1/23/17 1 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D Clinical Associate Professor University of Georgia College of Pharmacy Athens,Georgia 1 ! While there were 16,235 deaths involving prescription opioids in 2013, an increase of 1% from 2012, the number of deaths involving heroin increased dramatically.There were 8,257 heroin-related deaths in 2013, up 39% from 2012.Total drug overdose deaths in 2013 hit 43,982, up 6% from 2012. ! The larger issue of treatment for opioid use disorder remains.There is a shortage of medication assisted treatment programs. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), there were 1216 opioid treatment programs with 272,351 patients enrolled in them in the U.S. In 2010, 18,842 physicians possessed a DATA 2000 waiver to prescribe buprenorphine. More significantly, less than 24% of patients in treatment programs, or 65,000 patients, received medication assisted treatment for opioid addiction. ! Steven Burghart, DPh, MBA, BCPP ! President 2014-2015 College of Psychiatric and Neurological Pharmacists
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Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D Clinical Associate Professor University of Georgia College of Pharmacy Athens,Georgia
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! While there were 16,235 deaths involving prescription opioids in 2013, an increase of 1% from 2012, the number of deaths involving heroin increased dramatically. There were 8,257 heroin-related deaths in 2013, up 39% from 2012. Total drug overdose deaths in 2013 hit 43,982, up 6% from 2012.
! The larger issue of treatment for opioid use disorder remains. There is a shortage of medication assisted treatment programs. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), there were 1216 opioid treatment programs with 272,351 patients enrolled in them in the U.S. In 2010, 18,842 physicians possessed a DATA 2000 waiver to prescribe buprenorphine. More significantly, less than 24% of patients in treatment programs, or 65,000 patients, received medication assisted treatment for opioid addiction.
! Steven Burghart, DPh, MBA, BCPP ! President 2014-2015 College of Psychiatric and
Neurological Pharmacists
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! For many years, society viewed addiction as a moral failing, and substance misusers were almost always referred to with the familiar language of stigmatization—drunks, junkies, crackheads. So, addiction came as a double whammy—the addiction itself plus the burden of stigma, which compounded the lethality. “Addicts” were generally sent off to find help in 12-step programs outside of the medical and treatment communities. Eventually the concept of addiction as a biopsychosocial disease began to take hold, albeit one that had a simplistically envisioned goal—abstinence from everything for everybody. A variety of treatment approaches were developed, many extremely effective, but these developed alongside an enormous dose of attention from the criminal justice system.
! Debra Rothschild, PhD
! Which Type of Treatment? ! The Moral Model ! The Biopsychosocial Model ! The Harm Reduction Model ! The Drug Court Model ! Are the Opioid Treatment Programs closed systems?
What are the OTP systems doing to educate the healthcare practitioner of the future? Is MAT the only reasonable alternative to long term opioid addiction? Is there a bias against OTPs?
! Does OTPs remove the stigma of addiction or promote it ?
! It will take a multiple types of approaches for successful treatment of opioid addicts
! And this is why……………..
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Cornerstone of pain
management Mood altering properties
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The hypothesis that the dynorphin-kappa opioid receptor system may be a key component of the neuroplasticity associated with stress-induced mood disorders and the ‘dark side’ of addiction (withdrawal-negative affect stage) continues to gain preclinical and clinical experimental support. The endogenous kappa opioid peptides derived from prodynorphin encode the dysphoric, anxiogenic, and cognitive disrupting responses to behavioral stress exposure (Bruchas et al, 2010; Carroll and Carlezon, 2013)
! Opioid Receptors (mu, kappa, delta)-euphoria ! The Endogenous Opioid Peptide ! System(Endorphins/Dynorphins) ! Cellular Membrane Action- down regulation of ATP to
ADP (conversion of release of arrestin) ! Dopamine Pathways- decreased production, storage,
and transport
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! µ (mu): Dopamine o Activated by morphine: analgesia o Primary action site of all opioids o Distribution: primarily in CNS and also GI o Linked to substance use disorders
! µ (mu): ◦ Activated by morphine: Analgesia ◦ Primary action site of all opioids ◦ Distribution: primarily in CNS and also GI ◦ Linked to substance use disorders
! δ (delta): for endogenous peptides (endorphins)- Nerve Conduction- slows pain signal between the peripheral nervous system and the central nervous system(brain, hypothalamus, spinal cord)
! Five classes of opioid receptor o Mu(µ), Delta(δ), Kappa(κ) Nociceptin Subtypes (σ, ε receptors
! Subtype of µ, δ, κ receptor
! Structural characteristics** ( The more characteristics, the higher addiction liability) o Typical G-protein-coupled receptor
" Seven hydrophobic region " Three intracellular loops " Three extracellular loops " Intracellular carboxy-terminal tail " Extracellular amino-terminal tail
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Opioid Receptors ( II )
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Pure agonists
FULL
• Morphine • Heroin • oxycodone • Fentanyl
PARTIAL butorphanol
pentazocine
Antagonists
PURE naloxone
naltrexone
Mixed agonists/
antagonists
buprenorphine
nalbuphine
others
tramadol
In 1874, English chemist C.R. Wright ventured out into making a non-addictive form of codeine and morphine. In doing so he combined anhydrous morphine alkoid and acetic andhydride (Hodgson). This produced what is known as diacetylmorhpine (Hodgson). In short diacetylmorphine is an acetylated version of morphine.
Acetylation Morphine
Diacetlymorphine
Heroin
Morphine 1st metabolite (7-14 days)
6-MAM 2nd metabolite 15-30 days
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The reason for the that addicts can not stop using is once the dopaminergic system is deactivated (depleted) due to multiple neurobiological reasons- the reinforcing effects of the drug becomes more powerful than a mother’s love for her children. In 2016, the potencies of most street drugs (marijuana/heroin) have increased. This increased potency creates the increased reinforcing effects of dopamine thus increasing the addiction liability of the drug on the brain.
Opioid Addiction is Greater Than a Mother’s Love
(Dynorphin)
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Dopamine Primary chemical in the brain responsible for activating the reward pathway
During the preoccupation phase of addiction, dopamine is being released stimulating desire for a drug
During the intoxication phase, all the dopamine in the brain is released giving the user a euphoric feeling
During the withdrawal phase, the brain has run out of dopamine and can not function properly until more is made
You can think of a brain pathway as a power line that connects two brain regions. Brain pathways are made up of interconnected neurons along which signals are transmitted from one brain region to another.
Dopamine is the neurotransmitter used by the reward pathway. But there are other important pathways in the brain that utilize dopamine.
Generally, drugs that affect dopamine levels in the brain affect all of these dopamine pathways. http://www.youtube.com/watch?v=Tl8-C9ZuLTA
• Glutamate and GABA (gamma-aminobutyric acid) are the brain's major "workhorse" neurotransmitters.
• Over half of all brain synapses release glutamate, and 30-40% of all brain synapses release GABA.
• Since GABA is inhibitory and glutamate is excitatory, both neurotransmitters work together to control many processes, including the brain's overall level of excitation.
• Many of the drugs of abuse affect either glutamate or GABA or both to exert tranquilizing or stimulating effects on the brain.
Glutamate and GABA A System in Balance
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Heroin blocks the inhibitor
In the events of a heroin overdose, medical professionals and in some cases law enforcement administer naloxone, commonly reffered to as Narcan.
Narcan acts as an antagonist and reverses the traumatic effects of a heroin overdose by competing with morphine for the opiate receptors (mostly the mu receptors) and binding to them therefore reversing the effects of heroin overdosing such as respiratory depression and sedation (Meyer).
It is administered via I.V., I.M. or S.C. (sub cutaneously) and is excreted through the urine within 72 hours (A.P.A) .
One down fall to the usage of Narcan is the onset of withdrawal symptoms for the heroin user.
The onset of withdrawal symptoms vary among users. Typically those who use heroin once a day experience peak withdrawal effects within 36-48 hours of there last administered dose (A.P.A). Symptoms such as pain, restlessness and vomiting go away within in 7-10 days (Meyer).
There are several treatments for withdrawal, methadone is one of them.
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! Craving: memory of rewarding aspects of drug use superimposed on a negative emotional state o Compels drug-seeking in dependent individuals
! 3 Types of Cravings o Withdrawal induced o Cue-induced o Drug-induced
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! “Craving”- induced by stimuli that have been paired with drug self-administration such as environmental cues
! An animal model of craving- type 1 is cue induced reinstatement where a cue previously paired with access to drug reinstates responding for a lever that has been extinguished.
! Neurobiological substrates include glutamatergic projections from medial prefrontal cortex and basolateral amygdala to nucleus accumbens.
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! State of protracted abstinence in subjects with addiction or alcoholism weeks after acute withdrawal.
! Conceptualized as a state change characterized by anxiety and dysphoria or a residual negative emotional state that combines with Craving-Type 1 situations to produce relapse to excessive drug taking.
! Animal models of Craving-Type 2 include stress-induced reinstatement and increased drug taking in animals during protracted abstinence.
! Neurobiological substrates include residual activation of brain stress systems including corticotropin releasing factor and norepinephrine in the extended amygdala.
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1. Methadone • Full µ agonists • Once/day dosed • 40-60 mg/d: sufficient to block withdrawal sx.
3. Naltrexone • Opioid antagonist • Oral or injectable • This extended-release injectable medication is the most recent drug,
approved in October of 2010, for the treatment of opioid addiction.
4. Naloxone- Overdose Prevention
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Methadone helps alleviate withdrawal symptoms. When taken orally it occupies opiate receptors (like heroin) (Meyer). In a sense it acts like heroin by reducing the need for more heroin, therefore causing a reduction in withdrawal side effects (Meyer).
It is important to note that Methadone does not provide any of the euphoric effects that heroin does when administered.
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When coming off of heroin it is best to quit “cold turkey” and seek prescribed methadone treatment. When Narcan is used opiate receptors are more rapidly deprived of opiate compared to quitting “cold turkey” (Hart).
However, one complication with methadone is that some individuals will begin to become addicted to methadone if it is not prescribed in adequate amounts (Meyer).
! Prevents withdrawal symptoms o Buprenorphine: too weak to give a “high” o Naloxone: blocks the “high” from stronger opioids
! Serious side effects and death can occur if taken with benzodiazepines, sedatives, and alcohol
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! Buprenorphine o Agonist/antagonist o Half life 37 hours o Dosing 8-32mg/d o Can precipitate withdrawal o Absorption (poor oral)
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! Previous OD History ! Chronic Pain Patient ! Non or limited Heroin User ! Immunosuppressive patient ! Impaired Renal Function Patient ! Driving Requirements ! Current Knowledge of Substance Use Disorder
Pergolizzi J, Aloisi AM. Buprenorphine and Its Unique Pharmacological Profile. Pain Practice. 2010;10(5):428-450.
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! Office based o Increased access
! 20% of heroin dependent persons can get methadone ! Methadone not available in some states
o Any physician can be trained
! Safer in overdose ! Risk for diversion
o Can combine with Naloxone to ↓injection
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! Outcome o Retention in treatment
! Slightly lower than methadone ! 50% vs. 59%(buprenorphine vs. methadone)
o Heroin use ! Slightly worse than methadone (low dose) ! 38% vs. 40.5% (buprenorphine vs. methadone)
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! Antiretrovirals – Close monitoring required; atazanavir and atazanavir/ritonavir( increased sedation)
! Benzodiazepines – Close monitoring required; respiratory depression, coma, death
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! With repeated use
! Need ↑ doses to maintain effect
! Can see in pain patients
! Adaptation of receptors
! Different rates for each effect
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! After quit or ↓chronic use or antagonist ! Opposite to agonist effects ! DSM-5 criteria: 3+ (minutes to days): ◦ Unhappy mood
! ReVia- daily tablet ! Narcotic antagonist ! It does not decrease alcohol or opioid withdrawal
symptoms ! Treats the cravings, NOT the addiction ! A person cannot have any opioids in their system because
sudden withdrawal symptoms will result ! Must be opioid free for 7 to 10 days before starting
naltrexone
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Naloxone is a medication used to prevent opioid overdose deaths. The medication binds to opioid receptors and can rapidly reverse or block the effects of other opioids. In doing so, naloxone can very quickly restore normal respiration to a person whose breathing has slowed or stopped as a result of heroin use or the misuse of prescription opioids.
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! Recent use ! Life threatening ! Constricted pupils ! 1+: ◦ Drowsiness or coma ◦ Slurred speech ◦ Poor attention and memory
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! Heroin (diacetylmorphine) rapidly hydrolyzes to 6-monoacetylmorphine (6-MAM).
! This is then hydrolyzed to morphine. ! Heroin and 6-MAM are lipid soluble and can
cross the blood brain barrier readily. ! Morphine and 6-MAM are primarily
responsible for pharmacologic actions of heroin.
! Mechanism of Action: binds to opiate receptors in CNS. ◦ Inhibition of ascending pain pathways alters
perception and response to pain
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! Depresses respiration through MOR (mu) and DOR (kappa), primarily by direct depressant effects on rhythm generation.
! Decreases response to increased CO2. ! Depresses ventilation driven by hypoxia
Methadone prevents opioid withdrawal symptoms and reduces craving by activating opioid receptors in the brain. It has a long history of use in treatment of opioid dependence in adults, and is available in specially licensed methadone treatment programs. In some States, opioid-dependent adolescents between the ages of 16 and 18 may be eligible for methadone treatment, provided they have two documented failed treatments of opioid detoxification or drug-free treatment and have a written consent for methadone signed by a parent or legal guardian.
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! Diagnosis: DSM-5 ◦ Direct , empathic, non-judgmental
! Lab tests
◦ Urine, blood, others ◦ 12-36 hrs after use ◦ Targeted to morphine and most opiates ◦ Methadone: GC/MS
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! States allow 3 to 30 days supply to go home after a period of observation.
! Methadone Clinics – ◦ Crime does not increase around a
methadone clinic. (University of Maryland, 2012) ◦ Communities do not like them. ◦ Still the most effective treatment for
chronic Heroin addiction but is losing ground rapidly to public outcry and stigma
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! Overdose ◦ Emergency ◦ Support vital signs ◦ Naloxone: 0.4 mg q 2-3 min. SC/IV
Nazemroaya, M. (2006, October 17). The War in Afghanistan: Drugs, Money Laundering and the Banking System. Retrieved March 6, 2015, from http://www.globalresearch.ca/the-war-in-afghanistan-drugs-money-laundering-and-the-banking-system/3516
Haasen, C., Verthein, U., Degkwitz, P., Berger, J., Krausz, M., & Naber, D. (n.d.). Heroin-assisted Treatment For Opioid Dependence: Randomised Controlled Trial. The British Journal of Psychiatry, 55-62.
Opiate withdrawal: MedlinePlus Medical Encyclopedia. (n.d.). Retrieved March 6, 2015.
Methadone Replacement for Heroin | Patient.co.uk. (n.d.). Retrieved March 6, 2015.
Micromedex Mathias, R. (n.d.). Rate and Duration of Drug Activity Play
Major Roles. Retrieved March 6, 2015, from http://archives.drugabuse.gov/NIDA_Notes/NNVol12N2/NIDASupport.html
Increases in Poisoning and Methadone-Related Deaths: United States, 1999-2005. (2010, April 6). Retrieved March 6, 2015.