Pharmacokinetic-pharmacodynamic analysis of drug liking blockade by buprenorphine subcutaneous depot (CAM2038) in participants with opioid use disorder.

Buprenorphine is used to treat opioid use disorder (OUD). Weekly and monthly subcutaneous long-acting buprenorphine injections (CAM2038) provide more stable buprenorphine plasma levels and reduce the treatment burden, misuse, and diversion associated with sublingual transmucosal buprenorphine formulations. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship, a maximum inhibition (Imax) model was developed relating CAM2038 buprenorphine plasma concentration to drug liking maximum effect (Emax) visual analog scale (VAS; bipolar) score after intramuscular hydromorphone administration. Data included time-matched observations of buprenorphine plasma concentration and drug liking Emax VAS score after hydromorphone 18 mg administration in 47 non-treatment-seeking adults with moderate to severe OUD in a phase 2 study. Analysis used non-|linear mixed-effects modeling (NONMEM®). The final Imax model adequately described the PK/PD relationship between buprenorphine plasma concentration and drug liking Emax VAS score. Simulations showed drug liking was effectively blocked at low buprenorphine plasma concentrations (0.4 ng/mL) where the upper 95% confidence interval of the drug liking Emax VAS score was below the pre-defined 11-point complete blockade threshold. The buprenorphine plasma concentration required to achieve 90% of the maximal effect (IC90) of drug liking was 0.675 ng/mL. Interindividual variability in responses to buprenorphine was observed; some participants experienced fluctuating responses, and a few did not achieve drug liking blockade even with higher buprenorphine plasma concentrations. This affirms the need to individualize treatment and titrate doses for optimal treatment outcomes. PK/PD models were also developed for desire to use VAS and Clinical Opiate Withdrawal Scale (COWS) scores, with results aligned to those for drug liking.

High bioavailability, short half-life, and metabolism into hydromorphone-3-glucuronide following single intramuscular and intravenous administration of hydromorphone hydrochloride to great horned owls (Bubo virginianus).

OBJECTIVE: To determine the pharmacokinetic parameters of hydromorphone hydrochloride and its metabolite, hydromorphone-3-glucuronide (H3G), after a single IV and IM dose in great horned owls (Bubo virginianus). ANIMALS: 6 healthy adult great horned owls (3 females and 3 males). PROCEDURES: A single dose of hydromorphone (0.6 mg/kg) was administered once IM (pectoral muscles) and IV (left jugular) with a 6-week washout period between experiments. Blood samples were collected at 5 minutes and 0.5, 1.5, 2, 3, 6, 9, and 12 hours after drug administration. Plasma hydromorphone and H3G concentrations were determined with liquid chromatography-tandem mass spectrometry, and a noncompartmental analysis was used for the determination of pharmacokinetic parameters. RESULTS: Hydromorphone had a high bioavailability of 170.8 ± 37.6% and rapid elimination after IM administration and rapid plasma clearance and a large volume of distribution after IV administration. Mean Cmax was 225.46 ± 0.2 ng/mL at 13 minutes after IM injection. Mean volume of distribution and plasma drug clearance was 4.29 ± 0.5 L/kg and 62.11 ± 14.6 mL/min/kg, respectively, after IV administration. Mean t1/2 was 1.62 ± 0.36 and 1.35 ± 0.59 hours after IM and IV administration, respectively. The metabolite H3G was readily measured shortly after administration by both routes. CLINICAL RELEVANCE: A single dose of 0.6 mg/kg was well tolerated in all birds. Hydromorphone rapidly attained plasma concentrations following IM administration and had high bioavailability and short t1/2. This study is the first to document the presence of the metabolite H3G in avian species, which suggests similar hydromorphone metabolism as in mammals.

Steady-State Pharmacokinetics of Intravenous Hydromorphone in Japanese Patients With Renal Impairment and Cancer Pain.

Background: The opioid analgesic hydromorphone has a low renal excretion ratio; however, exposure after oral administration is several times higher in those with moderate or severe renal impairment. Objectives: We evaluated the impact of renal impairment on the steady-state pharmacokinetics of intravenously administered hydromorphone in patients with cancer being treated for pain. Design: This was an open-label, prospective, parallel-comparison, interventional clinical pharmacology study. Setting/Subjects: This study was conducted at one hospital in Japan. Using creatinine clearance (CLcr) values, patients were grouped according to kidney function: CLcr ≥90 mL/min (normal), 60-<90 mL/min (mild impairment), 30-<60 mL/min (moderate impairment), or <30 mL/min (severe impairment). Measurements: Hydromorphone was administered by constant infusion to patients at the same constant dose rate as at the time of enrollment. Hydromorphone and its glucuronide metabolite concentrations in plasma and urine were measured by liquid chromatography-mass spectrometry. Pharmacokinetic parameters at steady state were assessed using noncompartmental analysis. Results: Thirty-two patients were enrolled (normal, n = 3; mild, n = 10; moderate, n = 15; and severe, n = 4). Adjusted geometric mean ratios for hydromorphone steady-state clearance (CLss) for patients with impaired versus normal renal function were 0.69 (90% confidence interval [CI], 0.41-1.14), 0.52 (90% CI, 0.31-0.84), and 0.55 (90% CI, 0.30-1.02) for mild, moderate, or severe impairment, respectively. Exposures to the metabolite hydromorphone-3-glucuronide generally increased with renal impairment. No adverse event was reported. Conclusion: Hydromorphone CLss in patients with impaired renal function (moderate and severe) was decreased ∼50% of that of normal renal function.

Morphine or hydromorphone: which should be preferred? A systematic review.

OBJECTIVE: To systematically review available paediatric literature on comparisons between morphine (Mo) and hydromorphone (Hm), to guide clinicians to rationally use these medications. DESIGN: Systematic review within four databases for all studies published from 1963 to July 2019. SETTING: All paediatric settings. ELIGIBILITY: All studies comparing Mo to Hm in individuals younger than 21 years. MAIN OUTCOME MEASURES: The primary outcome was to compare clinical efficacy and side effects of Mo and Hm. The secondary outcomes were the comparison of pharmacokinetic profiles and the description of predefined Mo to Hm conversion ratios used across the paediatric literature. RESULTS: Among 754 abstracts reviewed, 59 full-text articles met inclusion criteria and 24 studies were included in the analysis: 4 studies compared pharmacodynamics of Mo and Hm and 20 studies reported the use of a predefined Mo to Hm conversion ratio. Most studies had a poor methodological quality. Available evidence suggests that, when given intravenously, the equianalgesic ratio of Mo to Hm is 5:1. Intravenous administration with this ratio results in a similar rate of adverse effects, including pruritus and nausea. The epidural administration with a ratio of 10:1 results in more pruritus and urinary retention with Mo than Hm. Pharmacokinetic data were reported in only one study. A wide range of pre-established ratios for different routes of administration were reported, but few were based on evidence. CONCLUSION: Current literature does not permit a rational choice between Mo and Hm. A ratio of 5:1 seems adequate for intravenous administration and leads to a similar rate of adverse effects.

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.

Intrathecal hydromorphone as an analgesia option for gynecology patients.

Enhanced recovery after surgery (ERAS) is a multimodal perioperative strategy originally developed to attenuate the postsurgical stress response in patients after colorectal surgery. Patients undergoing gynecologic surgery who had ERAS had significantly shorter hospital length of stay, reduced hospital-related costs, and acceptable pain management with reduced opioid use, without compromising patient satisfaction. Intrathecal hydromorphone is an effective alternative ERAS protocol analgesia for these patients and will not compromise patient outcomes or healthcare costs.

Single dose epidural hydromorphone in labour pain: maternal pharmacokinetics and neonatal exposure.

INTRODUCTION: Epidural hydromorphone could be useful in obstetric analgesia as there is a need for a more water-soluble opioid than sufentanil or fentanyl with prolonged analgesic effect. To our knowledge, the pharmacokinetics of epidural hydromorphone has not been evaluated in parturients. MATERIALS AND METHODS: In this pilot study, seven healthy parturients were given a single epidural dose of hydromorphone for labour pain. One parturient received 1.5 mg, two 0.75 mg and four 0.5 mg of hydromorphone hydrochloride. Dose was decreased due to nausea and pruritus. Hydromorphone's effect, adverse effects and plasma concentrations were evaluated. Neonatal drug exposure was evaluated by umbilical vein and artery opioid concentration at birth. Neonatal outcomes were assessed using Apgar and the Neurologic Adaptive Capacity Score (NACS). RESULTS: All patients received additional levobupivacaine doses on parturients' requests. The first dose was requested at a median of 163 min (range 19-303 min) after hydromorphone administration. A total of 12 opioid related expected adverse events were reported by seven parturients. All newborn outcomes were uneventful. Hydromorphone's distribution and elimination after single epidural dose seem similar to that reported for non-pregnant subjects after intravenous hydromorphone administration, but further research is required to confirm this observation. CONCLUSIONS: The optimal dose of hydromorphone in labour pain warrants further evaluation.

Pharmacokinetics and pharmacodynamics of hydromorphone hydrochloride in healthy horses.

OBJECTIVES: To determine the physiologic and behavioral effects and pharmacokinetic profile of hydromorphone administered intravenously (IV) to horses. STUDY DESIGN: Prospective, randomized, crossover study. ANIMALS: A group of six adult healthy horses weighing 585.2 ± 58.7 kg. METHODS: Each horse was administered IV hydromorphone (0.025 mg kg-1; treatment H0.025), hydromorphone (0.05 mg kg-1; treatment H0.05) or 0.9% saline in random order with a 7 day washout period. For each treatment, physiologic, hematologic, abdominal borborygmi scores and behavioral data were recorded over 5 hours and fecal output was totaled over 24 hours. Data were analyzed using repeated measures anova with significance at p < 0.05. Blood samples were collected in treatment H0.05 for quantification of plasma hydromorphone and hydromorphone-3-glucuronide and subsequent pharmacokinetic parameter calculation. RESULTS: Hydromorphone administration resulted in a dose-dependent increase in heart rate (HR) and systolic arterial pressure (SAP). HR and SAP were 59 ± 17 beats minute-1 and 230 ± 27 mmHg, respectively, in treatment H0.05 at 5 minutes after administration. No clinically relevant changes in respiratory rate, arterial gases or temperature were observed. The borborygmi scores in both hydromorphone treatments were lower than baseline values for 2 hours. Fecal output did not differ among treatments and no evidence of abdominal discomfort was observed. Recorded behaviors did not differ among treatments. For hydromorphone, mean ± standard deviation for volume of distribution at steady state, total systemic clearance and area under the curve until the last measured concentration were 1.00 ± 0.29 L kg-1, 106 ± 21 mL minute-1 kg-1 and 8.0 ± 1.5 ng hour mL-1, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Hydromorphone administered IV to healthy horses increased HR and SAP, decreased abdominal borborygmi and did not affect fecal output.

Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular administration in horses.

OBJECTIVE: To compare the pharmacokinetics and pharmacodynamics of hydromorphone in horses after intravenous (IV) and intramuscular (IM) administration. STUDY DESIGN: Randomized, masked, crossover design. ANIMALS: A total of six adult horses weighing [mean ± standard deviation (SD))] 447 ± 61 kg. METHODS: Horses were administered three treatments with a 7 day washout. Treatments were hydromorphone 0.04 mg kg⁻1 IV with saline administered IM (H-IV), hydromorphone 0.04 mg kg⁻1 IM with saline IV (H-IM), or saline IV and IM (P). Blood was collected for hydromorphone plasma concentration at multiple time points for 24 hours after treatments. Pharmacodynamic data were collected for 24 hours after treatments. Variables included thermal nociceptive threshold, heart rate (HR), respiratory frequency (fR), rectal temperature, and fecal weight. Data were analyzed using mixed-effects linear models. A p value of less than 0.05 was considered statistically significant. RESULTS: The mean ± SD hydromorphone terminal half-life (t1/2), clearance and volume of distribution of H-IV were 19 ± 8 minutes, 79 ± 12.9 mL minute⁻1 kg⁻1 and 1125 ± 309 mL kg⁻1. The t1/2 was 26.7 ± 9.25 minutes for H-IM. Area under the curve was 518 ± 87.5 and 1128 ± 810 minute ng mL⁻1 for H-IV and H-IM, respectively. The IM bioavailability was 217%. The overall thermal thresholds for both H-IV and H-IM were significantly greater than P (p < 0.0001 for both) and baseline (p = 0.006). There was no difference in thermal threshold between H-IV and H-IM. No difference was found in physical examination variables among groups or in comparison to baseline. Fecal weight was significantly less than P for H-IV and H-IM (p = 0.02). CONCLUSIONS AND CLINICAL RELEVANCE: IM hydromorphone has high bioavailability and provides a similar degree of antinociception to IV administration. IM hydromorphone in horses provides a similar degree and duration of antinociception to IV administration.

Pharmacokinetics and Abuse Potential of Asalhydromorphone, a Novel Prodrug of Hydromorphone, After Intranasal Administration in Recreational Drug Users.

OBJECTIVES: Hydromorphone (HM) is a potent µ-opioid receptor agonist with high susceptibility for abuse. A prodrug of hydromorphone, asalhydromorphone (ASAL-HM), has been designed to deter nonoral forms of abuse associated with hydromorphone. This study evaluated the intranasal (IN) pharmacokinetics and exploratory abuse potential of ASAL-HM compared with HM. DESIGN: Single-center, randomized, double-blind, crossover study. SETTING: Clinical research site. SUBJECTS: Healthy adult, nondependent recreational opioid users. METHODS: Subjects (N = 26) were randomized to receive IN administration of 16.1 mg of ASAL-HM and 8.0 mg of HM (molar-equivalent with respect to hydromorphone). Blood samples were taken through 24 hours postdose, and pharmacodynamic end points (Drug Liking, Feeling High, Take Drug Again, Overall Drug Liking) were assessed through eight hours postdose. Nasal irritation and safety were also assessed. RESULTS: Relative to IN HM, the rate (Cmax) and extent (area under the curve [AUC0-last, AUC0-inf]) of exposure to hydromorphone following IN ASAL-HM were reduced by ≥50%. Consistent with these findings, scores on "at-the-moment" (i.e., Drug Liking Emax, High Emax) and retrospective (i.e., Take Drug Again, Overall Drug Liking) end points were statistically significantly lower for IN ASAL-HM, with mean/median differences ranging from 11.4 to 25.0 points. ASAL-HM produced greater nasal-related effects, such as nasal burning and facial pain, and a lower incidence of typical opioid-related adverse events such as euphoria, pruritus, and somnolence. CONCLUSIONS: The novel hydromorphone prodrug ASAL-HM produced marked reductions in hydromorphone exposure and abuse-related effects following IN administration compared with HM. ASAL-HM has desirable molecular features for incorporation into putative abuse-deterrent immediate-release and extended-release hydromorphone products.

Effect of heart rate on the pharmacokinetics of fentanyl in dogs anesthetized with isoflurane and hydromorphone.

OBJECTIVE: To compare the pharmacokinetics of fentanyl at lower (LHR) or higher heart rate (HHR) in dogs anesthetized with isoflurane. STUDY DESIGN: Prospective, randomized, crossover controlled trial. ANIMALS: A group of six healthy 13-month-old male Beagle dogs weighing 9.9 ± 0.7 kg (mean ± standard deviation). METHODS: Dogs were allocated to two treatments: LHR (HR: 45-75 beats minute-1) and HHR (HR: 100-130 beats minute-1). Anesthesia was maintained with isoflurane and hydromorphone (0.1 mg kg-1 followed by 0.02-0.10 mg kg-1 hour-1) for both treatments. Glycopyrrolate was administered in HHR to maintain HR within the desired range. Afterwards, fentanyl (20 µg kg-1) was intravenously administered over 5 minutes. Arterial blood samples were collected for plasma fentanyl concentration measurement by liquid chromatography/mass spectrometry. The pharmacokinetics of fentanyl were compared between treatments and the differences were considered significant at p < 0.05. RESULTS: A three-compartment model best fitted the changes in plasma fentanyl concentration. Clearance (CL; mL minute-1 kg-1) was 33.2 (24.0-48.0) and 61.3 (44.5-72.7), maximum concentration (ng mL-1) 33.6 (23.4-36.6) and 20.0 (16.7-28.0), apparent volume of the rapid peripheral compartment (mL kg-1) 436 (352-723) and 925 (499-1887), apparent volume at steady state (mL kg-1) 4064 (3453-6546) and 7195 (5077-8601), cardiac index (CI; mL minute-1 m-2) 2.83 (1.98-3.67) and 4.91 (3.22-6.09) and HR (beats minute-1) 68 (49-72) and 120 (102-129) for LHR and HHR, respectively, with significant differences between treatments. Significant correlations (0.92 and 0.90) were found between CI and CL, and between HR and CL, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The increase in HR and the resultant improvement in cardiac output increased fentanyl CL and volume of distribution, which resulted in a decrease in plasma fentanyl concentration in isoflurane-anesthetized dogs.

The pharmacokinetics and pharmacodynamics of intravenous hydromorphone in horses.

OBJECTIVE: Describe the pharmacokinetics and pharmacodynamics of intravenous hydromorphone in healthy horses. STUDY DESIGN: Masked, randomized, cross-over, Latin square design. ANIMALS: A group of eight healthy adult horses METHODS: Horses were administered each of four treatments with an 8 day washout. Treatments groups included intravenous hydromorphone 0.02 mg kg-1 (LD), 0.04 mg kg-1 (MD), 0.08 mg kg-1 (HD) and saline (P). Blood samples for hydromorphone analysis were obtained for 24 hours after treatment. Plasma hydromorphone was quantified and pharmacokinetic parameters were determined using non-compartmental analysis. Pharmacodynamic data collected for 24 hours after treatment included thermal nociceptive threshold, heart rate (HR), respiratory rate (fR) and rectal temperature, and analyzed using mixed-effects linear models. RESULTS: Mean (± standard deviation) hydromorphone terminal half-life (t1/2), systemic clearance and apparent volume of distribution at steady state (Vdss) were 18.1 ± 18.6, 34.0 ± 12.8, and 41.3 ± 32.5 minutes, 66.6 ± 5.3, 550.0 ± 76.4, and 92.7 ± 13.9 mL kg-1 minute-1, and 1118 ± 369, 1460 ± 325 and 2242 ± 950 mL kg-1 for treatments LD, MD and HD, respectively. Thermal threshold increased significantly compared to baseline for all treatments for up to 12 hours. HR was elevated above baseline in treatments LD, MD and HD, extending to 30, 15 and 105 minutes after treatment, respectively. Respiratory rate was elevated above baseline in treatments MD and HD from 30 to 195 minutes and from 45 to 480 minutes after treatment, respectively. Temperature was elevated above baseline in treatment HD until 255 minutes after treatment. CONCLUSIONS: Hydromorphone exhibited a short t1/2, rapid clearance and large Vdss in horses. It also provided a dose-dependent increase in thermal threshold with associated increases in HR, fR and rectal temperature. CLINICAL RELEVANCE: Hydromorphone 0.04 mg kg-1 provided clinically relevant thermal antinociception with minimal adverse effects.

Pharmacokinetics of subcutaneously administered hydromorphone in bearded dragons (Pogona vitticeps) and red-eared slider turtles (Trachemys scripta elegans).

OBJECTIVE: To determine pharmacokinetic dosing strategy in bearded dragons (Pogona vitticeps) and red-eared sliders (Trachemys scripta elegans) based on two subcutaneously (SC) administered doses of hydromorphone (0.5 and 1.0 mg kg-1). STUDY DESIGN: Randomized crossover study. ANIMALS: Six healthy adult bearded dragons, seven healthy adult red-eared slider turtles. METHODS: Hydromorphone (0.5 and 1.0 mg kg-1; 2 mg mL-1) was administered SC dorsolateral to the scapulae in the bearded dragons and between the head and thoracic limb of the red-eared slider turtles. Blood was collected for hydromorphone plasma concentration analysis from the ventral tail vein in bearded dragons and subcarapacial sinus in turtles before (time 0) hydromorphone administration and at 0.5, 1, 6, 12 and 24 hours. RESULTS: The half-life of hydromorphone administered at 0.5 and 1.0 mg kg-1 was 2.54 and 3.05 hours in bearded dragons and 2.67 and 2.01 hours in red-eared sliders, respectively. The maximum plasma concentrations for 0.5 and 1.0 mg kg-1 were 142 and 369 ng mL-1 in bearded dragons and 1610 and 5142 ng mL-1 in red-eared sliders, respectively. Peak plasma concentrations were detected at 30 minutes for both species. Hydromorphone administered at both dosages provided plasma concentrations of 13-14 ng mL-1 for at least 24 hours in bearded dragons and of 5-6 ng mL-1 for at least 12 hours in red-eared sliders. Clinical sedation was observed for up to 1 hour posthydromorphone (1.0 mg kg-1) administration for five of six bearded dragons characterized by low body carriage and decreased response to stimuli. No evidence of clinical sedation was observed in red-eared sliders at either dose. CONCLUSIONS AND CLINICAL RELEVANCE: Recommended dosing strategy for hydromorphone is 0.5 mg kg-1 administered SC every 24 hours in bearded dragons and every 12-24 hours in red-eared sliders.

Prescription Opioid Type and the Likelihood of Prolonged Opioid Use After Orthopaedic Surgery.

INTRODUCTION: A common belief is that some narcotic medications have a higher association with prolonged use. We assessed whether the initial opiate type prescribed to postoperative, opiate-naive orthopaedic trauma patients was associated with prolonged opioid use. METHODS: We studied 17,961 adult, opiate-naive patients treated for a surgical musculoskeletal injury. Discharge prescription in morphine milligram equivalents (MMEs, a standardized dosing unit that allows for comparison across opioid types) was calculated. Opioid prescribing beyond 90 days after injury was defined as prolonged use. RESULTS: Initial analysis demonstrated a higher likelihood of prolonged use for patients discharged on hydromorphone or morphine versus hydrocodone. However, when we adjusted for discharge MME, only opioid quantity was predictive of prolonged use (P < 0.001). In addition, discharge MME was associated with opioid type (P < 0.01). DISCUSSION: Persistent opiate use was associated with discharge opioid quantity, not the opioid type. These results highlight the importance of calculating equivalence doses when selecting opioid types and considering amount of narcotics prescribed. LEVEL OF EVIDENCE: Level III.

[Opioid switch and change of route of administration in cancer patients treated by morphine]. / La morphine dans le cadre du changement d'opioïdes ou de voie d'administration, chez l'adulte avec une douleur due au cancer.

This paper reviewed the 2002 guidelines established by the National Federation of Cancer Centres. A group of experts nominated by the 3 French Societies involved in the treatment of cancer pain (AFSOS, SFAP, SFETD), established new guidelines ratios for morphine switching and/or changing of route of administration, in patients for whom either pain was not adequatly managed or adverse effects were unbearable. After a rapid reminder of the pharmacokinetics and metabolism properties of morphine, experts explained why the theory of opioid rotation (oxycodone, hydromorphone, fentanyl, methadone, tapentadol) using fixed equianalgesic ratios is not any more appropriate for a secure clinical practice. In the light of recent publications enhancing our knowledge on the efficacy of new drug switching ratios and for changing the route of administration of morphine, the group of experts recommended to use reconsidered switching ratios favoring security upon efficacy, to minimize overdosing and adverse effects. Consequently, after the new conversion ratio (using slow release opioids) was applied, a second titration should be done by means of normal release rescue formulations for breakthrough pain episodes. A smartphone App. OpioConvert® will be available for rapid and secure dose conversions.

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.

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.

The Conversion Ratio From Intravenous Hydromorphone to Oral Opioids in Cancer Patients.

CONTEXT: The lack of knowledge of the accurate conversion ratio (CR) between intravenous (IV) and oral hydromorphone and opioid rotation ratio (ORR) between IV hydromorphone and oral morphine equivalent daily dose (MEDD) may lead to poorly controlled pain or overdosing in cancer inpatients. OBJECTIVES: We aimed to determine the CR and ORR from IV hydromorphone to oral hydromorphone and MEDD (obtained from oral morphine and oxycodone). METHODS: A total of 4745 consecutive inpatient palliative care consults during 2010-14 were reviewed for conversions from IV hydromorphone to oral hydromorphone, morphine or oxycodone. Patient characteristics, symptoms, and opioid doses were determined in patients successfully discharged on oral opioids without readmission within one week. Linear regression analysis was used to estimate the CR or ORR between the 24 hour IV hydromorphone mg dose before conversion and the oral opioid mg dose used before discharge. RESULTS: Among 394 patients on IV hydromorphone, 147 underwent conversion to oral hydromorphone and 247 underwent rotation to oral morphine (163) or oxycodone (84). The median (interquartile range) CR from IV to PO hydromorphone was 2.5 (2.14-2.75) with correlation of 0.95 (P < 0.0001). The median ORR (interquartile range) from IV hydromorphone to MEDD was 11.46 (9.84-13.00) with correlation of 0.93(P < 0.0001). The median ORR was 11.54 in patients receiving <30 mg of IV hydromorphone/day and 9.86 in patients receiving ≥30 mg (P = 0.0004). CONCLUSION: Our study found that 1 mg of IV hydromorphone is equivalent to 2.5 mg of oral hydromorphone and 11.46 mg of MEDD. Hydromorphone at doses ≥30 mg/day may require a lower ORR to other opioids.

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.

When Hydromorphone Is Not Working, Try Loratadine: An Emergency Department Case of Loratadine as Abortive Therapy for Severe Pegfilgrastim-Induced Bone Pain.

BACKGROUND: Intractable bone pain is a notorious adverse effect of granulocyte-colony stimulating factors (G-CSFs), such as pegfilgrastim and filgrastim, which are given to help prevent neutropenia in patients who are undergoing chemotherapy. G-CSF-induced bone pain is surprisingly common and often refractory to treatment with conventional analgesics. CASE REPORT: This article describes an emergency department case of opiate and nonsteroidal anti-inflammatory drug-resistant pegfilgrastim-induced bone pain that was successfully alleviated with 10 mg of oral loratadine, allowing for discharge home. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case suggests that loratadine may be an easy to implement, safe, and effective therapy in the emergency department management of intractable bone pain caused by G-CSF use. Emergency physicians should be aware that loratadine may successfully relieve otherwise intractable G-CSF-induced bone pain and allow for discharge home.