Opioids have been used to alleviate moderate to severe pain. It was suggested that exposure to opioids can, paradoxically, cause a state of nociceptive sensitization, often referred to as opioid-induced hyperalgesia.1 Remifentanil is an ultrashort-acting opioid widely used as an intraoperative anesthetic because it provides adequate and controllable analgesia with a rapid onset of action. However, several studies in healthy volunteers demonstrated that IV infusion and withdrawal of remifentanil produces hyperalgesia.2–4 In the clinical setting, a high dose of intraoperative remifentanil increased postoperative pain and opioid consumption,5,6 whereas relatively low doses of intraoperative remifentanil were not associated with increased postoperative pain or opioid consumption.7,8 Joly et al.6 showed direct evidence that relatively high-dose intraoperative remifentanil induced hyperalgesia, leading to an increase of morphine consumption.
Postoperative hyperalgesia induced by either opioids or tissue damage received particular attention for several reasons. Hyperalgesia may augment postoperative pain because the amplification of noxious stimuli and sensitization, expressed as hyperalgesia, is considered a possible mechanism for the development of chronic pain after surgery.9–12 Thus, preemptive antihyperalgesia, in addition to analgesia, might be beneficial in the management of pain. The precise mechanism implicated in postoperative hyperalgesia is not yet entirely understood but central sensitization via N-methyl-D-aspartate (NMDA) receptor activation has been supposed to have an important role.1,13 Magnesium is an NMDA receptor antagonist and is thought to be involved in the modulation of pain.14–16 Previous studies in rats showed that the administration of magnesium sulfate suppressed fentanyl-induced hyperalgesia.17,18 Clinically, magnesium has been tried as an adjuvant in the management of postoperative pain, although the evidence of an effect of magnesium on the management of postoperative pain is not convincing.19 However, its antihyperalgesic property has not yet been tested in a postoperative setting.
We investigated whether an intraoperative high versus low dose of remifentanil increases postoperative hyperalgesia and whether intraoperative magnesium can prevent remifentanil-induced hyperalgesia in patients undergoing elective thyroidectomy.
This study was approved by the Institutional Ethics Committee of Yonsei University Health System (Ref.: 4-2009-0511) and registered with clinicaltrials.gov (Ref.: NCT01025245). Written informed consent was obtained from patients before randomization. Ninety patients scheduled for elective thyroidectomy were enrolled. Patients were included if they were 20 to 65 years old and ASA physical status I or II. The exclusion criteria were (1) history of chronic pain, drug or alcohol abuse, or psychiatric disease; (2) current regular use of analgesics, anticonvulsants, or antidepressants; (3) opioids taken within 24 hours of surgery; (4) renal disorder with a low glomerular filtration rate; (5) neuromuscular disorder; and (6) severe cardiac disease.
The evening before surgery, patients were instructed in the use of the verbal numerical rating scale (VNRS) and given a quantitative sensory test (QST) of mechanical pain threshold using von Frey filaments. Patients were randomized by computer-generated codes into 1 of 3 groups described below, and the group assignment for each patient was kept in sequentially numbered, sealed envelopes.
On the day of surgery, patients were premedicated with midazolam 0.05 mg/kg IM 30 minutes before induction of anesthesia. Anesthesia was induced with thiopental 4 to 5 mg/kg, followed by remifentanil 0.5 μg/kg. According to group assignment, an initial bolus of normal saline or magnesium sulfate was started. Endotracheal intubation was facilitated with rocuronium 0.7 mg/kg. After induction, patients underwent one of the following regimens: group LO received continuous infusion of remifentanil at 0.05 μg/kg/min and saline placebo. Group HI received a continuous infusion of remifentanil at 0.2 μg/kg/min and a saline placebo. Group HM received a continuous infusion of remifentanil at 0.2 μg/kg/min with an initial bolus of magnesium sulfate at 30 mg/kg over 15 minutes, followed by a maintenance infusion at 10 mg/kg/h. The dose of magnesium sulfate was based on previous trials that evaluated the analgesic effect of magnesium, ranging from a bolus of 30–50 mg/kg followed by an infusion at 8–15 mg/kg/h.19,20 We chose this dose because we expected that the antihyperalgesic effect of magnesium could result in decreased postoperative pain, and administration of magnesium at these doses did not provide significant adverse events. Remifentanil with magnesium sulfate or saline was administered until skin closure. Syringes containing remifentanil, magnesium sulfate, or saline were prepared and draped during anesthesia by a nurse who was not involved in the management and evaluation of patients. All other investigators were blinded to the group assignment. Anesthesia was maintained with remifentanil at the dose described above and sevoflurane at an end-tidal concentration of 1.6 vol% in 50% oxygen/air. An increase of ≥20% in systolic arterial blood pressure or heart rate (HR) from the baseline value, coughing, moving, and tearing were considered signs of inadequate anesthesia. In these cases, the sevoflurane concentration was increased by 0.3 vol% stepwise. Hypotension was defined as a mean arterial blood pressure (MAP) <60 mm Hg. In cases of hypotension, the sevoflurane concentration was decreased by 0.3 vol% stepwise. If hypotension persisted at 1.0 vol% end-tidal concentration of sevoflurane, additional IV fluids and an intermittent bolus of ephedrine 4 mg were given, as necessary. IV atropine 0.5 mg was administered to treat severe bradycardia (HR <45 bpm). Ondansetron 4 mg was given IV for prophylaxis of postoperative nausea and vomiting (PONV) 15 minutes before the end of surgery. After skin closure, administration of sevoflurane was stopped, and neostigmine 0.04 mg/kg with glycopyrrolate 0.008 mg/kg was given to antagonize any residual neuromuscular blockade. Antagonism of neuromuscular blockade was confirmed by the absence of visible fade on supramaximal double-burst stimulation at the orbicularis oculi. Tracheal extubation was performed when patients were able to respond to verbal commands, and the spontaneous respiratory rate exceeded 12 breaths/min.
HR and MAP were recorded before and after induction, at intubation, 1 hour after intubation, and at skin closure, extubation, and admission to the postanesthesia care unit (PACU). The total dose of remifentanil and magnesium sulfate during anesthesia, use of ephedrine, awakening time, and extubation time were recorded. Body temperature was maintained at 36.0°C ± 0.5°C. Awakening and extubation times were defined as time from remifentanil discontinuation to patients' responses to a verbal command and extubation, respectively.
In the PACU, patients were treated with fentanyl 1 μg/kg at each time they reported a VNRS score >4 or requested analgesics. After transfer to the general ward, patients were given tramadol 37.5 mg/acetaminophen 325 mg combination tablet (Ultracet®; Janssen Korea Ltd., Seoul, Republic of Korea), 1 tablet per os 3 times per day. Tramadol 50 mg IM was given as a rescue analgesic upon patient request or reported VNRS score >4.
Pain intensity was assessed by an 11-point VNRS (0–10; 0, no pain; 10, worst and intolerable pain) for 48 hours postoperatively, subdivided into 4 time periods: at PACU, 1 to 6 hours, 6 to 24 hours, and 24 to 48 hours. The worst pain during each time period was recorded. Possible complications, including PONV, dizziness, headache, drowsiness, and shivering, were also recorded at the same time. The intensity of nausea was assessed by an 11-point VNRS (0–10; 0, no nausea; 10, worst and intolerable nausea). The severity of PONV was determined according to VNRS score and presence of retching or vomiting: mild (1–3), moderate (4–6), and severe (7–10 or presence of retching, vomiting). Serum Ca2+ was measured at 2, 24, and 48 hours after surgery.
Mechanical Pain Threshold
The mechanical pain threshold was assessed using von Frey filaments (Touch Test™ Sensory Evaluators; Stoelting Co., Wood Dale, IL) preoperatively and repeated at 24 and 48 hours after surgery on the nondominant forearm and periincisional regions. With the patient's eyes closed, the investigator pressed the filament perpendicularly against the skin until it bowed and held it in place for approximately 1.5 seconds. The von Frey filament application started with the filament of target force 0.4 g and continued in ascending order of size, until the patient indicated the onset of pain as perceptional change from light touch to pricking sensation. Four additional applications were then performed according to the rules as follows. The responses, pricking sensation, were followed by a decrease in filament size. The nonresponses, touch sensation, were followed by an increase in filament size. The mechanical pain threshold (EI50) was calculated from the last 6 sequences (the first change of nonresponse to response and 4 applications thereafter) using Dixon's up-and-down method for small samples.21 The cutoff force ranged from 0.4 to 180 g. EI50 was calculated by the formula EI50 = Xf + kd, where Xf is the last intensity applied, k is the tabulated value for maximum likelihood estimate, and d is the log interval between intensities. Mechanical pain thresholds on the forearm were measured on areas 3, 6, and 9 cm distal to the middle of the antecubital crease of the nondominant arm, and a mean value was calculated. Periincisional mechanical pain thresholds were measured on an area 2 cm below the incision at 3 points (both ends and middle of the horizontal skin incision), and a mean value was calculated. Each measurement on the forearm and periincisional area was performed with an interval of 30 seconds.
In a preliminary study, periincisional mechanical pain thresholds at 24 hours after surgery were 3.0 ± 0.3 for group LO, 2.7 ± 0.5 for group HI, and 3.1 ± 0.4 for group HM (values are log10 of force in milligrams). The estimated sample size was 28 patients per group with a power of 80% at an α level of 0.05. Thus, the study size was set at 30 patients per group. Patient and anesthetic characteristics were analyzed using analysis of variance, χ2 test, or Fisher exact test, where appropriate. Mechanical pain thresholds, HR, MAP, and end-tidal sevoflurane concentrations were analyzed using a mixed model with covariance pattern model, in which unstructured covariance structure was chosen according to the least Akaike information criteria. Pain intensities were analyzed using the Kruskal-Wallis test. In cases of statistical significance, post hoc tests were conducted with Bonferroni adjustment. P values multiplied by a number of tests (3 × number of time point) were shown. Correlation of pain thresholds, pain intensities, and analgesic consumption were analyzed with Pearson correlation analysis. Values are expressed as mean ± SD, median (interquartile range), or the number of patients. Statistical analysis was performed with SAS (version 9.1.3; SAS Institute, Inc., Cary, NC). P < 0.05 was considered to be statistically significant.
Enrollment, group assignment, and analysis are shown in Figure 1. Patients and anesthetic characteristics were not significantly different among groups except total doses of remifentanil and magnesium sulfate and the number of patients treated with ephedrine (Table 1). There were more patients requiring ephedrine to treat hypotension in group HI than in group LO (10 vs 1, P = 0.008, Fisher exact test; Table 1).
Mechanical pain thresholds on the periincisional area and forearm were decreased at 24 and 48 hours postoperatively from their preoperative values in all 3 groups (P < 0.001, mixed model; Fig. 2). However, the decrease in pain threshold on the periincisional area from the preoperative values differed in degree according to the group. There was a larger decrease in pain threshold on the periincisional area at 24 and 48 hours postoperatively in group HI, as compared with the other 2 groups (P = 0.0007 and P = 0.0002 to group LO, P = 0.0001 and P = 0.0001 to group HM, mixed model; Fig. 2A). The 95% confidence intervals (CIs) for the mean difference of pain thresholds on the periincisional area at 24 and 48 hours postoperatively were 0.31 to 1.11 and 0.36 to 1.14 for group HI versus group LO, 0.45 to 1.26 and 0.54 to 1.32 for group HI versus group HM (values are log10 of force in milligrams). The change in pain threshold on the forearm was similar among the groups (P = 0.057, mixed model; Fig. 2B).
Pain intensities were similar among the 3 groups except at 48 hours postoperatively (Table 2). Group HI showed higher VNRS scores (median [interquartile range], 3 [2–4]) than group LO (2 [1–3], P = 0.0003, Kruskal-Wallis test) and group HM (2 [1–3], P = 0.0005, Kruskal-Wallis test) at 48 hours postoperatively. The 95% CIs for median difference in VNRS scores at 48 hours postoperatively were 1 to 2 for group HI versus group LO and 0 to 2 for group HI versus group HM. No correlation was observed between pain threshold on the periincisional area and pain intensities (Table 3). There were no significant differences in the number of patients who requested rescue analgesics in the PACU (P = 0.379, χ2 test) and in the general ward for 48 hours postoperatively (P = 0.104, χ2 test) among the 3 groups (Table 2). The number of doses of rescue analgesic in the PACU (P = 0.371, Fisher exact test) and in the general ward for 48 hours postoperatively (P = 0.170, Fisher exact test) was also similar among the groups. The 95% CI ranged widely for the difference in the percentage of patients who requested rescue analgesics in the PACU or for 48 hours postoperatively in the general ward (Table 2). No correlation was observed between pain threshold on the periincisional area and amount of rescue analgesic consumed for 48 hours postoperatively (Table 3).
Patients in group HM had a slower HR than those in group LO at 1 hourafter tracheal intubation (P = 0.010, mixed model; Table 4). MAP was lower in group HM than in groups LO and HI at intubation (P < 0.001 and P = 0.042; Table 4). In group LO, the end-tidal sevoflurane concentration was higher at 1 hour after intubation (P < 0.001 to group HI and HM) and skin closure (P = 0.007 to group HM, mixed model; Table 4).
There were no significant differences among the 3 groups in the incidence and severity of PONV, headache, dizziness, drowsiness, shivering, or treatment for hypocalcemia (mixed model; Table 5).
In this study, a relatively high dose of intraoperative remifentanil aggravated postoperative hyperalgesia, and intraoperative administration of magnesium prevented remifentanil-induced hyperalgesia.
Studies in healthy volunteers provided direct evidence for the existence of opioid-induced hyperalgesia even at low doses.2–4 However, increased postoperative pain or analgesic consumption, which could be an indirect clinical manifestation of opioid-induced hyperalgesia or acute tolerance in surgical patients, seems to be dependent on the doses of intraoperative remifentanil. Guignard et al.5 reported that a relatively high dose of intraoperative remifentanil was associated with increased postoperative pain and morphine consumption. This association was not shown in other studies,7,8 and these studies used lower doses of remifentanil than that in the study by Guignard et al. Moreover, without direct measures to assess hyperalgesia such as QST, the results are not easy to distinguish from acute tolerance.22 Clinical studies examining remifentanil-induced hyperalgesia by QST showed that, at a relatively high dose, remifentanil decreased the pain threshold,6,23 as shown in our results.
The mechanisms of remifentanil-induced hyperalgesia are not certain, but activation of the NMDA receptor system has been implicated in the development of opioid-induced hyperalgesia.1,13 Ketamine, an NMDA receptor antagonist, suppressed remifentanil-induced hyperalgesia in experimental studies3,4 and prevented aggravation of postoperative hyperalgesia in patients receiving relatively large doses of intraoperative remifentanil.6 Magnesium physiologically blocks the ion channel associated with the NMDA receptor at a normal membrane potential.24 Triggering of central sensitization involves neuronal depolarization, removal of the voltage-dependent magnesium block of the NMDA receptor, and entry of calcium ions into the postsynaptic neuron.25 Several experimental studies suggested a role of magnesium in the modulation of neuropathic pain.15,16 Also, magnesium deficiency induced hyperalgesia in rats, which was reversed by MK801, an NMDA receptor antagonist.14 Intraperitoneal administration of magnesium sulfate prevented hyperalgesia induced by subcutaneous fentanyl in rats.17 Intraplantar coadministration of fentanyl and magnesium prevented delayed hyperalgesia in rats.18 There has been little direct evidence that magnesium prevents opioid-induced hyperalgesia in humans. The results of our study suggest that magnesium might have a preventive effect on remifentanil-induced hyperalgesia.
Unlike what occurred in the periincisional area, a high dose of remifentanil did not significantly aggravate mechanical hyperalgesia on the forearm. Postoperative hyperalgesia can be induced either by drugs, such as remifentanil, or surgical nociception, a consequence of tissue and nerve trauma.12 Opioid- and nociception-induced hyperalgesia may have synergistic effects,26 and the lack of primary nociceptive input on the forearm could have affected the result.
This study showed poor correlation between opioid-induced hyperalgesia and clinical postoperative pain. We did not observe differences in pain intensity or rescue analgesic consumption among groups. Patients in group HI reported higher VNRS scores than the other 2 groups at 48 hours after surgery (VNRS score of 3 in group HI and 2 in groups LO and HM), which can hardly be regarded as clinically relevant. Whereas some studies reported the relation between the hyperalgesia on QST and clinical pain measures,6,10,27–29 others found a poor correlation between them,30,31 possibly because of multifactorial modulation of clinical pain. In addition, considering that hyperalgesia could be regarded as a sort of evoked pain, the presence of hyperalgesia might be more related to evoked pain by ambulation, coughing, or deep breathing than spontaneous pain. In our study, postoperative pain after thyroid surgery may be mostly characterized by spontaneous pain rather than evoked hyperalgesia. Aside from analgesic efficacy, the antihyperalgesic effect of magnesium could be clinically relevant because opioid-induced hyperalgesia may be one of the potential risk factors for the development of chronic pain after major surgery such as thoracotomy or laparotomy.9–12
Adverse events related to the administration of magnesium were not increased, although our study was underpowered to detect the difference in adverse effects. Hypermagnesemia can result in myocardial depression, cardiac conduction disturbance, and bradycardia. Patients receiving intraoperative magnesium had relatively low MAPs at intubation in this study, which could have been attributable to the magnesium bolus at that time. The number of patients who required ephedrine intraoperatively did not differ according to the magnesium treatment at the same dose of remifentanil. Magnesium can also enhance neuromuscular blockade. Czarnetzki et al.32 reported that administration of magnesium sulfate 60 mg/kg 15 minutes before induction reduces the onset time of rocuronium by approximately 35% and prolongs the total recovery time by approximately 25%. Also, the clinical model of rocuronium's action was prolonged in patients receiving a bolus of magnesium 4 g followed by maintenance infusion at 2 g/h for the treatment of preeclampsia.33 However, the amount of magnesium administered in this study was approximately half of the dose for the usual treatment of preeclampsia, and no patient exhibited clinical signs of profound neuromuscular blockade or experienced delayed extubation at the end of surgery. Administration of a large dose of magnesium, for example, in the treatment of preeclampsia, may cause transient hypocalcemia due to renal calcium loss or inhibition of parathyroid function.34,35 We administered a smaller amount of magnesium than used for the treatment of preeclampsia, and there were no differences in postoperative serum calcium concentrations or the number of patients receiving treatment for hypocalcemia. However, interpretation of hypocalcemia, a common complication after thyroidectomy, could possibly be confounded by the administration of magnesium.36
There are several limitations to our study. First, we did not measure serum magnesium concentrations. Magnesium deficiency can induce a decrease in the nociceptive threshold.14 We are not certain whether the increase in mechanical pain threshold with magnesium in our study was attributable to an effect of supraphysiologic levels of serum magnesium or prevention of hypomagnesemia. However, it is unlikely that our patients who were relatively healthy and receiving minor surgical intervention had significant perioperative hypomagnesemia. Second, the dose of remifentanil we used for the high-dose group was smaller than that used in other studies showing positive results. We could not administer a dose, such as 0.4 μg/kg/min, because of severe bradycardia and possible hypotension. The dose of remifentanil used in this study may be enough to induce hyperalgesia. Third, we assessed pain intensity 4 times during the study period and retrospectively recorded the worst pain during each time period. This assessment could have been biased because it was dependent on patients' recall. Also, more frequent assessments would be helpful to detect clinical relevance. Fourth, we did not quantitatively measure prolongation of neuromuscular blockade. Because magnesium can enhance the action of neuromuscular blocking drugs according to the dose administered, special caution is needed.
In conclusion, a relatively high dose of intraoperative remifentanil infusion aggravated postoperative hyperalgesia, and coadministration of magnesium sulfate prevented remifentanil-induced hyperalgesia in patients undergoing thyroidectomy. However, postoperative hyperalgesia did not show clinical relevance in terms of postoperative pain or analgesic consumption in patients undergoing thyroidectomy.
Name: Jong Wook Song, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Jong Wook Song has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Youn-Woo Lee, MD, PhD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Attestation: Youn-Woo Lee has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Kyung Bong Yoon, MD, PhD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Attestation: Kyung Bong Yoon has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Soo Jung Park, MD.
Contribution: This author helped conduct the study and analyze the data.
Attestation: Soo Jung Park has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Yon Hee Shim, MD, PhD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Yon Hee Shim has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
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