Page 100 - ITPS-7-3

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

Table 1. Key facts
Clonidine.
Locus coeruleus stimulation promotes the release of norepinephrine.
Reduces the severity of withdrawal from opioid use.
Narcotic replacement therapy
Methadone-synthetic opioid and buprenorphine (Subutex) are agonists.
Suboxone; buprenorphine/naloxone is an agonist/antagonist.
Buprenorphine and methadone maintenance are equally effective in retaining patients in substance abuse treatment and in reducing illicit opioid use.
Narcotic replacement therapies have high treatment compliance.
Reduce overdoses and Emergency Department treatment-seeking.
Subutex and suboxone induction and maintenance are available in outpatient or physician offices.
Disadvantages buprenorphine
Chronic blockade of opioid receptors has anti-reward effects, increasing relapse potential when coupled with a narcotic antagonist
Does not activate the areas of the brain associated with relapse in some studies.
Possible lack of effectiveness in patients who require high methadone doses.
Locks people into addiction and also causes a “zombie” like effect.
There is evidence of potential suicide ideation and accompanied depression.
Even in the injectable form of delivery, there is poor compliance.
Naltrexone
Naltrexone is an opioid antagonist.
Provides chronic opioid receptor blockade and prevents overdose and opioid intoxication.
Agonists are better at this than antagonists unless in mandated impaired physician programs with monitors.
The main issue with naltrexone is poor compliance, but it can be assisted with Pro-dopamine regulation like KB220 variants or other modalities like rTMS.
Positive effects of treatment
All forms of treatment are significantly less costly and more effective than no treatment.
Reduction or abstinence in illicit opioid use.
Reduction in the severity of withdrawal from opioid use.
Retention in treatment for persons enrolled in opioid withdrawal or opioid cessation programs.
Harm reduction
Summary Points
• The adverse effects of OUD include (fatal overdose, infectious disease transmission, elevated health care costs, public disorder, and crime) and the
available treatments.
• The alpha-2-adrenergic receptor a subtype of the alpha-2-adrenergic receptor secretes norepinephrine (NE).
• NE causes the symptoms of withdrawal.
• Withdrawal-symptoms include hypertension, tachycardia, and anxiety.
• Clonidine is a molecular agonist of the alpha-2A receptor.
• Gold et al. found that clonidine can reverse the effects of locus coeruleus stimulation.
[7]
• This noradrenergic hypothesis for opioid withdrawal changed the field.
• Successful comprehensive treatment programs that used clonidine to transition to long-acting injectable naltrexone for impaired physicians and
other very motivated patients with OUDs were confirmed in the 1980s.
• The naltrexone, despite poor compliance, provides chronic opioid receptor blockade that prevents overdose, opioid intoxication, and subsequent
re-addiction in recovered in motivated patients.
• The development of clonidine and naltrexone as treatment agents for OUD demonstrates that neurobiological advances could be translated from
rodents to non-human primates to man into new effective clinical approaches.
• The traditional narcotic substitution therapies, like methadone maintenance, provide agonistic activity but do not target or block delta or mu
receptors. The combination treatment of narcotic antagonism and mu receptor agonist therapy (even at minimal doses of naloxone) seems
parsimonious but may induce anti-reward
• Clinical studies indicate that buprenorphine maintenance is as effective as methadone but less cardiac adverse effects maintenance in retaining
patients in substance abuse treatment and in reducing illicit opioid use.
• Clinical studies indicate that buprenorphine maintenance is as effective as methadone maintenance in retaining patients in substance abuse
treatment and in reducing illicit opioid use.
• The negative effect on reward circuitry is that chronic blockade of opioid receptors, even with partial opioid agonist action, may ultimately block
dopaminergic activity, causing anti-reward effects and increasing relapse potential.
• Based on initial results with large populations receiving D2 agonist therapy with KB220, a safe, non-addicting, natural dopaminergic receptor
agonist that potentially up-regulates instead of down-regulating dopaminergic receptors could be a co-therapy for long-term treatment to prevent
relapse rather than the combination of buprenorphine/naloxone alone.
• Futuristic frontline modalities should include genetic addiction risk testing, which could lead to precision medicine by matching polymorphisms in
risk alleles with medications or nutraceuticals.
Abbreviations: rTMS: repetitive transcranial magnetic stimulation; OUD: Opioid use disorder.

Volume 7 Issue 3 (2024) 6 doi: 10.36922/itps.1918