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

2.4. Definitions of withdrawal treatment outcome success rates for both naltrexone and

Withdrawal from a substance is characterized in the buprenorphine. 35-38
Diagnostic and Statistical Manual for Mental Disorders, Gold’s group conducted a series of studies on LC
5 edition (DSM-5), as “a substance-specific problematic stimulation and ablation in rodents at the College of
th
behavioral change, with physiological and cognitive Medicine, University of Florida, in the early 1970s, and
concomitants, that is due to the cessation of, or reduction later at Yale in the late 1970s and early 1980s. These studies
in, heavy and prolonged substance use.” The International led Gold and his associates to hypothesize that the nucleus
th
Classification of Diseases, 10 edition, defines withdrawal LC might be responsible for some opioid withdrawal
as “a group of symptoms of variable clustering and syndrome symptoms. They continued this work with
severity occurring on absolute or relative withdrawal rats and non-human primates at Yale in the Aghajanian
of a psychoactive substance after persistent use of that and Redmond laboratories. Specifically, they stimulated
substance.” The characteristic clinical signs of opioid the LC and produced hypertension, tachycardia, and
withdrawal syndrome include hypertension, tachycardia, other signs of opioid withdrawal, including piloerection
mydriasis, piloerection (goosebumps), lacrimation, (bristling) in animals that had never been exposed to
rhinorrhea, yawning, insomnia, nausea, vomiting, and opioids. This LC electrical stimulation produced signs,
39
diarrhea. The progression of opioid withdrawal is symptoms, and behaviors similar to those induced
32
primarily influenced by the half-life of the specific opioid by the alpha-2 adrenergic antagonists yohimbine and
involved. Opioids characterized by short half-lives, such piperoxane. They could reverse the effects of electrical
40
as heroin (with a half-life of 3 – 5 h), prompt the onset stimulation with morphine, and this effect could be
of withdrawal symptoms within approximately 12 h after reversed again with the opioid antagonist naloxone.
41
the last dose. Conversely, discontinuation of opioids with Moreover, these researchers could reverse the effects
longer half-lives, such as methadone (with a half-life of of yohimbine and piperoxane with clonidine. They
42
up to 96 h), may lead to withdrawal symptoms emerging were also able to pre-empt the effects of these agents by
1 – 3 days following the last dose. Moreover, the duration lesioning the nucleus LC. 39
of the withdrawal syndrome typically aligns with the half-
life of the opioid. For instance, heroin withdrawal typically As a known alpha-2 adrenergic receptor agonist,
spans 4 – 5 days, while methadone withdrawal can extend clonidine was first tested in rodents and non-human
from 7 to 14 days and, in certain cases, persist for several primates and ultimately in humans in cases of both
weeks. Other than alpha-2 receptor agonists, other agents, precipitated and naturally occurring opioid withdrawal by
such as pro-dopamine regulators, may be useful adjuncts Gold’s group in the 1970s. This work (Gold et al., 1982),
to intervene in heightened NE activity during opioid recognized by the American Psychiatric Association with
withdrawal. the Foundations Fund Annual Award and Prize, represents
the first true translation of basic science into discoveries
2.5. Development of the locus coeruleus that help patients in psychiatry. 43
noradrenergic hyperactivity theory
2.6. Mechanisms in withdrawal symptomatology
In 1977, Gold’s group tested clonidine in humans with
OUD after opioid discontinuation and the emergence The noradrenergic hyperactivity theory for opioid
of withdrawal signs and symptoms as a test of the LC withdrawal changed the field in many ways. 34,42 First, it
noradrenergic hyperactivity theory. 33,34 These clinical provided the first neuroanatomy of opioid withdrawal,
scientists chose clonidine over other available alpha-2 which could be tested, and identified the roles of
adrenergic agonists because clonidine was widely used alpha-2 adrenergic and opioid inputs. This allowed for
worldwide and considered safe, effective, and approved by a better understanding of both opioid and non-opioid
the FDA for hypertension. During that period, the WHO treatments or withdrawal reversal methods. Second, it
was concerned about any medication that reversed opioid enabled physicians to explore and develop new opioid,
withdrawal in laboratory investigations. In the experiments, mixed opioid, and non-opioid treatments, including
clonidine acutely reversed opioid withdrawal, including pharmaceuticals and nutraceuticals. 44,45-50 Third, it
neonatal opioid withdrawal distress, reduced naloxone- introduced a new class of treatments, such as lofexidine,
precipitated withdrawal distress, facilitated rapid and guanfacine, and others, which use the same mechanism
ultra-rapid opioid detoxification, and provided an option of action–alpha-2 adrenergic agonist stimulation and
for impaired health professionals and others interested inhibition of the nucleus LC. 31,43,51 These treatments could
in a drug-free treatment. Clonidine also improved the potentially exhibit better side effect profiles and other
transition from opioid agonist to naltrexone and enhanced advantages. 36,52

Volume 7 Issue 3 (2024) 4 doi: 10.36922/itps.1918