By: Lunbao (Jerry) Huang, Pharm.D.  Candidate c/o 2013

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Pain is a very difficult condition to manage, as clinicians have only subjective findings to work with.  Opioid medications are currently the cornerstones for the management of moderate to severe pain; however, it is often problematic to determine a patient’s real ‘need’ for opioids.  Physicians’ clinical judgments help to create individualized medication regimens for patients with pain.  The need for specialized opioid dosing is most likely multifactorial, including both genetic and environmental predispositions to pain.  Health care providers must account for these factors by investigating pharmacogenomic relationships through pharmacokinetic and pharmacodynamic studies.  The field of pharmacogenomics is particularly under increasing investigation for the enhancement of drug therapy outcomes.  Differences in age, gender, and ethnicity have various effects on a drug’s receptor binding, potency, absorption, distribution, metabolism, and excretion.

Both age and gender are important determinants of central nervous system (CNS) structure and function.  Binding with the mu-opioid receptor within the CNS is of particular interest.  One study examined age- and gender-associated variations with positron emission tomography (PET) and the radiotracer carfentanil.¹  There were two analyses: first a retrospective analysis of a group of 24 men and 12 women, and second, a prospective study of a group of 12 men and 18 women.  This study found that the mu-opioid receptor binding potential (B_max/K_d) increased with age in neocortical areas of the brain.  Furthermore, there was higher mu-opioid binding in women.  In-vivo mu-opioid binding declined in postmenopausal women to levels below those of men.¹  This indicates that women’s reproductive status (reproductive age versus postmenopausal) may influence the function of CNS opioid receptor systems.  Therefore, data suggests that both age and gender are important variables to consider in the investigation of opioid systems in humans.

A study of pentazocine, an opioid that acts at kappa−receptors, revealed better postoperative analgesia in females than in males.²  There was a follow-up study for patients undergoing surgery for the removal of their wisdom teeth.  The study compared the analgesic efficacy of two other predominantly kappa−opioid analgesics, nalbuphine, and butorphanol.  Results confirmed that nalbuphine and butorphanol produced significantly greater analgesia in females as compared with males.  Authors concluded that kappa−opioid analgesia is greater in females than in males, most likely due to differences in kappa−opioid−activated endogenous pain modulating circuits.³

Metabolism of opioid medications also affects the efficacy of opiods.  Race is one of the determinants of CYP450 2D6 variability.  The prevalence of CYP2D6 poor metabolizers is approximately 6–10% in Caucasian populations, and as low as 2% in Asian populations.⁴  The frequency of poor metabolizers among blacks is greater than that for whites.  In addition, 2D6 enzyme appears to be greatest among Middle Eastern and North African populations.⁵ As we know, morphine is metabolized hepatically via conjugation with glucuronic acid.  The main metabolites are morphine-6-glucoronide (active analgesic) and morphine-3-glucuronide (inactive).  Minor metabolites include morphine-3-6-diglucuronide, normorphine (active), and morphine 3-ethereal sulfate.  The body metabolizes oxycodone via CYP3A4 to noroxycodone (weak analgesic), noroxymorphone, and alpha- and beta-noroxycodol.  CYP2D6 also mediates oxycodone metabolism to produce oxymorphone (analgesic), alpha-, and beta-oxymorphol.  Codeine is also bioactivated to morphine, a strong opioid agonist, by CYP2D6.  The efficacy and safety of codeine, morphine, and oxycodone are subject to CYP2D6 polymorphisms.  Codeine has little therapeutic effect in patients who are CYP2D6 poor metabolizers, whereas there is a higher risk of morphine toxicity in ultra-rapid metabolizers.  We fortunately have information interpreting CYP2D6 genotype test results to guide the dosing of codeine.⁶

In 2011, there was an announcement calling for translational and genetic research for identifying new targets for new analgesics to be developed based on pharmacogenomics^.7  Voltage-gated sodium, calcium, and potassium channels were addressed, for which SCN9A, CACNA1B, KCNQ2, KCNQ3, and yet undiscovered receptors could become new targets for pain control.  Research on the genetic modulation of pain has already identified variants in these genes; pharmacogenetic assessments of new analgesics could be relevant.  The increased number of pharmacogenetic modulators of analgesic actions presents opportunities for broader clinical implementation of genotyping information.

SOURCES:

1. Zubieta JK, Dannals RF, Frost JJ et al.  Gender and Age Influences on Human Brain Mu-Opioid Receptor Binding Measured by PET. Am J Psychiatry 1999;156:842—8.
2. Gear, R.W.  et al.  Gender difference in analgesic response to the kappa-opioid pentazocine.  Neurosci Lett 1996;205:207−9.
3. Gear RW, Gordon NC, Heller P et al.  Kappa−opioids produce significantly greater analgesia in women than in men.  Nature Med 1996;2:1248—50.
4. Rossi S (Ed.) Australian Medicines Handbook.  Adelaide: Australian Medicines Handbook.  (2004).
5. Gaedigk A, Bradford LD, Marcucci KA, Leeder JS.  Unique CYP2D6 activity distribution and genotype-phenotype discordance in black Americans.  Clin Pharmacol Ther 2002;72(1):76—89.
6. Crews KR, Gaedigk A, Dunnenberger HM, et al.  Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype.  Clin Pharmacol Ther 2012;91(2):321—6.
7. Lötsch J, Geisslinger G.  Pharmacogenetics of new analgesics.  Br J Pharmacol 2011;163(3):447—60.