Plasma Hydromorphone Concentrations Research Articles

Pharmacokinetics of a continuous intravenous infusion of hydromorphone in healthy dogs.

Dosing recommendations for hydromorphone intravenous constant rate infusion (IV CRI) are derived from simulations following IV bolus administration. While this extrapolated dose regimen has been described clinically, pharmacokinetics (PK) of hydromorphone infusions in dogs are not yet described. The study objective was to describe the PK of hydromorphone in healthy dogs receiving an IV bolus followed by an IV CRI for 48 h. A prospective, experimental study was performed involving the administration of hydromorphone (0.1 mg/kg IV bolus then IV CRI 0.01 mg/kg/h over a 48 h period) to 6 healthy Beagle dogs. Blood samples were collected at 16 time points between 0 and 58 h relative to the initial bolus. Plasma hydromorphone concentrations were analyzed by high pressure liquid chromatography with tandem mass spectrometry detection. Pharmacokinetic parameter estimates were obtained with compartmental methods using commercially available software. A two-compartment model with first order elimination was used. At the end of the infusion, median (range) plasma hydromorphone concentrations were 6.8 (5.5-19.6) ng/mL. The median total body clearance was 30.4 (19.8-36.7) mL/min/kg; volume of distribution at steady state was 4.5 (3.2-7.8) L/kg; and terminal elimination half-life was 11.2 (7.6-24.3) h. Hydromorphone (0.1 mg/kg IV bolus then IV CRI of 0.01 mg/kg/h) maintained steady-state plasma concentrations above the minimum human analgesic target in healthy Beagle dogs with minimal side effects. Further studies are needed to determine the effective plasma concentrations of hydromorphone in painful dogs.

Pharmacokinetics of hydrorphone hydrochloride after intravenous and subcutaneous administration in ferrets (Mustela putorius furo)

ObjectiveTo determine the pharmacokinetic profile of hydromorphone 0.2 mg kg–1 administered by the intravenous (IV) and subcutaneous (SC) route in ferrets. Study designRandomized, crossover study. AnimalsA group of eight adult ferrets weighting (mean ± standard deviation) 1.02 ± 0.22 kg. MethodsHydromorphone hydrochloride 0.2 mg kg–1 was administered IV or SC with a washout period of 7 days. Blood samples were collected from a jugular catheter before administration of hydromorphone and at 5, 10, 15, 20, 30, 45, 60, 90, 120, 240, 360, 480 and 720 minutes after hydromorphone administration. Plasma hydromorphone concentrations were determined by liquid chromatography/tandem mass spectrometry. Data were analyzed using a non-linear mixed effects model. ResultsThe hydromorphone effective half-life was (t1/2) 45 min–1. Systemic clearance (Cls) and the volume of distribution (Vdss) following IV administration were 84.8 mL kg–1 min–1 and 5.59 L kg–1, respectively. The maximum observed plasma concentration was 59.53 ± 14.02 ng mL–1 within 10 minutes following SC administration. The SC bioavailability was 102.0%. Conclusions and clinical relevanceAdministration of IV and SC hydromorphone (0.2 mg kg–1) was characterized by a high clearance, short terminal half-life and large volume of distribution. Hydromorphone plasma concentrations remained greater than 2 ng mL–1 for 2 hours in most ferrets, a threshold reported to provide antinociceptive effects in other species. Hydromorphone was well absorbed following SC injection, providing an alternative administration route for clinical use in ferrets.

Comparison of hydromorphone and butorphanol for management of pain in equine patients undergoing elective arthroscopy: a randomized clinical trial

ObjectiveTo compare the effects of hydromorphone and butorphanol in horses undergoing arthroscopy and describe the pharmacokinetics of hydromorphone in anesthetized horses. Study designRandomized controlled clinical trial. AnimalsA total of 40 adult horses admitted for elective arthroscopy. MethodsHorses were randomly assigned to be administered intravenous hydromorphone (0.04 mg kg–1; group TxH; n = 19) or butorphanol (0.02 mg kg–1; group TxB; n = 21) prior to surgery as part of a standardized anesthetic protocol. Pain was scored by two observers unaware of group assignment using the Equine Utrecht University Scale for Facial Assessment of Pain (EQUUS-FAP) and a composite pain scale (CPS) prior to surgery (baseline), 2 hours (P2) and 4 hours (P4) following recovery from anesthesia. Blood samples were collected at various time points for determination of plasma hydromorphone concentration using liquid chromatography–tandem mass spectrometry. Data were analyzed with a mixed-effect model. ResultsMedian (range) baseline EQUUS-FAP was 1.2 (0.0–4.0) with no effect of group, time points or interaction. Baseline CPS was similar between groups. Group TxH baseline CPS was 2.5 (0.0–10.0), increased at P2 [4.5 (0–10.0); p = 0.046] and returned to baseline values at P4 [3.0 (0.0–11.0)]. Group TxB baseline CPS was 2.0 (0.0–8.0), increased at P2 [3.5 (0.0–11.0); p = 0.009] and P4 [5.0 (0.0–11.0); p < 0.001]. Pharmacokinetic terminal half-life was 774 ± 82.3 minutes, area under the curve was 1362 ± 314 ng minutes mL–1, clearance was 30.7 ± 7.23 mL minute–1 kg–1 and volume of distribution at steady state was 884 ± 740 mL kg–1. ConclusionsHydromorphone, but not butorphanol, decreased CPS back to baseline at P4 after recovery. Clinical relevanceHydromorphone may provide superior postoperative analgesia compared with butorphanol in horses undergoing arthroscopy.

Pharmacokinetics of hydromorphone hydrochloride after intramuscular and intravenous administration of a single dose to orange-winged Amazon parrots (Amazona amazonica).

To evaluate the pharmacokinetics of hydromorphone hydrochloride after IM and IV administration to orange-winged Amazon parrots (Amazona amazonica). 8 orange-winged Amazon parrots (4 males and 4 females). Hydromorphone (1 mg/kg) was administered once IM. Blood samples were collected 5 minutes and 0.5, 1.5, 2, 3, 6, and 9 hours after drug administration. Plasma hydromorphone concentrations were determined with liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were calculated with a compartmental model. The experiment was repeated 1 month later with the same dose of hydromorphone administered IV. Plasma hydromorphone concentrations were > 1 ng/mL for 6 hours in 8 of 8 and 6 of 7 parrots after IM and IV injection, respectively. After IM administration, mean bioavailability was 97.6%, and mean maximum plasma concentration was 179.1 ng/mL 17 minutes after injection. Mean volume of distribution and plasma drug clearance were 4.24 L/kg and 64.2 mL/min/kg, respectively, after IV administration. Mean elimination half-lives were 1.74 and 1.45 hours after IM and IV administration, respectively. Hydromorphone hydrochloride had high bioavailability and rapid elimination after IM administration, with rapid plasma clearance and a large volume of distribution after IV administration in orange-winged Amazon parrots. Drug elimination half-lives were short. Further pharmacokinetic studies of hydromorphone and its metabolites, including investigation of multiple doses, different routes of administration, and sustained-release formulations, are recommended.

Pharmacokinetics of hydromorphone hydrochloride after intravenous and intramuscular administration in guinea pigs (Cavia porcellus).

To determine the pharmacokinetics of hydromorphone hydrochloride after IV and IM administration in guinea pigs (Cavia porcellus). 8 healthy adult guinea pigs (4 sexually intact females and 4 sexually intact males). In a crossover study, hydromorphone (0.3 mg/kg) was administered once IM (epaxial musculature) or IV (cephalic catheter) to each guinea pig at a 1-week interval (2 treatments/guinea pig). Blood samples were collected before and at predetermined intervals after drug administration via a vascular access port. Plasma hydromorphone concentrations were determined by liquid chromatography-tandem mass spectrometry. Noncompartmental analysis of data was used to calculate pharmacokinetic parameters. Mean ± SD clearance and volume of distribution for hydromorphone administered IV were 52.8 ± 13.5 mL/min/kg and 2.39 ± 0.479 L/kg, respectively. Mean residence time determined for the IV and IM administration routes was 0.77 ± 0.14 hours and 0.99 ± 0.34 hours, respectively. The maximum observed plasma concentration following IM administration of hydromorphone was 171.9 ± 29.4 ng/mL. No sedative effects were observed after drug administration by either route. Pharmacokinetic data indicated that hydromorphone at a dose of 0.3 mg/kg may be administered IV every 2 to 3 hours or IM every 4 to 5 hours to maintain a target plasma concentration between 2 and 4 ng/mL in guinea pigs. Hydromorphone had high bioavailability after IM administration. Further research is necessary to evaluate the effects of other doses and administration routes and the analgesic effects of hydromorphone in guinea pigs.

Lack of Influence by CYP3A4 and CYP3A5 Genotypes on Pain Relief by Hydrocodone in Postoperative Cesarean Section Pain Management.

Genetic polymorphisms of cytochrome P450 are contributors to variability in individual response to drugs. Within the P450 family, CYP2D6 is responsible for metabolizing hydrocodone, a widely prescribed opioid for pain management. Alternatively, CYP3A4 and CYP3A5 can form norhydrocodone and dihydrocodeine. We have previously found that in a postcesarean section cohort, the rate of hydromorphone formation was dependent on the genotype of CYP2D6 and that plasma hydromorphone, not hydrocodone, was predictive of pain relief. Blood was obtained from a postcesarean cohort that were surveyed for pain response and common side effects. Plasma samples were genotyped for CYP3A4/5, and their hydrocodone concentrations were measured by LC-MS. R statistical software was used to check for differences in the outcomes due to CYP3A4/5 and CYP2D6, and a multivariate regression model was fit to determine factors associated with pain score. Two-way ANOVA between CYP3A4/A5 and CYP2D6 phenotypes revealed that the former variants did not have a statistical significance on the outcomes, and only CYP2D6 phenotypes had a significant effect on total dosage (P = 0.041). Furthermore, a 3-way ANOVA analysis showed that CYP2D6 (P = 0.036) had a predictive effect on plasma hydromorphone concentrations, and CYP3A4/A5 did not have any effect on the measured outcomes. With respect to total dosages in a cesarean section population, these results confirm that CYP2D6 phenotypes are predictors for plasma hydromorphone concentration and pain relief, but CYP3A4/A5 phenotypes have no influence on pain relief or on side effects.

Evaluation of the thermal antinociceptive effects and pharmacokinetics of hydromorphone hydrochloride after intramuscular administration to cockatiels (Nymphicus hollandicus).

OBJECTIVE To evaluate the thermal antinociceptive effects and pharmacokinetics of hydromorphone hydrochloride after IM administration to cockatiels (Nymphicus hollandicus). ANIMALS 16 healthy adult cockatiels. PROCEDURES During the first of 2 study phases, each cockatiel received each of 4 treatments (hydromorphone at doses of 0.1, 0.3, and 0.6 mg/kg and saline [0.9% NaCl] solution [0.33 mL/kg; control], IM), with a 14-day interval between treatments. For each bird, foot withdrawal to a thermal stimulus was determined following assignment of an agitation-sedation score at predetermined times before and for 6 hours after each treatment. During the second phase, a subset of 12 birds received hydromorphone (0.6 mg/kg, IM), and blood samples were collected at predetermined times for 9 hours after drug administration. Plasma hydromorphone concentration was determined by liquid chromatography-mass spectrometry. Noncompartmental analysis of sparse data was used to calculate pharmacokinetic parameters. RESULTS Thermal withdrawal response did not differ among the 4 treatment groups at any time. Agitation-sedation scores following administration of the 0.3-and 0.6-mg/kg doses of hydromorphone differed significantly from those treated with saline solution and suggested the drug had a sedative effect. Plasma hydromorphone concentrations were > 1 ng/mL for 3 to 6 hours after drug administration in all birds. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that IM administration of hydromorphone at the evaluated doses did not increase the thermal withdrawal threshold of cockatiels despite plasma drug concentrations considered therapeutic for other species. Further research is necessary to evaluate the analgesic effects of hydromorphone in cockatiels.

Dose proportionality and pharmacokinetics of extended-release (OROS®) hydromorphone: A phase 1, open-label, randomized, crossover study in healthy Taiwanese subjects

Osmotic-controlled release oral delivery system (OROS®) hydromorphone - an extended-release preparation - is recommended long-term therapy for chronic pain patients. Dose proportionality of OROS hydromorphone has been shown in healthy Caucasian volunteers; however, no studies have been conducted in Asian populations. To determine whether ethnic differences affect the drug's pharmacokinetic (PK) profile, we evaluated the dose proportionality of OROS hydromorphone in healthy Taiwanese adults. This 12-week, open-label, 4-way crossover, phase 1 study randomly assigned subjects to 1 of 4 treatment sequences - single oral dose OROS hydromorphone: 8 mg, 16 mg, 32 mg, or 64 mg - along with 50 mg naltrexone. Dose proportionality was assessed using a linear mixed-effects model to estimate the slope of the regression line and its 90% CI for Cmax, AUC0-48h, and AUClast. Descriptive statistics measured plasma hydromorphone concentrations, PK parameters, laboratory analytes, and vital signs. 23 subjects completed the study; a single-dose of OROS hydromorphone increased plasma concentration steadily for 6 hours and sustained it at or near maximum levels for ~ 24 hours. After dose normalization to a 16 mg dose, all studied doses demonstrated dose proportionality for Cmax, AUClast, and AUC0-48h,as the slopes of the regression lines for Cmax, AUClast, and AUC0-48h were close to zero, and the 90% CIs within pre-specified limits. Adverse events were as expected for hydromorphone administered with concomitant naltrexone. Single doses of 8 mg, 16 mg, 32 mg, and 64 mg of OROS hydromorphone were found to be dose proportional for Cmax, AUClast, and AUC0-48h and were generally safe and well-tolerated in healthy Taiwanese adults.

Hydrocodone in postoperative personalized pain management: Pro-drug or drug?

BackgroundGenetic variations in enzymes that produce active metabolites from pro-drugs are well known. Such variability could account for some of the clinically observed differences in analgesia and side effects seen in postoperative patients. Using genotyping and quantitation of serum concentrations of hydrocodone and its metabolites, we sought to demonstrate the clinical effects of the metabolites of hydrocodone on pain relief. The objective of the current study was to determine whether CYP2D6 genotype and serum hydromorphone levels account for some of the variability in pain relief seen with hydrocodone in a cohort of women post-Cesarean section. MethodsIn 156 post-Cesarean section patients who received hydrocodone, we assessed serum opioid concentrations and CYP2D6 genotypes. Blood samples were collected at that time for genotyping and determination of concentrations of hydrocodone and metabolites by LC–MS/MS. Multivariate analysis was used to determine the relationship between CYP2D6 genotypes, pain relief, side effects, and serum concentrations of hydrocodone and hydromorphone. ResultsThe CYP2D6 genotyping results indicated that 60% of subjects were extensive, 30% intermediate, 3% poor, and 7% ultra-rapid metabolizers. In the poor metabolizers, the mean plasma hydromorphone concentration was 8-fold lower when compared to that of ultra-rapid metabolizers. Hydromorphone, and not hydrocodone concentrations correlated with pain relief. ConclusionsThis study shows that hydromorphone is generated at substantially different rates, dependent on CYP2D6 genotype. Pain relief correlated with plasma concentrations of hydromorphone, and not with hydrocodone. This suggests that pain relief will vary with CYP2D6 genotype. Inability to metabolize hydrocodone to hydromorphone as seen in the poor metabolizers should alert the clinician to consider alternative medications for managing pain postoperatively.

Pharmacokinetics of hydrocodone and hydromorphone after oral hydrocodone in healthy Greyhound dogs

The purpose of this study was to determine the pharmacokinetics of hydrocodone and its active metabolite hydromorphone in six healthy Greyhound dogs. Hydrocodone bitartrate was administered at a targeted dose of 0.5mg/kg PO. Plasma concentrations of hydrocodone and hydromorphone were determined by liquid chromatography triple quadrupole mass spectrometry. The mean hydrocodone CMAX was 11.73ng/mL at 0.74h with a terminal half-life of 1.60h. The mean hydromorphone CMAX was 5.2ng/mL at 1.37h with a terminal half-life of 3.07h. Mean plasma hydromorphone concentrations exceeded 2ng/mL from 0.5 to 8h after hydrocodone administration. Further studies assessing the antinociceptive effects of oral hydrocodone are needed.

(240) A pharmacokinetic profile of intranasal hydromorphone in emergency room trauma patients

Intranasal hydromorphone HCl is under development for the management of moderate to severe trauma pain. An element of this investigation was to assess plasma concentrations at near peak times, at the end of a typical dosing interval and across a range of doses being evaluated for relative clinical efficacy and tolerability. Intranasal administration of hydromorphone with a sprayer configured to deliver 2, 4, 6, 8 or 10mg of hydromorphone in 100 L of solution was studied in patients with pain 5 on a 0-10 scale and were evaluated as candidates for opioid treatment. Blood was obtained at baseline and a single dose of intranasal hydromorphone administered. Samples were collected at 30, 60 and 180 minutes following dosing then assayed using LC/MS/MS for plasma hydromorphone concentrations. Patients (n 113) were dosed with 2mg (n 14), 4mg (n 19), 6mg (n 33), 8mg (n 28) or 10mg (n 19) of intranasal hydromorphone. Analysis of plasma hydromorphone demonstrated a dose-related increase at most timepoints. The maximum measured concentration was observed at 30 minutes (mean 2.22ng/mL with 2mg, 4.26ng/mL with 4mg, 5.04ng/mL with 6mg, 6.21ng/mL with 8mg and 7.14ng/mL with 10mg). Concentrations observed following 2mg intranasal doses were similar to those seen for 2mg doses in healthy volunteers. Therapeutic concentrations of hydromorphone in acute pain approximate 4ng/mL. With this intranasal administration at the 30 minute timepoint, 2mg was at or above this concentration in 7% of patients, in 42% of patients with 4mg, in 63% of patients with 6mg, in 81% of patients with 8mg and in 95% of patients with 10mg indicating potential for rapid pain relief. We conclude that for trauma patients presenting to the ER, intranasal administration of this product resulted in rapid absorption of hydromorphone into the plasma. These plasma hydromorphone concentrations are consistent with analgesic concentrations reported in the literature. Supported by Intranasal Therapeutics, Inc.

Pharmacokinetic profile of a 24-hour controlled-release OROS formulation of hydromorphone in the presence of alcohol

ABSTRACTObjective: The purpose of this study was to investigate the pharmacokinetic properties of a novel, once-daily, controlled-release formulation of hydromorphone (OROS hydromorphone) in the presence of alcohol.* OROS is a registered trade name of ALZA Corporation, Mountain View, CA, USAResearch design and methods: In a single-centre, open-label, four-treatment, four-period, four-sequence, crossover study, two groups of 24 healthy subjects (fasted or fed) were randomised to receive four single doses of OROS hydromorphone 16 mg with solutions of either 0%, 4%, 20% or 40% alcohol, and with a naltrexone block.Main outcome measures: Plasma samples taken predose and at regular intervals up to 48 h after dosing were assayed for hydromorphone concentrations; a mixed-effect analysis of variance was done on log-transformed data. Bioequivalence was concluded if 90% confidence intervals of treatment mean ratios were between 80% and 125%.Results: Plasma hydromorphone concentrations were slightly higher after dosing with all alcohol treatments in both the fasted and fed subject groups. Median Tmax values were between 12 and 16 h and ranges were similar for all treatments. Cmax values increased after alcohol compared with no alcohol, with the increase slightly lower in the fed state. The greatest mean increase in Cmax observed was 1.3-fold in the fasted state and 1.1-fold in the fed state. Confidence intervals were within 80–125% for AUC but were slightly higher for Cmax.Conclusions: The pharmacokinetics of once-daily OROS hydromorphone were only minimally affected by alcohol, with no dose dumping of hydromorphone. The results indicate that the controlled-release properties of this formulation are maintained in the presence of alcohol.

A Multiple-Dose Phase I Study of Intranasal Hydromorphone Hydrochloride in Healthy Volunteers

We evaluated the pharmacokinetics, tolerability, and safety of 1 and 2 mg of intranasal hydromorphone hydrochloride in an open-label, single- and multiple-dose study. This Phase I study was conducted in 24 healthy volunteers (13 men and 11 women). Intranasal doses were delivered as 0.1-mL metered-dose sprays into one or both nostrils for 1- and 2-mg doses, respectively. Venous blood samples were taken serially from 0 to 12 h after the first single dose and the last (seventh) multiple dose. Plasma hydromorphone concentrations were determined by liquid chromatography/mass spectrometry/mass spectrometry. Noncompartmental analysis was used to estimate pharmacokinetic variables. After 7 intranasal doses of 1 and 2 mg (once every 6 h), mean +/- sd peak plasma concentrations of 2.8 +/- 0.7 ng/mL and 5.3 +/- 2.3 ng/mL, respectively, were observed. The median time to peak concentration was 20 min for both single and multiple doses. Dose proportionality was observed for the 1- and 2-mg doses. Adverse events included somnolence, dizziness, and bad taste after dose administration. Intranasal hydromorphone hydrochloride was well tolerated and demonstrated rapid nasal drug absorption and predictable accumulation. These results support clinical investigation of hydromorphone hydrochloride nasal spray for use as an alternative to oral and IM administration.

Pharmacokinetic and pharmacodynamic evaluation of intravenous hydromorphone in cats1

This study describes the pharmacokinetics of intravenous hydromorphone in cats and the simultaneous measurement of antinociceptive pharmacodynamic effects using a thermal threshold testing system. Following establishment of a baseline thermal threshold, six adult cats were administered 0.1 mg/kg of hydromorphone intravenously. Thermal threshold testing and blood collection were conducted simultaneously at predetermined time points. Plasma hydromorphone concentrations were determined by a liquid chromatographic-mass spectral method and pharmacokinetic analysis was performed by nonlinear least squares regression analysis. Plasma hydromorphone concentrations declined rapidly over time, and were below the limit of quantification of the assay (LOQ = 1.0 ng/mL) by 360 min. In contrast, thermal thresholds rose from a pretreatment value of 40.9 +/- 0.65 degrees C (mean +/- SEM) to instrument cut-out (55 degrees C) within 15 min and remained significantly elevated from 15-450 min after treatment. Inspection of the data revealed no direct correlation between plasma hydromorphone concentrations and the antinociceptive effect of this drug in cats. These findings support the importance of conducting pharmacokinetic studies in parallel with objective measurements of drug effect.

Opioids: clinical pharmacology: Clinical pharmacology of hydromorphone hydrochloride extended-release capsules following multiple-dose oral administration

A once-daily (q24h) hydromorphone hydrochloride extended-release (HHER) multiparticulate melt extrusion pellet formulation has been developed in capsule strengths of 12, 16, 24, and 32 mg. An extended-release formulation will avoid the need for frequent (q4-6h) administration of immediate-release hydromorphone (HHIR) to maintain analgesia in appropriate pain settings. On FDA approval, this product will be marketed as PalladoneTM Capsules. A randomized, multiple-dose, 2-way crossover study was conducted in healthy volunteers. Treatments consisted of a HHER 12-mg capsule q24h or a HHIR 3-mg tablet q6h each administered over a 5-day dosing period. For both treatments, predose (trough values) were assessed on days 1 through 5 while full PK profiles were obtained for 24 hours on day 5. The steady-state pharmacokinetics (PK) and safety profiles of hydromorphone (HMP) following HHER and HHIR dosing were determined. Plasma HMP concentrations were analyzed using a validated LC-MS/MS assay; appropriate PK and statistical methods were applied to the data obtained. Plasma HMP concentration profiles on day 5 were characterized by a much flatter profile for HHER q24h compared with HHIR q6h. Steady-state plasma HMP concentrations were achieved within 2 to 3 days following initiation of oral HHER dosing. Peak-to-trough fluctuation was approximately 2-fold or 200% lower for HHER than for HHIR. The total daily exposures of HHER and HHIR were bioequivalent. At steady state, HHER resulted in a lower Cmax, a later tmax, and a higher Cmin compared with the corresponding values obtained with HHIR. Following multiple dosing, HHER did not accumulate significantly with once-daily administration. Adverse events were those typically observed with opioid analgesics. Based on the multiple-dose PK and safety profiles, HHER is suitable for q24h administration.

Hydromorphone analgesia after intravenous bolus administration

This study investigated the analgesic effects of three intravenous bolus doses of hydromorphone (10, 20, 40 μg/kg) on experimental pain measures in normal humans. Ten healthy male volunteers participated in four study sessions, one for each of the hydromorphone doses as well as a placebo (saline). They received the four treatments in counterbalanced order under double-blind conditions and with study days at least 1 week apart. During each session subjects underwent repeated electrical tooth pulp stimulation at intensities sufficient to elicit a rating of `strong pain' before drug administration. Subjective pain reports (PRs) and dental evoked potential amplitude measures (EPs) served as analgesic effect indicators. We observed dose-dependent analgesia as measured by both PR ( P=0.009) and EP ( P=0.017). Area under the PR versus time curve as well as the EP versus time curve decreased in a log dose-dependent fashion. Although the peak effect was poorly defined, the onset of analgesia was rapid, within 5 min, and maximum analgesic effect was seen between 10 and 20 min after maximum plasma hydromorphone concentration. However, within sessions we found a poor correspondence between hydromorphone plasma concentration and effect. Compared to pain report data from other human studies done in our laboratory, hydromorphone has a shorter time to peak effect compared to morphine, and overall, hydromorphone hydrochloride is approximately five times as potent as morphine sulfate on a milligram basis.

Patient-controlled analgesia for mucositis pain in children: A three-period crossover study comparing morphine and hydromorphone

OBJECTIVES: (1) To test the safety and efficacy of a clinical protocol for administering opioid by using patient-controlled analgesia (PCA) for the management of mucositis pain in children after bone marrow transplantation, (2) to compare the efficacy, side-effect profile, and potency ratio of morphine with those of hydromorphone by using PCA as the method of opioid administration, and (3) to obtain pharmacokinetic data on hydromorphone and morphine in this population of children. METHODS: In this double-blind, three-period crossover study, patients were randomly assigned to receive either morphine (group 1) or hydromorphone (group 2) initially by means of PCA on days 1, 2, and 3 (period 1), to be followed on days 4, 5, and 6 (period 2) with the alternative opioid, followed by the opioid used at the commencement of the study on days 7, 8, and 9 (period 3). A clinical protocol for calculating the PCA commencement opioid dose and subsequent opioid-dose escalation was tested by measures of safety and efficacy. Measures of pain intensity and opioid side effects were made during the three periods. On the last study day (day 10), patients received a continuous infusion of opioid derived from the previous 24-hour PCA opioid requirement, and blood specimens were collected and stored for subsequent opioid analysis. RESULTS: Ten patients were enrolled in this study. Rapid escalation in opioid requirement commonly occurred at the commencement of PCA, followed by a variable plateau phase and then deescalation of opioid requirement after mucositis resolution. The measures demonstrated the safety and efficacy of the clinical protocol. In the concentrations used, there was no statistical difference between the mean daily pain, sedation, nausea and vomiting, and pruritus scores for both opioids (Friedman test). The analysis of variance of the log-total opioid doses per patient during periods 1, 2, and 3 indicated that patients used 27% more hydromorphone than expected from its presumed 7:1 ratio relative to morphine potency used in the PCA infusions. The mean plasma hydromorphone concentration was 4.7 ng/ml (range, 1.9 to 8.9 ng/ml), and the mean clearance was 51.7 ml/min per kilogram of body weight (range, 28.6 to 98.2 ml/min per kilogram). The mean plasma morphine, morphine-6-glucuronide, and morphine-3-glucuronide concentrations were 40.0 ng/ml (range, 15 to 62.5), 168.2 ng/ml (range, 54.4 to 231.9), and 391.0 ng/ml (range, 149.4 to 921.7), respectively. The mean morphine clearance was 34.3 ml/min per kilogram of body weight (range, 19.3 to 58.3). The mean molar ratios of morphine-6-glucuronide/morphine, morphine-3-glucuronide/morphine, and morphine-3-glucuronide/morphine-6-glucuronide were 2.48 (range, 1.4 to 3.3), 5.82 (range, 3.4 to 9.1), and 2.46 (range, 1.1 to 3.3), respectively. CONCLUSIONS: The safety and efficacy of a clinical protocol for the administration of opioids by means of PCA for mucositis pain after bone marrow transplantation was demonstrated. In this small study, hydromorphone was not superior to morphine in terms of analgesia or the side-effect profile: a larger study would be needed to show a difference. The clearances of hydromorphone and morphine in the children studied were generally greater than those previously recorded, but this finding may be related to disease or treatment variables. Apart from clearance, the morphine pharmacokinetics in the study population were similar to those previously recorded. Hydromorphone may be less potent in this population of children than indicated by adult equipotency tables. (J Pediatr 1996;129:722-8)

In vitro and in vivo studies of subcutaneous hydromorphone implants designed for the treatment of cancer pain

Unrelieved cancer pain remains a significant problem worldwide. Patients receive inadequate analgesia for a variety of complex and multifactorial reasons. Limited availability of opioids secondary to concerns about potential diversion of these medications for illicit use and poor compliance with oral regimens are significant factors in many countries. This study was designed to develop and test an implantable opioid delivery device capable of releasing a potent opioid subcutaneously at a continuous rate for 4 weeks. A low temperature solvent casting technique was used to formulate ethylene vinyl acetate (EVA) copolymer disks containing 50% hydromorphone by weight. The release characteristics of disks of different height and diameter, coated and uncoated, and with and without a central uncoated channel were studied. The effect of temperature and pH were also evaluated. In vitro assessments were conducted in phosphate buffer using UV spectrophotometry. In vivo studies employed New Zealand White Rabbits and a radioimmunoassay. Plasma levels following hydromorphone delivery by polymer, osmotic pump, and intravenous administration were compared. In vitro, uncoated EVA polymer disks measuring 1.05 cm in diameter and 0.27 cm in height released an initial large burst of hydromorphone. Coating the disks with 100–200 μM of poly(methyl-methacrylate) prevented drug egress from the polymer. A central uncoated channel measuring 1.25 mm in diameter in an otherwise coated polymer virtually eliminated the initial burst of drug release and provided near zero-order hydromorphone release at an average rate of 164 μg per hour for 4 weeks. Doubling the height of the polymer approximately doubled the release rate while doubling the diameter of the polymer extended the duration of drug release to over 8 weeks. In rabbits, stable plasma hydromorphone concentrations (23–37 ng/ml) were sustained for 4 weeks following implantation of 2 polymers with an uncoated central channel. No initial burst of hydromorphone release was noted. Increasing the number of polymers produced sustained and predictable increases in plasma hydromorphone concentrations. Plasma levels were similar with subcutaneous hydromorphone delivered by polymer and osmotic pump and much less variable than with intravenous bolus hydromorphone. A uniquely configured implantable drug delivery device has been developed using materials which are approved for human use. It safely and reproducibly releases hydromorphone for weeks in vitro and in vivo without an initial burst of drug release. Varying the thickness, diameter, and number of implants provides flexibility in the release rate and duration of release. This implantable opioid delivery device could provide a sustained subcutaneous infusion of hydromorphone to patients with cancer pain in developed and developins nations without pumps, catherers, or extensive outpatient support services. In addition, it should improve compliance and reduce concern regarding illicit diversion of opioids.

Multiple-Dose Evaluation of Intravenous Hydromorphone Pharmacokinetics in Normal Human Subjects

We measured the pharmacokinetics of hydromorphone in normal volunteers given three doses of the drug (10, 20, and 40 micrograms/kg) as intravenous 45-s injections on different days. Concentrations of hydromorphone in plasma from serial blood samples were measured by a high-performance liquid chromatography method specific for hydromorphone with a detection limit of 0.1 ng/mL. In all cases, plasma hydromorphone concentration versus time data for individual subjects were best described by a triexponential (instead of mono- or biexponential) function. Furthermore, we found that the pharmacokinetics of hydromorphone was independent of dose across the range studied. Averaged across doses, the distribution and terminal elimination half-lives were 1.27 min (t1/2 pi), 14.7 min (t1/2 alpha), and 184 min (t1/2 beta), respectively. Average values for systemic clearance, initial dilution volume, and steady-state volume of distribution were 1.66 L/min (Cl), 24.4 L (Vc), and 295 L (Vdss). Our results indicate that hydromorphone pharmacokinetic parameters are linear across a fourfold range of doses that are usually employed clinically and that previously reported pharmacokinetic values for hydromorphone (based on radioimmunoassay measurements) deserve reconsideration.

Comparison of continuous subcutaneous and intravenous hydromorphone infusions for management of cancer pain

To compare the safety and efficacy of subcutaneous and intravenous infusion of opioid analgesics, a randomised, double-blind, crossover trial was carried out in inpatients. 15 patients with severe cancer pain received two 48 h infusions of hydromorphone one subcutaneously and one intravenously in randomly allocated order. The study was made double-blind by the use of two infusion pumps throughout; during the active subcutaneous infusion the intravenous pump delivered saline and vice versa. Serial measurements of pain intensity, pain relief, mood, and sedation by means of visual analogue scales showed no clinically or statistically significant difference between the two infusion routes. Side-effects were slight, and the mean number of morphine injections for breakthrough pain did not differ significantly between the routes (4·8 [SD 4·5] for intravenous vs 5·3 [5·6] for subcutaneous). Plasma hydromorphone concentrations measured at 24 h and 48 h of infusion showed stable steady-state pharmacokinetics; the mean bioavailability from subcutaneous infusion was 78% of that with intravenous infusion. Because of the simplicity, technical advantages, and cost-effectiveness of continuous subcutaneous opioid infusion into the chest wall or trunk, intravenous opioid infusion for the management of severe cancer pain should be abandoned.