Dexmedetomidine as a Novel Countermeasure for Cocaine-Induced Central Sympathoexcitation in Cocaine-Addicted HumansNovelty and Significance
Cocaine-induced acute hypertension is mediated largely by increased central sympathetic nerve activity. We hypothesized that dexmedetomidine, a central sympatholytic, reverses cocaine-induced increases in sympathetic nerve activity, mean arterial pressure (MAP), and heart rate (HR) in cocaine-addicted subjects. First, we conducted a dose-finding study in 15 nontreatment-seeking cocaine-addicted subjects and 12 cocaine-naive healthy controls to find doses of intravenous dexmedetomidine that lower MAP and HR in the absence of acute-cocaine challenge. We then conducted a placebo-controlled treatment trial in 26 cocaine-addicted subjects to determine whether dexmedetomidine reverses MAP and HR increases after intranasal cocaine (3 mg/kg). Skin sympathetic nerve activity (measured in the second protocol) and skin vascular resistance (measured in both protocols) served as indices of cocaine-sensitive central sympathoexcitation. In doses up to 0.6 µg/kg IV, dexmedetomidine alone caused comparable dose-dependent decreases in blood pressure in cases and controls but a 1.0 µg/kg dose was required to lower HR. In cocaine-addicted subjects, low-dose dexmedetomidine (0.4 µg/kg; n=14) abolished cocaine-induced increases in skin sympathetic nerve activity (156±26 versus −15±22%, cocaine/placebo versus cocaine/dexmedetomidine; P<0.05), skin vascular resistance (+10±2 versus −2±3 U; P<0.05), and MAP (+6±1 versus −5±2 mm Hg; P<0.01) without affecting HR (+13±2 versus +9±2 bpm; P=ns). When dexmedetomidine was increased to 1 µg/kg (high dose; n=12) to reverse cocaine-induced increases in HR, MAP did not fall further and increased paradoxically in 4 of 12 subjects. Thus, in a low nonsedating dose, dexmedetomidine constitutes a putative new treatment for cocaine-induced acute hypertension but higher sedating doses can increase blood pressure unpredictably during acute-cocaine challenge and should be avoided.
Cocaine abuse is increasing worldwide among all income strata.1 By current estimates, 20% of Americans >12 years of age have tried cocaine, and 2.1 million Americans are current users.2 Cocaine is the most common illicit drug causing life-threatening cardiovascular emergencies, including acute coronary syndrome, stroke, sudden cardiac death, and hypertensive crisis.1,3–5
Current treatment recommendations for cocaine-induced acute hypertension and other cardiovascular emergencies are based on limited evidence,6 and standard first-line nitrate therapy is not always effective. Thus, new treatment targets and better evidence are required. The standard teaching is that cocaine blocks norepinephrine (NE) reuptake in peripheral sympathetic nerve terminals, thereby increasing (NE) in the synaptic cleft.7 On the contrary, studies by our group and others indicate that cocaine stimulates the mammalian cardiovascular system primarily by acting on the brain to increase central sympathetic nerve activity (SNA), with minimal contribution from peripheral NE transporter inhibition.8–12 Thus, SNA constitutes a putative new drug target for the management of cocaine-induced acute hypertension.
Dexmedetomidine, an intravenous central sympatholytic drug that is a more potent α2 adrenergic agonist than clonidine, is approved for conscious sedation in the intensive care unit.13 The drug acts in the central nervous system to augment α2 adrenoreceptor restraint on SNA to multiple tissues and vascular beds.14 Reasoning that dexmedetomidine might also be useful in the setting of cocaine overdose, we previously showed that even low nonsedating doses of dexmedetomidine can eliminate cocaine-induced increases in skin SNA, mean arterial pressure (MAP), and heart rate (HR).15 However, the clinical applicability of those data were limited by studying only cocaine-naive subjects receiving a low-dose cocaine (2 mg/kg) challenge, which is much lower than doses typically used by cocaine addicts.9
The aim of the current study was to test whether dexmedetomidine also reverses the increases in blood pressure (BP), HR, and skin SNA caused by a higher cocaine dose in nontreatment-seeking cocaine-addicted individuals, who represent the majority of patients presenting to emergency rooms with cocaine-induced cardiovascular complications.16 Two sequential series of studies were performed. First, we conducted a dose-finding study to detect the doses of intravenous dexmedetomidine needed to achieve controlled reductions in MAP and HR in the absence of acute-cocaine challenge. In this dexmedetomidine-suppression test, we compared responses of nontreatment-seeking cocaine-addicted subjects and age-matched cocaine-naive healthy controls. Because chronic cocaine exposure has been shown to reduce central α2 adrenergic receptor density17 and agonist sensitivity in rodents,17,18 we needed to know whether dexmedetomidine would be less effective as a central sympatholytic and thus higher doses needed in the setting of chronic cocaine addiction. We then conducted a placebo-controlled single-blind parallel arm treatment trial in a total of 26 cocaine-addicted subjects, to determine whether low- or high-dose dexmedetomidine reverses the acute increases in MAP and HR evoked by intranasal cocaine challenge (3 mg/kg).
We studied a total of 12 cocaine-naive control subjects and 30 nontreatment-seeking cocaine-addicted subjects (32 men and 10 women, 31–58 years). The protocol was approved by the institutional review board of the University of Texas Southwestern Medical Center at Dallas. All subjects were recruited through newspaper advertisements. Subjects were normotensive and had no history of cardiovascular disease. Cocaine addiction was documented by detection of cocaine or metabolites in urine samples (without other positive urine toxicology) at screening. All cocaine-addicted subjects refused drug rehabilitation; for ethical reasons, cocaine-addicted subjects who expressed any interest in drug rehabilitation were excluded from the study. All cocaine-addicted subjects were asked to abstain from cocaine or any other illicit drug use for 72 hours before study; cocaine abstinence was confirmed by undetectable plasma cocaine levels at the time of the study. None of the subjects from either group was taking any prescription or nonprescription drugs with cardiovascular or autonomic effects.
All experiments were performed under normothermic conditions (22°C) with the subjects supine. The HR, SNA, skin blood flow, and respiratory rate were recorded continuously with a multichannel digital data recorder (MacLab/8S ML780, AD Instruments, Inc, Colorado Springs, CO); BP was measured with a validated oscillometric Welch Allyn Vitalsigns Monitor (Tycos Instruments Inc, Skaneateles Falls, NY).
Recording of SNA
Multiunit recordings of postganglionic SNA were obtained with unipolar tungsten microelectrodes inserted selectively into muscle or skin nerve fascicles of the peroneal nerve, according to the technique by Valbo.19 The neural signals were amplified, filtered, rectified, and integrated with a nerve traffic analyzer to obtain a mean voltage display of sympathetic discharge. The criteria for acceptable recordings of skin SNA and muscle SNA have been described previously9,20 and detailed in the online-only Data Supplement.
All records were analyzed by the same investigator (A.K.), who scored the recorded data in a blinded fashion. The interobserver and intraobserver variability in identifying bursts are <10% and 5%, respectively.9,20
Measurement of Skin Blood Flow
Skin blood flow was measured by laser Doppler velocimetry (Advance Laser Flowmeter, Advance Co, Tokyo, Japan) with the probe placed on the plantar aspect of the first toe. Skin vascular resistance (resistance unit) was calculated as MAP X 100/skin blood flow (perfusion units).
Lower Body Negative Pressure
With the subject’s lower body enclosed in an airtight chamber, lower body negative pressure (LBNP) was applied at −40 mm Hg to unload the baroreceptors, thereby reflexively increasing HR.21
Plasma (NE) was determined by high-performance liquid chromatography (Quest Diagnostics, San Juan Capistrano, CA). The intraassay coefficient of variation was <5%. Plasma cocaine was determined by gas chromatography/mass spectrometry (Quest Diagnostics, Pittsburgh, PA). The interassay and intraassay variability of cocaine readings are <10%.
Assessment of Level of Sedation
During infusion of dexmedetomidine, the level of alertness/sedation was monitored with the Observer’s Assessment of Alertness/Sedation scale. A score of 5 correlates with maximum alertness and 1 indicates deep sleep.22
Dose-Finding Case–Control Study (19 Experiments in 15 Cocaine-Addicted Subjects and 15 Experiments in 12 Cocaine-Naive Subjects)
Dexmedetomidine-suppression testing was conducted to determine whether the drug would be less effective as a central sympatholytic and thus higher doses needed in the setting of chronic cocaine addiction.
Protocol 1A: We measured BP and HR at baseline and 10 minutes after intravenous infusion of dexmedetomidine (Hospira Inc, Lake Forest, IL) at a dose of 0.1, 0.2, and 0.3 μg/kg (each given over 1 minute), separated by 10 minutes, for a cumulative dose of 0.6 µg/kg (Figure S3 in the online-only Data Supplement). In this protocol, we also measured skin blood flow (using skin vascular resistance as an index of skin SNA), as well as muscle SNA and plasma NE to confirm that the dexmedetomidine acts centrally to reduce SNA to multiple vascular beds.
Protocol 1B: Because HR was unaffected by these 3 doses of dexmedetomidine in both groups of subjects, we conducted additional experiments in which we assessed HR and MAP responses to a higher dose of dexmedetomidine: 1 µg/kg infused intravenously over 10 minutes; HR and MAP were measured before and 10 minutes after dexmedetomidine infusion. These measurements were made both at rest and during 3 minutes of LBNP at −40 mm Hg, the latter to reflexively elevate the ambient HR level on which dexmedetomidine infusion was superimposed (Figure S4).
Randomized Controlled Treatment Trial (42 Experiments in 26 Cocaine-Addicted Subjects)
A single-blind, randomized, placebo-controlled, parallel, treatment trial was conducted to determine whether dexmedetomidine reverses increases in MAP and HR as well as skin SNA and skin vascular resistance after acute-cocaine challenge in cocaine-addicted subjects.
Based on our past work, skin SNA, rather muscle SNA, is the appropriate indicator of cocaine-induced central sympathetic activation. Because muscle SNA is tightly regulated by arterial baroreflexes, cocaine-induced sympathoexcitation is obscured by baroreflex-mediated sympathoinhibition such that muscle SNA actually decreases as BP rises with acute-cocaine challenge.23 Thus, cocaine causes no clear-cut increase in muscle SNA or plasma (NE)8 to test for its modulation by dexmedetomidine. In contrast, skin SNA is devoid of baroreflex regulation and therefore shows a consistently large and sustained increase after acute-cocaine challenge, thereby providing a sensitive and stable indicator of cocaine-induced central sympathoexcitation.9,15
After recording baseline MAP, HR, skin SNA, and skin blood flow, the cocaine solution was delivered into each nostril via a dropper at a dose of 3 mg/kg, which is 75% the standard clinical dose for rhinolaryngologic procedures.24 On completion of nasal administration of cocaine for 30 minutes, which is the time-to-peak effect of intranasal cocaine, a plasma cocaine level was drawn to ensure adequate intranasal absorption.
Subsequently, nontreatment-seeking cocaine-addicted subjects were randomized to 3 conditions of intranasal cocaine followed by the following: (1) placebo, intravenous normal saline over 10 minutes (n=16); (2) low-dose dexmedetomidine, 0.4 µg/kg IV >10 minutes (n=14); or (3) high-dose dexmedetomidine, 1 µg/kg IV >10 minutes (n=12). The MAP, HR, skin SNA, and skin blood flow were recorded at peak effect of cocaine (30 minutes) continuously for another 10 minutes after dexmedetomidine or saline (50 minutes after intranasal cocaine administration; Figure S5). After intranasal cocaine, MAP, HR, and skin SNA and vascular resistance rise >30 minutes to reach a new steady-state plateau for the next 45 to 60 minutes. We superimposed dexmedetomidine infusion over this steady-state cocaine response.
Subjects were blinded to condition assignment, but the physician-investigators were not blinded out of concern for patient safety; however, all records were analyzed with the investigator (A.K.) being blinded to subject identity and condition assignment.
Because a cohort of nontreatment-seeking cocaine-addicted subjects is difficult to recruit and maintain, whenever possible subjects participated in both the case–control study and in more than one arm of the treatment trial, leaving at least 30 days between additional studies on a given subject so as to allow ample time to eliminate carry-over effects from both intranasal cocaine (elimination half-life of 90 minutes) and intravenous dexmedetomidine (elimination half-life of 10 minutes). A sedation score was obtained for each subject before and after administration of each dose of dexmedetomidine or saline placebo.
SAS/STAT software, version 9.1 was used for all analyses. Presented P values are based on tests of contrasts within a mixed linear model of each response variable with fixed effects as described below, and random subject effects to account for correlation of multiple measurements on the same individual. To compare MAP, HR, skin blood flow, and other responses to graded doses of dexmedetomidine in cocaine-addicted versus cocaine-naive groups in the dose-finding case-control study, the fixed effects are group (2 levels: cases and controls), dose (4 levels: 0, 0.2, 0.4, and 0.6 µg/kg), and group×dose. To compare effects of dexmedetomidine versus placebo (intravenous normal saline) in reversing cocaine-induced increases in MAP, HR, and skin SNA in cocaine-addicted subjects, the fixed effects are group (2 levels: dexmedetomidine and saline), time (3 levels: baseline, 30 minutes, and 50 minutes), and group×time. A log transformation was used to reduce the skewness of skin blood flow and skin SNA, as determined previously.15
The baseline characteristics of subjects in the case–control study of dexmedetomidine-suppression testing are shown in Table 1. The 2 groups were well matched on most characteristics including age, sex, race/ethnicity (most being black men), body mass index, and baseline HR; however, cocaine-addicted subjects (who had a mean duration of cocaine addiction of 17±2 years) had higher systolic BP at baseline (P<0.05). The baseline characteristics of the cocaine-addicted subjects in the treatment trial are shown in Table 2.
In the initial dose-finding study, we studied 15 cases and 12 controls. Of these subjects, 10 cases and 7 controls participated in protocol 1A and 9 cases and 8 controls in protocol 1B. Multiple subjects participated in both subprotocols: 26 cocaine-addicted subjects participated in the treatment trial; of these, 12 cases had also participated in the case-control study. Of these 26 subjects who were challenged with intranasal cocaine, 16 subjects received placebo, 14 received low-dose dexmedetomidine, and 12 high-dose dexmedetomidine. Subjects were randomly assigned to 1 of the 3 treatment arms in protocol 2 (saline or low- or high-dose dexmedetomidine). If subjects participated in >1 of these 3 treatment arms, the order was random.
None of the subjects developed chest pain, ST-T changes on ECG, arrhythmia, or any other adverse events from cocaine or dexmedetomidine. None of the cocaine-addicted or cocaine-naive subjects had detectable plasma cocaine levels at the time of study.
Dose-Finding Case–Control Study: Dexmedetomidine-Suppression Testing
Figure 1A shows the results of dexmedetomidine-suppression testing in the 2 groups. Before dexmedetomidine, baseline MAP was higher in the cocaine-addicted subjects (P<0.05). The major new finding is that the cocaine-addicted subjects did not show evidence of any attenuation in the progressive dexmedetomidine-induced decreases in MAP and skin vascular resistance (or increase in skin blood flow). In contrast, HR was unaffected by cumulative doses of dexmedetomidine up to 0.6 µg/kg in both groups. Changes in muscle SNA and plasma NE are shown in the online-only Data Supplement (Table S1 and Figure S6).
When the dose was increased to 1 µg/kg in cocaine-addicted subjects, dexmedetomidine lowered HR by 4 bpm (P<0.05), both in the absence and presence of LBNP, whereas, in the cocaine-naive subjects, 1 µg/kg dexmedetomidine lowered HR only during LBNP (by 4.5 bpm; P<0.05; Figure 1B).
Randomized Controlled Treatment Trial in Cocaine-Addicted Subjects: Effects of Low- and High-Dose Dexmedetomidine Versus Placebo on Responses to Acute-Cocaine Challenge
With acute intranasal cocaine, the plasma cocaine level increased from 0 to 0.05±0.01 µg/mL in cocaine-addicted subjects. As shown in Figures 2A, 2B, and 3, placebo (n=16) was without effect whereas low-dose dexmedetomidine (0.4 µg/kg; n=14) abolished cocaine-induced increases in MAP (+6±1 versus −5±2 mm Hg, cocaine/placebo versus cocaine/dexmedetomidine; P<0.01), skin SNA (+156±26 versus −15±22%; P<0.05), and skin vascular resistance (+10±2 versus −2±3 U; P<0.05) without affecting HR (+13±2 versus +9±2 bpm; P=ns; Table S2).
When the dexmedetomidine dose was increased sufficiently (1 µg/kg; n=12) to reverse the cocaine-induced increase in HR (+13±2 versus +3±2 bpm, cocaine/placebo versus cocaine/dexmedetomidine; P<0.01), the average level of MAP did not fall further, with MAP increasing paradoxically in 4 of 12 subjects (Figure 3).
The subjects’ mean sedation score was unchanged from baseline with low-dose dexmedetomidine (5.0±0 versus 4.82±0.12) but decreased to 3.83±0.46 (P<0.05) with the higher dose.
In the absence of acute-cocaine challenge, we found that cocaine-naive and cocaine-addicted subjects show very similar depressor responses to dexmedetomidine but striking differences become apparent during acute-cocaine challenge. In cocaine-naive subjects, we had previously found that a low nonsedating dose of dexmedetomidine (0.4 μg/kg) readily reverses the acute cocaine-induced increase in both BP and HR, as well as skin SNA and skin vascular resistance reflecting cocaine’s central mechanism of action;15 on the contrary, the current study on cocaine-addicted subjects shows that the same low dose of dexmedetomidine reverses the cocaine-induced increases in MAP, skin SNA, and skin vascular resistance but it fails to affect the HR increase. We discovered that a much higher sedating dose of dexmedetomidine (1.0 μg/kg) is needed to counteract the modest HR rise with low-dose cocaine challenge but at the expense of increasing BP in one third of cocaine-addicted subjects. These new findings have important implications for considering dexmedetomidine as a putative new countermeasure for acute cocaine-induced hypertension in the clinical setting.
Although cocaine has been shown to block NE reuptake in peripheral sympathetic nerve terminals in ex vivo preparations,7 previous studies by our group in conscious humans8,9,15,25,26 as well as studies in conscious dogs11 and primates12 by other groups indicate that cocaine stimulates the mammalian cardiovascular system in vivo mainly by a central rather than a peripheral mechanism of action. Thus, a central sympatholytic drug might eliminate the adverse cardiovascular response at its central origin.
Although chronic cocaine exposure has been reported to cause downregulation of central α2 adrenergic signaling in rodents,18,27 we found no such evidence under the experimental conditions of these translational research studies in humans. Chronic cocaine exposure, for even >2 decades, did not impair the ability of dexmedetomidine to cause dose-dependent decreases in BP. Specifically, our initial dose-finding case–control study informed the subsequent treatment trial by showing that the 0.4 µg/kg dose of dexmedetomidine (used in previous study of cocaine-naive subjects) was sufficient to cause large reductions in MAP in cocaine-addicted subjects but that a >2-fold higher dose was needed to lower HR.
Dexmedetomidine, as hypothesized, proved to be a potent countermeasure to the central sympathomimetic action of cocaine in cocaine-addicted subjects. The low-dose dexmedetomidine completely abolished the large cocaine-induced increase in skin SNA—a regional sympathetic outflow that is not buffered by arterial baroreflexes and is thus exquisitely sensitive to central neural stimuli including small, nonintoxicating doses of cocaine.9 Low-dose dexmedetomidine also abolished the modest cocaine-induced increase in BP, although the cocaine dose was 50% higher than in a previous study of cocaine-naive subjects.15
However, dexmedetomidine was less potent against the chronotropic action of cocaine, because a higher sedating dose of dexmedetomidine (1 µg/kg)28,29 was required to reverse the cocaine-induced increase in HR in the cocaine-addicted subjects. The precise explanation for the HR–BP dissociation in our study is unclear, as both responses to cocaine are mediated by central sympathetic activation with no contribution from vagal withdrawal.9 Because higher doses of dexmedetomidine were also needed to slow HR in the absence of cocaine, our data suggest that the dexmedetomidine dose–response relation for decreased cardiac SNA targeted to the sinus node is shifted to the right or is less steep than the dose–response relation for decreased vasoconstrictor SNA targeted to the cutaneous and skeletal muscle circulations and possibly other vascular beds that regulate BP.
With the 1-µg/kg dose of dexmedetomidine needed to control HR during cocaine, the paradoxical increase in BP observed in one third of our cocaine-addicted subjects is most likely explained by direct agonist stimulation of vascular α2 adrenergic receptors that increase vascular resistance in regional beds other than the cutaneous circulation.30 The less potent α2 adrenergic agonist clonidine has been shown to evoke a large paradoxical pressor response caused by peripheral vasoconstriction in patients with sympathetic denervation because of primary autonomic failure.31 We speculate that in cocaine-addicted subjects low-dose dexmedetomidine consistently lowered BP during acute-cocaine challenge because the predominant effect was to stimulate α2 adrenergic receptors in the central nervous system, thereby lowering central sympathetic vasoconstrictor drive to multiple vascular beds, with little or no effect on vascular α2 receptors, whereas, with high-dose dexmedetomidine, SNA is suppressed, allowing direct peripheral vasoconstriction (via vascular α2 receptors) to be the dominate effect on BP in some subjects. However, neither skin SNA nor any of the other variables measured in these studies were predictive of the dexmedetomidine-induced pressor response.
Our study has several limitations. The 3-mg/kg dose of intranasal cocaine, though higher than used in past research, is still only ≈75% of the average dose used for rhinolaryngologic procedures.24 Whether dexmedetomidine can control acute severe hypertension at higher doses typically used by cocaine addicts or with massive cocaine overdose is unknown. Because most study subjects were black men, further studies would be needed to determine whether our findings are generalizable; however, cocaine addiction is more prevalent among blacks than whites (pushers having targeted low-income inner-city blacks with inexpensive crack cocaine)32,33 and more prevalent among black men than women.34 Moreover, there is no evidence that the cardiovascular effects of cocaine vary by race or gender.15,35 Skin SNA per se is not a major determinant of BP but constitutes a sensitive marker of centrally generated sympathetic activation targeted to the heart and multiple vascular beds during cocaine challenge.9 Muscle SNA plays at most a permissive role in the pressor response to cocaine, because the activity does not increase with cocaine but rather shows a smaller-than-expected decrease.8 An inherent limitation of microneurography is that the technique cannot be used to measure SNA in visceral nerves that drive BP such as the renal nerves; in experimental animals, multi-fiber renal SNA is regulated both by barorereflexes (like human muscle SNA) and by central nervous system stimuli (like human skin SNA).36 Because our study focused on BP and HR, the determinants of myocardial oxygen demand, additional studies will be needed to test dexmedetomidine’s ability to counteract cocaine-induced coronary vasoconstriction, a major mechanism of cocaine-related chest pain and acute coronary syndrome.6
Despite these limitations, the current data provide proof-of-concept for repurposing a central sympatholytic drug as a novel countermeasure for the acute cardiovascular complications of cocaine in cocaine-addicted humans, who represent the majority of patients encountered in the emergency room setting for drug-abuse related visits.16 The study of nontreatment-seeking cocaine-addicted persons allowed examination of higher doses of both cocaine and of dexmedetomidine than is feasible in cocaine-naive subjects. The new data move this work closer to clinical translation and reveal a nonlinearity in the dexmedetomidine-BP dose–response relation that highlights an important cautionary note for potential future clinical application. Specifically, dexmedetomidine would not be suitable as monotherapy because higher doses can cause unpredictable increases in BP, which could increase myocardial oxygen demands and exacerbate cocaine-induced myocardial ischemia. However, at nonsedating doses of 0.6 µg/kg or less, dexmedetomidine could be a useful adjunct in treating cocaine-induced acute hypertension that is refractory to standard first-line treatment with nitrates.6 As dexmedetomidine holds promise to impact treatment recommendations, further clinical research is warranted.
We thank Debbie Arbique, DNP, cFNP, for nursing assistance, Zhongyun Wang, MD, for research assistance, and Elizabeth Martin, PhD, for an insightful critique.
Sources of Funding
This work was supported by grants from the National Institute on Drug Abuse R01DA010064 (R.G.V.), F32DA027274 (A.C.K.), and from the Lincy Foundation (R.G.V.).
Clinical Trial Registration # NCT00338546.
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.112.203554/-/DC1.
- Received August 3, 2012.
- Revision received August 16, 2012.
- Accepted December 5, 2012.
- © 2013 American Heart Association, Inc.
- Qureshi AI,
- Suri MF,
- Guterman LR,
- Hopkins LN
- McCord J,
- Jneid H,
- Hollander JE,
- de Lemos JA,
- Cercek B,
- Hsue P,
- Gibler WB,
- Ohman EM,
- Drew B,
- Philippides G,
- Newby LK
- Tuncel M,
- Wang Z,
- Arbique D,
- Fadel PJ,
- Victor RG,
- Vongpatanasin W
- Vongpatanasin W,
- Mansour Y,
- Chavoshan B,
- Arbique D,
- Victor RG
- Vatner SF,
- Rutherford JD,
- Ochs HR
- Macey DJ,
- Smith HR,
- Nader MA,
- Porrino LJ
- Valbo AB HK-E,
- Torebjork HE,
- Wallin BG
- Abate NI,
- Mansour YH,
- Tuncel M,
- Arbique D,
- Chavoshan B,
- Kizilbash A,
- Howell-Stampley T,
- Vongpatanasin W,
- Victor RG
- Jacobsen TN,
- Morgan BJ,
- Scherrer U,
- Vissing SF,
- Lange RA,
- Johnson N,
- Ring WS,
- Rahko PS,
- Hanson P,
- Victor RG
- Jacobson AM,
- Hauser ST,
- Willett JB,
- Wolfsdorf JI,
- Dvorak R,
- Herman L,
- de Groot M
- Martin E,
- Ramsay G,
- Mantz J,
- Sum-Ping ST
- 33.↵Substance Abuse and Mental Health Services Administration (2005). Results from the 2004 National Survey on Drug Use and Health: National Findings (Office of Applied Studies, NSDUH Series H-28, DHHS Publication No. SMA 05-4062). Rockville, MD.
Novelty and Significance
What Is New?
Current treatment recommendations for cocaine-induced acute hypertension are based on limited evidence and standard first-line nitrate therapy is not always effective.
The current study demonstrates that dexmedetomidine, a potent central α2 agonist, when given at a low nonsedating dose, completely reverses the central sympathoexcitatory and blood pressure-raising effects of acute-cocaine challenge in nontreatment-seeking cocaine-addicted humans.
What Is Relevant?
Central sympatholysis with dexmedetomidine constitutes a novel countermeasure for cocaine-induced acute hypertension in cocaine-addicted humans, who represent the majority of patients encountered in the emergency room setting for drug-abuse–related visits.
When given in higher sedating doses, dexmedetomidine causes a paradoxical rise in blood pressure, likely from peripheral vasoconstriction related to unopposed action α2 vascular beds.
Dexmedetomidine, particularly at lower doses, could be a useful adjunct in treating cocaine-induced acute hypertension that is refractory to standard first-line treatment with nitrates.