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12 Articles in Volume 16, Issue #10
2016 Practical Clinical Advances: Ketamine and Metformin
Case Challenge: Amniotic Allograft Reduces Joint and Soft Tissue Pain
Challenges of Treating Young Patients With a Terminal Prognosis
Defining Palliative Care
Discussing Benefits of Palliative Care
Evaluation of Antiemetic Pharmacotherapy in the Setting of Opioid Withdrawal
Fibromyalgia, Chronic Fatigue, and Chronic Fatigue Syndrome
Gabapentin Dosing for Neuropathic Pain
IV Acetaminophen Reduces Need for Opioids in Burn Patients
Opioid-Induced Constipation: New and Emerging Therapies—Update 2016
Osteopathic Treatment Considerations For Head, Neck, and Facial Pain
Tips From the Field: Deconstructing the Art of Headache Medicine

Evaluation of Antiemetic Pharmacotherapy in the Setting of Opioid Withdrawal

As the dose of opioids used for chronic pain management decreases, patients who are put on a weaning program may experience withdrawal symptoms. Ondansetron, a well-known antiemetic, may be a safe and effective option for managing these symptoms.

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

Patients being weaned off opioids often experience opioid-induced nausea and vomiting. Antiemetic agents may help reduce these withdrawal symptoms.

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

Prochlorperazine belongs to the phenothiazine class of dopamine receptor antagonists; it preferentially binds to dopamine 2 (D2) receptors and, thus, has anti-dopaminergic effects in both the mesolimbic system and chemoreceptor trigger zone.8

Dopamine levels in the mesolimbic pathway are decreased in opioid tolerance and withdrawal, thus treating withdrawal symptoms with a medication that can further decrease the levels of dopamine in this reward pathway could, theoretically, exacerbate these symptoms. Unfortunately, there is a lack of evidence to support or oppose the use of dopamine antagonists for nausea and vomiting related to opioid withdrawal.

A study in morphine-dependent mice conducted in 2012 evaluated the use of phenothiazine antipsychotics to control jumping related to withdrawal precipitated by naloxone. The mice received increasing doses of morphine administered subcutaneously over the course of 3 days. On day 4, withdrawal was precipitated using a 50 mg/kg naloxone injection, and then mice received an intramuscular injection of either saline or 1 of 6 phenothiazine antipsychotics. The authors found that all 6 of the antipsychotics reduced the withdrawal-associated jumping behaviors in a dose-dependent manner.10

Although the results from this study showed promise for the use of phenothiazines to treat non-OWNV symptoms, other studies conversely suggest that high doses of dopaminergic antagonists (ie, haloperidol 0.5 to 1 mg/kg) can exacerbate opioid withdrawal symptoms.11,12 Unfortunately, the applicability of these results to humans is difficult. When choosing antiemetic therapy in patients discontinuing opioid therapy, judicious consideration of the abuse potential of these medications is paramount. Although they are not controlled substances, phenothiazines do have the potential to be abused.13

Another drug class commonly used to treat OWNV are the serotonin 3 (5-HT3) receptor antagonists (ie, ondansetron). Though the mechanism is not understood clearly, ondansetron may attenuate not just OWNV but also other opioid withdrawal symptoms. In an animal study, rats were treated with either saline or morphine for 4 days, and then half of the rats in each group received saline or naloxone followed by a varying dose of intraperitoneal ondansetron (0, 1, 2, or 4 mg/kg). Rats receiving ondansetron after naloxone-induced withdrawal had decreased withdrawal symptoms (frequent defecation, shakes, and jumping).14

In another rodent study, researchers exposed rats to increasing levels of morphine in their drinking water for 3 weeks and evaluated the effects of ondansetron on withdrawal symptoms—either before or during induction of opioid tolerance.15 The authors concluded that ondansetron treatment, both before and during opioid administration, reduced naloxone-precipitated withdrawal symptoms of wet-dog shakes, head shakes, paw tremor, diarrhea, chattering teeth, writhing, and chewing. No significant differences were noted between the ondansetron doses and timing of initiation.

Chu et al evaluated 8 healthy male volunteers who received either placebo (4 patients) or 8 mg of intravenous (IV) ondansetron (4 patients) before administration of morphine (10 mg/70 kg IV).16  Two hours after the drugs were administered, both treatment groups received 10 mg/70 kg of naloxone to induce withdrawal symptoms. Seven days later, the volunteers repeated the experiment but switched which medication they received (placebo or ondansetron).

Those who were pretreated with ondansetron reported a significant decrease in the Objective Opioid Withdrawal Scale (OOWS) score (76.4 ±22.6; P=0.0313). “Seven of the 8 volunteers developed objective signs of opioid withdrawal, and ondansetron pretreatment reduced these signs in all 7 affected individuals,” noted the authors. Symptoms included in the OOWS are provided in Table 1. The Subjective Opioid Withdrawal Scale (SOWS) scores were not statistically lower in those receiving ondansetron compared to those receiving placebo (4.1%±62.5, P>0.05).16 According to the researchers, “this report provides the first demonstration that a 5-HT3 antagonist can reduce the severity of opioid withdrawal symptoms in humans.”

A report from 2012 detailed the case of a 44-year-old female, who attempted to cut back on her opioid regimen after undergoing extensive orthopedic surgery to correct scoliosis.17 Following the surgeries (3 surgeries over 5 days), the patient had IV patient-controlled analgesia (PCA) with morphine. An attempt was made to switch to an epidural, but she had inadequate pain relief, so she was maintained on PCA through postoperative day 7. Following removal of the IV, the patient was prescribed a controlled-release oxycodone (OxyContin) regimen of 20 mg 3 times daily.

Almost 3 weeks after discharge from the hospital (25 days after receiving her first opioid), the patient attempted to reduce her daily dose to 40 mg by omitting her middle dose. The patient began to experience symptoms of withdrawal (anxiety, uncontrollable crying, cold flashes, piloerection, muscle twitching, tremors, hot flashes, diaphoresis, abdominal cramping, and nausea) by 5 p.m., which lasted for 48 hours. She was afraid to reduce the remaining doses of oxycodone and asked for assistance.

She began taking ondansetron 8 mg at 8 a.m. and 8 p.m. every day starting 48 hours before the next dose reduction, and she continued until 48 hours after the last dose of controlled-release oxycodone (total wean time, 10 days). The patient reported none of the previously mentioned opioid withdrawal symptoms after the ondansetron was initiated.17

Discussion

Patients with chronic pain are increasingly likely to require assistance reducing their doses of opioid analgesic therapy. Depending on the rate of dose reduction, many will experience opioid withdrawal symptoms, including nausea and vomiting. There is a lack of high-quality evidence to guide clinicians in choosing between antiemetics for these patients. The antiemetics discussed here all are used widely and recognized to be efficacious. However, given the differing effects on neurotransmitters, the authors sought to identify whether any specific antiemetic may be preferred for OWNV.  

Although a number of animal studies evaluated the use of anti-dopaminergic medications to palliate the symptoms of opioid withdrawal, evidence supporting the use of these agents was conflicting, with some studies showing the potential for high doses of these agents to exacerbate withdrawal symptoms. The serotonin receptor antagonist ondansetron had a limited amount of weak evidence supporting its use in the management of opioid withdrawal symptoms in both animal and human studies. None of the literature reviewed showed exacerbation of withdrawal symptoms precipitated by the initiation of ondansetron.

The American Society of Addiction Medicine guidelines do not preferentially recommend a specific antiemetic therapy; they state that “ondansetron or other agents” can be used to manage nausea in patients experiencing withdrawal.18

Conclusion

When choosing an antiemetic for the management of opioid withdrawal symptoms, clinicians should be cognizant of the safety, efficacy, and abuse potential of each therapy. Considering available literature, ondansetron appears to be preferred over dopamine-receptor antagonists in the treatment of opioid withdrawal symptoms, but evidence is lacking, and further investigation is warranted.

Last updated on: December 27, 2016
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