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INNOSC Theranostics and
Pharmacological Sciences Alpha-2A receptor agonist and addiction

2.7. Summary of empirical research activity in areas regulated by alpha-2 adrenergic and opioid

Several behavioral and biochemical studies support receptors, like the LC. The early clinical studies, combined
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Gold’s hypothesis that naloxone-precipitated withdrawal with more direct observations in rodents and non-human
can be attenuated by targeting the LC. Subsequent primate studies, are consistent with the hypothesis that
studies demonstrated that clonidine reduced morphine in humans, brain NE systems become hyperactive during
withdrawal-induced increases in regional cerebral opioid withdrawal and that clonidine suppresses this
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metabolic rates for glucose, irrespective of the distribution hyperactivity of NE systems.
of alpha-2 adrenergic receptors. Clonidine acts primarily 3. Modern architectural analysis of
at the LC and central amygdala, and it may also have
importance in other regions. 54 treatment for OUD: Inducing “dopamine
homeostasis” to treat protracted
Research conducted on non-human primates
has revealed that the noradrenergic LC may play a withdrawal
role in various aspects of the brain’s alarm function, In the United States, a national opioid epidemic has
4
encompassing attentiveness, arousal, anxiety, fear, and prompted the recommendation of three FDA-approved
terror, along with their physiological manifestations. medications for the prevention and treatment of OUD:
These investigations involved comparing the outcomes of methadone, buprenorphine, or naltrexone. There is ample
electrically stimulating the LC with minute electrodes to evidence of their efficacy; however, these medications are
the effects induced by other agents or conditions capable under-prescribed. The objective here is to briefly review
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of modulating LC activity. The findings suggested that and synthesize data from the available medical literature
endogenous morphine-like substances and opioids serve on these FDA-approved medications and provide a
to inhibit the activation of the LC system, and the onset of framework to demonstrate the optimal approach for
opioid withdrawal syndrome arises from the reactivation outpatient management of OUD.
of this LC-noradrenergic system. Clonidine, which Clonidine and lofexidine have improved and refined
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suppressed noradrenergic LC activity in low doses, was the medical approach to opioid withdrawal states while
therefore postulated to suppress opioid withdrawal signs
and symptoms. Many signs of opioid withdrawal produced transitioning opioid-dependent adults to extended-release
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through electrical or chemical stimulation of the nucleus injection naltrexone. Opioid agonists like methadone,
LC increase noradrenergic activity and the concentration mixed agonists like buprenorphine, and the combination
of the noradrenergic metabolite 3-methoxy-4-hydroxy- of buprenorphine with naltrexone and clonidine are now
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phenyl glycol within the brain. Clonidine, an alpha-2 used to treat OUD. The authors assessed the efficacy of
adrenergic agonist, can inhibit signs of opioid withdrawal two outpatient opioid detoxification methods and relapse
in animals and humans. 55 prevention in a trial transition induction to extended-
release (XR)-naltrexone. A 7-day detoxification regimen
Clonidine likely attenuates opioid withdrawal utilizing naltrexone with a single day of buprenorphine
syndrome due to the reduction of noradrenergic neuronal administration was followed by a gradual increase in
activity originating in the LC. However, alpha-2 adrenergic oral naltrexone doses, supplemented with clonidine and
receptors located throughout the body and other other medications. Similarly, a buprenorphine-assisted
mechanisms may also play a role. In a series of studies, detoxification protocol involved a 7-day tapering of
Gold’s group explored the LC alpha-2 adrenergic receptor buprenorphine, followed by a week-long interval before
selectivity and the neuroanatomical and pharmacological initiating XR-naltrexone, in accordance with official
anti-withdrawal action of clonidine (Table 1). Confirmation prescribing guidelines. The combination of naltrexone
of this hypothesis in rats, monkeys, and human subjects treatment and adjunctive clonidine facilitated complete
has added to the understanding of the mechanisms of withdrawal for 38 out of 40 methadone-dependent patients
opioid action and withdrawal. within a span of 4 – 5 days. Naltrexone dosing typically

Moreover, a double-blind, placebo-controlled, and commenced at 1 mg/day and was incrementally raised to
cross-over trial from Taylor et al. found that clonidine 50 mg/day over a 4-day period for most patients. Clonidine
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eliminated the symptomology of opioid withdrawal for administration helped mitigate the intensity of naltrexone-
240 – 360 min in 11 hospitalized OUD subjects. In the induced withdrawal symptoms. Significant reductions
longer term, the same patients, in an open pilot study of in blood pressure were observed without instances of
the effects of clonidine taken for 1 week, also experienced syncope, and although certain symptoms persisted,
the elimination of opioid abstinence symptoms. These data including anxiety, anorexia, insomnia, restlessness, and
suggest that opioid withdrawal is due to increased neuronal muscular aching, they were either substantially alleviated

Volume 7 Issue 3 (2024) 5 doi: 10.36922/itps.1918