Overdosing on immediate-release morphine solution has predictable adverse effects

To the Editor:

Prescribing responsibility inherently includes adequate ongoing monitoring for medication.

An overdose of morphine can cause respiratory depression; as with any medication, there is a therapeutic window above which toxicities occur. Despite the increasingly widespread use of extended-release morphine for chronic breathlessness when prescribed and monitored in line with international evidence-based recommendations, the literature is not replete with examples of opioid-induced respiratory depression.

Why was the case report by Politis et al. [1] published? Morphine causes drowsiness and obtundation when an overdose is taken. In addition to his 15 mg per 24 h extended-release morphine, the patient in the case report took 12 times his 4-hourly dose of immediate-release oral morphine solution. The effects he experienced are well-described toxicities on the product information and the patient information sheets in every filled prescription for every opioid. This is not about identifying a new danger; use morphine in an unsafe way and it will be an unsafe drug with predictable side-effects. This letter, therefore, highlights that the generic importance of good prescribing and prescribing responsibility inherently includes adequate ongoing monitoring.

The evidence base for the therapeutic clinical use of opioids in chronic breathlessness has been derived almost entirely from extended-release preparations of morphine [2, 3]. This choice of preparation was based on sound pharmacokinetic principles from studies done more than 20 years ago [4] and is borne out by the greater effect size in aggregated data from steady state studies [3]. Even when well with no comorbidities, anyone of us would probably experience toxicity from a statim dose of 30 mg immediate-release morphine solution. The goal of care is to increase the threshold at which the patient becomes breathless during exertion by adequately saturating opioid receptors and to decrease the distress caused by breathlessness in the person's life. This relies on adequate levels of background opioids. The use of as-needed immediate-release oral morphine solution will increase the risk of side-effects because of fluctuating serum levels and increase the potential for overdosing on immediate-release morphine solution.

The approach whereby an immediate-release opioid is used for episodes of breathlessness (usually induced by exertion) has been transferred from pain management without empiric data in breathlessness. However, given the current evidence about chronic breathlessness, it makes no sense to transfer an as-needed immediate-release morphine model that was not even fit for purpose in incident pain. As most episodes of exertion-induced breathlessness resolve with rest within 10 min [5, 6], no opioid preparation with a relevant pharmacokinetic profile has been studied in chronic breathlessness.

Patients need to be monitored as opioids are initiated and during follow-up in a way that is appropriate to the medication being prescribed. In settings where the medication is started during an acute exacerbation, it may be appropriate to review the person within days of discharge to explore whether they needed ongoing morphine.

The basis of the toxicity was that the patient took a much higher than prescribed dose of immediate-release oral morphine solution. When low-dose, extended-release morphine has been used in a steady state, such toxicity has not been reported. Sudden changes in renal function or dehydration due to diarrhoea may put even people in a steady state from regular, low-dose, extended-release morphine at risk of harm despite a history of symptomatic benefit. Part of a pharmacist discussing regular, low-dose, extended-release morphine with patients when this medication is initiated is that side-effects may emerge were renal function to worsen.

Chronic breathlessness continues to be a major health problem around the world and its relief a goal of care for millions of people [7]. The most robust evidence base to date is built on the use of regular, low-dose, extended-release morphine. Further research into safety and titration is ongoing. Such work will be crucial to strike the therapeutic balance between maximising symptomatic benefits and minimising any likelihood of harms in these frail people [8].

Disclosures