Evidence Of Opioid Withdrawal Research Articles

Opioid Modulation With Buprenorphine/Samidorphan as Adjunctive Treatment for Inadequate Response to Antidepressants: A Randomized Double-Blind Placebo-Controlled Trial

Major depressive disorder has been associated with dysregulation of the endogenous opioid system. The authors sought to determine whether opioid modulation achieved through administration of ALKS 5461, a combination of a μ- and κ-opioid partial agonist, buprenorphine, and a μ-opioid antagonist, samidorphan, would exhibit antidepressant activity in patients with major depression. A multicenter, randomized, double-blind, placebo-controlled, two-stage sequential parallel comparison design study was conducted in adults with major depression who had an inadequate response to one or two courses of antidepressant treatment. Participants were randomly assigned to receive adjunctive treatment with 2 mg/2 mg of buprenorphine/samidorphan (the 2/2 dosage group), 8 mg/8 mg of buprenorphine/samidorphan (the 8/8 dosage group), or placebo. Antidepressant effect was measured based on change from baseline to the end of 4 weeks of treatment on the 17-item Hamilton Depression Rating Scale (HAM-D), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Clinical Global Impressions severity scale (CGI-S). Compared with the placebo group, there were significantly greater improvements in the 2/2 dosage group across the three depression outcome measures (HAM-D: -2.8, 95% CI=-5.1, -0.6; MADRS: -4.9, 95% CI=-8.2, -1.6; CGI-S: -0.5, 95% CI=-0.9, -0.1). There was also evidence of improvement in the 8/8 dosage group, although it did not achieve statistical significance. Overall, the buprenorphine/samidorphan combinations were well tolerated, and there was no evidence of opioid withdrawal on treatment discontinuation. The buprenorphine/samidorphan combination is a novel and promising candidate for treatment of major depressive disorder in patients who have an inadequate response to standard antidepressants.

Laxatives or methylnaltrexone for the management of constipation in palliative care patients

Background: Constipation is common in palliative care; it can generate considerable suffering due to the unpleasant physical symptoms. In the first Cochrane Review on effectiveness of laxatives for the management of constipation in palliative care patients, published in 2006, no conclusions could be drawn because of the limited number of evaluations. This article describes the first update of this review. / Objectives: To determine the effectiveness of laxatives or methylnaltrexone for the management of constipation in palliative care patients. / Search methods: We searched databases including MEDLINE and CENTRAL (The Cochrane Library) in 2005 and in the update to August 2010. / Selection criteria: Randomised controlled trials (RCTs) evaluating laxatives for constipation in palliative care patients. In the update we also included RCTs on subcutaneous methylnaltrexone; an opioid-receptor antagonist that is now licensed for the treatment of opioid-induced constipation in palliative care when response to usual laxative therapy is insufficient. / Data collection and analysis: Two authors assessed trial quality and extracted data. The appropriateness of combining data from the studies depended upon clinical and outcome measure homogeneity. / Main results: We included seven studies involving 616 participants; all under-reported methodological features. In four studies the laxatives lactulose, senna, co-danthramer, misrakasneham, and magnesium hydroxide with liquid paraffin were evaluated. In three methylnaltrexone. In studies comparing the different laxatives evidence was inconclusive. Evidence on subcutaneous methylnaltrexone was clearer; in combined analysis (287 participants) methylnaltrexone, in comparison with a placebo, significantly induced laxation at 4 hours (odds ratio 6.95; 95% confidence interval 3.83 to 12.61). In combined analyses there was no difference in the proportion experiencing side effects, although participants on methylnaltrexone suffered more flatulence and dizziness. No evidence of opioid withdrawal was found. In one study severe adverse events, commonly abdominal pain, were reported that were possibly related to methylnaltrexone. A serious adverse event considered to be related to the methylnaltrexone also occurred; this involved a participant having severe diarrhoea, subsequent dehydration and cardiovascular collapse. / Authors' conclusions: The 2010 update found evidence on laxatives for management of constipation remains limited due to insufficient RCTs. However, the conclusions of this update have changed since the original review publication in that it now includes evidence on methylnaltrexone. Here it found that subcutaneous methylnaltrexone is effective in inducing laxation in palliative care patients with opioid-induced constipation and where conventional laxatives have failed. However, the safety of this product is not fully evaluated. Large, rigorous, independent trials are needed.

Oral naltrexone to enhance analgesia in patients receiving continuous intrathecal morphine for chronic pain: A randomized, double-blind, prospective pilot study

Years' worth of observations suggest that morphine has both inhibitory and excitatory actions, and that selective blockade of excitatory effects by low doses of opioid antagonists (e.g., naltrexone) may paradoxically enhance morphine analgesia. The purpose of this pilot study was to evaluate and compare the analgesic efficacy and safety of two different low doses of oral naltrexone given in addition to chronic intrathecal morphine infusions in patients with chronic nonmalignant pain (CNMP). After institutional review board approval, 15 patients with CNMP receiving continuous intrathecal morphine were admitted into a prospective, randomized, double-blind, placebo-controlled, seven-day pilot study. Patients were randomized into three treatment groups based on oral naltrexone dose: 100 microg (Group A, n = 3), 10 microg (Group B, n = 7), or placebo (Group C, n = 5). All patients continued with their constant intrathecal morphine infusion, and in addition they received one capsule of study medication every 12 hours for seven days. Other analgesics or coanalgesics were kept at a constant dose level throughout the study. Patients rated pain scores (visual analogue score [VAS]; 0 = no pain, 10 = worst pain imaginable) and side effects three times daily throughout the study period. Efficacy measures included pain intensity difference (PID) scores, constructed so that positive scores indicate a reduction in pain intensity and negative scores indicate a worsening of pain. Fifteen patients (six male, nine female) with a mean (SD) age of 55 (10) years and weight of 81 (21) kg completed the study. The mean (SD) baseline VAS pain intensity rating was similar in all three groups (6.8 [1.5]). Baseline pain VAS score minus the lowest daily pain VAS score yielded the peak PID score. The peak PID score from Day 1 was statistically (p < 0.05) highest (median PID score: 5.9) in Group A compared with Group C. There was a trend in PID scores across Days 2 through 7, with median PID scores higher (i.e., greater pain relief p = 0.07) in Group A. In the daily global pain assessments, the pain scores across Days 2 through 7 approached significance (least pain) in Group A compared to Group C (p = 0.07) or B (p = 0.08). Side effects were common (93 percent of patients), minor (headache, nausea, sedation, dry mouth), and similar across treatment groups. No serious adverse events were observed, and no evidence of opioid withdrawal was seen. 1) Patients with chronic pain who received oral naltrexone 100 microg BID in addition to their chronic intrathecal morphine infusions demonstrated the greatest improvement (p = 0.07) in their daily pain scores. Because of the small sample size, the results did not reach traditional levels of significance. 2) Side effects were common, minor, and similar across treatment groups. 3) No serious adverse events were recorded. 4) No evidence of opioid antagonist toxicity or opioid withdrawal was observed.

Evaluation of the direct myocardial efects of dexmedetomidine in the transplanted infant heart

Background The denervated state of the transplanted heart excludes it from central autonomic control. Dexmedetomidine (dex) is an imidazole with selective α2 adrenoceptor (α2AR) agonist properties. The α2AAR isoreceptor mediates central analgesic and sedative effects via the locus ceruleus. The central antihypertensive and antiarrhymic effect of dex is mediated via medullary imidazoline-1 receptors (I1R). While the desired effects of dex are centrally mediated, it has recently been determined that both α2AAR and I1R are present in the human heart. The hemodynamic significance of this is not understood. The denervated cardiac physiology of an infant cardiac transplant presents a unique opportunity to examine the direct myocardial effects of dex. Methods This report details the hemodynamic impact of dex on a 6 month old infant 4 weeks post transplant. Dex was administered at a rate of 0.8–1 μg/kg/hr with q6–8h loading doses of 1 μg/kg (on days 1–5) for 18 days in the PICU to facilitate withdrawal from a 3-mos. exposure to opioids. HR and BP assessments were made with an arterial line. Results Neither bradycardia nor hypotension occurred throughout the dex administration. The only evidence of opioid withdrawal was retching on days 4–6 accompanied by sinus tachycardia (200–220). Conclusions There was no hemodynamic impact of dex administered either by bolus or infusion technique. It may be that any effect was obscured by the catecholamines elaborated during opioid withdrawal. Clinical Pharmacology & Therapeutics (2005) 77, P70–P70; doi: 10.1016/j.clpt.2004.12.159

In alcohol-treated rats, naloxone decreases extracellular dopamine and increases acetylcholine in the nucleus accumbens: evidence of opioid withdrawal

Withdrawal from ethanol is aversive. The question is why. As with the withdrawal from morphine, nicotine, diazepam and sugar, the ethanol withdrawal state may involve an increase in nucleus accumbens (NAc) acetylcholine (ACh) causing an alteration of the dopamine (DA)–ACh balance in favor of ACh. Therefore the effects of acute and chronic alcohol (1 gm/kg/day i.p.) treatment on extracellular concentrations of NAc ACh and DA were determined before and after naloxone-precipitated withdrawal. Ethanol initially increased DA to 119% of baseline as measured by microdialysis. This was still the case on the 21st day of ethanol injection when DA increased to 126%. There was no effect of ethanol on ACh. However, naloxone (3 mg/kg s.c.) injected the next day decreased extracellular DA to 83% of baseline and caused a significant rise in ACh to 119%. This state of high ACh combined with low DA may contribute to the aversive aspects of alcohol withdrawal.

Treatment of opioid-induced constipation in hospice patients with methylnaltrexone

8279 Background: Methylnaltrexone (MNTX) is a selective opioid-receptor antagonist that does not cross the blood-brain barrier in humans. It has the potential to counteract the debilitating peripheral side effects of narcotic pain therapy without interruption of centrally-mediated analgesia or precipitation of withdrawal. MNTX is being developed for the treatment of opioid-induced constipation (OIC) which is refractory to laxatives and stool softeners. Methods: The activity and tolerability of MNTX were investigated in a series of phase 1 and 2 clinical trials. Normal subjects as well as patients receiving chronic opioids were treated with various doses of MNTX administered via intravenous and subcutaneous routes. Relief of OIC by subcutaneous MNTX was evaluated in hospice patients in phase 2 trials. Results: Results from completed studies demonstrate that MNTX was generally well tolerated and significantly reduced or prevented OIC, urinary retention, as well as other peripheral side effects of opioids. Subcutaneous MNTX provided rapid relief of OIC (median time ≈ 1 hr) in approximately 60% of terminally ill patients receiving active doses (≥ 5 mg). The median number of laxations per week increased to between 4 to 6 from ≤ 2 prior to baseline. The most frequent adverse events were transient mild abdominal cramping and flatulence. No evidence of opioid withdrawal or reversal of analgesia was observed in any clinical trial. Conclusions: MNTX is well tolerated and active in relieving OIC and other debilitating side effects of narcotic pain therapy. These findings strongly support further evaluation of subcutaneous MNTX in hospice patients experiencing OIC. Two pivotal phase 3 clinical trials in this setting are currently underway in the United States. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Progenics Pharmaceuticals, Inc. Progenics Pharmaceuticals, Inc. Progenics Pharmaceuticals, Inc.

Lack of evidence for opioid tolerance or dependence in rhesus monkeys following high-dose anabolic-androgenic steroid administration.

Prolonged use of high-dose anabolic-androgenic steroids (AAS) may induce a dependence syndrome, and emerging evidence suggests that AAS effects on endogenous opioid systems may contribute to AAS abuse. The present study tested the hypothesis that high dose AAS treatment enhances endogenous opioid activity in rhesus monkeys as revealed by 1) tolerance to the antinociceptive effects of the mu opioid agonist morphine and 2) physical dependence as indicated by evidence of opioid withdrawal following administration of the opioid antagonist naloxone. Three rhesus monkeys were treated for 14 days with 3.2 mg/kg/day testosterone propionate, and the effects of morphine (0.32-10 mg/kg) and naloxone (0.01-0.32 mg/kg) were examined both before and during treatment. Morphine antinociception was evaluated using a warm-water tail-withdrawal procedure, and naloxone-precipitated withdrawal was evaluated using checked behavioral signs and measures of ventilatory rate. Chronic testosterone administration for 14 days produced a 100-fold increase in mean plasma testosterone levels. However, testosterone treatment did not significantly alter the antinociceptive effects of morphine, and naloxone did not precipitate signs of opioid withdrawal either before or during testosterone treatment. These data do not support the hypothesis that high-dose AAS treatment enhances endogenous opioid activity in rhesus monkeys in a way that produces opioid tolerance or dependence.