Nefopam and Alfentanil Additively Reduce the Shivering Threshold in Humans whereas Nefopam and Clonidine Do Not

With approval from the Ethics Committee of Hôpital Ambroise Paré (Boulogne-Billancourt, France) and informed consent, we studied 15 healthy male volunteers. None was obese, taking medication, or had a history of thyroid disease, dysautonomia, or Raynaud’s syndrome.

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 study days. During the studies, the volunteers rested supine. They were minimally clothed, and ambient temperature was maintained near 20°C.

The study was conducted in a single-blind fashion. The volunteers were studied on four or six randomly-assigned days, each separated by at least 48 h: (1) control, no drug; (2) nefopam at a target plasma concentration of 0.1 μg/ml (Nefopam); (3) clonidine 2.5 μg/kg IV (Clonidine); (4) clonidine 2.5 μg/kg IV and nefopam at a target plasma concentration of 0.1 μg/ml combination (Combi 1); (5) alfentanil at a target plasma concentration of 0.15 μg/ml (Alfentanil); (6) nefopam and alfentanil combination at target concentrations of 0.1 μg/ml and 0.15 μg/ml, respectively (Combi 2).

An 18-cm-long 4.5-French catheter (Vygon, Ecouen, France) was introduced through an antecubital vein. This catheter was used for cold-fluid infusion and blood sampling. A venous catheter was inserted into the other arm for drug administration. Throughout the study period, mean skin temperature was maintained at 30°C by adjusting the ambient temperature.

Thermal manipulation began 30 min after the study drugs were started. Lactated Ringer’s solution cooled to 4°C was infused at rates sufficient to decrease tympanic membrane temperature 1 to 2°C/h. Fluid was given until the shivering threshold was identified or a total of 70 ml/kg was given. A pediatric forced-air cover connected to a warmer (Warm-touch, Mallinckrodt, Inc., St. Louis, MO) was rolled up around the arm used for cold solution infusion.

Nefopam and alfentanil were given intravenously via  an Orchestra® Base A (Fresenius Vial Inc, Brezins, France) connected to a local software written in Visual Basic 5.0 (Microsoft, Redmond, MA). The nefopam infusion profile was based on published pharmacokinetic data31and was designed to provide a time to peak plasma concentrations of 20 min with a mean elimination half-life of 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 infusion rates for the target plasma levels of alfentanil were determined using Shafer’s body surface adjusted pharmacokinetic modeling program, adjusted for age, sex, and weight.||

The choice for drug doses was based on two points: (1) achieving at least a 1°C decrease of shivering threshold; (2) avoiding toxicity. From previous data, a concentration of 0.1 μg · ml⁻¹of nefopam was chosen to obtain around a 1.5°C decrease of shivering threshold in our volunteers. For alfentanil, a target blood concentration of 150 ng/ml was chosen from published data.15With this dose, a 1°C shivering threshold decrease was expected with only minor respiratory depression and minimal sedation.

Pharmacokinetic parameters of clonidine disposition could be described by a two-compartment open model with a rapid distribution phase followed by a slow elimination phase.32Under these conditions, 30 min after bolus administration, plasmatic concentrations of clonidine remain almost unchanged over the 90–120 min necessary for triggering shivering and maintenance of clonidine perfusion is unnecessary. The dose of 2.5 μg/kg of clonidine was chosen from previously published data; 75 μg of clonidine given in volunteers weighing around 74 kg decreases shivering threshold by almost 0.5°C.30Because it decreases shivering threshold in a dose-dependent manner,33a clonidine dose of 2.5 μg was chosen to obtain a 1°C decrease of the shivering threshold.

Heart rate and pulse-oximeter saturation were monitored continuously. Arterial pressure was determined oscillometrically at the ankle at 10-min intervals, but it was also recorded at the shivering threshold. Oxygen consumption and carbon dioxide production were measured by a DeltaTrac metabolic monitor (Datex-Ohmeda, 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 patients 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 (T^Skin) was calculated from ten sites by using the formula34:

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.

Thermoregulatory vasoconstriction was determined by estimating fingertip blood flow, which was evaluated using forearm minus fingertip, skin-surface temperature gradients.35Gradients exceeding 0°C were indicative of vasoconstriction because this gradient corresponds to onset of the core-temperature plateau.36As in numerous previous studies, shivering was evaluated by a blinded observer and confirmed by a sustained increase in oxygen consumption to 25% above the baseline.

Sedation was evaluated by using the responsiveness component of a modified Observer’s Assessment of Alertness/Sedation score (table 1). Thermal comfort was assessed at each threshold with a 100-mm-long visual analog scale, with 50 mm defined as thermal comfort, 0 mm as the most intense imaginable sensation of cold, and 100 mm being the most intense imaginable sensation of warm. On each study day, sedation score and thermal comfort were obtained three times: (1) before drug administration, (2) before active cooling started, and (3) at the shivering threshold. Volunteers were questioned about side effects during loading dose and infusion period until shivering occurrence. The following side effects were systematically recorded: pain upon study-drug injection, pruritus, bradypnea, dizziness, headache, nausea, vomiting, dry mouth, palpitation, and epigastric pain.

A sustained increase in oxygen consumption (Vo²) exceeding 25% identified the shivering threshold. The baseline for this analysis was the steady-state value (no more than 5% variation in Vo²) after drug infusion but before core cooling started. On each study day, hemodynamic and Spo²data were averaged for each volunteer across the cooling period; these values were then averaged for all volunteers. Core and mean skin temperature data, as well as thermal comfort scores (visual analog scale) at the shivering threshold, were averaged across the volunteers for each study day. Sedation levels after drug infusion and at the shivering threshold were presented as the number of subjects having three different modified Observer’s Assessment of Alertness/Sedation score (5/4/3; see table 1) on each study day. Results on the four study days for each combination were compared by Kruskal-Wallis test and Student-Newman-Keuls tests for post hoc  comparison.

The synergistic interactions between nefopam and the two tested drugs (clonidine and alfentanil) were evaluated with the statistical methodology described by Slinker.37The study was designed as a two-factor experiment with two levels for each factor: the presence and absence of each of the two drugs. Also, assuming an additive effect, the expected reduction for the combination of nefopam and each tested drug was calculated as the sum of the individual effects of nefopam and clonidine or nefopam and alfentanil. With this model, a statistically significant, positive interaction term between the two drugs indicates that they act synergistically or antagonistically. Antagonism in this context simply means that the drug combination produces less effect than would be expected from the sum of the individual effects of each drug. A nonsignificant interaction term indicates that the drugs’ effects on the shivering threshold are additive.

A repeated-measures ANOVA was used because each volunteer in each drug set received all four treatments. Side effect frequencies were compared using a chi-square test and completed with a Fisher exact test. The software used for statistical tests was StatView version 5.0 (SAS Institute Inc, Cary, IN). Results are expressed as means ± SD; differences and the interaction term were considered statistically significant when P < 0.05.

Sixteen volunteers were enrolled in the study for a total of 72 sets of measurements. One volunteer completed only two sets of measurement, and those data were not included in our analysis. Ten volunteers completed four sets of measurement, and five volunteers completed six sets of measurement. For each interaction analysis, data from 10 volunteers were thus available.

The volunteers were 25 ± 6 yr old, weighed 70 ± 8 kg, and were 179 ± 5 cm tall. Mean loading doses of nefopam and clonidine were 45.5 ± 0.7 mg (0.7 ± 0.1 mg · kg⁻¹) and 170 ± 23 μg, respectively.

After the loading infusion, mean-arterial pressure was significantly lower with clonidine than on the other study days (table 2). Nefopam infusion alone or in combination with clonidine significantly increased heart rate. A significant mild sedation, as defined by the modified Observer’s Assessment of Alertness/Sedation, was observed after clonidine alone or in a combination dose compared to control and nefopam study days. Spo²values were similar on each study day. All of the volunteers were vasoconstricted before the cold-fluid infusion was started.

At the shivering threshold, mean arterial pressure remained significantly lower with clonidine than on the other study days. Heart rates were also significantly lower with clonidine. Mean skin temperatures at shivering were similar among the four study days. Sedation level at the shivering threshold did not differ among the four study days. Total amount of cold Ringer’s Lactate was significantly greater during Clonidine and Combi 1 study days than during Control study day (table 2).

Nefopam reduced the shivering threshold by 0.6 ± 0.3°C from 36.5 ± 0.3°C on the control day to 35.9 ± 0.3°C (P < 0.001), and clonidine reduced the shivering threshold by 0.5 ± 0.3°C to 36.0 ± 0.3°C (P < 0.001). The combination of nefopam and clonidine (Combi1) reduced the shivering threshold by 0.7 ± 0.4°C to 35.7 ± 0.2°C (P < 0.001). There was a significant interaction between the two drugs in terms of effect on the shivering threshold (P = 0.034). The combination of nefopam and clonidine thus reduced the shivering threshold no better than either drug alone, rather than being additive (fig. 1).

The volunteers were 25 ± 6 yr old, weighed 70 ± 8 kg, and were 179 ± 5 cm tall. Mean loading doses of nefopam and alfentanil were 45.7 ± 0.6 mg (0.6 ± 0.1 mg · kg⁻¹) and 1,275 ± 303 μg (18 ± 5 μg · kg⁻¹), respectively.

After the loading infusion, nefopam infusion alone or in combination significantly increased the heart rate compared to the other study days (table 3). Volunteers were mildly sedated, and Spo²was also significantly lower after alfentanil infusion, alone or in combination with nefopam. Mean arterial pressure was similar on each study day. All of the volunteers were vasoconstricted before the cold-fluid infusion was started.

At the shivering threshold, mean-arterial pressure, heart rate, Spo²and sedation level did not differ among the four study days. Mean skin temperature at shivering was lower during Combination 2 comparatively to Control (respectively 29.9 ± 0.8°C and 30.8 ± 0.6°C, P < 0.05). Thermal comfort was better with the alfentanil infusion than the other days. Significantly more cold Ringer’s lactate was required with alfentanil alone, and even more was necessary when alfentanil and nefopam were combined. Core cooling rates were similar among the four study days (table 3).

Nefopam reduced the shivering threshold by 0.7°C from 36.5 ± 0.3°C on the control day to 35.7 ± 0.3°C (P < 0.001), and alfentanil alone reduced the shivering threshold by 1.0°C to 35.5 ± 0.7°C (P < 0.001). The combination of nefopam and alfentanil (Combination 2) reduced the shivering threshold by 1.8 ± 0.6°C to 34.5 ± 0.7°C (P < 0.001). There was no interaction between the two drugs in terms of effect on the shivering threshold (P = 0.55). The combination of nefopam and alfentanil was thus additive  for shivering (fig. 2). A power calculation indicates that there is less than a 10% chance that the interaction is not additive.

Side effects experienced during different interaction studies are summarized in table 4. The volunteers were significantly more likely to become nauseated when nefopam was infused alone or in combination and when alfentanil alone was administered. However, only three volunteers experienced emesis (one during nefopam infusion, one during alfentanil infusion, and one during infusion of nefopam and alfentanil combination). Significantly more volunteers complained about having pain upon loading-dose injection when nefopam was infused alone or in combination with clonidine than other study days. Significantly more volunteers complained about having a dry mouth during the study when alfentanil was infused alone compared to Control or when it was combined with nefopam compared to all the other studied drugs. Pruritis occurred more frequently when alfentanil was infused alone or in combination with nefopam compared to all the other studied drugs. Also, bradypnea was observed more frequently when alfentanil was infused alone. There were six episodes of profuse sweating during the initial 30 min of nefopam administration.

All side effects spontaneously resolved within a few minutes after completion of the loading infusions, with the exception of a single volunteer, who experienced a second episode of vomiting during the maintenance of alfentanil infusion.

Our results confirm that nefopam reduces the shivering threshold without substantial toxicity. And combining nefopam with a small dose of alfentanil additively reduced the shivering threshold; that is, the combination reduced the shivering threshold as much as would be expected from the sum of the individual effects of each drug. These data thus support supplementing nefopam with an opioid if the nefopam alone is insufficient to block shivering. In contrast, combining nefopam with clonidine was ineffective and did not further reduce the shivering threshold. This combination thus appears to offer no advantage in terms of inducing therapeutic hypothermia.

There is currently little basis for recommending a specific target temperature for therapeutic hypothermia. Nonetheless, target temperatures from 33°C to 34°C are being used clinically by some physicians and in ongoing clinical trials.7,8,38The combination of nefopam and alfentanil reduced the shivering threshold to 34.5°C, which some might consider insufficiently hypothermic. However, the observed shivering threshold of 34.5°C must be interpreted in light of physiology of thermoregulatory shivering. We set mean skin temperature to 30–31°C, which is 3 to 4°C less than typical for stroke patients in a ward or intensive care unit setting. We used this low skin temperature with the aim of raising the shivering threshold and minimizing the risk from infusion of large amounts of cold fluid. Because skin temperature contributes 20% to control of shivering,39each degree centigrade of cutaneous warming will compensate for approximately 0.2°C core hypothermia; the threshold at a more typical skin temperature would thus have been well under 34°C. An additional factor to consider is that most stroke victims are elderly. Advanced age per se  impairs thermoregulatory responses.40,41It should thus be possible to induce comparable hypothermia in the elderly with even smaller drug doses or to induce greater hypothermia with similar drug doses.

The vasoconstriction threshold is of considerable interest, because vasoconstriction is an effective thermoregulatory response. Vasoconstriction is the primary autonomic defense against cool environments; once triggered, it prevents further hypothermia, even in anesthetized patients.36It is thus difficult to reduce the core temperature below the vasoconstriction threshold with surface cooling. Internal cooling, such as we used, has no such limitation because heat is removed directly from the core thermal compartment. A further advantage of internal cooling is that it can be combined with simultaneous gentle cutaneous warming, which improves thermal comfort42and reduces the vasoconstriction and shivering thresholds.43 

Nearly all antishivering drugs comparably reduce the vasoconstriction and shivering thresholds. An exception is meperidine, which disproportionately reduces the shivering threshold.44In contrast, the vasoconstriction threshold is unchanged with nefopam.21That vasoconstriction and shivering can be modulated independently is clinically important. Thermoregulatory vasoconstriction restrains heat content in the core compartment, and it thus speeds and prolongs core temperature changes when heat is directly removed from the thermal core.

Different combinations of antishivering drugs have been evaluated. In all cases, meperidine was tested in combination with other drugs, including buspirone,18dexmedetomidine,17or magnesium,45because of its special antishivering effect.44The combination of meperidine and the anxiolytic-drug buspirone has a favorable synergistic interaction.18For example, a combination of 0.3 μg · ml⁻¹intravenous meperidine and 30 mg of oral buspirone reduced the shivering threshold by 2.3°C at a mean skin temperature near 32°C. In the current study, we found that the combination of nefopam (100 ng · ml⁻¹) and alfentanil (150 ng · ml⁻¹) reduces shivering threshold by 2.0°C, which is similar. Thus, association of nefopam and a μ-agonist represents an interesting option for avoiding thermoregulatory shivering when therapeutic hypothermia is induced.

Numerous sites are involved in the control of the thermoregulatory shivering. Supraspinal sites are located in the hypothalamus, the pons, and the mesencephalon.24Nefopam is a strong inhibitor of serotonin in the corpus striatum and of norepinephrine in the hypothalamus.46and also has an effect in the pons. Clonidine activates presynaptic α²-adrenoceptors, which are present in sympathetic nerve endings and noradrenergic neurons in the central nervous system.47The locus coeruleus located in the upper brainstem is the largest noradrenergic cell group in the brain,47and the locus subcoeruleus, which is a circumscribed area ventromedially to the locus coeruleus, appears to be one of the most important relay station in the transmission of thermal information.24 

Clonidine and nefopam presumably both impair shivering via  the monoamine pathway and could do so at many levels of the neuraxis. However, a combination of the two drugs was significantly less effective than might be expected from their individual actions. The fact that the threshold with the two drugs combined was similar to the lower threshold with the separate thresholds, suggests the existence of a ceiling effect when both drugs are administered simultaneously. Adding a second drug in this context thus increases toxicity without (much) improving the desired therapeutic effect on shivering.

Nefopam directly interacts with α¹- and α²-adrenoceptors,22as well as antagonizing N -Methyl-d-Aspartate receptors.23Nefopam is not an opiate and does not interact with opiate receptors.48Alfentanil is a pure μ receptor agonist, and μ receptors are known to participate in central thermoregulatory control.24Additive effects of nefopam and alfentanil suggest that different pathways participate. Adding a second drug in this context is thus beneficial in that it improves the therapeutic effects and does so with minimal total toxicity.

A limitation of our study is that we did not measured blood concentrations of nefopam at shivering. However, the pharmacokinetic model we used is identical to that used in our previous study where blood was sampled at the sweating, vasoconstriction, and shivering thresholds. Target concentrations were 35 ng · ml⁻¹and 70 ng · ml⁻¹. At the first thermoregulatory threshold (sweating), plasma concentrations were respectively 32 ± 6 and 70 ± 16 ng · ml⁻¹. On each study day, the plasma concentrations decreased with time; but the concentrations at the shivering thresholds (respectively, 28 ± 4 and 55 ± 11 ng · ml⁻¹) were not significantly lower than at the sweating threshold. On the basis of our previous experience, we thus assume that plasma concentrations were close to target values and, more importantly, similar on each study day under the circumstances of the current study.

Based on previous experience with nefopam,49,50the side effects reported by our volunteers were expected. As in previous studies,21adverse events resolved spontaneously within 30 min even though the nefopam infusion continued. This pattern suggests that the toxicity is associated with rapid increases in cerebral concentration during loading, rather than steady-state concentrations per se . Bradypnea was observed in three volunteers during alfentanil infusion alone and in one volunteer when nefopam was combined with alfentanil. However, no profound decreases in oxygen saturation were observed, and concomitant administration of oxygen was never necessary. Alfentanil produced light sedation in some volunteers, but they remained responsive throughout.

Our nefopam loading dose of approximately 45 mg was about twice that usually prescribed for postoperative analgesia. Although there is not enormous experience with such a high dose, it appears to be safe.26For example, fatal overdose with nefopam has been reported only three times since the beginning of 1980s. In every case, blood concentration was 30–100 times the highest therapeutic concentrations.31New Zealand50and French49studies reviewed adverse drug reactions associated with nefopam over 10- to 12-yr periods. Only few toxicities were reported, and most of them were expected (nausea, sweating, dizziness, tachycardia, and vomiting). Among those considered as serious, most were neuropsychiatric (confusion, hallucination, delirium, or convulsion), cardiovascular (arterial hypotension, heart failure), or cutaneous or anaphylactic disorders and occurred at therapeutic dosage. All but one resolved after nefopam withdrawal.

In summary, nefopam and alfentanil additively reduced the shivering threshold in healthy adults. The doses we tested decreased the threshold by approximately 2°C, with only minimal respiratory toxicity. This combination might thus facilitate studies evaluating the putative benefits of therapeutic hypothermia.