Pharmacology of Opioids

Opioids are an important class of medicines. They are predominantly used in the treatment of pain – mild, moderate and severe – depending on which opioid is prescribed and for what indication.

We are going to examine opioids pharmacology according to the following classification:

  • Weak opioids
  • – Codeine, dihydrocodeine, tramadol (moderate pain)

  • Strong opioids
  • – Oxycodone, morphine, pethidine, hydromorphone, tapentadol

  • Compound opioids
  • – Codeine / dihydrocodeine with acetaminophen (paracetamol)

  • Opioid antagonists
  • – Naloxone, naltrexone

Of course, this list is not exhaustive. Nonetheless, it breaks opioids into a convenient and helpful classification from which we can build further our knowledge of opioids. Today’s guide serves as a mere introduction to what is a vast and clinically complex topic. With this in mind, let’s turn our attention to the indications that opioids are used to treat.

Opioids are used in the treatment of the following conditions:

  • Mild-to-moderate pain – where weaker medicines, such as acetaminophen (paracetamol), have proven either ineffective or insufficient. Compound opioids and weak opioids may be used for this indication.
  • Moderate-to-severe pain – whose use is warranted in more serious cases such as acute severe pain, chronic pain (where weaker opioids or NSAIDs have proven insufficient) and to relieve breathlessness in palliative care.
  • Narcotic addition – some opioids – such as buprenorphine – are available as implants, used to treat narcotic addition (often combined with an opioid antagonist, such as naloxone {see combination product, Suboxone}.
  • Opioid overdose – opioid antagonists include naloxone and naltrexone, medicines used to reverse the effects of opioids in cases of overdose. Opioid antagonists may also be combined with other opioid analgesics to reduce risk of misuse.

With these indications in mind, let’s learn more about opioids pharmacology – how they work to produce a therapeutic impact.

Mechanism of action

The primary mechanism of opioids involves agonism at mu-opioid receptors – G-coupled protein receptors that reduce pain transmission in the central nervous system.

However, activation of mu-opioid receptors has many other effects. For example – they reduce respiratory drive through receptor activation in the medulla; an effect which leads to the potentially fatal respiratory depression (see below).

Activation of opioid receptors in the chemoreceptor trigger zone (CTZ) induces an emetic effect, too.

Some weak and moderate opioids come with differing mechanisms of action.

For example – codeine and dihydrocodeine are metabolized in the liver, producing relatively small quantities of morphine (from codeine) and dihydromorphine (from dihydrocodeine). These metabolites are stronger agonists at mu-opioid receptors than parent compounds. In contrast, tramadol also works as a serotonin-norepinephrine reuptake inhibitor (SNRI). It is not known to what extent this activity influences its analgesic effect.

Some patients are deficient in the metabolizing enzyme, CYP2D6 (approximately 10 percent of Caucasians). This enzyme is involved in the metabolizing certain opioids – such as codeine, dihydrocodeine and tramadol – into their therapeutic metabolites.

Side effects

Opioids are associated with their own range of potential side effects. Side effect risk depends upon which opioid is chosen and the route of administration through which the drug is taken, among other factors.

For example – compound preparations are associated with relatively mild effects such as constipation, drowsiness and nausea whereas IV morphine is associated more with serious effects, such as respiratory depression.

Side effects linked to opioids include:

  • Nausea, vomiting
  • Constipation – reduced motility due to mu-opioid agonism in large intestine
  • Miosis – stimulation of the Edinger-Westphal nucleus in the brainstem
  • Dizziness
  • Itch – due to mu-opioid linked histamine release
  • Drowsiness
  • Euphoria – with stronger opioids or through overdose
  • Neurological depression
  • Respiratory depression

The last two are pronounced in overdose.

Tolerance and dependence remain very real risks, too – particularly with long-term use of stronger opioids. Tolerance refers to the need to administer higher doses to meet the same therapeutic effect as earlier doses. Dependence occurs on cessation of opioid use, where withdrawal effects take over.

Clinical considerations

When we talk about the clinical pharmacology of opioids, we need to think about the following factors:

  • That in the case of significant respiratory disease, opioids should be prescribed with caution as they worsen respiratory function and retain the capacity to cause respiratory failure.
  • Both the kidney and liver are used to eliminate opioids – meaning that doses should be reduced in patients with hepatic and renal disease.
  • Similarly, doses should be reduced in elderly patients – reducing the risk of neurological and respiratory effects, among others.
  • Tramadol is known to lower the seizure threshold. It should, then, be avoided in patients with epilepsy. It should also be avoided in patients taking other medicines that lower the seizure threshold – such as SSRIs.
  • Ideally, opioids should be avoided in patients taking other sedating drugs (benzodiazepines, antidepressants, Z-drugs etc.). Where patients require both classes of drug, close monitoring is essential.
  • Given the high propensity of opioids to cause constipation, it’s not uncommon for a laxative, such as senna, to be co-prescribed.
  • Codeine and dihydrocodeine should never be administered via the intravenous route as this route, for these medicines, may cause severe anaphylaxis.
  • Opioids should be avoided in patients with biliary colic because they have the capacity to induce spasm in the sphincter of Oddi – exacerbating pain.
  • Some opioids – such as fentanyl – can be used to treat chronic pain via a transdermal patch. IV fentanyl has also been used alongside other drugs – such as propofol and midazolam – for anesthesia and sedation procedures.

Opioids remain an important drug class in pain management – both for acute and chronic pain management. There are many opioids, each with their own range of indications and clinical recommendations. We recommend using this guide as an introduction to what is a difficult, if more complex clinical topic.

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