Articles: opioid.
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We previously reported a small series of mixed-efficacy μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist peptidomimetics featuring a tetrahydroquinoline scaffold and showed the promise of this series as effective analgesics after intraperitoneal administration in mice. We report here an expanded structure-activity relationship study of the pendant region of these compounds and focus in particular on the incorporation of heteroatoms into this side chain. These analogues provide new insight into the binding requirements for this scaffold at MOR, DOR, and the κ opioid receptor (KOR), and several of them (10j, 10k, 10m, and 10n) significantly improve upon the overall MOR agonist/DOR antagonist profile of our previous compounds. In vivo data for 10j, 10k, 10m, and 10n are also reported and show the antinociceptive potency and duration of action of compounds 10j and 10m to be comparable to those of morphine.
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Although alterations in not only the pain sensitivity but also the analgesic effects of opioids have been reported under conditions of stress, the influence of unpredictable chronic mild stress (UCMS) on the antinociceptive effects of opioid analgesics remains to be fully investigated. The present study examined the influence of UCMS on the thermal pain sensitivity and antinociceptive effects of two opioid analgesics, morphine (an agonist of opioid receptors) and tramadol (an agonist of μ-opioid receptor and an inhibitor of both noradrenaline and serotonin transporters). We also examined the effects of pretreatment with maprotiline (a noradrenaline reuptake inhibitor) and escitalopram (a serotonin reuptake inhibitor) on the antinociceptive action of morphine in mice under an UCMS condition. ⋯ We demonstrated that the antinociceptive effect of morphine but not tramadol was reduced in mice that had experienced UCMS. The reduced antinociceptive effect of morphine under the UCMS condition was ameliorated by pretreatment with maprotiline but not escitalopram. These results suggest that the reduced antinociceptive effects of morphine under conditions of chronic stress may be ameliorated by activation of the noradrenergic but not the serotonergic system.
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Ankle surgery is often done using a tourniquet. Ischemia/reperfusion injury caused by the tourniquet may increase postoperative pain. The study objective was to investigate the amount of opioids given to patients after ankle surgery with and without tourniquet. ⋯ We found an increase in postoperative opioid consumption correlated to tourniquet use. Possible preventive measures with antioxidant treatment to prevent ischemia/reperfusion injury should be investigated.
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Multicenter Study
Assessment of a Stool Symptom Screener and Understanding the Opioid-Induced Constipation Symptom Experience.
Many patients with chronic opioid-induced constipation (OIC) seek treatment to relieve their symptoms. A symptom screener may be useful in identifying symptomatic OIC patients. ⋯ OIC patients understood this Stool Symptom Screener, and its content was relevant to this highly symptomatic patient sample. Pain and bloating may be considered as additional symptoms for future versions of the screener. An emerging conceptual model of the OIC experience, laxative use, and symptoms is presented.
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Randomized Controlled Trial
New Formulation of Sustained Release Naloxone Can Reverse Opioid Induced Constipation Without Compromising the Desired Opioid Effects.
An international double-blind randomized placebo controlled study evaluated the safety and efficacy of four doses of a new sustained release naloxone capsule to treat Opioid Induced Constipation (OIC). ⋯ This Phase II study has shown that using a new sustained release formulation to deliver oral naloxone to the colon allows successful treatment of OIC without comprising the desired opioid effects.