Pharmacology

Exogenous opioids are typically used for analgesia, sedation, cough suppression, treatment of diarrhea or used recreationally (mainly for analgesia or sedation properties) – for more on clinical uses, see the effects and risks section. The following section will discuss pharmacology, specifically administration, dosage, mechanism of action and the effects of ultra-potent opioids.

Administration

Administration is typically oral, intravenous (IV), intramuscular (IM), subcutaneous (SQ) or transdermal, though recreational users have come up with many more methods of administration.

• Administration is key in toxicology – it can be just as important as dosage

For example: IV administration makes opioids (and other drugs) 100% bioavailable. Opioid are weak bases, making them highly ionized in the stomach (ionized substances are poorly absorbed in the stomach), thus oral administration reduces bioavailability of opioids to 50%. Therefore, orally ingested opioids, while still dangerous, are much less likely to produce toxicity at high doses than opioids which are administered intravenously.

Dosage

There are many opioids in current circulation for both clinical and recreational use. Synthetic opioids vary greatly in potency, and poor understanding of the relation between potency and safe dosage is one of the biggest causes of overdose among recreational users. For example, morphine is a common clinically used synthetic opioid with a starting dose of 0.1-0.2mg/kg to be administered every 4 hours when given IV (highest bio-availability).

Source: https://www.clearvuehealth.com/images/opioid_lethal_doses.jpg

See the chart above for a comparison of potency and lethal dosage for opioids and ultra-potent opioids. Once again, dosages of opioids are highly dependent on the route of administration, since the bio-availability of the opioid must be considered.

Mechanism of Action

Opioid receptors are neurotransmitter receptor G-coupled proteins which can be presynaptic (pictured above) or postsynaptic. Activation of G-proteins influences secondary intracellular enzymes, such as adenylate cyclase or phospholipase-C, to alter (often decrease) second messenger systems, such as cyclic adenosine monophosphate (cAMP). Alterations in secondary messenger systems and changes in gene expression produce the clinical effects of opioids.

• Presynaptic receptors function by inhibiting the opening of calcium (Ca2+) channels on the pre-synaptic neuron, as seen on the far left portion of the figure below. Inhibition of the channels prevent influx of Ca2+ into the presynaptic cell, which will inhibit the release of neurotransmitter from vesicles into the synaptic cleft – this inhibits pain signals.

• Postsynaptic receptors function by opening potassium (K+) channels on the postsynaptic cells, as seen in the central portion of the diagram below. The opening of potassium channels promotes the efflux of K+ from the postsynaptic cell, causing the cell to hyper-polarize. Cells in a hyper-polarized state cannot depolarize – this inhibits generation of an action potential on the postsynaptic cell.

Receptors are then further classified into 3 sub-categories: mu (μ), delta (Δ) or kappa (𝜅) receptors

• Mu (μ) receptors – binding of an opioid agonist to mu opioid receptors produces an intense analgesic (pain-relief) effect, as well as euphoria, miosis (pupil constriction) and respiratory depression. Most ultra-potent opioids preferentially bind mu opioid receptors.

• Delta (Δ) receptors – binding of an opioid agonist to kappa opioid receptors produces similar effects to mu receptors, however their exact mechanism is poorly understood. Binding to the kappa receptor produces analgesic (pain-relief) effects and respiratory depression (though neither are as intense as those produced by mu receptors) and play a role in protection from hypoxic injury (mostly in hibernating animals)

• Kappa (𝜅) receptors – binding of an agonist to kappa opioid receptors can only relieve mild to moderate pain, however it produces fewer adverse effects (less respiratory depression) than drugs which bind mu opioid receptors. For these reasons, kappa opioid agonists are currently of special interest in pharmaceutical development. Most clinically used opioids exclusively target the kappa opioid receptors (such as ) or preferentially target the mu opioid receptors (though they can still bind kappa opioid receptors; such as morphine, codeine or Fentanyl).

The mechanism of action, specifically the receptors targeted, are of notable significance when considering clinical applications and can help further our understanding of recreationally used ultra-potent opioids. Opioids can also bind the related sigma (σ) receptors, though they are not technically classified as an opioid receptor, they can produce many similar effects. Binding of an agonist (opioid or non-opioid) to sigma receptors produces dysphoria (intense fear or terror), hallucinations, stimulation of respiratory and vasomotor systems. Chronic use of opioids can lead to up-regulation of second messenger systems, such as cAMP, which are initially decreased by opioid receptor activation, thus, producing many cellular alterations and consequences.

Effects

Opioid receptors are mainly found in the brain, spinal cord, brainstem, intestines and other peripheral neurons. Their general effects within each of these tissues are as follows:

Central nervous system (CNS) – In the brain and spinal cord, the actions of opioids in both the ascending and descending pathways produces analgesic (pain-relief) and sedative effects. Activation of the reward axis in the brain leads to pleasurable emotions, which can promote addiction. Specifically, activation of the mu opioid receptors activates the central dopamine-mediated reward pathway, producing intense pleasurable effects and may induce euphoria. However, binding of opioids to mu opioid receptors in the medulla can also trigger nausea and vomiting.

Cardiovascular – Most opioids have little effect on the cardiovascular system with the exception of morphine. Morphine can cause low blood pressure by histamine-release induced vasodilation, leading to hypotension (low blood pressure), which can produce dizziness, weakness and even fainting.

Respiratory – Opioids produce a dose-dependent depression of the respiratory system, which is enhanced when opioids are given in combination with general anesthetics. Effects of opioid on the respiratory system also inhibit the cough reflex, which is ideal when intubating patients. Notably, death from an opioid overdose is caused by depression of the respiratory system, rather than cumulative toxicity of the opioids themselves – this can often be reversed with the administration of naloxone.

Intestines (GI tract) – Binding of opioids to receptors in the intestines reduces the propulsion of food through the large intestine, allowing for more water to be reabsorbed, producing dry stool and constipation. Opioids also cause constriction of the bile duct sphincter, increasing the pressure in the gallbladder, leading to stomach pain (also known as biliary colic).

Urinary system – Opioids lead to an increase in constriction of both the bladder sphincter and bladder walls, leading to an increased need to urinate but an increased difficulty to do so.

This chronic use of opioids also results in the slowing of synthesis of endorphins, which normally act in the brain to promote feelings of pleasure, well-being, and pain-relief. The decrease in endorphins, decreasing pleasurable feelings, produces tolerance of opioids, which prompts frequent users to continuously increase their dosage in attempt to reach the initial “high”.

Opioid antagonist (naloxone) – mechanism of action

Naloxone is an opioid antagonist that has a higher binding affinity for opioid receptors, specifically the mu opioid receptors in the brain, than exogenous opioids. Therefore, naloxone competitively binds and blocks opioid receptors, inhibiting the effects of opioids on their target cells. Naloxone is typically used to reverse an opioid overdose, predominantly as a result of recreational opioid use, and is generally administered either intramuscularly or nasally.