Note: This article originally appeared in the ASRA News, Volume 16, Issue 1, pp. 15-20 (February 2016).

Authors

Ignacio J. Badiola, MD
Instructor of Anesthesiology and Critical Care

Russell Bell, MD
Assistant Professor of Clinical Anesthesiology and Critical Care

Department of Anesthesiology and Critical Care
Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA

Introduction

The number of people addicted to prescription and illicit opioids continues to increase,^[1] thus increasing the number seeking addiction treatment. Many of these patients are maintained on opioid agonists, such as methadone, or partial opioid agonists, such as buprenorphine. Naltrexone and naloxone are both opioid receptor antagonists and occasionally used as well. This article will provide a brief review of common agents used in opioid-addicted/dependent patients as well as their perioperative pain management implications.

Methadone

Methadone was originally synthesized during World War II as an alternative to morphine. Methadone’s use was predominantly as maintenance therapy for opioid-addicted patients. During the last few decades, its use for analgesia has flourished. It has high affinity for mu and delta receptors. It also has activity on serotonergic and N-methyl-D-aspartate receptors. It is well absorbed and measurable in the bloodstream 30 minutes after ingestion with peak levels occurring 4 hours after ingestion. It is highly lipophilic and is stored in fat and slowly released into plasma. Elimination is biphasic with an alpha phase (8–12 hours) and a beta phase (30–60 hours) with the alpha phase corresponding to analgesia. The long beta phase prevents withdrawal symptoms. The slow clearance allows for once-a-day dosing for maintenance.^[2] However, more frequent dosing (ie, three or four times a day) is usually needed for analgesia.

Perioperative pain management of patients on methadone, for chronic pain management as well as maintenance therapy, can be challenging. These patients usually present with opioid tolerance and hyperalgesia. Because of the long halflife of methadone, there is possible accumulation and interaction with the usual higher doses of opioids given in the perioperative setting. Thus, monitoring of these patients for morbidity and adverse-related effects, such as respiratory depression, is imperative.

Buprenorphine

Buprenorphine is a highly lipophilic opioid agonist up to 50 times more potent than morphine. Considered a partial agonist with limited effect on the mu receptor, it can act as an antagonist when used along with a full agonist (ie, in the perioperative period). It tightly binds to the mu receptor. It has a slow dissociation from mu receptors, contributing to its long half-life. This renders its effect somewhat resistant to naloxone reversal. Unlike methadone, high doses of buprenorphine lead to mu receptor antagonism, thus limiting its properties on analgesia and respiratory depression.^[3] It is usually prescribed as Suboxone (buprenorphine + naloxone) or Subutex (burprenorphine) for maintenance therapy and as buprenorphine transdermal patch (Butrans) for pain management.

Naltrexone/Naloxone (Narcan)

Naltrexone and naloxone are opioid antagonists and bind to one or more of the opioid receptors (mu, kappa, and delta) but do not activate them. They are typically administered in suspected opioid overdoses and, in most circumstances, do not produce any effects in the absence of exogenous opioids. Antagonism of opioid receptors has variable effects ranging from mild hyperalgesia to hypoalgesia.^[4] In the presence of opioids, small doses (ie, 0.4 mg) reverse the effects of opioid agonists. Sedative and respiratory depressant effects are reversed and blood pressure, if depressed from opioids, increases.^[5] Rebound catecholamine release may lead to hypertension, tachycardia, and ventricular arrhythmia. In opioid-dependent patients, even small doses of an opioid antagonist can lead to severe withdrawal symptoms.

Two commonly used antagonists are naloxone and naltrexone. Naloxone is almost completely metabolized by first-pass metabolism, rendering it ineffective for oral use. It is usually given parenterally and has a half-life of about 1 hour. Naloxone can be combined with buprenorphine (Suboxone) to render it ineffective if abused intravenously. Naltrexone tends to be more efficacious when given orally. Peak concentrations of naltrexone occur within a couple of hours with a half-life of about 3 hours.

Perioperative Management

Perioperative pain management of patients on the previously described agents poses a significant challenge. No randomized controlled studies are available to guide management. Instead, most clinicians rely on case reports, guidelines set forth by their institution, or recommendations from other pain experts. Inadequate pain management in this group of patients is common. Alford et al^[6] describe the case of a 29-year-old woman receiving 90 mg a day of methadone for a history of heroin abuse who, after fracturing her olecranon process, was given 2 mg of intramuscular morphine over a 6-hour period. Her hospital regimen included only her baseline methadone dose along with ketorolac, and she was labeled as “drug seeking” for continuing to complain of pain.6 Their general recommendations regarding acute pain management in patients receiving opioid agonist therapy with methadone include uninterrupted therapy to address the patient’s baseline opioid requirement. This helps avoid withdrawal, which can possibly increase pain sensitivity. They also recommend aggressive pain management using nonopioid analgesics and nonpharmacologic therapies (ie, regional anesthesia). Opioid requirements will be higher (sometimes substantially higher) than what is typically used in an opioid-naïve patient with the same acute process.^[6]

Buprenorphine presents a challenge, as it tightly binds to the mu receptor. This competes with any full agonist given. Possible treatment options include continuing the buprenorphine, with the awareness that a significant amount of short-acting full agonist may be needed. Monitoring for opioid-related side effects should take place. Huang et al^[7] describe a case in which a patient underwent a closure of a Clagett window (thoracotomy for severe empyema where an open window in the lateral chest allows continuous drainage and irrigation of the cavity with antibiotics) who used 16 mg twice a day of buprenorphine/naloxone. This dosage was continued perioperatively, and, postoperatively, she required more than 70 mg of intravenous hydromorphone over a 24-hour period without adequate relief. Adding long-acting oral opioids was not effective.^[7]

Another option cited would be to divide the daily dose of the buprenorphine to be taken every 6 hours to take advantage of its analgesic properties. However, most patients who are not opioidnaïve will still need full agonists owing to both tolerance and the partial agonist properties of buprenorphine. If adequate time is available, the patient can be converted to a full agonist at least 3 days before surgery to allow sufficient metabolism and excretion of buprenorphine. A case report by Chern et al8 shows that this is no panacea. The authors converted a patient receiving 8 mg of buprenorphine every 8 hours to 20 mg of oral hydromorphone 5 days before having a vaginal mesh removed. On the day of surgery, the patient reported adequate pain control. Preoperatively, the patient received 400 mcg of fentanyl as part of a fentanyl challenge.^[8] In the operating room, the patient received another 600 mcg of fentanyl and remained conversant and awake. An additional 100 mcg of fentanyl was given for the 1-hour procedure. Upon emergence, the patient complained of severe pain. On transport to the postanesthesia care unit, 100–200 mcg boluses of fentanyl were administered. At the time of sign-out—between anesthesiology and the post anesthesia care unit (PACU)—1,000 mcg of fentanyl had been given since emergence, and the patient continued to report significant pain. During her PACU stay the patient received an additional 100 mcg of fentanyl and 8.5 mg of hydromorphone over a 2-hour period. She was subsequently discharged to the ward with a hydromorphone patient-controlled analgesia of 2 mg per hour basal rate and a demand dose of 0.6 mg every 10 minutes. She continued to reporther pain level at 7–8 out of 10.^[8]

In summary, there are no prospective randomized trials at this point to guide best treatment options. As the number of surgical cases continues to rise and the number of patients on opioid maintenance therapy continues to rise, anesthesiologists should expect to care for these patients more frequently during all phases of the perioperative period. Therefore, it is imperative that high-quality clinical trials and evidenced-based guidelines become available.

References

1. Manchikanti L, Fellows B, Alinani H, Pampati V. Therapeutic use, abuse, and nonmedical use of opioids: a ten-year perspective. Pain Physician 2010;13:401– 435.
2. Singh N, Fishman SM, Tokarz K. Methadone for chronic pain. In: Comprehensive Treatment of Chronic Pain by Medical, Interventional and Integrative Approaches. Deer TR, Leong MS, Buvanendran A, et al (eds). New York, New York: Springer 2013;145–150.
3. Katzung BG. Basic and Clinical Pharmacology. 10th ed. New York, New York: McGraw Hill Medical; 2007.
4. France CR, al’Absi M, Ring C, France JL, Harju A, Wittmers LE. Nociceptive flexion reflex and pain rating responses during endogenous opiate blockade with naltrexone in healthy young adults. Biol Psychol 2007;75:95–100.
5. Brunton L, Chabner B, Knollman B. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York, New York: McGraw Hill Medical; 2011.
6. Alford DP, Compton P, Samet JH. Acute pain management for patients receiving maintenance methadone or buprenorphine therapy. Ann Intern Med 2006;144:127–134.
7. Huang A, Katznelson R, de Perrot M, Clarke H. Perioperative management of a patient undergoing Clagett window closure stabilized on Suboxone(R) for chronic pain: a case report. Can J Anaesth 2014;61:826–831.
8. Chern SY, Isserman R, Chen L, Ashburn M, Liu R. Perioperative pain management for patients on chronic buprenorphine: a case report. J Anesth Clin Res 2013;3:1000250.