Anne Z. DePriest

Prescription Opioids. III. Disposition of Oxycodone in Oral Fluid and Blood Following Controlled Single-Dose Administration

Oxycodone (OC) is recommended to be included as an analyte tested in the proposed Substance Abuse and Mental Health Services Administration (SAMHSAs) Mandatory Guidelines for Federal Workplace Drug Testing Programs using Oral Fluid (OF) Specimens. This study demonstrates the time course of OC and metabolites, noroxycodone (NOC), oxymorphone (OM) and noroxymorphone (NOM), in near-simultaneous paired OF and whole blood (BL) specimens by liquid chromatography-tandem mass spectrometry (LC-MS-MS) (limit of detection = 1 ng/mL OF, 5 ng/mL BL). A single dose of OC 20 mg controlled-release was administered to 12 healthy subjects followed by specimen collections for 52 h. Analyte prevalence was as follows: OF, OC > NOC > OM; and BL, OC > NOC > NOM. OC and NOC were frequently detected within 15-30 min in OF and 30 min to 2 h in BL. NOM and OM appeared between 1.5-5 h post-dose. The mean OF-to-BL (OF:BL) ratios and correlations were 5.4 for OC (r = 0.719) and 1.0 for NOC (r = 0.651). The period of detection for OF exceeded BL by ∼2-fold at similar cutoff concentrations. At a 1 ng/mL cutoff for OF, the mean detection time was 34 h for OC and NOC. These data provide new information that should facilitate interpretation of OC test results.

Urine Drug Testing of Chronic Pain Patients. V. Prevalence of Propoxyphene Following its Withdrawal from the United States Market

Propoxyphene is an opioid analgesic that was surrounded by controversy concerning its safety and efficacy during its lifespan in the US market. Propoxyphene was withdrawn in November of 2010 from the US market and is still being detected one year post-withdrawal in urine specimens from the pain management population. In this study, the prevalence of propoxyphene was determined in a total of 417,914 urine specimens collected from 630 clinics involved in pain management located in 24 states during the period of January 1, 2010, through December 31, 2011. Propoxyphene and norpropoxyphene were measured in urine by a validated liquid chromatography-tandem mass spectrometry procedure with a lower limit of quantitation of 50 ng/mL. The positivity rate for propoxyphene prevalence declined sharply between November and December of 2010 and further declined at a gradual rate, ending in a prevalence of 0.27% (one out of every 370 specimens, n = 25,658) for the month of December 2011. The presented data provide evidence of the dramatic decline in the use of propoxyphene products since their removal from the medical market, and may be beneficial to US urine drug testing programs determining the need for continual monitoring of propoxyphene levels.

Prevalence of heroin markers in urine for pain management patients.

Surveys of current trends indicate heroin abuse is associated with nonmedical use of pain relievers. Consequently, there is an interest in evaluating the presence of heroin-specific markers in chronic pain patients who are prescribed controlled substances. A total of 926,084 urine specimens from chronic pain patients were tested for heroin/diacetylmorphine (DAM), 6-acetylmorphine (6AM), 6-acetylcodeine (6AC), codeine (COD), and morphine (MOR). Heroin and markers were analyzed using liquid chromatography tandem mass spectrometry (LC-MS-MS). Opiates were analyzed following hydrolysis using LC-MS-MS. The prevalence of heroin use was 0.31%, as 2871 were positive for one or more heroin-specific markers including DAM, 6AM, or 6AC (a known contaminant of illicit heroin). Of these, 1884 were additionally tested for the following markers of illicit drug use: 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), methamphetamine (MAMP), 11-nor-9-carboxy-Δ(9)-tetracannabinol (THCCOOH), and benzoylecgonine (BZE); 654 (34.7%) had positive findings for one or more of these analytes. The overall prevalence of heroin markers were as follows: DAM 1203 (41.9%), 6AM 2570 (89.5%), 6AC 1082 (37.7%). MOR was present in 2194 (76.4%) and absent (<LOQ) in 677 (23.6%) of the heroin-positive specimens. COD was present in 1218 (42.4%) specimens. Prevalence of combinations for specimens containing MOR were as follows: DAM only 13 (0.59%), 6AM only 1140 (52.0%), 6AC only 24 (1.1%), DAM/6AM/6AC 710 (32.4%), 6AM/6AC 188 (8.6%), DAM/6AM 113 (5.2%), DAM/6AC 6 (0.27%). Importantly, the prevalence of combinations for specimens without MOR were as follows: DAM only 161 (23.8%), 6AM only 217 (32.1%), 6AC only 92 (13.6%), DAM/6AM/6AC 50 (7.4%), 6AM/6AC 7 (1.0%), DAM/6AM 145 (21.4%), DAM/6AC 5 (0.74%). Unexpected patterns of excretion were observed, such as the presence of DAM and 6AC in the absence of 6AM and MOR; therefore, multiple heroin markers may be useful to assess for heroin use.

Prescribing Opioids for Chronic Noncancer Pain in Primary Care: Risk Assessment

Abstract The use of opioids for patients with chronic noncancer pain has increased dramatically, and with increasing use there is increasing concern about the potential for abuse and addiction during long-term treatment. Clinicians should avoid viewing formal or subjective risk assessment as a means of classifying patients into 2 distinct categories: compliant patients and substance abusers. The provider who perceives a patient as compliant may have a complacent attitude toward aberrant drug-related behavior, presuming that these signs reflect inadequately controlled pain, to be addressed by dose escalation. The provider who perceives a patient as a substance abuser may refuse to provide treatment for pain, leaving the patient to seek either illicit drugs or prescribed treatment from another provider. In fact, in seemingly compliant patients, any noncompliant use of opioids presents a safety risk regardless of the explanations offered. Even in known or suspected drug abusers, chronic pain warrants the use of adequate pharmacotherapy, although treatment in such cases may exclude drugs with high abuse potential. Thus, all aberrant drug-related behavior should be addressed within a treatment plan that combines adequate pain care with suitable interventions for the aberrant behavior, following current best practice strategies. This approach is consistent with the approach taken with other health conditions, such as diabetes or hypertension, for which it is understood that noncompliance with therapy presents a risk of harm.

Determining Zolpidem Compliance: Urinary Metabolite Detection and Prevalence in Chronic Pain Patients

Zolpidem (Ambien(®)) is the most prescribed insomnia treatment in the USA; however, little is known about zolpidem metabolite excretion in chronic pain patients. As zolpidem is extensively metabolized in vivo to zolpidem 4-phenyl carboxylic acid (ZCA), metabolite detection may provide improved accuracy for compliance determinations, thereby improving clinical decisions. Zolpidem and ZCA were extracted from 1 mL human urine by mixed-mode solid-phase extraction. Samples were analyzed by LC-MS-MS using positive electrospray ionization with multiple reaction monitoring mode employed for detection and quantification. Gradient chromatographic separation was achieved with a reversed-phase column in a rapid 1.8 min analysis. The assay was linear from 4 to 1,000 µg/L for zolpidem and 4 to 10,000 µg/L for ZCA. Interday recovery (bias) and imprecision (n = 20) were 100-107% of target and 2.4-3.7% relative standard deviation, respectively. Extraction efficiencies were 78-90%. Pain compliance samples (n = 3,142) were de-identified and analyzed for zolpidem and ZCA. Zolpidem was detected greater than limit of quantification in 720 specimens (22.9%), while ZCA was detected in 1,579 specimens (50.3%). Only five specimens contained zolpidem alone. ZCA was observed without parent zolpidem in 864 specimens, thereby increasing population detection rates by 27.5%. Addition of a zolpidem metabolite to compliance determinations substantially improved detection for zolpidem intake and also should prove useful in clinical and forensic settings.

Risks and responsibilities in prescribing opioids for chronic noncancer pain, part 2: best practices.

Abstract Opioids are increasingly prescribed to provide effective therapy for chronic noncancer pain, but increased use also means an increased risk of abuse. Primary care physicians treating patients with chronic noncancer pain are concerned about adverse events and risk of abuse and dependence associated with opioids, yet many prescribers do not follow established guidelines for the use of these agents, either through unawareness or in the mistaken belief that urine toxicology testing is all that is needed to monitor compliance and thwart abuse. Although there is no foolproof way to identify an abuser and prevent abuse, the best way to minimize the risk of abuse is to follow established guidelines for the use of opioids. These guidelines entail a careful assessment of the patient, the painful condition to be treated, and the estimated level of risk of abuse based on several factors: history of abuse and current or past psychiatric disorders; design of a therapeutic regimen that includes both pharmacotherapeutic and nonpharmacologic modalities; a formal written agreement with the patient that defines treatment expectations and responsibilities; selection of an appropriate agent, including consideration of formulations designed to deter tampering and abuse; initiation of treatment at a low dosage with titration in gradual increments as needed to achieve effective analgesia; regular reassessment to watch for signs of abuse, to perform drug monitoring, and to adjust medication as needed; and established protocols for actions to be taken in case of suspected abuse. By following these guidelines, physicians can prescribe opioids to provide effective analgesia while reducing the likelihood of abuse.

Prescription Opioids. VI. Metabolism and Excretion of Hydromorphone in Urine Following Controlled Single-Dose Administration

Oxymorphone (OM), a prescription opioid and metabolite of oxycodone, was included in the recently published proposed revisions to the Mandatory Guidelines for Federal Workplace Drug Testing Programs. To facilitate toxicological interpretation, this study characterized the time course of OM and its metabolite, noroxymorphone (NOM), in hydrolyzed and non-hydrolyzed urine specimens. Twelve healthy subjects were administered a single 10 mg controlled-release OM dose, followed by a periodic collection of pooled urine specimens for 54 h following administration. Analysis for free and total OM and NOM was conducted by liquid chromatography tandem mass spectrometry (LC-MS-MS), at a 50 ng/mL limit of quantitation (LOQ). Following enzymatic hydrolysis, OM and NOM were detected in 89.9% and 13.5% specimens, respectively. Without hydrolysis, OM was detected in 8.1% specimens, and NOM was not detected. The mean ratio of hydrolyzed OM to NOM was 41.6. OM was frequently detected in the first pooled collection 0-2 h post-dose, appearing at a mean of 2.4 h. NOM appeared at a mean of 8.3 h. The period of detection at the 50 ng/mL threshold averaged 50.7 h for OM and 11.0 h for NOM. These data support that OM analysis conducted using a 50 ng/mL threshold should include hydrolysis or optimize sensitivity for conjugated OM.

Pseudoephedrine and False-Positive Immunoassay Urine Drug Tests for Amphetamine

We would like to address an erroneous assertion in the review article entitled “Drug Testing in the Workplace” by Dr. Phan and colleagues regarding urinary excretion of pseudoephedrine and its propensity for causing false-positive immunoassay screening results. The authors have underestimated the risk of false-positives from pseudoephedrine ingestion with the Microgenics (Fremont, CA) cloned enzyme donor immunoassay (CEDIA) for amphetamine and Ecstasy due to a high cross-reactive threshold (pseudoephedrine concentration of 160,000 ng/ml), citing a mean pseudoephedrine concentration in fatal overdoses of 105,000 ng/ml. The authors concluded that employers may “confidently make the correct decision to deny employment based only on the CEDIA urine drug test results.” However, the reference they cited for these data published the concentration not as a mean, but as a single case. That same reference cites urine concentrations up to 291,000 ng/ml after single doses used commonly in clinical practice. Pseudoephedrine concentrations of 2,500,000 ng/ml have been reported in the Department of Defense drug testing program. In our laboratory testing of 1855 student and professional athletes, urinary pseudoephedrine concentrations ranged from 813–6,670,097 ng/ml (median 56,200 ng/ml). The risk of false-positive amphetamine immunoassay results from pseudoephedrine has been well established. 6 A false-positive rate of 75% was reported with the Microgenics DRI amphetamine-methamphetamine immunoassay due to presence of pseudoephedrine in 1104 urine samples. Many of these false-positives occurred at concentrations far below the published pseudoephedrine threshold, indicating that cross-reactivity in human specimens is sometimes greater than the limits reported by the manufacturer. Interpreting a “fatal” range of concentrations in urine is problematic. Given the estimated time course of excretion, urine concentrations may not reflect the current clinical state and may be quite low or absent in cases of acute overdose. Thus, we advise any employer or medical practitioner to exercise caution when interpreting nonnegative immunoassay results, as falsepositive results can and do occur.