The increasing number of surgical patients with chronic pain and opioid dependence represents a complex challenge in the perioperative period. This patient population has a high risk of opioid-induced hyperalgesia or tolerance, and may have an excessive need for opioids for up to 3 times that of opioid-naive patients, and an increased risk of postoperative pain.7,14,15 Furthermore, these patients are often discharged from hospital with a higher opioid prescription than before surgery.2
Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist blocking NMDA receptors in the central and peripheral nervous systems.3,25,33 Experimental studies suggest that ketamine attenuates central sensitization and hyperalgesia and thereby reduces postoperative opioid tolerance.3,26 Clinical trials in opioid-naive patients have demonstrated reduced opioid consumption and pain with subanesthetic IV doses of ketamine intraoperatively.3,12,19,22,26
Recently, intraoperative ketamine was suggested as an ideal candidate for managing perioperative pain in opioid-dependent patients with chronic pain.2 The evidence for this indication is still sparse, and only one clinical trial has addressed this issue.27 Loftus et al.23 demonstrated that ketamine reduced postoperative opioid consumption 0 to 48 hours postoperatively, and reduced pain 6 weeks after surgery in opioid-dependent patients. The trial, however, suffered from lack of standardization of the analgesic regimens.27
Thus, clinical trials are needed to clarify the role of ketamine for managing acute postoperative pain in opioid-dependent patients with chronic pain. Furthermore, data are needed on the role of perioperative ketamine for persistent postoperative pain.
The primary aim of this trial was to examine if intraoperative low-dose ketamine would reduce postoperative opioid consumption and acute pain compared with placebo in opioid-dependent patients. The primary outcome was 24-hour postoperative morphine consumption. Secondary outcomes were acute pain at rest and during mobilization 2 to 24 hours postoperatively, adverse effects, and persistent pain 6 months postoperatively.
This single-centre, prospective, randomized, blinded trial was approved by the Regional Research Ethics Committee and the Danish Data Protection Agency and registered at clinicaltrials.gov (NCT02085577) on March 11, 2014. The trial was performed at Rigshospitalet—Glostrup, Copenhagen University Hospital, Denmark during the period from May 19, 2014 to October 2, 2015, and was monitored by the Copenhagen University Hospital Good Clinical Practice Unit. The study fulfilled the guidelines for Good Clinical Practice and the Helsinki Declarations. The protocol, design, and reporting of the study complied with the Standard Protocol Items, Recommendations for Interventional Trials (SPIRIT) statement8 and the Consolidated Standards of Reporting Clinical Trials statement (CONSORT).30 All patients gave written informed consent before participating in the trial.
2.1. Inclusion and exclusion criteria
Patients undergoing lumbar fusion surgery during general anesthesia were approached for inclusion in the trial. Additional inclusion criteria were chronic back pain >3 months preoperatively, daily use of strong opioids for back pain >6 weeks preoperatively (morphine, oxycodone, tramadol, buprenorphine, fentanyl, or ketobemidone), age 18 to 85 years, American Society of Anesthesiologists (ASA) physical status classification of I to III, and body mass index between 18 to 40 kg/m2. Exclusion criteria were inability to cooperate, inability to speak or understand Danish, participation in other drug trials, daily use of methadone, previous or current psychotic episodes, uncontrolled hypertension, increased intraocular pressure, pregnancy, allergy to drugs applied in the trial, and alcohol or drug abuse.
2.2. Randomization and blinding
Patients were randomly assigned to 1 of 2 groups: S-ketamine bolus 0.5 mg/kg immediately after induction of anesthesia followed by infusion of S-ketamine 0.25 mg·kg−1·h−1, or placebo (bolus and infusion). Randomization was performed by the Capital Region Pharmacy according to a computer-generated block randomization list (each block containing 10 numbers) in a 1:1 ratio. Study medication and placebo were produced in identical ampules and pre-packed by the pharmacy in consecutively numbered boxes according to the computer-generated randomization list, containing identical 2 mL ampules of either S-ketamine (25 mg/mL) (Pfizer ApS, Denmark), or isotonic sodium chloride (NaCl) 9 mg/mL. After inclusion, patients were given the treatment corresponding to their randomization number. Information about treatment was concealed in consecutively numbered, sealed, opaque envelopes to enable unblinding in case of acute complications. The intervention was blinded to all patients, investigators, surgeons, and clinical personnel.
Before breaking the randomization code, enrolment of all patients and the 6-month follow-up period had ended; the data had been computed twice and afterwards double-checked in Microsoft Excel; exclusion of patients was decided, and statistical handling of the data was completed.
One hour before surgery, all patients received their usual dose of opioids and oral paracetamol 1000 mg. General anesthesia was induced and maintained with propofol (variable rate) and remifentanil (fixed rate 40 μg·kg−1·h−1). Rocuronium (0.6-1.0 mg/kg) was used to facilitate orotracheal intubation with a cuffed tube. Immediately after induction of anesthesia, patients received study medication according to randomization, that is either S-ketamine (25 mg/mL) bolus 0.5 mg/kg, followed by infusion S-ketamine 0.25 mg·kg−1·h−1 or placebo bolus followed by placebo infusion (isotonic NaCl bolus 0.02 mL/kg and infusion isotonic NaCl 0.01 mL·kg−1·h−1). The infusion was discontinued at last suture of the skin.
Hypotension was treated at the discretion of the anesthetic staff with isotonic NaCl, ephedrine (5-10 mg), and/or metaoxedrin (0.1-0.2 mg) intravenously.
The permanent spine surgeons at Centre for Rheumatology and Spine Diseases performed the lumbar fusion surgery. Forty-five minutes before expected completion of surgery, morphine 0.4 mg/kg was administered intravenously. If the patient was in unacceptable pain on awakening in the operating room, IV sufentanil bolus 5 μg was administered at the discretion of anesthetic staff.
For all patients, postoperative pain treatment during the first 24 hours consisted of 1000 mg oral paracetamol every 6 hours, starting 2 hours postoperatively, and the patients' usual opioid treatment. In addition, all patients received IV patient-controlled analgesia (PCA) with morphine (bolus 2.5 mg, lock-out time 5 minutes, and no background infusion). Rescue medication (IV morphine 2.5 mg p.n.) was administered by a nurse, in the postanesthesia care unit for the first postoperative hour in case the PCA was insufficient.
Moderate to severe nausea or vomiting as assessed by the patient was treated with IV ondansetron 4 mg, supplemented with 1 mg doses if needed. If ondansetron was ineffective, supplemental droperidol was available. No other analgesics, antiemetics, or sedative drugs were administered during the first 24 postoperative hours. After 24 hours, the PCA was discontinued and all patients were treated according to the department's standard regime.
2.4. Assessments and outcomes 0 to 24 hours postoperatively
Preoperatively, patients were guided by one of the investigators in the use of the visual analogue score (VAS)-scale and the PCA pump. The introduction to the VAS-scale and the PCA pump was standardized. All postoperative assessments were performed by the trial investigators or trained nurses.
Cumulated PCA IV morphine consumption was registered from 0 to 24 hours postoperatively. Pain and adverse effects were evaluated at 2, 6, 12, 18, and 24 hours postoperatively. Pain was assessed on a VAS-scale (0-100 mm; 0, no pain; 100, worst imaginable pain), at rest, and during mobilization defined as moving from recumbent position to sitting bedside. Nausea and sedation were evaluated by the patients on a verbal rating scale: none, light, moderate, and severe nausea or sedation (0-3). The number of vomiting episodes with a volume greater than 10 mL was assessed by the nurse, and registered by the investigator. The need for antiemetics in the first 24 hours postoperatively was recorded. Episodes of hallucinations or nightmares were recorded by asking the patient 24 hours postoperatively. Other potential adverse effects were recorded.
The primary outcome was total PCA morphine consumption 0 to 24 hours postoperatively.
Secondary outcomes included pain during mobilization 2 to 24 hours postoperatively calculated as a “weighted average level” area under the curve (AUC) (in mm) pain at rest (wAUC, 2-24 hours), morphine-related adverse events (nausea, vomiting, sedation, and postoperative use of antiemetics), episodes of hallucinations or night mares 0 to 24 hours postoperatively, and persistent pain 6 months postoperatively.
Preoperatively, all patients filled out 3 written questionnaires screening for chronic pain (Brief Pain Inventory), pain catastrophizing (Pain Catastrophizing Scale), and anxiety and depression (Hospital Anxiety and Depression Score).
The Brief Pain Inventory36 is summarized as a pain score, an interference score, and a total score. Data are calculated as mean values of scores on a range from 0 to 10, with 10 indicating the worst possible situation. The Pain Catastrophizing Scale32 is summarized as one total score (range 0-52) calculated as the sum of all scores. A higher score indicates a higher degree of catastrophizing. The Hospital Anxiety and Depression Scale5 results are summarized as an anxiety score, a depression score, and a total score. An anxiety or depression score ≥8 indicates that anxiety or depression is likely. A total score ≥16 indicates a significant level of distress.
Six months postoperatively, patients filled out 5 written questionnaires. The DaneSpine Questionnaire35 included questions about demographic data, back and leg pain (VAS 0-100 mm), back and leg pain compared with preoperative pain levels (0 = no pain before, 1 = gone, 2 = much better, 3 = somewhat better, 4 = unchanged, 5 = worse), use of analgesics, duration of sick leave, working capability, and contentment with the results of the operation.
The Oswestry Low Back Pain Disability Questionnaire17 is summarized as an Oswestry Index Score with a range 0 to 100: 0 to 20, minimal disability; 21 to 40, moderate disability; 41 to 60, severe disability; 61 to 80, crippling back pain; 81 to 100, bedbound.
The Short Form 36 survey (SF-36) is summarized as 2 summary scores, one for the physical component summary score and one for the mental component summary score as described by McDowell.27 Using norm-based scoring for the summary scores, each scale is scored to have the same mean (50) and SD (10) as in the general Swedish population, provided by the SF-36 organization. Anytime a scale score is below 50, health status is below average relative to the general Swedish population.
The EuroQol 5D Questionnaire (EQ-5D)17 contains 5 questions with a score from 1 to 3; a higher score corresponds to severe problems. An index score is calculated from the median of all questions. Furthermore, the questionnaire includes a self-rated health state: VAS 0 to 100, higher score corresponds to better health.
The Douleur Neuropathique 4 Questionnaire (DN4)6 is summarized as one total score. Answering positively to one question adds 1 point. The minimum score is 0; the maximum score is 10. A total score ≥4 indicates that pain is likely to be neuropathic.
If patients had not returned the questionnaires after 3 weeks, they received one written reminder.
2.6. Statistical methods
Prestudy data from our own department showed that patients with spinal fusion have a mean morphine consumption 0 to 24 hours postoperatively of 36 mg IV, SD 24. With a type 1 error (α) of 5% and a power (1 − β) of 80%, sample size calculations showed that 64 patients in each group were required to detect a 30% reduction in morphine consumption (primary outcome). Taking dropouts and uncertainty about our calculated SD into account, we decided to include 150 subjects.
We analysed data using SPSS version 22.0 for Windows (SPSS, Chicago, IL). We performed complete case analysis for the AUC calculations because very few data were missing. For the rest of the outcome measures, we analysed the available data.
Variables were tested for normal distribution by visual inspection and with the Kolmogorov–Smirnov test. Data are presented as mean and SD or 95% confidence interval (CI), medians and lower and upper quartiles or frequencies, as appropriate. Data that followed normal distribution (morphine consumption, VAS-pain) were compared using the independent samples t test. Pain is presented as weighted average AUC 2 to 24 hours (wAUC) (in mm) for the period calculated according to the method described by Altman.1 The Mann–Whitney U test was used for data that were not normally distributed (6-month follow-up, nausea, vomiting, sedation; use of antiemetics, hallucinations, and night mares). Categorical data were analysed using the χ2 test or Fisher exact test if any cells had expected counts less than 5. For comparisons of nausea and sedation scores, we calculated the arithmetic mean scores by attributing numerical values to the scores from each patient; none = 0, slight = 1, moderate = 2, and severe = 3. The nature of the hypothesis testing was 2-tailed.
P values of less than 0.05 were considered statistically significant. Secondary outcomes were Bonferroni corrected where relevant and by the number of times the outcomes were measured. The primary investigator performed all statistical analyses.
Two hundred eighty-three consecutive patients were considered for inclusion and eventually, 150 patients were included and randomly assigned to the treatment or the placebo group. Three patients were excluded and consequently, 147 patients were included in the final analysis, 74 and 73 patients in the ketamine and placebo groups, respectively (Fig. 1).
There were no significant differences in patient characteristics, or preoperative and perioperative characteristics between the 2 groups (Table 1). The preoperative daily use of opioids (oral morphine equivalents) was median 60 (33-80) mg and 58 (30-78) mg in the ketamine and placebo groups, respectively. The ketamine group received ketamine bolus 38 (33-43) mg and infusion 25 (20-34) mg intraoperatively. The placebo group received equivalent volumes of isotonic NaCl. In both groups, patients were operated on median 1 (1-2) lumbar spine segments.
3.1. Morphine consumption
The total 24-hour PCA morphine consumption was significantly reduced in the ketamine group compared with the placebo group: 79 (47) vs 121 (53) mg IV morphine with a mean difference of 42 mg (95% CI −59 to −25), P < 0.001. There was no significant difference in rescue IV morphine consumption during the first hour at the PACU postoperatively, median (quartiles): 13 (3-26) vs 15 (7-26) mg IV, P = 0.35.
3.2. Acute pain
Pain during mobilization (wAUC 2-24 hours) was comparable in the ketamine and placebo groups: 63 (21) vs 64 (18) mm respectively, with a mean difference of 1 mm (95% CI −8 to 5), P = 0.63 (Fig. 2). Likewise, for pain at rest (wAUC 2-24 hours), there was no significant difference between groups: 46 (19) vs 48 (20) mm in the ketamine and placebo groups, respectively, with a mean difference of 2 mm (95% CI −8 to 5), P = 0.62 (Fig. 3).
3.3. Adverse events
There were no significant differences in nausea scores or ondansetron consumption between groups 0 to 24 hours postoperatively, both regarding number of patients with nausea, and severity of nausea (Table 2). Three patients received droperidol because of insufficient effect of ondansetron. The total number of vomiting episodes 0 to 24 hours was lower in the ketamine group, but the difference was not significant. Sedation was generally low in both groups, but significantly reduced at 6 hours and 24 hours postoperatively in the ketamine group (Table 2). There was no significant difference between groups in episodes of hallucinations or nightmares assessed 24 hours postoperatively (Table 2). One patient in the ketamine group experienced 10 hallucinations 0 to 24 hours postoperatively. No other adverse events were reported.
3.4. Persistent pain
The DaneSpine Questionnaire: at 6 months postoperatively, back pain levels (VAS) seemed lower in the ketamine group compared with the placebo group; however, the difference was nonsignificant after Bonferroni correction (Table 3). For leg pain levels (VAS), there were no significant differences between groups (Table 3).
When asked how patients evaluated their actual back pain compared with preoperatively, the ketamine group reported significantly more improvement of their pain compared with the placebo group: median 3 (2-3) vs 4 (3-4) respectively, P < 0.006 (Table 3).
Walking distance was significantly longer in the ketamine group, P = 0.012 (Table 3).
No significant differences between groups were observed regarding daily use of analgesics. In the ketamine group, 44% (95% CI 30-58) and in the placebo group 62% (95% CI 48-75) of patients, respectively, had a daily use of opioids.
Results from the Oswestry Low Back Pain Disability Questionnaire, Short form 36 survey, EuroQol 5D Questionnaire, and The Douleur Neuropathique 4 Questionnaire are summarized in Table 4. The Oswestry index score demonstrated significantly less disability in the ketamine group, P = 0.006 (Table 4). No differences were demonstrated regarding Short form 36 survey, EuroQol 5D, or The Douleur Neuropathique 4 results.
Post hoc, we conducted an analysis of the effect of ketamine stratified by preoperative opioid consumption. Patients consuming ≥36 mg oral morphine equivalents daily, preoperatively achieved a reduction in 24-hour PCA IV morphine consumption of 37% when receiving intraoperative ketamine, P < 0.001 (74  mg vs 118  mg in the ketamine and placebo groups, respectively). Patients consuming <36 mg/24 h of morphine equivalents preoperatively had no significant effect of ketamine (Table 5).
We have demonstrated that intraoperative low-dose IV ketamine significantly reduced supplemental IV PCA morphine consumption during the first 24 hours after lumbar fusion surgery in opioid-dependent patients. Sedation was significantly reduced in the ketamine group.
Six months postoperatively, patients in the ketamine group reported significantly more improvement of their back pain compared with the placebo group; further, walking distance was improved compared with the placebo group. The Oswestry index score demonstrated significantly less disability in the ketamine group.
To our knowledge, only one previous trial has explored the effect of intraoperative ketamine infusion on chronic pain patients with opioid dependency.27 Loftus et al.23 reported a 30% reduction in total opioid consumption at 24 hours, and a 37% reduction at 48 hours. This finding is comparable with our results. However, the analgesics they used for PCA (primary outcome) were not standardized and included morphine, fentanyl, and hydromorphone, among others. Furthermore, the transition from PCA to oral analgesics at approximately 24 hours postoperatively was not standardized. Also, the ketamine group received intraoperative nonsteroidal anti-inflammatory analgesics (NSAIDs) more frequently than the placebo group (ketamine group: 26%; placebo group: 6.0%, P = 0.006), and the groups may not have been comparable because a significantly higher number of spine levels were operated on in the ketamine group.23
In our trial, the effect of low-dose perioperative ketamine was assessed with supplemental IV PCA morphine only. Apart from paracetamol to all patients, no further analgesics were used in the trial.
Our post hoc analysis showed that the ketamine-related reduction in morphine consumption was primarily due to reductions for opioid-dependent patients with a habitual consumption of oral morphine equivalents of ≥36 mg/24 hours preoperatively. This result is similar to results from Loftus et al.23
Loftus et al.23 reported a significant effect of ketamine on immediate, but not late postoperative pain after surgery. In this trial, we did not observe any effect of ketamine on acute pain levels, neither at rest nor during mobilization. A possible explanation could be that all patients may have titrated PCA morphine to equally acceptable pain levels in the 2 groups. This would support the reduced PCA morphine consumption as the true analgesic effect of perioperative low-dose ketamine.28 Interestingly, we found postoperative pain levels comparable with those preoperatively in both groups, which may be due to the chronic nature of this pain.
Similar to previous trials of intraoperative ketamine, we demonstrated limited side effects.12,23 We found no differences between groups regarding nausea and vomiting. Significantly lower sedation scores were demonstrated in the ketamine group 6 and 24 hours postoperatively, possibly due to the higher opioid consumption in the placebo group. Generally, sedation was mild, and the clinical relevance of this result is probably negligible. Overall, opioid-related side effects were low in this specific patient population, which could be due to opioid habituation.14
Regarding specific side effects related to ketamine (hallucinations and nightmares), we found no significant differences between groups. One patient in the ketamine group experienced 10 hallucinations 0 to 24 hours postoperatively. However, these hallucinations were not reported as unpleasant, and did not need intervention. Our findings are comparable with previous results when using subanesthetic doses of ketamine, despite our choice not to administer prophylactic benzodiazepine.12
Six months postoperatively, patients in the ketamine group reported significantly more improvement of their back pain compared with the placebo group. Furthermore, patients in the ketamine group reported a longer walking distance, and had less disability on the Oswestry index score.13 Persistent pain after surgery often has neuropathic characteristics,15,20,24 thus an increased DN4 score in the placebo group could have been expected, but this was not found. Our data do not clarify whether pain measured 6 months postoperatively was new onset pain from the operation or remaining chronic pain also present preoperatively. However, the reduced persistent pain levels can possibly be due to ketamine's blockage of the NMDA receptors and reduced wind-up and central sensitization.4,10 Recent evidence also indicate that ketamine has potent antidepressant qualities.31 Patients with chronic pain often have depression or depression-like symptoms as it was evident in our preoperative screening. We could, however, not demonstrate an effect of ketamine on mental health postoperatively. Whether this effect of ketamine in patients with chronic pain is short lived or has long-lasting impact needs further investigation.31
Loftus et al.23 found reduced pain levels 6 weeks postoperatively in the ketamine group. Pain levels 6 weeks postoperatively, however, may not be descriptive for the true risk of developing persistent pain which is usually defined as pain persisting beyond 3 months.29 Only 2 previous studies, none of which included patients with chronic pain and opioid dependency, have demonstrated effects of ketamine 6 months postoperatively.11,34 A review and meta-analysis investigated ketamine's role in preventing persistent postoperative pain.21 In this analysis, only one of the 9 pooled estimates of postoperative pain demonstrated marginally significant pain reduction.21 Current evidence is still too sparse to draw conclusions.
Our results regarding persistent pain are limited by the low response rate of 65% at the 6-month follow-up, rendering data with low strength to draw conclusions on ketamine's role in preventing persistent postoperative pain. We do not know the status of patients who did not respond. Our data must be considered exploratory secondary outcomes, and the sample size calculation was not based on these outcomes. The follow-up suffers from other well-known weaknesses of written questionnaires: a level of subjectivity, recall bias, interpretation of questions, and researcher imposition. Furthermore, it would have been ideal if the pain level method testing preoperatively and postoperatively was similar for an optimal comparison.
The strength of the overall trial is that few investigators were involved in the trial, leading to few protocol violations, and very few original data missing. Patient-groups were well matched for preoperative pain, opioid consumption, and a number of psychological factors. Surgery on the spine can induce severe postoperative pain and is associated with a high risk of persistent postsurgical pain, with a frequency of 5% to 75%.9,18 Lumbar fusion surgery is one of the top 6 surgeries with highest pain scores on the first postoperative day.16 We therefore considered spinal fusion surgery to pose a rather well-defined surgical model to investigate the effect of intraoperative ketamine in opioid-dependent patients.
In conclusion, intraoperative low-dose S-ketamine significantly reduced PCA-morphine consumption during the first 24 hours after lumbar fusion surgery in chronic opioid-dependent patients, confirming our primary hypothesis. There was no effect on acute postoperative pain levels. Patients receiving ketamine reported significantly more improvement of their back pain, improved walking distance, and less disability in the Oswestry index score 6 months postoperatively. These latter findings are exploratory, and needs further confirmation.
Conflicts of interest statement
J. B. Dahl discloses to have served as a member of the Editorial Boards of Acta Anaesthesiologica Scandinavia, Pain, BMC Anesthesiology, and Scandinavian Journal of Pain within the last 5 years. The remaining authors have no conflicts of interest to declare.
The study was supported by the Department of Neuroanesthesiology Rigshospitalet, Glostrup, Copenhagen University Hospital.
We acknowledge and thank the nurses at the Department of Neuroanesthesiology and the nurses and surgeons at the Centre for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup for their invaluable help and cooperation.
. Altman DG. Practical statistics for medical research. London: Chapman & Hall, 1991.
. Angst MS, Clark JD. Ketamine for managing perioperative pain in opioid-dependent patients with chronic pain: a unique indication? Anesthesiology 2010;113:514–15.
. Bell RF, Dahl JB, Moore RA, Kalso E. Peri-operative ketamine for acute post-operative pain: a quantitative and qualitative systematic review (Cochrane review). Acta Anaesthesiol Scand 2005;49:1405–28.
. Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev 2006:CD004603.
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Keywords:© 2017 International Association for the Study of Pain
Pain; Postoperative; Analgesia; Postoperative; Ketamine; Spine