Improved Detection of Opioid Use in Chronic Pain Patients through Monitoring of Opioid Glucuronides in Urine

When chronic pain patients are suspected of being non-compliant, their therapy can be withdrawn. Therefore, sensitive and specific confirmatory testing is important for identifying diversion and adherence. This work aimed to develop a novel liquid chromatography tandem mass spectrometry (LC-MS-MS) method to detect 14 opioids and six opioid glucuronide metabolites in urine with minimal sample preparation. Analytes included were morphine, oxymorphone, hydromorphone, oxycodone, hydrocodone, codeine, fentanyl, norfentanyl, 6-monoacetylmorphine, meperidine, normeperidine, propoxyphene, methadone, buprenorphine, morphine-3-glucuronide, morphine-6-glucuronide, oxymorphone glucuronide, hydromorphone glucuronide, codeine-6-glucuronide and norbuprenorphine glucuronide. Samples were processed by centrifugation and diluted in equal volume with a deuterated internal standard containing 14 opioids and four opioid glucuronides. The separation of all compounds was complete in nine minutes. The assay was linear between 10 and 1,000 ng/mL (fentanyl 0.25-25 ng/mL). Intra-assay imprecision (500 ng/mL, fentanyl 12.5 ng/mL) ranged from 1.0 to 8.4% coefficient of variation. Inter-assay precision ranged from 2.9 to 6.0%. Recovery was determined by spiking five patient specimens with opioid and opioid glucuronide standards at 100 ng/mL (fentanyl 2.5 ng/mL). Recoveries ranged from 82 to 107% (median 98.9%). The method correlated with our current quantitative LC-MS-MS assay for opioids, which employs different chromatography. Internal standards were not available for every analyte to critically evaluate for ion suppression. Instead, a novel approach was designed to achieve the most rigorous quality control possible, in which the recovery of each analyte was evaluated in each negative sample.     

Possible effects of normetabolites on the subjective and reinforcing characteristics of opioids in animals and man.

When an opioid capable of forming active metabolites is administered, the total pharmacology is the result of interactions of the opioid and such metabolites, especially normetabolites. Normetabolites may affect the morphine-like characteristics of certain opioids and thus influence their reinforcement in animals and man. Most opioids, when administered in single doses, are positively reinforcing in addicts. Oral administration, as compared with parenteral, facilitates the formation of normetabolites. When chronically administered, many opioids, including acetylmethadol, meperidine, morphine, codeine, propoxyphene, and levorphanol, show evidence of a longer half-life for their normetabolites. Normetabolites may have aversive characteristics and thus impair positive reinforcement of the parent drug in animals and man. For example, addicts do not like chronic oral morphine or chronic oral codeine. Conversely, methadone, the normetabolites of which are inactive, is well accepted during chronic oral administration. Drugs which inhibit N-demethylation will increase the agonist potency of opioids having inactive normetabolites (e.g., methadone) but will decrease the agonist potency of opioids having more potent normetabolites than the parent (e.g., acetylmethadol). The divergent responses of addicts to single doses of opiates as compared with chronic doses indicate that chronic addiction tests in man are needed befored relative abuse liability can be predicted.     

Possible influence of opioid normetabolites on the onset,magnitude and quality of the opioid abstinence syndrome

Dependence is viewed as a dynamic state which may be altered with time respecting pattern, magnitude and quality of physical dependence, due in part to the interaction of the parent opioid with its normetabolites. The principal metabolites of acetylmethadol are noracetylmethadol and dinor-acetylmethadol; they are active morphine-like agonists, and their long half-life and accumulation in the plasma apparently account for the delayed onset of abstinence (72 h) after the acetylmethadol is withdrawn. The normetabolites of propoxyphene, norpropoxyphene and dinorpropoxyphene, are very weak morphine-like agonists. Because they accumulate in the plasma in a high ratio compared with the parent compound, they may well account, at least in part, for the relatively mild abstinence that follows propoxyphene withdrawal. Normeperidine is inactive as a morphine-like agonist and appears to have a different action in that it primarily is a convulsant. Although the formation and accumulation of normeperidine may account in part for the characteristics of its abstinence syndrome, undoubtedly a dominant factor is the disappearance of meperidine from the blood plasma (70% per hour in the dog and 17% per hour in man). In the case of normorphine, norcodeine and norlevorphanol, there is difficulty in direct addiction tests in man in elevating the dosage as compared to the parent compound, primarily because of excessive sedation and respiratory depression. Examination of the source of abstinence scores for subcutaneous normorphine, oral norcodeine, oral codeine, oral morphine, subcutaneous morphine, and oral methadone suggests that these compounds may be divided into two categories. Normorphine and norcodeine are in one category and methadone is in the other, probably because of methadone's incapacity to form active normetabolites. The relevance of the observations to comparative studies of abuse of opioids is illustrated.     

Oral fluid drug testing of chronic pain patients. I. Positive prevalence rates of licit and illicit drugs

Oral fluid compliance monitoring of chronic pain patients is an analytical challenge because of the limited specimen volume and the number of drugs that require detection. This study evaluated oral fluid for monitoring pain patients and compared results to urine studies of similar populations. Oral fluid specimens were analyzed from 6441 pain patients from 231 pain clinics in 20 states. Specimens were screened with 14 ELISA assays and non-negative specimens were confirmed by LC-MS-MS for 40 licit and illicit drugs and metabolites. There was an 83.9% positive screening rate (n=5401) of which 98.7% (n=5329) were confirmed at ≥ LOQ concentrations for at least one analyte. The prevalence of confirmed positive drug groups was as follows: opiates > oxycodone > benzodiazepines > methadone ≈ carisoprodol > fentanyl > cannabinoids ≈ tramadol > cocaine > amphetamines ≈ propoxyphene ≈ buprenorphine > barbiturates > methamphetamine. Approximately 11.5% of the study population of pain patients apparently used one or more illicit drugs (cannabis, cocaine, methamphetamine and/or MDMA). Overall, the pattern of licit and illicit drugs and metabolites observed in oral fluid paralleled results reported earlier for urine, indicating that oral fluid is a viable option for use in compliance monitoring programs of chronic pain patients.     

Enzyme immunoassay validation for the detection of buprenorphine in urine

A solid-phase enzyme immunoassay involving microtiter plates was proposed by Microgenics to screen buprenorphine in urine. The intra-assay precision at 10 ng/mL was 7.7% (coefficient of variation). The immunoassay was determined to have no cross-reactivity with codeine, dihydrocodeine, morphine, ethylmorphine, 6-monoacetylmorphine, methadone, pholcodine, propoxyphene, dextromoramide, and dextromethorphan at 1 and 10 mg/L. A low cross-reactivity (3% at 1 ng/mL) was observed at low concentrations of norbuprenorphine. After comparing this new immunological test (Singlestep ELISA) for 76 urine specimens with our validated high-performance liquid chromatography-electrospray mass spectrometry (HPLC-ES-MS) procedure, an optimum cutoff concentration of 2 ng/mL was determined for the kit. At this cutoff, the screening assay was able to determine more than 90% of true results with 43.4% true positives and 48.7% true negatives. Four positive urines (5.3%) were not confirmed by HPLC-ES-MS. In only one case, the negative urine test was confirmed as positive by HPLC-ES-MS (buprenorphine: 62.5 ng/mL). Buprenorphine concentrations determined by HPLC-ES-MS ranged from 1.2 to 1052 ng/mL. Of the four potential adulterants (hypochloride 50 mL/L, sodium nitrite 50 g/L, liquid soap 50 mL/L, and sodium chloride 50 g/L) that might be added to a positive urine specimen, none were able to cause a false-negative response by the immunoassay. The results of this study support the concept that the Singlestep ELISA for buprenorphine determination in urine should be considered as a new, valided screening procedure.     

Uniform assessment and ranking of opioid μ receptor binding constants for selected opioid drugs

The safe disposal of unused opioid drugs is an area of regulatory concern. While toilet flushing is recommended for some drugs to prevent accidental exposure, there is a need for data that can support a more consistent disposal policy based on an assessment of relative risk. For drugs acting at the Mu-opioid receptor (MOR), published measurements of binding affinity (K(i)) are incomplete and inconsistent due to differences in methodology and assay system, leading to a wide range of values for the same drug thus precluding a simple and meaningful relative ranking of drug potency. Experiments were conducted to obtain K(i)'s for 19 approved opioid drugs using a single binding assay in a cell membrane preparation expressing recombinant human MOR. The K(i) values obtained ranged from 0.1380 nM (sufentanil) to 12.486 μM (tramadol). The drugs were separated into three categories based upon their K(i) values: K(i) > 100 nM (tramadol, codeine, meperidine, propoxyphene and pentazocine), K(i)=1-100 nM (hydrocodone, oxycodone, diphenoxylate, alfentanil, methadone, nalbuphine, fentanyl and morphine) and K(i) < 1 nM (butorphanol, levorphanol, oxymorphone, hydromorphone, buprenorphine and sufentanil). These data add to the understanding of the pharmacology of opioid drugs and support the development of a more consistent labeling policies regarding safe disposal.     

Effects of renal insufficiency on the pharmacokinetics and pharmacodynamics of opioid analgesics

The disposition and pharmacologic activities of morphine, meperidine, methadone, propoxyphene, dihydrocodeine, and codeine are reviewed. Dose-related toxicities of these opioid analgesics include mental obtundation, respiratory depression, and hypotension. Furthermore, convulsions have been associated with normeperidine and cardiac toxicities with norpropoxyphene. Hepatic metabolism is the primary route of elimination, except for methadone, for which there is also significant renal excretion. Although the pharmacokinetics of morphine are unchanged in renal insufficiency, accumulation of active metabolites may lead to narcosis. Similar accumulation of normeperidine and norpropoxyphene, metabolites of meperidine and propoxyphene, respectively, as well as propoxyphene itself, and dihydrocodeine and codeine may explain reports of adverse reactions in patients with impaired renal function. A high index of suspicion of opioid-induced toxicities should be maintained in patients who have renal dysfunction and receive opioids.     

Validation of the Immunalysis microplate ELISA for the detection of buprenorphine and its metabolite norbuprenorphine in urine

The purpose of this study was to validate the Immunalysis Buprenorphine Microplate enzyme-linked immunosorbent assay (ELISA) for the detection of buprenorphine in urine samples. Sixty-nine urine samples were obtained from volunteers on the Subutex treatment program and from routine samples submitted to the laboratory for buprenorphine testing. For ELISA analysis, samples were diluted 1:10 with K(2)HPO(4) (0.1M, pH 7.0). The limit of detection was calculated as 0.5 ng/mL buprenorphine. The intra-assay and interday precision was 3.8% (n = 10) and 8.6% (n = 50) respectively at 1 ng/mL buprenorphine. At a low concentration of norbuprenorphine (1 ng/mL), the immunoassay demonstrated a cross-reactivity of 78%. A higher cross-reactivity of 116% was observed at a higher concentration of norbuprenorphine (10 ng/mL). Dihydrocodeine, codeine, tramadol, morphine, propoxyphene, methadone, and EDDP were tested at concentrations of 10 ng/mL and 10,000 ng/mL and demonstrated no cross-reactivity with the assay. For liquid chromatography-tandem mass spectrometry (LC-MS-MS), deuterated internal standard mixture, 1M acetate buffer (pH 5.0), and b-glucuronidase were added to the standards and samples, which were then incubated for 3 h at 60 degrees C. After incubation, 3 mL K(2)HPO(4) (0.1M, pH 6.0) was added and the pH altered to pH 6.0 using 1M KOH. Buprenorphine and norbuprenorphine were subsequently extracted by solid-phase. Twenty-one samples were confirmed positive and 48 samples were confirmed negative by LC-MS-MS. Using a cut-off value of 0.5 ng/mL buprenorphine, the immunoassay demonstrated a sensitivity and specificity of 100%.     

Retention rate and illicit opioid use during methadone maintenance interventions: a meta-analysis

The efficacy of methadone maintenance in opioid addiction was assessed in terms of programme retention rate and reduction of illicit opioid use by means of a meta-analysis of randomised, controlled and double blind clinical trials. The results were compared with interventions using buprenorphine and levo-acetylmethadol (LAAM). Trials were identified from the PubMed database from 1966 to December 1999 using the major medical subject headings 'methadone' and 'randomised controlled trial'. Data for a total of 1944 opioid-dependent patients from 13 studies were analysed. Sixty-four percent of patients received methadone, administered either as fixed or adjusted doses. Thus, 890 patients received > or = 50 mg/day (high dose group) and 392 were given < 50 mg/day (low dose group). Of 662 controls, 131 received placebo, 350 buprenorphine (265 at doses > or = 8 mg/day and 85 at doses < 8 mg/day) and 181 LAAM. High doses of methadone were more effective than low doses in the reduction of illicit opioid use (odds ratio [OR] 1.72, 95% confidence interval [CI] 1.26--2.36). High doses of methadone were significantly more effective than low doses of buprenorphine (< 8 mg/day) for retention rates and illicit opioid use, but similar to high doses of buprenorphine (> or = 8 mg/day) for both parameters. Patients treated with LAAM had more risk of failure of retention than those receiving high doses of methadone (OR 1.92, 95% CI 1.32--2.78). It is proposed that in agonist-maintenance programmes, oral methadone at doses of 50 mg/day or higher is the drug of choice for opioid dependence.     

Sensitization and tolerance to the discriminative stimulus effects of mu-opioid agonists

The discriminative stimulus effects of several μ-opioid agonists were examined under conditions of opioid sensitization or tolerance, i.e., before and after 1-week SC infusions of naloxone or μ-opioid agonists. Rats were trained to discriminate 3.0 mg/kg morphine from saline using a two-lever, discrete trial, shock-avoidance/escape procedure. The rats generalized completely to morphine, fentanyl, meperidine, buprenorphine, and etorphine, and partially to pentazocine. A 7-day infusion of naloxone (0.3 mg/kg per h) potentiated the discriminative stimulus effects of all of these drugs. The magnitude of the increased potency varied indirectly with the efficacy of the μ-opioid agonists; potency ratios (pre-infusion ED₅₀/post-infusion ED₅₀) ranged from 1.58 (etorphine) to 3.58 (pentazocine). Stimulus generalization to morphine, fentanyl, and meperidine also was examined following infusions of equieffective doses of each of these three drugs. Differences among drugs were generally small, and failed to reach statistical significance. Nonetheless, the induction of μ-opioid tolerance did seem to vary with the efficacy of the three μ-opioid agonists. Thus, meperidine (6.25 mg/kg per h), which has the lowest efficacy of the drugs infused, produced the greatest shift to the right of the stimulus-generalization curves of these three drugs; the post-meperidine PR ranged between 0.40 and 0.61. Fentanyl (0.1 mg/kg per h), a drug with a higher efficacy at μ-opioid receptors, did not produce tolerance to the discriminative stimulus effects of morphine, fentanyl, or meperidine; potency ratios ranged from 0.50 to 0.75. Potency ratios for buprenorphine, etorphine, fentanyl, meperidine, and morphine after 7-day morphine infusions (0.75 mg/kg per h) ranged from 0.38 (buprenorphine) to 0.80 (etorphine). Morphine induced significant tolerance only to the discriminative stimulus effects of fentanyl. Our results suggest that different cellular mechanisms underlie the development of tolerance and sensitization to the discriminative stimulus effects of μ-opioid agonists.     

Urine concentrations of fentanyl and norfentanyl during application of Duragesic transdermal patches

A study of the urinary concentration of fentanyl (F) and its major metabolite norfentanyl (NF) in chronic pain patients treated with the Duragesic continuous release transdermal patches is presented. These patches are available in 10, 20, 30, and 40 cm(2) sizes releasing 25, 50, 75, and 100 microg/h F, respectively. F is rapidly and extensively metabolized, with NF as the major metabolite. Five hundred-forty six random urine specimens were collected from chronic pain patients wearing 25, 50, 75, or 100 ug F transdermal patches. Urine specimens were collected from hours after application to several days later after continuous F release. Each specimen was analyzed for F, NF, creatinine, and pH. Additionally, each was screened by enzyme immunoassay for the following: amphetamines, barbiturates, benzodiazepines, cocaine metabolite, methadone, phencyclidine, d-propoxyphene, opiates, and marijuana metabolites. All positive screening results were confirmed by gas chromatography-mass spectrometry (GC-MS). F and NF were isolated from urine by solid-phase extraction then identified and quantified by GC-MS in SIM mode. The LODs and LOQs for F and NF were 3 ng/mL, respectively. The results of F and NF analysis of urine form those wearing 25-microg patches (N = 142) was mean F, 47 ng/mL with a range of 0 to 983 ng/mL, and 97% of the specimens contained < 200 ng/mL and mean NF, 175 ng/mL with a range of 0-980 ng/mL, while 95% of the specimens contained < 400 ng/mL. The results of F and NF analysis of urine form those wearing 50 microg patches (N = 184) was: mean F, 74 ng/mL with a range of 0 to 589 ng/mL, and 92% of the specimens contained < 200 ng/mL and mean NF, 257 ng/mL with a range of 0-2200 ng/mL, and 98% of the specimens contained < 1000 ng/mL. The results of F and NF analysis of urine form those wearing 75 microg patches (N = 85) was mean F, 107 ng/mL with a range of 0 to 1280 ng/mL, and 98% of the specimens contained < 400 ng/mL and mean NF, 328 ng/mL with a range of 0-5630 ng/mL, and 99% of the specimens contained < 1000 ng/mL. The results of F and NF analysis of urine form those wearing 100 ug patches (N = 135) was mean F, 100 ng/mL with a range of 0 to 1080 ng/mL, while 96% of the specimens contained < 400 ng/mL and mean NF, 373 ng/mL with a range of 0-5730 ng/mL, and 95% of the specimens contained < 1000 ng/mL. The incidence of other drugs detected as a percentage the specimens was opiates, 48%, benzodiazepines, 43%; barbiturates, 3%; methadone, 4%; marijuana metabolite, 3%; and cocaine metabolite, 1%. With the exception of F and/or NF, no other drugs were detected in 25% of the specimens. These data demonstrate the wide variation in concentrations of F and NF in random urine specimens following application of Duragesic patches. However, these values obtained during therapeutic use far exceed concentrations previously reported in fatal poisoning. In general, one may expect to find urine NF concentrations 3-4 times higher than those of F.     

Opioid Addicts at Admission vs. Slow-Release Oral Morphine,Methadone, and Sublingual Buprenorphine Maintenance Treatment Participants

With use of a randomized study design, quality of life (QOL) and physical symptoms of opioid addicts at admission were compared with slow-release oral morphine, methadone, and sublingual buprenorphine maintenance program participants after 6 months of treatment. The study was conducted from February to July 2004 in the outpatient drug user treatment center at University Department of Psychiatry at Innsbruck, providing maintenance treatment programs and detoxification in Tyrol, Austria. One hundred twenty opioid users seeking treatment were compared with 120 opioid-dependent patients retained for 6 months on a slow-release oral morphine, methadone, or sublingual buprenorphine maintenance program. The German version (“Berlin Quality of Life Profile”) of the Lancashire Quality of Life Profile was used, and illicit opioid use was determined by urinalysis. Physical symptoms were measured by using the Opioid Withdrawal Scale. Urinalyses revealed a significantly lower consumption of cocaine and opioids in all three substitution groups than in patients at admission (p < 0.001 and p ≤ 0.004, respectively). Both the buprenorphine and the methadone maintenance group showed significantly more favorable values than opioid clients at admission for stomach cramps (p ≤ 0.002), muscular tension (p ≤ 0.027), general pain (p ≤ 0.001), feelings of coldness (p ≤ 0.000), heart pounding (p ≤ 0.008), runny eyes (p ≤ 0.047), and aggressions (p ≤ 0.009). Patients who received slow-release oral morphine treatment generally showed the least favorable QOL scores compared with patients at admission or sublingual buprenorphine and methadone clients. Patients in the sublingual buprenorphine or methadone program showed nearly the same QOL scores. The buprenorphine and the methadone maintenance group showed significantly more favorable values than opioid clients at admission regarding leisure time (p ≤ 0.019), finances (p ≤ 0.014), mental health (p ≤ 0.010), and overall satisfaction (p ≤ 0.010). Slow-release oral morphine is a well-established treatment for pain, but more research is required to evaluate it as a treatment for heroin dependence. The present data indicate that slow-release oral morphine could have some disadvantages compared with sublingual buprenorphine and methadone in QOL, physical symptoms, and additional consumption. The results further suggest that buprenorphine treatment is as effective as methadone in effects on quality of life and physical symptoms.     

Opioid addicts at admission vs. slow-release oral morphine, methadone, and sublingual buprenorphine maintenance treatment participants

With use of a randomized study design, quality of life (QOL) and physical symptoms of opioid addicts at admission were compared with slow-release oral morphine, methadone, and sublingual buprenorphine maintenance program participants after 6 months of treatment. The study was conducted from February to July 2004 in the outpatient drug user treatment center at University Department of Psychiatry at Innsbruck, providing maintenance treatment programs and detoxification in Tyrol, Austria. One hundred twenty opioid users seeking treatment were compared with 120 opioid-dependent patients retained for 6 months on a slow-release oral morphine, methadone, or sublingual buprenorphine maintenance program. The German version ("Berlin Quality of Life Profile") of the Lancashire Quality of Life Profile was used, and illicit opioid use was determined by urinalysis. Physical symptoms were measured by using the Opioid Withdrawal Scale. Urinalyses revealed a significantly lower consumption of cocaine and opioids in all three substitution groups than in patients at admission (p < 0.001 and p < or = 0.004, respectively). Both the buprenorphine and the methadone maintenance group showed significantly more favorable values than opioid clients at admission for stomach cramps (p < or = 0.002), muscular tension (p < or = 0.027), general pain (p < or = 0.001), feelings of coldness (p < or = 0.000), heart pounding (p < or = 0.008), runny eyes (p < or = 0.047), and aggressions (p < or = 0.009). Patients who received slow-release oral morphine treatment generally showed the least favorable QOL scores compared with patients at admission or sublingual buprenorphine and methadone clients. Patients in the sublingual buprenorphine or methadone program showed nearly the same QOL scores. The buprenorphine and the methadone maintenance group showed significantly more favorable values than opioid clients at admission regarding leisure time (p < or = 0.019), finances (p < or = 0.014), mental health (p < or = 0.010), and overall satisfaction (p < or = 0.010). Slow-release oral morphine is a well-established treatment for pain, but more research is required to evaluate it as a treatment for heroin dependence. The present data indicate that slow-release oral morphine could have some disadvantages compared with sublingual buprenorphine and methadone in QOL, physical symptoms, and additional consumption. The results further suggest that buprenorphine treatment is as effective as methadone in effects on quality of life and physical symptoms.     

Evidence of morphine metabolism to hydromorphone in pain patients chronically treated with morphine

Minor metabolic pathways in human subjects have been shown to exist for the conversion of codeine to hydrocodone but have not been reported for the metabolic conversion of morphine to hydromorphone. In this study, urine specimens were collected in an out-patient setting from 13 pain patients who were chronically treated with morphine and other opioids (methadone, oxycodone, and fentanyl). The chronic pain patients were chosen for study because they were treated with high-dose morphine and had no personal or family history of addiction. Results of the initial evaluation and follow up of these patients with random urine tests did not indicate opioid misuse. The specimens were analyzed by GC-MS for the presence of hydromorphone. The reporting limit for hydromorphone was 100 ng/mL. Ten of the 13 morphine-treated patients excreted hydromorphone in minor amounts ranging 120 to 1400 ng/mL. Concurrent morphine concentrations were exceedingly high in these 10 patients and frequently exceeded the upper limit of linearity (> 10,000 ng/mL) of the assay. The ratio of hydromorphone to morphine ranged from 0.015 to 0.024. Morphine concentrations in the three patients in which hydromorphone was not detected tended to be lower than those observed in other patients. For comparison, one additional patient was included in the study, who was prescribed both morphine and hydromorphone. Concentrations of hydromorphone in this patient were in the range of 3400-13,000 ng/mL, while concurrent morphine concentrations were in the range of 3200-6600 ng/mL. These data are highly suggestive that hydromorphone can be produced as a minor metabolite of morphine in humans. Although additional studies in more restricted settings are needed, it is recommended that interpretation of low urinary concentrations of hydromorphone in combination with high concentrations of morphine in morphine-treated pain patients should not be considered as conclusive evidence of hydromorphone misuse.     

Effects of buprenorphine and methadone in methadone-maintained subjects

Buprenorphine, a partial mu opioid agonist, is an experimental medication under development for the treatment of opioid dependence as an alternative to methadone maintenance. The present study examined the relationship between level of opioid physical dependence and response to buprenorphine administration as part of a program to develop procedures for transferring patients from methadone to buprenorphine treatment. This laboratory study characterized the agonist and antagonist effects of acute doses of buprenorphine and methadone in subjects maintained on either 30 (n=7) or 60 (n=6) mg/day oral methadone. Test doses of placebo [sl. and PO), methadone (15, 30, and 60 mg PO) and buprenorphine (2, 4, and 8 mg sl.) were administered to volunteers residing on a closed residential unit. Subjective, physiological, observer-rated, and cognitive/psychomotor measures were collected for 6.5 h after test doses. Test doses of methadone, but not buprenorphine, constricted pupils and produced dose-related increases on subjective report measures reflecting opioid agonist drug effects. Agonist effects of methadone were more prominent in the 30 mg than in the 60 mg methadone maintenance condition. Buprenorphine, but not methadone, precipitated opioid withdrawal signs and symptoms that were more prominent in the 60 mg than in the 30 mg methadone maintenance condition. These findings suggest that abrupt transition from methadone to buprenorphine may produce patient discomfort that is positively related to both methadone maintenance dose and buprenorphine transition dose.     

Urinary buprenorphine concentrations in patients treated with suboxone as determined by liquid chromatography-mass spectrometry and CEDIA immunoassay

We report on the utility of urine total buprenorphine, total norbuprenorphine, and creatinine concentrations in patients treated with Suboxone (a formulation containing buprenorphine and naloxone), used increasingly for the maintenance or detoxification of patients dependent on opiates such as heroin or oxycodone. Patients received 8-24 mg/day buprenorphine. Two-hundred sixteen urine samples from 70 patients were analyzed for both total buprenorphine and total norbuprenorphine by liquid chromatography-mass spectrometry (LC-MS-MS). Buprenorphine concentrations in all 176 samples judged to be unadulterated averaged 164 ng/mL, with a standard deviation (SD) of 198 ng/mL. Nine samples (4.2%) had metabolite-parent drug ratios < 0.02, and 33 (15.3%) had no detectable buprenorphine. The metabolite/parent drug ratio in 166 samples had a range of 0.07-23.0 (mean = 4.52; SD = 3.97). Fifteen of 96 available urine samples (16.7%) had creatinine less than 20 mg/dL. We also found sample adulteration in 7 (7.3%) available samples. Using a 5 ng/mL urine buprenorphine cutoff, the sensitivity and specificity of the Microgenics homogeneous enzyme immunoassay versus LC-MS-MS were 100% and 87.5%, respectively. The 5 ng/mL cutoff Microgenics CEDIA buprenorphine assay results agreed analytically with LC-MS-MS in 97.9% of samples.     

A new highly specific buprenorphine immunoassay for monitoring buprenorphine compliance and abuse

Urine buprenorphine screening is utilized to assess buprenorphine compliance and to detect illicit use. Robust screening assays should be specific for buprenorphine without cross-reactivity with other opioids, which are frequently present in patients treated for opioid addiction and chronic pain. We evaluated the new Lin-Zhi urine buprenorphine enzyme immunoassay (EIA) as a potentially more specific alternative to the Microgenics cloned enzyme donor immunoassay (CEDIA) by using 149 urines originating from patients treated for chronic pain and opioid addiction. The EIA methodology offered specific detection of buprenorphine use (100%) (106/106) and provided superior overall agreement with liquid chromatography-tandem mass spectrometry, 95% (142/149) and 91% (135/149) using 5 ng/mL (EIA[5]) and 10 ng/mL (EIA[10]) cutoffs, respectively, compared to CEDIA, 79% (117/149). CEDIA generated 27 false positives, most of which were observed in patients positive for other opioids, providing an overall specificity of 75% (79/106). CEDIA also demonstrated interference from structurally unrelated drugs, chloroquine and hydroxychloroquine. CEDIA and EIA[5] yielded similar sensitivities, both detecting 96% (22/23) of positive samples from patients prescribed buprenorphine, and 88% (38/43) and 81% (35/43), respectively, of all positive samples (illicit and prescribed users). The EIA methodology provides highly specific and sensitive detection of buprenorphine use, without the potential for opioid cross-reactivity.     

Initiation of injectable opioid agonist treatment in hospital: A case report

Uncontrolled opioid withdrawal and pain often drive inpatients with opioid use disorder to leave hospital against medical advice, resulting in suboptimal medical and addiction treatment. When oral opioid agonist treatments such as methadone and buprenorphine/naloxone fail for management of craving and withdrawal, injectable opioid agonist treatment may serve to retain patients in care and link them to addiction services. We describe the case of a 47‐year‐old man with a severe, active opioid use disorder and daily use of illicitly manufactured fentanyl, who was re‐admitted to hospital for post‐operative management after leaving against medical advice due to uncontrolled opioid withdrawal. Intravenous hydromorphone was used to retain him in care, allowing for completion of his antibiotics and enrolment in ongoing community injectable opioid agonist treatment.     

Buprenorphine versus methadone in the treatment of opioid-dependent cocaine users

This study compared the efficacy of buprenorphine to methadone for decreasing cocaine use in patients with combined opioid and cocaine use. Participants (n=51) were enrolled in a 26-week treatment program and randomly assigned to either buprenorphine or methadone. Dosing was double-blind and double-dummy. Patients were stabilized on either 8 mg sublingual buprenorphine or 50 mg oral methadone, with dose increases given in response to continued illicit cocaine use or opioid use through week 16 of treatment. Maximum doses possible were 16 mg buprenorphine and 90 mg methadone. Average doses achieved were 11.2 mg buprenorphine and 66.6 mg methadone; 49% of the patients received the maximum doses possible. Urine samples were collected three times per week, and there was no significant difference in the rate of cocaine positive urines for the intent-to-treat sample (69% for buprenorphine versus 63% for methadone). For patients who remained in treatment through the flexible dosing period (n=28), there were significant decreases in cocaine positive urines over time (P<0.01), but no significant differences between groups or group × time effects. Buprenorphine and methadone were equally effective on measures of treatment retention, urine results for opioids, and compliance with attendance and counseling. These results demonstrate no selective efficacy of either buprenorphine or methadone in attenuating cocaine use in this population, but do provide further support for the equivalent efficacy of buprenorphine and methadone in the treatment of opioid dependence.Presented at the 55th Annual Scientific Meeting, The College on Problems of Drug Dependence, Toronto, Canada (Mune 17, 1993)