Gene Variant May Be Key to Fentanyl Response : Patients with the genetic variant didn't require as much fentanyl as did the patients without the variant.


PALM DESERT, CALIF. — Women with a common genetic variant on the μ-opioid receptor had a markedly reduced need for intrathecal fentanyl during labor, raising the strong possibility that genes influence analgesic response to the drug.

An international research team that was led by Ruth Landau, M.D., of the University Hospital of Geneva, announced their findings at the annual meeting of the Society for Obstetric Anesthesia and Perinatology.

Genetic polymorphism of the μ-opioid receptor is very common, found in roughly 10%–28% of the world's population.

When Dr. Landau and her associates genotyped the DNA of 113 nulliparous Swiss women at less than 35 weeks' gestation, the A118G variant was discovered in 32%.

Patients who went into spontaneous early labor and requested analgesia all received a starting dose of 18 mcg of fentanyl with a testing interval between patients of 2 mcg.

After that point, their fentanyl dose was allocated in a blinded fashion according to an up-down allocation protocol until anesthesia success was reached, defined as a visual analog score of 1 or less for at least 60 minutes.

Failure was defined as a patient not reaching that degree of pain relief within 20 minutes, or analgesia wearing off before 60 minutes.

Anesthesiologists and parturients were blinded as to genotype and total fentanyl doses required for successful anesthesia success.

Among 37 patients who have thus far met the study criteria, adequate pain relief was obtained at a dosage of 16 mcg in patients with the genetic A118G variant and 26.8 mcg in patients with the more typical gene receptor.

The difference between the two patient groups was very highly significant.

“We have demonstrated a highly significant 1.68-fold potentiation of intrathecal fentanyl effect by μ-opioid receptor A118 polymorphism,” said Dr. Landau, who is chief of the anesthesiology clinic at the university.

“We were very impressed. We were expecting—I guess hoping for—a difference, but we didn't think it would be this big,” she said.

Results of the study are preliminary, and enrollment continues.

Nonetheless, a number of other intriguing findings have already begun to emerge.

In a separate analysis of 52 patients whose labor was induced, fentanyl was administered in small to high doses in a random fashion until successful anesthesia was achieved. In that group, three women with the genetic variant achieved success at less than 10 mcg of fentanyl, a strikingly low dose.

Another five patients from the original genotyped cohort had such rapid cervical dilation they could not be included in the medication analysis. Interestingly, four of the five had the genetic variant although they represented a much smaller number of total patients in the cohort.

Dr. Landau posed a number of possible explanations for the differences between patients with and without the gene variant.

The intrathecal fentanyl may have an enhanced effect on individuals with the polymorphism: These patients may have altered pain perception, or their labor progress may be different from individuals without the genetic variant.

“We are continuing to investigate this [difference],” she said.

Since its cloning in 1993, the μ-opioid receptor polymorphism has been the subject of numerous studies by investigators curious about its potential link to opiate addiction and alcoholism, according to Dr. Landau.

In vitro studies have shown that the variant greatly increases the binding affinity and potency of β-endorphins, but not morphine, and that it may alter the toxicity profile of morphine 6 glucuronide response.

Carriers of the polymorphism have been shown to have an increased pain threshold when exposed to pressure pain. she said.

Next Article: