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Postoperative pain

Effects of a single subanaesthetic dose of ketamine on pain and mood after laparoscopic bariatric surgery

A randomised double-blind placebo controlled study

Wang, Jing; Echevarria, Ghislaine C.; Doan, Lisa; Ekasumara, Nydia; Calvino, Steven; Chae, Floria; Martinez, Erik; Robinson, Eric; Cuff, Germaine; Franco, Lola; Muntyan, Igor; Kurian, Marina; Schwack, Bradley F.; Bedrosian, Andrea S.; Fielding, George A.; Ren-Fielding, Christine J.

Author Information
European Journal of Anaesthesiology: January 2019 - Volume 36 - Issue 1 - p 16-24
doi: 10.1097/EJA.0000000000000860
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Abstract

Introduction

Ketamine is an effective analgesic that can be administered pre-operatively, intra-operatively or postoperatively.1–10 Although pre-operative administration of a single bolus dose of ketamine prior to incision has shown mixed results,11–17 its use as a continuous infusion intra-operatively or postoperatively can reduce opioid consumption after surgery.3–10,18–21 Recently, however, ketamine has emerged as a powerful antidepressant and anxiolytic with enduring effects that last a week after a single subanaesthetic dose in the range of 0.3 to 0.5 mg kg−1.22–25 Low doses in this range also have the advantage of ease of administration and a better safety profile than continuous infusion. Acute postoperative pain can lead to depressed mood which further complicates recovery 1 to 2 weeks after surgery.26–30 Thus, mood and pain, especially the affective component of pain, are intimately linked in the postoperative period. Given the data from the field of psychiatry, an intriguing hypothesis is that a single-dose (0.4 mg kg−1) administration of ketamine after surgery may be able to relieve postoperative pain and improve mood, thus facilitating recovery.

Over half a million bariatric procedures are performed annually world-wide for the treatment of obesity,31 with most done laparoscopically.32,33 High levels of postoperative pain remain common in these patients.34,35 In addition, bariatric patients carry a 37 to 45% risk for mood disorders,36,37 and depressed mood is associated with increased pain and poorer postsurgical outcomes.34,37–39 The only study of ketamine in this patient group found that the pre-induction administration of ketamine and clonidine led to decreased pain scores and opioid consumption immediately after surgery.40 However, no studies have examined the use of postoperative ketamine for pain control in bariatric patients, and very few studies have examined the effect of ketamine on postoperative mood.

The aim of this study was to evaluate the antinociceptive effect of ketamine in patients undergoing laparoscopic gastric bypass or gastrectomy. We hypothesised that a single, subanaesthetic dose of ketamine would relieve postoperative pain and improve mood in this patient group.

Methods

We performed a randomised, double-blind, placebo-controlled, two-arm parallel, single-centre study on the effect of a single postoperative dose of ketamine in adults undergoing laparoscopic gastric bypass or gastrectomy. This study was approved by the New York University School of Medicine Institutional Review Board. This trial is registered at ClinicalTrials.gov (Identifier NCT02452060). It was conducted in accordance with the original protocol.

Overall study design

English-speaking patients between the ages of 18 and 65 years who were undergoing laparoscopic gastric bypass or sleeve gastrectomy were eligible for inclusion. Exclusion criteria included American Society of Anesthesiologists physical status greater than III, cognitive impairment, past ketamine misuse or abuse, schizophrenia, use of antipsychotic drugs, known sensitivity or allergy to ketamine, use of medication that interferes with the hepatic metabolism and renal clearance of ketamine, and a history of chest pain, cardiac arrhythmia, stroke, head trauma, or intracranial mass or haemorrhage. Written informed consent was obtained from all participants.

Patients were randomised 1 : 1 to receive either ketamine or placebo using a computer-generated random sequence in blocks of four. The randomisation list was sent to the hospital pharmacy who prepared the study drugs in 50 ml bags with an identical appearance. Study participants, investigators and care providers were blinded to the allocation.

Shortly after admission to the postanaesthesia care unit (PACU), if a participant was considered medically stable by a study physician, intravenous ketamine 0.4 mg kg−1 (by ideal body weight) or 0.9% saline (placebo) was administered at identical volume and rate, over 20 min. This dose was selected in light of data from the field of psychiatry. In practice, ketamine infusion typically began 45 to 60 min after arrival in the PACU.

There were no other alterations in anaesthetic, surgical or postsurgical care. Participants were administered a general anaesthetic with a combination of intravenous and inhalational anaesthetics. Adjunctive regional blocks were not performed. There was no restriction on the use of other analgesics throughout the hospital stay. According to the clinical protocol for postbariatric surgery, all participants received intravenous hydromorphone through a patient-controlled analgesia (PCA) system on arrival in the PACU. PCA was continued until patients were able to tolerate oral intake, at which time analgesia changed to oral opioids (starting dose: oxycodone 10 mg every 4 h as needed). In addition, all participants received the following adjuvant analgesics: oral paracetamol 1000 mg every 6 h, oral gabapentin 125 mg every 8 h and intravenous ketorolac 30 mg every 4 h as needed.

Outcome measures

The primary outcome measure was the pain visual analogue scale score (VAS) (0 = no pain and 10 = worst pain imaginable). Secondary outcomes were scores on the following questionnaires: first, short-form McGill's Pain Questionnaire (SF-MPQ)41; second, Beck Depression Inventory (BDI)42,43; third, Montgomery–Asberg Depression Rating Scale (MADRS)44; and fourth, Quality of Recovery (QoR-15) form.45 VAS and SF-MPQ assess pain. BDI and MADRS are well established questionnaires for the assessment of mood, often used in depression studies.42–44 The QoR-15 assesses overall satisfaction with postoperative recovery.45 BDI, MADRS and QoR-15 were assessed prior to surgery in the preadmission clinic. Prior to discharge from the PACU, VAS and SF-MPQ were assessed. All questionnaires were assessed on postoperative days (PODs) 1, 2 and 7. If a patient had been discharged prior to POD 2 or 7, a member of the study team contacted the patient by telephone to complete the questionnaires. Additional secondary outcomes included length of hospital stay, opioid use throughout the hospital stay, spirometry use within the first 24 h and time to get out-of-bed to chair (the latter two measures assess functional recovery). All opioid doses were converted to morphine intravenous equivalent (with www.hopweb.org). Exploratory secondary measures include measurement of serum markers. However, all patients refused additional blood analysis.

Statistical analysis

The sample size calculation was based on postoperative pain scores from patients undergoing laparoscopic bariatric surgery.46 Using a constant SD (3) in all the repeated measurements and assuming a correlation between them of 0.8, 41 patients per arm were needed to detect a between-group difference of at least two points in the postoperative VAS score with a power of 0.8 and an α level of 0.05. A total of 50 patients per arm were enrolled to allow for potential dropouts.

Personal and intra-operative data between groups were analysed using Student's t test or Wilcoxon rank-sum test, based on the results of the Shapiro–Wilk test. We used χ2 and Fisher's exact test for inferences on proportions.

The fixed effects of the intervention (group: ketamine vs. placebo), time and group-by-time interaction on the different end points (postoperative VAS, SF-MPQ, BDI, MADRS and QoR-15) were modelled using the linear mixed effect model with random intercept for subjects.47,48 The models for BDI, QoR-15 and MADRS were adjusted for baseline (pre-intervention) values. Akaike's Information Criteria was used to select the covariance structure for the residuals. All available data were used. In the presence of a group-by-time interaction, group comparisons at individual time points were made (contrast analysis) and results were adjusted for multiple comparisons using the Bonferroni correction; otherwise marginal means were used. A log-transformation of the outcome data was made to ensure normality of residuals, assessed using QQ plot, as needed.

Data are expressed as mean ± SD or median [interquartile range], unless otherwise stated. A two-sided P value of less than 0.05 was considered significant. All analyses were performed with STATA/SE version 14.1 (StataCorp LP, College Station, Texas, USA) and R software version 3.3.2 (R Foundation, Vienna, Austria).

Results

A total of 100 patients were enrolled in the study (Fig. 1). Eight withdrew consent before intravenous administration of the study drug shortly after arrival in the PACU, five in the ketamine group and three in the placebo group. Two experienced surgical complications in the first 24 h after surgery and were excluded from the analysis (Fig. 1). Both groups were similar with respect to patient characteristics (Table 1), and intra-operative data (Table 2).

Fig. 1
Fig. 1:
CONSORT flow-chart showing the progression of participants through the study and data for analysis.
Table 1
Table 1:
Baseline characteristics
Table 2
Table 2:
Intra-operative and postoperative data

The change in VAS score over time is shown in Fig. 2a. The scores decreased over time (time effect P ≤ 0.001), but no significant differences between groups were seen (group-by-time interaction P = 0.966; marginal group effect P = 0.137).

  1. Affective scale: Figure 2b shows the change in SF-MPQ affective scale over time. The analysis showed that the change in the affective score over time depends on the level of group variable (group-by-time interaction P = 0.034). The contrast analysis of time@group (effects for time at each level of group) showed that the affective scores in the placebo group remained not significantly different from PACU to POD 2, decreasing only by POD 7 (Bonferroni adjusted P < 0.001). In the ketamine group a significant decrease in the scores was seen as early as POD 2 (Bonferroni adjusted P < 0.001). The contrast analysis of group@time showed that the scores on POD 2 were significantly lower in the ketamine group than the placebo group (Bonferroni adjusted P = 0.022).
  2. Sensory scale: Figure 2c shows the change in SF-MPQ sensory scale over time. The values decreased over time (time effect P < 0.001), but no significant differences between groups were seen (group-by-time interaction P = 0.197; marginal group effect P = 0.179).
  3. Total scale: Figure 2d shows the change in SF-MPQ total scores over time. The group-by-time interaction was NS (P = 0.099). The marginal model (only main effects, without the interaction term) showed a significant overall effect of group (P = 0.034), confirming that the ketamine group demonstrated an overall decrease in the total scores for SF-MPQ, when compared with the placebo group.
Fig. 2
Fig. 2:
Scores on visual analogue score and short-form McGill's questionnaires for participants after study drug administration in the postanaesthesia care unit and on postoperative days 1, 2 and 7. Values are presented as mean and bootstrap standard error (based on 10 000 replications). (a) There was no significant difference in visual analogue scores between groups. (b) Scores on the affective scale of short-form McGill's Pain Questionnaire significant decreased in the ketamine group as early as postoperative day 2 (Bonferroni adjusted P < 0.001), compared with placebo group which only decreased by postoperative day 7. The scores on postoperative day 2 were also significantly lower in the ketamine group than the placebo group (Bonferroni adjusted P = 0.022). (c) No significant differences were detected on the sensory scores of short-form McGill's Pain Questionnaire between groups. (d) The scores on the total scale of short-form McGill's Pain Questionnaire in the ketamine group were smaller in magnitude overall, compared with the placebo group (P = 0.034).

The change in BDI over time is shown in Fig. 3a. The values decreased over time (time effect P < 0.001), but no significant differences between groups were seen (analysis adjusted for baseline scores; group-by-time interaction P = 0.389; marginal group effect P = 0.491). The change in MADRS over time is shown in Fig. 3b. The values decreased over time (time effect P ≤ 0.001), but no significant differences between groups were seen (analysis adjusted for baseline scores; group-by-time interaction P = 0.674; marginal group effect P = 0.350). The change in QoR-15 over time is shown in Fig. 3c. The values increased significantly over time (time effect P ≤ 0.001), but no significant differences between groups were seen (analysis adjusted for baseline scores; group-by-time interaction P = 0.366; marginal group effect P = 0.712). To better understand the relationship between pre-operative mood, postoperative pain, and responsiveness to ketamine, we plotted postoperative VAS against pre-operative BDI and MADRS scores. We did not find any positive correlation between postoperative VAS and pre-operative BDI and MADRS; however, it should be noted that all MADRS scores were less than 15, and most BDI scores were less than 20, demonstrating at best, mild depression symptoms pre-operatively.

Fig. 3
Fig. 3:
Scores on mood and postoperative recovery indices for participants at baseline and after study drug administration on postoperative days 1, 2 and 7. Values are presented as mean and bootstrap standard error (based on 10 000 replications). (a) Beck Depression Inventory. (b) Montgomery–Asberg Depression Rating Scale. (c) Quality of Recovery 15. There were no significant differences between ketamine and placebo groups on these indices.

No statistically significant differences between groups were seen in spirometry use within the first 24 h, time to get out-to-bed to chair, total postoperative opioid usage and length of hospital stay (Table 2). Nor was there any difference in intra-operative analgesia or postoperative adjuvant analgesic administrations.

There was no significant difference in terms of side effects between treatment and placebo groups (Table 3). The most common side effect in both groups was dizziness and light-headedness. All side effects were self-limited and did not require medical treatment beside verbal assurance.

Table 3
Table 3:
Side effects

Discussion

The current randomised, placebo-controlled study investigated the use of a single administration of a subanaesthetic dose of ketamine in the postoperative setting. We investigated the impact of a single, low dose of ketamine compared with placebo, on pain and mood after surgery. Pain was measured by VAS and SF-MPQ, whereas mood was assessed by MADRS and BDI indices, and also the affective scores on the SF-MPQ. We did not find any difference between the two groups in VAS, MADRS or BDI scores. However, ketamine administration did improve the affective pain experience, as evaluated by the affective score and the total score of SF-MPQ, starting by POD 2. Two interesting conclusions can be drawn from our study with implications for postoperative pain management. First, ketamine can provide dissociative analgesia that is selective for the affective component of pain. Second, this effect on pain-associated affect is relatively enduring, and far outlasts the well known analgesic half-life of ketamine.

In previous peri-operative studies, ketamine was administered as a continuous infusion, often initiated in the OR and sometimes extended into the postoperative period. Many of these protocols have resulted in reductions of opioid use; the studies were not powered to examine pain scores.3–6,18–21,49 In the recent PODCAST study, however, ketamine at 0.5 or 1 mg kg−1 was administered and compared with a placebo that was given prior to incision in 672 older adults.17 In this study, there were no differences amongst the three groups for secondary outcomes of postoperative pain scores and opioid consumption.17 Reasons why a single dose prior to incision might not improve postoperative pain include the pharmacokinetics of ketamine (half-life less than 3 h) and the use-dependent nature of ketamine analgesia.50 Our study differs from these previous studies; ketamine was administered as a single postoperative dose (within 30 min), whereas in most earlier studies on intra-operative and postoperative use of ketamine, the drug was infused continuously.3–6 One previous study has shown that a single-dose of ketamine (0.25 mg kg−1) in combination with morphine delivered modestly superior analgesia to morphine alone.51 Our results on VAS score and opioid use are generally compatible with findings from single-dose administrations of ketamine performed in pre-operative studies, including the PODCAST study.11–17 In most cases, a pre or postinduction administration of single-dose ketamine has not resulted in long lasting changes in VAS scores.52 What our study highlights is that single-dose ketamine can have an effect on specific affective components of pain.

The observed improvement in SF-MPQ on POD 2 in our study is novel and has the potential to influence clinical care. It was not only statistically significant, but given a difference of 25% improvement in the ketamine group compared with the placebo group, it was also clinically significant. SF-MPQ is a well validated measure for pain in clinical studies.53–55 In contrast to VAS, SF-MPQ scales provide a more comprehensive evaluation of pain. They are especially useful for distinguishing the affective and sensory components of pain. There are two possible explanations for this improvement in SF-MPQ scores. First, there was a modest trend of improvement in VAS across all time points in the ketamine group, and so it is possible that a more comprehensive evaluation tool such as SF-MPQ could more efficiently identify the subtle effect of ketamine on pain. Second, ketamine selectively improved the affective component of pain. This second explanation is more probable, as ketamine had a comparatively small effect on the sensory scale of SF-MPQ, in contrast to its effect on the affective and total scales (the effect on total scale is probably the result of improvement on the affective scale).

Single-dose administrations of ketamine are known to be highly effective for treating refractory depression, anxiety, and other affective disorders.22–25,56 Affective symptoms of pain, such as the aversive response to pain and mood changes associated with pain, are well correlated with mood,57 and bariatric patients are at higher risk for depressed mood.36,37 Furthermore, postoperative pain itself can lead to changes in mood and affect which further complicates treatment and recovery.26–28 In this study, we did not observe any difference in MADRS and BDI. Nor did we find any positive correlation between baseline MADRS/BDI scores and postoperative pain severity. However, the baseline MADRS/BDI scores for these patients were overall quite low, indicating a lack of severe depression symptoms pre-operatively. These low baseline depression scores may be the result of younger and healthier patients in our study, compared with other studies.36 It should be noted that MADRS and BDI are more useful for patients who suffer from serious depression such as major depressive disorder, and these scales may not be suitable for the analysis of more subtle depressive symptoms in postoperative patients. In contrast, SF-MPQ is more specific for pain, including postoperative pain. Thus, in our study, even though patients in general demonstrated, at best, mild depressive symptoms on MADRS and BDI, their mood and affect were not normal, as shown by their scores in the affective symptoms on the SF-MPQ. At the same time, it is conceivable that ketamine could have a bigger impact on a patient group with a higher comorbidity of mood disorders. Therefore, our results on the affective component of pain are in fact compatible with earlier psychiatric studies and demonstrate a unique analgesic feature of ketamine. As a general anaesthetic, ketamine is known to have dissociative properties. Our study here indicates that as an analgesic agent, ketamine also possesses this unique property. A single dose of ketamine can selectively relieve the affective processing of pain without necessarily having any long-term impact on the sensory transmission of pain. These results also suggest that ketamine may be able to improve postoperative mood, but future studies with more specific neuropsychometric tests are obviously needed to validate the effect of a single dose of ketamine on postoperative mood in patients who do not have pre-operative mood disorders.

The unique dissociative feature of ketamine analgesia is also found in the timing of the therapeutic effect. The peak effect seen on the SF-MPQ – 2 days after the administration of a single dose of ketamine – strongly corresponds with previous studies of this drug on depression and anxiety. In these studies, peak pharmacological effects on mood were achieved between 24 and 48 h.3–6 In contrast, in previous postoperative studies, improvements in pain scores were temporally linked with ketamine infusion. Therefore, the pharmacological mechanism for single-dose ketamine on the affective component of pain is probably different from that of continuous infusion. The analgesic properties of ketamine are thought to derive from blockade of peripheral sodium channels and central N-methyl-D-aspartate receptors.58,59 However, as an analgesic, the half-life of ketamine is relatively short, approximately 45 min.60 In contrast, the effect of ketamine seen in our study on the affective pain score peaked 2 days after infusion. Previous studies have indicated that a potential mechanism of action for ketamine is enhanced excitatory neurotransmission through the prefrontal cortex and hippocampus, brain regions known for the regulation of mood and affect, as ketamine can increase brain-derived neurotrophic factor signalling and enhance the translation of proteins required for the synaptic machinery in these brain regions.61,62 Such mechanisms have been shown to mediate the long-lasting antidepressant and anxiolytic effects of ketamine61–63 and they may very well play a role in the effect of this drug on the affective component of pain observed in the current study.

The advantage of a single-dose ketamine infusion is its suitability for clinical practice. The first 48 h after surgery represent the greatest risk for affective and cognitive impairment, and our results suggest that ketamine may be an important therapy in this period. Furthermore, in contrast to continuous ketamine infusion, which requires close monitoring for neurological and cardiovascular side effects, a single administration of ketamine is much easier to implement. In our study, side effects were not significantly different between ketamine and placebo groups. In the ketamine group, we observed five cases of mild psychiatric effects such as euphoria and dysphoria, which were self-limiting. Overall, the incidence of psychiatric side effects in the ketamine group (5/44) is slightly lower than previous studies using similar doses,12 further demonstrating the safety of ketamine at this dose (0.4 mg kg−1) in the PACU setting.

There are several limitations to our study. First, due to a lack of studies on single-dose ketamine in the postoperative setting, and a shortage of pain studies after bariatric surgery, our power analysis was based on the effect of continuous infusion of dexmedetomidine on VAS score for postbariatric surgery patients.46 In retrospect, the lack of impact of ketamine on the VAS in our study may in part be attributed to a lower than expected baseline postoperative pain score in our patient group. A second, similar limitation of our study is the low baseline MADRS and BDI scores of participants, indicating a lack of severe depression symptoms, as discussed above. Although this is probably the result of younger and healthier patients in our study compared with other studies,36,37 it is conceivable that ketamine could have a bigger impact on a patient group with a higher comorbidity of mood disorders. A third limitation of our study relates to streamlined postoperative care at our institution. All participants received PCA postoperatively and were discharged from hospital at approximately the same time. Adherence to these protocols probably contributed to the lack of difference in the length of hospital stay and the daily usage of opioids after surgery. In addition, the overall dose of opioid was low in both the ketamine and control groups. Nevertheless, there was a trend for lower opioid consumption in the ketamine group, particularly on POD 2, and it is possible that in a properly powered study with more strict exclusion criteria, a single-dose administration of ketamine may have an enduring effect in reducing postoperative opioid use. Reduction in opioid requirement can be expected from ketamine treatment, as opioid consumption is associated with depressed mood in the postoperative period, and ketamine is a powerful antidepressant.64 Future studies of larger sample sizes should be used to examine the effect of single-dose ketamine on opioid consumption.

In conclusion, we found that the administration of a single subanaesthetic dose of ketamine can reduce the affective component of pain after laparoscopic bariatric surgery. For the moment, the most effective analgesic method for ketamine remains peri-operative or postoperative continuous infusions. Our results, however, support the use of a single low-dose administration of ketamine after surgery, especially as this therapy is associated with a lower risk profile. In the future, however, larger studies of more diverse postsurgical cohorts are needed to validate the usefulness of a postoperative single-dose administration of ketamine. Our study also emphasises the need to examine the efficacy of ketamine on higher risk groups defined by a higher opioid requirement, greater psychiatric comorbidity and more severe postoperative pain.

Acknowledgements relating to this article

Assistance with the study: we would like to thank Drs Shengping Zou, Christopher Denatale, Kristoffer Padjen, Qian Chen, Fahad Khan for their care of human subjects in the study, and helpful suggestions and insights into our study and the article.

Financial support and sponsorship: this work was supported by the Anaesthesia Department Research Fund of the New York University (New York, NY, USA).

Conflicts of interest: none.

Presentation: none.

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