Topic 16: Opiates and Opioids

Question 1

What is an opiate?

Answer 1

natural narcotic opioid alkyloids found in the opium poppy

Question 2

What is an opioid?

Answer 2

any natural or synthetic compound or the endogenous peptides that exert biological effects at the opioid receptors

Question 3

What is the difference between opiates and opioids?

Answer 3

not all opioids are opiates, but all opiates or opioids

Question 4

What are the major psychoactive opiates?

Answer 4

morphine
codeine
thebaine

Question 5

How do opiate structures cause their effect?

Answer 5

natural opiates have greatly varied effects due to a number of relatively minor alterations in chemical structure

this lead pharmaceutical development of numerous semi-synthetic and synthetic opioids

Question 6

What is the pharmacological use of natural opiates?

Answer 6

analgesic: still the most potent and effective pain relivers known, widely used (both morphine and derivatives)

antitussive: cough suppressant, codeine has decreased analgesic effect but retains antitussive effects

decreased gastric motility: can be used to treat diarrhea especially pathogenic, loperamide is an opioid derivative that does not penetrate the BBB and is used to treat diarrhea

Question 7

What are the routes of administration of opiates?

Answer 7

oral administration: morphine readily absorbed through GI but high variability, codeine has more consistent oral absorption

subcutaneous, intramuscular (morphine), or intravenous (common recreational route): more stable systemic levels

inhalation: historic route of (recreational) administration for raw opium is smoking

Question 8

What are semi-synthetic opioids?

Answer 8

diacetylmorphine first synthesized in 1874 by C.R. Alder Wright who was seeking morphine analogues with decreased addictive potential

marketed in 1898 by Bayer pharmaceutical under the trade name Heroin as a cough suppressant, analgesic, and cure for morphine addiction

development of numerous semi-synthetic opioids followed the isolation of morphine and codeine and subsequent discovery of the structures

some semi-synthetic opioids are found naturally but generally synthesized from morphine or thebaine for pharmaceutical use

Question 9

What is oral administration of heroin?

Answer 9

heroin administration by oral route produces the same potency and efficacy as morphine

first pass metabolism of heroin yields morphine as the major metabolite

Question 10

What is intravenous administration of heroin?

Answer 10

IV heroin is dramatically more potent and rapid than morphine due to increased lipophilic structure (increased BBB permeability)

rapid uptake into the brain, where it is metabolized to morphine to exert psychoactive effects

Question 11

What is inhalation or intranasal administration of heroin?

Answer 11

occasional routes for recreational use

“freebase” heroin can be smoked while other preparations can be finely ground and snorted

Question 12

What are the therapeutic effects of opioids?

Answer 12

at small or moderate doses (5-10 mg morphine) opioids exert limited psychoactive effects

muscle relaxation, drowsiness, decreased sensitivity to external or internal stimuli, pain relief, impaired concentration, constriction of pupils, dream-filled sleep, effects in the limbic system

Question 13

What are the subjective effects of recreational doses of opioids?

Answer 13

euphoria or elation (in contrast to relaxed state at lower doses)

dysphoria in some users

“rush” - most pronounced by IV

Question 14

What is the “rush” experienced at recreational doses of opioids?

Answer 14

most pronounced by IV

rapid, intense state of euphoria

described by non-addicts as a sudden flush of warmth located in the pit of the stomach

described by others as a “whole-body orgasm”

not the means of addiction but provides a strong reinforcement

Question 15

What are the physiological effects of high doses of opioids?

Answer 15

pinprick pupils

nausea and vomiting: opioids can act at the chemoreceptor trigger zone in the area postrema to induce the vomit reflex

moderate respiratory depression

Question 16

What the recreational use of opioids?

Answer 16

long history of recreational use

opium, morphine, heroin, fentanyl are well known drugs of abuse

prescription opioids (oxycontin) are one of the fasted growing classes of drugs of abuse

Question 17

What is opioid tolerance?

Answer 17

tolerance to opioids develops quickly and reflects various modes of tolerance

tolerance to respiratory and euphoric effects develops more rapidly than tolerance to analgesic effects

prolongs the usefulness in long-term pain management, unfortunately constipation does not develop tolerance

Question 18

What are the types of opioid tolerance?

Answer 18

metabolic tolerance: some increase in drug metabolism

behavioral tolerance: highly relevant in addicts

pharmacodynamic tolerance: principal mechanism of tolerance - decreased expression of opioid receptors

Question 19

What is rebound hyperactivity?

Answer 19

withdrawal is heavily influenced by mechanisms of drug tolerance and dependence (pharmacodynamic mechanisms)

receptor systems affected by opioids compensate to restore homeostasis in the continued presence of drug

removal of drug upsets homeostasis in the opposite direction of drug use

withdrawal produced neurochemical and behavioral changes that are often opposite the effects of intoxication: rebound hyperactivity

Question 20

What is the timeline of opioid withdrawal?

Answer 20

begins 6-12 hours after last administration, peaks 26-72 hours, persists less than 1 week

severity of withdrawal depends on daily dose, less severe with less potent opiates (e.g., codeine)

for most, withdrawal resembles a bad flu

withdrawal symptoms stop immediately by opioid administration, induced by opioid antagonists

withdrawal symptoms reduced by alcohol

Question 21

What is the first stage of opioid withdrawal?

Answer 21

restlessness and agitation is first sign

excess yawning, agitation, violence

chills, hot flashes, shortness of breath

intense piloerection (goosebumps) - origin of the term “cold turkey”

increasing drowsiness and deep sleep (often 8-12 hours)

Question 22

What is the second stage of opioid withdrawal?

Answer 22

cramps in stomach, back, legs

vomiting, diarrhea, profuse sweating

twitching of the extremities - shaking of hands and kicking of legs

symptoms become progressively less severe until gradually disappearing

Question 23

What is opioid overdose?

Answer 23

high doses of opioids can cause death

usually IV heroin or morphine

comatose state, pinpoint pupils, and severe respiratory depression occur with high doses

lowers seizure threshold - convulsions common

death occurs by sever respiratory depression or combination of suppressed cough reflex, unconsciousness, and vomiting

contaminants such as quinine (used to cut heroin) are a probable cause of many overdoses - causes frothing at the mouth and nose and death by pulmonary edema

affected by behavioral tolerance - drug use outside conditioned environment can lead to increased drug effects

OD can be treated using opioid antagonists (i.e., naloxone)

Question 24

What are the chronic effects of opioid use?

Answer 24

major side-effect of clinical (or recreational) opioid use is constipation: does to develop tolerance, remains an issue with long-term use

hormone imbalance: hypogonadism in majority of chronic opioid users, amenorrhea by suppressing luteinizing hormone

opioid-induced hyperalgesia: chronic opioid use alters the homeostasis of pain signaling pathways, with time pain thresholds decrease resulting in increased sensitivity to pain - often mistaken for tolerance resulting in increased dosage

Question 25

What are maintenance therapies for opioid addictions?

Answer 25

proposed on the premise that the real harm of opioid abuse is caused by the illegality and expense of the drug

many adverse health effects of opioid abuse are due to impurities in drug and spread of diseases (i.e., HIV, hepatitis) due to unsafe administration

Question 26

What is the British system of addiction management?

Answer 26

provides heroin prescriptions to addicts at public expense

cheap, reliable, and safe sources allows users to maintain a healthy, normal life and career

decreased death rates, reduced criminal behavior, improved function and social integration of addicts, decreased transmission of HIV and hepatitis

effectively cheaper long-term to prescribe heroin than to pay health care and judicial costs associated with addictions

Question 27

What is the methadone maintenance (US system) of opioid addiction management?

Answer 27

synthetic opioid administered orally

decreased euphoric effects

effects last ~24 hours in preventing withdrawal symptoms

competitive for receptor sites with morphine (blocks euphoric effects of heroin if co-administered)

reduces associated morbidity and mortality

80-90% relapse rates

Question 28

What is methadone?

Answer 28

methadone has decreased potency and decreased psychoactive effects but has a much longer duration of effect

methadone withdrawal is much less severe than heroin

Question 29

What is LAAM (levacetylmethadol)?

Answer 29

orally administrable maintenance drug

comparable to methadone therapy but longer lasting - up to 72 hours (administration required only 3x per week)

some risk of life-threatening ventricular rhythm disorders (not widely used)

Question 30

What is Buprenorphine?

Answer 30

analgesic, mixed agonist-antagonist at different opioid receptors

similar to methadone, but fewer adverse effects (no respiratory depression)

is itself addictive, but though easier to kick than heroin

investigational use in neonatal abstinence - infants born to opioid addicted mothers

suboxone is currently favored in Canada - buprenorphine and naloxone