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Common side effects

In this video, Dr Victoria Hewitt outlines the pathophysiology of opioid side effects and describes their management principles.
In this video, we will look at the non-analgesic effects of opioids and their physiological mechanisms in order to better understand their management. Opioid receptors vary in terms of their anatomical distribution, affinity to bind different opioids, and the physiological effects they mediate. Nausea and vomiting is a common but usually transitory side effect. Even low doses of opioids activate receptors in the chemoreceptor trigger zone, located in the floor of the fourth ventricle, causing nausea and vomiting. Tolerance to this effect usually develops within days. Mu receptors in the vestibular epithelium activate histamine and cholinergic pathways that input the vomiting centre. Opioids slow gastric emptying, causing nausea and vomiting with chronic use.
Opioid induced nausea and vomiting is a cross-receptor effect, which may explain why the evidence for opioid switching is weak. Instead, appropriate antiemetics should be prescribed. Constipation is the most common side effect of opioids. They reduce the tone and contractility of enteric smooth muscle, increasing bowel transit time . They also reduce secretions into the bowel and increase sphincter tone. All the receptor types slow enteric smooth muscle. Opioid rotation is therefore unlikely to be beneficial. Furthermore, tolerance to GI side effects does not usually develop, so laxatives must be prescribed prophylactically. A much feared effect of opioids is respiratory depression. Opioid receptors in the brain stem depress respiratory function.
As with nausea and vomiting, tolerance to respiratory depression occurs within days of starting opioids or increasing the dose. This is why opioids must be initiated at a low dose and gradually titrated to effect. The correct management is to reverse or reduce the dose, depending on the clinical situation. Switching opioids will not be beneficial. Whilst opioids can improve sleep by reducing pain, studies demonstrate they disrupt REM and non-REM sleep. In addition, opioid related respiratory depression is more pronounced during sleep. The neurological effects of opioids are caused by the accumulation of toxic metabolites. If elimination of these metabolites is insufficient– for instance, due to renal failure– plasma levels rise, they cross the blood brain barrier, and exert central neurotoxic effects.
Any factors which precipitate or exacerbate this toxic state must be managed and the opioid prescription changed. Either the dose is reduced, or the opioids switched, or both. These are the most common encountered side effects in clinical practice, but opioids exhibit many other effects, including itch, immunosuppression, and endocrine dysfunction. Specialist advice should always be sought if any side effect is intractable or proves difficult to manage.

Studies suggest that up to 80% of patients taking an opioid experience at least one side effect, often leading to the discontinuation of treatment. Understanding how and why they arise equips clinicians with the knowledge to recognise and manage them safely.

Opioid receptors

Stimulation of opioid receptors is responsible for some of the commonly-observed side effects of opioids. Nausea, for instance, occurs when opioids circulating in the bloodstream activate opioid receptors in the chemoreceptor trigger zone (CTZ). When this reaches a certain threshold neurotransmitters that activate the vomiting centre pathways are released. These include dopamine, which is why the dopamine antagonists haloperidol and metoclopramide are recommended for opioid-induced nausea.

This is only one cause nausea and vomiting related to opioids. A full assessment is required to exclude other causes such as constipation, gastric stasis and vestibular disturbance. Even unpalatable preparations – such as liquids and solutions – can be an issue.

Individual variation

Due to genetic variations in the expression of receptors, side effects of opioids can vary considerably between individuals. The exception to this is constipation, which occurs in virtually all patients (except those with short bowels, for instance following surgery).

Development of tolerance

Some side effects disappear as the patient develops tolerance to them. Tolerance develops due to changes at the cellular level involving the activated G-protein subunit. Opioid receptors in the enteric nervous system have different cellular properties to those elsewhere with regards to the development of tolerance. In addition, opioids are universally constipating, suggesting there is little individual genetic variation in this subset of opioid receptors.

Switching opioids

There are two different rationale for switching opioids in order to manage their side effects. Firstly, the drug’s pharmacokinetics may be causing toxicity and conversion to another opioid may be safer for the patient. For example, the accumulation of toxic metabolites of morphine in severe renal failure is best managed by conversion to an opioid whose metabolites are inactive. Secondly, the receptor-subtype profile differs between opioids.

Although the latter may, in theory, prevent the development of certain side effects, it is not generally recommended. Outcomes are unpredictable due to genetic variation in individual receptor expression and a lack of research evidence in humans. Nevertheless, it is not uncommon to see an opioid being switched to manage side efects in practice. We will discuss this further at the end of this week.

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