Oral naltrexone-bupropion extended-release (Contrave, Orexigen Therapeutics Inc, La Jolla, CA) is a weight-management drug approved in the United States by the Food and Drug Administration in 2014 as an adjunct in chronically obese adults. The drug is currently approved for use in adults with a body mass index (BMI) of at least 30 kg/m2 or adults with a BMI of at least 27 kg/m2 with at least 1 concurrent weight-related condition including hypertension, dyslipidemia, and type 2 diabetes.1 Naltrexone is a competitive opioid receptor antagonist, and bupropion is an antidepressant with norepinephrine/dopamine reuptake inhibitor properties. The synergistic effects of the 2 medications act on the food reward system, consequently resulting in effective weight loss when used alongside modest lifestyle adjustments.2,3
We present a case of difficult pain control in the perioperative period in an obese patient taking Contrave (combination of 16 mg naltrexone and 180 mg bupropion). Naltrexone and its active metabolite 6-β-naltrexol competitively bind to µ-, κ-, and δ-opioid receptors of the central nervous system, effectively blocking the analgesic effects of administered opioids.4 This complicates perioperative management. Resistance to opioid analgesia poses major therapeutic challenges for physicians treating overweight and obese patients, many of whom undergo bariatric or orthopedic surgeries where severe postoperative pain is likely.5,6
The patient provided written consent for the publication of this case report.
A 42-year-old obese woman (BMI = 30.2 kg/m2), with anxiety and cervical radiculopathy secondary to a large C5–C6 disk herniation, presented for spine surgery after having taken Contrave and alprazolam (Xanax, Pfizer Inc, New York, NY) within 12 hours of surgery. The patient was not seen in a preoperative clinic because of the acute nature of her injury. Given the recent ingestion of Contrave, concern for inadequate postoperative analgesia was discussed with the patient. After an interdisciplinary discussion among the anesthesiologists, surgeons, and patient, a decision was made to proceed with the procedure because the patient was experiencing paresthesias from the disk herniation. A multimodal analgesia strategy was employed in an attempt to manage her pain. The patient received acetaminophen 1000 mg and gabapentin 600 mg per os preoperatively and intravenous ketamine 500 mg, fentanyl 500 µg, and midazolam 2 mg intraoperatively. Anesthesia was maintained with continuous infusions of ketamine (10 µg/kg/min), propofol (125 µg/kg/min), and remifentanil (0.2 µg/kg/min). Depth of anesthesia was monitored with a bispectral index monitor, with bispectral index values of 25 to 60. At the end of the procedure, the surgeons performed a field block with 40 mL liposomal bupivacaine.
The patient underwent successful anterior cervical diskectomy and fusion. However, with extensive neck dissection and bone resection, the risk of postoperative pain was increased. The endotracheal tube was removed in the operating room after a 90-minute procedure and the patient was transferred to the postanesthesia care unit (PACU). The patient remained in the PACU for 10 hours and was assessed every 1 to 2 hours for neurologic deficit and pain level using a numeric rating scale (1–10). The postoperative pain management regimen consisted of a hydromorphone patient-controlled analgesic (PCA) pump (bolus dose of 0.3 mg every 8 minutes), acetaminophen 1000 mg intravenously every 6 hours, and diazepam 5 mg per os as needed. An opioid-tolerant PCA regimen was chosen for concerns that Contrave would limit the efficacy of a lower dose regimen. Diazepam was prescribed because of the patient’s history of anxiety. The highest pain level recorded in the PACU was 4/10, and overall, the PACU nurse noted that the patient’s pain was well controlled. The patient was ultimately admitted to the step-down unit for overnight monitoring because of surgical concerns for postoperative hematoma formation and subsequent airway compression caused by intraoperative surgical problems.
The patient experienced a single episode of oversedation and oxygen desaturation to 82% while using the hydromorphone PCA pump to reduce her severe pain (8/10). The patient’s oxygenation was monitored continuously in the step-down unit. This episode was suspected to be caused by previously undiagnosed obstructive sleep apnea. After the episode, the patient continued to receive 1000 mg intravenous acetaminophen every 6 hours and used the hydromorphone PCA pump without further incidents. While the pain was not fully controlled overnight, the pain management team was hesitant to increase the dose of the hydromorphone given the episode of desaturation. The patient was placed on a nonrebreathing mask with 100% oxygen for the remainder of the evening. The diazepam order was unchanged as it was prescribed as needed, and the patient ultimately did not require it.
On postoperative day (POD) 1, the patient reported continued pain (4/10), but the overall intensity had diminished. The pain service discontinued the hydromorphone PCA pump and transitioned the patient to an oral regimen consisting of hydromorphone 2 mg every 3 hours. The patient reported pain in the surgical site without the paresthesias that she previously experienced in her right arm. She described the surgical site pain as continuous and aching. She reported pain scores of 4 to 5/10 and 6/10 with physical therapy during POD 1, and the pain scores decreased to 2 to 3/10 on POD 2 before her discharge home.
This case report highlights the challenges anesthesiologists and surgeons face when managing acute pain in a patient using Contrave in the immediate perioperative period. Despite the application of intraoperative multimodal analgesia, the postoperative multimodal pain control regimen remained inadequate for our patient. Given that Contrave has proven to be an effective adjunctive therapy for weight loss, this drug may become increasingly common and strategies are needed to guide the management of acute pain in these patients.
After a single oral dose of Contrave, the mean elimination half-life of naltrexone-extended-release (ER) is approximately 5 hours. After twice the daily dose, naltrexone-ER does not accumulate but its major active metabolite 6-β-naltrexol does with an accumulation ratio of approximately 3. The peak plasma concentration of naltrexone-ER occurs within 1 hour of administration and declines according to biphasic kinetics. The manufacturer recommends discontinuing the drug before anticipated opioid therapy, though no specific interval is provided. However, the manufacturer does suggest that without the ability to monitor the levels of naltrexone-ER in patients who have taken Contrave before surgery, administering opioids would be dangerous.7 While it is ideal to discontinue the drug well ahead of scheduled surgery to avoid complications, this does not address patients on Contrave who require urgent or emergent medical treatments that necessitate opioids for acute pain management.
In the case of our patient, spine surgery proceeded despite her recent intake of Contrave because of persisting paresthesias from disk herniation. Preoperatively, the patient was given acetaminophen and gabapentin, and intraoperatively, she was given ketamine in an effort to maximize nonopioid pain relief. While the use of remifentanil during surgery can lead to opioid-induced hyperalgesia, it was used in this case to minimize movement without utilization of a paralytic agent.8 There was a concern (since the patient could not be given nondepolarizing muscle relaxants due to neuromonitoring) that the patient may move during surgery given the antagonism at the opioid receptors. Although upward of 0.5 minimum alveolar concentration (MAC) of inhalational agents could have been used, local guidelines prohibit its use in the operating room when neuromonitoring is being utilized. Therefore, a propofol infusion alone allowed for adequate amnesia during the procedure. A field block with liposomal bupivacaine was performed by the surgical team to further minimize pain through nonopioid mechanisms, though it was likely inadequate for full pain control.9
Postoperatively, our patient experienced intense pain despite a multimodal approach including nonopioid pain medications. This could be attributed to multiple factors in addition to the opioid receptor blockade by Contrave. Contrave may lower the threshold of acute opioid tolerance that remifentanil is known to cause, leading to increased postoperative pain, and thus necessitating larger doses of opioids or the addition of nonopioid analgesics for pain relief.10 Multimodal postoperative nonopioid regimens have been shown to be comparable to opioid-based techniques for controlling postoperative pain in obese patients. A nonopioid regimen including ketamine, clonidine, lidocaine, ketamine, magnesium sulfate, and methylprednisolone was as effective as fentanyl for controlling postoperative pain after gastric bypass surgery.11 A similar regimen could be adapted for future management of patients taking Contrave. However, the ceiling effect of most nonopioid analgesics would likely limit their use for severe pain, as was the case in our patient.
Currently, there are no specific recommendations for the perioperative management of patients taking Contrave. However, the potential blockade of opioid receptors by Contrave draws parallels with the more commonly used drug Suboxone (buprenorphine/naloxone; Suboxone, Indivior Inc, Richmond, VA), which also presents as a clinically complex situation in which perioperative pain management is difficult. Recommendations for Suboxone are limited and often conflicting, with some reports recommending continuation of the drug alongside the use of high-dose full-opioid agonists to manage pain through the perioperative period, while other reports recommend discontinuation before surgery.12 These reports provide no useful generalization to the optimal management of Contrave patients.
We suggest anesthesiologists, surgeons, and other clinicians alike have their patients suspend the use of Contrave well in advance before surgery. While no specific guideline exists, incidental findings suggest that several weeks may be an appropriate time frame.2 The manufacturer recommends a 7- to 10-day period between discontinuation of opioids before the initiation of Contrave. Waiting 5 times the elimination half-life after discontinuation would likely be sufficient for the drug to be eliminated from the body. If emergency surgery is required, patients taking Contrave will have to rely on a multimodal analgesia approach perioperatively that may not adequately manage pain postoperatively. In addition, preoperative patient preparation should include considerations for postponing or canceling elective surgeries and discussing the potential risk for increased postoperative pain compared to a nonuser.
This case report aims to highlight the lack of strategies for perioperative management of patients on Contrave therapy and to provide information that may assist other clinicians who manage similar patients. Additional research and discussion is necessary to develop an optimized approach to perioperative pain management for patients taking Contrave.
Name: Allen Ninh, BS.
Contribution: This author helped write the manuscript.
Name: Sang Kim, MD.
Contribution: This author helped provide care to the patient and made contributions and edits to the manuscript.
Name: Andrew Goldberg, MD.
Contribution: This author helped provide care to the patient and made contributions and edits to the manuscript.
This manuscript was handled by: Hans-Joachim Priebe, MD, FRCA, FCAI.
2. Tek C. Naltrexone HCl/bupropion HCl for chronic weight management in obese adults: patient selection and perspectives. Patient Prefer Adherence. 2016;10:751–759.
3. Greig SL, Keating GM. Naltrexone ER/bupropion ER: a review in obesity management. Drugs. 2015;75:1269–1280.
4. Codd EE, Shank RP, Schupsky JJ, Raffa RB. Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther. 1995;274:1263–1270.
5. Dudley KA, Tavakkoli A, Andrews RA, Seiger AN, Bakker JP, Patel SR. Interest in bariatric surgery among obese patients with obstructive sleep apnea. Surg Obes Relat Dis. 2015;11:1146–1151.
6. Welton KL, Gagnier JJ, Urquhart AG. Proportion of obese patients presenting to orthopedic total joint arthroplasty clinics. Orthopedics. 2016;39:e127–e133.
7. Contrave (R) [package insert]. 2016.La Jolla, CA: Orexigen Therapeutics Inc
8. Reed A, Woo P. Levine, et al. Phonomicrosurgery and office-based laryngology. In: Anesthesiology and Otolaryngology. 2013New York: Springer-Verlag Publishing; 147–171.
9. Lambrechts M, O’Brien MJ, Savoie FH, You Z. Liposomal extended-release bupivacaine for postsurgical analgesia. Patient Prefer Adherence. 2013;7:885–890.
10. Kim SH, Stoicea N, Soghomonyan S, Bergese SD. Intraoperative use of remifentanil and opioid induced hyperalgesia/acute opioid tolerance: systematic review. Front Pharmacol. 2014;5:108.
11. Feld JM, Laurito CE, Beckerman M, Vincent J, Hoffman WE. Non-opioid analgesia improves pain relief and decreases sedation after gastric bypass surgery. Can J Anaesth. 2003;50:336–341.
12. Huang A, Katznelson R, de Perrot M, Clarke H. Perioperative management of a patient undergoing Clagett window closure stabilized on Suboxone® for chronic pain: a case report. Can J Anaesth. 2014;61:826–831.