Advances in Addiction management-Challenges and opportunities

Dr. Ashwin Mohan, MD (PGI), PGDMLE (NLSUI)

Scope

•Basic neuroscience of SUD- overview

•Pharmacological management

•Newer targets of medications

•Challenges and opportunities

•Excludes:

•Discussion of individual disorders and treatments

•Clinical guidelines

•Ethical and legal issues

Loading…

The neurobiology of addiction

•Three-stage addiction cycle framework:

•binge/intoxication,

•withdrawal/negative affect, and

•preoccupation/anticipation.

•multiple neuroadaptations in three corresponding domains:

•(1) increased incentive salience,

•(2) decreased brain reward and increased stress, and

•(3) compromised executive function;

•and in three major neurocircuits: basal ganglia, extended amygdala, and prefrontal cortex

Loading…

Conceptual framework for the neurobiological basis of substance use disorders

Challenges

•Clinical: poor response rates, retention, relapse, inadequate treatment, comorbidities

•Ethical: voluntary/involuntary, consent. Capacity, substitution, use of psychoactive medications

•Regulatory: legal challenges, controlled medications, availability and accessibility

•Socioeconomic: stigma, discrimination, poor understanding of addiction, cost

•GREATEST CHALLENGE: Treatment providers

•Not offering optimum treatment, optimum duration, optimum doses

•Focus on detoxification and not relapse prevention

•Refusal to use evidence based treatments

•Focus on abstinence and not individual

•Offering psychosocial and not pharmacological treatment

•Inadequate understanding of biological basis of addiction

•Poor understanding of biological basis of treatments

•Therapeutic nihilism

Challenges

Challenges of Substances

•New/Novel Psychoactive Substances

•Prescription drugs- opioids, gabapentenoids, ketamine

•Cannabinoids- natural and synthetic

•Cutting with other substances

•Increased potency/purity/concentration

•Different routes of administration

•misuse/abuse of treatments themselves

Responding to challenges

•Understanding the disorders better

•Understanding the psychopharmacology of approved medications better

•Understanding the off label uses of medications better

•Understanding the symptoms and treating them better

Levels of alcohol’s effects on the brain

•Level 1: Genetic factors in AUD

•Level 2: Alcohol-induced alterations in epigenetic regulation

•Level 3: Alcohol’s effects on transcriptional activity

•Level 4: Alternative splicing

•Level 5: Alcohol and protein translation

•Level 6: The role of posttranslational modifications

•Level 7: Impact of chronic drinking on neuromodulators and neural circuits

Loading…

Molecular pathways in alcohol use disorder

Neurotransmitter/Modulator Systems and Molecular Targets of Ethanol

Approved medications

Hyperkatifeia/Negative Reinforcement

•defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse

•a driving force for negative reinforcement in addiction

•Medications that reverse hyperkatifeia by resetting brain stress, antistress, and emotional pain systems and returning them to homeostasis

•promising new targets for medication development

Within-system neurocircuitry associated with hyperkatifeia in the withdrawal/negative affect stage

Between-system extended amygdala circuitry associated with hyperkatifeia

Psychopharmacology of existing medications

•Naltrexone

•The opiate antagonist naltrexone was first synthesized in 1963

•clinical trials targeting heroin addiction began in 1973 and led to its approval by the FDA in 1984

•data now exist on the use of naltrexone in substance addictions beyond opiates, including alcohol use disorder, for which it was approved in 1995, as well as nicotine and stimulant use disorders

•A large body of evidence exists to support a role for endogenous opioid pathways in the pathophysiology of addiction

•similarities have been described between the two categories of substance and behavioral addictions

Nlatrexone

•Neurocognitive research has yielded valuable data on the role of impulsivity

•a trait that has been linked to both substance and behavioral addictions

•may be caused by disruptions within the opioid system

•evidence for a shared role of the endogenous opioid system in addiction helps explain how naltrexone, an opioid antagonist, may be effective across a broad spectrum of addiction.

•Impulsivity has been suggested as a trait vulnerability marker for addiction risk involving underlying brain circuits and neurotransmitter systems

•Understanding the interrelationships among these three components may lead to the development of targeted treatments

Psychedelics

•The classic psychedelics comprise three main classes of chemicals

•plant- derived indoleamines, including N,N- dimethyltryptamine (DMT), 5- methoxy- DMT, psilocybin

•The second class are phenylalkylamines, including mescaline (derived from the peyote cactus) and synthetic ‘amphetamines

•The third group of compounds are semi- synthetic ergolines, such as LSD

Psychedelics

•Therapeutic effects have been observed across classic and non-classic psychedelics

•These medications may provide a novel treatment for addictive disorders.

•Capable of producing significant and enduring positive changes in the management of patients suffering from substance use disorder.

•Moreover, they yield results after a single-dose administration- as pharmacologic adjuncts in the treatment of this condition.

•positive effects of psychedelics in the treatment of substance use disorder is due to the modulation of multiple distinct brain networks

Loading…

Ketamine

•Ketamine belongs to the chemical class of drugs known as arylcyclohexylamines

•has a good safety profile and lacks the major drawback that many other anaesthetics have: respiratory suppression.

•ketamine is normally administered intravenously, rapidly induces dissociation, sedation and analgesia.

•At sub-anaesthetic doses, it can also produce psychedelic experiences

•ketamine is classically considered a non-competitive N-methyl-Daspartate (NMDA) receptor antagonist, it is actually a wide ranging pleiotropic molecule that affects a variety of receptors and cellular processes

Ketamine

•Ketamine’s potential mechanisms of action in addiction

•Plasticity, neurogenesis and synaptogenesis

•Disruption of functional networks

•Rapid antidepressant effects

•Reconsolidation

•Mystical experiences and psychedelic effects

•studies suggest that ketamine may improve the ability to establish and maintain abstinence in SUDs. Improvement in cravings, motivation to quit, and self administration have been shown

Cannabidiol

•several reports suggest that cannabidiol (CBD) presents beneficial effects relevant for the management of neurological disorders such as epilepsy, multiple sclerosis, Parkinson’s, or Alzheimer’s diseases

•Large body of evidence pointing out that CBD improves cognition, neurogenesis and presents anxiolytic, antidepressant, antipsychotic, and neuroprotective effects

•suggesting potential usefulness for the treatment of neuropsychiatric diseases and SUD

•the effects of CBD on the regulation of the reinforcing, motivational and withdrawal-related effects of different drugs of abuse such as alcohol, opioids (morphine, heroin), cannabinoids, nicotine, and psychostimulants (cocaine, amphetamine).

Cannabidiol

•neurobiological mechanisms that might be underlying the ‘anti-addictive’ action of CBD through the regulation of dopaminergic, opioidergic, serotonergic, and endocannabinoid systems as well as hippocampal neurogenesis

•CBD may reduce the consumption, motivation or relapse of alcohol,

•Opioids (i.e., heroin, morphine) and psychostimulants

•(amphetamine, methamphetamine, and cocaine), as well as

•the withdrawal-related signs of morphine and cocaine.

Lemboraxant

•hypocretin/orexin plays a broad and important role in physiological functions ranging from addiction, stress, and anxiety to sleep, energy metabolism, and homeostatic regulation.

•many lines of evidence support the idea that orexin receptor signaling contributes strongly for higher-salience addiction related states.

•This includes responding with more motivating rewards and/or greater response requirements, individual differences in motivation and drive, and anxiety and stress related contributions.

Memantine

•Memantine is used for the treatment of moderate-to-severe Alzheimer’s disease

•Memantine is a unique glutamatergic medication with proven ability to attenuate drug addiction in preclinical models

•Memantine has shown efficacy in reducing alcohol and opiate craving, consumption, and withdrawal severity.

•Glutamate is the main excitatory neurotransmitter in the brain and is of critical importance for the synaptic and circuit mechanisms that underlie opioid addiction

•Opioid memories formed over the course of repeated drug use and withdrawal can become powerful stimuli that trigger craving and relapse,

•and glutamatergic neurotransmission is essential for the formation and maintenance of these memories.

Memantine

•memantine has shown unique ability to reverse substance-induced neuroinflammatory response

•the effect of substance abuse on glutamatergic homeostasis varies based on the stage of addiction and the particular substance of abuse,

•it is critically important to examine the utility of memantine with a more precise focus on glutamatergic state (hyperglutamatergic vs hypoglutamatergic)

•divergent clinical and behavioral effects of memantine and ketamine could be a consequence of multiple differences between the drugs.

•Their very different pharmaco-kinetics along with differences in their actions at binding sites

Reconsolidation blockade

•the possibility of erasing, or significantly weakening, memory through targeted disruption of memory reconsolidation

•memories become destabilized under certain conditions of retrieval and require restabilization to persist in the brain

•βAR antagonism: the βAR antagonist propranolol as an amnestic agent. Propranolol was shown to reduce craving in individuals with a range of substance use disorders

•Blockade of βARs has also been shown to disrupt the reconsolidation of conditioned hyperactivity

•NMDAR antagonism

Reconsolidation blockade

•Cannabinoids: The precise mechanism of cannabidiol’s mnemonic effects is unclear

•directly disrupting reconsolidation, but it may also enhance extinction

•more generally anxiolytic, leading to an “updating” of a memory’s salience during the reconsolidation window, in addition to acute reductions in drug memory expression

•Blocking glucocorticoid receptors with mifepristone

•research should continue to characterize the mechanisms that underlie reconsolidation and probe its potential limits (or not) in more translationally relevant procedures

•reconsolidation blockade offers a highly innovative approach for the treatment of drug addiction

The potential role of oxytocin in addiction

•Targeting the brain OXT system has the potential to treat addiction to all major classes of addictive substances

• And to intervene across all stages of the addiction cycle

•rebalancing core neural systems that become dysregulated over the course of addiction

•traditionally known for its well-established peripheral effects on gestation, lactation, and parturition

•been implicated in a broad array of centrally-mediated functions ranging from

•sexual behavior and feeding to social interaction, maternal care and affiliative behaviors, motor activity, fear, stress, anxiety, as well as (social) memory and reward processes

Oxytocin

•oxytocin and OXTRs expression in limbic brain areas such as the ventral tegmental area (VTA), amygdala, bed nucleus of the stria terminalis (BNST), hippocampus (HPC), nucleus accumbens (NAc), prefrontal cortex (mPFC)

•Interferes with Systems Involved in Drug Consumption, Intoxication, and Reward

•Interference with Systems Involved in Drug Withdrawal

•Interference with Neurobiological Systems Involved in Drug Relapse

Neural Substrates of Addiction Overlap with the Brain Oxytocin(OXT) and Stress Systems

•Brainr eward system(green),

•Stress system(red),

•And behavioural control and memory(blue)

Protein Kinases and Addiction

•Recent evidence suggests that drugs of abuse interact with and change a common network of signaling pathways that include specific protein kinases.

•Have been implicated in various aspects of drug addiction including acute drug effects, drug self-administration, withdrawal, reinforcement, sensitization, and tolerance

•PKC isozymes can be classified into three subgroups

•the conventional PKCs (cPKC, α, β, and γ), the novel PKCs (nPKC, δ, ε, η, and θ), and the atypical PKCs (aPKC, ζ, and ι/λ).

•Addictive drugs can activate PKCs by stimulating dopamine D2, opioid, or cannabinoid receptors

Protein Kinases and Addiction

•PKCs may play an important role in drug-induced synaptic plasticity

•have numerous downstream effects resulting in changes in gene transcription and protein synthesis that contribute to long-term changes in neural networks involved in addiction

•Pharmacological manipulation of PKC isozymes may produce beneficial effects in the treatment of addiction

•may reduce alcohol intake

•increasing sensitivity to the analgesic effects of opiates

•may inhibit the acute effects of amphetamine and possibly other psychostimulants

•Also serve acute and long-term molecular plasticity that directly supports the various types of drug memories

•Are excellent pharmacological targets to prevent the establishment of drug memories

Drug addiction: a curable mental disorder?

•Drug addiction is a chronic, relapsing brain disorder.

•Multiple neural networks in the brain including the reward system (e.g., the mesocorticolimbic system),

•the anti-reward/stress system (e.g., the extended amygdala),

•and the central immune system, are involved in the development of drug addiction and relapse after withdrawal from drugs of abuse.

•the current treatments that target specific receptors, approaches that target the molecular candidates in the reward and anti-reward systems is promising to treat drug addiction.

•The neuroimmune system is a relatively novel target that is of significant clinical interest. However, the role of neuroimmune system in drug addiction remains poorly understudied.

•gene therapy could be a powerful strategy, despite that this approach remains in its infancy

Personalizing the Treatment of Substance Use Disorders

•The existing pharmacopoeia for substance use disorders is severely limited.

•The FDA has approved medications only for alcohol, nicotine, and opioid use disorders, and currently there are no approved medications for cannabis, cocaine, methamphetamine, or inhalant use disorders.

•the development of treatments for addiction was aimed at bringing about cessation of drug consumption (abstinence),

•TREATING THE DIMENSIONS OF SUBSTANCE USE DISORDER

•medications that would address specific symptoms of withdrawal, such as cravings, depression, cognitive impairments, pain, and sleep problems

•a more holistic and individualized approach to treatment

•current understanding of the mechanistic processes underlying addiction identifies a much broader set of clinically beneficial outcomes

•opportunity to target discrete neurobiological processes

•Personalize interventions to the unique deficits in a given individual and across the course of an individual’s disorder

TOWARD THE FUTURE

•Neuroscience has revealed that addiction involves a set of interconnected processes that can be targeted strategically

•factors traditionally associated with recovery are components of treatment.

•Addiction is a complex disorder that involves brain circuits necessary for survival and one that is strongly influenced by genes, development, and social factors

•Understand the underlying mechanisms well enough that we can turn this complexity into an opportunity to include these dimensions as targets for substance use disorder treatment

•personalize interventions to accommodate the unique neurobiological characteristics and social contexts of individual patients.

•Addiction is an evolving disorder that changes through time and across the lifespan of the individual