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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)

Neuropsychopharmacology 41, 373-374 (January 2016) | doi:10.1038/npp.2015.258.

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Charles Chavkin and George F Koob

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Semi- synthetics

Natural alkaloids morphine heroin

codeine oxycodone

hydrocodone

thebaine buprenorphine naloxone

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OPIOIDS fully synthetic

OPIATES

Bind to opioid receptors

Morphine-like action

DSM-5: OPIOIDS

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Morphine can arise in the blood and urine through the administration of morphine itself or through the

metabolism of heroin or codeine

Morphine

Morphine Codeine Heroin

6-MAM

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Brennan,MJ, Heit,HAChronic Pain: Overcoming Treatment Barriers for Effective Outcomes, Medscape Pharmacists CE, 12/8/2004

!  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

!  δ (delta): Endorphins for endogenous peptides (brain, hypothalamus, spinal cord)

!  κ (kappa): Dynorphins analgesia, endocrine changes and dysphoria (brain-amygdala, spinal cord)

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!  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)

! κ (kappa): analgesia, endocrine changes and dysphoria (brain-amygdala, spinal cord) [dynorphins] Stress Reduction

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!  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

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Fig.8  

1.)Behaviors-Pleasure 2.)Euphoria-Addiction 3.)Movement-Parkinson’s Disease-EPS 4.)Perception-Psychosis

Dopamine Neural Pathways

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2 3

4

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  Circuit #1 Use- Dopamine   Relief/Like

  Pleasure/Pain circuit Meso-accumbens

  Circuit #2 Abuse-Endorphins   Repeat/Want

  Desire and urge circuit Basolateral n. of amygdala

  Circuit #3 Addiction-Dynorphin A/B   Need/Craving

  Pathologic desire & demand circuit Periaqueducal gray of brain stem Stimulation of the periaqueductal gray

matter of the midbrain activates enkephalin-releasing neurons that project to the raphe nuclei in the brainstem.

Enkephalin (endogenous opioid neurotransmitter), binds to mu opioid receptors.

Role of Glutamate and Dopamine Neurotransmission in Relapse

to Drug-Seeking Behavior

From: Cornish JL and Kalivas PW, J Addict Dis, 2001, 20:43-54.

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(Image from CNSForum)

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.

2.  Buprenorphine and Buprenorphine/Naloxone •  µ Receptor partial agonist •  Kappa receptor partial antagonist •  12-16 mg/d •  Combination ↓ risk of diversion

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).

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OPIOID MORPHINE METHADONE

Plasma ½ life ~3 hr 24 hr

Duration - analgesia

~5 hr ~6 hr

Stored in body Limited Significant

IM/oral potency

6/1 2/1

Elimination Kidney>>Gut Kidney=Gut

40 © AMSP 40

! Buprenorphine: opioid partial agonist

! Naloxone: opioid antagonist

!  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

◦ Muscle aches ◦ Tearing/runny nose ◦ Pupillary dilation ◦ Goose bumps or sweating ◦ Nausea/Vomiting ◦ Diarrhea – Fever - Yawning

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!  Vivitrol- monthly injection o  $$$expensive$$$

!  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

through carotid and aortic body chemosensors.

!  Mechanical effects: ◦  Increased chest wall rigidity ◦  Diminishing upper airway patency

!  Maximal respiratory depression occurs within 5-10 minutes of IV administration of morphine ◦  Including morphine-like opioids

!  This effect occurs more rapidly with lipid-soluble agents.

!  Respiratory Depression !  Constipation !  Sedation !  Nausea and Vomiting !  Tolerance !  Dependence !  Addiction/abuse

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! ↓ or eliminate use

! ↓ risks: ◦ Overdose ◦  IV use ◦ Substance Use Disorder

! Address: ◦ Co-morbid conditions ◦ Psychosocial outcomes ◦ Somatic needs

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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

! Withdrawal ◦ Rating scales: CINA, COWS ◦ Opioid substitution with gradual ↓ ◦ Symptomatic treatment

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!  Initial detox at a residential facility to cover other drugs of abuse. If opiate only, direct to IOP Opiate detox facility.

! The patient begins a taper on Buprenorphine/Naloxone. Cravings diminish. The patient is more open to hearing, maybe not retaining, but hearing.

! Concentrate on acceptance of duration and addiction as identified barriers to recovery. (Treatment Plans)

! The patient transitions to a Outpatient licensed detox facility. Enrolls in the Outpatient program and the Detox program.

! The patient continues the buprenorphine taper for 4 to 8 weeks, while in the outpatient program.

! Treatment planning continues to be focused on accepting what is required to recovery from opiates….Duration and Acceptance.

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" The patient either finishes the IOP or ends the taper.

" The patient is continued in the Outpatient Detox program, usually one day per week.

" The 7 to 10 day period after the last dose of buprenorphine/naloxone. The after last dose Vivitrol/Revia can be administered is the crossroads.

" A meaningful therapeutic relationship where gains can be maintained is crucial at this and future moments in treatment.

" Use of something like Clonidine and Trazadone will help get through the 7 to 10 days and address the patients need for “medication”.

! At this point, a sponsor and a home group should be in place, and are required for outcomes.

! The patient is worked and worked to continue to see the benefits of the shot, Motivation Interviewing works well here.

!  Family is brought in to sessions to comment on improvements they have seen.

! Barrier is still acceptance of duration and addiction.

! When chronic & relapsing condition ! Most studies for heroin dependence ! Goals:

1.  Achieve a stable dose that !  Suppresses withdrawal !  ↓ craving !  Block effects of illicit opioids

2.  Facilitate and promote rehabilitation

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1.  Methadone !  Full µ agonists !  Once/day dosed !  40-60 mg/d: sufficient to block withdrawal sx.

2.  Buprenorphine/Naloxone !  µ Receptor partial agonist !  Kappa receptor partial antagonist !  12-16 mg/d !  Combination ↓ risk of diversion

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! Specialized programs ! Cognitive behavioral therapy ! Behavioral therapy ! Psychodynamic/interpersonal ! Recovery-oriented therapies ! Group and Family therapy ! Self-help groups: NA, Al-Anon

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! Heroin is the most potent opioid to the population on the planet

!  Long term use (3 + years) causes severe CNS damage

! Results in Tolerance and substance use disorders

!  Learn that medications will be necessary for successful detox and stabilization

! Monitor effectiveness and side effects 72

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