Evaluation of Antiemetic Pharmacotherapy in the Setting of Opioid Withdrawal
The current opioid epidemic (both prescription opioids and illicit heroin and fentanyl) has created one of the worst drug abuse problems in American history. Millions of Americans rely on opioid medications, whether these medications are prescribed or acquired illicitly. Nearly 250 million opioid prescriptions were written in America in 2013. On an average day in America, 78 people die from an opioid overdose.1
In an effort to curtail accidental deaths, the Centers for Disease Control and Prevention (CDC) released new opioid prescribing guidelines earlier this year.2 In the guidelines, the CDC presented the following recommendations (among others):
- Before prescribing opioid therapy for chronic pain, providers should establish treatment goals. Clinicians should continue to prescribe opioid therapy only if there are clinical benefits—pain relief and restoration of functioning—that outweigh the risks to patient safety.
- When initiating opioid therapy for chronic pain, providers should prescribe immediate-release opioids rather than extended-release or long-acting opioids when possible.
- To mitigate the risk of opioid-related harm, providers should offer naloxone to patients at increased risk of opioid overdose, defined in the CDC guidelines as those with a history of overdose or substance use disorder, those taking >50 morphine milligram equivalents (MME) per day, or those receiving concurrent benzodiazepine therapy.
To provide patients with the safest pain management therapy and comply with the recommendations from the CDC, clinicians have begun to wean patients from long-term opioid therapy when the patients are no longer benefiting from such therapy. Although these guidelines underline the severity of this issue, which are voluntary recommendations, they provide little guidance on optimal management strategies for weaning opioids for the chronic pain patient. As a consequence, patients experience opioid withdrawal symptoms as these medications are being removed from their therapeutic regimen.
The intent of this article is not to provide a guideline on how to wean a patient from opioids, but to investigate existing strategies for the treatment of opioid-withdrawal–related nausea and vomiting (OWNV), specifically the use of antiemetic medications, considering the neurophysiologic changes that occur.
Literature Search Of Withdrawal Symptoms
The authors performed a PubMed search using combinations of the following MeSH terms: morphine dependence, antipsychotic agents, substance withdrawal syndrome, naloxone, ondansetron, prochlorperazine, promethazine, and nucleus accumbens. In addition, PubMed keyword searches were performed using combinations of the following terms: opioid withdrawal, nausea, nucleus accumbens, and prochlorperazine. Google Scholar searches were performed with combinations of the following keywords: opioid withdrawal, pathophysiology, nausea, serotonin, and dopamine.
Physical dependence to opioids will develop in virtually all patients receiving long-term opioid therapy. Although physical dependence can be a sign of addiction, the term physical dependence is not synonymous with addiction.3 Therefore, if it is determined that a patient can be weaned off opioids, it is important to wean slowly to avoid unpleasant withdrawal symptoms, including irritability, anxiety, diaphoresis, yawning, rhinorrhea, and lacrimation. Without intervention, withdrawal symptoms will progress into flu-like symptoms, chills, myalgia, fever, abdominal cramping, nausea and vomiting, diarrhea, and tachycardia, among others.
The goal of this search was to find literature on how opioid withdrawal affects neurotransmitters and leads to typical withdrawal symptoms. Articles that appeared to meet this criterion were then evaluated for inclusion based on relevance to the topic of this paper.
Neurophysiology Of Withdrawal
To select pharmacotherapy for the management of OWNV symptoms, a cursory understanding of the neurophysiologic changes that occur as a consequence of chronic opioid administration followed by significant dose reduction or discontinuation is paramount.
Most clinically prescribed opioids are selective agonists of the μ-opioid receptor. This g-protein-coupled receptor is expressed in both the peripheral and central nervous system (CNS). When μ-opioid receptors in the CNS are activated, dopamine is released in the nucleus accumbens of the mesolimbic reward system. This dopamine release creates the sensation of euphoria, with other areas of the CNS linking this feeling to precipitating events (ie, the ingestion of an opioid). This mechanism provides the general basis for cravings and, ultimately, addiction (substance use disorder). Repeated opioid exposure leads to a blunted release of dopamine in the nucleus accumbens, necessitating progressively larger doses to replicate previous feelings of pleasure.4,5
Equally important in the pathophysiology of opioid withdrawal is the locus coeruleus (LC). In an opioid-naive individual, norepinephrine (NE) release is modulated by intracellular cyclic adenosine monophosphate (cAMP). Norepinephrine released from the LC regulates alertness, wakefulness, muscle tone, respiratory rate, and blood pressure. LC cells express μ-opioid receptors that modulate the release of NE. Activation of these μ-opioid receptors inhibits adenylyl cyclase (AC) in LC cells, resulting in decreased intracellular concentrations of cAMP and decreased NE release. In a compensatory mechanism, the body upregulates the levels of ATP and the expression of AC in these cells to maintain somewhat normal NE secretion.
When opioid administration is significantly decreased, the inhibition of AC is abruptly terminated, and intracellular cAMP levels rise dramatically. As cAMP levels rise, NE is produced in excess, leading to withdrawal symptoms, such as diaphoresis, mydriasis, hypertension, and anxiety, as well as nausea and vomiting.4,5
The role of serotonin—if any—in opioid tolerance and withdrawal is not well understood. In an animal study, researchers measured levels of serotonin in the dorsal raphe nuclei of rats at various times after implantation of morphine pellets, and then compared them to placebo. The researchers found that there was a transient increase of serotonin in the morphine group compared to the placebo group that leveled off once tolerance was achieved.6 A contradictory study with similar design, however, leaves the role of serotonin in opioid tolerance and withdrawal questionable.7 Other signaling molecules, such as enkephalins and tumor necrosis factor-α, also are believed to play a role in opioid tolerance and withdrawal.8
Treating Opioid Withdrawal Nausea and Vomiting
Dopamine receptor antagonists have several clinical uses, including the control of nausea and vomiting. Of the dopamine receptor antagonists, promethazine and prochlorperazine are 2 of the more commonly used agents for this indication, with prochlorperazine possessing significantly greater dopaminergic inhibition.9