Red hair and opiods

A 22 y/o 65 kg female presented for bilateral osteotomies of the jaw for hypognathia. The patient was otherwise healthy, with the only previous anesthetic for a knee surgery. She experienced post operative nausea, but did not state that she had any other problems. She was on no medications and did not have any allergies. The maxillofacial surgeon indicated that there was a possibility that the jaw would be wired shut at the end of surgery. This made avoidance of POV an important consideration.

Anesthetic plan: GETA via nasal intubation, with a propofol infusion. Preinduction 2 mg versed and 150 mcg fentanyl were given. Induction was with 120 mg propofol and succinylcholine for paralysis. The intubation was smooth. An infusion of propofol was started at 250 mcg/kg/min to get a load on board. The patient was prepped and draped and the surgeon began to place local anesthetic prior to starting the procedure. The patient immediately began coughing on the ETT, so a bolus of propofol was given and an additional dose of succinylcholine. Bradycardia ensued and atropine 0.6mg was given. This resulted in a HR of 80 to 90 bpm. Surgery was started. Early on in surgery the patient started to move again (very slightly). Another bolus of propofol was administered plus 100 mcg fentanyl and the rate turned to 300 mcg/kg/min. The patient stayed at this level for 45 minutes or so. The surgeon then requested that the systolic BP be lowered to 100 mmHg. Since the infusion rate was already quite high, fentanyl was given 150 mcg, and labetalol 10 mg. This was repeated several times over the next 30 to 45 min. HR and BP remained elevated (104 bpm and 130s systolic). A total of 500 mcg of fentanyl was titrated in the first 1 hr and 45 min of the case. Since this female only weighed 65 kg, it was considered an adequate dose. At this point, 30 mg of esmolol plus 5 mg of hydralazine were given in an attempt to bring the SBP closer to 100 mmHg. This was repeated 15 min later with minimal effect. At this point sevoflurane was started and BP and HR improved slightly. Propofol was titrated back. Another 500 mcg of fentanyl was given over 30 min. At this point, since BP and HR were slightly improved (SBP 110's to 115's and HR 90's) sevoflurane was titrated down and then off. Propofol was at 250 mcg/kg/min. After 3 hr and 15 min the propofol infusion began to run low and the case was finishing. Since the SBP was now climbing higher, sevoflurane was restarted and propofol was titrated down and then off. The SBP and HR now came down again and were controlled for the rest of the case.

The case lasted for 4 hours. During this time the patient received 1000 mcg fentanyl, 3,400mg propofol, 50 mg labetalol, 100 mg esmolol, 10 mg hydralazine, 1 mg propanolol, and 30 mg ketorolac. It appears that she was tolerant to opioids and propofol to some degree, but responded as expected to sevoflurane. At the end of the case she emerged promptly, breathing about 17 bpm, and was conversant. She denied any pain during her PACU stay.


The decision to use a propofol infusion complicated the anesthetic management. This decision was based on her high apfel score (4/4), the fact that she had previous nausea after surgery, and that she could possibly have her jaw wired shut. Since propofol as an anesthetic can only be done prophylacticaly, this was done. Decadron and zofran were also given. In the end, the surgeon decided not to wire her jaw shut.


So, does the redhead phenotype really have any bearing on physiologic responsiveness to anesthetics and/or narcotic pain medications? Red hair is linked to a recessive gene known as the melanocortin-1 receptor gene (MC1R). This gene is expressed on melanocytes which causes them to produce eumelanin, a dark pigment. In patients with two mutant genes, pheomelanin is produced instead which results in the red head phenotype. Importantly, the melanocortin 1 receptor is present in the CNS in addition to the melanocytes. Particularly in the pituitary gland, glial cells, and cells in the periaqueductal gray matter and locus ceruleus. The last two are well known to be associated with pain modulation.


In clinical studies, it was found that red headed individuals were more sensitive to pentazocine (1). Pentazocine is a Kappa ligand. The endogenous endorphin, dynorphin binds to the kappa receptor, but also binds to and antagonizes the melanocortin receptors (including MC1R). It is unclear exactly how this might express itself clinically. Liem EB et al. showed that the MAC for desflurane was higher in red headed inviduals vs. those without red hair (6.2% vs. 5.2%) (2). In a later publication, the previous authors also tested red haired individuals to their response to a variety of painful stimuli: eletric shock, cold pain, and thermal pain. Redheads were more sensitive to cold pain and had a lower threshold for heat pain tolerance. SQ lidocaine was less effective in redheads than subjects with dark hair (3). In my case report, the patient was also resistant to propofol. An ASA abstract was presented in 2004, showing no difference between females with red hair vs dark hair in their reponse to varying propofol infusions. There was a trend towards red heads being more resistant to propofol, and had the study enrolled a larger number, it may have becomes statistically significant (4). Also in 2004, Xing et al. (5) looked at mice with a mutant MCR1 gene vs wild type mice. They compared their response to four inhalational anesthetics (Isoflurane, Desflurane, Sevoflurane, and Halothane). Within the individual groups of anesthetics, there was no difference in MAC values between mutant and wild type mice. However, when all anesthetic groups were combined, the total demonstrated that mutant mice (MCR1 mutant), indeed had a small increase in MAC of 5.5%.

Unfortunately, outside of these few studies, we have little else to go on to aid us in our understanding of the red hair phenotype and response to different anesthetics or analgesics. A mechanism as to why the red hair phenotype would be more suscetptible to pain, or at least, less responsive to anesthetics is theoretical. The current hypothesis states that a mutant MCR1 receptor would allow melanocortin ligands (melanocortins) to exert a strong negative feedback on the hypothalamus and thus decrease proopiomelanocortin (POMC) the prohormone giving rise to endogenous endorphins as well as other melanocortins (ACTH, and alpha, beta and gamma Melanocyte Stimulating Hormones). Alpha-MSH has the strongest affinity to MCR1, and thus would be produced in much greater amounts if upregulated due to inability to bind to MCR1 mutant receptors. Contreras and Takemori found that alpha-MSH indeed can antagonize the analgesic effect of morphine. Other studies have shown that in rats, administering alpha-MSH can induce hyperalgesia. This could explain the high dose of fentanyl (1000 mcg) required in the present case discussion. Furthermore, MCR3 and MCR4 are also responsive to melanocortins, but are predominantly found in the nervous system. Several studies have shown that these receptors modulate hyperalgesia, pain, behaviour, stress and food intake. In patients with normal MCR1 genes, alpha-MSH will predominantly bind to MCR1, given the high affinity of the this ligand for the receptor. However, in mutant type MCR1, alpha-MSH will be available for binding to the MCR3 & 4 receptors, and thus, greater modulation of pain behavior and hyperalgesia will be found. Although MCR1 is not as ubiquitous in the CNS as MCR3 & 4, it is expressed in the PAG, and thus, can and does affect nociception (1).



In summary, this case demonstrates unusually high aneshetic requirements in a young, opioid naive, female patient with the red hair phenotype. While certainly a variety of genetic markers likely affect any one patient's response to anesthetic/analgesic medications, certainly, the melanocortins offer one additional pathway for pain to be modulated. Given that the red hair phenotype has an altered melanocortin pathway, a pathway also known to modulate analgesia in animal and human studies, it is likely that this case represents an example of an aberrant melanocortin pathway resulting in increased anesthetic requirements.













1) Mogil JS, Wilson SG, Chesler EJ, Rankin AI et al. The Melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Proc Natl Acad Sci USA 2003; 100:4867-72.









2) Liem EB, Lin CM, Suleman MI, Doufas AG, Gregg RG, Veauthier JM, Loyd G, and Sessler DI. Anesthetic Requirement is Increased in Redheads. Anesthesiology 2004; 101:279-83.




3). Liem EB, Joiner TV, Tsueda K, Sessler DI. Increased Sensitivity to Thermal Pain and Reduced Subcutaneous Lidocaine Efficacy in Redheads. Anesthesiology 2005; 102:509-14.



4) Doufas AG, Shah YM, Komatsu R, Sengupta P, Sessler DI. The hypnotic Requirement for Propofol in Women with Red Hair: Preliminary Results. A-1605 2004.

5) Xing Y, Sonner JM, Eger EI, Cascio M, Sessler DI. Mice with a Melanocortin 1 Receptor Mutation Have a Slightly Greater Minimum Alveolar Concentration than Control Mice. Anesthesiology 2004; 101:544-6.