Role of gabapentinoids in post-operative pain management in thoracic surgeries: A single-centre propensity score-matched audit

ABSTRACT

Background and Aims:

The analgesic role of gabapentinoids following thoracic surgeries is not clear. In this study, we evaluated the benefits of gabapentinoids for pain management in patients undergoing thoracic onco-surgery in terms of opioids and non-steroidal anti-inflammatory drugs (NSAIDs) sparing effect. We also compared pain scores (PSs), number of days of active surveillance by the acute pain service team, and side effects associated with gabapentinoids.

Methods:

After ethics-committee approval, data were retrieved retrospectively from clinical sheets, an electronic database, and nurses’ charts from a tertiary cancer care hospital. Propensity score matching was performed for six covariates, that is, age, gender, American Society of Anesthesiologists grading, surgical approach, analgesia modality, and worst PS in the first 24 hours performed. A total of 272 patients were grouped into group N (not given gabapentinoids, n = 174) and group Y (given, n = 98).

Results:

The median opioid consumption in terms of fentanyl equivalent by group N was 800 µg [inter-quartile range (IQR): 280–900], and the median opioid consumption by group Y was 400 µg (IQR: 100–690) (p = 0.001). The median number of rescue doses of NSAIDs administered to group N was 8 (IQR = 4–10), and the median number of rescue doses to group Y was 3 (IQR = 2–5) (p = 0.001). No difference was found in subsequent PS and for the number of days under acute pain service surveillance for either group. Group Y had an increased incidence of giddiness compared to group N (p = 0.006), with a relative reduction in post-operative nausea and vomiting scores (p = 0.32).

Conclusion:

Gabapentinoids used following thoracic onco-surgeries result in a significant reduction in concomitant use of NSAIDs and opioids. There is an increased incidence of dizziness with the use of these drugs.

INTRODUCTION

Thoracotomy is associated with high pain scores (PSs) in the post-operative period and demands vigorous pain management.[1] Ineffective pain relief impedes deep breathing, coughing, and mobilisation, culminating in atelectasis and pneumonia. A multi-modal approach aimed at adequate analgesia with minimal side effects is advocated for pain management in thoracic surgeries.[2] The negative effects of opioids on feeding and bowel movements are known. Analgesic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to reduce the need for opioids in post-operative management.[3] However, multiple pathways for the mechanism of action of NSAIDs make them prone to undesirable adverse effects such as renal dysfunction, delayed wound healing, and increased risk of bleeding.[4] Surgical trauma causes stimulation of nociceptive receptors. Gabapentinoids (pregabalin, gabapentin) attenuate this central sensitisation of nociceptive receptors and decrease the dorsal horn neuron hyper-excitability caused by the surgical trauma. Therefore, gabapentinoids have been recommended for peri-operative usage to improve acute pain after surgery.

In our hospital, patients posted for thoracic surgeries receive pregabalin 75 mg oral in the morning of surgery, but gabapentinoids are not routinely continued in the post-operative period, given their possible side effects.[5] A few patients, based on treating pain physician preferences, are started early on gabapentinoids in addition to opioids and NSAIDs as a part of multi-modal management. The literature suggests the harmful effects of NSAIDs and opioids, and hence, the early addition of gabapentinoids may be a suitable component of multi-modal analgesia after thoracic surgeries. The primary aim of this retrospective audit was to determine the analgesic efficacy (defined as the need for concurrent administration of NSAIDs and opioids) of gabapentinoids following thoracic onco-surgeries in the immediate post-operative period (96 hours). The study also compares the pain scores, incidence of side effects, and post-operative nausea and vomiting (PONV) between patients who received and did not receive gabapentinoids in the post-operative period.

METHODS

This retrospective audit was initiated after ethics-committee approval (reg.no.ECR/149/inst/MH/2013) from our institute on 13/11/19. In this study, all adult patients (18–80 years) who underwent open or minimally invasive thoracic onco-surgeries (i.e. lung, oesophageal, or mediastinal surgeries) at our tertiary-care cancer centre from January 2018 to June 2019 were included. Patients needing ventilatory support for more than 24 hours post-surgery, re-explorations, inoperable cases following mediastinoscopy, and those with incomplete data sheets were excluded. In our hospital, pain management protocols are initiated during the intra-operative period and all post-operative patients are followed up for pain control by the acute pain service (APS). For open surgeries, epidural analgesia is the gold standard in the absence of contraindication, whereas in minimally invasive procedures, multi-modal analgesia is preferred. All patients receive tablet pregabalin 75 mg in the morning of the scheduled surgery as a standard institution protocol. In the post-operative period, open thoracotomies receive epidural analgesia, and patients undergoing minimal invasive surgeries are started on intravenous opioid-based patient-controlled analgesia (PCA IV) pumps. Paracetamol (500 mg to 1 gm) is administered 6–8 hours orally or intravenously as per feasibility. NSAIDs are the preferred rescue analgesics of choice in the case of inadequate pain relief. The addition of adjuvant analgesics such as gabapentinoids is, however, as per treating pain physician preference. The patients are under active surveillance of the APS till the epidural/regional catheters/PCA IV are removed and pain is controlled by oral/mediations. Inadequate pain control inadvertently leads to longer periods of follow-up by the APS team. In this retrospective audit, patients’ details inclusive of demographics and relevant post-operative parameters were recorded from the APS sheets, electronic medical records (EMRs), operative theatre database, and nurses’ charts. Data included age, gender, surgery offered, surgical approach (minimally invasive or open surgery), and details of post-operative pain management. The primary modality of post-operative pain management was expressed in categories based on the modality of pain relief (i.e., epidural analgesia/PCAIV/epidural analgesia with PCAIV/regional catheters/intercostal blocks/other) [Table 1].

Table 1.

Details of confounders accounted for during propensity matching

Variable (n=272)	Group N (n=174)	Group Y ( n=98)	P
Age (years)
Mean (±sd)	46 (±16)	43 (±17)	0.186
Gender
Male	119	68
Female	55	30	0.865
ASA physical status
ASA I	90	54
ASA II	74	40	0.536
ASA III	10	4
Surgery details
Open lung surgeries	71	37
Open oesophageal surgeries	34	16	0.596
Minimally invasive lung surgeries	31	20
Minimally invasive oesophageal surgery	5	2
Others	24	17
Mediastinal mass surgeries	9	6
Analgesia
Epidural analgesia	116	63	0.692
Epidural analgesia+PCA ( IV)	8	3
PCA (IV)	14	12
Single shot intercostal block	28	14
Others (local anaesthetic drug infiltration/erector-spinae block/paravertebral catheter or single shot block)	8	6
Worst PS: 0-24 hours post-surgery
Mild (PS=1-3)	165	61
Moderate (PS=4-6)	96	35	0.588
Severe (PS=7-10)	11	4

PCA=Patient Controlled Analgesia; PS=Pain Score; ASA=American Society of Anesthesiologists; SD=Standard deviation; IV=Intravenous, n=Number. Group N, Patients not given gabapentinoids., Group Y, patients given gabapentinoids

Based on whether gabapentinoids were added up to 72 hours of surgery, patients were divided into two groups – group Y (those who received gabapentinoids) and group N (those who did not receive gabapentinoids). To negate the influence of confounders, a propensity-matched model was selected and data in both groups were matched for age, gender, American Society of Anesthesiologists (ASA) physical grading, surgical approach, pain management modality, and worst Pain scores (PSs) recorded at end of 24 hours. Because all patients receive paracetamol as a part of pain management protocol, the need for rescue was defined as any other oral or intravenous (IV) analgesic advised, including opioids and NSAIDs. The number of drugs/doses received was recorded. As patients received opioids in different formulations, all different opioid formulations were converted into fentanyl equivalent doses. Because data were matched for pain management techniques, opioids used in epidural analgesia were not included in fentanyl dose calculation. Diclofenac was the NSAID of choice with an occasional prescription of etoricoxib. To account for the variability in the duration of action, a single dose of 24-hour medication was considered equivalent to 3 doses of 8-hourly medications. Worst PS was defined as the maximum PS recorded at movement from 24 hours to 96 hours. The number of days recorded by the pain services was noted. The number of days the APS team followed up with an individual patient was recorded. The instances where gabapentinoids had to be discontinued (probably because of side effects) were also captured. A waiver of written, informed patient consent was approved owing to the retrospective nature of the study. All statistical analyses were performed on Statistical Package for Social Sciences (SPSS) version 25.

RESULTS

A total of 522 patients underwent major thoracic surgical procedures from January 2018 to June 2019. Twelve patients received mechanical ventilation in the post-operative period beyond 24 hours, and hence, their data were not included [Figure 1]. Data of 14 patients were excluded from the study because of inoperability. A total of 496 patients were qualified for propensity matching; data of 272 patients were matched and clubbed into two groups in the ratio of 2:1. Group N (n = 174) included patients who did not receive gabapentinoids, whereas group Y (n = 98) included patients who received gabapentinoids. In group Y, in 44 patients (45%), gabapentinoids were started on post-operative day (POD) 1 evening. The remaining patients received gabapentinoids from POD2 morning till POD3 morning. Eighty-eight out of ninety-eight patients in Group Y were given pregabalin 75 mg once a day, whereas 10 patients received 300 mg gabapentin once a day for up to 5–7 days [Table 1]. The median opioid consumption by the group in terms of fentanyl equivalent by group N was 800 μg [inter-quartile range (IQR): 280–900], and the median opioid consumption by group Y was 400 μg (100–690) (p 0.001) [Figure 2]. The median number of rescue doses of NSAIDs administered in by group N was 8 (IQR = 4–10), and the median number of rescue doses by group Y was 3 (IQR = 2–5) (p = 0.001) [Figure 3]. No difference was seen in the worst PS (24–96 hours period), group N: 3 (IQR: 2–3) versus group Y: 3 (IQR: 2–3), p = 0.85. We found no difference in the median number of days under APS surveillance for both groups, group N: 4 (IQR: 3–4) versus group Y: 4 (IQR: 3–4), p = 0.43. As far as side effects were concerned, seven patients in group Y had dizziness, which resulted in the stoppage of gabapentinoids, whereas only one patient in group N has similar episodes, p = 0.006. Only one patient from group Y had PONV, whereas five patients from group N had PONV, p = 0.32.

Figure 1.

Flow chart of patients’ data analysis. hrs: hours

Figure 2.

BOX PLOT graph showing opioid consumption; X-axis: Group N, patients not given gabapentinoids. Group Y, patients given gabapentinoids. Y-axis: Total opioids consumed calculated as fentanyl equivalents

Figure 3.

BOX PLOT graph showing NSAIDS consumption; X-axis: Group N, patients not given gabapentinoids. Group Y, patients given gabapentinoids. Y-axis: Total NSAIDS consumed calculated as diclofenac equivalents

DISCUSSION

A significant reduction in the use of opioids by 50% and a 63% reduction in the use of NSAIDs were seen with the use of gabapentinoids in the post-operative period in this propensity-matched audit. The benefit of gabapentinoids in the post-operative period has been varied in the literature. In a previous randomised controlled trial, an opioid-sparing effect was seen with the use of gabapentin 1200 mg pre-operatively, followed by 600 mg in the post-operative period.[6,7] The study included patients undergoing ear, orthopaedic, mastectomy, thoracic, and abdominal/pelvic operations. However, a recent systemic review and metanalysis, which compared 281 trials, showed no favourable results for peri-operative usage of gabapentin on PS of post-operative patients.[8] There were no significant effects of gabapentinoids on acute, sub-acute, or chronic pain management in post-operative patients. This included trials with varied patient populations inclusive of patients posted for orthopaedic, cardiothoracic, ear, and spine surgeries. The pain following thoracic surgery is substantial.[9] Hence, we looked at studies exclusively performed in this sub-group. Studies evaluating the role of single doses administered pre-operatively have shown varied results, with a few trials in favour[10,11] and a few with no benefit.[12] Patients who received pregabalin before surgery and were continued on the drug in the post-operative period reported lower pain, reduced opioid consumption, and significantly lower neuropathic pain on follow-up when compared to control groups.[8,13] In our audit, we also found a 50% reduction in opioid consumption in the gabapentinoids group when compared to the control group. The role of NSAIDs in opioid-sparing pain management is proven and has been advocated in enhanced recovery after surgery (ERAS) programmes. With growing evidence of adverse events with the use of NSAIDS, one needs to be cautious with its use in coelomic surgeries.[14] There exists limited evidence on the association between the use of gabapentin and NSAID consumption. A benefit was seen with the use of gabapentin over diclofenac concerning analgesic efficacy and duration of analgesia for chronic pain management after thoracic surgery.[15] We found a positive association in our study, with a reduction of NSAID use in patients who were started on gabapentinoids. This NSAID sparing effect is favourable in the patients undergoing thoracic surgeries fearing the renal adverse effect in fluid-restricted patients.[16,17] Gabapentinoids have the advantage of being devoid of major side effects.[8] Although dizziness and somnolence have been noted in 22–29% population on pregabalin, they are well tolerated.[18] In a meta-analysis review performed with 132 trials by Cochrane standards with Grading of Recommendations, Assessment , Development and Evaluation(GRADE), the assessment showed a risk ratio of 1.61 for serious adverse side effects associated with pregabalin usage in post-operative patients.[19] In our trial, an increased incidence of giddiness was noted in the gabapentinoids group (7%) versus (0.5%)in the control group. The incidence of PONV was less in patients who had received gabapentinoids; this could be explained by the opioid-sparing effect seen in these patients.[20] In our institute, the continuation of pregabalin in the post-operative period, although based on patients’ pain scores, is heavily biased on treating physician preference. To standardise protocols, this audit was planned. This audit is retrospective, and limitations of the same do exist. However, the strength of this study is that we have taken care of confounding factors by using propensity-matched data accounting for important confounders, mainly age, gender, ASA grading, surgical approach, pain management modality, and worst PS (worst scores in the first 24 hours). There remains the possibility that the patients with more severe pain are the ones who received extra analgesics inclusive of the gabapentinoids. Keeping this in mind, we ensured that the two groups were matched on the basis of the worst PS at the end of 24 hours. Also, we had 496 patients who were qualified for propensity matching; the data of 272 patients were matched and clubbed into two groups in the ratio of 2:1 for those who did not receive and those who received gabapentinoids. The results of the propensity matching [Table 1] confirm that the two groups were well matched for confounders. This study is one of the major single institutional data for this cohort. The data included were restricted to the immediate post-operative period (96 hours). The patients were not followed up for long-term benefits. We hope to do the same in a future study. Then the impact of the reduction of opioids on bowel motility and hospital discharge was not assessed in detail. Also, we did not analyse hard endpoints for NSAID use inclusive of alterations in renal function and anastomotic leaks. Finally, there was variation with respect to the dose and preparation of gabapentinoids used. Both the drugs were used in the usual recommended doses in the post-operative period. However, based on this audit, we are unable to comment on the optimum dosing and preparation of gabapentinoids in the post-operative period. Also, the benefits are seen following addition of gabapentinoids as per our study results; their efficacy in terms of actual analgesic effect needs to be established by future prospective, randomised trials.

CONCLUSION

Incorporation of gabapentinoids in the post-operative period has an opioid and NSAID sparing role. However, the associated side effects leading to dizziness cannot be ignored, suggesting limiting the use of these drugs in patients with a high requirement of analgesics.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.