Hydromorphone-3-glucuronide Research Articles

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).

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). 6 healthy adult great horned owls (3 females and 3 males). 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. 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. 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.

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.

Detecting opioid metabolites in exhaled breath condensate (EBC)

Exhaled breath condensate (EBC) collection provides a promising matrix for bioanalysis of endogenous biomarkers of health and also for exogenous compounds like drugs. There is little information regarding drugs and their metabolites contained in breath, as well as their pharmacokinetics. In this present work, we use a simple and non-invasive technique to collect EBC from chronic pain patients using different analgesic opioid drugs to manage pain. Six patients received continuous infusion of morphine and hydromorphone intravenously (IV), together with other analgesic drugs (IV and orally). Repeated sampling of serum and EBC was done at two time points separated by 90 min. The EBC was collected using a glass tube surrounded by dry ice, and an ethanol solvent wash of the glass was performed after EBC extraction to retrieve the apolar compounds stuck to the glass surface. All samples were analyzed with liquid chromatography coupled to mass spectrometry (LC-MS/MS) to identify possible metabolites present in the sample, and to quantify the drugs being used. Several metabolites, such as normorphine (norM), norhydromorphone (norHM) and dihydromorphone (diHM) were detected in both fractions, while hydromorphone 3-glucuronide (HM 3G) was only detected in the solvent rinse fraction. Results were correlated to explain the pharmacokinetics of the main drugs administered. This pilot study presented promising correlations between drug concentrations in blood and breath at different time points for norM, norHM and HM 3G.

Pain management in chronic kidney disease: The pharmacokinetics and pharmacodynamics of hydromorphone and hydromorphone-3-glucuronide in hemodialysis patients

To describe the pharmacokinetics of hydromorphone (HM) and its primary metabolite hydromorphone-3-glucuronide (H3G) both on and off dialysis in relation to the pharmacodynamic measurements of pain. Prospective, open-label, observational study. Canadian, university-based renal program. Twelve anuric hemodialysis patients with chronic pain, established on immediate-release HM. HM and H3G plasma concentrations were measured during and between hemodialysis treatments using a reverse-phase high-performance liquid chromatography assay with liquid chromatography/mass spectrometer/mass spectrometer detection. The McGill Pain Questionnaire (MPQ) and a Visual Analogue Scale (VAS) were used to measure pain. Noncompartmental analyses were conducted. Adverse effects were recorded. HM did not substantially accumulate (accumulation factor R = 2.7 (1.6)), most likely due to the rapid conversion to H3G. Conversely, H3G accumulated between dialysis treatments (R = 12.5 (12.1)) but appeared to be effectively removed during hemodialysis (1.8 (0.7), p = 0.03). HM resulted in > 65 percent reduction in pain over dosing intervals. Mean MPQ pain scores decreased from 39.8 (18.2) to 12.3 (16.2) on dialysis and from 35.0 (18.5) to 15.5 (13.6) between dialysis treatments. Mean VAS pain scores decreased from 7.5 (2.5) to 3.0 (1.5) on dialysis and from 5.9 (3.2) to 4.4 (1.6) between dialysis treatments. No clinically significant opioid toxicity was observed. The accumulation of H3G between hemodialysis treatments was associated with greater sensory-type pain (r = 0.76, p < 0.0001) and reduced duration of analgesia. HM may be a safe and effective opioid for use in selected hemodialysis patients.

Incidence of Hydromorphone-Induced Neuroexcitation in Hospice Patients

To date, there are no known published studies that prospectively followed hospice patients receiving hydromorphone to evaluate the development of hydromorphone-induced neuroexcitation (HINE). The first objective of this study was to determine the incidence of HINE. The second objective was to identify factors influencing the presence or absence of HINE symptoms in hospice patients. This was a noninterventional, prospective study. This study population included hospice patients 18 years of age or older who were admitted to one of two Nathan Adelson Hospice inpatient units in Las Vegas, Nevada, and were initiated on a scheduled regimen of hydromorphone. A total of 156 patients were enrolled and analyzed in this study. Data collection was performed by the study investigators using a standard data tracking form, including hospice diagnosis, gender, renal function, hydromorphone regimen, and whether or not the patient experienced neuroexcitatory symptoms. Data collection occurred from November 2010 to March 2011. Based on the data collected in this study, it appears that the likelihood of HINE does increase with larger doses, increasing age, increasing serum creatinine, and the presence of malignant neoplasm. However, after adjusting for the variables in the logistic regression model, diagnosis of malignant neoplasm was not a significant predictor of HINE. Future studies may focus on evaluating metabolite levels, such as hydromorphone-3-glucuronide (H3G), in patients developing HINE symptoms. This may help to determine if the metabolites of opioids, such as H3G, are involved in the development of the neurotoxic symptoms.

Morphine and Hydromorphone-Induced Hyperalgesia in a Hospice Patient

Opioids including morphine and hydromorphone are widely used for control of moderate to severe pain and dyspnea in hospice and palliative care patients. Accumulation of the active morphine-3-glucuronide (M3G) and hydromorphone-3-glucuronide (H3G) metabolites is one proposed mechanism for the development of neuroexcitatory effects including allodynia and opioid-induced hyperalgesia (OIH). We report the case of a 43-year-old female hospice patient with metastatic non-small cell lung cancer who initially developed allodynia following morphine administration and again following administration of hydromorphone. The allodynia resolved both times following the discontinuation of the opioid and rotation to a different opioid regimen. Potential opioid-induced neuroexcitatory treatment options include opioid rotation to an agent with inactive metabolites, use of adjuvant pain medications for opioid-sparing effects, management of undesired symptoms (e.g., myoclonus), or increasing opioid clearance with intravenous (IV) fluids. Although the incidence is not well defined in the literature, hospice and palliative care clinicians should suspect OIH in patients with allodynia and/or hyperalgesia, especially when repeated dose escalations do not improve analgesia or pain escalates following opioid dose titration.

Adverse Effects in Hospice Patients with Chronic Kidney Disease Receiving Hydromorphone

Pain is one the most common symptoms experienced by palliative care patients. The treatment of pain involves the use of strong opioids such as hydromorphone, morphine, methadone, fentanyl, oxycodone, oxymorphone, or levorphanol for moderate to severe pain. Hydromorphone is metabolized by the liver to hydromorphone-3-glucuronide (H3G), a compound that can potentially cause neuroexcitatory phenomena with accumulation. Pharmacokinetic studies have shown that H3G levels in patients with renal insufficiency are 4 times as high as those with normal renal function; however, reports have been conflicting as to whether or not it is safe to use hydromorphone in renal insufficiency. In this study we sought to determine the prevalence of neuroexcitation in patients with renal insufficiency who were given hydromorphone, as measured by the glomerular filtration rate (GFR), and to investigate factors associated with increased risk of neuroexcitation in this patient group. For the 12- month period from June 2007 through June 2008, charts of inpatient hospice patients that showed a glomerular filtration rate of <60 (mL/min/1.73 m(2)) and hydromorphone administration for pain control via continuous infusion were reviewed for the occurrence of neuroexcitatory effects, including tremor, myoclonus, agitation, cognitive dysfunction, and seizures. Overall prevalence of neuroexcitatory effects were: tremor 11 (20%), myoclonus 11 (20%), agitation 26 (48%), and cognitive dysfunction 21 (39%). No seizures were observed. No neuroexcitatory effects were observed for the lowest quartile of dose or duration of hydromorphone. There was a strong and graded increase in neuroexcitatory effects with increasing quartile of dose or duration of hydromorphone for agitation (dose, p<0.0001; duration, p<0.0001) and cognitive dysfunction (dose, p<0.0002; duration, p<0.002). Consistent but weaker trends were observed for tremor and myoclonus. Parenteral hydromorphone has few neuroexcitatory symptoms until H3G accumulates past a neurotoxic threshold, such as might occur with increasing dose or duration, which, when exceeded, causes neuroexcitatory symptoms to manifest.

Correlation between myoclonus and the 3-glucuronide metabolites in patients treated with morphine or hydromorphone: A pilot study

The 3-glucuronide metabolites of morphine and hydromorphone have been implicated as a causative factor for patients exhibiting myoclonus. The primary goal of this study was to determine plasma levels of morphine-3-glucuronide (M3G) or hydromorphone-3-glucuronide (H3G) in patients demonstrating myoclonus and identify any trends or associations between the two. Patients were recruited from San Diego Hospice and the Institute for Palliative Medicine's inpatient unit. A prospective convenience sample comprised of 17 subjects, 12 with myoclonus and 5 without myoclonus. Analysis included demographic, metabolic and clinical variables. Plasma was assayed via high performance liquid chromatography for morphine, M3G, and morphine-6-glucuronide or hydromorphone and hydromorphone-3-glucuronide. No trends or associations were identified between plasma levels of M3G or H3G and myoclonus. Ratio levels of 3-glucuronide metabolite to their corresponding parent opioid were dramatically lower than anticipated. In this small pilot study, it appears that the serum levels of metabolites M3G and H3G do not correlate with myoclonus.

Hydromorphone-3-glucuronide: A more potent neuro-excitant than its structural analogue, morphine-3-glucuronide

In humans, hydromorphone (HMOR) is metabolised principally by conjugation with glucuronic acid to form hydromorphone-3-glucuronide (H3G), a close structural analogue of morphine-3-glucuronide (M3G), the major metabolite of morphine. In a previous study we described the biochemical synthesis of H3G together with a preliminary evaluation of its pharmacology which revealed that it is a neuro-excitant in rats in a manner analogous to M3G. Thus the aims of the current study were to quantify the neuro-excitatory behaviours evoked by intracerebroventricular (icv) H3G in the rat and to define its potency relative to M3G. Groups of adult male Sprague-Dawley rats received icv injections (1 μL) of H3G (1 – 3 μg), M3G (2 – 7μg) or vehicle via a stainless steel guide cannula that had been implanted stereotaxically seven days prior to drug administration. Behavioural excitation was monitored by scoring fifteen different behaviours (myoclonic jerks, chewing, wet-dog-shakes, rearing, tonic-clonic-convulsions, explosive motor behaviour, grooming, exploring, general activity, eating, staring, ataxia, righting reflex, body posture, touch evoked agitation) immediately prior to icv injection and at the following post-dosing times: 5, 15, 25, 35, 50, 65 and 80 min. H3G produced dose-dependent behavioural excitation in a manner analogous to that reported previously for M3G by our laboratory and reproduced herein. H3G was found to be approximately 2.5-fold more potent than M3G, such that the mean (± S.D.) ED 50 values were 2.3 (± 0.1) μg and 6.1 (± 0.6) μg respectively. Thus, our data clearly imply that if H3G crosses the BBB with equivalent efficiency to M3G, then the myoclonus, allodynia and seizures observed in some patients dosed chronically with large systemic doses of HMOR, are almost certainly due to the accumulation of sufficient H3G in the central nervous system, to evoke behavioural excitation.

Development and validation of a sensitive method for hydromorphone in human plasma by normal phase liquid chromatography–tandem mass spectrometry

Liquid chromatography coupled with tandem mass spectrometry (LC–MS–MS) was developed for the quantitation of hydromorphone (HYD), an opiate analgesic, in human plasma. A simple liquid–liquid extraction was used to extract the analyte and its deuterated internal standard (d 3-HYD). Chromatographic separation of hydromorphone from its metabolite hydromorphone-3-glucuronide (H3G) was necessary because of the significant H3G fragmentation to HYD before Q1 of the mass spectrometer, which could result in false detection as HYD in the multiple reaction mode (MRM). This separation was achieved using a 50×2 mm, I.D. silica column (5 μm) and a mobile phase of acetonitrile–water–formic acid (80:20:1, v/v/v). The method was validated in the concentration range 0.05–10 ng ml −1 in plasma and met the acceptance criteria of industry guidelines for accuracy, precision, and stability.

Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites.

1. Morphine is recommended by the World Health Organization as the drug of choice for the management of moderate to severe cancer pain. 2. Education of health professionals in the past decade has resulted in a large increase in the prescribing of opioids, such as morphine, and in the magnitude of the doses administered, resulting in an improvement in the quality of pain relief available for many cancer patients. 3. However, the reported incidence of neuroexcitatory side effects (allodynia, myoclonus, seizures) in patients administered large doses of systemic morphine or its structural analogue, hydromorphone (HMOR), has also increased. 4. Clinically, increasing the magnitude of the morphine or HMOR dose administered to patients already exhibiting neuroexcitatory opioid related side effects, results in an exacerbation rather than an attenuation of the excitatory behaviours. 5. In contrast, cessation of the opioid or rotation to a structurally dissimilar opioid (e.g. from morphine/HMOR to methadone or fentanyl), usually results in a restoration of analgesia and resolution of the neuroexcitatory opioid side effects over a period of hours to days. 6. To explain the clinical success of 'opioid rotation', it is essential to understand the in vivo metabolic fate of morphine and HMOR. 7. Following systemic administration, morphine and HMOR are metabolized primarily to the corresponding 3-glucuronide metabolites, morphine-3-glucuronide (M3G) and hydromorphone-3-glucuronide (H3G), which are not only devoid of analgesic activity but evoke a range of dose-dependent excitatory behaviours, including allodynia, myoclonus and seizures, following intracerebroventricular (i.c.v.) administration to rats. 8. Several studies have shown that, following chronic oral or subcutaneous morphine administration to patients with cancer pain, the cerebrospinal fluid (CSF) concentrations of M3G exceed those of morphine and morphine-6-glucuronide (analgesically active morphine metabolite) by approximately two- and five-fold, respectively. 9. These findings suggest that when the M3G concentration (or H3G by analogy) in the CSF exceeds the neuroexcitatory threshold, excitatory behaviours will be evoked in patients. 10. Thus, rotation of the opioid from morphine/HMOR to a structurally dissimilar opioid, such as methadone or fentanyl, will allow clearance of M3G/H3G from the patient central nervous system over hours to days, thereby producing a time-dependent resolution of the neuroexcitatory behaviours while maintaining analgesia with methadone or fentanyl.

Hydromorphone-3-glucuronide: Biochemical synthesis and preliminary pharmacological evaluation

Hydromorphone-3-glucuronide (H3G) was synthesized biochemically using rat liver microsomes, uridine-5′-diphosphoglucuronic acid (UDPGA) and the substrate, hydromorphone. Initially, the crude putative H3G product was purified by ethyl acetate precipitation and washing with acetonitrile. Final purification was achieved using semi-preparative high-performance-liquid-chromatography (HPLC) with ultraviolet (UV) detection. The purity of the final H3G product was shown by HPLC with electrochemical and ultraviolet detection to be > 99.9% and it was produced in a yield of ≈ 60% (on a molar basis). The chemical structure of the putative H3G was confirmed by enzymatic hydrolysis of the glucuronide moiety using β-glucuronidase, producing a hydrolysis product with the same HPLC retention time as the hydromorphone reference standard. Using HPLC with tandem mass spectrometry (HPLC-MS-MS) in the positive ionization mode, the molecular mass (M+1) was found to be 462 g/mol, in agreement with H3G's expected molecular weight of 461 g/mol. Importantly, proton-NMR indicated that the glucuronide moiety was attached at the 3-phenolic position of hydromorphone. A preliminary evaluation of H3G's intrinsic pharmacological effects revealed that following icv administration to adult male Sprague-Dawley rats in a dose of 5 μg, H3G evoked a range of excitatory behavioural effects including chewing, rearing, myoclonus, ataxia and tonic-clonic convulsions, in a manner similar to that reported previously for the glucuronide metabolites of morphine, morphine-3-glucuronide and normorphine-3-glucuronide.

Emerging Neuropsychiatric Toxicities of Opioids

Pain is a common complication of cancer. As a result of educational efforts, there has been an appropriate increase in the use of opioids. The increase has resulted in a greater detection of a spectrum of neuro-psychiatric adverse effects that include cognitive failure, hallucinations, delirium, severe sedation, generalized myoclonus, hyperalgesia, allodynia and seizures. Various putative mechanisms have been postulated including the neuro-sensitizing effects of opioid metabolites. Numerous metabolites including morphine-3-glu-curonide, morphine-6-glucuronide, hydromorphone 3-glucuronide, and normeperidine have been implicated. Morphine-3-glucuronide appears to cause hyperexcitability via non-opioid receptor mechanisms which are not yet well defined. Renal impairment, high opioid doses, prolonged opioid administration, borderline cognition, dehydration, neuropathic pain and the presence of other psycho-active drugs have consistently been reported to be correlates of opioid associated CNS irritability. Var...

Sensitive and specific radioimmunoassays for opiates using commercially available materials. I: Methods for the determinations of morphine and hydromorphone

Sensitive and specific radioimmunoassay (RIA) methods for the analysis of morphine and hydromorphone in human plasma samples using commercially available materials were developed. The limit of quantitation was 0.3 ng/mL of plasma for morphine and 50 pg/mL of plasma for hydromorphone. An extraction step preceding the RIA quantitatively removed morphine, leaving 99% morphine-3-glucuronide (M3G) and 95% hydromorphone-3-glucuronide (H3G) in the aqueous phase. The specificity of the morphine RIA method for the analysis of clinical samples was confirmed by HPLC quantitation. The antiserum used in the hydromorphone RIA method cross reacted slightly with H3G at 0.66%. However, analysis of clinical samples using the direct versus the extraction RIA showed that the extraction step was necessary for the specific determination of hydromorphone in pharmacokinetic studies. After extraction, only 0.033% of the H3G present in plasma samples would be observed as interference for the free hydromorphone. The RIA methods were shown to be accurate and reproducible with almost 100% recovery of morphine and hydromorphone. They offer convenient alternatives to chromatographic methods for pharmacokinetic studies.