Preemptive low-dose intravenous ketamine in the management of acute and chronic postoperative pain following laparoscopic cholecystectomy: a prospective randomized control study.

Preemptive analgesia with intravenous ketamine has been utilized as a part of multi-modal analgesia for acute postoperative pain following laparoscopic cholecystectomy with mixed outcomes. We tested the effectiveness of low-dose ketamine for acute and chronic postoperative pain after laparoscopic cholecystectomy in a randomized controlled experiment. The study involved 50 individuals who had a laparoscopic cholecystectomy under general anesthesia. All the patients were separated into two equal groups. The ketamine and control groups were given 0.5 mg/kg ketamine and 2 mL of normal saline, respectively, at 15 minutes before incision. Patients in the ketamine group had a significantly lower numeric pain rating scale score at 0 minutes than those in the control group. The numeric pain rating scale score of the ketamine group was considerably greater than the control group after a half-hour interval. At other time periods, there was no significant difference in numeric pain rating scale scores between the two groups. The ketamine group had a greater duration of analgesia and sedation score than the control group. The cumulative tramadol demand at 24 hours and the incidence of chronic pain did not differ significantly across the groups. Substantial analgesic effect of intravenous ketamine lasted only up to 30 min postoperatively. There was no discernible effect in terms of chronic pain prevention.

INTRODUCTION

Despite the fact that laparoscopic cholecystectomy (LC) is associated with decreased discomfort and impairment, 17–41% of patients experience significant pain in the postoperative period,1 and 3.4–7% of patients have persistent pain.2 As an adjuvant to multimodal analgesia, preemptive analgesia has been proven to improve analgesic efficacy and reduce the overall analgesic requirement.3 It has a protective impact on the nociceptive system, which means it not only relieves surgical pain but also prevents chronic pain from developing.4 Preemptive analgesia is usually achieved with ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist. It operates by affecting central sensitization and neural modulation. Although it is routinely used in a variety of procedures, there is no conclusive evidence that it is useful in LC.56 Its dosage and administration technique are also not well defined. Traditionally, ketamine has been used as a single low-dosage bolus or as a bolus followed by infusion. The adverse effects generally associated with ketamine infusion have been observed to be absent in a single bolus dose.7

The current research seeks to explore the preemptive analgesic efficacy of intravenous (IV) ketamine in a single bolus dosage of 0.5 mg/kg and its role in the prevention of acute and chronic pain in LC which is a brief and minimally invasive operation.

SUBJECTS AND METHODS

This was a prospective, randomized, triple-blind study undertaken in a tertiary care hospital's anesthesia department. On June 24, 2016, the Institutional Ethics Committee of the School of Medical Sciences & Research and Sharda Hospital, Sharda University, Greater Noida (approval No. IEC/2016/76-A/04) granted ethical approval for the study (), and it was registered with the Clinical Trial Registry – India (No. REF/2021/10/037604). For protocol reporting, this study followed the CONsolidated Standards Of Reporting Trials (CONSORT) declaration ().

Study Population

The study included 50 patients undergoing elective LC under general anesthesia of Grade I or II (American Society of Anesthesiologists).8 Patients ranged in age from 20 to 60 years old and were of either sex. All of the patients gave written informed consent () after counselling. Numeric pain rating scale (NRS), was used for pain assessment postoperatively.9 Patients were instructed about the NRS, with 0 representing no pain and 10 being the most severe pain imaginable before surgery. Choledocholithiasis, acute pancreatitis, current opiate usage, pregnancy, difficulty to interpret NRS, and conversion of LC to open cholecystectomy were all criteria for exclusion.

The lead investigator used a computer-generated random number technique to randomize the patients. The patients were divided into two groups (n = 25 per group): control and ketamine groups. Allocation sequence concealment was done by putting the group allocated in a sealed envelope. After a patient was transferred to the operating room, the envelope was opened by an anesthesiologist who did not participate in the study and the medication solution was prepared accordingly. The patient, attending anesthesiologist, and the nurse who recorded the postoperative data were all blinded to the grouping information in the study.

Anesthetic protocol

Patients were given standardized premedication with IV injections of midazolam (0.025 mg/kg; CelonLabs Pvt. Ltd., Telangana, India), fentanyl (2 g/kg; Verve Healthcare Ltd., Dehradun, India), and ondansetron (0.1 mg/kg; Cipla Ltd., Hyderabad, India) after fasting for eight hours. Patients in the control group received 2 mL of normal saline, while those in the ketamine group received 0.5 mg/kg ketamine (Baxter Pharmaceuticals India Pvt. Ltd., Ahmedabad, India) diluted to 2 mL intravenously 15 minutes before surgery.

2 mg/kg IV propofol (Neon Labs Ltd., Mumbai, India) was used to induce general anesthesia, and 0.1 mg/kg IV vecuronium bromide was used to establish muscular relaxation (Celon labs Pvt. Ltd.). The patient was intubated and anesthesia was maintained with 0.8–1% isoflurane in a mixture of oxygen and nitrous oxide (Triokaa Pharmaceuticals Ltd., Ahmedabad, India). During surgery, the minimum alveolar concentrations of isoflurane and propofol were monitored.

During operation, the intraabdominal pressure was kept below 1.176 kPa. Non-invasive monitoring was used to record hemodynamic data (mean arterial pressure and heart rate) every 5 minutes. During surgery, all patients received 1.5 mg/kg IV diclofenac sodium (Daffodils Pharma Centinal Ltd., Jawahar Nagar, India) as an analgesic. It was repeated at 8 and 16 hours after surgery.

Isoflurane and nitrous oxide were terminated at the end of surgery, and neuromuscular blockade was reversed with a mixture of neostigmine (0.04 mg/kg; Neon Labs Ltd.) and glycopyrrolate (0.01 mg/kg; Neon Labs Ltd.) before the patient was extubated. The patients were then moved to the recovery area. For data recording purposes, 0 minutes was taken as the time when the patient was received by nursing staff in postoperative recovery area.

Data collection

The nursing staff used NRS to record pain scores at 0, 30 minutes, 1, 2, 4, 6, 8, 12, and 24 hours after surgery, or whenever the patient complained of pain. Sedation scores (1 = alert, 2 = asleep, alert after arousal, 3 = sleeping, sleepy after arousal, 4 = asleep, difficult to arouse, and 5 = unarousable) were also recorded at the same interval.10 When the patient's pain was equal to or greater than NRS 4, an IV injection of tramadol (2 mg/kg; Magnet Labs Pvt Ltd., New Delhi, India) was given as a rescue analgesic. The time interval between 0 and the first need for a rescue analgesic was recorded and referred to as the duration of analgesia (DOA). Ketamine side effects such as hallucination, nausea, and vomiting were identified and noted. Chronic pain was defined as the pain which developed after LC, lasted at least for 2 months and other possible causes of pain such as chronic infection and malignancy were excluded.11 Patients were contacted on phone every 15 days for any residual pain, up to 6 months after surgery, to document chronic discomfort.

The primary goal was to see if 0.5 mg/kg ketamine had a preemptive analgesic effect in individuals undergoing LC. As secondary outcomes, sedation score, DOA, cumulative requirement of rescue analgesic (tramadol), incidence of side effects in 24 hours postoperatively and occurrence of chronic pain in both the groups were assessed and recorded.

Sample size calculation

We conducted a pilot study in 7 patients and calculated that 23 cases in each group were required for the study with a significance of 0.05 and a power of 90% (AI-Therapy Statistics BETA, https://www.ai-therapy.com/psychology-statistics). To account for any dropouts, each group was given a total of 25 patients.

Statistical analysis

The Statistical Package for the Social Sciences (SPSS) for Windows version 20.0 was used to analyze the data (IBM, Armonk, NY, USA). The number of patients or the mean standard deviation (SD) was used to record the data. Student's t-test was used to compare demographic data, surgery duration, NRS score, DOA, and cumulative rescue analgesic demand between groups. To investigate disparities in categorical data, the Chi-square test was used. P values of ≤ 0.05 were considered significant. The biostatistician from Vardhman Mahavir Medical College, Safdarjung Hospital reviewed the statistical methodologies used in this work.

RESULTS

From July 14, 2016 to September 9, 2017, 50 patients were enrolled in the trial. In all the cases LC was successfully completed and no patient was lost to follow-up ().

Consort flow diagram.

Patient characteristics

Both groups had similar demographic profiles in terms of age, weight, and sex distribution, as well as operation length (). The intraoperative hemodynamic characteristics (mean arterial pressure and heart rate) were also comparable between groups (). In both groups, propofol during induction and the minimal alveolar concentration of isoflurane throughout operation were comparable (). Both groups of patients were given the same intraoperative analgesics (fentanyl 2 g/kg and diclofenac sodium 1.5 mg/kg).

Changes in mean arterial pressure and heart rate during surgery in both groups.

Note: Data are expressed as mean (n = 25) and were analyzed by Student's t-test. Gr. K.: Ketamine group; Gr. S.: control group; HR: heart ratio; MAP: mean arterial pressure.

Comparison of analgesia

Patients in the ketamine group had a significantly lower NRS score at extubation than those in the control group (P = 0.000; ). Patients in the control group received rescue analgesia as soon as they arrived in the recovery area. As a result, the NRS score of the ketamine group was considerably greater than the control group at the half-hour interval. Also, about 30 minutes after surgery, the majority of the patients in the ketamine group complained of pain with NRS ≥ 4, necessitating the use of a rescue analgesic. At all other time periods, there was no significant difference in NRS score between the two groups.

The patients in the ketamine group had a longer DOA than the patients in the control group (P = 0.000). There was a significant difference in the sedation scores between both groups at 0 minutes (P = 0.000). Sedation scores were comparable in both groups at 30 minutes onwards. Cumulative requirement of tramadol in 24 hours postoperatively was comparable in both groups ().

Comparison of side effects

None of the patients reported hallucinations in any of the groups. Incidences of nausea and vomiting were also comparable in both groups (). There were no complications or unintended side effects of ketamine in the study.

Comparison of chronic pain

Number of patients reporting pain 15, 30 and 45 days postoperatively was comparable in both groups. None of the patients complained of pain 60 days postoperatively till the last follow-up at 6 months. There were no dropouts ().

DISCUSSION

Postoperative pain management is critical for surgery patients to have a better recovery. Free nerve endings in peripheral nerves called nociceptors detect pain signals from injured tissues. Myelinated A delta nociceptors cause a sudden sharp pain response known as “first pain,” whereas unmyelinated C nociceptors cause a longer delayed reaction known as “second pain.” Excessive firing of C fibers before and after surgery produces the production of excitatory amino acids such as aspartate, glutamate, and substance P. These chemicals bind to the NMDA and 2-amino-3 hydroxyl-5-methyl-4 isoxazole propionic acid receptors.12 Inflammatory and neuropathic pains are exacerbated by NMDA receptor activation, which leads to secondary hyperalgesia. The activation of NMDA receptors causes translational alterations in second order neurons, which may be the cause of chronic pain.4 Preemptive analgesia is a treatment that begins before painful stimuli and continues during the surgical procedure to minimize the physiological effects of nociception. As a result, immediate postoperative pain may be decreased, and chronic pain development may be avoided.13

Opioids, NMDA receptor antagonists, nonsteroidal anti-inflammatory medications, local anesthetics, and gabapentin are now used for preemptive analgesia.14 Ketamine is the best studied NMDA receptor antagonist among them.

Ketamine has been used as a preemptive analgesic in LC as a single low-dose bolus or as an infusion along with the bolus dosage.7131516171819 When given as a bolus, low dosage IV ketamine is defined as a dose of no more than 1 mg/kg.20 Because of its high affinity for NMDA receptors, even at low dosages, ketamine is thought to reduce central sensitization.21 Because LC is a relatively brief, minimally invasive procedure, a single bolus low dosage of ketamine was employed to alleviate postoperative pain in the current study. In LC, Morro et al.17 and Kotsovolis et al.16 utilized 0.4 mg/kg and 0.3 mg/kg ketamine bolus, respectively, and observed no benefit in postoperative analgesia. Launo et al.15 and Singh et al.7 found that 0.7 mg/kg ketamine had positive effects, but also reported a significant increase in unfavorable effects. We utilized 0.5 mg/kg IV ketamine based on the findings of Singh et al.7 and Wang et al.13 who exhibited a strong preemptive analgesic benefit with no side effects at a similar dosage for acute pain following LC. We investigated the effects of the same dose on acute and chronic pain following LC.

Although the NRS score in the ketamine group was much lower than that in the control group at extubation, all of the patients in the ketamine group required rescue analgesia within 30 minutes postoperatively. This brief DOA could be the result of a single tiny bolus of ketamine.17 To demonstrate postoperative analgesic effects of ketamine, a higher dose may be required, but the risk of side effects may limit its use.15 With an IV ketamine dose of 0.7 mg/kg, Launo et al.15 found a DOA of nearly one hour with substantial side effects. Singh et al.,7 on the other hand, reported a DOA of 1.98 hours with 0.5 mg/kg ketamine, with no significant difference in DOA between 1, 0.75 and 0.5 mg/kg ketamine.

It is also likely that, for ketamine to be effective as a pre-emptive analgesic, even for minimally invasive procedures like LC, it needs to be given throughout the surgical procedure and for a period of time after surgery, to prevent central and peripheral pain pathways from being sensitized.17 In a meta-analysis, Zhu et al.22 found that IV ketamine infusion combined with a pre-operative bolus dose significantly lowers post-operative pain scores and opioid usage in LC patients. Patients in the control group got alert at zero minutes, while those in the ketamine group became alert after 30 minutes. No other study has evaluated the level of sedation. Despite the fact that Singh et al.7 and Wang et al.13 observed a considerable reduction in opioid demand in just 24 hours, we discovered no significant change in opioid requirement in both groups, even when the dosages were the same.

At different time intervals, there was no significant difference in the incidence of chronic pain in both groups. Both groups of patients were pain-free two months after surgery, with no recurrence until the final follow-up at six months. Following LC, Bisgard et al.23 found chronic pain in 18 of 150 patients, concluding that the incidence of chronic pain is highly related to the intensity of acute pain. Low levels of acute pain were found to be associated with a lower incidence of chronic pain in our study. In this context, no previous research has looked into the influence of low-dose ketamine on the occurrence of chronic pain.

The limitation of our study was that we did not explore the analgesic effect on dynamic pain. To assess the adequate analgesic efficacy of IV ketamine and its side effects, future investigations using high-quality randomized control trials with large sample sizes comparing different dosages and administration strategies (bolus versus infusion) are required.

In conclusion, IV ketamine in single bolus dose of 0.5 mg/kg showed significant analgesic effect lasting only up to half an hour postoperatively. There was no significant chronic pain after LC.

Additional files

: Hospital ethics approval.

: CONSORT checklist.

: Informed consent form.

FORM OF INFORMED CONSENT

Additional file 2

CONSORT 2010 checklist of information to include when reporting a randomised trial*

Section/Topic	Item No	Checklist item	Reported on page No
Title and abstract
	1a	Identification as a randomised trial in the title	1
	1b	Structured summary of trial design, methods, results, and conclusions(for specific guidance see CONSORT for abstracts)	1
Introduction
Background and objectives	2a	Scientific background and explanation of rationale	2
	2b	Specific objectives or hypotheses	2
Methods
Trial design	3a	Description of trial design (such as parallel, factorial) including allocation ratio	2
	3b	Important changes to methods after trial commencement (such as eligibility criteria), with reasons	NA
Participants	4a	Eligibility criteria for participants	2
	4b	Settings and locations where the data were collected	2
Interventions	5	The interventions for each group with sufficient details to allow replication, including how and when they were actually administered	3
Outcomes	6a	Completely defined pre-specified primary and secondary outcome measures, including how and when they were assessed	4
	6b	Any changes to trial outcomes after the trial commenced,with reasons	NA
Sample size	7a	How sample size was determined	4
	7b	When applicable, explanation of any interimanalyses and stopping guidelines	NA
Randomisation:
Sequencegeneration	8a	Method used to generate the random allocation sequence	2
	8b	Type of randomisation; details of any restriction (such asblocking and block size)	2
Allocationconcealmentmechanism	9	Mechanism used to implement the random allocationsequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned	2
Implementation	10	Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions	2
Blinding	11a	If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how	3
	11b	If relevant, description of the similarity of interventions	NA
Statisticalmethods	12a	Statistical methods used to compare groups for primary and secondary outcomes	4
	12b	Methods for additional analyses, such as subgroup analyses and adjusted analyses	4
Results
Participant flow (a diagram is strongly recommended)	13a	For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analysed for the primary outcome	4
	13b	For each group, losses and exclusions after randomisation,together with reasons	4
Recruitment	14a	Datesdefining the periods of recruitment and follow-up	4
	14b	Why the trial ended or was stopped	NA
Baseline data	15	A table showing baseline demographic and clinical characteristics for each group	5
Numbers analysed	16	For each group, number of participants (denominator)included in each analysis and whether the analysis was by original assigned groups	5,6,7
Outcomes and estimation	17a	For each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95%confidence interval)	5,6,7
	17b	For binary outcomes, presentation of both absolute and relative effect sizes is recommended	-
Ancillary analyses	18	Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing pre-specified from exploratory	NA
Harms	19	All important harms or unintended effects in each group(for specific guidance see CONSORT for harms)	7
Discussion
Limitations	20	Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses	9
Generalisability	21	Generalisability (external validity, applicability) of the trial findings	9
Interpretation	22	Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence	8,9
Other information
Registration	23	Registration number and name of trial registry	2
Protocol	24	Where the full trial protocol can be accessed, if available	10
Funding	25	Sources of funding and other support (such as supply of drugs),role of funders	9

*We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and Elaboration for important clarifications on all the items. If relevant, we also recommend reading CONSORT extensions for cluster randomised trials, non-inferiority and equivalence trials, non-pharmacological treatments, herbal interventions, and pragmatic trials. Additional extensions are forthcoming: for those and for up to date references relevant to this checklist, see .

Table 1

Demographic and operative characteristics of the patients after laparoscopic cholecystectom

	Control (n=25)	Ketamine (n=25)	P-value
Age (yr)	37.64±15.22	33.44±10.84	0.737
Sex (male/female)	10/15	11/14	–
Weight (kg)	55.16±8.92	56.04±9.49	0.798
Duration of surgery (min)	57.96±7.46	52.96±15.62	0.155
Propofol requirement (mg)	108.73±14.52	107.73±16.65	0.76
Minimum alveolar	0.90±0.07	0.93±0.07	0.7
concentration of isoflurane

Note: Data are expressed as mean ± SD (n = 25) and were analyzed by Student’s t-test, except sex.

Table 2

Duration of analgesia, tramadol requirement and NRS at different time intervals in patients after laparoscopic cholecystectomy

	Control (n=25)	Ketamine (n=25)	P-value
Duration of analgesia (min)	1.76±2.047	16.58±6.57	0
NRS
0 min	3.76±0.97	1.68±0.69	0
30 min	1.48±0.65	3.96±0.79	0
1 h	1.04±0.68	1.44±0.77	0.056
2 h	1.08±0.70	1.40±0.76	0.13
4 h	1.20±0.76	1.44±0.82	0.29
6 h	1.60±1.19	1.76±1.09	0.623
8 h	1.76±1.36	2.28±1.34	0.18
12 h	1.60±1.26	2.04±1.17	0.207
24 h	1.12±0.67	1.44±0.82	0.137
Cumulative requirement of tramadol in 24 h (mg)	150.00±51.08	132.00±7.61	0.208
Sedation scorea
Extubation	1.08±0.28	3.04±0.61	0
30 min	1.00±0.00	1.12±0.33	0.07
1 h	1.00±0.00	1.00±0.00	–
Chronic pain
15 d	1.44±1.83	1.44±1.73	1
30 d	0.72±1.46	0.52±1.05	0.58
45 d	0.12±0.44	0.12±0.60	1
60 d	0.00±0.00	0.00±0.00	–

Note: Data are expressed as mean ± SD and were analyzed by Student’s t-test.

Table 3

Incidence of hallucination and nausea/vomiting in patients after laparoscopic cholecystectomy

	Control (n=25)	Ketamine (n=25)	P-value
Hallucination	0	0	–
Nausea/vomiting	5	5	0.905

Note: Data are expressed as number and were analyzed by Chi-square test.

Table 4

Incidence of chronic pain in patients after laparoscopic cholecystectomy

Time point	Control (n=25)	Ketamine (n=25)	P-value
15 d	8(32)	7(28)	0.757
30 d	6(24)	6(24)	1.000
45 d	4(16)	3(12)	0.683
60 d	0	0	–

Note: Data are expressed as number (percentage) and were analyzed by Chisquare test.