Opioid-induced adverse effects and their management

Pain is common and can occur in almost all patients with cancer. Adequate cancer pain relief is often times limited by physician and patient fears of opioid-related adverse effects. As many as 30% of patients with cancer have poor outcomes from their pain because of adverse effects and improper pain control.

The European Association for Palliative Care Research Network compiled evidence-based clinical practice recommendations to aid in better management of opioid-related adverse effects. Dose reduction, symptomatic pharmacologic management, opioid rotation and change of route of administration were approaches considered for the management of these adverse effects. This article will focus primarily on the symptomatic pharmacologic approach of managing opioid-related adverse effects.

Nausea and vomiting

Nausea has been observed in 15% to 30% of patients with cancer and does not need prophylactic treatment at the start of opioid therapy. Tolerance generally develops and nausea may go away within one week. The causes of nausea include stimulation of the chemoreceptor trigger zone, decreased gastrointestinal motility and increased vestibular sensitivity. Treatments may include metoclopramide, antipsychotics, serotonin antagonists, antihistamines and corticosteroids. None of the antiemetics have proven to be superior, and selection will be patient specific.

Consequently, metoclopramide is considered a first-line option for its effect on the chemoreceptor trigger zone and increasing gastric motility. Haloperidol and atypical antipsychotics such as olanzapine and quetiapine may be used in patients with nausea, in addition to hallucinations, delirium or anxiety. Chlorpromazine has been used, although its use is limited by its adverse effect profile. Serotonin antagonists are favored if nausea and vomiting are chemotherapy- related, but caution with excessive use of serotonin antagonists should be used in patients taking opioids because they may cause constipation. In addition, antihistamines have been used if nausea is related to vestibular sensitivity; otherwise, their use is reserved if other agents are ineffective because of sedative and anticholinergic adverse effects. Also, corticosteroids can be considered when nausea is refractory to other agents.

Constipation

Constipation is common and occurs in up to 70% of patients taking opioids. Tolerance rarely develops, and it has been shown to be dose-related. The best management is prevention and adequate hydration. Patients should be encouraged to have a bowel movement every one to two days. Similar to antiemetics, there are no studies proving that one laxative is best. A common approach is starting with a stimulant laxative such as sennosides with or without docusate.

If needed, the addition of an osmotic laxative such as lactulose or polyethylene glycol can be considered. Lactulose may cause nausea with its sweet taste and may cause some cramping in certain patients. Polyethylene glycol is better-tolerated by some patients, but its cost and initial onset of three days or longer may limit its use. Bulk-forming laxatives should be avoided because they are not as effective for opioid-induced constipation and require that patients take in at least 1 L of water concomitantly.

For palliative patients, methylnaltrexone (Relistor, Progenics), a peripherally acting mu-opioid receptor antagonist, may be considered for opioid-induced constipation if fecal impaction and obstruction is ruled out. Methylnaltrexone is dosed based on weight and given subcutaneously every other day, as needed, but no more than one dose in 24 hours. For patients weighing 38 kg to less than 62 kg, the dose is 8 mg, and for those weighing 62 kg to 114 kg, the dose is 12 mg. If the patient weighs outside of the dosing ranges, the dose can be calculated at 0.15mg/kg. The most common symptoms of methylnaltrexone are abdominal pain, nausea and flatulence.

Use of psychostimulants

Sedation occurs in 20% to 60% of patients assigned opioids, but tolerance usually develops within a few days to a week. If sedation persists after other causes have been ruled out or if pain is uncontrolled with lower opioid doses, psychostimulants such as methylphenidate, dextroamphetamine, caffeine and modafinil may be considered. Contraindications to their use include past psychiatric history, history of addiction, seizures, arrhythmias, congestive heart failure or angina.

Methylphenidate is the agent used most often at a usual dose of 5 mg twice daily, with doses given in the morning and early afternoon to avoid insomnia. The use of modafinil is limited by its lack of clinical trials and its cost. Pilot and retrospective studies showed promise in the use of donepezil for sedation; however, a double blind, randomized, placebo-controlled trial proved it was not better than placebo for cancer-related fatigue.

Altered cognitive function

Altered cognitive function (eg, hallucinations, confusion and delirium) can occur with opioid initiation or dose escalation. Other causes of altered cognitive function should be evaluated before initiating treatment. Dose reduction of the opioid may be attempted; however, antipsychotics may be used to manage cognitive impairment. Both haloperidol and chlorpromazine have been useful in the treatment of delirium. Haloperidol is favored over chlorpromazine for causing less sedation and low potential in causing hypotension. Atypical antipsychotics have also been effective for delirium. The use of benzodiazepines is limited to adjunctive therapy with other antipsychotics in severe cases because it can increase sedation and has the potential to worsen delirium.

Myoclonus

Myoclonus is another dose-related complication of opioids and is characterized by asymmetrical muscle jerks. Patients should be monitored for its appearance when opioid doses are increased.

General management is to reduce the opioid dose if pain is controlled; otherwise, an opioid rotation may be necessary to alleviate this symptom. If needed, baclofen and benzodiazepines have been recommended, although they should be reserved as a last resort because these agents may increase sedation and precipitate delirium.

Pruritus

Pruritus has been observed in up to 10% of patients with cancer and is more likely to occur with epidural or intrathecal administration of opioids.

The mechanism is believed to be related to histamine release; therefore, patients may benefit with antihistamines. Newer antihistamines may be favored for their less sedative potential, although limited by their cost.

Other options include topical treatment with cool compresses or moisturizers.

Opioid-induced adverse effects can also manifest as symptoms of other conditions and should be considered when new symptoms arise after initiating or escalating the dose of opioids.

A significant number of patients may experience adverse effects with their opioid regimen. Careful evaluation of the patient, along with the treatments reviewed here, may help improve pain control, as well as quality of life.

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