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Mixing of Metaphors
Naltrexone has always been primarily about utilization for opioid treatment, with a one-off orphan application for alcohol abuse as a secondary, and little understood application.
After Dupont abandoned their patent protection-- it became like a fumbled football-- a product with billion-dollar potential-- up for grabs to any enterprising company to exploit-- and Alkermes did exactly that-- with minimal development costs to take a known and proven 30 year old drug-- and use the exact formulation to develop a injectible delivery system, with a suspension release (depot system)-- a low cost and high reward endeavor. Alkermes has spent a substantial amount of money in marketing the product, as well as employing lobbyists to enact legislation favorable towards the sales, immediate availability, and insurance coverage of the extremely pricy medication, whereas it's open-source generic counterpart-- oral naltrexone-- is at most $2 a pill.
Additionally, the application and dosage warrant a separate discussion below-- as either naltrexone in oral form, or naltrexone in a depot deposit (injectable time-release suspension), do nothing to prevent to either taking any form of opioids, or ingesting alcohol. It just simply prevents the subject from deriving the expected benefit of the euphoric high.
Alkermes states in its original 2006 label insert for Vivitrol as filed with the FDA:
Mechanism of Action
Naltrexone is an opioid antagonist with highest affinity for the mμ opioid receptor. Naltrexone has few, if any, intrinsic actions besides its opioid blocking properties.
However, it does produce some pupillary constriction, by an unknown mechanism. The administration of VIVITROL is not associated with the development of tolerance or dependence. In subjects physically dependent on opioids, VIVITROL will precipitate withdrawal symptomatology.
Occupation of opioid receptors by naltrexone may block the effects of endogenous opioid peptides. The neurobiological mechanisms responsible for the reduction in alcohol consumption observed in alcohol-dependent patients treated with naltrexone are not entirely understood. However, involvement of the endogenous opioid system is suggested by preclinical data.
Additionally, in their most current labeling and medication guide FDA submission and approval on FDA's website, it specifically states this:
INDICATIONS AND USAGE
VIVITROL contains naltrexone, an opioid antagonist, and is indicated for the treatment of alcohol dependence in patients who are able to abstain from alcohol in an outpatient setting prior to initiation of treatment with VIVITROL. Patients should not be actively drinking at the time of initial VIVITROL administration (1.1).
VIVITROL is indicated for the prevention of relapse to opioid dependence, following opioid detoxification (1.2).
VIVITROL should be part of a comprehensive management program that includes psychosocial support (1).
In the above disclosure in the very first paragraph second sentence of the Clinical Pharmacology description of the Vivitrol label Alkermes filed with the FDA, it states:
Naltrexone has few, if any, intrinsic actions besides its opioid blocking properties.
Naltrexone and Vivitrol have only one short-term physiologicaleffect-- blocking the endorphins created by the ingestion of opioids, alcohol, sex, gambling, or maybe even running. This is a process that must be coupled with some form of therapy that capitalizes on this unique (but short lasting) effect to accomplish a modification of abusive behavior
Therefore a basis of this equation-- is the definition of addiction-- the persistent craving for opioids, or alcohol, or sex, or gambling, or whatever substance (in my own case-- admittedly Gummi Bears) or activity produces the endorphins. Nobody is born an alcoholic, or drug addict, or gambler-- these are acquired vices, and a result of conditioned responses.
Without the intention to be crass or tacky-- but as a necessary analogy to demonstrate the physiological effects of naltrexone, I will compare it to a very popular self-administered drug- Viagra. Male erectile dysfunction has been defined as the persistent inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance.
Viagra has only one physiological effect-- enhances relaxation of the cavernosal smooth muscle, increases blood flow leading to increased intracavemosal pressure and penile rigidity. It decreases catabolism of cGMP, which Sildenafil restores natural erectile response to various sexual stimuli but does not cause erection in the absence of stimuli.
In other words, like naltrexone-- it has only one single physiological response. It has a little to do with the male libido (the sexual stimulus) as naltrexone would affect the persistent cravings.
If any of the ED (erectile dysfunction) drug manufacturers were to bring a 30-day time-release injection to market-- while it might be extremely popular with those extremely sexually active, however it would be cost prohibitive if priced accordingly in the cost range of Vivitrol. Sildenafil (Viagra), vardenafil (Levitra, Staxyn), tadalafil (Cialis) and avanafil (Stendra), are all priced in the $10 - $15 range. They are not taken daily... that are PRN-- as required by the patient.
The prescribed dosing of both naltrexone [daily] and Vivitrol [monthly]-- would be similar to taking Viagra every day-- generally unnecessary (although highly sexually active couples might have sex daily), and expensive.
As a preventative to either drinking or taking drugs... naltrexone's only deterrent is the subject's cognition that they won't get high or buzzed.
In the real world practical applications-- this suppression can be defeated by simply not taking a naltrexone orally in the anticipation of desiring to attain the euphoric high-- but this is usually the point of no return where the drinkers hit black-out stage-- so it becomes a cognitive and rational issue where adjunctive psychosocial therapy plays an important role in the overall treatment.
With Vivitrol, the intentional non-compliance is a non-issue... the naltrexone is in systemic depot.
However, what must be taken into consideration is the distinction of the difference between the treatment of AUD, that is impractical [and unethical] in the treatment of Opioid addiction-- is the methodology and application of a treatment protocol in conjunction with the physiological action of naltrexone of blocking the brain's endorphins with the opioid receptors.
In all the clinical research and studies, they all discuss and focus on overall reduction of alcohol intake resultant from vivitrol/ naltrexone. How can that be, when the labeled instructions first require abstinence from alcohol? This is an oxymoron-- numerous clinical studies of a drug that the manufacturers admittedly do not understand:
"The neurobiological mechanisms responsible for the reduction in alcohol consumption observed in alcohol-dependent patients treated with naltrexone are not entirely understood."
... that are predicated on an off-label application in contravention to the manufacturers directions.
In this case-- the directions application of naltrexone (and nalmefene) for AUD is simply wrong. What they are correct about-- is that they don't understand the behavioral psychology aspects of using their drug's unique properties in conjunction with an efficacious behavioral modification treatment plan. This is analogous to Pfizer presuming to figure out the connection between the physiological action of Viagra as a Vasodilator in treating erectile dysfunction, and defining the psychology intertwined with an orgasm. It is worth noting for those unfamiliar with this, that Viagra has no connection with male libido or desire... as naltrexone has nothing to do with cravings and addiction.
The researchers and clinicians are on the right path, and the drug manufacturers are simply wrong-- except for their disclaimer about understanding the interaction of the suppression of endorphins with addiction. It is like trying to define what goes on in one's mind that will trigger an orgasm.
Alcohol is a legal substance, consumption socially acceptable, and an integral part of an AUD sufferers lifestyle. Opioid addiction is a completely different set of circumstances-- sharing the same physiological basis-- addiction to the endorphins created by either substances, or by psychological stimuli (gambling, sex addiction, pedophilia, etc).
While it has been established that there is a certain genetic predisposition for certain individuals to become addicted to endorphins-- whereby such discoveries of the pleasurable endorphins earlier in life... lead to the conditioning process of pursuing the substance or activity that feeds the brain with such flood of endorphins.
The proper utilization of naltrexone within a treatment method, incorporates the necessity of continued drinking-- not abstention from alcohol-- which may render the subject sober for x amount of time, but invariably will lead to a relapse-- as the unsatisfied cravings become more intensified over time-- just like a land mine-- waiting for whatever event may trigger such relapse.
-- continued consumption of alcohol while on a pre-emptive self dosing of naltrexone.
In the same manner that a male would dose with a Viagra in anticipation of having sex, an AUD sufferer would voluntarily self-dose with a naltrexone-- a habit that will be routine for the rest of their lives. The result in not necessarily total abstention-- it is more abbreviated and mitigated drinking sessions-- unable to achieve any pleasurable results.
As a deterrent, Vivitrol has little effect-- other than the cognition that a subject won't get the euphoric high they seek. Once they stop taking monthly Vivitrol injections, all they need is one instance... one relapse... and they are once again a raging drug addict that "fell of the horse". There is no cumulative effect.
This is different with alcohol, however, if one disobeys the instructions. If they continue to drink while on Vivitrol, they will be ultimately drinking less, and with moderation-- if they continue drinking on their own volition. They will NOT be experiencing any gratification or "reward" from the alcohol, and soon the brain's neural pathways will begin disassociating themselves from alcohol's pleasurable effects-- ultimately achieving extinction of the cravings for alcohol. Nonetheless, there is always the future chance of a relapse long beyond at point that Vivitrol injections are ceased, simply by having a single social drink... where the subject "self-justifies" that they are no longer an alcoholic-- and that they can handle a drink or two. This could be ameliorated by the commitment and determination to always take a naltrexone pill before drinking-- a habit that is developed in the Sinclair Method using oral naltrexone-- rather than the expensive, and ineffectual injectable alternative.
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