the case report by megarbane and colleagues   reminds us that full tolerance to the opioid effects of methadone may never fully develop , even after long - term methadone maintenance treatment . thus , even in tolerant patients , intake of a dose that is too high , up - titration of methadone dosage that is too rapid , or introduction of strong inhibitor(s ) of methadone metabolism could cause life - threatening respiratory depression . interestingly , the maximal observed ( r , s)-methadone plasma concentration ( 1204 ng / ml ) in this case report is not , as stated , three times higher than peak levels in patients treated with a daily dosage in excess of 80 mg ( mean dose  standard deviation : 134  82 mg / day , n = 209 ) . actually , it is only 68% higher than the mean peak ( r , s)-methadone concentration ( 715  395 ng / ml ) and half the highest measured peak ( r , s)-methadone concentration . there are many factors that can contribute to the interindividual variability in sensitivity to respiratory depression following intake of a high dose of methadone in tolerant patients . simultaneous intakes of other central respiratory depressing agents such as benzodiazepines and alcohol are important risk factors . the case report gives no indication as to whether alcohol was also used by the patient , although screening of blood for benzodiazepines , opiates , buprenorphine , cocaine and tetrahydrocannabinol was negative except for methadone . the patient declared that the only other substance taken with methadone was 2 mg flunitrazepam . if this was true , then it is unlikely that this small quantity of flunitrazepam , in a patient who already had a history of occasional use of this benzodiazepine , could be a major factor contributing to the episode of respiratory depression . in recent years interest in pharmacogenetic studies has grown ; these studies aim to achieve a better understanding of interindividual variability in the response to treatment . some tentative explanations for this variability might come from both pharmacokinetic and pharmacodynamic lines of inquiry . at the pharmacokinetic level , the first factor to consider is the enzymes that are involved in the metabolism of methadone , which is mainly mediated by cytochrome p450 ( cyp)2b6 and cyp3a4 , with a minor contribution from cyp2d6 . cyp2b6 exhibits stereoselectivity toward the ( s)-enantiomer of methadone , which is almost inactive as a -opioid receptor agonist . in contrast , cyp3a4 is not stereoselective   and cyp2d6 could be stereoselective toward the active form of methadone , namely ( r)-methadone . it has been demonstrated that activity of these enzymes can be impaired as a result of genetic   and environmental ( for example , inhibition of their activity by comedication and/or diet ) factors . however , low metabolic activity can not be proposed as an explanation for the episode of respiratory depression in the case described by megarbane and colleagues   because a short half - life for both enantiomers of methadone was measured , suggesting rapid metabolism . a second factor that possibly contributes to interindividual sensitivity to methadone is the permeability glycoprotein ( pgp ) , which is a transmembrane efflux transporter expressed in various human tissues , including intestine , liver and blood - brain barrier . genetic polymorphisms have been described for pgp that can contribute to differences in blood concentrations of methadone . more importantly , a major role for pgp in limiting access of xenobiotics to the brain has been demonstrated in vivo in pgp - deficient mice , with little influence on blood concentrations . interindividual variability in pgp activity is therefore a strong candidate in genetically mediated sensitivity to methadone - induced respiratory depression . another factor that may be involved in methadone pharmacokinetics is the strong blood binding of methadone to plasma proteins , in particular to -acid glycoprotein , which could significantly alter methadone pharmacokinetics . however , despite the presence of genetic polymorphisms in 1-acid glycoprotein and differential binding of methadone to its variants , it is presently not possible to determine whether and to what extent this could influence sensitivity to respiratory depression . at the pharmacodynamic level the most interesting factors are genetic polymorphisms described for the -opioid receptor , in particular the 118a > g single nucleotide polymorphism at exon 1 of the oprm1 gene . in vitro , the variant protein has been demonstrated to exhibit three times greater binding affinity for the endopeptide -endorphin , whereas binding to substances such as morphine , fentanyl , methadone and naloxone were unaffected . however , in vivo , ( r)-methadone had 1.74 times lower miotic potency ( p < 0.001 ) in carriers of the variant 118 g allele as compared with noncarriers . in addition , alfentanil concentrations that were two to four times greater were needed in homozygous carriers of the 118 g allele as compared with wild - type subjects to produce the same degree of analgesia , and 10 to 12 times higher alfentanyl concentrations were needed to produce the same degree of respiratory depression . this suggests an important difference in sensitivity to respiratory depression depending on whether the 118a > g single nucleotide polymorphism is present . it should be noted that although genetic polymorphism in the -opioid receptor appears an interesting candidate for contributing to interindividual variability in sensitivity to opioid agonist induced respiratory depression , caution should be exercised when extrapolating the data from these single - dose studies to cases of overdose in tolerant patients . however , the 118a > g polymorphism in the human -opioid receptor gene also affects response to treatment after multiple doses as well , because cancer patients homozygous for the 118 g allele need higher morphine doses to achieve pain control . in summary , studies are needed to elucidate the interindividual variability in sensitivity to respiratory depression among opioid - dependant patients receiving methadone maintenance treatment . in this regard , genetic polymorphism in cyp isozymes , pgp and the -opioid receptor would be interesting factors to consider in future investigations .
in this issue of critical care , megarbane and colleagues present a case report of methadone - induced respiratory depression and conduct a toxicokinetic / toxicodynamic evaluation . an opioid - dependent patient receiving methadone maintenance treatment ( daily dose 70 mg ) was found unconscious after ingesting 240 mg methadone and 2 mg flunitrazepam . 
 significant improvement in consciousness was achieved after an intravenous bolus of 0.3 mg naloxone followed by a continuous infusion of naloxone at 0.3 mg / hour . in patients receiving methadone maintenance treatment , 
 an occasional intake of two to four times the usual daily dose of methadone is not an exceptional occurrence . 
 however , few such patients experience episodes of life - threatening respiratory depression . here 
 , we discuss whether recent pharmacogenetic data could help us to understand interindividual variability in sensitivity to respiratory depression and , ultimately , to predict which patients are most likely to be affected .