			Home About us Contact

Analgesic Tolerance (analgesic + tolerance)

Distribution by Scientific Domains

Medical Sciences	75%

Selected Abstracts

Negligible Analgesic Tolerance Seen with Extended Release Oxymorphone: A Post Hoc Analysis of Open-Label Longitudinal Data

PAIN MEDICINE, Issue 8 2010
R. Norman Harden MD
Abstract Objective., To examine the development of analgesic tolerance in patients on oxymorphone extended-release (OxymER). Design.,Post hoc analysis of data from a previously conducted prospective 1 year multi-center open-label extension study in which patients were able to titrate as needed. Patients., Sample of 153 hip and knee osteoarthritis (OA) subjects on OxymER. Primary analyses were limited to study completers (n = 62) due to the large amount of missing data for the noncompleters (n = 91). Outcome Measures., Main outcome measures included OxymER doses (pill counts) and pain intensity ratings using a visual analog scale at monthly visits. Results., There were significant dose increases from weeks 1 to 2 and 2 to 6 (P < 0.05). Doses stabilized around week 6, suggesting the completion of what we defined as "titration." Both doses and pain ratings were stable when this titration phase was excluded from the analysis (P = 0.751; P = 0.056, respectively). Only 28% of the patients had any dose changes following this titration. While there was a significantly greater dose at week 52 compared with week 10 (P = 0.010), the increase in dose became insignificant after excluding four subjects who required two dose increases (P = 0.103). Conclusions., The results showed that most of the titration/dose stabilization changes occurred within the first 10 weeks. A minority (28%) of subjects required dosage increases after this (defined) titration period. Pain reports stabilized statistically after 2 weeks. The findings of this post hoc analysis suggest a lack of opioid tolerance in the majority (72%) of these OA patients who completed this study following a defined titration period on OxymER. Summary., This post hoc analysis of oxymorphone ER consumption in osteoarthritis pain vs pain report showed that most dose changes occurred during an initial "titration period" as defined. Following this titration few subjects increased dose and analgesia remained stable. These findings suggest a lack of longitudinal opioid tolerance in the majority of those OA subjects who completed the trial. [source]

Blocking the R-type (Cav2.3) Ca2+ channel enhanced morphine analgesia and reduced morphine tolerance

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2004
Kazuaki Yokoyama
Abstract Morphine is the drug of choice to treat intractable pain, although prolonged administration often causes undesirable side-effects including analgesic tolerance. It is speculated that voltage-dependent Ca2+ channels (VDCCs) play a key role in morphine analgesia and tolerance. To examine the subtype specificity of VDCCs in these processes, we analysed mice lacking N-type (Cav2.2) or R-type (Cav2.3) VDCCs. Systemic morphine administration or exposure to warm water swim-stress, known to induce endogenous opioid release, resulted in greater analgesia in Cav2.3,/, mice than in controls. Moreover, Cav2.3,/, mice showed resistance to morphine tolerance. In contrast, Cav2.2,/, mice showed similar levels of analgesia and tolerance to control mice. Intracerebroventricular (i.c.v.) but not intrathecal (i.t.) administration of morphine reproduced the result of systemic morphine in Cav2.3,/, mice. Furthermore, i.c.v. administration of an R-type channel blocker potentiated morphine analgesia in wild-type mice. Thus, the inhibition of R-type Ca2+ current could lead to high-efficiency opioid therapy without tolerance. [source]

Src promotes delta opioid receptor (DOR) desensitization by interfering with receptor recycling

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 1 2009
Elodie Archer-Lahlou
Abstract An important limitation in the clinical use of opiates is progressive loss of analgesic efficacy over time. Development of analgesic tolerance is tightly linked to receptor desensitization. In the case of delta opioid receptors (DOR), desensitization is especially swift because receptors are rapidly internalized and are poorly recycled to the membrane. In the present study, we investigated whether Src activity contributed to this sorting pattern and to functional desensitization of DORs. A first series of experiments demonstrated that agonist binding activates Src and destabilizes a constitutive complex formed by the spontaneous association of DORs with the kinase. Src contribution to DOR desensitization was then established by showing that pre-treatment with Src inhibitor PP2 (20 ,M; 1 hr) or transfection of a dominant negative Src mutant preserved DOR signalling following sustained exposure to an agonist. This protection was afforded without interfering with endocytosis, but suboptimal internalization interfered with PP2 ability to preserve DOR signalling, suggesting a post-endocytic site of action for the kinase. This assumption was confirmed by demonstrating that Src inhibition by PP2 or its silencing by siRNA increased membrane recovery of internalized DORs and was further corroborated by showing that inhibition of recycling by monensin or dominant negative Rab11 (Rab11S25N) abolished the ability of Src blockers to prevent desensitization. Finally, Src inhibitors accelerated recovery of DOR-G,l3 coupling after desensitization. Taken together, these results indicate that Src dynamically regulates DOR recycling and by doing so contributes to desensitization of these receptors. [source]