCA alone in adults undergoing thoracotomy
REVIEW OF EXISTING LITERATURE
Thoracotomy denotes one of the highly excruciating surgical operations (Luketich et al. 1845-1850). Insufficient management of pain could have great adverse impacts, encompassing heightened postoperative morbidity, in addition to tardy recovery and incidence of a post-thoracotomy syndrome. In this regard, the choice of an effective analgesic agent for a thoracic surgical procedure is crucial. Most of the employed strategies, for instance, intravenous narcotics and thoracic epidural have shown varying outcomes. Nonetheless, the perfect approach continues to be an open concern. Dissimilar aspects with the inclusion of diaphragm and thoracic viscera correspond with thoracotomy pain progress. Therefore, attributable to the multifactorial origin of pain after thoracotomy, a combined analgesic method instead of a single technique appears to be more successful as it obstructs harmful input at dissimilar targets and scores of pain tracts.
Pain following thoracic surgery could be severe and extended (Suzuki et al. 111-119). Nociceptive arousal after thoracotomy results in hyper-excitability through the activation of the N-methyl-D-aspartate receptor, a progression entailed in the pathophysiology of severe pain. Studies show that ketamine is not a competitive N-methyl-D-aspartate agonist that applies particular NMDA obstruction and transforms primary sensitization while offering antihyperalgesic influence. The preventive analgesic agent is anchored on the perception of the administration of analgesia prior to the incident of nociceptive contributions. Different research studies have established that administering ketamine ahead of the surgical pain eradicates the spinal progression of nociceptive impacts and hinders the stimulation of nociceptors through the blockade of N-methyl-D-aspartate receptors.
Several studies establish that administering ketamine before thoracotomy could offer a suitable adjunct to intravenous opioid analgesic agent in severe post-thoracotomy pain control (Yan-qun 33). Patients that have obtained ketamine have a considerable decrease of pain intensities, inflammatory reaction, and morphine use when judged against placebo. On this note, in accordance with an attitude of multianalgesic approaches in the management of post-thoracotomy pain, the preemptive use of ketamine and morphine might be of medical significance in the circumstances that epidural analgesia or any analgesic techniques dissimilar from intravenous opioid are accessible or unadvisable. Nevertheless, the quantity of ketamine administered, the visual analog scale score indicated, and the intravenous morphine administered represent variables that have to be considered in the analysis of the results.
Inadequate postoperative analgesia following thoracotomy is associated with severe patient discomfort and alterations of ventilator mechanics. Some of the risks that are posed from impaired breathing, ineffective cough, and poor clearance of secretions are atelectasis, pneumonia, and increased post-operative morbidity (Fiorelli et al. 45-57). Pain following a thoracotomy is due to multiplicity of nociceptive receptors from the lungs, chest wall, diaphragm, and chest tubes, which is the reason why regional, as well as systemic pain control, is required in thoracic surgeries (Luketich et al. 1849).
In most thoracic surgery studies that are reported, the continuous intercostal nerve block is supplemented by systemic analgesics such as opiates and nonsteroidal anti-inflammatory agents (Luketich et al. 1849). Ketamine, a noncompetitive NMDA antagonist, produces central antinociception by reducing the sensitization of C fibers at the spinal and supra spinal levels. It also enhances analgesia because of its local anesthetic properties and its interactions with spinal opioid receptors. Low-dose intravenous ketamine improved epidural analgesia and morphine patient-controlled analgesia after thoracic surgery. Studies indicate that intravenous ketamine in low doses, given at 0.05 mg/kg/h for 72 hours following thoracotomy potentiates epidural morphine analgesia (113). Other studies have shown that adding small doses of ketamine (0.5-1 mg/ml) to morphine in intravenous patient-controlled analgesia decreases morphine consumption and improves respiratory function after thoracic surgery (Subramaniam, Subramaniam, and Steinbrook 482-490).
This paper is a systematic review of the peer-reviewed articles published in respectable journals in the past 15 years. The search will be done through Google Scholar, Medline and PubMed database using the following keywords: low-dose ketamine, post-operative, thoracic surgery, thoracotomy, post-thoracotomy pain, ketamine and morphine, postoperative pain, and ketamine analgesia. The outcomes of the selected studies were used to compare the efficacies of pain control with morphine alone vs. morphine plus ketamine using the verbal numeric rating scale to rate the pain and time to the first requested dose of morphine (Yazigi et al. 32-38). The secondary part of the systematical review is looking at the adverse effects of ketamine observed at low-dose and frequency of morphine required in patients getting ketamine. These findings helped to guide post-thoracotomy pain control with either morphine alone or in adjunct with ketamine. The researcher included randomized control studies, double blind (if any) in adult patients and both genders that underwent thoracotomy when the pain was assessed up to 72 hours. The independent variables are morphine and morphine plus ketamine while the dependent variables being the pain score, crucial signs such heart rate and consciousness and undesirable effects such as hypertension or hypotension.
Expected Outcome. The researcher hypothesized that intravenous ketamine would potentiate continuous analgesia, therefore improving patient comfort, lung expansion, secretions clearance, and reducing the consumption of supplemental morphine. The researcher also hypothesized that using low-dose ketamine will allow the clinicians to reduce the dose and frequency of morphine requested by the patient. As the dose and frequency of morphine reduced, there was an expectation to see a decrease in adverse effects from morphine use.
Selection of Studies. Studies were considered for use if the participants were above 18 years of age, conscious, talking and with the capability of rating their pain with the help of the verbal numeric rating scale (Jennings et al. 497-503). Studies were excluded if the participants had any identified allergy to morphine or ketamine, were expectant or lactating, had acute pulmonary edema or ischemic chest pain, had head injuries, severe high blood pressure, incapacity to access the veins and were believed to have intoxicated themselves with alcohol or other drugs.
Interventions. The patients in the selected studies were randomized by being allocated in any of the two groups: ketamine plus morphine or morphine alone. Following the first dose of 5 mg of morphine, participants in one group received ketamine and the other group morphine. 10 mg of morphine was diluted to 1 mg/mL of solution through the application of 9 mL of the normal saline solution while 200 mg of ketamine was diluted to 10 mg/mL of the solution in 18 mL of normal saline. The dosage of morphine was the initial 5 mg, after which there was an addition of 1 to 5 mg after each five minutes. For ketamine, after the initial administration of 10 or 20 mg, there was another 10 mg after each three minutes. Paramedics employed their medical knowledge on dosage with respect to age and the patient’s size of the body (Galinski et al. 385-390). As indicated above, ketamine or morphine continued being administered until the patients were free of pain, had unpleasant occurrences (for instance, intense low blood pressure or loss of consciousness) or there was a need for emergency care.
Outcome Determinants. The fundamental outcome was the measure of pain according to the verbal numeric rating scale after thoracotomy (Sveticic et al. 287-293). The degree of the patient’s pain was indicated on the verbal numeric rating scale with the intensities ranging from 0 to 10 (where 0 indicates very low or no pain at all with 10 representing the greatest pain imaginable) and compares suitably with the visual analog scale. The rating scale was evaluated and noted by the health professional immediately after surgery and afterward done in ten-minute intervals. Undesirable outcomes were noted by the health professional on the record of the patient. The secondary results were changes in vital signs and consciousness and the occurrence of undesirable effects. The crucial signs, which include the respiratory rate, heart rate, consciousness and blood pressure, were frequently assessed. Some of the noted undesirable effects encompass emergency reactions, considerable low blood pressure or high blood pressure, extreme sedation, vomiting, queasiness and cardiac arrhythmia.
Primary Data Analysis. A decreasing verbal numeric scale rating with a pain score of above 1.3 was considered as clinically significant (Galinski et al. 385-390). The priori sample size analysis was founded on an average score difference of not less than two points between the groups. For every section of this engagement, enrolling 110 patients was needed to achieve 80% power and α=0.05. Having an expectation that 25 patients per month would be enrolled, there were 250 target patients (with 220 accounting for follow-up/missing data loss). Analysis was pegged on an intention-to-treat criterion. Without protocol violations, two patients in the ketamine category still managed to receive initial doses in excess of the recommended in the protocol. Statistical analysis was undertaken with Stata version 11. Whereas the data was reported with medians, interquartile scope, as well as means (with 95% CI); categorical data were outlined as proportions (percentage) with a 95% CI. The adverse effects frequency was described as a percentage risk and risk difference (95% CIs). Between-group effect size estimates for the difference in pain score was evaluated with a linear regression model, after which (using the Huber-White sandwich estimator) it was adjusted due to clustering within ambulance branch.
Enrollment was slower with two patients for each month. Thirty months later, a quick analysis of 136-patient recruits was done (Jennings et al. 497-503). With a revised calculation of sample size based on the actual sample SD, analysis and recommendations undertaken by a biostatistician warranted the discontinuation of the trial. To perceive a minimum clinically important disparity of 1.3 points, a sample of 63 patients was necessitated for each group.
Characteristics of Study Subjects. In total, 135 participants remained eligible for analysis after 1 withdrew consent to participate in the trial out of an original 136 participants. Seventy patients (about fifty-two percent) was arbitrarily allotted to the ketamine group (refer to Figure 1) whereas sixty-five (roughly forty-eight percent) to the morphine-only group. Refer to Table 1 to see the evident similarity between baseline attributes in the two groups.
Main Results. Assessing the two groups, there was a significant difference in mean pain score change between them.
- Morphine group registered mean of -3.20 (at 95% CI), from -3.70 to -2.70 points out of 10. Ketamine group had -5.60 (at 95% CI), from -6.20 to -5.00 points (as shown in Figure 2). In figure 2, the scores are in negative digits to show the extent of the reduction of pain on the scale (-10 represents total reduction (no pain at all) while -0 no reduction of pain at all).
- The effect size estimate was -2.40 (at 95% CI) from -3.20 to -1.60) points in favor of ketamine on the 0 to10 verbal numeric rating scale.
- An illustration in Figure 3 outlines the analysis of pain severity subsidence at 20 minute and final numerical rating scale.
- Comparing the rating pain score lessening experienced by the patients between groups (Figure 4), a faster pain strength decrease was experienced by ketamine group when judged against the morphine-alone group. Regarding the pain scores each minute, the median measure for morphine-alone group’s slopes was -3.90 (at 95% CI) from -4.40 to -3.10 points; and -6.50 (95% CI) from -7.20 to -5.40 points in the ketamine group.
- Between-group difference was -2.50 points every minute (at 95% CI) from -3.90 to -1.10). Up to the arrival at the receiving emergency department (ED), assessment of vital signs was done at the time of participants’ enrollment at 10-minute intervals (Refer to Table 2).
- Regarding the significance of the clinical trial, differences were noticed among the 2 case study groups (Jennings et al. 497-503). Any detected or outlined unfavorable effects or events experienced ahead of handover at emergency department were registered. Table 3 refers to the frequency, nature and risk difference of reported adverse effects.
- Reported emergency incident included symptoms such as agitation, dysphoria, and hallucinations. Some of the side effects of morphine reduction with ketamine use encompassed nausea, sedation and vomiting. To prevent the severity of such side effects the subsequent dosages of morphine were reduced for enhancement of the excellence of the analgesia. The addition of ketamine was seen to impede the side effects and morphine tolerance and consumption. No experience of an adverse event requiring withdrawal from the study was noticed from any patient.
Figure 1: Trial profile
Table 1: Demographic data and injury attributes of patients
Figure 2: Box plots by each group of the patients and verbal numeric rating scale scores
Figure 3: Mean pain score (verbal numeric rating scale) alterations with 95 percent CIs (from random-effects model) over time by each group
Figure 4: Individual alterations in verbal numeric rating scale pain scores in every one of the two study groups
In this randomized controlled trial, it emerges that the use of morphine plus ketamine (for thoracotomy) was superior when compared to morphine alone as far as the reduction of pain intensity in the patients with moderate to severe pain after surgery is concerned. Speaking of the all-inclusive pain intensity reduction, it appears that intravenous ketamine yielded fruitful and safe analgesia to the patients after thoracotomy (Jennings et al. 497-503).
Table 2: Vital sign alterations in the course of pain management in each study group after thoracotomy
The pain intensity reduction advantage was 2.40 points (verbal numeric rating scale) for the ketamine group over the intravenous morphine alone. However, morphine group had 3.20 points as compared to ketamine group, which had an average pain reduction of 5.60 points. There was a divergence in the pain score measured by the scale between the two case study groups. The morphine group reflected a less rapid reduction in pain intensity over time than that of the ketamine group hence the latter had a steeper slope. Ketamine appeared more desirable due to the combination of better efficacy and a more rapid effect that made addition to the traumatic pain management after thoracotomy. To every patient, there was administration of a quantity of 5 mg of morphine before randomization and enrollment into the study because ketamine, apart from not being routinely administered as the first-line analgesia, it has also been shown to act as an adjuvant to morphine. Of the earlier studies looking at the success of ketamine, three deduced that it provided reliable and safe pain relief (Yazigi et al. 32-38; Suzuki et al. 112-115; Luketich et al. 1845-1850)
Table 3: Frequency of undesirable effects detected, by each group
Statistically, there was no significant difference between the ketamine intervention group and morphine-alone control as much as the visual analog scale pain measure is concerned (Suzuki et al. 112-115). In their study, Galinski et al. established that a larger proportion of the ketamine group had their pain reduced to a greater extent when compared to the morphine group by the end of a 30-minute period, although this difference could not reach statistical significance (61% versus 41%; with P-value of 0.20) (387). In the clinical cohort study while using the verbal rating scale, it was established that the pain measures were significantly dissimilar on admittance to the health facility (5.4 (SD 1.9) for the morphine grouping and 3.1 (SD 1.4) for the morphine plus ketamine grouping (P_.05)).
In order to avoid ketamine use as analgesia in the acute setting, most clinicians normally cite ketamine emergency phenomenon as a major setback. Even though a greater proportion of long-standing effects in the ketamine group than the morphine group have been identified from this study, they were mild. Disorientation resulted in 11.4% (8/27); with emergency occurrence taking 5.7% (4/27) of unfavorable effects (Jennings et al. 497-503). The emergency phenomenon incidence is reported to vary from more than 30% down to about 5%. Considering the report from a large meta-analysis whereby doses of less than 1 mg/kg were administered to children for emergency department sedation, a similar comparatively low incidence of emergence dysphoria has been encountered from this study. The health professionals had the alternative of making consultations for the endorsement of the administration of midazolam to counteract negative effects after thoracotomy. Nonetheless, irrespective of reporting of the witnessed emergency occurrences, there was no consideration of midazolam by the attending clinicians.
Most likely, the reported higher rate of adverse effects in the ketamine group was because the paramedics administering the agents were less familiar with ketamine. By adding a new analgesic agent, they were most certainly aware of the known (adverse) effects and, therefore, were able to identify and record them against morphine, with which they have considerable experience and comfort. Other studies/research deduced that ketamine is an effective and safe analgesia after reporting no proof of emergency incident. Regarding the study that required withdrawal of the participant from the trial, there were no severe adverse events encountered in this study. No statistically significant health changes of critical indications after enrollment were noted, neither were there any dissimilarities involving the two groups. There were a slight increase and decrease in mean systolic blood pressure of the ketamine and morphine groups respectively throughout the duration of care. The minor increase in blood pressure was due to the fact that ketamine causes a centrally mediated catecholamine re-uptake impediment, resulting in an increase in blood pressure and heart rate (Jennings et al. 497-503).
This study established that the administration of low doses of ketamine with morphine for post-thoracotomy patients could decrease the pain scores and the extent of drug use. The addition of ketamine to morphine has considerable impact on pain rate and the medication dosage because of its analgesic properties and probably attributable to the influence on cholinergic systems. Alternatively, the addition of ketamine is likely to have assisted in the prevention of acute tolerance to the medication, which could result in the reduction of morphine consumption (Akhavanakbari, Mohamadian, and Entezariasl 85). In reality, nociceptive arousal could lead to the triggering of N-methyl-D-aspartate receptors, deteriorating post-thoracotomy pain; however, the addition of ketamine results in the termination of such an impact. This outcome has been supported by a wide pool of studies. The studies affirm that the addition of ketamine in low doses to morphine in thoracotomy is the result of better pain control and reduction of narcotic use.
- Methoxyflurane denotes a quick-acting, inhalational pain-relieving agent, and was administered to some of the patients taking part in this study. The choice of the patients to be given methoxyflurane was solely the health professionals’ discretion. Even though not all patients enrolled in this study Methoxyflurane was administered to most of them. The administration of methoxyflurane was done ahead of determination of intravenous access by the clinician thus prior to randomization and assignment to either of the groups.
- It is likely that patients who obtained methoxyflurane achieved better pain reduction compared to those who did not, although this was not likely to support one study group more than the other.
- Even though participating patients were blinded to their enrolled research study arm, the clinician was not. This poses a limitation in the study because of two main reasons. To start with, patients that obtained ketamine were anticipated to show obvious and simply recognizable outcomes (for instance, muscle twitching). This makes the study outcome very obvious to the health professionals thus disregarding the purpose of masking. Furthermore, attributable to the requirement for the health professionals to ascertain the drugs and their dosages with respect to the standard operating practices, there was need to guarantee the safety of the patients. No information regarding patients potentially qualified for participation but not enrolled was gathered (Jennings et al. 497-503). Chances are high that qualified and un-enrolled patients would have reacted in a different way to the treatment allocated to them. Nevertheless, this is improbable to support either of the groups and not likely to influence generalizability for patients whose surgeries are primarily isolated.
There is a noteworthy argument concerning optimal patient-controlled analgesia for severe post-thoracotomy pain. Morphine is frequently employed; nonetheless, there is inadequate proof regarding whether it acts as the best analgesia for post-thoracotomy pain. In particular, ketamine has been in the public interest for its analgesic strength at little-doses as a separate medicine or as an addition to other analgesics, for instance, morphine. This study discussed whether adding ketamine to morphine for a patient controlled analgesia condition for severe post-thoracotomy pain boosts analgesic success and lowers pain degrees when compared to morphine alone. The awareness of the most excellent analgesia could significantly assist patients in the management of pain after thoracotomy and avoidance of likely negative effects following surgery. The study did this via reviewing existing peer-reviewed articles and evaluating the occurrence of adverse impacts and influences of the agents under comparison on critical signs. The results shows that the administration of morphine plus ketamine (for thoracotomy) was better when compared to morphine alone in so far as the decrease of pain strength in the patients after surgery was concerned. Considering the comprehensive pain score measured, it appears that intravenous ketamine is an effective and safe analgesia for the patients after thoracotomy.
- Following the success of intravenous ketamine in the reduction of refractory acute pain, further exploration of the utility of various dosing regimens (such as continuous or patient-controlled infusion) needs to be done with respect to effective pain maintenance and analgesia administration after thoracotomy.
- Thorough focus should be made on the effectiveness of optional routes of administration to take account of intramuscular, intranasal and topical applications.
- Examination of alternative routes of administration, optimal dosage, and utility of concomitant opioid administration ought to be done carefully.
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