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Anesth Analg 2005;100:169-174
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000138037.19757.ED

PAIN MEDICINE

Nefopam and Ketamine Comparably Enhance Postoperative Analgesia

Barbara Kapfer, MD*, Pascal Alfonsi, MD*, Bruno Guignard, MD*, Daniel I. Sessler, MD{dagger}, and Marcel Chauvin, MD*,{ddagger}

*Department of Anesthesia and {ddagger}INSERM E 332, Hôpital Ambroise Pare, Assistance Publique Hôpitaux de Paris, Boulogne, France; and {dagger}Outcomes Research Institute and Departments of Anesthesiology and Pharmacology, University of Louisville, Louisville, Kentucky

Address correspondence and reprint requests to Marcel Chauvin, MD, Department of Anesthesia, Hôpital Ambroise Pare, Assistance Publique Hôpitaux de Paris, Boulogne 92100, France. Address e-mail to marcel.chauvin{at}apr.ap-hop-paris.fr


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Opioids alone sometimes provide insufficient postoperative analgesia. Coadministration of drugs may reduce opioid use and improve opioid efficacy. We therefore tested the hypothesis that the administration of ketamine or nefopam to postoperative patients with pain only partly alleviated by morphine reduces the amount of subsequent opioid necessary to produce adequate analgesia. Patients (n = 77) recovering from major surgery were given up to 9 mg of IV morphine. Those who still had pain were randomly assigned to blinded administration of 1) isotonic saline (control group; n = 21), 2) ketamine 10 mg (ketamine group; n = 22), or 3) nefopam 20 mg (nefopam group; n = 22). Three-milligram morphine boluses were subsequently given at 5-min intervals until adequate analgesia was obtained, until 60 min elapsed after the beginning of study drug administration, or until ventilation became insufficient (respiratory rate <10 breaths/min or saturation by pulse oximetry <95%). Supplemental morphine (i.e., after test drug administration) requirements were significantly more in the control group (mean ± SD; 17 ± 10 mg) than in the nefopam (10 ± 5 mg; P < 0.005) or ketamine (9 ± 5 mg; P < 0.001) groups. Morphine titration was successful in all ketamine and nefopam patients but failed in four control patients (two because of respiratory toxicity and two because of persistent pain). Tachycardia and profuse sweating were more frequent in patients given nefopam, and sedation was more intense with ketamine; however, the incidence of other potential complications did not differ among groups.

IMPLICATIONS: Ketamine 10 mg and nefopam 20 mg comparably potentiate opioid analgesia; each reduces opioid requirements by approximately 40%. Ketamine administration was associated with sedation, whereas nefopam produced tachycardia and sweating. However, none of the side effects was serious. Either drug can thus be used to potentiate opioid analgesia.


   Introduction
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 Abstract
 Introduction
Methods
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 Discussion
 References
 
IV morphine titration usually provides rapid and effective postoperative analgesia. However, side effects sometimes occur and may require discontinuation of morphine titration before sufficient pain relief is obtained (1). These cases can be considered a failure of morphine titration.

The combination of non-opioid analgesics with morphine provides a morphine-sparing effect and may decrease dose-limiting toxicity. This concept is the basis of multimodal analgesia (2). The morphine requirement reduction during morphine titration has the dual advantage of more rapidly obtaining a desired level of analgesia while decreasing the risk of morphine titration failure. Better postoperative analgesia may decrease the time spent by nurses titrating morphine; similarly, it may reduce the amount of time patients need to stay in the postanesthesia care unit (PACU).

Small-dose ketamine possesses N-methyl-D-aspartate (NMDA) receptor noncompetitive antagonist properties through a magnesium-dependent channel blockade (3). Several studies demonstrate that it improves opioid analgesia (4). It decreases perioperative opioid analgesic requirements, facilitates passive knee mobilization after arthroscopic anterior ligament repair (5), and improves mobilization after arthroscopic meniscectomy by alleviating provoked pain (6). Potentiation between opioids and ketamine was demonstrated in an animal study (7) and was suggested in a volunteer study (8), whereas another volunteer report favored only an additive association (9). Furthermore, ketamine attenuates the development of acute analgesic tolerance to opioids in rats (10) and suppress the rebound hyperalgesia observed after opioid exposure in volunteers (11). A recent study (12) demonstrated that the combined administration of small-dose ketamine and morphine promptly and satisfactorily resolved pain that was unresponsive to IV morphine alone.

Nefopam (Acupan®; Laboratory Biocodex, France) is a centrally acting non-opioid analgesic. It has been available since 1976 in most Western European countries for IV and oral administration and has been available for IV administration in France since 1996. IV nefopam quickly produces potent inhibition of the nociceptive flexion reflex in human (13). Nefopam 20 mg is equipotent with morphine 6–12 mg (14,15). It provides morphine-sparing effects when given postoperatively (16,17). We therefore tested the hypothesis that the administration of ketamine or nefopam to postoperative patients resistant to morphine speeds the onset of adequate analgesia while triggering fewer opioid side effects than with continued administration of morphine alone.


   Methods
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Results
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After informed consent, and with institutional approval, we enrolled 77 patients who were ASA physical status I or II, aged 18–65 yr, and scheduled for major elective open abdominal (colectomy by laparotomy), urologic (nephrectomy by lombotomy), or orthopedic (hip or knee arthroplasty) surgery under general anesthesia. Exclusion criteria included surgery performed with regional anesthesia, history of chronic pain, regular medication with analgesics, drug or alcohol abuse, psychiatric disorders, morbid obesity, and cardiovascular, renal, or hepatic diseases.

Postoperative pain was evaluated with a five-point verbal rating scale (VRS): 0 = no pain, 1 = light pain, 2 = moderate pain, 3 = intense pain, and 4 = severe pain. Use of this scale was explained to participating patients at the preanesthetic visit the evening before surgery. Sedation was scored with a numeric scale of 0–3: 0 = patient fully awake, 1 = patient somnolent and responsive to verbal commands, 2 = patient somnolent and responsive to tactile stimulation, and 3 = patient asleep and responsive to painful stimulation.

Routine anesthetic safety monitors were used throughout surgery and postoperative recovery. These included respiratory rate, oxygen saturation (SpO2), mean arterial blood pressure, and heart rate. Values were recorded at 5-min intervals along with pain and sedation scores. Tachycardia was defined by a heart rate that exceeded 100 bpm for 5 continuous minutes. Side effects were also recorded, including the incidence of nausea, vomiting, pruritus, dysphoria (including hallucinations and nightmares), diplopia, dizziness, dry mouth, and profuse sweating.

Patients were given lorazepam 1 mg orally the night before surgery, but no premedication was given on the day of the surgery. General anesthesia was induced with thiopental and atracurium and was maintained with isoflurane in 50% nitrous oxide and sufentanil 0.3–1.3 µg · kg–1 · min–1. No analgesic other than sufentanil was used during surgery. All patients were mechanically ventilated. Both isoflurane and sufentanil administration were discontinued 15–30 min before the end of surgery. Neuromuscular relaxation was antagonized at skin closure, and patients were tracheally extubated before the transfer to the PACU. After surgery, patients were given oxygen supplementation at 5 L/min via a face mask.

When patients were sufficiently alert and complained of pain (VRS ≥2), postoperative analgesia was provided by titrating morphine in 3-mg increments every 5 min until adequate pain relief was obtained. Adequate pain relief was defined as a VRS pain score <2. Morphine was titrated by a single investigator (BK). Patients who had adequate pain relief (VRS <2) 5 min after the third bolus of morphine were excluded from the study.

The remaining patients were randomly assigned to one of three groups: 1) isotonic saline (control), 2) ketamine 10 mg, or 3) nefopam 20 mg. Each study drug was given IV in a double-blind fashion over 12 min. Randomization was based on computer-generated codes that were maintained in sequentially numbered opaque envelopes until just before use. The beginning of study drug infusion was considered elapsed Time 0.

Subsequently, morphine titration (3 mg every 5 min) was resumed until the VRS was <2 or until 60 min had elapsed after Time 0. Opioid given after the test drugs (i.e., Time 0) was considered supplemental morphine. However, morphine titration was stopped when patients had a respiratory rate <10 breaths/min, the SpO2 as measured by pulse oximeter was <95%, or the sedation score was >2. Otherwise, they were observed until reappearance of a VRS pain score ≥2.

Our sample size estimate was based on the expected differences in morphine titration dose, excluding the initial 9 mg (i.e., supplemental dose) between treated and untreated patients. In a preliminary study of 15 patients who did not obtain adequate postoperative analgesia from 9 mg of morphine, we found that supplemental morphine consumption was 19 ± 8 mg (mean ± SD). Twenty-two patients per group were thus required to provide an 80% power for detecting a 35% difference in supplemental morphine consumption at an {alpha} level of 0.05. We therefore planned to include 66 patients requiring more than 9 mg of morphine for postoperative pain relief; 22 were assigned to each treatment group.

Our primary end-point was morphine consumption after test drug administration. The secondary end-points were 1) failure of morphine titration to produce adequate analgesia after administration of the test drug and 2) the delay between the end of morphine titration and reappearance of a VRS pain score ≥2 in patients who obtained adequate analgesia from morphine after administration of the test drug. Morphine titration was considered a failure if pain persisted (VRS ≥2) for 60 min after Time 0 or if morphine administration was stopped because of respiratory depression, inadequate oxyhemoglobin saturation, or excessive sedation (sedation score >2).

In all cases, normality was assessed with the Kolmogorov-Smirnov test. Potential confounding factors and responses in the three treatment groups were compared with analysis of variance and the Bonferroni-Dunn test for post hoc analysis. Pain and sedation scores, titration failure, and adverse events were compared by using {chi}2 tests. Data are presented as mean ± SD unless otherwise indicated; P < 0.05 was considered statistically significant.


   Results
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 Abstract
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 Methods
 Results
Discussion
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Seventy-seven patients were enrolled in the study. Sixty-six patients did not obtain adequate postoperative pain relief from 9 mg of morphine. One patient was subsequently excluded from the control group because of a protocol deviation. Consequently, data analysis was restricted to 65 patients.

The three treatment groups were comparable with respect to demographic and morphometric characteristics, the type and length of surgical procedures, and intraoperative sufentanil dose. The interval between the end of sufentanil administration and the beginning of morphine titration was also similar in the three groups (Table 1).


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  		Table 1. Patient Characteristics, Surgery, and Opioid Management
 
Supplemental morphine requirements (i.e., after test drug administration) were significantly larger in the control group than in the nefopam (P < 0.005) or ketamine (P < 0.001) groups (Table 2). There were also significantly more failures of morphine titration in the control patients than in patients given ketamine or nefopam. Morphine titration was interrupted in two control patients because of inadequate ventilation; morphine titration failed in two other control patients because pain remained unacceptable after 1 h of treatment. However, there were no significant differences between the ketamine and nefopam groups. Furthermore, the time between obtaining adequate analgesia and return of pain (VRS ≥2) was similar in all three groups (Table 2). Tachycardia and profuse sweating were more frequent in patients given nefopam than in the two other groups (Table 3).


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  		Table 2. Morphine Titration
 

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  		Table 3. Adverse Events
 
Pain relief after starting infusion of the test drug was obtained more rapidly in the nefopam and ketamine groups than in the control group (Fig. 1). Sedation scores were greater in the ketamine patients than in the other two groups at 10, 15, and 20 min after beginning infusion of the treatment drug. However, sedation scores never reached 3 in any patient (Fig. 2).



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  		Figure 1. Percentage of patients with little or no pain (verbal rating scale [VRS] pain score <2) after beginning infusion of saline, ketamine, or nefopam. Pain scores were significantly less in the nefopam and ketamine groups than in the control group after 30 and 45 elapsed minutes (*P < 0.01). There were no significant differences between the ketamine and nefopam groups at any time.

 


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  		Figure 2. Percentage of patients with a sedation score >1 after the start of the treatment infusion. Sedation scores were significantly greater in the patients given ketamine than in the patients given either nefopam or saline at 10, 15, and 20 elapsed minutes. *P < 0.05 compared with the nefopam and control groups.

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study demonstrates that, in patients with pain only partly alleviated by morphine, IV administration of nefopam or small-dose ketamine improves the effects of subsequent morphine titration. Specifically, 40% less subsequent morphine was necessary to obtain adequate pain relief in patients given either nefopam or ketamine. Furthermore, morphine titration had to be discontinued in four patients in the control group, whereas morphine proved successful in all patients in each of the treatment groups.

More of our patients were resistant to morphine than reported in a recent study (12) in which only 22% of patients were resistant to 2-mg boluses of morphine given every 4–5 minutes for 25–30 minutes. Moreover, the mean titration in the control group used larger morphine doses than in other previous reports (18). These differences presumably result because we included only major surgeries in our study as compared with other studies (12,18). Our results are nonetheless consistent with Weinbroum’s study (12), in that resistant patients who were subsequently given ketamine required only one-third of the morphine that patients not treated with morphine required. Analgesia from small-dose ketamine is thought to result from its action as a noncompetitive NMDA receptor antagonist (3). Opioids not only exert an antinociceptive effect, but also activate central NMDA processes, resulting in hyperalgesia and acute opioid tolerance (19). NMDA receptor antagonists, such as small-dose ketamine, have been demonstrated to increase the analgesic effect of opioids, likely by limiting these NMDA-mediated facilitating processes (10,11).

The exact mechanism of action of nefopam remains unknown. However, it is a centrally-acting antinociceptive compound (20,21) with supraspinal and spinal sites of action (22) and does not bind to opiate receptors (23). It inhibits monoamine reuptake (24), modulates descending serotoninergic pain (25), and may also interact with a dopaminergic pathway (26). Moreover, nefopam shows preemptive analgesic effects in a rat model of neuropathy (27), which involves the activation of NMDA receptors (28). However, it appears that nefopam modulates glutaminergic transmission presynaptically via inhibition of voltage-sensitive sodium channels rather than via an NMDA receptor antagonism like ketamine (29).

Nefopam was as effective as ketamine in producing a morphine-sparing effect in resistant patients. These results are consistent with other postoperative studies (16,17). Nefopam has been shown to produce a morphine-sparing effect of 30%–50%, with variable improvement in pain scores (16,17). Moreover, nefopam reduces the thermal hyperalgesia induced by incision of the plantaris muscle of one hindpaw of rats (30). Also, as shown previously with ketamine, nefopam produces an antihyperalgesic effect.

Both ketamine and nefopam comparably reduced the amount of morphine required to produce adequate analgesia. The dose of nefopam (20 mg) was relatively large and is a dose that by itself is clearly analgesic. It is impossible to determine, from our study design, the relative analgesic and antihyperalgesic contributions of nefopam to the observed reduction in the morphine requirement. In contrast, 10 mg of ketamine is an extremely small dose that by itself produces a trivial analgesic—but nonetheless exerts a powerful antihyperalgesic—effect (4).

The most frequent side effects were sedation in the ketamine group and tachycardia and profuse sweating in the nefopam group. This finding is consistent with previous observations (17,23). Mimoz et al. (17) reported less frequent tachycardia with a continuous infusion of nefopam over 30 minutes (compared with 12 minutes in our patients); however, the proportion of patients with profuse sweating was similar. Reduced morphine consumption in the two treatment groups did not decrease the incidence of nausea, as might be expected (although our study had little power to evaluate the incidence of nausea). However, the incidence of postoperative nausea and vomiting (PONV) is often not reduced by morphine-sparing strategies (31,32). Furthermore, nefopam is reportedly emetic (23), a finding that is consistent with the relatively frequent PONV observed in the nefopam patients.

Despite sedation in the ketamine group, all patients of this group were easily arousable and able to evaluate their pain level with VRS pain score. It is thus unlikely that accurate evaluation of pain was precluded by sedation. Because ketamine is readily available and is not associated with side effects, other than moderate sedation in the doses we used, it may be preferable to nefopam as a coanalgesic treatment for patients resistant to opioids alone. We also note that nefopam is not even available in all European countries, much less in the United States, whereas ketamine is readily available worldwide.

Different types of surgery were included, and this may constitute a limitation of our study. However, most of our patients (86%) underwent abdominal surgery (colectomy by laparotomy), and no differences were observed in the distribution of surgical procedures among the three treatment groups.

In summary, ketamine 10 mg and nefopam 20 mg comparably potentiate opioid analgesia; each reduces opioid need by approximately 40%. Ketamine administration was associated with sedation, whereas nefopam produced tachycardia and sweating. However, none of the observed side effects was serious. Either drug can thus be used to potentiate opioid analgesia, although ketamine may be preferable and is more readily available.


   Acknowledgments
 
Supported by National Institutes of Health Grant GM 061655 (Bethesda, MD), the Gheens Foundation (Louisville, KY), the Joseph Drown Foundation (Los Angeles, CA), and the Commonwealth of Kentucky Research Challenge Trust Fund (Louisville, KY).


   References
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Accepted for publication June 21, 2004.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2005 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press