Abstract

Objectives

Dexamethasone has demonstrated analgesic properties and is used as an adjunctive pain agent for many procedures. We evaluated the efficacy of a single, intermediate dose of dexamethasone on post-operative analgesic consumption, and pain scores for lumbar spine surgery.

Methods

Eighty patients aged between 18 and 70 scheduled for lumbar decompressive laminectomy were randomly allocated into two groups to receive either intravenous 0.2 mg/kg dexamethasone (group D = 40) or normal saline (group P = 40) before anesthetic induction. Post-operative total morphine consumption and the respective pain score at the PACU, 4, 6, 12, 24 and 48 h were evaluated. In addition, any adverse events were recorded.

Results

Total post-operative morphine consumption within 48 h was significantly lower in group D (34.5 vs. 42.5 mg, p = 0.031); however, the respective morphine consumption at each assessment was similar between groups. The respective NRS pain score at rest and upon movement in both groups was not significantly different for any time comparison. The average NRS pain score at rest and upon movement within 48 h was similar in both groups (i.e., NRS at rest Group D 3.6 vs. Group P 3.8, p = 0.936, and NRS for movement Group D 6.2 vs. Group P 6.3, p = 0.791). The adverse events within 48 h were also similar and serious complications (i.e., respiratory depression or surgical infection) were not found in either group.

Conclusion

A single, intermediate dose of dexamethasone before anesthetic induction could minimally decrease post-operative morphine consumption within 48 h after lumbar decompressive laminectomy without any effect on the pain score.

Keywords

Analgesic effect; Decompressive laminectomy; Dexamethasone; Postoperative pain; Spine surgery;

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1. Introduction

Spine surgery is a major orthopedic procedure, often resulting in severe acute post-operative pain, which is challenging to manage.^1–3 Inadequate pain control can lead to several poor outcomes, including lung atelectasis, pneumonia, delayed ambulation, and prolonged hospital stay.^3,4 An increase in catecholamine and cortisol levels can, moreover, cause cardiac ischemia and suppress the immune system, especially among the critically ill and elderly.² Improper acute pain management is also associated with the development of chronic pain, which is more difficult to treat, thus eroding quality of life.¹

Opioids are effective and potent analgesics; however, various side effects occur when high doses of opioids are used (i.e., nausea, vomiting, itching, gastrointestinal and bladder dysfunction, drowsiness, and respiratory depression).⁵

There is currently no consensus on the best techniques for the management post-operative pain; however, a multimodal analgesia approach using a combination of analgesic agents could improve the efficacy of pain control while reducing post-operative opioid consumption and their common and dangerous side effects.^3,4,6

A previous meta-analysis revealed that an intermediate dose (0.1–0.2 mg/kg) of dexamethasone significantly decreases post-operative opioid consumption and pain scores for many surgical procedures (e.g., breast, thyroid, and laparoscopic surgery).⁷After conducting various minor and major orthopedic procedures, glucocorticoids (i.e., betamethasone, methylprednisolone, and dexamethasone) have had an observable analgesic effect^8–13; however, there have been only few studies on the effect of dexamethasone on spine surgery and the direct analgesic effect of an intermediate dose of dexamethasone on spine surgery has yet to be evaluated.

We hypothesized that a single, intermediate dose of dexamethasone would ameliorate the post-operative analgesic effect after spine surgery in terms of decreased post-operative opioid consumption and pain score.

2. Methods

This controlled, randomized, triple blind study was approved by our Institutional Review Board and was conducted in accordance with Good Clinical Practices and the Declaration of Helsinki. The study was registered at www.clinicaltrials.in.th (No. TCTR20160830001). We followed the CONSORT recommendations for reporting randomized, controlled clinical trials (Fig. 1).

After obtaining written informed consent from all participants, we enrolled 90 patients of either sex, between 18 and 70 years of age. We included participants who (a) had an ASA physical status of between 1 and 3; (b) were scheduled for elective lumbar spine decompressive laminectomy under general anesthesia; and, (c) could operate a patient-controlled analgesic (PCA) device. We excluded patients who (a) had undergone more than three levels of laminectomy; (b) had any known allergy or contraindication to dexamethasone; (c) had received chronic steroid or opioids; or, (d) had severe hepatic or renal impairment, previous lumbar spine surgery, pregnancy or lactation, and diabetic mellitus.

All participants were instructed how to assess pain using a numeric rating scale pain score (NRS), ranging from 0 = no pain to 10 = the worst possible pain, and on how to operate a PCA device.

The patients were randomized into 2 groups: the dexamethasone group (Group D = 40 patients) and the placebo group (Group P = 40 patients), using block of four randomization with a computer generated random number (http://www.randomizer.org/). The sequential random number code was enclosed in a sealed opaque envelope. To ensure blinding, we (a) assigned a nurse not involved in the process of patient evaluation to prepare the study drug solution according to the code and kept the randomization code confidential until the data were analyzed; and, (b) masked all patients, physicians, and data recorders to the group allocation.

The study drug for both groups was prepared and appeared to be the same clear solution. For group D, we prepared dexamethasone (Lordexa^® L.B.S. Laboratory LTD. Bangkok, Thailand) 0.2 mg/kg, mixed in normal saline (0.9%) to a final volume of 5 mL. Normal saline (0.9%) was used to prepare the placebo for group P.

In the operating room, all patients were monitored as per standard general anesthesia, including electrocardiogram, non-invasive blood pressure, pulse oximetry, and end-tidal partial pressure of carbon dioxide (EtCO₂). Before induction, the study drug solution was injected. The anesthetic techniques were standardized in all groups. Anesthesia was induced with propofol (2 mg/kg) and fentanyl (1.5 μg/kg). Orotracheal intubation was facilitated with cisatracurium 0.2 mg/kg. Maintenance of anesthesia was done with sevoflurane in a mixture of 60% nitrous oxide and 40% oxygen, and 0.5 μg/kg of fentanyl as needed. No other analgesic drugs were administered within 48 h after surgery.

The surgery was performed using standardized surgical techniques among the 3 experienced spinal surgeons. After the surgery, all of the patients were evaluated and extubated as soon as they met the criteria and morphine sulphate 2 mg was given intravenously before they left the operating room.

Upon arrival at the post anesthetic care unit (PACU), all of the patients received the same post-operative pain control protocol. PCA devices were provided and discontinued 48 h after surgery. Fifty milliliters of PCA solution containing 1 mg/mL morphine was prepared and programmed as 1 mg per dose. The lockout interval was 5 min, with a 1-h limit of 10 mg.

The primary outcome was post-operative morphine consumption from the PCA device at the PACU, 4, 6, 12, 24 and 48 h. The secondary outcomes were the post-operative NRS pain score at rest and upon movement. We also recorded any adverse events, including respiratory depression (respiratory rate < 8 breaths/min), sedation, nausea, vomiting and surgical site infection. Respiratory depression and surgical site infection were recorded as ‘Yes’ or ‘No’. Sedation was scored: 0 = fully conscious, 1 = mild sedation, 2 = marked sedation, 3 = cannot wake-up. Nausea and vomiting were scored as 0 = no symptoms, 1 = mild, 2 = need treatment, and 3 = need treatment more than once.

The statistical analysis was based on a repeated measures design with each subject being measured 6 times. According to previous study,¹⁴ a sample size of at least 35 patients in each group was required to have 80% power for detecting a 15 mg difference in morphine consumption (α = 0.05) for a two-sided comparison test. To compensate for possible patient drop-outs, we planned to recruit 80 patients.

Demographic variables were presented as means and standard deviations for continuous parametric data and medians with ranges for the nonparametric data. Categorical variables were reported as proportions. All continuous variables were tested for normality using a normal q–q plot.

The respective total morphine consumption and pain score between groups was compared at each time point, using the Student t-test or the Mann–Whitney Ustatistics as appropriate. Repeated measures analysis of variance using the generalized estimating equation model was used to account for correlations among observations from the same subject over time with respect to morphine doses and pain scores.

The end-point data were analyzed on an intention-to-treat basis using STATA version 10.0 software (Stata, Collage Station, TX).

3. Results

Ninety patients met the eligibility criteria, but 7 refused to participate, 2 others were taking NSAIDs intraoperatively, and 1 had the operation cancelled. Thus, 80 patients were enrolled and randomized into 2 groups; 40 to the dexamethasone group (D) and 40 to the placebo group (P). All of the participants were followed up and assessed on an intention-to-treat basis (Fig. 1). The baseline characteristics and surgical data were summarized and there was no significant difference between groups (Table 1).

Post-operative total morphine consumption was lower in group D for all 6 time assessments but without any statistically significant differences among times (Table 2). Cumulative morphine consumption within 48 h in group D was significantly lower than group P (34.5 vs. 42.5 mg, mean difference = 8.0, p value = 0.031) (Table 3).

There were no significant differences among times between the two groups in terms of NRS pain score at rest or upon movement (Table 2). The respective average NRS pain score at rest or upon movement within 48 h between groups was also not significantly different (Table 3). Adverse events within 48 h were also similar and serious complications (viz., respiratory depression and surgical site infection) were not found in either group (Table 4).

4. Discussion

Our results demonstrated the analgesic effect of intermediate-dose dexamethasone on spinal surgery in terms of decreasing 48-h post-operative morphine consumption, this result corresponds with many previous studies.^{11,12,15–21}; however, based on the overall evaluation within 48 h, there was only an 18.8% mean reduction in morphine consumption, which is a modest reduction of clinically relevant factors (Table 3).

We did not observe any significant difference between groups in the NRS pain score whether at rest or upon movement perhaps because post-operative pain management was provided by intravenous morphine via the PCA technique, which allows the patient to operate and receive the optimal dose of morphine to make them feel comfortable. A similar result was previously reported in two other studies.^17,20

The analgesic mechanism of action of dexamethasone could be that it (a) causes inhibition of production of inflammatory mediators (i.e., prostaglandin and bradykinin), (b) prevents reduction in the “pain threshold” that can occur because of surgery, (c) reduces tissue swelling because of anti-inflammatory effects, and (d) inhibits nerve compression by inflammatory tissue.^15,22–24

A meta-analysis demonstrated, intermediate- to high-dose dexamethasone has an implicit analgesic efficacy in various procedures whereas a low dose has only an anti-emesis effect.⁷ The analgesic effect for a major procedure, however, remains uncertain. According to a systematic review by Holte and Kehlet,²⁴ an analgesic effect was not observed in major abdominal surgery after glucocorticoid administration whereas for many less extended surgeries, especially dental procedures, substantially reduced postoperative pain was achieved.

Liu et al.¹⁵ similarly reported that 10 mg dexamethasone given intravenously during induction in major gynecological surgery provided only minimal pain reduction. Lee et al.²⁵ studied major orthopedic surgery including corrective spinal surgery, hip arthroplasty, and knee arthroplasty and did not find any effect of dexamethasone on pain intensity or postoperative morphine consumption. A systematic review and meta-analysis by Waldron et al.²⁶ including 5796 patients given 1.25–20 mg dexamethasone in a single-dose intravenously showed a small analgesic effect of dexamethasone on pain score and opioid consumption. Taken together, we hypothesized that dexamethasone might only be beneficial for less extensive procedures and have a relatively small influence on extensive and invasive procedures. Thus there would be a relatively small analgesic effect of dexamethasone on major procedures such as spine surgery as in our study.

The timing of dexamethasone administration might be another important issue. In the current study, we administered dexamethasone before anesthetic induction based on the two previous clinical trials. Jokela et al.¹⁷ and Bagchi et al.²⁷ demonstrated that dexamethasone administered just before induction can reduce pain intensity during tonsillectomy and laparoscopic hysterectomy. Some studies, however, debate this. For example, Waldron et al.²⁶ demonstrated that pre-operative rather than intra-operative administration of dexamethasone was more effective in reducing 24 h pain scores. Similarly, Thue et al.¹⁹ and Holte and Kehlet²⁴ suggested that dexamethasone should be administered earlier than just before induction to gain the maximal effect.

Glucocorticoids must diffuse across the cell membrane in order to alter gene transcription and protein synthesis. This process takes 1–2 h, hence the onset time of dexamethasone.^23,28 Relatedly, the activation of early mediators of the metabolic response to injury occur immediately after the surgical incision, so administration of dexamethasone should be at least 1 h before surgery to achieve the maximal effect of the drug and to minimize pain and inflammation. In our study, dexamethasone was injected just before anesthetic induction (usually 30–40 min before skin incision) which may have been too late to achieve the maximal effect of dexamethasone, which would explain the relatively small analgesic effect of dexamethasone in our study.

We confirmed the safety of single, intermediate-dose dexamethasone as per previous studies^7,17–20,29; whereas Waldron²⁶ found an increase in blood sugar compared to the control group without any correlation to surgical wound infection. Knowing this, we excluded diabetics to ensure patient safety.

We did not observe any differences between groups in the incidence of PONV and sedation; however, the PONV and sedation scores were higher in the placebo group, corresponding to a higher dose of total morphine consumption as used by the placebo group (Table 4).

The strength of our study is that this is the first triple-blinded, clinical trial to evaluate intermediate-dose dexamethasone for its analgesic effect on spine surgery. We, however, only investigated single-dose and single time administration of dexamethasone. Future studies should focus on different administration time points and different doses.

In conclusion, single, intravenous, intermediate dose dexamethasone before induction provided a modest decrease in post-operative morphine consumption within 48 h of lumbar decompressive laminectomy. Serious side effects were not observed.

Conflicts of interest

All contributing authors have no conflicts of interest to declare.

Acknowledgements

The authors thank (a) Dr. Jitjira Chaiyarit, statistician from the Clinical Epidemiology Unit, Faculty of Medicine, Khon Kaen University for the statistical analysis; and (b) Mr. Bryan Roderick Hamman for assistance with the English-language presentation of the manuscript under the aegis of the Publication Clinic, Research Affairs, Faculty of Medicine, Khon Kaen University.