The pharmacological management of postoperative pain in patients with bone or soft tissue malignancy uses various regimens of opioids and their congeners that are often only of partial benefit (1). The patient-controlled epidural analgesia (PCEA) technique has widespread use because it controls pain more effectively and at doses as small as possible as determined by the patient and as safe as possible as determined by the anesthesiologist. PCEA has become the common postoperative analgesia technique in painful bone and soft tissue procedures among our patients, especially after surgery under epidural or under the combination of general and epidural anesthesia. The use of epidural analgesia perioperatively bestows pain control during various surgical procedures (2–4), thereby also reducing the amount of general anesthetics that are probably the main cause of immediate postoperative sedation and disorientation.
The N-methyl-d-aspartate (NMDA) receptors modulate acute pain and the subsequent central sensitization (5,6). NMDA receptor antagonists reduce these processes without depressing hemodynamic or respiration variables associated with hazardous consequences that may derive from opioids and other postoperative analgesics that are mostly administered IV or IM. This is especially pertinent in patients who undergo prolonged and large musculoskeletal tumor resections and when wakefulness and full orientation are required shortly after surgery. NMDA-receptor inhibition, particularly preincisionally (7–9), has shown to preempt the arousal of the spinal cord by periphery-originated pain. Dextromethorphan (DM) is a noncompetitive NMDA receptor antagonist. Its neurophysiological activity resembles that of ketamine, but it has a less frequent rate of side effects (e.g., dizziness or nausea) and a long history of clinical safety (10).
We have previously demonstrated that preoperative oral DM reduces short- (6 h), medium- (24 h), and long-term (up to 3 days) self-administered morphine and diclofenac requirements after medium-sized surgery under either epidural or general anesthesia (11,12). We also recently documented the beneficial effects of DM in patients who underwent surgery under general anesthesia for bone and soft tissue malignancies and who later used IV patient-controlled analgesia (PCA) (13).
The aim of the present study was to compare any augmented benefit (primary efficacy) of DM with the postoperative PCEA versus IV-PCA (secondary efficacy) pain control in orthopedic oncological patients who had been operated on under combined general and epidural anesthesia.
One-hundred-twenty ASA physical status I–III patients who underwent lower body bone and soft-tissue cancer surgery under combined general and epidural anesthesia were enrolled in this prospective, randomized, double-blinded, placebo-controlled study that had been approved by our institutional human research and ethics committee. All patients, without exception, experienced preoperative cancer-associated pain that was satisfactorily controlled by nonsteroidal antiinflammatory drugs (NSAIDs). All participants signed a Helsinki-approved informed consent and were given full explanation of DM, the IV-PCA and PCEA techniques, and the linear visual analog scale (VAS) from the anesthesiologist 24 h before surgery. Exclusion criteria included allergy to opioids, bupivacaine, ropivacaine, or NSAIDs, a history of chronic pain or psychiatric disorders, and the use of centrally-acting drugs of any sort. Patients younger than 18 yr and pregnant women were also excluded from the study. Baseline cardiovascular and respiratory variables were recorded for all patients during the anesthesiologist’s premedication visit. Because significant changes in vital signs (e.g., after epidural placement of local anesthetic) might affect cognition or pain sensation, >20% variation from those recorded during the premedication visit or a Spo2 <92% under 40% face mask oxygen at any time postoperatively led to the exclusion of the patient from the study from that point onwards. Finally, individuals in whom the regional block failed and surgery was performed under general anesthesia alone were also withdrawn from the study.
The 120 enrolled patients were randomly allocated into 2 sets of postoperative analgesia regimen, one of IV-PCA and one of PCEA (60 patients/set). Randomization was based on computer-generated codes that were maintained in opaque envelopes until the operation was over, when the attending physician decided to connect the patient to a PCA device. Each set consisted of one group that received 90 mg DM orally 90 min before surgery and during the next two postoperative days and another group that received placebo (in capsules of similar appearance) in a double-blinded manner; no other premedication drugs were used. The 90-mg dose was selected because this dosage was found to be effective and resulted in minimal, acceptable side effects (11–13).
The perioperative and study-long monitoring plan included the measurement of heart rate by a 5-lead electrocardiograph, systolic and diastolic blood pressures, respiratory rate, and fingertip pulse oximetry (AS3™, Datex-Ohmeda®, Helsinki, Finland).
In the operating room, when all variables were within physiological ranges, each patient received 0.5% bupivacaine 12–14 mL injected into the epidural space, always at the level of L4-S1, aiming at obtaining sensory block up to dermatomes T8-T10. A Portex® (SIMS Portex Ltd., Hythe, Kent, UK) epidural catheter was inserted epidurally and secured in place; additional intraoperative doses of the local anesthetic were administered based on clinical signs.
Each patient was then administered general anesthesia. After a fentanyl bolus of 1.0 μg/kg and propofol 2–2.5 mg/kg for induction by slow IV injection, succinylcholine 1.5 mg/kg was given to enable endotracheal intubation. The maintenance anesthetics fresh gas flow consisted of a 1:1 mixture of oxygen and nitrous oxide. Additional doses of fentanyl were administered as deemed necessary by the attending anesthesiologist based on clinical circumstances. Propofol was infused intraoperatively at a constant rate of 10–30 μg · kg−1 · min−1, and atracurium was infused as necessary to facilitate artificial respiration and surgical maneuvers. The administration of atracurium was stopped at approximately 10 min before the end of surgery, and nitrous oxide was stopped at the time of placement of the last suture, whereupon the patient inhaled pure oxygen. Neuromuscular relaxation was not reversed pharmacologically as reported in our previous studies (8,12,13); the patients resumed spontaneous respiration and were tracheally extubated based on standard train-of-four and clinical criteria.
The same surgical and anesthesia teams performed all the procedures. Surgery consisted of muscle and bone tumor resection, bone curettage, or segmental resection followed by internal fixation or artificial prosthetic insertion, with or without tissue and/or bone reconstruction.
Intra- and postoperative fluid administration and blood replacement followed measurements of hemodynamic variables, estimated blood loss, hemoglobin concentration, and the amount of urine collected via an indwelling urinary catheter. At the end of surgery, the patients were taken to the postanesthesia care unit (PACU) for the short-term postoperative follow-up. No additional drugs were administered perioperatively in any of the groups.
On the patient’s first postoperative complaint of pain intensity >4 on a 10-point VAS, a PCA device was attached to the patient’s epidural or IV line (after randomization) and activated by the attending anesthesiologist who was blinded as to the patient’s group assignment and who attended all the patients in the PACU. The study protocol dictated that any patient who exhibited a combative or incoherent state while demanding analgesia would be excluded from the study from that time on. The attending anesthesiologist administered the first 2 mL requested IV or epidural analgesic dose according to the appropriate set: 1 mg/mL morphine IV (13) or ropivacaine 1.6 mg plus fentanyl 4 μg/mL epidurally. The device then delivered similar boluses whenever the patient pushed the button, with a 7-min lockout period in the IV-PCA set and a 15-min lockout period in the PCEA set. The PCEA analgesia protocol also included a background epidural dose of 2 mL/h of the given drug-mixture. The resultant PCEA volume of 10–12 mL/h has been found to be safe and effective for controlling postoperative pain (14), and it has been used in our institution satisfactorily in similar patients. During the patients’ stay in the PACU, two additional hourly doses of IV-PCA or PCEA boluses could be administered manually by the attending anesthesiologist on the patient’s demand; further requests to relieve pain were satisfied with 75 mg diclofenac IM.
The patients remained in the PACU for 4 h after PCA was connected to assure the recognition of possible late-onset pain, untoward effects, or sedation. They were then transferred to the Orthopedic Oncology Unit. The analgesic device was available to each patient for a maximum of 96 h after surgery unless the patient had made no use of it for 12 consecutive h, whereupon it was disconnected.
During patients’ stay in the PACU, the following variables were assessed by the attending physician every 15 min for the first hour and every 30 min thereafter. In the ward, the self-rated scores as well as vital signs were recorded 4-hourly. The variables were assessed using the 10-cm chiroscience gauge:
- Subjectively rated pain intensity, using a 0–10 VAS (0 = no pain; 10 = unbearable pain).
- Subjectively rated sedation, based on a 1–10 VAS (1 = fully awake; 10 = heavily sedated).
- Subjectively rated 1–10 VAS feeling of well-being (1 = sad; 10 = happy, cheerful).
The rate of PCEA or IV-PCA activation (i.e., the number of times the delivery button was pressed) was recorded hourly with the intent to distinguish between true small requirement versus a large demand for analgesics that might not have been met because some requests could have been made during the lockout period of the device (12,13). Patients whose daily total use of the device resulted in an activation-to-delivery rate ratio >1.5 were graded as “excessive users” on that given day (13). Throughout the study, any complaint of an untoward effect was noted by the attending physician and treated accordingly.
On disconnection from the device, each patient was asked to score the overall maximal pain intensity throughout the study period and was queried on the occurrence of side effects according to a standardized checklist of known adverse reactions attributed to the analgesics and DM; this information was added to the above-mentioned medical data. Finally, the length of time the patients needed an indwelling urinary catheter, the time that had passed until each patient left bed for the first time postoperatively, and the number of days from surgery to discharge home were recorded as well.
The analyses were performed at the Statistical Laboratory of the School of Mathematics, Tel Aviv University, using the SPSS Release for Windows, Version 11.01 (Chicago, IL). A pre-study power table where δ (the mean difference in pain VAS recorded in a pilot study) equalled 2.7 ± 1 in the PCEA-DM set and 3.3 ± 1.1 in the IV-PCA-DM set, α = 0.05 and power = 0.94, resulted in the need for a minimum of 10 patients in each group. The demographic data (age, weight) and background characteristics (baseline heart and respiratory rates, Spo2, and systolic and diastolic blood pressures), the ASA physical class, the duration of surgery, and the amounts of intraoperative drugs, fluids, and blood administrations of the four study groups, as well as the end-surgery upper thoracic dermatome sensory block limit, were compared using two-way analysis of variance (ANOVA) (after drug and analgesia variables). Patients’ gender distribution was analyzed using the χ2 test. The effects of DM and the type of analgesia on the patients’ self-rated pain, sedation, and on feeling VAS were analyzed using two-way ANOVA with repeated measures. The rates of the hourly applied PCEA and IV-PCA devices were square-rooted to obtain their normal distribution; the results were then analyzed by two-way ANOVA with repeated measures. The number of patients in each group for whom the ratio between the daily activation and actual delivery was “excessive” was compared using the Fisher’s exact test. The number of times the patients demanded the rescue drug and the rate of side effects among the groups were also analyzed using Fisher’s exact test. Statistical analyses of the duration of urinary catheter being kept in place, the time to first ambulation, and the day of discharge in the various groups were also performed using two-way ANOVA. The ANOVA tests were always followed by the post hoc Tukey’s method test. The background data of patients excluded from the study were analyzed following the intent-to-analyze format. All values are expressed as mean ± sd, with significance defined as P ≤ 0.05.
The 120 patients who were originally enrolled in the study were randomized (n = 60 for PCEA and n = 60 for IV-PCA) and underwent double-blinded allocation to intervention (n = 30 for DM or placebo per individual set). Seven individuals were lost to follow-up after randomization, two PCEA-DM, one IV-PCA-DM, and one PCEA-placebo because they required prolonged postoperative ventilation and three others (all IV-PCA-placebo patients) because of violated protocol. None of the rest was excluded from the analyses. Table 1 lists the demographic, surgical, and anesthesia data; the baseline values of the vital signs were all within physiological ranges throughout anesthesia and the study period, and none was significantly different among the groups (data not shown). At no time were there signs of respiratory depression (respiratory rate <6 breaths/min, Spo2 <92% on 40% oxygen by face mask) among the patients, and the postoperative upper limit sensory block was similar among the groups (Table 1). All patients were discharged uneventfully to the ward at the end of the stay in the PACU.
Overall, the IV-PCA patients had worse scores of pain, sedation, and feeling of well being compared with the PCEA patients; the DM-treated groups self-rated themselves better than the placebo receivers. There was a corresponding difference in the use of the PCA devices among all the groups. Subjectively evaluated pain intensity (0–10 VAS) evidenced a significant (P < 0.01) drug/analgesia interaction during the entire postoperative period. Specifically, pain was better controlled by PCEA compared with IV-PCA, and DM had an augmented beneficial effect over placebo in each analgesia set (Fig. 1). The overall maximal self-rated pain score that was recorded at the end of the fourth day of the study (or when disconnected from the PCA, Table 2) was significantly (P < 0.01, drug/analgesia effect) higher for the placebo than for the DM groups; the IV-PCA-DM patients also rated their maximal pain significantly higher than the corresponding PCEA subjects.
The patients’ subjective levels of sedation and feeling of well-being (Fig. 2, upper and lower plane, respectively) indicated that DM was associated with overall better scores than placebo; the PCEA-treated subjects also self-scored their sedation and feelings better than the IV-PCA subjects (P < 0.01, drug/analgesia effect). The two variables improved over time to a larger extent for the PCEA than for the IV-PCA patients (time/drug/analgesia effect, P < 0.05).
The overall use of analgesics was the least in the DM-PCEA group (Fig. 3, Table 2). By the end of the fourth study day, or when the devices were deactivated, PCEA was still in use by 11 placebo patients compared with 5 patients in the DM group and by 19 placebo and 10 DM patients in the IV-PCA patients (P < 0.05 and P < 0.01, respectively, Fisher’s exact test). Also, the overall rate of demands for the rescue drug was significantly more frequent (P < 0.05, Fisher’s exact test) in the placebo group compared with the DM-PCEA group and in the entire IV-PCA set (Table 2). The number of patients whose daily application of the device was ≥50% of the actual delivery rate (i.e., “excessive users”) was more in the placebo groups compared with the DM ones, and the IV-PCAs were more than the PCEAs (Table 2). Finally, the total number of patients who required a urinary indwelling catheter for >24 h was significantly less (P < 0.01, Fischer exact test) in the IV-PCA-DM group compared with their placebo counterparts but similar in the two groups that composed the PCEA set (Table 2).
The rate of side effects recorded among the placebo patients was two- to threefold more frequent than that of the DM patients (P < 0.01, Fisher’s exact test); the rate for the IV-PCA patients was twofold more than that of the PCEA patients (P < 0.01, Fisher’s exact test)(Table 2). The side effects consisted almost exclusively of nausea, vomiting (72% in IV-PCA patients, similarly distributed between the two drug groups), and pruritus (equally distributed between the IV-PCA and the PCEA); they were temporary and promptly alleviated by appropriate medications.
All the DM-treated patients could get out of bed for the first time significantly earlier than the placebo patients (1.5 ± 0.8 versus 2.1 ± 1.1 days, P = 0.02, drug effect); the PCEA patients ambulated only slightly and nonsignificantly earlier than their IV-PCA counterparts (Table 2). Importantly, in no PCEA case was there motor blockade of the lower limbs that prevented the patients from early ambulation. As for the day the patients were discharged home, there were no statistical differences either between the test drug groups or between the two analgesia techniques, although the DM-treated patients left the hospital ∼1 day earlier on average than their respective placebo recipients.
The effects of PCEA were superior to those of the IV-PCA mainly in the DM-treated patients. We contend that this was attributable to the augmented effect of DM on top of ropivacaine plus fentanyl epidurally (instead of morphine IV, drug and analgesia effects) and in association with the intraoperative combined anesthesia technique: all acted to preempt the intra- and postsurgical pain (9,15,16). In essence, the binding of DM to the firing NMDA receptors results in modifying the receptors’ gated Ca2+ current, which, if it persists, is followed by a heightening of the intensity of the primary nociceptive stimulus (i.e., the “wind up” phenomenon) and the triggering of secondary sensory pain (6,7,9,17). The particular potential of DM in reducing the wind up phenomenon, which transforms acute pain into chronic pain syndromes, and its oral availability made DM an attractive drug in chronic pain management (18–20). In addition, DM has a higher therapeutic ratio than, for example, ketamine, endowing it with a high safety profile even in prolonged administrations (10). DM is then rapidly metabolized in the liver (21), where it is transformed to dextrorphan, its active and more potent derivative as an NMDA antagonist (17). It was suggested that the side effects documented in clinical studies (i.e., dizziness, nausea, vomiting, drowsiness) (5) that were attributed to the oral administration of DM might be mediated by this metabolite’s acting at the phencyclidine receptorial site rather than the DM itself (22).
Unlike previous DM studies, which excluded patients who had suffered from pain associated with the original pathology (5,8,11,23,24), all our oncological patients suffered from a variable degree of preoperative pain. This further underlines the advantage of DM with each analgesic combination because, although not yet proven clinically, the preexisting hyperexcitability and sustained wind-up conditions that could exist within the central nervous system because of preoperative pain was followed by an intensification of peripheral pain stimuli during surgery (6,7,20,25). Such changes in the nervous system plasticity were discussed by our group when DM was used to attenuate phantom pain (20), and it was also reviewed and discussed by Waxman (26). Once preexcited silent synapses have been activated again (intra- or postoperatively in our patients), they would tend to remain functionally active and continue to send messages to the brain even when an acceptable or low level of a painful stimulus exists. This hypothesis coincides with orthopedic oncological patients’ severe pain and the more frequent rate of PCA application by the IV route compared with the epidural mode. At the same time, as glutamate is one of the excitatory amino acids involved in the activation of NMDA receptors during pain-induced neural hyperexcitability, it further explains our use of DM to test its role in attenuating pain in each set of this particular type of patients (27). Furthermore, in a previous study, we reported the additive clinical effects of DM and lidocaine epidurally (11,12), whereas others showed that ketamine plus epidural morphine and lidocaine anesthesia provided better postoperative analgesia than ketamine and systemic morphine combined with general anesthesia (28). The current, better, epidural data are also supported by the findings that both NMDA and the non-NMDA glutamate receptor antagonists can interact with lidocaine synergistically at the spinal level (29). Taken together, all these data would support our findings that DM accentuated the PCEA effect so that patients perceived pain at a lower intensity than the IV-PCA, despite the existence of preoperative pain.
DM’s attenuation of acute postoperative pain and the reduction of analgesic consumption were reviewed by us in an earlier publication (5). Despite the results of several double-blinded studies in which acute pain did not benefit from DM (5), many others found it useful. The beneficial effects of pre- and postincision oral DM on postoperative pain had first been studied in patients undergoing general surgery (5,11,23), whereby the consumption of morphine and other analgesics were found to be reduced compared with placebo-treated individuals. A single DM premedication dose of 30 or 45 mg orally administered 60 min before tonsillectomy was effective in reducing post-tonsillectomy pain sensations in adult patients, even on swallowing, in addition to reducing the pain score and diclofenac requirement for up to 7 days (23). The same efficacy was reported when 40 mg oral DM was given to patients who had also been premedicated the night before surgery and 3 times/day for 48 hours after hysterectomy, and there were very few side effects (30). When comparing pre- versus postincisional 40 mg DM given IM, the authors found that the former produced better postoperative pain relief and reduced meperidine IM consumption during the 48 hours after laparoscopic cholecystectomy in adult patients than did postincisional administration (31).
Our group was the first—and apparently the only one thus far—to assess the effectiveness of oral 60 and 90 mg DM in patients who were operated under epidural anesthesia (11,12). In a subsequent study on orthopedic oncological patients, we also showed that IV-PCA morphine consumption and pain intensity, as well as other subjectively rated variables, were better in the patients who were treated orally with 90 mg DM (13). We believe the present report to be the first investigation to show the possible benefits of DM administration in association with both IV-PCA or PCEA analgesia in patients undergoing major surgery for bone malignancy under combined general and epidural anesthesia. This anesthesia technique has been proven to better preempt perioperative pain and is associated with reduced levels of stress hormones, anxiety, and depression as compared with general anesthesia alone, although transiently (2–4), thus it is very much applicable to the extensive painful procedures that our patients were expected to experience as compared with more limited procedures that were performed in our previous studies (11,12).
We briefly note that although several studies found PCEA to have better effects as compared with IV-PCA, even in orthopedic procedures (13,32,33), none dealt with either orthopedic oncological patients or its use after combined general and epidural anesthesia. In this regard, one limitation of our study’s methodology is that the two techniques could not be blinded; nevertheless, they could be compared for the number of “excessive” users in each set because our study patients used the PCA device in each of them.
The incidence of side effects is indicative of the clinical applicability of an analgesic regimen. No patient withdrew from the present study and all untoward side effects were temporary and tolerable. This is compatible with the results in our previous studies (8,11–13) in patients premedicated either once or three times with DM. The relative lack of side effects in the DM patients, even though the drug was administered for three consecutive days, may attest to its appropriate dosage and overall safety in opposition to the conclusions of others (24,34). From a clinical perspective, despite the possible relative sympatholytic effect of ropivacaine, neither it nor DM affected the patients hemodynamically, and there were no detectable signs of respiratory depression despite the addition of fentanyl to the epidural solution. The combined DM plus PCEA effect did not worsen sedation: rather, it was associated with better feelings of well-being. These data are also consistent with the findings of our previous studies (8,11–13). Nevertheless, we are of the opinion that our sedation scores are slightly better compared with those reported elsewhere, probably because of the subjective method of collecting the data and because of the patients using fewer IV opioids. Also, the overall small number of side effects among the PCEA patients compared with both our present and previous studies where IV-PCA was administered in orthopedic oncological patients (13) also supports our earlier contention that morphine and general anesthesia were the main causes for the side effects during the first two postoperative days. Thus, the remarkable level of safety of DM (5,10) is particularly promising for the orthopedic oncological patients who characteristically use large postoperative dosages of analgesics. Finally, it is reasonable that more PCEA patients would require an indwelling catheter after the first 24 h postoperatively, with no distinction between DM and placebo patients, despite the proven lack of a motor block.
The observation that DM patients benefited from early ambulation although no difference was found between the two sets of analgesia techniques with regard to first ambulation is of singular importance because of the nature of the procedures that our patients underwent and the possible respiratory complications associated with them. This was one of our expectations when using DM in association with postoperative PCEA versus the PCA-morphine (13). We suspected that PCEA patients would ambulate earlier than the IV-PCA patients, possibly because they were less sedated, but this did not occur; rather, the PCEA set of patients were out of bed only slightly earlier. Indeed, previous attempts have failed to demonstrate any significant differences between IV-PCA and PCEA in this regard (35), despite the fact that regional anesthesia seems to reduce surgical morbidity (36). The present finding of DM-associated early ambulation is the first report of its kind. We had previously failed to demonstrate this benefit (13), probably because of the limited population size. The same weight of importance should be given to the time the patients were discharged home, and both variables appear to be important indications of the patient’s rate and quality of recovery.
In conclusion, oral DM 90 mg given once preoperatively and for 2 additional days postoperatively helped to reduce pain intensity. It minimized sedation and spared analgesics for ∼48 hours after bone malignancy surgery operation when administered with IV-PCA as well as with PCEA. The DM effect, however, was more evident in the PCEA than in the IV-PCA set of patients. There was no apparent negative effect of continuous DM administration at the described dose, but rather a better feeling of well-being and quicker ambulation, although it was not shown to accelerate the time of discharge home. The results of this evaluation in orthopedic oncological patients with severe postoperative pain (1,37) add information to our previous assessment of DM in a similar milieu (13) and suggest that the combined DM and PCEA pain control techniques are optimal and superior to the IV-PCA technique.
The authors thank Esther Eshkol for editorial assistance.
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