Opioid+Addiction

= = toc

Opiates are an alkaloid class of drugs that include: morphine, Oxycodone, Fentanyl and many more (NIDA 2017). Theses drugs commonly produce pain relief, euphoria and a sense of well-being (NIDA 2017). Although these drugs are commonly prescribed to treat pain, they come with a high risk for addiction and overdose. A commonly held view is that individuals that are prescribed opioids to treat pain are at a high risk of developing dependence and addiction. However, this scenario only accounts for up to 12% of instances of opioid use disorder, while 75% report that they started with someone else’s prescription (Szalavitz 2016). Addressing opioid abuse is at the forefront of American politics with up to 2 billion dollars being committed to mitigating this epidemic in the latest draft of the America's health care bill (Blue 2017).

= History = The earliest use of opioid’s [|analgesic] and euphoric properties can be traced back to the Sumerians cultivation of opium poppies in 3400 BC (The Atlantic 2017). In 1806, Fredrick Serturner characterized the active component of opium, morphine (Brownstein, 1993). Subsequent isolation of opioid alkaloids such as [|Oxycodone] (MacLaurn 2015) and Heroin (Askwith 1998) were developed in the 19th century as attempt to make a less addictive, more potentate analgesic. Although more potent, Oxycodone and Heroin have since been shown to be extremely addictive. Widespread use and abuse across the 20th century lead to increased regulation through the Controlled Substances Act of 1970 and President Richard Nixon War on Drugs of 1973 (The Atlantic 2017). In the 21st century, the acknowledgement of pain as a fifth vital sign has lead to a drastic increase in opioid prescriptions and instances of opioid abuse (The Atlantic 2017).

= Diagnosis = The American Psychiatric Association defines opioid use disorder in the [|Diagnostic and Statistical Manual V] as: A problematic pattern of opioid use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period: 1. Opioids are often taken in larger amounts or over a longer period than was intended. 2. There is a persistent desire or unsuccessful efforts to cut down or control opioid use. 3. A great deal of time is spent in activities necessary to obtain the opioid, use the opioid, or recover from its effects. 4. Craving, or a strong desire or urge to use opioids. 5. Recurrent opioid use resulting in a failure to fulfill major role obligations at work, school, or home. 6. Continued opioid use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of opioids. 7. Important social, occupational, or recreational activities are given up or reduced because of opioid use. 8. Recurrent opioid use in situations in which it is physically hazardous. 9. Continued opioid use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance. 10. Tolerance, as defined by either of the following: a. A need for markedly increased amounts of opioids to achieve intoxication or desired effect. b. A markedly diminished effect with continued use of the same amount of an opioid. Note: This criterion is not considered to be met for those taking opioids solely under appropriate medical supervision. 11. Withdrawal, as manifested by either of the following: a. The characteristic opioid withdrawal syndrome (refer to Criteria A and B of the criteria set for opioid withdrawal). b. Opioids (or a closely related substance) are taken to relieve or avoid withdrawal symptoms. (American Psychiatric Association 2013)

This set of criteria combined the previous distinction in the DSM IV between dependence and abuse into one disorder (Hasin et al. 2013). However, many are dissatisfied with the fact this DSM V makes no distinction between differing levels of severity in opioid use disorder (Hasin et al. 2013).

= Epidemiology = Currently, opioid addiction in a serious problem in modernized society to the point of being called an epidemic. In 2010 it was found that approximately 15.5 million individuals were addicted to opioids and this number is on the rise (Degenhardt et al. 2014). In the U.S. alone there are over 2 million affected individuals (ASAM 2016). From 1999 to 2010 prescription opioid overdose increased as much as 400% in the US, with heroin overdoses increasing at a similar rate (ASAM 2016). It is estimated that 91 Americans die from opioid overdose every day (CDC 2016).

= Neuron’s Role in Opioid Addiction = [|Neurons] are the pathways by which the brain sends and receives information (Freudenrich 2001). These cells consist of a cell body many small projections, dendrites, and a long projection the axon (Freudenrich 2001). In general, when a certain level of on input is achieved the cells axon depolarizes; this causes an electrical signal to travel down the axon ultimately release chemical messengers called neurotransmitters (Freudenrich 2001). The junction where two neurons meet is referred to as a synapse (Freudenrich 2001). Additionally, these chemical messengers are excitatory it the contribute to the depolarization of the receiving neuron and inhibitory if they cause hyperpolarization (Neurogistics 2017). Finally, compounds can also bind to receptors on neurons usually meant for neurotransmitters and modulate the effects elicited by the neurotransmitter (New Health Guide 2014). If these compounds increase the action of the neurotransmitter they are agonistic and if the decrease the neurotransmitters effects they are antagonistic (New Health Guide 2014).

Figure 1. Model of a neuron (nueroems 2014).

Neural Mechanism of Pain Transmission
Pain transmission is initiated by detection of a painful stimulus by nociceptors (Reddi 2013). Innervation of these nociceptors translate the noxious stimulus into an electrical current that travels along fast conducting neurons, Aβ fibres, to the central nervous system (CNS) (Reddi 2013). These nerve cells then terminal in the dorsal horn of the spinal cord releasing excitatory neurotransmitters such as substance P and glutamate (Reddi 2013). If these neurotransmitters are expressed in sufficient levels to cause depolarization of the postsynaptic neuron, pain is transmitted to the thalamus and cerebral cortex (Reddi 2013). It should be noted that some pain processing can occur at the dorsal root ganglia (DRG) of the spine and allows an individual to react to a painful stimulus without necessitating higher level processing (Custers 2015).

Opioids Effects on Neurons
Analgesic alkaloids like morphine elicit their effects by agnostically binding to opioid receptors on the neurons membranes (Al-Hasani and Bruchas 2011). Although all opioid receptors are inhibitory [|G coupled proteins], there are four different subtypes of opioid receptors including mu, kappa, delta and opioid receptor like 1 (Al-Hasani and Bruchas 2011). Opioid receptor agonists mediate pain presynaptically by lessening the release of excitatory neurotransmitters and post synaptically by hyperpolarizing the cell through K+ and Ca++ channels (Chahl 1996). Both of these events decrease the likelihood the postsynaptic nerve will depolarize and carry on the painful stimulus (Chahl 1996).

Figure 2. Synaptic model for opioid action (Chahl 1996).

Neuronal Mechanism for Tolerance
Neuronal tolerance to opiates occurs through two major mechanisms. Firstly, prolonged use of opioids lead to desensitization of G-coupled opioid receptors (Raehal and Laura 2005).

Figure 3. Opioid induced G protein activation (Al-Hasani 2011).

In this mechanism opioid receptors are decoupled from their corresponding G proteins or possess augmented G proteins that are unable to evoke downstream mechanisms responsible for analgesia (Dupen 2007). Secondly, neurons can decrease the surface density of opioid receptors through endocytosis to decrease the cell's response to pain killers (Gainetdinov et al. 2004). Presently, targeting G-coupled proteins is a burgeoning field (Ghanemi 2015). However, the balance between helpful and hurtful control of this widespread mechanism is significant barrier to therapeutic targeting (Ghanemi 2015).

= Neuroglial Cells Role in Opioid Addiction = Neuroglial cells, or glia derived from the Greek word for “glue”, constitute 90% of the cells in the human brain (Purves et al. 2001). Although they do not participate in electrical signal propagation, these a important to the maintenance and upkeep of neurons (Purves et al. 2001). Within the CNS there are three major types of glial cells: astrocytes, microglia and oligodendrocytes (Purves et al. 2001). Astrocytes are responsible for linking neurons to blood vessels, providing them with glucose and bussing neurotransmitters out of the extracellular environment (Pocock and Hooper 2006). Microglia are the immune cells of the CNS (Pocock and Hooper 2006). Although largely inactive under basal conditions, microglia respond to adverse circumstances in the CNS such as pathological invasion and injury (Pocock and Hooper 2006). Finally, oligodendrocytes act as neuronal insulators to speed up action potential propagation.

Toll-like receptor 4
[|Toll-like receptor 4 (TLR4)], is a receptor that under normal conditions responds to lipopolysaccharide (LPS), a compound found in the cell walls of gram-negative bacteria (NCBI 2017). Upon detection of LPS, TLR4 receptors initiate a signaling cascade that result in the release of proinflammatory cytokines and immune system activation (NCBI 2017). Additionally, opioids have been demonstrated to bind to TLR4 and elicit to the same downstream effects as LPS binding (Hutchinson et al. 2007). Similarly, LPS administration in rats has been found to cause morphine tolerance in morphine naive rats (Eidson et al. 2007).

Figure 4. Morphine effectiveness in naive rats (Eidson et al. 2007).

While this receptor in known to be key to pro inflammatory and opioid pathologies, researcher have not yet deduced what constitutes an agonist or. an antagonist (Li et al. 2016). However, in silico auto docking simulations represent a promising frontier for new therapies (Li et al. 2016).

Astrocytes
[|Astrocytes] become activated upon detection of pro inflammatory cytokines, chemokines and a variety of other factors (Watkins et al. 2007). Morphologically, astrocyte activation is characterized by expression of glial fibrillary acidic protein (GFAP) in order to reinforce its cytoskeleton (Miguel-Hidalgo 2009). Physiologically, astrocyte activation leads to a neglect of removal of extracellular excitatory neurotransmitters (Pekney and Nilsson 2005). Astrocyte activation even leads to release of tumor necrosis factor (TNF) which can increase presynaptic release of excitatory neurotransmitters (Watkins et al. 2007) and down regulation of inhibitory GABA receptors. Taken together these effects create a excitatory extracellular environment without inhibition as a counterbalance that leads to easier conduction in pain signaling pathways. Researchers have targeted the deactivation of astrocytes in through by utilizing AV411 or Ibudilast to attenuate opioid tolerance in rats (Hutchinson et al. 2009). The current research as presented a clear-cut case that activation of astrocytes creates and extracellular environment conducive to pain transmission. This is a form of tolerance because subsequent opioid doses need to be higher to elicit the same analgesic effects. Therefore, targeting astrocytes may be an effective method to treat opioid tolerance. Additionally, this also explains a number of withdrawal symptoms because the excitatory extracellular environment mimics aspects of chronic pain and creates a negative effect on the user while sober. However, many of the drugs currently being tested lack specificity. These treatments may have widespread effects not relevant to alleviating opioid use disorder.

Microglia
[|Microglia] are activated by opioids via the TLR4 mediated pathway (Watkins et al. 2009). Consensus among researchers points to initial activation of microglia, this change then induces activation in astrocytes (Watkins et al. 2009). Additionally, activated microglial production of proinflammatory cytokines and TNF induces activation neighboring microglia and astrocytes (Watkins et al. 2009). Activation of neighboring microglia creates a bidirectional system to maintain an agitated state, opioid tolerance (Hutchinson et al. 2007), and even chronic pain (Ru-Rong et al. 2013). Researchers have use minocycline to temper microglia activation which resulted in a decrease in opioid tolerance, addiction and morphine induce respiratory depression (Hutchinson et al. 2008). Despite the fact that this approach has been efficacious in animal models, the fact that is shuts down the brain's immune system means it could open up individuals to infection.

= Treatment =

Cognitive Behavioral Therapy
[|Cognitive behavioral therapy] is a physiological approach to behavior modification by which a individual’s thought process is analyzed in an attempt to alter it to elicit a different outcome (NACBT 2017). In a rehab context, CBT is used in drug rehabilitation to analyze the conditions that lead an individual to use drugs and attempting to augment the thinking behind this compulsion.

Figure 5. Pictorial representation of CBT (Cognitive behavioral therapy Los Angeles)

Although this is a very common approach to aiding individuals in getting sober, recent research has concluded it efficacy to be limited. When comparing patients receiving CBT and drug replacement therapy versus a group just receiving drug replacement therapy, recovery rates were identical (Fiellin et al. 2013). However, this technique has been shown to helpful in preventing relapse in patients already sober (Marlatt and Donovan 2005).

12 step programs
[|12 step programs] began with the establishment of Alcoholics Anonymous (AA) in 1935 (Addiction.com 2015). However, since is formation these programs have expanded to everything from sex addiction and narcotic abuse. These programs utilize community based group therapy as a support mechanism to treat addiction (Addiction.com 2015). Although anecdotal accounts praise this method, it has been impossible for researchers to study this treatment as it is intrinsically anonymous.

Drug Replacement Therapy
Drug replacement therapy, in the context to opioid addiction, is defined as the administration of a substitute long-term drug that occupies the opioid receptor to prevent withdrawal and the desired effects of additional opioid administration (Solutiontoaddiction.com 2012). [|Suboxone] (Buprenorphine) and [|methadone] are by far the most common opioid replacement treatments (LaMotte 2016). Figure 6. Suboxone(Buprenophrine) mechanism of action (Khanna and Pillarisetti 2015). Ideally, an reforming addict is meant to slowly reduce the level of maintenance drug and eventually quit both opioids and the drug replacement (Solutiontoaddiction.com 2012). Although drug replacement therapies are especially effective when combined with psychological treatment, the replacement drugs are addictive and can be abused (LaMotte 2016).

= Future Potential Treatments =

Vaccines
Recent research out of Scripps University points to the potential opioid vaccine (Bremer et al. 2016). In this study researchers were able to use an opioid vaccine to generate an antigen in rat’s immune system to recognize and extinguish in vivo administered Fentanyl (Bremer et al. 2016). This vaccine was effectual in preventing overdose (Bremer et al. 2016). In the paper, the researchers state “fentanyl dosing was incapable of overriding the protective capacity of the vaccine (Bremer et al. 2016).” Additionally, post mortem tissue analysis revealed the ED50 of rats treated with the vaccine to be more the 400% higher (Bremer et al. 2016). Finally, the vaccine also attenuated Fentanyl psychoactivity (Bremer et al. 2016). This treatment could represent a quantum leap in long-term opioid addiction research. Furthermore, this therapy is drug specific and therefore could be used to treat a wide scope of drug addictions. However, further research is needed to explore side effects of this treatment. Additionally, this vaccine removes the benefits of opioids and thus neutralizes their beneficial effects (Bremer et al. 2016).

Surgery
Although not presently applicable to opioid addiction, researchers are exploring surgical procedures as a way to alleviate cocaine addiction (Chen et al. 2013). Before proceeding, it should be noted that a multitude addictions share a common pathway in the brain (Nester 2005). Therefore, this treatment may be relevant to a opioid addiction and a litany of other abuse disorders. In this study, Chen et al. et al. were able to curb cocaine seeking behaviors by stimulating cocaine addicted rats pre limbic system (Chen et al. 2013). However, this approach is invasive and the cognitive consequences have not been explored in humans.

= Conclusion = Current epidemiological data confirms that opioid addiction and overdose is a major problem in the world. While traditional biological and psychological treatments some what effective in rehabilitating drug addicted individuals, there is a clear need to develop new therapies. However, many of the treatments being researched have unintended or unknown consequences. A review of the research has demonstrated a need to elucidate these unknown effects on humans. Additionally, the need for more targeted treatments, such as vaccines, are promising but require more research and human trials to determine their efficacy.

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