� CLINICAL INVESTIGATIONSAnesthesiology 2004; 101:279–83 © 2004 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.

Anesthetic Requirement Is Increased in RedheadsEdwin B. Liem, M.D.,* Chun-Ming Lin, M.D.,† Mohammad-Irfan Suleman, M.D.,‡ Anthony G. Doufas, M.D., Ph.D.,*Ronald G. Gregg, Ph.D.,§ Jacqueline M. Veauthier, Ph.D.,� Gary Loyd, M.D.,# Daniel I. Sessler, M.D.**

Background: Age and body temperature alter inhalationalanesthetic requirement; however, no human genotype is asso-ciated with inhalational anesthetic requirement. There is ananecdotal impression that anesthetic requirement is increasedin redheads. Furthermore, red hair results from distinct muta-tions of the melanocortin-1 receptor. Therefore, the authorstested the hypothesis that the requirement for the volatile an-esthetic desflurane is greater in natural redheaded than in dark-haired women.

Methods: The authors studied healthy women with bright red(n � 10) or dark (n � 10) hair. Blood was sampled for subse-quent analyses of melanocortin-1 receptor alleles. Anesthesiawas induced with sevoflurane and maintained with desfluranerandomly set at an end-tidal concentration between 5.5 and7.5%. After an equilibration period, a noxious electrical stimu-lation (100 Hz, 70 mA) was transmitted through bilateral intra-dermal needles. If the volunteer moved in response to stimula-tion, desflurane was increased by 0.5%; otherwise, it wasdecreased by 0.5%. This was continued until volunteers“crossed over” from movement to nonmovement (or viceversa) four times. Individual logistic regression curves wereused to determine desflurane requirement (P50). Desfluranerequirements in the two groups were compared using Mann–Whitney nonparametric two-sample test; P < 0.05 was consid-ered statistically significant.

Results: The desflurane requirement in redheads (6.2 vol%[95% CI, 5.9–6.5]) was significantly greater than in dark-hairedwomen (5.2 vol% [4.9–5.5]; P � 0.0004). Nine of 10 redheadswere either homozygous or compound heterozygotes for mu-tations on the melanocortin-1 receptor gene.

Conclusions: Red hair seems to be a distinct phenotype linked

to anesthetic requirement in humans that can also be traced toa specific genotype.

INHALATIONAL anesthetic requirements are remarkablyuniform in humans, mainly being affected by age andbody temperature.1,2 However, some anesthesiologistsshare an anecdotal impression that patients with naturalred hair require more anesthesia than patients with otherhair colors. The phenotype of nearly all red-haired indi-viduals can be traced to distinct mutations of the mela-nocortin-1 receptor gene (MC1R).3–5

The human MC1R is expressed on the surface of me-lanocytes and is a key regulator of intracellular signalingto the melanin biosynthetic pathway governing pigmentformation. The red hair phenotype results from excesspheomelanin production. Production of this yellow-redpigment results from well-described mutations of theMC1R.3–6 In contrast, when a normal (consensus) MC1Ris expressed, the predominant pigment produced bymelanocytes is eumelanin (dark brown) and the typicaleumelanin-to-pheomelanin ratio is high.

An easily identifiable human phenotype that can betraced to a distinct genotype presents an opportunity toidentify a genetic influence on anesthetic sensitivity inhumans. Distinct genetic factors have been shown tocontribute to anesthetic requirements in various animalspecies, including mice,7 nematodes (Caenorhabditiselegans),8 and fruit flies (Drosophila melanogaster).9

However, a similar association has yet to be establishedin humans. Therefore, we tested the hypothesis thatwomen with natural red hair have a greater desfluranerequirement than women with dark hair.

Materials and Methods

With approval of the University of Louisville HumanStudies Committee and written informed consent, werecruited 20 white women aged between 18 and 40 yr,with natural bright red or dark (black or dark brown)hair. The study subjects were regarded as white if theywere mainly of northern European descent as indicatedby self-report. The subjects were drawn from GreaterLouisville, Kentucky, an urban area with a populationexceeding 1,000,000. The number of subjects was basedon an a priori estimate that 10 subjects in each groupwould provide 90% power for detecting a 0.8% differ-ence in desflurane requirement (e.g., 5.8% to 5.0%) be-tween the two groups using a two-tailed, unpaired t testwith an � of 0.05 and an estimate of the SD of 0.55.

Because it remains unclear whether sex could cause

This article is featured in “This Month in Anesthesiology.”Please see this issue of ANESTHESIOLOGY, page 5A.�

* Assistant Professor, OUTCOMES RESEARCH™ Institute and Department of Anes-thesiology, ‡ Resident, # Associate Professor, Department of Anesthesiology,§ Associate Professor, Department of Biochemistry, ** Vice Dean for Research,Director OUTCOMES RESEARCH™ Institute, Distinguished University Research Chair,Lolita & Samuel Weakley Professor of Anesthesiology and Pharmacology, Univer-sity of Louisville. † Research Fellow, Department of Anaesthesiology, ChangGung Memorial Hospital, Taipei, Taiwan, R.O.C. � Research Associate, Depart-ment of Chemistry and Biochemistry, University of Texas.

Received from the OUTCOMES RESEARCH™ Institute and the Departments ofAnesthesiology, Biochemistry and Molecular Biology, and Pharmacology andToxicology, University of Louisville, Louisville, Kentucky, and the Department ofChemistry, University of Texas, Austin, Texas. Submitted for publication Septem-ber 9, 2003. Accepted for publication December 8, 2003. Supported by grant No.GM 061655 from the National Institutes of Health, Bethesda, Maryland; theJoseph Drown Foundation, Los Angeles, California; and the Commonwealth ofKentucky Research Challenge Trust Fund, Louisville, Kentucky. Dr. Veauthier isthe recipient of an Postdoctoral Fellowship (F32 GM20834) from the NationalInstitutes of Health, Bethesda, Maryland. None of the authors have any financialinterest in products related to this study. These data were presented in abstractform at the Annual Meeting of the American Society of Anesthesiologists, Or-lando, Florida, October 12–16, 2002.

Address reprint requests to Dr. Sessler: OUTCOMES RESEARCH™ Institute, 501 EastBroadway, Louisville, Kentucky 40202. Address electronic mail to: sessler@louisville.edu. On the World Wide Web: www.or.org. Individual article reprints may bepurchased through the Journal Web site, www.anesthesiology.org.

Anesthesiology, V 101, No 2, Aug 2004 279

significant differences in anesthetic requirement,10,11 onlywomen were included. Exclusion criteria included chemi-cal hair treatment, any history of medical or psychiatricproblems, any history of chronic pain problems, possiblepregnancy, body mass index greater than 30 kg/m2, recre-ational drug usage, and medication usage other than oralcontraceptives.

ProtocolStudies were started in the morning each day because

circadian rhythms slightly influence anesthetic require-ment.12 The effect of the menstrual cycle on anestheticrequirement is unclear; however, pain threshold variesas a function of the menstrual cycle.13 Therefore, studieswere restricted to the first 10 days of the participants’menstrual cycles unless they took oral contraceptives.

The subjects fasted and refrained from smoking for atleast 8 h before arriving at the laboratory. No premedi-cation was given or allowed. Routine anesthetic safetymonitors were applied in an operating room setting.Core body temperature was measured from the tym-panic membrane using Mon-a-Therm® thermocouples(Tyco-Mallinckrodt, Inc., St. Louis, MO). General anes-thesia was induced with sevoflurane in 100% oxygen;5 min later, a laryngeal mask airway (Laryngeal AirwayMask Co., Henley-on-Thames, United Kingdom) was in-serted, and sevoflurane was discontinued. Anesthesia wasthen subsequently maintained solely with desflurane andventilation was assisted until spontaneous breathing wasreestablished. A forced-air warming cover positionedover the trunk (Bair Hugger; Augustine Medical, Inc.,Eden Prairie, MN) was used to maintain normothermia.

There was a 45-min equilibration period after induc-tion of anesthesia. Based on pharmacokinetic data,14 thisallowed sufficient time for sevoflurane concentrations todecrease to insignificant levels. It also gave time for thedesflurane concentrations to equilibrate, such that theratio of inspired (FI) to end-tidal concentrations (FA)closely approached 1.0.

After the equilibration period, a noxious electricalstimulation (100 Hz, 60–70 mA) was applied bilaterallyfor 10 s through needles inserted intradermally into theanterior thighs. A tetanic stimulus even 20% of thisintensity is unbearable to unanesthetized subjects but isnot consciously sensed during anesthesia.

An independent investigator (one out of a group offour investigators was selected for each study session)was brought into the study room just before each stim-ulation period to evaluate movement in response to thenoxious electrical stimulation and left within a few min-utes after each stimulus. A positive response was definedas gross purposeful movement of the legs or arms withinthe first minute after stimulation. Grimacing and headmovement were not considered purposeful responses.

The independent investigator was not blinded to thehair color and skin complexion of each volunteer be-

cause of the practical and technical difficulties involvedwith the latter, but the independent investigator wasblinded to the desflurane concentration on the vaporizerdial and those from the gas analyzer readings. In addi-tion, the initial concentration of desflurane was ran-domly set between 4.5 and 7.5 end-tidal vol% to preventthe blinded investigator from guessing the actual desflu-rane concentration based on a uniform startingconcentration.

The desflurane concentration was increased by 0.5 end-tidal vol% (e.g., from 5.5 to 6%) when the volunteer movedin response to electrical stimulation or decreased by 0.5%when the volunteer did not move. The new end-tidal con-centration was maintained for at least 15 min to allow fullequilibration between alveolar and brain concentrationsbefore repeating electrical stimulation. To prevent de-sensitization at the needle insertion sites, the stimulatingneedles were moved cranially by 1 cm after each stimu-lation period. The up-and-down sequence was continueduntil participants “crossed over” from movement to non-movement (or vice versa) four times. This procedure,known as the Dixon up-and-down method, is a standardtechnique for evaluating anesthetic potency.15

Anesthetic concentration was continuously deter-mined from end-expired gas with a monitor accurate towithin 0.1% (Datex-Engstrom, Helsinki, Finland). Atequilibrium, end-expired desflurane values are essen-tially equal to brain concentration.16

For verification of hair color, hair samples were ob-tained from the nape of the volunteers’ necks, and theratio of eumelanin to total melanin in the hair was de-termined spectrophotometrically as described by Ozekiet al.17 The total amount of eumelanin and pheomelaninwas determined by the absorbance at 500 nm (A500), andthe amount of eumelanin alone was determined by theabsorbance at 650 nm (A650). Red hair has an A650:A500

ratio near 0.13, whereas black hair has an A650:A500 rationear 0.30; the ratios for blond and brown hair are inbetween. Blood was sampled for subsequent analyses ofMC1R alleles (see Appendix: Details of GeneticAnalysis).

Data AnalysisDemographic, morphometric, and spectrophotomet-

ric hair analysis data for the volunteers with red or darkhair were compared using unpaired, two-tailed t tests. Ineach individual, anesthetic requirement was determinedby correlation of responses to noxious electrical stimu-lation (movement or no movement) with end-expireddesflurane concentration using logistic regression. Thedesflurane requirement for each group was defined asthe average of the individual concentrations. Desfluranerequirements in the two groups were compared usingthe Mann–Whitney nonparametric two-sample test. Re-sults are presented as means (95% confidence intervals);P � 0.05 was considered statistically significant.

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Results

Demographic and morphometric data were similar inthe groups (table 1). Average core temperatures weresimilar for both groups (table 1). Hair analysis confirmedthat volunteers had typical ratios of eumelanin to totalmelanin for red or dark hair color (table 1).

The volunteers with red hair required significantlymore desflurane (mean, 6.2 [95% CI, 5.9–6.5]) thanthose with dark hair (mean, 5.2 [95% CI, 4.9–5.5]; P �0.0004) (fig. 1). This represents an increase of 19% in thedesflurane partial pressure.

The single nucleotide polymorphism analysis revealedthat 9 of the 10 redheads had the following variantMC1R alleles (compared to consensus protein): R151C/Y152X, R151C/D294H, R151C/R160W (2 subjects),D294H/D294H, Y152�/R160W, R151C/29insA, R151C/V60L, R160W/D84E. One remaining redhead volunteercarried the R151C mutation on a single allele. In thedark-haired volunteers, 5 of 10 carried a single mutantallele (D294H, R160W, R151C [3 subjects]), and theremaining 5 showed consensus MC1R alleles at thetested locations.

Discussion

Anesthetic requirement in redheads was increased19%, a difference that was highly statistically significant(P � 0.0004). The results confirm anecdotal clinicalimpressions that anesthetic requirement is greater inredheads.

Inhalational anesthetic requirement is typically quanti-fied in terms of the minimum alveolar requirement(MAC), the anesthetic concentration that prevents move-ment in response to skin incision in half of the popula-tion.18 The reported desflurane MAC in the literature forthis age group is 7.25%.19 We used an analog of MAC inthis study by applying repeated noxious electrical stim-ulation.20 The mean values for desflurane requirement inboth our study groups (6.2% for red hair and 5.2% fordark hair) are lower than the reported MAC but areexpected with this model because anesthetic require-ment depends on the type and intensity of the appliedstimulation.21 Skin incision is a supramaximal stimulusthat fully activates pain receptors and pathways. Electri-cal stimulation is not, and it therefore provides gradedactivation of pain pathways. Movement in response toelectrical stimulation can thus be blocked by partialpressures lower than those required to prevent move-ment in response to skin incision.20

Chemical hair analysis also indicated that the volun-teers had in fact been correctly assigned to each haircolor group. Results of the DNA analysis in our volun-teers were consistent with previously reports.3–6 Threeparticular mutations of the MC1R alleles (R151C,R160W, and D294H) are present in the majority of red-heads, with at least one of these three alleles found in93% of those with red hair.22 These variant MC1R allelesbehave as recessive mutations.6 Although many otherdiscovered allele variants do not affect function, it hasbeen shown that MC1R variants V60L, R142H, R151C,R160W, and D294H lead to melanocortin-1 receptorsthat are unable to stimulate intracellular cyclic adenosinemonophosphate production as efficiently as the wild-type receptor when activated.23 Presumably, early singlenucleotide insertions (e.g., ins29) also result in loss offunction because the frame shift leads to many otherdifferent amino acid substitutions. Our DNA analysisshowed that all 10 red-haired volunteers in this studycarried at least one dysfunctional or diminished functionMC1R allele, and 8 carried two such alleles. The func-tional significance of mutation D84E, carried by one ofthe remaining two red haired subjects, remains un-known, but this mutation is also strongly associated withred hair, having an odds ratio of 63 for red hair relativeto the consensus MC1R allele.22 In the dark-hairedgroup, there was no clear evidence for the effect ofheterozygosity on anesthetic requirement.

In addition to its expression on melanocytes, the pres-ence of MC1R also has been identified in human pitu-

Table 1. Patient Characteristics, Eumelanin/Total MelaninRatios (A650/A500), and Desflurane Requirements [Mean (95%confidence interval)]

Red Hair Dark Hair P Value

No. of volunteers 10 10 —Age, yr 24 (21–27) 24 (21–27) 1.0Height, cm 159 (155–164) 162 (158–165) 0.42Weight, kg 60 (54–66) 61 (55–67) 0.89Average core

temperature, °C36.52 36.45 0.63

A650/A500 ratio 0.13 (0.11–0.17) 0.27 (0.22–0.31) 0.0001Desflurane

requirement, %6.2 (5.9–6.5) 5.2 (4.9–5.4) 0.0004

Fig. 1. Anesthetic requirement for individual participants (circles)with group means (squares) and 95% confidence intervals.

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itary tissue and glial cells and in cells of the humanperiaqueductal gray matter.24,25 The essential qualitiesproduced by inhaled anesthetics, namely amnesia andimmobility, are mediated through actions on the centralnervous system. However, the central nervous system isnot a major site of MC1R expression.26 Furthermore,studies suggest that immobility may be mediatedthrough the spinal cord rather than higher centers,27,28

and severing of higher centers from the cord does notchange MAC.28,29

A recent study by Mogil et al.30 suggests a possible rolefor the MC1R gene in female specific pain modulation.Women with two variant MC1R alleles displayed signif-icantly greater analgesia in response to the � opioidpentazocine compared to those with one or zero variantMC1R variant alleles. Whether this finding would trans-late into a greater underlying sensitivity to the dynor-phin, the endogenous � receptor ligand, remains un-clear. Interestingly, dynorphin peptides can also bind tomelanocortin receptors (including MC1R) and act asantagonists.31 However, to the extent that the results ofMogil et al. suggest an increased underlying sensitivity tocertain endogenous opioids in subjects with red hair, wemight expect reduced anesthetic requirement in redheads if such a system was tonically active; this would bethe opposite of what we observed in this study.

Modulation of analgesic mechanism could possiblyalso occur from interaction between the various mela-nocortin receptors. MC1R is part of a family of melano-cortin receptors (MC1R, MC2R, MC3R, MC4R, andMC5R)32,33 that are all stimulated by the same ligands(melanocortins �-melanocyte-stimulating hormone[MSH], �-MSH, �-MSH, and adrenocorticotropic hor-mone). The receptor subtypes have different physiologicfunctions and tissue distributions.26 In fact, MC3R andMC4R are much more abundant in the central nervoussystem than MC1R but have similar affinities for �-MSHand adrenocorticotropic hormone.26 A functional antag-onism between the opioid and melanocortin systems hasbeen suggested because the receptors are colocalizedthroughout the central nervous system, including thelocus ceruleus, where their regulatory activities opposeeach other.34 Furthermore, acute intrathecal administra-tion of the MC4R antagonist SHU9119 reduces cold andmechanical allodynia in a rat neuropathic pain model35

and can be antagonized by low doses of naloxone.36

The mechanisms controlling production of �-MSH re-main unclear, but most pituitary functions are controlledby negative feedback systems that increase hormone re-lease with end-organ failure. The observation that �-MSHinjection into the paraventricular hypothalamic nucleusdecreases POMC gene expression is consistent with thishypothesis.37 It is thus not unreasonable to postulatethat MCR1 dysfunction could similarly activate a feed-back system that increases central �-MSH concentration.

Sex is an additional phenotype that may be associated

with anesthetic requirement. For example, Goto et al.10

report that xenon MAC for elderly Japanese women was26% less than xenon MAC for elderly Japanese men. Incontrast, the results from another study suggested thatwomen require more desflurane using a similar model ofelectrical stimulation as this study.38 Most recently, how-ever, prospective11 and retrospective39 studies failed toidentify any sex difference in MAC. Therefore, sex doesnot seem to have a consistent or clinically importanteffect on anesthetic requirement.

In summary, our results confirm anecdotal clinical im-pressions that anesthetic requirement is greater in red-heads. The observed 19% difference between the twogroups makes red hair a distinct phenotype that corre-lates with inhalational anesthetic requirement in humansand can be traced to a specific genotype.

The authors thank Jonathan L. Sessler, Ph.D. (Professor, University of Texas,Austin, Texas), Ozan Akça, M.D. (Assistant Professor, University of Louisville,Louisville, Kentucky), and Gilbert Haugh, M.S. (Statistician), Jane Williams (Re-search Technologist), and Nancy Alsip, Ph.D. (Medical Editor; all from theUniversity of Louisville), for their assistance.

Appendix: Details of Genetic AnalysisDNA was extracted from either clotted or unclotted blood using

PureGene DNA isolation kits (Gentra Systems, Inc., Minneapolis, MN).A 1,238-bp fragment encompassing the coding region of MCR1 wasamplified by polymerase chain reaction (PCR) using primers describedby Miller et al.40 The PCR mix contained the following in 20 �l:50–100 ng DNA, 0.3 �M of each primer (1F: 5'-AGATGGAAGGAG-GCAGGCAT-3' and 1R: 5'-CCGCGCTTCAACACTTCAGAGATCA-3'),0.2 �M of each dNTP, 1.5 �M MgSO4, 2.5% DMSO, 1� KOD PCR buffer,and 0.4 U KOD Hot Start Taq polymerase (Novagen Inc., Madison, WI).The DNA was amplified for 36 cycles (0.5 min at 94°C, 0.5 min at 67°C,1.5 min at 72°C) after activating the polymerase by incubation for2 min at 94°C. Amplified PCR products were analyzed by agarose gelelectrophoresis. For single nucleotide polymorphism (SNP) analyses,the full-length PCR products were used as templates after a 1,000-folddilution. Fragments containing the region of variants of interest(R151C, D294H, R142H, R160W, and Y152�) were amplified usingthe primer pairs and conditions described above, except the concen-tration of dNTPs was decreased 10-fold. SNPs were detected using theCEQ8000 SNP detection kit (Beckman-Coulter Inc., Fullerton, CA).Amplification and SNP interrogation primers were D294H (amplifica-tion: 5'-TCATCGTCCTCTGCCCCGAG-3', 5'-ACACTTAAAGCGCGTG-CACCGC-3'; SNP detection: 5'-TTTCTCGCCCTCATCATCTGCAATGC-CATCATC-3'), R142H, R151C, R160W, and Y152� (amplification: 5'-GCAGCAGCTGGACAATGTCATT-3', 5'-TGGTCGTAGTAGGCGATGAA-3'; SNP interrogation: R142H, 5'-TCTGCTTCCTGGGCGCCAT-CGCC-GTGGACC–3'; R151C, 5'-TCGCCGTGGACCGCTACATCTCCATCTTCT-ACGCACTG-3'; R160W, 5'-AGATGGCCGCAACGGCTCGCC-GCGCCC-3';Y152X, 5'-CTACATCTCCATCTTCTACGCACTGCGCTA-3').

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