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Journal of Analytical Toxicology logoLink to Journal of Analytical Toxicology
. 2020 Jun 15;44(7):741–746. doi: 10.1093/jat/bkaa069

A Case Study Evaluating the Efficacy of an Ad Hoc Hospital Collection Device for Fentanyl in Infant Oral Fluid

Ashley M Gesseck 1,2, Justin L Poklis 3, Carl E Wolf 4,5, Jie Xu 6, Aamir Bashir 7, Karen D Hendricks-Muñoz 8, Michelle R Peace 9,✉
PMCID: PMC7549304  PMID: 32591773

Abstract

Neonatal drug exposure is currently assessed using meconium, urine, blood, hair, or umbilical cord tissue/blood. Due to the invasiveness, challenges, and limitations of collection, and/or analytical difficulties of these matrices, oral fluid may be a more desirable matrix in diagnosing opioid exposure and risk for opioid withdrawal in neonatal abstinence syndrome. Traditional oral fluid collection devices are not viable options as they are too large for neonates’ mouths and may contain chemicals on the collection pad. Unstimulated and stimulated infant oral fluid samples have been used for therapeutic drug monitoring as an alternative matrix to blood. The objective of this study was to assess the viability of a simple oral fluid collection system using a sterile foam-tipped swab rinsed in phosphate-buffered saline. Two infants were administered fentanyl for post-operative pain relief while hospitalized in the Neonatal Intensive Care Units at the Children’s Hospital of Richmond of Virginia Commonwealth University. Oral fluid samples were collected at 16 h, 2 days, and/or 7 days following the start of intravenous infusion of fentanyl. Samples were analyzed by ultra-high-pressure liquid chromatography–tandem mass spectrometry for fentanyl and norfentanyl after solid-phase extraction. In one of the three samples tested, fentanyl and norfentanyl were detected at concentrations of 28 and 78 ng/mL, respectively. Based on the infusion rate, the theoretical oral fluid fentanyl concentration at steady state was calculated to be 33 ng/mL.

Introduction

The opioid epidemic has become a familiar national news headline over the past two decades. The rate of drug overdose deaths caused by synthetic opioids other than methadone (i.e., fentanyl, fentanyl analogs, etc.) has increased over 30-fold from 0.3 to 9.9 per 100,000 during the period of 1999–2018 (1). The rate of opioid-related inpatient and emergency department visits has increased from 181.4 to 296.9 and 107.4 to 243.5 per 100,000, respectively from 2009 to 2016 (2). From 2000 to 2009, there was over a four-fold increase in mothers diagnosed to be dependent on or using opiates, increasing from 1.19 per 1,000 delivering mothers in 2000 to 5.63 per 1,000 in 2009 (3). In 2018, Substance Abuse and Mental Health Services Administration (SAMHSA) reported that 0.9% of pregnant women reported opioid use in the past month which was down from 1.4% in 2017 and 1.2% in 2016 (4).

Despite the ongoing opioid epidemic, fentanyl, a synthetic opioid remains a regularly prescribed drug for pain, and is used for intra-operative analgesia in hospitals. Fentanyl was synthesized in 1960 and approved for clinical use in 1968. It was used for intravenous analgesia in a 1:50 ratio with droperidol due to the concerns of fentanyl potency and the potential for abuse. Fentanyl was approved for use alone in low doses (50 μg) in 1972, and then high doses (50 μg/kg) in place of morphine for valvular and coronary heart surgery in the mid-1980s. Fentanyl has evolved to intrathecal, epidural, transdermal, transmucosal, buccal, sublingual and nasal administrations for anesthesia, analgesia, sedation, anxiolysis, chronic pain (from cancer and non-cancer), and breakthrough pain. One oral transmucosal administration, Oralet, was developed specifically to be child-friendly for use before surgery (5).

Fentanyl is commonly prescribed in the neonatal intensive care units (NICU) for its analgesic, sedative and anesthetic properties (6). While the pharmacokinetics of fentanyl in adults is well-studied and understood, the same is not true for children, infants, or neonates. One study demonstrates that children aged 2.7–11 years have different fentanyl pharmacokinetics compared to adults causing an under prediction of expected plasma concentration, which may be better described using a two-compartment model with age and weight as covariates (7). However, in neonates, gestational age and birth weight may only contribute up to 20% of the variance each (8). Many factors may alter the elimination of fentanyl in neonates including decreased expression of the enzyme, CYP3A4, responsible for the production of the primary hepatic metabolite norfentanyl in fentanyl metabolism (9, 10), decreased liver function leading to a lower hepatic extraction ratio (11), and increased intra-abdominal pressure leading to decreased hepatic clearance (12, 13). In adults, fentanyl clearance is estimated to range from 0.4 to 1.5 L/min (14) and terminal elimination half-life is estimated to range from 3 to 4 h (15). In neonates, fentanyl elimination is prolonged; initial and steady-state plasma concentrations will be lower than in adults given the same μg/kg dose (12). The clearance of fentanyl in infants and neonates has been reported to be: 11.5 ± 4 mL/min/kg (8), 12.8 ± 7.3 mL/min/kg (15), and 17.94 ± 4.4 mL/min/kg (12). The fentanyl terminal elimination half-life in infants and neonates has been reported to be 141 ± 98 min (15), 187–807 min (13), 317 ± 70 min (12), and 1,062 ± 558 min (16). In the Collins et al. study, all patients had undergone surgery (16). Koehntop et al. reports a 1.5–3x increase in half-life with increased abdominal pressure due to pathology and/or surgical lesion (12). According to Gauntlett et al., clearance of fentanyl is affected by the blood flow to the liver; increased abdominal pressure decreases blood flow to the portal vein which supplies 90% of the blood (13). No studies have demonstrated a change in volume of distribution, thereby leading to a direct correlation between decreased clearance and increased half-life.

Oral fluid is a mixture of fluid from the salivary glands, termed saliva, cellular debris, and other materials (17, 18). Diffusion of drugs and/or metabolites from blood to oral fluid mainly occurs by passive diffusion and is dependent on the salivary glands and tissues of the oral cavity being highly perfused (18). Many factors may affect the amount of drug diffusion from blood to oral fluid including: protein binding in plasma, pH of oral fluid, lipophilicity, physical size, and pKa of the drug (17, 18). The pKa of fentanyl is 8.4 (19) and the pH of adult oral fluid is 6.2–7.4 (17). Fentanyl is 84 ± 2% protein bound in adult plasma (20), 70% bound in term infants, and 77% bound in pre-term (<37 weeks gestation) infants (21). The oral fluid pH, amylase activity, and concentrations of phosphate and IgA in infants are lower than in adults. The oral fluid concentrations of chloride, calcium, and magnesium are higher in infants than adults. The concentrations of sodium, potassium, and total protein are similar in infant oral fluid and adults. (22)

Prior reports indicate the use of umbilical cord tissue/blood (23–28), meconium (25–32), urine (25–29), blood (26, 27), or hair (26–29) for the detection of neonatal drug exposure. Of these, umbilical cord and meconium are presently the most widely used (27). Due to the invasiveness, challenges, limitations in collecting specimens, and/or analytical difficulties of these matrices, oral fluid may be a more desirable matrix in diagnosing opioid exposure and risk for opioid withdrawal in neonatal abstinence syndrome (NAS). Traditional oral fluid collection devices are not viable options due to potential chemicals on the collection pad and being too large for neonates’ mouth. Unstimulated and stimulated infant oral fluid samples have been used for therapeutic drug monitoring as an alternative matrix to blood (33–38). Only one of the six studies used a commercial device, Salimetrics Salivary Collection System (Salimetrics, LLC, State College, PA, USA), for the collection of oral fluid from pre-term infants between the ages of 4 and 11 weeks after birth (35).

The objective of this study was to assess the viability of a simple oral fluid collection using a sterile foam-tipped swab rinsed in phosphate-buffered saline (PBS). The ad hoc collection device was evaluated using oral fluid samples collected from two infants that were administered fentanyl for post-operative pain relief while hospitalized in the NICU at the Children’s Hospital of Richmond of Virginia Commonwealth University (VCU). Oral fluid samples collected at 16 h, 2 days, and/or 7 days following the start of intravenous infusion of fentanyl were analyzed by ultra-high-pressure liquid chromatography–tandem mass spectrometry (UPLC–MS-MS) for fentanyl and norfentanyl after solid-phase extraction (SPE).

Case History

Infant 1 was a pre-term male born at 24 weeks gestation with a birthweight of 510 grams being treated for bowel reanastomosis and compartment syndrome. On Day 140 after birth, the infant received a continuous fentanyl infusion of 7 μg/kg/h at a current weight of 3,500 g for the operative pain management after bowel reanastomosis and compartment syndrome with silo placement post necrotizing enterocolitis surgery. Sample 1A was collected after 7 days of treatment on Day 147 after birth. Fentanyl infusion remained constant until Day 167 after birth when the fentanyl infusion was increased to 40 μg/kg/h with the addition of 0.7 mg midazolam/h daily at a current weight of 3,370 g for continued pain relief. Sample 1B was collected on the second day of treatment, Day 169 after birth.

Infant 2 was a pre-term male born at 24 weeks gestation with a birthweight of 750 grams being treated for necrotizing enterocolitis and formation of mucus fistula. On Day 89 after birth, the infant received a continuous fentanyl infusion of 4 μg/kg/h for 11 h at a current weight of 2,250 g for the treatment of operative and postoperative care of bowel resection for necrotizing enterocolitis and formation of mucus fistula and ileostomy. Sample 2 was collected 5 h following termination of treatment.

Experimental

Oral fluid collection

Oral fluid samples were collected at the Children’s Hospital of Richmond at VCU prior to feeding from two infants using a dry, soft, sterile foam-tipped swab (Puritan Medical Products, Guilford, ME, USA) that was rolled along the infant’s oral mucosal surface of the mouth, inner cheeks, and tongue until saturated. Saturated swabs were estimated to collect 100 μL of oral fluid. The swabs were rinsed in 2.0 mL of PBS 1x, pH 7.4, (Quality Biological, Inc.; Gaithersburg, MD) and discarded. The ad hoc collection device was made for clinical evaluations with a predefined volume of PBS. The PBS was transported on ice to the laboratory, the contents were centrifuged, and the supernatant was stored at −80°C until being analyzed by UPLC–MS-MS for fentanyl and norfentanyl after SPE.

Solid-phase extraction

Oral fluid samples were extracted using a previously validated method for fentanyl (39). In brief, an aliquot of 100 μL matrix-matched calibrators, controls, or collected sample was diluted 1:10 with water, mixed and allowed to stand for 1 h. Internal standard was added at a concentration of 5 ng fentanyl-d5 and norfentanyl-d5 to 1.0 mL of diluted sample treated with the addition of 1.0 mL of 100 mM phosphate buffer (pH 6.0). SPEC MP3 SPE columns (Agilent Technologies, Inc., Santa Clara, CA) were conditioned with 0.4 mL of methanol followed by 0.4 mL of 100 mM phosphate buffer (pH 6.0). Samples were added to the columns and aspirated. Columns were washed consecutively with 0.4 mL water and 100 mM acetic acid. Columns were allowed to dry under vacuum, and samples were eluted with 1.0 mL of 78:20:2 dichloromethane:isopropanol:ammonium hydroxide (v:v:v). The eluent was evaporated with nitrogen and reconstituted with 100 μL of 10 mM ammonium formate and 0.1% formic acid in water.

UPLC–MS-MS

Following SPE, oral fluid samples were analyzed using a previously validated method for fentanyl (39). In brief, a 5-μL injection of sample was analyzed by UPLC–MS-MS on a Xevo® TQD with an ACQUITY UPLC® (Waters Corporation, Milford, MA). Chromatographic separation was achieved by using a gradient consisting of 10 mM ammonium formate and 0.1% formic acid in water (mobile phase A) and methanol (mobile phase B) at a flow rate of 0.6 mL/min on an Ultra Biphenyl, 2.1 x 50 mm, 3 μm, (Restek Corporation, Bellefonte, PA) column at 40°C. The gradient profile was: ramp from 5% B to 40% from 0.0 to 1.5 min, ramp to 100% B from 1.5 to 3.0 min, hold 100% B until 3.5 min, and then return to 5% B at 3.6 min and hold until 4.0 min. The MS parameters were as follows: source temperature, 150°C; capillary voltage, 3.00 kV; desolvation temperature, 600°C; gas flow rate, 650 L/h; cone flow, 100 L/h. Samples were acquired using multiple reaction monitoring mode, the following transition ions (m/z) with corresponding collision energies (eV) in parentheses were monitored in positive mode, fentanyl: 337 > 105 (36) and 337 > 188 (24), fentanyl-d5: 342 > 105 (36) and 342 > 188 (24), norfentanyl: 233 > 84 (16) and 233 > 177 (14) and norfentanyl-d5: 238 > 85 (16) and 238 > 182 (14). The limits of quantitation and detection were administratively set by the laboratory to 10 ng/mL for both analytes due to the 20-fold dilution factor that occurs during collection.

Theoretical concentrations

Theoretical concentrations were calculated based on values and formulas from previously published studies with infusion rates from this study. A schematic of the calculations using sample 1B as an example is demonstrated in Figure 1. The mean concentration at steady state is equal to the infusion rate divided by the clearance (40). Clearance for a normal infant is equal to 17.94 mL/min/kg (12) and clearance for a compromised infant with suspected increased abdominal pressure due to surgery is between 5.98 and 11.96 mL/min/kg based on a 1.5–3x increase in half-life (12). Infusion rate for sample 1A is equal to 7 μg/kg/h (weight = 3.50 kg), infusion rate for sample 1B is equal to 40 μg/kg/h (weight = 3.37 kg), and infusion rate of sample 2 is equal to 4 μg/kg/h (weight = 2.25 kg). The amount of unbound fentanyl is equal to one minus the amount of bound fentanyl. The amount of bound fentanyl in term infants is 70% (21). It was assumed that 100% of the unbound fentanyl was able to cross from the plasma into the saliva (18). Therefore, the theoretical oral fluid concentration at steady-state is equal to the unbound fraction of fentanyl times the infusion rate divided by the clearance (Eq. 1).

Figure 1.

Figure 1

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Calculations for determination of fentanyl theoretical concentration using sample 1B. Abbreviations: RateINF, rate of fentanyl intravenous infusion; Cl, clearance; Css-OF, theoretical steady-state concentration of fentanyl in oral fluid; Conc., concentration.

Results

Sample 1A

An oral fluid sample was collected from infant 1 on Day 147 after birth, after continuous infusion of fentanyl for 7 days at a rate of 24.5 μg/hr. Using Eq. 1, the theoretical oral fluid concentrations at steady state for fentanyl were 2 ng/mL assuming no decrease in clearance without surgery and 6 ng/mL assuming a threefold decrease in clearance due to surgery and increased intra-abdominal pressure. Fentanyl and norfentanyl were not detected in the oral fluid.

Sample 1B

An oral fluid sample was collected from infant 1 on Day 169 after birth, 2 days following the increase in fentanyl infusion rate to 135 μg/h with the addition of 0.7 mg midazolam/h. Using Eq. 1, the theoretical oral fluid concentrations for fentanyl at steady state were 11 ng/mL assuming no decrease in clearance without surgery and 33 ng/mL assuming a threefold decrease in clearance due to surgery and increased intra-abdominal pressure. Fentanyl and norfentanyl were measured in oral fluid at concentrations of 28 and 79 ng/mL, respectively.

Sample 2

An oral fluid sample was collected from infant 2 on Day 89 after birth, 5 h following an 11-h infusion of fentanyl at a rate of 9 μg/h. Using Eq. 1, the theoretical oral fluid concentrations for fentanyl at steady state were 1 ng/mL assuming no decrease in clearance without surgery and 3 ng/mL assuming a threefold decrease in clearance due to surgery and increased intra-abdominal pressure. Fentanyl and norfentanyl were not detected in the oral fluid.

Discussion

Fentanyl has been previously demonstrated to reach steady-state plasma concentrations in neonates within 24–48 h (8). Steady-state kinetics were assumed for all samples in this study for the purpose of all calculations, even though sample 2 only received a fentanyl infusion at a constant rate for 11 h, and the sample was collected 5 h post termination of infusion.

The measured concentration of fentanyl in the oral fluid of sample 1B was 28 ng/mL, which is within 20% of the theoretical value assuming a threefold decrease in clearance due to surgery and increased intra-abdominal pressure, 33 ng/mL. The observed concentration, as well as theoretical concentration, are within range of a reported steady-state concentration of 22.7 ± 5.3 ng/mL in patients aged 0.5–9 years (n = 9, mean age = 4.4 years) after being given a bolus of 30 μg/kg followed by continuous infusion of 0.3 μg/kg/min (15).

The detection of fentanyl and norfentanyl in sample 1B demonstrates proof of concept that the simple collection using a sterile foam-tipped swab rinsed in PBS is viable for the collection of oral fluid from infants and neonates for the detection of fentanyl, and similarly related compounds. Obtaining a concentration within 20% of the theoretical values demonstrates that good recovery was obtained with this collection technique. Due to the large upfront dilution factor in the collection procedure, the assumed theoretical steady-state concentrations of 2–6 and 1–3 ng/mL for sample 1A and 2, respectively, are below the limit of detection of the method (10 ng/mL). Due to the requirement of low limits of detection, additional swabs should be used for collections and a highly sensitive method is required for future studies.

The two infants in this study were pre-term with ages between 89 and 169 days after birth at the time of sample collection. Difficulty of obtaining permission for sample collection of infants in treatment resulted in a total of three specimens. Due to the chronological age at time of collection, a full-term infant's protein content was assumed to be closer to that of the two pre-term infants in this study. Even though previous protein binding studies completed on umbilical cord blood collected at time of birth demonstrate a lower percentage of free fentanyl in pre-term infants compared to full-term infants (21).

These findings are supported by previous studies, summarized in Table I, which demonstrated oral fluid to be a successful alternate matrix for blood in the therapeutic drug monitoring in infants and children. While the literature demonstrates the viability of oral fluid analysis for neonates and infants, future studies need to assess any differences between stimulated and unstimulated collections, as well as the construction of the collection device. Future studies are also needed to assess the stability and recovery of analytes of interest from the collection device.

Table I.

Previous Studies Using Oral Fluid for Therapeutic Drug Monitoring in Infants and Children

Analyte Patients Collection method Results Ref.
Theophylline 13 Infants
2–10 weeks		 Stimulated-saliva with citric acid crystals Consistent concentrations with unbound plasma, ratio of saliva to plasma larger in infants than children 33
27 Children
2–16 years
Digoxin 18 Children
2 months–14 years		 Stimulated-saliva with citric acid crystals High individual variability in saliva to plasma ratio 34
Caffeine 29 Pre-term infants
4–11 weeks		 Salimetrics salivary collection system Salivary concentrations high correlated with plasma 35
Cortisol 87 Infants
1–6 h		 Stimulated-saliva with grape Kool-Aid powder or citric acid crystals mixed with sucrose Saliva compares favorably to other body fluids 36
Caffeine 140 Pre-term infants
3–90 days

  1. Unstimulated with non-woven gauze

  2. Stimulated-saliva with one drop of a 1% citric acid solution added to non-woven gauze

  3. Stimulated-saliva with one drop of a 1% citric acid solution into cheek of infant 5–10 min prior to collection with non-woven gauze

 Similar saliva to plasma ratios with all collection methods, strongest correlation using third collection method 37
Theophylline 8 Pre-term infants
3–59 days		 Unstimulated saliva by suctioning with syringe Serum and saliva concentrations are approximately equal, saliva concentration may be clinically useful when plasma is not available, but should not be used for therapeutic drug monitoring 38
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Other factors can impact the amount of drug that can diffuse across the plasma membrane and into the oral fluid. Oral fluid pH, lipophilicity of the drug, and pKa/ionization of the drug can affect the amount of unbound drug that is able to diffuse across the membrane (18). The pH of oral fluid in infants under 6 months of age of approximately 6.1 (22) is near the bottom of the normal pH range for adults, 6.2–7.4 (17). As such, differences in the ionization of fentanyl are minimal and oral fluid analytical results would be similar. Crouch et al. reported significant inter- and intra-subject variability for codeine saliva-to-plasma ratios in adults (17), and Bista et al. observed higher fentanyl concentrations in saliva than plasma in adults, indicating the possibility of active transport (41), but similar norfentanyl concentrations in saliva and plasma leading to higher fentanyl concentrations in oral fluid than norfentanyl (42). Bista et al. reports there is no predictive correlation between saliva and plasma concentrations due to the lack of an obvious relationship between the two (41, 42). Heiskanen et al. reports an oral fluid to plasma ratio of 3.0 for fentanyl, also indicating the possibility of active transport, but also states large individual variation (19). For the purposes of this study, the assumption was made that 100% of the unbound fraction of fentanyl in the blood would transfer to the oral fluid and that no active transport occurs. Additionally, the potential impact of saliva pH was not evaluated.

Conclusion

This preliminary study demonstrates that the use of a sterile foam-tipped swab rinsed in PBS is an acceptable alternate to traditional collection devices for the detection of fentanyl in infants. Despite the limited number of samples, this study still provides useful and relevant information. Oral fluid has the potential to create a rapid, non-invasive method of detection of drugs in neonates and infants, which can be used to diagnose opioid exposure and risk for NAS prior to the onset of symptoms. This collection has the potential to be used for the evaluation of neonate and infant pharmacokinetics, including steady-state determination, therapeutic drug monitoring, and accidental drug exposure.

Acknowledgements

All samples were collected under VCU IRB number HM20006070.

Contributor Information

Ashley M Gesseck, Integrative Life Sciences Doctoral Program, Virginia Commonwealth University, PO Box 84230, Richmond, VA 23284-0203, USA; Department of Forensic Science, Virginia Commonwealth University, PO Box 843079, Richmond, VA 23284-3079, USA.

Justin L Poklis, Department of Pharmacology & Toxicology, Virginia Commonwealth University, PO Box 980613, Richmond, VA 23298-0613, USA.

Carl E Wolf, Department of Forensic Science, Virginia Commonwealth University, PO Box 843079, Richmond, VA 23284-3079, USA; Department of Pathology, Virginia Commonwealth University, PO Box 980662, Richmond, VA 23298-0662, USA.

Jie Xu, Division of Neonatal Medicine, Department of Pediatrics, Children’s Hospital of Richmond at VCU, Virginia Commonwealth University School of Medicine, PO Box 980646, Richmond, VA 23298-0646, USA.

Aamir Bashir, Division of Neonatal Medicine, Department of Pediatrics, Children’s Hospital of Richmond at VCU, Virginia Commonwealth University School of Medicine, PO Box 980646, Richmond, VA 23298-0646, USA.

Karen D Hendricks-Muñoz, Division of Neonatal Medicine, Department of Pediatrics, Children’s Hospital of Richmond at VCU, Virginia Commonwealth University School of Medicine, PO Box 980646, Richmond, VA 23298-0646, USA.

Michelle R Peace, Department of Forensic Science, Virginia Commonwealth University, PO Box 843079, Richmond, VA 23284-3079, USA.

Funding

This project was supported by Award No. 2016-DN-BX-0150, awarded by the National Institute of Justice, Office of Justice Programs, U.S. Department of Justice and the National Institutes of Health Award No. P30DA033934.

Conflicts of Interest

The authors have no conflict of interest with this work.

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