Opiates and Opioids

Question 1

What is an opiate?

Answer 1

Natural narcotic opioid alkyloids found in the
opium poppy (Papaver somniferum)

Question 2

What are opioids?

Answer 2

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

Question 3

Describe natural opiates

Answer 3

• Major psychoactive opiates:
• Morphine
• Codeine
• Thebaine

Question 4

Describe pharmacological use of natural opiates

Answer 4

• Analgesic– still the most potent and effective pain relievers 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 esp.
  pathogenic (e.g. dysentery)
• Loperamide is an opioid derivative that does not penetrate the BBB and is
  used to treat diarrhea

Question 5

Describe semi-synthetic opioids

Answer 5

• 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

Question 6

Describe opioid administration

Answer 6

• Semi-synthetic opioids can generally be administered by the same routes
  as morphine
• Oral– heroin administration by oral route produces the same potency and
  efficacy as morphine
• First pass metabolism of heroin yields morphine as the major metabolite
• Intravenous– 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
• Inhalation or intranasal– occasional routes for recreational use
• ‘freebase’ heroin can be smoked while other preparations can be finely ground and snorted

Question 7

Describe high doses of opioids

Answer 7

• Subjective effects at recreational doses:
• Euphoria or elation (in contrast to relaxed state at lower
  doses)
• Dysphoria in some users
• ‘Rush’ – 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
• Physiological effects:
• 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 8

Describe opioid tolerance

Answer 8

• 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
• Metabolic tolerance – some increase in drug metabolism
• Behavioural tolerance – highly relevant in addicts
• Pharmacodynamic tolerance – principal mechanism of tolerance – decreased
  expression of opioid receptors

Question 9

Describe opioid withdrawal

Answer 9

• Much less severe than withdrawal from barbiturates or alcohol
• Severe alcohol withdrawal can be fatal, opioids never fatal

Question 10

Describe rebound hyperactivity

Answer 10

• 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 produces
  neurochemical and
  behavioural changes that are often opposite
  the effects of intoxication
• Rebound hyperactivity

Question 11

Describe first stage withdrawal

Answer 11

• Begins 6-12 hours after last administration, peaks 26-72 hours, persists
  less than 1 week
• First stage:
• 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 12

Describe second stage withdrawal

Answer 12

• Second stage:
• Cramps in stomach, back, legs
• Vomiting, diarrhea, profuse sweating
• Twitching of the extremities – shaking of hands and kicking of legs – origin of the term ‘kicking the habit’
• Symptoms become progressively less severe until gradually disappearing

Question 13

Describe opioid overdose

Answer 13

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

Lowers seizure threshold – convulsions common

• Death occurs by severe respiratory depression or combination of suppressed cough reflex, unconsciousness, and vomiting
• 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 14

Describe chronic effects of opioid use

Answer 14

• Major side-effect of clinical (or recreational) opioid use is constipation
• Does not develop tolerance, remains an issue with long-term use
• Opioid-induced hyperalgesia
• Chronic opioid use alters the homeostasis of pain signalling pathways
• With time pain thresholds decrease resulting in increased sensitivity to pain – often
  mistaken for tolerance resulting in increased dosage

Question 15

Describe management of addictions

Answer 15

• Maintenance therapies 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
• British system provides heroin prescriptions to addicts at public
  expense
• Cheap, reliable, and safe source allows users to maintain a healthy, normal life and career
• Decreased death rates, reduced criminal behaviour, 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 16

Describe methadone maintenance

Answer 16

• 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
• Methadone withdrawal is
  much less severe than
  heroin.

Question 17

Describe LAAM

Answer 17

• LAAM (Levacetylmethadol)
• 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 18

Describe buprenorphine

Answer 18

• Investigational use in neonatal abstinence – infants born to opioid addicted mothers
• Suboxone is currently favoured in Canada – buprenorphine and naloxone