The Effects of Nefopam on the Gain and Maximum Intensity of Shivering in Healthy Volunteers

Yoshie Taniguchi, MD,* Syed Z. Ali, MD,* Oliver Kimberger, MD,* Sandra Zmoos, CRNA,* Rolf Lauber, PhD,* Monica Markstaller, MD,* and Andrea Kurz, MD†

BACKGROUND: Mild hypothermia has been shown to improve neurologic outcome after cardiac arrest. Nefopam, a centrally acting, nonsedative analgesic, decreases the threshold of shivering, but not vasoconstriction, and thus might be a suitable drug for induction of therapeutic hypothermia. However, not only the threshold but also the gain and maximum intensity of shivering define the thermoregulatory properties of a drug and thus are clinically important. Therefore, we evaluated the gain and maximum intensity of shivering at 2 different doses of nefopam and placebo. METHODS: Seven healthy volunteers were randomly assigned to 3 study days: (1) control (saline), (2) small-dose nefopam (50 ng/mL), and (3) large-dose nefopam (100 ng/mL). On all study days volunteers were cooled using central venous infusion of cold IV fluid while mean skin temperature was maintained at 31°C. Core temperature was recorded at the tympanic membrane. Threshold, gain, and maximum intensity of shivering were evaluated using oxygen consumption. RESULTS: Both 50 and 100 ng/mL nefopam significantly reduced the shivering threshold as well as the gain of shivering: shivering threshold: 35.6°C Ϯ 0.2°C (control); 35.2°C Ϯ 0.3°C (small dose); 34.9°C Ϯ 0.5°C (large dose), P ϭ 0.004; gain of shivering: 597 Ϯ 235 mL ⅐ minϪ1 ⅐ °CϪ1 (control); 438 Ϯ 178 mL ⅐ minϪ1 ⅐ °CϪ1 (small dose); 301 Ϯ 134 mL ⅐ minϪ1 ⅐ °CϪ1 (large dose), P ϭ 0.028. Maximum intensity of shivering did not differ among the 3 treatments. CONCLUSIONS: Nefopam significantly reduced the gain of shivering. This reduction, in combi- nation with a reduced shivering threshold, will allow clinicians to cool patients even further when therapeutic hypothermia is indicated. (Anesth Analg 2010;111:409–14)

ild hypothermia provides substantial protection compound that is structurally related to orphenadrine and against cerebral1–4 and myocardial ischemia in diphenhydramine.7 It is a centrally acting analgesic7,8 with Manimals.5,6 In humans, mild hypothermia im- both supraspinal15,16 and spinal sites of action.17,18 Nefo- proves neurologic outcome and reduces mortality after pam is neither an opiate nor a nonsteroidal noninflamma- 19 cardiac arrest.6–8 tory drug and does not induce respiratory depression, 20 Mild hypothermia with core temperatures between 33°C even in postoperative patients. Mechanisms involved in and 34°C is relatively easy to induce during general anesthe- the thermoregulatory effect of nefopam are not clearly sia because anesthetics profoundly impair thermoregulatory established. responses5,9–11 such as arteriovenous shunt vasoconstriction Clinical studies indicate that nefopam treats or prevents postoperative shivering.21–23 It decreases the shivering and shivering. Other analgesic and sedative drugs, for ex- 24 ample, meperidine,6 buspirone,12 dexmedetomidine,13 and threshold without altering the vasoconstriction threshold. clonidine,14 comparably reduce the vasoconstriction and shiv- It might thus be a potent drug for induction of therapeutic hypothermia. However, not only the shivering threshold ering threshold. However, all of these drugs, when used in but also the gain and maximum intensity of a thermoregu- sufficient concentrations to impair thermoregulatory con- latory response define the thermoregulatory properties of a trol, have severe side effects such as sedation and respira- drug and are thus of great clinical importance. Once the tory depression. There is thus considerable interest in shivering threshold is reached, shivering usually progresses identifying drugs that defeat thermoregulatory defenses quickly to its maximum intensity in a nonsedated and non- against hypothermia without causing side effects in awake anesthetized person. Once maximum intensity for shivering is patients. reached, further cooling is almost impossible. Nefopam might Nefopam, a nonsedative analgesic, seems to have im- not only delay the shivering threshold but also the gain of portant thermoregulatory properties. It is a benzoxazocine shivering, which would allow cooling to even lower core temperatures before maximum intensity of shivering is From the *Department of Anaesthesiology, University of Bern, Bern, Swit- reached. Furthermore, nefopam might decrease the maximum zerland; and †Department of Outcomes Research, Cleveland Clinic, Cleve- land, Ohio. intensity of shivering, which in itself would foster cooling. Accepted for publication December 7, 2009. Therefore, we evaluated the gain and maximum intensity of Disclosure: The authors report no conflicts of interest. shivering with 2 different doses of nefopam. Presented as a poster presentation at the 2005 Annual Meeting of the American Society of Anaesthesiologists in Atlanta, Georgia. METHODS Address correspondence and reprint requests to Andrea Kurz, MD, Depart- With approval from the IRB of the University Hospital of ment of Outcomes Research, Anesthesia Institute, Cleveland Clinic, Cleve- land, OH 43195. Address e-mail to [email protected]. Bern and written informed consent, we studied 7 healthy Copyright © 2010 International Anesthesia Research Society volunteers (5 men and 2 women) on 3 days. Medical history DOI: 10.1213/ANE.0b013e3181e332bb and physical examination were performed. Volunteers who

August 2010 • Volume 111 • Number 2 www.anesthesia-analgesia.org 409 Nefopam Reduces Gain of Shivering used any medication or reported a history of alcohol or is a skin temperature at which volunteers are vasocon- drug abuse were excluded from the study. stricted and feel slightly cold but have not yet started to shiver. Choosing this particular mean skin temperature Treatment Protocol restricts IV fluid amounts. Each thermoregulatory study Studies started at approximately 8:00 am. Volunteers fasted ended upon detection of maximum intensity of shivering. for 8 hours and avoided alcohol and drugs for 24 hours Subsequently, volunteers were warmed until they were before each study day. During the study, volunteers were normothermic and comfortable. minimally clothed and rested supine on a standard patient An interval of at least 48 hours elapsed between study bed equipped with a water mattress. Ambient temperature days; before subsequent treatment, a blood sample was was maintained between 20°C and 22°C. Volunteers were obtained to ensure that nefopam had been eliminated from studied on 3 randomly assigned days, each separated by at the previous study day. least 2 days: (1) control (saline), (2) nefopam at a target plasma concentration of 50 ng/mL (small dose), and (3) nefopam at a Measurements target concentration of 100 ng/mL (large dose). Heart rate was measured continuously using an electrocar- Nefopam was administered IV via the right antecubital diogram and oxygen saturation using a pulse oximeter. vein as bolus plus maintenance regimen. The infusion Blood pressure was determined oscillometrically at profile was based on published pharmacokinetic data.24,25 5-minute intervals as well as from the arterial line. Core The time to peak plasma concentration was 20 minutes; the temperature was recorded from the tympanic membrane mean elimination half-life was approximately 240 minutes. (Mallinckrodt Anesthesiology Products, Inc., St. Louis, This dosing scheme is intended to rapidly achieve thera- MO). Tympanic probes were inserted into both ears by the peutic concentrations, minimize side effects during the volunteer until the thermocouple touched the tympanic initial phase, and maintain a therapeutic level throughout membrane; appropriate placement was confirmed when the study. the volunteer detected a gentle rubbing of the attached A 20-gauge catheter was inserted into a radial artery for wire. Additionally, a temperature difference Յ0.2°C con- blood sampling. To qualify for arterial catheterization, firmed correct placement. The aural canal was occluded volunteers were required to have no recent wrist trauma, with cotton, the probe taped securely in place, and a gauze and normal Allen test. Arterial lines were placed by anes- bandage was positioned over the external ear. Mean skin- thesiologists or physicians experienced in the procedure. If surface temperatures were calculated from measurements insertion of the arterial line was not possible with 3 at 15 area-weighted sites. Temperatures were recorded at attempts, the study was aborted. Blood samples were 1-minute intervals from thermocouples connected to Iso- collected from the arterial line via a 3-way stopcock. After Thermex௡ thermometers with an accuracy of 0.1°C (Colum- each sample, the arterial line was flushed with 0.9% sodium bus Instruments Corp., Columbus, OH).26 chloride. The arterial line remained in place for up to 15 Oxygen consumption, as measured by a Vmax meta- hours after nefopam administration for additional blood bolic monitor (Sensor Medics Corp., Yorba Linda, CA), was sampling to further evaluate nefopam pharmacokinetics used to quantify shivering; the system was used in canopy (unpublished data). We had no complications with the mode on the 3 study days. This system provides measure- arterial lines. ments with an absolute accuracy of 5% to 10%.27 Measure- A 30-cm central venous catheter was inserted with ments were averaged over 1-minute intervals and recorded sterile technique by an anesthesiologist in the volunteer’s every minute. A sustained increase in oxygen consumption left antecubital vein and used for infusion of cold Ringer of 20% identified the shivering threshold. Oxygen con- lactate solution. During infusion of cold IV fluid, the upper sumption is the “gold standard” for shivering intensity arm was kept warm to avoid discomfort for the volunteers. because it represents integrated metabolic rate. The central venous catheter was removed after each study We also evaluated known side effects of nefopam such day and no complications were observed. Once stable as nausea and vomiting, pain at the injection site, and dry predicted nefopam plasma concentrations were achieved mouth every 30 minutes throughout the study. (approximately 30 minutes after start of the infusion), Ringer lactate solution cooled to approximately 4°C was Determination of Nefopam infused via the left antecubital vein on all study days at Plasma Concentrations rates sufficient to decrease tympanic membrane tempera- Plasma samples were stored at Ϫ20°C until analysis. Before ture approximately 2.4°C/h, i.e., approximately 0.2°C ev- extraction, plasma samples for nefopam analysis were ery 5 minutes. The core temperature cooling rate was allowed to thaw at room temperature, vortexed, and then restricted to Ͻ2.5°C/h because this rate was unlikely to centrifuged at 2000 rpm for 5 minutes. To 0.5 mL of plasma, trigger any dynamic thermoregulatory response.3 Fluid 0.5 mL deionized water, internal standard (imipramine was given until the maximum intensity (shivering intensity hydrochloride; ICN Biomedicals, Inc., Aurora, OH) and no longer increases, despite a continued decrease in core 30 ␮L orthophosphoric acid were added and vortexed. temperature) of shivering was identified or a total of up to Samples were analyzed by gas chromatography–mass se- 60 mL/kg fluid was administered. Throughout the study, lective detector (MSD) (model 6890 with a 5972A MSD and the volunteers’ mean skin temperatures were kept at 31°C automatic injector; Agilent Technologies, Santa Clara, CA). using a forced-air whole body cover on top of the volun- Aliquots of 1 ␮L were injected in splitless mode onto a teers and a circulating water mattress under the volunteers. Varian FactorFour VF-Xms (Varian, Inc., Palo Alto, CA), A temperature of 31°C was chosen specifically because this 12 m, 0.2-mm inside diameter capillary column with a

410 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA 0.33-␮m film. The helium flow rate was 0.8 mL/min. Table 1. Results Operating temperatures of the gas chromatography were: injector 250°C, MSD transfer line 280°C, oven 140°C for 0.2 Small Large P Control dose dose value minute increasing (25°C/min) to 280°C, hold 1 minute. The Nefopam total NA 16.6 Ϯ 5.5 31.2 Ϯ 9.2 0.003 MSD was operated in the electron impact mode (70 eV) infusion dose (mg) with selected ion monitoring with a dwell time of 100 Cold fluid total 35.9 Ϯ 5.8 38.7 Ϯ 9.8 43.9 Ϯ 13 0.33 milliseconds each. Selected ion monitoring ions for quanti- amount (mL/kg) tation were m/z 225 and 235 for nefopam and internal NA ϭ not applicable. standard, respectively. The data were processed with pro- Data are mean Ϯ SD. prietary mass spectrometer control software (HP G1701AA; Hewlett-Packard, Palo Alto, CA). Ն All calibration curves had correlation coefficients 0.99. onset of shivering and the maximum intensity were in- ϭ Coefficient of variation of intraday reproducibility (n 10) cluded. The resulting values among volunteers were then was for nefopam at 301, 103, and 10.3 ng/mL blood content averaged. Results on the 3 study days were compared 2.0%, 2.2%, and 3.7%, respectively. Coefficient of variation using repeated measures of analysis of variance. of interday reproducibility at the same concentrations (n ϭ 6) was 4.5%, 5.3%, and 7.4%, respectively. Mean recovery of RESULTS ϭ nefopam (n 15) at concentrations of 10 to 300 ng/mL was Volunteers were aged 27 Ϯ 6 years, weighed 76 Ϯ 12 kg, 92.5% (range, 87%–104%). The limit of quantification at a and were 180 Ϯ 6 cm tall. The volunteers required slightly signal-to-noise ratio of 10:1 was 4.4 ng/mL. The limit of more fluid for core cooling when nefopam was adminis- detection at a signal-to-noise ratio of 3:1 was 1.3 ng/mL. tered (Table 1). Heart rate was similar on all study days whereas mean arterial blood pressure increased with the Data Analysis large dose of nefopam. However, this increase was small A 20% sustained increase in oxygen consumption identified and clinically unimportant. Furthermore, thermal comfort the shivering threshold. The cutaneous contribution to was similar on all 3 days (Table 2). Known side effects of sweating and to vasoconstriction and shivering is linear. nefopam such as nausea and vomiting and pain at the We thus used measured skin and core temperatures in °C at injection site were not observed in this study. One volun- the threshold to calculate the core-temperature threshold teer experienced dry mouth during the first hour after drug that would have been observed with a fixed skin tempera- administration. Ϯ ture of 31°C: As per protocol, nefopam plasma levels were 56 10 ng/mL and 99 Ϯ 15 ng/mL for small and large doses, ␤ respectively (Table 1). A total amount of approximately 17 ؉ ͩ ͪ ؊ mg nefopam was administered on the small-dose day and ؍ TCore (calculated) TCore [TSkin TSkin (designated)] ؊␤ approximately 32 mg on the large-dose day. According to 1 protocol, skin temperature was Ϸ31°C on all study days where the fractional contribution of mean skin tempera- throughout the entire study (Table 2). ␤ Ϯ ture to the threshold was termed .TCore(calculated) thus The calculated shivering threshold was 35.6°C 0.2°C equals the measured core temperature, TCore, plus a on the control day. As in previous studies, nefopam sig- small correction factor consisting of ␤/(1 Ϫ ␤) multiplied nificantly decreased the shivering threshold with the low Ϯ by the difference between actual (TSkin) and designated and the high dose of nefopam (small dose: 35.2°C 0.3°C; Ϯ ϭ [TSkin(designated)] skin temperatures. We have previously large dose: 34.9°C 0.5°C; P 0.0041) (Table 2). However, described the derivation, limitations, and validation of low and high dose did not differ significantly. The high this equation. We used a ␤ of 0.2 for shivering. The dose of nefopam also significantly reduced the gain of Ϫ Ϫ designated skin temperature was set at 31°C. shivering (control day: 597 Ϯ 235 mL ⅐ min 1 ⅐ °C 1; small Ϫ Ϫ The gain of shivering was determined as the slope of dose: 438 Ϯ 178 mL ⅐ min 1 ⅐ °C 1; and large dose: 301 Ϯ Ϫ Ϫ oxygen consumption versus core temperature regression 134 mL ⅐ min 1 ⅐ °C 1; P ϭ 0.028) (Fig. 1). The core tem- during its initial ascent toward the maximum observed perature at maximum intensity of shivering was signifi- value. Slopes were calculated for each volunteer and each cantly lower on the small-dose and high-dose days study day and then averaged among volunteers. Maximum compared with control. Maximum intensity of shivering intensity of shivering was identified by an oxygen con- did not differ among the 3 studies days (Table 2). sumption that failed to increase further despite continued reduction in core temperature. In both cases, the data series DISCUSSION were smoothed using 5-minute running average filters. The Mild hypothermia has been shown to improve outcome shivering threshold, gains, and maximum intensity were after cardiac arrest1,2 and its application has been advised determined post hoc by an investigator blinded to treat- by the International Liaison Committee on Resuscitation28 ment and core temperature. Results on the 3 study days and the European Resuscitation Council.29 Currently, in- were averaged using repeated measures of analysis of vestigators conducting several clinical trials are studying variance. mild hypothermia in patients with ischemic heart injury, Hemodynamic responses, ambient temperature, relative brain trauma, and ischemic stroke. In the majority of humidity, and end-tidal Pco2 on each study day were first studies, hypothermia is induced by anesthetics often in averaged for each volunteer; data obtained between the combination with muscle relaxants to suppress shivering.

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Table 2. Major Results Control Small dose Large dose P value Heart rate (bpm) 66 Ϯ 462Ϯ 563Ϯ 7 0.346 Mean arterial blood pressure (mm Hg) 93 Ϯ 497Ϯ 6 100 Ϯ 5* 0.049 Thermal comfort (mm) 26 Ϯ 12 25 Ϯ 727Ϯ 9 0.96 Nefopam plasma concentration (ng/mL) NA 56.2 Ϯ 10.3 98.8 Ϯ 14.7 Ͻ0.001 Initial core temperature (°C) 36.6 Ϯ 0.2 36.6 Ϯ 0.4 36.5 Ϯ 0.3 0.736 Mean skin temperature throughout study (°C) 31.0 Ϯ 0.1 31.1 Ϯ 0.2 31.0 Ϯ 0.1 0.154 Core temperature at shivering (°C) 36.4 Ϯ 0.2 35.7 Ϯ 0.2* 35.6 Ϯ 0.5* 0.0037 Calculated shivering threshold (°C) 35.6 Ϯ 0.2 35.2 Ϯ 0.3* 34.9 Ϯ 0.5* 0.0041 Gain (mL ⅐ minϪ1 ⅐ °CϪ1) 597 Ϯ 235 438 Ϯ 178 301 Ϯ 134* 0.028 Core temperature at maximum intensity (°C) 35.8 Ϯ 0.3 35.1 Ϯ 0.3* 34.8 Ϯ 0.5* 0.0003 Calculated threshold at maximum intensity (°C) 35.1 Ϯ 0.3 34.4 Ϯ 0.3* 34.0 Ϯ 0.6* 0.0004 Maximum intensity (mL/min) 739 Ϯ 130 639 Ϯ 105 669 Ϯ 86 0.23 NA ϭ not applicable. Data are mean Ϯ SD. * Significant difference compared with control.

respiratory depression, even in postoperative patients.20 Clinical studies indicate that nefopam treats or prevents postoperative shivering.21–23 Mechanisms involved in the thermoregulatory effect of nefopam are not clearly estab- lished. However, in vitro and in vivo studies indicate that nefopam’s analgesic properties are related to its potent inhi- bition of serotonin (5-hydroxytryptamine), norepinephrine, and dopamine synaptosomal uptake. Monoamines are in- volved in the thermoregulatory pathways. The balance be- tween 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. Nefo- pam may therefore promote hypothermia via a monoamine Figure 1. The slopes of the oxygen consumption versus core mechanism. Other properties of nefopam may also contribute temperature relations (determined using liner regression). The gains to its antishivering action. Nefopam may have a direct ⅐ Ϫ1 ⅐ Ϫ1 ␣ for control and small and large doses were 597 mL min °C interaction with 2-adrenoceptors. Nefopam, similar to 2 Ϫ1 Ϫ1 2 (r ϭ 0.99), 438 mL ⅐ min ⅐ °C (r ϭ 0.99), and 301 orphenadrine, is also a noncompetitive N-methyl-d-aspartate mL ⅐ minϪ1 ⅐ °CϪ1 (r2 ϭ 0.99), respectively. The horizontal SD bars indicate variability in the shivering thresholds on each study day. (NMDA) receptor antagonist. Magnesium sulfate and ket- Regression equations: control: y ϭ 22 Ϫ 0.6x; small dose: y ϭ 16 Ϫ amine, which are competitive NMDA receptor antagonists, 0.5x; high dose: y ϭ 11 Ϫ 0.3x. inhibit postanesthetic shivering. Inhibition of NMDA recep- tors may thus contribute to the antishivering effect of nefo- pam. Nefopam is available in Europe, but is not approved by Although anesthetics reduce shivering and vasoconstric- the Food and Drug Administration for use in the United tion thresholds by 2°C to 3°C, these drugs are, unsurpris- States. ingly, not the first choice for induction of mild hypothermia Alfonsi et al.24 showed that moderate doses of nefopam in the awake patient; they cause significant sedation, respi- decrease the threshold of shivering to a core temperature of ratory depression, and jeopardize airway patency. approximately 35°C without affecting the vasoconstriction Consequently, numerous investigators have searched threshold. Furthermore, side effects, e.g., nausea, pain upon for other drugs or drug combinations that decrease vaso- injection, or dry mouth, were minimal and of short dura- constriction and shivering thresholds. One of the most effective antishivering drugs is meperidine.30 Meperidine tion. Nefopam did not impair ventilation. Although this affects both shivering and vasoconstriction thresholds, but study defined the shivering threshold, the thermoregula- reduces the shivering threshold to a greater extent (by a tory response is further described by the gain and maxi- factor of 2) compared with the vasoconstriction threshold.31 mum intensity of shivering. Gain determines the extent to However, when used as a single drug, large plasma con- which the response intensity increases with further devia- centrations of meperidine are necessary to reduce shivering tion of the core temperature from the triggering threshold. thresholds below 34°C, leading to sedation and respiratory Maximum intensity is the maximum response, which even depression. Smaller doses of meperidine in combination with further deviation from the core temperature remains with other drugs (buspirone,12 dexmedetomidine,13 or unchanged. As demonstrated by our study, 100 ng/mL magnesium32) have proven helpful. nefopam significantly decreased the gain of shivering but We investigated nefopam, a centrally acting, nonseda- did not affect maximum intensity. Clinically, this is impor- tive analgesic. Nefopam is neither an opiate nor a nonste- tant: once shivering is triggered, core temperature de- roidal noninflammatory drug.19 Nefopam does not induce creases approximately 1°C before the maximum intensity

412 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA of shivering. An approximate 1°C reduction in the shiver- In the study by Alfonsi et al., the volunteers were signifi- ing threshold is itself unlikely to be sufficient for induction cantly more likely to become nauseated or to complain of pain of therapeutic hypothermia in unanesthetized patients. upon injection or a dry mouth during the study when However, if the gain of shivering is decreased as well, nefopam was infused. In our current study, we did not see patients probably can be actively cooled until maximum these side effects, most likely because we administered the intensity of shivering is reached, which would allow a drug as a target-controlled infusion. We observed a significant further reduction of core temperature of 0.5°C to 1.0°C. increase in arterial blood pressure on the high-dose nefopam Furthermore, it is likely that nefopam combined with other day. However, we believe that this increase is not clinically drugs will produce substantial thermoregulatory tolerance important. Furthermore, this increase might have been only with minimal side effects. Alfonsi et al.33 recently showed partially attributable to nefopam’s effects. In many hypother- that the combination of nefopam with alfentanil reduces the mia volunteer studies, slight increases in arterial blood pres- shivering threshold more than nefopam and the ␣-agonist sure at low core temperatures are observed with intense clonidine, and the combination of nefopam with alfentanil shivering. In the current study, the high dose of nefopam was was more effective than either alfentanil or nefopam alone. associated with the lowest core temperatures, which might Furthermore, induction of hypothermia via internal cooling in have contributed to the slight increase in mean arterial blood combination with skin-surface warming significantly reduces pressure. the shivering threshold.34 Thus, the combination of skin A limitation of our study is that it was conducted in warming and nefopam administration might be a powerful young, healthy volunteers. Results from volunteer studies approach to therapeutic hypothermia, when hypothermia is cannot always be extrapolated to clinical situations. For induced by internal cooling. example, 0.12 mg/kg nefopam seemed to have a greater Furthermore, only a few anesthetics or epidural anes- effect in patients recovering from neurosurgery.35 Indeed, thesia decrease the shivering threshold and have an effect only 2 of 20 patients shivered at a mean core temperature of on gain of shivering as well. However, neither general nor 33.6°C. However, there were numerous factors that pre- neuraxial anesthesia are helpful for the purpose of thera- sumably contributed to thermoregulatory inhibition in peutic hypothermia. Moreover, meperidine, which repre- these patients including residual anesthesia and opioids, sents the gold standard for shivering inhibition, fails to cutaneous warming to 36.5°C, and neurosurgery per se. reduce gain of shivering. For these reasons, findings of our In summary, the high dose of nefopam significantly re- study are clinically relevant because nefopam is the first duced the gain of shivering. This reduction, in combination drug with a significant effect on the shivering threshold with a reduced shivering threshold, will allow clinicians to that does not have sedative, respiratory, or hemodynamic cool patients even further when therapeutic hypothermia is effects and that reduces gain of shivering, allowing further indicated. There were no adverse side effects, suggesting that core temperature decrease after the shivering threshold is even a relatively high dose of the drug can be used for an achieved. extended period of time to suppress thermoregulatory cold For the purpose of our study, we administered a total of responses. approximately 17 mg nefopam on the low-dose day and 32 mg nefopam on the high-dose day. Nefopam reduced both REFERENCES 1. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, the shivering threshold and the gain of shivering. This is Gutteridge G, Smith K. 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