Patients with delirium should be assessed for other symptoms that suggest opioid neurotoxicity, for example, tactile hallucinations, agitation, myoclonus, allodynia, hyperalgesia, and possibly seizures. It is postulated that this toxic state relates to the accumulation of the parent opioid compound or its metabolites.[11,13] Intervention in the form of dose reduction or opioid switching in association with assisted hydration typically allows for clearing of the offending opioid or its metabolites.
On identifying opioid toxicity, therefore, it is important to search for other precipitants such as dehydration or infection. A common clinical scenario consists of a patient with infection who may become drowsy, take less fluid, become dehydrated, and then exhibit signs of opioid toxicity, including delirium. Therapeutic intervention should target the triad of precipitants in this scenario. (Refer to the Opioid switching (Opioid rotation) section in the PDQ summary on Pain for more information.)
Symptomatic Management: The Role of Pharmacologic Agents
No pharmacological treatment has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of delirium. Evidence and clinical experience suggest that antipsychotics play a major role in the treatment of delirium; however, only a few of these studies were conducted in patients with cancer. Antipsychotics are antidopaminergic agents and include typical antipsychotics such as haloperidol  and the newer atypical antipsychotic agents such as olanzapine, risperidone, and quetiapine.[15,16];[Level of evidence: I]
All antipsychotics presumably work by blocking the postsynaptic dopamine receptors, primarily in the mesolimbic region. However, simultaneous blockade of striatal dopamine receptors by these agents can cause extrapyramidal side effects (EPS) such as abnormal involuntary movements, akathisia, parkinsonian symptoms, and cogwheeling. The typical antipsychotics such as haloperidol carry a higher risk of EPS. The newer atypical antipsychotics have additional effects on the serotonin system that help reduce the EPS.
Antipsychotics have a complex mechanism of action with effects on several other neurotransmitter systems. Atypical antipsychotics have been associated with higher risk of weight gain and metabolic issues because of these effects on other neurotransmitter systems. All antipsychotics have been associated with anticholinergic side effects and negative effects on the cardiovascular and cerebrovascular systems, depending on the medication and dosing used.
Haloperidol, a neuroleptic agent with potent antidopaminergic properties, is still considered the drug of choice for the treatment of delirium in the patient with cancer;[1,7] however, the evidence remains limited. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of hospitalized patients with delirium and acquired immunodeficiency syndrome suggested that haloperidol and chlorpromazine were equivalent in efficacy, and both were associated with a low prevalence of EPS. Lorazepam, however, was ineffective and associated with adverse effects, resulting in early closure of this arm of the protocol.[Level of evidence: I] The optimal dose range of haloperidol for patients with delirium has not been determined. Consensus guidelines recommended initial doses in the range of 1 to 2 mg every 2 to 4 hours as needed and lower starting doses, such as 0.5 mg every 4 hours as needed, in elderly patients.