Naltrexone is a pure opioid antagonist that competes with and displaces opioids at opioid receptor sites with greatest affinity for the μ-opioid receptor.1 Although useful to reverse the effects of an opioid overdose, naltrexone is also used to prevent relapse to both opioid and alcohol dependence by reducing cravings in patients who have completed detoxification programs.2, a Newer formulations, such as an extended-release, once-monthly injectable form of naltrexone (XR naltrexone), are also available as an alternative to daily oral dosing. This case report describes the perioperative challenges of providing anesthesia to a young woman with a history of opioid dependence receiving maintenance therapy with XR naltrexone undergoing surgery for thyroid cancer.
After approval from our IRB, full consent was obtained from the patient for the publication of this case report.
Our case describes a 22-year-old woman with thyroid cancer presenting for total thyroidectomy and unilateral neck dissection. The patient had a medical and social history significant for heroin abuse status post detoxification and for the past year had been receiving maintenance therapy with XR naltrexone to help prevent relapse and deter opioid use. The first time the patient received XR naltrexone, she “tested” its efficacy by using heroin the same day as her naltrexone injection. She was surprised that she was unable to detect any effects from the heroin. Periodically, she would attempt to overcome the opioid receptor blockade, and frequently used an amount of heroin in excess of her usual dose, but again was usually unable to detect any effects. At day 26 of 30 in her treatment regimen, however, she was able to elicit some opioid agonist effects, albeit at a much reduced level. As a direct result of her inability to experience the effects of heroin and other opioid agonists while treated with XR naltrexone, she had stopped illicit drug use entirely. She last received XR naltrexone approximately 3½ weeks before her scheduled procedure and was due for her next dose in a few days.
General anesthesia was induced with propofol (150 mg), succinylcholine (100 mg), and remifentanil (150 mg). Further muscle relaxation was not used because neuromonitoring was performed throughout the case. The patient received 8 mg of dexamethasone before surgical incision, and anesthesia was maintained with 60% nitrous oxide along with infusions of ketamine (2 mg/kg/h), propofol (30–40 mcg/kg/min), and remifentanil (0.2–0.25 mcg/kg/min) for the duration of the surgery (approximately 4 hours). Before emergence from anesthesia, an ultrasound-guided unilateral superficial cervical plexus block using 15 mL of 0.25% bupivacaine was performed, and 1 g of acetaminophen was given intravenous (IV). The remifentanil infusion was stopped approximately 10 minutes before emergence. After emergence from anesthesia, the trachea was extubated without incident, and her pain level score in the postanesthesia care unit was 0 of 10 on a Visual Analog Scale. Overnight, the patient experienced a 4 of 10 pain score at the surgical site and received acetaminophen 650 mg by mouth for 2 doses 6 hours apart with good relief (1 of 10 pain score). Additionally, she complained of a 6 of 10 odynophagia score for which she received benzocaine-menthol 15-3.6 mg lozenges and thereafter reported a 1 of 10 pain score. The patient was discharged home the next day (postoperative day 1) with minimal pain (2 of 10) at the surgical site. The patient did not require and did not take any pain medications after discharge. Although the patient could have received her next dose of XR naltrexone soon after discharge, she made a personal decision to attempt abstinence without her medication. However, at the recommendation of her outpatient physicians and family, she did reinstitute XR naltrexone 3 months after her surgery and has remained abstinent and continues maintenance with XR naltrexone at the time of this writing.
XR naltrexone is encapsulated in polyactide-co-glycolide microspheres (similar to absorbable suture material) and placed in aqueous suspension for intramuscular injection.b The clinical efficacy of this formulation in patients with opioid dependence was demonstrated in a randomized, double-blind, placebo-controlled, multicenter trial (ALK21-013; N = 250). Patients receiving XR naltrexone had significantly more (median) opioid-free days verified by urine testing, lower craving scores, and lower relapse rates compared with those receiving placebo. After a single intramuscular monthly injection of 380 mg, the naltrexone plasma concentration peaks in 1 to 2 hours and is detectable for >35 days at a therapeutic concentration of >1 ng/mL (Fig. 1). Additionally, the average plasma concentration over 28 days (area under the curve) is 4-fold larger than that with oral naltrexone at its standard maintenance dose of 50 mg/d.3
Patients abusing opioids develop a tolerance to the effects of opioids as well as most of their side effects including respiratory depression. In addition, when a patient begins chronic treatment with an antagonist such as XR naltrexone, the newfound absence of agonist activity reduces tolerance to the effects of the opioid as well as its side effects. Moreover, chronic opioid antagonism has been shown to increase the density of opioid receptors in the brain (i.e., upregulation) as well as increase the sensitivity to opioid agonists.4–7 These changes result in a combined increased risk for side effects should the opioid receptor blockade be overcome.
The ability for XR naltrexone to block agonist activity decreases over the monthly dosing period, despite the maintenance of a “therapeutic” plasma concentration >1 ng/mL (Fig. 1). Although it is difficult to ascertain exactly when during the month receptor blockade can be overcome, case reports (as well as this report) suggest that the ability to overcome blockade occurs usually in the fourth week of dosing with increasing “success” as the month proceeds. This has led some providers who treat patients at high risk for relapse to reduce the dosing interval to 3 weeks rather than 1 month.8 Furthermore, patients who surreptitiously use opioid agonists and soon after (within a few days) receive a re-dosing of XR naltrexone may undergo opioid withdrawal, as has been described in several case reports.8,9 This depends on when they last used an agonist, how much they used, and when they received their naltrexone. To prevent the likelihood of withdrawal, the Food and Drug Administration released a warning advising that patients remain opioid agonist–free for 7 to 10 days before their next dose of XR naltrexone.c
As a result of these aforementioned changes, surgical patients receiving XR naltrexone present unique challenges to anesthesia providers that include an altered response to opioid agonists. Based on the timing of their last XR naltrexone dose, patients may be refractory to opioid agonists or potentially more sensitive. Early in the monthly treatment regimen (within the first 2 weeks), minimal to no analgesia may occur after opioid agonist administration, whereas by the fourth week, the opioid receptor antagonism may be overcome with a sufficiently large dose of opioid agonist. However, the patient may be more sensitive to the side effects and be at risk for significant respiratory depression or hemodynamic compromise because of receptor upregulation and increased receptor sensitivity to opioid agonists.4–7
Our patient presented for a total thyroidectomy with radical neck dissection, which would have been difficult to accomplish using sedation and local anesthesia alone. Had only a thyroidectomy been needed, nonopioid analgesics with local and regional anesthesia (in this case a superficial cervical plexus block) would have sufficed.
In our patient, anesthesia consisting of nitrous oxide along with infusions of propofol, ketamine, and remifentanil was useful for several reasons. Nitrous oxide and ketamine provide both sedation as well as analgesia via antagonism of N-methyl-D-aspartate receptors.1 Additionally, continuous IV ketamine infusions have been shown to reduce pain scores and decrease opioid requirements by 30% to 50% in the first 24 hours after surgery.10 Remifentanil was chosen because it provides both surgical analgesia that is quickly and readily titratable and is a unique opioid because it is rapidly metabolized by nonspecific plasma and red blood cell esterases.11 Furthermore, by using ultra-short-acting remifentanil and no other opioid agonists, we were able to ensure that there would not be any residual opioid effect by the time she was transferred to the postanesthesia care unit. Providing the patient received no other opioids postoperatively, her next dose of XR naltrexone soon after discharge from the hospital would not be precluded.
Regional anesthesia, nonopioid analgesics, dexamethasone and acetaminophen were used in addition to our primary anesthetic. Dexamethasone is useful for its antiemetic and anti-inflammatory properties (especially in head and neck surgeries) and provides postoperative analgesia that reduces opioid requirements in a variety of settings.12,13 Intravenous acetaminophen reduces 24-hour opioid requirements by as much as 30%.14 Other nonopioid medications considered were neuropathic medications such as gabapentin and pregabalin and nonsteroidal anti-inflammatory drugs such as IV ketorolac. Gabapentin and pregabalin require preoperative administration for maximal efficacy and were not considered until after surgery had begun, but likely would have been helpful in reducing postoperative pain. Nonsteroidal anti-inflammatory drugs would also have been helpful but were withheld after a discussion with the surgical team due to the extent of the neck dissection performed. For regional anesthesia, we performed an ultrasound-guided superficial cervical plexus block after the neck dissection to provide postoperative analgesia for as long as possible. This could have been performed preoperatively to help with surgical analgesia. Furthermore, a superficial cervical plexus block was selected over a deep or combined cervical plexus block due to the probable lower risk of complications and increased ease of administration.15
Some patients receiving XR naltrexone may require opioids for postoperative pain relief. There is little literature on the acute pain management of these patients, especially those receiving newer formulations such as XR naltrexone.16,17 It is known, however, that these patients will have an altered response to opioid agonists that may significantly deviate from responses observed in a typical patient. Depending on the timing of the last XR naltrexone dose, a response could either be attenuated or enhanced. The likely effective dose may be multiples of what is expected to achieve analgesia, and based on animal studies, this level may be 6 to 20 times the usual dose.18 As such, opioid titration should occur under close observation and appropriate monitoring to include frequent assessment of pain, sedation, respiratory depression, and hemodynamic status (especially bradycardia and hypotension). Capnography should be considered.
In conclusion, providing surgical and postoperative analgesia for a patient receiving XR naltrexone can be challenging. Regional and local anesthetic techniques as well as nonopioid and adjuvant analgesics should be considered. A preoperative evaluation by a pain management physician, if available, can include a discussion of expectations for postoperative management and the timing of the next scheduled XR naltrexone dose. If nonopioid modalities prove ineffective or are contraindicated, the effects of opioid titration should be closely observed and appropriately monitored.
a FDA Vivitrol medication guide. Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM206669.pdf. Accessed February 27, 2014.
b FDA Vivitrol description. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021897s005s010lbl.pdf. Accessed February 27, 2014.
c FDA Vivitrol safety information. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm208449.htm. Accessed February 27, 2014.
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