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      Repeat-dose steady-state pharmacokinetic evaluation of once-daily hydromorphone extended-release (OROS ® hydromorphone ER) in patients with chronic pain

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          Abstract

          Objective

          To characterize the steady-state pharmacokinetic profile of hydromorphone extended-release (ER) in patients with chronic pain taking concomitant medications.

          Methods

          This open-label repeat-dose study enrolled 22 patients (mean age, 51.4 years; 81.8% female). All patients were receiving at least one concomitant medication; 86.4% were receiving at least two concomitant medications and 81.8% were receiving at least three. Patients receiving a stable dose of an opioid were converted to hydromorphone ER at a 5:1 ratio (morphine equivalent:hydromorphone). The dose was titrated to adequate analgesia over 3–14 days and stabilized between 8–48 mg. Oral morphine immediate-release was permitted for breakthrough pain. Area under the concentration–time curve from 0–24 hours (AUC 0–24), maximum plasma concentration (C max), trough plasma concentration (C min), average plasma concentration (C avg), and degree of fluctuation (100 × [(C max − C min) ÷ C avg]) were calculated based on data from 14 patients.

          Results

          Dose-normalized to 16 mg, mean pharmacokinetic parameter values were: AUC 0–24, 41.1 ng · h/mL; C max, 2.6 ng/mL; C min, 1.1 ng/mL; C avg, 1.7 ng/mL; and the degree of fluctuation was 99.6%. The pharmacokinetic profile of hydromorphone ER was linear and consistent with dose proportionality. Mean pain intensity difference scores showed statistically significant improvement from 2–21 hours after dosing. Sixteen (72.7%) patients reported at least one adverse event (AE). The most common were constipation (31.8%), headache (22.7%), and vomiting (13.6%). One patient discontinued treatment due to vomiting. No deaths, serious AEs, or unexpected AEs occurred.

          Conclusion

          These findings replicate and extend the steady-state pharmacokinetic profile of hydromorphone ER, previously characterized in healthy volunteers, to a population of chronic pain patients taking numerous concomitant medications.

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          Most cited references 39

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          Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain.

          Use of chronic opioid therapy for chronic noncancer pain has increased substantially. The American Pain Society and the American Academy of Pain Medicine commissioned a systematic review of the evidence on chronic opioid therapy for chronic noncancer pain and convened a multidisciplinary expert panel to review the evidence and formulate recommendations. Although evidence is limited, the expert panel concluded that chronic opioid therapy can be an effective therapy for carefully selected and monitored patients with chronic noncancer pain. However, opioids are also associated with potentially serious harms, including opioid-related adverse effects and outcomes related to the abuse potential of opioids. The recommendations presented in this document provide guidance on patient selection and risk stratification; informed consent and opioid management plans; initiation and titration of chronic opioid therapy; use of methadone; monitoring of patients on chronic opioid therapy; dose escalations, high-dose opioid therapy, opioid rotation, and indications for discontinuation of therapy; prevention and management of opioid-related adverse effects; driving and work safety; identifying a medical home and when to obtain consultation; management of breakthrough pain; chronic opioid therapy in pregnancy; and opioid-related policies. Safe and effective chronic opioid therapy for chronic noncancer pain requires clinical skills and knowledge in both the principles of opioid prescribing and on the assessment and management of risks associated with opioid abuse, addiction, and diversion. Although evidence is limited in many areas related to use of opioids for chronic noncancer pain, this guideline provides recommendations developed by a multidisciplinary expert panel after a systematic review of the evidence.
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            Opioids in chronic non-cancer pain: systematic review of efficacy and safety.

            Opioids are used increasingly for chronic non-cancer pain. Controversy exists about their effectiveness and safety with long-term use. We analysed available randomised, placebo-controlled trials of WHO step 3 opioids for efficacy and safety in chronic non-cancer pain. The Oxford Pain Relief Database (1950-1994) and Medline, EMBASE and the Cochrane Library were searched until September 2003. Inclusion criteria were randomised comparisons of WHO step 3 opioids with placebo in chronic non-cancer pain. Double-blind studies reporting on pain intensity outcomes using validated pain scales were included. Fifteen randomised placebo-controlled trials were included. Four investigations with 120 patients studied intravenous opioid testing. Eleven studies (1025 patients) compared oral opioids with placebo for four days to eight weeks. Six of the 15 included trials had an open label follow-up of 6-24 months. The mean decrease in pain intensity in most studies was at least 30% with opioids and was comparable in neuropathic and musculoskeletal pain. About 80% of patients experienced at least one adverse event, with constipation (41%), nausea (32%) and somnolence (29%) being most common. Only 44% of 388 patients on open label treatments were still on opioids after therapy for between 7 and 24 months. The short-term efficacy of opioids was good in both neuropathic and musculoskeletal pain conditions. However, only a minority of patients in these studies went on to long-term management with opioids. The small number of selected patients and the short follow-ups do not allow conclusions concerning problems such as tolerance and addiction.
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              Treatment of chronic non-cancer pain.

              Chronic pain is a pervasive problem that affects the patient, their significant others, and society in many ways. The past decade has seen advances in our understanding of the mechanisms underlying pain and in the availability of technically advanced diagnostic procedures; however, the most notable therapeutic changes have not been the development of novel evidenced-based methods, but rather changing trends in applications and practices within the available clinical armamentarium. We provide a general overview of empirical evidence for the most commonly used interventions in the management of chronic non-cancer pain, including pharmacological, interventional, physical, psychological, rehabilitative, and alternative modalities. Overall, currently available treatments provide modest improvements in pain and minimum improvements in physical and emotional functioning. The quality of evidence is mediocre and has not improved substantially during the past decade. There is a crucial need for assessment of combination treatments, identification of indicators of treatment response, and assessment of the benefit of matching of treatments to patient characteristics. Copyright © 2011 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                Journal of Pain Research
                Dove Medical Press
                1178-7090
                2012
                09 November 2012
                : 5
                : 523-533
                Affiliations
                [1 ]Clinical Pharmacology, Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium
                [2 ]Global Medical Affairs, Janssen-Cilag, Baar, Switzerland
                [3 ]Established Products, Johnson and Johnson Pharmaceutical Research and Development, Titusville, NJ, USA
                Author notes
                Correspondence: Joris Vandenbossche, Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium, Tel +0032 1460 6734, Email jvdbossc@ 123456its.jnj.com
                Article
                jpr-5-523
                10.2147/JPR.S33807
                3500920
                23166450
                © 2012 Vandenbossche et al, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                Categories
                Original Research

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