Lack of Analgesic Activity of Morphine-6-glucuronide after Short-term Intravenous Administration in Healthy Volunteers

Background The analgesic activity of morphine-6-glucuronide (M-6-G) is well recognized for its contribution to the effects of morphine and its possible use as an opioid analgesic with a wider therapeutic range than morphine. The present study attempted to quantify the relative contribution of M-6-G to analgesia observed after systemic administration of morphine. Methods In a placebo-controlled, sixfold crossover study in 20 healthy men, the effects of M-6-G were assessed at steady-state plasma concentrations of M-6-G identical to and two and three times higher than those measured after administration of morphine. Morphine and M-6-G were administered as an intravenous bolus followed by infusion over 4 h. Dosage A was M-6-G-bolus of 0.015 mg/kg plus infusion of 0.0072 mg x kg(-1) x h(-1). Dosage B was M-6-G-bolus of 0.029 mg/kg plus infusion of 0.014 mg x kg(-1) x h(-1). Dosage C was M-6-G-bolus of 0.044 mg/kg plus infusion of 0.022 mg x kg(-1) x h(-1). Dosage D was a morphine bolus of 0.14 mg/kg plus infusion of 0.05 mg x kg(-1) x h(-1) for 4 h. Dosage E was M-6-G combined with morphine (doses A + D). Dosage F was a placebo. The analgesic effects of M-6-G and morphine were measured before administration of the bolus and after 3.5 h using an experimental pain model based on pain-related cortical potentials and pain ratings after specific stimulation of the nasal nociceptor with short pulses of gaseous carbon dioxide. Results Morphine significantly reduced subjective and objective pain correlates compared with placebo. In contrast, M-6-G produced no statistically significant effects. The addition of M-6-G to morphine did not increase the effects of morphine. Morphine produced significantly more side effects than M-6-G. Conclusion After short-term intravenous administration at doses that produce plasma concentrations of M-6-G similar to those seen after administration of morphine, M-6-G had no analgesic effects in the present placebo-controlled study in healthy volunteers.

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Long-term safety, tolerability, and efficacy of OROS® hydromorphone in patients with chronic pain

Journal of Opioid Management ◽

10.5055/jom.2009.0011 ◽

2018 ◽

Vol 5 (2) ◽

pp. 97 ◽

Cited By ~ 20

Author(s):

Mark Wallace, MD ◽

Dwight E. Moulin, MD ◽

Richard L. Rauck, MD ◽

Sarita Khanna, PhD ◽

Iulia Cristina Tudor, PhD ◽

...

Keyword(s):

Chronic Pain ◽

Plasma Concentrations ◽

Brief Pain Inventory ◽

The United States ◽

Short Term ◽

Open Label ◽

Safety And Efficacy ◽

Analgesic Effects ◽

N 93

Objective: To assess the safety and efficacy of long-term repeated dosing of OROS® hydromorphone in chronic pain patients.Design: This multicenter, open-label extension trial enrolled patients from three short-term OROS® hydromorphone trials.Setting: Fifty-six centers in the United States and Canada.Patients: Adults with chronic cancer pain or chronic nonmalignant pain who were receiving stable doses of OROS® hydromorphone (≥8 mg/day). Three hundred and eighty-eight patients were enrolled, 106 patients completed at least 12 months of therapy.Interventions: OROS® hydromorphone (individualized doses) was administered once daily.Main outcome measures: Safety and efficacy (Brief Pain Inventory and patient and investigator global evaluations) were assessed at monthly visits.Results: The median duration of extended OROS® hydromorphone therapy was 274 days. The median daily dose of study medication was 32.0 mg at extension-study baseline, 40.0 mg at month 3, and 48.0 mg at months 6, 9, and 12, respectively. The most frequently reported adverse events were nausea (n = 93, 24.0 percent) and constipation (n = 75, 19.3 percent). The analgesic effects of OROS® hydromorphone, assessed using the Brief Pain Inventory, were maintained throughout the extension. At 12 months, 72.4 percent of patients and 75.9 percent of investigators rated overall treatment as good, very good, or excellent.Conclusions: Once-daily OROS® hydromorphone is an osmotically driven, controlled-release preparation that may be particularly well suited to long-term use, because it provides consistent plasma concentrations and sustained around-the-clock analgesia. In this study, the benefits of OROS® hydromorphone attained in short-term studies were maintained in the long-term when daily administration was continued.

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Pharmacodynamics of Orally Administered Sustained- release Hydromorphone in Humans

Anesthesiology ◽

10.1097/00000542-200101000-00014 ◽

2001 ◽

Vol 94 (1) ◽

pp. 63-73 ◽

Cited By ~ 65

Author(s):

Martin S. Angst ◽

David R. Drover ◽

Jörn Lötsch ◽

Bhamini Ramaswamy ◽

Sujata Naidu ◽

...

Keyword(s):

Plasma Concentration ◽

Sustained Release ◽

Analgesic Effect ◽

Time Course ◽

Plasma Concentrations ◽

Experimental Pain ◽

Immediate Release ◽

Double Blind ◽

Sustained Release Formulation ◽

Analgesic Effects

Background The disposition kinetics of hydromorphone generally necessitates oral administration every 4 h of the conventional immediate-release tablet to provide sustained pain relief. This trial examined time course and magnitude of analgesia to experimental pain after administration of sustained-release hydromorphone as compared with that after immediate-release hydromorphone or placebo. Methods Using a 4 x 4 Latin square double-blind design, 12 subjects were randomized to receive a single dose of 8, 16, and 32 mg sustained-release hydromorphone and placebo. The same subjects had received 8 mg immediate-release hydromorphone before this study. Using an electrical experimental pain paradigm, analgesic effects were assessed for up to 30 h after administration, and venous hydromorphone plasma concentrations were measured at corresponding times. Results The hydromorphone plasma concentration peaked significantly later (12.0 h [12.0--18.0] vs. 0.8 h [0.8--1.0]; median and interquartile range) but was maintained significantly longer at greater than 50% of peak concentration (22.7 +/- 8.2 h vs. 1.1 +/- 0.7 h; mean +/- SD) after sustained-release than after immediate-release hydromorphone. Similarly, sustained-release hydromorphone produced analgesic effects that peaked significantly later (9.0 h [9.0--12.0] vs. 1.5 h [1.0--2.0]) but were maintained significantly longer at greater than 50% of peak analgesic effect (13.3 +/- 6.3 h vs. 3.6 +/- 1.7 h). A statistically significant linear relation between the hydromorphone plasma concentration and the analgesic effect on painful stimuli existed. Conclusion A single oral dose of a new sustained-release formulation of hydromorphone provided analgesia to experimental pain beyond 24 h of its administration.

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Analgesic activity of allopurinol and febuxostat in experimental animals

International Journal of Basic & Clinical Pharmacology ◽

10.18203/2319-2003.ijbcp20181005 ◽

2018 ◽

Vol 7 (4) ◽

pp. 603

Author(s):

Yajnesh P. Sahu ◽

Sachchidanand Pandey ◽

Sabita Mohapatra

Keyword(s):

Acetic Acid ◽

Analgesic Activity ◽

Physical Dependence ◽

Experimental Pain ◽

Opioid Analgesics ◽

Analgesic Nephropathy ◽

Tail Flick ◽

Tail Flick Test ◽

Analgesic Effects ◽

Peripheral Analgesia

Background: Currently, two classes of analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics are used to manage pain in different clinical situations. Chronic uses of these drugs have various adverse effects like gastric ulceration/bleeding, analgesic nephropathy and respiratory depression, physical dependence, addiction, respectively. Xanthine oxidase inhibitors, used for chronic gout, might have a role in alleviation of pain, as per literature survey. Hence, the present study was carried out to evaluate the potential analgesic activity of allopurinol and febuxostat in different experimental models.Methods: The analgesic activity of allopurinol and febuxostat was assessed by employing two different experimental pain models-tail flick latency model in rats for central analgesia and acetic acid induced writhing model in mice for peripheral analgesia and was compared with tramadol and aspirin.Results: Allopurinol and febuxostat produced significant central and peripheral analgesic effects as is evident from increase in reaction time in tail flick test and inhibition in number of writhes in acetic acid induced writhing test.Conclusions: The results of the present study demonstrate marked analgesic effect of allopurinol and febuxostat.

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Analgesic effects of lamotrigine and phenytoin on cold-induced pain: a crossover placebo-controlled study in healthy volunteers

Pain ◽

10.1016/s0304-3959(98)00068-2 ◽

1998 ◽

Vol 76 (3) ◽

pp. 357-363 ◽

Cited By ~ 44

Author(s):

James Webb ◽

Farhad Kamali

Keyword(s):

Healthy Volunteers ◽

Controlled Study ◽

Analgesic Effects

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The analgesic effects of acupuncture on experimental pain threshold and somatosensory evoked potentials in healthy volunteers

Complementary Therapies in Medicine ◽

10.1016/s0965-2299(96)80074-4 ◽

1996 ◽

Vol 4 (4) ◽

pp. 219-225 ◽

Cited By ~ 6

Author(s):

Mark I. Johnson ◽

Sujata Kundu ◽

Heather Ashton ◽

Richard Marsh ◽

John Thompson

Keyword(s):

Evoked Potentials ◽

Healthy Volunteers ◽

Somatosensory Evoked Potentials ◽

Pain Threshold ◽

Experimental Pain ◽

Analgesic Effects

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Pharmacokinetic Characterisation and Comparison of Bioavailability of Intranasal Fentanyl, Transmucosal, and Intravenous Administration through a Three-Way Crossover Study in 24 Healthy Volunteers

Pain Research and Management ◽

10.1155/2021/2887773 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

S. Nardi-Hiebl ◽

J. W. Ndieyira ◽

Y. Al Enzi ◽

W. Al Akkad ◽

T. Koch ◽

...

Keyword(s):

Healthy Volunteers ◽

Intravenous Administration ◽

Intranasal Administration ◽

Geometric Mean ◽

Plasma Concentrations ◽

Pharmacokinetic Parameters ◽

Published Data ◽

Open Label ◽

Single Dose Study ◽

Transmucosal Administration

Background. For more than 60 years, the synthetic opioid fentanyl has been widely used in anaesthesia and analgesia. While the intravenous formulation is primarily used for general anaesthesia and intensive care settings, the drug’s high lipophilic properties also allow various noninvasive routes of administration. Published data suggest that intranasal administration is also attractive for use as intranasal patient-controlled analgesia (PCA). A newly developed intranasal fentanyl formulation containing 47 μg fentanyl, intravenous fentanyl, and oral transmucosal fentanyl citrate were characterised, and bioavailability was compared to assess the suitability of the intranasal formulation for an intranasal PCA product. Methods. 27 healthy volunteers were enrolled in a single-centre, open-label, randomised (order of treatments), single-dose study in a three-period crossover design. The pharmacokinetics of one intranasal puff of fentanyl formulation (47 μg, 140 mL per puff), one short intravenous infusion of 50 μg fentanyl, and one lozenge with an integrated applicator (200 μg fentanyl) were studied, and bioavailability was calculated. Blood samples were collected over 12 hours, and plasma concentrations of fentanyl were determined by HPLC with MS/MS detection. Results. 24 volunteers completed the study. The geometric mean of AUC0-tlast was the highest with oral transmucosal administration (1106 h ∗ pg/ml, CV% = 32.86), followed by intravenous (672 h ∗ pg/ml, CV% = 32.18) and intranasal administration (515 h ∗ pg/ml, CV% = 30.10). Cmax was 886 pg/ml (CV% = 59.38) for intravenous, 338 pg/ml (CV% = 45.61) for intranasal, and 310 pg/ml (CV% = 29.58) for oral transmucosal administration. tmax was shortest for intravenous administration (0.06 h, SD = 0.056), followed by intranasal (0.21 h, SD = 0.078) and oral transmucosal administration (1.20 h, SD = 0.763). Dose-adjusted relative bioavailability was determined to be 74.70% for the intranasal formulation and 41.25% for the oral transmucosal product. In total, 38 adverse events (AEs) occurred. Fourteen AEs were potentially related to the investigational items. No serious AE occurred. Conclusion. Pharmacokinetic parameters and bioavailability of the investigated intranasal fentanyl indicated suitability for its intended use as an intranasal PCA option.

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