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Nefopam, a Nonsedative Benzoxazocine Analgesic, Selectively Reduces the Shivering Threshold in Unanesthetized Subjects
Author Affiliations & Notes
  • Pascal Alfonsi, M.D.
    *
  • Frederic Adam, M.D.
    *
  • Andrea Passard, M.D.
    *
  • Bruno Guignard, M.D.
    *
  • Daniel I. Sessler, M.D.
  • Marcel Chauvin, M.D.
  • * Attending Anesthesiologist, ‡ Professor and Chair, Department of Anesthesia, Hôpital Ambroise Paré, Assistance Publique-Hopitaux de Paris. † Associate Dean of Research, Director Outcomes Research™ Institute, Distinguished University Research Chair, Lolita and Samuel Weakley Professor of Anesthesiology and Pharmacology, University of Louisville.
  • Received from the Department of Anesthesiology, Hôpital Ambroise Paré, Assistance Publique-Hopitaux de Paris, Boulogne, France; and the Outcomes Research™ Institute and the Departments of Anesthesiology and Pharmacology, University of Louisville, Louisville, Kentucky.
Article Information
Education
Education   |   January 2004
Nefopam, a Nonsedative Benzoxazocine Analgesic, Selectively Reduces the Shivering Threshold in Unanesthetized Subjects
Anesthesiology 1 2004, Vol.100, 37-43. doi:
Anesthesiology 1 2004, Vol.100, 37-43. doi:
MAKING patients even a few degrees hypothermic provides more protection against tissue ischemia than available drugs. Hypothermia has been shown to improve neurologic outcomes after out-of-hospital cardiac arrest 1,2 and is being tested for stroke and acute myocardial infarction. A difficulty with inducing hypothermia in humans is that even small reductions in core temperature trigger aggressive thermoregulatory defenses, including arteriovenous shunt vasoconstriction and shivering. 3 Therefore, there is considerable interest in identifying drugs that defeat thermoregulatory defenses against hypothermia. Many drugs are known to induce thermoregulatory tolerance, but most are anesthetics 4,5 or major sedatives. 6 A potential alternative is nefopam, a nonsedative analgesic.
Nefopam is a benzoxazocine compound that is structurally related to orphenadrine and diphenhydramine. 7 It is a centrally acting analgesic 7,8 with both supraspinal 9,10 and spinal sites of action. 11,12 Nefopam is neither an opiate nor a nonsteroidal noninflammatory drug. 13 Nefopam does not induce respiratory depression, even postoperatively. 14 It is available in Europe but is not approved by the Food and Drug Administration in the United States.
Clinical studies indicate that nefopam treats or prevents postoperative shivering. 15–17 For example, 0.15 mg/kg nefopam is as effective as 3 μg/kg clonidine in preventing postoperative shivering after orthopedic or abdominal surgery, 16 and 20 mg nefopam is as effective as 150 μg clonidine or 50 mg meperidine for prevention of shivering after hypothermic neurosurgery. 17 However, patients given nefopam awaken sooner and experience less hypotension than those given clonidine.
Available data suggest that nefopam may inhibit thermoregulatory shivering without producing the sedative and hemodynamic effect of α2agonists or the respiratory consequences of opiates. Therefore, we evaluated the effects of nefopam on the three major thermoregulatory responses in humans: sweating, vasoconstriction, and shivering. Our specific hypothesis was that nefopam reduces the vasoconstriction and shivering thresholds.
Materials and Methods
With approval from the Ethics Committee of Hôpital Ambroise Paré (Boulogne, France) and informed consent, we studied nine healthy male volunteers. None of the volunteers were obese, were taking medication, or had a history of thyroid disease, dysautonomia, or Raynaud syndrome.
Protocol
The volunteers had a light breakfast and refrained from caffeine for at least 8 h before the study. To avoid circadian fluctuations, studies were scheduled so that thermoregulatory responses were triggered at similar times on each of the 3 study days. During the studies, the volunteers rested in a supine position. They were minimally clothed, and ambient temperature was maintained between 20° and 22°C. The study was conducted in a double-blind, crossover fashion. The volunteers were studied on 3 randomly assigned days, each separated by at least 6 days: (1) control (saline), (2) nefopam at a target plasma concentration of 35 ng/ml (low dose), and (3) nefopam at a target concentration of 70 ng/ml (high dose).
An intravenous catheter was inserted into the right forearm for fluid and nefopam administration. Lactated Ringer’s solution was given as necessary to maintain mean arterial blood pressure greater than 60 mmHg. A 14-gauge catheter was inserted into a left antecubital vein and used for blood sampling.
Nefopam was given intravenously via  a computer-controlled syringe pump. The infusion profile was based on published pharmacokinetic data. 18 The time to peak plasma concentration was 20 min; the mean elimination half-life is approximately 240 min. This dosing scheme was intended to rapidly achieve therapeutic concentrations, minimize side effects during the initial phase, and maintain a therapeutic level throughout the study. The mean maximal target concentration (70 ng/ml) corresponds to a dose of 20 mg nefopam, which is a dose commonly used for postoperative analgesia. 7 
Thermal manipulation began 30 min after the study drug was started. To minimize redistribution hypothermia, we prewarmed the volunteers for 30 min with a full-body forced-air warmer (Warm-touch; Mallinckrodt, Inc., St. Louis, MO) on low and a circulating-water mattress (Cincinnati Sub-Zero, Cincinnati, OH) set at 37°C. Throughout the protocol, the arms were protected from active warming and cooling to avoid locally mediated vasomotion. However, all other skin below the neck was similarly manipulated throughout each study day.
Skin and core temperatures were first gradually increased with a forced-air warmer and circulating-water mattress until sweating was observed. Skin and core temperatures were then gradually decreased, by using the circulating-water mattress. As in previous studies, 5 the sweating threshold was determined first because this threshold deviates least from normal body temperature. This protocol allowed a considerably shorter study day than if we had first cooled to shivering and then rewarmed all the way to the sweating threshold. The study ended each day when shivering was detected. Core temperature changes were restricted at approximately 2°C/h because this rate is unlikely to trigger dynamic thermoregulatory responses.
Measurements
Heart rate and pulse oximeter saturation were monitored continuously. Arterial pressure was determined oscillometrically at the ankle at 10-min intervals but also recorded at the sweating, vasoconstriction, and shivering thresholds. Oxygen consumption and carbon dioxide production were measured by a DeltaTrac metabolic monitor (Datex, Inc., Helsinki, Finland). The system was used in canopy mode with measurements averaged over 1-min intervals and recorded every minute.
Core temperature was measured at the tympanic membrane. The aural probe was inserted until the patient felt the thermocouple touch the tympanic membrane; appropriate placement was confirmed when they easily detected a gentle rubbing of the attached wire. The probe was then securely taped in place, the aural canal was occluded with cotton, and the external ear was covered with a gauze bandage. Mean skin temperature (TSkin) was calculated from 10 sites, using the formula:
All temperatures were measured using Ellab thermometers and probes (Ellab, Inc., Copenhagen, Denmark); they were electronically recorded at 10-s intervals until the end of the study.
A gauze compress was applied every 5 min on the forehead. As in previous studies, 19 the appearance of moisture on the compress defined onset of sweating. This method correlates well with quantitative techniques. 20 Fingertip blood flow was evaluated using forearm minus fingertip skin-surface temperature gradients. 21 Gradients exceeding 0°C were indicative of vasoconstriction because this gradient corresponds to onset of the core temperature plateau. 22 As in numerous previous studies, shivering was evaluated by a blinded observer and confirmed by a sustained increase in oxygen consumption to 30% greater than baseline.
Venous blood was sampled for nefopam concentrations when the volunteer reached the sweating, vasoconstriction, and shivering thresholds. Blood components were separated in a refrigerated centrifuge for 30 min, and the plasma samples were isolated and then stored at −20°C for subsequent analysis with high-performance liquid chromatography. Methanol (100 μl) was added to tubes containing 1-ml aliquots of plasma and the internal standard imipramine (1.5 mg/l, 0.1 ml). Solutions were alkalinized with a buffer solution (pH 12) and vortexed for 5 s. Cyclohexane (8 ml) was added, and the samples were agitated for 15 min and centrifuged for 10 min. The organic phase was transferred to a tube containing 0.3 ml HCl (0.1 N) and agitated and centrifuged again. The organic phase was discarded, and 200 μl of the aqueous phase was transferred and evaporated to dryness under nitrogen at 45°C. Samples were reconstituted in 0.2 ml mobile phase. The mobile phase was 300:700: acetonitrile/phosphate buffer, pH 6. Separation was accomplished at 4°C using a 150 × 4.6-mm, 5-μm C-18 column (Waters Associates, Milford, MA) with a flow rate of 1.2 ml/min. Ultraviolet absorbance was monitored at 210 nm. The response was linear to at least 100 ng/ml, with a detection limit of 1 ng/ml. The within-day coefficient of variation was 4.4% at 50 ng/ml, and the interday coefficient of variation was 2.4% at 50 ng/ml.
Thermal comfort was assessed at each threshold with a 100-mm visual analog scale, with 50 mm defined as thermal comfort, 0 mm as the most intense imaginable sensation of cold, and 100 mm as the most intense imaginable sensation of warm. Pain on nefopam injection, dizziness, headache, nausea, dry mouth, palpitation, and epigastric pain were recorded.
Statistical Analysis
The cutaneous contribution to sweating 23 and to vasoconstriction and shivering 24 is linear. Therefore, we used measured skin and core temperatures in degrees centigrade at each threshold to calculate the core temperature threshold that would have been observed had the skin been maintained at a single designated temperature:EQUATION
where the fractional contribution of mean skin temperature to the threshold was termed β. Therefore, T  Core(calculated)equals the measured core temperature, T  Core, plus a small correction factor consisting of β/(1 −β) multiplied by the difference between actual (T  skin) and designated [T  skin(designated)] skin temperatures. We have previously described the derivation, validation, and limitations of this equation. 4 The coefficient of cutaneous contribution (β) was taken as 0.1 for sweating 23 and 0.2 for vasoconstriction and shivering. 24 The designated skin temperature was set at 34°C because that is a typical intraoperative value.
From the calculated core temperature thresholds on each study day, individual nefopam concentration–response curves for the sweating, vasoconstriction, and shivering thresholds were determined with linear regression. The average slopes and correlation coefficients (r  2) for the individual volunteers were then computed from these values. The average thresholds with each nefopam target dose were also computed.
Results at each target nefopam concentration were compared with repeated-measures analysis of variance and Bonferroni-Dunn tests for post hoc  comparison. Side effect frequencies were compared using a chi-square test. Results are presented as mean ± SD or percent; P  < 0.05 was considered statistically significant.
Results
The volunteers were 30 ± 5 yr old, weighed 73 ± 15 kg, and were 177 ± 3 cm tall.
By design, plasma nefopam concentrations differed significantly on the low-dose (30 ng/ml) and the high-dose (60 ng/ml) days. On each study day, the plasma concentrations decreased with time, but the concentrations at the vasoconstriction and shivering thresholds were not significantly lower than at the sweating threshold. The rate at which skin temperature changed varied from 2.9 to 4.3°C/h, but the rate at which core temperature changed was restricted to less than 2°C/h throughout the study.
Nefopam did not significantly modify the slope for sweating (0.0 ± 4.9°C ·μg−1· ml; r  2= 0.73 ± 0.32) or vasoconstriction (−3.6 ± 5.0°C ·μg−1· ml; r  2= 0.47 ± 0.41). In contrast, nefopam produced a significant concentration-dependent decrease in the shivering slope of 16.8 ± 9.3°C ·μg−1· ml (r  2= 0.89 ± 0.09;fig. 1) and in the shivering threshold of 0.9 ± 0.4°C (P  ≤ 0.001;table 1). The average values for each threshold are shown in figure 2.
Fig. 1. Individual effects of increasing plasma nefopam concentration on the core temperatures triggering sweating (open circles  and thin line  ), vasoconstriction (filled circles  and medium line  ), and shivering (open triangles  and thick line  ) in nine volunteers. Nefopam did not significantly change the sweating or vasoconstriction thresholds; however, the slope of shivering decreased significantly by 16.7 ± 9.5°C ·μg−1· ml, and the shivering threshold decreased by 0.9 ± 0.4°C. All of the thresholds (at a designated skin temperature of 34°C) were calculated from measured skin and core temperatures.
Fig. 1. Individual effects of increasing plasma nefopam concentration on the core temperatures triggering sweating (open circles 
	and thin line 
	), vasoconstriction (filled circles 
	and medium line 
	), and shivering (open triangles 
	and thick line 
	) in nine volunteers. Nefopam did not significantly change the sweating or vasoconstriction thresholds; however, the slope of shivering decreased significantly by 16.7 ± 9.5°C ·μg−1· ml, and the shivering threshold decreased by 0.9 ± 0.4°C. All of the thresholds (at a designated skin temperature of 34°C) were calculated from measured skin and core temperatures.
Fig. 1. Individual effects of increasing plasma nefopam concentration on the core temperatures triggering sweating (open circles  and thin line  ), vasoconstriction (filled circles  and medium line  ), and shivering (open triangles  and thick line  ) in nine volunteers. Nefopam did not significantly change the sweating or vasoconstriction thresholds; however, the slope of shivering decreased significantly by 16.7 ± 9.5°C ·μg−1· ml, and the shivering threshold decreased by 0.9 ± 0.4°C. All of the thresholds (at a designated skin temperature of 34°C) were calculated from measured skin and core temperatures.
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Table 1. Major Results
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Table 1. Major Results
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Fig. 2. Average sweating, vasoconstriction, and shivering thresholds at each nefopam concentration. Results are shown as mean ± SD.
Fig. 2. Average sweating, vasoconstriction, and shivering thresholds at each nefopam concentration. Results are shown as mean ± SD.
Fig. 2. Average sweating, vasoconstriction, and shivering thresholds at each nefopam concentration. Results are shown as mean ± SD.
×
Nefopam administration did not significantly increase the sweating-to-vasoconstriction interthreshold range but did increase the vasoconstriction-to-shivering interthreshold range (table 1). Nefopam did not modify thermal sensation in volunteers. Heart rate after 30 min of saline was 72 ± 7 beats/min; after low-dose nefopam, it was 89 ± 15 beats/min and 89 ± 18 beats/min after high-dose nefopam. Therefore, both concentrations of nefopam significantly increased heart rate. Heart rates and mean arterial pressures were similar at each threshold on each of the study days (table 1).
Side effects experienced during nefopam administration are summarized in table 2. The volunteers were significantly more likely to become nauseated or to report pain on injection or a dry mouth during the study when nefopam rather than saline was infused. Profuse sweating during the initial 30 min of drug administration (and not associated with cutaneous warming) was observed in two volunteers during low- and high-dose nefopam administration. All side effects spontaneously resolved a few minutes after the end of the loading dose and did not recur during the steady state concentration infusion or the thermal manipulations. The volunteers fell asleep three times during loading of saline, seven times during low-dose nefopam, and five times during high-dose nefopam. All volunteers responded readily to their names, and none experienced speech impairment at any time during the study. None of the volunteers fell asleep during the thermal manipulations.
Table 2. Side Effects
Image not available
Table 2. Side Effects
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Discussion
Most drugs with thermoregulatory actions, including anesthetics, 4,5 sedatives, 25,26 and opioids, 27 synchronously reduce the vasoconstriction and shivering thresholds. In fact, the only distinct exception is meperidine, which reduces the shivering threshold twice as much as the vasoconstriction threshold 28 —via  unknown mechanisms. 29 However, meperidine has distinct effects on vasoconstriction as well as shivering. In contrast, nefopam reduced the shivering threshold nearly 1°C without having any important effect on the vasoconstriction or sweating thresholds. This novel pattern has not previously been reported for any centrally acting drug. (Muscle relaxants, including dantrolene, impair shivering alone but do so peripherally.)
That vasoconstriction and shivering can be modulated independently is clinically important. With thermal manipulations mediated by surface heat exchange, for example, vasoconstriction slows heat transfer in unanesthetized subjects. 30,31 Therefore, it is preferable in such circumstances to inhibit both vasoconstriction and shivering. Shivering similarly impairs thermal manipulations via  internal heat-exchanging catheters. However, vasoconstriction may speed  core temperature changes when heat is directly inserted or removed from the thermal core by decreasing the amount of heat that is dissipated into peripheral tissues. Furthermore, thermoregulatory vasodilation is associated with a reduction of approximately 20 mmHg in mean arterial pressure, which may be suboptimal in some patients (e.g.  , stroke victims). 32 Therefore, it is likely that better understanding of thermoregulatory pharmacology will allow clinicians to optimize therapeutic temperature manipulations.
The thermoregulatory system is highly redundant, with afferent and efferent signals being integrated and modulated at numerous levels within the neuraxis. This complexity has impeded understanding of the molecular, cellular, and neurologic mechanisms that control normal body temperature, much less pharmacologic inhibition of normal thermoregulatory control. Therefore, it is of considerable physiologic interest to identify a drug that centrally impairs shivering without any apparent effect on vasoconstriction.
Mechanisms involved in the thermoregulatory effect of nefopam are not clearly established. However, in vitro  and in vivo  studies indicate that the analgesic properties of nefopam are related to its potent inhibition of serotonin (5-hydroxytryptamine), norepinephrine, and dopamine synaptosomal uptake. 10,12,33–35 Monoamines are involved in the thermoregulatory pathways. 36,37 The balance between modulator 5-hydroxytryptamine and norepinephrine inputs may be responsible for short-term thermoregulatory adaptive modifications of the heat-defense and cold-defense responses, with monoamines promoting hypothermia. 38 Therefore, nefopam may promote hypothermia via  a monoamine mechanism.
Other properties of nefopam may also contribute to its antishivering action. Nefopam may have a direct interaction with α2adrenoceptors. 12 Nefopam, like orphenadrine, is also a noncompetitive N  -methyl-d-aspartate (NMDA) receptor antagonist. 39 Magnesium sulfate and ketamine, which are competitive NMDA receptor antagonists, inhibit postanesthetic shivering. 40,41 Therefore, inhibition of NMDA receptors may contribute to the antishivering effect of nefopam.
Numerous sites are involved in the control of the thermoregulatory shivering. Supraspinal sites are located in the hypothalamus, the pons, and the mesencephalon. 38 In the rat, nefopam is a strong inhibitor of serotonin in the corpus striatum and of norepinephrine in the hypothalamus. 42 Nefopam also has an effect in the pons that may partially explain its antishivering effect. 34,35,42 Specific regional actions of nefopam may therefore explain its ability to impair shivering without similarly reducing the vasoconstriction threshold.
Alpha-2 agonists, such as clonidine and dexmedetomidine, have little 43 or no effect 25,44 on the sweating threshold, but both lower the vasoconstriction and shivering thresholds. 25,44,45 These observations suggest that adrenoceptors are more involved in heat retention or production responses than in heat dissipation responses. Nefopam has a strong affinity for norepinephrine and serotonergic uptake sites 34,35; however, the serotonergic analgesic effect seems to be principally on descending pathways. 46 Therefore, nefopam’s lack of effect on the sweating threshold might be explained by its central noradrenergic effects.
The spinal cord possesses thermoregulatory effectors that are normally under the inhibition of supraspinal centers. 47 In rats, nefopam reduces the noxiously evoked spinal c-Fos protein expression 11 and depresses the tail-flick test after intrathecal injection. 48 In humans, nefopam decreases the Hoffman reflex in patients with back pain, 49 indicating that nefopam affects human spinal motor neurons. However, it is difficult to even speculate to what extent spinal mechanisms contribute to the observed thermoregulatory effects of nefopam.
Tramadol is also a synaptic norepinephrine and serotonin uptake inhibitor. 50 It slightly lowers the sweating threshold and synchronously decreases the vasoconstriction and shivering thresholds. 51 However, tramadol possesses an opiate effect and naloxone partially returned the thermoregulatory responses to control values. 51 The different actions of tramadol and nefopam on autonomic thermoregulatory responses may thus be explained by the opioid properties of tramadol.
Based on previous experience with nefopam, 52 we expected the side effects reported by our volunteers. All the adverse events disappeared spontaneously within 30 min even though the nefopam infusion continued. Therefore, it seemed that adverse events were due to rapid increases in cerebral concentration during loading rather than steady state concentrations per se  . Both nefopam and tramadol administration are often associated with profuse sweating. 7,50 However, sweating was transitory and unassociated with any reduction in the sweating threshold. Therefore, an additional possibility is that sweating in response to nefopam administration may result from direct simulation of eccrine glands rather than a thermoregulatory phenomenon.
In our unanesthetized volunteers, a typical postoperative analgesic blood nefopam concentration (70 ng/ml, which resulted from administration of approximately 20 mg) decreased the shivering threshold by roughly 1°C. In contrast, 0.12 mg/kg nefopam seemed to have a greater effect in patients recovering from neurosurgery. 53 Only 2 of 20 patients shivered at a mean core temperature of 33.6°C. However, there were numerous factors that presumably contributed to thermoregulatory inhibition in these patients, including residual anesthesia and opioids, cutaneous warming to 36.5°C, and neurosurgery per se  .
A reduction of approximately 1°C in the shivering threshold is itself unlikely to be sufficient for induction of therapeutic hypothermia in unanesthetized patients. However, nefopam does not impair ventilation, and its other side effects are minimal and of short duration. Therefore, it is likely that nefopam could be combined with other drugs to produce substantial thermoregulatory tolerance with minimal side effects. This strategy has been used, for example, with meperidine and buspirone, which synergistically reduce the shivering threshold. 54 
Plasma nefopam concentrations were slightly greater during sweating than at the vasoconstriction or shivering thresholds. Greater concentrations at sweating presumably resulted from an imperfection in our computer-controlled infusion profile because core temperature changes only slightly in the thermoregulatory model we used; furthermore, metabolism would presumably be increased at higher temperatures rather than the reverse. In any case, modest differences in plasma nefopam concentrations are of little consequence in this study because our primary analysis was based on individual concentration–response regressions.
In summary, nefopam administration had little effect on the sweating or vasoconstriction thresholds. However, the shivering threshold was reduced approximately 1°C by a plasma concentration of 55 ng/ml. This novel pattern has not previously been reported for any centrally acting drug. That pharmacologic modulations of vasoconstriction and shivering can be separated is of considerable clinical and physiologic interest.
References
Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346: 557–63Bernard, SA Gray, TW Buist, MD Jones, BM Silvester, W Gutteridge, G Smith, K
The Hypothermia after Cardiac Arrest Study Group: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346: 549–56The Hypothermia after Cardiac Arrest Study Group:,
Lopez M, Sessler DI, Walter K, Emerick T, Ozaki M: Rate and gender dependence of the sweating, vasoconstriction, and shivering thresholds in humans. A nesthesiology 1994; 80: 780–8Lopez, M Sessler, DI Walter, K Emerick, T Ozaki, M
Matsukawa T, Kurz A, Sessler DI, Bjorksten AR, Merrifield B, Cheng C: Propofol linearly reduces the vasoconstriction and shivering thresholds. A nesthesiology 1995; 82: 1169–80Matsukawa, T Kurz, A Sessler, DI Bjorksten, AR Merrifield, B Cheng, C
Annadata R, Sessler DI, Tayefeh F, Kurz A, Dechert M: Desflurane slightly increases the sweating threshold but produces marked, nonlinear decreases in the vasoconstriction and shivering thresholds. A nesthesiology 1995; 83: 1205–11Annadata, R Sessler, DI Tayefeh, F Kurz, A Dechert, M
Kurz A, Xiong J, Sessler DI, Plattner O, Christensen R, Dechert M, Ikeda T: Isoflurane produces marked and nonlinear decreases in the vasoconstriction and shivering thresholds 1997; 813: 778–85Kurz, A Xiong, J Sessler, DI Plattner, O Christensen, R Dechert, M Ikeda, T
Heel RC, Brogden RN, Pakes GE, Speight TM, Avery GS: Nefopam: A review of its pharmacological properties and therapeutic efficacy. Drugs 1980; 19: 249–67Heel, RC Brogden, RN Pakes, GE Speight, TM Avery, GS
Guirimand F, Dupont X, Bouhassira D, Brasseur L, Chauvin M: Nefopam strongly depresses the nociceptive flexion (R(III)) reflex in humans. Pain 1999; 80: 399–404Guirimand, F Dupont, X Bouhassira, D Brasseur, L Chauvin, M
Ohkubo Y, Nomura K, Yamaguchi I: Involvement of dopamine in the mechanism of action of FR64822, a novel non-opioid antinociceptive compound. Eur J Pharmacol 1991; 204: 121–5Ohkubo, Y Nomura, K Yamaguchi, I
Fuller RW, Snoddy HD: Evaluation of nefopam as a monoamine uptake inhibitor in vivo in mice. Neuropharmacology 1993; 32: 995–9Fuller, RW Snoddy, HD
Buritova J, Besson JM: Effects of nefopam on the spinal nociceptive processes: A c-Fos protein study in the rat. Eur J Pharmacol 2002; 441: 67–74Buritova, J Besson, JM
Gray AM, Nevinson MJ, Sewell RD: The involvement of opioidergic and noradrenergic mechanisms in nefopam antinociception. Eur J Pharmacol 1999; 365: 149–57Gray, AM Nevinson, MJ Sewell, RD
Dordoni PL, Della Ventura M, Stefanelli A, Iannace E, Paparella P, Rocca B, Accorra F: Effect of ketorolac, ketoprofen and nefopam on platelet function. Anaesthesia 1994; 49: 1046–9Dordoni, PL Della Ventura, M Stefanelli, A Iannace, E Paparella, P Rocca, B Accorra, F
Bhatt AM, Pleuvry BJ, Maddison SE: Respiratory and metabolic effects of oral nefopam in human volunteers. Br J Clin Pharmacol 1981; 11: 209–11Bhatt, AM Pleuvry, BJ Maddison, SE
Bilotta F, Pietropaoli P, Sanita R, Liberatori G, Rosa G: Nefopam and tramadol for the prevention of shivering during neuraxial anesthesia. Reg Anesth Pain Med 2002; 27: 380–4Bilotta, F Pietropaoli, P Sanita, R Liberatori, G Rosa, G
Piper SN, Suttner SW, Schmidt CC, Maleck WH, Kumle B, Boldt J: Nefopam and clonidine in the prevention of postanesthetic shivering. Anaesthesia 1999; 54: 695–9Piper, SN Suttner, SW Schmidt, CC Maleck, WH Kumle, B Boldt, J
Rosa G, Pinto G, Orsi P, de Blasi RA, Conti G, Sanita R, La Rosa I, Gasparetto A: Control of post anaesthetic shivering with nefopam hydrochloride in mildly hypothermic patients after neurosurgery. Acta Anaesthesiol Scand 1995; 39: 90–95Rosa, G Pinto, G Orsi, P de Blasi, RA Conti, G Sanita, R La Rosa, I Gasparetto, A
Mather GG, Labroo R, Le Guern ME, Lepage F, Gillardin JM, Levy RH: Nefopam enantiomers: Preclinical pharmacology/toxicology and pharmacokinetic characteristics in healthy subjects after intravenous administration. Chirality 2000; 12: 153–9Mather, GG Labroo, R Le Guern, ME Lepage, F Gillardin, JM Levy, RH
Sessler DI: The sweating threshold during isoflurane anesthesia in humans. Anesth Analg 1991; 73: 300–3Sessler, DI
Washington D, Sessler DI, Moayeri A, Merrifield B, Prager M, McGuire J, Belani K, Hudson S, Schroeder M: Thermoregulatory responses to hyperthermia during isoflurane anesthesia in humans. J Appl Physiol 1993; 74: 82–7Washington, D Sessler, DI Moayeri, A Merrifield, B Prager, M McGuire, J Belani, K Hudson, S Schroeder, M
Rubinstein EH, Sessler DI: Skin-surface temperature gradients correlate with fingertip blood flow in humans. A nesthesiology 1990; 73: 541–5Rubinstein, EH Sessler, DI
Kurz A, Sessler DI, Christensen R, Dechert M: Heat balance and distribution during the core-temperature plateau in anesthetized humans. A nesthesiology 1995; 83: 491–9Kurz, A Sessler, DI Christensen, R Dechert, M
Nadel ER, Mitchell JW, Stolwijk JA: Control of local and total sweating during exercise transients. Int J Biometeorol 1971; 15: 201–6Nadel, ER Mitchell, JW Stolwijk, JA
Cheng C, Matsukawa T, Sessler DI, Ozaki M, Kurz A, Merrifield B, Lin H, Olofsson P: Increasing mean skin temperature linearly reduces the core-temperature thresholds for vasoconstriction and shivering in humans 1995; 82: 1160–8Cheng, C Matsukawa, T Sessler, DI Ozaki, M Kurz, A Merrifield, B Lin, H Olofsson, P
Talke P, Tayefeh F, Sessler DI, Jeffrey R, Noursalehi M, Richardson C: Dexmedetomidine does not alter the sweating threshold, but comparably and linearly decreases the vasoconstriction and shivering thresholds. A nesthesiology 1997; 87: 835–41Talke, P Tayefeh, F Sessler, DI Jeffrey, R Noursalehi, M Richardson, C
Kurz A, Sessler DI, Annadata R, Dechert M, Christensen R, Bjorksten AR: Midazolam minimally impairs thermoregulatory control. Anesth Analg 1995; 81: 393–8Kurz, A Sessler, DI Annadata, R Dechert, M Christensen, R Bjorksten, AR
Kurz A, Go JC, Sessler DI, Kaer K, Larson MD, Bjorksten AR: Alfentanil slightly increases the sweating threshold and markedly reduces the vasoconstriction and shivering thresholds. A nesthesiology 1995; 83: 293–9Kurz, A Go, JC Sessler, DI Kaer, K Larson, MD Bjorksten, AR
Kurz A, Ikeda T, Sessler DI, Larson MD, Bjorksten AR, Dechert M, Christensen R: Meperidine decreases the shivering threshold twice as much as the vasoconstriction threshold 1997; 86: 1046–54Kurz, A Ikeda, T Sessler, DI Larson, MD Bjorksten, AR Dechert, M Christensen, R
Greif R, Laciny S, Rajek AM, Larson MD, Bjorksten AR, Doufas AG, Bakhshandeh M, Mokhtarani M, Sessler DI: Neither nalbuphine nor atropine possess special antishivering activity. Anesth Analg 2001; 93: 620–7Greif, R Laciny, S Rajek, AM Larson, MD Bjorksten, AR Doufas, AG Bakhshandeh, M Mokhtarani, M Sessler, DI
Plattner O, Ikeda T, Sessler DI, Christensen R, Turakhia M: Postanesthetic vasoconstriction slows peripheral-to-core transfer of cutaneous heat, thereby isolating the core thermal compartment. Anesth Analg 1997; 85: 899–906Plattner, O Ikeda, T Sessler, DI Christensen, R Turakhia, M
Szmuk P, Ezri T, Sessler DI, Stein A, Geva D: Spinal anesthesia speeds active postoperative rewarming. A nesthesiology 1997; 87: 1050–4Szmuk, P Ezri, T Sessler, DI Stein, A Geva, D
Emmett JD: A review of heart rate and blood pressure responses in the cold in healthy subjects and coronary artery disease patients. J Cardiopulm Rehabil 1995; 15: 19–24Emmett, JD
Esposito E, Romandini S, Merlo-Pich E, Mennini T, Samanin R: Evidence of the involvement of dopamine in the analgesic effect of nefopam. Eur J Pharmacol 1986; 128: 157–64Esposito, E Romandini, S Merlo-Pich, E Mennini, T Samanin, R
Rosland JH, Hole K: The effect of nefopam and its enantiomers on the uptake of 5-hydroxytryptamine, noradrenaline and dopamine in crude rat brain synaptosomal preparations. J Pharm Pharmacol 1990; 42: 437–8Rosland, JH Hole, K
Tresnak-Rustad NJ, Wood ME: In vitro biochemical effects of nefopam hydrochloride, a new analgesic agent. Biochem Pharmacol 1981; 30: 2847–50Tresnak-Rustad, NJ Wood, ME
Quan N, Xin L, Ungar AL, Blatteis CM: Preoptic norepinephrine-induced hypothermia is mediated by alpha 2-adrenoceptors. Am J Physiol 1992; 262: R407–11Quan, N Xin, L Ungar, AL Blatteis, CM
Hellon RF: Monoamines, pyrogens and cations: Their actions on central control of body temperature. Pharmacol Rev 1974; 26: 289–321Hellon, RF
De Witte J, Sessler DI: Perioperative shivering: Physiology and pharmacology. A nesthesiology 2002; 96: 467–84De Witte, J Sessler, DI
Fernandez-Sanchez MT, Diaz-Trelles R, Groppetti A, Manfredi B, Brini AT, Biella G, Sotgiu ML, Novelli A: Nefopam, an analogue of orphenadrine, protects against both NMDA receptor-dependent and independent veratridine-induced neurotoxicity. Amino Acids 2002; 23: 31–6Fernandez-Sanchez, MT Diaz-Trelles, R Groppetti, A Manfredi, B Brini, AT Biella, G Sotgiu, ML Novelli, A
Sharma DR, Thakur JR: Ketamine and shivering (letter). Anaesthesia 1990; 45: 252–3Sharma, DR Thakur, JR
Kizilirmak S, Karakas SE, Akça O, Ozkan T, Yavru A, Pembeci K, Sessler DI, Telci L: Magnesium sulfate stops postanesthetic shivering. Ann N Y Acad Sci 1997; 813: 799–806Kizilirmak, S Karakas, SE Akça, O Ozkan, T Yavru, A Pembeci, K Sessler, DI Telci, L
Koe BK: Molecular geometry of inhibitors of the uptake of catecholamines and serotonin in synaptosomal preparations of rat brain. J Pharmacol Exp Ther 1976; 199: 649–61Koe, BK
Delaunay L, Herail T, Sessler DI, Lienhart A, Bonnet F: Clonidine increases the sweating threshold, but does not reduce the gain of sweating. Anesth Analg 1996; 83: 844–8Delaunay, L Herail, T Sessler, DI Lienhart, A Bonnet, F
Nicolaou G, Chen AA, Johnston CE, Kenny GP, Bristow GK, Giesbrecht GG: Clonidine decreases vasoconstriction and shivering thresholds, without affecting the sweating threshold. Can J Anaesth 1997; 44: 636–42Nicolaou, G Chen, AA Johnston, CE Kenny, GP Bristow, GK Giesbrecht, GG
Delaunay L, Bonnet F, Liu N, Beydon L, Catoire P, Sessler DI: Clonidine comparably decreases the thermoregulatory thresholds for vasoconstriction and shivering in humans. A nesthesiology 1993; 79: 470–4Delaunay, L Bonnet, F Liu, N Beydon, L Catoire, P Sessler, DI
Hunskaar S, Fasmer OB, Broch OJ, Hole K: Involvement of central serotonergic pathways in nefopam-induced antinociception. Eur J Pharmacol 1987; 138: 77–82Hunskaar, S Fasmer, OB Broch, OJ Hole, K
Simon E: Temperature regulation: The spinal cord as a site of extrahypothalamic thermoregulatory functions. Rev Physiol Biochem Pharmacol 1974; 71: 1–76Simon, E
Bernatzky G, Jurna I: Intrathecal injection of codeine, buprenorphine, tilidine, tramadol and nefopam depresses the tail-flick response in rats. Eur J Pharmacol 1986; 120: 75–80Bernatzky, G Jurna, I
Tobin WE, Gold RH: Nefopam hydrochloride: A novel muscle relaxant. J Clin Pharmacol New Drugs 1972; 12: 230–8Tobin, WE Gold, RH
Scott LJ, Perry CM: Tramadol: A review of its use in perioperative pain. Drugs 2000; 60: 139–76Scott, LJ Perry, CM
De Witte JL, Kim JS, Sessler DI, Bastanmehr H, Bjorksten AR: Tramadol reduces the sweating, vasoconstriction, and shivering thresholds. Anesth Analg 1998; 87: 173–9De Witte, JL Kim, JS Sessler, DI Bastanmehr, H Bjorksten, AR
Pillans PI, Woods DJ: Adverse reactions associated with nefopam. N Z Med J 1995; 108: 382–4Pillans, PI Woods, DJ
Bilotta F, Pietropaoli P, La Rosa I, Spinelli F, Rosa G: Effects of shivering prevention on haemodynamic and metabolic demands in hypothermic postoperative neurosurgical patients. Anaesthesia 2001; 56: 514–9Bilotta, F Pietropaoli, P La Rosa, I Spinelli, F Rosa, G
Mokhtarani M, Mahgoub AN, Morioka N, Doufas AG, Dae M, Shaughnessy TE, Bjorksten AR, Sessler DI: Buspirone and meperidine synergistically reduce the shivering threshold. Anesth Analg 2001; 93: 1233–9Mokhtarani, M Mahgoub, AN Morioka, N Doufas, AG Dae, M Shaughnessy, TE Bjorksten, AR Sessler, DI
Fig. 1. Individual effects of increasing plasma nefopam concentration on the core temperatures triggering sweating (open circles  and thin line  ), vasoconstriction (filled circles  and medium line  ), and shivering (open triangles  and thick line  ) in nine volunteers. Nefopam did not significantly change the sweating or vasoconstriction thresholds; however, the slope of shivering decreased significantly by 16.7 ± 9.5°C ·μg−1· ml, and the shivering threshold decreased by 0.9 ± 0.4°C. All of the thresholds (at a designated skin temperature of 34°C) were calculated from measured skin and core temperatures.
Fig. 1. Individual effects of increasing plasma nefopam concentration on the core temperatures triggering sweating (open circles 
	and thin line 
	), vasoconstriction (filled circles 
	and medium line 
	), and shivering (open triangles 
	and thick line 
	) in nine volunteers. Nefopam did not significantly change the sweating or vasoconstriction thresholds; however, the slope of shivering decreased significantly by 16.7 ± 9.5°C ·μg−1· ml, and the shivering threshold decreased by 0.9 ± 0.4°C. All of the thresholds (at a designated skin temperature of 34°C) were calculated from measured skin and core temperatures.
Fig. 1. Individual effects of increasing plasma nefopam concentration on the core temperatures triggering sweating (open circles  and thin line  ), vasoconstriction (filled circles  and medium line  ), and shivering (open triangles  and thick line  ) in nine volunteers. Nefopam did not significantly change the sweating or vasoconstriction thresholds; however, the slope of shivering decreased significantly by 16.7 ± 9.5°C ·μg−1· ml, and the shivering threshold decreased by 0.9 ± 0.4°C. All of the thresholds (at a designated skin temperature of 34°C) were calculated from measured skin and core temperatures.
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Fig. 2. Average sweating, vasoconstriction, and shivering thresholds at each nefopam concentration. Results are shown as mean ± SD.
Fig. 2. Average sweating, vasoconstriction, and shivering thresholds at each nefopam concentration. Results are shown as mean ± SD.
Fig. 2. Average sweating, vasoconstriction, and shivering thresholds at each nefopam concentration. Results are shown as mean ± SD.
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Table 1. Major Results
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Table 1. Major Results
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Table 2. Side Effects
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Table 2. Side Effects
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