Alpha2 Adrenergic Agonists for the Management of Opioid Withdrawal

Discipline of Pharmacology, University of Adelaide, Frome Road, Adelaide, South Australia, Australia, 5005.
Cochrane database of systematic reviews (Online) (Impact Factor: 6.03). 02/2009; 3(2):CD002024. DOI: 10.1002/14651858.CD002024.pub3
Source: PubMed


Withdrawal is a necessary step prior to drug-free treatment or as the end point of long-term substitution treatment.
To assess the effectiveness of interventions involving the use of alpha2-adrenergic agonists to manage opioid withdrawal.
We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2008), MEDLINE (January 1966-July 2008), EMBASE (January 1985-2008 Week 31), PsycINFO (1967 to 7 August 2008) and reference lists of articles. We also contacted manufacturers in the field.
Controlled trials comparing alpha2-adrenergic agonists with reducing doses of methadone, symptomatic medications or placebo, or comparing different alpha2-adrenergic agonists to modify the signs and symptoms of withdrawal in participants who were opioid dependent.
One author assessed studies for inclusion and undertook data extraction. Inclusion decisions and the overall process were confirmed by consultation between all authors.
Twenty-four studies, involving 1631 participants, were included. Twenty-one were randomised controlled trials.Thirteen studies compared a treatment regime based on an alpha2-adrenergic agonist with one based on reducing doses of methadone. Diversity in study design, assessment and reporting of outcomes limited the extent of quantitative analysis.Alpha2-adrenergic agonists are more effective than placebo in ameliorating withdrawal, and despite higher rates of adverse effects, are associated with significantly higher rates of completion of treatment.For the comparison of alpha2-adrenergic agonist regimes with reducing doses of methadone, there were insufficient data for statistical analysis, but withdrawal intensity appears similar to or marginally greater with alpha2-adrenergic agonists, while signs and symptoms of withdrawal occur and resolve earlier. Participants stay in treatment longer with methadone. No significant difference was detected in rates of completion of withdrawal with adrenergic agonists compared to reducing doses of methadone, or clonidine compared to lofexidine. Clonidine is associated with more adverse effects than reducing doses of methadone. Lofexidine does not reduce blood pressure to the same extent as clonidine, but is otherwise similar to clonidine
Clonidine and lofexidine are more effective than placebo for the management of withdrawal from heroin or methadone. No significant difference in efficacy was detected for treatment regimes based on clonidine or lofexidine, and those based on reducing doses of methadone over a period of around 10 days but methadone is associated with fewer adverse effects than clonidine, and lofexidine has a better safety profile than clonidine.

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    • "Although clonidine has been available for the purpose of detoxification for many years, it does have some notable disadvantages. These include not being effective in relieving some of the subjective components of opioid withdrawal and the undesirable side effects of sedation and hypotension (Gossop, 1988; Gowing et al., 2009; Jasinski et al., 1985). Given its pharmacological characteristics, Suboxone (buprenorphine/naltrexone ) may be a suitable alternative. "
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    ABSTRACT: This retrospective quality improvement study was to evaluate if Suboxone therapy reduced the risk of terminating treatment against medical advice compared with the use clonidine in men aged 18--55 years. Data were collected through chart review for all opioid-addicted male clients admitted voluntarily to a community-based treatment center between July 1, 2009, and December 30, 2009. The chi-square test of independence between treatment completion and treatment noncompletion was found to be significant at the 5% critical level (P = .027) for Suboxone therapy. Suboxone treatment decreased premature termination of opioid detoxification completion when compared with clonidine.
    Full-text · Article · Aug 2012 · Archives of psychiatric nursing
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    • "Dynorphin synthesis increase and CREB phosphorylation decrease in spinal cord, PAG and hypothalamus may account for the accumulated effects of multiple 100 Hz EA in early phase of morphine withdrawal, and the latter may also be implicated the long-term effects of multiple EA. Despite the fact that a line of pharmacological interventions are available to alleviate opiate withdrawal symptoms including methadone [3], buprenorphine [19], clonidine [20] and Chinese traditional herbal medicine [35], etc., acupuncture and related techniques (including EA) have been used as effective complementary approaches to remedy drug addiction [12]. It may help to provide an effective procedure of using EA for clinical detoxification. "
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    ABSTRACT: Drug addiction, as well as learning and memory, share common mechanisms in terms of neural circuits and intracellular signaling pathways. In the present study, the role of N-methyl-D-aspartate (NMDA) receptors, particularly those containing NR2B subunits, in morphine-induced conditioned place preference (CPP) and Morris water maze (MWM) learning and memory task was investigated. CPP was used as a paradigm for assessing the rewarding effect of morphine, and MWM was used to measure spatial learning and memory in male Sprague-Dawley rats. We found that ifenprodil, an antagonist highly selective for NR2B-containing NMDA receptors, dose-dependently blocked the development, maintenance and reinstatement of morphine-induced CPP, without evident impairment of the acquisition and retrieval of spatial memory in the MWM task. However, the consolidation of spatial memory was disrupted by a high dose (10 mg/kg) of ifenprodil. These results clearly demonstrate that NR2B-containing NMDA receptors are actively involved in addiction memory induced by morphine conditioning, but not in the acquisition and retrieval of spatial learning and memory. In conclusion, NR2B-containing NMDA receptors can be considered potential targets for the treatment of opiate addiction.
    Full-text · Article · Mar 2011 · Neurochemical Research
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    • "In this regard, the use of clonidine, an alpha-2 agonist for the suppression of withdrawal effects, has met with limited success but has provided an important lead for future research to explore possible mechanisms that are distal to the opioid receptor and are affected during opioid dependence. Pharmacological manipulations of these mechanisms can yield therapeutic strategies that employ non-opioid agents for the control of opioid dependence and withdrawal.7 To evolve such alternative therapeutic modalities, it is imperative that a clear understanding of the role of neurotransmitters/second messengers and ionic fluxes across the membrane during the development of dependence and in the control of withdrawal symptoms is essential.8,9 "
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    ABSTRACT: The present study was conducted to investigate the effect of potassium channel openers and blockers on morphine withdrawal syndrome. Mice were rendered dependent on morphine by subcutaneous injection of morphine; four hours later, withdrawal was induced by using an opioid antagonist, naloxone. Mice were observed for 30 minutes for the withdrawal signs ie, the characteristic jumping, hyperactivity, urination and diarrhea. ATP-dependent potassium (K(+) (ATP)) channel modulators were injected intraperitoneally (i.p.) 30 minutes before the naloxone. It was found that a K(+) (ATP) channel opener, minoxidil (12.5-50 mg/kg i.p.), suppressed the morphine withdrawal significantly. On the other hand, the K(+) (ATP) channel blocker glibenclamide (12.5-50 mg/kg i.p.) caused a significant facilitation of the withdrawal. Glibenclamide was also found to abolish the minoxidil's inhibitory effect on morphine withdrawal. The study concludes that K(+) (ATP) channels play an important role in the genesis of morphine withdrawal and K(+) (ATP) channel openers could be useful in the management of opioid withdrawal. As morphine opens K(+) (ATP) channels in neurons, the channel openers possibly act by mimicking the effects of morphine on neuronal K(+) currents.
    Preview · Article · Nov 2010 · Substance Abuse: Research and Treatment
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