Opioid-induced nausea and vomiting

The opioids are highly effective analgesics and are widely used postoperatively and in the treatment of cancer pain.  The World Health Organisation's pain ladder advocates a step-wise approach to the use of analgesics, where opioids are added-in as the third and final step for severe pain.  Nausea and vomiting are undesirable side effects associated with the use of the opioid analgesics.

Nausea and vomiting is distressing for patients and carers and can have medical consequences in both the post-operative setting and in cancer patients and imposes an economic burden.

The aetiology and risk factors for opioid-induced nausea and vomiting

Nausea or vomiting is apparent in up to 50% of patients taking opioids for relief of chronic pain conditions ^[1]. Medication with opioids is a major contributory factor to post-operative nausea and vomiting.  For example the incidence of nausea and vomiting in patients undergoing minor gynaecological surgery has been reported to increase from 18% in a control group to more than 60% in patients receiving morphine or pethidine^[2].

The incidence of nausea and vomiting varies little with the opioid analgesic used, although some opioids have been reported to induce slightly less nausea and vomiting than others^[1],[3].  This may be related to functional differences in the various opioid receptors.

The time course of nausea and vomiting varies with the opioid used, presumably reflecting the pharmacokinetic profiles.  For example, pethidine has a more rapid and shorter lasting effect than morphine^[4].  The route of administration also plays a part. Intravenous morphine has a lower emetic potential than the same drug administered by theintramuscular route^[4].    

The risk factors involved in opioid-induced nausea and vomiting following post-operative use have been described elsewhere.  Previous exposure to opioids, for example when used in long-term cancer pain can reduce the risk as patients develop tolerance, though treatment may still be required as increasing doses of opioids are used to control the pain as the cancer develops.

The causes of opioid-induced nausea and vomiting

Opioids are thought to induce nausea and vomiting by a direct action on the Chemoreceptor Trigger Zone (CTZ), an area of the hind brain, which is outside the blood-brain barrier.  This is supported by evidence showing that ablation of the CTZ prevents the induction of vomiting by opioids^[5].  The mechanism of action of opioids in emesis is, however, complicated.  Biphasic dose-response curves have been reported and in certain circumstances, opioids can have anti-emetic actions^[6].

The three known types of opioid receptor (kappa - κ, delta - δ and mu - μ) are all thought to play a role in opioid-induced nausea and vomiting.

The factors involved with opioid-induced nausea and vomiting are summarised in Figure 7

Figure 7 The factors involved in opioid-induced nausea and vomiting

The consequences of opioid-induced nausea and vomiting

The opioids are highly effective analgesics and are widely used postoperatively and in the treatment of cancer pain.  When opioids are used post-operatively patients have little opportunity to develop tolerance to the emetic effects.

As with other forms of nausea and vomiting, opioid-induced nausea and vomiting can be very distressing and result in practical consequences for patients and carers, it can lead to medical complications and it imposes an economic burden.

Practical consequences

Nausea and vomiting can be very distressing for patients when they are already feeling uncomfortable and anxious, for example post-operatively or as a result of the underlying cancer.  Carers or medical personnel will also have to clear up after patients.

Medical complications

The medical implications of post-operative opioid-induced nausea and vomiting include the risk that the powerful muscular contractions associated with nausea and vomiting could lead to damage to the stitches of wounds and to an increased risk of bleeding, so affecting the outcome of the operation.  There is also a possibility of the regurgitation of stomach contents, leading to risks of respiratory obstruction, pulmonary inflammation and aspiration pneumonia.  Electrolyte imbalance and dehydration can occur if PONV is severe, which can be a particular issue with young children.  Finally the delayed ability to take oral therapy and nutrition may be a concern.

In cancer patients there is the additional complication of weight loss if nausea and vomiting is severe in already frail patients.  The delayed ability to take oral therapy for patients who are likely to be undergoing treatment with a number of other drugs can also be a concern.

Economic burden

There have been many studies that have tried to quantify the costs associated with PONV (see for example ^[7], ^[8], ^[9]).  The factors generally considered to be important are personnel time in clearing up and material costs of disposable products, laundry, caring for patients, delayed discharge, unplanned admission leading to bed blocking, delayed surgical throughput and potential re-operation costs.  Indeed an Audit Commission Report in 1997 ^[10] reported that the most common cause for unplanned overnight hospitalisation after surgery is PONV.

Similar factors also apply for opioid-induced nausea and vomiting in cancer patients, though the burden may be carried by the carer at home or by the hospice.

The management of opioid-induced nausea and vomiting

Anti-histamines, anti-muscarinics and dopamine receptor antagonists are effective in opioid-induced nausea and vomiting^[4].  The selective 5-HT₃ antagonists have occasionally been reported to reduce emesis associated with patient-controlled analgesia^[11] but more frequently they are reported to be inactive against nausea and vomiting induced by opioid analgesics^[12],^[13]. Opioid receptor antagonists are, not unexpectedly, very effective at inhibiting nausea and vomiting resulting from opioid agonists.  However, such agents will also inhibit the desired analgesic effects.

In palliative care for cancer patients it is common for anti-emetics to be combined with other drugs in syringe-drivers for constant infusion - see for example the Palliative Care Formulary for details^[14].  This makes it important to consider the compatibilites of different drugs and their stability over periods of up to 24 hours.

The drug treatment of opioid-induced nausea and vomiting is summarised in Figure 8.

Summary

• Many opioids are very effective analgesics and they are frequently used for post-operative analgesia and in palliative care
• Nausea and vomiting are undesirable side effects associated with the use of opioids
• Medication with opioids is a major contributory factor to post-operative nausea and vomiting (PONV), though tolerance can develop when used chronically, for example in palliative care.
• Opioids are thought to induce nausea and vomiting by a direct action on the chemoreceptor trigger zone (CTZ).
• Opioid-induced nausea and vomiting can be distressing to patients, may have medical implications and has economic consequences
• Anti-histamines, anti-muscarinics and dopamine receptor antagonists have efficacy against opioid-induced nausea and vomiting.

References