Another approach to the substitution hypothesis has been proposed by Ameisen (92, 141), who hypothesized that there is a deficit of GHB in the brain of AUD patients. The definition of substitution, limited to the notion that substitution should strictly involve substances that act on the same receptors, has been questioned. In addictology, a substitution substance is a substance that acts on the same receptors as the targeted substance of abuse.
The Road to Misuse and Abuse
Many adverse effects may in large part be explained by an early occurring activation of brain areas containing high densities of GABA-B receptors. In these latter patients, the dose increase may have been limited by adverse effects, but it happens that some patients reach very high doses (superior to 400 mg/day) without achieving a state of indifference. It is also proposed that this action of baclofen is made possible by the fact that baclofen and alcohol act on similar brain systems in certain regions of the brain.
AUD and Need for Other Medications
Cruz HG, Ivanova T, Lunn ML, Stoffel M, Slesinger PA, Lüscher C. Bi-directional effects of GABA(B) receptor agonists on the mesolimbic dopamine system. Convergent evidence from alcohol-dependent humans and rats for a hyperdopaminergic state in protracted abstinence. Chronic baclofen desensitizes GABA(B)-mediated G-protein activation and stimulates phosphorylation of kinases in mesocorticolimbic rat brain. Fox HC, Bergquist KL, Hong KI, Sinha R. Stress-induced and alcohol cue-induced craving in recently abstinent alcohol-dependent individuals. Gupta M, Verma P, Rastogi R, Arora S, Elwadhi D. Randomized open-label trial of baclofen for relapse prevention in alcohol dependence.
- Despite the lack of consistent evidence of efficacy, baclofen is frequently used off-label to treat AUD, especially in some European countries and Australia (70).
- The variable densities of GABA-B receptors may have important implications regarding the use of baclofen in the treatment of AUD, given that, when a patient takes baclofen activation of regions with high densities should have clearer and more immediate physiological and behavioral consequences than the activation of regions with low densities.
- This review on the mode of action of baclofen from a clinical standpoint and with a biological perspective highlighted three potential modes of action of baclofen; namely on dopamine, functional connectivity, and as a substitution drug.
- Baclofen also has important neuromodulatory effects in the amygdala, through its inhibitory action on neurotransmitters and complex effects on second-messenger signaling (37).
- Preclinical models have demonstrated that a direct inactivation of some of these structures can suppress craving or the reinstatement of drinking.
- In one study, participants with recent (past 6 months) mental disorders, other than AUD, were excluded (48).
Baclofen in the Treatment of Patients With Alcohol Use Disorder and Other Mental Health Disorders
- The definition of substitution, limited to the notion that substitution should strictly involve substances that act on the same receptors, has been questioned.
- The presence of a psychiatric comorbidity may be amongst the abovementioned factors playing a role in explaining different responses to baclofen treatment in terms of alcohol drinking outcomes.
- Comparison of the effects of allopregnanolone with direct GABAergic agonists on ethanol self-administration with and without concurrently available sucrose.
- This differs from those who have been cured by using other methods, for whom abstinence most generally requires a lot of effort, and for whom craving for alcohol often returns when they resume some alcohol drinking or see alcohol cues.
- The dose of baclofen needed to achieve this effect could be very variable from one subject to another in relation to each individual’s variable strength of the Pavlovian association between the cue and the reward.
AUD is a chronic relapsing disorder characterized by an increased motivation to seek alcohol and drink compulsively, with an increasing loss of control over drinking, progressing from impulsivity to compulsivity (15). In any event, a state of indifference can be reached in a substantial number of patients, and one of the aims of the present article is to try to address the concept of indifference in biological terms. Those who are indifferent to alcohol can drink a glass of an alcoholic beverage, they do not finish the glass, they do not want to continue drinking, they feel nothing, while they remain unchanged for other aspects of their life, which they enjoy normally. In people indifferent to alcohol, the experience of drinking or seeing alcohol cues has changed completely, as if alcohol had no meaning to them anymore.
It is sometimes used for the treatment of opioid withdrawal symptoms, and may be superior for this purpose to the more-commonly used clonidine. The interaction may increase the sedative effects of all ingested sedatives and as such is not generally recommended. Baclofen should be avoided in the setting of chronic kidney disease and end stage renal disease as even small doses can cause excessive toxicity. It is sometimes used transdermally (applied topically to the skin) in combination with gabapentin and clonidine prepared at a compounding pharmacy. It may also be used for hiccups and muscle spasms near the end of life, and off-label to treat alcohol use disorder or opioid withdrawal symptoms.
The pharmacogenetics of alcohol use disorder. Typologies of alcohol dependence. Pharmacotherapy of alcoholism – an update on approved and off-label medications. Therefore, future efforts should also focus on profiling these compounds from a toxicology and safety standpoint, in order to bring them to the clinical setting and test their safety and potential efficacy in humans. Despite the lack of consistent evidence of efficacy, baclofen is frequently used off-label to treat AUD, especially in some European countries and Australia (70).
Baclofen (Lioresal, Fleqsuvy, and others) – Uses, Side Effects, and More
It is well established that there is a very important relation between stress and alcohol use (34, 35). The learning of cue-reward associations is a slow process causing long-lasting synaptic plasticity changes in cortico-limbic-striatal circuitry, via multiple gene and protein expression. Some reach it at moderate doses, some at high or very high doses. Patients call it “my threshold.” The threshold of indifference is unique to each patient.
The use of medications for AUD among these latter patients is even lower than among AUD patients without other comorbid mental disorders, because of the concern of medication-alcohol interactions (15). In clinical practice, these conditions are frequent and contribute to a further reduction in the available treatment choices for AUD patients. Unfortunately, no definitive conclusions can be drawn due to the lack of specific analyses on whether baclofen efficacy is different in AUD patients with comorbid psychiatric disorders vs. those without. Therefore, the aim here was to conduct a narrative review of the scientific literature related to the use of baclofen in AUD, both in patients with and without concomitant psychiatric disorders.
Baclofen Abuse and Addiction Treatment Options
Tell your healthcare provider if you used baclofen during your pregnancy, especially near the end of your pregnancy. If you use baclofen on a regular basis during pregnancy, your baby may have withdrawal symptoms that can be life-threatening. Your healthcare provider will advise you if you should use baclofen while you are pregnant or trying to get pregnant. It is not known if or how baclofen could affect pregnancy or harm an unborn baby.
Baclofen and GHB share several common neurobiological effects, including GABA-B activation; among alcohol, baclofen and GHB, only GHB occurs naturally in the brain and has brain specific receptors. These clinical similarities raise the possibility that baclofen and alcohol act on the same brain systems, and that baclofen could be a substitution treatment for alcohol dependence. The above-mentioned study by Keegan et al. shows that chronic baclofen treatment induces plastic changes in a number of structures and systems, most of which are part of, or are closely linked with, the brain’s reward network. The enduring reduction of dopaminergic systems activity in patients’ brains logically implies that drugs used in the treatment of AUD should enhance dopamine function to restore brain circuits disrupted by alcohol use. Many preclinical see (2), for review and clinical studies have demonstrated the efficacy of baclofen in the treatment of several addictive disorders, including alcohol use disorder (AUD) (3–10), even though negative results have also been published (11, 12).
Contact Zinnia Health today to explore how we help people overcome baclofen addiction and take the first steps towards your recovery. If you’re looking for a trusted team of providers who can help guide you toward the right treatment plan, Zinnia Health can help. Regardless of the type of treatment program you choose to enroll in, a variety of therapies will support you both physically and mentally. Some people thrive with the flexibility that outpatient programs provide, especially if they have a lot of friends and family around to help them stick to their treatment plan. With outpatient treatment, you may be asked to attend therapy sessions throughout the week and have regular appointments with your healthcare providers.
Kääriäinen I. Effects of aminooxyacetic acid and baclofen on the catalepsy and on the increase of mesolimbic and striatal dopamine turnover induced by haloperidol in rats. Spanagel R. Aberrant choice behavior in alcoholism. Pertussis toxin blocks 5-HT1A and GABAB receptor-mediated inhibition of serotonergic neurons. GABAA and GABAB receptor site distribution in the rat central nervous system. Reynaud M, Aubin HJ, Trinquet F, Zakine B, Dano C, Dematteis M, et al. Hudgson P, Weightman D. Baclofen in the treatment of spasticity.
Research
Stop taking baclofen and get help right away if you have any of the following symptoms of a serious allergic reaction. In the U.S., you can report side effects to the FDA at /medwatch or by calling 800-FDA-1088. Tell your healthcare provider if you have any of these side effects that bother you.
A randomized, placebo-controlled study of high-dose baclofen in alcohol-dependent patients-the ALPADIR study. It remains that chronic alcohol consumption impacts many brain systems and that GABA-B may interfere with some of these effects with potential clinical advantages, assimilated to substitution or not. Even though alcohol does not directly act on GABA-B, it increases GABA(B1) and GABA(B2) receptor expression in different parts of the brain, while baclofen partially reverses these effects (87). The biological bases of craving and drinking in response to stress or alcohol cues have been extensively studied in preclinical models of alcohol addiction and in AUD patients themselves. Instead, it is often preceded by a period of a slow decrease of craving; but almost all patients who reach a state of indifference say that at a certain dose they felt a complete change in their attitude toward alcohol. This shows that baclofen can have an effect on dopaminergic systems during treatment of AUD patients, but this effect can be that of a hyper- or a hypo-dopaminergic effect, and that it occurs in a minority of patients.
Baclofen’s ability of to produce major depression during treatment of AUD is a subject of discussion see (79); if this were the case, it is certainly very rare. Baclofen and other GABA-B agonists microinjected into the VTA suppress alcohol-seeking behavior (70), alcohol consumption (71), and alcohol-induced conditioned place preference (72). The second is that microinjection of baclofen directly into the VTA blocks the behavioral response to cues and the cue-evoked firing of subpopulations of NAc neurons that respond to predictive cues (69).
The problem with baclofen and alcohol is that they do not act on the same receptors. In a recently published guidance for baclofen treatment of AUD, primarily written by expert patients, the quest for the threshold of indifference was clearly described baclofen addiction potential (79). For the majority of patients, baclofen treatment is a quest to reach the threshold of indifference. Therefore, the effects of baclofen on neuroimmune/neurotransmitter systems may participate in a normalization of functional connectivity in patients with AUD.
Intensive Outpatient Treatment
In one study, participants with recent (past 6 months) mental disorders, other than AUD, were excluded (48). In both studies, participants received 30 mg/day baclofen for approximately a week. The daily doses of baclofen ranged from 30 to ~150 mg. Patients received daily doses of baclofen, ranging from 50 to 120 mg, and were followed for a timeframe ranging from 8 to 52 weeks.
Patients should have reversible spasticity so that baclofen treatment will aid in restoring residual function. Use of baclofen and monoamine oxidase inhibitors (MAOIs) can result in greater depression of brain function as well as low blood pressure. The recommended oral dose of baclofen is mg daily. Do not stop taking baclofen without talking to your doctor, especially if you have taken large doses for a long time.
