Neurologic Disorders Flashcards
a) What conditions do Opioid-related disorders encompass?
b) How is Opioid use disorder diagnosed with DSM-V?
c) What are the 4 known opioid receptors?
a) Opioid use disorder, Opioid Intoxication and Opioid withdrawal
b) The repeated use of opiates while producing problems in two or more areas in a 12-month period.
Problems include:
- Tolerance
- Withdrawal
- Use of greater amounts of opioids than intended
- Craving, and
- Use despite adverse consequences
NB: Recently the amount of problems required for this diagnosis has reduced from three to two.
c) mu, kappa, delta, and nociceptin/orphanin
a) Describe how opioids inhibit the activity of widely distributed neuronal types
b) What is the major effects of this inhibition?
a) Opioids activate G protein-coupled, inwardly rectifying potassium channels (GIRKs), increasing permeability to potassium ions to cause hyperpolarization, which inhibits the production of action potentials.
b) Analgesia, sedation, and drug reinforcement, are produced through this inhibition of neurons that belong to specific brain pathways.
a) How does the euphoric effect occur with opioid medication?
a) Most opioid actions are related to specific neuroanatomic locations of mu receptors. Reinforcing and euphoric effects of opioids relate primarily to activation of the mesolimbic dopaminergic pathway from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), where opioids increase synaptic levels of dopamine. The “high” only occurs when the rate of change in dopamine is fast. Therefore, routes of administration that slowly increase opioid blood and brain levels, such as oral and transdermal routes, are effective for analgesia and sedation but do not produce an opioid “high” that follows smoking and intravenous routes.
a) What occurs with large opioid doses, what happens if this continues over weeks/months, and what drives the withdrawal symptoms?
b) What is the MOA in Clonidine and how is it relevant for opioid withdrawal?
a) With large opioid doses, there is saturation and activation of all of its mu receptors, action potentials cease. When opioid use (inhibitory effect) is sustained over weeks/months, a secondary set of adaptive changes occur that lead to tolerance and withdrawal symptoms. Withdrawal symptoms reflect, in part, overactivity of Noradrenergic (NE) neurons in the Locus coeruleus (LC). This NE neuronal activation during withdrawal has important treatment implications, e.g. use of the alpha-2 agonist clonidine to treat opioid withdrawal. Other contributors to withdrawal include deficits within the dopamine reward system.
b) Clonidine is an alpha-2 adrenergic agonist that stimulates alpha-2 adrenoceptors in the brain stem, activating an inhibitory neuron which results in reduced sympathetic outflow from the CNS (e.g. decrease in peripheral resistance, renal vascular resistance, HR, and BP). This is beneficial when opioid withdrawal is causing NE overactivity.
a) Describe the mechanism of mu-receptor activation by endogenous opioids and exogenous opioids
a) Endorphins (endogenous opioids) act on the mu-receptor by inhibiting the cAMP> PKA >CREB cascade within the LC in the brain stem via inhibition of Gi/o protein influence on adenylyl cyclase (AC). Acute opioid use does the same, however chronic use UPREGULATES cAMP in an attempt to oppose this opioid-induced inhibitory influence. Upregulation of this system is involved in opioid tolerance, and when the opioid is removed, unopposed NE transmission is involved in withdrawal.
a) How quickly can opioid tolerance develop?
b) Where and how are opioids metabolised?
c) What is the half-life of short vs long acting opioids?
a) With chronic daily use, it can develop within 6-8 weeks.
NB: Tolerance appear to be a pharmacodynamic effect.
b) Metabolism occurs in the liver, primarily through cytochrome P450 systems of 2D6 and 3A4. This is then conjugated (combined) to glucuronic acid and excreted in the faeces.
c) The plasma half-lives generally range from 2.5 to 3 h for morphine and >22 h for methadone. The shortest half-lives of several minutes are for fentanyl-related opioids and the longest are for buprenorphine and its active metabolites, which can block opioid withdrawal for up to 3 days after a single dose.
a) After how long do symptoms of withdrawal start?
b) What are the initial symptoms and how long does the acute course of withdrawal last?
c) Describe the symptoms of the secondary phase of withdrawal and how long this lasts.
a) Symptoms of opioid withdrawal begin 8–10 h after the last dose.
b) Initial symptoms include lacrimation, rhinorrhea, yawning, and sweating. Restless sleep followed by weakness, chills, goosebumps, nausea and vomiting, muscle aches, and involuntary movements, hyperpnea, hyperthermia, and hypertension occur in later stages of the withdrawal syndrome.
c) Secondary phase of withdrawal lasts for 26–30 weeks and is characterized by hypotension, bradycardia, hypothermia, mydriasis (dilated pupils), and decreased responsiveness of the respiratory center to carbon dioxide.
a) What other organs can be affected by opioids and how?
a) -Inhibition of pituitary hormones corticotropin-releasing hormone (CRF) and luteinizing hormone (LH), which reduces levels of cortisol and sex hormones, causing impaired stress responses and reduced libido.
- Increase in prolactin also contributes to the reduced sex drive in males.
- Reduction in Thyrotropin and increase in Growth Hormone.
- Respiratory depression results from insensitivity of brainstem neurons to increased carbon dioxide.
- Aspiration pneumonia in OD is commonly related to loss of the gag reflex.
- Reduction in gut motility, leading to nausea, constipation, anorexia and weight loss.
- Orthostatic hypotension due to histamine release + peripheral blood vessel dilatation.
- Interaction with other medications including inducers of cytochrome P450 system such as Rifampin & Carbamazepine.
NB: Sudden Deaths can occur with methadone use due to constipation and toxic megacolon as well as prolonged QT intervals.
a) What are the various possible complications of IV opioid use?
b) What are the symptoms of opioid OD?
c) What is the reversal agent for opioid OD and what is the immediate dose?
d) What is the maintenance dose and why is it needed?
e) Can OD be tested for?
a) -Sharing of syringes leading to infections with HEP B and HIV/AIDS etc
- Bacterial infection leading to septic complications such as meningitis, osteomyelitis, and abscesses in organs
- Death
b) Shallow/slow RR, pupillary miosis (mydriasis does not occur until significant brain anoxia supervenes), bradycardia, hypothermia, and stupor/coma
c) Naloxone: Pure opioid antagonist that competes and displaces opioids at opioid receptor sites. Dose 400-800mcg IV every 2-3mins. Patient should improve after 1 minute. Reconsider diagnosis if no improvement after 10mg given.
NB: It is important to note that the goal is to reverse respiratory depression and not to administer so much that it precipitates opioid withdrawal
Because naloxone only lasts a few hours and most opioids last considerably longer-Maintenance dose is generally 2/3 of the dose needed to awaken the patient. It should continue via continuous IV drip for ongoing antagonism for 24-72h depending on the opioid used in the OD.
NB: Naloxone dosing is not necessary if the patient has been intubated.
e) Blood or urine drug screen toxicology can confirm a suspected diagnosis, but immediate management must be based on clinical criteria. If naloxone is not administered, progression to respiratory and cardiovascular collapse leading to death occurs.
a) What are the general options in Opioid Treatment?
b) What if a patient presents with OD of Buprenorpine?
c) What if naloxone isnt working, what other sedative drug commonly causes similar effects?
d) What is the antagonist for the above medication and what is the dose?
e) What other medical management may be required in the case of OD?
a) Beyond acute treatment of opioid OD with naloxone, the two treatment options are opioid maintenance or detoxification.
b) Naloxone may be required in total doses of >10mg. Primary Buprenorpine OD is nearly impossible because it is a partial opioid agonist, meaning at higher doses, it has more antagonist rather an agonist activity. For example buprenorpine OD producing profound opioid antagonism may precipitate opioid withdrawal in a person who has opioid use disorder on morphine or methadone.
c) Benzodiazepines e.g Diazepam, Alprazolam, Clonazepam, Lorazepam, Midazolam, Oxazepam, Temazepam
d) Flumazenil. 0.3-1mg repeated as necessary to a total of 2mg. Due to most benzodiazepines remaining active for considerably longer than flumazenil, a maintenance dose of half that needed to waken the patient can be given hourly by continuous infusion (0.1-0.4mg/hour)
e) Oxygen and positive-pressure breathing, IV fluids, pressor agents for hypotension, and cardiac monitoring to detect QT prolongation, which might require specific treatment. Activated charcoal and gastric lavage may be helpful for oral ingestions, but intubation will be needed if the patient is stuporous.
a) Describe the methodone & Buprenorphine programs available and the issues this causes
b) What withdrawal symptoms does clonidine specifically reduce? What are teh Clonidine side effects?
c) What other opioid antagonist can be used in the treatment of Opioid detoxification?
a) Detoxification using methadone ranges from 2-3 weeks to 180 days. This approach is controversial given the relative effectiveness of methadone mainenance and the low success rates of detoxification. Buprenorphine does not have significantly better outcomes than methadone, but if superior to clonidine in the L-T.
b) Lacrimation, rhinorrhea, muscle pain, joint pain, restlessness, and gastrointestinal symptoms. SE include dizziness, sedation, lethargy, and dry mouth.
c) Naltrexone is a pure opioid antagonist at opioid receptor sites, showing the highest affinity for mu receptors. It;s used for treatment in alcohol use disorder however is also used for the blockade of effects of exogenously administered opioids.
a) How does methadone work when substituting for heroin?
b) What are the options for Buprenorphine maintenance?
a) Once daily methadone dose replaces 3-4x daily heroin. It saturates the opioid receptors and blocks the euphoria of additional opioids by inducing a high opioid tolerance.
b) Buprenorphine is a partial agonist of mu-opioid receptors with a slow onset and long duration of action. Its partial agonism reduces the risk of unintentional overdose but limits its efficacy to patients who need the equivalent of only 60–70 mg of methadone, and many patients in methadone maintenance require higher doses up to 150 mg daily. Buprenorphine Depots are becoming more available, however require specialist clinics for this.
a) What about opioid antagonist medications for opioid dependence?
b) What is the rationale for using opioid antagonist medications in this setting?
c) What are teh options for medication free treatments of opioid dependence?
a) Naltrexone may be used after withdrawal to assist with abstinence, however it does not relieve persistent withdrawal symptoms such as anxiety or insomnia.
NB: Naltrexone maintenance combined with psychosocial therapy is effective in reducing heroin use, but medication adherence is low. Depot injections lasting up to 4 weeks improve adherence, retention, and drug use.
b) The rationale for using narcotic antagonist therapy is that blocking the action of self-administered opioids should eventually extinguish the habit, but this therapy is poorly accepted by patients.
c) Medication-free treatments can be done in inpatient, residential, or outpatient settings, but 1- to 5-year outcomes are very poor compared to pharmacotherapy except for residential settings lasting 6–18 months.
NB: The above residential programs involve counseling, behavioural treatments, and teaching skills to cope with stress.
a) What are the mainstays of preventing opioid dependence?
a) Opioids are the most common drugs accessed by adolescents who begin a pattern of illicit drug use.
- Major source is family members.
- Pain management should be provision of sufficient opioids for pain over as short a period of time possible.
- Dispose of remaining opioids, not save them in the medicine cabinet, because this behavior leads to diversion by adolescents.
