Opioid disorders

Table of Contents

1. Overview

  • related to opium poppy plant - papaver somniferum
  • oldest drug (predates recorded history)
  • from the greek word "opos" (juice)
  • liquid from unripe poppy seed capsule when it is notched
  • Sumerians ca 3000BC cultivated and isolated opium
  • 8th century to China, 10th and 13th century from Asia minor to Europe
  • smoking opium reached its peak in 17th century china
    • china then tried to criminalize opium use
    • british and french commercial interests were not pleased
    • opium wars in 19th century
  • Serturner in 1806 isolated active ingredient in opium and called it Morphine after Morpheus, god of dreams
  • US Pure Food and Drug Act of 1906 after drug use was gradually linked to crime
  • 1920s clinics which treated opioid use problems were shut down
  • 1970 Controlled Substance Act: heroin was categorized as schedule 1 drug (no valid medical use)
    • Morphine, oxycodone, methadone: schedule 2
  • 1960s: regulation is insufficient: new treatments (NA)
  • residential substance abuse treatment centers were less available
    • then 2000 Drug abuse treatment act: physicians+training can prescribe schudule 2,3,4 drugs

2. Dx

  • central aspect: compulsive aspect of drug-using behaviour
  • 2/11 criteria of impairment
    • impaired control
    • social impairment
    • risky use
    • tolerance and withdrawal
  • use disorder, intoxication, withdrawal
  • DSM-V = DSM-IV dependence + abuse
  • mild to severe on a continuum

2.1. ICD-10

  • focuses on physical and mental health issues
  • excludes social impairment “Harmful patterns of use are often criticized by others and frequently associated with adverse social consequences of various kinds. The fact that a pattern of use or a particular substance is disapproved of by another person or by the culture, or may have led to socially negative consequences such as arrest or marital arguments, is not in itself evidence of harmful use.”

3. Epidemiology

  • UN estimates 0.3% of global population abused opioids in 2009
  • In US, multiple surveillance systems
    • NSDUH: prevalence
    • MTF: 8,10,12 grade students
    • TEDS: all ages in treatment centers
  • World Drug Report: review of drug markets
  • heroin
    • 4.5m, 1.8%
    • increasing since 2002: use in past month has doubled (160k to 330k)
    • 14% of inpatient admissions, behind alcohol and marijuana
    • 60% white, 22% black, 22% hispanic, predominantly male
  • prescription opioid misuse
    • 37m lifetime (14%), 12.5m past-year (5%), 5m past-month (2%)
    • mostly 26-29yo

4. Etiology

  • genetic, epigenetic, synaptic plasticity, alterations in neural circuits, coping skills, abnormal patterns of thoughts and behaviours, dysfunction in family and social environment
  • complex interaction between these factors
  • e.g. peer pressure to initiate, but genetic differences (more euphoria vs N/V or vise versa) to continue

5. Neurobiology

5.1. Genetics

  • linkage in chromosome 14 (NRXN3 gene), 17
  • male-specific linkage on chromosome 10q and potentially 4q
  • functional polymorphisms in OPRM/D/K, positive associate with OPRD1 (delta), needs replication
  • study in 2013 genome wide: potassium and calcium signaling pathways and long-term potentiation of calcium signaling

5.2. Molecules

  • shared
    • 3 ring phenanthrene structure
    • methylamine group

5.3. Receptors

  • G protein-couple receptors (GPCR)
    • opioids as ligands, respond to endorphins (opioid compounds)
  • brain, spinal cord, digestive tract
  • four types: delta, kappa, mu, nociceptin
  • two signal transduction pathways
    • classical
      • potassium channel Kir3: hyperpolarization, inhibits neural activity
    • alternative
      • induction of beta-arrestin recruitment and binding to phosphorylated opioid receptors to regulate traffic: development of tolerance
    • both
      • reduce Ca2+ content, compensatory upregulation of vesicular Ca2+ content during development of opiate tolerance
      • mu, kappa, delta: inhibit adenylyl cyclase then inhibit cAMP-dependent Ca2+ influx
  • tolerance
    • chronic agonist use: downregulation
      • does not happen consistently with every agonist
    • receptors may be desensitized and uncoupled from downstream pathways
      • chronic exposure changes levels of secondary messengers and upregulation of adenylyl cyclase

5.4. Pharmacology

  • agonist: diverse array of responses according to which type is activated
  • antagonist: binds but not signal
    • naloxone, naltrexone: mu competitive antagonist
  • partial agonist
    • buprenorphine
  • mu receptor: associated with opioid use disorders
    • oxycodone, morphine, hydromorphone, heroin: different in their affinity, other receptor binding, pharmacokinetics
      • e.g. heroin is more lipid soluble than morphine and more easily crosses the blood brain barrier to produce its effect
    • analgesic, resp depression, miosis, euphoria, drowsiness, decreased ability to concentrate, hypothalamus is affected resulting in endocrine changes, increased smooth muscle and GI tract tone (constipation)
  • kappa receptor
    • analgesic, dysphoria, no pupillary change

5.5. Neural circuits

  • mu receptor mediates reinforcement
    • blockade attenuates self-administration
  • opioid drug conditioning is mediated by hyperpolarization and inhibition in
    • afferent neurons of ventral tegmental area (dopaminergic neurons are activated in this area)
      • nucleus accumbens ventral palladium, prefrontal cortex, amygdala, thalamus
      • known as cortical-pallidal-striatal circuit
      • high density of receptors reciprocal connections
      • blockade of mu receptors in VTA and nucleus accumbens attenuates self-administration
      • damage to nucleus accumbens can abolish self-administration

5.5.1. In chronic exposure

  • cessation: decrease in dopaminergic transmission: anhedonia and dysphoria in the early phase of cessation
  • alters activity of nucleus accumbens neurons that are the primary targets of dopaminergic neurons
    • output GABA, dynorphin, enkephalin, substance P: project to VTA
    • changes in output neurons contribute to opiate withdrawal
  • naloxone primarily blocks mu in nucleus accumbens, amygdala, VTA, locus ceruleus.
  • long term abstinence in animal models has produced hypersensitivity in dopaminergic neurons, with more dopamine release subsequently with the same dose of drugs
  • also induces other circuit reconfigurations

5.6. Relapse

  • stress, renewed contact with drug, drug cues and increased availability
  • mesolimbic dopamine system mediates priming effects of opiates in drug-seeking behaviours
    • intra-nucleus accumbens injection of amphetamine which stimulates dopamine release can reinstate heroin seeking
    • dopamine D2 receptor antagonists block heroin-induced reinstatement of drug seeking
  • stress: CRF releasing neurons: ?glutamatergic neurons: seeking behaviour
  • cue-induced relapse: likely prefrontal cortex and AMPA receptor plasticity, poorly understood

5.7. Psychosocial factors

  • Social attitudes, peer pressure, individual temperament, and drug availability
  • presence of a significant number of opioid users in a neighborhood: subculture of experimentation
  • more novelty seeking, risk-taking, and impulsivity traits
  • significant proportion of heroin users meet the criteria for antisocial personality disorder
  • single-parent families, and poor parental functioning

6. Dx

6.1. Intoxication

  • as above

6.2. Withdrawal

  • symptoms
    • anxiety, irritability, restlessness, achy feeling in legs and back, increased sensitivity to pain
    • severe: nausea and vomiting, abdo cramps, diarrhea, severe muscle aches, lacrimation and rhinorrhea, yawning, pupillary dilation, sweating and chills
    • very severe: fever, insomnia, confusion, delirium
  • spontaneous
    • usually several weeks of opioid use is necessary for withdrawal after
    • 6-8 hours post short-acting
    • 24h post long-acting (e.g. methadone)
    • severity peaks 36-48h
    • resolves 5-7 days for short-acting, 2+ weeks for long-acting
  • precipitated
    • can occur even after a few doses of an opioid
    • naloxone: minutes
    • naltrexone: 2-3 hours
      • more severe than spontaneous, resolves 2-3 days
    • buprenorphine cessation: milder than spontaneous
  • protracted
    • months
    • depressed mood, recurrent urge to use opioids
    • from alterations and remodeling of the neural circuitry associated with withdrawal (serotonergic and dopaminergic systems)
  • COWS (Clinical Opioid Withdrawal Scale)
    • pulse, sweating, restlessness, pupil size, bone/joint ache, running nose or tearing, GI upset and tremor, yawning, anxiety, gooseflesh skin

7. Toxicology

  • no biomarker
  • urine test
    • first detectable 2-6 hours after use
    • morphine, heroin, codeine, hydrocodone: 1-3 days after use
    • methadone: 4 days after single use, longer with repeated use
    • poppy seeds in baking can produce positive results
    • fully synthetic require specific tox screen
      • methadone, fentanyl, buprenorphine, tramodol, oxycodone
  • hair testing
    • better for chronic use
    • can't detect anything in the last week
  • saliva
    • immediately after smoking or injection
    • 1-2h after swallowing

8. DDx

  • watch for chronic pain (pseudoaddiction) and intermittent pain syndromes (e.g. sickle cell)

9. Course and prognosis

  • highly variable
  • 1/3 of recreational users develop moderate-to-severe use disorder
  • rates are lower among Rx recreational users
  • NSDUH: 10% who report lifetime use of heroin and 6% of Rx meet DSM-IV criteria for dependence in the past year
    • no reliable way to determine who will end up there
    • major risk: psychiatric disorder and IV heroin use
  • most often chronic and relapsing course
  • most common reasons for seeking abstinence are accumulating occupational, family, financial, and legal problems, feelings of fatigue and exhaustion with activities needed to maintain daily use, and inevitable periods of withdrawal.
  • In most cases, more than one treatment episode is necessary
    • if respond well: cumulative effect of treatment episodes
    • Many patients who have had positive experience in the treatment will be able to recognize high-risk situations and protect themselves from relapse or will be able to return to the treatment after the first few episodes of drug use
  • Predictors of treatment outcome—legitimate work, low crime, less drug use, family relationships, and psychological adjustment—are favorable indicators for good long-term prognosis
  • no differences in modality of treatment
  • overdose most common cause of death
    • most overdoses are non-lethal (1/25-50 are lethal)
    • still significant (CNS damage as a result of anoxia)
      • transverse myelitis, amblyopia, lpexitis, peripheral neuropathy, parkinsonian syndrome, movement disorder, intellectual impairment, personality changes
  • hep C: leading infectious cause of death

10. Comorbidity

  • mood, anxiety, or another substance use disorder
  • mood, antisocial, anxiety, AUD
  • schizophrenia and bipolar: initially higher use, but after 6 months of treatment: comparable success to single diagnosis group

11. Tx

  • test for HIV/HepB/HepC
  • liver, CBC, metabolic (poor nutrition, and acute intoxication can cause metabolic abnormalities and leukocytosis)
  • CXR: pulmonary fibrosis (injection with microcrystalline talc or cotton particulates)
  • ECG: methadone QTc
  • physical exam: lymphatic obstruction, edema, needle marks, infections (thrombophlebitis, abscess), nasal irritation and necrosis, skin atrophy, scars, hyperpigmentation (chronic use), endocarditis (fever, murmur)
  • rehab, abstinence
  • naltrexone, naloxone, buprenorphine

11.1. overdose

  • medical emergency
  • unconscious, resp depression
  • ABC, oxygen
  • Naloxone as soon as possible: 0.2-0.4mg to maintain resp
  • 1-2mg in patient with apnea or cardio arrest
  • repeat administration every 60-90min (half-life) or IV infusion if used long-acting opioid (can go back to coma after)
  • IM or SubQ if no IV
  • 2-3mins: increase in resp rate and pupillary dilation
  • if no response, do 1-2mg in 2-3mins
  • if no response after total 10mg: alternative diagnosis (OD by alcohol or benzo)
  • acute lung injury can be seen in rapid overdose reversals in marked hypoventilation (frothing, hypoxia, rales)

11.2. withdrawal

  • detox
    • provide safe removal of opioid and physiological dependence
    • stabilize physical and mental health for them to initiate relapse-prevention treatment
    • necessary before naltrexone can be started, but not necessary before agonist treatment (methadone and buprenorphine)
    • detox without relapse prevention: 90% relapse rate
      • higher risk of OD as detox removes physiological tolerance that's protective
    • location: inpatient
      • for severe and multi substance use (sedative-hypnotic + opioid)
    • strategies
      • agonist assisted: more severe later
      • symptomatic treatment with nonopioid medication: more severe early
      • antagonist assisted with symptomatic treatment: more severe early
  • symptomatic
    • autonomic arousal
      • sweating, restlessness, tremor, rhinorrhea
      • alpha-2 agonist clonidine (+sedation): PO 0.1-0.3mg TID-QID
        • risk of postural hypotension
      • lofexidene: lower hypotension risk
    • anxiety and psychomotor agitation
      • benzo
        • clonazepam 0.5-2.0mg 2-4x/day
        • oxazepam 15-30 2-4x/day
        • unsafe with opioids, use in inpatient settings
      • clonidine can help, not much
      • antihistamines
        • diphenhydramine
        • hydroxyzine
    • insomnia
      • rarely can it be completely treated
      • zolpidem 5-10
      • zopiclone 7.5-15
      • trazodone 50-150
      • quetiapine 50-200
    • pain
      • NSAID
      • antispasmodic (cyclobenzaprine)
    • GI distress
      • antiemetic (ondansetron)
      • diarrhea (loperamide)
  • agonist
    • methadone: start 20-30 PO
      • if withdrawal symptoms persist, repeat in 2-4h
      • generally no more than 40 in first 24h, but can be higher if symptomatic after 6-8h in inpatient setting
      • after 24-48h of dose stabilization, reduce by 10-20% or 5mg per day
      • inpatient detox usually complete in 1 week
      • outpatient: no more than 40 for first day
        • can increase 10mg every 2-3 days
        • 40-60 is enough usually, not enough to prevent craving
        • if continue to use, goal should be stabilization (detox deferred):
          • no opioid use, craving, or withdrawal symptoms
      • gradual dose reduction of 3% per week (better than 10%/week)
      • watch for negative expectancy effect (expect withdrawal and get distressed)
    • buprenorphine
      • 2 formulations: sublingual and combo (+naloxone in 4:1 ratio)
      • starting dose when withdrawing
      • location: inpatient
        • start with 2mg and repeat until no withdrawal symptoms, usually 8-12mg in first day
        • taper on second day, decrease by 2mg per day, last 2 days decrease by 1mg per day
        • half-life 31-35h
      • location: outpatient
        • first day inpatient to minimize risk of precipitated withdrawal
        • arrive in withdrawal (~12h post)
        • first dose 2mg, monitor for precipitated withdrawal
          • if not, repeat every 2 hours until no withdrawal symptoms, take home dose
          • if yes, wait 4-6 hours before repeat dose, treat symptomatically

11.3. Use disorder

  • CBT
  • motivational interviewing
  • social interventions
  • NA

Author: Armin

Created: 2022-09-15 Thu 13:42