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ANALGESIA

Ketamine and Lornoxicam for Preventing a Fentanyl-Induced Increase in Postoperative Morphine Requirement

Yu Xuerong, MD^*, Huang Yuguang, MD^*, Ju Xia, MD, and Wang Hailan, MD

From the *Department of Anesthesiology, Peking Union Medical College Hospital, China; Department of Anesthesiology, Anqing Hospital, Anhui Province, China; and Department of Anesthesiology, The 4th People’s Hospital of Hengshui, Hebei Province, China.

Address correspondence and reprint requests to Huang Yuguang, MD, Department of Anesthesiology, Peking Union Medical College Hospital, Shuaifuyuan No.1, Dongcheng District, Beijing, China. Address e-mail to yxr313{at}yahoo.com.cn.

Abstract

BACKGROUND: N-methyl-d-aspartate receptor antagonists and nonsteroidal anti-inflammatory drugs are believed to prevent opioid-induced hyperalgesia and/or acute opioid tolerance, which could cause an increase in postoperative opioid requirement. In this randomized, double-blind, placebo-controlled study, we investigated whether co-administration of ketamine or lornoxicam and fentanyl could prevent the increase of postoperative morphine requirement induced by fentanyl alone.

METHODS: Ninety females undergoing total abdominal hysterectomy with spinal anesthesia were randomly assigned to six groups consisting of placebo (normal saline, C), fentanyl (three bolus of 1 µg · kg^–1, F), ketamine (infusion of 15 µg · kg^–1 · min^–1, K), ketamine and fentanyl (infusion of 15 µg · kg^–1 · min^–1 ketamine plus three bolus of 1 µg · kg^–1 fentanyl, FK), lornoxicam (one bolus of 8 mg, L), and lornoxicam and fentanyl (one bolus of 8 mg lornoxicam plus three bolus of 1 µg · kg^–1 fentanyl, FL). Cumulative morphine consumption, pain score, and adverse effects were recorded at 1, 3, 6, 12, 24, and 48 h postoperatively.

RESULTS: Cumulative morphine consumption in Group F was significantly more than that in Group C at 3, 6, and 12 h postoperatively (P < 0.05). Postoperative cumulative morphine consumption was similar in Groups C, K, FK, L, and FL. No differences in postoperative pain scores were observed among groups. More patients in Groups K and FK had hallucinations during and/or after surgery than those in Group C (P < 0.05).

CONCLUSIONS: Our data suggest that the increase of postoperative morphine requirements induced by intraoperative administration of fentanyl could be prevented by ketamine or lornoxicam.

Opioids are widely used in the perioperative period because of their profound analgesic effect. However, some recent experimental and clinical data point to the development of two phenomena after acute exposure to opioids: acute opioid tolerance and hyperalgesia.1,2 Tolerance to opioids is defined as a progressive reduction of their analgesic effect, thus explaining the need for a larger dose to achieve the same pharmacological effect. Opioid-caused-hyperalgesia means a more than normal sensitivity to pain that may result from a painful stimulus or a lowered pain threshold after opioid administration. Other than classical central sensitization provoked by the injury itself, opioid treatment is believed to induce an enhancement of postoperative hyperalgesia. Both of these two phenomena may lead to an increase in opioid requirement in the postoperative period.3–6

Activation of N-methyl-d-aspartate (NMDA) receptors in the spinal cord has been shown to play a pivotal role in the development and maintenance of central neuron sensitization underlying the behavioral manifestations of pain, such as hyperalgesia, allodynia, and spontaneous pain.7 Moreover, NMDA receptor antagonists also enhance opioid-induced analgesia and prevent opioid tolerance or opioid-induced hyperalgesia.7–9 Ketamine is a noncompetitive antagonist of the phencyclidine site of the NMDA receptor. Low doses have been proposed to prevent opioid-induced tolerance and hyperalgesia.10 Therefore, numerous investigators have tried to prevent the occurrence of acute opioid tolerance and/or hyperalgesia by co-administration of ketamine and opioids. Some studies were conclusive,3,11,12 whereas others failed to demonstrate any effect of ketamine.5

Lornoxicam is a nonsteroidal anti-inflammatory drug (NSAID) with potent analgesic and anti-inflammatory activity and belongs to the class of oxicams. NSAIDs produce their therapeutic effect by inhibiting cyclooxygenase (COX) activity and thus reducing prostaglandins synthesis. The combination of NSAIDs with morphine has been used clinically for pain management for decades, particularly for terminal cancer patients.13 The interactions of NSAIDs and morphine have also been reported for the visceral nociception and neuropathic pain model.14 More recently, some researchers showed that COX inhibitors could attenuate opioid tolerance in animal models15 and in humans.16

The purpose of this randomized, placebo-controlled, double-blind study was to test the hypothesis that co-administration of low-dose ketamine or lornoxicam combined with fentanyl could prevent the increase of postoperative morphine requirement induced by intraoperative administration of fentanyl alone.

METHODS

The study was approved by the Human Investigation Committee of Peking Union Medical College Hospital. After obtaining written informed consent, 90 ASA physical status I-II female patients undergoing total abdominal hysterectomy were recruited for the randomized, placebo-controlled, double-blind study. The age of these patients was between 18 and 65 yr. Exclusion criteria included a history of diabetes, chronic pain, psychiatric disease, hypersensitivity to ketamine, lornoxicam or opioids, the administration of an opioid within the 2 wk before surgery, drug or alcohol abuse, or the inability to understand the use of a patient-controlled analgesia (PCA) device. According to a computer-generated table of random number assignments, each patient was assigned to one of six double-blind groups. All studied solutions were prepared by an anesthesiologist who was not involved in the patient’s care. The patient, the surgeon, the anesthesiologist who delivered anesthesia and the nurse who recorded the postoperative data also were blinded to the study solutions. After collecting all the data, randomization was revealed and the statistical analysis was done.

The day before surgery, patients were taught how to use the visual analog scale (VAS; 0 = no pain, 10 = worst imaginable pain) and the PCA pump. They were specifically instructed to self-deliver analgesia any time they began to feel pain. Each patient and nurses who would record postoperative data were told that patients might have one or several drug side effects (nausea, vomiting, hallucination, dizziness, and itching) during or after surgery.

Before anesthesia in each patient, an anesthesiologist, who was not involved in the patient’s care, prepared three syringes according to the randomization list. The first syringe contained the bolus dose. For the lornoxicam group (L) and the fentanyl-lornoxicam group (FL), the syringe contained 4 mg · mL^–1 of lornoxicam. For the other groups, the syringe contained normal saline of the same volume. For continuous infusion, the second syringe, with a capacity of 50 mL, contained either 30 µg · kg^–1 · mL^–1 (according to the patient’s body weight) of ketamine for the ketamine group (K) and the fentanyl–ketamine group (FK) or normal saline for the other groups. The third syringe contained 50 µg · mL^–1 of fentanyl for the F group, the FK group, and the FL group or the same volume of normal saline for the other groups.

All patients received standard spinal anesthesia. Heavy specific gravity bupivacaine 3 mL (total 10 mg) was given. The anesthesia level was controlled between T4 and T6. All patients were administered midazolam 0.05 mg · kg^–1 10 min before surgery. Five minutes before skin incision, 2 mL of the bolus in the first syringe was administered IV. For Groups L and FL, this corresponded to a dose of 8 mg of lornoxicam. After skin incision, a continuous infusion of 30 mL · h^–1, contained in the second syringe, was delivered by an infusion pump and was continued until 20 min before the end of the surgery. In Groups K and FK, this corresponded to a ketamine dose of 15 µg · kg^–1 · min^–1. From 5 min after skin incision, all patients received three boluses in the third syringe at 15-min intervals. This corresponded to a dose of 1 µg · kg^–1 per bolus, resulting in total doses of 3 µg · kg^–1 of fentanyl for Groups F, FK, and FL. Arterial blood pressure, heart rate, oxygen saturation, duration of surgery, postoperative sensory block time, and adverse effects (nausea, vomiting, dizziness, and hallucination) during surgery were noted.

The PCA device was connected IV after surgery. It was programmed to deliver a bolus of 1 mg of morphine on demand, with a lockout interval of 5 min and without a background infusion. No other analgesics were administered during the 48-h observation period. At 1, 3, 6, 12, 24, and 48 h, analgesia was recorded using a VAS at rest, ranging from 0 (no pain) to 10 (worst imaginable pain). At the same time points, the cumulative amount of PCA morphine and adverse effects (nausea, vomiting, hallucination, dizziness, and itching) were noted.

Postoperative morphine consumption was used to calculate the statistical power. Based on previous studies within our research team, the mean morphine consumption for the initial postoperative 48 h in these patients was 27 mg (standard deviation, 10 mg). We considered a 40% difference in morphine consumption between the control group (C) and the other five groups individually to be clinically relevant. A sample size estimate indicated that at least 14 patients per group would give a power of 80% at an level of 0.05 for detecting a difference in morphine consumption of at least 40%. The study size was thus prospectively set to 90 patients.

All statistical analyses were performed using SPSS 11.0. Variables were presented as mean ± sd and were evaluated with a nonparametric analysis of variance. Patient characteristic data and the rates of adverse effects were compared by using a ² test. A significance level of 0.05 was used.

RESULTS

Ninety patients, 15 per group, were enrolled in this study. None were excluded. The six groups were matched for age, weight, duration of surgery, and postoperative sensory block time (Table 1).

Table 2 and Figure 1 show cumulative morphine consumption for Groups C, F, K, and FK across the 48-h study period. Patients in Group F consumed more morphine (3rd h: 10.8 ± 6.1 mg; 6th h: 16.2 ± 8.3 mg; 12th h: 21.2 ± 10.6 mg) than those in Group C (3rd h: 6.1 ± 3.1 mg; 6th h: 9.5 ± 5.0 mg; 12th h: 14.3 ± 6.5 mg) at the 3rd, 6th, and 12th h postoperatively. Cumulative PCA morphine consumption did not differ significantly during any of the intervals among Groups C, K, and FK. All patients had similar VAS values at rest at all times postoperatively (Table 3).

View larger version (9K): [in this window] [in a new window]   Figure 1. Cumulative postoperative morphine consumption of Groups C (control), F (fentanyl), K (ketamine), and FK (fentanyl+ketamine) in the initial 48 h after total abdominal hysterectomy (n = 15). *Cumulative postoperative morphine consumption was significantly more in Group F than in Group C at 3, 6, and 12 h after surgery (P < 0.05). Cumulative postoperative morphine consumption was similar in Groups C, K, and FK at each time point in the initial 48 h after surgery (P > 0.05).

Table 2 and Figure 2 show cumulative morphine consumption for Groups C, F, L, and FL across the 48-h study period. Cumulative PCA morphine consumption did not differ significantly during any of the intervals among Groups C, L, and FL. All patients had the similar VAS values at rest at any time point postoperatively (Table 3).

View larger version (13K): [in this window] [in a new window]   Figure 2. Cumulative postoperative morphine consumption of Groups C (control), F (fentanyl), L (lornoxicam), and FL (fentanyl+lornoxicam) in the initial 48 h after total abdominal hysterectomy (n = 15). *Cumulative postoperative morphine consumption was significantly more in Group F than in Group C at 3, 6, and 12 h after surgery (P < 0.05). Cumulative postoperative morphine consumption was similar in Groups C, L, and FL at each time point in the initial 48 h after surgery (P > 0.05).

The incidences of intraoperative and postoperative nausea and/or vomiting are shown in Table 4. There was no significant difference among groups (P > 0.05). More patients in Groups K and FK had hallucinations during and/or after surgery than those in Group C (P < 0.05). No patient reported dizziness or itching after surgery.

DISCUSSION

The results of the present study show that intraoperative administration of 3 µg · kg^–1 fentanyl induces greater postoperative morphine consumption in patients undergoing total abdominal hysterectomy. Cumulative postoperative morphine consumption was significantly larger in Group F than in Group C at 3, 6, and 12 h after surgery. Because patients used the PCA system and were instructed to self-deliver analgesia at any time they began to feel pain, postoperative VAS at rest during the first postoperative 48 h was similar in all groups. These findings support the hypothesis that intraoperative administration of fentanyl is associated with the development of clinically relevant acute opioid tolerance or hyperalgesia, but we have no evidence to distinguish between these two phenomena. Some evidence suggested that opioid analgesics could elicit delayed hyperalgesia (exaggerated nociceptive response to noxious stimulation) in experimental models after repeated opioid administration7 or continuous delivery.17,18 Increasing pain sensitivity could explain a reduction of the opioid analgesic effect. If hyperalgesia is not considered, it will give the impression of less analgesia (i.e., apparent tolerance) when a new opioid is administered.8 If tolerance and pain facilitation share some common pathways, then animals (or humans) with acute tolerance to opioids should develop hyperalgesia after opioid administration. There are several studies supporting the hypothesis that a mixture of these two phenomena (tolerance and delayed hyperalgesia) may be produced by acute exposure to large doses of opioids.9,17,19 Further studies should be performed to distinguish between these two mechanisms to demonstrate which is more effective.

We hypothesized that acute opioid tolerance or opioid-induced hyperalgesia may be more likely to occur with large doses of short-acting drugs such as remifentanil. Many studies focused on remifentanil, which can cause hyperalgesia and acute opioid tolerance.1–3,6,12,16 Because fentanyl has a longer duration than remifentanil, Chia et al.4 reported that patients receiving high-dose fentanyl for total abdominal hysterectomy had higher pain intensity at 4 and 8 h postoperatively, more fentanyl consumption and more frequent incidence of emesis in the 16-h postoperative period than those in the low-dose group. The dosage of the high-dose and low-dose group was 15 and 1 µg · kg^–1, respectively. In that study, it was not possible to deny the control group intraoperative analgesia. In the present study, patients received spinal anesthesia, so that intraoperative analgesia was not necessary. We found that, compared with the control group, a smaller dose of fentanyl of only 3 µg · kg^–1 could also increase postoperative opioid consumption.

Tolerance to opioids or hyperalgesia induced by intraoperative opioid administration may develop within minutes. In the present study, however, cumulative postoperative morphine consumption was similar in Group F and Group C at 1 h postoperatively. This may have been due to postoperative sensory block, which was recovered after 70 to 90 min postoperatively.

In this study, patients who received ketamine combined with fentanyl before and during the operation (Group FK) had the same cumulative postoperative morphine consumption as the patients in Group C during the first 48 h after surgery. There was also no difference of cumulative postoperative morphine consumption between Group C and Group K (in this group patients only received ketamine, but not fentanyl). We found that a small dose of ketamine itself could not prevent postoperative morphine consumption, but it could prevent the increase of postoperative morphine consumption induced by intraoperative administration of fentanyl. Some studies showed that acute opioid tolerance and/or hyperalgesia might be induced by activation of NMDA systems and low doses of ketamine, a noncompetitive antagonist of the NMDA receptor, has been proposed to prevent opioid-induced tolerance and/or hyperalgesia and reduce the postoperative opioid requirements.3,11,12 However, Ganne et al.5 showed that low-dose ketamine added to a remifentanil-based propofol anesthesia did not reduce morphine consumption after major ear, nose, and throat surgery. This could be because of the dose and protocol of ketamine administration. Small dose ketamine has been defined as <1 mg · kg^–1 when delivered as an IV bolus and <20 µg · kg^–1 · min^–1 when delivered as a continuous infusion.20 In that study, a low-dose regimen (IV ketamine 0.15 mg · kg^–1 before induction and 2 µg · kg^–1 · min^–1 during anesthesia) was used to avoid the potential deleterious effects of ketamine. In our study, we gave patients ketamine 15 µg · kg^–1 · min^–1 before and during the operation. The dosage was much more than that of Ganne et al’s study, but it did cause some side effects, such as hallucination during and/or after the surgery while the dosage prevented the increase of postoperative morphine consumption caused by intraoperative administration of fentanyl. Perhaps a more suitable dosage of ketamine could be found.

In the present study, patients who received lornoxicam before fentanyl (Group FL) had the same cumulative postoperative morphine consumption as patients in Group C during the first 48 h after surgery. The patients who received lornoxicam only (Group L) had no sparing of postoperative morphine consumption compared with patients in Group C. Lornoxicam therefore did not have direct preemptive effects, but preventive administration of the lornoxicam significantly diminished the acute opioid tolerance and/or hyperalgesia caused by fentanyl.

COX inhibitors can reduce the development of opioid tolerance in animals.15 However, the exact mechanism of the central analgesic interaction of COX inhibitors and opioids is not yet clear. It was found that inducible nitric oxide synthase activation might increase nitric oxide (NO) release, and subsequently increase the prostaglandins release, via activating COX.21 Prostaglandins E₂ was shown to stimulate the NO release from rat spinal cord by NMDA receptor activation through the EP₁ receptors.22 Many NMDA actions are mediated by the production of NO, and nitric oxide synthase inhibitors can also attenuate or prevent opioid tolerance.23 Considering all these findings, we propose that COX inhibitors might modulate morphine’s antinociceptive tolerance via interaction with the NMDA–NO system. In this study, the preventive effects of ketamine and lornoxicam might perform the same way, although some studies have reported that NMDA receptor antagonists were more effective in reducing opioid-induced hyperalgesia than NSAIDs.24,25 In this study, lornoxicam had the same effect as ketamine in preventing the increase of postoperative morphine consumption induced by intraoperative administration of fentanyl. Because of its fewer side effects, lornoxicam seems to be preferable to ketamine.

In summary, our study suggests that intraoperative administration of fentanyl increases postoperative morphine consumption, which can be prevented by co-administration of ketamine or lornoxicam.

Footnotes

Accepted for publication July 23, 2008.

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