Evaluation of Antiemetic Pharmacotherapy in the Setting of Opioid Withdrawal
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
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