Immediate-release Hydromorphone Research Articles

Characterizing safer supply prescribing of immediate release hydromorphone for individuals with opioid use disorder across Ontario, Canada.

In response to the ongoing overdose crisis, some clinicians in Canada have started prescribing immediate release hydromorphone (IRH) as an alternative to the toxic unregulated drug supply. This practice is often referred to as safer supply. We aimed to identify and characterize patients receiving safer supply IRH and their prescribers in Ontario. Using provincial administrative health data, we identified individuals with opioid use disorder prescribed safer supply IRH from January 2016 to March 2020 and reported the number of initiations over time. We summarized demographic, health, and medication use characteristics among patients who received safer supply IRH, and examined select clinical outcomes including retention and death. Finally, we characterized prescribers of safer supply IRH and compared frequent and infrequent prescribers. We identified 534 initiations of safer supply IRH (447 distinct individuals) from 155 prescribers. Initiations increased over time with a peak in the third quarter of 2019 (103 initiations). Patients' median age was 42 (interquartile range [IQR] 34-50), and most were male (60.2%), urban residents, (96.2%), and in the lowest neighborhood income quintile (55.7%), with 13.9% having overdosed in the previous one year. The prevalence of HIV was 13.9%. The median duration on IRH was 272 days (IQR 30-1,244) and OAT was co-prescribed in 62.9% of courses. Death while receiving IRH or within 7 days of discontinuation was rare (≤5 courses;≤0.94 per person-year for each). Clinicians are increasingly prescribing safer supply IRH in Ontario. Patients prescribed safer supply IRH had demographic and clinical characteristics associated with high risk of death from opioid-related overdose. Short-term deaths among people receiving safer supply IRH were rare.

Hydromorphone and the risk of infective endocarditis among people who inject drugs: a population-based, retrospective cohort study

The incidence of infective endocarditis related to injection drug use is increasing. On the basis of clinical practice and epidemiological and in-vitro data, we postulated that exposure to controlled-release hydromorphone is associated with an increased risk of infective endocarditis among people who inject drugs. We used linked health administrative databases in Ontario, Canada, to assemble a retrospective cohort of adults (aged 18-55 years) who inject drugs for the period of April 1, 2006, to Sept 30, 2015. Cases of infective endocarditis among this cohort were identified using International Classification of Diseases 10 codes. We estimated exposure to hydromorphone and risk of infective endocarditis among this cohort in two ways. First, in a population-level analysis, we identified patients living in regions with high (≥25%) and low (≤15%) hydromorphone prescription rates and, after matching 1:1 on various baseline characteristics, compared their frequency of infective endocarditis. Second, in a patient-level analysis including only those with prescription drug data, we identified those who had filled prescriptions (ie, received the drug from the pharmacy) for controlled-release or immediate-release hydromorphone and, after matching 1:1 on various baseline characteristics, compared their frequency of infective endocarditis with that of patients who had filled prescriptions for other opioids. Between April 1, 2006, and Sept 30, 2015, 60 529 patients had evidence of injection drug use, 733 (1·2%, 95% CI 1·1-1·3) of whom had infective endocarditis. In the population-level analysis of 32 576 matched patients, we identified 254 (1·6%) admissions with infective endocarditis in regions with high hydromorphone use and 113 (0·7%) admissions in regions with low use (adjusted odds ratio [OR] 2·2, 95% CI 1·8-2·8, p<0·0001). In the patient-level analysis of 3884 matched patients, the frequency of infective endocarditis was higher among patients who filled prescriptions for hydromorphone than among those who filled prescriptions for non-hydromorphone opioids (2·8% [109 patients] vs 1·1% [41 patients]; adjusted OR 2·5, 95% CI 1·8-3·7, p<0·0001). This significant association was seen for controlled-release hydromorphone (3·9% [73 of 1895 patients] vs 1·1% [20 of 1895]; adjusted OR 3·3, 95% CI 2·1-5·6, p<0·0001), but not for immediate-release hydromorphone (1·8% [36 of 1989] vs 1·1% [21 of 1989]; 1·7, 0·9-3·6, p=0·072. Among people who inject drugs, the risk of infective endocarditis is significantly higher for those exposed to controlled-release hydromorphone than to other opioids. This association might be mediated by the controlled-release mechanism and should be the subject of further investigation. Ontario Ministry of Health and Long-Term Care, Academic Medical Organization of Southwestern Ontario, Schulich School of Medicine and Dentistry (Western University), and Lawson Health Research Institute.

A controlled-release oral opioid supports S. aureus survival in injection drug preparation equipment and may increase bacteremia and endocarditis risk.

BackgroundInjection drug use-associated endocarditis (IDUaIE) incidence in Ontario has recently been associated with hydromorphone prescribing rates. Staphylococcus aureus causes the majority of cases of IDUaIE in Ontario and across North America. Hydromorphone controlled-release (Hydromorphone-CR) requires a complex technique for injection and therefore provides multiple opportunities for contamination. Hydromorphone-CR contains several excipients, which could enhance staphylococcal survival and increase risk of contaminating the injectate.MethodsUsed injection drug preparation equipment (cookers/filters) was collected from persons who inject drugs (PWID), rinsed with water, and plated on Mannitol salt agar. Bacterial isolates from bacteremic PWID were used to assess the survival of S. aureus and Streptococcus pyogenes on cookers/filters with Hydromorphone-CR, hydromorphone immediate-release (Hydromorphone-IR) or oxycodone controlled-release (Oxycodone-CR). The solutions spiked with S. aureus were heated and the remaining viable bacteria enumerated.ResultsS. aureus was detected in 12/87 (14%, 95%CI 8–23%) cookers/filters samples used for injection of Hydromorphone-CR. Hydromorphone-CR was the only opioid associated with greater survival of methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) on cookers/filters when compared to sterile water vehicle control. There was a ~2 log reduction in the number of S. aureus that survived when cookers/filters were heated.Conclusion14% of all cookers/filters used in the preparation of Hydromorphone-CR were contaminated with S. aureus. Hydromorphone-CR prolongs the survival of MRSA and MSSA in cookers/filters. Heating cookers/filters may be a harm-reduction strategy.

1023. A Controlled-Release Prescription Oral Opioid Can Prolong S. aureus Survival in Injection Drug Preparation Equipment and Potentially Increase Bacteremia Risk

Background S. aureus is the most common pathogen associated with injection drug use-associated endocarditis (IDUaIE). Our center has a high incidence of IDUaIE and the opiate of choice in our population is hydromorphone-controlled release (HCR), a prescribed oral opiate widely used in Canada and Europe. The complex technique for preparation for injection provides multiple opportunities for contamination of the solution and the controlled-release preparation contains several excipients (carbohydrates, protein, and iron), which could enhance Staphylococcal survival. A large amount of drug remains in the injection drug preparation equipment (IDPE) after each use and therefore, used IDPE is saved by people who inject drugs (PWID) for subsequent reuse by adding more water and then injecting the solution intravenously.MethodsUsed IDPE was collected from active PWID, rinsed with sterile water, aspirated into a syringe in a technique which mimicked reuse of equipment by PWID, and then plated on Mannitol salt agar (MSA). Bacterial isolates from local bacteremic PWID were used to test the survival of S. aureus (MRSA and MSSA) and S. pyogenes on unused IDPE with HCR or hydromorphone immediate release (HIR). The solutions were aspirated using techniques similar to that of local PWID and then plated on MSA and Blood agar.ResultsA total of 109 used IDPE samples were collected between March 2017 and March 2018. S. aureus was detected in 15/94 (16%) IDPE samples that had been used for injection of HMC (seven MRSA, seven MSSA, and two borderline resistant [one sample contained both MRSA and MSSA]), but 0/15 (0%) samples used for hydromorphone immediate release (HIR). HCR, but not HM, was associated with greater survival of MSSA and MRSA (but not S. pyogenes) in solutions of the drug when compared with sterile water vehicle control (Figure 1). There was a 2-log reduction in the number of viable S. aureus when IDPE containing HCR solutions spiked with MRSA or MSSA were heated with a cigarette lighter until bubbling (<10 seconds).ConclusionIDPE that has been used in the preparation of HCR is frequently contaminated with S. aureus; and in vitro HCR, but not HM, prolongs the survival of MRSA and MSSA. Heating IDPE may be an effective harm-reduction strategy to reduce bacterial complications of injection of HCR. Disclosures All authors: No reported disclosures.

Efficacy of a new once daily hydromorphone formulation in comparison with twice daily administration in chronic pain: a randomized, double-blind, cross-over study

Objective Efficacy and safety of a novel multiple-unit hydromorphone once daily (HOD) was compared to an established hydromorphone twice daily (HTD) regimen in patients with moderate-to-severe chronic pain.Design and methods The results from a randomized, double-blind, multicenter, cross-over trial in patients (n = 37) with chronic malignant or non-malignant pain are reported. The primary efficacy parameter was current pain on 0–100 mm VAS assessed four times daily and prior to intake of rescue medication (immediate-release hydromorphone) throughout the last 5 days with each treatment (after an 8 day build-up period to avoid carry-over effects). Total daily dose of hydromorphone (TDD: 8–32 mg/day) was kept stable during the double-blind treatment phase.Results The difference observed in mean current pain (−0.92 mm VAS) over the 5 day assessment period between HOD and HTD (28.44 mm vs. 29.36 mm VAS) was found to lack clinical relevance, as the 95% CI (−4.10 to 2.28 mm VAS) did not exceed the prespecified limit for non-inferiority of 9 mm VAS. Results from the full analysis set were consistent with per protocol data confirming robustness, as did the data for 12 h recalled pain assessed at 08:00 h and 20:00 h, showing no significant differences between once and twice daily medication. Both treatments produced effective and stable pain control with only minor day-to-day and intra-day fluctuations. Switching between treatments was suitable, considering both efficacy and safety, as no relevant or significant differences in adverse events were seen (25.0% HOD, 24.3% HTD). Most frequently typical side-effects of opioid therapy were observed, such as nausea, vomiting and headache.Conclusion Although this study was of short duration and included a limited number of patients, the results confirm that the new HOD is as effective and safe as the established HTD.

A prospective multicentre study to evaluate the efficacy and tolerability of osmotic release oral system (OROS) hydromorphone in opioid-naive cancer patients: Results of the Korean South West Oncology Group study.

Osmotic release oral system (OROS) hydromorphone is a potent, long-acting opioid analgesic, effective and safe for controlling cancer pain in patients who have received other strong opioids. To date, few studies have examined the efficacy of hydromorphone for pain relief in opioid-naive cancer patients. A prospective, open-label, multicentre trial was conducted to determine the efficacy and tolerability of OROS hydromorphone as a single and front-line opioid therapy for patients experiencing moderate to severe cancer pain. OROS hydromorphone was administered to patients who had not previously received strong, long-acting opioids. The baseline evaluation (visit 1) was followed by two evaluations (visits 2 and 3) performed two and 14 weeks later, respectively. The starting dose of OROS hydromorphone was 4 mg⁄day and was increased every two days when pain control was insufficient. Immediate-release hydromorphone was the only accepted alternative strong opioid for relief of breakthrough pain. The efficacy, safety and tolerability of OROS hydromorphone, including the effects on quality of life, and patients' and investigators' global impressions on pain relief were evaluated. The primary end point was pain intensity difference (PID) at visit 2 relative to visit 1 (expressed as %PID). A total of 107 patients were enrolled in the present study. An improvement in pain intensity of >50% (≥50% PID) was observed in 51.0% of the full analysis set and 58.6% of the per-protocol set. The mean pain score, measured using a numerical rating scale, was significantly reduced after two weeks of treatment, and most adverse events were manageable. Quality of life also improved, and >70% of patients and investigators were satisfied with the treatment. OROS hydromorphone provided effective pain relief and improved quality of life in opioid-naive cancer patients. As a single and front-line treatment, OROS hydromorphone delivered rapid pain control.

Complementary pharmacokinetic measures to further define the profile of once-daily OROS hydromorphone ER during single-dose and steady-state dosing

Conventional measures such as maximum plasma concentration (Cmax) and area under the concentration versus time curve (AUC) may be insufficient to fully describe the pharmacokinetic (PK) profile of extended-release (ER) formulations. A complementary measure, the half-value duration (HVD), corresponds to the period of time during a dosing cycle that plasma concentration is at or above half the value of the maximal concentration (i.e. ≥50% Cmax). The current post-hoc analysis uses data from 2 previously published studies comparing the PK profiles and HVD of OROS hydromorphone ER (16 mg administered once daily) and immediate-release (IR) hydromorphone (4 mg administered every 6 hours), calculating single-dose and steady-state condition values. Bioequivalence was demonstrated between the 2 formulations. Mean steady-state once-daily OROS hydromorphone ER concentrations were elevated for most of the 24-hour dosing period and for significantly longer than with the dose-equivalent IR hydromorphone regimen. The duration of time spent ≥50% Cmax was, on average, 2.7 times longer at steady state for the ER formulation, which also maintained steady-state hydromorphone plasma concentrations, with 65% lower mean degree of fluctuation versus IR hydromorphone. Both formulations appeared to be well tolerated.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-2-625) contains supplementary material, which is available to authorized users.

Abuse liability of oral formulations of hydromorphone in opioid-experienced, recreational drug users: importance of onset of effect

Rate of onset is an important determinant of the abuse liability of opioid formulations. OROS hydromorphone ER is a once-daily opioid formulation that releases hydromorphone at a controlled rate. The objective of this study was to compare the abuse-related effects of various formulations of hydromorphone, with particular emphasis on early time intervals after drug administration. This was a double-blind, placebo-controlled, randomized study in subjects (N=28) with a history of recreational opioid use. In phase A, subjects received immediate-release (IR) hydromorphone 8 mg, intact OROS hydromorphone ER 16 and 32 mg, a milled preparation of OROS hydromorphone ER 8 mg, and placebo in a crossover design. In phase B, subjects who tolerated all treatments in Phase A received single doses of IR hydromorphone (8 mg) and OROS hydromorphone ER (64 mg). Time to maximum effect (TEmax) and area under the effect curve at 2 hours (AUE0-2) were assessed for subject-rated outcomes of “high”, “drug liking”, and “euphoria”. All formulations produced effects significantly different than placebo (P<0.05). For all subject-rated outcomes, the TEmax for all intact doses of OROS hydromorphone ER (range: 7.8-13.3 hours) was greater than the TEmax for 8 mg IR hydromorphone (range: 2.4-3.5 hours) (P<0.05). For AUE0-2, all intact doses of OROS hydromorphone ER produced significantly lower levels of “high” and “euphoria” compared with 8 mg hydromorphone IR (P<0.05). The effects of milled OROS hydromorphone ER were similar to those of IR hydromorphone. The slower onset of effect and decreased reports of “high” and “euphoria” suggest that OROS hydromorphone ER may have less abuse liability than IR hydromorphone when intact tablets are taken whole. Technical editorial and writing assistance provided by Synchrony Medical, LLC, funded by Mallinckrodt Inc., a Covidien company, Hazelwood, MO. Rate of onset is an important determinant of the abuse liability of opioid formulations. OROS hydromorphone ER is a once-daily opioid formulation that releases hydromorphone at a controlled rate. The objective of this study was to compare the abuse-related effects of various formulations of hydromorphone, with particular emphasis on early time intervals after drug administration. This was a double-blind, placebo-controlled, randomized study in subjects (N=28) with a history of recreational opioid use. In phase A, subjects received immediate-release (IR) hydromorphone 8 mg, intact OROS hydromorphone ER 16 and 32 mg, a milled preparation of OROS hydromorphone ER 8 mg, and placebo in a crossover design. In phase B, subjects who tolerated all treatments in Phase A received single doses of IR hydromorphone (8 mg) and OROS hydromorphone ER (64 mg). Time to maximum effect (TEmax) and area under the effect curve at 2 hours (AUE0-2) were assessed for subject-rated outcomes of “high”, “drug liking”, and “euphoria”. All formulations produced effects significantly different than placebo (P<0.05). For all subject-rated outcomes, the TEmax for all intact doses of OROS hydromorphone ER (range: 7.8-13.3 hours) was greater than the TEmax for 8 mg IR hydromorphone (range: 2.4-3.5 hours) (P<0.05). For AUE0-2, all intact doses of OROS hydromorphone ER produced significantly lower levels of “high” and “euphoria” compared with 8 mg hydromorphone IR (P<0.05). The effects of milled OROS hydromorphone ER were similar to those of IR hydromorphone. The slower onset of effect and decreased reports of “high” and “euphoria” suggest that OROS hydromorphone ER may have less abuse liability than IR hydromorphone when intact tablets are taken whole. Technical editorial and writing assistance provided by Synchrony Medical, LLC, funded by Mallinckrodt Inc., a Covidien company, Hazelwood, MO.

Efficacy and tolerability of OROS hydromorphone extended release in patients with moderate to severe osteoarthritis pain: a phase 3, flexible-dose, randomized, double-blind, placebo-controlled study

This randomized, placebo-controlled, double-blind study evaluated OROS hydromorphone ER for reducing moderate-to-severe osteoarthritis pain. The study consisted of a conversion/titration phase (1-4 weeks) and double-blind phase (12 weeks), with enriched enrollment randomized withdrawal design. During conversion/titration, opioid-tolerant patients were converted to OROS hydromorphone ER at ∼75% of the equianalgesic dose of their previous opioid dosage (5:1 morphine:hydromorphone), using dosages of 8-48 mg/d. Immediate-release hydromorphone (2-16 mg/d) was provided as rescue medication. On days 1-14 of double-blind treatment, patients randomized to placebo + rescue medication had OROS hydromorphone ER doses tapered to discontinuation (blind was maintained); remaining patients were maintained at their stable dose. The primary outcome measure was change from baseline to Week 12 in mean pain intensity. Three hundred thirty-four patients entered conversion/titration; 200 were randomized (100 to each group). Mean pain intensity decreased from 6.9 at screening to 3.0 at end of conversion/titration. During double-blind treatment, reductions in pain intensity were generally maintained in both treatment groups (mean [SE], 3.6 [0.2] at Week 12 for both groups), with no significant differences between treatment groups. Patients receiving placebo + rescue medication used significantly more rescue medication tablets/day than those receiving active treatment (mean [SE], 1.5 [0.1] vs 1.1 [0.1]; P=0.006). Commonly reported AEs during conversion/titration (constipation. 17.5%; nausea, 15.7%; somnolence, 8.3%) and double-blind treatment (constipation, 20.0%; nausea, 14.0%; vomiting, 9.0%) occurred more frequently in patients receiving OROS hydromorphone ER. Using the present trial design, there was failure to demonstrate sustained efficacy of active treatment versus placebo + rescue medication, perhaps due to higher use of rescue medication in the latter group. Technical editorial and writing assistance provided by Synchrony Medical, LLC, funded by Mallinckrodt Inc., a Covidien company, Hazelwood, MO.

Dose Equivalence of Immediate-Release Hydromorphone and Once-Daily Osmotic-Controlled Extended-Release Hydromorphone: A Randomized, Double-Blind Trial Incorporating a Measure of Assay Sensitivity

Dose selection of a once-daily, osmotic-controlled extended-release (ER) hydromorphone assumes that this drug and immediate-release (IR) hydromorphone are dose equivalent. This trial evaluated dose equivalence using a measure of assay sensitivity. Patients were converted to open-label IR hydromorphone, underwent dose titration, and those on a satisfactory dose entered a randomized, double-blind phase receiving 7 days of: 1) hydromorphone IR 5 times/day at approximately this dose; 2) once-daily hydromorphone ER at this dose; or 3) once-daily hydromorphone ER at one-half this dose. Efficacy was measured using breakthrough medication use, pain, sleep, and global assessments. Of 148 patients, 113 (76%) were randomized. IR and full-dose ER groups produced comparable effects on all measures. Although the prespecified primary analysis of the difference in total daily dose of breakthrough medication between the full-dose ER and half-dose ER groups was not significant, more patients in the half-dose ER group required an increase in breakthrough medication (P = .026) and the half-dose ER group both increased the number of breakthrough doses (P = .026) and had greater percent change in the total daily dose of breakthrough medication (P = .037) than the full-dose group, suggesting that switching from IR to ER hydromorphone at the same daily dose provides equivalent analgesia. PerspectiveIn a randomized, double-blind trial, the same total daily dose of immediate-release hydromorphone and once-daily osmotic-controlled extended-release hydromorphone had comparable effects. Detection of different effects between blinded dose levels was used as a measure of assay sensitivity. The measure of assay sensitivity can enhance the interpretation of dose equivalence or noninferiority trials.

P-37 - The effect of pharmacokinetic parameters on euphoria, drug liking following different oral hydromorphone formulations in opioid-experienced, non-dependent, recreational drug users

One factor of opioid attractiveness with recreational abuse is the rate of drug absorption and corollary pharmacodynamic experience. In this study, the relationship between abuse potential and the pharmacokinetic profile (maximum plasma concentration [Cmax] and time to maximum plasma concentration [Tmax]) of differing formulations of hydromorphone and placebo was explored in recreational drug users. This post-hoc analysis of a double-blind, placebo-controlled, randomized, 2-phase, crossover study of subjects with histories of recreational opioid use who received single oral doses of placebo and of 2 formulations of hydromorphone: immediate-release (IR) hydromorphone 8 mg (Dilaudid®) and once-daily hydromorphone extended-release (ER) (EXALGOtm) at doses of 16, 32, and 64 mg intact and 8 mg milled to disrupt the extended-release properties of EXALGO tablets. When adjusted for dose, Cmax for all intact once-daily hydromorphone ER treatments, yielded significantly lower Cmax compared with 8-mg IR hydromorphone ( P < 0.001). Tmax was delayed and AQ (Cmax/Tmax) was lower with all intact once-daily hydromorphone ER doses compared with 8 mg IR hydromorphone. In the 28 subjects completing all treatments and included in the final analyses, the intact once-daily hydromorphone ER formulations had significantly lower liking and euphoria effects for the first 4 hours ( P < 0.05) compared with the 8 mg IR and 8 mg milled hydromorphone ER tablets. If liking and euphoria effects drives opioid use, then once-daily hydromorphone ER intact may be less attractive than IR hydromorphone or hydromorphone ER milled. Delaying the peak in plasma concentrations may be associated with reduced abuse liability.

A Randomized Study of the Effects of Food on the Pharmacokinetics of Once-Daily Extended-Release Hydromorphone in Healthy Volunteers

This randomized, open-label, crossover study investigated the influence of food on the pharmacokinetics of extended-release hydromorphone in 30 healthy volunteers. Participants received extended-release hydromorphone 16 mg in the fasted state and immediately after a high-fat breakfast. In addition, the pharmacokinetics of a 16-mg dose of extended-release hydromorphone and a 16-mg daily dose (4 mg qid) of immediate-release hydromorphone in the fasted state were compared. Treatments were separated by washout periods of 7 to 14 days. Naltrexone was given throughout each treatment period to block the opioid effects of hydromorphone. The 90% confidence intervals (CIs) of the ratios of geometric means for maximum plasma concentrations (C(max)) and area under the plasma concentration-time curve (AUC) for extended-release hydromorphone in the fed and fasted states were within the bioequivalence criteria range of 80% to 125%. In the fasted state, the 90% CIs of the ratios of AUC geometric means for extended-release hydromorphone and immediate-release hydromorphone were also within the bioequivalence range. Both hydromorphone treatments were well tolerated. This study shows that the bioavailability of extended-release hydromorphone is not affected by food and that the bioavailability of extended-release hydromorphone under fasting conditions is comparable with that of the immediate-release formulation when administered at the same total daily dose.

T621 EFFICACY AND SAFETY OF IMMEDIATE-RELEASE HYDROMORPHONE FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN PALLIATIVE CARE PATIENTS WITH CANCER PAIN

European Journal of Pain SupplementsVolume 5, Issue S1 p. 86-87 T621 EFFICACY AND SAFETY OF IMMEDIATE-RELEASE HYDROMORPHONE FOR THE MANAGEMENT OF BREAKTHROUGH PAIN IN PALLIATIVE CARE PATIENTS WITH CANCER PAIN K.E. Clemens, K.E. Clemens Department of Palliative Medicine, MediClin Robert Janker Klinik Bonn, Bonn, GermanySearch for more papers by this authorE. Klaschik, E. Klaschik Department of Palliative Medicine, MediClin Robert Janker Klinik Bonn, Bonn, GermanySearch for more papers by this author K.E. Clemens, K.E. Clemens Department of Palliative Medicine, MediClin Robert Janker Klinik Bonn, Bonn, GermanySearch for more papers by this authorE. Klaschik, E. Klaschik Department of Palliative Medicine, MediClin Robert Janker Klinik Bonn, Bonn, GermanySearch for more papers by this author First published: 30 January 2012 https://doi.org/10.1016/S1754-3207(11)70295-4Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume5, IssueS1September 2011Pages 86-87 RelatedInformation

Characterization of the steady-state pharmacokinetic profile of once-daily hydromorphone ER (OROS hydromorphone) versus IR hydromorphone in healthy volunteers

OROS® hydromorphone is a once-daily, extended-release (ER) formulation of hydromorphone that produces sustained, monophasic delivery of hydromorphone over 24 hours. A previous study in healthy volunteers has demonstrated that once-daily hydromorphone ER 16 mg reaches steady state after 4 days. At steady state, the mean (± SD) degree of peak-to-trough fluctuation in plasma concentration was 60.5% ± 41.1% for once-daily hydromorphone ER compared with 172% ± 57.6% with immediate-release (IR) hydromorphone.

Steady-state pharmacokinetics of extended-release hydromorphone (OROS® hydromorphone): A randomized study in healthy volunteers

The steady-state pharmacokinetics of an extended-release formulation of hydromorphone, OROS hydromorphone, was investigated in a randomized, open-label, crossover study in healthy volunteers. Participants were randomly assigned to receive 16 mg of OROS hydromorphone once daily and 4 mg of immediate-release hydromorphone four times daily for five consecutive days. The two treatments were separated by a washout period of 7-14 days. Naltrexone was given throughout both treatment periods to block the opioid effects of hydromorphone. Steady-state hydromorphone concentrations were statistically analyzed using Helmert contrasts to determine when steady state was reached. A total of 30 participants were enrolled, of whom 29 completed both treatment periods. The two treatments produced comparable steady-state plasma drug concentrations, but peak-to-trough fluctuations were smaller with OROS hydromorphone (61 percent vs 172 percent) in comparison with immediate release hydromorphone. Overall systemic exposure to hydromorphone was similar between the two formulations. The ratio of the geometric means between the two formulations for the area under the concentration-time curves at steady state was 105.2 percent with a 90% confidence interval (CI) of 99.8-110.8 (geometric mean: 102.7 percent; 90% CI: 97.6-108.2 after correcting for measured drug content), which was within the bioequivalence range (80-125 percent). The analysis of Helmert contrasts showed that steady state conditions were attained by day 4. Both treatments were well tolerated. This study shows that OROS hydromorphone maintains steady-state plasma drug concentrations within the same range as immediate-release hydromorphone at the same total daily dose, with less fluctuation.

A randomized, double-blind study of OROS hydromorphone extended release (ER) compared to placebo in opioid-tolerant patients with moderate-to-severe osteoarthritis (OA) pain

Chronic pain associated with osteoarthritis (OA) contributes substantially to both individual disability and societal healthcare burden and often requires treatment with around-the-clock opioids. This was a 12-week, randomized, placebo-controlled, double-blind trial evaluating the efficacy and safety of once-daily OROS hydromorphone ER in the treatment of chronic OA in opioid-tolerant patients. Patients who had a diagnosis of moderate-to-severe chronic OA and required daily scheduled opioid analgesics (oral morphine equivalent doses between 40 - 320 mg/day) for ≥2 months prior to screening, were eligible for inclusion. Following a dose conversion, patients were enrolled in a 1-4 week titration phase. Those patients who established a stable dose of study medication were randomized to receive either OROS hydromorphone ER (individually titrated to 12, 16, 24, 32, 40, 48, or 64 mg doses) or placebo. Immediate-release hydromorphone (2, 4, or 8 mg) was supplied as rescue medication. The primary efficacy variable was the mean change from baseline to week 12 or final visit in average weekly pain intensity scores on 11-point Numeric Rating Scale (NRS) obtained from patient diaries. Secondary efficacy variables included the mean change from baseline to the entire 12-week treatment phase (AUC analysis) based on diary NRS scores, mean change from baseline to each post-baseline clinic visit based on visit NRS scores, time to treatment failure, patient global assessments, disability assessment, rescue medication use, and total drop-out analysis. Safety assessments included overall adverse events (AEs), serious AEs, vital signs, standard laboratory tests, and ECG. Full efficacy and safety results will be presented. (Supported by Neuromed Pharmaceuticals and Covidien Pharmaceuticals.)

Use of Hydromorphone, with Particular Reference to the OROS® Formulation, in the Elderly

The prevalence of pain increases with age. However, pain is often inadequately managed in elderly people, which undermines quality of life. Pain has been associated with depression, sleep disturbances, impaired ambulation, and increased healthcare use and costs. Effective treatment of pain improves the overall quality of life. However, pain management is complicated by the presence of multiple co-morbidities in elderly people, which increases the likelihood of polypharmacy, and therefore increases the chance of potential drug-drug interactions. Polypharmacy is also associated with poor adherence to therapy. Age-related pharmacokinetic and pharmacodynamic changes reduce the therapeutic index of drugs. Therefore, elderly people are more likely to suffer from adverse events and increased sensitivity to the analgesic properties of opioids. OROS hydromorphone (Jurnista) is a once-daily, extended-release formulation that uses the OROS push-pull technology to provide controlled release of the semi-synthetic opioid hydromorphone. Compared with conventional immediate-release hydromorphone, OROS hydromorphone provides more consistent delivery of hydromorphone with lower peak concentrations and less variability in plasma concentrations over time. The bioavailability of hydromorphone from OROS hydromorphone is minimally affected by food or alcohol (ethanol). Hydromorphone is mainly metabolized in the liver and is excreted in the urine. Unlike morphine, hydromorphone does not have an active 6-glucuronide metabolite. This metabolite of morphine can accumulate in the presence of renal failure; therefore, the lack of an active 6-glucuronide metabolite makes hydromorphone a useful alternative to morphine in elderly patients with renal failure. However, hydromorphone is similar to morphine in that it is metabolized to hydromorphone-3-glucuronide, which may be neuroexcitatory. Because of its low plasma protein binding and low probability of interfering with the metabolism of other drugs, hydromorphone may be especially suitable for patients taking multiple medications. OROS hydromorphone is an effective analgesic that is well tolerated and provides more stable plasma concentrations than immediate-release forms of hydromorphone. Its once-daily administration offers an advantage over immediate-release forms and longer-acting formulations that require twice-daily administration. This means OROS hydromorphone will be more convenient for elderly patients and may improve adherence, resulting in improved pain relief and quality of life.

Evaluation of the Abuse Potential of Extended Release Hydromorphone Versus Immediate Release Hydromorphone

Immediate release (IR) hydromorphone has experienced significant misuse and abuse. An extended release (ER) hydromorphone formulation has been developed to provide sustained pain relief and may reduce the likelihood for abuse by delaying absorption. In this double-blind, placebo-controlled, randomized, 2-part crossover study, the abuse potential of single oral doses of hydromorphone ER (intact: 16-, 32-, and 64-mg; milled: 8-mg) was compared with 8-mg hydromorphone IR and placebo. After drug administration, subjects with a history of recreational opioid use completed a series of assessments, including subjective effects visual analog scales (eg, drug liking) and Addiction Research Center Inventory With Cole Modification, at several timepoints up to 48 hours postdose. Independent of formulation, maximum at-the-moment drug liking was higher for hydromorphone versus placebo. Maximum drug liking occurred earlier and was higher for 8-mg IR versus 16-mg ER but similar to 32- and 64-mg ER. Most positive effects were lower after 16-mg ER compared with other doses, including 8-mg IR. Bad drug effects were higher for hydromorphone ER, particularly the 64-mg dose. Milled 8-mg ER produced similar subjective effects to 8-mg IR. Comparison of scores after administration of 8-mg IR on 2 separate occasions showed that most assessments exhibited good test-retest reliability, although some scores declined marginally between test and retest. Delayed onset of good drug effects and prominent bad drug effects of hydromorphone ER suggest that, when administered intact, this formulation may have lower abuse potential than hydromorphone IR.

Correlates of Nonmedical Use of Hydromorphone and Hydrocodone

Over the past decade, the misuse and abuse of opioid medications in the United States has risen dramatically. Although data show a substantial variation in the nonmedical use of individual opioids, relatively little is known about risk factors for the nonmedical use of specific opioid products. This study compared the prevalence and correlates of the nonmedical use of oral immediate-release hydromorphone (marketed under the brand name of Dilaudid), versus that of hydrocodone combination products using a nationally representative sample of the civilian noninstitutionalized United States population aged 12 years or older. Data were from the 2003 National Survey on Drug Use and Health. An estimated 31.3 million individuals reported lifetime nonmedical use of an opioid analgesic. Of these, 2.9 percent reported lifetime nonmedical use of Dilaudid, and 51.9 percent reported lifetime nonmedical use of hydrocodone combination products exclusive of nonmedical Dilaudid use. Nonmedical Dilaudid users were likely to be older, Caucasian, and to have reported a higher lifetime prevalence of heroin, cocaine and injection drug use, as well as nonmedical use of other opioids. Nonmedical Dilaudid users were at higher risk for engaging in more serious substance abuse-related behaviors than those who reported lifetime nonmedical use of hydrocodone combination products.

Multicenter, open-label, prospective evaluation of the conversion from previous opioid analgesics to extended-release hydromorphone hydrochloride administered every 24 hours to patients with persistent moderate to severe pain

Background: Hydromorphone hydrochloride is a μ-opioid agonist with dose-dependent analgesic properties. Extended-release hydromorphone hydrochloride (ER hydromorphone HCl) capsules have been developed for administration every 24 hours. Objectives: This prospective evaluation focused on the first (ie, conversion) phase of 2 identically designed, randomized, controlled studies that compared the safety and efficacy of once-daily ER hydromorphone HCl capsules with immediate-release hydromorphone hydrochloride (IR hydromorphone HCl) tablets administered 4 times daily in the treatment of persistent moderate to severe cancer- and noncancer-related pain. Methods: Patients being treated with opioid analgesics for persistent moderate to severe pain were conerted to ER hydromorphone HCl using an 8:1 conversion ratio. The dose was titrated to attain an average pain intensity (API) score ≤ 4 on a 0- to 10-point numeric rating scale. Supplemental oral IR hydromorphone HCl tablets were used as rescue medication at a dose of one eighth to one sixth of the daily ER hydromorphone HCl dose. Results: A total of 343 patients (272 [79%] with cancer pain; mean age, 57.8 years) were enrolled and converted to ER hydromorphone HCl from their previous opioids. About half (51%) were women. At baseline, the mean (SD) API score was 5.3 (2.1). Mean (SD) API scores were 4.7 (2.0) after the first 48 hours and 3.4 (2.1) by the end of titration. After 4 to 21 days of titration, 239 (70%) patients reached stabilization defined as a ≥ 48-hour period with an API score of ≤4, unchanged ER hydromorphone HCl dose, and ≤ 2 rescue doses per day. The stabilized patients had mean (SD) API scores of 2.7 (1.1) at the end of titration. At stabilization, 102 (43%) of 239 patients remained at their initial conversion dose, 129 (54%) had a dose increase, and 8 (3%) had a dose decrease. Frequent (≥10% of patients) adverse events that occurred within the first 48 hours after conversion and during the entire titration phase were nausea, somnolence, headache, constipation, vomiting, and dizziness. Conclusion: In this prospective evaluation of theconversion and titration phase of 2 randomized, controlled studies, a conversion ratio of 8:1 mg of oral morphine to oral ER hydromorphone HCl was found to be clinically useful in patients with persistent moderate to severe cancer-related or noncancer-related pain.