Rifampin Reduces the Plasma Concentrations of Oral and Intravenous Hydromorphone in Healthy Volunteers.

BACKGROUND: Several opioids are metabolized by the inducible cytochrome P450 (CYP) 3A isozymes. Coadministration with strong inducers of drug metabolism, such as rifampin, can dramatically reduce systemic exposure to these opioids. As the CYP metabolism of hydromorphone is of minor importance, we studied in healthy volunteers whether hydromorphone would be an effective analgesic for patients who concomitantly receive the prototypical enzyme inducer rifampin. METHODS: In this paired, randomized, crossover study, 12 participants received oral placebo or rifampin for 8 days. Oral hydromorphone (2.6 mg) was administered on day 6 followed by intravenous hydromorphone (0.02 mg/kg) on day 8. Hydromorphone and hydromorphone-3-glucuronide (HM3G) plasma concentrations were measured for 24 hours and psychomotor responses, including perceived drug effect, change in pupil diameter, and cold pressor threshold were evaluated for 6 hours. Our primary outcome was the change in the area under the concentration-time curve (AUC0-last) of oral and intravenous hydromorphone after pretreatment with rifampin or placebo. Pharmacodynamic parameters and other pharmacokinetic parameters were analyzed as secondary outcomes. RESULTS: Rifampin reduced the AUC0-last of oral and intravenous hydromorphone by 43% (ratio to control: 0.57, 90% confidence interval [CI], 0.50-0.65) and 26% (ratio to control: 0.74, 90% CI, 0.69-0.79), respectively. The maximum concentration of oral hydromorphone was reduced by 37% (ratio to control: 0.63, 90% CI, 0.55-0.72), and oral bioavailability decreased from 33% to 26% (ratio to control: 0.78, 90% CI, 0.67-0.91) in the rifampin phase compared with placebo. The HM3G-to-hydromorphone ratio increased by 50% (90% CI, 25-79) and 42% (90% CI, 29-55) after oral and intravenous hydromorphone, respectively. Rifampin did not significantly affect the pharmacodynamic parameters. CONCLUSIONS: Rifampin significantly reduces the concentrations of oral and intravenous hydromorphone. This interaction is due to an increase in the first-pass and systemic metabolism of hydromorphone, likely involving induction of uridine 5'-diphospho- glucuronosyltransferase enzymes by rifampin. The enhancement of hydromorphone elimination should be considered when managing pain of patients who are treated with strong enzyme inducers.

Prospective Association of Serum Opioid Levels and Clinical Outcomes in Patients With Cancer Pain Treated With Intrathecal Opioid Therapy.

BACKGROUND: Opioids remain the mainstay of cancer pain management but are associated with systemic toxicity. In refractory cancer pain, intrathecal therapy (ITT) is associated with improved pain control, reduced systemic side effects, and improved survival. It has been assumed that ITT decreases systemic serum opioid levels and their associated toxicity, but there are limited data to support this assumption. This study hypothesizes that serum opioid levels decrease with ITT. Secondary objectives include comparative measures of pain, bowel function, and other cancer-related symptoms. METHODS: Fifty-one cancer patients undergoing ITT for cancer pain were recruited in a prospective observational study. Daily oral morphine equivalency (OME) dose, serum opioid levels, Brief Pain Inventory (BPI), MD Anderson Symptom Inventory (MDASI), and a constipation questionnaire were obtained at the time of implant, and 4 and 8 weeks postoperatively. RESULTS: Average baseline daily OME was 375 mg (median, 240; interquartile range, 150-405; range, 0-3160), mean serum morphine concentration was 53.7 ng/mL (n = 17), and mean oxycodone concentration was 73.7 ng/mL (n = 20). At 4 weeks, 87.5% of patients had discontinued non-IT opioids, and 53% had undetectable (<2 ng/mL) serum opioid concentrations. At 8 weeks, 92% remained off all non-IT opioids and 59% had undetectable serum opioid levels. IT morphine doses >4.2 mg/d were invariably associated with detectable serum levels; with doses <4.2 mg, morphine was undetectable in 80% of subjects. IT hydromorphone doses >6.8 mg/d were detectable in the serum. Using linear mixed model analyses, there were statistically significant decreases in the mean "worst pain," "average pain," and MD Anderson symptom severity and interference scores at 4 and 8 weeks. This change was independent of serum opioid levels; when analyzed separately, there was no difference in the pain scores of subjects with detectable serum opioid levels compared to those with undetectable levels at 4 and 8 weeks. Constipation ranked as "quite a bit" or "very much" decreased from 58.7% to 19.2% of subjects at week 4 (P < .001) and to 37.5% at 8 weeks (P = .23). A very low complication rate was observed. CONCLUSIONS: ITT for cancer pain was associated with a marked reduction in serum opioid concentrations, with the majority of patients having undetectable serum levels. Reducing serum opioid concentrations in cancer patients may have implications with respect to restoring bowel function, improving fatigue, and promoting the integrity of antitumor immune function and warrants further study.

Development of a method for the determination of hydromorphone in plasma by LC-MS.

A simple high-performance liquid chromatography method for the determination of hydromorphone in small volume plasma has been developed. Following solid-phase extraction using Oasis HLB cartridges, samples were separated by reverse-phase high-performance liquid chromatography on an Atlantis T3 4.6 × 150 mm column (3.0 µm) and quantified using mass spectrometry. The mobile phase was a mixture of water with 0.1% formic acid and acetonitrile with 0.1% formic acid (91:9). The standard curve ranged from 1 to 500 ng/mL. Intra- and Inter-assay variability for hydromorphone was <10%, and the average recovery was >90%. The LLOQ was 1 ng/mL. This method was successfully applied to the analysis of hydromorphone samples at this institution. This method could be useful to those investigators dealing with small sample volumes, particularly when conducting pharmacokinetic studies that require multiple sampling from the same animal.

Patient-controlled Analgesia with Target-controlled Infusion of Hydromorphone in Postoperative Pain Therapy.

BACKGROUND: Patient-controlled analgesia (PCA) is a common method for postoperative pain therapy, but it is characterized by large variation of plasma concentrations. PCA with target-controlled infusion (TCI-PCA) may be an alternative. In a previous analysis, the authors developed a pharmacokinetic model for hydromorphone. In this secondary analysis, the authors investigated the feasibility and efficacy of TCI-PCA for postoperative pain therapy with hydromorphone. METHODS: Fifty adult patients undergoing cardiac surgery were enrolled in this study. Postoperatively, hydromorphone was applied intravenously during three sequential periods: (1) as TCI with plasma target concentrations of 1 to 2 ng/ml until extubation; (2) as TCI-PCA with plasma target concentrations between 0.8 and 10 ng/ml during the following 6 to 8 h; and (3) thereafter as PCA with a bolus dose of 0.2 mg until the next morning. During TCI-PCA, pain was regularly assessed using the 11-point numerical rating scale (NRS). A pharmacokinetic/pharmacodynamic model was developed using ordinal logistic regression based on measured plasma concentrations. RESULTS: Data of 43 patients aged 40 to 81 yr were analyzed. The hydromorphone dose during TCI-PCA was 0.26 mg/h (0.07 to 0.93 mg/h). The maximum plasma target concentration during TCI-PCA was 2.3 ng/ml (0.9 to 7.0 ng/ml). The NRS score under deep inspiration was less than 5 in 83% of the ratings. Nausea was present in 30%, vomiting in 9%, and respiratory insufficiency in 5% of the patients. The EC50 of hydromorphone for NRS of 4 or less was 4.1 ng/ml (0.6 to 12.8 ng/ml). CONCLUSION: TCI-PCA with hydromorphone offered satisfactory postoperative pain therapy with moderate side effects.

Pharmacokinetics of ammonium sulfate gradient loaded liposome-encapsulated oxymorphone and hydromorphone in healthy dogs.

OBJECTIVE: To evaluate the pharmacokinetics, in dogs, of liposome-encapsulated oxymorphone and hydromorphone made by the ammonium sulfate gradient loading technique (ASG). ANIMALS: Four healthy purpose-bred Beagles aged 9.5 ± 3.2 months and weighing 13.4 ± 2.3 kg. STUDY DESIGN: Randomized cross-over design. METHODS: Each dog was given either 4.0 mg kg(-1) of ASG-oxymorphone or 8.0 mg kg(-1) of ASG-hydromorphone SC on separate occasions with a 3-month washout period. Blood was collected at baseline and at serial time points up to 1032 hours (43 days) after injection for determination of serum opioid concentrations. Serum opioid concentrations were measured with HPLC-MS and pharmacokinetic parameters were calculated using commercial software and non-compartmental methods. RESULTS: Serum concentrations of oxymorphone remained above the limit of quantification for 21 days, while those for hydromorphone remained above the limit of quantification for 29 days. Cmax for ASG-oxymorphone was 7.5 ng mL(-1) ; Cmax for ASG-hydromorphone was 5.7 ng mL(-1) . CONCLUSIONS AND CLINICAL RELEVANCE: Oxymorphone and hydromorphone, when encapsulated into liposomes using the ammonium sulfate gradient loading technique, result in measureable serum concentrations for between 3 to 4 weeks. This formulation may have promise in the convenient use of opioids for clinical treatment of chronically painful conditions in dogs.

Pharmacokinetics of a controlled-release liposome-encapsulated hydromorphone administered to healthy dogs.

The purpose of the study was to assess the pharmacokinetics of liposome-encapsulated (DPPC-C) hydromorphone administered intravenously (IV) or subcutaneously (SC) to dogs. A total of eight healthy Beagles aged 12.13 +/- 1.2 months and weighing 11.72 +/- 1.10 kg were used. Dogs randomly received liposome encapsulated hydromorphone, 0.5 mg/kg IV (n = 6), 1.0 mg/kg (n = 6), 2.0 mg/kg (n = 6), or 3.0 mg/kg (n = 7) SC with a 14-28 day washout between trials. Blood was sampled at serial intervals after drug administration. Serum hydromorphone concentrations were measured using liquid chromatography with mass spectrometry. Serum concentrations of hydromorphone decreased rapidly after IV administration of the DPPC-C formulation (half-life = 0.52 h, volume of distribution = 12.47 L/kg, serum clearance = 128.97 mL/min/kg). The half-life of hydromorphone after SC administration of DPPC-C formulation at 1.0, 2.0, and 3.0 mg/kg was 5.22, 31.48, and 24.05 h, respectively. The maximum serum concentration normalized for dose (C(MAX)/D) ranged between 19.41-24.96 ng/mL occurring at 0.18-0.27 h. Serum hydromorphone concentrations fluctuated around 4.0 ng/mL from 6-72 h after 2.0 mg/kg and mean concentrations remained above 4 ng/mL for 96 h after 3.0 mg/kg DPPC-C hydromorphone. Liposome-encapsulated hydromorphone (DPPC-C) administered SC to healthy dogs provided a sustained duration of serum hydromorphone concentrations.

Pharmacokinetics of hydromorphone hydrochloride in healthy dogs.

OBJECTIVE: To assess the pharmacokinetics of hydromorphone administered intravenously (IV) or subcutaneously (SC) to dogs. STUDY DESIGN: Randomized experimental trial. ANIMALS: Seven healthy male neutered Beagles aged 12.13 +/- 1.2 months and weighing 11.72 +/- 1.10 kg. METHODS: The study was a randomized Latin square block design. Dogs were randomly assigned to receive hydromorphone hydrochloride 0.1 mg kg(-1) or 0.5 mg kg(-1) IV (n = 4 dogs) or 0.1 mg kg(-1) (n = 6) or 0.5 mg kg(-1) (n = 5) SC on separate occasions with a minimum 14-day washout between experiments. Blood was sampled via a vascular access port at serial intervals after drug administration. Serum was analyzed by mass spectrometry. Pharmacokinetic parameters were determined with computer software. RESULTS: Serum concentrations of hydromorphone decreased quickly after both routes of administration of either dose. The serum half-life, clearance, and volume of distribution after IV hydromorphone at 0.1 mg kg(-1) were 0.57 hours (geometric mean), 106.28 mL minute(-1) kg(-1), and 5.35 L kg(-1), and at 0.5 mg kg(-1) were 1.00 hour, 60.30 mL minute(-1) kg(-1), and 5.23 L kg(-1), respectively. The serum half-life after SC hydromorphone at 0.1 mg kg(-1) and 0.5 mg kg(-1) was 0.66 hours and 1.11 hours, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Hydromorphone has a short half-life, suggesting that frequent dosing intervals are needed. Based on pharmacokinetic parameters calculated in this study, 0.1 mg kg(-1) IV or SC q 2 hours or a constant rate infusion of hydromorphone at 0.03 mg kg(-1) hour(-1) are suggested for future studies to assess the analgesic effect of hydromorphone.

Discordant Umbilical Cord Drug Testing Results in Monozygotic Twins.

Our laboratory received segments of umbilical cord that originated from identical twins for routine toxicology analysis. The specimens were analyzed multiple times by liquid chromatography tandem mass spectrometry. The umbilical cord from newborn #1 was positive for hydromorphone only (1.06 ng/g), and the umbilical cord from newborn #2 was positive for hydromorphone (0.81 ng/g) and benzoylecgonine (5.41 ng/g). The hydromorphone results are consistent with maternal administration of hydromorphone; however, the cause of the discrepant benzoylecgonine results in the umbilical cords from the identical twins is unknown.

Pharmacokinetic profile of a 24-hour controlled-release OROS formulation of hydromorphone in the presence and absence of food.

BACKGROUND: The objective of this study was to compare the pharmacokinetic profile of a novel, once-daily, controlled-release formulation of hydromorphone (OROS hydromorphone) under fasting conditions with that immediately after a high-fat breakfast in healthy volunteers. The effect of the opioid antagonist naltrexone on fasting hydromorphone pharmacokinetics also was evaluated. METHODS: In an open-label, three-way, crossover study, 30 healthy volunteers were randomized to receive a single dose of 16 mg OROS hydromorphone under fasting conditions, 16 mg OROS hydromorphone under fed conditions, or 16 mg OROS hydromorphone under fasting conditions with a naltrexone 50-mg block. Plasma samples taken pre-dose and at regular intervals up to 48 hours post-dose were assayed for hydromorphone concentrations. Analysis of variance was performed on log-transformed data; for mean ratios of 0.8 to 1.2 (20%), differences were considered minimal. Bioequivalence was reached if 90% confidence intervals (CI) of treatment mean ratios were between 80% and 125%. RESULTS: The mean geometric ratios of the fed and fasting treatment groups for maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-t; AUC0-infinity) were within 20%. Confidence intervals were within 80% to 125% for AUC0-t and AUC0-infinity but were slightly higher for Cmax (105.9% and 133.3%, respectively). With naltrexone block, the hydromorphone Cmax increased by 39% and the terminal half-life decreased by 4.5 hours. There was no significant change in Tmax, AUC0-t or AUC0-infinity. CONCLUSION: Standard bioavailability measures show minimal effect of food on the bioavailability of hydromorphone from OROS hydromorphone. Naltrexone co-administration results in a slight increase in the rate of absorption but not the extent of absorption.

External Validation of a Recently Developed Population Pharmacokinetic Model for Hydromorphone During Postoperative Pain Therapy.

BACKGROUND AND OBJECTIVE: We recently developed a new population pharmacokinetic model for hydromorphone in patients including age and bodyweight as covariates. The aim of the present study was to evaluate prospectively the predictive performance of this new model during postoperative pain therapy. METHODS: This was a prospective, single-blinded, randomized, single-center study with two parallel arms. Fifty patients aged 40-85 years undergoing cardiac surgery involving thoracotomy were enrolled. Hydromorphone was administered postoperatively on the intensive care unit as target controlled infusion (TCI) for patient controlled analgesia (TCI-PCA) using the new pharmacokinetic model, or as conventional patient controlled analgesia (PCA). Arterial blood samples were taken for measurement of the hydromorphone plasma concentration. The predictive performance of the pharmacokinetic model was assessed by the median performance error (MDPE), the median absolute performance error (MDAPE), wobble and divergence. For comparison, the performance indices were also determined for three older models from the literature. RESULTS: 903 plasma concentrations of 41 patients were analyzed. The mean values (95 % CI) of MDPE, MDAPE, wobble and divergence for the new pharmacokinetic model were 11.2 % (3.9 to 18.7 %), 28.5 % (23.9 to 33.0 %), 21.4 % (18.0 to 24.9 %) and -1.6 %/h (-2.3 to -0.8 %/h). When compared with older models from the literature, performance was better with less overshoot after bolus doses. CONCLUSION: The new pharmacokinetic model of hydromorphone showed a good precision and a better performance than older models. It is therefore suitable for TCI with hydromorphone during postoperative pain therapy. TRIAL REGISTRATION: EudraCT 2013-002875-16, Clinical Trials NCT02035709.

Hydromorphone-related fatalities in ontario.

The interpretation of drug intoxication in death investigations is based on the available published literature. In the case of hydromorphone, the literature is limited. This report serves to facilitate the evaluation of cases where hydromorphone may be implicated in a fatality through the examination of 251 hydromorphone-positive cases in the province of Ontario from 1985 to 2003. Thirty-three of these cases were selected for review in greater detail. In four cases in which hydromorphone was the sole drug detected and death was attributed to hydromorphone toxicity, concentrations ranged from 77 to 2684 ng/mL. Hydromorphone concentrations ranged from 21 to 441 ng/mL in 28 cases in which at least one other drug was detected. In five deaths attributed to natural causes, blood hydromorphone concentrations ranged from 75 to 423 ng/mL. The results of this study emphasize the importance of case specific information. Fatalities due to hydromorphone occurred at 51 ng/mL and greater; however, tolerant users of this drug, as seen in the deaths attributed to natural causes, may achieve incidental concentrations that would otherwise be considered fatal. Hydromorphone was detected and quantitated using gas chromatography-mass spectrometry.

GC-MS quantitation of codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, oxycodone, and oxymorphone in blood.

A method is described for the simultaneous analysis of seven opiates, codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, oxycodone, and oxymorphone, in blood samples by gas chromatography-mass spectrometry (GC-MS). One milliliter of blood is combined with an internal standard mixture containing 200 ng of each of the seven deuterated opiates. Two milliliters of acetonitrile is added to precipitate the proteins and cellular material. After centrifugation, the clear supernatant is removed, and the acetonitrile is evaporated. The remaining aqueous portion is adjusted to pH 9 with sodium bicarbonate buffer, and the drugs are extracted into chloroform/ trifluoroethanol (10:1). The organic extractant is transferred and dried under nitrogen. The residue is reconstituted in dilute hydrochloric acid and washed consecutively with hexane and chloroform. The purified aqueous portion is adjusted to pH 9 with bicarbonate buffer, and the drugs are again extracted into chloroform/trifluoroethanol (10:1). The organic portion is removed from the aqueous fraction and dried under nitrogen. The residue is consecutively derivatized with methoxyamine and propionic anhydride using pyridine as a catalyst. The ketone groups on hydrocodone, hydromorphone, oxycodone, and oxymorphone are converted to methoximes. Hydroxyl groups present at the O(3) and O(6) positions of codeine, morphine, 6-acetylmorphine, hydromorphone, and oxymorphone are converted to their respective propionyl esters. After a post-derivatization purification step, the extracts are analyzed by full scan GC-MS using electron impact ionization. The method is linear to at least 2000 ng/mL. Day-to-day precision (N = 15) at 500 ng/mL and 75 ng/mL were less than 10% for all seven targeted opiates. Extraction efficiencies at these two concentrations ranged from 50% to 68%. For each opiate, the limit of quantitation was 10 ng/mL, and the limit of detection was 2 ng/mL.

The development of a high-performance liquid chromatography-tandem mass spectrometric method for simultaneous quantification of morphine, morphine-3-ß-glucuronide, morphine-6-ß-glucuronide, hydromorphone, and normorphine in serum.

OBJECTIVES: Development and validation of a selective, robust high-performance liquid chromatography-tandem mass spectrometric (HPLC/MS-MS) method for the quantification of morphine, morphine-3-ß-glucuronide, morphine-6-ß-glucuronide, hydromorphone, and normorphine in human serum. DESIGN AND METHODS: Drug-free human serum samples spiked with morphine, morphine-3-ß-glucuronide, morphine-6-ß-glucuronide, hydromorphone, and normorphine were prepared by protein precipitation using methanol containing the internal standards. Samples were injected onto a Thermo Scientific AccuCore PFP column for chromatographic separation. Detection was achieved using a Thermo Scientific TSQ Vantage mass spectrometer. Assay validation followed the new Clinical and Laboratory Standards Institute (CLSI) C62-A guidelines. RESULTS: The analytical measuring range for all analytes was determined to be 5 to 1000 ng/mL. Intra- and inter-assay precision for three quality control levels were ≤ 7.0% and ≤ 13.5%, respectively. Carryover, stability, linearity, matrix effects, extraction and processing efficiency and method comparison characteristics were acceptable relative to the CLSI C62 guidelines. CONCLUSION: The validation of this HPLC-MS/MS method demonstrated a robust and rapid assay for the quantification of morphine, morphine-3-ß-glucuronide, morphine-6-ß-glucuronide, hydromorphone, and normorphine.

Single-dose evaluation of safety, tolerability and pharmacokinetics of newly formulated hydromorphone immediate-release and hydrophilic matrix extended-release tablets in healthy Japanese subjects without co-administration of an opioid antagonist.

This single dose, open-label study investigated the safety, tolerability and pharmacokinetics of single oral doses of newly formulated immediate-release (IR) and hydrophilic matrix extended-release (ER) hydromorphone tablets in healthy Japanese subjects without co-administration of an opioid antagonist under fasting and fed conditions. Plasma and urinary concentrations of hydromorphone and metabolites were measured by liquid-chromatography tandem mass-spectroscopy. Following administration of the ER tablet, plasma concentrations of hydromorphone slowly increased with a median tmax of 5.0 h and the Cmax decreased to 37% of the IR tablet, while the AUC0-inf was comparable with that of the IR tablet when administered at the same dose. The degree of fluctuation in the plasma concentration for the ER tablet was much lower than that of the IR tablet and certain levels of plasma concentrations were maintained after 24 h of ER dosing. The AUC0-inf and Cmax increased with food for both IR and ER tablets. The AUC0-inf of hydromorphone-3-glucoside was one-tenth of that of hydromorphone-3-glucuronide. A single oral administration of the hydromorphone tablets would be well-tolerated in healthy Japanese subjects despite a lack of co-administration of an opioid antagonist and the newly developed ER hydromorphone tablets may have the appropriate PK characteristics for once-daily dosing.

Pharmacokinetics of hydrocodone and tramadol administered for control of postoperative pain in dogs following tibial plateau leveling osteotomy.

OBJECTIVE: To evaluate the pharmacokinetics of hydrocodone (delivered in combination with acetaminophen) and tramadol in dogs undergoing tibial plateau leveling osteotomy (TPLO). ANIMALS: 50 client-owned dogs. PROCEDURES: Dogs were randomly assigned to receive tramadol hydrochloride (5 to 7 mg/kg, PO, q 8 h; tramadol group) or hydrocodone bitartrate-acetaminophen (0.5 to 0.6 mg of hydrocodone/kg, PO, q 8 h; hydrocodone group) following TPLO with standard anesthetic and surgical protocols. Blood samples were collected for pharmacokinetic analysis of study drugs and their metabolites over an 8-hour period beginning after the second dose of the study medication. RESULTS: The terminal half-life, maximum serum concentration, and time to maximum serum concentration for tramadol following naïve pooled modeling were 1.56 hours, 155.6 ng/mL, and 3.90 hours, respectively. Serum concentrations of the tramadol metabolite O-desmethyltramadol (M1) were low. For hydrocodone, maximum serum concentration determined by naïve pooled modeling was 7.90 ng/mL, and time to maximum serum concentration was 3.47 hours. The terminal half-life for hydrocodone was 15.85 hours, but was likely influenced by delayed drug absorption in some dogs and may not have been a robust estimate. Serum concentrations of hydromorphone were low. CONCLUSIONS AND CLINICAL RELEVANCE: The pharmacokinetics of tramadol and metabolites were similar to those in previous studies. Serum tramadol concentrations varied widely, and concentrations of the active M1 metabolite were low. Metabolism of hydrocodone to hydromorphone in dogs was poor. Further study is warranted to assess variables that affect metabolism and efficacy of these drugs in dogs.

Hydromorphone levels and pain control in patients with severe chronic pain.

To better understand the use of narcotic analgesics, the hydromorphone concentration was measured in serum samples from 43 patients with chronic severe pain who were receiving this drug. At the time of blood sampling, pain intensity, mood, and cognitive performance were assessed. There was large individual variation in the dose-drug level relationship. Seven patients with bone or soft tissue pain and drug levels of greater than or equal to 4 ng/ml had good pain control, whereas 10 did not. None of 15 patients with levels less than 4 ng/ml had pain control, despite drug doses similar to those given patients with higher levels. Thus 60% of the patients without control of their pain had hydromorphone levels below the lowest level that produced pain control. No patient with pain from nerve infiltration or compression had good pain control, irrespective of the drug level or dose. Poor mood correlated with high pain intensity and low drug level. Impaired cognitive performance was not related to drug level. Knowing that there is a low concentration of narcotic in the blood of a patient with chronic severe pain who is receiving high drug doses and who shows lack of both efficacy and side effects may reassure health care professionals that further narcotic dosage escalation is appropriate.

CSF and blood pharmacokinetics of hydromorphone and morphine following lumbar epidural administration.

Sixteen consenting patients scheduled for elective thoracotomy were enrolled into a randomized trial of epidural morphine and hydromorphone. Each patient had a lumbar epidural catheter placed preoperatively for the purpose of post-thoracotomy analgesia. Shortly before the end of the operative procedure each patient received 5 mg of morphine and 0.75 mg of hydromorphone via the epidural catheter. Blood was sampled at regular intervals following the opiate administration and patients were randomized to 1 of 7 cervical CSF sampling times. Blood and CSF samples were assayed for morphine and hydromorphone concentration to determine blood and CSF pharmacokinetic profiles. A maximum blood morphine concentration of 60 +/- 25 ng/ml (mean +/- S.D.) was obtained at 11 +/- 6 min (mean +/- S.D.). The blood hydromorphone peak of 14 +/- 13 ng/ml (mean +/- S.D.) occurred 8 +/- 6 min (mean +/- S.D.). The mean peak CSF opioid concentrations of 1581 ng/ml for morphine and 309 ng/ml for hydromorphone occurred 60 min after epidural administration. The blood and CSF pharmacokinetic profiles for morphine and hydromorphone are presented. These profiles are similar for the two drugs after lumbar epidural administration.

Hydromorphone transfer into breast milk after intranasal administration.

STUDY OBJECTIVES: To determine the distribution of hydromorphone into breast milk and the potential exposure of the suckling infant, and whether the distribution of hydromorphone into milk can be predicted accurately by a passive diffusion model. DESIGN: Single-dose, pharmacokinetic study. SETTING: University clinical research unit. PATIENTS: Eight lactating, nonsmoking, healthy women aged 24-32 years. INTERVENTION: Hydromorphone HCl 2 mg was given intranasally to the women to characterize its pharmacokinetics and extent of its transfer into breast milk. MEASUREMENTS AND MAIN RESULTS: Plasma and milk samples were analyzed using liquid chromatography with tandem mass spectrometry detection. The milk:plasma ratio (M:P) was calculated as the total area under the concentration-time curve (AUC) of the milk divided by the total AUC of the plasma. Predicted in vitro M:P ratios were calculated using a diffusion model. Protein binding in milk and plasma, partitioning into milk fat (whole milk:skim milk ratios), as well as pH partitioning between plasma and milk were incorporated in the model. Protein binding was determined by equilibrium dialysis. Protein binding was minimal in both milk and plasma, with unbound fractions of 1 and 0.84, respectively There was little partitioning into milk fat, as demonstrated by the whole milk:skim milk ratio of 0.98. The observed and predicted M:P ratios +/- SD for hydromorphone were 2.57 +/- 0.47 and 1.11 +/- 0.28, respectively. The 95% confidence interval for the observed M:P ratio overlapped the confidence interval of the predicted M:P ratio, a finding that supports a role for both passive diffusion and active transport as mechanisms of hydromorphone transfer into milk. CONCLUSION: Hydromorphone distributes rapidly from plasma into breast milk; however, the drug does not partition into fat. The suckling infant would receive approximately 0.67% of the maternal dose of hydromorphone (adjusted for body weight). As this is a limited exposure, further studies are needed to determine any potential impact to an infant who is fed breast milk from a mother treated with hydromorphone.

Effect of fluticasone propionate nasal spray on bioavailability of intranasal hydromorphone hydrochloride in patients with allergic rhinitis.

STUDY OBJECTIVE: To investigate the effect of the nasal corticosteroid fluticasone propionate on the bioavailability and pharmacokinetics of single-dose intranasal hydromorphone hydrochloride in patients with allergic rhinitis. DESIGN: Randomized, three-way, crossover pharmacokinetic study. SETTING: University clinical research unit. PATIENTS: Twelve patients with allergic rhinitis. INTERVENTION: Hydromorphone hydrochloride 2.0 mg was administered by intravenous infusion (treatment A), intranasal spray without allergic rhinitis treatment (treatment B), and intranasal spray after 6 days of fluticasone propionate (treatment C). Blood samples were collected serially from 0-16 hours. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetic parameters were determined by noncompartmental methods. An analysis of variance (ANOVA) model was used for statistical analysis. Mean (% coefficient of variation) absolute bioavailability of intranasal hydromorphone was 51.9% (28.2) and 46.9% (30.3) in patients with allergic rhinitis with and without treatment with fluticasone propionate, respectively. Mean maximum concentration (Cmax) values were 3.02 and 3.56 ng/ml, respectively. No statistical differences in Cmax and area under the concentration versus time curve were detected between intranasal treatments. Bioavailability values for both intranasal treatments were lower than those in healthy volunteers (57%). Median time to Cmax (Tmax) values were significantly different (p=0.02) for treatments B and C (15 and 30 min, respectively) using rank-transformed Tmax for ANOVA. Adverse effects were consistent with known effects of hydromorphone administered by other routes, with the exception of bad taste after intranasal administration. CONCLUSION: Hydromorphone was rapidly absorbed after nasal administration, with maximum concentrations occurring for most subjects within 30 minutes. Allergic rhinitis may affect pain management strategies for intranasal hydromorphone, with a delay in onset of action for patients treated with fluticasone propionate.

Simultaneous determination of hydrocodone and hydromorphone in human plasma by liquid chromatography with tandem mass spectrometric detection.

A rapid, sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS-MS) method has been developed and validated for the simultaneous analysis of hydrocodone (HYC) and its metabolite hydromorphone (HYM) in human plasma. A robotic liquid handler and a 96-channel liquid handling workstation were used to aliquot samples, to add internal standard (I.S.), and to extract analytes of interest. A 96-well mixed-mode solid-phase cartridge plate was used to extract the analytes and I.S. The chromatographic separation was on a silica column (50 x 3 mm, 5-microm) with a mobile phase consisting of acetonitrile, water and trifluoroacetic acid (TFA) (92:8:0.01, v/v). The run time for each injection was 2.5 min with the retention times of approximately 2.1 and 2.2 min for HYC and HYM, respectively. The tandem mass spectrometric detection was by monitoring singly charged precursor-->product ion transition 300-->199 (m/z) for HYC, and 28-->185 (m/z) for HYM. The validated calibration curve range was 0.100-100 ng/ml, based on a plasma volume of 0.3 ml. The correlation coefficients were greater than or equal to 0.9996 for both HYC and HYM. The low limit of quantitation (LLOQ) was 0.100 ng/ml for both HYC and HYM with signal-to-noise ratio (S/N) of 50 and 10. respectively. The deuterated analytes, used as internal standards, were monitored at mass transitions 303-->199 (m/z) for HYC-d3 and 289-->185 (m/z) for HYM-d3. The inter-day (n= 17) precision of the quality control (QC) samples were < or = 3.5% RSD (relative standard deviation) for HYC and < or = 4.7% RSD for HYM, respectively. The inter-day accuracy of the QC samples were < or = 2.1% RE (relative error) for HYC and < or = 1.8% RE for HYM. The intra-day (n=6) precision and accuracy of the QC samples were < or = 2.6% RSD and < or = 3.0% RE for HYC, and < or = 4.7% RSD and < or = 2.4% RE for HYM. There was no significant deviation from the nominal values after a 5-fold dilution of high concentration QC samples by blank matrix. The QC samples were stable when kept at room temperature for 24-h or experienced three freeze-thaw cycles. The extraction recoveries were 86% for HYC and 78% for HYM. No detectable carryover was observed when a blank sample was injected immediately after a 2500 ng/ml sample that was 25-fold more concentrated than the upper limit of quantitation (ULOQ).